Cutis

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

To the Editor:

A 60-year-old woman with a history of lymphoma presented to the emergency department for evaluation of intermittent diarrhea and vomiting of 2 weeks’ duration. On presentation, a rather large dressing covering the entire right half of the face was noted. Removal of the bandage revealed a necrotic, extensively destructive, right-sided facial lesion with a fully exposed ocular globe (Figure 1). The patient lived alone and was accompanied by a neighbor, who disclosed that the lesion had been neglected and enlarged over the last 15 years. Moreover, the neighbor reported that the patient had recently experienced several episodes of vertigo and frequent falls.

On admission to the hospital, dermatology was consulted and initial workup included computed tomography (CT) scan of the head and maxillofacial region, which showed a destructive process involving the right frontotemporal bone, maxillofacial region, sphenoid, and skull base with exposure of intracranial contents (Figure 2). An aggressive wound care regimen was instituted. Biopsy of the wound margin revealed nodular and focally infiltrative basal cell carcinoma (BCC) (Figure 3). Culture of the necrotic bone grew Rhizopus, a causative organism of mucormycosis, and the patient was treated with posaconazole. A CT scan of the chest and abdomen showed multiple bilateral pulmonary nodules and necrotic lymph nodes in the left hilum and left axilla. The patient refused bronchoscopy to further evaluate the pulmonary nodules. Ultrasound-guided biopsy of the left axillarylymph node revealed metastatic disease (Figure 4).

Several days into her hospitalization, the patient developed radicular pain in both arms and weakness in all 4 extremities. A CT scan of the neck revealed a pathologic fracture of the C7 vertebrae. Several medical and surgical services as well as psychiatry were consulted. Given the extensive nature of the disease involvement with limited treatment options, the patient sought to forego further interventions and was discharged to hospice care.

Basal cell carcinomas rarely metastasize, with a reported incidence of 0.0028% to 0.5%.¹ The likelihood of metastasis is most closely related to tumor size and depth of invasion. Tumors greater than 3 cm in diameter have a 2% incidence of metastatic spread and/or death. The incidence of metastatic spread and/or death is estimated to be 25% for tumors with a diameter of 5 cm and 50% for tumors with a diameter of 10 cm or greater.² Other risk factors for metastatic spread include long duration of disease, failure to respond to conventional treatment, and prior radiation treatment in the affected area.¹ In one review, the median interval between onset of BCC and metastasis was 9 years.³ In our case, 15 years of neglect most likely led to the aggressiveness of the tumor. Although the workup in our patient was limited per her request, there was no evidence that her lymphoma had recurred or that she was in any other way immunocompromised. Unfortunately, in this patient’s case, the local destructiveness of the carcinoma with subsequent bony invasion and necrosis was complicated with secondary Rhizopus infection. A PubMed search of articles indexed for MEDLINE using the terms basal cell carcinoma and mucormycosis revealed no other reported cases of BCC associated with mucormycosis; therefore, our case represents a rare presentation of this association. Rhinocerebral mucormycosis is the most common manifestation of mucormycosis and more commonly occurs in diabetics with ketoacidosis and in severely debilitated or immunosuppressed individuals.⁴ The extensive bony destruction, especially of the nasal region, of our patient’s tumor likely led to secondary infection with Rhizopus.

Approximately 85% of all metastatic BCCs originate in the head and neck region, with lymph nodes being the first site of metastasis and involved in approximately half of all cases.^1,4 Metastases to the lungs, bone, liver, and other viscera can occur with advanced disease. Metastasis generally portends a poor prognosis, with survival rarely exceeding 1.5 years. Until recently, therapeutic options for metastatic disease were limited, with marginal response to chemotherapy with methotrexate, fluorouracil, bleomycin, and cisplatin.⁴ Vismodegib, a novel smoothened receptor inhibitor that blocks the sonic hedgehog pathway implicated in BCC carcinogenesis, offers a new promising treatment for management and control of advanced disease.⁵

To the Editor:

A 60-year-old woman with a history of lymphoma presented to the emergency department for evaluation of intermittent diarrhea and vomiting of 2 weeks’ duration. On presentation, a rather large dressing covering the entire right half of the face was noted. Removal of the bandage revealed a necrotic, extensively destructive, right-sided facial lesion with a fully exposed ocular globe (Figure 1). The patient lived alone and was accompanied by a neighbor, who disclosed that the lesion had been neglected and enlarged over the last 15 years. Moreover, the neighbor reported that the patient had recently experienced several episodes of vertigo and frequent falls.

On admission to the hospital, dermatology was consulted and initial workup included computed tomography (CT) scan of the head and maxillofacial region, which showed a destructive process involving the right frontotemporal bone, maxillofacial region, sphenoid, and skull base with exposure of intracranial contents (Figure 2). An aggressive wound care regimen was instituted. Biopsy of the wound margin revealed nodular and focally infiltrative basal cell carcinoma (BCC) (Figure 3). Culture of the necrotic bone grew Rhizopus, a causative organism of mucormycosis, and the patient was treated with posaconazole. A CT scan of the chest and abdomen showed multiple bilateral pulmonary nodules and necrotic lymph nodes in the left hilum and left axilla. The patient refused bronchoscopy to further evaluate the pulmonary nodules. Ultrasound-guided biopsy of the left axillarylymph node revealed metastatic disease (Figure 4).

Several days into her hospitalization, the patient developed radicular pain in both arms and weakness in all 4 extremities. A CT scan of the neck revealed a pathologic fracture of the C7 vertebrae. Several medical and surgical services as well as psychiatry were consulted. Given the extensive nature of the disease involvement with limited treatment options, the patient sought to forego further interventions and was discharged to hospice care.

Basal cell carcinomas rarely metastasize, with a reported incidence of 0.0028% to 0.5%.¹ The likelihood of metastasis is most closely related to tumor size and depth of invasion. Tumors greater than 3 cm in diameter have a 2% incidence of metastatic spread and/or death. The incidence of metastatic spread and/or death is estimated to be 25% for tumors with a diameter of 5 cm and 50% for tumors with a diameter of 10 cm or greater.² Other risk factors for metastatic spread include long duration of disease, failure to respond to conventional treatment, and prior radiation treatment in the affected area.¹ In one review, the median interval between onset of BCC and metastasis was 9 years.³ In our case, 15 years of neglect most likely led to the aggressiveness of the tumor. Although the workup in our patient was limited per her request, there was no evidence that her lymphoma had recurred or that she was in any other way immunocompromised. Unfortunately, in this patient’s case, the local destructiveness of the carcinoma with subsequent bony invasion and necrosis was complicated with secondary Rhizopus infection. A PubMed search of articles indexed for MEDLINE using the terms basal cell carcinoma and mucormycosis revealed no other reported cases of BCC associated with mucormycosis; therefore, our case represents a rare presentation of this association. Rhinocerebral mucormycosis is the most common manifestation of mucormycosis and more commonly occurs in diabetics with ketoacidosis and in severely debilitated or immunosuppressed individuals.⁴ The extensive bony destruction, especially of the nasal region, of our patient’s tumor likely led to secondary infection with Rhizopus.

Approximately 85% of all metastatic BCCs originate in the head and neck region, with lymph nodes being the first site of metastasis and involved in approximately half of all cases.^1,4 Metastases to the lungs, bone, liver, and other viscera can occur with advanced disease. Metastasis generally portends a poor prognosis, with survival rarely exceeding 1.5 years. Until recently, therapeutic options for metastatic disease were limited, with marginal response to chemotherapy with methotrexate, fluorouracil, bleomycin, and cisplatin.⁴ Vismodegib, a novel smoothened receptor inhibitor that blocks the sonic hedgehog pathway implicated in BCC carcinogenesis, offers a new promising treatment for management and control of advanced disease.⁵

To the Editor:

A 60-year-old woman with a history of lymphoma presented to the emergency department for evaluation of intermittent diarrhea and vomiting of 2 weeks’ duration. On presentation, a rather large dressing covering the entire right half of the face was noted. Removal of the bandage revealed a necrotic, extensively destructive, right-sided facial lesion with a fully exposed ocular globe (Figure 1). The patient lived alone and was accompanied by a neighbor, who disclosed that the lesion had been neglected and enlarged over the last 15 years. Moreover, the neighbor reported that the patient had recently experienced several episodes of vertigo and frequent falls.

On admission to the hospital, dermatology was consulted and initial workup included computed tomography (CT) scan of the head and maxillofacial region, which showed a destructive process involving the right frontotemporal bone, maxillofacial region, sphenoid, and skull base with exposure of intracranial contents (Figure 2). An aggressive wound care regimen was instituted. Biopsy of the wound margin revealed nodular and focally infiltrative basal cell carcinoma (BCC) (Figure 3). Culture of the necrotic bone grew Rhizopus, a causative organism of mucormycosis, and the patient was treated with posaconazole. A CT scan of the chest and abdomen showed multiple bilateral pulmonary nodules and necrotic lymph nodes in the left hilum and left axilla. The patient refused bronchoscopy to further evaluate the pulmonary nodules. Ultrasound-guided biopsy of the left axillarylymph node revealed metastatic disease (Figure 4).

Several days into her hospitalization, the patient developed radicular pain in both arms and weakness in all 4 extremities. A CT scan of the neck revealed a pathologic fracture of the C7 vertebrae. Several medical and surgical services as well as psychiatry were consulted. Given the extensive nature of the disease involvement with limited treatment options, the patient sought to forego further interventions and was discharged to hospice care.

Basal cell carcinomas rarely metastasize, with a reported incidence of 0.0028% to 0.5%.¹ The likelihood of metastasis is most closely related to tumor size and depth of invasion. Tumors greater than 3 cm in diameter have a 2% incidence of metastatic spread and/or death. The incidence of metastatic spread and/or death is estimated to be 25% for tumors with a diameter of 5 cm and 50% for tumors with a diameter of 10 cm or greater.² Other risk factors for metastatic spread include long duration of disease, failure to respond to conventional treatment, and prior radiation treatment in the affected area.¹ In one review, the median interval between onset of BCC and metastasis was 9 years.³ In our case, 15 years of neglect most likely led to the aggressiveness of the tumor. Although the workup in our patient was limited per her request, there was no evidence that her lymphoma had recurred or that she was in any other way immunocompromised. Unfortunately, in this patient’s case, the local destructiveness of the carcinoma with subsequent bony invasion and necrosis was complicated with secondary Rhizopus infection. A PubMed search of articles indexed for MEDLINE using the terms basal cell carcinoma and mucormycosis revealed no other reported cases of BCC associated with mucormycosis; therefore, our case represents a rare presentation of this association. Rhinocerebral mucormycosis is the most common manifestation of mucormycosis and more commonly occurs in diabetics with ketoacidosis and in severely debilitated or immunosuppressed individuals.⁴ The extensive bony destruction, especially of the nasal region, of our patient’s tumor likely led to secondary infection with Rhizopus.

Approximately 85% of all metastatic BCCs originate in the head and neck region, with lymph nodes being the first site of metastasis and involved in approximately half of all cases.^1,4 Metastases to the lungs, bone, liver, and other viscera can occur with advanced disease. Metastasis generally portends a poor prognosis, with survival rarely exceeding 1.5 years. Until recently, therapeutic options for metastatic disease were limited, with marginal response to chemotherapy with methotrexate, fluorouracil, bleomycin, and cisplatin.⁴ Vismodegib, a novel smoothened receptor inhibitor that blocks the sonic hedgehog pathway implicated in BCC carcinogenesis, offers a new promising treatment for management and control of advanced disease.⁵

In an era when we have access to a dizzying array of biologics for psoriasis treatment, it is easy to forget that topical therapies are still the bread and butter of treatment. For the majority of patients living with psoriasis, topical treatment is the only therapy they receive; indeed, a recent study examining a large national payer database found that 86% of psoriasis patients were managed with topical medications only.¹ Thus, it is extremely important to understand how to optimize topical treatments, recognize pitfalls in management, and utilize newer agents that can been added to our treatment armamentarium for psoriasis.

In general, steroids have been the mainstay of topical treatment of psoriasis. Their broad anti-inflammatory activity works well against both the visible signs and symptoms of psoriasis as well as the underlying inflammatory milieu of the disease; however, these treatments are not without their downsides. Hypothalamic-pituitary-adrenal (HPA) axis suppression, especially in higher-potency topical steroids, is a serious concern that limits their use. In one study comparing lotion and cream formulations of clobetasol propionate, HPA axis suppression was seen in 80% (8/10) of adults in the lotion group and 30% (3/10) in the cream group after 4 weeks of treatment.² These findings are not new; a 1987 study found that patients using less than 50 g of topical clobetasol per week, which is considered a low dose, could still exhibit HPA axis suppression.³ Severe HPA axis suppression may occur; one study of various topical steroids found some degree of HPA axis suppression in 38% (19/50) of patients, with a direct correlation with topical steroid potency.⁴ Additionally, cutaneous side effects such as striae formation, atrophy, and the possibility of tachyphylaxis must be considered. Various treatment regimens have been developed to limit topical steroid use, including steroid-sparing medications (eg, calcipotriene) used in conjunction with topical steroids, systemic treatments (eg, phototherapy) added on, or higher-potency topical steroids rotated with lower-potency steroids. Implementing other agents, such as topical retinoids or keratolytics, into the treatment regimen also is an important consideration in the overall approach to topical psoriasis therapy.

