Dermpath Diagnosis

The Diagnosis: Cutaneous Collagenous Vasculopathy 

Cutaneous collagenous vasculopathy (CCV) is an idiopathic microangiopathy of the small vessels in the superficial dermis. A condition first identified by Salama and Rosenthal¹ in 2000, CCV likely is underreported, as its clinical mimickers are not routinely biopsied.² It presents as asymptomatic telangiectatic macules, initially on the lower extremities and often spreading to the trunk. Cutaneous collagenous vasculopathy often is seen in middle-aged adults, and most patients have comorbidities such as hypertension, diabetes mellitus, or cardiovascular disease. The exact etiology of this disease is unknown.^3,4 

Histopathologically, CCV is characterized by dilated superficial vessels with thickened eosinophilic walls. The eosinophilic material is composed of hyalinized type IV collagen, which is periodic acid-Schiff positive and diastase resistant (Figure 1).^3,4 Stains for amyloid are negative.  

Generalized essential telangiectasia (GET) is a condition that presents with symmetric, blanchable, erythematous telangiectases.⁵ These lesions can occur alone or can accompany systemic diseases. Similar to CCV, the telangiectases tend to begin on the legs before gradually spreading to the trunk; however, this process more often is seen in females and occurs at an earlier age. Unlike CCV, GET can occur on mucosal surfaces, with cases of conjunctival and oral involvement reported.⁶ Generalized essential telangiectasia usually is a diagnosis of exclusion.^7,8 It is thought that many CCV lesions have been misclassified clinically as GET, which highlights the importance of biopsy. Microscopically, GET is distinct from CCV in that the superficial dermis lacks thick-walled vessels.^5,7 Although usually not associated with systemic diseases or progressive morbidity, treatment options are limited.⁸ 

Livedoid vasculopathy, also known as atrophie blanche, is caused by fibrin thrombi occlusion of dermal vessels. Clinically, patients have recurrent telangiectatic papules and painful ulcers on the lower extremities that gradually heal, leaving behind white stellate scars. It is caused by an underlying prothrombotic state with a superimposed inflammatory response.⁹ Livedoid vasculopathy primarily affects middle-aged women, and many patients have comorbidities such as scleroderma or systemic lupus erythematosus. Histologically, the epidermis often is ulcerated, and thrombi are visualized within small vessels. Eosinophilic fibrinoid material is deposited in vessel walls, including but not confined to vessels at the base of the epidermal ulcer (Figure 2). The fibrinoid material is periodic acid-Schiff positive and diastase resistant and can be highlighted with immunofluorescence, which may help to distinguish this entity from CCV.^1,9 As the disease progresses, vessels are diffusely hyalinized, and there is epidermal atrophy and dermal sclerosis. Treatment options include antiplatelet and fibrinolytic drugs with a multidisciplinary approach to resolve pain and scarring.⁹ 

Primary systemic amyloidosis is a rare condition, and cutaneous manifestations are seen in approximately one-third of affected individuals. Amyloid deposition results in waxy papules that predominantly affect the face and periorbital areas but also may occur on the neck, flexural areas, and genitalia.⁵ Because the amyloid deposits also can be found within vessel walls, hemorrhagic lesions may occur. Microscopically, amorphous eosinophilic material can be found within the vessel walls, similar to CCV (Figure 3A); however, when stained with Congo red, cutaneous amyloidosis shows waxy red-orange material involving the vessel walls and exhibits apple green birefringence under polarization (Figure 3B).¹⁰ Amyloid also will be negative for type IV collagen, fibronectin, and laminin, whereas CCV will be positive.⁵

The Diagnosis: Cutaneous Collagenous Vasculopathy 

Cutaneous collagenous vasculopathy (CCV) is an idiopathic microangiopathy of the small vessels in the superficial dermis. A condition first identified by Salama and Rosenthal¹ in 2000, CCV likely is underreported, as its clinical mimickers are not routinely biopsied.² It presents as asymptomatic telangiectatic macules, initially on the lower extremities and often spreading to the trunk. Cutaneous collagenous vasculopathy often is seen in middle-aged adults, and most patients have comorbidities such as hypertension, diabetes mellitus, or cardiovascular disease. The exact etiology of this disease is unknown.^3,4 

Histopathologically, CCV is characterized by dilated superficial vessels with thickened eosinophilic walls. The eosinophilic material is composed of hyalinized type IV collagen, which is periodic acid-Schiff positive and diastase resistant (Figure 1).^3,4 Stains for amyloid are negative.  

Generalized essential telangiectasia (GET) is a condition that presents with symmetric, blanchable, erythematous telangiectases.⁵ These lesions can occur alone or can accompany systemic diseases. Similar to CCV, the telangiectases tend to begin on the legs before gradually spreading to the trunk; however, this process more often is seen in females and occurs at an earlier age. Unlike CCV, GET can occur on mucosal surfaces, with cases of conjunctival and oral involvement reported.⁶ Generalized essential telangiectasia usually is a diagnosis of exclusion.^7,8 It is thought that many CCV lesions have been misclassified clinically as GET, which highlights the importance of biopsy. Microscopically, GET is distinct from CCV in that the superficial dermis lacks thick-walled vessels.^5,7 Although usually not associated with systemic diseases or progressive morbidity, treatment options are limited.⁸ 

Livedoid vasculopathy, also known as atrophie blanche, is caused by fibrin thrombi occlusion of dermal vessels. Clinically, patients have recurrent telangiectatic papules and painful ulcers on the lower extremities that gradually heal, leaving behind white stellate scars. It is caused by an underlying prothrombotic state with a superimposed inflammatory response.⁹ Livedoid vasculopathy primarily affects middle-aged women, and many patients have comorbidities such as scleroderma or systemic lupus erythematosus. Histologically, the epidermis often is ulcerated, and thrombi are visualized within small vessels. Eosinophilic fibrinoid material is deposited in vessel walls, including but not confined to vessels at the base of the epidermal ulcer (Figure 2). The fibrinoid material is periodic acid-Schiff positive and diastase resistant and can be highlighted with immunofluorescence, which may help to distinguish this entity from CCV.^1,9 As the disease progresses, vessels are diffusely hyalinized, and there is epidermal atrophy and dermal sclerosis. Treatment options include antiplatelet and fibrinolytic drugs with a multidisciplinary approach to resolve pain and scarring.⁹ 

Primary systemic amyloidosis is a rare condition, and cutaneous manifestations are seen in approximately one-third of affected individuals. Amyloid deposition results in waxy papules that predominantly affect the face and periorbital areas but also may occur on the neck, flexural areas, and genitalia.⁵ Because the amyloid deposits also can be found within vessel walls, hemorrhagic lesions may occur. Microscopically, amorphous eosinophilic material can be found within the vessel walls, similar to CCV (Figure 3A); however, when stained with Congo red, cutaneous amyloidosis shows waxy red-orange material involving the vessel walls and exhibits apple green birefringence under polarization (Figure 3B).¹⁰ Amyloid also will be negative for type IV collagen, fibronectin, and laminin, whereas CCV will be positive.⁵

The Diagnosis: Cutaneous Collagenous Vasculopathy 

Cutaneous collagenous vasculopathy (CCV) is an idiopathic microangiopathy of the small vessels in the superficial dermis. A condition first identified by Salama and Rosenthal¹ in 2000, CCV likely is underreported, as its clinical mimickers are not routinely biopsied.² It presents as asymptomatic telangiectatic macules, initially on the lower extremities and often spreading to the trunk. Cutaneous collagenous vasculopathy often is seen in middle-aged adults, and most patients have comorbidities such as hypertension, diabetes mellitus, or cardiovascular disease. The exact etiology of this disease is unknown.^3,4 

Histopathologically, CCV is characterized by dilated superficial vessels with thickened eosinophilic walls. The eosinophilic material is composed of hyalinized type IV collagen, which is periodic acid-Schiff positive and diastase resistant (Figure 1).^3,4 Stains for amyloid are negative.  

