Dermatopathology

The Diagnosis: Degos Disease 

The pathophysiology of Degos disease (malignant atrophic papulosis) is unknown.¹ Histopathology demonstrates a wedge-shaped area of dermal necrosis with edema and mucin deposition extending from the papillary dermis to the deep reticular dermis. Occluded vessels, thrombosis, and perivascular lymphocytic infiltrates also may be seen, particularly at the dermal subcutaneous junction and at the periphery of the wedge-shaped infarction. The vascular damage that occurs may be the result of vasculitis, coagulopathy, or endothelial cell dysfunction.¹  

Patients typically present with small, round, erythematous papules that eventually develop atrophic porcelain white centers and telangiectatic rims. These lesions most commonly occur on the trunk and arms. In the benign form of atrophic papulosis, only the skin is involved; however, systemic involvement of the gastrointestinal tract and central nervous system can occur, resulting in bowel perforation and stroke, respectively.¹ Although there is no definitive treatment of Degos disease, successful therapy with aspirin or dipyridamole has been reported.¹ Eculizumab, a monoclonal antibody that binds C5, and treprostinil, a prostacyclin analog, are emerging treatment options.^2,3 The differential diagnosis of Degos disease may include granuloma annulare, guttate extragenital lichen sclerosus, livedoid vasculopathy, and lymphomatoid papulosis.  

Granuloma annulare may clinically mimic the erythematous papules seen in early Degos disease, and histopathology can be used to distinguish between these two disease processes. Localized granuloma annulare is the most common variant and clinically presents as pink papules and plaques in an annular configuration.⁴ Histopathology demonstrates an unremarkable epidermis; however, the dermis contains degenerated collagen surrounded by palisading histiocytes as well as lymphocytes. Similar to Degos disease, increased mucin is seen within these areas of degeneration, but occluded vessels and thrombosis typically are not seen (Figure 1).^4,5  

Guttate extragenital lichen sclerosus initially presents as polygonal, bluish white papules that coalesce into plaques.⁶ Over time, these lesions become more atrophic and may mimic Degos disease but appear differently on histopathology. Histopathology of lichen sclerosus classically demonstrates atrophy of the epidermis with loss of the rete ridges and vacuolar surface changes. Homogenization of the superficial/papillary dermis with an underlying bandlike lymphocytic infiltrate also is seen (Figure 2).⁶

Livedoid vasculopathy is characterized by chronic recurrent ulceration of the legs secondary to thrombosis and subsequent ischemia. In the initial phase of this disease, livedo reticularis is seen followed by the development of ulcerations. As these ulcerations heal, they leave behind porcelain white scars referred to as atrophie blanche.⁷ The areas of scarring in livedoid vasculopathy are broad and angulated, differentiating them from the small, round, porcelain white macules in end-stage Degos disease. Histopathology demonstrates thrombosis and fibrin occlusion of the upper and mid dermal vessels. Very minimal perivascular infiltrate typically is seen, but when it is present, the infiltrate mostly is lymphocytic. Hyalinization of the vessel walls also is seen, particularly in the atrophie blanche stage (Figure 3).⁷  

Lymphomatoid papulosis classically presents with pruritic red papules that often spontaneously involute. After resolution of the primary lesions, atrophic varioliform scars may be left behind that can resemble Degos disease.⁸ Classically, there are 5 histopathologic subtypes: A, B, C, D, and E. Type A is the most common type of lymphomatoid papulosis, and histopathology demonstrates a dermal lymphocytic infiltrate that consists of cells arranged in small clusters. Numerous medium- to large-sized atypical lymphocytes with prominent nucleoli and abundant cytoplasm are seen, and mitotic figures are common (Figure 4).⁸ 

Our case was particularly interesting because the patient was 2 to 3 weeks pregnant. Degos disease in pregnancy appears to be quite exceptional. A PubMed search of articles indexed for MEDLINE using the terms Degos disease and pregnancy revealed only 4 other cases reported in the literature.^9-12 With the exception of a single case that was complicated by severe abdominal pain requiring labor induction, the other reported cases resulted in uncomplicated pregnancies.^9-12 Conversely, our patient's pregnancy was complicated by gestational hypertension and fetal hydrops requiring a preterm cesarean delivery. Furthermore, the infant had multiple complications, which were attributed to both placental insufficiency and a coagulopathic state.  

Our patient also was found to have a heterozygous factor V Leiden mutation on workup. A PubMed search using the terms factor V Leiden mutation and Degos disease revealed 2 other cases of factor V Leiden mutation-associated Degos disease.^13,14 The importance of factor V Leiden mutations in patients with Degos disease currently is unclear. 

The Diagnosis: Degos Disease 

The pathophysiology of Degos disease (malignant atrophic papulosis) is unknown.¹ Histopathology demonstrates a wedge-shaped area of dermal necrosis with edema and mucin deposition extending from the papillary dermis to the deep reticular dermis. Occluded vessels, thrombosis, and perivascular lymphocytic infiltrates also may be seen, particularly at the dermal subcutaneous junction and at the periphery of the wedge-shaped infarction. The vascular damage that occurs may be the result of vasculitis, coagulopathy, or endothelial cell dysfunction.¹  

Patients typically present with small, round, erythematous papules that eventually develop atrophic porcelain white centers and telangiectatic rims. These lesions most commonly occur on the trunk and arms. In the benign form of atrophic papulosis, only the skin is involved; however, systemic involvement of the gastrointestinal tract and central nervous system can occur, resulting in bowel perforation and stroke, respectively.¹ Although there is no definitive treatment of Degos disease, successful therapy with aspirin or dipyridamole has been reported.¹ Eculizumab, a monoclonal antibody that binds C5, and treprostinil, a prostacyclin analog, are emerging treatment options.^2,3 The differential diagnosis of Degos disease may include granuloma annulare, guttate extragenital lichen sclerosus, livedoid vasculopathy, and lymphomatoid papulosis.  

Granuloma annulare may clinically mimic the erythematous papules seen in early Degos disease, and histopathology can be used to distinguish between these two disease processes. Localized granuloma annulare is the most common variant and clinically presents as pink papules and plaques in an annular configuration.⁴ Histopathology demonstrates an unremarkable epidermis; however, the dermis contains degenerated collagen surrounded by palisading histiocytes as well as lymphocytes. Similar to Degos disease, increased mucin is seen within these areas of degeneration, but occluded vessels and thrombosis typically are not seen (Figure 1).^4,5  

Guttate extragenital lichen sclerosus initially presents as polygonal, bluish white papules that coalesce into plaques.⁶ Over time, these lesions become more atrophic and may mimic Degos disease but appear differently on histopathology. Histopathology of lichen sclerosus classically demonstrates atrophy of the epidermis with loss of the rete ridges and vacuolar surface changes. Homogenization of the superficial/papillary dermis with an underlying bandlike lymphocytic infiltrate also is seen (Figure 2).⁶

Livedoid vasculopathy is characterized by chronic recurrent ulceration of the legs secondary to thrombosis and subsequent ischemia. In the initial phase of this disease, livedo reticularis is seen followed by the development of ulcerations. As these ulcerations heal, they leave behind porcelain white scars referred to as atrophie blanche.⁷ The areas of scarring in livedoid vasculopathy are broad and angulated, differentiating them from the small, round, porcelain white macules in end-stage Degos disease. Histopathology demonstrates thrombosis and fibrin occlusion of the upper and mid dermal vessels. Very minimal perivascular infiltrate typically is seen, but when it is present, the infiltrate mostly is lymphocytic. Hyalinization of the vessel walls also is seen, particularly in the atrophie blanche stage (Figure 3).⁷  

Lymphomatoid papulosis classically presents with pruritic red papules that often spontaneously involute. After resolution of the primary lesions, atrophic varioliform scars may be left behind that can resemble Degos disease.⁸ Classically, there are 5 histopathologic subtypes: A, B, C, D, and E. Type A is the most common type of lymphomatoid papulosis, and histopathology demonstrates a dermal lymphocytic infiltrate that consists of cells arranged in small clusters. Numerous medium- to large-sized atypical lymphocytes with prominent nucleoli and abundant cytoplasm are seen, and mitotic figures are common (Figure 4).⁸ 

Our case was particularly interesting because the patient was 2 to 3 weeks pregnant. Degos disease in pregnancy appears to be quite exceptional. A PubMed search of articles indexed for MEDLINE using the terms Degos disease and pregnancy revealed only 4 other cases reported in the literature.^9-12 With the exception of a single case that was complicated by severe abdominal pain requiring labor induction, the other reported cases resulted in uncomplicated pregnancies.^9-12 Conversely, our patient's pregnancy was complicated by gestational hypertension and fetal hydrops requiring a preterm cesarean delivery. Furthermore, the infant had multiple complications, which were attributed to both placental insufficiency and a coagulopathic state.  

Our patient also was found to have a heterozygous factor V Leiden mutation on workup. A PubMed search using the terms factor V Leiden mutation and Degos disease revealed 2 other cases of factor V Leiden mutation-associated Degos disease.^13,14 The importance of factor V Leiden mutations in patients with Degos disease currently is unclear. 

The Diagnosis: Degos Disease 

The pathophysiology of Degos disease (malignant atrophic papulosis) is unknown.¹ Histopathology demonstrates a wedge-shaped area of dermal necrosis with edema and mucin deposition extending from the papillary dermis to the deep reticular dermis. Occluded vessels, thrombosis, and perivascular lymphocytic infiltrates also may be seen, particularly at the dermal subcutaneous junction and at the periphery of the wedge-shaped infarction. The vascular damage that occurs may be the result of vasculitis, coagulopathy, or endothelial cell dysfunction.¹  

Patients typically present with small, round, erythematous papules that eventually develop atrophic porcelain white centers and telangiectatic rims. These lesions most commonly occur on the trunk and arms. In the benign form of atrophic papulosis, only the skin is involved; however, systemic involvement of the gastrointestinal tract and central nervous system can occur, resulting in bowel perforation and stroke, respectively.¹ Although there is no definitive treatment of Degos disease, successful therapy with aspirin or dipyridamole has been reported.¹ Eculizumab, a monoclonal antibody that binds C5, and treprostinil, a prostacyclin analog, are emerging treatment options.^2,3 The differential diagnosis of Degos disease may include granuloma annulare, guttate extragenital lichen sclerosus, livedoid vasculopathy, and lymphomatoid papulosis.  

Granuloma annulare may clinically mimic the erythematous papules seen in early Degos disease, and histopathology can be used to distinguish between these two disease processes. Localized granuloma annulare is the most common variant and clinically presents as pink papules and plaques in an annular configuration.⁴ Histopathology demonstrates an unremarkable epidermis; however, the dermis contains degenerated collagen surrounded by palisading histiocytes as well as lymphocytes. Similar to Degos disease, increased mucin is seen within these areas of degeneration, but occluded vessels and thrombosis typically are not seen (Figure 1).^4,5  

Guttate extragenital lichen sclerosus initially presents as polygonal, bluish white papules that coalesce into plaques.⁶ Over time, these lesions become more atrophic and may mimic Degos disease but appear differently on histopathology. Histopathology of lichen sclerosus classically demonstrates atrophy of the epidermis with loss of the rete ridges and vacuolar surface changes. Homogenization of the superficial/papillary dermis with an underlying bandlike lymphocytic infiltrate also is seen (Figure 2).⁶

Livedoid vasculopathy is characterized by chronic recurrent ulceration of the legs secondary to thrombosis and subsequent ischemia. In the initial phase of this disease, livedo reticularis is seen followed by the development of ulcerations. As these ulcerations heal, they leave behind porcelain white scars referred to as atrophie blanche.⁷ The areas of scarring in livedoid vasculopathy are broad and angulated, differentiating them from the small, round, porcelain white macules in end-stage Degos disease. Histopathology demonstrates thrombosis and fibrin occlusion of the upper and mid dermal vessels. Very minimal perivascular infiltrate typically is seen, but when it is present, the infiltrate mostly is lymphocytic. Hyalinization of the vessel walls also is seen, particularly in the atrophie blanche stage (Figure 3).⁷  

Lymphomatoid papulosis classically presents with pruritic red papules that often spontaneously involute. After resolution of the primary lesions, atrophic varioliform scars may be left behind that can resemble Degos disease.⁸ Classically, there are 5 histopathologic subtypes: A, B, C, D, and E. Type A is the most common type of lymphomatoid papulosis, and histopathology demonstrates a dermal lymphocytic infiltrate that consists of cells arranged in small clusters. Numerous medium- to large-sized atypical lymphocytes with prominent nucleoli and abundant cytoplasm are seen, and mitotic figures are common (Figure 4).⁸ 

Our case was particularly interesting because the patient was 2 to 3 weeks pregnant. Degos disease in pregnancy appears to be quite exceptional. A PubMed search of articles indexed for MEDLINE using the terms Degos disease and pregnancy revealed only 4 other cases reported in the literature.^9-12 With the exception of a single case that was complicated by severe abdominal pain requiring labor induction, the other reported cases resulted in uncomplicated pregnancies.^9-12 Conversely, our patient's pregnancy was complicated by gestational hypertension and fetal hydrops requiring a preterm cesarean delivery. Furthermore, the infant had multiple complications, which were attributed to both placental insufficiency and a coagulopathic state.  

Our patient also was found to have a heterozygous factor V Leiden mutation on workup. A PubMed search using the terms factor V Leiden mutation and Degos disease revealed 2 other cases of factor V Leiden mutation-associated Degos disease.^13,14 The importance of factor V Leiden mutations in patients with Degos disease currently is unclear. 

The Diagnosis: Paraneoplastic Acanthosis Nigricans 

Histopathologic examination demonstrated verrucous epidermal hyperplasia (Figure, A). Fungal organisms were identified with an Alcian blue and periodic acid-Schiff stain (Figure, B). The organisms demonstrated a vertical orientation in relation to the mucosal surface, which was consistent with candidal organisms.  

Given the rapid eruption of these plaques, the distribution on the oral and palmar surfaces (tripe palms), and the minimal improvement with both systemic steroids and antifungal treatment, a diagnosis of paraneoplastic acanthosis nigricans with secondary candidal infection was made. Drug-induced cheilitis was considered; however, improvement with discontinuation of the suspected offending drug would have been expected. Although chronic mucocutaneous candidiasis was possible, more prompt improvement upon initiation of systemic antifungal therapy would have been observed. Oral Crohn disease should be included in the differential, but it was unlikely given the lack of granulomas on pathology and absence of history of gastrointestinal tract symptoms. Melkersson-Rosenthal syndrome also was unlikely given the lack of facial nerve palsy as well as the lack of granulomas on pathology. Furthermore, none of these options would be associated with tripe palms, as seen in our patient.  

Acanthosis nigricans is a localized skin disorder characterized by hyperpigmented velvety plaques arising in flexural and intertriginous regions. Although most cases (80%) are associated with idiopathic or benign conditions, the link between acanthosis nigricans and an underlying malignancy has been well documented.^1-3 Most commonly associated with an underlying intra-abdominal malignancy (often gastric carcinoma), the lesions of paraneoplastic acanthosis nigricans are indistinguishable from their benign counterparts^.1,4 When the condition presents abruptly and extensively in a nonobese patient, prompt workup for malignancy should be initiated. Rapid onset and atypical distribution (ie, palmar, perioral, or mucosal) more commonly is associated with a paraneoplastic etiology.^5,6 

Histopathology for acanthosis nigricans shows hyperkeratosis and epidermal papillomatosis. Horn pseudocyst formation is possible, but usually no hyperpigmentation is observed. The findings typically are indistinguishable from seborrheic keratoses, epidermal nevi, or lesions of confluent and reticulated papillomatosis of Gougerot and Carteaud.² 

The underlying pathogenesis of acanthosis nigricans is poorly understood. In the benign subtype, insulin resistance commonly has been described. In the paraneoplastic subtype, it is proposed that the tumor produces a transforming growth factor that mimics epidermal growth factor and leads to keratinocyte proliferation.^7,8 Paraneoplastic acanthosis nigricans has the potential to arise at any point of tumor development, further contributing to the diagnostic challenge. Treatment of the skin lesions involves management of the underlying malignancy. Unfortunately, many such malignancies often are at an advanced stage, and subsequent prognosis is poor.² 

The Diagnosis: Paraneoplastic Acanthosis Nigricans 

Histopathologic examination demonstrated verrucous epidermal hyperplasia (Figure, A). Fungal organisms were identified with an Alcian blue and periodic acid-Schiff stain (Figure, B). The organisms demonstrated a vertical orientation in relation to the mucosal surface, which was consistent with candidal organisms.  

Given the rapid eruption of these plaques, the distribution on the oral and palmar surfaces (tripe palms), and the minimal improvement with both systemic steroids and antifungal treatment, a diagnosis of paraneoplastic acanthosis nigricans with secondary candidal infection was made. Drug-induced cheilitis was considered; however, improvement with discontinuation of the suspected offending drug would have been expected. Although chronic mucocutaneous candidiasis was possible, more prompt improvement upon initiation of systemic antifungal therapy would have been observed. Oral Crohn disease should be included in the differential, but it was unlikely given the lack of granulomas on pathology and absence of history of gastrointestinal tract symptoms. Melkersson-Rosenthal syndrome also was unlikely given the lack of facial nerve palsy as well as the lack of granulomas on pathology. Furthermore, none of these options would be associated with tripe palms, as seen in our patient.  

Acanthosis nigricans is a localized skin disorder characterized by hyperpigmented velvety plaques arising in flexural and intertriginous regions. Although most cases (80%) are associated with idiopathic or benign conditions, the link between acanthosis nigricans and an underlying malignancy has been well documented.^1-3 Most commonly associated with an underlying intra-abdominal malignancy (often gastric carcinoma), the lesions of paraneoplastic acanthosis nigricans are indistinguishable from their benign counterparts^.1,4 When the condition presents abruptly and extensively in a nonobese patient, prompt workup for malignancy should be initiated. Rapid onset and atypical distribution (ie, palmar, perioral, or mucosal) more commonly is associated with a paraneoplastic etiology.^5,6 

Histopathology for acanthosis nigricans shows hyperkeratosis and epidermal papillomatosis. Horn pseudocyst formation is possible, but usually no hyperpigmentation is observed. The findings typically are indistinguishable from seborrheic keratoses, epidermal nevi, or lesions of confluent and reticulated papillomatosis of Gougerot and Carteaud.² 

The underlying pathogenesis of acanthosis nigricans is poorly understood. In the benign subtype, insulin resistance commonly has been described. In the paraneoplastic subtype, it is proposed that the tumor produces a transforming growth factor that mimics epidermal growth factor and leads to keratinocyte proliferation.^7,8 Paraneoplastic acanthosis nigricans has the potential to arise at any point of tumor development, further contributing to the diagnostic challenge. Treatment of the skin lesions involves management of the underlying malignancy. Unfortunately, many such malignancies often are at an advanced stage, and subsequent prognosis is poor.² 

The Diagnosis: Paraneoplastic Acanthosis Nigricans 

Histopathologic examination demonstrated verrucous epidermal hyperplasia (Figure, A). Fungal organisms were identified with an Alcian blue and periodic acid-Schiff stain (Figure, B). The organisms demonstrated a vertical orientation in relation to the mucosal surface, which was consistent with candidal organisms.  

Given the rapid eruption of these plaques, the distribution on the oral and palmar surfaces (tripe palms), and the minimal improvement with both systemic steroids and antifungal treatment, a diagnosis of paraneoplastic acanthosis nigricans with secondary candidal infection was made. Drug-induced cheilitis was considered; however, improvement with discontinuation of the suspected offending drug would have been expected. Although chronic mucocutaneous candidiasis was possible, more prompt improvement upon initiation of systemic antifungal therapy would have been observed. Oral Crohn disease should be included in the differential, but it was unlikely given the lack of granulomas on pathology and absence of history of gastrointestinal tract symptoms. Melkersson-Rosenthal syndrome also was unlikely given the lack of facial nerve palsy as well as the lack of granulomas on pathology. Furthermore, none of these options would be associated with tripe palms, as seen in our patient.  