Notably, a number of newly approved topical treatments for psoriasis have emerged, and more are in the pipeline. When evaluating these agents, important considerations include safety, length of treatment course, and efficacy. Several of these agents hold promise for patients with psoriasis.

The newest agent, halobetasol propionate lotion 0.01%, was approved for treatment of psoriasis in October 2018. Compared to halobetasol 0.05% cream or ointment, halobetasol propionate lotion 0.01% has one-fifth the concentration of the active ingredient with the same degree of success in efficacy scores.⁹ This reduction in drug concentration is possible because the proprietary lotion base allows for better drug delivery of the active ingredient. Importantly, HPA axis suppression was assessed over an 8-week period of use and no suppression was noted.⁹ Generic class I steroids should only be used for 2 weeks, which is the standard treatment period used in comparator trials; however, many patients will still have active lesions on their body after 2 weeks of treatment, and if using generic clobetasol or betamethasone dipropionate, the choice becomes whether to keep applying the medication and risk HPA axis suppression and cutaneous side effects or switch to a less effective treatment. However, some of the newer agents are indicated for 4 to 8 weeks of treatment.

Utilizing other classes of agents such as retinoids and keratolytics in our treatment armamentarium for psoriasis often is helpful. It has long been known that tazarotene can be combined with topical steroids for increased efficacy and limitation of the irritating effects of the retinoid.¹⁰ Similarly, keratolytics play a role in allowing a topically applied medication to penetrate deep enough to affect the underlying inflammation of psoriasis. Medications that include salicylic acid or urea may help to remove ostraceous scales from thick psoriasis lesions that would otherwise prevent delivery of topical steroids to achieve clinically meaningful results. For scalp psoriasis, there are salicylic acid solutions as well as newer agents such as a dimethicone-based topical product.¹¹

Nonsteroidal topical anti-inflammatories also have been used off label for psoriasis treatment. These agents are especially useful in patients who were not successfully treated with calcipotriene or need adjunctive therapy. Although not extremely effective against plaque psoriasis, topical tacrolimus in particular seems to have a place in the treatment of inverse psoriasis where it can be utilized without concern for long-term side effects.¹² Crisaborole ointment, a topical medication approved for treatment of atopic dermatitis, was studied in phase 2 trials, but development has not progressed for a psoriasis indication.¹³ It is reasonable to consider this medication in the same way that tacrolimus has been used, however, considering that the mechanism of action—phosphodiesterase type 4 inhibition—has successfully been implemented in an oral medication to treat psoriasis, apremilast.

There are numerous topical medications in the pipeline that are being developed to treat psoriasis. Of them, the most relevant is a fixed-dose combination of halobetasol propionate 0.01% and tazarotene 0.045% in a proprietary lotion vehicle. A decision from the US Food and Drug Administration is expected in the first quarter of 2019. This medication capitalizes on the aforementioned synergistic effects of tazarotene and a superpotent topical steroid to achieve improved efficacy. Similar to halobetasol lotion 0.01%, this product was evaluated over an 8-week period, and no HPA axis suppression was observed. Efficacy was significantly improved versus both placebo and either halobetasol or tazarotene alone.¹⁴

Overall, it is promising that after a long period of relative stagnancy, we have numerous new agents available and upcoming for the topical treatment of psoriasis. For the vast majority of patients, topical medications still represent the mainstay of treatment, and it is important that we have access to better, safer medications in this category.

In an era when we have access to a dizzying array of biologics for psoriasis treatment, it is easy to forget that topical therapies are still the bread and butter of treatment. For the majority of patients living with psoriasis, topical treatment is the only therapy they receive; indeed, a recent study examining a large national payer database found that 86% of psoriasis patients were managed with topical medications only.¹ Thus, it is extremely important to understand how to optimize topical treatments, recognize pitfalls in management, and utilize newer agents that can been added to our treatment armamentarium for psoriasis.

In general, steroids have been the mainstay of topical treatment of psoriasis. Their broad anti-inflammatory activity works well against both the visible signs and symptoms of psoriasis as well as the underlying inflammatory milieu of the disease; however, these treatments are not without their downsides. Hypothalamic-pituitary-adrenal (HPA) axis suppression, especially in higher-potency topical steroids, is a serious concern that limits their use. In one study comparing lotion and cream formulations of clobetasol propionate, HPA axis suppression was seen in 80% (8/10) of adults in the lotion group and 30% (3/10) in the cream group after 4 weeks of treatment.² These findings are not new; a 1987 study found that patients using less than 50 g of topical clobetasol per week, which is considered a low dose, could still exhibit HPA axis suppression.³ Severe HPA axis suppression may occur; one study of various topical steroids found some degree of HPA axis suppression in 38% (19/50) of patients, with a direct correlation with topical steroid potency.⁴ Additionally, cutaneous side effects such as striae formation, atrophy, and the possibility of tachyphylaxis must be considered. Various treatment regimens have been developed to limit topical steroid use, including steroid-sparing medications (eg, calcipotriene) used in conjunction with topical steroids, systemic treatments (eg, phototherapy) added on, or higher-potency topical steroids rotated with lower-potency steroids. Implementing other agents, such as topical retinoids or keratolytics, into the treatment regimen also is an important consideration in the overall approach to topical psoriasis therapy.

Notably, a number of newly approved topical treatments for psoriasis have emerged, and more are in the pipeline. When evaluating these agents, important considerations include safety, length of treatment course, and efficacy. Several of these agents hold promise for patients with psoriasis.

The newest agent, halobetasol propionate lotion 0.01%, was approved for treatment of psoriasis in October 2018. Compared to halobetasol 0.05% cream or ointment, halobetasol propionate lotion 0.01% has one-fifth the concentration of the active ingredient with the same degree of success in efficacy scores.⁹ This reduction in drug concentration is possible because the proprietary lotion base allows for better drug delivery of the active ingredient. Importantly, HPA axis suppression was assessed over an 8-week period of use and no suppression was noted.⁹ Generic class I steroids should only be used for 2 weeks, which is the standard treatment period used in comparator trials; however, many patients will still have active lesions on their body after 2 weeks of treatment, and if using generic clobetasol or betamethasone dipropionate, the choice becomes whether to keep applying the medication and risk HPA axis suppression and cutaneous side effects or switch to a less effective treatment. However, some of the newer agents are indicated for 4 to 8 weeks of treatment.

Utilizing other classes of agents such as retinoids and keratolytics in our treatment armamentarium for psoriasis often is helpful. It has long been known that tazarotene can be combined with topical steroids for increased efficacy and limitation of the irritating effects of the retinoid.¹⁰ Similarly, keratolytics play a role in allowing a topically applied medication to penetrate deep enough to affect the underlying inflammation of psoriasis. Medications that include salicylic acid or urea may help to remove ostraceous scales from thick psoriasis lesions that would otherwise prevent delivery of topical steroids to achieve clinically meaningful results. For scalp psoriasis, there are salicylic acid solutions as well as newer agents such as a dimethicone-based topical product.¹¹

Nonsteroidal topical anti-inflammatories also have been used off label for psoriasis treatment. These agents are especially useful in patients who were not successfully treated with calcipotriene or need adjunctive therapy. Although not extremely effective against plaque psoriasis, topical tacrolimus in particular seems to have a place in the treatment of inverse psoriasis where it can be utilized without concern for long-term side effects.¹² Crisaborole ointment, a topical medication approved for treatment of atopic dermatitis, was studied in phase 2 trials, but development has not progressed for a psoriasis indication.¹³ It is reasonable to consider this medication in the same way that tacrolimus has been used, however, considering that the mechanism of action—phosphodiesterase type 4 inhibition—has successfully been implemented in an oral medication to treat psoriasis, apremilast.

There are numerous topical medications in the pipeline that are being developed to treat psoriasis. Of them, the most relevant is a fixed-dose combination of halobetasol propionate 0.01% and tazarotene 0.045% in a proprietary lotion vehicle. A decision from the US Food and Drug Administration is expected in the first quarter of 2019. This medication capitalizes on the aforementioned synergistic effects of tazarotene and a superpotent topical steroid to achieve improved efficacy. Similar to halobetasol lotion 0.01%, this product was evaluated over an 8-week period, and no HPA axis suppression was observed. Efficacy was significantly improved versus both placebo and either halobetasol or tazarotene alone.¹⁴

Overall, it is promising that after a long period of relative stagnancy, we have numerous new agents available and upcoming for the topical treatment of psoriasis. For the vast majority of patients, topical medications still represent the mainstay of treatment, and it is important that we have access to better, safer medications in this category.

In an era when we have access to a dizzying array of biologics for psoriasis treatment, it is easy to forget that topical therapies are still the bread and butter of treatment. For the majority of patients living with psoriasis, topical treatment is the only therapy they receive; indeed, a recent study examining a large national payer database found that 86% of psoriasis patients were managed with topical medications only.¹ Thus, it is extremely important to understand how to optimize topical treatments, recognize pitfalls in management, and utilize newer agents that can been added to our treatment armamentarium for psoriasis.

In general, steroids have been the mainstay of topical treatment of psoriasis. Their broad anti-inflammatory activity works well against both the visible signs and symptoms of psoriasis as well as the underlying inflammatory milieu of the disease; however, these treatments are not without their downsides. Hypothalamic-pituitary-adrenal (HPA) axis suppression, especially in higher-potency topical steroids, is a serious concern that limits their use. In one study comparing lotion and cream formulations of clobetasol propionate, HPA axis suppression was seen in 80% (8/10) of adults in the lotion group and 30% (3/10) in the cream group after 4 weeks of treatment.² These findings are not new; a 1987 study found that patients using less than 50 g of topical clobetasol per week, which is considered a low dose, could still exhibit HPA axis suppression.³ Severe HPA axis suppression may occur; one study of various topical steroids found some degree of HPA axis suppression in 38% (19/50) of patients, with a direct correlation with topical steroid potency.⁴ Additionally, cutaneous side effects such as striae formation, atrophy, and the possibility of tachyphylaxis must be considered. Various treatment regimens have been developed to limit topical steroid use, including steroid-sparing medications (eg, calcipotriene) used in conjunction with topical steroids, systemic treatments (eg, phototherapy) added on, or higher-potency topical steroids rotated with lower-potency steroids. Implementing other agents, such as topical retinoids or keratolytics, into the treatment regimen also is an important consideration in the overall approach to topical psoriasis therapy.

Notably, a number of newly approved topical treatments for psoriasis have emerged, and more are in the pipeline. When evaluating these agents, important considerations include safety, length of treatment course, and efficacy. Several of these agents hold promise for patients with psoriasis.

The newest agent, halobetasol propionate lotion 0.01%, was approved for treatment of psoriasis in October 2018. Compared to halobetasol 0.05% cream or ointment, halobetasol propionate lotion 0.01% has one-fifth the concentration of the active ingredient with the same degree of success in efficacy scores.⁹ This reduction in drug concentration is possible because the proprietary lotion base allows for better drug delivery of the active ingredient. Importantly, HPA axis suppression was assessed over an 8-week period of use and no suppression was noted.⁹ Generic class I steroids should only be used for 2 weeks, which is the standard treatment period used in comparator trials; however, many patients will still have active lesions on their body after 2 weeks of treatment, and if using generic clobetasol or betamethasone dipropionate, the choice becomes whether to keep applying the medication and risk HPA axis suppression and cutaneous side effects or switch to a less effective treatment. However, some of the newer agents are indicated for 4 to 8 weeks of treatment.

Utilizing other classes of agents such as retinoids and keratolytics in our treatment armamentarium for psoriasis often is helpful. It has long been known that tazarotene can be combined with topical steroids for increased efficacy and limitation of the irritating effects of the retinoid.¹⁰ Similarly, keratolytics play a role in allowing a topically applied medication to penetrate deep enough to affect the underlying inflammation of psoriasis. Medications that include salicylic acid or urea may help to remove ostraceous scales from thick psoriasis lesions that would otherwise prevent delivery of topical steroids to achieve clinically meaningful results. For scalp psoriasis, there are salicylic acid solutions as well as newer agents such as a dimethicone-based topical product.¹¹

Nonsteroidal topical anti-inflammatories also have been used off label for psoriasis treatment. These agents are especially useful in patients who were not successfully treated with calcipotriene or need adjunctive therapy. Although not extremely effective against plaque psoriasis, topical tacrolimus in particular seems to have a place in the treatment of inverse psoriasis where it can be utilized without concern for long-term side effects.¹² Crisaborole ointment, a topical medication approved for treatment of atopic dermatitis, was studied in phase 2 trials, but development has not progressed for a psoriasis indication.¹³ It is reasonable to consider this medication in the same way that tacrolimus has been used, however, considering that the mechanism of action—phosphodiesterase type 4 inhibition—has successfully been implemented in an oral medication to treat psoriasis, apremilast.

