Cutis

Almost half of Crohn disease (CD) patients experience a dermatologic manifestation of the disease. A rare entity, metastatic CD (MCD) presents a diagnostic challenge without a high index of suspicion. Its etiology is not well defined; however, it appears to be an autoimmune response to gut antigens. Herein, we review the etiology/epidemiology, diagnostic criteria, and treatment for this uncommon condition.

Epidemiology and Clinical Characteristics of MCD

Metastatic CD was first described by Parks et al1 in 1965 and refers to a diverse collection of macroscopic dermatologic manifestations in tissue not contiguous with the gastrointestinal (GI) tract. To be classified as MCD, the tissue must demonstrate characteristic histopathologic findings, which invariably include noncaseating granulomas.

Crohn disease may affect any part of the GI tract from the mouth to anus, with a multitude of associated cutaneous manifestations having been described. The terminal ileum is the most commonly affected portion of the GI tract in CD, but the large intestine also may be involved in 55% to 80% of cases.² The incidence of non-MCD-associated anal lesions seems to correlate with intestinal involvement in that as few as 25% of patients with ileal-localized CD have anal lesions compared to nearly 80% of patients with large intestinal involvement.³

It has been estimated that 18% to 44% of patients with CD have some form of cutaneous manifestation,⁴ with MCD being a rare subcategory. As few as 100 cases have been described from 1965 to the present.⁵ The presence of MCD does not correlate well with severity of intestinal CD, and although a majority of MCD cases present after at least 6 months of GI symptoms,⁶ there are instances in which MCD presents without prior or existing evidence of intestinal CD.⁷

With regard to MCD, the term metastatic is sometimes supplanted in the literature by cutaneous to avoid any implication of cancer; however, due to a myriad of dermatologic manifestations, both terms can cause confusion. The categorization of the various types of cutaneous findings in CD is well summarized in a review by Palamaras et al8 with the following classifications: (1) granulomatous by direct extension (oral or perianal), (2) MCD lesions (genital and nongenital), (3) immune-related lesions, and (4) lesions from nutritional deficiencies. Of the cutaneous manifestations relating to CD, MCD is the least common cutaneous categorical manifestation and is further divided into subcategories of genital and nongenital lesions.⁸

The nongenital distribution of MCD is the more common variety in adults and particularly seems to affect the legs and plantar surfaces (38%), the trunk and abdomen (24%), and the face (15%).^5,9 These nongenital MCD manifestations are most commonly described as nodules, ulcerations, or erythematous to purple plaques, and less commonly described as abscesses, pustules, or papules.

The sequence of cutaneous symptoms of MCD relative to intestinal disease depends to some degree on patient age. In adults diagnosed with MCD, it has been noted that a GI flare is expected 2 months to 4 years after diagnosis; however, in children the subsequent GI flare has been noted to vary more widely from 9 months to 14 years following presentation of MCD.⁸ Furthermore, roughly 50% of children diagnosed with MCD present concomitantly with their first symptoms of a GI flare, whereas 70% of adults with MCD had been previously diagnosed with intestinal CD.⁸ In one review of 80 reported cases of MCD, 20% (16/80) had no symptoms of intestinal disease at the time of MCD diagnosis, and the majority of the asymptomatic cases were in children; interestingly, the majority of these same children were diagnosed with CD months to years later.⁹

Both the location and characteristics of cutaneous findings in MCD correlate with age.⁹ Metastatic CD has been identified in all age groups; however, lymphedema is more common in children/young adults, while nodules, ulceration, and fistulating disease are more often seen in adults.¹⁰ Affected children and adolescents with MCD range from 5 to 17 years of age, with a mean age at disease onset of 11.1 years and equal incidence in males and females.⁸ Adults with MCD range from 18 to 78 years of age, with a mean age at presentation of 38.4 years.^8,11

Concerning anatomic location of disease, adults with MCD most commonly have nodules with or without plaques on the arms and legs and less commonly in the genital area.⁸ In contrast, children with MCD are more prone to genital lesions, with up to 85% of cases including some degree of genital erythematous or nonerythematous swelling with or without induration.⁸ Genitourinary complications of CD as a broad category, however, are estimated to occur in only 5% to 20% of intestinal CD cases in both children and adults.¹²

There have been conflicting reports regarding gender predilection in MCD. Based on a review by Samitz et al¹³ of 200 cases of CD over an 18-year period, 22% of patients with CD were found to have cutaneous manifestations--presumably not MCD but rather perianal, perineal, vulvar fistulae, fissures, or abscesses--with a male to female preponderance of almost 2 to 1. A more recent review of the literature by Palamaras et al⁸ in 2008 reported that contiguous non-MCD affects adult females and children more often than adult males, with 63% adult cases being female. This review seems to be more congruent with other reports in the literature implicating that females are twice as commonly affected by MCD than males.^9,14

Pathophysiology

The etiology of MCD has not been well defined. One proposed mechanism of the distal tissue involvement of MCD is through passage of antigens to the skin with subsequent granulomatous response at the level of the dermis.¹⁰ Another proposed mechanism suggests antibody sensitization to gut antigens, possibly bacterial antigens, that then coincidentally cross-react with analogous skin antigens.^8,14 Burgdorf¹¹ supported this notion in a 1981 report in which it was suggested that the granulomatous reaction was related to deposition of immune complexes in the skin. Slater et al¹⁵ and Tatnall et al¹⁶ offered a variation of Burgdorf's notion, suggesting that it was sensitized T cells to circulating antigens that were the initiators of granuloma formation in the periphery.

An examination of MCD tissue in 1990 by Shum and Guenther¹⁷ under electron microscopy and immunofluorescence provided evidence against prior studies that purported to have identified immune complexes as the causative agents of MCD. In this study, the authors found no evidence of immune complexes in the dermis of MCD lesions. In addition, an attempt to react serum antibodies of a patient with MCD, which were postulated to have IgG, IgM, and IgA antibodies to specific gut antigens, yielded no response when reacted with the tongue, ileum, and colon tissue from a rat. As a culminant finding, the authors also noted MCD dermis tissue with granulomas without vasculitis, suggesting a T-cell mediated type IV hypersensitivity response with a secondary vasculitis from T-cell origin lymphokines and T-cell mediated monocyte activation.¹⁷

Research implicating other immunologic entities involved in the pathophysiology of CD such as β-2 integrin,¹⁸ CD14⁺ monocytes,¹⁹ and the role of the DNA repair gene MLH1 (mutL homolog 1)²⁰ have been considered but without a clearly definitive role in the manifestations of MCD.

The utility of metronidazole in the treatment of MCD has been suggested as evidence that certain bacteria in the gut may either serve as the causative antigen or may induce its formation²¹; however, the causative antigen has yet to be identified, and whether it travels distally to the skin or merely resembles a similar antigen normally present in the dermis has not yet been determined. Some research has used in situ polymerase chain reaction techniques to attempt to detect similar microbial pathogens in both the vasculature of active bowel lesions and in the skin, but to date, bacterial RNA noted to be present in the gut vasculature adjacent to CD lesions has not been detected in skin lesions.²²

Diagnosis

Physical Findings

Overall, it is estimated that roughly 56% of all MCD cases affect the external genitalia.²³ The classic appearance of MCD includes well-demarcated ulcerations in the areas of intertriginous skin folds with or without diffuse edema and tenderness to palpation.²³ Although MCD has been historically noted as having a predilection for moist skin folds, there are numerous case reports of MCD all over the body, including the face,^7,24-29 retroauricular areas,³⁰ arms and legs,^16,17,31-34 lower abdomen,^3,5 under the breasts,¹ perineum,³⁵ external genitalia,^1,9,36-40 and even the lungs⁴¹ and bladder.⁴²

As a dermatologic disease, MCD has been referred to as yet another great imitator, both on the macroscopic and microscopic levels.⁸ As such, more common causes of genital edema should be considered first and investigated based on the patient's history, physical examination, skin biopsy, lymphangiogram, ultrasound, and cystogram.⁴³ Ultrasonography and color Doppler sonography have been shown to be helpful in patients with genital involvement. This modality can evaluate not only the presence of normal testes but also intratesticular and scrotal wall fluid, especially when the physical examination reveals swelling that makes testicle palpation more difficult.⁶ Clinically, the correct diagnosis of MCD often is made through suspicion of inflammatory bowel disease based on classic symptoms and/or physical findings including abdominal pain, weight loss, bloody stool, diarrhea, perianal skin tags, and anal fissures or fistulas. Any of these GI findings should prompt an intestinal biopsy to rule out any histologic evidence of CD.

Metastatic CD affecting the vulva often presents with vulvar pain and pruritus and may clinically mimic a more benign disease such as balanitis plasmacellularis, also referred to as Zoon vulvitis.²³ Similar to MCD on any given body surface, there is dramatic variation in the macroscopic presentation of vulvar MCD, with physical examination findings ranging from bilateral diffuse, edematous, deeply macerated, red, ulcerated lesions over the vulva with lymphadenopathy to findings of bilateral vulvar pain with yellow drainage from the labia majora.²³ There have been cases of vulvar MCD that include exquisite vulvar pain but without structural abnormalities including normal uterus, cervix, adnexa, rectovaginal septum, and rectum. In these more nebulous cases of vulvar MCD, the diagnosis often is discovered incidentally when nonspecific diagnostic imaging suggests underlying CD.²³

Beyond the case-by-case variations on physical examination, the great difficulty in diagnosis, particularly in children, occurs in the absence of any GI symptoms and therefore no logical consideration of underlying CD. Consequently, there have been cases of children presenting with irritation of the vulva who were eventually diagnosed with MCD only after erroneous treatment of contact dermatitis, candidiasis, and even consideration of sexual abuse.³⁷ Because it is so rare and obscure among practicing clinicians, the diagnosis of MCD often is considered only after irritation or swelling of the external genitalia has not responded to standard therapies. If and when the diagnosis of MCD is considered in children, it has been suggested to screen patients for anorectal stricture, as case studies have found the condition to be relatively common in this subpopulation.⁴⁴

In the less common case of adults with genitourinary symptoms that suggest possible MCD, the differential diagnosis for penile or vaginal ulcers should include contact and irritant dermatitis, chronic infectious lesions (eg, hidradenitis suppurativa, actinomycosis, tuberculosis),⁴⁵ sexually transmitted ulcerative diseases (eg, chancroid, lymphogranuloma venereum, herpes genitalia, granuloma inguinale),⁴⁶ drug reactions, and even extramammary Paget disease.⁴⁷

Histologic Findings

Because MCD has so much macroscopic variation and can present anywhere on the surface of the body, formal diagnosis relies on microscopy. As an added measure of difficulty in diagnosis, one random biopsy of a suspicious segment of tissue may not contain the expected histologic findings; therefore, clinical suspicion may warrant a second biopsy.¹⁰ There have been reported cases of an adult patient without history of CD presenting with a lesion that resembled a more common pathology, such as a genital wart, and the correct diagnosis of MCD with pseudocondylomatous morphology was made only after intestinal manifestations prompted the clinician to consider such an unusual diagnosis.⁴⁸

From a histopathologic perspective, MCD is characterized by discrete, noncaseating, sarcoidlike granulomas with abundant multinucleated giant cells (Langhans giant cells) in the superficial dermis (papillary), deep dermis (reticular), and adipose tissue (Figure).^8,17 In the presence of concomitant intestinal disease, the granulomas of both the intestinal and dermal tissues should share the same microscopic characteristics.⁸ In addition, copious neutrophils and granulomas surrounding the microvasculature have been described,³⁴ as well as general lymphocyte and plasma cell infiltrate.⁴⁵ Some histologic samples have included collagen degeneration termed necrobiosis in the middle dermal layer as another variable finding in MCD.^14,34

On microscopy, it has been reported that use of Verhoeff-van Gieson staining may be helpful to highlight the presence of neutrophil obstruction within the dermal vasculature, particularly the arterial lumen, as well as to aid in highlighting swelling of the endothelium with fragmentation of the internal elastic lamina.¹⁷ Although not part of the routine diagnosis, electron microscopy of MCD tissue samples have confirmed hypertrophy of the endothelial cells composing the capillaries with resulting extravasation of fibrin, red blood cells, lymphocytes, and epithelioid histiocytes.¹⁷ Observation of tissue under direct immunofluorescence has been less helpful, as it has shown only nonspecific fibrinogen deposition within the dermis and dermal vessels.¹⁷

In an article on treatment of MCD, Escher et al⁴³ reinforced that the macroscopic findings of MCD are diverse, and the microscopic findings characteristic of MCD also can be mimicked by other etiologies such as sarcoidosis, tuberculosis, fungal infections, lymphogranuloma venereum, leishmaniasis, and connective tissue disorders.⁴³ As such, the workup to rule out infectious, anatomic, and autoimmune etiologies should be diverse. Often, the workup for MCD will include special stains such as Ziehl-Neelsen stain to rule out Mycobacterium tuberculosis and acid-fast bacilli and Fite stain to consider atypical mycobacteria. Other tests such as tissue culture, chest radiograph, tuberculin skin test (Mantoux test), IFN-γ release assay, or polarized light microscopy may rule out infectious etiologies.^9,49 Serologic testing might include VDRL test, Treponema pallidum hemagglutination assay, hepatitis B, hepatitis C, and human immunodeficiency virus.⁵

Crohn disease is characterized histologically by sarcoidlike noncaseating granulomas, and as such, it is important to differentiate MCD from sarcoidosis prior to histologic analysis. Sarcoidosis also can be considered much less likely with a normal chest radiograph and in the absence of increased serum calcium and angiotensin-converting enzyme levels.⁷ The differentiation of sarcoidosis from MCD on the microscopic scale is subtle but is sometimes facilitated in the presence of an ulcerated epidermis or lymphocytic/eosinophilic infiltrate and edema within the dermis, all suggestive of MCD.¹⁴

Metastatic CD also should be differentiated from erythema nodosum and pyoderma gangrenosum, which are among the most common cutaneous findings associated with CD.¹⁴ Pyoderma gangrenosum can be distinguished histologically by identifying copious neutrophilic infiltrate with pseudoepitheliomatous hyperplasia.⁵⁰

Treatment

Because MCD is relatively rare, there are no known randomized trials suggesting a particular medical or surgical treatment. In a review of perineal MCD from 2007, the 40-year-old recommendation by Moutain³ opting for surgical debridement versus medical management still resonates, particularly for perineal disease, as an effective measure in all but the mildest of presentations.⁵¹ However, recent case reports also suggest that the tumor necrosis factor α (TNF-α) inhibitors such as infliximab and adalimumab should be considered prior to surgery even with severe perineal MCD.⁵¹ Moreover, even if medical management with TNF-α inhibitors or some combination of immunosuppressants and antibiotics does not eradicate the disease, it often helps reduce the size of the ulcers prior to surgery.⁵² With a limited understanding of MCD, one might think that removal of the affected bowel would eliminate cutaneous disease, but it has been shown that this strategy is not effective.^53,54

The composition and location of the particular lesion affects the trajectory of treatment. For example, MCD manifesting as local ulcers and plaques has been described as responding well to topical and intralesional steroids.^10,55,56 In the case of penile swelling and/or phimosis, circumcision has been helpful to improve the patient's ability to void as well as to attain and maintain erection.¹⁰ In the case of scrotal swelling secondary to MCD, early treatment (ie, within 4 to 6 months) with oral steroids and/or metronidazole is likely beneficial to prevent refractory edematous organization of the tissue.⁵⁷

As a general rule, an effective treatment will include a combination of an immunosuppressant, antibiotic therapy, and sometimes surgery. The most commonly used immunosuppressant agents include topical or intralesional steroids, infliximab,^43,58 cyclosporine A,^59,60 dapsone, minocycline, thalidomide, methotrexate, mycophenolate mofetil, sulfasalazine, azathioprine, tacrolimus, and 6-mercaptopurine.⁴ Steroids have been the conventional treatment of extraintestinal manifestations of CD⁶¹; however, perineal CD has been poorly controlled with systemic steroids.⁶² If steroids are found not to be effective, sometimes agents such as dapsone or thalidomide are considered. One case report noted stabilization of MCD penile ulcers with oral thalidomide 300 mg once daily, oral minocycline 100 mg once daily, and topical tacrolimus 0.3% with benzocaine twice daily with continuation of prednisolone and methotrexate as parts of previously unsuccessful regimen.⁵²

Metronidazole is perhaps the most commonly used antibiotic, having been a component of many successful regimens.^4,63 For example, a 27-year-old patient with MCD presenting as a nonhealing ulcerative lesion in the subcoronal area of the penis and scrotum was treated successfully with a 6-month course of mesalamine, prednisone, and metronidazole.⁴⁵ Another case report of vulvar MCD reported initial success with intravenous methylprednisolone, ciprofloxacin, and metronidazole.²³ The primary limitation of metronidazole is that subsequent tapering of the dose seems to result in recurrence of disease.⁶⁴ Consequently, patients must remain on the antibiotic for an indeterminate course, with dosages ranging from 5 mg/kg daily in adolescents⁶⁵ to 1000 to 1500 mg daily in adults.⁶⁶

Of the various immunosuppressants available, infliximab has been listed in numerous reports as a successful agent in both the induction and maintenance of extraintestinal manifestations of CD including MCD.^67-71 Infliximab has been reported to be effective in the treatment of penile and scrotal edema secondary to MCD that did not respond to other immunosuppressants including oral prednisolone, azathioprine, and cyclosporine.⁴³ Infliximab may be a good option to help heal draining fistulas, particularly in combination with an antibiotic such as metronidazole and ciprofloxacin, which helps to prevent abscess formation during healing.⁷² The response to infliximab has been dramatic, with resolution of cutaneous lesions after just 6 weeks in some cases.⁷³ The dosing regimen of infliximab has been suggested at 5 mg/kg administered at 0, 2, and 6 weeks, with subsequent maintenance infusions every 10 weeks,⁷⁰ or at 0, 4, and 12 weeks, with subsequent infusions every 8 weeks.⁴³

Adalimumab may be considered as an alternative to infliximab and is potentially less allergenic as a fully humanized monoclonal antibody to TNF-α, which also has been used successfully to both induce and maintain remission of moderate to severe CD.^42,74,75 Proposed dosing of adalimumab includes a loading dose of 160 mg subcutaneously on day 1, followed by an 80-mg dose 2 weeks later and a 40-mg maintenance dose every other week indefinitely.⁴⁸ Of note, adalimumab has been noted in the literature to have many potential side effects, including one particular case in which severe headaches were attributed to its use.⁵⁹ As a consequence of the headaches, the patient was switched from adalimumab to cyclosporine and responded well with no subsequent flare-ups on follow-up.

In summary, treatment of MCD depends on cutaneous location, severity, physician experience with certain antibiotics or immunosuppressants, availability of medication, and patient disposition. It seems reasonable to attempt medical management with one or more medical regimens before committing to surgical intervention. Furthermore, even with debridement, curettage, skin graft, or other surgical strategy, the patient is likely to require some period of immunosuppression to provide long-lasting remission.

Conclusion

Patients with inflammatory bowel disease often develop dermatologic sequelae, with MCD being a rare but serious process. Patients may present with a wide array of physical concerns and symptoms, many resembling other disease processes. As such, education and a high index of suspicion are needed for proper diagnosis and treatment.

Almost half of Crohn disease (CD) patients experience a dermatologic manifestation of the disease. A rare entity, metastatic CD (MCD) presents a diagnostic challenge without a high index of suspicion. Its etiology is not well defined; however, it appears to be an autoimmune response to gut antigens. Herein, we review the etiology/epidemiology, diagnostic criteria, and treatment for this uncommon condition.

Epidemiology and Clinical Characteristics of MCD

Metastatic CD was first described by Parks et al1 in 1965 and refers to a diverse collection of macroscopic dermatologic manifestations in tissue not contiguous with the gastrointestinal (GI) tract. To be classified as MCD, the tissue must demonstrate characteristic histopathologic findings, which invariably include noncaseating granulomas.