Acanthosis nigricans is a localized skin disorder characterized by hyperpigmented velvety plaques arising in flexural and intertriginous regions. Although most cases (80%) are associated with idiopathic or benign conditions, the link between acanthosis nigricans and an underlying malignancy has been well documented.^1-3 Most commonly associated with an underlying intra-abdominal malignancy (often gastric carcinoma), the lesions of paraneoplastic acanthosis nigricans are indistinguishable from their benign counterparts^.1,4 When the condition presents abruptly and extensively in a nonobese patient, prompt workup for malignancy should be initiated. Rapid onset and atypical distribution (ie, palmar, perioral, or mucosal) more commonly is associated with a paraneoplastic etiology.^5,6 

Histopathology for acanthosis nigricans shows hyperkeratosis and epidermal papillomatosis. Horn pseudocyst formation is possible, but usually no hyperpigmentation is observed. The findings typically are indistinguishable from seborrheic keratoses, epidermal nevi, or lesions of confluent and reticulated papillomatosis of Gougerot and Carteaud.² 

The underlying pathogenesis of acanthosis nigricans is poorly understood. In the benign subtype, insulin resistance commonly has been described. In the paraneoplastic subtype, it is proposed that the tumor produces a transforming growth factor that mimics epidermal growth factor and leads to keratinocyte proliferation.^7,8 Paraneoplastic acanthosis nigricans has the potential to arise at any point of tumor development, further contributing to the diagnostic challenge. Treatment of the skin lesions involves management of the underlying malignancy. Unfortunately, many such malignancies often are at an advanced stage, and subsequent prognosis is poor.² 

Case Report

A 67-year-old woman presented with a painful expanding ulcer on the left leg and a new nearby ulcer of 2 months’ duration. She initially was seen 2 months prior for a wound on the left knee due to a fall as well as cellulitis, which was treated with intravenous vancomycin and ceftriaxone. Wound cultures were negative for bacteria, and she was discharged without antibiotics. She presented to the emergency department 1 month later for malodorous discharge of the first ulcer with zero systemic inflammatory response syndrome criteria; no fever; and no abnormal heart rate, respiratory rate, or leukocyte count. She was discharged with wound care. After 3 weeks, she returned with a second ulcer and worsening drainage but zero systemic inflammatory response syndrome criteria. She had a medical history of Crohn disease with 9-year remission, atrial fibrillation, pacemaker, mitral valve replacement, chronic obstructive pulmonary disease, and a 51 pack-year smoking history.

Physical examination of the left leg revealed a 3×3-cm deep lesion (ulcer A) on the distal left thigh located superomedial to the knee (Figure 1) as well as a 2×1-cm deep lesion (ulcer B) on the anteromedial knee with undermining and tunneling (Figure 2). A large amount of malodorous tan bloody discharge was present on both ulcers. There were no signs of induration or crepitus.Due to concerns of skin and soft tissue infection (SSTI) or osteomyelitis, a bone scan and wound and blood cultures were ordered. The patient was started on vancomycin and piperacillin-tazobactam in the emergency department, which later was augmented with cefepime. Trauma surgery scheduled debridement for the following morning with suspicion of necrotizing fasciitis. Additional consultations were requested, including infectious disease, wound care, and dermatology. Dermatology evaluated the wound, performed a punch biopsy, and canceled debridement due to unclear diagnosis. The clinical differential at that time included pyoderma gangrenosum (PG), atypical vasculitis, or infection. Additional workup revealed positive antineutrophil cytoplasmic antibodies but negative proteinase 3 and myeloperoxidase, disfavoring vasculitis. Wound cultures grew Staphylococcus aureus and Pseudomonas aeruginosa.

Comment

Pyoderma gangrenosum is a rare inflammatory skin condition that classically presents as tender papules or pustules evolving into painful ulcers, most commonly on the lower extremities. Pyoderma gangrenosum has a propensity to exhibit pathergy, the hyperreactivity of the skin in response to minor trauma. This phenomenon in PG manifests as the rapid evolution from pustule to ulceration with violaceous undermining borders.

Diagnosis of PG
Pyoderma gangrenosum has been described as a diagnosis of exclusion, as its findings frequently mimic SSTIs. Important findings to obtain are histology, history, ulcer morphology, and response to treatment.

In 2018, Maverakis et al¹ proposed diagnostic criteria for classic ulcerative PG (Table 1). A diagnosis of PG can be made if the patient meets 1 major criterion and 4 minor criteria. Our case met 0 major criteria and 5 minor criteria: history of inflammatory bowel disease (IBD); history of pustule ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, with at least 1 on an anterior lower leg; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Although our patient’s biopsy demonstrated a mixed infiltrate, PG was not excluded due to spontaneous resolution at the time of biopsy, emphasizing the need to biopsy subsequent new lesions if neutrophils are not initially seen.¹ Pyoderma gangrenosum frequently is associated with IBD, most often Crohn disease, as seen in our patient.^2-4 Although IBD classically is associated with smoking, studies have yet to conclude if smoking is a predictive factor of PG.⁵ Our patient presented with an initial ulcer that evolved into 2 ulcers, similar to a case of bilateral ulcers.⁶

Management of PG
A gold standard of treatment of PG does not exist, but the goal is to promote wound healing. Patients with limited disease typically can be managed with wound care and topical steroids or calcineurin inhibitors, though data on efficacy are limited. However, our patient had more extensive disease and needed to be treated with systemic therapy. First-line therapy for extensive disease includes oral prednisone or cyclosporine for patients who cannot tolerate systemic corticosteroids.¹² Second-line and adjunctive therapy options include dapsone, minocycline, methotrexate, and infliximab. Our patient was prescribed a 7-month course of dapsone with outpatient dermatology and demonstrated resolution of both ulcers. Dapsone was tapered from a daily dose of 100 mg to 50 mg to 25 mg to none over the course of 2 to 3 months. Close monitoring with wound care is recommended, and petroleum jelly can be used for dry skin around the lesion for comfort.

Conclusion

The diagnosis of PG is challenging because it relies heavily on clinical signs and often mimics SSTI. Gathering a detailed medical history is critical to make the diagnosis of PG. In a patient with associated features of PG, dermatologic consultation and biopsy of skin lesions should be considered. Physicians should evaluate for suspected PG prior to proceeding with surgical intervention to avoid unnecessary amputation. The diagnostic criteria for classic ulcerative PG are gaining wider acceptance and are a useful tool for clinicians.

Case Report

A 67-year-old woman presented with a painful expanding ulcer on the left leg and a new nearby ulcer of 2 months’ duration. She initially was seen 2 months prior for a wound on the left knee due to a fall as well as cellulitis, which was treated with intravenous vancomycin and ceftriaxone. Wound cultures were negative for bacteria, and she was discharged without antibiotics. She presented to the emergency department 1 month later for malodorous discharge of the first ulcer with zero systemic inflammatory response syndrome criteria; no fever; and no abnormal heart rate, respiratory rate, or leukocyte count. She was discharged with wound care. After 3 weeks, she returned with a second ulcer and worsening drainage but zero systemic inflammatory response syndrome criteria. She had a medical history of Crohn disease with 9-year remission, atrial fibrillation, pacemaker, mitral valve replacement, chronic obstructive pulmonary disease, and a 51 pack-year smoking history.

Physical examination of the left leg revealed a 3×3-cm deep lesion (ulcer A) on the distal left thigh located superomedial to the knee (Figure 1) as well as a 2×1-cm deep lesion (ulcer B) on the anteromedial knee with undermining and tunneling (Figure 2). A large amount of malodorous tan bloody discharge was present on both ulcers. There were no signs of induration or crepitus.Due to concerns of skin and soft tissue infection (SSTI) or osteomyelitis, a bone scan and wound and blood cultures were ordered. The patient was started on vancomycin and piperacillin-tazobactam in the emergency department, which later was augmented with cefepime. Trauma surgery scheduled debridement for the following morning with suspicion of necrotizing fasciitis. Additional consultations were requested, including infectious disease, wound care, and dermatology. Dermatology evaluated the wound, performed a punch biopsy, and canceled debridement due to unclear diagnosis. The clinical differential at that time included pyoderma gangrenosum (PG), atypical vasculitis, or infection. Additional workup revealed positive antineutrophil cytoplasmic antibodies but negative proteinase 3 and myeloperoxidase, disfavoring vasculitis. Wound cultures grew Staphylococcus aureus and Pseudomonas aeruginosa.

Comment

Pyoderma gangrenosum is a rare inflammatory skin condition that classically presents as tender papules or pustules evolving into painful ulcers, most commonly on the lower extremities. Pyoderma gangrenosum has a propensity to exhibit pathergy, the hyperreactivity of the skin in response to minor trauma. This phenomenon in PG manifests as the rapid evolution from pustule to ulceration with violaceous undermining borders.

Diagnosis of PG
Pyoderma gangrenosum has been described as a diagnosis of exclusion, as its findings frequently mimic SSTIs. Important findings to obtain are histology, history, ulcer morphology, and response to treatment.

In 2018, Maverakis et al¹ proposed diagnostic criteria for classic ulcerative PG (Table 1). A diagnosis of PG can be made if the patient meets 1 major criterion and 4 minor criteria. Our case met 0 major criteria and 5 minor criteria: history of inflammatory bowel disease (IBD); history of pustule ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, with at least 1 on an anterior lower leg; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Although our patient’s biopsy demonstrated a mixed infiltrate, PG was not excluded due to spontaneous resolution at the time of biopsy, emphasizing the need to biopsy subsequent new lesions if neutrophils are not initially seen.¹ Pyoderma gangrenosum frequently is associated with IBD, most often Crohn disease, as seen in our patient.^2-4 Although IBD classically is associated with smoking, studies have yet to conclude if smoking is a predictive factor of PG.⁵ Our patient presented with an initial ulcer that evolved into 2 ulcers, similar to a case of bilateral ulcers.⁶

Management of PG
A gold standard of treatment of PG does not exist, but the goal is to promote wound healing. Patients with limited disease typically can be managed with wound care and topical steroids or calcineurin inhibitors, though data on efficacy are limited. However, our patient had more extensive disease and needed to be treated with systemic therapy. First-line therapy for extensive disease includes oral prednisone or cyclosporine for patients who cannot tolerate systemic corticosteroids.¹² Second-line and adjunctive therapy options include dapsone, minocycline, methotrexate, and infliximab. Our patient was prescribed a 7-month course of dapsone with outpatient dermatology and demonstrated resolution of both ulcers. Dapsone was tapered from a daily dose of 100 mg to 50 mg to 25 mg to none over the course of 2 to 3 months. Close monitoring with wound care is recommended, and petroleum jelly can be used for dry skin around the lesion for comfort.

Conclusion

The diagnosis of PG is challenging because it relies heavily on clinical signs and often mimics SSTI. Gathering a detailed medical history is critical to make the diagnosis of PG. In a patient with associated features of PG, dermatologic consultation and biopsy of skin lesions should be considered. Physicians should evaluate for suspected PG prior to proceeding with surgical intervention to avoid unnecessary amputation. The diagnostic criteria for classic ulcerative PG are gaining wider acceptance and are a useful tool for clinicians.

Case Report

A 67-year-old woman presented with a painful expanding ulcer on the left leg and a new nearby ulcer of 2 months’ duration. She initially was seen 2 months prior for a wound on the left knee due to a fall as well as cellulitis, which was treated with intravenous vancomycin and ceftriaxone. Wound cultures were negative for bacteria, and she was discharged without antibiotics. She presented to the emergency department 1 month later for malodorous discharge of the first ulcer with zero systemic inflammatory response syndrome criteria; no fever; and no abnormal heart rate, respiratory rate, or leukocyte count. She was discharged with wound care. After 3 weeks, she returned with a second ulcer and worsening drainage but zero systemic inflammatory response syndrome criteria. She had a medical history of Crohn disease with 9-year remission, atrial fibrillation, pacemaker, mitral valve replacement, chronic obstructive pulmonary disease, and a 51 pack-year smoking history.

Physical examination of the left leg revealed a 3×3-cm deep lesion (ulcer A) on the distal left thigh located superomedial to the knee (Figure 1) as well as a 2×1-cm deep lesion (ulcer B) on the anteromedial knee with undermining and tunneling (Figure 2). A large amount of malodorous tan bloody discharge was present on both ulcers. There were no signs of induration or crepitus.Due to concerns of skin and soft tissue infection (SSTI) or osteomyelitis, a bone scan and wound and blood cultures were ordered. The patient was started on vancomycin and piperacillin-tazobactam in the emergency department, which later was augmented with cefepime. Trauma surgery scheduled debridement for the following morning with suspicion of necrotizing fasciitis. Additional consultations were requested, including infectious disease, wound care, and dermatology. Dermatology evaluated the wound, performed a punch biopsy, and canceled debridement due to unclear diagnosis. The clinical differential at that time included pyoderma gangrenosum (PG), atypical vasculitis, or infection. Additional workup revealed positive antineutrophil cytoplasmic antibodies but negative proteinase 3 and myeloperoxidase, disfavoring vasculitis. Wound cultures grew Staphylococcus aureus and Pseudomonas aeruginosa.

Comment

Pyoderma gangrenosum is a rare inflammatory skin condition that classically presents as tender papules or pustules evolving into painful ulcers, most commonly on the lower extremities. Pyoderma gangrenosum has a propensity to exhibit pathergy, the hyperreactivity of the skin in response to minor trauma. This phenomenon in PG manifests as the rapid evolution from pustule to ulceration with violaceous undermining borders.

Diagnosis of PG
Pyoderma gangrenosum has been described as a diagnosis of exclusion, as its findings frequently mimic SSTIs. Important findings to obtain are histology, history, ulcer morphology, and response to treatment.

In 2018, Maverakis et al¹ proposed diagnostic criteria for classic ulcerative PG (Table 1). A diagnosis of PG can be made if the patient meets 1 major criterion and 4 minor criteria. Our case met 0 major criteria and 5 minor criteria: history of inflammatory bowel disease (IBD); history of pustule ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, with at least 1 on an anterior lower leg; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Although our patient’s biopsy demonstrated a mixed infiltrate, PG was not excluded due to spontaneous resolution at the time of biopsy, emphasizing the need to biopsy subsequent new lesions if neutrophils are not initially seen.¹ Pyoderma gangrenosum frequently is associated with IBD, most often Crohn disease, as seen in our patient.^2-4 Although IBD classically is associated with smoking, studies have yet to conclude if smoking is a predictive factor of PG.⁵ Our patient presented with an initial ulcer that evolved into 2 ulcers, similar to a case of bilateral ulcers.⁶

Management of PG
A gold standard of treatment of PG does not exist, but the goal is to promote wound healing. Patients with limited disease typically can be managed with wound care and topical steroids or calcineurin inhibitors, though data on efficacy are limited. However, our patient had more extensive disease and needed to be treated with systemic therapy. First-line therapy for extensive disease includes oral prednisone or cyclosporine for patients who cannot tolerate systemic corticosteroids.¹² Second-line and adjunctive therapy options include dapsone, minocycline, methotrexate, and infliximab. Our patient was prescribed a 7-month course of dapsone with outpatient dermatology and demonstrated resolution of both ulcers. Dapsone was tapered from a daily dose of 100 mg to 50 mg to 25 mg to none over the course of 2 to 3 months. Close monitoring with wound care is recommended, and petroleum jelly can be used for dry skin around the lesion for comfort.

Conclusion

The diagnosis of PG is challenging because it relies heavily on clinical signs and often mimics SSTI. Gathering a detailed medical history is critical to make the diagnosis of PG. In a patient with associated features of PG, dermatologic consultation and biopsy of skin lesions should be considered. Physicians should evaluate for suspected PG prior to proceeding with surgical intervention to avoid unnecessary amputation. The diagnostic criteria for classic ulcerative PG are gaining wider acceptance and are a useful tool for clinicians.

To the Editor:

Urticarial vasculitis (UV) is a clinicopathologic entity. It manifests as an eruption of erythematous wheals that clinically resemble urticaria, but the lesions of UV last longer, may leave residual hyperpigmentation, and may or may not be pruritic.¹ Therapies most often employed include oral antihistamines and systemic immunosuppressant drugs such as corticosteroids, dapsone, colchicine, or hydroxychloroquine.² We present a woman with UV who successfully was treated with omalizumab.

A 49-year-old woman presented to our outpatient clinic with generalized pruritic skin rashes of 2 years’ duration. She also described swelling on the upper eyelids 2 times monthly. She used several antihistamines (up to 4 times daily) and was taking systemic corticosteroids and antidepressants. Physical examination revealed generalized erythematous and edematous papules and plaques on the trunk and extremities (Figure 1). At follow-up a few days later, we observed that the lesions were lasting for more than 24 hours, but there was no residual pigmentation. According to clinical concerns and the association with angioedema, we initially thought the diagnosis was chronic urticaria and angioedema. The patient had no extracutaneous manifestations such as fever, arthralgia, or lymphadenopathy. Routine laboratory examinations including antinuclear antibodies were within reference range. She had normal C3 and C4 levels and an elevated total IgE level (344 IU/mL [reference range, 0–170 IU/mL]). Because the IgE level was elevated and she had no response to the highest dosages of antihistamines, we decided to start omalizumab therapy. Prior to starting omalizumab, we performed a skin biopsy for histopathologic and direct immunofluorescence examinations for UV, as the duration of the lesions was more than 24 hours. Histopathologic examination revealed lymphocytes within the vessel wall and perivascular lymphocytic infiltration with eosinophils (Figure 2). On direct immunofluorescence, perivascular IgA deposition was observed (Figure 3). Histopathologic findings were associated with lymphocytic vasculitis. Systemic involvement was not detected on detailed laboratory and radiologic examinations.

After the first application of omalizumab, the lesions disappeared within a few days. She was treated with subcutaneous omalizumab 300 mg every 4 weeks for 6 months, and we did not observe any adverse effects related to the drug. There was no relapse after therapy cessation.

Omalizumab is a recombinant humanized anti-IgE monoclonal antibody that is approved by the US Food and Drug Administration for treatment of chronic idiopathic urticaria.^3-5 Studies have suggested that omalizumab might play an important role in the treatment of other potentially IgE-mediated disease processes including allergic asthma, atopic dermatitis, allergic rhinitis, nasal polyposis, and severe ocular allergies.⁶ The proposed mechanism of action of omalizumab includes reduction of free IgE through the reversible formation of tiny, biologically inert complexes; targeting IgE-expressing B cells; and inhibiting production of IgE. Because it reduces free IgE, omalizumab has been used in normal IgE or hyper-IgE situations. Omalizumab also induces eosinophil apoptosis; increases IL-2, IL-3, tumor necrosis factor α, and IFN-γ; and reduces IL-4.⁷ A number of off-label uses have been described such as atopic dermatitis, bullous pemphigoid, hyper-IgE syndrome, cutaneous mastocytosis, toxic epidermal necrolysis, and eosinophilic granulomatosis with polyangitis.⁸ There are no clinical studies of omalizumab for UV, and only a few case reports have shown that omalizumab also might be beneficial for this condition.^2-4 Diez et al⁴ reported 3 cases of women aged 28, 51, and 54 years with spontaneous chronic urticaria with autoimmune and pressure components as well as vasculitis whose symptoms completely improved after starting omalizumab. Kai et al³ successfully treated a patient with normocomplementemic UV with omalizumab and suggested that omalizumab markedly improved the patient’s quality of life with chronic urticaria and UV. Ghazanfar and Thomsen² reported the case of a 68-year-old man diagnosed with histopathologically confirmed leukocytoclastic vasculitis. He had used systemic corticosteroid therapy and dapsone without notable improvement. The patient was switched to subcutaneous omalizumab 300 mg once every 4 weeks; after 1 month, he observed complete remission of the UV and symptoms.²

Our case suggests that omalizumab has a beneficial effect on patients with UV. Omalizumab may be effective in UV through its reduction of IgE, as in chronic urticaria, and through downstream effects on cellular activation mechanisms (possibly a reduction in chemotaxis or immune complex formation). However, the mechanism of action of omalizumab for UV remains, in part, unresolved. It is not known whether omalizumab is efficacious against both normocomplementemic and hypocomplementemic UV. Further studies with a greater number of patients are needed to confirm the effects of omalizumab for vasculitic patients.

