Cutis

Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformis, is a relatively rare cutaneous disorder of pregnancy wherein lesions typically appear in the third trimester and resolve after delivery; however, lesions may persist through the postpartum period. Pustular psoriasis of pregnancy may be considered a fifth dermatosis of pregnancy, alongside the classic dermatoses of atopic eruption of pregnancy, intrahepatic cholestasis of pregnancy, pemphigoid gestationis, and pruritic urticarial papules and plaques of pregnancy.¹

As PPP is a rare disease, its effects on maternal-fetal health outcomes and management remain to be elucidated. Though maternal mortality is rare in PPP, it is a unique dermatosis of pregnancy because it may be associated with severe systemic maternal symptoms.² Fetal morbidity and mortality are less predictable in PPP, with reported cases of stillbirth, fetal anomalies, and neonatal death thought to be due largely to placental insufficiency, even with control of symptoms.^1,3 Given the risk of serious harm to the fetus, reporting of cases and discussion of PPP management is critical.

Case Report

An otherwise healthy 29-year-old G2P1 woman at 32 weeks’ gestation presented to our emergency department with a 1-week history of a pruritic, burning rash that started on the thighs then spread diffusely. She denied any similar rash in her prior pregnancy. She was not currently taking any medications except for prenatal vitamins and denied any systemic symptoms. The patient’s obstetrician initiated treatment with methylprednisolone 50 mg once daily for the rash 3 days prior to the current presentation, which had not seemed to help. On physical examination, edematous pink plaques studded with 1- to 2-mm collarettes of scaling and sparse 1-mm pustules involving the arms, chest, abdomen, back, groin, buttocks, and legs were noted. The plaques on the back and inner thighs had a peripheral rim of desquamative scaling. There were pink macules on the palms, and superficial desquamation was noted on the lips. The oral mucosa was otherwise spared (Figure 1).

Biopsy specimens from the left arm revealed discrete subcorneal pustules with mild acanthosis of the epidermis with spongiosis (Figure 2). The papillary dermis showed a sparse infiltrate of neutrophils with many marginated neutrophils within vessels. Direct immunofluorescence was negative for human IgG, IgA, IgM, complement component 3, and fibrinogen. Laboratory workup revealed leukocytosis of 21.5×10⁹/L (reference range, 4.5–11.0×10⁹/L) with neutrophilic predominance of 73.6% (reference range, 56%), an elevated erythrocyte sedimentation rate (ESR) of 40 mm/h (reference range, 0–20 mm/h), and a mild hypocalcemia of 8.6 mg/dL (reference range, 8.2–10.2 mg/dL). The patient was started on methylprednisone 40 mg once daily with a plan to taper the dose by 8 mg every 5 days.

At 35 weeks’ gestation, the patient continued to report pruritus and burning in the areas where the rash had developed. The morphology of the rash had changed considerably, as she now had prominent, annular, pink plaques with central clearing, trailing scaling, and a border of subtle pustules on the legs. There also were rings of desquamative scaling on the palms. During follow-up at 37 weeks’ gestation, the back, chest, and abdomen were improved from the initial presentation, and annular pink plaques with central clearing were noted on the legs (Figure 3). Given the clinical and histopathologic findings, a diagnosis of PPP was made. It was recommended that she undergo increased fetal surveillance with close obstetric follow-up. Weekly office visits with obstetrics and twice-weekly Doppler ultrasounds and fetal nonstress tests were deemed appropriate management. The patient was scheduled for induction at 39 weeks’ gestation given the risk for potential harm to the fetus. She was maintained on low-dose methylprednisolone 4 mg once daily for the duration of the pregnancy. The patient continued to have gradual improvement of the rash at the low treatment dose.

Following induction at 39 weeks’ gestation, the patient vaginally delivered a healthy, 6-lb male neonate at an outside hospital. She reported that the burning sensation improved within hours of delivery, and systemic steroids were stopped after delivery. At a follow-up visit 3 weeks postpartum, considerable improvement of the rash was noted with no evidence of pustules. Fading pink patches with a superficial scaling were noted on the back, chest, abdomen, arms, legs (Figure 4), and fingertips. The patient was counseled that PPP could recur in subsequent pregnancies and that she should be aware of the potential risks to the fetus.

Comment

In our patient, the diagnosis of PPP was supported by the presence of erythematous, coalescent plaques with small pustules at the margins and central erosions as well as the histologic findings of subcorneal pustules with mild acanthosis of the epidermis with spongiosis and a sparse neutrophilic infiltrate into the dermis. Laboratory studies showing leukocytosis and an elevated ESR, which are often seen in PPP, also were noted.

The typical presentation of PPP is characterized by lesions that initially develop in skin folds with centrifugal spread.³ The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet typically are spared with occasional involvement of oral and esophageal mucosae. Biopsy findings typically include spongiform pustules with neutrophil invasion into the epidermis. Typical laboratory findings include electrolyte derangements with elevated ESR and leukocytosis.¹

Diagnosis of PPP is critical given the potential for associated fetal morbidity and mortality.⁴ Anticipatory guidance for the patient also is necessary, as PPP can recur with subsequent pregnancies or even use of oral contraceptive pills (OCPs). Notably, a patient with recurrences of PPP with each of 9 pregnancies also experienced a recurrence when taking a combination estrogen/progesterone OCP, but not with an estrogen-only diethylstilbestrol OCP.⁵ Although the pathophysiology is not entirely understood, the development of PPP is thought to be related to the hormonal changes that occur in the third trimester, most notably due to elevated progesterone levels.² The presence of progesterone in OCPs and recurrences associated with their use supports this altered hormonal state, contributing to the underlying pathophysiology of PPP.

Pustular psoriasis of pregnancy can occur in women without any personal or family history of psoriasis, and as such, it is unclear whether PPP is a separate entity or a hormonally induced variation of generalized pustular psoriasis. Recent evidence included reports of women with PPP who had a mutation in the IL-36 receptor antagonist, leading to a relative abundance of IL-36 inflammatory cytokines.⁶As the cytokine profile during pregnancy is physiologically altered to favor a T helper 2–cell state, the altered expression of cytokines is believed to trigger an inflammatory response conducive to the development of PPP.² This mutation in the IL-36 receptor antagonist also is found in individuals with generalized pustular psoriasis, suggesting an overlap of disease etiology related to these cytokine interactions.^2,7,8

The mainstay of treatment for PPP is oral corticosteroids. Cases of PPP that are unresponsive to systemic steroids have been documented, requiring treatment with cyclosporine.⁹ Antitumor necrosis factors also have been used safely during pregnancy.¹⁰ Narrowband UVB phototherapy also has been proposed as a treatment alternative for patients who do not respond to oral corticosteroids.¹¹

Conclusion

Pustular psoriasis of pregnancy is a rare dermatosis of pregnancy that, unlike most other common dermatoses of pregnancy, is associated with adverse fetal outcomes. Diagnosis and management of PPP are critical to ensure the best care and outcomes for the patient and fetus and for a successful delivery of a healthy neonate. Our patient with PPP presented with involvement of the body, palms, and oral mucosa in the absence of systemic symptoms. Close follow-up and comanagement with the patient’s obstetrician ensured safe outcomes for the patient and the neonate.

Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformis, is a relatively rare cutaneous disorder of pregnancy wherein lesions typically appear in the third trimester and resolve after delivery; however, lesions may persist through the postpartum period. Pustular psoriasis of pregnancy may be considered a fifth dermatosis of pregnancy, alongside the classic dermatoses of atopic eruption of pregnancy, intrahepatic cholestasis of pregnancy, pemphigoid gestationis, and pruritic urticarial papules and plaques of pregnancy.¹

As PPP is a rare disease, its effects on maternal-fetal health outcomes and management remain to be elucidated. Though maternal mortality is rare in PPP, it is a unique dermatosis of pregnancy because it may be associated with severe systemic maternal symptoms.² Fetal morbidity and mortality are less predictable in PPP, with reported cases of stillbirth, fetal anomalies, and neonatal death thought to be due largely to placental insufficiency, even with control of symptoms.^1,3 Given the risk of serious harm to the fetus, reporting of cases and discussion of PPP management is critical.

Case Report

An otherwise healthy 29-year-old G2P1 woman at 32 weeks’ gestation presented to our emergency department with a 1-week history of a pruritic, burning rash that started on the thighs then spread diffusely. She denied any similar rash in her prior pregnancy. She was not currently taking any medications except for prenatal vitamins and denied any systemic symptoms. The patient’s obstetrician initiated treatment with methylprednisolone 50 mg once daily for the rash 3 days prior to the current presentation, which had not seemed to help. On physical examination, edematous pink plaques studded with 1- to 2-mm collarettes of scaling and sparse 1-mm pustules involving the arms, chest, abdomen, back, groin, buttocks, and legs were noted. The plaques on the back and inner thighs had a peripheral rim of desquamative scaling. There were pink macules on the palms, and superficial desquamation was noted on the lips. The oral mucosa was otherwise spared (Figure 1).

Biopsy specimens from the left arm revealed discrete subcorneal pustules with mild acanthosis of the epidermis with spongiosis (Figure 2). The papillary dermis showed a sparse infiltrate of neutrophils with many marginated neutrophils within vessels. Direct immunofluorescence was negative for human IgG, IgA, IgM, complement component 3, and fibrinogen. Laboratory workup revealed leukocytosis of 21.5×10⁹/L (reference range, 4.5–11.0×10⁹/L) with neutrophilic predominance of 73.6% (reference range, 56%), an elevated erythrocyte sedimentation rate (ESR) of 40 mm/h (reference range, 0–20 mm/h), and a mild hypocalcemia of 8.6 mg/dL (reference range, 8.2–10.2 mg/dL). The patient was started on methylprednisone 40 mg once daily with a plan to taper the dose by 8 mg every 5 days.

At 35 weeks’ gestation, the patient continued to report pruritus and burning in the areas where the rash had developed. The morphology of the rash had changed considerably, as she now had prominent, annular, pink plaques with central clearing, trailing scaling, and a border of subtle pustules on the legs. There also were rings of desquamative scaling on the palms. During follow-up at 37 weeks’ gestation, the back, chest, and abdomen were improved from the initial presentation, and annular pink plaques with central clearing were noted on the legs (Figure 3). Given the clinical and histopathologic findings, a diagnosis of PPP was made. It was recommended that she undergo increased fetal surveillance with close obstetric follow-up. Weekly office visits with obstetrics and twice-weekly Doppler ultrasounds and fetal nonstress tests were deemed appropriate management. The patient was scheduled for induction at 39 weeks’ gestation given the risk for potential harm to the fetus. She was maintained on low-dose methylprednisolone 4 mg once daily for the duration of the pregnancy. The patient continued to have gradual improvement of the rash at the low treatment dose.

Following induction at 39 weeks’ gestation, the patient vaginally delivered a healthy, 6-lb male neonate at an outside hospital. She reported that the burning sensation improved within hours of delivery, and systemic steroids were stopped after delivery. At a follow-up visit 3 weeks postpartum, considerable improvement of the rash was noted with no evidence of pustules. Fading pink patches with a superficial scaling were noted on the back, chest, abdomen, arms, legs (Figure 4), and fingertips. The patient was counseled that PPP could recur in subsequent pregnancies and that she should be aware of the potential risks to the fetus.

Comment

In our patient, the diagnosis of PPP was supported by the presence of erythematous, coalescent plaques with small pustules at the margins and central erosions as well as the histologic findings of subcorneal pustules with mild acanthosis of the epidermis with spongiosis and a sparse neutrophilic infiltrate into the dermis. Laboratory studies showing leukocytosis and an elevated ESR, which are often seen in PPP, also were noted.

The typical presentation of PPP is characterized by lesions that initially develop in skin folds with centrifugal spread.³ The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet typically are spared with occasional involvement of oral and esophageal mucosae. Biopsy findings typically include spongiform pustules with neutrophil invasion into the epidermis. Typical laboratory findings include electrolyte derangements with elevated ESR and leukocytosis.¹

Diagnosis of PPP is critical given the potential for associated fetal morbidity and mortality.⁴ Anticipatory guidance for the patient also is necessary, as PPP can recur with subsequent pregnancies or even use of oral contraceptive pills (OCPs). Notably, a patient with recurrences of PPP with each of 9 pregnancies also experienced a recurrence when taking a combination estrogen/progesterone OCP, but not with an estrogen-only diethylstilbestrol OCP.⁵ Although the pathophysiology is not entirely understood, the development of PPP is thought to be related to the hormonal changes that occur in the third trimester, most notably due to elevated progesterone levels.² The presence of progesterone in OCPs and recurrences associated with their use supports this altered hormonal state, contributing to the underlying pathophysiology of PPP.