Crohn disease may affect any part of the GI tract from the mouth to anus, with a multitude of associated cutaneous manifestations having been described. The terminal ileum is the most commonly affected portion of the GI tract in CD, but the large intestine also may be involved in 55% to 80% of cases.² The incidence of non-MCD-associated anal lesions seems to correlate with intestinal involvement in that as few as 25% of patients with ileal-localized CD have anal lesions compared to nearly 80% of patients with large intestinal involvement.³

It has been estimated that 18% to 44% of patients with CD have some form of cutaneous manifestation,⁴ with MCD being a rare subcategory. As few as 100 cases have been described from 1965 to the present.⁵ The presence of MCD does not correlate well with severity of intestinal CD, and although a majority of MCD cases present after at least 6 months of GI symptoms,⁶ there are instances in which MCD presents without prior or existing evidence of intestinal CD.⁷

With regard to MCD, the term metastatic is sometimes supplanted in the literature by cutaneous to avoid any implication of cancer; however, due to a myriad of dermatologic manifestations, both terms can cause confusion. The categorization of the various types of cutaneous findings in CD is well summarized in a review by Palamaras et al8 with the following classifications: (1) granulomatous by direct extension (oral or perianal), (2) MCD lesions (genital and nongenital), (3) immune-related lesions, and (4) lesions from nutritional deficiencies. Of the cutaneous manifestations relating to CD, MCD is the least common cutaneous categorical manifestation and is further divided into subcategories of genital and nongenital lesions.⁸

The nongenital distribution of MCD is the more common variety in adults and particularly seems to affect the legs and plantar surfaces (38%), the trunk and abdomen (24%), and the face (15%).^5,9 These nongenital MCD manifestations are most commonly described as nodules, ulcerations, or erythematous to purple plaques, and less commonly described as abscesses, pustules, or papules.

The sequence of cutaneous symptoms of MCD relative to intestinal disease depends to some degree on patient age. In adults diagnosed with MCD, it has been noted that a GI flare is expected 2 months to 4 years after diagnosis; however, in children the subsequent GI flare has been noted to vary more widely from 9 months to 14 years following presentation of MCD.⁸ Furthermore, roughly 50% of children diagnosed with MCD present concomitantly with their first symptoms of a GI flare, whereas 70% of adults with MCD had been previously diagnosed with intestinal CD.⁸ In one review of 80 reported cases of MCD, 20% (16/80) had no symptoms of intestinal disease at the time of MCD diagnosis, and the majority of the asymptomatic cases were in children; interestingly, the majority of these same children were diagnosed with CD months to years later.⁹

Both the location and characteristics of cutaneous findings in MCD correlate with age.⁹ Metastatic CD has been identified in all age groups; however, lymphedema is more common in children/young adults, while nodules, ulceration, and fistulating disease are more often seen in adults.¹⁰ Affected children and adolescents with MCD range from 5 to 17 years of age, with a mean age at disease onset of 11.1 years and equal incidence in males and females.⁸ Adults with MCD range from 18 to 78 years of age, with a mean age at presentation of 38.4 years.^8,11

Concerning anatomic location of disease, adults with MCD most commonly have nodules with or without plaques on the arms and legs and less commonly in the genital area.⁸ In contrast, children with MCD are more prone to genital lesions, with up to 85% of cases including some degree of genital erythematous or nonerythematous swelling with or without induration.⁸ Genitourinary complications of CD as a broad category, however, are estimated to occur in only 5% to 20% of intestinal CD cases in both children and adults.¹²

There have been conflicting reports regarding gender predilection in MCD. Based on a review by Samitz et al¹³ of 200 cases of CD over an 18-year period, 22% of patients with CD were found to have cutaneous manifestations--presumably not MCD but rather perianal, perineal, vulvar fistulae, fissures, or abscesses--with a male to female preponderance of almost 2 to 1. A more recent review of the literature by Palamaras et al⁸ in 2008 reported that contiguous non-MCD affects adult females and children more often than adult males, with 63% adult cases being female. This review seems to be more congruent with other reports in the literature implicating that females are twice as commonly affected by MCD than males.^9,14

Pathophysiology

The etiology of MCD has not been well defined. One proposed mechanism of the distal tissue involvement of MCD is through passage of antigens to the skin with subsequent granulomatous response at the level of the dermis.¹⁰ Another proposed mechanism suggests antibody sensitization to gut antigens, possibly bacterial antigens, that then coincidentally cross-react with analogous skin antigens.^8,14 Burgdorf¹¹ supported this notion in a 1981 report in which it was suggested that the granulomatous reaction was related to deposition of immune complexes in the skin. Slater et al¹⁵ and Tatnall et al¹⁶ offered a variation of Burgdorf's notion, suggesting that it was sensitized T cells to circulating antigens that were the initiators of granuloma formation in the periphery.

An examination of MCD tissue in 1990 by Shum and Guenther¹⁷ under electron microscopy and immunofluorescence provided evidence against prior studies that purported to have identified immune complexes as the causative agents of MCD. In this study, the authors found no evidence of immune complexes in the dermis of MCD lesions. In addition, an attempt to react serum antibodies of a patient with MCD, which were postulated to have IgG, IgM, and IgA antibodies to specific gut antigens, yielded no response when reacted with the tongue, ileum, and colon tissue from a rat. As a culminant finding, the authors also noted MCD dermis tissue with granulomas without vasculitis, suggesting a T-cell mediated type IV hypersensitivity response with a secondary vasculitis from T-cell origin lymphokines and T-cell mediated monocyte activation.¹⁷

Research implicating other immunologic entities involved in the pathophysiology of CD such as β-2 integrin,¹⁸ CD14⁺ monocytes,¹⁹ and the role of the DNA repair gene MLH1 (mutL homolog 1)²⁰ have been considered but without a clearly definitive role in the manifestations of MCD.

The utility of metronidazole in the treatment of MCD has been suggested as evidence that certain bacteria in the gut may either serve as the causative antigen or may induce its formation²¹; however, the causative antigen has yet to be identified, and whether it travels distally to the skin or merely resembles a similar antigen normally present in the dermis has not yet been determined. Some research has used in situ polymerase chain reaction techniques to attempt to detect similar microbial pathogens in both the vasculature of active bowel lesions and in the skin, but to date, bacterial RNA noted to be present in the gut vasculature adjacent to CD lesions has not been detected in skin lesions.²²

Diagnosis

Physical Findings

Overall, it is estimated that roughly 56% of all MCD cases affect the external genitalia.²³ The classic appearance of MCD includes well-demarcated ulcerations in the areas of intertriginous skin folds with or without diffuse edema and tenderness to palpation.²³ Although MCD has been historically noted as having a predilection for moist skin folds, there are numerous case reports of MCD all over the body, including the face,^7,24-29 retroauricular areas,³⁰ arms and legs,^16,17,31-34 lower abdomen,^3,5 under the breasts,¹ perineum,³⁵ external genitalia,^1,9,36-40 and even the lungs⁴¹ and bladder.⁴²

As a dermatologic disease, MCD has been referred to as yet another great imitator, both on the macroscopic and microscopic levels.⁸ As such, more common causes of genital edema should be considered first and investigated based on the patient's history, physical examination, skin biopsy, lymphangiogram, ultrasound, and cystogram.⁴³ Ultrasonography and color Doppler sonography have been shown to be helpful in patients with genital involvement. This modality can evaluate not only the presence of normal testes but also intratesticular and scrotal wall fluid, especially when the physical examination reveals swelling that makes testicle palpation more difficult.⁶ Clinically, the correct diagnosis of MCD often is made through suspicion of inflammatory bowel disease based on classic symptoms and/or physical findings including abdominal pain, weight loss, bloody stool, diarrhea, perianal skin tags, and anal fissures or fistulas. Any of these GI findings should prompt an intestinal biopsy to rule out any histologic evidence of CD.

Metastatic CD affecting the vulva often presents with vulvar pain and pruritus and may clinically mimic a more benign disease such as balanitis plasmacellularis, also referred to as Zoon vulvitis.²³ Similar to MCD on any given body surface, there is dramatic variation in the macroscopic presentation of vulvar MCD, with physical examination findings ranging from bilateral diffuse, edematous, deeply macerated, red, ulcerated lesions over the vulva with lymphadenopathy to findings of bilateral vulvar pain with yellow drainage from the labia majora.²³ There have been cases of vulvar MCD that include exquisite vulvar pain but without structural abnormalities including normal uterus, cervix, adnexa, rectovaginal septum, and rectum. In these more nebulous cases of vulvar MCD, the diagnosis often is discovered incidentally when nonspecific diagnostic imaging suggests underlying CD.²³

Beyond the case-by-case variations on physical examination, the great difficulty in diagnosis, particularly in children, occurs in the absence of any GI symptoms and therefore no logical consideration of underlying CD. Consequently, there have been cases of children presenting with irritation of the vulva who were eventually diagnosed with MCD only after erroneous treatment of contact dermatitis, candidiasis, and even consideration of sexual abuse.³⁷ Because it is so rare and obscure among practicing clinicians, the diagnosis of MCD often is considered only after irritation or swelling of the external genitalia has not responded to standard therapies. If and when the diagnosis of MCD is considered in children, it has been suggested to screen patients for anorectal stricture, as case studies have found the condition to be relatively common in this subpopulation.⁴⁴

In the less common case of adults with genitourinary symptoms that suggest possible MCD, the differential diagnosis for penile or vaginal ulcers should include contact and irritant dermatitis, chronic infectious lesions (eg, hidradenitis suppurativa, actinomycosis, tuberculosis),⁴⁵ sexually transmitted ulcerative diseases (eg, chancroid, lymphogranuloma venereum, herpes genitalia, granuloma inguinale),⁴⁶ drug reactions, and even extramammary Paget disease.⁴⁷

Histologic Findings

Because MCD has so much macroscopic variation and can present anywhere on the surface of the body, formal diagnosis relies on microscopy. As an added measure of difficulty in diagnosis, one random biopsy of a suspicious segment of tissue may not contain the expected histologic findings; therefore, clinical suspicion may warrant a second biopsy.¹⁰ There have been reported cases of an adult patient without history of CD presenting with a lesion that resembled a more common pathology, such as a genital wart, and the correct diagnosis of MCD with pseudocondylomatous morphology was made only after intestinal manifestations prompted the clinician to consider such an unusual diagnosis.⁴⁸

From a histopathologic perspective, MCD is characterized by discrete, noncaseating, sarcoidlike granulomas with abundant multinucleated giant cells (Langhans giant cells) in the superficial dermis (papillary), deep dermis (reticular), and adipose tissue (Figure).^8,17 In the presence of concomitant intestinal disease, the granulomas of both the intestinal and dermal tissues should share the same microscopic characteristics.⁸ In addition, copious neutrophils and granulomas surrounding the microvasculature have been described,³⁴ as well as general lymphocyte and plasma cell infiltrate.⁴⁵ Some histologic samples have included collagen degeneration termed necrobiosis in the middle dermal layer as another variable finding in MCD.^14,34

On microscopy, it has been reported that use of Verhoeff-van Gieson staining may be helpful to highlight the presence of neutrophil obstruction within the dermal vasculature, particularly the arterial lumen, as well as to aid in highlighting swelling of the endothelium with fragmentation of the internal elastic lamina.¹⁷ Although not part of the routine diagnosis, electron microscopy of MCD tissue samples have confirmed hypertrophy of the endothelial cells composing the capillaries with resulting extravasation of fibrin, red blood cells, lymphocytes, and epithelioid histiocytes.¹⁷ Observation of tissue under direct immunofluorescence has been less helpful, as it has shown only nonspecific fibrinogen deposition within the dermis and dermal vessels.¹⁷

In an article on treatment of MCD, Escher et al⁴³ reinforced that the macroscopic findings of MCD are diverse, and the microscopic findings characteristic of MCD also can be mimicked by other etiologies such as sarcoidosis, tuberculosis, fungal infections, lymphogranuloma venereum, leishmaniasis, and connective tissue disorders.⁴³ As such, the workup to rule out infectious, anatomic, and autoimmune etiologies should be diverse. Often, the workup for MCD will include special stains such as Ziehl-Neelsen stain to rule out Mycobacterium tuberculosis and acid-fast bacilli and Fite stain to consider atypical mycobacteria. Other tests such as tissue culture, chest radiograph, tuberculin skin test (Mantoux test), IFN-γ release assay, or polarized light microscopy may rule out infectious etiologies.^9,49 Serologic testing might include VDRL test, Treponema pallidum hemagglutination assay, hepatitis B, hepatitis C, and human immunodeficiency virus.⁵

Crohn disease is characterized histologically by sarcoidlike noncaseating granulomas, and as such, it is important to differentiate MCD from sarcoidosis prior to histologic analysis. Sarcoidosis also can be considered much less likely with a normal chest radiograph and in the absence of increased serum calcium and angiotensin-converting enzyme levels.⁷ The differentiation of sarcoidosis from MCD on the microscopic scale is subtle but is sometimes facilitated in the presence of an ulcerated epidermis or lymphocytic/eosinophilic infiltrate and edema within the dermis, all suggestive of MCD.¹⁴

Metastatic CD also should be differentiated from erythema nodosum and pyoderma gangrenosum, which are among the most common cutaneous findings associated with CD.¹⁴ Pyoderma gangrenosum can be distinguished histologically by identifying copious neutrophilic infiltrate with pseudoepitheliomatous hyperplasia.⁵⁰

Treatment

Because MCD is relatively rare, there are no known randomized trials suggesting a particular medical or surgical treatment. In a review of perineal MCD from 2007, the 40-year-old recommendation by Moutain³ opting for surgical debridement versus medical management still resonates, particularly for perineal disease, as an effective measure in all but the mildest of presentations.⁵¹ However, recent case reports also suggest that the tumor necrosis factor α (TNF-α) inhibitors such as infliximab and adalimumab should be considered prior to surgery even with severe perineal MCD.⁵¹ Moreover, even if medical management with TNF-α inhibitors or some combination of immunosuppressants and antibiotics does not eradicate the disease, it often helps reduce the size of the ulcers prior to surgery.⁵² With a limited understanding of MCD, one might think that removal of the affected bowel would eliminate cutaneous disease, but it has been shown that this strategy is not effective.^53,54

The composition and location of the particular lesion affects the trajectory of treatment. For example, MCD manifesting as local ulcers and plaques has been described as responding well to topical and intralesional steroids.^10,55,56 In the case of penile swelling and/or phimosis, circumcision has been helpful to improve the patient's ability to void as well as to attain and maintain erection.¹⁰ In the case of scrotal swelling secondary to MCD, early treatment (ie, within 4 to 6 months) with oral steroids and/or metronidazole is likely beneficial to prevent refractory edematous organization of the tissue.⁵⁷

As a general rule, an effective treatment will include a combination of an immunosuppressant, antibiotic therapy, and sometimes surgery. The most commonly used immunosuppressant agents include topical or intralesional steroids, infliximab,^43,58 cyclosporine A,^59,60 dapsone, minocycline, thalidomide, methotrexate, mycophenolate mofetil, sulfasalazine, azathioprine, tacrolimus, and 6-mercaptopurine.⁴ Steroids have been the conventional treatment of extraintestinal manifestations of CD⁶¹; however, perineal CD has been poorly controlled with systemic steroids.⁶² If steroids are found not to be effective, sometimes agents such as dapsone or thalidomide are considered. One case report noted stabilization of MCD penile ulcers with oral thalidomide 300 mg once daily, oral minocycline 100 mg once daily, and topical tacrolimus 0.3% with benzocaine twice daily with continuation of prednisolone and methotrexate as parts of previously unsuccessful regimen.⁵²

Metronidazole is perhaps the most commonly used antibiotic, having been a component of many successful regimens.^4,63 For example, a 27-year-old patient with MCD presenting as a nonhealing ulcerative lesion in the subcoronal area of the penis and scrotum was treated successfully with a 6-month course of mesalamine, prednisone, and metronidazole.⁴⁵ Another case report of vulvar MCD reported initial success with intravenous methylprednisolone, ciprofloxacin, and metronidazole.²³ The primary limitation of metronidazole is that subsequent tapering of the dose seems to result in recurrence of disease.⁶⁴ Consequently, patients must remain on the antibiotic for an indeterminate course, with dosages ranging from 5 mg/kg daily in adolescents⁶⁵ to 1000 to 1500 mg daily in adults.⁶⁶

Of the various immunosuppressants available, infliximab has been listed in numerous reports as a successful agent in both the induction and maintenance of extraintestinal manifestations of CD including MCD.^67-71 Infliximab has been reported to be effective in the treatment of penile and scrotal edema secondary to MCD that did not respond to other immunosuppressants including oral prednisolone, azathioprine, and cyclosporine.⁴³ Infliximab may be a good option to help heal draining fistulas, particularly in combination with an antibiotic such as metronidazole and ciprofloxacin, which helps to prevent abscess formation during healing.⁷² The response to infliximab has been dramatic, with resolution of cutaneous lesions after just 6 weeks in some cases.⁷³ The dosing regimen of infliximab has been suggested at 5 mg/kg administered at 0, 2, and 6 weeks, with subsequent maintenance infusions every 10 weeks,⁷⁰ or at 0, 4, and 12 weeks, with subsequent infusions every 8 weeks.⁴³

Adalimumab may be considered as an alternative to infliximab and is potentially less allergenic as a fully humanized monoclonal antibody to TNF-α, which also has been used successfully to both induce and maintain remission of moderate to severe CD.^42,74,75 Proposed dosing of adalimumab includes a loading dose of 160 mg subcutaneously on day 1, followed by an 80-mg dose 2 weeks later and a 40-mg maintenance dose every other week indefinitely.⁴⁸ Of note, adalimumab has been noted in the literature to have many potential side effects, including one particular case in which severe headaches were attributed to its use.⁵⁹ As a consequence of the headaches, the patient was switched from adalimumab to cyclosporine and responded well with no subsequent flare-ups on follow-up.

In summary, treatment of MCD depends on cutaneous location, severity, physician experience with certain antibiotics or immunosuppressants, availability of medication, and patient disposition. It seems reasonable to attempt medical management with one or more medical regimens before committing to surgical intervention. Furthermore, even with debridement, curettage, skin graft, or other surgical strategy, the patient is likely to require some period of immunosuppression to provide long-lasting remission.

Conclusion

Patients with inflammatory bowel disease often develop dermatologic sequelae, with MCD being a rare but serious process. Patients may present with a wide array of physical concerns and symptoms, many resembling other disease processes. As such, education and a high index of suspicion are needed for proper diagnosis and treatment.

Almost half of Crohn disease (CD) patients experience a dermatologic manifestation of the disease. A rare entity, metastatic CD (MCD) presents a diagnostic challenge without a high index of suspicion. Its etiology is not well defined; however, it appears to be an autoimmune response to gut antigens. Herein, we review the etiology/epidemiology, diagnostic criteria, and treatment for this uncommon condition.

Epidemiology and Clinical Characteristics of MCD

Metastatic CD was first described by Parks et al1 in 1965 and refers to a diverse collection of macroscopic dermatologic manifestations in tissue not contiguous with the gastrointestinal (GI) tract. To be classified as MCD, the tissue must demonstrate characteristic histopathologic findings, which invariably include noncaseating granulomas.