There are numerous topical medications in the pipeline that are being developed to treat psoriasis. Of them, the most relevant is a fixed-dose combination of halobetasol propionate 0.01% and tazarotene 0.045% in a proprietary lotion vehicle. A decision from the US Food and Drug Administration is expected in the first quarter of 2019. This medication capitalizes on the aforementioned synergistic effects of tazarotene and a superpotent topical steroid to achieve improved efficacy. Similar to halobetasol lotion 0.01%, this product was evaluated over an 8-week period, and no HPA axis suppression was observed. Efficacy was significantly improved versus both placebo and either halobetasol or tazarotene alone.¹⁴

Overall, it is promising that after a long period of relative stagnancy, we have numerous new agents available and upcoming for the topical treatment of psoriasis. For the vast majority of patients, topical medications still represent the mainstay of treatment, and it is important that we have access to better, safer medications in this category.

The Diagnosis: Metastatic Cancer

Further workup of patient 1 revealed an alkaline phosphatase level of 743 U/L (reference range, 30–120 U/L), total bilirubin level of 8.5 mg/dL (reference range, 0.3–1.2 mg/dL), and a white blood cell count of 14,000/μL (reference range, 4500–11,000/μL). Computed tomography of the abdomen and pelvis demonstrated cancer of unknown primary site that had metastasized to the colon, liver, and lungs. There was suspicion for potential colon cancer as the primary disease; however, based on the cutaneous findings, a skin biopsy was performed to confirm the diagnosis. Histology and immunohistochemistry revealed adenocarcinoma tumor cells positive for CDX2 (caudal type homeobox 2) and cytokeratin (CK) 7 with a subset positive for CK-20. The cells were negative for estrogen receptor, progesterone receptor, mammaglobin, gross cystic disease fluid protein, and GATA3 (GATA binding protein 3). Immunohistochemistry was most consistent with pancreatic cancer. During palliative percutaneous transhepatic biliary drainage placement, a liver biopsy confirmed the skin biopsy results.

Further workup of patient 2 revealed a white blood cell count of 13,000/μL (reference range, 4500–11,000/μL). Computed tomography of the chest, abdomen, and pelvis revealed metastatic disease to the lungs with a suspicion for colon cancer as the primary site. Biopsy of the skin lesion revealed a mucin-producing adenocarcinoma, and immunohistochemistry was positive for keratin (AE1/AE3), CK-20, and CDX2, consistent with metastatic colon carcinoma. Immunohistochemistry of the biopsied skin lesion was nonreactive for CK-7. The patient had a colonoscopy that revealed a fungating, partially obstructing, circumferential large mass in the ascending colon.

Metastasis to the skin from visceral malignancies is not uncommon and may represent the first evidence of widespread disease, particularly in breast cancer or mucosal cancers of the head and neck.¹ Cutaneous metastasis of colon cancer is uncommon and cutaneous metastasis of pancreatic cancer is rare. Furthermore, nonumbilical sites are much more common than umbilical sites for cutaneous metastatic disease.² Pancreatic cancer is estimated to be the origin of a cutaneous umbilical metastasis, frequently termed Sister Mary Joseph nodule, in 7% to 9% of cases; colon cancer is estimated to account for 13% to 15% of cases.³ Sister Mary Joseph nodule or sign refers to a nodule often bulging into the umbilicus, signifying metastasis from a
malignant cancer.

In a study of cutaneous metastases, 10% (42/420) of patients with metastatic disease had cutaneous metastasis; 0.48% (2/420) were due to pancreatic cancer and 4.3% (18/420) were due to colon cancer.⁴ In another review, 63 cases of cutaneous metastasis of pancreatic cancer were found, 43 of which were nonumbilical.² 

On immunohistochemistry, CK-7 positivity is highly specific for pancreatic cancer.² Cytokeratin 7 often is used in conjunction with CK-20 to differentiate various types of glandular tumors. CDX2 is a highly sensitive and specific marker for adenocarcinomas of intestinal origin.⁵ The negative estrogen receptor, progesterone receptor, mammaglobin, gross cystic disease fluid protein, and GATA3 stains are useful in excluding breast cancer (patient 1 had history of breast cancer).

When cutaneous involvement is present in pancreatic cancer, the disease usually is widespread. Multiple studies have reported involvement of other organs with cutaneous metastasis at rates of 88.9%,6 90.3%,7 and 93.5%.² However, early recognition of metastatic cancerous lesions can lead to earlier diagnosis and earlier palliative treatment, perhaps prolonging median survival time in patients. In a review of 63 patients with cutaneous metastatic pancreatic cancer, the authors found a median survival time of 5 months, with surgery, chemotherapy, radiation therapy, or a combination helping to improve survival time from a median of 3.0 to 8.3 months.²

The location of lesions and duration of disease in both patients was atypical for arthropod assault. Acyclovir-resistant herpes zoster rarely is reported outside of human immunodeficiency patients; in addition, there was a lack of clear dermatomal distribution. Although cutaneous Crohn disease can manifest as pink papules, it is rare and unlikely as a presenting symptom. Cutaneous sarcoidosis can take many different skin manifestations, and patients can have cutaneous involvement without systemic manifestation. In both patients, medical history was more indicative of metastatic cancer than the other options in the differential diagnosis.

Cutaneous metastasis from colon cancer and pancreatic cancer is rare, and the prognosis is poor in these cases; however, in the appropriate clinical scenario, especially in a patient with a history of cancer, sinister etiologies should be considered for firm red papules of the umbilicus. Skin biopsy coupled with immunohistochemical staining can assist in identifying the primary malignancy.

The Diagnosis: Metastatic Cancer

Further workup of patient 1 revealed an alkaline phosphatase level of 743 U/L (reference range, 30–120 U/L), total bilirubin level of 8.5 mg/dL (reference range, 0.3–1.2 mg/dL), and a white blood cell count of 14,000/μL (reference range, 4500–11,000/μL). Computed tomography of the abdomen and pelvis demonstrated cancer of unknown primary site that had metastasized to the colon, liver, and lungs. There was suspicion for potential colon cancer as the primary disease; however, based on the cutaneous findings, a skin biopsy was performed to confirm the diagnosis. Histology and immunohistochemistry revealed adenocarcinoma tumor cells positive for CDX2 (caudal type homeobox 2) and cytokeratin (CK) 7 with a subset positive for CK-20. The cells were negative for estrogen receptor, progesterone receptor, mammaglobin, gross cystic disease fluid protein, and GATA3 (GATA binding protein 3). Immunohistochemistry was most consistent with pancreatic cancer. During palliative percutaneous transhepatic biliary drainage placement, a liver biopsy confirmed the skin biopsy results.

Further workup of patient 2 revealed a white blood cell count of 13,000/μL (reference range, 4500–11,000/μL). Computed tomography of the chest, abdomen, and pelvis revealed metastatic disease to the lungs with a suspicion for colon cancer as the primary site. Biopsy of the skin lesion revealed a mucin-producing adenocarcinoma, and immunohistochemistry was positive for keratin (AE1/AE3), CK-20, and CDX2, consistent with metastatic colon carcinoma. Immunohistochemistry of the biopsied skin lesion was nonreactive for CK-7. The patient had a colonoscopy that revealed a fungating, partially obstructing, circumferential large mass in the ascending colon.

Metastasis to the skin from visceral malignancies is not uncommon and may represent the first evidence of widespread disease, particularly in breast cancer or mucosal cancers of the head and neck.¹ Cutaneous metastasis of colon cancer is uncommon and cutaneous metastasis of pancreatic cancer is rare. Furthermore, nonumbilical sites are much more common than umbilical sites for cutaneous metastatic disease.² Pancreatic cancer is estimated to be the origin of a cutaneous umbilical metastasis, frequently termed Sister Mary Joseph nodule, in 7% to 9% of cases; colon cancer is estimated to account for 13% to 15% of cases.³ Sister Mary Joseph nodule or sign refers to a nodule often bulging into the umbilicus, signifying metastasis from a
malignant cancer.

In a study of cutaneous metastases, 10% (42/420) of patients with metastatic disease had cutaneous metastasis; 0.48% (2/420) were due to pancreatic cancer and 4.3% (18/420) were due to colon cancer.⁴ In another review, 63 cases of cutaneous metastasis of pancreatic cancer were found, 43 of which were nonumbilical.² 

On immunohistochemistry, CK-7 positivity is highly specific for pancreatic cancer.² Cytokeratin 7 often is used in conjunction with CK-20 to differentiate various types of glandular tumors. CDX2 is a highly sensitive and specific marker for adenocarcinomas of intestinal origin.⁵ The negative estrogen receptor, progesterone receptor, mammaglobin, gross cystic disease fluid protein, and GATA3 stains are useful in excluding breast cancer (patient 1 had history of breast cancer).

When cutaneous involvement is present in pancreatic cancer, the disease usually is widespread. Multiple studies have reported involvement of other organs with cutaneous metastasis at rates of 88.9%,6 90.3%,7 and 93.5%.² However, early recognition of metastatic cancerous lesions can lead to earlier diagnosis and earlier palliative treatment, perhaps prolonging median survival time in patients. In a review of 63 patients with cutaneous metastatic pancreatic cancer, the authors found a median survival time of 5 months, with surgery, chemotherapy, radiation therapy, or a combination helping to improve survival time from a median of 3.0 to 8.3 months.²

The location of lesions and duration of disease in both patients was atypical for arthropod assault. Acyclovir-resistant herpes zoster rarely is reported outside of human immunodeficiency patients; in addition, there was a lack of clear dermatomal distribution. Although cutaneous Crohn disease can manifest as pink papules, it is rare and unlikely as a presenting symptom. Cutaneous sarcoidosis can take many different skin manifestations, and patients can have cutaneous involvement without systemic manifestation. In both patients, medical history was more indicative of metastatic cancer than the other options in the differential diagnosis.

Cutaneous metastasis from colon cancer and pancreatic cancer is rare, and the prognosis is poor in these cases; however, in the appropriate clinical scenario, especially in a patient with a history of cancer, sinister etiologies should be considered for firm red papules of the umbilicus. Skin biopsy coupled with immunohistochemical staining can assist in identifying the primary malignancy.

The Diagnosis: Metastatic Cancer

Further workup of patient 1 revealed an alkaline phosphatase level of 743 U/L (reference range, 30–120 U/L), total bilirubin level of 8.5 mg/dL (reference range, 0.3–1.2 mg/dL), and a white blood cell count of 14,000/μL (reference range, 4500–11,000/μL). Computed tomography of the abdomen and pelvis demonstrated cancer of unknown primary site that had metastasized to the colon, liver, and lungs. There was suspicion for potential colon cancer as the primary disease; however, based on the cutaneous findings, a skin biopsy was performed to confirm the diagnosis. Histology and immunohistochemistry revealed adenocarcinoma tumor cells positive for CDX2 (caudal type homeobox 2) and cytokeratin (CK) 7 with a subset positive for CK-20. The cells were negative for estrogen receptor, progesterone receptor, mammaglobin, gross cystic disease fluid protein, and GATA3 (GATA binding protein 3). Immunohistochemistry was most consistent with pancreatic cancer. During palliative percutaneous transhepatic biliary drainage placement, a liver biopsy confirmed the skin biopsy results.

Further workup of patient 2 revealed a white blood cell count of 13,000/μL (reference range, 4500–11,000/μL). Computed tomography of the chest, abdomen, and pelvis revealed metastatic disease to the lungs with a suspicion for colon cancer as the primary site. Biopsy of the skin lesion revealed a mucin-producing adenocarcinoma, and immunohistochemistry was positive for keratin (AE1/AE3), CK-20, and CDX2, consistent with metastatic colon carcinoma. Immunohistochemistry of the biopsied skin lesion was nonreactive for CK-7. The patient had a colonoscopy that revealed a fungating, partially obstructing, circumferential large mass in the ascending colon.