Pustular psoriasis of pregnancy can occur in women without any personal or family history of psoriasis, and as such, it is unclear whether PPP is a separate entity or a hormonally induced variation of generalized pustular psoriasis. Recent evidence included reports of women with PPP who had a mutation in the IL-36 receptor antagonist, leading to a relative abundance of IL-36 inflammatory cytokines.⁶As the cytokine profile during pregnancy is physiologically altered to favor a T helper 2–cell state, the altered expression of cytokines is believed to trigger an inflammatory response conducive to the development of PPP.² This mutation in the IL-36 receptor antagonist also is found in individuals with generalized pustular psoriasis, suggesting an overlap of disease etiology related to these cytokine interactions.^2,7,8

The mainstay of treatment for PPP is oral corticosteroids. Cases of PPP that are unresponsive to systemic steroids have been documented, requiring treatment with cyclosporine.⁹ Antitumor necrosis factors also have been used safely during pregnancy.¹⁰ Narrowband UVB phototherapy also has been proposed as a treatment alternative for patients who do not respond to oral corticosteroids.¹¹

Conclusion

Pustular psoriasis of pregnancy is a rare dermatosis of pregnancy that, unlike most other common dermatoses of pregnancy, is associated with adverse fetal outcomes. Diagnosis and management of PPP are critical to ensure the best care and outcomes for the patient and fetus and for a successful delivery of a healthy neonate. Our patient with PPP presented with involvement of the body, palms, and oral mucosa in the absence of systemic symptoms. Close follow-up and comanagement with the patient’s obstetrician ensured safe outcomes for the patient and the neonate.

Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformis, is a relatively rare cutaneous disorder of pregnancy wherein lesions typically appear in the third trimester and resolve after delivery; however, lesions may persist through the postpartum period. Pustular psoriasis of pregnancy may be considered a fifth dermatosis of pregnancy, alongside the classic dermatoses of atopic eruption of pregnancy, intrahepatic cholestasis of pregnancy, pemphigoid gestationis, and pruritic urticarial papules and plaques of pregnancy.¹

As PPP is a rare disease, its effects on maternal-fetal health outcomes and management remain to be elucidated. Though maternal mortality is rare in PPP, it is a unique dermatosis of pregnancy because it may be associated with severe systemic maternal symptoms.² Fetal morbidity and mortality are less predictable in PPP, with reported cases of stillbirth, fetal anomalies, and neonatal death thought to be due largely to placental insufficiency, even with control of symptoms.^1,3 Given the risk of serious harm to the fetus, reporting of cases and discussion of PPP management is critical.

Case Report

An otherwise healthy 29-year-old G2P1 woman at 32 weeks’ gestation presented to our emergency department with a 1-week history of a pruritic, burning rash that started on the thighs then spread diffusely. She denied any similar rash in her prior pregnancy. She was not currently taking any medications except for prenatal vitamins and denied any systemic symptoms. The patient’s obstetrician initiated treatment with methylprednisolone 50 mg once daily for the rash 3 days prior to the current presentation, which had not seemed to help. On physical examination, edematous pink plaques studded with 1- to 2-mm collarettes of scaling and sparse 1-mm pustules involving the arms, chest, abdomen, back, groin, buttocks, and legs were noted. The plaques on the back and inner thighs had a peripheral rim of desquamative scaling. There were pink macules on the palms, and superficial desquamation was noted on the lips. The oral mucosa was otherwise spared (Figure 1).

Biopsy specimens from the left arm revealed discrete subcorneal pustules with mild acanthosis of the epidermis with spongiosis (Figure 2). The papillary dermis showed a sparse infiltrate of neutrophils with many marginated neutrophils within vessels. Direct immunofluorescence was negative for human IgG, IgA, IgM, complement component 3, and fibrinogen. Laboratory workup revealed leukocytosis of 21.5×10⁹/L (reference range, 4.5–11.0×10⁹/L) with neutrophilic predominance of 73.6% (reference range, 56%), an elevated erythrocyte sedimentation rate (ESR) of 40 mm/h (reference range, 0–20 mm/h), and a mild hypocalcemia of 8.6 mg/dL (reference range, 8.2–10.2 mg/dL). The patient was started on methylprednisone 40 mg once daily with a plan to taper the dose by 8 mg every 5 days.

At 35 weeks’ gestation, the patient continued to report pruritus and burning in the areas where the rash had developed. The morphology of the rash had changed considerably, as she now had prominent, annular, pink plaques with central clearing, trailing scaling, and a border of subtle pustules on the legs. There also were rings of desquamative scaling on the palms. During follow-up at 37 weeks’ gestation, the back, chest, and abdomen were improved from the initial presentation, and annular pink plaques with central clearing were noted on the legs (Figure 3). Given the clinical and histopathologic findings, a diagnosis of PPP was made. It was recommended that she undergo increased fetal surveillance with close obstetric follow-up. Weekly office visits with obstetrics and twice-weekly Doppler ultrasounds and fetal nonstress tests were deemed appropriate management. The patient was scheduled for induction at 39 weeks’ gestation given the risk for potential harm to the fetus. She was maintained on low-dose methylprednisolone 4 mg once daily for the duration of the pregnancy. The patient continued to have gradual improvement of the rash at the low treatment dose.

Following induction at 39 weeks’ gestation, the patient vaginally delivered a healthy, 6-lb male neonate at an outside hospital. She reported that the burning sensation improved within hours of delivery, and systemic steroids were stopped after delivery. At a follow-up visit 3 weeks postpartum, considerable improvement of the rash was noted with no evidence of pustules. Fading pink patches with a superficial scaling were noted on the back, chest, abdomen, arms, legs (Figure 4), and fingertips. The patient was counseled that PPP could recur in subsequent pregnancies and that she should be aware of the potential risks to the fetus.

Comment

In our patient, the diagnosis of PPP was supported by the presence of erythematous, coalescent plaques with small pustules at the margins and central erosions as well as the histologic findings of subcorneal pustules with mild acanthosis of the epidermis with spongiosis and a sparse neutrophilic infiltrate into the dermis. Laboratory studies showing leukocytosis and an elevated ESR, which are often seen in PPP, also were noted.

The typical presentation of PPP is characterized by lesions that initially develop in skin folds with centrifugal spread.³ The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet typically are spared with occasional involvement of oral and esophageal mucosae. Biopsy findings typically include spongiform pustules with neutrophil invasion into the epidermis. Typical laboratory findings include electrolyte derangements with elevated ESR and leukocytosis.¹

Diagnosis of PPP is critical given the potential for associated fetal morbidity and mortality.⁴ Anticipatory guidance for the patient also is necessary, as PPP can recur with subsequent pregnancies or even use of oral contraceptive pills (OCPs). Notably, a patient with recurrences of PPP with each of 9 pregnancies also experienced a recurrence when taking a combination estrogen/progesterone OCP, but not with an estrogen-only diethylstilbestrol OCP.⁵ Although the pathophysiology is not entirely understood, the development of PPP is thought to be related to the hormonal changes that occur in the third trimester, most notably due to elevated progesterone levels.² The presence of progesterone in OCPs and recurrences associated with their use supports this altered hormonal state, contributing to the underlying pathophysiology of PPP.

Pustular psoriasis of pregnancy can occur in women without any personal or family history of psoriasis, and as such, it is unclear whether PPP is a separate entity or a hormonally induced variation of generalized pustular psoriasis. Recent evidence included reports of women with PPP who had a mutation in the IL-36 receptor antagonist, leading to a relative abundance of IL-36 inflammatory cytokines.⁶As the cytokine profile during pregnancy is physiologically altered to favor a T helper 2–cell state, the altered expression of cytokines is believed to trigger an inflammatory response conducive to the development of PPP.² This mutation in the IL-36 receptor antagonist also is found in individuals with generalized pustular psoriasis, suggesting an overlap of disease etiology related to these cytokine interactions.^2,7,8

The mainstay of treatment for PPP is oral corticosteroids. Cases of PPP that are unresponsive to systemic steroids have been documented, requiring treatment with cyclosporine.⁹ Antitumor necrosis factors also have been used safely during pregnancy.¹⁰ Narrowband UVB phototherapy also has been proposed as a treatment alternative for patients who do not respond to oral corticosteroids.¹¹

Conclusion

Pustular psoriasis of pregnancy is a rare dermatosis of pregnancy that, unlike most other common dermatoses of pregnancy, is associated with adverse fetal outcomes. Diagnosis and management of PPP are critical to ensure the best care and outcomes for the patient and fetus and for a successful delivery of a healthy neonate. Our patient with PPP presented with involvement of the body, palms, and oral mucosa in the absence of systemic symptoms. Close follow-up and comanagement with the patient’s obstetrician ensured safe outcomes for the patient and the neonate.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

Myth: Children eventually outgrow atopic dermatitis and therefore do not need treatment

The negative impact of atopic dermatitis (AD) on quality of life in the pediatric population often prompts parents/guardians to inquire about whether a child with AD will ever outgrow their disease. If remission is expected as the child gets older, many may question if it is necessary to pursue treatment or just let the disease run its course. Although AD often is reported to resolve soon after the first decade of life, symptoms can persist well into the second decade and beyond, suggesting that AD may be a lifelong disease with periods of waxing and waning symptoms that require persistent treatment throughout the patient’s life.

A 2014 study included 7157 children with AD (mean age of disease onset, 1.7 years) who were enrolled in the Pediatric Eczema Elective Registry (PEER) program between the ages of 2 and 17 years with measurement of disease activity at regular 6-month intervals for up to 5 years. The study results indicated that more than 80% of patients at every age (age range, 2–26 years) had symptoms of AD and/or were using medication to treat their disease, and the majority (64%) of patients had never reported a 6-month period during which they achieved clearance of symptoms without medication. At the age of 20 years, 50% of patients reported at least 1 lifetime 6-month period during which they were both symptom and treatment free. In another study of adolescents with AD who also had AD in childhood (N=82), 48% of patients remained in the same AD severity grades and 13% deteriorated from childhood to adolescence; only 39% of patients showed improvement in disease severity from childhood to adolescence. The findings of these reports are contradictory to conventional clinical teaching, which indicates that AD generally resolves by age 12 in 50% to 70% of children.

Even though some children with AD may experience periods of disease clearance, these findings often do not persist and should not be confused with a permanent remission. Most patients require continued treatment with medications to achieve relief of symptoms. Therefore, physicians should not assure parents/guardians that a child can outgrow AD; rather, they should educate pediatric patients and their caregivers about the potentially lifelong disease course and encourage early intervention to mitigate symptoms and manage comorbidities as the patient ages.

Myth: Children eventually outgrow atopic dermatitis and therefore do not need treatment

The negative impact of atopic dermatitis (AD) on quality of life in the pediatric population often prompts parents/guardians to inquire about whether a child with AD will ever outgrow their disease. If remission is expected as the child gets older, many may question if it is necessary to pursue treatment or just let the disease run its course. Although AD often is reported to resolve soon after the first decade of life, symptoms can persist well into the second decade and beyond, suggesting that AD may be a lifelong disease with periods of waxing and waning symptoms that require persistent treatment throughout the patient’s life.

A 2014 study included 7157 children with AD (mean age of disease onset, 1.7 years) who were enrolled in the Pediatric Eczema Elective Registry (PEER) program between the ages of 2 and 17 years with measurement of disease activity at regular 6-month intervals for up to 5 years. The study results indicated that more than 80% of patients at every age (age range, 2–26 years) had symptoms of AD and/or were using medication to treat their disease, and the majority (64%) of patients had never reported a 6-month period during which they achieved clearance of symptoms without medication. At the age of 20 years, 50% of patients reported at least 1 lifetime 6-month period during which they were both symptom and treatment free. In another study of adolescents with AD who also had AD in childhood (N=82), 48% of patients remained in the same AD severity grades and 13% deteriorated from childhood to adolescence; only 39% of patients showed improvement in disease severity from childhood to adolescence. The findings of these reports are contradictory to conventional clinical teaching, which indicates that AD generally resolves by age 12 in 50% to 70% of children.

Even though some children with AD may experience periods of disease clearance, these findings often do not persist and should not be confused with a permanent remission. Most patients require continued treatment with medications to achieve relief of symptoms. Therefore, physicians should not assure parents/guardians that a child can outgrow AD; rather, they should educate pediatric patients and their caregivers about the potentially lifelong disease course and encourage early intervention to mitigate symptoms and manage comorbidities as the patient ages.

Myth: Children eventually outgrow atopic dermatitis and therefore do not need treatment

The negative impact of atopic dermatitis (AD) on quality of life in the pediatric population often prompts parents/guardians to inquire about whether a child with AD will ever outgrow their disease. If remission is expected as the child gets older, many may question if it is necessary to pursue treatment or just let the disease run its course. Although AD often is reported to resolve soon after the first decade of life, symptoms can persist well into the second decade and beyond, suggesting that AD may be a lifelong disease with periods of waxing and waning symptoms that require persistent treatment throughout the patient’s life.

A 2014 study included 7157 children with AD (mean age of disease onset, 1.7 years) who were enrolled in the Pediatric Eczema Elective Registry (PEER) program between the ages of 2 and 17 years with measurement of disease activity at regular 6-month intervals for up to 5 years. The study results indicated that more than 80% of patients at every age (age range, 2–26 years) had symptoms of AD and/or were using medication to treat their disease, and the majority (64%) of patients had never reported a 6-month period during which they achieved clearance of symptoms without medication. At the age of 20 years, 50% of patients reported at least 1 lifetime 6-month period during which they were both symptom and treatment free. In another study of adolescents with AD who also had AD in childhood (N=82), 48% of patients remained in the same AD severity grades and 13% deteriorated from childhood to adolescence; only 39% of patients showed improvement in disease severity from childhood to adolescence. The findings of these reports are contradictory to conventional clinical teaching, which indicates that AD generally resolves by age 12 in 50% to 70% of children.