To the Editor:

Urticarial vasculitis (UV) is a clinicopathologic entity. It manifests as an eruption of erythematous wheals that clinically resemble urticaria, but the lesions of UV last longer, may leave residual hyperpigmentation, and may or may not be pruritic.¹ Therapies most often employed include oral antihistamines and systemic immunosuppressant drugs such as corticosteroids, dapsone, colchicine, or hydroxychloroquine.² We present a woman with UV who successfully was treated with omalizumab.

A 49-year-old woman presented to our outpatient clinic with generalized pruritic skin rashes of 2 years’ duration. She also described swelling on the upper eyelids 2 times monthly. She used several antihistamines (up to 4 times daily) and was taking systemic corticosteroids and antidepressants. Physical examination revealed generalized erythematous and edematous papules and plaques on the trunk and extremities (Figure 1). At follow-up a few days later, we observed that the lesions were lasting for more than 24 hours, but there was no residual pigmentation. According to clinical concerns and the association with angioedema, we initially thought the diagnosis was chronic urticaria and angioedema. The patient had no extracutaneous manifestations such as fever, arthralgia, or lymphadenopathy. Routine laboratory examinations including antinuclear antibodies were within reference range. She had normal C3 and C4 levels and an elevated total IgE level (344 IU/mL [reference range, 0–170 IU/mL]). Because the IgE level was elevated and she had no response to the highest dosages of antihistamines, we decided to start omalizumab therapy. Prior to starting omalizumab, we performed a skin biopsy for histopathologic and direct immunofluorescence examinations for UV, as the duration of the lesions was more than 24 hours. Histopathologic examination revealed lymphocytes within the vessel wall and perivascular lymphocytic infiltration with eosinophils (Figure 2). On direct immunofluorescence, perivascular IgA deposition was observed (Figure 3). Histopathologic findings were associated with lymphocytic vasculitis. Systemic involvement was not detected on detailed laboratory and radiologic examinations.

After the first application of omalizumab, the lesions disappeared within a few days. She was treated with subcutaneous omalizumab 300 mg every 4 weeks for 6 months, and we did not observe any adverse effects related to the drug. There was no relapse after therapy cessation.

Omalizumab is a recombinant humanized anti-IgE monoclonal antibody that is approved by the US Food and Drug Administration for treatment of chronic idiopathic urticaria.^3-5 Studies have suggested that omalizumab might play an important role in the treatment of other potentially IgE-mediated disease processes including allergic asthma, atopic dermatitis, allergic rhinitis, nasal polyposis, and severe ocular allergies.⁶ The proposed mechanism of action of omalizumab includes reduction of free IgE through the reversible formation of tiny, biologically inert complexes; targeting IgE-expressing B cells; and inhibiting production of IgE. Because it reduces free IgE, omalizumab has been used in normal IgE or hyper-IgE situations. Omalizumab also induces eosinophil apoptosis; increases IL-2, IL-3, tumor necrosis factor α, and IFN-γ; and reduces IL-4.⁷ A number of off-label uses have been described such as atopic dermatitis, bullous pemphigoid, hyper-IgE syndrome, cutaneous mastocytosis, toxic epidermal necrolysis, and eosinophilic granulomatosis with polyangitis.⁸ There are no clinical studies of omalizumab for UV, and only a few case reports have shown that omalizumab also might be beneficial for this condition.^2-4 Diez et al⁴ reported 3 cases of women aged 28, 51, and 54 years with spontaneous chronic urticaria with autoimmune and pressure components as well as vasculitis whose symptoms completely improved after starting omalizumab. Kai et al³ successfully treated a patient with normocomplementemic UV with omalizumab and suggested that omalizumab markedly improved the patient’s quality of life with chronic urticaria and UV. Ghazanfar and Thomsen² reported the case of a 68-year-old man diagnosed with histopathologically confirmed leukocytoclastic vasculitis. He had used systemic corticosteroid therapy and dapsone without notable improvement. The patient was switched to subcutaneous omalizumab 300 mg once every 4 weeks; after 1 month, he observed complete remission of the UV and symptoms.²

Our case suggests that omalizumab has a beneficial effect on patients with UV. Omalizumab may be effective in UV through its reduction of IgE, as in chronic urticaria, and through downstream effects on cellular activation mechanisms (possibly a reduction in chemotaxis or immune complex formation). However, the mechanism of action of omalizumab for UV remains, in part, unresolved. It is not known whether omalizumab is efficacious against both normocomplementemic and hypocomplementemic UV. Further studies with a greater number of patients are needed to confirm the effects of omalizumab for vasculitic patients.

To the Editor:

Urticarial vasculitis (UV) is a clinicopathologic entity. It manifests as an eruption of erythematous wheals that clinically resemble urticaria, but the lesions of UV last longer, may leave residual hyperpigmentation, and may or may not be pruritic.¹ Therapies most often employed include oral antihistamines and systemic immunosuppressant drugs such as corticosteroids, dapsone, colchicine, or hydroxychloroquine.² We present a woman with UV who successfully was treated with omalizumab.

A 49-year-old woman presented to our outpatient clinic with generalized pruritic skin rashes of 2 years’ duration. She also described swelling on the upper eyelids 2 times monthly. She used several antihistamines (up to 4 times daily) and was taking systemic corticosteroids and antidepressants. Physical examination revealed generalized erythematous and edematous papules and plaques on the trunk and extremities (Figure 1). At follow-up a few days later, we observed that the lesions were lasting for more than 24 hours, but there was no residual pigmentation. According to clinical concerns and the association with angioedema, we initially thought the diagnosis was chronic urticaria and angioedema. The patient had no extracutaneous manifestations such as fever, arthralgia, or lymphadenopathy. Routine laboratory examinations including antinuclear antibodies were within reference range. She had normal C3 and C4 levels and an elevated total IgE level (344 IU/mL [reference range, 0–170 IU/mL]). Because the IgE level was elevated and she had no response to the highest dosages of antihistamines, we decided to start omalizumab therapy. Prior to starting omalizumab, we performed a skin biopsy for histopathologic and direct immunofluorescence examinations for UV, as the duration of the lesions was more than 24 hours. Histopathologic examination revealed lymphocytes within the vessel wall and perivascular lymphocytic infiltration with eosinophils (Figure 2). On direct immunofluorescence, perivascular IgA deposition was observed (Figure 3). Histopathologic findings were associated with lymphocytic vasculitis. Systemic involvement was not detected on detailed laboratory and radiologic examinations.

After the first application of omalizumab, the lesions disappeared within a few days. She was treated with subcutaneous omalizumab 300 mg every 4 weeks for 6 months, and we did not observe any adverse effects related to the drug. There was no relapse after therapy cessation.

Omalizumab is a recombinant humanized anti-IgE monoclonal antibody that is approved by the US Food and Drug Administration for treatment of chronic idiopathic urticaria.^3-5 Studies have suggested that omalizumab might play an important role in the treatment of other potentially IgE-mediated disease processes including allergic asthma, atopic dermatitis, allergic rhinitis, nasal polyposis, and severe ocular allergies.⁶ The proposed mechanism of action of omalizumab includes reduction of free IgE through the reversible formation of tiny, biologically inert complexes; targeting IgE-expressing B cells; and inhibiting production of IgE. Because it reduces free IgE, omalizumab has been used in normal IgE or hyper-IgE situations. Omalizumab also induces eosinophil apoptosis; increases IL-2, IL-3, tumor necrosis factor α, and IFN-γ; and reduces IL-4.⁷ A number of off-label uses have been described such as atopic dermatitis, bullous pemphigoid, hyper-IgE syndrome, cutaneous mastocytosis, toxic epidermal necrolysis, and eosinophilic granulomatosis with polyangitis.⁸ There are no clinical studies of omalizumab for UV, and only a few case reports have shown that omalizumab also might be beneficial for this condition.^2-4 Diez et al⁴ reported 3 cases of women aged 28, 51, and 54 years with spontaneous chronic urticaria with autoimmune and pressure components as well as vasculitis whose symptoms completely improved after starting omalizumab. Kai et al³ successfully treated a patient with normocomplementemic UV with omalizumab and suggested that omalizumab markedly improved the patient’s quality of life with chronic urticaria and UV. Ghazanfar and Thomsen² reported the case of a 68-year-old man diagnosed with histopathologically confirmed leukocytoclastic vasculitis. He had used systemic corticosteroid therapy and dapsone without notable improvement. The patient was switched to subcutaneous omalizumab 300 mg once every 4 weeks; after 1 month, he observed complete remission of the UV and symptoms.²

Our case suggests that omalizumab has a beneficial effect on patients with UV. Omalizumab may be effective in UV through its reduction of IgE, as in chronic urticaria, and through downstream effects on cellular activation mechanisms (possibly a reduction in chemotaxis or immune complex formation). However, the mechanism of action of omalizumab for UV remains, in part, unresolved. It is not known whether omalizumab is efficacious against both normocomplementemic and hypocomplementemic UV. Further studies with a greater number of patients are needed to confirm the effects of omalizumab for vasculitic patients.

The Diagnosis: Granular Cell Tumor 

Histopathologic analysis from the axillary excision demonstrated cords and sheets of large polygonal cells in the dermis with uniform, oval, hyperchromatic nuclei and ample pink granular-staining cytoplasm (quiz images). An infiltrative growth pattern was noted; however, there was no evidence of conspicuous mitoses, nuclear pleomorphism, or necrosis. These results in conjunction with the immunohistochemistry findings were consistent with a benign granular cell tumor (GCT), a rare neoplasm considered to have neural/Schwann cell origin.^1-3 

Our case demonstrates the difficulty in clinically diagnosing cutaneous GCTs. The tumor often presents as a solitary, 0.5- to 3-cm, asymptomatic, firm nodule^4,5; however, GCTs also can appear verrucous, eroded, or with other variable morphologies, which can create diagnostic challenges.^5,6 Accordingly, a 1980 study of 110 patients with GCTs found that the preoperative clinical diagnosis was incorrect in all but 3 cases,⁷ emphasizing the need for histologic evaluation. Benign GCTs tend to exhibit sheets of polygonal tumor cells with eosinophilic granular cytoplasm and small central nuclei.^3,5 The cytoplasmic granules are periodic acid-Schiff positive and diastase resistant.⁶ Many cases feature pseudoepitheliomatous hyperplasia, which can misleadingly resemble squamous cell carcinoma.^3,5,6 Of note, invasive growth patterns on histology can occur with benign GCTs, as in our patient's case, and do not impact prognosis.^3,4 On immunohistochemistry, benign, atypical, and malignant GCTs often stain positive for S-100 protein, vimentin, neuron-specific enolase, SOX10, and CD68.^1,3  

Although our patient's GCTs were benign, an estimated 1% to 2% are malignant.^1,4 In 1998, Fanburg-Smith et al¹ defined 6 histologic criteria that characterize malignant GCTs: necrosis, tumor cell spindling, vesicular nuclei with large nucleoli, high nuclear to cytoplasmic ratio, increased mitosis, and pleomorphism. Neoplasms with 3 or more of these features are classified as malignant, those with 1 or 2 are considered atypical, and those with only pleomorphism or no other criteria met are diagnosed as benign.¹  

Multiple GCTs have been reported in 10% to 25% of cases and, as highlighted in our case, can occur in both a metachronous and synchronous manner.^2-4,6 Our patient developed a solitary GCT on the inferior lip 3 years prior to the appearance of 2 additional GCTs within 6 months of each other. The presence of multiple GCTs has been associated with genetic syndromes, such as neurofibromatosis type 1 and Noonan syndrome with multiple lentigines^3,8; however, as our case demonstrates, multiple GCTs can occur in nonsyndromic patients as well. When multiple GCTs develop at distant sites, they can resemble metastasis.³ To differentiate these clinical scenarios, Machado et al³ proposed utilizing histology and anatomic location. Multiple tumors with benign characteristics on histology likely represent multiple GCTs, whereas tumors arising at sites common to GCT metastasis, such as lymph node, bone, or viscera, are more concerning for metastatic disease. It has been suggested that patients with multiple GCTs should be monitored with physical examination and repeat magnetic resonance imaging or computed tomography every 6 to 12 months.² Given our patient's presentation with new tumors arising within 6 months of one another, we recommended a 6-month follow-up interval rather than 1 year. Due to the rarity of GCTs, clinical trials to define treatment guidelines and recommendations have not been performed.³ However, the most commonly utilized treatment modality is wide local excision, as performed in our patient.^2,4 

Melanoma, atypical fibroxanthoma (AFX), xanthoma, and leiomyosarcoma may be difficult to distinguish from GCT.^1,3,4 Melanoma incidence has increased dramatically over the last several decades, with rates in the United States rising from 6.8 cases per 100,000 individuals in the 1970s to 20.¹ in the early 2000s. Risk factors for its development include UV radiation exposure and particularly severe sunburns during childhood, along with a number of host risk factors such as total number of melanocytic nevi, family history, and fair complexion.⁹ Histologically, it often demonstrates irregularly distributed, poorly defined melanocytes with pagetoid spread and dyscohesive nests (Figure 1).¹⁰ Melanoma metastasis occasionally can present as a soft-tissue mass and often stains positive for S-100 and vimentin, thus resembling GCT^1,4; however, unlike melanoma, GCTs lack melanosomes and stain negative for more specific melanocyte markers, such as melanoma antigen recognized by T cells 1 (MART-1).^1,3,4 
Atypical fibroxanthoma is a cutaneous neoplasm with fibrohistiocytic mesenchymal origin.¹¹ These tumors typically arise on the head and neck in elderly individuals, particularly men with sun-damaged skin. They often present as superficial, rapidly growing nodules with the potential to ulcerate and bleed.^11,12 Histologic features include pleomorphic spindle and epithelioid cells, whose nuclei appear hyperchromatic with atypical mitoses (Figure 2).¹² Granular cell changes occur infrequently with AFXs, but in such cases immunohistochemistry can readily distinguish AFX from GCT. Although both tend to stain positive for CD68 and vimentin, AFXs lack S-100 protein and SOX10 expression that frequently is observed in GCTs.^3,12  

Xanthomas are localized lipid deposits in the connective tissue of the skin that often arise in association with dyslipidemia.¹³ They typically present as soft to semisolid yellow papules, plaques, or nodules. Their clinical appearance can resemble GCTs; however, histologic analysis enables differentiation with ease, as xanthomas demonstrate characteristic foam cells, consisting of lipid-laden macrophages (Figure 3).¹³  

Cutaneous leiomyosarcoma is a rare dermal neoplasm, accounting for 2% to 3% of all sarcomas.¹⁴ They typically occur in White males during the fifth to seventh decades of life and often present as asymptomatic lesions on the lower extremities. They frequently arise from pilar smooth muscle. Unlike uterine and soft-tissue leiomyosarcoma, cutaneous leiomyosarcoma tends to follow an indolent course and rarely metastasizes.¹⁴ Histologically, these tumors display intersecting, well-defined, spindle-cell fascicles with abundant eosinophilic cytoplasm and cigar-shaped, blunt-ended nuclei (Figure 4).¹⁵ Occasionally, leiomyosarcomas can demonstrate cytoplasmic granularity due to lysosome accumulation⁴; nevertheless, the diagnosis usually can be elucidated by examining more typical histologic areas and utilizing immunohistochemistry, which often stains positive for α-smooth muscle actin, desmin, and h-caldesmon.^4,15 

The Diagnosis: Granular Cell Tumor 

Histopathologic analysis from the axillary excision demonstrated cords and sheets of large polygonal cells in the dermis with uniform, oval, hyperchromatic nuclei and ample pink granular-staining cytoplasm (quiz images). An infiltrative growth pattern was noted; however, there was no evidence of conspicuous mitoses, nuclear pleomorphism, or necrosis. These results in conjunction with the immunohistochemistry findings were consistent with a benign granular cell tumor (GCT), a rare neoplasm considered to have neural/Schwann cell origin.^1-3 

Our case demonstrates the difficulty in clinically diagnosing cutaneous GCTs. The tumor often presents as a solitary, 0.5- to 3-cm, asymptomatic, firm nodule^4,5; however, GCTs also can appear verrucous, eroded, or with other variable morphologies, which can create diagnostic challenges.^5,6 Accordingly, a 1980 study of 110 patients with GCTs found that the preoperative clinical diagnosis was incorrect in all but 3 cases,⁷ emphasizing the need for histologic evaluation. Benign GCTs tend to exhibit sheets of polygonal tumor cells with eosinophilic granular cytoplasm and small central nuclei.^3,5 The cytoplasmic granules are periodic acid-Schiff positive and diastase resistant.⁶ Many cases feature pseudoepitheliomatous hyperplasia, which can misleadingly resemble squamous cell carcinoma.^3,5,6 Of note, invasive growth patterns on histology can occur with benign GCTs, as in our patient's case, and do not impact prognosis.^3,4 On immunohistochemistry, benign, atypical, and malignant GCTs often stain positive for S-100 protein, vimentin, neuron-specific enolase, SOX10, and CD68.^1,3  

Although our patient's GCTs were benign, an estimated 1% to 2% are malignant.^1,4 In 1998, Fanburg-Smith et al¹ defined 6 histologic criteria that characterize malignant GCTs: necrosis, tumor cell spindling, vesicular nuclei with large nucleoli, high nuclear to cytoplasmic ratio, increased mitosis, and pleomorphism. Neoplasms with 3 or more of these features are classified as malignant, those with 1 or 2 are considered atypical, and those with only pleomorphism or no other criteria met are diagnosed as benign.¹  

Multiple GCTs have been reported in 10% to 25% of cases and, as highlighted in our case, can occur in both a metachronous and synchronous manner.^2-4,6 Our patient developed a solitary GCT on the inferior lip 3 years prior to the appearance of 2 additional GCTs within 6 months of each other. The presence of multiple GCTs has been associated with genetic syndromes, such as neurofibromatosis type 1 and Noonan syndrome with multiple lentigines^3,8; however, as our case demonstrates, multiple GCTs can occur in nonsyndromic patients as well. When multiple GCTs develop at distant sites, they can resemble metastasis.³ To differentiate these clinical scenarios, Machado et al³ proposed utilizing histology and anatomic location. Multiple tumors with benign characteristics on histology likely represent multiple GCTs, whereas tumors arising at sites common to GCT metastasis, such as lymph node, bone, or viscera, are more concerning for metastatic disease. It has been suggested that patients with multiple GCTs should be monitored with physical examination and repeat magnetic resonance imaging or computed tomography every 6 to 12 months.² Given our patient's presentation with new tumors arising within 6 months of one another, we recommended a 6-month follow-up interval rather than 1 year. Due to the rarity of GCTs, clinical trials to define treatment guidelines and recommendations have not been performed.³ However, the most commonly utilized treatment modality is wide local excision, as performed in our patient.^2,4 

Melanoma, atypical fibroxanthoma (AFX), xanthoma, and leiomyosarcoma may be difficult to distinguish from GCT.^1,3,4 Melanoma incidence has increased dramatically over the last several decades, with rates in the United States rising from 6.8 cases per 100,000 individuals in the 1970s to 20.¹ in the early 2000s. Risk factors for its development include UV radiation exposure and particularly severe sunburns during childhood, along with a number of host risk factors such as total number of melanocytic nevi, family history, and fair complexion.⁹ Histologically, it often demonstrates irregularly distributed, poorly defined melanocytes with pagetoid spread and dyscohesive nests (Figure 1).¹⁰ Melanoma metastasis occasionally can present as a soft-tissue mass and often stains positive for S-100 and vimentin, thus resembling GCT^1,4; however, unlike melanoma, GCTs lack melanosomes and stain negative for more specific melanocyte markers, such as melanoma antigen recognized by T cells 1 (MART-1).^1,3,4 
Atypical fibroxanthoma is a cutaneous neoplasm with fibrohistiocytic mesenchymal origin.¹¹ These tumors typically arise on the head and neck in elderly individuals, particularly men with sun-damaged skin. They often present as superficial, rapidly growing nodules with the potential to ulcerate and bleed.^11,12 Histologic features include pleomorphic spindle and epithelioid cells, whose nuclei appear hyperchromatic with atypical mitoses (Figure 2).¹² Granular cell changes occur infrequently with AFXs, but in such cases immunohistochemistry can readily distinguish AFX from GCT. Although both tend to stain positive for CD68 and vimentin, AFXs lack S-100 protein and SOX10 expression that frequently is observed in GCTs.^3,12  