Metastasis to the skin from visceral malignancies is not uncommon and may represent the first evidence of widespread disease, particularly in breast cancer or mucosal cancers of the head and neck.¹ Cutaneous metastasis of colon cancer is uncommon and cutaneous metastasis of pancreatic cancer is rare. Furthermore, nonumbilical sites are much more common than umbilical sites for cutaneous metastatic disease.² Pancreatic cancer is estimated to be the origin of a cutaneous umbilical metastasis, frequently termed Sister Mary Joseph nodule, in 7% to 9% of cases; colon cancer is estimated to account for 13% to 15% of cases.³ Sister Mary Joseph nodule or sign refers to a nodule often bulging into the umbilicus, signifying metastasis from a
malignant cancer.

In a study of cutaneous metastases, 10% (42/420) of patients with metastatic disease had cutaneous metastasis; 0.48% (2/420) were due to pancreatic cancer and 4.3% (18/420) were due to colon cancer.⁴ In another review, 63 cases of cutaneous metastasis of pancreatic cancer were found, 43 of which were nonumbilical.² 

On immunohistochemistry, CK-7 positivity is highly specific for pancreatic cancer.² Cytokeratin 7 often is used in conjunction with CK-20 to differentiate various types of glandular tumors. CDX2 is a highly sensitive and specific marker for adenocarcinomas of intestinal origin.⁵ The negative estrogen receptor, progesterone receptor, mammaglobin, gross cystic disease fluid protein, and GATA3 stains are useful in excluding breast cancer (patient 1 had history of breast cancer).

When cutaneous involvement is present in pancreatic cancer, the disease usually is widespread. Multiple studies have reported involvement of other organs with cutaneous metastasis at rates of 88.9%,6 90.3%,7 and 93.5%.² However, early recognition of metastatic cancerous lesions can lead to earlier diagnosis and earlier palliative treatment, perhaps prolonging median survival time in patients. In a review of 63 patients with cutaneous metastatic pancreatic cancer, the authors found a median survival time of 5 months, with surgery, chemotherapy, radiation therapy, or a combination helping to improve survival time from a median of 3.0 to 8.3 months.²

The location of lesions and duration of disease in both patients was atypical for arthropod assault. Acyclovir-resistant herpes zoster rarely is reported outside of human immunodeficiency patients; in addition, there was a lack of clear dermatomal distribution. Although cutaneous Crohn disease can manifest as pink papules, it is rare and unlikely as a presenting symptom. Cutaneous sarcoidosis can take many different skin manifestations, and patients can have cutaneous involvement without systemic manifestation. In both patients, medical history was more indicative of metastatic cancer than the other options in the differential diagnosis.

Cutaneous metastasis from colon cancer and pancreatic cancer is rare, and the prognosis is poor in these cases; however, in the appropriate clinical scenario, especially in a patient with a history of cancer, sinister etiologies should be considered for firm red papules of the umbilicus. Skin biopsy coupled with immunohistochemical staining can assist in identifying the primary malignancy.

Limb amputation is a major life-changing event that markedly affects a patient’s quality of life as well as his/her ability to participate in activities of daily living. The most prevalent causes for amputation include vascular diseases, diabetes mellitus, trauma, and cancer, respectively.^1,2 For amputees, maintaining prosthetic use is a major physical and psychological undertaking that benefits from a multidisciplinary team approach. Although individuals with lower limb amputations are disproportionately impacted by skin disease due to the increased mechanical forces exerted over the lower limbs, patients with upper limb amputations also develop dermatologic conditions secondary to wearing prostheses.

Approximately 185,000 amputations occur each year in the United States.³ Although amputations resulting from peripheral vascular disease or diabetes mellitus tend to occur in older individuals, amputations in younger patients usually occur from trauma.² The US military has experienced increasing numbers of amputations from trauma due to the ongoing combat operations in the Middle East. Although improvements in body armor and tactical combat casualty care have reduced the number of preventable deaths, the number of casualties surviving with extremity injuries requiring amputation has increased.^4,5 As of October 2017, 1705 US servicemembers underwent major limb amputations, with 1914 lower limb amputations and 302 upper limb amputations. These amputations mainly impacted men aged 21 to 29 years, but female servicemembers also were affected, and a small group of servicemembers had multiple amputations.⁶

One of the most common medical problems that amputees face during long-term care is skin disease, with approximately 75% of amputees using a lower limb prosthesis experiencing skin problems. In general, amputees experience nearly 65% more dermatologic concerns than the general population.⁷ In one study of 97 individuals with transfemoral amputations, some of the most common issues associated with socket prosthetics included heat and sweating in the prosthetic socket (72%) as well as sores and skin irritation from the socket (62%).⁸ Given the high incidence of skin disease on residual limbs, dermatologists are uniquely positioned to keep the amputee in his/her prosthesis and prevent prosthetic abandonment.

Complications Following Amputation

Although US military servicemembers who undergo amputations receive the very best prosthetic devices and rehabilitation resources, they still experience prosthesis abandonment.⁹ Despite the fact that prosthetic limbs and prosthesis technology have substantially improved over the last 2 decades, one study indicated that the high frequency of problems affecting tissue viability at residual limbs is due to the age-old problem of prosthetic fit.¹⁰ In patients with the most advanced prostheses, poor fit still results in mechanical damage to the skin, as the residual limb is exposed to unequal and shearing forces across the amputation site as well as high pressures that cause a vaso-occlusive effect.^11,12 Issues with poor fit are especially important for more active patients, as they normally want to immediately return to their vigorous preinjury lifestyles. In these patients, even a properly fitting prosthetic may not be able to overcome the fact that the residual limb skin is not well suited for the mechanical forces generated by the prosthesis and the humid environment of the socket.^1,13 Another complicating factor is the dynamic nature of the residual limb. Muscle atrophy, changes in gait, and weight gain or loss can lead to an ill-fitting prosthetic and subsequent skin breakdown.

There are many case reports and review articles describing the skin problems in amputees.^1,14-17 The Table summarizes these conditions and outlines treatment options for each.^15,18-20

Most skin diseases on residual limbs are the result of mechanical skin breakdown, inflammation, infection, or combinations of these processes. Overall, amputees with diabetes mellitus and peripheral vascular disease tend to have skin disease related to poor perfusion, whereas amputees who are active and healthy tend to have conditions related to mechanical stress.^{7,13,14,17,21,22} Bui et al¹⁷ reported ulcers, abscesses, and blisters as the most common skin conditions that occur at the site of residual limbs; however, other less common dermatologic disorders such as skin malignancies, verrucous hyperplasia and carcinoma, granulomatous cutaneous lesions, acroangiodermatitis, and bullous pemphigoid also are seen.^23-26 Buikema and Meyerle¹⁵ hypothesize that these conditions, as well as the more common skin diseases, are partly from the amputation disrupting blood and lymphatic flow in the residual limb, which causes the site to act as an immunocompromised district that induces dysregulation of neuroimmune regulators.

It is important to note that skin disease on residual limbs is not just an acute problem. Long-term follow-up of 247 traumatic amputees from the Vietnam War showed that almost half of prosthesis users (48.2%) reported a skin problem in the preceding year, more than 38 years after the amputation. Additionally, one-quarter of these individuals experienced skin problems approximately 50% of the time, which unfortunately led to limited use or total abandonment of the prosthesis for the preceding year in 56% of the veterans surveyed.²¹

Other complications following amputation indirectly lead to skin problems. Heterotopic ossification, or the formation of bone at extraskeletal sites, has been observed in up to 65% of military amputees from recent operations in Iraq and Afghanistan.^27,28 If symptomatic, heterotopic ossification can lead to poor prosthetic fit and subsequent skin breakdown. As a result, it has been reported that up to 40% of combat-related lower extremity amputations may require excision of heterotopic ossificiation.²⁹

Amputation also can result in psychologic concerns that indirectly affect skin health. A systematic review by Mckechnie and John³⁰ suggested that despite heterogeneity between studies, even using the lowest figures demonstrated the significance anxiety and depression play in the lives of traumatic amputees. If left untreated, these mental health issues can lead to poor residual limb hygiene and prosthetic maintenance due to reductions in the patient’s energy and motivation. Studies have shown that proper hygiene of residual limbs and silicone liners reduces associated skin problems.^19,31

Role of the Dermatologist

Routine care and conservative management of amputee skin problems often are accomplished by prosthetists, primary care physicians, nurses, and physical therapists. In one study, more than 80% of the most common skin problems affecting amputees could be attributed to the prosthesis itself, which highlights the importance of the continued involvement of the prosthetist beyond the initial fitting period.¹³ However, when a skin problem becomes refractory to conservative management, referral to a dermatologist is prudent; therefore, the dermatologist is an integral member of the multidisciplinary team that provides care for amputees.

The dermatologist often is best positioned to diagnose skin diseases that result from wearing prostheses and is well versed in treatments for short-term and long-term management of skin disease on residual limbs. The dermatologist also can offer prophylactic treatments to decrease sweating and hair growth to prevent potential infections and subsequent skin breakdown. Additionally, proper education on self-care has been shown to decrease the amount of skin problems and increase functional status and quality of life for amputees.^32,33 Dermatologists can assist with the patient education process as well as refer amputees to a useful resource from the Amputee Coalition website (www.amputee-coalition.org) to provide specific patient education on how to maintain skin on the residual limb to prevent skin disease.

Current Treatments and Future Directions

Skin disorders affecting residual limbs usually are conditions that dermatologists commonly encounter and are comfortable managing in general practice. Additionally, dermatologists routinely treat hyperhidrosis and conduct laser hair removal, both of which are effective prophylactic adjuncts for amputee skin health. There are a few treatments for reducing residual limb hyperhidrosis that are particularly useful. Although first-line treatment of residual limb hyperhidrosis often is topical aluminum chloride, it requires frequent application and often causes considerable skin irritation when applied to residual limbs. Alternatively, intradermal botulinum toxin has been shown to successfully reduce sweat production in individuals with residual limb hyperhidrosis and is well tolerated.³⁴ A 2017 case report discussed the use of microwave thermal ablation of eccrine coils using a noninvasive 3-step hyperhidrosis treatment system on a bilateral below-the-knee amputee. The authors reported the patient tolerated the procedure well with decreased dermatitis and folliculitis, leading to his ability to wear a prosthetic for longer periods of time.³⁵

Ablative fractional resurfacing with a CO₂ laser is another key treatment modality central to amputees, more specifically to traumatic amputees. A CO₂ laser can decrease skin tension and increase skin mobility associated with traumatic scars as well as decrease skin vulnerability to biofilms present in chronic wounds on residual limbs. It is believed that the pattern of injury caused by ablative fractional lasers disrupts biofilms and stimulates growth factor secretion and collagen remodeling through the concept of photomicrodebridement.³⁶ The ablative fractional resurfacing approach to scar therapy and chronic wound debridement can result in less skin injury, allowing the amputee to continue rehabilitation and return more quickly to prosthetic use.³⁷

One interesting area of research in amputee care involves the study of novel ways to increase the skin’s ability to adapt to mechanical stress and load bearing and accelerate wound healing on the residual limb. Multiple studies have identified collagen fibril enlargement as an important component of skin adaptation, and biomolecules such as decorin may enhance this process.^38-40 The concept of increasing these biomolecules at the correct time during wound healing to strengthen the residual limb tissue currently is being studied.³⁹

Another encouraging area of research is the involvement of fibroblasts in cutaneous wound healing and their role in determining the phenotype of residual limb skin in amputees. The clinical application of autologous fibroblasts is approved by the US Food and Drug Administration for cosmetic use as a filler material and currently is under research for other applications, such as skin regeneration after surgery or manipulating skin characteristics to enhance the durability of residual limbs.⁴¹

Future preventative care of amputee skin may rely on tracking residual limb health before severe tissue injury occurs. For instance, Rink et al⁴² described an approach to monitor residual limb health using noninvasive imaging (eg, hyperspectral imaging, laser speckle imaging) and noninvasive probes that measure oxygenation, perfusion, skin barrier function, and skin hydration to the residual limb. Although these limb surveillance sensors would be employed by prosthetists, the dermatologist, as part of the multispecialty team, also could leverage the data for diagnosis and treatment considerations.

Final Thoughts

The dermatologist is an important member of the multidisciplinary team involved in the care of amputees. Skin disease is prevalent in amputees throughout their lives and often leads to abandonment of prostheses. Although current therapies and preventative treatments are for the most part successful, future research involving advanced technology to monitor skin health, increasing residual limb skin durability at the molecular level, and targeted laser therapies are promising. Through engagement and effective collaboration with the entire multidisciplinary team, dermatologists will have a considerable impact on amputee skin health.

Limb amputation is a major life-changing event that markedly affects a patient’s quality of life as well as his/her ability to participate in activities of daily living. The most prevalent causes for amputation include vascular diseases, diabetes mellitus, trauma, and cancer, respectively.^1,2 For amputees, maintaining prosthetic use is a major physical and psychological undertaking that benefits from a multidisciplinary team approach. Although individuals with lower limb amputations are disproportionately impacted by skin disease due to the increased mechanical forces exerted over the lower limbs, patients with upper limb amputations also develop dermatologic conditions secondary to wearing prostheses.