Even though some children with AD may experience periods of disease clearance, these findings often do not persist and should not be confused with a permanent remission. Most patients require continued treatment with medications to achieve relief of symptoms. Therefore, physicians should not assure parents/guardians that a child can outgrow AD; rather, they should educate pediatric patients and their caregivers about the potentially lifelong disease course and encourage early intervention to mitigate symptoms and manage comorbidities as the patient ages.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

Cutaneous melanoma is a considerable public health concern. In the United States, an estimated 87,110 cases were diagnosed in 2017, and more than 9000 deaths are expected as result of this disease in 2018.¹ Early diagnosis of melanoma is associated with favorable survival rates (5-year overall survival rates for melanoma in situ and stage IA melanoma, 99% and 97%, respectively).² In contrast, the prognosis for advanced-stage melanoma is poor, with a 5-year survival rate of 16% for patients with stage IV disease. Therefore, early detection is critical to reducing mortality in melanoma patients.³

The term Hispanic refers to a panethnic category primarily encompassing Mexican-Americans, Cubans, and Puerto Ricans, as well as individuals from the Caribbean and Central and South America. These populations are diverse in birth origin, primary language, acculturation, distinct ethnic traditions, education level, and occupation. Hispanics in the United States are heterogeneous in many dimensions related to health risks, health care use, and health outcomes.⁴ Genetic predisposition, lifestyle risks, and access to and use of health care services can shape melanoma diagnosis, treatment, and progression across Hispanic populations differently than in other populations.

In this review, the epidemiology and clinical presentation of melanoma in US Hispanics is summarized, and recommendations for a research agenda to advance understanding of this disease in the most rapidly growing segment of the US population is provided.

Melanoma Incidence, Presentation, and Outcomes in US Hispanics

In the period from 2008 to 2012, the age-adjusted incidence of melanoma in US Hispanics (4.6 per 100,00 men and 4.2 per 100,00 women) was lower than in NHWs.⁵ Garnett et al⁵ reported a decline in melanoma incidence in US Hispanics between 2003 and 2012—an observation that stands in contrast to state-level studies in California and Florida, in which small but substantial increases in melanoma incidence among Hispanics were reported.^6,7 The rising incidence of melanomas thicker than 1.5 mm at presentation among Hispanic men living in California is particularly worrisome.⁶ Discrepancies in incidence trends might reflect changes in incidence over time or differences in state-level registry reporting of melanoma.⁵

Despite a lower overall incidence of melanoma in US Hispanics, those who do develop the disease are 2.4 times more likely (age-adjusted odds ratio) to present with stage III disease (confidence interval, 1.89-3.05)⁸ and are 3.64 times more likely to develop distant metastases (confidence interval, 2.65-5.0) than NHWs.^3,7,9-13 Disparities also exist in the diagnosis of childhood melanoma: Hispanic children and adolescents who have a diagnosis of melanoma are 3 times more likely to present with advanced disease than NHW counterparts.¹⁴ Survival analyses by age and stage show considerably lower survival among Hispanic patients compared to NHW patients with stage I and II disease. In part, worse survival outcomes among Hispanics are the result of the pattern of more advanced disease at presentation.^8,14,15

Late presentation for evaluation of melanomas in Hispanics has been attributed to a number of variables, including a lack of skin cancer awareness and knowledge,^9,16 a lower rate of self- and physician-performed skin examinations,¹⁰ differences in tumor biology,⁹ and socioeconomic forces.^7,17

In a previous study investigating the relationship between neighborhood characteristics and tumor stage at melanoma diagnosis in Hispanic men in California, Texas, and Florida, several key findings emerged.¹⁷ First, residency in a census tract with a high density of immigrants (California, Texas) and a high composition of Hispanics (California, Florida) was an important predictor of a late-stage melanoma diagnosis in fully adjusted models. Additionally, the strength of association between measures of socioeconomic status (ie, poverty and education) and tumor stage at melanoma diagnosis was attenuated in multivariate models when enclaves and availability of primary care resources were taken into account. Hispanic melanoma cases in areas with a low density of primary care physicians had an increased likelihood of late-stage diagnosis in California and Texas. The probability of late-stage diagnosis was concentrated in specific regions along the United States–Mexico border, in south central California, and along the southeastern coast of Florida. Lastly, in Texas, Hispanic men aged 18 to 34 years and 35 to 49 years were at an increased risk of late-stage melanoma diagnosis compared to men 65 years and older.¹⁷

Demographic and Clinical Characteristics of Melanoma in Hispanic Patients

Among Hispanics, white Hispanics comprise the majority of melanoma cases.⁵ Median age at diagnosis is younger in Hispanics compared to whites.^5,6 Hispanic men typically are older (median age, 61 years) than Hispanic women (median age, 52 years) at diagnosis.⁵ Similar to what is seen in NHWs, young Hispanic women experience a higher melanoma incidence than young Hispanic men.⁵ Among older Hispanics, melanoma is more common in men.^5,8

Melanomas located on the lower extremities and hips are more prevalent in Hispanics than in NHWs.^5,8,18 Among Hispanics, there are age- and sex-based variations in the anatomic location of primary tumors: in Hispanic men, truncal tumors predominate, and in Hispanic women, tumors of the lower extremities are most common across all age groups.⁵ The incidence of melanomas located in the head and neck region increases with age for both Hispanic men and women.

For melanomas in which the histologic type is known, superficial spreading melanoma is the most common subtype among Hispanics.^5,17,19 Acral lentiginous melanomas and nodular melanomas are more common among Hispanics than among NHWs.^5,17,19

The observation that Hispanics with melanoma are more prone to lower-extremity tumors and nodular and acral lentiginous melanoma subtypes than NHWs suggests that UV exposure history may be of less importance in this population. Although numerous studies have explored melanoma risk factors in NHWs, there is a striking paucity of such studies in Hispanics. For example, there are conflicting data regarding the role of UV exposure in melanoma risk among Hispanics. Hu et al²⁰ found that UV index and latitude correlated with melanoma risk in this population, whereas Eide et al²¹ found no association between UV exposure and melanoma incidence in Hispanics. A prospective study involving a multiethnic cohort (of whom 40 of the 107 participants were Hispanic) found no clear association between a history of sunburn and melanoma risk in Hispanics.¹⁸

Strategies for Reducing Disparities in Outcomes

Our knowledge of melanoma epidemiology in Hispanics derives mainly from secondary analyses of state-level and national cancer registry data sets.^{5-8,13-15,17,19,20} These administrative data sources often are limited by missing data (eg, tumor thickness, histologic subtype) or lack important patient-level information (eg, self-identified race and ethnicity, health insurance status). Additionally, the manner in which data are collected and integrated into research varies; for example, socioeconomic measures often are reported as either area-based or composite measures. Thus, there is a need to improve the consistency of reporting on demographic and socioeconomic measures across studies. Polite et al²² recommended standardization of reporting criteria and that a standard set of demographic and socioeconomic status measures be included in clinical registries and research protocols.²² Researchers should strive to collect self-reported information on race and ethnicity, as well as the most granular level of detail on health insurance status, ancestry, and immigration status.

The host phenotypic characteristics of melanoma in NHWs are well understood, but the biological and environmental determinants of melanoma risk in Hispanics and other minorities are unknown. For example, fair complexion, red hair, blue eyes, increased freckling density, and the presence of numerous dysplastic and common melanocytic nevi indicate a propensity toward cutaneous melanoma.^23,24 However, the relevance of such risk factors in Hispanics is unknown and has not been widely investigated in this patient population. Park et al¹⁸ found that a person’s sunburn susceptibility phenotype (defined as hair and eye color, ability to tan, and skin reaction to sunlight) was associated with an increased risk of melanoma among nonwhite, multiracial individuals. However, this study was limited by a small number of minority cases, which included only 40 Hispanic participants with melanoma.¹⁸ There is a need for rigorous observational studies to clearly define the phenotypic characteristics, sun-exposure behavior patterns, and genetic contributors to melanoma genesis in Hispanics.

The biologic determinants of postdiagnosis survival in Hispanics with melanoma are not well understood. It is unknown if genetic predisposition modifies melanoma risk in Hispanics. For example, the frequency of BRAF gene mutation or other driver mutations in US Hispanics has been understudied. It is important to know if mutation frequency patterns differ in Hispanics patients compared to NHWs because this knowledge could have considerable implications for treatment. Several recommendations should be considered to address these knowledge gaps. First, there is a need for development or enhancement of melanoma biorepositories, which should include tumor and nontumor specimens from a diverse sample of melanoma patients. Additionally, multi-institutional and multidisciplinary consortiums need to be created in order to amass a number of Hispanic melanoma patients to identify genetic, biologic, and behavioral risk factors specific to this subgroup of patients. The AMBER Consortium, which focuses on breast cancer epidemiology and risk in black women, is a model for the type of consortium needed for the study of melanoma in Hispanics.²⁵ Lastly, community engagement will be central to developing sustainable recruitment and data-collection efforts.²⁶ Involvement of key stakeholders will provide an in-depth assessment of community needs as well as real-time feedback on the process and practicality of research questions. Buy-in from affected communities also may facilitate dissemination of research findings to affected communities.

Conclusion

Hispanics are more likely to present with an advanced stages of disease and have higher melanoma-specific mortality rates than NHWs. Regrettably, a huge knowledge gap exists regarding contributors and solutions to melanoma disparities among this fast-growing, understudied segment of the US population. Accordingly, critical research is needed to address the most pressing questions regarding melanoma risk and poor outcomes among Hispanics to foster implementation of interventional efforts in prevention, early detection, and treatment. A multi-institutional and multidisciplinary approach across multiple levels is needed to eliminate disparate outcomes. Although melanoma is relatively uncommon among Hispanics, studies of melanoma in Hispanics (given their diverse genetic ancestry and migration) provide a unique backdrop against which researchers can explicate melanoma etiology—thus benefiting Hispanics and non-Hispanics alike.

Cutaneous melanoma is a considerable public health concern. In the United States, an estimated 87,110 cases were diagnosed in 2017, and more than 9000 deaths are expected as result of this disease in 2018.¹ Early diagnosis of melanoma is associated with favorable survival rates (5-year overall survival rates for melanoma in situ and stage IA melanoma, 99% and 97%, respectively).² In contrast, the prognosis for advanced-stage melanoma is poor, with a 5-year survival rate of 16% for patients with stage IV disease. Therefore, early detection is critical to reducing mortality in melanoma patients.³

The term Hispanic refers to a panethnic category primarily encompassing Mexican-Americans, Cubans, and Puerto Ricans, as well as individuals from the Caribbean and Central and South America. These populations are diverse in birth origin, primary language, acculturation, distinct ethnic traditions, education level, and occupation. Hispanics in the United States are heterogeneous in many dimensions related to health risks, health care use, and health outcomes.⁴ Genetic predisposition, lifestyle risks, and access to and use of health care services can shape melanoma diagnosis, treatment, and progression across Hispanic populations differently than in other populations.

In this review, the epidemiology and clinical presentation of melanoma in US Hispanics is summarized, and recommendations for a research agenda to advance understanding of this disease in the most rapidly growing segment of the US population is provided.

Melanoma Incidence, Presentation, and Outcomes in US Hispanics

In the period from 2008 to 2012, the age-adjusted incidence of melanoma in US Hispanics (4.6 per 100,00 men and 4.2 per 100,00 women) was lower than in NHWs.⁵ Garnett et al⁵ reported a decline in melanoma incidence in US Hispanics between 2003 and 2012—an observation that stands in contrast to state-level studies in California and Florida, in which small but substantial increases in melanoma incidence among Hispanics were reported.^6,7 The rising incidence of melanomas thicker than 1.5 mm at presentation among Hispanic men living in California is particularly worrisome.⁶ Discrepancies in incidence trends might reflect changes in incidence over time or differences in state-level registry reporting of melanoma.⁵

Despite a lower overall incidence of melanoma in US Hispanics, those who do develop the disease are 2.4 times more likely (age-adjusted odds ratio) to present with stage III disease (confidence interval, 1.89-3.05)⁸ and are 3.64 times more likely to develop distant metastases (confidence interval, 2.65-5.0) than NHWs.^3,7,9-13 Disparities also exist in the diagnosis of childhood melanoma: Hispanic children and adolescents who have a diagnosis of melanoma are 3 times more likely to present with advanced disease than NHW counterparts.¹⁴ Survival analyses by age and stage show considerably lower survival among Hispanic patients compared to NHW patients with stage I and II disease. In part, worse survival outcomes among Hispanics are the result of the pattern of more advanced disease at presentation.^8,14,15

Late presentation for evaluation of melanomas in Hispanics has been attributed to a number of variables, including a lack of skin cancer awareness and knowledge,^9,16 a lower rate of self- and physician-performed skin examinations,¹⁰ differences in tumor biology,⁹ and socioeconomic forces.^7,17

In a previous study investigating the relationship between neighborhood characteristics and tumor stage at melanoma diagnosis in Hispanic men in California, Texas, and Florida, several key findings emerged.¹⁷ First, residency in a census tract with a high density of immigrants (California, Texas) and a high composition of Hispanics (California, Florida) was an important predictor of a late-stage melanoma diagnosis in fully adjusted models. Additionally, the strength of association between measures of socioeconomic status (ie, poverty and education) and tumor stage at melanoma diagnosis was attenuated in multivariate models when enclaves and availability of primary care resources were taken into account. Hispanic melanoma cases in areas with a low density of primary care physicians had an increased likelihood of late-stage diagnosis in California and Texas. The probability of late-stage diagnosis was concentrated in specific regions along the United States–Mexico border, in south central California, and along the southeastern coast of Florida. Lastly, in Texas, Hispanic men aged 18 to 34 years and 35 to 49 years were at an increased risk of late-stage melanoma diagnosis compared to men 65 years and older.¹⁷

Demographic and Clinical Characteristics of Melanoma in Hispanic Patients

Among Hispanics, white Hispanics comprise the majority of melanoma cases.⁵ Median age at diagnosis is younger in Hispanics compared to whites.^5,6 Hispanic men typically are older (median age, 61 years) than Hispanic women (median age, 52 years) at diagnosis.⁵ Similar to what is seen in NHWs, young Hispanic women experience a higher melanoma incidence than young Hispanic men.⁵ Among older Hispanics, melanoma is more common in men.^5,8

Melanomas located on the lower extremities and hips are more prevalent in Hispanics than in NHWs.^5,8,18 Among Hispanics, there are age- and sex-based variations in the anatomic location of primary tumors: in Hispanic men, truncal tumors predominate, and in Hispanic women, tumors of the lower extremities are most common across all age groups.⁵ The incidence of melanomas located in the head and neck region increases with age for both Hispanic men and women.