Crohn disease may affect any part of the GI tract from the mouth to anus, with a multitude of associated cutaneous manifestations having been described. The terminal ileum is the most commonly affected portion of the GI tract in CD, but the large intestine also may be involved in 55% to 80% of cases.² The incidence of non-MCD-associated anal lesions seems to correlate with intestinal involvement in that as few as 25% of patients with ileal-localized CD have anal lesions compared to nearly 80% of patients with large intestinal involvement.³

It has been estimated that 18% to 44% of patients with CD have some form of cutaneous manifestation,⁴ with MCD being a rare subcategory. As few as 100 cases have been described from 1965 to the present.⁵ The presence of MCD does not correlate well with severity of intestinal CD, and although a majority of MCD cases present after at least 6 months of GI symptoms,⁶ there are instances in which MCD presents without prior or existing evidence of intestinal CD.⁷

With regard to MCD, the term metastatic is sometimes supplanted in the literature by cutaneous to avoid any implication of cancer; however, due to a myriad of dermatologic manifestations, both terms can cause confusion. The categorization of the various types of cutaneous findings in CD is well summarized in a review by Palamaras et al8 with the following classifications: (1) granulomatous by direct extension (oral or perianal), (2) MCD lesions (genital and nongenital), (3) immune-related lesions, and (4) lesions from nutritional deficiencies. Of the cutaneous manifestations relating to CD, MCD is the least common cutaneous categorical manifestation and is further divided into subcategories of genital and nongenital lesions.⁸

The nongenital distribution of MCD is the more common variety in adults and particularly seems to affect the legs and plantar surfaces (38%), the trunk and abdomen (24%), and the face (15%).^5,9 These nongenital MCD manifestations are most commonly described as nodules, ulcerations, or erythematous to purple plaques, and less commonly described as abscesses, pustules, or papules.

The sequence of cutaneous symptoms of MCD relative to intestinal disease depends to some degree on patient age. In adults diagnosed with MCD, it has been noted that a GI flare is expected 2 months to 4 years after diagnosis; however, in children the subsequent GI flare has been noted to vary more widely from 9 months to 14 years following presentation of MCD.⁸ Furthermore, roughly 50% of children diagnosed with MCD present concomitantly with their first symptoms of a GI flare, whereas 70% of adults with MCD had been previously diagnosed with intestinal CD.⁸ In one review of 80 reported cases of MCD, 20% (16/80) had no symptoms of intestinal disease at the time of MCD diagnosis, and the majority of the asymptomatic cases were in children; interestingly, the majority of these same children were diagnosed with CD months to years later.⁹

Both the location and characteristics of cutaneous findings in MCD correlate with age.⁹ Metastatic CD has been identified in all age groups; however, lymphedema is more common in children/young adults, while nodules, ulceration, and fistulating disease are more often seen in adults.¹⁰ Affected children and adolescents with MCD range from 5 to 17 years of age, with a mean age at disease onset of 11.1 years and equal incidence in males and females.⁸ Adults with MCD range from 18 to 78 years of age, with a mean age at presentation of 38.4 years.^8,11

Concerning anatomic location of disease, adults with MCD most commonly have nodules with or without plaques on the arms and legs and less commonly in the genital area.⁸ In contrast, children with MCD are more prone to genital lesions, with up to 85% of cases including some degree of genital erythematous or nonerythematous swelling with or without induration.⁸ Genitourinary complications of CD as a broad category, however, are estimated to occur in only 5% to 20% of intestinal CD cases in both children and adults.¹²

There have been conflicting reports regarding gender predilection in MCD. Based on a review by Samitz et al¹³ of 200 cases of CD over an 18-year period, 22% of patients with CD were found to have cutaneous manifestations--presumably not MCD but rather perianal, perineal, vulvar fistulae, fissures, or abscesses--with a male to female preponderance of almost 2 to 1. A more recent review of the literature by Palamaras et al⁸ in 2008 reported that contiguous non-MCD affects adult females and children more often than adult males, with 63% adult cases being female. This review seems to be more congruent with other reports in the literature implicating that females are twice as commonly affected by MCD than males.^9,14

Pathophysiology

The etiology of MCD has not been well defined. One proposed mechanism of the distal tissue involvement of MCD is through passage of antigens to the skin with subsequent granulomatous response at the level of the dermis.¹⁰ Another proposed mechanism suggests antibody sensitization to gut antigens, possibly bacterial antigens, that then coincidentally cross-react with analogous skin antigens.^8,14 Burgdorf¹¹ supported this notion in a 1981 report in which it was suggested that the granulomatous reaction was related to deposition of immune complexes in the skin. Slater et al¹⁵ and Tatnall et al¹⁶ offered a variation of Burgdorf's notion, suggesting that it was sensitized T cells to circulating antigens that were the initiators of granuloma formation in the periphery.

An examination of MCD tissue in 1990 by Shum and Guenther¹⁷ under electron microscopy and immunofluorescence provided evidence against prior studies that purported to have identified immune complexes as the causative agents of MCD. In this study, the authors found no evidence of immune complexes in the dermis of MCD lesions. In addition, an attempt to react serum antibodies of a patient with MCD, which were postulated to have IgG, IgM, and IgA antibodies to specific gut antigens, yielded no response when reacted with the tongue, ileum, and colon tissue from a rat. As a culminant finding, the authors also noted MCD dermis tissue with granulomas without vasculitis, suggesting a T-cell mediated type IV hypersensitivity response with a secondary vasculitis from T-cell origin lymphokines and T-cell mediated monocyte activation.¹⁷

Research implicating other immunologic entities involved in the pathophysiology of CD such as β-2 integrin,¹⁸ CD14⁺ monocytes,¹⁹ and the role of the DNA repair gene MLH1 (mutL homolog 1)²⁰ have been considered but without a clearly definitive role in the manifestations of MCD.

The utility of metronidazole in the treatment of MCD has been suggested as evidence that certain bacteria in the gut may either serve as the causative antigen or may induce its formation²¹; however, the causative antigen has yet to be identified, and whether it travels distally to the skin or merely resembles a similar antigen normally present in the dermis has not yet been determined. Some research has used in situ polymerase chain reaction techniques to attempt to detect similar microbial pathogens in both the vasculature of active bowel lesions and in the skin, but to date, bacterial RNA noted to be present in the gut vasculature adjacent to CD lesions has not been detected in skin lesions.²²

Diagnosis

Physical Findings

Overall, it is estimated that roughly 56% of all MCD cases affect the external genitalia.²³ The classic appearance of MCD includes well-demarcated ulcerations in the areas of intertriginous skin folds with or without diffuse edema and tenderness to palpation.²³ Although MCD has been historically noted as having a predilection for moist skin folds, there are numerous case reports of MCD all over the body, including the face,^7,24-29 retroauricular areas,³⁰ arms and legs,^16,17,31-34 lower abdomen,^3,5 under the breasts,¹ perineum,³⁵ external genitalia,^1,9,36-40 and even the lungs⁴¹ and bladder.⁴²

As a dermatologic disease, MCD has been referred to as yet another great imitator, both on the macroscopic and microscopic levels.⁸ As such, more common causes of genital edema should be considered first and investigated based on the patient's history, physical examination, skin biopsy, lymphangiogram, ultrasound, and cystogram.⁴³ Ultrasonography and color Doppler sonography have been shown to be helpful in patients with genital involvement. This modality can evaluate not only the presence of normal testes but also intratesticular and scrotal wall fluid, especially when the physical examination reveals swelling that makes testicle palpation more difficult.⁶ Clinically, the correct diagnosis of MCD often is made through suspicion of inflammatory bowel disease based on classic symptoms and/or physical findings including abdominal pain, weight loss, bloody stool, diarrhea, perianal skin tags, and anal fissures or fistulas. Any of these GI findings should prompt an intestinal biopsy to rule out any histologic evidence of CD.

Metastatic CD affecting the vulva often presents with vulvar pain and pruritus and may clinically mimic a more benign disease such as balanitis plasmacellularis, also referred to as Zoon vulvitis.²³ Similar to MCD on any given body surface, there is dramatic variation in the macroscopic presentation of vulvar MCD, with physical examination findings ranging from bilateral diffuse, edematous, deeply macerated, red, ulcerated lesions over the vulva with lymphadenopathy to findings of bilateral vulvar pain with yellow drainage from the labia majora.²³ There have been cases of vulvar MCD that include exquisite vulvar pain but without structural abnormalities including normal uterus, cervix, adnexa, rectovaginal septum, and rectum. In these more nebulous cases of vulvar MCD, the diagnosis often is discovered incidentally when nonspecific diagnostic imaging suggests underlying CD.²³

Beyond the case-by-case variations on physical examination, the great difficulty in diagnosis, particularly in children, occurs in the absence of any GI symptoms and therefore no logical consideration of underlying CD. Consequently, there have been cases of children presenting with irritation of the vulva who were eventually diagnosed with MCD only after erroneous treatment of contact dermatitis, candidiasis, and even consideration of sexual abuse.³⁷ Because it is so rare and obscure among practicing clinicians, the diagnosis of MCD often is considered only after irritation or swelling of the external genitalia has not responded to standard therapies. If and when the diagnosis of MCD is considered in children, it has been suggested to screen patients for anorectal stricture, as case studies have found the condition to be relatively common in this subpopulation.⁴⁴

In the less common case of adults with genitourinary symptoms that suggest possible MCD, the differential diagnosis for penile or vaginal ulcers should include contact and irritant dermatitis, chronic infectious lesions (eg, hidradenitis suppurativa, actinomycosis, tuberculosis),⁴⁵ sexually transmitted ulcerative diseases (eg, chancroid, lymphogranuloma venereum, herpes genitalia, granuloma inguinale),⁴⁶ drug reactions, and even extramammary Paget disease.⁴⁷

Histologic Findings

Because MCD has so much macroscopic variation and can present anywhere on the surface of the body, formal diagnosis relies on microscopy. As an added measure of difficulty in diagnosis, one random biopsy of a suspicious segment of tissue may not contain the expected histologic findings; therefore, clinical suspicion may warrant a second biopsy.¹⁰ There have been reported cases of an adult patient without history of CD presenting with a lesion that resembled a more common pathology, such as a genital wart, and the correct diagnosis of MCD with pseudocondylomatous morphology was made only after intestinal manifestations prompted the clinician to consider such an unusual diagnosis.⁴⁸

From a histopathologic perspective, MCD is characterized by discrete, noncaseating, sarcoidlike granulomas with abundant multinucleated giant cells (Langhans giant cells) in the superficial dermis (papillary), deep dermis (reticular), and adipose tissue (Figure).^8,17 In the presence of concomitant intestinal disease, the granulomas of both the intestinal and dermal tissues should share the same microscopic characteristics.⁸ In addition, copious neutrophils and granulomas surrounding the microvasculature have been described,³⁴ as well as general lymphocyte and plasma cell infiltrate.⁴⁵ Some histologic samples have included collagen degeneration termed necrobiosis in the middle dermal layer as another variable finding in MCD.^14,34

On microscopy, it has been reported that use of Verhoeff-van Gieson staining may be helpful to highlight the presence of neutrophil obstruction within the dermal vasculature, particularly the arterial lumen, as well as to aid in highlighting swelling of the endothelium with fragmentation of the internal elastic lamina.¹⁷ Although not part of the routine diagnosis, electron microscopy of MCD tissue samples have confirmed hypertrophy of the endothelial cells composing the capillaries with resulting extravasation of fibrin, red blood cells, lymphocytes, and epithelioid histiocytes.¹⁷ Observation of tissue under direct immunofluorescence has been less helpful, as it has shown only nonspecific fibrinogen deposition within the dermis and dermal vessels.¹⁷

In an article on treatment of MCD, Escher et al⁴³ reinforced that the macroscopic findings of MCD are diverse, and the microscopic findings characteristic of MCD also can be mimicked by other etiologies such as sarcoidosis, tuberculosis, fungal infections, lymphogranuloma venereum, leishmaniasis, and connective tissue disorders.⁴³ As such, the workup to rule out infectious, anatomic, and autoimmune etiologies should be diverse. Often, the workup for MCD will include special stains such as Ziehl-Neelsen stain to rule out Mycobacterium tuberculosis and acid-fast bacilli and Fite stain to consider atypical mycobacteria. Other tests such as tissue culture, chest radiograph, tuberculin skin test (Mantoux test), IFN-γ release assay, or polarized light microscopy may rule out infectious etiologies.^9,49 Serologic testing might include VDRL test, Treponema pallidum hemagglutination assay, hepatitis B, hepatitis C, and human immunodeficiency virus.⁵

Crohn disease is characterized histologically by sarcoidlike noncaseating granulomas, and as such, it is important to differentiate MCD from sarcoidosis prior to histologic analysis. Sarcoidosis also can be considered much less likely with a normal chest radiograph and in the absence of increased serum calcium and angiotensin-converting enzyme levels.⁷ The differentiation of sarcoidosis from MCD on the microscopic scale is subtle but is sometimes facilitated in the presence of an ulcerated epidermis or lymphocytic/eosinophilic infiltrate and edema within the dermis, all suggestive of MCD.¹⁴

Metastatic CD also should be differentiated from erythema nodosum and pyoderma gangrenosum, which are among the most common cutaneous findings associated with CD.¹⁴ Pyoderma gangrenosum can be distinguished histologically by identifying copious neutrophilic infiltrate with pseudoepitheliomatous hyperplasia.⁵⁰

Treatment

Because MCD is relatively rare, there are no known randomized trials suggesting a particular medical or surgical treatment. In a review of perineal MCD from 2007, the 40-year-old recommendation by Moutain³ opting for surgical debridement versus medical management still resonates, particularly for perineal disease, as an effective measure in all but the mildest of presentations.⁵¹ However, recent case reports also suggest that the tumor necrosis factor α (TNF-α) inhibitors such as infliximab and adalimumab should be considered prior to surgery even with severe perineal MCD.⁵¹ Moreover, even if medical management with TNF-α inhibitors or some combination of immunosuppressants and antibiotics does not eradicate the disease, it often helps reduce the size of the ulcers prior to surgery.⁵² With a limited understanding of MCD, one might think that removal of the affected bowel would eliminate cutaneous disease, but it has been shown that this strategy is not effective.^53,54

The composition and location of the particular lesion affects the trajectory of treatment. For example, MCD manifesting as local ulcers and plaques has been described as responding well to topical and intralesional steroids.^10,55,56 In the case of penile swelling and/or phimosis, circumcision has been helpful to improve the patient's ability to void as well as to attain and maintain erection.¹⁰ In the case of scrotal swelling secondary to MCD, early treatment (ie, within 4 to 6 months) with oral steroids and/or metronidazole is likely beneficial to prevent refractory edematous organization of the tissue.⁵⁷

As a general rule, an effective treatment will include a combination of an immunosuppressant, antibiotic therapy, and sometimes surgery. The most commonly used immunosuppressant agents include topical or intralesional steroids, infliximab,^43,58 cyclosporine A,^59,60 dapsone, minocycline, thalidomide, methotrexate, mycophenolate mofetil, sulfasalazine, azathioprine, tacrolimus, and 6-mercaptopurine.⁴ Steroids have been the conventional treatment of extraintestinal manifestations of CD⁶¹; however, perineal CD has been poorly controlled with systemic steroids.⁶² If steroids are found not to be effective, sometimes agents such as dapsone or thalidomide are considered. One case report noted stabilization of MCD penile ulcers with oral thalidomide 300 mg once daily, oral minocycline 100 mg once daily, and topical tacrolimus 0.3% with benzocaine twice daily with continuation of prednisolone and methotrexate as parts of previously unsuccessful regimen.⁵²

Metronidazole is perhaps the most commonly used antibiotic, having been a component of many successful regimens.^4,63 For example, a 27-year-old patient with MCD presenting as a nonhealing ulcerative lesion in the subcoronal area of the penis and scrotum was treated successfully with a 6-month course of mesalamine, prednisone, and metronidazole.⁴⁵ Another case report of vulvar MCD reported initial success with intravenous methylprednisolone, ciprofloxacin, and metronidazole.²³ The primary limitation of metronidazole is that subsequent tapering of the dose seems to result in recurrence of disease.⁶⁴ Consequently, patients must remain on the antibiotic for an indeterminate course, with dosages ranging from 5 mg/kg daily in adolescents⁶⁵ to 1000 to 1500 mg daily in adults.⁶⁶

Of the various immunosuppressants available, infliximab has been listed in numerous reports as a successful agent in both the induction and maintenance of extraintestinal manifestations of CD including MCD.^67-71 Infliximab has been reported to be effective in the treatment of penile and scrotal edema secondary to MCD that did not respond to other immunosuppressants including oral prednisolone, azathioprine, and cyclosporine.⁴³ Infliximab may be a good option to help heal draining fistulas, particularly in combination with an antibiotic such as metronidazole and ciprofloxacin, which helps to prevent abscess formation during healing.⁷² The response to infliximab has been dramatic, with resolution of cutaneous lesions after just 6 weeks in some cases.⁷³ The dosing regimen of infliximab has been suggested at 5 mg/kg administered at 0, 2, and 6 weeks, with subsequent maintenance infusions every 10 weeks,⁷⁰ or at 0, 4, and 12 weeks, with subsequent infusions every 8 weeks.⁴³

Adalimumab may be considered as an alternative to infliximab and is potentially less allergenic as a fully humanized monoclonal antibody to TNF-α, which also has been used successfully to both induce and maintain remission of moderate to severe CD.^42,74,75 Proposed dosing of adalimumab includes a loading dose of 160 mg subcutaneously on day 1, followed by an 80-mg dose 2 weeks later and a 40-mg maintenance dose every other week indefinitely.⁴⁸ Of note, adalimumab has been noted in the literature to have many potential side effects, including one particular case in which severe headaches were attributed to its use.⁵⁹ As a consequence of the headaches, the patient was switched from adalimumab to cyclosporine and responded well with no subsequent flare-ups on follow-up.

In summary, treatment of MCD depends on cutaneous location, severity, physician experience with certain antibiotics or immunosuppressants, availability of medication, and patient disposition. It seems reasonable to attempt medical management with one or more medical regimens before committing to surgical intervention. Furthermore, even with debridement, curettage, skin graft, or other surgical strategy, the patient is likely to require some period of immunosuppression to provide long-lasting remission.

Conclusion

Patients with inflammatory bowel disease often develop dermatologic sequelae, with MCD being a rare but serious process. Patients may present with a wide array of physical concerns and symptoms, many resembling other disease processes. As such, education and a high index of suspicion are needed for proper diagnosis and treatment.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Cutaneous myoepithelial tumors are rare neoplasms but are being increasingly recognized and reported in the literature.^1-7 Myoepithelial tumors are related to benign mixed tumors of the skin but lack the epithelial ductules that are present in mixed tumors. Cutaneous myoepithelial tumors may show a variety of architectural, cytological, and stromal features. Their immunophenotype usually is characterized by coexpression of an epithelial marker (eg, keratin, epithelial membrane antigen [EMA]) and S-100 protein; they also may express a variety of other myoepithelial markers, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin.⁷ EWS RNA binding protein 1 (EWSR1) and pleomorphic adenoma gene 1 (PLAG1) gene rearrangement has been detected in subsets of these tumors on in situ hybridization.^8-10

Malignant myoepithelial tumors of the skin, also referred to as cutaneous myoepithelial carcinomas, are exceedingly rare. Including the current case, a search of PubMed articles indexed for MEDLINE and Google Scholar using the terms myoepithelial carcinoma and cutaneous revealed 12 cases that have been reported in the literature (Table).^1-7,11-13 These tumors often occur in the head and neck areas and the lower extremities and display a bimodal age distribution, generally occurring in patients younger than 21 years and older than 50 years of age; they also show a slight female predominance. Available follow-up data from the literature have shown local recurrence or metastasis in 3 cases^3,4,6; however, in one case the metastatic focus was not histologically identified.⁴ Cutaneous myoepithelial carcinoma presenting with metastatic disease further limits treatment options. Here, we describe a case of metastatic cutaneous myoepithelial carcinoma in a 47-year-old man, a rare example of cutaneous myoepithelial carcinoma with histologically documented metastatic disease at the initial presentation.