Approximately 185,000 amputations occur each year in the United States.³ Although amputations resulting from peripheral vascular disease or diabetes mellitus tend to occur in older individuals, amputations in younger patients usually occur from trauma.² The US military has experienced increasing numbers of amputations from trauma due to the ongoing combat operations in the Middle East. Although improvements in body armor and tactical combat casualty care have reduced the number of preventable deaths, the number of casualties surviving with extremity injuries requiring amputation has increased.^4,5 As of October 2017, 1705 US servicemembers underwent major limb amputations, with 1914 lower limb amputations and 302 upper limb amputations. These amputations mainly impacted men aged 21 to 29 years, but female servicemembers also were affected, and a small group of servicemembers had multiple amputations.⁶

One of the most common medical problems that amputees face during long-term care is skin disease, with approximately 75% of amputees using a lower limb prosthesis experiencing skin problems. In general, amputees experience nearly 65% more dermatologic concerns than the general population.⁷ In one study of 97 individuals with transfemoral amputations, some of the most common issues associated with socket prosthetics included heat and sweating in the prosthetic socket (72%) as well as sores and skin irritation from the socket (62%).⁸ Given the high incidence of skin disease on residual limbs, dermatologists are uniquely positioned to keep the amputee in his/her prosthesis and prevent prosthetic abandonment.

Complications Following Amputation

Although US military servicemembers who undergo amputations receive the very best prosthetic devices and rehabilitation resources, they still experience prosthesis abandonment.⁹ Despite the fact that prosthetic limbs and prosthesis technology have substantially improved over the last 2 decades, one study indicated that the high frequency of problems affecting tissue viability at residual limbs is due to the age-old problem of prosthetic fit.¹⁰ In patients with the most advanced prostheses, poor fit still results in mechanical damage to the skin, as the residual limb is exposed to unequal and shearing forces across the amputation site as well as high pressures that cause a vaso-occlusive effect.^11,12 Issues with poor fit are especially important for more active patients, as they normally want to immediately return to their vigorous preinjury lifestyles. In these patients, even a properly fitting prosthetic may not be able to overcome the fact that the residual limb skin is not well suited for the mechanical forces generated by the prosthesis and the humid environment of the socket.^1,13 Another complicating factor is the dynamic nature of the residual limb. Muscle atrophy, changes in gait, and weight gain or loss can lead to an ill-fitting prosthetic and subsequent skin breakdown.

There are many case reports and review articles describing the skin problems in amputees.^1,14-17 The Table summarizes these conditions and outlines treatment options for each.^15,18-20

Most skin diseases on residual limbs are the result of mechanical skin breakdown, inflammation, infection, or combinations of these processes. Overall, amputees with diabetes mellitus and peripheral vascular disease tend to have skin disease related to poor perfusion, whereas amputees who are active and healthy tend to have conditions related to mechanical stress.^{7,13,14,17,21,22} Bui et al¹⁷ reported ulcers, abscesses, and blisters as the most common skin conditions that occur at the site of residual limbs; however, other less common dermatologic disorders such as skin malignancies, verrucous hyperplasia and carcinoma, granulomatous cutaneous lesions, acroangiodermatitis, and bullous pemphigoid also are seen.^23-26 Buikema and Meyerle¹⁵ hypothesize that these conditions, as well as the more common skin diseases, are partly from the amputation disrupting blood and lymphatic flow in the residual limb, which causes the site to act as an immunocompromised district that induces dysregulation of neuroimmune regulators.

It is important to note that skin disease on residual limbs is not just an acute problem. Long-term follow-up of 247 traumatic amputees from the Vietnam War showed that almost half of prosthesis users (48.2%) reported a skin problem in the preceding year, more than 38 years after the amputation. Additionally, one-quarter of these individuals experienced skin problems approximately 50% of the time, which unfortunately led to limited use or total abandonment of the prosthesis for the preceding year in 56% of the veterans surveyed.²¹

Other complications following amputation indirectly lead to skin problems. Heterotopic ossification, or the formation of bone at extraskeletal sites, has been observed in up to 65% of military amputees from recent operations in Iraq and Afghanistan.^27,28 If symptomatic, heterotopic ossification can lead to poor prosthetic fit and subsequent skin breakdown. As a result, it has been reported that up to 40% of combat-related lower extremity amputations may require excision of heterotopic ossificiation.²⁹

Amputation also can result in psychologic concerns that indirectly affect skin health. A systematic review by Mckechnie and John³⁰ suggested that despite heterogeneity between studies, even using the lowest figures demonstrated the significance anxiety and depression play in the lives of traumatic amputees. If left untreated, these mental health issues can lead to poor residual limb hygiene and prosthetic maintenance due to reductions in the patient’s energy and motivation. Studies have shown that proper hygiene of residual limbs and silicone liners reduces associated skin problems.^19,31

Role of the Dermatologist

Routine care and conservative management of amputee skin problems often are accomplished by prosthetists, primary care physicians, nurses, and physical therapists. In one study, more than 80% of the most common skin problems affecting amputees could be attributed to the prosthesis itself, which highlights the importance of the continued involvement of the prosthetist beyond the initial fitting period.¹³ However, when a skin problem becomes refractory to conservative management, referral to a dermatologist is prudent; therefore, the dermatologist is an integral member of the multidisciplinary team that provides care for amputees.

The dermatologist often is best positioned to diagnose skin diseases that result from wearing prostheses and is well versed in treatments for short-term and long-term management of skin disease on residual limbs. The dermatologist also can offer prophylactic treatments to decrease sweating and hair growth to prevent potential infections and subsequent skin breakdown. Additionally, proper education on self-care has been shown to decrease the amount of skin problems and increase functional status and quality of life for amputees.^32,33 Dermatologists can assist with the patient education process as well as refer amputees to a useful resource from the Amputee Coalition website (www.amputee-coalition.org) to provide specific patient education on how to maintain skin on the residual limb to prevent skin disease.

Current Treatments and Future Directions

Skin disorders affecting residual limbs usually are conditions that dermatologists commonly encounter and are comfortable managing in general practice. Additionally, dermatologists routinely treat hyperhidrosis and conduct laser hair removal, both of which are effective prophylactic adjuncts for amputee skin health. There are a few treatments for reducing residual limb hyperhidrosis that are particularly useful. Although first-line treatment of residual limb hyperhidrosis often is topical aluminum chloride, it requires frequent application and often causes considerable skin irritation when applied to residual limbs. Alternatively, intradermal botulinum toxin has been shown to successfully reduce sweat production in individuals with residual limb hyperhidrosis and is well tolerated.³⁴ A 2017 case report discussed the use of microwave thermal ablation of eccrine coils using a noninvasive 3-step hyperhidrosis treatment system on a bilateral below-the-knee amputee. The authors reported the patient tolerated the procedure well with decreased dermatitis and folliculitis, leading to his ability to wear a prosthetic for longer periods of time.³⁵

Ablative fractional resurfacing with a CO₂ laser is another key treatment modality central to amputees, more specifically to traumatic amputees. A CO₂ laser can decrease skin tension and increase skin mobility associated with traumatic scars as well as decrease skin vulnerability to biofilms present in chronic wounds on residual limbs. It is believed that the pattern of injury caused by ablative fractional lasers disrupts biofilms and stimulates growth factor secretion and collagen remodeling through the concept of photomicrodebridement.³⁶ The ablative fractional resurfacing approach to scar therapy and chronic wound debridement can result in less skin injury, allowing the amputee to continue rehabilitation and return more quickly to prosthetic use.³⁷

One interesting area of research in amputee care involves the study of novel ways to increase the skin’s ability to adapt to mechanical stress and load bearing and accelerate wound healing on the residual limb. Multiple studies have identified collagen fibril enlargement as an important component of skin adaptation, and biomolecules such as decorin may enhance this process.^38-40 The concept of increasing these biomolecules at the correct time during wound healing to strengthen the residual limb tissue currently is being studied.³⁹

Another encouraging area of research is the involvement of fibroblasts in cutaneous wound healing and their role in determining the phenotype of residual limb skin in amputees. The clinical application of autologous fibroblasts is approved by the US Food and Drug Administration for cosmetic use as a filler material and currently is under research for other applications, such as skin regeneration after surgery or manipulating skin characteristics to enhance the durability of residual limbs.⁴¹

Future preventative care of amputee skin may rely on tracking residual limb health before severe tissue injury occurs. For instance, Rink et al⁴² described an approach to monitor residual limb health using noninvasive imaging (eg, hyperspectral imaging, laser speckle imaging) and noninvasive probes that measure oxygenation, perfusion, skin barrier function, and skin hydration to the residual limb. Although these limb surveillance sensors would be employed by prosthetists, the dermatologist, as part of the multispecialty team, also could leverage the data for diagnosis and treatment considerations.

Final Thoughts

The dermatologist is an important member of the multidisciplinary team involved in the care of amputees. Skin disease is prevalent in amputees throughout their lives and often leads to abandonment of prostheses. Although current therapies and preventative treatments are for the most part successful, future research involving advanced technology to monitor skin health, increasing residual limb skin durability at the molecular level, and targeted laser therapies are promising. Through engagement and effective collaboration with the entire multidisciplinary team, dermatologists will have a considerable impact on amputee skin health.

Limb amputation is a major life-changing event that markedly affects a patient’s quality of life as well as his/her ability to participate in activities of daily living. The most prevalent causes for amputation include vascular diseases, diabetes mellitus, trauma, and cancer, respectively.^1,2 For amputees, maintaining prosthetic use is a major physical and psychological undertaking that benefits from a multidisciplinary team approach. Although individuals with lower limb amputations are disproportionately impacted by skin disease due to the increased mechanical forces exerted over the lower limbs, patients with upper limb amputations also develop dermatologic conditions secondary to wearing prostheses.

Approximately 185,000 amputations occur each year in the United States.³ Although amputations resulting from peripheral vascular disease or diabetes mellitus tend to occur in older individuals, amputations in younger patients usually occur from trauma.² The US military has experienced increasing numbers of amputations from trauma due to the ongoing combat operations in the Middle East. Although improvements in body armor and tactical combat casualty care have reduced the number of preventable deaths, the number of casualties surviving with extremity injuries requiring amputation has increased.^4,5 As of October 2017, 1705 US servicemembers underwent major limb amputations, with 1914 lower limb amputations and 302 upper limb amputations. These amputations mainly impacted men aged 21 to 29 years, but female servicemembers also were affected, and a small group of servicemembers had multiple amputations.⁶

One of the most common medical problems that amputees face during long-term care is skin disease, with approximately 75% of amputees using a lower limb prosthesis experiencing skin problems. In general, amputees experience nearly 65% more dermatologic concerns than the general population.⁷ In one study of 97 individuals with transfemoral amputations, some of the most common issues associated with socket prosthetics included heat and sweating in the prosthetic socket (72%) as well as sores and skin irritation from the socket (62%).⁸ Given the high incidence of skin disease on residual limbs, dermatologists are uniquely positioned to keep the amputee in his/her prosthesis and prevent prosthetic abandonment.

Complications Following Amputation

Although US military servicemembers who undergo amputations receive the very best prosthetic devices and rehabilitation resources, they still experience prosthesis abandonment.⁹ Despite the fact that prosthetic limbs and prosthesis technology have substantially improved over the last 2 decades, one study indicated that the high frequency of problems affecting tissue viability at residual limbs is due to the age-old problem of prosthetic fit.¹⁰ In patients with the most advanced prostheses, poor fit still results in mechanical damage to the skin, as the residual limb is exposed to unequal and shearing forces across the amputation site as well as high pressures that cause a vaso-occlusive effect.^11,12 Issues with poor fit are especially important for more active patients, as they normally want to immediately return to their vigorous preinjury lifestyles. In these patients, even a properly fitting prosthetic may not be able to overcome the fact that the residual limb skin is not well suited for the mechanical forces generated by the prosthesis and the humid environment of the socket.^1,13 Another complicating factor is the dynamic nature of the residual limb. Muscle atrophy, changes in gait, and weight gain or loss can lead to an ill-fitting prosthetic and subsequent skin breakdown.

There are many case reports and review articles describing the skin problems in amputees.^1,14-17 The Table summarizes these conditions and outlines treatment options for each.^15,18-20

Most skin diseases on residual limbs are the result of mechanical skin breakdown, inflammation, infection, or combinations of these processes. Overall, amputees with diabetes mellitus and peripheral vascular disease tend to have skin disease related to poor perfusion, whereas amputees who are active and healthy tend to have conditions related to mechanical stress.^{7,13,14,17,21,22} Bui et al¹⁷ reported ulcers, abscesses, and blisters as the most common skin conditions that occur at the site of residual limbs; however, other less common dermatologic disorders such as skin malignancies, verrucous hyperplasia and carcinoma, granulomatous cutaneous lesions, acroangiodermatitis, and bullous pemphigoid also are seen.^23-26 Buikema and Meyerle¹⁵ hypothesize that these conditions, as well as the more common skin diseases, are partly from the amputation disrupting blood and lymphatic flow in the residual limb, which causes the site to act as an immunocompromised district that induces dysregulation of neuroimmune regulators.