Xanthomas are localized lipid deposits in the connective tissue of the skin that often arise in association with dyslipidemia.¹³ They typically present as soft to semisolid yellow papules, plaques, or nodules. Their clinical appearance can resemble GCTs; however, histologic analysis enables differentiation with ease, as xanthomas demonstrate characteristic foam cells, consisting of lipid-laden macrophages (Figure 3).¹³  

Cutaneous leiomyosarcoma is a rare dermal neoplasm, accounting for 2% to 3% of all sarcomas.¹⁴ They typically occur in White males during the fifth to seventh decades of life and often present as asymptomatic lesions on the lower extremities. They frequently arise from pilar smooth muscle. Unlike uterine and soft-tissue leiomyosarcoma, cutaneous leiomyosarcoma tends to follow an indolent course and rarely metastasizes.¹⁴ Histologically, these tumors display intersecting, well-defined, spindle-cell fascicles with abundant eosinophilic cytoplasm and cigar-shaped, blunt-ended nuclei (Figure 4).¹⁵ Occasionally, leiomyosarcomas can demonstrate cytoplasmic granularity due to lysosome accumulation⁴; nevertheless, the diagnosis usually can be elucidated by examining more typical histologic areas and utilizing immunohistochemistry, which often stains positive for α-smooth muscle actin, desmin, and h-caldesmon.^4,15 

The Diagnosis: Granular Cell Tumor 

Histopathologic analysis from the axillary excision demonstrated cords and sheets of large polygonal cells in the dermis with uniform, oval, hyperchromatic nuclei and ample pink granular-staining cytoplasm (quiz images). An infiltrative growth pattern was noted; however, there was no evidence of conspicuous mitoses, nuclear pleomorphism, or necrosis. These results in conjunction with the immunohistochemistry findings were consistent with a benign granular cell tumor (GCT), a rare neoplasm considered to have neural/Schwann cell origin.^1-3 

Our case demonstrates the difficulty in clinically diagnosing cutaneous GCTs. The tumor often presents as a solitary, 0.5- to 3-cm, asymptomatic, firm nodule^4,5; however, GCTs also can appear verrucous, eroded, or with other variable morphologies, which can create diagnostic challenges.^5,6 Accordingly, a 1980 study of 110 patients with GCTs found that the preoperative clinical diagnosis was incorrect in all but 3 cases,⁷ emphasizing the need for histologic evaluation. Benign GCTs tend to exhibit sheets of polygonal tumor cells with eosinophilic granular cytoplasm and small central nuclei.^3,5 The cytoplasmic granules are periodic acid-Schiff positive and diastase resistant.⁶ Many cases feature pseudoepitheliomatous hyperplasia, which can misleadingly resemble squamous cell carcinoma.^3,5,6 Of note, invasive growth patterns on histology can occur with benign GCTs, as in our patient's case, and do not impact prognosis.^3,4 On immunohistochemistry, benign, atypical, and malignant GCTs often stain positive for S-100 protein, vimentin, neuron-specific enolase, SOX10, and CD68.^1,3  

Although our patient's GCTs were benign, an estimated 1% to 2% are malignant.^1,4 In 1998, Fanburg-Smith et al¹ defined 6 histologic criteria that characterize malignant GCTs: necrosis, tumor cell spindling, vesicular nuclei with large nucleoli, high nuclear to cytoplasmic ratio, increased mitosis, and pleomorphism. Neoplasms with 3 or more of these features are classified as malignant, those with 1 or 2 are considered atypical, and those with only pleomorphism or no other criteria met are diagnosed as benign.¹  

Multiple GCTs have been reported in 10% to 25% of cases and, as highlighted in our case, can occur in both a metachronous and synchronous manner.^2-4,6 Our patient developed a solitary GCT on the inferior lip 3 years prior to the appearance of 2 additional GCTs within 6 months of each other. The presence of multiple GCTs has been associated with genetic syndromes, such as neurofibromatosis type 1 and Noonan syndrome with multiple lentigines^3,8; however, as our case demonstrates, multiple GCTs can occur in nonsyndromic patients as well. When multiple GCTs develop at distant sites, they can resemble metastasis.³ To differentiate these clinical scenarios, Machado et al³ proposed utilizing histology and anatomic location. Multiple tumors with benign characteristics on histology likely represent multiple GCTs, whereas tumors arising at sites common to GCT metastasis, such as lymph node, bone, or viscera, are more concerning for metastatic disease. It has been suggested that patients with multiple GCTs should be monitored with physical examination and repeat magnetic resonance imaging or computed tomography every 6 to 12 months.² Given our patient's presentation with new tumors arising within 6 months of one another, we recommended a 6-month follow-up interval rather than 1 year. Due to the rarity of GCTs, clinical trials to define treatment guidelines and recommendations have not been performed.³ However, the most commonly utilized treatment modality is wide local excision, as performed in our patient.^2,4 

Melanoma, atypical fibroxanthoma (AFX), xanthoma, and leiomyosarcoma may be difficult to distinguish from GCT.^1,3,4 Melanoma incidence has increased dramatically over the last several decades, with rates in the United States rising from 6.8 cases per 100,000 individuals in the 1970s to 20.¹ in the early 2000s. Risk factors for its development include UV radiation exposure and particularly severe sunburns during childhood, along with a number of host risk factors such as total number of melanocytic nevi, family history, and fair complexion.⁹ Histologically, it often demonstrates irregularly distributed, poorly defined melanocytes with pagetoid spread and dyscohesive nests (Figure 1).¹⁰ Melanoma metastasis occasionally can present as a soft-tissue mass and often stains positive for S-100 and vimentin, thus resembling GCT^1,4; however, unlike melanoma, GCTs lack melanosomes and stain negative for more specific melanocyte markers, such as melanoma antigen recognized by T cells 1 (MART-1).^1,3,4 
Atypical fibroxanthoma is a cutaneous neoplasm with fibrohistiocytic mesenchymal origin.¹¹ These tumors typically arise on the head and neck in elderly individuals, particularly men with sun-damaged skin. They often present as superficial, rapidly growing nodules with the potential to ulcerate and bleed.^11,12 Histologic features include pleomorphic spindle and epithelioid cells, whose nuclei appear hyperchromatic with atypical mitoses (Figure 2).¹² Granular cell changes occur infrequently with AFXs, but in such cases immunohistochemistry can readily distinguish AFX from GCT. Although both tend to stain positive for CD68 and vimentin, AFXs lack S-100 protein and SOX10 expression that frequently is observed in GCTs.^3,12  

Xanthomas are localized lipid deposits in the connective tissue of the skin that often arise in association with dyslipidemia.¹³ They typically present as soft to semisolid yellow papules, plaques, or nodules. Their clinical appearance can resemble GCTs; however, histologic analysis enables differentiation with ease, as xanthomas demonstrate characteristic foam cells, consisting of lipid-laden macrophages (Figure 3).¹³  

Cutaneous leiomyosarcoma is a rare dermal neoplasm, accounting for 2% to 3% of all sarcomas.¹⁴ They typically occur in White males during the fifth to seventh decades of life and often present as asymptomatic lesions on the lower extremities. They frequently arise from pilar smooth muscle. Unlike uterine and soft-tissue leiomyosarcoma, cutaneous leiomyosarcoma tends to follow an indolent course and rarely metastasizes.¹⁴ Histologically, these tumors display intersecting, well-defined, spindle-cell fascicles with abundant eosinophilic cytoplasm and cigar-shaped, blunt-ended nuclei (Figure 4).¹⁵ Occasionally, leiomyosarcomas can demonstrate cytoplasmic granularity due to lysosome accumulation⁴; nevertheless, the diagnosis usually can be elucidated by examining more typical histologic areas and utilizing immunohistochemistry, which often stains positive for α-smooth muscle actin, desmin, and h-caldesmon.^4,15 

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma  

Microscopic analysis showed a dense proliferation of mononuclear cells filling and expanding the dermis with focal epidermotropism (Figure 1). Immunohistochemistry demonstrated strong and diffuse staining for CD3, CD4, and CD30 (Figure 2) and lack of staining for anaplastic lymphoma kinase (ALK). Workup to exclude systemic disease was initiated and included unremarkable computed tomography (CT) of the neck, chest, abdomen, and pelvis along with no abnormal cells on bone marrow biopsy. Complete blood cell count, basic metabolic panel, and lactate dehydrogenase were within reference range. Given the lack of evidence for systemic involvement, a diagnosis of primary cutaneous anaplastic large cell lymphoma (PC-ALCL) was made. The treatment plan for our patient with a solitary lesion was localized radiation therapy. 

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass a spectrum of conditions, with premalignant lymphomatoid papulosis (LyP) at one extreme and the malignant PC-ALCL on the other.¹ The diagnosis of PC-ALCL is made by clinicopathologic correlation, and lesions typically present abruptly as solitary or grouped nodules with a tendency to ulcerate over time. Spontaneous regression has been reported, but relapse in the skin is frequent.² 

A representative, typically excisional, biopsy should be performed if the clinician suspects PC-ALCL. Histologic criteria include a dense dermal infiltrate of large pleomorphic cells and the expression of CD30 in at least 75% of tumor cells.³ Primary cutaneous anaplastic large cell lymphoma typically lacks the ALK gene translocation with the nucleophosmin gene, NPM, that is common in systemic disease; however, a small subset of PC-ALCL may be ALK positive and indicate a higher chance of transformation into systemic disease.²

 The extent of the lymphoma should be staged to exclude the possibility of systemic disease. This assessment includes a complete physical examination; laboratory investigation, including complete blood cell count with differential and blood chemistries; and radiography. A positron emission tomography-CT scan of the neck, chest, abdomen, and pelvis, or a whole-body integrated positron emission tomography-CT are sufficient for the radiographic examination.³ 

The initial choice of treatment for solitary or localized PC-ALCL is localized radiation therapy or low-dose methotrexate. Targeted therapy such as brentuximab has been shown to be effective for those with multifocal systemic involvement or refractory disease.² Cure rates from radiation therapy alone approach 95%.³ It is important to highlight radiation therapy as the initial management plan to increase awareness and to avoid inappropriate treatment of PC-ALCL with traditional chemotherapy. 

Large lesions of LyP may appear similar to PC-ALCL on histopathology, making the two entities difficult to distinguish. However, in contrast to PC-ALCL, LyP classically has a different clinical course characterized by waxing and waning crops of lesions that typically are smaller (<1 cm) than those of PC-ALCL.² Large cell transformation of mycosis fungoides is another entity to consider, but these patients usually have a known history of mycosis fungoides.⁴ 

Keratoacanthomas, considered to be a variant of a well-differentiated squamous cell carcinoma, present as rapidly enlarging crateriform nodules with a keratotic core. They usually are found on the head and neck or sun-exposed areas of the extremities and may regress spontaneously.⁵ Histology will show atypical, highly differentiated squamous epithelia. Merkel cell carcinoma also has a predilection for the head and neck in older patients and may present as a rapidly growing nodule. However, histology will show an aggressive tumor with small round blue cells, and immunohistochemistry will show the characteristic paranuclear dot staining for CK20 along with staining for various neuroendocrine markers. Similarly, atypical fibroxanthoma is a low-grade sarcoma that also presents on the head and neck of elderly sun-damaged patients.⁵ Histology will show dermal proliferation of spindle cells that often extend up against the epidermis along with pleomorphism and atypical mitoses. Basal cell carcinoma is a common tumor that can present on the head and neck in sun-damaged patients. Nodular basal cell carcinomas can enlarge and ulcerate, but growth is seen over years rather than weeks.⁵ Histology characteristically will show tumor islands composed of basaloid cells with peripheral palisading and clefting between the tumor islands and the stroma.  

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma  

Microscopic analysis showed a dense proliferation of mononuclear cells filling and expanding the dermis with focal epidermotropism (Figure 1). Immunohistochemistry demonstrated strong and diffuse staining for CD3, CD4, and CD30 (Figure 2) and lack of staining for anaplastic lymphoma kinase (ALK). Workup to exclude systemic disease was initiated and included unremarkable computed tomography (CT) of the neck, chest, abdomen, and pelvis along with no abnormal cells on bone marrow biopsy. Complete blood cell count, basic metabolic panel, and lactate dehydrogenase were within reference range. Given the lack of evidence for systemic involvement, a diagnosis of primary cutaneous anaplastic large cell lymphoma (PC-ALCL) was made. The treatment plan for our patient with a solitary lesion was localized radiation therapy. 

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass a spectrum of conditions, with premalignant lymphomatoid papulosis (LyP) at one extreme and the malignant PC-ALCL on the other.¹ The diagnosis of PC-ALCL is made by clinicopathologic correlation, and lesions typically present abruptly as solitary or grouped nodules with a tendency to ulcerate over time. Spontaneous regression has been reported, but relapse in the skin is frequent.² 

A representative, typically excisional, biopsy should be performed if the clinician suspects PC-ALCL. Histologic criteria include a dense dermal infiltrate of large pleomorphic cells and the expression of CD30 in at least 75% of tumor cells.³ Primary cutaneous anaplastic large cell lymphoma typically lacks the ALK gene translocation with the nucleophosmin gene, NPM, that is common in systemic disease; however, a small subset of PC-ALCL may be ALK positive and indicate a higher chance of transformation into systemic disease.²

 The extent of the lymphoma should be staged to exclude the possibility of systemic disease. This assessment includes a complete physical examination; laboratory investigation, including complete blood cell count with differential and blood chemistries; and radiography. A positron emission tomography-CT scan of the neck, chest, abdomen, and pelvis, or a whole-body integrated positron emission tomography-CT are sufficient for the radiographic examination.³ 

The initial choice of treatment for solitary or localized PC-ALCL is localized radiation therapy or low-dose methotrexate. Targeted therapy such as brentuximab has been shown to be effective for those with multifocal systemic involvement or refractory disease.² Cure rates from radiation therapy alone approach 95%.³ It is important to highlight radiation therapy as the initial management plan to increase awareness and to avoid inappropriate treatment of PC-ALCL with traditional chemotherapy. 

Large lesions of LyP may appear similar to PC-ALCL on histopathology, making the two entities difficult to distinguish. However, in contrast to PC-ALCL, LyP classically has a different clinical course characterized by waxing and waning crops of lesions that typically are smaller (<1 cm) than those of PC-ALCL.² Large cell transformation of mycosis fungoides is another entity to consider, but these patients usually have a known history of mycosis fungoides.⁴ 

Keratoacanthomas, considered to be a variant of a well-differentiated squamous cell carcinoma, present as rapidly enlarging crateriform nodules with a keratotic core. They usually are found on the head and neck or sun-exposed areas of the extremities and may regress spontaneously.⁵ Histology will show atypical, highly differentiated squamous epithelia. Merkel cell carcinoma also has a predilection for the head and neck in older patients and may present as a rapidly growing nodule. However, histology will show an aggressive tumor with small round blue cells, and immunohistochemistry will show the characteristic paranuclear dot staining for CK20 along with staining for various neuroendocrine markers. Similarly, atypical fibroxanthoma is a low-grade sarcoma that also presents on the head and neck of elderly sun-damaged patients.⁵ Histology will show dermal proliferation of spindle cells that often extend up against the epidermis along with pleomorphism and atypical mitoses. Basal cell carcinoma is a common tumor that can present on the head and neck in sun-damaged patients. Nodular basal cell carcinomas can enlarge and ulcerate, but growth is seen over years rather than weeks.⁵ Histology characteristically will show tumor islands composed of basaloid cells with peripheral palisading and clefting between the tumor islands and the stroma.  

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma  

Microscopic analysis showed a dense proliferation of mononuclear cells filling and expanding the dermis with focal epidermotropism (Figure 1). Immunohistochemistry demonstrated strong and diffuse staining for CD3, CD4, and CD30 (Figure 2) and lack of staining for anaplastic lymphoma kinase (ALK). Workup to exclude systemic disease was initiated and included unremarkable computed tomography (CT) of the neck, chest, abdomen, and pelvis along with no abnormal cells on bone marrow biopsy. Complete blood cell count, basic metabolic panel, and lactate dehydrogenase were within reference range. Given the lack of evidence for systemic involvement, a diagnosis of primary cutaneous anaplastic large cell lymphoma (PC-ALCL) was made. The treatment plan for our patient with a solitary lesion was localized radiation therapy. 

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass a spectrum of conditions, with premalignant lymphomatoid papulosis (LyP) at one extreme and the malignant PC-ALCL on the other.¹ The diagnosis of PC-ALCL is made by clinicopathologic correlation, and lesions typically present abruptly as solitary or grouped nodules with a tendency to ulcerate over time. Spontaneous regression has been reported, but relapse in the skin is frequent.² 

A representative, typically excisional, biopsy should be performed if the clinician suspects PC-ALCL. Histologic criteria include a dense dermal infiltrate of large pleomorphic cells and the expression of CD30 in at least 75% of tumor cells.³ Primary cutaneous anaplastic large cell lymphoma typically lacks the ALK gene translocation with the nucleophosmin gene, NPM, that is common in systemic disease; however, a small subset of PC-ALCL may be ALK positive and indicate a higher chance of transformation into systemic disease.²

 The extent of the lymphoma should be staged to exclude the possibility of systemic disease. This assessment includes a complete physical examination; laboratory investigation, including complete blood cell count with differential and blood chemistries; and radiography. A positron emission tomography-CT scan of the neck, chest, abdomen, and pelvis, or a whole-body integrated positron emission tomography-CT are sufficient for the radiographic examination.³ 

The initial choice of treatment for solitary or localized PC-ALCL is localized radiation therapy or low-dose methotrexate. Targeted therapy such as brentuximab has been shown to be effective for those with multifocal systemic involvement or refractory disease.² Cure rates from radiation therapy alone approach 95%.³ It is important to highlight radiation therapy as the initial management plan to increase awareness and to avoid inappropriate treatment of PC-ALCL with traditional chemotherapy. 

Large lesions of LyP may appear similar to PC-ALCL on histopathology, making the two entities difficult to distinguish. However, in contrast to PC-ALCL, LyP classically has a different clinical course characterized by waxing and waning crops of lesions that typically are smaller (<1 cm) than those of PC-ALCL.² Large cell transformation of mycosis fungoides is another entity to consider, but these patients usually have a known history of mycosis fungoides.⁴ 

Keratoacanthomas, considered to be a variant of a well-differentiated squamous cell carcinoma, present as rapidly enlarging crateriform nodules with a keratotic core. They usually are found on the head and neck or sun-exposed areas of the extremities and may regress spontaneously.⁵ Histology will show atypical, highly differentiated squamous epithelia. Merkel cell carcinoma also has a predilection for the head and neck in older patients and may present as a rapidly growing nodule. However, histology will show an aggressive tumor with small round blue cells, and immunohistochemistry will show the characteristic paranuclear dot staining for CK20 along with staining for various neuroendocrine markers. Similarly, atypical fibroxanthoma is a low-grade sarcoma that also presents on the head and neck of elderly sun-damaged patients.⁵ Histology will show dermal proliferation of spindle cells that often extend up against the epidermis along with pleomorphism and atypical mitoses. Basal cell carcinoma is a common tumor that can present on the head and neck in sun-damaged patients. Nodular basal cell carcinomas can enlarge and ulcerate, but growth is seen over years rather than weeks.⁵ Histology characteristically will show tumor islands composed of basaloid cells with peripheral palisading and clefting between the tumor islands and the stroma.  

According to National Institutes of Health estimates, more than 90,000 new cases of melanoma were diagnosed in 2018.¹ Overall 5-year survival for patients with melanoma exceeds 90%, but individual survival estimates are highly dependent on stage at diagnosis, and survival decreases markedly with metastasis. Therefore, early and accurate diagnosis is critical.

Diagnosis of melanocytic neoplasms usually is performed by dermatopathologists through microscopic examination of stained tissue biopsy sections, a technically simple and effective method that enables a definitive diagnosis of benign nevus or malignant melanoma to be made in most cases. However, approximately 15% of all biopsied melanocytic lesions will exhibit some degree of histopathologic ambiguity,^2-4 meaning that some of their microscopic features will be characteristic of a benign nevus while others will suggest the possibility of malignant melanoma. Diagnostic interpretations often vary in these cases, even among experts, and a definitive diagnosis of benign or malignant may be difficult to achieve by microscopy alone.^2-4 Because of the marked reduction in survival once a melanoma has metastasized, these diagnostically ambiguous lesions often are treated as possible malignant melanomas with complete surgical excision (or re-excision). However, some experts suggest that many histopathologically ambiguous melanocytic neoplasms are, in fact, benign,⁵ a notion supported by epidemiologic evidence.^6,7 Therefore, excision of many ambiguous melanocytic neoplasms might be avoided if definitive diagnosis could be achieved.