Case Report

A 47-year-old man who underwent a renal transplant 19 years prior presented with a weeping, ulcerated, mildly tender lesion on the scalp of 4 months’ duration with neck and back pain of 3 months’ duration. Physical examination demonstrated a 6-cm area of ulceration on the anterior crown of the scalp with adjacent enlarged keratoacanthomalike craters and satellite nodules (Figure 1). He was previously diagnosed with basal cell carcinoma (BCC) of the scalp at an outside institution 4 years prior and was treated with radiation therapy. The prior scalp biopsy for BCC diagnosis was unavailable for review. The patient had a history of chronic eczematous dermatitis in the waistband area that had been present for 19 years and another BCC with nodular and infiltrative patterns on the left helix. Of note, he also had been taking long-term immunosuppressant medications (ie, cyclosporine, azathioprine) for maintenance following the renal transplant.

Because of the extensive ulceration of the primary lesion, a shave biopsy of the scalp was performed on an adjacent satellite nodule. Histopathologic findings showed an intradermal neoplasm characterized by poorly cohesive cells exhibiting epithelioid to plasmacytoid morphologic features surrounded by abundant chondromyxoid stroma. Ductular differentiation was not identified (Figure 2A). The neoplastic cells displayed hyperchromatic nuclei with marked nuclear pleomorphism and atypical mitotic figures (Figure 2B). On immunohistochemistry the tumor cells stained positive for cytokeratin AE1/AE3 (Figure 3), S-100 protein (Figure 4), and p63, and were negative for calponin, desmin, melan-A, cytokeratin 7, and brachyury (Figure 5).

Radiographic imaging was performed due to the patient’s history of neck and back pain. Magnetic resonance imaging showed innumerable slightly expansile, T1-hypointense, T2-hyperintense, and robustly enhancing lesions involving the cervical, thoracic, lumbar, and sacral spine, as well as the thoracic ribs and bilateral iliac bones. There was no evidence of soft tissue tumor around the bone lesions. Ventral cervical spinal cord compression was detected at the C4 vertebra, causing a symptomatic radiculopathy; however, due to widely metastatic disease, the patient was not considered appropriate for neurosurgical intervention of the compression. Computerized tomography of the chest, abdomen, and pelvis did not identify any visceral source of malignancy, though multiple bilaterally enlarged cervical lymph nodes were identified on magnetic resonance imaging.

Fine needle aspiration of a left iliac bone lesion demonstrated neoplastic cells and chondromyxoid stroma essentially identical to the features shown in the skin biopsy (Figure 6). Given the morphologic features of the tumor and coexpression of cytokeratin and S-100 protein, the findings were interpreted as primary cutaneous myoepithelial carcinoma with disseminated metastatic lesions. The patient began treatment with carboplatin and paclitaxel chemotherapy. To combat the symptomatic bone pain and upper extremity radiculopathy, palliative radiation was administered to the cervical spine, lumbar spine, and right sacrum (30 Gy to each site in 10 fractions at 3 Gy per fraction). Despite the attempted chemotherapy and radiation, the patient continued to decline, and after 2 months, he elected to pursue palliative care. The patient died after 3 months in palliative care (5 months after the initial presentation).

Comment

Myoepithelial cells normally surround ducts in secretory organs, such as the breasts, salivary glands, and cutaneous sweat glands. Myoepithelial neoplasms are well recognized in the salivary glands^14,15; however, myoepithelial neoplasms also can arise in other sites, including the soft tissue^4,5,16-18 and skin.^{1-3,7,11,19,20} Myoepithelioma of soft tissue was first described by Burke et al²¹ in 1995 and later described in the skin by Fernandez-Figueras et al²² in 1998. Since then, diagnostic criteria for cutaneous myoepithelial neoplasms have evolved, suggesting a spectrum of disease rather than a single distinct entity.¹¹ Most often, cutaneous myoepithelial carcinomas arise as soft nodular lesions in the head and neck areas or extremities of adults. The nodules typically are nontender and range in size from 0.5 to 18.0 cm. Our review of the literature revealed 11 additional cases of cutaneous myoepithelial carcinomas have been reported, ranging in size from 0.7 to 7.0 cm (Table). In our case, the main lesion was 6 cm, mildly tender, ulcerated, and accompanied by satellite nodules.

Histologically, cutaneous myoepithelial tumors typically are well-defined, dermal-based nodules with no connection to the overlying epidermis. Similar to myoepithelial tumors of other sites, they can be diagnostically challenging due to the heterogeneity of both their architectural and cytological features. The presence of a chondromyxoid or hyalinized stroma is common but not always present. Neoplastic myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show growth patterns in clusters, cords, glands, or sheets. Focal epithelial cells can be present. Although benign myoepithelial neoplasms with overt ductal differentiation are consistent with cutaneous mixed tumors (chondroid syringomas), those without ducts are characterized as myoepitheliomas. It is uncertain if cases with only focal ductal differentiation should be classified as mixed tumors or as myoepitheliomas. Malignant myoepithelial tumors show infiltrative borders, nuclear pleomorphism, coarse nuclear chromatin, prominent nucleoli, and increased mitotic activity. A 2003 study by Hornick and Fletcher¹⁶ found that cytologic atypia was the primary predictor of malignant behavior for myoepithelial neoplasms of the soft tissue.

Despite a wide variety of expression patterns, immunohistochemistry is critical in demonstrating myoepithelial differentiation and establishing a diagnosis of a myoepithelial neoplasm. Most cases display coexpression of epithelial markers, including keratins and/or EMA as well as S-100 protein. Myogenic markers also may be variably expressed; however, the absence of myogenic markers does not exclude the diagnosis of a myoepithelial tumor. Commonly expressed epithelial markers are cytokeratin AE1/AE3, cytokeratin 8/18, and EMA, while commonly expressed myogenic markers include muscle specific actin and smooth muscle actin.^5,7,11,19 Myoepithelial tumors also may express calponin, p63, and glial fibrillary acidic protein.¹⁶

Molecular studies also can aid in the diagnosis of myoepithelial tumors. A study by Antonescu et al⁸ demonstrated EWSR1 gene rearrangement in 45% (30/66) of extrasalivary myoepithelial tumors and the absence of EWSR1 gene rearrangement in salivary gland myoepithelial tumors. The authors also showed that EWSR1-negative tumors were more likely to be superficially located, display ductal differentiation, and possess a benign clinical course.⁸ In another study, Bahrami et al²³ suggested that a subset of mixed tumors, specifically those with tubuloductal differentiation, are genetically linked to salivary gland pleomorphic adenomas, which was achieved by the coexpression of the PLAG1 protein and PLAG1 gene rearrangement on immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Of the 19 cases evaluated, 11 (58%) expressed nuclear staining for PLAG1 immunohistochemistry; 8 of those 11 showed positive gene rearrangement for PLAG1 using FISH. These findings raise the possibility that cutaneous mixed tumors may be more closely related to those of the salivary glands, while deep myoepithelial tumors that lack ductal differentiation may represent a distinct group. Similar to the study by Antonescu et al,⁸ Flucke et al¹⁰ investigated EWSR1 gene rearrangement but limited their sample to cutaneous tumors, including myoepitheliomas, mixed tumors, and myoepithelial carcinoma. The authors found that 44% of cases (7/16) expressed EWSR1; this expression suggests that cutaneous myoepithelial tumors may have a genetic relationship to their soft tissue, bone, and visceral counterparts.¹⁰

Myoepithelial tumors display a broad spectrum of morphologic features; however, one of the most common growth patterns is that of oval to round cells forming cords and chains in a chondromyxoid stroma. As such, the histopathologic differential diagnosis for myoepithelial tumors includes other epithelioid or round-cell neoplasms with similar growth patterns including extraskeletal myxoid chondrosarcoma (EMC), ossifying fibromyxoid tumor of soft parts, and extra-axial soft tissue chordoma. Extraskeletal myxoid chondrosarcoma bears the closest similarity to myoepithelial tumors both histologically and by ancillary studies. It typically possesses cords or chains of small round tumor cells set in a chondromyxoid or myxoid background. In contrast to myoepithelial tumors, which typically have more abundant cytoplasm and can show at least focal areas of spindle cell growth, the cells of EMC are more uniform, small, round cells with relatively scant cytoplasm. Extraskeletal myxoid chondrosarcomas lack the typical myoepithelial coexpression of cytokeratin and S-100 protein, with a minority of EMCs expressing S-100 protein but rarely cytokeratin. Most cases of EMC possess a balanced t(9;22) translocation involving the EWSR1 gene,²⁴ a finding that could lead to confusion with soft tissue myoepithelial tumors, which also may show EWSR1 rearrangement on FISH. Ossifying fibromyxoid tumor of soft parts is also composed of round cells arranged in cords in a myxoid or fibrous stroma; the majority of cases also display a peripheral rim of mature bone, a feature that is not typically seen in myoepithelial tumors. Similar to myoepithelial tumors, ossifying fibromyxoid tumor of soft parts often is positive for S-100 protein; however, it rarely is positive for cytokeratins. Ossifying fibromyxoid tumor of soft parts has been shown to have a rearrangement of the PHD finger protein 1 (PHF1) gene in approximately half of cases, a molecular finding that has not been reported for myoepithelial tumors.²⁵ Finally, extra-axial soft tissue chordomas, though quite rare, may possess striking similarities to myoepithelial tumors both histopathologically and immunohistochemically. Chordomas are composed of epithelioid cells arranged in nests, nodules, and chains with a variably myxoid background. A variable amount of cells with bubbly cytoplasm (known as physaliphorous cells) can be seen. High mitotic activity is not a characteristic feature in chordomas. They classically coexpress cytokeratins and S-100 protein, similar to myoepithelial tumors. A subset of myoepitheliomas with similar histologic features to chordoma was historically referred to as parachordoma.^26,27 The distinction between these 2 entities was challenging until the relatively recent advent of brachyury, a sensitive and specific nuclear marker of chordoma; extra-axial soft tissue chordomas and their central counterparts both express nuclear brachyury, while myoepitheliomas (including those with a parachordoma histologic pattern) do not.²⁸ Our case did not display physaliphorous cells but did demonstrate abundant nuclear pleomorphism and high mitotic activity. In addition, immunohistochemical staining was negative for brachyury.

Because cutaneous myoepithelial tumors are relatively rare, a well-defined standard of care for treatment is lacking. Surgical excision is the primary treatment method in most reported cases in the literature.^17,19 Miller et al²⁹ reported the successful treatment of recurrent cutaneous myoepitheliomas with Mohs micrographic surgery. Chemotherapy may be useful in the setting of metastatic myoepithelial carcinomas in adults, but reported results are inconsistent.^30,31 Radiation treatment of recurrent or metastatic disease has not been shown to be effective. A study of children treated with surgical resection and chemotherapy using ifosfamide, cisplatin, and etoposide followed by radiation therapy showed positive results.³²

Our case highlights several challenges that may arise in establishing a diagnosis of cutaneous myoepithelial carcinoma with disseminated metastases. The diagnostic difficulty in our case was compounded by the advanced nature of the lesion at the time of presentation. Given the rarity of metastatic cutaneous myoepithelial carcinomas and the lack of a prior primary diagnosis of a malignant myoepithelioma, the index of suspicion for this entity was not high. A report of myoepithelial carcinoma of the parotid gland metastatic to the skin has been reported,³³ but in the absence of salivary gland involvement or other visceral lesions, metastasis from any source other than our patient’s cutaneous scalp lesion is unlikely. The histopathologic features in combination with the characteristic immunophenotype, unique clinical setting, and radiographic findings were essential to arriving at the correct diagnosis. Unlike previously reported metastatic lesions, our case is unique in that metastatic lesions were identified at the time of initial clinical presentation.

Conclusion

Cutaneous myoepithelial carcinomas are exceedingly rare tumors with a wide range of histopathologic and immunohistochemical findings. In challenging cases, studies for EWSR1 or PLAG1 gene rearrangement can be helpful. Furthermore, this case illustrates the potential for widespread dissemination of myoepithelial carcinomas requiring clinical evaluation and imaging studies to exclude metastatic lesions.

Cutaneous myoepithelial tumors are rare neoplasms but are being increasingly recognized and reported in the literature.^1-7 Myoepithelial tumors are related to benign mixed tumors of the skin but lack the epithelial ductules that are present in mixed tumors. Cutaneous myoepithelial tumors may show a variety of architectural, cytological, and stromal features. Their immunophenotype usually is characterized by coexpression of an epithelial marker (eg, keratin, epithelial membrane antigen [EMA]) and S-100 protein; they also may express a variety of other myoepithelial markers, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin.⁷ EWS RNA binding protein 1 (EWSR1) and pleomorphic adenoma gene 1 (PLAG1) gene rearrangement has been detected in subsets of these tumors on in situ hybridization.^8-10

Malignant myoepithelial tumors of the skin, also referred to as cutaneous myoepithelial carcinomas, are exceedingly rare. Including the current case, a search of PubMed articles indexed for MEDLINE and Google Scholar using the terms myoepithelial carcinoma and cutaneous revealed 12 cases that have been reported in the literature (Table).^1-7,11-13 These tumors often occur in the head and neck areas and the lower extremities and display a bimodal age distribution, generally occurring in patients younger than 21 years and older than 50 years of age; they also show a slight female predominance. Available follow-up data from the literature have shown local recurrence or metastasis in 3 cases^3,4,6; however, in one case the metastatic focus was not histologically identified.⁴ Cutaneous myoepithelial carcinoma presenting with metastatic disease further limits treatment options. Here, we describe a case of metastatic cutaneous myoepithelial carcinoma in a 47-year-old man, a rare example of cutaneous myoepithelial carcinoma with histologically documented metastatic disease at the initial presentation.

Case Report

A 47-year-old man who underwent a renal transplant 19 years prior presented with a weeping, ulcerated, mildly tender lesion on the scalp of 4 months’ duration with neck and back pain of 3 months’ duration. Physical examination demonstrated a 6-cm area of ulceration on the anterior crown of the scalp with adjacent enlarged keratoacanthomalike craters and satellite nodules (Figure 1). He was previously diagnosed with basal cell carcinoma (BCC) of the scalp at an outside institution 4 years prior and was treated with radiation therapy. The prior scalp biopsy for BCC diagnosis was unavailable for review. The patient had a history of chronic eczematous dermatitis in the waistband area that had been present for 19 years and another BCC with nodular and infiltrative patterns on the left helix. Of note, he also had been taking long-term immunosuppressant medications (ie, cyclosporine, azathioprine) for maintenance following the renal transplant.

Because of the extensive ulceration of the primary lesion, a shave biopsy of the scalp was performed on an adjacent satellite nodule. Histopathologic findings showed an intradermal neoplasm characterized by poorly cohesive cells exhibiting epithelioid to plasmacytoid morphologic features surrounded by abundant chondromyxoid stroma. Ductular differentiation was not identified (Figure 2A). The neoplastic cells displayed hyperchromatic nuclei with marked nuclear pleomorphism and atypical mitotic figures (Figure 2B). On immunohistochemistry the tumor cells stained positive for cytokeratin AE1/AE3 (Figure 3), S-100 protein (Figure 4), and p63, and were negative for calponin, desmin, melan-A, cytokeratin 7, and brachyury (Figure 5).

Radiographic imaging was performed due to the patient’s history of neck and back pain. Magnetic resonance imaging showed innumerable slightly expansile, T1-hypointense, T2-hyperintense, and robustly enhancing lesions involving the cervical, thoracic, lumbar, and sacral spine, as well as the thoracic ribs and bilateral iliac bones. There was no evidence of soft tissue tumor around the bone lesions. Ventral cervical spinal cord compression was detected at the C4 vertebra, causing a symptomatic radiculopathy; however, due to widely metastatic disease, the patient was not considered appropriate for neurosurgical intervention of the compression. Computerized tomography of the chest, abdomen, and pelvis did not identify any visceral source of malignancy, though multiple bilaterally enlarged cervical lymph nodes were identified on magnetic resonance imaging.

Fine needle aspiration of a left iliac bone lesion demonstrated neoplastic cells and chondromyxoid stroma essentially identical to the features shown in the skin biopsy (Figure 6). Given the morphologic features of the tumor and coexpression of cytokeratin and S-100 protein, the findings were interpreted as primary cutaneous myoepithelial carcinoma with disseminated metastatic lesions. The patient began treatment with carboplatin and paclitaxel chemotherapy. To combat the symptomatic bone pain and upper extremity radiculopathy, palliative radiation was administered to the cervical spine, lumbar spine, and right sacrum (30 Gy to each site in 10 fractions at 3 Gy per fraction). Despite the attempted chemotherapy and radiation, the patient continued to decline, and after 2 months, he elected to pursue palliative care. The patient died after 3 months in palliative care (5 months after the initial presentation).

Comment

Myoepithelial cells normally surround ducts in secretory organs, such as the breasts, salivary glands, and cutaneous sweat glands. Myoepithelial neoplasms are well recognized in the salivary glands^14,15; however, myoepithelial neoplasms also can arise in other sites, including the soft tissue^4,5,16-18 and skin.^{1-3,7,11,19,20} Myoepithelioma of soft tissue was first described by Burke et al²¹ in 1995 and later described in the skin by Fernandez-Figueras et al²² in 1998. Since then, diagnostic criteria for cutaneous myoepithelial neoplasms have evolved, suggesting a spectrum of disease rather than a single distinct entity.¹¹ Most often, cutaneous myoepithelial carcinomas arise as soft nodular lesions in the head and neck areas or extremities of adults. The nodules typically are nontender and range in size from 0.5 to 18.0 cm. Our review of the literature revealed 11 additional cases of cutaneous myoepithelial carcinomas have been reported, ranging in size from 0.7 to 7.0 cm (Table). In our case, the main lesion was 6 cm, mildly tender, ulcerated, and accompanied by satellite nodules.

Histologically, cutaneous myoepithelial tumors typically are well-defined, dermal-based nodules with no connection to the overlying epidermis. Similar to myoepithelial tumors of other sites, they can be diagnostically challenging due to the heterogeneity of both their architectural and cytological features. The presence of a chondromyxoid or hyalinized stroma is common but not always present. Neoplastic myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show growth patterns in clusters, cords, glands, or sheets. Focal epithelial cells can be present. Although benign myoepithelial neoplasms with overt ductal differentiation are consistent with cutaneous mixed tumors (chondroid syringomas), those without ducts are characterized as myoepitheliomas. It is uncertain if cases with only focal ductal differentiation should be classified as mixed tumors or as myoepitheliomas. Malignant myoepithelial tumors show infiltrative borders, nuclear pleomorphism, coarse nuclear chromatin, prominent nucleoli, and increased mitotic activity. A 2003 study by Hornick and Fletcher¹⁶ found that cytologic atypia was the primary predictor of malignant behavior for myoepithelial neoplasms of the soft tissue.