It is important to note that skin disease on residual limbs is not just an acute problem. Long-term follow-up of 247 traumatic amputees from the Vietnam War showed that almost half of prosthesis users (48.2%) reported a skin problem in the preceding year, more than 38 years after the amputation. Additionally, one-quarter of these individuals experienced skin problems approximately 50% of the time, which unfortunately led to limited use or total abandonment of the prosthesis for the preceding year in 56% of the veterans surveyed.²¹

Other complications following amputation indirectly lead to skin problems. Heterotopic ossification, or the formation of bone at extraskeletal sites, has been observed in up to 65% of military amputees from recent operations in Iraq and Afghanistan.^27,28 If symptomatic, heterotopic ossification can lead to poor prosthetic fit and subsequent skin breakdown. As a result, it has been reported that up to 40% of combat-related lower extremity amputations may require excision of heterotopic ossificiation.²⁹

Amputation also can result in psychologic concerns that indirectly affect skin health. A systematic review by Mckechnie and John³⁰ suggested that despite heterogeneity between studies, even using the lowest figures demonstrated the significance anxiety and depression play in the lives of traumatic amputees. If left untreated, these mental health issues can lead to poor residual limb hygiene and prosthetic maintenance due to reductions in the patient’s energy and motivation. Studies have shown that proper hygiene of residual limbs and silicone liners reduces associated skin problems.^19,31

Role of the Dermatologist

Routine care and conservative management of amputee skin problems often are accomplished by prosthetists, primary care physicians, nurses, and physical therapists. In one study, more than 80% of the most common skin problems affecting amputees could be attributed to the prosthesis itself, which highlights the importance of the continued involvement of the prosthetist beyond the initial fitting period.¹³ However, when a skin problem becomes refractory to conservative management, referral to a dermatologist is prudent; therefore, the dermatologist is an integral member of the multidisciplinary team that provides care for amputees.

The dermatologist often is best positioned to diagnose skin diseases that result from wearing prostheses and is well versed in treatments for short-term and long-term management of skin disease on residual limbs. The dermatologist also can offer prophylactic treatments to decrease sweating and hair growth to prevent potential infections and subsequent skin breakdown. Additionally, proper education on self-care has been shown to decrease the amount of skin problems and increase functional status and quality of life for amputees.^32,33 Dermatologists can assist with the patient education process as well as refer amputees to a useful resource from the Amputee Coalition website (www.amputee-coalition.org) to provide specific patient education on how to maintain skin on the residual limb to prevent skin disease.

Current Treatments and Future Directions

Skin disorders affecting residual limbs usually are conditions that dermatologists commonly encounter and are comfortable managing in general practice. Additionally, dermatologists routinely treat hyperhidrosis and conduct laser hair removal, both of which are effective prophylactic adjuncts for amputee skin health. There are a few treatments for reducing residual limb hyperhidrosis that are particularly useful. Although first-line treatment of residual limb hyperhidrosis often is topical aluminum chloride, it requires frequent application and often causes considerable skin irritation when applied to residual limbs. Alternatively, intradermal botulinum toxin has been shown to successfully reduce sweat production in individuals with residual limb hyperhidrosis and is well tolerated.³⁴ A 2017 case report discussed the use of microwave thermal ablation of eccrine coils using a noninvasive 3-step hyperhidrosis treatment system on a bilateral below-the-knee amputee. The authors reported the patient tolerated the procedure well with decreased dermatitis and folliculitis, leading to his ability to wear a prosthetic for longer periods of time.³⁵

Ablative fractional resurfacing with a CO₂ laser is another key treatment modality central to amputees, more specifically to traumatic amputees. A CO₂ laser can decrease skin tension and increase skin mobility associated with traumatic scars as well as decrease skin vulnerability to biofilms present in chronic wounds on residual limbs. It is believed that the pattern of injury caused by ablative fractional lasers disrupts biofilms and stimulates growth factor secretion and collagen remodeling through the concept of photomicrodebridement.³⁶ The ablative fractional resurfacing approach to scar therapy and chronic wound debridement can result in less skin injury, allowing the amputee to continue rehabilitation and return more quickly to prosthetic use.³⁷

One interesting area of research in amputee care involves the study of novel ways to increase the skin’s ability to adapt to mechanical stress and load bearing and accelerate wound healing on the residual limb. Multiple studies have identified collagen fibril enlargement as an important component of skin adaptation, and biomolecules such as decorin may enhance this process.^38-40 The concept of increasing these biomolecules at the correct time during wound healing to strengthen the residual limb tissue currently is being studied.³⁹

Another encouraging area of research is the involvement of fibroblasts in cutaneous wound healing and their role in determining the phenotype of residual limb skin in amputees. The clinical application of autologous fibroblasts is approved by the US Food and Drug Administration for cosmetic use as a filler material and currently is under research for other applications, such as skin regeneration after surgery or manipulating skin characteristics to enhance the durability of residual limbs.⁴¹

Future preventative care of amputee skin may rely on tracking residual limb health before severe tissue injury occurs. For instance, Rink et al⁴² described an approach to monitor residual limb health using noninvasive imaging (eg, hyperspectral imaging, laser speckle imaging) and noninvasive probes that measure oxygenation, perfusion, skin barrier function, and skin hydration to the residual limb. Although these limb surveillance sensors would be employed by prosthetists, the dermatologist, as part of the multispecialty team, also could leverage the data for diagnosis and treatment considerations.

Final Thoughts

The dermatologist is an important member of the multidisciplinary team involved in the care of amputees. Skin disease is prevalent in amputees throughout their lives and often leads to abandonment of prostheses. Although current therapies and preventative treatments are for the most part successful, future research involving advanced technology to monitor skin health, increasing residual limb skin durability at the molecular level, and targeted laser therapies are promising. Through engagement and effective collaboration with the entire multidisciplinary team, dermatologists will have a considerable impact on amputee skin health.

To the Editor:

A 50-year-old woman presented with an asymptomatic eruption on the dorsal aspect of the hands, abdomen, and face of 6 months’ duration. The eruption was associated with generalized arthralgia and fatigue. Within several weeks of onset of the cutaneous eruption, the patient developed swelling in the hands as well as worsening arthralgia. She was treated for presumed Lyme borreliosis but reported no improvement in the symptoms. She was then referred to dermatology for further management.

Physical examination revealed red-orange, edematous, monomorphic papulonodules scattered on the nasolabial folds, upper lip, and along the dorsal aspect of the hands and fingers (Figure 1). A brown rippled plaque was present on the left lower abdomen. The oral mucosa and nails were unremarkable. Laboratory studies showed elevated total cholesterol (244 mg/dL [reference range, <200 mg/dL]), low-density lipoproteins (130 mg/dL [reference range, 10–30 mg/dL]), aspartate aminotransferase (140 U/L [reference range, 10–30 U/L]), alanine aminotransferase (110 U/L [reference range, 10–40 U/L]), and total bilirubin (1.5 mg/dL [reference range, 0.3–1.2 mg/dL]). White blood cell count and C-reactive protein levels were within reference range. An antinuclear antibody titer of 1:80 with a homogenous pattern was found, and aldolase levels were elevated. Laboratory investigations for rheumatoid factor, Lyme disease, tuberculosis, hepatitis, and human immunodeficiency virus were negative. A chest radiograph was normal.

Multicentric reticulohistiocytosis typically presents with a severe erosive arthropathy known as arthritis mutilans. Patients display a symmetric polyarthritis that commonly involves the elbows, wrists, and proximal and distal aspects of the interphalangeal joints. Onset and progression can be rapid, and the erosive nature leads to deformities in up to 45% of patients.^2,5,6 Cutaneous findings arise an average of 3 years after the development of arthritis, though one-fifth of patients will initially present with cutaneous findings followed by the development of arthritis at any time.^3,6 Clinical features include flesh-colored to reddish brown or yellow papulonodules that range in size from several millimeters to 2 cm. The lesions most commonly occur on the face (eg, ears, nose, paranasal cheeks), scalp, dorsal and lateral aspects of the hands and fingers, and overlying articular regions of the extremities. Characteristic periungual lesions classically are referred to as coral beads.^4,6 Patients commonly report pruritus that may precede the development of the papules and nodules. Other cutaneous manifestations include xanthelasma, nail changes, and a photodistributed erythematous maculopapular eruption that may mimic dermatomyositis.⁶

Cutaneous findings of MRH can mimic rheumatoid nodules, gout, Gottron papules of dermatomyositis, lipoid proteinosis, sarcoidosis, lepromatous leprosy, granuloma annulare, xanthoma, xanthogranuloma, and fibroxanthoma.^6,7 Histopathologic features may distinguish MRH from such entities. Findings include fairly well-circumscribed aggregates of large multinucleated giant cells with characteristic eosinophilic ground-glass cytoplasm. Histiocytes stain positively for CD68, HAM56, CD11b, and CD14, and variably for factor XIIIa. CD68, which is expressed by monocytes/macrophages, has been universally reported to be the most reliable marker of MRH. Negative staining for S-100 and CD1a supports a non-Langerhans origin for the involved histiocytes. If arthritic symptoms predominate, MRH must be distinguished from rheumatoid and psoriatic arthritis.^6,7

Mucosal involvement occurs in approximately 50% of patients and includes the presence of nodules in the oral, nasal, and pharyngeal mucosae, as well as eye structures.^2,3 Histiocytic infiltration has been documented in the heart, lungs, thyroid, liver, stomach, kidneys, muscle, bone marrow, and urogenital tract. Histiocytes also can invade the cartilage of the ears and nose causing disfigurement and characteristic leonine facies. Pathologic fractures may occur with bone involvement.⁵

Systemic features associated with MRH include hyperlipidemia, diabetes mellitus, thyroid disease, hypergammaglobulinemia, and various autoimmune diseases. Patients less frequently report fever and weight loss.^2,5,6,8 Additionally, a positive tuberculin test occurs in 12% to 50% of patients.⁶ Various autoimmune diseases occur in 6% to 17% of cases including systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, dermatomyositis, Sjögren syndrome, and primary biliary cirrhosis.^2,5,6,8 The most clinically salient feature of MRH is its association with malignant conditions, which occur in up to 31% of patients. A variety of cancers have been reported in association with MRH, including breast, cervical, ovarian, stomach, penile, lymphoma, mesothelioma, and melanoma.⁷

The etiology of MRH is unclear. Although onset may precede the development of a malignant condition and regress with treatment, it cannot be considered a true paraneoplastic disorder, as it has no association with a specific cancer and does not typically parallel the disease course.^6,9 Reports of increased levels of inflammatory mediators released from macrophages and endothelial cells, specifically IL-12, IL-1β, IL-6, and tumor necrosis factor α (TNF-α), have been thought to drive the destruction of bone and cartilage.⁶ In particular, TNF-α acts to indirectly induce destruction by stimulating proteolytic activity in macrophages, similar to the pathogenesis of joint damage in rheumatoid arthritis.⁸ Osteoclastic activity may play a role in the pathogenesis of MRH, as multinucleated giant cells in MRH can mature into osteoclasts by receptor activated nuclear factor–κB ligand signaling. In addition, patients treated with bisphosphonates have had decreased lacunar resorption.^2,8

Initial management of MRH should include screening for hyperlipidemia, hypergammaglobulinemia, hyperglycemia, thyroid dysfunction, and autoimmune diseases, as well as age-appropriate cancer screening. Imaging studies should evaluate for the presence of erosive arthritis. There are no well-defined treatment algorithms for MRH due to the rarity of the disease, and recommendations largely rely on case reports. Although spontaneous remission typically occurs within 5 to 10 years, the risk for joint destruction argues for early pharmacologic intervention. Current management includes the use of nonsteroidal anti-inflammatory drugs and various immunosuppressants including oral glucocorticoids, cyclophosphamide, chlorambucil, methotrexate, or azathioprine.² A combination of methotrexate with cyclophosphamide or glucocorticoids also has shown efficacy.¹⁰ Anti–TNF-α agents, such as etanercept, adalimumab, and infliximab, have been used with some success.² Tumor necrosis factor α inhibitors used in combination with oral glucocorticoids and methotrexate may have an increased benefit.^2,9,11 Evidence suggesting that TNF-α plays a role in the destruction of bone and cartilage led to the successful use of infliximab in combination with oral glucocorticoids and methotrexate, which prevented possible development of antibodies to infliximab and increased its efficacy.¹² Bisphosphonate use in combination with glucocorticoids and methotrexate may prevent joint destruction without the serious adverse events associated with anti–TNF-α agents.^2,9,13,14

To the Editor:

A 50-year-old woman presented with an asymptomatic eruption on the dorsal aspect of the hands, abdomen, and face of 6 months’ duration. The eruption was associated with generalized arthralgia and fatigue. Within several weeks of onset of the cutaneous eruption, the patient developed swelling in the hands as well as worsening arthralgia. She was treated for presumed Lyme borreliosis but reported no improvement in the symptoms. She was then referred to dermatology for further management.