For melanomas in which the histologic type is known, superficial spreading melanoma is the most common subtype among Hispanics.^5,17,19 Acral lentiginous melanomas and nodular melanomas are more common among Hispanics than among NHWs.^5,17,19

The observation that Hispanics with melanoma are more prone to lower-extremity tumors and nodular and acral lentiginous melanoma subtypes than NHWs suggests that UV exposure history may be of less importance in this population. Although numerous studies have explored melanoma risk factors in NHWs, there is a striking paucity of such studies in Hispanics. For example, there are conflicting data regarding the role of UV exposure in melanoma risk among Hispanics. Hu et al²⁰ found that UV index and latitude correlated with melanoma risk in this population, whereas Eide et al²¹ found no association between UV exposure and melanoma incidence in Hispanics. A prospective study involving a multiethnic cohort (of whom 40 of the 107 participants were Hispanic) found no clear association between a history of sunburn and melanoma risk in Hispanics.¹⁸

Strategies for Reducing Disparities in Outcomes

Our knowledge of melanoma epidemiology in Hispanics derives mainly from secondary analyses of state-level and national cancer registry data sets.^{5-8,13-15,17,19,20} These administrative data sources often are limited by missing data (eg, tumor thickness, histologic subtype) or lack important patient-level information (eg, self-identified race and ethnicity, health insurance status). Additionally, the manner in which data are collected and integrated into research varies; for example, socioeconomic measures often are reported as either area-based or composite measures. Thus, there is a need to improve the consistency of reporting on demographic and socioeconomic measures across studies. Polite et al²² recommended standardization of reporting criteria and that a standard set of demographic and socioeconomic status measures be included in clinical registries and research protocols.²² Researchers should strive to collect self-reported information on race and ethnicity, as well as the most granular level of detail on health insurance status, ancestry, and immigration status.

The host phenotypic characteristics of melanoma in NHWs are well understood, but the biological and environmental determinants of melanoma risk in Hispanics and other minorities are unknown. For example, fair complexion, red hair, blue eyes, increased freckling density, and the presence of numerous dysplastic and common melanocytic nevi indicate a propensity toward cutaneous melanoma.^23,24 However, the relevance of such risk factors in Hispanics is unknown and has not been widely investigated in this patient population. Park et al¹⁸ found that a person’s sunburn susceptibility phenotype (defined as hair and eye color, ability to tan, and skin reaction to sunlight) was associated with an increased risk of melanoma among nonwhite, multiracial individuals. However, this study was limited by a small number of minority cases, which included only 40 Hispanic participants with melanoma.¹⁸ There is a need for rigorous observational studies to clearly define the phenotypic characteristics, sun-exposure behavior patterns, and genetic contributors to melanoma genesis in Hispanics.

The biologic determinants of postdiagnosis survival in Hispanics with melanoma are not well understood. It is unknown if genetic predisposition modifies melanoma risk in Hispanics. For example, the frequency of BRAF gene mutation or other driver mutations in US Hispanics has been understudied. It is important to know if mutation frequency patterns differ in Hispanics patients compared to NHWs because this knowledge could have considerable implications for treatment. Several recommendations should be considered to address these knowledge gaps. First, there is a need for development or enhancement of melanoma biorepositories, which should include tumor and nontumor specimens from a diverse sample of melanoma patients. Additionally, multi-institutional and multidisciplinary consortiums need to be created in order to amass a number of Hispanic melanoma patients to identify genetic, biologic, and behavioral risk factors specific to this subgroup of patients. The AMBER Consortium, which focuses on breast cancer epidemiology and risk in black women, is a model for the type of consortium needed for the study of melanoma in Hispanics.²⁵ Lastly, community engagement will be central to developing sustainable recruitment and data-collection efforts.²⁶ Involvement of key stakeholders will provide an in-depth assessment of community needs as well as real-time feedback on the process and practicality of research questions. Buy-in from affected communities also may facilitate dissemination of research findings to affected communities.

Conclusion

Hispanics are more likely to present with an advanced stages of disease and have higher melanoma-specific mortality rates than NHWs. Regrettably, a huge knowledge gap exists regarding contributors and solutions to melanoma disparities among this fast-growing, understudied segment of the US population. Accordingly, critical research is needed to address the most pressing questions regarding melanoma risk and poor outcomes among Hispanics to foster implementation of interventional efforts in prevention, early detection, and treatment. A multi-institutional and multidisciplinary approach across multiple levels is needed to eliminate disparate outcomes. Although melanoma is relatively uncommon among Hispanics, studies of melanoma in Hispanics (given their diverse genetic ancestry and migration) provide a unique backdrop against which researchers can explicate melanoma etiology—thus benefiting Hispanics and non-Hispanics alike.

Cutaneous melanoma is a considerable public health concern. In the United States, an estimated 87,110 cases were diagnosed in 2017, and more than 9000 deaths are expected as result of this disease in 2018.¹ Early diagnosis of melanoma is associated with favorable survival rates (5-year overall survival rates for melanoma in situ and stage IA melanoma, 99% and 97%, respectively).² In contrast, the prognosis for advanced-stage melanoma is poor, with a 5-year survival rate of 16% for patients with stage IV disease. Therefore, early detection is critical to reducing mortality in melanoma patients.³

The term Hispanic refers to a panethnic category primarily encompassing Mexican-Americans, Cubans, and Puerto Ricans, as well as individuals from the Caribbean and Central and South America. These populations are diverse in birth origin, primary language, acculturation, distinct ethnic traditions, education level, and occupation. Hispanics in the United States are heterogeneous in many dimensions related to health risks, health care use, and health outcomes.⁴ Genetic predisposition, lifestyle risks, and access to and use of health care services can shape melanoma diagnosis, treatment, and progression across Hispanic populations differently than in other populations.

In this review, the epidemiology and clinical presentation of melanoma in US Hispanics is summarized, and recommendations for a research agenda to advance understanding of this disease in the most rapidly growing segment of the US population is provided.

Melanoma Incidence, Presentation, and Outcomes in US Hispanics

In the period from 2008 to 2012, the age-adjusted incidence of melanoma in US Hispanics (4.6 per 100,00 men and 4.2 per 100,00 women) was lower than in NHWs.⁵ Garnett et al⁵ reported a decline in melanoma incidence in US Hispanics between 2003 and 2012—an observation that stands in contrast to state-level studies in California and Florida, in which small but substantial increases in melanoma incidence among Hispanics were reported.^6,7 The rising incidence of melanomas thicker than 1.5 mm at presentation among Hispanic men living in California is particularly worrisome.⁶ Discrepancies in incidence trends might reflect changes in incidence over time or differences in state-level registry reporting of melanoma.⁵

Despite a lower overall incidence of melanoma in US Hispanics, those who do develop the disease are 2.4 times more likely (age-adjusted odds ratio) to present with stage III disease (confidence interval, 1.89-3.05)⁸ and are 3.64 times more likely to develop distant metastases (confidence interval, 2.65-5.0) than NHWs.^3,7,9-13 Disparities also exist in the diagnosis of childhood melanoma: Hispanic children and adolescents who have a diagnosis of melanoma are 3 times more likely to present with advanced disease than NHW counterparts.¹⁴ Survival analyses by age and stage show considerably lower survival among Hispanic patients compared to NHW patients with stage I and II disease. In part, worse survival outcomes among Hispanics are the result of the pattern of more advanced disease at presentation.^8,14,15

Late presentation for evaluation of melanomas in Hispanics has been attributed to a number of variables, including a lack of skin cancer awareness and knowledge,^9,16 a lower rate of self- and physician-performed skin examinations,¹⁰ differences in tumor biology,⁹ and socioeconomic forces.^7,17

In a previous study investigating the relationship between neighborhood characteristics and tumor stage at melanoma diagnosis in Hispanic men in California, Texas, and Florida, several key findings emerged.¹⁷ First, residency in a census tract with a high density of immigrants (California, Texas) and a high composition of Hispanics (California, Florida) was an important predictor of a late-stage melanoma diagnosis in fully adjusted models. Additionally, the strength of association between measures of socioeconomic status (ie, poverty and education) and tumor stage at melanoma diagnosis was attenuated in multivariate models when enclaves and availability of primary care resources were taken into account. Hispanic melanoma cases in areas with a low density of primary care physicians had an increased likelihood of late-stage diagnosis in California and Texas. The probability of late-stage diagnosis was concentrated in specific regions along the United States–Mexico border, in south central California, and along the southeastern coast of Florida. Lastly, in Texas, Hispanic men aged 18 to 34 years and 35 to 49 years were at an increased risk of late-stage melanoma diagnosis compared to men 65 years and older.¹⁷

Demographic and Clinical Characteristics of Melanoma in Hispanic Patients

Among Hispanics, white Hispanics comprise the majority of melanoma cases.⁵ Median age at diagnosis is younger in Hispanics compared to whites.^5,6 Hispanic men typically are older (median age, 61 years) than Hispanic women (median age, 52 years) at diagnosis.⁵ Similar to what is seen in NHWs, young Hispanic women experience a higher melanoma incidence than young Hispanic men.⁵ Among older Hispanics, melanoma is more common in men.^5,8

Melanomas located on the lower extremities and hips are more prevalent in Hispanics than in NHWs.^5,8,18 Among Hispanics, there are age- and sex-based variations in the anatomic location of primary tumors: in Hispanic men, truncal tumors predominate, and in Hispanic women, tumors of the lower extremities are most common across all age groups.⁵ The incidence of melanomas located in the head and neck region increases with age for both Hispanic men and women.

For melanomas in which the histologic type is known, superficial spreading melanoma is the most common subtype among Hispanics.^5,17,19 Acral lentiginous melanomas and nodular melanomas are more common among Hispanics than among NHWs.^5,17,19

The observation that Hispanics with melanoma are more prone to lower-extremity tumors and nodular and acral lentiginous melanoma subtypes than NHWs suggests that UV exposure history may be of less importance in this population. Although numerous studies have explored melanoma risk factors in NHWs, there is a striking paucity of such studies in Hispanics. For example, there are conflicting data regarding the role of UV exposure in melanoma risk among Hispanics. Hu et al²⁰ found that UV index and latitude correlated with melanoma risk in this population, whereas Eide et al²¹ found no association between UV exposure and melanoma incidence in Hispanics. A prospective study involving a multiethnic cohort (of whom 40 of the 107 participants were Hispanic) found no clear association between a history of sunburn and melanoma risk in Hispanics.¹⁸

Strategies for Reducing Disparities in Outcomes

Our knowledge of melanoma epidemiology in Hispanics derives mainly from secondary analyses of state-level and national cancer registry data sets.^{5-8,13-15,17,19,20} These administrative data sources often are limited by missing data (eg, tumor thickness, histologic subtype) or lack important patient-level information (eg, self-identified race and ethnicity, health insurance status). Additionally, the manner in which data are collected and integrated into research varies; for example, socioeconomic measures often are reported as either area-based or composite measures. Thus, there is a need to improve the consistency of reporting on demographic and socioeconomic measures across studies. Polite et al²² recommended standardization of reporting criteria and that a standard set of demographic and socioeconomic status measures be included in clinical registries and research protocols.²² Researchers should strive to collect self-reported information on race and ethnicity, as well as the most granular level of detail on health insurance status, ancestry, and immigration status.

The host phenotypic characteristics of melanoma in NHWs are well understood, but the biological and environmental determinants of melanoma risk in Hispanics and other minorities are unknown. For example, fair complexion, red hair, blue eyes, increased freckling density, and the presence of numerous dysplastic and common melanocytic nevi indicate a propensity toward cutaneous melanoma.^23,24 However, the relevance of such risk factors in Hispanics is unknown and has not been widely investigated in this patient population. Park et al¹⁸ found that a person’s sunburn susceptibility phenotype (defined as hair and eye color, ability to tan, and skin reaction to sunlight) was associated with an increased risk of melanoma among nonwhite, multiracial individuals. However, this study was limited by a small number of minority cases, which included only 40 Hispanic participants with melanoma.¹⁸ There is a need for rigorous observational studies to clearly define the phenotypic characteristics, sun-exposure behavior patterns, and genetic contributors to melanoma genesis in Hispanics.