Generalized essential telangiectasia (GET) is a condition that presents with symmetric, blanchable, erythematous telangiectases.⁵ These lesions can occur alone or can accompany systemic diseases. Similar to CCV, the telangiectases tend to begin on the legs before gradually spreading to the trunk; however, this process more often is seen in females and occurs at an earlier age. Unlike CCV, GET can occur on mucosal surfaces, with cases of conjunctival and oral involvement reported.⁶ Generalized essential telangiectasia usually is a diagnosis of exclusion.^7,8 It is thought that many CCV lesions have been misclassified clinically as GET, which highlights the importance of biopsy. Microscopically, GET is distinct from CCV in that the superficial dermis lacks thick-walled vessels.^5,7 Although usually not associated with systemic diseases or progressive morbidity, treatment options are limited.⁸ 

Livedoid vasculopathy, also known as atrophie blanche, is caused by fibrin thrombi occlusion of dermal vessels. Clinically, patients have recurrent telangiectatic papules and painful ulcers on the lower extremities that gradually heal, leaving behind white stellate scars. It is caused by an underlying prothrombotic state with a superimposed inflammatory response.⁹ Livedoid vasculopathy primarily affects middle-aged women, and many patients have comorbidities such as scleroderma or systemic lupus erythematosus. Histologically, the epidermis often is ulcerated, and thrombi are visualized within small vessels. Eosinophilic fibrinoid material is deposited in vessel walls, including but not confined to vessels at the base of the epidermal ulcer (Figure 2). The fibrinoid material is periodic acid-Schiff positive and diastase resistant and can be highlighted with immunofluorescence, which may help to distinguish this entity from CCV.^1,9 As the disease progresses, vessels are diffusely hyalinized, and there is epidermal atrophy and dermal sclerosis. Treatment options include antiplatelet and fibrinolytic drugs with a multidisciplinary approach to resolve pain and scarring.⁹ 

Primary systemic amyloidosis is a rare condition, and cutaneous manifestations are seen in approximately one-third of affected individuals. Amyloid deposition results in waxy papules that predominantly affect the face and periorbital areas but also may occur on the neck, flexural areas, and genitalia.⁵ Because the amyloid deposits also can be found within vessel walls, hemorrhagic lesions may occur. Microscopically, amorphous eosinophilic material can be found within the vessel walls, similar to CCV (Figure 3A); however, when stained with Congo red, cutaneous amyloidosis shows waxy red-orange material involving the vessel walls and exhibits apple green birefringence under polarization (Figure 3B).¹⁰ Amyloid also will be negative for type IV collagen, fibronectin, and laminin, whereas CCV will be positive.⁵

The Diagnosis: Targetoid Hemosiderotic Hemangioma 

Targetoid hemosiderotic hemangioma (THH), also known as hobnail hemangioma, is a benign vascular tumor that usually occurs in young or middle-aged adults. It most commonly presents on the extremities or trunk as an isolated red-brown plaque or papule.^1,2 Histologically, THH is characterized by superficial dilated ectatic vessels with underlying proliferating vascular channels lined by plump hobnail endothelial cells.¹ Targetoid hemosiderotic hemangioma typically involves the dermis and spares the subcutis. The vascular channels may contain erythrocytes as well as pale eosinophilic lymph, as seen in our patient (quiz image). The deeper dermis contains vascular spaces that are more angulated and smaller and appear to be dissecting through the collagen bundles or collapsed.^1,3 A variable amount of hemosiderin deposition and extravasated erythrocytes are seen.^2,3 Histologic features evolve with the age of the lesion. Increasing amounts of hemosiderin deposition and erythrocyte extravasation may correspond histologically to the recent clinical color change reported by the patient.  

Verrucous hemangioma is a rare congenital vascular abnormality that is characterized by dilated vessels in the papillary dermis along with acanthosis, hyperkeratosis, and irregular papillomatosis, as seen in angiokeratoma.⁴ However, the vascular proliferation composed of variably sized, thin-walled capillaries extends into the deep dermis as well as the subcutis (Figure 1). Verrucous hemangioma most commonly is reported on the legs and generally starts as a violaceous patch that progresses into a hyperkeratotic verrucous plaque or nodule.^5,6  

Angiokeratoma is characterized by superficial vascular ectasia of the papillary dermis in association with overlying acanthosis, hyperkeratosis, and rete elongation.⁷ The dilated vascular spaces appear encircled by the epidermis (Figure 2). Intravascular thrombosis can be seen within the ectatic vessels.⁷ In contrast to verrucous hemangioma, angiokeratoma is limited to the papillary dermis. Therefore, obtaining a biopsy of sufficient depth is necessary for differentiation.⁸ There are 5 clinical presentations of angiokeratoma: sporadic, angiokeratoma of Mibelli, angiokeratoma of Fordyce, angiokeratoma circumscriptum, and angiokeratoma corporis diffusum (Fabry disease). Angiokeratomas may present on the lower extremities, tongue, trunk, and scrotum as hyperkeratotic, dark red to purple or black papules.⁷ 

There are 3 clinical stages of Kaposi sarcoma: patch, plaque, and nodular stages. The patch stage is characterized histologically by vascular channels that dissect through the dermis and extend around native vessels (the promontory sign)(Figure 3).^9,10 These features can show histologic overlap with THH. The plaque stage shows a more diffuse dermal vascular proliferation, increased cellularity of spindle cells, and possible extension into the subcutis.^9,10 Focal plasma cells, hemosiderin, and extravasated red blood cells can be seen. The nodular stage is characterized by a proliferation of spindle cells with red blood cells squeezed between slitlike vascular spaces, hyaline globules, and scattered mitotic figures, but not atypical forms.¹⁰ In this stage, plasma cells and hemosiderin are more readily identifiable. A biopsy from the nodular stage is unlikely to enter the histologic differential diagnosis with THH. Clinically, there are 4 variants of Kaposi sarcoma: the classic or sporadic form, an endemic form, iatrogenic, and AIDS associated. Overall, it is more common in males and can occur at any age.¹⁰ Human herpesvirus 8 is seen in all forms, and infected cells can be highlighted by the immunohistochemical stain for latent nuclear antigen 1.^9,10 

Angiosarcoma is a malignant endothelial tumor of soft tissue, skin, bone, and visceral organs.^11,12 Clinically, cutaneous angiosarcoma can present in a variety of ways, including single or multiple bluish red lesions that can ulcerate or bleed; violaceous nodules or plaques; and hematomalike lesions that can mimic epithelial neoplasms including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma.^11,13,14 The cutaneous lesions most commonly occur on sun-exposed skin, particularly on the face and scalp.¹² Other clinical variants that are important to recognize are postradiation angiosarcoma, characterized by MYC gene amplification, and lymphedema-associated angiosarcoma (Stewart-Treves syndrome). Angiosarcoma can have a variety of morphologic features, ranging from well to poorly differentiated. Classically, angiosarcoma is characterized by infiltrating vascular spaces lined by atypical endothelial cells (Figure 4). Poorly differentiated angiosarcoma can demonstrate spindle, epithelioid, or polygonal cells with increased mitotic activity, pleomorphism, and irregular vascular spaces.¹¹ Endothelial markers such as ERG (erythroblast transformation specific-related gene)(nuclear) and CD31 (membranous) can be used to aid in the diagnosis of a poorly differentiated lesion. Epithelioid angiosarcoma also occasionally stains with cytokeratins.^13,14  

The Diagnosis: Targetoid Hemosiderotic Hemangioma 

Targetoid hemosiderotic hemangioma (THH), also known as hobnail hemangioma, is a benign vascular tumor that usually occurs in young or middle-aged adults. It most commonly presents on the extremities or trunk as an isolated red-brown plaque or papule.^1,2 Histologically, THH is characterized by superficial dilated ectatic vessels with underlying proliferating vascular channels lined by plump hobnail endothelial cells.¹ Targetoid hemosiderotic hemangioma typically involves the dermis and spares the subcutis. The vascular channels may contain erythrocytes as well as pale eosinophilic lymph, as seen in our patient (quiz image). The deeper dermis contains vascular spaces that are more angulated and smaller and appear to be dissecting through the collagen bundles or collapsed.^1,3 A variable amount of hemosiderin deposition and extravasated erythrocytes are seen.^2,3 Histologic features evolve with the age of the lesion. Increasing amounts of hemosiderin deposition and erythrocyte extravasation may correspond histologically to the recent clinical color change reported by the patient.  