Despite a wide variety of expression patterns, immunohistochemistry is critical in demonstrating myoepithelial differentiation and establishing a diagnosis of a myoepithelial neoplasm. Most cases display coexpression of epithelial markers, including keratins and/or EMA as well as S-100 protein. Myogenic markers also may be variably expressed; however, the absence of myogenic markers does not exclude the diagnosis of a myoepithelial tumor. Commonly expressed epithelial markers are cytokeratin AE1/AE3, cytokeratin 8/18, and EMA, while commonly expressed myogenic markers include muscle specific actin and smooth muscle actin.^5,7,11,19 Myoepithelial tumors also may express calponin, p63, and glial fibrillary acidic protein.¹⁶

Molecular studies also can aid in the diagnosis of myoepithelial tumors. A study by Antonescu et al⁸ demonstrated EWSR1 gene rearrangement in 45% (30/66) of extrasalivary myoepithelial tumors and the absence of EWSR1 gene rearrangement in salivary gland myoepithelial tumors. The authors also showed that EWSR1-negative tumors were more likely to be superficially located, display ductal differentiation, and possess a benign clinical course.⁸ In another study, Bahrami et al²³ suggested that a subset of mixed tumors, specifically those with tubuloductal differentiation, are genetically linked to salivary gland pleomorphic adenomas, which was achieved by the coexpression of the PLAG1 protein and PLAG1 gene rearrangement on immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Of the 19 cases evaluated, 11 (58%) expressed nuclear staining for PLAG1 immunohistochemistry; 8 of those 11 showed positive gene rearrangement for PLAG1 using FISH. These findings raise the possibility that cutaneous mixed tumors may be more closely related to those of the salivary glands, while deep myoepithelial tumors that lack ductal differentiation may represent a distinct group. Similar to the study by Antonescu et al,⁸ Flucke et al¹⁰ investigated EWSR1 gene rearrangement but limited their sample to cutaneous tumors, including myoepitheliomas, mixed tumors, and myoepithelial carcinoma. The authors found that 44% of cases (7/16) expressed EWSR1; this expression suggests that cutaneous myoepithelial tumors may have a genetic relationship to their soft tissue, bone, and visceral counterparts.¹⁰

Myoepithelial tumors display a broad spectrum of morphologic features; however, one of the most common growth patterns is that of oval to round cells forming cords and chains in a chondromyxoid stroma. As such, the histopathologic differential diagnosis for myoepithelial tumors includes other epithelioid or round-cell neoplasms with similar growth patterns including extraskeletal myxoid chondrosarcoma (EMC), ossifying fibromyxoid tumor of soft parts, and extra-axial soft tissue chordoma. Extraskeletal myxoid chondrosarcoma bears the closest similarity to myoepithelial tumors both histologically and by ancillary studies. It typically possesses cords or chains of small round tumor cells set in a chondromyxoid or myxoid background. In contrast to myoepithelial tumors, which typically have more abundant cytoplasm and can show at least focal areas of spindle cell growth, the cells of EMC are more uniform, small, round cells with relatively scant cytoplasm. Extraskeletal myxoid chondrosarcomas lack the typical myoepithelial coexpression of cytokeratin and S-100 protein, with a minority of EMCs expressing S-100 protein but rarely cytokeratin. Most cases of EMC possess a balanced t(9;22) translocation involving the EWSR1 gene,²⁴ a finding that could lead to confusion with soft tissue myoepithelial tumors, which also may show EWSR1 rearrangement on FISH. Ossifying fibromyxoid tumor of soft parts is also composed of round cells arranged in cords in a myxoid or fibrous stroma; the majority of cases also display a peripheral rim of mature bone, a feature that is not typically seen in myoepithelial tumors. Similar to myoepithelial tumors, ossifying fibromyxoid tumor of soft parts often is positive for S-100 protein; however, it rarely is positive for cytokeratins. Ossifying fibromyxoid tumor of soft parts has been shown to have a rearrangement of the PHD finger protein 1 (PHF1) gene in approximately half of cases, a molecular finding that has not been reported for myoepithelial tumors.²⁵ Finally, extra-axial soft tissue chordomas, though quite rare, may possess striking similarities to myoepithelial tumors both histopathologically and immunohistochemically. Chordomas are composed of epithelioid cells arranged in nests, nodules, and chains with a variably myxoid background. A variable amount of cells with bubbly cytoplasm (known as physaliphorous cells) can be seen. High mitotic activity is not a characteristic feature in chordomas. They classically coexpress cytokeratins and S-100 protein, similar to myoepithelial tumors. A subset of myoepitheliomas with similar histologic features to chordoma was historically referred to as parachordoma.^26,27 The distinction between these 2 entities was challenging until the relatively recent advent of brachyury, a sensitive and specific nuclear marker of chordoma; extra-axial soft tissue chordomas and their central counterparts both express nuclear brachyury, while myoepitheliomas (including those with a parachordoma histologic pattern) do not.²⁸ Our case did not display physaliphorous cells but did demonstrate abundant nuclear pleomorphism and high mitotic activity. In addition, immunohistochemical staining was negative for brachyury.

Because cutaneous myoepithelial tumors are relatively rare, a well-defined standard of care for treatment is lacking. Surgical excision is the primary treatment method in most reported cases in the literature.^17,19 Miller et al²⁹ reported the successful treatment of recurrent cutaneous myoepitheliomas with Mohs micrographic surgery. Chemotherapy may be useful in the setting of metastatic myoepithelial carcinomas in adults, but reported results are inconsistent.^30,31 Radiation treatment of recurrent or metastatic disease has not been shown to be effective. A study of children treated with surgical resection and chemotherapy using ifosfamide, cisplatin, and etoposide followed by radiation therapy showed positive results.³²

Our case highlights several challenges that may arise in establishing a diagnosis of cutaneous myoepithelial carcinoma with disseminated metastases. The diagnostic difficulty in our case was compounded by the advanced nature of the lesion at the time of presentation. Given the rarity of metastatic cutaneous myoepithelial carcinomas and the lack of a prior primary diagnosis of a malignant myoepithelioma, the index of suspicion for this entity was not high. A report of myoepithelial carcinoma of the parotid gland metastatic to the skin has been reported,³³ but in the absence of salivary gland involvement or other visceral lesions, metastasis from any source other than our patient’s cutaneous scalp lesion is unlikely. The histopathologic features in combination with the characteristic immunophenotype, unique clinical setting, and radiographic findings were essential to arriving at the correct diagnosis. Unlike previously reported metastatic lesions, our case is unique in that metastatic lesions were identified at the time of initial clinical presentation.

Conclusion

Cutaneous myoepithelial carcinomas are exceedingly rare tumors with a wide range of histopathologic and immunohistochemical findings. In challenging cases, studies for EWSR1 or PLAG1 gene rearrangement can be helpful. Furthermore, this case illustrates the potential for widespread dissemination of myoepithelial carcinomas requiring clinical evaluation and imaging studies to exclude metastatic lesions.

Cutaneous myoepithelial tumors are rare neoplasms but are being increasingly recognized and reported in the literature.^1-7 Myoepithelial tumors are related to benign mixed tumors of the skin but lack the epithelial ductules that are present in mixed tumors. Cutaneous myoepithelial tumors may show a variety of architectural, cytological, and stromal features. Their immunophenotype usually is characterized by coexpression of an epithelial marker (eg, keratin, epithelial membrane antigen [EMA]) and S-100 protein; they also may express a variety of other myoepithelial markers, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin.⁷ EWS RNA binding protein 1 (EWSR1) and pleomorphic adenoma gene 1 (PLAG1) gene rearrangement has been detected in subsets of these tumors on in situ hybridization.^8-10

Malignant myoepithelial tumors of the skin, also referred to as cutaneous myoepithelial carcinomas, are exceedingly rare. Including the current case, a search of PubMed articles indexed for MEDLINE and Google Scholar using the terms myoepithelial carcinoma and cutaneous revealed 12 cases that have been reported in the literature (Table).^1-7,11-13 These tumors often occur in the head and neck areas and the lower extremities and display a bimodal age distribution, generally occurring in patients younger than 21 years and older than 50 years of age; they also show a slight female predominance. Available follow-up data from the literature have shown local recurrence or metastasis in 3 cases^3,4,6; however, in one case the metastatic focus was not histologically identified.⁴ Cutaneous myoepithelial carcinoma presenting with metastatic disease further limits treatment options. Here, we describe a case of metastatic cutaneous myoepithelial carcinoma in a 47-year-old man, a rare example of cutaneous myoepithelial carcinoma with histologically documented metastatic disease at the initial presentation.

Case Report

A 47-year-old man who underwent a renal transplant 19 years prior presented with a weeping, ulcerated, mildly tender lesion on the scalp of 4 months’ duration with neck and back pain of 3 months’ duration. Physical examination demonstrated a 6-cm area of ulceration on the anterior crown of the scalp with adjacent enlarged keratoacanthomalike craters and satellite nodules (Figure 1). He was previously diagnosed with basal cell carcinoma (BCC) of the scalp at an outside institution 4 years prior and was treated with radiation therapy. The prior scalp biopsy for BCC diagnosis was unavailable for review. The patient had a history of chronic eczematous dermatitis in the waistband area that had been present for 19 years and another BCC with nodular and infiltrative patterns on the left helix. Of note, he also had been taking long-term immunosuppressant medications (ie, cyclosporine, azathioprine) for maintenance following the renal transplant.

Because of the extensive ulceration of the primary lesion, a shave biopsy of the scalp was performed on an adjacent satellite nodule. Histopathologic findings showed an intradermal neoplasm characterized by poorly cohesive cells exhibiting epithelioid to plasmacytoid morphologic features surrounded by abundant chondromyxoid stroma. Ductular differentiation was not identified (Figure 2A). The neoplastic cells displayed hyperchromatic nuclei with marked nuclear pleomorphism and atypical mitotic figures (Figure 2B). On immunohistochemistry the tumor cells stained positive for cytokeratin AE1/AE3 (Figure 3), S-100 protein (Figure 4), and p63, and were negative for calponin, desmin, melan-A, cytokeratin 7, and brachyury (Figure 5).

Radiographic imaging was performed due to the patient’s history of neck and back pain. Magnetic resonance imaging showed innumerable slightly expansile, T1-hypointense, T2-hyperintense, and robustly enhancing lesions involving the cervical, thoracic, lumbar, and sacral spine, as well as the thoracic ribs and bilateral iliac bones. There was no evidence of soft tissue tumor around the bone lesions. Ventral cervical spinal cord compression was detected at the C4 vertebra, causing a symptomatic radiculopathy; however, due to widely metastatic disease, the patient was not considered appropriate for neurosurgical intervention of the compression. Computerized tomography of the chest, abdomen, and pelvis did not identify any visceral source of malignancy, though multiple bilaterally enlarged cervical lymph nodes were identified on magnetic resonance imaging.

Fine needle aspiration of a left iliac bone lesion demonstrated neoplastic cells and chondromyxoid stroma essentially identical to the features shown in the skin biopsy (Figure 6). Given the morphologic features of the tumor and coexpression of cytokeratin and S-100 protein, the findings were interpreted as primary cutaneous myoepithelial carcinoma with disseminated metastatic lesions. The patient began treatment with carboplatin and paclitaxel chemotherapy. To combat the symptomatic bone pain and upper extremity radiculopathy, palliative radiation was administered to the cervical spine, lumbar spine, and right sacrum (30 Gy to each site in 10 fractions at 3 Gy per fraction). Despite the attempted chemotherapy and radiation, the patient continued to decline, and after 2 months, he elected to pursue palliative care. The patient died after 3 months in palliative care (5 months after the initial presentation).

Comment

Myoepithelial cells normally surround ducts in secretory organs, such as the breasts, salivary glands, and cutaneous sweat glands. Myoepithelial neoplasms are well recognized in the salivary glands^14,15; however, myoepithelial neoplasms also can arise in other sites, including the soft tissue^4,5,16-18 and skin.^{1-3,7,11,19,20} Myoepithelioma of soft tissue was first described by Burke et al²¹ in 1995 and later described in the skin by Fernandez-Figueras et al²² in 1998. Since then, diagnostic criteria for cutaneous myoepithelial neoplasms have evolved, suggesting a spectrum of disease rather than a single distinct entity.¹¹ Most often, cutaneous myoepithelial carcinomas arise as soft nodular lesions in the head and neck areas or extremities of adults. The nodules typically are nontender and range in size from 0.5 to 18.0 cm. Our review of the literature revealed 11 additional cases of cutaneous myoepithelial carcinomas have been reported, ranging in size from 0.7 to 7.0 cm (Table). In our case, the main lesion was 6 cm, mildly tender, ulcerated, and accompanied by satellite nodules.

Histologically, cutaneous myoepithelial tumors typically are well-defined, dermal-based nodules with no connection to the overlying epidermis. Similar to myoepithelial tumors of other sites, they can be diagnostically challenging due to the heterogeneity of both their architectural and cytological features. The presence of a chondromyxoid or hyalinized stroma is common but not always present. Neoplastic myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show growth patterns in clusters, cords, glands, or sheets. Focal epithelial cells can be present. Although benign myoepithelial neoplasms with overt ductal differentiation are consistent with cutaneous mixed tumors (chondroid syringomas), those without ducts are characterized as myoepitheliomas. It is uncertain if cases with only focal ductal differentiation should be classified as mixed tumors or as myoepitheliomas. Malignant myoepithelial tumors show infiltrative borders, nuclear pleomorphism, coarse nuclear chromatin, prominent nucleoli, and increased mitotic activity. A 2003 study by Hornick and Fletcher¹⁶ found that cytologic atypia was the primary predictor of malignant behavior for myoepithelial neoplasms of the soft tissue.

Despite a wide variety of expression patterns, immunohistochemistry is critical in demonstrating myoepithelial differentiation and establishing a diagnosis of a myoepithelial neoplasm. Most cases display coexpression of epithelial markers, including keratins and/or EMA as well as S-100 protein. Myogenic markers also may be variably expressed; however, the absence of myogenic markers does not exclude the diagnosis of a myoepithelial tumor. Commonly expressed epithelial markers are cytokeratin AE1/AE3, cytokeratin 8/18, and EMA, while commonly expressed myogenic markers include muscle specific actin and smooth muscle actin.^5,7,11,19 Myoepithelial tumors also may express calponin, p63, and glial fibrillary acidic protein.¹⁶

Molecular studies also can aid in the diagnosis of myoepithelial tumors. A study by Antonescu et al⁸ demonstrated EWSR1 gene rearrangement in 45% (30/66) of extrasalivary myoepithelial tumors and the absence of EWSR1 gene rearrangement in salivary gland myoepithelial tumors. The authors also showed that EWSR1-negative tumors were more likely to be superficially located, display ductal differentiation, and possess a benign clinical course.⁸ In another study, Bahrami et al²³ suggested that a subset of mixed tumors, specifically those with tubuloductal differentiation, are genetically linked to salivary gland pleomorphic adenomas, which was achieved by the coexpression of the PLAG1 protein and PLAG1 gene rearrangement on immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Of the 19 cases evaluated, 11 (58%) expressed nuclear staining for PLAG1 immunohistochemistry; 8 of those 11 showed positive gene rearrangement for PLAG1 using FISH. These findings raise the possibility that cutaneous mixed tumors may be more closely related to those of the salivary glands, while deep myoepithelial tumors that lack ductal differentiation may represent a distinct group. Similar to the study by Antonescu et al,⁸ Flucke et al¹⁰ investigated EWSR1 gene rearrangement but limited their sample to cutaneous tumors, including myoepitheliomas, mixed tumors, and myoepithelial carcinoma. The authors found that 44% of cases (7/16) expressed EWSR1; this expression suggests that cutaneous myoepithelial tumors may have a genetic relationship to their soft tissue, bone, and visceral counterparts.¹⁰

Myoepithelial tumors display a broad spectrum of morphologic features; however, one of the most common growth patterns is that of oval to round cells forming cords and chains in a chondromyxoid stroma. As such, the histopathologic differential diagnosis for myoepithelial tumors includes other epithelioid or round-cell neoplasms with similar growth patterns including extraskeletal myxoid chondrosarcoma (EMC), ossifying fibromyxoid tumor of soft parts, and extra-axial soft tissue chordoma. Extraskeletal myxoid chondrosarcoma bears the closest similarity to myoepithelial tumors both histologically and by ancillary studies. It typically possesses cords or chains of small round tumor cells set in a chondromyxoid or myxoid background. In contrast to myoepithelial tumors, which typically have more abundant cytoplasm and can show at least focal areas of spindle cell growth, the cells of EMC are more uniform, small, round cells with relatively scant cytoplasm. Extraskeletal myxoid chondrosarcomas lack the typical myoepithelial coexpression of cytokeratin and S-100 protein, with a minority of EMCs expressing S-100 protein but rarely cytokeratin. Most cases of EMC possess a balanced t(9;22) translocation involving the EWSR1 gene,²⁴ a finding that could lead to confusion with soft tissue myoepithelial tumors, which also may show EWSR1 rearrangement on FISH. Ossifying fibromyxoid tumor of soft parts is also composed of round cells arranged in cords in a myxoid or fibrous stroma; the majority of cases also display a peripheral rim of mature bone, a feature that is not typically seen in myoepithelial tumors. Similar to myoepithelial tumors, ossifying fibromyxoid tumor of soft parts often is positive for S-100 protein; however, it rarely is positive for cytokeratins. Ossifying fibromyxoid tumor of soft parts has been shown to have a rearrangement of the PHD finger protein 1 (PHF1) gene in approximately half of cases, a molecular finding that has not been reported for myoepithelial tumors.²⁵ Finally, extra-axial soft tissue chordomas, though quite rare, may possess striking similarities to myoepithelial tumors both histopathologically and immunohistochemically. Chordomas are composed of epithelioid cells arranged in nests, nodules, and chains with a variably myxoid background. A variable amount of cells with bubbly cytoplasm (known as physaliphorous cells) can be seen. High mitotic activity is not a characteristic feature in chordomas. They classically coexpress cytokeratins and S-100 protein, similar to myoepithelial tumors. A subset of myoepitheliomas with similar histologic features to chordoma was historically referred to as parachordoma.^26,27 The distinction between these 2 entities was challenging until the relatively recent advent of brachyury, a sensitive and specific nuclear marker of chordoma; extra-axial soft tissue chordomas and their central counterparts both express nuclear brachyury, while myoepitheliomas (including those with a parachordoma histologic pattern) do not.²⁸ Our case did not display physaliphorous cells but did demonstrate abundant nuclear pleomorphism and high mitotic activity. In addition, immunohistochemical staining was negative for brachyury.

Because cutaneous myoepithelial tumors are relatively rare, a well-defined standard of care for treatment is lacking. Surgical excision is the primary treatment method in most reported cases in the literature.^17,19 Miller et al²⁹ reported the successful treatment of recurrent cutaneous myoepitheliomas with Mohs micrographic surgery. Chemotherapy may be useful in the setting of metastatic myoepithelial carcinomas in adults, but reported results are inconsistent.^30,31 Radiation treatment of recurrent or metastatic disease has not been shown to be effective. A study of children treated with surgical resection and chemotherapy using ifosfamide, cisplatin, and etoposide followed by radiation therapy showed positive results.³²

Our case highlights several challenges that may arise in establishing a diagnosis of cutaneous myoepithelial carcinoma with disseminated metastases. The diagnostic difficulty in our case was compounded by the advanced nature of the lesion at the time of presentation. Given the rarity of metastatic cutaneous myoepithelial carcinomas and the lack of a prior primary diagnosis of a malignant myoepithelioma, the index of suspicion for this entity was not high. A report of myoepithelial carcinoma of the parotid gland metastatic to the skin has been reported,³³ but in the absence of salivary gland involvement or other visceral lesions, metastasis from any source other than our patient’s cutaneous scalp lesion is unlikely. The histopathologic features in combination with the characteristic immunophenotype, unique clinical setting, and radiographic findings were essential to arriving at the correct diagnosis. Unlike previously reported metastatic lesions, our case is unique in that metastatic lesions were identified at the time of initial clinical presentation.

Conclusion

Cutaneous myoepithelial carcinomas are exceedingly rare tumors with a wide range of histopathologic and immunohistochemical findings. In challenging cases, studies for EWSR1 or PLAG1 gene rearrangement can be helpful. Furthermore, this case illustrates the potential for widespread dissemination of myoepithelial carcinomas requiring clinical evaluation and imaging studies to exclude metastatic lesions.

UV radiation from sun exposure is a risk factor for most types of skin cancer.¹ Despite comprising only 1% of the body's surface area, the periocular region is the location of approximately 5% to 10% of skin cancers described in one US study.² The efficacy of sunscreen in preventing skin cancer is widely accepted, and the American Academy of Dermatology recommends application of broad-spectrum UVA/UVB sunscreen with a sun protection factor of 30 or higher to help prevent skin cancer.^3-5

RELATED ARTICLE: Sun Protection for Infants: Parent Behaviors and Beliefs

Reducing the risk of skin cancer from sun exposure relies on many factors, including completeness of application. A number of studies have demonstrated incomplete sunscreen application on the hairline, ears, neck, and dorsal feet.^6-8 The purpose of this study was to assess the completeness of facial sunscreen self-application in oculofacial surgery patients using UV photography.