The biologic determinants of postdiagnosis survival in Hispanics with melanoma are not well understood. It is unknown if genetic predisposition modifies melanoma risk in Hispanics. For example, the frequency of BRAF gene mutation or other driver mutations in US Hispanics has been understudied. It is important to know if mutation frequency patterns differ in Hispanics patients compared to NHWs because this knowledge could have considerable implications for treatment. Several recommendations should be considered to address these knowledge gaps. First, there is a need for development or enhancement of melanoma biorepositories, which should include tumor and nontumor specimens from a diverse sample of melanoma patients. Additionally, multi-institutional and multidisciplinary consortiums need to be created in order to amass a number of Hispanic melanoma patients to identify genetic, biologic, and behavioral risk factors specific to this subgroup of patients. The AMBER Consortium, which focuses on breast cancer epidemiology and risk in black women, is a model for the type of consortium needed for the study of melanoma in Hispanics.²⁵ Lastly, community engagement will be central to developing sustainable recruitment and data-collection efforts.²⁶ Involvement of key stakeholders will provide an in-depth assessment of community needs as well as real-time feedback on the process and practicality of research questions. Buy-in from affected communities also may facilitate dissemination of research findings to affected communities.

Conclusion

Hispanics are more likely to present with an advanced stages of disease and have higher melanoma-specific mortality rates than NHWs. Regrettably, a huge knowledge gap exists regarding contributors and solutions to melanoma disparities among this fast-growing, understudied segment of the US population. Accordingly, critical research is needed to address the most pressing questions regarding melanoma risk and poor outcomes among Hispanics to foster implementation of interventional efforts in prevention, early detection, and treatment. A multi-institutional and multidisciplinary approach across multiple levels is needed to eliminate disparate outcomes. Although melanoma is relatively uncommon among Hispanics, studies of melanoma in Hispanics (given their diverse genetic ancestry and migration) provide a unique backdrop against which researchers can explicate melanoma etiology—thus benefiting Hispanics and non-Hispanics alike.

The Diagnosis: Lues Maligna

Laboratory evaluation demonstrated a total CD4 count of 26 cells/μL (reference range, 443-1471 cells/μL) with a viral load of 1,770,111 copies/mL (reference range, 0 copies/mL), as well as a positive rapid plasma reagin (RPR) test with a titer of 1:8 (reference range, nonreactive). A reactive treponemal antibody test confirmed a true positive RPR test result. Viral culture as well as direct fluorescence antibodies for varicella-zoster virus and an active vesicle of herpes simplex virus (HSV) were negative. Serum immunoglobulin titers for varicella-zoster virus demonstrated low IgM with a positive IgG demonstrating immunity without recent infection. Blood and lesional skin tissue cultures were negative for additional infectious etiologies including bacterial and fungal elements. A lumbar puncture was not performed.

Biopsy of a papulonodule on the left arm demonstrated a lichenoid lymphohistiocytic infiltrate with superficial and deep inflammation (Figure 1). Neutrophils also were noted within a follicle with ballooning and acantholysis within the follicular epithelium. Additional staining for Mycobacterium, HSV-1, HSV-2, and Treponema were negative. In the clinical setting, this histologic pattern was most consistent with secondary syphilis. Pityriasis lichenoides et varioliformis acuta also was included in the histopathologic differential diagnosis by a dermatopathologist (M.C.).

Based on the clinical, microbiologic, and histopathologic findings, a diagnosis of lues maligna (cutaneous secondary syphilis) with a vesiculonecrotic presentation was made. The patient's low RPR titer was attributed to profound immunosuppression, while a confirmation of syphilis infection was made with treponemal antibody testing. Histopathologic examination was consistent with lues maligna and did not demonstrate evidence of any other infectious etiologies.

Following 7 days of intravenous penicillin, the patient demonstrated dramatic improvement of all skin lesions and was discharged receiving once-weekly intramuscular penicillin for 4 weeks. In accordance with the diagnosis, the patient demonstrated rapid improvement of the lesions following appropriate antibiotic therapy.

After the diagnosis of lues maligna was made, the patient disclosed a sexual encounter with a male partner 6 weeks prior to the current presentation, after which he developed a self-resolving genital ulcer suspicious for a primary chancre.

Increasing rates of syphilis transmission have been attributed to males aged 15 to 44 years who have sexual encounters with other males.¹ Although syphilis commonly is known as the great mimicker, syphilology texts state that lesions are not associated with syphilis if vesicles are part of the cutaneous eruption in an adult.² However, rare reports of secondary syphilis presenting as vesicles, pustules, bullae, and pityriasis lichenoides et varioliformis acuta-like eruptions also have been documented.^2-4

Initial screening for suspected syphilis involves sensitive, but not specific, nontreponemal RPR testing reported in the form of a titer. Nontreponemal titers in human immunodeficiency virus-positive individuals can be unusually high or low, fluctuate rapidly, and/or be unresponsive to antibiotic therapy.¹

Lues maligna is a rare form of malignant secondary syphilis that most commonly presents in human immunodeficiency virus-positive hosts.⁵ Although lues maligna often presents with ulceronodular lesions, 2 cases presenting with vesiculonecrotic lesions also have been reported.⁶ Patients often experience systemic symptoms including fever, fatigue, and joint pain. Rapid plasma reagin titers can range from 1:8 to 1:128 in affected individuals.⁶ Diagnosis is dependent on serologic and histologic confirmation while ruling out viral, fungal, and bacterial etiologies. Characteristic red-brown lesions of secondary syphilis involving the palms and soles (Figure 2) alsoaid in diagnosis.¹ Additionally, identification of the Jarisch-Herxheimer reaction following treatment and rapid response to antibiotic therapy are helpful diagnostic findings.^6,7 While histopathologic examination of lues maligna typically does not reveal evidence of spirochetes, it also is important to rule out other infectious etiologies.⁷

Our case emphasizes the importance of early recognition and treatment of the variable clinical, laboratory, and histologic presentations of lues maligna.

The Diagnosis: Lues Maligna

Laboratory evaluation demonstrated a total CD4 count of 26 cells/μL (reference range, 443-1471 cells/μL) with a viral load of 1,770,111 copies/mL (reference range, 0 copies/mL), as well as a positive rapid plasma reagin (RPR) test with a titer of 1:8 (reference range, nonreactive). A reactive treponemal antibody test confirmed a true positive RPR test result. Viral culture as well as direct fluorescence antibodies for varicella-zoster virus and an active vesicle of herpes simplex virus (HSV) were negative. Serum immunoglobulin titers for varicella-zoster virus demonstrated low IgM with a positive IgG demonstrating immunity without recent infection. Blood and lesional skin tissue cultures were negative for additional infectious etiologies including bacterial and fungal elements. A lumbar puncture was not performed.

Biopsy of a papulonodule on the left arm demonstrated a lichenoid lymphohistiocytic infiltrate with superficial and deep inflammation (Figure 1). Neutrophils also were noted within a follicle with ballooning and acantholysis within the follicular epithelium. Additional staining for Mycobacterium, HSV-1, HSV-2, and Treponema were negative. In the clinical setting, this histologic pattern was most consistent with secondary syphilis. Pityriasis lichenoides et varioliformis acuta also was included in the histopathologic differential diagnosis by a dermatopathologist (M.C.).

Based on the clinical, microbiologic, and histopathologic findings, a diagnosis of lues maligna (cutaneous secondary syphilis) with a vesiculonecrotic presentation was made. The patient's low RPR titer was attributed to profound immunosuppression, while a confirmation of syphilis infection was made with treponemal antibody testing. Histopathologic examination was consistent with lues maligna and did not demonstrate evidence of any other infectious etiologies.

Following 7 days of intravenous penicillin, the patient demonstrated dramatic improvement of all skin lesions and was discharged receiving once-weekly intramuscular penicillin for 4 weeks. In accordance with the diagnosis, the patient demonstrated rapid improvement of the lesions following appropriate antibiotic therapy.

After the diagnosis of lues maligna was made, the patient disclosed a sexual encounter with a male partner 6 weeks prior to the current presentation, after which he developed a self-resolving genital ulcer suspicious for a primary chancre.

Increasing rates of syphilis transmission have been attributed to males aged 15 to 44 years who have sexual encounters with other males.¹ Although syphilis commonly is known as the great mimicker, syphilology texts state that lesions are not associated with syphilis if vesicles are part of the cutaneous eruption in an adult.² However, rare reports of secondary syphilis presenting as vesicles, pustules, bullae, and pityriasis lichenoides et varioliformis acuta-like eruptions also have been documented.^2-4

Initial screening for suspected syphilis involves sensitive, but not specific, nontreponemal RPR testing reported in the form of a titer. Nontreponemal titers in human immunodeficiency virus-positive individuals can be unusually high or low, fluctuate rapidly, and/or be unresponsive to antibiotic therapy.¹

Lues maligna is a rare form of malignant secondary syphilis that most commonly presents in human immunodeficiency virus-positive hosts.⁵ Although lues maligna often presents with ulceronodular lesions, 2 cases presenting with vesiculonecrotic lesions also have been reported.⁶ Patients often experience systemic symptoms including fever, fatigue, and joint pain. Rapid plasma reagin titers can range from 1:8 to 1:128 in affected individuals.⁶ Diagnosis is dependent on serologic and histologic confirmation while ruling out viral, fungal, and bacterial etiologies. Characteristic red-brown lesions of secondary syphilis involving the palms and soles (Figure 2) alsoaid in diagnosis.¹ Additionally, identification of the Jarisch-Herxheimer reaction following treatment and rapid response to antibiotic therapy are helpful diagnostic findings.^6,7 While histopathologic examination of lues maligna typically does not reveal evidence of spirochetes, it also is important to rule out other infectious etiologies.⁷

Our case emphasizes the importance of early recognition and treatment of the variable clinical, laboratory, and histologic presentations of lues maligna.

The Diagnosis: Lues Maligna

Laboratory evaluation demonstrated a total CD4 count of 26 cells/μL (reference range, 443-1471 cells/μL) with a viral load of 1,770,111 copies/mL (reference range, 0 copies/mL), as well as a positive rapid plasma reagin (RPR) test with a titer of 1:8 (reference range, nonreactive). A reactive treponemal antibody test confirmed a true positive RPR test result. Viral culture as well as direct fluorescence antibodies for varicella-zoster virus and an active vesicle of herpes simplex virus (HSV) were negative. Serum immunoglobulin titers for varicella-zoster virus demonstrated low IgM with a positive IgG demonstrating immunity without recent infection. Blood and lesional skin tissue cultures were negative for additional infectious etiologies including bacterial and fungal elements. A lumbar puncture was not performed.

Biopsy of a papulonodule on the left arm demonstrated a lichenoid lymphohistiocytic infiltrate with superficial and deep inflammation (Figure 1). Neutrophils also were noted within a follicle with ballooning and acantholysis within the follicular epithelium. Additional staining for Mycobacterium, HSV-1, HSV-2, and Treponema were negative. In the clinical setting, this histologic pattern was most consistent with secondary syphilis. Pityriasis lichenoides et varioliformis acuta also was included in the histopathologic differential diagnosis by a dermatopathologist (M.C.).

Based on the clinical, microbiologic, and histopathologic findings, a diagnosis of lues maligna (cutaneous secondary syphilis) with a vesiculonecrotic presentation was made. The patient's low RPR titer was attributed to profound immunosuppression, while a confirmation of syphilis infection was made with treponemal antibody testing. Histopathologic examination was consistent with lues maligna and did not demonstrate evidence of any other infectious etiologies.

Following 7 days of intravenous penicillin, the patient demonstrated dramatic improvement of all skin lesions and was discharged receiving once-weekly intramuscular penicillin for 4 weeks. In accordance with the diagnosis, the patient demonstrated rapid improvement of the lesions following appropriate antibiotic therapy.

After the diagnosis of lues maligna was made, the patient disclosed a sexual encounter with a male partner 6 weeks prior to the current presentation, after which he developed a self-resolving genital ulcer suspicious for a primary chancre.

Increasing rates of syphilis transmission have been attributed to males aged 15 to 44 years who have sexual encounters with other males.¹ Although syphilis commonly is known as the great mimicker, syphilology texts state that lesions are not associated with syphilis if vesicles are part of the cutaneous eruption in an adult.² However, rare reports of secondary syphilis presenting as vesicles, pustules, bullae, and pityriasis lichenoides et varioliformis acuta-like eruptions also have been documented.^2-4

Initial screening for suspected syphilis involves sensitive, but not specific, nontreponemal RPR testing reported in the form of a titer. Nontreponemal titers in human immunodeficiency virus-positive individuals can be unusually high or low, fluctuate rapidly, and/or be unresponsive to antibiotic therapy.¹

Lues maligna is a rare form of malignant secondary syphilis that most commonly presents in human immunodeficiency virus-positive hosts.⁵ Although lues maligna often presents with ulceronodular lesions, 2 cases presenting with vesiculonecrotic lesions also have been reported.⁶ Patients often experience systemic symptoms including fever, fatigue, and joint pain. Rapid plasma reagin titers can range from 1:8 to 1:128 in affected individuals.⁶ Diagnosis is dependent on serologic and histologic confirmation while ruling out viral, fungal, and bacterial etiologies. Characteristic red-brown lesions of secondary syphilis involving the palms and soles (Figure 2) alsoaid in diagnosis.¹ Additionally, identification of the Jarisch-Herxheimer reaction following treatment and rapid response to antibiotic therapy are helpful diagnostic findings.^6,7 While histopathologic examination of lues maligna typically does not reveal evidence of spirochetes, it also is important to rule out other infectious etiologies.⁷

Our case emphasizes the importance of early recognition and treatment of the variable clinical, laboratory, and histologic presentations of lues maligna.