A gene expression signature was developed and validated for use as an adjunct to traditional methods of differentiating malignant melanocytic neoplasms from their benign counterparts.^8-11 This test quantifies the RNA transcripts produced by 14 genes known to be overexpressed in malignant melanomas by comparison to benign nevi. These values are then combined algorithmically with measurements of 9 reference genes to produce an objective numerical score that is classified as benign, malignant, or indeterminate. When used by board-certified dermatopathologists and dermatologists confronting ambiguous melanocytic lesions, the test produces substantial increases in definitive diagnoses and prompts changes in treatment recommendations.^12,13 However, the long-term consequences of foregoing surgical excision of melanocytic neoplasms that are diagnostically ambiguous but classified as benign by this test have not yet been formally assessed. In the current study, prospectively tested patients whose ambiguous melanocytic neoplasms were classified as benign by the gene expression signature were followed for up to 4.5 years to evaluate the long-term safety of treatment decisions aligned with benign test results.

Methods

Study Population
As part of a prior study,¹² US-based dermatopathologists submitted tissue sections from biopsied melanocytic neoplasms determined to be diagnostically ambiguous by histopathology for analysis with the gene expression signature (Myriad Genetics, Inc). Diagnostically ambiguous lesions were those lesions that were described as ambiguous, uncertain, equivocal, indeterminate, or other synonymous terms by the submitting dermatopathologist and therefore lacked a confident diagnosis of benign or malignant prior to testing. Patients initially were tested between May 2014 and August 2014, with samples submitted through a prospective clinical experience study designed to assess the impact of the test on diagnosis and treatment decisions. This study was performed under an institutional review board waiver of consent (Quorum #33403/1).

Patients were eligible for inclusion in the current study if their biopsy specimens (1) had an uncertain preliminary diagnosis according to the submitting dermatopathologist (pretest diagnosis of indeterminate); (2) received a negative (benign) score from the gene expression test; (3) were treated as benign by the dermatologist(s) involved in follow-up care; and (4) were submitted by a single site (St. Joseph Medical Center, Houston, Texas). Although a single dermatopathology site was used for this study, multiple dermatologists were involved in the final treatment of these patients. Patients with benign scores who received additional intervention were excluded, as they may have a lower rate of adverse events (ie, metastasis) than those who did not receive intervention and would therefore skew the analysis population. A total of 25 patients from the prior study met these inclusion criteria. The previously collected¹² pretest and posttest de-identified data were compiled from the commercial laboratory databases, and the patients were followed from the time of testing via medical record review performed by the dermatology providers at participating sites. Clinical follow-up data were collected using study-specific case report forms (CRFs) that captured the following: (1) the dates and results of clinical follow-up visits; (2) the type(s) of treatment and interventions (if any) performed at those visits; (3) the specific indication for any intervention performed; (4) any evidence of persistent, locally recurrent, and/or distant melanocytic neoplasia (whether definitively attributable to the tested lesion or not); and (5) death from any cause. The CRF assigned interventions to 1 of 5 categories: excision, excision with sentinel lymph node biopsy, referral to dermatologic or other surgeon, examination only (without surgical intervention), and other. Selection of other required a free-text description of the treatment and indications. Pertinent information not otherwise captured by the CRF also was recordable as free text.

Gene Expression Testing
Gene expression testing was carried out at the time of specimen submission in the prior study¹² as described previously.¹⁴ Briefly, formalin-fixed, paraffin-embedded, unstained tissue sections and/or tissue blocks were submitted for testing along with a single hematoxylin and eosin–stained slide used to identify and designate the representative portion(s) of the lesion to be tested. These areas were macrodissected from unstained tissue sections and pooled for RNA extraction. Expression of 14 biomarker genes and 9 reference genes was measured via quantitative reverse transcription–polymerase chain reaction, performed in triplicate for each individual gene. The assay score was generated through application of a weighted algorithm to the expression values generated through quantitative reverse transcription–polymerase chain reaction. Scores were plotted on a scale ranging from −16.7 to 11.1, with scores from 0.0 to 11.1 classified as malignant, scores from −16.7 to −2.1 as benign, and scores from −2.1 to −0.1 as indeterminate.

Statistical Analysis
Demographic and other baseline characteristics of the patient population were summarized. Follow-up time was calculated as the interval between the date a patient’s gene expression test result was first issued to the provider and the date of the patient’s last recorded visit during the study period. All patient dermatology office visits within the designated follow-up period were documented, with a nonstandard number of visits and follow-up time across all study patients. Statistical analyses were conducted using SAS software (SAS Institute Inc), R software version 3.5.0 (R Foundation for Statistical Computing), and IBM SPSS Statistics software (IBM SPSS Statistics for Windows, Version 25).

Results

Patient Sample
A total of 25 ambiguous melanocytic neoplasms from 25 patients met the study inclusion criteria of a benign gene expression result with subsequent treatment as a benign neoplasm during follow-up. The patient sample statistics are summarized in Table 1. Most patients were younger than 65 years, with an average age at the time of biopsy of 48.4 years. All 25 neoplasms produced negative (benign) gene expression signature scores, all were diagnosed as benign nevi posttest by the submitting dermatopathologist, and all patients were initially treated in accordance with the benign diagnosis by the dermatologist(s) involved in clinical follow-up care. Prior to testing with the gene expression signature, most of these histopathologically indeterminate lesions received differential diagnoses, the most common of which were dysplastic nevus (84%), melanoma arising from a nevus (72%), and superficial spreading melanoma (64%; eTable). After testing with the gene expression signature and receiving a benign score, most lesions received a single differential diagnosis of dysplastic nevus (88%).

Follow-up and Survival
Clinical follow-up time ranged from 0.6 to 53.3 months, with a mean duration (SD) of 38.5 (16.6) months, and patients attended an average of 4 postbiopsy dermatology appointments (mean [SD], 4.6 [3.6]). According to the participating dermatology care providers, none of the 25 patients developed any indication during follow-up that the diagnosis of benign nevus was inaccurate. No patient had evidence of locally recurrent or metastatic melanoma, and none died during the study period.

Treatment/Interventions
The treatment recorded in the CRF was examination only for 21 of 25 patients, excision for 3, and other for 1 (Table 2). Because the explanation for the selection of other in this case described an excision performed at the same anatomic location as the biopsy, this treatment also was considered an excision for purposes of the study analyses. The 3 excisions all occurred at the first postbiopsy dermatology encounter. Across all follow-up visits, no additional surgical interventions occurred (Table 2).

The third excision (case 3) involved a 32-year-old woman with a pigmented lesion on the abdomen (Table 3; Figure, E and F). The clinical description was irregular-appearing black papule, nevus with atypia, and the histopathologic differential diagnosis again included dysplastic nevus, superficial spreading melanoma, and melanoma arising within a preexisting nevus. The gene expression signature result was benign (score, −7.2), and the final diagnosis issued within the accompanying pathology report was nevus with moderate junctional dysplasia. Despite the benign diagnosis, excision was performed 89 days after test result availability, with apparent residual pigmentation as the specified indication. As with the other 2 cases, the treating dermatologist confirmed that neither clinical features nor follow-up events suggested malignancy.

Comment

This study followed a cohort of 25 patients with histopathologically ambiguous melanocytic neoplasms that were classified as benign by a diagnostic gene expression test with the intent of determining the outcomes of patients whose treatment aligned with their benign test result. All patients initially were managed according to their test result. During an average posttest clinical follow-up time of more than 3 years (38.5 months), the 25 biopsied lesions, most of which received a differential diagnosis of dysplastic nevus, were regarded as benign nevi by their dermatologists, and the vast majority (88%) received no further surgical intervention. Three patients underwent subsequent excision of the biopsied lesion, with patient or physician preference as the indication in each instance. None of the 25 patients developed evidence of local recurrence, metastasis, or other findings that prompted doubt of the benign diagnosis. The absence of adverse events during clinical follow-up, particularly given that most lesions were not subjected to further intervention, supports use of the gene expression test as a safe and effective adjunct to the diagnosis and treatment of ambiguous melanocytic neoplasms by dermatologists and dermatopathologists.

Ambiguous melanocytic neoplasms evaluated without the aid of molecular adjuncts often result in equivocal or less-than-definitive diagnoses, and further surgical intervention is commonly undertaken to mitigate against the possibility of a missed melanoma.¹³ In this study, treatment that was aligned with the benign test result allowed most patients to avoid further surgical intervention, which suggests that adjunctive use of the gene signature can contribute to reductions in the physical and economic burdens imposed by unnecessary surgical interventions.^15,16 Moreover, any means of increasing accurate and definitive diagnoses may produce an immediate impact on health outcomes by reducing the anxiety that uncertainty often provokes in patients and health care providers alike.

Study Limitations
This study must be interpreted within the context of its limitations. Obtaining meaningful patient outcome data is a common challenge in health care research due to the requisite length of follow-up and sometimes the lack of definitive evidence of adverse events. This is particularly difficult for melanocytic neoplasms because of an apparent inclination for patients with benign diagnoses to abandon follow-up and an increasing tendency for even minimal diagnostic uncertainty to prompt complete excision. Additionally, the only definitive clinical outcome for melanocytic neoplasms is distant metastasis, which (fortunately for patients) is relatively rare. Not surprisingly, studies documenting clinical outcomes of patients with ambiguous melanocytic neoplasms tested prospectively with diagnostic adjuncts are scarce, and this study’s sample size and clinical follow-up compare favorably with the few that exist.^17,18 Although most melanomas declare themselves through recurrence or metastasis within several years of initial biopsy,^1,19 some are clinically dormant for as long as 10 years after initial detection.^20,21 This may be particularly true for the small or early-stage lesions that now comprise the majority of biopsied neoplasms, and such events would go undetected by this study and many others. It also must be recognized that uneventful follow-up, regardless of duration, cannot prove that a biopsied melanocytic neoplasm was benign. Although only 5 patients had a follow-up time of less than 2 years (the time frame in which most recurrence or metastasis will occur), it cannot be definitively proven that a minimum of 2 years recurrence- or metastasis-free survival indicates a benign lesion. Many early-stage malignant melanomas are eradicated by complete excision or even by the initial biopsy if margins are uninvolved.

Because these limitations are intrinsic to melanocytic neoplasms and current management strategies, they pertain to all investigations seeking insights into biological potential through clinical outcomes. Similarly, all current diagnostic tools and procedures have the potential for sampling error, including histopathology. The rarity of adverse outcomes (recurrence and metastasis) in patients with benign test results within this cohort indicates that false-negative results are uncommon, which is further evidenced by a similar rarity of adverse events in prior studies of the gene expression signature.^8-10,22 A particular strength of this study is that most of the ambiguous melanocytic neoplasms followed did not undergo excision after the initial biopsy, an increasingly uncommon situation that may increase their likelihood to be informative.

It must be emphasized that the gene expression test, similar to other diagnostic adjuncts, is neither a replacement for histopathologic interpretation nor a substitute for judgment. As with all tests, it can produce false-positive and false-negative results. Therefore, it should always be interpreted within the constellation of the many other data points that must be considered when making a distinction between benign nevus and malignant melanoma, including but not limited to patient age, family and personal history of melanoma, anatomic location, clinical features, and histopathologic findings. As is the case for many diseases, careful consideration of all relevant input is necessary to minimize the risk of misdiagnosis that might occur should any single data point prove inaccurate, including the results of adjunctive molecular tests.

Conclusion

Ancillary methods are emerging as useful tools for the diagnostic evaluation of melanocytic neoplasms that cannot be assigned definitive diagnoses using traditional techniques alone. This study suggests that patients with ambiguous melanocytic neoplasms may benefit from diagnoses and treatment decisions aligned with the results of a gene expression test, and that for those with a benign result, simple observation may be a safe alternative to surgical excision. This expands upon prior observations of the test’s influence on diagnoses and treatment decisions and supports its role as part of dermatopathologists’ and dermatologists’ decision-making process for histopathologically ambiguous melanocytic lesions.

According to National Institutes of Health estimates, more than 90,000 new cases of melanoma were diagnosed in 2018.¹ Overall 5-year survival for patients with melanoma exceeds 90%, but individual survival estimates are highly dependent on stage at diagnosis, and survival decreases markedly with metastasis. Therefore, early and accurate diagnosis is critical.

Diagnosis of melanocytic neoplasms usually is performed by dermatopathologists through microscopic examination of stained tissue biopsy sections, a technically simple and effective method that enables a definitive diagnosis of benign nevus or malignant melanoma to be made in most cases. However, approximately 15% of all biopsied melanocytic lesions will exhibit some degree of histopathologic ambiguity,^2-4 meaning that some of their microscopic features will be characteristic of a benign nevus while others will suggest the possibility of malignant melanoma. Diagnostic interpretations often vary in these cases, even among experts, and a definitive diagnosis of benign or malignant may be difficult to achieve by microscopy alone.^2-4 Because of the marked reduction in survival once a melanoma has metastasized, these diagnostically ambiguous lesions often are treated as possible malignant melanomas with complete surgical excision (or re-excision). However, some experts suggest that many histopathologically ambiguous melanocytic neoplasms are, in fact, benign,⁵ a notion supported by epidemiologic evidence.^6,7 Therefore, excision of many ambiguous melanocytic neoplasms might be avoided if definitive diagnosis could be achieved.

A gene expression signature was developed and validated for use as an adjunct to traditional methods of differentiating malignant melanocytic neoplasms from their benign counterparts.^8-11 This test quantifies the RNA transcripts produced by 14 genes known to be overexpressed in malignant melanomas by comparison to benign nevi. These values are then combined algorithmically with measurements of 9 reference genes to produce an objective numerical score that is classified as benign, malignant, or indeterminate. When used by board-certified dermatopathologists and dermatologists confronting ambiguous melanocytic lesions, the test produces substantial increases in definitive diagnoses and prompts changes in treatment recommendations.^12,13 However, the long-term consequences of foregoing surgical excision of melanocytic neoplasms that are diagnostically ambiguous but classified as benign by this test have not yet been formally assessed. In the current study, prospectively tested patients whose ambiguous melanocytic neoplasms were classified as benign by the gene expression signature were followed for up to 4.5 years to evaluate the long-term safety of treatment decisions aligned with benign test results.

Methods

Study Population
As part of a prior study,¹² US-based dermatopathologists submitted tissue sections from biopsied melanocytic neoplasms determined to be diagnostically ambiguous by histopathology for analysis with the gene expression signature (Myriad Genetics, Inc). Diagnostically ambiguous lesions were those lesions that were described as ambiguous, uncertain, equivocal, indeterminate, or other synonymous terms by the submitting dermatopathologist and therefore lacked a confident diagnosis of benign or malignant prior to testing. Patients initially were tested between May 2014 and August 2014, with samples submitted through a prospective clinical experience study designed to assess the impact of the test on diagnosis and treatment decisions. This study was performed under an institutional review board waiver of consent (Quorum #33403/1).

Patients were eligible for inclusion in the current study if their biopsy specimens (1) had an uncertain preliminary diagnosis according to the submitting dermatopathologist (pretest diagnosis of indeterminate); (2) received a negative (benign) score from the gene expression test; (3) were treated as benign by the dermatologist(s) involved in follow-up care; and (4) were submitted by a single site (St. Joseph Medical Center, Houston, Texas). Although a single dermatopathology site was used for this study, multiple dermatologists were involved in the final treatment of these patients. Patients with benign scores who received additional intervention were excluded, as they may have a lower rate of adverse events (ie, metastasis) than those who did not receive intervention and would therefore skew the analysis population. A total of 25 patients from the prior study met these inclusion criteria. The previously collected¹² pretest and posttest de-identified data were compiled from the commercial laboratory databases, and the patients were followed from the time of testing via medical record review performed by the dermatology providers at participating sites. Clinical follow-up data were collected using study-specific case report forms (CRFs) that captured the following: (1) the dates and results of clinical follow-up visits; (2) the type(s) of treatment and interventions (if any) performed at those visits; (3) the specific indication for any intervention performed; (4) any evidence of persistent, locally recurrent, and/or distant melanocytic neoplasia (whether definitively attributable to the tested lesion or not); and (5) death from any cause. The CRF assigned interventions to 1 of 5 categories: excision, excision with sentinel lymph node biopsy, referral to dermatologic or other surgeon, examination only (without surgical intervention), and other. Selection of other required a free-text description of the treatment and indications. Pertinent information not otherwise captured by the CRF also was recordable as free text.

Gene Expression Testing
Gene expression testing was carried out at the time of specimen submission in the prior study¹² as described previously.¹⁴ Briefly, formalin-fixed, paraffin-embedded, unstained tissue sections and/or tissue blocks were submitted for testing along with a single hematoxylin and eosin–stained slide used to identify and designate the representative portion(s) of the lesion to be tested. These areas were macrodissected from unstained tissue sections and pooled for RNA extraction. Expression of 14 biomarker genes and 9 reference genes was measured via quantitative reverse transcription–polymerase chain reaction, performed in triplicate for each individual gene. The assay score was generated through application of a weighted algorithm to the expression values generated through quantitative reverse transcription–polymerase chain reaction. Scores were plotted on a scale ranging from −16.7 to 11.1, with scores from 0.0 to 11.1 classified as malignant, scores from −16.7 to −2.1 as benign, and scores from −2.1 to −0.1 as indeterminate.

Statistical Analysis
Demographic and other baseline characteristics of the patient population were summarized. Follow-up time was calculated as the interval between the date a patient’s gene expression test result was first issued to the provider and the date of the patient’s last recorded visit during the study period. All patient dermatology office visits within the designated follow-up period were documented, with a nonstandard number of visits and follow-up time across all study patients. Statistical analyses were conducted using SAS software (SAS Institute Inc), R software version 3.5.0 (R Foundation for Statistical Computing), and IBM SPSS Statistics software (IBM SPSS Statistics for Windows, Version 25).

Results

Patient Sample
A total of 25 ambiguous melanocytic neoplasms from 25 patients met the study inclusion criteria of a benign gene expression result with subsequent treatment as a benign neoplasm during follow-up. The patient sample statistics are summarized in Table 1. Most patients were younger than 65 years, with an average age at the time of biopsy of 48.4 years. All 25 neoplasms produced negative (benign) gene expression signature scores, all were diagnosed as benign nevi posttest by the submitting dermatopathologist, and all patients were initially treated in accordance with the benign diagnosis by the dermatologist(s) involved in clinical follow-up care. Prior to testing with the gene expression signature, most of these histopathologically indeterminate lesions received differential diagnoses, the most common of which were dysplastic nevus (84%), melanoma arising from a nevus (72%), and superficial spreading melanoma (64%; eTable). After testing with the gene expression signature and receiving a benign score, most lesions received a single differential diagnosis of dysplastic nevus (88%).

Follow-up and Survival
Clinical follow-up time ranged from 0.6 to 53.3 months, with a mean duration (SD) of 38.5 (16.6) months, and patients attended an average of 4 postbiopsy dermatology appointments (mean [SD], 4.6 [3.6]). According to the participating dermatology care providers, none of the 25 patients developed any indication during follow-up that the diagnosis of benign nevus was inaccurate. No patient had evidence of locally recurrent or metastatic melanoma, and none died during the study period.

Treatment/Interventions
The treatment recorded in the CRF was examination only for 21 of 25 patients, excision for 3, and other for 1 (Table 2). Because the explanation for the selection of other in this case described an excision performed at the same anatomic location as the biopsy, this treatment also was considered an excision for purposes of the study analyses. The 3 excisions all occurred at the first postbiopsy dermatology encounter. Across all follow-up visits, no additional surgical interventions occurred (Table 2).