Verrucous hemangioma is a rare congenital vascular abnormality that is characterized by dilated vessels in the papillary dermis along with acanthosis, hyperkeratosis, and irregular papillomatosis, as seen in angiokeratoma.⁴ However, the vascular proliferation composed of variably sized, thin-walled capillaries extends into the deep dermis as well as the subcutis (Figure 1). Verrucous hemangioma most commonly is reported on the legs and generally starts as a violaceous patch that progresses into a hyperkeratotic verrucous plaque or nodule.^5,6  

Angiokeratoma is characterized by superficial vascular ectasia of the papillary dermis in association with overlying acanthosis, hyperkeratosis, and rete elongation.⁷ The dilated vascular spaces appear encircled by the epidermis (Figure 2). Intravascular thrombosis can be seen within the ectatic vessels.⁷ In contrast to verrucous hemangioma, angiokeratoma is limited to the papillary dermis. Therefore, obtaining a biopsy of sufficient depth is necessary for differentiation.⁸ There are 5 clinical presentations of angiokeratoma: sporadic, angiokeratoma of Mibelli, angiokeratoma of Fordyce, angiokeratoma circumscriptum, and angiokeratoma corporis diffusum (Fabry disease). Angiokeratomas may present on the lower extremities, tongue, trunk, and scrotum as hyperkeratotic, dark red to purple or black papules.⁷ 

There are 3 clinical stages of Kaposi sarcoma: patch, plaque, and nodular stages. The patch stage is characterized histologically by vascular channels that dissect through the dermis and extend around native vessels (the promontory sign)(Figure 3).^9,10 These features can show histologic overlap with THH. The plaque stage shows a more diffuse dermal vascular proliferation, increased cellularity of spindle cells, and possible extension into the subcutis.^9,10 Focal plasma cells, hemosiderin, and extravasated red blood cells can be seen. The nodular stage is characterized by a proliferation of spindle cells with red blood cells squeezed between slitlike vascular spaces, hyaline globules, and scattered mitotic figures, but not atypical forms.¹⁰ In this stage, plasma cells and hemosiderin are more readily identifiable. A biopsy from the nodular stage is unlikely to enter the histologic differential diagnosis with THH. Clinically, there are 4 variants of Kaposi sarcoma: the classic or sporadic form, an endemic form, iatrogenic, and AIDS associated. Overall, it is more common in males and can occur at any age.¹⁰ Human herpesvirus 8 is seen in all forms, and infected cells can be highlighted by the immunohistochemical stain for latent nuclear antigen 1.^9,10 

Angiosarcoma is a malignant endothelial tumor of soft tissue, skin, bone, and visceral organs.^11,12 Clinically, cutaneous angiosarcoma can present in a variety of ways, including single or multiple bluish red lesions that can ulcerate or bleed; violaceous nodules or plaques; and hematomalike lesions that can mimic epithelial neoplasms including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma.^11,13,14 The cutaneous lesions most commonly occur on sun-exposed skin, particularly on the face and scalp.¹² Other clinical variants that are important to recognize are postradiation angiosarcoma, characterized by MYC gene amplification, and lymphedema-associated angiosarcoma (Stewart-Treves syndrome). Angiosarcoma can have a variety of morphologic features, ranging from well to poorly differentiated. Classically, angiosarcoma is characterized by infiltrating vascular spaces lined by atypical endothelial cells (Figure 4). Poorly differentiated angiosarcoma can demonstrate spindle, epithelioid, or polygonal cells with increased mitotic activity, pleomorphism, and irregular vascular spaces.¹¹ Endothelial markers such as ERG (erythroblast transformation specific-related gene)(nuclear) and CD31 (membranous) can be used to aid in the diagnosis of a poorly differentiated lesion. Epithelioid angiosarcoma also occasionally stains with cytokeratins.^13,14  

The Diagnosis: Targetoid Hemosiderotic Hemangioma 

Targetoid hemosiderotic hemangioma (THH), also known as hobnail hemangioma, is a benign vascular tumor that usually occurs in young or middle-aged adults. It most commonly presents on the extremities or trunk as an isolated red-brown plaque or papule.^1,2 Histologically, THH is characterized by superficial dilated ectatic vessels with underlying proliferating vascular channels lined by plump hobnail endothelial cells.¹ Targetoid hemosiderotic hemangioma typically involves the dermis and spares the subcutis. The vascular channels may contain erythrocytes as well as pale eosinophilic lymph, as seen in our patient (quiz image). The deeper dermis contains vascular spaces that are more angulated and smaller and appear to be dissecting through the collagen bundles or collapsed.^1,3 A variable amount of hemosiderin deposition and extravasated erythrocytes are seen.^2,3 Histologic features evolve with the age of the lesion. Increasing amounts of hemosiderin deposition and erythrocyte extravasation may correspond histologically to the recent clinical color change reported by the patient.  

Verrucous hemangioma is a rare congenital vascular abnormality that is characterized by dilated vessels in the papillary dermis along with acanthosis, hyperkeratosis, and irregular papillomatosis, as seen in angiokeratoma.⁴ However, the vascular proliferation composed of variably sized, thin-walled capillaries extends into the deep dermis as well as the subcutis (Figure 1). Verrucous hemangioma most commonly is reported on the legs and generally starts as a violaceous patch that progresses into a hyperkeratotic verrucous plaque or nodule.^5,6  

Angiokeratoma is characterized by superficial vascular ectasia of the papillary dermis in association with overlying acanthosis, hyperkeratosis, and rete elongation.⁷ The dilated vascular spaces appear encircled by the epidermis (Figure 2). Intravascular thrombosis can be seen within the ectatic vessels.⁷ In contrast to verrucous hemangioma, angiokeratoma is limited to the papillary dermis. Therefore, obtaining a biopsy of sufficient depth is necessary for differentiation.⁸ There are 5 clinical presentations of angiokeratoma: sporadic, angiokeratoma of Mibelli, angiokeratoma of Fordyce, angiokeratoma circumscriptum, and angiokeratoma corporis diffusum (Fabry disease). Angiokeratomas may present on the lower extremities, tongue, trunk, and scrotum as hyperkeratotic, dark red to purple or black papules.⁷ 

There are 3 clinical stages of Kaposi sarcoma: patch, plaque, and nodular stages. The patch stage is characterized histologically by vascular channels that dissect through the dermis and extend around native vessels (the promontory sign)(Figure 3).^9,10 These features can show histologic overlap with THH. The plaque stage shows a more diffuse dermal vascular proliferation, increased cellularity of spindle cells, and possible extension into the subcutis.^9,10 Focal plasma cells, hemosiderin, and extravasated red blood cells can be seen. The nodular stage is characterized by a proliferation of spindle cells with red blood cells squeezed between slitlike vascular spaces, hyaline globules, and scattered mitotic figures, but not atypical forms.¹⁰ In this stage, plasma cells and hemosiderin are more readily identifiable. A biopsy from the nodular stage is unlikely to enter the histologic differential diagnosis with THH. Clinically, there are 4 variants of Kaposi sarcoma: the classic or sporadic form, an endemic form, iatrogenic, and AIDS associated. Overall, it is more common in males and can occur at any age.¹⁰ Human herpesvirus 8 is seen in all forms, and infected cells can be highlighted by the immunohistochemical stain for latent nuclear antigen 1.^9,10 

Angiosarcoma is a malignant endothelial tumor of soft tissue, skin, bone, and visceral organs.^11,12 Clinically, cutaneous angiosarcoma can present in a variety of ways, including single or multiple bluish red lesions that can ulcerate or bleed; violaceous nodules or plaques; and hematomalike lesions that can mimic epithelial neoplasms including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma.^11,13,14 The cutaneous lesions most commonly occur on sun-exposed skin, particularly on the face and scalp.¹² Other clinical variants that are important to recognize are postradiation angiosarcoma, characterized by MYC gene amplification, and lymphedema-associated angiosarcoma (Stewart-Treves syndrome). Angiosarcoma can have a variety of morphologic features, ranging from well to poorly differentiated. Classically, angiosarcoma is characterized by infiltrating vascular spaces lined by atypical endothelial cells (Figure 4). Poorly differentiated angiosarcoma can demonstrate spindle, epithelioid, or polygonal cells with increased mitotic activity, pleomorphism, and irregular vascular spaces.¹¹ Endothelial markers such as ERG (erythroblast transformation specific-related gene)(nuclear) and CD31 (membranous) can be used to aid in the diagnosis of a poorly differentiated lesion. Epithelioid angiosarcoma also occasionally stains with cytokeratins.^13,14  