The clinical practice of dermatology is changing at a rapid pace. Advances in technology and new inventions in rapid diagnostics are revolutionizing how physicians approach medical care. In 2009, the Health Information Technology for Economic and Clinical Health Act of 2009¹ ushered in the era of electronic medical records, along with a series of associated challenges.² In 2014, the potential reach of medical expertise in the United States was expanded with the creation of the Interstate Medical Licensure Compact, which offers an expedited pathway to licensure for physicians seeking to practice in multiple states as a way to increase access to health care in underserved or rural areas via telemedicine.³ In early 2017, a computer algorithm was able to perform on par with board-certified dermatologists when distinguishing between clinical images of biopsy-proven benign and malignant skin lesions.⁴ Recently, Microsoft announced a partnership with rural telecommunications providers to bring high-speed broadband Internet service to millions of Americans using television white space technology, which can improve access to health care services through the implementation of telemedicine and other connected health technologies in rural communities.⁵

Given these advances, how does today’s dermatologist integrate into the future of the specialty? If leveraged properly, current technologies such as teledermatology and patient portals integrated with electronic medical records can be beneficial to dermatology practices by improving access to care, facilitating triage of patients, and improving communication between patients and health care team members. Herein, we discuss some of the emerging technologies that have the potential to shape clinical dermatology practice and remove barriers to care.

Virtual Reality

Teledermatology can be practiced through live video or, more commonly, via a store-and-forward method in which dermatologists review clinical photographs and the patient's history asynchronously with the in-office visit.⁶ Virtual reality has the potential to augment teledermatology services by enabling a live, interactive visit that more closely models the traditional face-to-face visit. Virtual reality already is available for patients at home with the use of a commercially marketed headset and a smartphone, and the marriage of virtual reailty and telemedicine has the potential to transform health care.

Virtual reality also can be used to deliver an essential component of the physical examination of a patient: sensory information from palpation. Haptic feedback, also known as haptics, is used to relay force and tactile information to the user of a device (eg, a haptic glove).⁷ In dermatology, this information pertains to the skin texture, skin profile, and physical properties (eg, stiffness, temperature).⁸ Assessing the texture of the skin surface can help when distinguishing epidermal processes such as psoriasis versus atopic dermatitis or when evaluating edema, induration, and depth of a leg ulcer.⁹

One model for conducting a teledermatology encounter that captures sensory information would consist of a haptic probe located at a referring medical provider’s office for examining patients and a master robot that controls the probe located at the consulting dermatologist’s facility.⁸ Another model converts 2-dimensional images taken from traditional full-body optical imaging systems into virtual 3-dimensional (3D) images that can be felt using a haptic device.^10,11 In this method, the user is able to both visualize and touch the skin surface at the same time. Currently, 3D imaging of skin lesions is available in the form of a specialized handheld imager that allows the dermatologist to appreciate the texture and elevation of single lesions when viewing clinical photographs. Additionally, full-body 3D mapping of the skin surface is available for monitoring pigmented lesions or other diseases of the skin.^12,13

Artificial Intelligence and Machine Learning

Computer algorithms can be helpful in assisting physicians with disease diagnosis. Machine learning is a subfield of artificial intelligence (AI) in which computer programs learn automatically from experience without explicit programming instructions. A machine learning algorithm uses a labeled data set known as a training set to create a function that can make predictions about new inputs in the future.¹⁴ The algorithm can successively compare its predicted outputs with the correct outputs and modify its function as errors are found; for example, a database of images of healthy skin as well as the skin of psoriasis patients can be fed into a machine learning algorithm that picks up features such as color and skin texture from the labeled photographs, allowing it to learn how to diagnose psoriasis.¹⁵

In one instance, researchers at Stanford University (Stanford, California) used approximately 130,000 images representing over 2000 different skin diseases in order to train their machine learning algorithm to recognize benign and malignant skin lesions.⁴ Although the algorithm was able to match the performance of experienced dermatologists in many diagnostic categories, further testing in a real-world clinical setting still needs to be done. In the future, nondermatologists may have the option to consult with decision-support systems that include image analysis software, such as the one developed at Stanford University, for making decisions in triage or diagnosis, which may be critical in areas where access to a dermatologist is limited.⁴ Future AI systems also may provide supplemental assistance in managing patients to dermatology trainees until they have the experience of a more established dermatologist.

Currently, AI cannot match general human intelligence and life experience; therefore, physicians will continue to make the final decisions when it comes to diagnosis and treatment. In the future, AI algorithms may integrate into clinical dermatology practice, leading to more accurate triage of lesions, potentially streamlined referral to dermatologists for skin conditions that require prompt consultation, and improved quality of care.

Summary

In conclusion, emerging technologies have the power to augment and revolutionize dermatology practice. Savvy dermatologists may incorporate new tools in a way that works for their practice, leading to increased efficiency and improved patient outcomes. Eventually, the technology that is most beneficial to clinical practice will likely be adopted by and integrated into mainstream dermatologic care, making it available for the majority of clinicians to use.

The clinical practice of dermatology is changing at a rapid pace. Advances in technology and new inventions in rapid diagnostics are revolutionizing how physicians approach medical care. In 2009, the Health Information Technology for Economic and Clinical Health Act of 2009¹ ushered in the era of electronic medical records, along with a series of associated challenges.² In 2014, the potential reach of medical expertise in the United States was expanded with the creation of the Interstate Medical Licensure Compact, which offers an expedited pathway to licensure for physicians seeking to practice in multiple states as a way to increase access to health care in underserved or rural areas via telemedicine.³ In early 2017, a computer algorithm was able to perform on par with board-certified dermatologists when distinguishing between clinical images of biopsy-proven benign and malignant skin lesions.⁴ Recently, Microsoft announced a partnership with rural telecommunications providers to bring high-speed broadband Internet service to millions of Americans using television white space technology, which can improve access to health care services through the implementation of telemedicine and other connected health technologies in rural communities.⁵

Given these advances, how does today’s dermatologist integrate into the future of the specialty? If leveraged properly, current technologies such as teledermatology and patient portals integrated with electronic medical records can be beneficial to dermatology practices by improving access to care, facilitating triage of patients, and improving communication between patients and health care team members. Herein, we discuss some of the emerging technologies that have the potential to shape clinical dermatology practice and remove barriers to care.

Virtual Reality

Teledermatology can be practiced through live video or, more commonly, via a store-and-forward method in which dermatologists review clinical photographs and the patient's history asynchronously with the in-office visit.⁶ Virtual reality has the potential to augment teledermatology services by enabling a live, interactive visit that more closely models the traditional face-to-face visit. Virtual reality already is available for patients at home with the use of a commercially marketed headset and a smartphone, and the marriage of virtual reailty and telemedicine has the potential to transform health care.

Virtual reality also can be used to deliver an essential component of the physical examination of a patient: sensory information from palpation. Haptic feedback, also known as haptics, is used to relay force and tactile information to the user of a device (eg, a haptic glove).⁷ In dermatology, this information pertains to the skin texture, skin profile, and physical properties (eg, stiffness, temperature).⁸ Assessing the texture of the skin surface can help when distinguishing epidermal processes such as psoriasis versus atopic dermatitis or when evaluating edema, induration, and depth of a leg ulcer.⁹

One model for conducting a teledermatology encounter that captures sensory information would consist of a haptic probe located at a referring medical provider’s office for examining patients and a master robot that controls the probe located at the consulting dermatologist’s facility.⁸ Another model converts 2-dimensional images taken from traditional full-body optical imaging systems into virtual 3-dimensional (3D) images that can be felt using a haptic device.^10,11 In this method, the user is able to both visualize and touch the skin surface at the same time. Currently, 3D imaging of skin lesions is available in the form of a specialized handheld imager that allows the dermatologist to appreciate the texture and elevation of single lesions when viewing clinical photographs. Additionally, full-body 3D mapping of the skin surface is available for monitoring pigmented lesions or other diseases of the skin.^12,13

Artificial Intelligence and Machine Learning

Computer algorithms can be helpful in assisting physicians with disease diagnosis. Machine learning is a subfield of artificial intelligence (AI) in which computer programs learn automatically from experience without explicit programming instructions. A machine learning algorithm uses a labeled data set known as a training set to create a function that can make predictions about new inputs in the future.¹⁴ The algorithm can successively compare its predicted outputs with the correct outputs and modify its function as errors are found; for example, a database of images of healthy skin as well as the skin of psoriasis patients can be fed into a machine learning algorithm that picks up features such as color and skin texture from the labeled photographs, allowing it to learn how to diagnose psoriasis.¹⁵

In one instance, researchers at Stanford University (Stanford, California) used approximately 130,000 images representing over 2000 different skin diseases in order to train their machine learning algorithm to recognize benign and malignant skin lesions.⁴ Although the algorithm was able to match the performance of experienced dermatologists in many diagnostic categories, further testing in a real-world clinical setting still needs to be done. In the future, nondermatologists may have the option to consult with decision-support systems that include image analysis software, such as the one developed at Stanford University, for making decisions in triage or diagnosis, which may be critical in areas where access to a dermatologist is limited.⁴ Future AI systems also may provide supplemental assistance in managing patients to dermatology trainees until they have the experience of a more established dermatologist.

Currently, AI cannot match general human intelligence and life experience; therefore, physicians will continue to make the final decisions when it comes to diagnosis and treatment. In the future, AI algorithms may integrate into clinical dermatology practice, leading to more accurate triage of lesions, potentially streamlined referral to dermatologists for skin conditions that require prompt consultation, and improved quality of care.

Summary

In conclusion, emerging technologies have the power to augment and revolutionize dermatology practice. Savvy dermatologists may incorporate new tools in a way that works for their practice, leading to increased efficiency and improved patient outcomes. Eventually, the technology that is most beneficial to clinical practice will likely be adopted by and integrated into mainstream dermatologic care, making it available for the majority of clinicians to use.

The clinical practice of dermatology is changing at a rapid pace. Advances in technology and new inventions in rapid diagnostics are revolutionizing how physicians approach medical care. In 2009, the Health Information Technology for Economic and Clinical Health Act of 2009¹ ushered in the era of electronic medical records, along with a series of associated challenges.² In 2014, the potential reach of medical expertise in the United States was expanded with the creation of the Interstate Medical Licensure Compact, which offers an expedited pathway to licensure for physicians seeking to practice in multiple states as a way to increase access to health care in underserved or rural areas via telemedicine.³ In early 2017, a computer algorithm was able to perform on par with board-certified dermatologists when distinguishing between clinical images of biopsy-proven benign and malignant skin lesions.⁴ Recently, Microsoft announced a partnership with rural telecommunications providers to bring high-speed broadband Internet service to millions of Americans using television white space technology, which can improve access to health care services through the implementation of telemedicine and other connected health technologies in rural communities.⁵

Given these advances, how does today’s dermatologist integrate into the future of the specialty? If leveraged properly, current technologies such as teledermatology and patient portals integrated with electronic medical records can be beneficial to dermatology practices by improving access to care, facilitating triage of patients, and improving communication between patients and health care team members. Herein, we discuss some of the emerging technologies that have the potential to shape clinical dermatology practice and remove barriers to care.

Virtual Reality

Teledermatology can be practiced through live video or, more commonly, via a store-and-forward method in which dermatologists review clinical photographs and the patient's history asynchronously with the in-office visit.⁶ Virtual reality has the potential to augment teledermatology services by enabling a live, interactive visit that more closely models the traditional face-to-face visit. Virtual reality already is available for patients at home with the use of a commercially marketed headset and a smartphone, and the marriage of virtual reailty and telemedicine has the potential to transform health care.

Virtual reality also can be used to deliver an essential component of the physical examination of a patient: sensory information from palpation. Haptic feedback, also known as haptics, is used to relay force and tactile information to the user of a device (eg, a haptic glove).⁷ In dermatology, this information pertains to the skin texture, skin profile, and physical properties (eg, stiffness, temperature).⁸ Assessing the texture of the skin surface can help when distinguishing epidermal processes such as psoriasis versus atopic dermatitis or when evaluating edema, induration, and depth of a leg ulcer.⁹

One model for conducting a teledermatology encounter that captures sensory information would consist of a haptic probe located at a referring medical provider’s office for examining patients and a master robot that controls the probe located at the consulting dermatologist’s facility.⁸ Another model converts 2-dimensional images taken from traditional full-body optical imaging systems into virtual 3-dimensional (3D) images that can be felt using a haptic device.^10,11 In this method, the user is able to both visualize and touch the skin surface at the same time. Currently, 3D imaging of skin lesions is available in the form of a specialized handheld imager that allows the dermatologist to appreciate the texture and elevation of single lesions when viewing clinical photographs. Additionally, full-body 3D mapping of the skin surface is available for monitoring pigmented lesions or other diseases of the skin.^12,13

Artificial Intelligence and Machine Learning

Computer algorithms can be helpful in assisting physicians with disease diagnosis. Machine learning is a subfield of artificial intelligence (AI) in which computer programs learn automatically from experience without explicit programming instructions. A machine learning algorithm uses a labeled data set known as a training set to create a function that can make predictions about new inputs in the future.¹⁴ The algorithm can successively compare its predicted outputs with the correct outputs and modify its function as errors are found; for example, a database of images of healthy skin as well as the skin of psoriasis patients can be fed into a machine learning algorithm that picks up features such as color and skin texture from the labeled photographs, allowing it to learn how to diagnose psoriasis.¹⁵

In one instance, researchers at Stanford University (Stanford, California) used approximately 130,000 images representing over 2000 different skin diseases in order to train their machine learning algorithm to recognize benign and malignant skin lesions.⁴ Although the algorithm was able to match the performance of experienced dermatologists in many diagnostic categories, further testing in a real-world clinical setting still needs to be done. In the future, nondermatologists may have the option to consult with decision-support systems that include image analysis software, such as the one developed at Stanford University, for making decisions in triage or diagnosis, which may be critical in areas where access to a dermatologist is limited.⁴ Future AI systems also may provide supplemental assistance in managing patients to dermatology trainees until they have the experience of a more established dermatologist.