Methods

This single-site, cross-sectional, qualitative study assessed the completeness of facial sunscreen self-application among patients from a single surgeon's (J.A.W.) cosmetic and tertiary-care oculofacial surgery practice at the Duke Eye Center (Durham, North Carolina) between March 2016 and May 2016. Approval from the Duke University institutional review board was obtained, and the research adhered to the tenets of the Declaration of Helsinki and complied with the Health Insurance Portability and Accountability Act. Informed consent was obtained from all patients, and patients could elect to provide specific written consent for publication of photographs in scientific presentations and publications. Patients younger than 18 years of age; those with known sensitivity to sunscreen or its ingredients; and those with an active lesion, rash, or open wound were excluded from the study.

After obtaining informed consent, patients were photographed using a camera with a UV lens in natural outdoor lighting, first without sunscreen and again after self-application of a sunscreen of their choosing using their routine application technique. Completeness of sunscreen application was graded independently by 3 oculofacial surgeons (N.A.L., J.L., J.A.W.) as complete, partial, none, or cannot determine for 15 facial regions. The majority response was used for analysis.

Results

Forty-four patients were enrolled in the study. Six patients were disqualified due to use of mineral-based formulations (zinc oxide and/or titanium dioxide), as these sunscreens could not be visualized using UV photography. The age range of the remaining 38 patients was 28 to 74 years; 26% (10/38) were men and 74% (28/38) were women.

Complete sunscreen application was most frequently performed on the cheeks (97% [37/38]), chin (95% [36/38]), forehead (92% [35/38]), and temples (92% [35/38]). Complete absence of sunscreen coverage was most common on the lower eyelid margin (84% [32/38]), upper eyelid margin (82% [31/38]), medial canthus (71% 27/38]), and upper eyelid (66% [25/38])(Table)(Figure).

Comment

UV radiation-related skin cancers frequently occur in the periocular area, presumably because it is a frequent site of UV exposure. Clothing, sunglasses, and hats can be used to aid in protection from UV radiation, but these products are only regulated by the US Food and Drug Administration if the product claims to prevent skin cancer. Sunscreen is a proven method of protection from UV radiation and the prevention of skin cancer but must be properly applied for it to be effective.^1,2,5,6 Incomplete sunscreen application has been demonstrated in numerous studies. Lademann et al7 studied sunscreen application among 60 beachgoers in Germany and found they typically missed the hairline, ears, and dorsal feet. In a study of 10 women with photosensitivity in England who were asked to apply sunscreen in their routine manner, Azurdia et al⁶ found the posterior neck, lateral neck, temples, and ears, respectively, were the most frequently missed sites. Yang et al⁸ assessed sunscreen application in 39 dermatologists and 41 photosensitive patients in China and found the neck, ears, dorsal hands, hairline, temples, and perioral region, respectively, were most commonly left unprotected.

Our study investigated detailed facial self-application of sunscreen and found excellent coverage of the larger facial units such as the forehead, cheeks, chin, and temples. The brow, medial canthus, lateral canthus, and upper and lower eyelids and eyelid margins were infrequently protected with sunscreen during routine application. Our opinion is that patients are unaware that eyelid sunscreen application is important. They may be afraid that the products will sting or cause damage if they get in the eyes. Although some products do sting if they get into the eyes, there is no evidence that sunscreens cause injury to the eyes. The US Food and Drug Administration does not have clear guidelines about applying sunscreens in the periocular area, but in general, mineral blocks are recommended because they have less chance of irritation. Several companies make such products that are designed to be applied to the eyelids.

Limitations of our study included a small sample size and a majority female demographic, which may have affected the results, as women generally are more familiar with the application of lotions to the face. Additionally, the patients were recruited from a tertiary-care clinic and may have had periocular malignancy or may have previously received counseling on the importance of sunscreen use.

Conclusion

Cancer reconstruction of the periocular area is challenging, and even in the best of hands, a patient's quality of life may be negatively affected by postreconstructive appearance or suboptimal function, resulting in ocular exposure. The authors recommend counseling patients on the importance of good sun protection habits, including daily application of sunscreen to the face and periocular region to prevent malignancy in these delicate areas.

UV radiation from sun exposure is a risk factor for most types of skin cancer.¹ Despite comprising only 1% of the body's surface area, the periocular region is the location of approximately 5% to 10% of skin cancers described in one US study.² The efficacy of sunscreen in preventing skin cancer is widely accepted, and the American Academy of Dermatology recommends application of broad-spectrum UVA/UVB sunscreen with a sun protection factor of 30 or higher to help prevent skin cancer.^3-5

RELATED ARTICLE: Sun Protection for Infants: Parent Behaviors and Beliefs

Reducing the risk of skin cancer from sun exposure relies on many factors, including completeness of application. A number of studies have demonstrated incomplete sunscreen application on the hairline, ears, neck, and dorsal feet.^6-8 The purpose of this study was to assess the completeness of facial sunscreen self-application in oculofacial surgery patients using UV photography.

Methods

This single-site, cross-sectional, qualitative study assessed the completeness of facial sunscreen self-application among patients from a single surgeon's (J.A.W.) cosmetic and tertiary-care oculofacial surgery practice at the Duke Eye Center (Durham, North Carolina) between March 2016 and May 2016. Approval from the Duke University institutional review board was obtained, and the research adhered to the tenets of the Declaration of Helsinki and complied with the Health Insurance Portability and Accountability Act. Informed consent was obtained from all patients, and patients could elect to provide specific written consent for publication of photographs in scientific presentations and publications. Patients younger than 18 years of age; those with known sensitivity to sunscreen or its ingredients; and those with an active lesion, rash, or open wound were excluded from the study.

After obtaining informed consent, patients were photographed using a camera with a UV lens in natural outdoor lighting, first without sunscreen and again after self-application of a sunscreen of their choosing using their routine application technique. Completeness of sunscreen application was graded independently by 3 oculofacial surgeons (N.A.L., J.L., J.A.W.) as complete, partial, none, or cannot determine for 15 facial regions. The majority response was used for analysis.

Results

Forty-four patients were enrolled in the study. Six patients were disqualified due to use of mineral-based formulations (zinc oxide and/or titanium dioxide), as these sunscreens could not be visualized using UV photography. The age range of the remaining 38 patients was 28 to 74 years; 26% (10/38) were men and 74% (28/38) were women.

Complete sunscreen application was most frequently performed on the cheeks (97% [37/38]), chin (95% [36/38]), forehead (92% [35/38]), and temples (92% [35/38]). Complete absence of sunscreen coverage was most common on the lower eyelid margin (84% [32/38]), upper eyelid margin (82% [31/38]), medial canthus (71% 27/38]), and upper eyelid (66% [25/38])(Table)(Figure).

Comment

UV radiation-related skin cancers frequently occur in the periocular area, presumably because it is a frequent site of UV exposure. Clothing, sunglasses, and hats can be used to aid in protection from UV radiation, but these products are only regulated by the US Food and Drug Administration if the product claims to prevent skin cancer. Sunscreen is a proven method of protection from UV radiation and the prevention of skin cancer but must be properly applied for it to be effective.^1,2,5,6 Incomplete sunscreen application has been demonstrated in numerous studies. Lademann et al7 studied sunscreen application among 60 beachgoers in Germany and found they typically missed the hairline, ears, and dorsal feet. In a study of 10 women with photosensitivity in England who were asked to apply sunscreen in their routine manner, Azurdia et al⁶ found the posterior neck, lateral neck, temples, and ears, respectively, were the most frequently missed sites. Yang et al⁸ assessed sunscreen application in 39 dermatologists and 41 photosensitive patients in China and found the neck, ears, dorsal hands, hairline, temples, and perioral region, respectively, were most commonly left unprotected.

Our study investigated detailed facial self-application of sunscreen and found excellent coverage of the larger facial units such as the forehead, cheeks, chin, and temples. The brow, medial canthus, lateral canthus, and upper and lower eyelids and eyelid margins were infrequently protected with sunscreen during routine application. Our opinion is that patients are unaware that eyelid sunscreen application is important. They may be afraid that the products will sting or cause damage if they get in the eyes. Although some products do sting if they get into the eyes, there is no evidence that sunscreens cause injury to the eyes. The US Food and Drug Administration does not have clear guidelines about applying sunscreens in the periocular area, but in general, mineral blocks are recommended because they have less chance of irritation. Several companies make such products that are designed to be applied to the eyelids.

Limitations of our study included a small sample size and a majority female demographic, which may have affected the results, as women generally are more familiar with the application of lotions to the face. Additionally, the patients were recruited from a tertiary-care clinic and may have had periocular malignancy or may have previously received counseling on the importance of sunscreen use.

Conclusion

Cancer reconstruction of the periocular area is challenging, and even in the best of hands, a patient's quality of life may be negatively affected by postreconstructive appearance or suboptimal function, resulting in ocular exposure. The authors recommend counseling patients on the importance of good sun protection habits, including daily application of sunscreen to the face and periocular region to prevent malignancy in these delicate areas.

UV radiation from sun exposure is a risk factor for most types of skin cancer.¹ Despite comprising only 1% of the body's surface area, the periocular region is the location of approximately 5% to 10% of skin cancers described in one US study.² The efficacy of sunscreen in preventing skin cancer is widely accepted, and the American Academy of Dermatology recommends application of broad-spectrum UVA/UVB sunscreen with a sun protection factor of 30 or higher to help prevent skin cancer.^3-5

RELATED ARTICLE: Sun Protection for Infants: Parent Behaviors and Beliefs

Reducing the risk of skin cancer from sun exposure relies on many factors, including completeness of application. A number of studies have demonstrated incomplete sunscreen application on the hairline, ears, neck, and dorsal feet.^6-8 The purpose of this study was to assess the completeness of facial sunscreen self-application in oculofacial surgery patients using UV photography.

Methods

This single-site, cross-sectional, qualitative study assessed the completeness of facial sunscreen self-application among patients from a single surgeon's (J.A.W.) cosmetic and tertiary-care oculofacial surgery practice at the Duke Eye Center (Durham, North Carolina) between March 2016 and May 2016. Approval from the Duke University institutional review board was obtained, and the research adhered to the tenets of the Declaration of Helsinki and complied with the Health Insurance Portability and Accountability Act. Informed consent was obtained from all patients, and patients could elect to provide specific written consent for publication of photographs in scientific presentations and publications. Patients younger than 18 years of age; those with known sensitivity to sunscreen or its ingredients; and those with an active lesion, rash, or open wound were excluded from the study.

After obtaining informed consent, patients were photographed using a camera with a UV lens in natural outdoor lighting, first without sunscreen and again after self-application of a sunscreen of their choosing using their routine application technique. Completeness of sunscreen application was graded independently by 3 oculofacial surgeons (N.A.L., J.L., J.A.W.) as complete, partial, none, or cannot determine for 15 facial regions. The majority response was used for analysis.

Results

Forty-four patients were enrolled in the study. Six patients were disqualified due to use of mineral-based formulations (zinc oxide and/or titanium dioxide), as these sunscreens could not be visualized using UV photography. The age range of the remaining 38 patients was 28 to 74 years; 26% (10/38) were men and 74% (28/38) were women.

Complete sunscreen application was most frequently performed on the cheeks (97% [37/38]), chin (95% [36/38]), forehead (92% [35/38]), and temples (92% [35/38]). Complete absence of sunscreen coverage was most common on the lower eyelid margin (84% [32/38]), upper eyelid margin (82% [31/38]), medial canthus (71% 27/38]), and upper eyelid (66% [25/38])(Table)(Figure).

Comment

UV radiation-related skin cancers frequently occur in the periocular area, presumably because it is a frequent site of UV exposure. Clothing, sunglasses, and hats can be used to aid in protection from UV radiation, but these products are only regulated by the US Food and Drug Administration if the product claims to prevent skin cancer. Sunscreen is a proven method of protection from UV radiation and the prevention of skin cancer but must be properly applied for it to be effective.^1,2,5,6 Incomplete sunscreen application has been demonstrated in numerous studies. Lademann et al7 studied sunscreen application among 60 beachgoers in Germany and found they typically missed the hairline, ears, and dorsal feet. In a study of 10 women with photosensitivity in England who were asked to apply sunscreen in their routine manner, Azurdia et al⁶ found the posterior neck, lateral neck, temples, and ears, respectively, were the most frequently missed sites. Yang et al⁸ assessed sunscreen application in 39 dermatologists and 41 photosensitive patients in China and found the neck, ears, dorsal hands, hairline, temples, and perioral region, respectively, were most commonly left unprotected.

Our study investigated detailed facial self-application of sunscreen and found excellent coverage of the larger facial units such as the forehead, cheeks, chin, and temples. The brow, medial canthus, lateral canthus, and upper and lower eyelids and eyelid margins were infrequently protected with sunscreen during routine application. Our opinion is that patients are unaware that eyelid sunscreen application is important. They may be afraid that the products will sting or cause damage if they get in the eyes. Although some products do sting if they get into the eyes, there is no evidence that sunscreens cause injury to the eyes. The US Food and Drug Administration does not have clear guidelines about applying sunscreens in the periocular area, but in general, mineral blocks are recommended because they have less chance of irritation. Several companies make such products that are designed to be applied to the eyelids.

Limitations of our study included a small sample size and a majority female demographic, which may have affected the results, as women generally are more familiar with the application of lotions to the face. Additionally, the patients were recruited from a tertiary-care clinic and may have had periocular malignancy or may have previously received counseling on the importance of sunscreen use.

Conclusion

Cancer reconstruction of the periocular area is challenging, and even in the best of hands, a patient's quality of life may be negatively affected by postreconstructive appearance or suboptimal function, resulting in ocular exposure. The authors recommend counseling patients on the importance of good sun protection habits, including daily application of sunscreen to the face and periocular region to prevent malignancy in these delicate areas.

The Diagnosis: Mucormycosis

Skin biopsy and histology revealed broad, wide-angle, branched, nonseptate hyphae suggestive of mucormycosis infection (Figure 1). Computed tomography of the abdomen and pelvis revealed marked stranding in the vulvar region and urothelial thickening and enhancement suggestive of infection (Figure 2). Computed tomography of the chest demonstrated multiple irregular nodules in the bilateral upper lobes consistent with disseminated mucormycosis (Figure 3). The patient was started on intravenous amphotericin B and posaconazole. Surgery was not pursued given the poor prognosis of her refractory acute lymphoblastic leukemia, pancytopenia, and disseminated fungal infection. The patient was discharged home with hospice care.

Mucormycosis is an infection caused by fungi that belong to the order Mucorales. The most common genera responsible for human disease are Rhizopus, Mucor, and Rhizomucor, which are organisms ubiquitous in nature and found in soil.¹ Mucorales hyphae are widely branched and primarily nonseptate, which distinguishes them from hyphae of ascomycetous molds such as Aspergillus, which are narrowly branched and septate.

Mucormycosis primarily affects immunocompromised individuals. The overall incidence of mucormycosis is difficult to estimate, and the risk for infection varies based on the patient population. For example, the incidence of mucormycosis in hematologic malignancy ranges from 1% to 8% and from 0.4% to 16.0% in solid organ transplant recipients.² One large series of 929 cases noted that the most common risk factors were associated with impaired immune function including diabetes mellitus and diabetic ketoacidosis (36% of cases), hematologic malignancy (17%), and solid organ (7%) or bone marrow transplantation (5%). Other risk factors include neutropenia, steroid therapy, and other immunocompromising conditions.³ Healthy individuals have a strong natural immunity to mucormycosis and rarely are affected by the disease.²

The host response to Mucorales is primarily driven by phagocyte-mediated killing via oxidative metabolites and cationic peptides called defensins.¹ Thus, severely neutropenic patients are at high risk for developing mucormycosis.¹ In contrast, it appears as though AIDS patients are not at increased risk for mucormycosis, supporting the theory that T lymphocytes are not involved in the host response.¹ The conditions of diabetic ketoacidosis leave patients susceptible to mucormycosis for several reasons. First, hyperglycemia and low pH induce phagocyte dysfunction and thus inhibit the host response to Mucorales.⁴ Second, these organisms have an active ketone reductase system that may allow them to grow more readily in high glucose, acidic conditions.¹ Third, diabetic ketoacidosis conditions increase serum free iron, and Mucorales utilizes host iron for cell growth and development.¹ Individuals such as hemodialysis patients receiving the iron chelator deferoxamine also are at risk for mucormycosis, as Rhizopus can bind to this molecule and transport the bound iron intracellularly for growth utilization.¹

Mucormycosis infection is characterized by infarction and rapid necrosis of host tissues resulting from vascular infiltration by fungal hyphae. The most common site of infection is rhino-orbital-cerebral (39%), followed by lungs (24%) and skin (19%).³ Dissemination occurs in 23% of cases.³ Inoculation most commonly occurs via inhalation of airborne fungal spores by an immunocompromised host with resultant fungal proliferation in the paranasal sinuses, bronchioles, or alveoli. Gastrointestinal tract infection is presumed to occur via ingestion of spores.⁵

Cutaneous infection, as in our patient, occurs via the inoculation of spores into the dermis through breaks in the skin such as from intravenous lines, urinary catheters, injection sites, surgical sites, and traumatic wounds. Cutaneous infections typically present as a single erythematous, painful, indurated papule that rapidly progresses to a necrotic ulcer with overlying black eschar. In some cases, the progression may be more indolent over the course of several weeks.² There are few reported cases of primary vulvar mucormycosis, as in our patient.^6,7 The previously reported cases involved severely immunocompromised patients who developed large necrotic lesions over the vulva that demonstrated widely branching, nonseptate hyphae on histologic examination. Each patient required extensive surgical debridement with systemic antifungal treatment.^6,7

A timely diagnosis of mucormycosis often hinges on a high index of suspicion on behalf of the clinician. A fungal etiology always should be considered for an infection in an immunocompromised patient. Furthermore, nonresponse to antibiotic treatment should be an important diagnostic clue that the infection could be fungal in origin. The definitive diagnosis of mucormycosis is confirmed by tissue biopsy and the presence of broad, widely branching, nonseptate hyphae seen on histopathologic examination.

Treatment involves aggressive surgical debridement of all necrotic tissues and elimination of predisposing factors for infection such as hyperglycemia, metabolic acidosis, deferoxamine administration, and immunosuppressive medications. Early initiation of antifungal therapy with the lipid formulation of amphotericin B is recommended. Oral posaconazole or isavuconazole typically are used as step-down therapy after a favorable clinical response with initial amphotericin B treatment. Deferasirox, in contrast to deferoxamine, is an iron chelator that may reduce the pathogenicity of Mucorales and may help as an adjunctive therapy.⁸ In addition, hyperbaric oxygen therapy may have limited benefit in some cases.⁹ In spite of these treatments, the overall mortality of mucormycosis is 50% or higher and approaches nearly 100% in cases of disseminated disease, such as in our patient.^1,3

The Diagnosis: Mucormycosis

Skin biopsy and histology revealed broad, wide-angle, branched, nonseptate hyphae suggestive of mucormycosis infection (Figure 1). Computed tomography of the abdomen and pelvis revealed marked stranding in the vulvar region and urothelial thickening and enhancement suggestive of infection (Figure 2). Computed tomography of the chest demonstrated multiple irregular nodules in the bilateral upper lobes consistent with disseminated mucormycosis (Figure 3). The patient was started on intravenous amphotericin B and posaconazole. Surgery was not pursued given the poor prognosis of her refractory acute lymphoblastic leukemia, pancytopenia, and disseminated fungal infection. The patient was discharged home with hospice care.

Mucormycosis is an infection caused by fungi that belong to the order Mucorales. The most common genera responsible for human disease are Rhizopus, Mucor, and Rhizomucor, which are organisms ubiquitous in nature and found in soil.¹ Mucorales hyphae are widely branched and primarily nonseptate, which distinguishes them from hyphae of ascomycetous molds such as Aspergillus, which are narrowly branched and septate.