Physical examination revealed red-orange, edematous, monomorphic papulonodules scattered on the nasolabial folds, upper lip, and along the dorsal aspect of the hands and fingers (Figure 1). A brown rippled plaque was present on the left lower abdomen. The oral mucosa and nails were unremarkable. Laboratory studies showed elevated total cholesterol (244 mg/dL [reference range, <200 mg/dL]), low-density lipoproteins (130 mg/dL [reference range, 10–30 mg/dL]), aspartate aminotransferase (140 U/L [reference range, 10–30 U/L]), alanine aminotransferase (110 U/L [reference range, 10–40 U/L]), and total bilirubin (1.5 mg/dL [reference range, 0.3–1.2 mg/dL]). White blood cell count and C-reactive protein levels were within reference range. An antinuclear antibody titer of 1:80 with a homogenous pattern was found, and aldolase levels were elevated. Laboratory investigations for rheumatoid factor, Lyme disease, tuberculosis, hepatitis, and human immunodeficiency virus were negative. A chest radiograph was normal.

Multicentric reticulohistiocytosis typically presents with a severe erosive arthropathy known as arthritis mutilans. Patients display a symmetric polyarthritis that commonly involves the elbows, wrists, and proximal and distal aspects of the interphalangeal joints. Onset and progression can be rapid, and the erosive nature leads to deformities in up to 45% of patients.^2,5,6 Cutaneous findings arise an average of 3 years after the development of arthritis, though one-fifth of patients will initially present with cutaneous findings followed by the development of arthritis at any time.^3,6 Clinical features include flesh-colored to reddish brown or yellow papulonodules that range in size from several millimeters to 2 cm. The lesions most commonly occur on the face (eg, ears, nose, paranasal cheeks), scalp, dorsal and lateral aspects of the hands and fingers, and overlying articular regions of the extremities. Characteristic periungual lesions classically are referred to as coral beads.^4,6 Patients commonly report pruritus that may precede the development of the papules and nodules. Other cutaneous manifestations include xanthelasma, nail changes, and a photodistributed erythematous maculopapular eruption that may mimic dermatomyositis.⁶

Cutaneous findings of MRH can mimic rheumatoid nodules, gout, Gottron papules of dermatomyositis, lipoid proteinosis, sarcoidosis, lepromatous leprosy, granuloma annulare, xanthoma, xanthogranuloma, and fibroxanthoma.^6,7 Histopathologic features may distinguish MRH from such entities. Findings include fairly well-circumscribed aggregates of large multinucleated giant cells with characteristic eosinophilic ground-glass cytoplasm. Histiocytes stain positively for CD68, HAM56, CD11b, and CD14, and variably for factor XIIIa. CD68, which is expressed by monocytes/macrophages, has been universally reported to be the most reliable marker of MRH. Negative staining for S-100 and CD1a supports a non-Langerhans origin for the involved histiocytes. If arthritic symptoms predominate, MRH must be distinguished from rheumatoid and psoriatic arthritis.^6,7

Mucosal involvement occurs in approximately 50% of patients and includes the presence of nodules in the oral, nasal, and pharyngeal mucosae, as well as eye structures.^2,3 Histiocytic infiltration has been documented in the heart, lungs, thyroid, liver, stomach, kidneys, muscle, bone marrow, and urogenital tract. Histiocytes also can invade the cartilage of the ears and nose causing disfigurement and characteristic leonine facies. Pathologic fractures may occur with bone involvement.⁵

Systemic features associated with MRH include hyperlipidemia, diabetes mellitus, thyroid disease, hypergammaglobulinemia, and various autoimmune diseases. Patients less frequently report fever and weight loss.^2,5,6,8 Additionally, a positive tuberculin test occurs in 12% to 50% of patients.⁶ Various autoimmune diseases occur in 6% to 17% of cases including systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, dermatomyositis, Sjögren syndrome, and primary biliary cirrhosis.^2,5,6,8 The most clinically salient feature of MRH is its association with malignant conditions, which occur in up to 31% of patients. A variety of cancers have been reported in association with MRH, including breast, cervical, ovarian, stomach, penile, lymphoma, mesothelioma, and melanoma.⁷

The etiology of MRH is unclear. Although onset may precede the development of a malignant condition and regress with treatment, it cannot be considered a true paraneoplastic disorder, as it has no association with a specific cancer and does not typically parallel the disease course.^6,9 Reports of increased levels of inflammatory mediators released from macrophages and endothelial cells, specifically IL-12, IL-1β, IL-6, and tumor necrosis factor α (TNF-α), have been thought to drive the destruction of bone and cartilage.⁶ In particular, TNF-α acts to indirectly induce destruction by stimulating proteolytic activity in macrophages, similar to the pathogenesis of joint damage in rheumatoid arthritis.⁸ Osteoclastic activity may play a role in the pathogenesis of MRH, as multinucleated giant cells in MRH can mature into osteoclasts by receptor activated nuclear factor–κB ligand signaling. In addition, patients treated with bisphosphonates have had decreased lacunar resorption.^2,8

Initial management of MRH should include screening for hyperlipidemia, hypergammaglobulinemia, hyperglycemia, thyroid dysfunction, and autoimmune diseases, as well as age-appropriate cancer screening. Imaging studies should evaluate for the presence of erosive arthritis. There are no well-defined treatment algorithms for MRH due to the rarity of the disease, and recommendations largely rely on case reports. Although spontaneous remission typically occurs within 5 to 10 years, the risk for joint destruction argues for early pharmacologic intervention. Current management includes the use of nonsteroidal anti-inflammatory drugs and various immunosuppressants including oral glucocorticoids, cyclophosphamide, chlorambucil, methotrexate, or azathioprine.² A combination of methotrexate with cyclophosphamide or glucocorticoids also has shown efficacy.¹⁰ Anti–TNF-α agents, such as etanercept, adalimumab, and infliximab, have been used with some success.² Tumor necrosis factor α inhibitors used in combination with oral glucocorticoids and methotrexate may have an increased benefit.^2,9,11 Evidence suggesting that TNF-α plays a role in the destruction of bone and cartilage led to the successful use of infliximab in combination with oral glucocorticoids and methotrexate, which prevented possible development of antibodies to infliximab and increased its efficacy.¹² Bisphosphonate use in combination with glucocorticoids and methotrexate may prevent joint destruction without the serious adverse events associated with anti–TNF-α agents.^2,9,13,14

To the Editor:

A 50-year-old woman presented with an asymptomatic eruption on the dorsal aspect of the hands, abdomen, and face of 6 months’ duration. The eruption was associated with generalized arthralgia and fatigue. Within several weeks of onset of the cutaneous eruption, the patient developed swelling in the hands as well as worsening arthralgia. She was treated for presumed Lyme borreliosis but reported no improvement in the symptoms. She was then referred to dermatology for further management.

Physical examination revealed red-orange, edematous, monomorphic papulonodules scattered on the nasolabial folds, upper lip, and along the dorsal aspect of the hands and fingers (Figure 1). A brown rippled plaque was present on the left lower abdomen. The oral mucosa and nails were unremarkable. Laboratory studies showed elevated total cholesterol (244 mg/dL [reference range, <200 mg/dL]), low-density lipoproteins (130 mg/dL [reference range, 10–30 mg/dL]), aspartate aminotransferase (140 U/L [reference range, 10–30 U/L]), alanine aminotransferase (110 U/L [reference range, 10–40 U/L]), and total bilirubin (1.5 mg/dL [reference range, 0.3–1.2 mg/dL]). White blood cell count and C-reactive protein levels were within reference range. An antinuclear antibody titer of 1:80 with a homogenous pattern was found, and aldolase levels were elevated. Laboratory investigations for rheumatoid factor, Lyme disease, tuberculosis, hepatitis, and human immunodeficiency virus were negative. A chest radiograph was normal.

Multicentric reticulohistiocytosis typically presents with a severe erosive arthropathy known as arthritis mutilans. Patients display a symmetric polyarthritis that commonly involves the elbows, wrists, and proximal and distal aspects of the interphalangeal joints. Onset and progression can be rapid, and the erosive nature leads to deformities in up to 45% of patients.^2,5,6 Cutaneous findings arise an average of 3 years after the development of arthritis, though one-fifth of patients will initially present with cutaneous findings followed by the development of arthritis at any time.^3,6 Clinical features include flesh-colored to reddish brown or yellow papulonodules that range in size from several millimeters to 2 cm. The lesions most commonly occur on the face (eg, ears, nose, paranasal cheeks), scalp, dorsal and lateral aspects of the hands and fingers, and overlying articular regions of the extremities. Characteristic periungual lesions classically are referred to as coral beads.^4,6 Patients commonly report pruritus that may precede the development of the papules and nodules. Other cutaneous manifestations include xanthelasma, nail changes, and a photodistributed erythematous maculopapular eruption that may mimic dermatomyositis.⁶

Cutaneous findings of MRH can mimic rheumatoid nodules, gout, Gottron papules of dermatomyositis, lipoid proteinosis, sarcoidosis, lepromatous leprosy, granuloma annulare, xanthoma, xanthogranuloma, and fibroxanthoma.^6,7 Histopathologic features may distinguish MRH from such entities. Findings include fairly well-circumscribed aggregates of large multinucleated giant cells with characteristic eosinophilic ground-glass cytoplasm. Histiocytes stain positively for CD68, HAM56, CD11b, and CD14, and variably for factor XIIIa. CD68, which is expressed by monocytes/macrophages, has been universally reported to be the most reliable marker of MRH. Negative staining for S-100 and CD1a supports a non-Langerhans origin for the involved histiocytes. If arthritic symptoms predominate, MRH must be distinguished from rheumatoid and psoriatic arthritis.^6,7

Mucosal involvement occurs in approximately 50% of patients and includes the presence of nodules in the oral, nasal, and pharyngeal mucosae, as well as eye structures.^2,3 Histiocytic infiltration has been documented in the heart, lungs, thyroid, liver, stomach, kidneys, muscle, bone marrow, and urogenital tract. Histiocytes also can invade the cartilage of the ears and nose causing disfigurement and characteristic leonine facies. Pathologic fractures may occur with bone involvement.⁵

Systemic features associated with MRH include hyperlipidemia, diabetes mellitus, thyroid disease, hypergammaglobulinemia, and various autoimmune diseases. Patients less frequently report fever and weight loss.^2,5,6,8 Additionally, a positive tuberculin test occurs in 12% to 50% of patients.⁶ Various autoimmune diseases occur in 6% to 17% of cases including systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, dermatomyositis, Sjögren syndrome, and primary biliary cirrhosis.^2,5,6,8 The most clinically salient feature of MRH is its association with malignant conditions, which occur in up to 31% of patients. A variety of cancers have been reported in association with MRH, including breast, cervical, ovarian, stomach, penile, lymphoma, mesothelioma, and melanoma.⁷

The etiology of MRH is unclear. Although onset may precede the development of a malignant condition and regress with treatment, it cannot be considered a true paraneoplastic disorder, as it has no association with a specific cancer and does not typically parallel the disease course.^6,9 Reports of increased levels of inflammatory mediators released from macrophages and endothelial cells, specifically IL-12, IL-1β, IL-6, and tumor necrosis factor α (TNF-α), have been thought to drive the destruction of bone and cartilage.⁶ In particular, TNF-α acts to indirectly induce destruction by stimulating proteolytic activity in macrophages, similar to the pathogenesis of joint damage in rheumatoid arthritis.⁸ Osteoclastic activity may play a role in the pathogenesis of MRH, as multinucleated giant cells in MRH can mature into osteoclasts by receptor activated nuclear factor–κB ligand signaling. In addition, patients treated with bisphosphonates have had decreased lacunar resorption.^2,8

Initial management of MRH should include screening for hyperlipidemia, hypergammaglobulinemia, hyperglycemia, thyroid dysfunction, and autoimmune diseases, as well as age-appropriate cancer screening. Imaging studies should evaluate for the presence of erosive arthritis. There are no well-defined treatment algorithms for MRH due to the rarity of the disease, and recommendations largely rely on case reports. Although spontaneous remission typically occurs within 5 to 10 years, the risk for joint destruction argues for early pharmacologic intervention. Current management includes the use of nonsteroidal anti-inflammatory drugs and various immunosuppressants including oral glucocorticoids, cyclophosphamide, chlorambucil, methotrexate, or azathioprine.² A combination of methotrexate with cyclophosphamide or glucocorticoids also has shown efficacy.¹⁰ Anti–TNF-α agents, such as etanercept, adalimumab, and infliximab, have been used with some success.² Tumor necrosis factor α inhibitors used in combination with oral glucocorticoids and methotrexate may have an increased benefit.^2,9,11 Evidence suggesting that TNF-α plays a role in the destruction of bone and cartilage led to the successful use of infliximab in combination with oral glucocorticoids and methotrexate, which prevented possible development of antibodies to infliximab and increased its efficacy.¹² Bisphosphonate use in combination with glucocorticoids and methotrexate may prevent joint destruction without the serious adverse events associated with anti–TNF-α agents.^2,9,13,14

To the Editor:

We report an interesting clinical case of dermatomyositis (DM) that presented with an associated malignancy (small cell lung cancer). This patient also had an unusual clinical finding of predominantly unilateral, confluent, erythematous papules on the knee, a cutaneous sign that is seldom described in the DM literature. This case serves to reinforce the classic findings and associations of DM, in addition to the uncommon manifestation of predominantly unilateral papules on the knee.