The third excision (case 3) involved a 32-year-old woman with a pigmented lesion on the abdomen (Table 3; Figure, E and F). The clinical description was irregular-appearing black papule, nevus with atypia, and the histopathologic differential diagnosis again included dysplastic nevus, superficial spreading melanoma, and melanoma arising within a preexisting nevus. The gene expression signature result was benign (score, −7.2), and the final diagnosis issued within the accompanying pathology report was nevus with moderate junctional dysplasia. Despite the benign diagnosis, excision was performed 89 days after test result availability, with apparent residual pigmentation as the specified indication. As with the other 2 cases, the treating dermatologist confirmed that neither clinical features nor follow-up events suggested malignancy.

Comment

This study followed a cohort of 25 patients with histopathologically ambiguous melanocytic neoplasms that were classified as benign by a diagnostic gene expression test with the intent of determining the outcomes of patients whose treatment aligned with their benign test result. All patients initially were managed according to their test result. During an average posttest clinical follow-up time of more than 3 years (38.5 months), the 25 biopsied lesions, most of which received a differential diagnosis of dysplastic nevus, were regarded as benign nevi by their dermatologists, and the vast majority (88%) received no further surgical intervention. Three patients underwent subsequent excision of the biopsied lesion, with patient or physician preference as the indication in each instance. None of the 25 patients developed evidence of local recurrence, metastasis, or other findings that prompted doubt of the benign diagnosis. The absence of adverse events during clinical follow-up, particularly given that most lesions were not subjected to further intervention, supports use of the gene expression test as a safe and effective adjunct to the diagnosis and treatment of ambiguous melanocytic neoplasms by dermatologists and dermatopathologists.

Ambiguous melanocytic neoplasms evaluated without the aid of molecular adjuncts often result in equivocal or less-than-definitive diagnoses, and further surgical intervention is commonly undertaken to mitigate against the possibility of a missed melanoma.¹³ In this study, treatment that was aligned with the benign test result allowed most patients to avoid further surgical intervention, which suggests that adjunctive use of the gene signature can contribute to reductions in the physical and economic burdens imposed by unnecessary surgical interventions.^15,16 Moreover, any means of increasing accurate and definitive diagnoses may produce an immediate impact on health outcomes by reducing the anxiety that uncertainty often provokes in patients and health care providers alike.

Study Limitations
This study must be interpreted within the context of its limitations. Obtaining meaningful patient outcome data is a common challenge in health care research due to the requisite length of follow-up and sometimes the lack of definitive evidence of adverse events. This is particularly difficult for melanocytic neoplasms because of an apparent inclination for patients with benign diagnoses to abandon follow-up and an increasing tendency for even minimal diagnostic uncertainty to prompt complete excision. Additionally, the only definitive clinical outcome for melanocytic neoplasms is distant metastasis, which (fortunately for patients) is relatively rare. Not surprisingly, studies documenting clinical outcomes of patients with ambiguous melanocytic neoplasms tested prospectively with diagnostic adjuncts are scarce, and this study’s sample size and clinical follow-up compare favorably with the few that exist.^17,18 Although most melanomas declare themselves through recurrence or metastasis within several years of initial biopsy,^1,19 some are clinically dormant for as long as 10 years after initial detection.^20,21 This may be particularly true for the small or early-stage lesions that now comprise the majority of biopsied neoplasms, and such events would go undetected by this study and many others. It also must be recognized that uneventful follow-up, regardless of duration, cannot prove that a biopsied melanocytic neoplasm was benign. Although only 5 patients had a follow-up time of less than 2 years (the time frame in which most recurrence or metastasis will occur), it cannot be definitively proven that a minimum of 2 years recurrence- or metastasis-free survival indicates a benign lesion. Many early-stage malignant melanomas are eradicated by complete excision or even by the initial biopsy if margins are uninvolved.

Because these limitations are intrinsic to melanocytic neoplasms and current management strategies, they pertain to all investigations seeking insights into biological potential through clinical outcomes. Similarly, all current diagnostic tools and procedures have the potential for sampling error, including histopathology. The rarity of adverse outcomes (recurrence and metastasis) in patients with benign test results within this cohort indicates that false-negative results are uncommon, which is further evidenced by a similar rarity of adverse events in prior studies of the gene expression signature.^8-10,22 A particular strength of this study is that most of the ambiguous melanocytic neoplasms followed did not undergo excision after the initial biopsy, an increasingly uncommon situation that may increase their likelihood to be informative.

It must be emphasized that the gene expression test, similar to other diagnostic adjuncts, is neither a replacement for histopathologic interpretation nor a substitute for judgment. As with all tests, it can produce false-positive and false-negative results. Therefore, it should always be interpreted within the constellation of the many other data points that must be considered when making a distinction between benign nevus and malignant melanoma, including but not limited to patient age, family and personal history of melanoma, anatomic location, clinical features, and histopathologic findings. As is the case for many diseases, careful consideration of all relevant input is necessary to minimize the risk of misdiagnosis that might occur should any single data point prove inaccurate, including the results of adjunctive molecular tests.

Conclusion

Ancillary methods are emerging as useful tools for the diagnostic evaluation of melanocytic neoplasms that cannot be assigned definitive diagnoses using traditional techniques alone. This study suggests that patients with ambiguous melanocytic neoplasms may benefit from diagnoses and treatment decisions aligned with the results of a gene expression test, and that for those with a benign result, simple observation may be a safe alternative to surgical excision. This expands upon prior observations of the test’s influence on diagnoses and treatment decisions and supports its role as part of dermatopathologists’ and dermatologists’ decision-making process for histopathologically ambiguous melanocytic lesions.

According to National Institutes of Health estimates, more than 90,000 new cases of melanoma were diagnosed in 2018.¹ Overall 5-year survival for patients with melanoma exceeds 90%, but individual survival estimates are highly dependent on stage at diagnosis, and survival decreases markedly with metastasis. Therefore, early and accurate diagnosis is critical.

Diagnosis of melanocytic neoplasms usually is performed by dermatopathologists through microscopic examination of stained tissue biopsy sections, a technically simple and effective method that enables a definitive diagnosis of benign nevus or malignant melanoma to be made in most cases. However, approximately 15% of all biopsied melanocytic lesions will exhibit some degree of histopathologic ambiguity,^2-4 meaning that some of their microscopic features will be characteristic of a benign nevus while others will suggest the possibility of malignant melanoma. Diagnostic interpretations often vary in these cases, even among experts, and a definitive diagnosis of benign or malignant may be difficult to achieve by microscopy alone.^2-4 Because of the marked reduction in survival once a melanoma has metastasized, these diagnostically ambiguous lesions often are treated as possible malignant melanomas with complete surgical excision (or re-excision). However, some experts suggest that many histopathologically ambiguous melanocytic neoplasms are, in fact, benign,⁵ a notion supported by epidemiologic evidence.^6,7 Therefore, excision of many ambiguous melanocytic neoplasms might be avoided if definitive diagnosis could be achieved.

A gene expression signature was developed and validated for use as an adjunct to traditional methods of differentiating malignant melanocytic neoplasms from their benign counterparts.^8-11 This test quantifies the RNA transcripts produced by 14 genes known to be overexpressed in malignant melanomas by comparison to benign nevi. These values are then combined algorithmically with measurements of 9 reference genes to produce an objective numerical score that is classified as benign, malignant, or indeterminate. When used by board-certified dermatopathologists and dermatologists confronting ambiguous melanocytic lesions, the test produces substantial increases in definitive diagnoses and prompts changes in treatment recommendations.^12,13 However, the long-term consequences of foregoing surgical excision of melanocytic neoplasms that are diagnostically ambiguous but classified as benign by this test have not yet been formally assessed. In the current study, prospectively tested patients whose ambiguous melanocytic neoplasms were classified as benign by the gene expression signature were followed for up to 4.5 years to evaluate the long-term safety of treatment decisions aligned with benign test results.

Methods

Study Population
As part of a prior study,¹² US-based dermatopathologists submitted tissue sections from biopsied melanocytic neoplasms determined to be diagnostically ambiguous by histopathology for analysis with the gene expression signature (Myriad Genetics, Inc). Diagnostically ambiguous lesions were those lesions that were described as ambiguous, uncertain, equivocal, indeterminate, or other synonymous terms by the submitting dermatopathologist and therefore lacked a confident diagnosis of benign or malignant prior to testing. Patients initially were tested between May 2014 and August 2014, with samples submitted through a prospective clinical experience study designed to assess the impact of the test on diagnosis and treatment decisions. This study was performed under an institutional review board waiver of consent (Quorum #33403/1).

Patients were eligible for inclusion in the current study if their biopsy specimens (1) had an uncertain preliminary diagnosis according to the submitting dermatopathologist (pretest diagnosis of indeterminate); (2) received a negative (benign) score from the gene expression test; (3) were treated as benign by the dermatologist(s) involved in follow-up care; and (4) were submitted by a single site (St. Joseph Medical Center, Houston, Texas). Although a single dermatopathology site was used for this study, multiple dermatologists were involved in the final treatment of these patients. Patients with benign scores who received additional intervention were excluded, as they may have a lower rate of adverse events (ie, metastasis) than those who did not receive intervention and would therefore skew the analysis population. A total of 25 patients from the prior study met these inclusion criteria. The previously collected¹² pretest and posttest de-identified data were compiled from the commercial laboratory databases, and the patients were followed from the time of testing via medical record review performed by the dermatology providers at participating sites. Clinical follow-up data were collected using study-specific case report forms (CRFs) that captured the following: (1) the dates and results of clinical follow-up visits; (2) the type(s) of treatment and interventions (if any) performed at those visits; (3) the specific indication for any intervention performed; (4) any evidence of persistent, locally recurrent, and/or distant melanocytic neoplasia (whether definitively attributable to the tested lesion or not); and (5) death from any cause. The CRF assigned interventions to 1 of 5 categories: excision, excision with sentinel lymph node biopsy, referral to dermatologic or other surgeon, examination only (without surgical intervention), and other. Selection of other required a free-text description of the treatment and indications. Pertinent information not otherwise captured by the CRF also was recordable as free text.

Gene Expression Testing
Gene expression testing was carried out at the time of specimen submission in the prior study¹² as described previously.¹⁴ Briefly, formalin-fixed, paraffin-embedded, unstained tissue sections and/or tissue blocks were submitted for testing along with a single hematoxylin and eosin–stained slide used to identify and designate the representative portion(s) of the lesion to be tested. These areas were macrodissected from unstained tissue sections and pooled for RNA extraction. Expression of 14 biomarker genes and 9 reference genes was measured via quantitative reverse transcription–polymerase chain reaction, performed in triplicate for each individual gene. The assay score was generated through application of a weighted algorithm to the expression values generated through quantitative reverse transcription–polymerase chain reaction. Scores were plotted on a scale ranging from −16.7 to 11.1, with scores from 0.0 to 11.1 classified as malignant, scores from −16.7 to −2.1 as benign, and scores from −2.1 to −0.1 as indeterminate.

Statistical Analysis
Demographic and other baseline characteristics of the patient population were summarized. Follow-up time was calculated as the interval between the date a patient’s gene expression test result was first issued to the provider and the date of the patient’s last recorded visit during the study period. All patient dermatology office visits within the designated follow-up period were documented, with a nonstandard number of visits and follow-up time across all study patients. Statistical analyses were conducted using SAS software (SAS Institute Inc), R software version 3.5.0 (R Foundation for Statistical Computing), and IBM SPSS Statistics software (IBM SPSS Statistics for Windows, Version 25).

Results

Patient Sample
A total of 25 ambiguous melanocytic neoplasms from 25 patients met the study inclusion criteria of a benign gene expression result with subsequent treatment as a benign neoplasm during follow-up. The patient sample statistics are summarized in Table 1. Most patients were younger than 65 years, with an average age at the time of biopsy of 48.4 years. All 25 neoplasms produced negative (benign) gene expression signature scores, all were diagnosed as benign nevi posttest by the submitting dermatopathologist, and all patients were initially treated in accordance with the benign diagnosis by the dermatologist(s) involved in clinical follow-up care. Prior to testing with the gene expression signature, most of these histopathologically indeterminate lesions received differential diagnoses, the most common of which were dysplastic nevus (84%), melanoma arising from a nevus (72%), and superficial spreading melanoma (64%; eTable). After testing with the gene expression signature and receiving a benign score, most lesions received a single differential diagnosis of dysplastic nevus (88%).

Follow-up and Survival
Clinical follow-up time ranged from 0.6 to 53.3 months, with a mean duration (SD) of 38.5 (16.6) months, and patients attended an average of 4 postbiopsy dermatology appointments (mean [SD], 4.6 [3.6]). According to the participating dermatology care providers, none of the 25 patients developed any indication during follow-up that the diagnosis of benign nevus was inaccurate. No patient had evidence of locally recurrent or metastatic melanoma, and none died during the study period.

Treatment/Interventions
The treatment recorded in the CRF was examination only for 21 of 25 patients, excision for 3, and other for 1 (Table 2). Because the explanation for the selection of other in this case described an excision performed at the same anatomic location as the biopsy, this treatment also was considered an excision for purposes of the study analyses. The 3 excisions all occurred at the first postbiopsy dermatology encounter. Across all follow-up visits, no additional surgical interventions occurred (Table 2).

The third excision (case 3) involved a 32-year-old woman with a pigmented lesion on the abdomen (Table 3; Figure, E and F). The clinical description was irregular-appearing black papule, nevus with atypia, and the histopathologic differential diagnosis again included dysplastic nevus, superficial spreading melanoma, and melanoma arising within a preexisting nevus. The gene expression signature result was benign (score, −7.2), and the final diagnosis issued within the accompanying pathology report was nevus with moderate junctional dysplasia. Despite the benign diagnosis, excision was performed 89 days after test result availability, with apparent residual pigmentation as the specified indication. As with the other 2 cases, the treating dermatologist confirmed that neither clinical features nor follow-up events suggested malignancy.

Comment

This study followed a cohort of 25 patients with histopathologically ambiguous melanocytic neoplasms that were classified as benign by a diagnostic gene expression test with the intent of determining the outcomes of patients whose treatment aligned with their benign test result. All patients initially were managed according to their test result. During an average posttest clinical follow-up time of more than 3 years (38.5 months), the 25 biopsied lesions, most of which received a differential diagnosis of dysplastic nevus, were regarded as benign nevi by their dermatologists, and the vast majority (88%) received no further surgical intervention. Three patients underwent subsequent excision of the biopsied lesion, with patient or physician preference as the indication in each instance. None of the 25 patients developed evidence of local recurrence, metastasis, or other findings that prompted doubt of the benign diagnosis. The absence of adverse events during clinical follow-up, particularly given that most lesions were not subjected to further intervention, supports use of the gene expression test as a safe and effective adjunct to the diagnosis and treatment of ambiguous melanocytic neoplasms by dermatologists and dermatopathologists.

Ambiguous melanocytic neoplasms evaluated without the aid of molecular adjuncts often result in equivocal or less-than-definitive diagnoses, and further surgical intervention is commonly undertaken to mitigate against the possibility of a missed melanoma.¹³ In this study, treatment that was aligned with the benign test result allowed most patients to avoid further surgical intervention, which suggests that adjunctive use of the gene signature can contribute to reductions in the physical and economic burdens imposed by unnecessary surgical interventions.^15,16 Moreover, any means of increasing accurate and definitive diagnoses may produce an immediate impact on health outcomes by reducing the anxiety that uncertainty often provokes in patients and health care providers alike.

Study Limitations
This study must be interpreted within the context of its limitations. Obtaining meaningful patient outcome data is a common challenge in health care research due to the requisite length of follow-up and sometimes the lack of definitive evidence of adverse events. This is particularly difficult for melanocytic neoplasms because of an apparent inclination for patients with benign diagnoses to abandon follow-up and an increasing tendency for even minimal diagnostic uncertainty to prompt complete excision. Additionally, the only definitive clinical outcome for melanocytic neoplasms is distant metastasis, which (fortunately for patients) is relatively rare. Not surprisingly, studies documenting clinical outcomes of patients with ambiguous melanocytic neoplasms tested prospectively with diagnostic adjuncts are scarce, and this study’s sample size and clinical follow-up compare favorably with the few that exist.^17,18 Although most melanomas declare themselves through recurrence or metastasis within several years of initial biopsy,^1,19 some are clinically dormant for as long as 10 years after initial detection.^20,21 This may be particularly true for the small or early-stage lesions that now comprise the majority of biopsied neoplasms, and such events would go undetected by this study and many others. It also must be recognized that uneventful follow-up, regardless of duration, cannot prove that a biopsied melanocytic neoplasm was benign. Although only 5 patients had a follow-up time of less than 2 years (the time frame in which most recurrence or metastasis will occur), it cannot be definitively proven that a minimum of 2 years recurrence- or metastasis-free survival indicates a benign lesion. Many early-stage malignant melanomas are eradicated by complete excision or even by the initial biopsy if margins are uninvolved.

Because these limitations are intrinsic to melanocytic neoplasms and current management strategies, they pertain to all investigations seeking insights into biological potential through clinical outcomes. Similarly, all current diagnostic tools and procedures have the potential for sampling error, including histopathology. The rarity of adverse outcomes (recurrence and metastasis) in patients with benign test results within this cohort indicates that false-negative results are uncommon, which is further evidenced by a similar rarity of adverse events in prior studies of the gene expression signature.^8-10,22 A particular strength of this study is that most of the ambiguous melanocytic neoplasms followed did not undergo excision after the initial biopsy, an increasingly uncommon situation that may increase their likelihood to be informative.

It must be emphasized that the gene expression test, similar to other diagnostic adjuncts, is neither a replacement for histopathologic interpretation nor a substitute for judgment. As with all tests, it can produce false-positive and false-negative results. Therefore, it should always be interpreted within the constellation of the many other data points that must be considered when making a distinction between benign nevus and malignant melanoma, including but not limited to patient age, family and personal history of melanoma, anatomic location, clinical features, and histopathologic findings. As is the case for many diseases, careful consideration of all relevant input is necessary to minimize the risk of misdiagnosis that might occur should any single data point prove inaccurate, including the results of adjunctive molecular tests.

Conclusion

Ancillary methods are emerging as useful tools for the diagnostic evaluation of melanocytic neoplasms that cannot be assigned definitive diagnoses using traditional techniques alone. This study suggests that patients with ambiguous melanocytic neoplasms may benefit from diagnoses and treatment decisions aligned with the results of a gene expression test, and that for those with a benign result, simple observation may be a safe alternative to surgical excision. This expands upon prior observations of the test’s influence on diagnoses and treatment decisions and supports its role as part of dermatopathologists’ and dermatologists’ decision-making process for histopathologically ambiguous melanocytic lesions.

The Diagnosis: Seborrheic Keratosis-like Melanoma 

Seborrheic keratosis (SK) is a benign neoplasm commonly encountered on the skin and frequently diagnosed by clinical examination alone. Seborrheic keratosis-like melanomas are melanomas that clinically or dermatoscopically resemble SKs and thus can be challenging to accurately diagnose. Melanomas can have a hyperkeratotic or verrucous appearance^1-3 and can even exhibit dermatoscopic and microscopic features that are found in SKs such as comedolike openings and milialike cysts as well as acanthosis and pseudohorn cysts, respectively.²  

In our patient, histopathology revealed SK-like architecture with hyperorthokeratosis, papillomatosis, pseudohorn cyst formation, and basaloid acanthosis (Figure). However, within the lesion was an asymmetric proliferation of nested atypical melanocytes with melanin pigment production. The atypical melanocytes filled and expanded papillomatous projections without notable pagetoid growth and extended into the dermis. There was a background congenital nevus component. These findings were diagnostic of invasive malignant melanoma, extending to a Breslow depth of 5.5 mm. A follow-up sentinel lymph node biopsy was negative for metastatic melanoma. The clinical and histologic findings did not show melanoma in the surrounding skin to suggest colonization of an SK by an adjacent melanoma. The clinical history of a long-standing lesion in conjunction with a congenital nevus component on histology favored a diagnosis of melanoma arising in association with a congenital nevus with an SK-like architecture rather than arising in a preexisting SK or de novo melanoma.  