Mucormycosis primarily affects immunocompromised individuals. The overall incidence of mucormycosis is difficult to estimate, and the risk for infection varies based on the patient population. For example, the incidence of mucormycosis in hematologic malignancy ranges from 1% to 8% and from 0.4% to 16.0% in solid organ transplant recipients.² One large series of 929 cases noted that the most common risk factors were associated with impaired immune function including diabetes mellitus and diabetic ketoacidosis (36% of cases), hematologic malignancy (17%), and solid organ (7%) or bone marrow transplantation (5%). Other risk factors include neutropenia, steroid therapy, and other immunocompromising conditions.³ Healthy individuals have a strong natural immunity to mucormycosis and rarely are affected by the disease.²

The host response to Mucorales is primarily driven by phagocyte-mediated killing via oxidative metabolites and cationic peptides called defensins.¹ Thus, severely neutropenic patients are at high risk for developing mucormycosis.¹ In contrast, it appears as though AIDS patients are not at increased risk for mucormycosis, supporting the theory that T lymphocytes are not involved in the host response.¹ The conditions of diabetic ketoacidosis leave patients susceptible to mucormycosis for several reasons. First, hyperglycemia and low pH induce phagocyte dysfunction and thus inhibit the host response to Mucorales.⁴ Second, these organisms have an active ketone reductase system that may allow them to grow more readily in high glucose, acidic conditions.¹ Third, diabetic ketoacidosis conditions increase serum free iron, and Mucorales utilizes host iron for cell growth and development.¹ Individuals such as hemodialysis patients receiving the iron chelator deferoxamine also are at risk for mucormycosis, as Rhizopus can bind to this molecule and transport the bound iron intracellularly for growth utilization.¹

Mucormycosis infection is characterized by infarction and rapid necrosis of host tissues resulting from vascular infiltration by fungal hyphae. The most common site of infection is rhino-orbital-cerebral (39%), followed by lungs (24%) and skin (19%).³ Dissemination occurs in 23% of cases.³ Inoculation most commonly occurs via inhalation of airborne fungal spores by an immunocompromised host with resultant fungal proliferation in the paranasal sinuses, bronchioles, or alveoli. Gastrointestinal tract infection is presumed to occur via ingestion of spores.⁵

Cutaneous infection, as in our patient, occurs via the inoculation of spores into the dermis through breaks in the skin such as from intravenous lines, urinary catheters, injection sites, surgical sites, and traumatic wounds. Cutaneous infections typically present as a single erythematous, painful, indurated papule that rapidly progresses to a necrotic ulcer with overlying black eschar. In some cases, the progression may be more indolent over the course of several weeks.² There are few reported cases of primary vulvar mucormycosis, as in our patient.^6,7 The previously reported cases involved severely immunocompromised patients who developed large necrotic lesions over the vulva that demonstrated widely branching, nonseptate hyphae on histologic examination. Each patient required extensive surgical debridement with systemic antifungal treatment.^6,7

A timely diagnosis of mucormycosis often hinges on a high index of suspicion on behalf of the clinician. A fungal etiology always should be considered for an infection in an immunocompromised patient. Furthermore, nonresponse to antibiotic treatment should be an important diagnostic clue that the infection could be fungal in origin. The definitive diagnosis of mucormycosis is confirmed by tissue biopsy and the presence of broad, widely branching, nonseptate hyphae seen on histopathologic examination.

Treatment involves aggressive surgical debridement of all necrotic tissues and elimination of predisposing factors for infection such as hyperglycemia, metabolic acidosis, deferoxamine administration, and immunosuppressive medications. Early initiation of antifungal therapy with the lipid formulation of amphotericin B is recommended. Oral posaconazole or isavuconazole typically are used as step-down therapy after a favorable clinical response with initial amphotericin B treatment. Deferasirox, in contrast to deferoxamine, is an iron chelator that may reduce the pathogenicity of Mucorales and may help as an adjunctive therapy.⁸ In addition, hyperbaric oxygen therapy may have limited benefit in some cases.⁹ In spite of these treatments, the overall mortality of mucormycosis is 50% or higher and approaches nearly 100% in cases of disseminated disease, such as in our patient.^1,3

The Diagnosis: Mucormycosis

Skin biopsy and histology revealed broad, wide-angle, branched, nonseptate hyphae suggestive of mucormycosis infection (Figure 1). Computed tomography of the abdomen and pelvis revealed marked stranding in the vulvar region and urothelial thickening and enhancement suggestive of infection (Figure 2). Computed tomography of the chest demonstrated multiple irregular nodules in the bilateral upper lobes consistent with disseminated mucormycosis (Figure 3). The patient was started on intravenous amphotericin B and posaconazole. Surgery was not pursued given the poor prognosis of her refractory acute lymphoblastic leukemia, pancytopenia, and disseminated fungal infection. The patient was discharged home with hospice care.

Mucormycosis is an infection caused by fungi that belong to the order Mucorales. The most common genera responsible for human disease are Rhizopus, Mucor, and Rhizomucor, which are organisms ubiquitous in nature and found in soil.¹ Mucorales hyphae are widely branched and primarily nonseptate, which distinguishes them from hyphae of ascomycetous molds such as Aspergillus, which are narrowly branched and septate.

Mucormycosis primarily affects immunocompromised individuals. The overall incidence of mucormycosis is difficult to estimate, and the risk for infection varies based on the patient population. For example, the incidence of mucormycosis in hematologic malignancy ranges from 1% to 8% and from 0.4% to 16.0% in solid organ transplant recipients.² One large series of 929 cases noted that the most common risk factors were associated with impaired immune function including diabetes mellitus and diabetic ketoacidosis (36% of cases), hematologic malignancy (17%), and solid organ (7%) or bone marrow transplantation (5%). Other risk factors include neutropenia, steroid therapy, and other immunocompromising conditions.³ Healthy individuals have a strong natural immunity to mucormycosis and rarely are affected by the disease.²

The host response to Mucorales is primarily driven by phagocyte-mediated killing via oxidative metabolites and cationic peptides called defensins.¹ Thus, severely neutropenic patients are at high risk for developing mucormycosis.¹ In contrast, it appears as though AIDS patients are not at increased risk for mucormycosis, supporting the theory that T lymphocytes are not involved in the host response.¹ The conditions of diabetic ketoacidosis leave patients susceptible to mucormycosis for several reasons. First, hyperglycemia and low pH induce phagocyte dysfunction and thus inhibit the host response to Mucorales.⁴ Second, these organisms have an active ketone reductase system that may allow them to grow more readily in high glucose, acidic conditions.¹ Third, diabetic ketoacidosis conditions increase serum free iron, and Mucorales utilizes host iron for cell growth and development.¹ Individuals such as hemodialysis patients receiving the iron chelator deferoxamine also are at risk for mucormycosis, as Rhizopus can bind to this molecule and transport the bound iron intracellularly for growth utilization.¹

Mucormycosis infection is characterized by infarction and rapid necrosis of host tissues resulting from vascular infiltration by fungal hyphae. The most common site of infection is rhino-orbital-cerebral (39%), followed by lungs (24%) and skin (19%).³ Dissemination occurs in 23% of cases.³ Inoculation most commonly occurs via inhalation of airborne fungal spores by an immunocompromised host with resultant fungal proliferation in the paranasal sinuses, bronchioles, or alveoli. Gastrointestinal tract infection is presumed to occur via ingestion of spores.⁵

Cutaneous infection, as in our patient, occurs via the inoculation of spores into the dermis through breaks in the skin such as from intravenous lines, urinary catheters, injection sites, surgical sites, and traumatic wounds. Cutaneous infections typically present as a single erythematous, painful, indurated papule that rapidly progresses to a necrotic ulcer with overlying black eschar. In some cases, the progression may be more indolent over the course of several weeks.² There are few reported cases of primary vulvar mucormycosis, as in our patient.^6,7 The previously reported cases involved severely immunocompromised patients who developed large necrotic lesions over the vulva that demonstrated widely branching, nonseptate hyphae on histologic examination. Each patient required extensive surgical debridement with systemic antifungal treatment.^6,7

A timely diagnosis of mucormycosis often hinges on a high index of suspicion on behalf of the clinician. A fungal etiology always should be considered for an infection in an immunocompromised patient. Furthermore, nonresponse to antibiotic treatment should be an important diagnostic clue that the infection could be fungal in origin. The definitive diagnosis of mucormycosis is confirmed by tissue biopsy and the presence of broad, widely branching, nonseptate hyphae seen on histopathologic examination.

Treatment involves aggressive surgical debridement of all necrotic tissues and elimination of predisposing factors for infection such as hyperglycemia, metabolic acidosis, deferoxamine administration, and immunosuppressive medications. Early initiation of antifungal therapy with the lipid formulation of amphotericin B is recommended. Oral posaconazole or isavuconazole typically are used as step-down therapy after a favorable clinical response with initial amphotericin B treatment. Deferasirox, in contrast to deferoxamine, is an iron chelator that may reduce the pathogenicity of Mucorales and may help as an adjunctive therapy.⁸ In addition, hyperbaric oxygen therapy may have limited benefit in some cases.⁹ In spite of these treatments, the overall mortality of mucormycosis is 50% or higher and approaches nearly 100% in cases of disseminated disease, such as in our patient.^1,3

The Diagnosis: Nevus Lipomatosus Cutaneous Superficialis

A punch biopsy was obtained from a skin lesion, which showed orthokeratosis, irregular acanthosis, papillomatosis, intense edema in the upper dermis, and mature fat lobules that dissected collagen fibers in the reticular dermis (Figure). Classical-type nevus lipomatosus cutaneous superficialis (NLCS) was diagnosed based on these clinical and histopathological findings. The patient was referred to the plastic surgery clinic for total excision of all lesions.

Nevus lipomatosus cutaneous superficialis is a rare hamartoma characterized by ectopic deposition of mature adipose tissue in the dermis.¹ It was first described by Hoffmann and Zurhelle² in 1921. Clinically, NLCS is classified into 2 subtypes: classical (multiple) and solitary. Classical-type NLCS is characterized by multiple pedunculated or sessile, soft, cerebriform, yellowish papules and nodules, especially in the pelvic area. Solitary-type NLCS presents as a sessile papule or nodule with no predilection for localization. Although the classical form of NLCS generally occurs in the first 2 decades of life, the solitary form usually appears in adulthood.³ Nevus lipomatosus cutaneous superficialis has no gender predilection and there is no genetic or congenital defect association.^1,4

The pathogenesis of NLCS still is unknown, but some theories have been proposed, such as the development of adipose metaplasia secondary to degeneration of connective tissue, the formation of a true nevus resulting from heterotopic development of adipose tissue, and the development of mature adipocytes from pericytes in dermal vessels.^1,5 

Histopathology of NLCS shows clusters of ectopic mature adipose tissue in varying rates (10%-50%) between collagen bundles in the dermis. Characteristically, there is no connection between the ectopic mature adipose tissue and the subcutaneous adipose tissue.³ The differential diagnosis of NLCS includes neurofibroma, lymphangioma, sebaceous nevus, fibroepithelial polyps, leiomyoma, and lipomas.^1,6

Treatment of NLCS generally involves basic surgical excision; however, patients treated with CO₂ laser also have been reported in the literature.⁵ Because of the growth tendency and the large size of the classical form of NLCS, recurrence may occur, as in our case. In such cases, gradual surgical excision is recommended.⁵ We present this case to indicate that undesirable surgical results or relapse may occur in untreated patients because of lesion growth and delayed diagnosis.

The Diagnosis: Nevus Lipomatosus Cutaneous Superficialis

A punch biopsy was obtained from a skin lesion, which showed orthokeratosis, irregular acanthosis, papillomatosis, intense edema in the upper dermis, and mature fat lobules that dissected collagen fibers in the reticular dermis (Figure). Classical-type nevus lipomatosus cutaneous superficialis (NLCS) was diagnosed based on these clinical and histopathological findings. The patient was referred to the plastic surgery clinic for total excision of all lesions.

Nevus lipomatosus cutaneous superficialis is a rare hamartoma characterized by ectopic deposition of mature adipose tissue in the dermis.¹ It was first described by Hoffmann and Zurhelle² in 1921. Clinically, NLCS is classified into 2 subtypes: classical (multiple) and solitary. Classical-type NLCS is characterized by multiple pedunculated or sessile, soft, cerebriform, yellowish papules and nodules, especially in the pelvic area. Solitary-type NLCS presents as a sessile papule or nodule with no predilection for localization. Although the classical form of NLCS generally occurs in the first 2 decades of life, the solitary form usually appears in adulthood.³ Nevus lipomatosus cutaneous superficialis has no gender predilection and there is no genetic or congenital defect association.^1,4

The pathogenesis of NLCS still is unknown, but some theories have been proposed, such as the development of adipose metaplasia secondary to degeneration of connective tissue, the formation of a true nevus resulting from heterotopic development of adipose tissue, and the development of mature adipocytes from pericytes in dermal vessels.^1,5 

Histopathology of NLCS shows clusters of ectopic mature adipose tissue in varying rates (10%-50%) between collagen bundles in the dermis. Characteristically, there is no connection between the ectopic mature adipose tissue and the subcutaneous adipose tissue.³ The differential diagnosis of NLCS includes neurofibroma, lymphangioma, sebaceous nevus, fibroepithelial polyps, leiomyoma, and lipomas.^1,6

Treatment of NLCS generally involves basic surgical excision; however, patients treated with CO₂ laser also have been reported in the literature.⁵ Because of the growth tendency and the large size of the classical form of NLCS, recurrence may occur, as in our case. In such cases, gradual surgical excision is recommended.⁵ We present this case to indicate that undesirable surgical results or relapse may occur in untreated patients because of lesion growth and delayed diagnosis.

The Diagnosis: Nevus Lipomatosus Cutaneous Superficialis

A punch biopsy was obtained from a skin lesion, which showed orthokeratosis, irregular acanthosis, papillomatosis, intense edema in the upper dermis, and mature fat lobules that dissected collagen fibers in the reticular dermis (Figure). Classical-type nevus lipomatosus cutaneous superficialis (NLCS) was diagnosed based on these clinical and histopathological findings. The patient was referred to the plastic surgery clinic for total excision of all lesions.

Nevus lipomatosus cutaneous superficialis is a rare hamartoma characterized by ectopic deposition of mature adipose tissue in the dermis.¹ It was first described by Hoffmann and Zurhelle² in 1921. Clinically, NLCS is classified into 2 subtypes: classical (multiple) and solitary. Classical-type NLCS is characterized by multiple pedunculated or sessile, soft, cerebriform, yellowish papules and nodules, especially in the pelvic area. Solitary-type NLCS presents as a sessile papule or nodule with no predilection for localization. Although the classical form of NLCS generally occurs in the first 2 decades of life, the solitary form usually appears in adulthood.³ Nevus lipomatosus cutaneous superficialis has no gender predilection and there is no genetic or congenital defect association.^1,4

The pathogenesis of NLCS still is unknown, but some theories have been proposed, such as the development of adipose metaplasia secondary to degeneration of connective tissue, the formation of a true nevus resulting from heterotopic development of adipose tissue, and the development of mature adipocytes from pericytes in dermal vessels.^1,5 

Histopathology of NLCS shows clusters of ectopic mature adipose tissue in varying rates (10%-50%) between collagen bundles in the dermis. Characteristically, there is no connection between the ectopic mature adipose tissue and the subcutaneous adipose tissue.³ The differential diagnosis of NLCS includes neurofibroma, lymphangioma, sebaceous nevus, fibroepithelial polyps, leiomyoma, and lipomas.^1,6

Treatment of NLCS generally involves basic surgical excision; however, patients treated with CO₂ laser also have been reported in the literature.⁵ Because of the growth tendency and the large size of the classical form of NLCS, recurrence may occur, as in our case. In such cases, gradual surgical excision is recommended.⁵ We present this case to indicate that undesirable surgical results or relapse may occur in untreated patients because of lesion growth and delayed diagnosis.

As lifelong learners, physicians are encouraged and expected to share their knowledge base with budding residents and students. Effective communication is essential to the utmost delivery of clinical knowledge and pearls. Lecture delivery is important for all stages of learning, and adapting efficient techniques early in one's career is critical for the transmission of ideas and teaching points. These tips were created to help formulate guidelines for physician presentations and are open for interpretation. These well-meaning suggestions can be integrated into one's toolbox to foster an enthusiastic educational arena.

Step 1: Know Your Key Message 

First and foremost, one should ruminate over the overall message of the lecture. Consider at least 3 main points you want the learner to gain and remember on completion of the lecture. Additionally, it is crucial to think about the audience who will be present for your message and how to deliver your ideas clearly and effectively. Be cognizant of the knowledge base of your listeners and gauge how much initial background information is needed; conversely, if the audience is familiar with the material, excessive introductory material may be unnecessary and cause inattentiveness. Simplicity, both within the inherent message itself and the content and layout, can ameliorate the transmission of data regardless of the audience. A mentor once told me that no slide should contain more than 13 lines of text. Furthermore, if you are counting the number of lines, then you likely need to reduce the text and simplify the slide. Each slide should contain a maximum of 3 or 4 bullet points.¹ Convoluted figures should be avoided and key points should be highlighted. Overall, know your take-home message and provide the listener with simplistic text and images to convey the key ideas at their educational level.

Step 2: Prepare

Preparation is of utmost importance. Reading over the slides several times prior to the presentation is vital. You are the assumed expert on the topic and meticulously knowing the subject matter helps with the confidence of your delivery. Ease of subject matter also helps you, as the presenter, to rely less on verbatim reading of the slides and allows you to interact more with your audience. It is important to be familiar with the order of your presentation as well as the phrases and figures provided.² Flipping back and forth through slides can be distracting to the audience and can make the order of your presentation seem incongruous, presenting as a hastily constructed lecture. If you are prepared, you can engage your audience and provide additional information that is not on the slides to maintain interest. Remember that reading the slides can reduce your voice to a monotone, subtracting enthusiasm and energy from the delivery of your talk.² Rehearsal helps give you the freedom to confidently and proudly present your subject material.

Step 3: Be Animated 

You are the main attraction and the performer of this lecture. Radiate the confidence you gained from being prepared with the ability to engage in eye contact and gestures as needed to convey your point. Regularly shift your focus around the room to attempt to involve as many people as possible in your talk.² Your main focus should be your audience and not your slides; the slides should simply help guide your talk.³ During your presentation, you also can ask rhetorical questions that you can then answer to keep the group engaged (eg, "So, what does this tell us?" or "What would you do next?"). These questions demonstrate to your audience that you are interested in their attention and can help reciprocate the enthusiasm. Use language that involves your audience as a group participant. For example, when looking at visual aids, introduce them by saying "If we look at this table, we can see that . . ." or "This figure shows us that . . ."^2,3 Additionally, be cognizant of the volume and pace of your voice. During key points, you may want to slightly raise your voice and slow your pace for emphasis. Anxiety can make all presenters speed through their material; however, try to be mindful of the rhythm of your speech. With preparation you should be able to accurately gauge the length of your presentation but also adapt to the necessary time constraints if too much time is spent on one point early on. Most would believe that all good lectures end at least a few minutes early to allow for questions and comprehension of the material as well as to provide your audience with time to move on to their next engagement or clinical duty. 

Step 4: Encourage Active Participation

Active audience participation is shown by a multitude of studies to provide the highest level of comprehension.^4,5 In a crossover study conducted by Bleske et al,⁴ 30 students were divided into 2 groups and were taught 6 therapeutic topics, with 3 topics provided by conventional lecture and 3 topics taught by team-based learning. At the end of the educational series, the students were surveyed to evaluate their confidence and attitudes. Students demonstrated not only higher examination scores with team-based learning but higher confidence in their ability to transmit the information garnered through therapeutic recommendations.⁴ Although small, this study highlights the intuitive notion that active learning with subject material, either by sharing ideas with colleagues or having small brainstorming discussions throughout lectures, helps consolidate the information for long-term memory and comprehension.