The Diagnosis: Subcutaneous Panniculitislike T-cell Lymphoma 

Subcutaneous panniculitislike T-cell lymphoma (SPTCL) is a rare form of cutaneous lymphoma of mature cytotoxic T cells simulating panniculitis and preferentially infiltrating the subcutaneous tissue.¹ Subcutaneous panniculitislike T-cell lymphoma can affect all ages but predominantly affects younger individuals, with 20% being younger than 20 years.² It is a rare lymphoma that accounts for less than 1% of all non-Hodgkin lymphomas.³ It presents clinically as multiple subcutaneous masses, nodules, or plaques generally on the trunk or extremities.^1,2 The skin surrounding the nodules may be erythematous, and the nodules may become necrotic; however, ulceration typically is not seen. Systemic symptoms such as fever, night sweats, and chills are present in half of cases.¹ According to the World Health Organization, cytopenia and elevated liver function tests are common, and a hemophagocytic syndrome may be present in 15% to 20% of cases.³ The presence of a hemophagocytic syndrome yields a poor prognosis.^1,3 Current guidelines denote that SPTCL T-cell receptor (TCR) αβ; is a distinct entity from the TCRγδ; phenotype, known as cutaneous γδ-positive T-cell lymphoma.^3,4 Cutaneous γδ-positive T-cell lymphoma is associated with rapid decline and a worse prognosis.⁴  

Histology of SPTCL is characteristic for a lobular panniculitislike infiltrate.¹ The heavy subcutaneous lymphoid infiltrate is composed of atypical small- to medium-sized lymphocytes with mature chromatin and inconspicuous nucleoli lining adipocytes. The dense inflammatory infiltrate composed predominantly of neoplastic T cells and macrophages may diffusely invade into the subcutaneous tissue.¹ Admixed histocytes and karyorrhectic debris as well as rimming of the lymphocytes around the fat cells is typical and was seen in our patient (quiz image). The T cells of SPTCL have the following immunophenotype: TCR-beta F1⁺, CD3⁺, CD4^-, CD8⁺, CD56^-. They can express numerous cytotoxic proteins, such as T1a-1, granzyme B, and perforin.^2,3 Although the CD8⁺ T cells may be sparse, they generally surround the adipocytes in a rimming manner and may distort the adipocyte membrane.¹  

Lupus erythematosus profundus (LEP) is a form of chronic cutaneous lupus that affects the deep dermis and fat.⁵ It also can present clinically as tender plaques or nodules. It most frequently involves the upper arms, shoulders, face, or buttocks--areas that are less commonly involved in other panniculitides.⁶ Histologically, LEP is similar to chronic discoid lupus with features such as epidermal atrophy, interface changes, and a thickened basement membrane (Figure 1). Lupus erythematosus profundus can present as a lobular panniculitis with mucin as well as a superficial and deep lymphocytic infiltrate that can involve the septa.⁵ Some cases of LEP have a predominantly lobular lymphocytic panniculitis in the absence of the typical epidermal or dermal changes of lupus erythematosus. Lymphoid follicles with germinal center formation are present in half of cases and reportedly are characteristic of LEP.^6,7 The lymphoid follicles often have plasma cells, can extend into the septa as well as in between collagen bundles, and may have nuclear fragmentation.⁵ Another characteristic feature of LEP is hyaline sclerosis of lobules with focal extension into the interlobular septa. Immunofluorescence studies usually show linear deposition of IgM and C3 at the dermoepidermal junction. Antinuclear antibodies can be present in patients who have LEP but are not entirely specific.⁶  

Lupus erythematosus profundus and SPTCL are part of a spectrum and may have overlapping clinical and histopathologic characteristics; therefore, distinguishing them may be difficult.^6-8 It is important to monitor these patients closely, as their disease may progress to lymphoma.⁶ Patients with SPTCL are more likely to present with advanced symptoms such as fever and hepatosplenomegaly and to succumb to hemophagocytic syndrome than patients with LEP.⁹  

Although SPTCL usually is clonal, several cases of LEP with clonality also have been described. Clonal LEP cases generally are identified in patients who present with fever and cytopenia.⁸ Lymphoid atypia and morphologic abnormalities may be seen in cases of LEP, further complicating the distinction between LEP and SPTCL. An elevated Ki67 level may be seen in cases of SPTCL with periadipocytic rimming.⁹ LeBlanc et al¹⁰ used Ki67 "hot spots" along with CD8 immunohistochemistry to identify atypical lymphocytes associated with SPTCL. Lymphocyte rimming was defined by the presence of CD8⁺ lymphocytes with an elevated Ki67 index. Clinical, histopathologic, and molecular findings all should be used when dealing with challenging cases.  

Fat necrosis can occur in any part of the body where trauma has occurred and can be associated with many disease processes. Patients typically present with a palpable mass, but a clinical history of trauma is not always present. Histopathologic findings include necrotic fat alongside lipid-laden foamy macrophages and scattered inflammatory cells (Figure 2).¹¹ Fragments of normal as well as degenerating adipose tissue and multinucleated giant cells can be present.  

Erythema nodosum (EN) is the most frequently encountered panniculitis and usually is seen in women in early adulthood.¹² Patients present with several tender subcutaneous nodules and plaques that most commonly are present on the anterior surface of the legs.^12,13 Patients may have a constellation of symptoms including fever and leukocytosis, but the disorder generally is self-limited.¹² Erythema nodosum may be associated with a variety of diseases or infections including sarcoidosis, inflammatory bowel disease, and malignancy.¹⁴ The etiology of EN is diverse; therefore, a proper clinical workup may be necessary. Histopathology is that of a septal panniculitis with lymphocytes, histiocytes, and occasional eosinophils (Figure 3).¹³  

Lipodermatosclerosis also occurs on the legs, most commonly in patients with venous insufficiency.^12,15 Patients present clinically with pain, induration, redness, or swelling of the legs. Histopathology predominantly is characterized by membranous fat necrosis, fibrosis, and fatty microcysts that may be lined by a thickened hyaline membrane (Figure 4). Lipodermatosclerosis lesions generally do not resolve spontaneously and may need to be treated.¹⁶ 

The Diagnosis: Subcutaneous Panniculitislike T-cell Lymphoma 

Subcutaneous panniculitislike T-cell lymphoma (SPTCL) is a rare form of cutaneous lymphoma of mature cytotoxic T cells simulating panniculitis and preferentially infiltrating the subcutaneous tissue.¹ Subcutaneous panniculitislike T-cell lymphoma can affect all ages but predominantly affects younger individuals, with 20% being younger than 20 years.² It is a rare lymphoma that accounts for less than 1% of all non-Hodgkin lymphomas.³ It presents clinically as multiple subcutaneous masses, nodules, or plaques generally on the trunk or extremities.^1,2 The skin surrounding the nodules may be erythematous, and the nodules may become necrotic; however, ulceration typically is not seen. Systemic symptoms such as fever, night sweats, and chills are present in half of cases.¹ According to the World Health Organization, cytopenia and elevated liver function tests are common, and a hemophagocytic syndrome may be present in 15% to 20% of cases.³ The presence of a hemophagocytic syndrome yields a poor prognosis.^1,3 Current guidelines denote that SPTCL T-cell receptor (TCR) αβ; is a distinct entity from the TCRγδ; phenotype, known as cutaneous γδ-positive T-cell lymphoma.^3,4 Cutaneous γδ-positive T-cell lymphoma is associated with rapid decline and a worse prognosis.⁴  

Histology of SPTCL is characteristic for a lobular panniculitislike infiltrate.¹ The heavy subcutaneous lymphoid infiltrate is composed of atypical small- to medium-sized lymphocytes with mature chromatin and inconspicuous nucleoli lining adipocytes. The dense inflammatory infiltrate composed predominantly of neoplastic T cells and macrophages may diffusely invade into the subcutaneous tissue.¹ Admixed histocytes and karyorrhectic debris as well as rimming of the lymphocytes around the fat cells is typical and was seen in our patient (quiz image). The T cells of SPTCL have the following immunophenotype: TCR-beta F1⁺, CD3⁺, CD4^-, CD8⁺, CD56^-. They can express numerous cytotoxic proteins, such as T1a-1, granzyme B, and perforin.^2,3 Although the CD8⁺ T cells may be sparse, they generally surround the adipocytes in a rimming manner and may distort the adipocyte membrane.¹  