Because our patient did not have multiple widespread SKs and reported rapid growth in the lesion in the last 6 months, there was concern for a malignant neoplasm. However, in patients with numerous SKs or areas of chronically sun-damaged skin, it can be difficult to identify suspicious lesions. It is important for clinicians to remain aware of SK-like melanomas and have a lower threshold for biopsy of any changing or symptomatic lesion that clinically resembles an SK. In our case, the history of change and the markedly different clinical appearance of the lesion in comparison to our patient's SKs prompted the biopsy. Criteria have been proposed to help differentiate these entities under dermoscopy, with melanoma showing the presence of the blue-black sign, pigment network, pseudopods or streaks, and/or the blue-white veil.⁴ 

Cutaneous metastases classically present as dermal nodules, plaques, or ulcers.^5,6 A rare pigmented case of metastatic breast adenocarcinoma clinically mimicking melanoma has been reported.⁷ There is limited literature on the dermoscopic features of cutaneous metastases, but it appears that polymorphic vascular patterns are most common.^5,8 The possibility of a metastatic melanoma involving an SK is a theoretical consideration, but there was no prior history of melanoma in our patient, and the histologic findings were consistent with primary melanoma. There was no histologic evidence of pigmented metastatic breast carcinoma or metastatic lung carcinoma.  

Pigmented malignant hidroacanthoma simplex and pigmented porocarcinomas are rare malignant sweat gland tumors.^9-11 Their benign counterparts are the more commonly encountered hidroacanthoma simplex (intraepidermal poroma) and poroma. Pigmented malignant hidroacanthoma simplex has been reported to clinically mimic an irritated SK.¹⁰ The histopathology of our case did not have features of malignant hidroacanthoma simplex or porocarcinoma. Pigmented squamous cell carcinoma is an uncommon variant of squamous cell carcinoma, and histopathology would reveal proliferation of atypical keratinocytes.¹²  

The Diagnosis: Seborrheic Keratosis-like Melanoma 

Seborrheic keratosis (SK) is a benign neoplasm commonly encountered on the skin and frequently diagnosed by clinical examination alone. Seborrheic keratosis-like melanomas are melanomas that clinically or dermatoscopically resemble SKs and thus can be challenging to accurately diagnose. Melanomas can have a hyperkeratotic or verrucous appearance^1-3 and can even exhibit dermatoscopic and microscopic features that are found in SKs such as comedolike openings and milialike cysts as well as acanthosis and pseudohorn cysts, respectively.²  

In our patient, histopathology revealed SK-like architecture with hyperorthokeratosis, papillomatosis, pseudohorn cyst formation, and basaloid acanthosis (Figure). However, within the lesion was an asymmetric proliferation of nested atypical melanocytes with melanin pigment production. The atypical melanocytes filled and expanded papillomatous projections without notable pagetoid growth and extended into the dermis. There was a background congenital nevus component. These findings were diagnostic of invasive malignant melanoma, extending to a Breslow depth of 5.5 mm. A follow-up sentinel lymph node biopsy was negative for metastatic melanoma. The clinical and histologic findings did not show melanoma in the surrounding skin to suggest colonization of an SK by an adjacent melanoma. The clinical history of a long-standing lesion in conjunction with a congenital nevus component on histology favored a diagnosis of melanoma arising in association with a congenital nevus with an SK-like architecture rather than arising in a preexisting SK or de novo melanoma.  

Because our patient did not have multiple widespread SKs and reported rapid growth in the lesion in the last 6 months, there was concern for a malignant neoplasm. However, in patients with numerous SKs or areas of chronically sun-damaged skin, it can be difficult to identify suspicious lesions. It is important for clinicians to remain aware of SK-like melanomas and have a lower threshold for biopsy of any changing or symptomatic lesion that clinically resembles an SK. In our case, the history of change and the markedly different clinical appearance of the lesion in comparison to our patient's SKs prompted the biopsy. Criteria have been proposed to help differentiate these entities under dermoscopy, with melanoma showing the presence of the blue-black sign, pigment network, pseudopods or streaks, and/or the blue-white veil.⁴ 

Cutaneous metastases classically present as dermal nodules, plaques, or ulcers.^5,6 A rare pigmented case of metastatic breast adenocarcinoma clinically mimicking melanoma has been reported.⁷ There is limited literature on the dermoscopic features of cutaneous metastases, but it appears that polymorphic vascular patterns are most common.^5,8 The possibility of a metastatic melanoma involving an SK is a theoretical consideration, but there was no prior history of melanoma in our patient, and the histologic findings were consistent with primary melanoma. There was no histologic evidence of pigmented metastatic breast carcinoma or metastatic lung carcinoma.  

Pigmented malignant hidroacanthoma simplex and pigmented porocarcinomas are rare malignant sweat gland tumors.^9-11 Their benign counterparts are the more commonly encountered hidroacanthoma simplex (intraepidermal poroma) and poroma. Pigmented malignant hidroacanthoma simplex has been reported to clinically mimic an irritated SK.¹⁰ The histopathology of our case did not have features of malignant hidroacanthoma simplex or porocarcinoma. Pigmented squamous cell carcinoma is an uncommon variant of squamous cell carcinoma, and histopathology would reveal proliferation of atypical keratinocytes.¹²  

The Diagnosis: Seborrheic Keratosis-like Melanoma 

Seborrheic keratosis (SK) is a benign neoplasm commonly encountered on the skin and frequently diagnosed by clinical examination alone. Seborrheic keratosis-like melanomas are melanomas that clinically or dermatoscopically resemble SKs and thus can be challenging to accurately diagnose. Melanomas can have a hyperkeratotic or verrucous appearance^1-3 and can even exhibit dermatoscopic and microscopic features that are found in SKs such as comedolike openings and milialike cysts as well as acanthosis and pseudohorn cysts, respectively.²  

In our patient, histopathology revealed SK-like architecture with hyperorthokeratosis, papillomatosis, pseudohorn cyst formation, and basaloid acanthosis (Figure). However, within the lesion was an asymmetric proliferation of nested atypical melanocytes with melanin pigment production. The atypical melanocytes filled and expanded papillomatous projections without notable pagetoid growth and extended into the dermis. There was a background congenital nevus component. These findings were diagnostic of invasive malignant melanoma, extending to a Breslow depth of 5.5 mm. A follow-up sentinel lymph node biopsy was negative for metastatic melanoma. The clinical and histologic findings did not show melanoma in the surrounding skin to suggest colonization of an SK by an adjacent melanoma. The clinical history of a long-standing lesion in conjunction with a congenital nevus component on histology favored a diagnosis of melanoma arising in association with a congenital nevus with an SK-like architecture rather than arising in a preexisting SK or de novo melanoma.  

Because our patient did not have multiple widespread SKs and reported rapid growth in the lesion in the last 6 months, there was concern for a malignant neoplasm. However, in patients with numerous SKs or areas of chronically sun-damaged skin, it can be difficult to identify suspicious lesions. It is important for clinicians to remain aware of SK-like melanomas and have a lower threshold for biopsy of any changing or symptomatic lesion that clinically resembles an SK. In our case, the history of change and the markedly different clinical appearance of the lesion in comparison to our patient's SKs prompted the biopsy. Criteria have been proposed to help differentiate these entities under dermoscopy, with melanoma showing the presence of the blue-black sign, pigment network, pseudopods or streaks, and/or the blue-white veil.⁴ 

Cutaneous metastases classically present as dermal nodules, plaques, or ulcers.^5,6 A rare pigmented case of metastatic breast adenocarcinoma clinically mimicking melanoma has been reported.⁷ There is limited literature on the dermoscopic features of cutaneous metastases, but it appears that polymorphic vascular patterns are most common.^5,8 The possibility of a metastatic melanoma involving an SK is a theoretical consideration, but there was no prior history of melanoma in our patient, and the histologic findings were consistent with primary melanoma. There was no histologic evidence of pigmented metastatic breast carcinoma or metastatic lung carcinoma.  

Pigmented malignant hidroacanthoma simplex and pigmented porocarcinomas are rare malignant sweat gland tumors.^9-11 Their benign counterparts are the more commonly encountered hidroacanthoma simplex (intraepidermal poroma) and poroma. Pigmented malignant hidroacanthoma simplex has been reported to clinically mimic an irritated SK.¹⁰ The histopathology of our case did not have features of malignant hidroacanthoma simplex or porocarcinoma. Pigmented squamous cell carcinoma is an uncommon variant of squamous cell carcinoma, and histopathology would reveal proliferation of atypical keratinocytes.¹²  

The Diagnosis: Sweet Syndrome 

Sweet syndrome, alternatively known as acute febrile neutrophilic dermatosis, typically presents with variably tender, erythematous papules, plaques, or nodules in middle-aged adults.¹ Systemic symptoms such as fever, fatigue, and arthralgia often accompany these cutaneous findings.^1,2 Although the pathophysiology has not been fully elucidated, this syndrome frequently is associated with infections, especially upper respiratory illnesses; medications; and malignancies. Among cases of malignancy-associated Sweet syndrome, hematologic malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome, are more common than solid organ malignancies.^1,2 Sweet syndrome may precede the associated malignancy by several months; thus, patients without an identifiable trigger for Sweet syndrome should be closely followed.² Treatment with systemic steroids typically is effective.^1,3 Typical histologic features include papillary dermal edema and a brisk neutrophilic infiltrate in the superficial to mid dermis (quiz image).⁴ Overlying epidermal spongiosis with or without vesiculation also can be seen.⁴ Leukocytoclasia and endothelial swelling without fibrinoid necrosis are typical, though full-blown leukocytoclastic vasculitis can be seen.^3,4 A histiocytoid variant also has been described in which the dermal infiltrate is composed of mononuclear cells reminiscent of histiocytes that are thought to be immature cells of myeloid origin. This variant histologically can simulate leukemia cutis.⁵  

Perniosis, also known as chilblains, typically presents with red to violaceous macules or papules on acral sites, particularly the distal fingers and toes.^6,7 It tends to affect young women more frequently than other demographic groups. Although the pathophysiology is not fully understood, perniosis is thought to represent an abnormal inflammatory response to cold environmental conditions. It can occur as an idiopathic disorder or in association with various systemic illnesses including lupus erythematosus.^6,7 The typical histologic findings include papillary dermal edema and a lymphocytic infiltrate in the superficial to deep dermis, often with perivascular and perieccrine accentuation (Figure 1).^3,6 Other less common microscopic findings include sparse keratinocyte necrosis, basal layer vacuolar change, swelling of endothelial cells, and lymphocytic vasculitis.⁶ The lesions typically resolve spontaneously within a few weeks, but in some cases they may be chronic.³ 

Polymorphous light eruption, a common photodermatosis induced by UV light exposure, typically presents in adolescence or early adulthood with a female predominance. Patients usually develop this pruritic rash on sun-exposed skin other than the face and dorsal aspects of the hands in the spring or early summer upon increased sun exposure after the winter season.^3,8 Consistent sunlight exposure throughout the summer months results in decreased flares. Various cutaneous morphologies including papules, vesicles, and plaques can be seen.^3,8 Histologic findings include papillary dermal edema and a perivascular lymphocytic infiltrate in the superficial to deep dermis (Figure 2).⁴  

Tinea corporis, a superficial cutaneous dermatophyte infection, typically presents as annular scaly plaques with central clearing. Vesicles and pustules also can be seen.³ The diagnosis can be confirmed via fungal culture, identification of hyphae on microscopic examination of skin scrapings using potassium hydroxide, or cutaneous biopsy. Histologic clues to diagnosis include a "compact stratum corneum (either uniform or forming a layer beneath a basket weave stratum corneum), parakeratosis, mild spongiosis, and neutrophils in the stratum corneum" (Figure 3).⁹ Papillary dermal edema also may be present, though this finding less commonly is reported.^9,10 Because fungal hyphae can be difficult to identify on hematoxylin and eosin-stained slides, special stains such as periodic acid-Schiff or Grocott-Gomori methenamine-silver may be helpful.⁹ These infections are managed with topical or oral antifungal medications.  

Wells syndrome, also known as eosinophilic cellulitis, presents with an acute eruption that can clinically resemble bacterial cellulitis.³ It has been described in children and adults with various clinical morphologies including plaques, bullae, papulovesicles, and papulonodules. Peripheral eosinophilia may be present.¹¹ The clinical lesions usually resolve spontaneously in a few weeks to months, but recurrences are typical.^3,11 Histologic findings include papillary dermal edema with or without subepidermal bulla formation and epidermal spongiosis as well as a mixed inflammatory infiltrate with a predominance of eosinophils and flame figures (Figure 4).⁴ Flame figures are collagen fibers coated with major basic protein and other constituents of degranulated eosinophils.³ Although flame figures often are present in Wells syndrome, they are not specific to this condition.^3,4 Some consider Wells syndrome an exaggerated reaction pattern rather than a specific entity.³ 

The Diagnosis: Sweet Syndrome 

Sweet syndrome, alternatively known as acute febrile neutrophilic dermatosis, typically presents with variably tender, erythematous papules, plaques, or nodules in middle-aged adults.¹ Systemic symptoms such as fever, fatigue, and arthralgia often accompany these cutaneous findings.^1,2 Although the pathophysiology has not been fully elucidated, this syndrome frequently is associated with infections, especially upper respiratory illnesses; medications; and malignancies. Among cases of malignancy-associated Sweet syndrome, hematologic malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome, are more common than solid organ malignancies.^1,2 Sweet syndrome may precede the associated malignancy by several months; thus, patients without an identifiable trigger for Sweet syndrome should be closely followed.² Treatment with systemic steroids typically is effective.^1,3 Typical histologic features include papillary dermal edema and a brisk neutrophilic infiltrate in the superficial to mid dermis (quiz image).⁴ Overlying epidermal spongiosis with or without vesiculation also can be seen.⁴ Leukocytoclasia and endothelial swelling without fibrinoid necrosis are typical, though full-blown leukocytoclastic vasculitis can be seen.^3,4 A histiocytoid variant also has been described in which the dermal infiltrate is composed of mononuclear cells reminiscent of histiocytes that are thought to be immature cells of myeloid origin. This variant histologically can simulate leukemia cutis.⁵  

Perniosis, also known as chilblains, typically presents with red to violaceous macules or papules on acral sites, particularly the distal fingers and toes.^6,7 It tends to affect young women more frequently than other demographic groups. Although the pathophysiology is not fully understood, perniosis is thought to represent an abnormal inflammatory response to cold environmental conditions. It can occur as an idiopathic disorder or in association with various systemic illnesses including lupus erythematosus.^6,7 The typical histologic findings include papillary dermal edema and a lymphocytic infiltrate in the superficial to deep dermis, often with perivascular and perieccrine accentuation (Figure 1).^3,6 Other less common microscopic findings include sparse keratinocyte necrosis, basal layer vacuolar change, swelling of endothelial cells, and lymphocytic vasculitis.⁶ The lesions typically resolve spontaneously within a few weeks, but in some cases they may be chronic.³ 

Polymorphous light eruption, a common photodermatosis induced by UV light exposure, typically presents in adolescence or early adulthood with a female predominance. Patients usually develop this pruritic rash on sun-exposed skin other than the face and dorsal aspects of the hands in the spring or early summer upon increased sun exposure after the winter season.^3,8 Consistent sunlight exposure throughout the summer months results in decreased flares. Various cutaneous morphologies including papules, vesicles, and plaques can be seen.^3,8 Histologic findings include papillary dermal edema and a perivascular lymphocytic infiltrate in the superficial to deep dermis (Figure 2).⁴  

Tinea corporis, a superficial cutaneous dermatophyte infection, typically presents as annular scaly plaques with central clearing. Vesicles and pustules also can be seen.³ The diagnosis can be confirmed via fungal culture, identification of hyphae on microscopic examination of skin scrapings using potassium hydroxide, or cutaneous biopsy. Histologic clues to diagnosis include a "compact stratum corneum (either uniform or forming a layer beneath a basket weave stratum corneum), parakeratosis, mild spongiosis, and neutrophils in the stratum corneum" (Figure 3).⁹ Papillary dermal edema also may be present, though this finding less commonly is reported.^9,10 Because fungal hyphae can be difficult to identify on hematoxylin and eosin-stained slides, special stains such as periodic acid-Schiff or Grocott-Gomori methenamine-silver may be helpful.⁹ These infections are managed with topical or oral antifungal medications.  

Wells syndrome, also known as eosinophilic cellulitis, presents with an acute eruption that can clinically resemble bacterial cellulitis.³ It has been described in children and adults with various clinical morphologies including plaques, bullae, papulovesicles, and papulonodules. Peripheral eosinophilia may be present.¹¹ The clinical lesions usually resolve spontaneously in a few weeks to months, but recurrences are typical.^3,11 Histologic findings include papillary dermal edema with or without subepidermal bulla formation and epidermal spongiosis as well as a mixed inflammatory infiltrate with a predominance of eosinophils and flame figures (Figure 4).⁴ Flame figures are collagen fibers coated with major basic protein and other constituents of degranulated eosinophils.³ Although flame figures often are present in Wells syndrome, they are not specific to this condition.^3,4 Some consider Wells syndrome an exaggerated reaction pattern rather than a specific entity.³ 

The Diagnosis: Sweet Syndrome 

Sweet syndrome, alternatively known as acute febrile neutrophilic dermatosis, typically presents with variably tender, erythematous papules, plaques, or nodules in middle-aged adults.¹ Systemic symptoms such as fever, fatigue, and arthralgia often accompany these cutaneous findings.^1,2 Although the pathophysiology has not been fully elucidated, this syndrome frequently is associated with infections, especially upper respiratory illnesses; medications; and malignancies. Among cases of malignancy-associated Sweet syndrome, hematologic malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome, are more common than solid organ malignancies.^1,2 Sweet syndrome may precede the associated malignancy by several months; thus, patients without an identifiable trigger for Sweet syndrome should be closely followed.² Treatment with systemic steroids typically is effective.^1,3 Typical histologic features include papillary dermal edema and a brisk neutrophilic infiltrate in the superficial to mid dermis (quiz image).⁴ Overlying epidermal spongiosis with or without vesiculation also can be seen.⁴ Leukocytoclasia and endothelial swelling without fibrinoid necrosis are typical, though full-blown leukocytoclastic vasculitis can be seen.^3,4 A histiocytoid variant also has been described in which the dermal infiltrate is composed of mononuclear cells reminiscent of histiocytes that are thought to be immature cells of myeloid origin. This variant histologically can simulate leukemia cutis.⁵  

Perniosis, also known as chilblains, typically presents with red to violaceous macules or papules on acral sites, particularly the distal fingers and toes.^6,7 It tends to affect young women more frequently than other demographic groups. Although the pathophysiology is not fully understood, perniosis is thought to represent an abnormal inflammatory response to cold environmental conditions. It can occur as an idiopathic disorder or in association with various systemic illnesses including lupus erythematosus.^6,7 The typical histologic findings include papillary dermal edema and a lymphocytic infiltrate in the superficial to deep dermis, often with perivascular and perieccrine accentuation (Figure 1).^3,6 Other less common microscopic findings include sparse keratinocyte necrosis, basal layer vacuolar change, swelling of endothelial cells, and lymphocytic vasculitis.⁶ The lesions typically resolve spontaneously within a few weeks, but in some cases they may be chronic.³ 

Polymorphous light eruption, a common photodermatosis induced by UV light exposure, typically presents in adolescence or early adulthood with a female predominance. Patients usually develop this pruritic rash on sun-exposed skin other than the face and dorsal aspects of the hands in the spring or early summer upon increased sun exposure after the winter season.^3,8 Consistent sunlight exposure throughout the summer months results in decreased flares. Various cutaneous morphologies including papules, vesicles, and plaques can be seen.^3,8 Histologic findings include papillary dermal edema and a perivascular lymphocytic infiltrate in the superficial to deep dermis (Figure 2).⁴  

Tinea corporis, a superficial cutaneous dermatophyte infection, typically presents as annular scaly plaques with central clearing. Vesicles and pustules also can be seen.³ The diagnosis can be confirmed via fungal culture, identification of hyphae on microscopic examination of skin scrapings using potassium hydroxide, or cutaneous biopsy. Histologic clues to diagnosis include a "compact stratum corneum (either uniform or forming a layer beneath a basket weave stratum corneum), parakeratosis, mild spongiosis, and neutrophils in the stratum corneum" (Figure 3).⁹ Papillary dermal edema also may be present, though this finding less commonly is reported.^9,10 Because fungal hyphae can be difficult to identify on hematoxylin and eosin-stained slides, special stains such as periodic acid-Schiff or Grocott-Gomori methenamine-silver may be helpful.⁹ These infections are managed with topical or oral antifungal medications.  