Currently, AI cannot match general human intelligence and life experience; therefore, physicians will continue to make the final decisions when it comes to diagnosis and treatment. In the future, AI algorithms may integrate into clinical dermatology practice, leading to more accurate triage of lesions, potentially streamlined referral to dermatologists for skin conditions that require prompt consultation, and improved quality of care.

Summary

In conclusion, emerging technologies have the power to augment and revolutionize dermatology practice. Savvy dermatologists may incorporate new tools in a way that works for their practice, leading to increased efficiency and improved patient outcomes. Eventually, the technology that is most beneficial to clinical practice will likely be adopted by and integrated into mainstream dermatologic care, making it available for the majority of clinicians to use.

The Diagnosis: Cutaneous Deposits Of Myeloma

Cutaneous deposits of myeloma are a rare skin manifestation of multiple myeloma that typically occur in less than 5% of patients.^1,2 The lesions represent monoclonal proliferations of plasma cells and arise from direct extension of a neoplastic mass or less commonly from hematogenous or lymphatic spread. This secondary cutaneous involvement by plasma cell myeloma has been referred to in the literature as metastatic or extramedullary cutaneous plasmacytoma.^1,2 This condition must be distinguished from cutaneous plasma cell infiltrates without underlying bone marrow involvement, classified by the World Health Organization as primary cutaneous marginal zone B-cell lymphoma and previously referred to as primary cutaneous plasmacytoma.³

Clinically, cutaneous deposits of myeloma manifest as erythematous to violaceous papules, plaques, or nodules with a smooth surface and firm consistency.^1,2 The lesions typically occur on the trunk and less commonly on the head, neck, arms, and legs. In a review of  83 cases of metastatic cutaneous plasmacytoma and primary cutaneous plasmacytoma in multiple myeloma, Kato et al⁴ found that 52% (43/83) of cases occurred in IgG myelomas and 23% (19/83) in IgA myelomas.

In our patient, a 4-mm punch biopsy of an umbilical plaque demonstrated a dense infiltrate of atypical plasmacytoid cells through the full thickness of the dermis with nuclear pleomorphism, prominent nucleoli, and frequent mitoses (Figure 1). Immunohistochemical staining was positive for IgA λ light chain (Figure 2A) and CD138 (Figure 2B) and was negative for CD20, which was consistent with the patient's known plasma cell myeloma. Positron emission tomography revealed progression of underlying disease compared to prior studies with hypermetabolic mediastinal, retroperitoneal, and pelvic side wall lymphadenopathy, as well as extensive hypermetabolic soft tissue masses with involvement of the periumbilical region.

The differential diagnosis for violaceous periumbilical plaques includes cutaneous marginal zone B-cell lymphoma (primary or secondary) or T-cell lymphoma (primary or secondary), cutaneous metastases from solid organ or hematologic malignancies (eg, Sister Mary Joseph nodule), AIDS-associated Kaposi sarcoma (plum-colored plaques that may be extensive), and cutaneous endometriosis (umbilical nodules that may develop in women after surgical excision of endometrial tissue).

The mainstay of therapy for secondary cutaneous involvement of plasma cell myeloma includes treatment with chemotherapy and local radiotherapy.^1,2,5 After the diagnosis of cutaneous deposits of myeloma was made in our patient, he was treated with bortezomib, cyclophosphamide with dexamethasone, and local radiotherapy to symptomatic bony lesions; however, he was unresponsive to therapy and the disease progressed with numerous extramedullary lesions of the mediastinum, gastrointestinal tract, and retroperitoneum 2 months later. The patient developed hydronephrosis from external renal compression necessitating nephrostomy tube and malignant pleural effusions requiring intubation. He experienced rapid clinical decline and died 3 months after the initial presentation due to multiorgan failure.

Cutaneous deposits of myeloma are a sign of underlying disease progression in plasma cell myeloma and often herald a fulminant course (eg, death within 12 months of presentation), as seen in our patient.⁵ Clinicians should be aware of this rare manifestation of plasma cell myeloma and pursue aggressive therapy given the poor prognostic nature of these cutaneous findings.

The Diagnosis: Cutaneous Deposits Of Myeloma

Cutaneous deposits of myeloma are a rare skin manifestation of multiple myeloma that typically occur in less than 5% of patients.^1,2 The lesions represent monoclonal proliferations of plasma cells and arise from direct extension of a neoplastic mass or less commonly from hematogenous or lymphatic spread. This secondary cutaneous involvement by plasma cell myeloma has been referred to in the literature as metastatic or extramedullary cutaneous plasmacytoma.^1,2 This condition must be distinguished from cutaneous plasma cell infiltrates without underlying bone marrow involvement, classified by the World Health Organization as primary cutaneous marginal zone B-cell lymphoma and previously referred to as primary cutaneous plasmacytoma.³

Clinically, cutaneous deposits of myeloma manifest as erythematous to violaceous papules, plaques, or nodules with a smooth surface and firm consistency.^1,2 The lesions typically occur on the trunk and less commonly on the head, neck, arms, and legs. In a review of  83 cases of metastatic cutaneous plasmacytoma and primary cutaneous plasmacytoma in multiple myeloma, Kato et al⁴ found that 52% (43/83) of cases occurred in IgG myelomas and 23% (19/83) in IgA myelomas.

In our patient, a 4-mm punch biopsy of an umbilical plaque demonstrated a dense infiltrate of atypical plasmacytoid cells through the full thickness of the dermis with nuclear pleomorphism, prominent nucleoli, and frequent mitoses (Figure 1). Immunohistochemical staining was positive for IgA λ light chain (Figure 2A) and CD138 (Figure 2B) and was negative for CD20, which was consistent with the patient's known plasma cell myeloma. Positron emission tomography revealed progression of underlying disease compared to prior studies with hypermetabolic mediastinal, retroperitoneal, and pelvic side wall lymphadenopathy, as well as extensive hypermetabolic soft tissue masses with involvement of the periumbilical region.

The differential diagnosis for violaceous periumbilical plaques includes cutaneous marginal zone B-cell lymphoma (primary or secondary) or T-cell lymphoma (primary or secondary), cutaneous metastases from solid organ or hematologic malignancies (eg, Sister Mary Joseph nodule), AIDS-associated Kaposi sarcoma (plum-colored plaques that may be extensive), and cutaneous endometriosis (umbilical nodules that may develop in women after surgical excision of endometrial tissue).

The mainstay of therapy for secondary cutaneous involvement of plasma cell myeloma includes treatment with chemotherapy and local radiotherapy.^1,2,5 After the diagnosis of cutaneous deposits of myeloma was made in our patient, he was treated with bortezomib, cyclophosphamide with dexamethasone, and local radiotherapy to symptomatic bony lesions; however, he was unresponsive to therapy and the disease progressed with numerous extramedullary lesions of the mediastinum, gastrointestinal tract, and retroperitoneum 2 months later. The patient developed hydronephrosis from external renal compression necessitating nephrostomy tube and malignant pleural effusions requiring intubation. He experienced rapid clinical decline and died 3 months after the initial presentation due to multiorgan failure.

Cutaneous deposits of myeloma are a sign of underlying disease progression in plasma cell myeloma and often herald a fulminant course (eg, death within 12 months of presentation), as seen in our patient.⁵ Clinicians should be aware of this rare manifestation of plasma cell myeloma and pursue aggressive therapy given the poor prognostic nature of these cutaneous findings.

The Diagnosis: Cutaneous Deposits Of Myeloma

Cutaneous deposits of myeloma are a rare skin manifestation of multiple myeloma that typically occur in less than 5% of patients.^1,2 The lesions represent monoclonal proliferations of plasma cells and arise from direct extension of a neoplastic mass or less commonly from hematogenous or lymphatic spread. This secondary cutaneous involvement by plasma cell myeloma has been referred to in the literature as metastatic or extramedullary cutaneous plasmacytoma.^1,2 This condition must be distinguished from cutaneous plasma cell infiltrates without underlying bone marrow involvement, classified by the World Health Organization as primary cutaneous marginal zone B-cell lymphoma and previously referred to as primary cutaneous plasmacytoma.³

Clinically, cutaneous deposits of myeloma manifest as erythematous to violaceous papules, plaques, or nodules with a smooth surface and firm consistency.^1,2 The lesions typically occur on the trunk and less commonly on the head, neck, arms, and legs. In a review of  83 cases of metastatic cutaneous plasmacytoma and primary cutaneous plasmacytoma in multiple myeloma, Kato et al⁴ found that 52% (43/83) of cases occurred in IgG myelomas and 23% (19/83) in IgA myelomas.

In our patient, a 4-mm punch biopsy of an umbilical plaque demonstrated a dense infiltrate of atypical plasmacytoid cells through the full thickness of the dermis with nuclear pleomorphism, prominent nucleoli, and frequent mitoses (Figure 1). Immunohistochemical staining was positive for IgA λ light chain (Figure 2A) and CD138 (Figure 2B) and was negative for CD20, which was consistent with the patient's known plasma cell myeloma. Positron emission tomography revealed progression of underlying disease compared to prior studies with hypermetabolic mediastinal, retroperitoneal, and pelvic side wall lymphadenopathy, as well as extensive hypermetabolic soft tissue masses with involvement of the periumbilical region.

The differential diagnosis for violaceous periumbilical plaques includes cutaneous marginal zone B-cell lymphoma (primary or secondary) or T-cell lymphoma (primary or secondary), cutaneous metastases from solid organ or hematologic malignancies (eg, Sister Mary Joseph nodule), AIDS-associated Kaposi sarcoma (plum-colored plaques that may be extensive), and cutaneous endometriosis (umbilical nodules that may develop in women after surgical excision of endometrial tissue).

The mainstay of therapy for secondary cutaneous involvement of plasma cell myeloma includes treatment with chemotherapy and local radiotherapy.^1,2,5 After the diagnosis of cutaneous deposits of myeloma was made in our patient, he was treated with bortezomib, cyclophosphamide with dexamethasone, and local radiotherapy to symptomatic bony lesions; however, he was unresponsive to therapy and the disease progressed with numerous extramedullary lesions of the mediastinum, gastrointestinal tract, and retroperitoneum 2 months later. The patient developed hydronephrosis from external renal compression necessitating nephrostomy tube and malignant pleural effusions requiring intubation. He experienced rapid clinical decline and died 3 months after the initial presentation due to multiorgan failure.

Cutaneous deposits of myeloma are a sign of underlying disease progression in plasma cell myeloma and often herald a fulminant course (eg, death within 12 months of presentation), as seen in our patient.⁵ Clinicians should be aware of this rare manifestation of plasma cell myeloma and pursue aggressive therapy given the poor prognostic nature of these cutaneous findings.

One of the most severe complications of systemic medications is the development of a life-threatening rash, especially toxic epidermal necrolysis (TEN). Most patients can expect a full recovery if the complicating medication is discontinued early on in its course.¹ When suspected TEN does not improve despite discontinuation of the detrimental medication, other diseases must be considered, particularly immunobullous and infectious etiologies. Treatment of these diseases differs substantially; therefore, a quick diagnosis is crucial. We present a case of a patient with an acute blistering eruption that was initially diagnosed and managed as TEN but physical examination and histopathologic confirmed another diagnosis. We review key examination findings that can help differentiate the causes of an acute blistering eruption with mucosal involvement, allowing for earlier diagnosis and treatment of these patients.

Case Report

An 85-year-old immunocompetent man was admitted to an outside hospital with a pruritic blistering eruption associated with myalgia, weakness, and fatigue of 3 weeks’ duration. The eruption initiated on the scalp and face and then spread down to the trunk and proximal arms and legs, with oral erosions also reported. An outside dermatologist was consulted on admission and performed a skin biopsy; the initial pathology was read as TEN. The patient was admitted to our institution on the same day, and all potentially complicating medications were stopped. He was treated with intravenous (IV) methylprednisolone sodium succinate 125 mg twice daily for 4 days and prednisone 40 mg daily for 9 days. With the rash worsening, the patient was restarted on methylprednisolone sodium succinate 40 mg every 8 hours approximately 3 weeks after admission, along with IV immunoglobulin at 2 g/kg over 3 days. When the patient did not respond to treatment, he was transferred to the University of California Irvine Medical Center for a higher level of care.

At that time, physical examination revealed numerous confluent erosions with honey-colored crust involving the entire face (Figure 1A) and sharp demarcation at the cutaneous lip (Figure 1B). There was a large erosion on the dorsal aspect of the tongue, but the rest of the oral mucosa was spared. The trunk and proximal extremities showed numerous grouped, punched-out erosions with scalloped borders (Figure 1C). A repeat skin biopsy showed an ulcer with viral cytopathic changes. Immunoperoxidase studies demonstrated positive staining for herpes simplex virus (HSV) type 1 (Figure 2). The original slides were a frozen section from an outside facility and could not be obtained. A tissue culture and direct fluorescent antibody also confirmed HSV-1, and the patient was diagnosed with disseminated herpes. He was rapidly tapered off of the steroids and started on IV acyclovir 10 mg/kg every 8 hours for 21 days. All prior erosions reepithelialized within 7 days of treatment (Figure 3). The patient had an otherwise uncomplicated hospital course and was discharged on hospital day 21.