Lupus erythematosus profundus (LEP) is a form of chronic cutaneous lupus that affects the deep dermis and fat.⁵ It also can present clinically as tender plaques or nodules. It most frequently involves the upper arms, shoulders, face, or buttocks--areas that are less commonly involved in other panniculitides.⁶ Histologically, LEP is similar to chronic discoid lupus with features such as epidermal atrophy, interface changes, and a thickened basement membrane (Figure 1). Lupus erythematosus profundus can present as a lobular panniculitis with mucin as well as a superficial and deep lymphocytic infiltrate that can involve the septa.⁵ Some cases of LEP have a predominantly lobular lymphocytic panniculitis in the absence of the typical epidermal or dermal changes of lupus erythematosus. Lymphoid follicles with germinal center formation are present in half of cases and reportedly are characteristic of LEP.^6,7 The lymphoid follicles often have plasma cells, can extend into the septa as well as in between collagen bundles, and may have nuclear fragmentation.⁵ Another characteristic feature of LEP is hyaline sclerosis of lobules with focal extension into the interlobular septa. Immunofluorescence studies usually show linear deposition of IgM and C3 at the dermoepidermal junction. Antinuclear antibodies can be present in patients who have LEP but are not entirely specific.⁶  

Lupus erythematosus profundus and SPTCL are part of a spectrum and may have overlapping clinical and histopathologic characteristics; therefore, distinguishing them may be difficult.^6-8 It is important to monitor these patients closely, as their disease may progress to lymphoma.⁶ Patients with SPTCL are more likely to present with advanced symptoms such as fever and hepatosplenomegaly and to succumb to hemophagocytic syndrome than patients with LEP.⁹  

Although SPTCL usually is clonal, several cases of LEP with clonality also have been described. Clonal LEP cases generally are identified in patients who present with fever and cytopenia.⁸ Lymphoid atypia and morphologic abnormalities may be seen in cases of LEP, further complicating the distinction between LEP and SPTCL. An elevated Ki67 level may be seen in cases of SPTCL with periadipocytic rimming.⁹ LeBlanc et al¹⁰ used Ki67 "hot spots" along with CD8 immunohistochemistry to identify atypical lymphocytes associated with SPTCL. Lymphocyte rimming was defined by the presence of CD8⁺ lymphocytes with an elevated Ki67 index. Clinical, histopathologic, and molecular findings all should be used when dealing with challenging cases.  

Fat necrosis can occur in any part of the body where trauma has occurred and can be associated with many disease processes. Patients typically present with a palpable mass, but a clinical history of trauma is not always present. Histopathologic findings include necrotic fat alongside lipid-laden foamy macrophages and scattered inflammatory cells (Figure 2).¹¹ Fragments of normal as well as degenerating adipose tissue and multinucleated giant cells can be present.  

Erythema nodosum (EN) is the most frequently encountered panniculitis and usually is seen in women in early adulthood.¹² Patients present with several tender subcutaneous nodules and plaques that most commonly are present on the anterior surface of the legs.^12,13 Patients may have a constellation of symptoms including fever and leukocytosis, but the disorder generally is self-limited.¹² Erythema nodosum may be associated with a variety of diseases or infections including sarcoidosis, inflammatory bowel disease, and malignancy.¹⁴ The etiology of EN is diverse; therefore, a proper clinical workup may be necessary. Histopathology is that of a septal panniculitis with lymphocytes, histiocytes, and occasional eosinophils (Figure 3).¹³  

Lipodermatosclerosis also occurs on the legs, most commonly in patients with venous insufficiency.^12,15 Patients present clinically with pain, induration, redness, or swelling of the legs. Histopathology predominantly is characterized by membranous fat necrosis, fibrosis, and fatty microcysts that may be lined by a thickened hyaline membrane (Figure 4). Lipodermatosclerosis lesions generally do not resolve spontaneously and may need to be treated.¹⁶ 

The Diagnosis: Subcutaneous Panniculitislike T-cell Lymphoma 

Subcutaneous panniculitislike T-cell lymphoma (SPTCL) is a rare form of cutaneous lymphoma of mature cytotoxic T cells simulating panniculitis and preferentially infiltrating the subcutaneous tissue.¹ Subcutaneous panniculitislike T-cell lymphoma can affect all ages but predominantly affects younger individuals, with 20% being younger than 20 years.² It is a rare lymphoma that accounts for less than 1% of all non-Hodgkin lymphomas.³ It presents clinically as multiple subcutaneous masses, nodules, or plaques generally on the trunk or extremities.^1,2 The skin surrounding the nodules may be erythematous, and the nodules may become necrotic; however, ulceration typically is not seen. Systemic symptoms such as fever, night sweats, and chills are present in half of cases.¹ According to the World Health Organization, cytopenia and elevated liver function tests are common, and a hemophagocytic syndrome may be present in 15% to 20% of cases.³ The presence of a hemophagocytic syndrome yields a poor prognosis.^1,3 Current guidelines denote that SPTCL T-cell receptor (TCR) αβ; is a distinct entity from the TCRγδ; phenotype, known as cutaneous γδ-positive T-cell lymphoma.^3,4 Cutaneous γδ-positive T-cell lymphoma is associated with rapid decline and a worse prognosis.⁴  

Histology of SPTCL is characteristic for a lobular panniculitislike infiltrate.¹ The heavy subcutaneous lymphoid infiltrate is composed of atypical small- to medium-sized lymphocytes with mature chromatin and inconspicuous nucleoli lining adipocytes. The dense inflammatory infiltrate composed predominantly of neoplastic T cells and macrophages may diffusely invade into the subcutaneous tissue.¹ Admixed histocytes and karyorrhectic debris as well as rimming of the lymphocytes around the fat cells is typical and was seen in our patient (quiz image). The T cells of SPTCL have the following immunophenotype: TCR-beta F1⁺, CD3⁺, CD4^-, CD8⁺, CD56^-. They can express numerous cytotoxic proteins, such as T1a-1, granzyme B, and perforin.^2,3 Although the CD8⁺ T cells may be sparse, they generally surround the adipocytes in a rimming manner and may distort the adipocyte membrane.¹  

Lupus erythematosus profundus (LEP) is a form of chronic cutaneous lupus that affects the deep dermis and fat.⁵ It also can present clinically as tender plaques or nodules. It most frequently involves the upper arms, shoulders, face, or buttocks--areas that are less commonly involved in other panniculitides.⁶ Histologically, LEP is similar to chronic discoid lupus with features such as epidermal atrophy, interface changes, and a thickened basement membrane (Figure 1). Lupus erythematosus profundus can present as a lobular panniculitis with mucin as well as a superficial and deep lymphocytic infiltrate that can involve the septa.⁵ Some cases of LEP have a predominantly lobular lymphocytic panniculitis in the absence of the typical epidermal or dermal changes of lupus erythematosus. Lymphoid follicles with germinal center formation are present in half of cases and reportedly are characteristic of LEP.^6,7 The lymphoid follicles often have plasma cells, can extend into the septa as well as in between collagen bundles, and may have nuclear fragmentation.⁵ Another characteristic feature of LEP is hyaline sclerosis of lobules with focal extension into the interlobular septa. Immunofluorescence studies usually show linear deposition of IgM and C3 at the dermoepidermal junction. Antinuclear antibodies can be present in patients who have LEP but are not entirely specific.⁶  

Lupus erythematosus profundus and SPTCL are part of a spectrum and may have overlapping clinical and histopathologic characteristics; therefore, distinguishing them may be difficult.^6-8 It is important to monitor these patients closely, as their disease may progress to lymphoma.⁶ Patients with SPTCL are more likely to present with advanced symptoms such as fever and hepatosplenomegaly and to succumb to hemophagocytic syndrome than patients with LEP.⁹  

Although SPTCL usually is clonal, several cases of LEP with clonality also have been described. Clonal LEP cases generally are identified in patients who present with fever and cytopenia.⁸ Lymphoid atypia and morphologic abnormalities may be seen in cases of LEP, further complicating the distinction between LEP and SPTCL. An elevated Ki67 level may be seen in cases of SPTCL with periadipocytic rimming.⁹ LeBlanc et al¹⁰ used Ki67 "hot spots" along with CD8 immunohistochemistry to identify atypical lymphocytes associated with SPTCL. Lymphocyte rimming was defined by the presence of CD8⁺ lymphocytes with an elevated Ki67 index. Clinical, histopathologic, and molecular findings all should be used when dealing with challenging cases.  

Fat necrosis can occur in any part of the body where trauma has occurred and can be associated with many disease processes. Patients typically present with a palpable mass, but a clinical history of trauma is not always present. Histopathologic findings include necrotic fat alongside lipid-laden foamy macrophages and scattered inflammatory cells (Figure 2).¹¹ Fragments of normal as well as degenerating adipose tissue and multinucleated giant cells can be present.  