Additionally, teaching in a medical environment can present unique challenges, as participants may feel anxiety over having right or wrong answers due to fear of inadequacy among their scholarly peers. Neher et al⁶ proposed a 5-step "microskills" model for teaching young physicians, and although it is intended for a clinical setting, it also can be applied to engaging and answering questions from a medical audience in general. Their model focuses on the teacher, or in our case the lecturer, asking a question and then applying the following model: (1) get a commitment, (2) probe for supporting evidence, (3) teach general rules, (4) reinforce what was done right, and (5) correct mistakes.⁶ After asking your question, the student commits to an answer and must then provide supporting details for their choice, thus feeling more responsible for their collaborative role in problem-solving. Based on their answer, you can then teach your general rule, provide positive feedback on what the student said accurately, and ultimately correct any erroneous information. This prototype of learning is best utilized in the clinical setting but also can enhance participant engagement in lectures while maintaining an inviting educational environment. 

Step 5: Summarize 

Lastly, conclude your presentation with at least 3 memorable points. What was the point of the presentation? What message do you want your audience to take with them and apply to clinical care? Reiterating the key points through repetition is crucial for long-term memory. Leave the audience with additional thoughts for exploration and subsequent discussion. How can your work or topic be further translated into additional projects for investigation? If the lecture material contains abundant clinical information beyond 3 points, a handout can be helpful to avoid having learners struggling to keep up with notes. This piece of take-home material can serve as a tool for subsequent study and to stimulate enhanced memory of the subject material provided. A strong concluding message can consolidate and remind learners of the scope of the topic and highlight the vital information that should be retained.

Final Thoughts

In summary, the clinical lecturer provides a unique teaching experience, and all physicians should feel proficient in formulating and delivering an educational lecture. These simple tips that call for the teacher to know and prepare his/her key message to deliver an animated and engaged presentation and then to summarize key findings are suggestions for the utmost transmission of data and ideas for all learners.

Acknowledgment
A special thank you to Joan E. St. Onge, MD (Miami, Florida), for her help providing resources for this topic. 

As lifelong learners, physicians are encouraged and expected to share their knowledge base with budding residents and students. Effective communication is essential to the utmost delivery of clinical knowledge and pearls. Lecture delivery is important for all stages of learning, and adapting efficient techniques early in one's career is critical for the transmission of ideas and teaching points. These tips were created to help formulate guidelines for physician presentations and are open for interpretation. These well-meaning suggestions can be integrated into one's toolbox to foster an enthusiastic educational arena.

Step 1: Know Your Key Message 

First and foremost, one should ruminate over the overall message of the lecture. Consider at least 3 main points you want the learner to gain and remember on completion of the lecture. Additionally, it is crucial to think about the audience who will be present for your message and how to deliver your ideas clearly and effectively. Be cognizant of the knowledge base of your listeners and gauge how much initial background information is needed; conversely, if the audience is familiar with the material, excessive introductory material may be unnecessary and cause inattentiveness. Simplicity, both within the inherent message itself and the content and layout, can ameliorate the transmission of data regardless of the audience. A mentor once told me that no slide should contain more than 13 lines of text. Furthermore, if you are counting the number of lines, then you likely need to reduce the text and simplify the slide. Each slide should contain a maximum of 3 or 4 bullet points.¹ Convoluted figures should be avoided and key points should be highlighted. Overall, know your take-home message and provide the listener with simplistic text and images to convey the key ideas at their educational level.

Step 2: Prepare

Preparation is of utmost importance. Reading over the slides several times prior to the presentation is vital. You are the assumed expert on the topic and meticulously knowing the subject matter helps with the confidence of your delivery. Ease of subject matter also helps you, as the presenter, to rely less on verbatim reading of the slides and allows you to interact more with your audience. It is important to be familiar with the order of your presentation as well as the phrases and figures provided.² Flipping back and forth through slides can be distracting to the audience and can make the order of your presentation seem incongruous, presenting as a hastily constructed lecture. If you are prepared, you can engage your audience and provide additional information that is not on the slides to maintain interest. Remember that reading the slides can reduce your voice to a monotone, subtracting enthusiasm and energy from the delivery of your talk.² Rehearsal helps give you the freedom to confidently and proudly present your subject material.

Step 3: Be Animated 

You are the main attraction and the performer of this lecture. Radiate the confidence you gained from being prepared with the ability to engage in eye contact and gestures as needed to convey your point. Regularly shift your focus around the room to attempt to involve as many people as possible in your talk.² Your main focus should be your audience and not your slides; the slides should simply help guide your talk.³ During your presentation, you also can ask rhetorical questions that you can then answer to keep the group engaged (eg, "So, what does this tell us?" or "What would you do next?"). These questions demonstrate to your audience that you are interested in their attention and can help reciprocate the enthusiasm. Use language that involves your audience as a group participant. For example, when looking at visual aids, introduce them by saying "If we look at this table, we can see that . . ." or "This figure shows us that . . ."^2,3 Additionally, be cognizant of the volume and pace of your voice. During key points, you may want to slightly raise your voice and slow your pace for emphasis. Anxiety can make all presenters speed through their material; however, try to be mindful of the rhythm of your speech. With preparation you should be able to accurately gauge the length of your presentation but also adapt to the necessary time constraints if too much time is spent on one point early on. Most would believe that all good lectures end at least a few minutes early to allow for questions and comprehension of the material as well as to provide your audience with time to move on to their next engagement or clinical duty. 

Step 4: Encourage Active Participation

Active audience participation is shown by a multitude of studies to provide the highest level of comprehension.^4,5 In a crossover study conducted by Bleske et al,⁴ 30 students were divided into 2 groups and were taught 6 therapeutic topics, with 3 topics provided by conventional lecture and 3 topics taught by team-based learning. At the end of the educational series, the students were surveyed to evaluate their confidence and attitudes. Students demonstrated not only higher examination scores with team-based learning but higher confidence in their ability to transmit the information garnered through therapeutic recommendations.⁴ Although small, this study highlights the intuitive notion that active learning with subject material, either by sharing ideas with colleagues or having small brainstorming discussions throughout lectures, helps consolidate the information for long-term memory and comprehension.

Additionally, teaching in a medical environment can present unique challenges, as participants may feel anxiety over having right or wrong answers due to fear of inadequacy among their scholarly peers. Neher et al⁶ proposed a 5-step "microskills" model for teaching young physicians, and although it is intended for a clinical setting, it also can be applied to engaging and answering questions from a medical audience in general. Their model focuses on the teacher, or in our case the lecturer, asking a question and then applying the following model: (1) get a commitment, (2) probe for supporting evidence, (3) teach general rules, (4) reinforce what was done right, and (5) correct mistakes.⁶ After asking your question, the student commits to an answer and must then provide supporting details for their choice, thus feeling more responsible for their collaborative role in problem-solving. Based on their answer, you can then teach your general rule, provide positive feedback on what the student said accurately, and ultimately correct any erroneous information. This prototype of learning is best utilized in the clinical setting but also can enhance participant engagement in lectures while maintaining an inviting educational environment. 

Step 5: Summarize 

Lastly, conclude your presentation with at least 3 memorable points. What was the point of the presentation? What message do you want your audience to take with them and apply to clinical care? Reiterating the key points through repetition is crucial for long-term memory. Leave the audience with additional thoughts for exploration and subsequent discussion. How can your work or topic be further translated into additional projects for investigation? If the lecture material contains abundant clinical information beyond 3 points, a handout can be helpful to avoid having learners struggling to keep up with notes. This piece of take-home material can serve as a tool for subsequent study and to stimulate enhanced memory of the subject material provided. A strong concluding message can consolidate and remind learners of the scope of the topic and highlight the vital information that should be retained.

Final Thoughts

In summary, the clinical lecturer provides a unique teaching experience, and all physicians should feel proficient in formulating and delivering an educational lecture. These simple tips that call for the teacher to know and prepare his/her key message to deliver an animated and engaged presentation and then to summarize key findings are suggestions for the utmost transmission of data and ideas for all learners.

Acknowledgment
A special thank you to Joan E. St. Onge, MD (Miami, Florida), for her help providing resources for this topic. 

As lifelong learners, physicians are encouraged and expected to share their knowledge base with budding residents and students. Effective communication is essential to the utmost delivery of clinical knowledge and pearls. Lecture delivery is important for all stages of learning, and adapting efficient techniques early in one's career is critical for the transmission of ideas and teaching points. These tips were created to help formulate guidelines for physician presentations and are open for interpretation. These well-meaning suggestions can be integrated into one's toolbox to foster an enthusiastic educational arena.

Step 1: Know Your Key Message 

First and foremost, one should ruminate over the overall message of the lecture. Consider at least 3 main points you want the learner to gain and remember on completion of the lecture. Additionally, it is crucial to think about the audience who will be present for your message and how to deliver your ideas clearly and effectively. Be cognizant of the knowledge base of your listeners and gauge how much initial background information is needed; conversely, if the audience is familiar with the material, excessive introductory material may be unnecessary and cause inattentiveness. Simplicity, both within the inherent message itself and the content and layout, can ameliorate the transmission of data regardless of the audience. A mentor once told me that no slide should contain more than 13 lines of text. Furthermore, if you are counting the number of lines, then you likely need to reduce the text and simplify the slide. Each slide should contain a maximum of 3 or 4 bullet points.¹ Convoluted figures should be avoided and key points should be highlighted. Overall, know your take-home message and provide the listener with simplistic text and images to convey the key ideas at their educational level.

Step 2: Prepare

Preparation is of utmost importance. Reading over the slides several times prior to the presentation is vital. You are the assumed expert on the topic and meticulously knowing the subject matter helps with the confidence of your delivery. Ease of subject matter also helps you, as the presenter, to rely less on verbatim reading of the slides and allows you to interact more with your audience. It is important to be familiar with the order of your presentation as well as the phrases and figures provided.² Flipping back and forth through slides can be distracting to the audience and can make the order of your presentation seem incongruous, presenting as a hastily constructed lecture. If you are prepared, you can engage your audience and provide additional information that is not on the slides to maintain interest. Remember that reading the slides can reduce your voice to a monotone, subtracting enthusiasm and energy from the delivery of your talk.² Rehearsal helps give you the freedom to confidently and proudly present your subject material.

Step 3: Be Animated 

You are the main attraction and the performer of this lecture. Radiate the confidence you gained from being prepared with the ability to engage in eye contact and gestures as needed to convey your point. Regularly shift your focus around the room to attempt to involve as many people as possible in your talk.² Your main focus should be your audience and not your slides; the slides should simply help guide your talk.³ During your presentation, you also can ask rhetorical questions that you can then answer to keep the group engaged (eg, "So, what does this tell us?" or "What would you do next?"). These questions demonstrate to your audience that you are interested in their attention and can help reciprocate the enthusiasm. Use language that involves your audience as a group participant. For example, when looking at visual aids, introduce them by saying "If we look at this table, we can see that . . ." or "This figure shows us that . . ."^2,3 Additionally, be cognizant of the volume and pace of your voice. During key points, you may want to slightly raise your voice and slow your pace for emphasis. Anxiety can make all presenters speed through their material; however, try to be mindful of the rhythm of your speech. With preparation you should be able to accurately gauge the length of your presentation but also adapt to the necessary time constraints if too much time is spent on one point early on. Most would believe that all good lectures end at least a few minutes early to allow for questions and comprehension of the material as well as to provide your audience with time to move on to their next engagement or clinical duty. 

Step 4: Encourage Active Participation

Active audience participation is shown by a multitude of studies to provide the highest level of comprehension.^4,5 In a crossover study conducted by Bleske et al,⁴ 30 students were divided into 2 groups and were taught 6 therapeutic topics, with 3 topics provided by conventional lecture and 3 topics taught by team-based learning. At the end of the educational series, the students were surveyed to evaluate their confidence and attitudes. Students demonstrated not only higher examination scores with team-based learning but higher confidence in their ability to transmit the information garnered through therapeutic recommendations.⁴ Although small, this study highlights the intuitive notion that active learning with subject material, either by sharing ideas with colleagues or having small brainstorming discussions throughout lectures, helps consolidate the information for long-term memory and comprehension.

Additionally, teaching in a medical environment can present unique challenges, as participants may feel anxiety over having right or wrong answers due to fear of inadequacy among their scholarly peers. Neher et al⁶ proposed a 5-step "microskills" model for teaching young physicians, and although it is intended for a clinical setting, it also can be applied to engaging and answering questions from a medical audience in general. Their model focuses on the teacher, or in our case the lecturer, asking a question and then applying the following model: (1) get a commitment, (2) probe for supporting evidence, (3) teach general rules, (4) reinforce what was done right, and (5) correct mistakes.⁶ After asking your question, the student commits to an answer and must then provide supporting details for their choice, thus feeling more responsible for their collaborative role in problem-solving. Based on their answer, you can then teach your general rule, provide positive feedback on what the student said accurately, and ultimately correct any erroneous information. This prototype of learning is best utilized in the clinical setting but also can enhance participant engagement in lectures while maintaining an inviting educational environment. 

Step 5: Summarize 

Lastly, conclude your presentation with at least 3 memorable points. What was the point of the presentation? What message do you want your audience to take with them and apply to clinical care? Reiterating the key points through repetition is crucial for long-term memory. Leave the audience with additional thoughts for exploration and subsequent discussion. How can your work or topic be further translated into additional projects for investigation? If the lecture material contains abundant clinical information beyond 3 points, a handout can be helpful to avoid having learners struggling to keep up with notes. This piece of take-home material can serve as a tool for subsequent study and to stimulate enhanced memory of the subject material provided. A strong concluding message can consolidate and remind learners of the scope of the topic and highlight the vital information that should be retained.

Final Thoughts

In summary, the clinical lecturer provides a unique teaching experience, and all physicians should feel proficient in formulating and delivering an educational lecture. These simple tips that call for the teacher to know and prepare his/her key message to deliver an animated and engaged presentation and then to summarize key findings are suggestions for the utmost transmission of data and ideas for all learners.

Acknowledgment
A special thank you to Joan E. St. Onge, MD (Miami, Florida), for her help providing resources for this topic. 

Oral or injected medications for psoriasis can be burdensome for patients, making them inclined to use alternative therapies such as phototherapy and other nondrug therapies, according to a public meeting hosted by the US Food and Drug Administration (FDA) to hear patient perspectives on psoriasis. Approximately 70 psoriasis patients or patient representatives attended the meeting in person and others attended through a live webcast.

More than half of participants indicated that they have used phototherapy. Both positive and negative experiences were reported. One participant reported that a home UVB 3-panel light box "dramatically changed [his/her] life." Other participants indicated phototherapy was less successful for them. Participants also indicated fears about skin cancer.

RELATED ARTICLE: Does UVB phototherapy cause skin cancer?

However, several participants reported that phototherapy was more effective when used in combination with other medical therapies. Similarly, most participants indicated using 1 or more nondrug therapies to manage their psoriatic symptoms. Approximately one-third used over-the-counter products, such as coal tar, salicylic acid, and Epsom salt. Slightly more than one-fourth indicated the importance of complementary or alternative therapy, including exercise and meditation, to manage their psoriasis symptoms. Diet modifications, such as eliminating alcohol, sugar, processed foods, drugs, gluten, and tobacco, also were reported as successful.

RELATED ARTICLE: Yoga for dermatologic conditions

RELATED VIDEO: Answering patient questions about diet

Psoriasis patients emphasized that an effective multimodal approach including drug, phototherapy, and nondrug therapies usually is done through trial and error based on each patient's individual needs. Dermatologists would benefit from knowing that nearly all participants in this public meeting indicated they value the benefits of nondrug therapies, and combination therapies using drug and nondrug therapies should be discussed with patients.

The psoriasis public meeting in March 2016 was the FDA's 18th patient-focused drug development meeting. The FDA sought this information to have a greater understanding of the burden of psoriasis on patients and the treatments currently used to treat psoriasis and its symptoms. This information will help guide the FDA as they consider future drug approvals.

Oral or injected medications for psoriasis can be burdensome for patients, making them inclined to use alternative therapies such as phototherapy and other nondrug therapies, according to a public meeting hosted by the US Food and Drug Administration (FDA) to hear patient perspectives on psoriasis. Approximately 70 psoriasis patients or patient representatives attended the meeting in person and others attended through a live webcast.

More than half of participants indicated that they have used phototherapy. Both positive and negative experiences were reported. One participant reported that a home UVB 3-panel light box "dramatically changed [his/her] life." Other participants indicated phototherapy was less successful for them. Participants also indicated fears about skin cancer.

RELATED ARTICLE: Does UVB phototherapy cause skin cancer?

However, several participants reported that phototherapy was more effective when used in combination with other medical therapies. Similarly, most participants indicated using 1 or more nondrug therapies to manage their psoriatic symptoms. Approximately one-third used over-the-counter products, such as coal tar, salicylic acid, and Epsom salt. Slightly more than one-fourth indicated the importance of complementary or alternative therapy, including exercise and meditation, to manage their psoriasis symptoms. Diet modifications, such as eliminating alcohol, sugar, processed foods, drugs, gluten, and tobacco, also were reported as successful.

RELATED ARTICLE: Yoga for dermatologic conditions

RELATED VIDEO: Answering patient questions about diet

Psoriasis patients emphasized that an effective multimodal approach including drug, phototherapy, and nondrug therapies usually is done through trial and error based on each patient's individual needs. Dermatologists would benefit from knowing that nearly all participants in this public meeting indicated they value the benefits of nondrug therapies, and combination therapies using drug and nondrug therapies should be discussed with patients.

The psoriasis public meeting in March 2016 was the FDA's 18th patient-focused drug development meeting. The FDA sought this information to have a greater understanding of the burden of psoriasis on patients and the treatments currently used to treat psoriasis and its symptoms. This information will help guide the FDA as they consider future drug approvals.

Oral or injected medications for psoriasis can be burdensome for patients, making them inclined to use alternative therapies such as phototherapy and other nondrug therapies, according to a public meeting hosted by the US Food and Drug Administration (FDA) to hear patient perspectives on psoriasis. Approximately 70 psoriasis patients or patient representatives attended the meeting in person and others attended through a live webcast.

More than half of participants indicated that they have used phototherapy. Both positive and negative experiences were reported. One participant reported that a home UVB 3-panel light box "dramatically changed [his/her] life." Other participants indicated phototherapy was less successful for them. Participants also indicated fears about skin cancer.

RELATED ARTICLE: Does UVB phototherapy cause skin cancer?

However, several participants reported that phototherapy was more effective when used in combination with other medical therapies. Similarly, most participants indicated using 1 or more nondrug therapies to manage their psoriatic symptoms. Approximately one-third used over-the-counter products, such as coal tar, salicylic acid, and Epsom salt. Slightly more than one-fourth indicated the importance of complementary or alternative therapy, including exercise and meditation, to manage their psoriasis symptoms. Diet modifications, such as eliminating alcohol, sugar, processed foods, drugs, gluten, and tobacco, also were reported as successful.

RELATED ARTICLE: Yoga for dermatologic conditions

RELATED VIDEO: Answering patient questions about diet

Psoriasis patients emphasized that an effective multimodal approach including drug, phototherapy, and nondrug therapies usually is done through trial and error based on each patient's individual needs. Dermatologists would benefit from knowing that nearly all participants in this public meeting indicated they value the benefits of nondrug therapies, and combination therapies using drug and nondrug therapies should be discussed with patients.

The psoriasis public meeting in March 2016 was the FDA's 18th patient-focused drug development meeting. The FDA sought this information to have a greater understanding of the burden of psoriasis on patients and the treatments currently used to treat psoriasis and its symptoms. This information will help guide the FDA as they consider future drug approvals.