Comment

A patient with an acute generalized blistering eruption requires urgent workup and treatment given the potentially devastating sequelae. Toxic epidermal necrolysis and immunobullous diseases often are the first diagnoses to be ruled out. Certainly infections such as HSV can cause a vesicular and erosive eruption, especially in the setting of a poorly controlled dermatitis, but they typically are not in the same differential as the other diagnoses.

Clinical Presentation
This case highlights 2 key physical examination findings that can alert the clinician to a possible underlying herpetic infection. First, the distribution of this patient’s oral lesions was telling. In most cases of TEN or pemphigus vulgaris, there is notable involvement of the oral mucosa, particularly the buccal and labial mucosa. Although herpes can involve any mucocutaneous surface, it does have a predilection for keratinized tissue, with the tongue and cutaneous lip commonly involved.^2,3 Our patient had a solitary linear erosion on the dorsal aspect of the tongue, but the rest of the oral cavity was strikingly spared. In addition, the erosions around the mouth stopped right at the cutaneous lip, sparing the labial mucosa (Figure 1B).

Second, the configuration of the erosions on the trunk, arms, and legs was diagnostic. Herpes classically presents as a cluster of vesicles overlying an erythematous base. When these vesicles rupture, punched-out erosions are left behind. Because these vesicles often are grouped, they can develop a scalloped border, which is a helpful indicator of HSV (Figure 1C). When these erosions become more confluent and irregular, the distinction from other conditions may not be as clear. A careful skin examination often can show areas that have preserved this herpetiform configuration.

Immune Compromise
Additionally, this case is illustrative of how immunosuppression and immunocompromise can affect the clinical presentation of HSV infection. Herpetic infections in the immunocompromised host tend to have a more protracted course, with chronic enlarging ulcers involving multiple sites. Furthermore, the morphology often is atypical, with ulcerodestructive, pustular, exophytic, and verrucous features as illustrated in this case. It is important to be mindful of these characteristics of HSV to properly diagnose an immunocompromised host.

Conclusion

This case is a good reminder that not everything that blisters and involves the mucosa is due to a hypersensitivity state such as TEN and Stevens-Johnson syndrome or an immunobullous disorder such as pemphigus vulgaris and pemphigus vegetans. The fact that this patient was worsening despite drug cessation, high-dose steroids, and IV immunoglobulin should have indicated a misdiagnosis. This case also shows that the early histopathologic findings of disseminated HSV and TEN can be nonspecific, and viral cytopathic changes may not always be obvious early in the disease.

Disseminated HSV should be considered in the differential diagnosis of a patient with an acute blistering eruption with mucosal involvement, and careful history and physical examination should be taken to rule out a viral etiology.

One of the most severe complications of systemic medications is the development of a life-threatening rash, especially toxic epidermal necrolysis (TEN). Most patients can expect a full recovery if the complicating medication is discontinued early on in its course.¹ When suspected TEN does not improve despite discontinuation of the detrimental medication, other diseases must be considered, particularly immunobullous and infectious etiologies. Treatment of these diseases differs substantially; therefore, a quick diagnosis is crucial. We present a case of a patient with an acute blistering eruption that was initially diagnosed and managed as TEN but physical examination and histopathologic confirmed another diagnosis. We review key examination findings that can help differentiate the causes of an acute blistering eruption with mucosal involvement, allowing for earlier diagnosis and treatment of these patients.

Case Report

An 85-year-old immunocompetent man was admitted to an outside hospital with a pruritic blistering eruption associated with myalgia, weakness, and fatigue of 3 weeks’ duration. The eruption initiated on the scalp and face and then spread down to the trunk and proximal arms and legs, with oral erosions also reported. An outside dermatologist was consulted on admission and performed a skin biopsy; the initial pathology was read as TEN. The patient was admitted to our institution on the same day, and all potentially complicating medications were stopped. He was treated with intravenous (IV) methylprednisolone sodium succinate 125 mg twice daily for 4 days and prednisone 40 mg daily for 9 days. With the rash worsening, the patient was restarted on methylprednisolone sodium succinate 40 mg every 8 hours approximately 3 weeks after admission, along with IV immunoglobulin at 2 g/kg over 3 days. When the patient did not respond to treatment, he was transferred to the University of California Irvine Medical Center for a higher level of care.

At that time, physical examination revealed numerous confluent erosions with honey-colored crust involving the entire face (Figure 1A) and sharp demarcation at the cutaneous lip (Figure 1B). There was a large erosion on the dorsal aspect of the tongue, but the rest of the oral mucosa was spared. The trunk and proximal extremities showed numerous grouped, punched-out erosions with scalloped borders (Figure 1C). A repeat skin biopsy showed an ulcer with viral cytopathic changes. Immunoperoxidase studies demonstrated positive staining for herpes simplex virus (HSV) type 1 (Figure 2). The original slides were a frozen section from an outside facility and could not be obtained. A tissue culture and direct fluorescent antibody also confirmed HSV-1, and the patient was diagnosed with disseminated herpes. He was rapidly tapered off of the steroids and started on IV acyclovir 10 mg/kg every 8 hours for 21 days. All prior erosions reepithelialized within 7 days of treatment (Figure 3). The patient had an otherwise uncomplicated hospital course and was discharged on hospital day 21.

Comment

A patient with an acute generalized blistering eruption requires urgent workup and treatment given the potentially devastating sequelae. Toxic epidermal necrolysis and immunobullous diseases often are the first diagnoses to be ruled out. Certainly infections such as HSV can cause a vesicular and erosive eruption, especially in the setting of a poorly controlled dermatitis, but they typically are not in the same differential as the other diagnoses.

Clinical Presentation
This case highlights 2 key physical examination findings that can alert the clinician to a possible underlying herpetic infection. First, the distribution of this patient’s oral lesions was telling. In most cases of TEN or pemphigus vulgaris, there is notable involvement of the oral mucosa, particularly the buccal and labial mucosa. Although herpes can involve any mucocutaneous surface, it does have a predilection for keratinized tissue, with the tongue and cutaneous lip commonly involved.^2,3 Our patient had a solitary linear erosion on the dorsal aspect of the tongue, but the rest of the oral cavity was strikingly spared. In addition, the erosions around the mouth stopped right at the cutaneous lip, sparing the labial mucosa (Figure 1B).

Second, the configuration of the erosions on the trunk, arms, and legs was diagnostic. Herpes classically presents as a cluster of vesicles overlying an erythematous base. When these vesicles rupture, punched-out erosions are left behind. Because these vesicles often are grouped, they can develop a scalloped border, which is a helpful indicator of HSV (Figure 1C). When these erosions become more confluent and irregular, the distinction from other conditions may not be as clear. A careful skin examination often can show areas that have preserved this herpetiform configuration.

Immune Compromise
Additionally, this case is illustrative of how immunosuppression and immunocompromise can affect the clinical presentation of HSV infection. Herpetic infections in the immunocompromised host tend to have a more protracted course, with chronic enlarging ulcers involving multiple sites. Furthermore, the morphology often is atypical, with ulcerodestructive, pustular, exophytic, and verrucous features as illustrated in this case. It is important to be mindful of these characteristics of HSV to properly diagnose an immunocompromised host.

Conclusion

This case is a good reminder that not everything that blisters and involves the mucosa is due to a hypersensitivity state such as TEN and Stevens-Johnson syndrome or an immunobullous disorder such as pemphigus vulgaris and pemphigus vegetans. The fact that this patient was worsening despite drug cessation, high-dose steroids, and IV immunoglobulin should have indicated a misdiagnosis. This case also shows that the early histopathologic findings of disseminated HSV and TEN can be nonspecific, and viral cytopathic changes may not always be obvious early in the disease.

Disseminated HSV should be considered in the differential diagnosis of a patient with an acute blistering eruption with mucosal involvement, and careful history and physical examination should be taken to rule out a viral etiology.

One of the most severe complications of systemic medications is the development of a life-threatening rash, especially toxic epidermal necrolysis (TEN). Most patients can expect a full recovery if the complicating medication is discontinued early on in its course.¹ When suspected TEN does not improve despite discontinuation of the detrimental medication, other diseases must be considered, particularly immunobullous and infectious etiologies. Treatment of these diseases differs substantially; therefore, a quick diagnosis is crucial. We present a case of a patient with an acute blistering eruption that was initially diagnosed and managed as TEN but physical examination and histopathologic confirmed another diagnosis. We review key examination findings that can help differentiate the causes of an acute blistering eruption with mucosal involvement, allowing for earlier diagnosis and treatment of these patients.

Case Report

An 85-year-old immunocompetent man was admitted to an outside hospital with a pruritic blistering eruption associated with myalgia, weakness, and fatigue of 3 weeks’ duration. The eruption initiated on the scalp and face and then spread down to the trunk and proximal arms and legs, with oral erosions also reported. An outside dermatologist was consulted on admission and performed a skin biopsy; the initial pathology was read as TEN. The patient was admitted to our institution on the same day, and all potentially complicating medications were stopped. He was treated with intravenous (IV) methylprednisolone sodium succinate 125 mg twice daily for 4 days and prednisone 40 mg daily for 9 days. With the rash worsening, the patient was restarted on methylprednisolone sodium succinate 40 mg every 8 hours approximately 3 weeks after admission, along with IV immunoglobulin at 2 g/kg over 3 days. When the patient did not respond to treatment, he was transferred to the University of California Irvine Medical Center for a higher level of care.

At that time, physical examination revealed numerous confluent erosions with honey-colored crust involving the entire face (Figure 1A) and sharp demarcation at the cutaneous lip (Figure 1B). There was a large erosion on the dorsal aspect of the tongue, but the rest of the oral mucosa was spared. The trunk and proximal extremities showed numerous grouped, punched-out erosions with scalloped borders (Figure 1C). A repeat skin biopsy showed an ulcer with viral cytopathic changes. Immunoperoxidase studies demonstrated positive staining for herpes simplex virus (HSV) type 1 (Figure 2). The original slides were a frozen section from an outside facility and could not be obtained. A tissue culture and direct fluorescent antibody also confirmed HSV-1, and the patient was diagnosed with disseminated herpes. He was rapidly tapered off of the steroids and started on IV acyclovir 10 mg/kg every 8 hours for 21 days. All prior erosions reepithelialized within 7 days of treatment (Figure 3). The patient had an otherwise uncomplicated hospital course and was discharged on hospital day 21.

Comment

A patient with an acute generalized blistering eruption requires urgent workup and treatment given the potentially devastating sequelae. Toxic epidermal necrolysis and immunobullous diseases often are the first diagnoses to be ruled out. Certainly infections such as HSV can cause a vesicular and erosive eruption, especially in the setting of a poorly controlled dermatitis, but they typically are not in the same differential as the other diagnoses.

Clinical Presentation
This case highlights 2 key physical examination findings that can alert the clinician to a possible underlying herpetic infection. First, the distribution of this patient’s oral lesions was telling. In most cases of TEN or pemphigus vulgaris, there is notable involvement of the oral mucosa, particularly the buccal and labial mucosa. Although herpes can involve any mucocutaneous surface, it does have a predilection for keratinized tissue, with the tongue and cutaneous lip commonly involved.^2,3 Our patient had a solitary linear erosion on the dorsal aspect of the tongue, but the rest of the oral cavity was strikingly spared. In addition, the erosions around the mouth stopped right at the cutaneous lip, sparing the labial mucosa (Figure 1B).

Second, the configuration of the erosions on the trunk, arms, and legs was diagnostic. Herpes classically presents as a cluster of vesicles overlying an erythematous base. When these vesicles rupture, punched-out erosions are left behind. Because these vesicles often are grouped, they can develop a scalloped border, which is a helpful indicator of HSV (Figure 1C). When these erosions become more confluent and irregular, the distinction from other conditions may not be as clear. A careful skin examination often can show areas that have preserved this herpetiform configuration.

Immune Compromise
Additionally, this case is illustrative of how immunosuppression and immunocompromise can affect the clinical presentation of HSV infection. Herpetic infections in the immunocompromised host tend to have a more protracted course, with chronic enlarging ulcers involving multiple sites. Furthermore, the morphology often is atypical, with ulcerodestructive, pustular, exophytic, and verrucous features as illustrated in this case. It is important to be mindful of these characteristics of HSV to properly diagnose an immunocompromised host.

Conclusion

This case is a good reminder that not everything that blisters and involves the mucosa is due to a hypersensitivity state such as TEN and Stevens-Johnson syndrome or an immunobullous disorder such as pemphigus vulgaris and pemphigus vegetans. The fact that this patient was worsening despite drug cessation, high-dose steroids, and IV immunoglobulin should have indicated a misdiagnosis. This case also shows that the early histopathologic findings of disseminated HSV and TEN can be nonspecific, and viral cytopathic changes may not always be obvious early in the disease.

Disseminated HSV should be considered in the differential diagnosis of a patient with an acute blistering eruption with mucosal involvement, and careful history and physical examination should be taken to rule out a viral etiology.