Erythema nodosum (EN) is the most frequently encountered panniculitis and usually is seen in women in early adulthood.¹² Patients present with several tender subcutaneous nodules and plaques that most commonly are present on the anterior surface of the legs.^12,13 Patients may have a constellation of symptoms including fever and leukocytosis, but the disorder generally is self-limited.¹² Erythema nodosum may be associated with a variety of diseases or infections including sarcoidosis, inflammatory bowel disease, and malignancy.¹⁴ The etiology of EN is diverse; therefore, a proper clinical workup may be necessary. Histopathology is that of a septal panniculitis with lymphocytes, histiocytes, and occasional eosinophils (Figure 3).¹³  

Lipodermatosclerosis also occurs on the legs, most commonly in patients with venous insufficiency.^12,15 Patients present clinically with pain, induration, redness, or swelling of the legs. Histopathology predominantly is characterized by membranous fat necrosis, fibrosis, and fatty microcysts that may be lined by a thickened hyaline membrane (Figure 4). Lipodermatosclerosis lesions generally do not resolve spontaneously and may need to be treated.¹⁶ 

The Diagnosis: Subcutaneous Granuloma Annulare 

Subcutaneous granuloma annulare (SGA), also known as deep GA, is a rare variant of GA that usually occurs in children and young adults. It presents as single or multiple, nontender, deep dermal and/or subcutaneous nodules with normal-appearing skin usually on the anterior lower legs, dorsal aspects of the hands and fingers, scalp, or buttocks.^1-3 The pathogenesis of SGA as well as GA is not fully understood, and proposed inciting factors include trauma, insect bite reactions, tuberculin skin testing, vaccines, UV exposure, medications, and viral infections.^3-6 A cell-mediated, delayed-type hypersensitivity reaction to an unknown antigen also has been postulated as a possible mechanism.⁷ Treatment usually is not necessary, as the nature of the condition is benign and the course often is self-limited. Spontaneous resolution occurs within 2 years in 50% of patients with localized GA.^4,8 Surgery usually is not recommended due to the high recurrence rate (40%-75%).^4,9  

Absence of epidermal change in this entity obfuscates clinical recognition, and accurate diagnosis often depends on punch or excisional biopsies revealing characteristic histopathology. The histology of SGA consists of palisaded granulomas with central areas of necrobiosis composed of degenerated collagen, mucin deposition, and nuclear dust from neutrophils that extend into the deep dermis and subcutis.² The periphery of the granulomas is lined by palisading epithelioid histiocytes with occasional multinucleated giant cells.^10,11 Eosinophils often are present.¹² Colloidal iron and Alcian blue stains can be used to highlight the abundant connective tissue mucin of the granulomas.⁴  

The histologic differential diagnosis of SGA includes rheumatoid nodule, necrobiosis lipoidica, epithelioid sarcoma, and tophaceous gout.² Rheumatoid nodules are the most common dermatologic presentation of rheumatoid arthritis and are found in up to 30% to 40% of patients with the disease.^13-15 They present as firm, painless, subcutaneous papulonodules on the extensor surfaces and at sites of trauma or pressure. Histologically, rheumatoid nodules exhibit a homogenous and eosinophilic central area of necrobiosis with fibrin deposition and absent mucin deep within the dermis and subcutaneous tissue (Figure 1). In contrast, granulomas in SGA usually are pale and basophilic with abundant mucin.²  

Necrobiosis lipoidica is a rare chronic granulomatous disease of the skin that most commonly occurs in young to middle-aged adults and is strongly associated with diabetes mellitus.¹⁶ It clinically presents as yellow to red-brown papules and plaques with a peripheral erythematous to violaceous rim usually on the pretibial area. Over time, lesions become yellowish atrophic patches and plaques that sometimes can ulcerate. Histopathology reveals areas of horizontally arranged, palisaded, and interstitial granulomatous dermatitis intermixed with areas of degenerated collagen and widespread fibrosis extending from the superficial dermis into the subcutis (Figure 2).² These areas lack mucin and have an increased number of plasma cells. Eosinophils and/or lymphoid nodules occasionally can be seen.^17,18 

Epithelioid sarcoma is a rare malignant soft tissue sarcoma that tends to occur on the distal extremities in younger patients, typically aged 20 to 40 years, often with preceding trauma to the area. It usually presents as a solitary, poorly defined, hard, subcutaneous nodule. Histologic analysis shows central areas of necrosis and degenerated collagen surrounded by epithelioid and spindle cells with hyperchromatic and pleomorphic nuclei and mitoses (Figure 3).² These tumor cells express positivity for keratins, vimentin, epithelial membrane antigen, and CD34, while they usually are negative for desmin, S-100, and FLI-1 nuclear transcription factor.^2,4,19  

Tophaceous gout results from the accumulation of monosodium urate crystals in the skin. It clinically presents as firm, white-yellow, dermal and subcutaneous papulonodules on the helix of the ear and the skin overlying joints. Histopathology reveals palisaded granulomas surrounding an amorphous feathery material that corresponds to the urate crystals that were destroyed with formalin fixation (Figure 4). When the tissue is fixed with ethanol or is incompletely fixed in formalin, birefringent urate crystals are evident with polarization.²⁰

The Diagnosis: Subcutaneous Granuloma Annulare 

Subcutaneous granuloma annulare (SGA), also known as deep GA, is a rare variant of GA that usually occurs in children and young adults. It presents as single or multiple, nontender, deep dermal and/or subcutaneous nodules with normal-appearing skin usually on the anterior lower legs, dorsal aspects of the hands and fingers, scalp, or buttocks.^1-3 The pathogenesis of SGA as well as GA is not fully understood, and proposed inciting factors include trauma, insect bite reactions, tuberculin skin testing, vaccines, UV exposure, medications, and viral infections.^3-6 A cell-mediated, delayed-type hypersensitivity reaction to an unknown antigen also has been postulated as a possible mechanism.⁷ Treatment usually is not necessary, as the nature of the condition is benign and the course often is self-limited. Spontaneous resolution occurs within 2 years in 50% of patients with localized GA.^4,8 Surgery usually is not recommended due to the high recurrence rate (40%-75%).^4,9  

Absence of epidermal change in this entity obfuscates clinical recognition, and accurate diagnosis often depends on punch or excisional biopsies revealing characteristic histopathology. The histology of SGA consists of palisaded granulomas with central areas of necrobiosis composed of degenerated collagen, mucin deposition, and nuclear dust from neutrophils that extend into the deep dermis and subcutis.² The periphery of the granulomas is lined by palisading epithelioid histiocytes with occasional multinucleated giant cells.^10,11 Eosinophils often are present.¹² Colloidal iron and Alcian blue stains can be used to highlight the abundant connective tissue mucin of the granulomas.⁴  

The histologic differential diagnosis of SGA includes rheumatoid nodule, necrobiosis lipoidica, epithelioid sarcoma, and tophaceous gout.² Rheumatoid nodules are the most common dermatologic presentation of rheumatoid arthritis and are found in up to 30% to 40% of patients with the disease.^13-15 They present as firm, painless, subcutaneous papulonodules on the extensor surfaces and at sites of trauma or pressure. Histologically, rheumatoid nodules exhibit a homogenous and eosinophilic central area of necrobiosis with fibrin deposition and absent mucin deep within the dermis and subcutaneous tissue (Figure 1). In contrast, granulomas in SGA usually are pale and basophilic with abundant mucin.²  

Necrobiosis lipoidica is a rare chronic granulomatous disease of the skin that most commonly occurs in young to middle-aged adults and is strongly associated with diabetes mellitus.¹⁶ It clinically presents as yellow to red-brown papules and plaques with a peripheral erythematous to violaceous rim usually on the pretibial area. Over time, lesions become yellowish atrophic patches and plaques that sometimes can ulcerate. Histopathology reveals areas of horizontally arranged, palisaded, and interstitial granulomatous dermatitis intermixed with areas of degenerated collagen and widespread fibrosis extending from the superficial dermis into the subcutis (Figure 2).² These areas lack mucin and have an increased number of plasma cells. Eosinophils and/or lymphoid nodules occasionally can be seen.^17,18 