Wells syndrome, also known as eosinophilic cellulitis, presents with an acute eruption that can clinically resemble bacterial cellulitis.³ It has been described in children and adults with various clinical morphologies including plaques, bullae, papulovesicles, and papulonodules. Peripheral eosinophilia may be present.¹¹ The clinical lesions usually resolve spontaneously in a few weeks to months, but recurrences are typical.^3,11 Histologic findings include papillary dermal edema with or without subepidermal bulla formation and epidermal spongiosis as well as a mixed inflammatory infiltrate with a predominance of eosinophils and flame figures (Figure 4).⁴ Flame figures are collagen fibers coated with major basic protein and other constituents of degranulated eosinophils.³ Although flame figures often are present in Wells syndrome, they are not specific to this condition.^3,4 Some consider Wells syndrome an exaggerated reaction pattern rather than a specific entity.³ 

The Diagnosis: Bullous Amyloidosis 

A punch biopsy from the left temple showed deposits of amorphous eosinophilic material at the tips of dermal papillae and in the papillary dermis with hemorrhage present (Figure 1). A diagnosis of amyloidosis was confirmed on the biopsy of the skin bulla. The low κ/λ light chain ratio and M-spike with notably elevated free λ light chains in both serum and urine were consistent with a λ light chain primary systemic amyloidosis. The patient was seen by hematology and oncology. A bone marrow biopsy demonstrated that 15% to 20% of the clonal-cell population was λ light chain restricted. Eosinophilic extracellular deposits found in the adjacent soft tissue and bone marrow space were confirmed as amyloid with apple green birefringence under polarized light on Congo red stain and metachromatic staining with crystal violet. The patient ultimately was diagnosed with λ light chain multiple myeloma and primary systemic amyloidosis. 

Our patient was treated with a combination therapy of bortezomib, cyclophosphamide, and dexamethasone on 21-day cycles, with bortezomib on days 1, 4, 8, and 11. She had received 3 cycles of chemotherapy before developing diarrhea, hypotension, acute on chronic heart failure, and acute renal failure requiring hospitalization. She had several related complications due to amyloid light chain (AL) amyloidosis and subsequently died 16 days after her initial hospitalization from complications of methicillin-resistant Staphylococcus aureus bacteremia and septic shock. 

Amyloidosis is the pathologic deposition of abnormal protein in the extracellular space of any tissue. Various soluble precursor proteins can make up amyloid, and these proteins polymerize into insoluble fibrils that damage the surrounding parenchyma. The clinical presentation of amyloidosis varies depending on the affected tissue as well as the constituent protein. The amyloidoses are divided into localized cutaneous, primary systemic, and secondary systemic variants. The initial distinction in amyloidosis is determining whether it is skin limited or systemic. Localized cutaneous amyloidosis comprises 30% to 40% of all amyloidosis cases and is further divided into 3 main subtypes: macular, lichen, and nodular amyloidosis.¹ Macular and lichen amyloidosis are composed of keratin derivatives and typically are induced by patients when rubbing or scratching the skin. Histologically, macular and lichen amyloidosis are restricted to the superficial papillary dermis.¹ Nodular amyloidosis is composed of λ or κ light chain immunoglobulins, which are produced by cutaneous infiltrates of monoclonal plasma cells. Histologically, nodular amyloidosis is characterized by a diffuse dermal infiltrate of amorphous eosinophilic material.¹ Primary systemic amyloidosis is associated with an underlying plasma cell dyscrasia, and unlike secondary keratinocyte-derived amyloid, it can involve internal organs. Similar to nodular amyloidosis, primary systemic amyloidosis is composed of AL proteins, and it is histologically similar to nodular amyloidosis.¹ 

Primary systemic AL amyloidosis commonly affects individuals aged 50 to 60 years. Males and females are equally affected. Macroglossia and periorbital purpura are some of the pathognomonic presentations in AL amyloidosis. The major cause of death in these patients is cardiac and renal involvement. Renal involvement commonly presents as nephrotic syndrome, and cardiac involvement can present as a restrictive cardiomyopathy with dyspnea. Other symptoms include edema, hepatosplenomegaly, bleeding diathesis, and carpal tunnel syndrome.² An evaluation for AL amyloidosis should include a complete review of systems and physical examination with studies such as complete blood cell count, comprehensive metabolic panel, serum and urine protein electrophoresis and immunofixation, and electrocardiogram. 

Cutaneous involvement in AL amyloidosis most commonly includes yellowish waxy papules, nodules, and plaques but also can include purpura and petechiae.² Bullous amyloidosis, as seen in our patient, is a rare cutaneous presentation of AL amyloidosis that usually is negative for the Nikolsky sign (Figure 2). Bullae form due to weakness in amyloid-laden dermal connective tissue.³ Eighty-eight percent of cases of bullous amyloidosis have systemic involvement.¹ Some cases have reported a familial linkage, suggesting there might be a genetic component to the disease.⁴ A PubMed search of articles indexed for MEDLINE using the terms bullous amyloidosis, bullous, amyloidosis, and amyloid revealed fewer than 35 cases of bullous amyloidosis in the English-language literature.⁵ Bullae can be located intradermally or subepidermally and commonly are hemorrhagic but also can be translucent, tender, and tense. 

A study of electron microscopy in a patient with systemic bullous amyloidosis demonstrated amyloid and keratinocyte protrusions that perforated the dermis through the spaces in the lamina densa. The study concluded that the disintegration of the lamina densa and expansion of the intercellular spaces between keratinocytes were the causes of skin fragility as well as fluid exudation.⁵ Trauma or friction to the skin are local precipitating factors for blister formation in bullous amyloidosis.  

Bullae can become apparent at any stage of AL amyloidosis, but they generally increase in size and number over time and are most common in intertriginous areas. Bullous amyloid lesions, especially those located in intertriginous areas, can have secondary impetiginization.⁶ In many cases, patients who present with bullous amyloidosis ultimately will be diagnosed with multiple myeloma or another plasma cell dyscrasia. In AL amyloidosis, only 10% to 15% of cases meet criteria for multiple myeloma, whereas 80% or more patients have a monoclonal gammopathy of undetermined significance.⁷  

The prognosis of cutaneous amyloidosis depends on the extent of organ involvement and response to treatment. Treatment is aimed at eliminating clonal plasma cell populations to decrease the production of light chains, thereby decreasing protein burden and amyloid progression. Historically, treatment options included cytotoxic chemotherapy such as oral melphalan and dexamethasone, followed by hematopoietic stem cell transplant. More recent treatment options include bortezomib, thalidomide, pomalidomide, and lenalidomide.⁸ Our patient received a regimen of bortezomib, cyclophosphamide, and dexamethasone that is used for patients with extensive multiple myeloma.  

The differential diagnosis in our patient included bullous drug eruption, which should be considered if the bullae are reoccurring at the same location and in association with the administration of a culprit drug. Bullous pemphigoid is preceded by pruritus, and biopsy demonstrates subepidermal bullae with associated eosinophilic infiltrate. Epidermolysis bullosa acquisita can present with milia and a linear pattern along the basement membrane zone with direct immunofluorescence. Traumatic purpura usually present with the classic shape and hue of an ecchymosis, and the patient will have a history of trauma. 

Cutaneous involvement of amyloidosis can be an early clue to the diagnosis of plasma cell dyscrasia. Early diagnosis and treatment can portend a better prognosis and prevent progression to renal or cardiac disease. 

The Diagnosis: Bullous Amyloidosis 

A punch biopsy from the left temple showed deposits of amorphous eosinophilic material at the tips of dermal papillae and in the papillary dermis with hemorrhage present (Figure 1). A diagnosis of amyloidosis was confirmed on the biopsy of the skin bulla. The low κ/λ light chain ratio and M-spike with notably elevated free λ light chains in both serum and urine were consistent with a λ light chain primary systemic amyloidosis. The patient was seen by hematology and oncology. A bone marrow biopsy demonstrated that 15% to 20% of the clonal-cell population was λ light chain restricted. Eosinophilic extracellular deposits found in the adjacent soft tissue and bone marrow space were confirmed as amyloid with apple green birefringence under polarized light on Congo red stain and metachromatic staining with crystal violet. The patient ultimately was diagnosed with λ light chain multiple myeloma and primary systemic amyloidosis. 

Our patient was treated with a combination therapy of bortezomib, cyclophosphamide, and dexamethasone on 21-day cycles, with bortezomib on days 1, 4, 8, and 11. She had received 3 cycles of chemotherapy before developing diarrhea, hypotension, acute on chronic heart failure, and acute renal failure requiring hospitalization. She had several related complications due to amyloid light chain (AL) amyloidosis and subsequently died 16 days after her initial hospitalization from complications of methicillin-resistant Staphylococcus aureus bacteremia and septic shock. 

Amyloidosis is the pathologic deposition of abnormal protein in the extracellular space of any tissue. Various soluble precursor proteins can make up amyloid, and these proteins polymerize into insoluble fibrils that damage the surrounding parenchyma. The clinical presentation of amyloidosis varies depending on the affected tissue as well as the constituent protein. The amyloidoses are divided into localized cutaneous, primary systemic, and secondary systemic variants. The initial distinction in amyloidosis is determining whether it is skin limited or systemic. Localized cutaneous amyloidosis comprises 30% to 40% of all amyloidosis cases and is further divided into 3 main subtypes: macular, lichen, and nodular amyloidosis.¹ Macular and lichen amyloidosis are composed of keratin derivatives and typically are induced by patients when rubbing or scratching the skin. Histologically, macular and lichen amyloidosis are restricted to the superficial papillary dermis.¹ Nodular amyloidosis is composed of λ or κ light chain immunoglobulins, which are produced by cutaneous infiltrates of monoclonal plasma cells. Histologically, nodular amyloidosis is characterized by a diffuse dermal infiltrate of amorphous eosinophilic material.¹ Primary systemic amyloidosis is associated with an underlying plasma cell dyscrasia, and unlike secondary keratinocyte-derived amyloid, it can involve internal organs. Similar to nodular amyloidosis, primary systemic amyloidosis is composed of AL proteins, and it is histologically similar to nodular amyloidosis.¹ 

Primary systemic AL amyloidosis commonly affects individuals aged 50 to 60 years. Males and females are equally affected. Macroglossia and periorbital purpura are some of the pathognomonic presentations in AL amyloidosis. The major cause of death in these patients is cardiac and renal involvement. Renal involvement commonly presents as nephrotic syndrome, and cardiac involvement can present as a restrictive cardiomyopathy with dyspnea. Other symptoms include edema, hepatosplenomegaly, bleeding diathesis, and carpal tunnel syndrome.² An evaluation for AL amyloidosis should include a complete review of systems and physical examination with studies such as complete blood cell count, comprehensive metabolic panel, serum and urine protein electrophoresis and immunofixation, and electrocardiogram. 

Cutaneous involvement in AL amyloidosis most commonly includes yellowish waxy papules, nodules, and plaques but also can include purpura and petechiae.² Bullous amyloidosis, as seen in our patient, is a rare cutaneous presentation of AL amyloidosis that usually is negative for the Nikolsky sign (Figure 2). Bullae form due to weakness in amyloid-laden dermal connective tissue.³ Eighty-eight percent of cases of bullous amyloidosis have systemic involvement.¹ Some cases have reported a familial linkage, suggesting there might be a genetic component to the disease.⁴ A PubMed search of articles indexed for MEDLINE using the terms bullous amyloidosis, bullous, amyloidosis, and amyloid revealed fewer than 35 cases of bullous amyloidosis in the English-language literature.⁵ Bullae can be located intradermally or subepidermally and commonly are hemorrhagic but also can be translucent, tender, and tense. 

A study of electron microscopy in a patient with systemic bullous amyloidosis demonstrated amyloid and keratinocyte protrusions that perforated the dermis through the spaces in the lamina densa. The study concluded that the disintegration of the lamina densa and expansion of the intercellular spaces between keratinocytes were the causes of skin fragility as well as fluid exudation.⁵ Trauma or friction to the skin are local precipitating factors for blister formation in bullous amyloidosis.  

Bullae can become apparent at any stage of AL amyloidosis, but they generally increase in size and number over time and are most common in intertriginous areas. Bullous amyloid lesions, especially those located in intertriginous areas, can have secondary impetiginization.⁶ In many cases, patients who present with bullous amyloidosis ultimately will be diagnosed with multiple myeloma or another plasma cell dyscrasia. In AL amyloidosis, only 10% to 15% of cases meet criteria for multiple myeloma, whereas 80% or more patients have a monoclonal gammopathy of undetermined significance.⁷  

The prognosis of cutaneous amyloidosis depends on the extent of organ involvement and response to treatment. Treatment is aimed at eliminating clonal plasma cell populations to decrease the production of light chains, thereby decreasing protein burden and amyloid progression. Historically, treatment options included cytotoxic chemotherapy such as oral melphalan and dexamethasone, followed by hematopoietic stem cell transplant. More recent treatment options include bortezomib, thalidomide, pomalidomide, and lenalidomide.⁸ Our patient received a regimen of bortezomib, cyclophosphamide, and dexamethasone that is used for patients with extensive multiple myeloma.  

The differential diagnosis in our patient included bullous drug eruption, which should be considered if the bullae are reoccurring at the same location and in association with the administration of a culprit drug. Bullous pemphigoid is preceded by pruritus, and biopsy demonstrates subepidermal bullae with associated eosinophilic infiltrate. Epidermolysis bullosa acquisita can present with milia and a linear pattern along the basement membrane zone with direct immunofluorescence. Traumatic purpura usually present with the classic shape and hue of an ecchymosis, and the patient will have a history of trauma. 

Cutaneous involvement of amyloidosis can be an early clue to the diagnosis of plasma cell dyscrasia. Early diagnosis and treatment can portend a better prognosis and prevent progression to renal or cardiac disease. 

The Diagnosis: Bullous Amyloidosis 

A punch biopsy from the left temple showed deposits of amorphous eosinophilic material at the tips of dermal papillae and in the papillary dermis with hemorrhage present (Figure 1). A diagnosis of amyloidosis was confirmed on the biopsy of the skin bulla. The low κ/λ light chain ratio and M-spike with notably elevated free λ light chains in both serum and urine were consistent with a λ light chain primary systemic amyloidosis. The patient was seen by hematology and oncology. A bone marrow biopsy demonstrated that 15% to 20% of the clonal-cell population was λ light chain restricted. Eosinophilic extracellular deposits found in the adjacent soft tissue and bone marrow space were confirmed as amyloid with apple green birefringence under polarized light on Congo red stain and metachromatic staining with crystal violet. The patient ultimately was diagnosed with λ light chain multiple myeloma and primary systemic amyloidosis. 

Our patient was treated with a combination therapy of bortezomib, cyclophosphamide, and dexamethasone on 21-day cycles, with bortezomib on days 1, 4, 8, and 11. She had received 3 cycles of chemotherapy before developing diarrhea, hypotension, acute on chronic heart failure, and acute renal failure requiring hospitalization. She had several related complications due to amyloid light chain (AL) amyloidosis and subsequently died 16 days after her initial hospitalization from complications of methicillin-resistant Staphylococcus aureus bacteremia and septic shock. 

Amyloidosis is the pathologic deposition of abnormal protein in the extracellular space of any tissue. Various soluble precursor proteins can make up amyloid, and these proteins polymerize into insoluble fibrils that damage the surrounding parenchyma. The clinical presentation of amyloidosis varies depending on the affected tissue as well as the constituent protein. The amyloidoses are divided into localized cutaneous, primary systemic, and secondary systemic variants. The initial distinction in amyloidosis is determining whether it is skin limited or systemic. Localized cutaneous amyloidosis comprises 30% to 40% of all amyloidosis cases and is further divided into 3 main subtypes: macular, lichen, and nodular amyloidosis.¹ Macular and lichen amyloidosis are composed of keratin derivatives and typically are induced by patients when rubbing or scratching the skin. Histologically, macular and lichen amyloidosis are restricted to the superficial papillary dermis.¹ Nodular amyloidosis is composed of λ or κ light chain immunoglobulins, which are produced by cutaneous infiltrates of monoclonal plasma cells. Histologically, nodular amyloidosis is characterized by a diffuse dermal infiltrate of amorphous eosinophilic material.¹ Primary systemic amyloidosis is associated with an underlying plasma cell dyscrasia, and unlike secondary keratinocyte-derived amyloid, it can involve internal organs. Similar to nodular amyloidosis, primary systemic amyloidosis is composed of AL proteins, and it is histologically similar to nodular amyloidosis.¹ 

Primary systemic AL amyloidosis commonly affects individuals aged 50 to 60 years. Males and females are equally affected. Macroglossia and periorbital purpura are some of the pathognomonic presentations in AL amyloidosis. The major cause of death in these patients is cardiac and renal involvement. Renal involvement commonly presents as nephrotic syndrome, and cardiac involvement can present as a restrictive cardiomyopathy with dyspnea. Other symptoms include edema, hepatosplenomegaly, bleeding diathesis, and carpal tunnel syndrome.² An evaluation for AL amyloidosis should include a complete review of systems and physical examination with studies such as complete blood cell count, comprehensive metabolic panel, serum and urine protein electrophoresis and immunofixation, and electrocardiogram. 

Cutaneous involvement in AL amyloidosis most commonly includes yellowish waxy papules, nodules, and plaques but also can include purpura and petechiae.² Bullous amyloidosis, as seen in our patient, is a rare cutaneous presentation of AL amyloidosis that usually is negative for the Nikolsky sign (Figure 2). Bullae form due to weakness in amyloid-laden dermal connective tissue.³ Eighty-eight percent of cases of bullous amyloidosis have systemic involvement.¹ Some cases have reported a familial linkage, suggesting there might be a genetic component to the disease.⁴ A PubMed search of articles indexed for MEDLINE using the terms bullous amyloidosis, bullous, amyloidosis, and amyloid revealed fewer than 35 cases of bullous amyloidosis in the English-language literature.⁵ Bullae can be located intradermally or subepidermally and commonly are hemorrhagic but also can be translucent, tender, and tense. 

A study of electron microscopy in a patient with systemic bullous amyloidosis demonstrated amyloid and keratinocyte protrusions that perforated the dermis through the spaces in the lamina densa. The study concluded that the disintegration of the lamina densa and expansion of the intercellular spaces between keratinocytes were the causes of skin fragility as well as fluid exudation.⁵ Trauma or friction to the skin are local precipitating factors for blister formation in bullous amyloidosis.  

Bullae can become apparent at any stage of AL amyloidosis, but they generally increase in size and number over time and are most common in intertriginous areas. Bullous amyloid lesions, especially those located in intertriginous areas, can have secondary impetiginization.⁶ In many cases, patients who present with bullous amyloidosis ultimately will be diagnosed with multiple myeloma or another plasma cell dyscrasia. In AL amyloidosis, only 10% to 15% of cases meet criteria for multiple myeloma, whereas 80% or more patients have a monoclonal gammopathy of undetermined significance.⁷  

The prognosis of cutaneous amyloidosis depends on the extent of organ involvement and response to treatment. Treatment is aimed at eliminating clonal plasma cell populations to decrease the production of light chains, thereby decreasing protein burden and amyloid progression. Historically, treatment options included cytotoxic chemotherapy such as oral melphalan and dexamethasone, followed by hematopoietic stem cell transplant. More recent treatment options include bortezomib, thalidomide, pomalidomide, and lenalidomide.⁸ Our patient received a regimen of bortezomib, cyclophosphamide, and dexamethasone that is used for patients with extensive multiple myeloma.  

The differential diagnosis in our patient included bullous drug eruption, which should be considered if the bullae are reoccurring at the same location and in association with the administration of a culprit drug. Bullous pemphigoid is preceded by pruritus, and biopsy demonstrates subepidermal bullae with associated eosinophilic infiltrate. Epidermolysis bullosa acquisita can present with milia and a linear pattern along the basement membrane zone with direct immunofluorescence. Traumatic purpura usually present with the classic shape and hue of an ecchymosis, and the patient will have a history of trauma. 

Cutaneous involvement of amyloidosis can be an early clue to the diagnosis of plasma cell dyscrasia. Early diagnosis and treatment can portend a better prognosis and prevent progression to renal or cardiac disease.