A 68-year-old woman presented with several cutaneous manifestations including the classic findings of photo distributed erythema on the arms and face, a heliotrope rash, Gottron papules, and confluent pink papules on the left knee (Figure 1). The patient also had one of the more rare manifestations of DM, flagellate erythema on the back (Figure 2). She had a history of breast cancer and was found to have metastatic small cell lung cancer at the time of the DM diagnosis.

To the Editor:

We report an interesting clinical case of dermatomyositis (DM) that presented with an associated malignancy (small cell lung cancer). This patient also had an unusual clinical finding of predominantly unilateral, confluent, erythematous papules on the knee, a cutaneous sign that is seldom described in the DM literature. This case serves to reinforce the classic findings and associations of DM, in addition to the uncommon manifestation of predominantly unilateral papules on the knee.

A 68-year-old woman presented with several cutaneous manifestations including the classic findings of photo distributed erythema on the arms and face, a heliotrope rash, Gottron papules, and confluent pink papules on the left knee (Figure 1). The patient also had one of the more rare manifestations of DM, flagellate erythema on the back (Figure 2). She had a history of breast cancer and was found to have metastatic small cell lung cancer at the time of the DM diagnosis.

To the Editor:

We report an interesting clinical case of dermatomyositis (DM) that presented with an associated malignancy (small cell lung cancer). This patient also had an unusual clinical finding of predominantly unilateral, confluent, erythematous papules on the knee, a cutaneous sign that is seldom described in the DM literature. This case serves to reinforce the classic findings and associations of DM, in addition to the uncommon manifestation of predominantly unilateral papules on the knee.

A 68-year-old woman presented with several cutaneous manifestations including the classic findings of photo distributed erythema on the arms and face, a heliotrope rash, Gottron papules, and confluent pink papules on the left knee (Figure 1). The patient also had one of the more rare manifestations of DM, flagellate erythema on the back (Figure 2). She had a history of breast cancer and was found to have metastatic small cell lung cancer at the time of the DM diagnosis.

The Diagnosis: Fordyce Granules 

Fordyce granules are prevalent benign anatomic variations that occur in approximately 80% of the population.¹ The spots usually present as multiple (usually >10) 1- to 2-mm, painless, yellow-white papules in a symmetric bilateral distribution. They are normal superficial sebaceous glands seen on mucosal surfaces including the oral mucosa, lips, and genitalia. The papules are asymptomatic, and patients often are unaware of their presence. They can appear at any age and can last for months to years. No treatment is indicated, and patients need only reassurance.¹ 

There are several differential diagnoses.² Granular cell tumors present as solitary, yellowish or pink, slightly indurated, nonmobile, firm masses that usually measure less than 2 cm in diameter and can be associated with local paresthesia. The oral cavity is the second most common site after the skin and usually involves the dorsum of the tongue; however, granular cell tumors also may develop in the substance of the buccal mucosa, lips, or floor of the mouth. On histopathology, the neoplasm is composed of cells with granular cytoplasm that is of neural origin. Granular cell tumors are slow growing and may be present for months. The mean age of onset is in the fourth decade, and females are more likely to be affected. Excisional biopsy is diagnostic and curative.²  

Mucoceles of the mouth are solitary, bluish clear, fluctuant, dome-shaped, well-demarcated nodules that usually appear on the lower lip.³ They are caused by rupture of a salivary gland duct due to minor trauma. Mucin is excreted into the surrounding soft tissues, leading to abrupt nontender swelling over the next several weeks. If they originate deeper within the lip they may appear normal in color. Most range from 1 to 2 mm in diameter but can grow to up to several centimeters in size. Other affected sites may include the ventral tongue, posterior buccal mucosa, or soft palate. Excisional biopsy and conservative surgical excision are recommended for diagnosis and management, respectively.³  

Oral leukoplakia is a sharply demarcated, white, mucosal plaque that represents either epithelial dysplasia, carcinoma in situ, invasive carcinoma, or hyperkeratosis of unknown etiology. It is a clinical diagnosis of exclusion. The patient may present with a hoarse voice and history of tobacco use. The risk for malignant transformation to squamous cell carcinoma varies from 0% to 20% over the course of 30
years.⁴  The lesions occur on any mucosal surface, cannot be rubbed off, and usually are asymptomatic.⁵ The ventral tongue, floor of the mouth, and soft palate are associated with epithelial dysplasia and invasive carcinoma more often than other mucosal sites. There are 2 main types of leukoplakia: localized (unilateral plaque) and proliferative. Because of the risk for cancer, biopsy always is indicated and should be taken from different areas of the lesion (ie, red, verrucous, or nodular areas) if the lesion is nonhomogeneous. Treatment involves excision in the setting of dysplasia or invasive carcinoma. Photodynamic therapy has been shown to reduce the size of oral leukoplakia lesions and is being studied as an alternative therapy.⁵  

Herpes simplex virus type 1 is a common infection of the oral mucosa that classically causes multiple vesicular lesions with an inflammatory erythematous base.⁶ The lesions are painful and may last for 10 to 14 days. Patients also may develop systemic symptoms such as fever and malaise. Once primary infection with herpes simplex virus has occurred, the virus lives in a latent state in ganglion neurons and can reactivate.⁶ 
 

The Diagnosis: Fordyce Granules 

Fordyce granules are prevalent benign anatomic variations that occur in approximately 80% of the population.¹ The spots usually present as multiple (usually >10) 1- to 2-mm, painless, yellow-white papules in a symmetric bilateral distribution. They are normal superficial sebaceous glands seen on mucosal surfaces including the oral mucosa, lips, and genitalia. The papules are asymptomatic, and patients often are unaware of their presence. They can appear at any age and can last for months to years. No treatment is indicated, and patients need only reassurance.¹ 

There are several differential diagnoses.² Granular cell tumors present as solitary, yellowish or pink, slightly indurated, nonmobile, firm masses that usually measure less than 2 cm in diameter and can be associated with local paresthesia. The oral cavity is the second most common site after the skin and usually involves the dorsum of the tongue; however, granular cell tumors also may develop in the substance of the buccal mucosa, lips, or floor of the mouth. On histopathology, the neoplasm is composed of cells with granular cytoplasm that is of neural origin. Granular cell tumors are slow growing and may be present for months. The mean age of onset is in the fourth decade, and females are more likely to be affected. Excisional biopsy is diagnostic and curative.²  

Mucoceles of the mouth are solitary, bluish clear, fluctuant, dome-shaped, well-demarcated nodules that usually appear on the lower lip.³ They are caused by rupture of a salivary gland duct due to minor trauma. Mucin is excreted into the surrounding soft tissues, leading to abrupt nontender swelling over the next several weeks. If they originate deeper within the lip they may appear normal in color. Most range from 1 to 2 mm in diameter but can grow to up to several centimeters in size. Other affected sites may include the ventral tongue, posterior buccal mucosa, or soft palate. Excisional biopsy and conservative surgical excision are recommended for diagnosis and management, respectively.³  

Oral leukoplakia is a sharply demarcated, white, mucosal plaque that represents either epithelial dysplasia, carcinoma in situ, invasive carcinoma, or hyperkeratosis of unknown etiology. It is a clinical diagnosis of exclusion. The patient may present with a hoarse voice and history of tobacco use. The risk for malignant transformation to squamous cell carcinoma varies from 0% to 20% over the course of 30
years.⁴  The lesions occur on any mucosal surface, cannot be rubbed off, and usually are asymptomatic.⁵ The ventral tongue, floor of the mouth, and soft palate are associated with epithelial dysplasia and invasive carcinoma more often than other mucosal sites. There are 2 main types of leukoplakia: localized (unilateral plaque) and proliferative. Because of the risk for cancer, biopsy always is indicated and should be taken from different areas of the lesion (ie, red, verrucous, or nodular areas) if the lesion is nonhomogeneous. Treatment involves excision in the setting of dysplasia or invasive carcinoma. Photodynamic therapy has been shown to reduce the size of oral leukoplakia lesions and is being studied as an alternative therapy.⁵  

Herpes simplex virus type 1 is a common infection of the oral mucosa that classically causes multiple vesicular lesions with an inflammatory erythematous base.⁶ The lesions are painful and may last for 10 to 14 days. Patients also may develop systemic symptoms such as fever and malaise. Once primary infection with herpes simplex virus has occurred, the virus lives in a latent state in ganglion neurons and can reactivate.⁶ 
 

The Diagnosis: Fordyce Granules 

Fordyce granules are prevalent benign anatomic variations that occur in approximately 80% of the population.¹ The spots usually present as multiple (usually >10) 1- to 2-mm, painless, yellow-white papules in a symmetric bilateral distribution. They are normal superficial sebaceous glands seen on mucosal surfaces including the oral mucosa, lips, and genitalia. The papules are asymptomatic, and patients often are unaware of their presence. They can appear at any age and can last for months to years. No treatment is indicated, and patients need only reassurance.¹ 

There are several differential diagnoses.² Granular cell tumors present as solitary, yellowish or pink, slightly indurated, nonmobile, firm masses that usually measure less than 2 cm in diameter and can be associated with local paresthesia. The oral cavity is the second most common site after the skin and usually involves the dorsum of the tongue; however, granular cell tumors also may develop in the substance of the buccal mucosa, lips, or floor of the mouth. On histopathology, the neoplasm is composed of cells with granular cytoplasm that is of neural origin. Granular cell tumors are slow growing and may be present for months. The mean age of onset is in the fourth decade, and females are more likely to be affected. Excisional biopsy is diagnostic and curative.²  

Mucoceles of the mouth are solitary, bluish clear, fluctuant, dome-shaped, well-demarcated nodules that usually appear on the lower lip.³ They are caused by rupture of a salivary gland duct due to minor trauma. Mucin is excreted into the surrounding soft tissues, leading to abrupt nontender swelling over the next several weeks. If they originate deeper within the lip they may appear normal in color. Most range from 1 to 2 mm in diameter but can grow to up to several centimeters in size. Other affected sites may include the ventral tongue, posterior buccal mucosa, or soft palate. Excisional biopsy and conservative surgical excision are recommended for diagnosis and management, respectively.³  

Oral leukoplakia is a sharply demarcated, white, mucosal plaque that represents either epithelial dysplasia, carcinoma in situ, invasive carcinoma, or hyperkeratosis of unknown etiology. It is a clinical diagnosis of exclusion. The patient may present with a hoarse voice and history of tobacco use. The risk for malignant transformation to squamous cell carcinoma varies from 0% to 20% over the course of 30
years.⁴  The lesions occur on any mucosal surface, cannot be rubbed off, and usually are asymptomatic.⁵ The ventral tongue, floor of the mouth, and soft palate are associated with epithelial dysplasia and invasive carcinoma more often than other mucosal sites. There are 2 main types of leukoplakia: localized (unilateral plaque) and proliferative. Because of the risk for cancer, biopsy always is indicated and should be taken from different areas of the lesion (ie, red, verrucous, or nodular areas) if the lesion is nonhomogeneous. Treatment involves excision in the setting of dysplasia or invasive carcinoma. Photodynamic therapy has been shown to reduce the size of oral leukoplakia lesions and is being studied as an alternative therapy.⁵  

Herpes simplex virus type 1 is a common infection of the oral mucosa that classically causes multiple vesicular lesions with an inflammatory erythematous base.⁶ The lesions are painful and may last for 10 to 14 days. Patients also may develop systemic symptoms such as fever and malaise. Once primary infection with herpes simplex virus has occurred, the virus lives in a latent state in ganglion neurons and can reactivate.⁶