Epithelioid sarcoma is a rare malignant soft tissue sarcoma that tends to occur on the distal extremities in younger patients, typically aged 20 to 40 years, often with preceding trauma to the area. It usually presents as a solitary, poorly defined, hard, subcutaneous nodule. Histologic analysis shows central areas of necrosis and degenerated collagen surrounded by epithelioid and spindle cells with hyperchromatic and pleomorphic nuclei and mitoses (Figure 3).² These tumor cells express positivity for keratins, vimentin, epithelial membrane antigen, and CD34, while they usually are negative for desmin, S-100, and FLI-1 nuclear transcription factor.^2,4,19  

Tophaceous gout results from the accumulation of monosodium urate crystals in the skin. It clinically presents as firm, white-yellow, dermal and subcutaneous papulonodules on the helix of the ear and the skin overlying joints. Histopathology reveals palisaded granulomas surrounding an amorphous feathery material that corresponds to the urate crystals that were destroyed with formalin fixation (Figure 4). When the tissue is fixed with ethanol or is incompletely fixed in formalin, birefringent urate crystals are evident with polarization.²⁰

The Diagnosis: Subcutaneous Granuloma Annulare 

Subcutaneous granuloma annulare (SGA), also known as deep GA, is a rare variant of GA that usually occurs in children and young adults. It presents as single or multiple, nontender, deep dermal and/or subcutaneous nodules with normal-appearing skin usually on the anterior lower legs, dorsal aspects of the hands and fingers, scalp, or buttocks.^1-3 The pathogenesis of SGA as well as GA is not fully understood, and proposed inciting factors include trauma, insect bite reactions, tuberculin skin testing, vaccines, UV exposure, medications, and viral infections.^3-6 A cell-mediated, delayed-type hypersensitivity reaction to an unknown antigen also has been postulated as a possible mechanism.⁷ Treatment usually is not necessary, as the nature of the condition is benign and the course often is self-limited. Spontaneous resolution occurs within 2 years in 50% of patients with localized GA.^4,8 Surgery usually is not recommended due to the high recurrence rate (40%-75%).^4,9  

Absence of epidermal change in this entity obfuscates clinical recognition, and accurate diagnosis often depends on punch or excisional biopsies revealing characteristic histopathology. The histology of SGA consists of palisaded granulomas with central areas of necrobiosis composed of degenerated collagen, mucin deposition, and nuclear dust from neutrophils that extend into the deep dermis and subcutis.² The periphery of the granulomas is lined by palisading epithelioid histiocytes with occasional multinucleated giant cells.^10,11 Eosinophils often are present.¹² Colloidal iron and Alcian blue stains can be used to highlight the abundant connective tissue mucin of the granulomas.⁴  

The histologic differential diagnosis of SGA includes rheumatoid nodule, necrobiosis lipoidica, epithelioid sarcoma, and tophaceous gout.² Rheumatoid nodules are the most common dermatologic presentation of rheumatoid arthritis and are found in up to 30% to 40% of patients with the disease.^13-15 They present as firm, painless, subcutaneous papulonodules on the extensor surfaces and at sites of trauma or pressure. Histologically, rheumatoid nodules exhibit a homogenous and eosinophilic central area of necrobiosis with fibrin deposition and absent mucin deep within the dermis and subcutaneous tissue (Figure 1). In contrast, granulomas in SGA usually are pale and basophilic with abundant mucin.²  

Necrobiosis lipoidica is a rare chronic granulomatous disease of the skin that most commonly occurs in young to middle-aged adults and is strongly associated with diabetes mellitus.¹⁶ It clinically presents as yellow to red-brown papules and plaques with a peripheral erythematous to violaceous rim usually on the pretibial area. Over time, lesions become yellowish atrophic patches and plaques that sometimes can ulcerate. Histopathology reveals areas of horizontally arranged, palisaded, and interstitial granulomatous dermatitis intermixed with areas of degenerated collagen and widespread fibrosis extending from the superficial dermis into the subcutis (Figure 2).² These areas lack mucin and have an increased number of plasma cells. Eosinophils and/or lymphoid nodules occasionally can be seen.^17,18 

Epithelioid sarcoma is a rare malignant soft tissue sarcoma that tends to occur on the distal extremities in younger patients, typically aged 20 to 40 years, often with preceding trauma to the area. It usually presents as a solitary, poorly defined, hard, subcutaneous nodule. Histologic analysis shows central areas of necrosis and degenerated collagen surrounded by epithelioid and spindle cells with hyperchromatic and pleomorphic nuclei and mitoses (Figure 3).² These tumor cells express positivity for keratins, vimentin, epithelial membrane antigen, and CD34, while they usually are negative for desmin, S-100, and FLI-1 nuclear transcription factor.^2,4,19  

Tophaceous gout results from the accumulation of monosodium urate crystals in the skin. It clinically presents as firm, white-yellow, dermal and subcutaneous papulonodules on the helix of the ear and the skin overlying joints. Histopathology reveals palisaded granulomas surrounding an amorphous feathery material that corresponds to the urate crystals that were destroyed with formalin fixation (Figure 4). When the tissue is fixed with ethanol or is incompletely fixed in formalin, birefringent urate crystals are evident with polarization.²⁰

The Diagnosis: Piloleiomyoma 

Leiomyoma cutis, also known as cutaneous leiomyoma, is a benign smooth muscle tumor first described in 1854.¹ Cutaneous leiomyoma is comprised of 3 distinct types that depend on the origin of smooth muscle tumor: piloleiomyoma (arrector pili muscle), angioleiomyoma (tunica media of arteries/veins), and genital leiomyoma (dartos muscle of the scrotum and labia majora, erectile muscle of nipple).² It affects both sexes equally, though some reports have noted an increased prevalence in females. Piloleiomyomas commonly present on the extensor surfaces of the extremities (solitary) and trunk (multiple).¹ Tumors most often present as firm flesh-colored or pink-brown papulonodules. They can be linear, dermatomal, segmental, or diffuse, and often are painful. Clinical differential diagnosis for painful skin tumors is aided by the acronym "BLEND AN EGG": blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor.³ For isolated lesions, surgical excision is the treatment of choice. For numerous lesions in which excision would not be feasible, intralesional corticosteroids, medications (eg, calcium channel blockers, alpha blockers, nitroglycerin), and botulinum toxin have been used for pain relief.⁴  

Notably, multiple cutaneous leiomyomas can be seen in association with uterine leiomyomas in Reed syndrome due to an autosomal-dominant or de novo mutation in the fumarate hydratase gene, FH. Reed syndrome is associated with a lifetime risk for renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer) in 15% of cases with FH mutations.⁵ In our patient, both immunohistochemical staining and blood testing for FH were performed. Immunohistochemistry revealed notably diminished staining with only weak patchy granular cytoplasmic staining present (Figure 1). Genetic testing revealed heterozygosity for a pathogenic variant of the FH gene, consistent with a diagnosis of Reed syndrome.  

Histologically, the differential diagnosis includes other spindle cell tumors, such as dermatofibroma, neurofibroma, and dermatomyofibroma. The histologic appearance varies depending on the type, with piloleiomyoma typically located within the reticular dermis with possible subcutaneous extension. Fascicles of eosinophilic smooth muscle cells in an interlacing arrangement often ramify between neighboring dermal collagen; these smooth muscle cells contain cigar-shaped, blunt-ended nuclei with a perinuclear clear vacuole. Marked epidermal hyperplasia is possible.⁶ A close association with a nearby hair follicle frequently is noted. Although differentiated smooth muscle cells usually are evident on hematoxylin and eosin, positive staining for smooth muscle actin (SMA) and desmin can aid in diagnosis.⁷ Immunohistochemical staining for FH has proven to be highly specific (97.6%) with moderate sensitivity (70.0%).⁸ Angioleiomyomas appear as well-demarcated dermal to subcutaneous tumors composed of smooth muscle cells surrounding thick-walled vaculature.⁹ Scrotal and vulvar leiomyomas are composed of eosinophilic spindle cells, though vulvar leiomyomas have shown epithelioid differentiation.¹⁰ Nipple leiomyomas appear similar to piloleiomyomas on histology with interlacing smooth muscle fiber bundles.  

Eccrine spiradenoma is a relatively uncommon adnexal tumor derived from eccrine sweat glands. It most often presents as a small, painful or tender, intradermal nodule (or rarely as nodules) on the head or ventral trunk.¹¹ There is no sexual predilection. It affects adults at any age but most often from 15 to 35 years. Although rare, malignant transformation is possible. Histologically, eccrine spiradenomas appear as a well-demarcated dermal tumor composed of bland basaloid cells with minimal cytoplasm, often with numerous admixed lymphocytes and variably prominent vasculature (Figure 2). Eosinophilic basement membrane material can be seen within or surrounding the nodules of tumor cells. Multiple spiradenomas can occur in the setting of Brooke-Spiegler syndrome, which is an autosomal-dominant disorder due to an inherited mutation in the CYLD gene. Spiradenomas are benign neoplasms, and surgical excision with clear margins is the treatment of choice.¹²  

Dermatofibroma, also known as cutaneous benign fibrous histiocytoma, is a firm, flesh-colored papule or nodule that most often presents on the lower extremities. It typically is seen in women aged 20 to 40 years.¹³ The etiology is uncertain, and dermatofibromas often spontaneously develop, though there are inconsistent reports of development with local trauma including insect bites and puncture wounds. The dimple sign refers to skin dimpling with lateral pressure.¹³ Most commonly, dermatofibromas consist of a dermal proliferation of bland fibroblastic cells with entrapment of dermal collagen bundles at the periphery of the tumors (Figure 3). The fibroblastic cells often are paler and less eosinophilic than smooth muscle cells seen in cutaneous leiomyomas, with tapered nuclei that lack a perinuclear vacuole. Admixed histocytes and other inflammatory cells often are present. Overlying epidermal hyperplasia and/or hyperpigmentation also may be present. Numerous histologic variants have been described, including cellular, epithelioid, aneurysmal, atypical, and hemosiderotic types.¹⁴ Immunohistochemical stains may show patchy positive staining for SMA, but h-caldesmon and desmin typically are negative.  

Neurofibroma is a tumor derived from neuromesenchymal tissue with nerve axons. They form through neuromesenchyme (eg, Schwann cells, mast cells, perineural cells, endoneural fibroblast) proliferation. Solitary neurofibromas occur most commonly in adults and have no gender predilection. The most common presentation is an asymptomatic, solitary, soft, flesh-colored papulonodule.¹⁵ Clinical variants include pigmented, diffuse, and plexiform, with plexiform neurofibromas almost always being consistent with a diagnosis of neurofibromatosis type 1. Histologically, neurofibromas present as dermal or subcutaneous nodules composed of randomly arranged spindle cells with wavy tapered nuclei within a loose collagenous stroma (Figure 4).¹⁶ The spindle cells in neurofibromas will stain positively for S-100 protein and SOX-10 and negatively for SMA and desmin.  

Angiolipoma is a benign tumor composed of adipocytes that also contains vasculature.¹⁷ The majority of cases are of unknown etiology, though familial cases have been described. They typically present as multiple painful or tender (differentiating from lipomas) subcutaneous swellings over the forearms in individuals aged 20 to 30 years.¹⁸ On histopathology, angiolipomas appear as well-circumscribed subcutaneous tumors containing mature adipocytes intermixed with small capillary vessels, some of which contain luminal fibrin thrombi (Figure 5).  

The Diagnosis: Piloleiomyoma 

Leiomyoma cutis, also known as cutaneous leiomyoma, is a benign smooth muscle tumor first described in 1854.¹ Cutaneous leiomyoma is comprised of 3 distinct types that depend on the origin of smooth muscle tumor: piloleiomyoma (arrector pili muscle), angioleiomyoma (tunica media of arteries/veins), and genital leiomyoma (dartos muscle of the scrotum and labia majora, erectile muscle of nipple).² It affects both sexes equally, though some reports have noted an increased prevalence in females. Piloleiomyomas commonly present on the extensor surfaces of the extremities (solitary) and trunk (multiple).¹ Tumors most often present as firm flesh-colored or pink-brown papulonodules. They can be linear, dermatomal, segmental, or diffuse, and often are painful. Clinical differential diagnosis for painful skin tumors is aided by the acronym "BLEND AN EGG": blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor.³ For isolated lesions, surgical excision is the treatment of choice. For numerous lesions in which excision would not be feasible, intralesional corticosteroids, medications (eg, calcium channel blockers, alpha blockers, nitroglycerin), and botulinum toxin have been used for pain relief.⁴  

Notably, multiple cutaneous leiomyomas can be seen in association with uterine leiomyomas in Reed syndrome due to an autosomal-dominant or de novo mutation in the fumarate hydratase gene, FH. Reed syndrome is associated with a lifetime risk for renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer) in 15% of cases with FH mutations.⁵ In our patient, both immunohistochemical staining and blood testing for FH were performed. Immunohistochemistry revealed notably diminished staining with only weak patchy granular cytoplasmic staining present (Figure 1). Genetic testing revealed heterozygosity for a pathogenic variant of the FH gene, consistent with a diagnosis of Reed syndrome.  

Histologically, the differential diagnosis includes other spindle cell tumors, such as dermatofibroma, neurofibroma, and dermatomyofibroma. The histologic appearance varies depending on the type, with piloleiomyoma typically located within the reticular dermis with possible subcutaneous extension. Fascicles of eosinophilic smooth muscle cells in an interlacing arrangement often ramify between neighboring dermal collagen; these smooth muscle cells contain cigar-shaped, blunt-ended nuclei with a perinuclear clear vacuole. Marked epidermal hyperplasia is possible.⁶ A close association with a nearby hair follicle frequently is noted. Although differentiated smooth muscle cells usually are evident on hematoxylin and eosin, positive staining for smooth muscle actin (SMA) and desmin can aid in diagnosis.⁷ Immunohistochemical staining for FH has proven to be highly specific (97.6%) with moderate sensitivity (70.0%).⁸ Angioleiomyomas appear as well-demarcated dermal to subcutaneous tumors composed of smooth muscle cells surrounding thick-walled vaculature.⁹ Scrotal and vulvar leiomyomas are composed of eosinophilic spindle cells, though vulvar leiomyomas have shown epithelioid differentiation.¹⁰ Nipple leiomyomas appear similar to piloleiomyomas on histology with interlacing smooth muscle fiber bundles.  

Eccrine spiradenoma is a relatively uncommon adnexal tumor derived from eccrine sweat glands. It most often presents as a small, painful or tender, intradermal nodule (or rarely as nodules) on the head or ventral trunk.¹¹ There is no sexual predilection. It affects adults at any age but most often from 15 to 35 years. Although rare, malignant transformation is possible. Histologically, eccrine spiradenomas appear as a well-demarcated dermal tumor composed of bland basaloid cells with minimal cytoplasm, often with numerous admixed lymphocytes and variably prominent vasculature (Figure 2). Eosinophilic basement membrane material can be seen within or surrounding the nodules of tumor cells. Multiple spiradenomas can occur in the setting of Brooke-Spiegler syndrome, which is an autosomal-dominant disorder due to an inherited mutation in the CYLD gene. Spiradenomas are benign neoplasms, and surgical excision with clear margins is the treatment of choice.¹²  

Dermatofibroma, also known as cutaneous benign fibrous histiocytoma, is a firm, flesh-colored papule or nodule that most often presents on the lower extremities. It typically is seen in women aged 20 to 40 years.¹³ The etiology is uncertain, and dermatofibromas often spontaneously develop, though there are inconsistent reports of development with local trauma including insect bites and puncture wounds. The dimple sign refers to skin dimpling with lateral pressure.¹³ Most commonly, dermatofibromas consist of a dermal proliferation of bland fibroblastic cells with entrapment of dermal collagen bundles at the periphery of the tumors (Figure 3). The fibroblastic cells often are paler and less eosinophilic than smooth muscle cells seen in cutaneous leiomyomas, with tapered nuclei that lack a perinuclear vacuole. Admixed histocytes and other inflammatory cells often are present. Overlying epidermal hyperplasia and/or hyperpigmentation also may be present. Numerous histologic variants have been described, including cellular, epithelioid, aneurysmal, atypical, and hemosiderotic types.¹⁴ Immunohistochemical stains may show patchy positive staining for SMA, but h-caldesmon and desmin typically are negative.  

Neurofibroma is a tumor derived from neuromesenchymal tissue with nerve axons. They form through neuromesenchyme (eg, Schwann cells, mast cells, perineural cells, endoneural fibroblast) proliferation. Solitary neurofibromas occur most commonly in adults and have no gender predilection. The most common presentation is an asymptomatic, solitary, soft, flesh-colored papulonodule.¹⁵ Clinical variants include pigmented, diffuse, and plexiform, with plexiform neurofibromas almost always being consistent with a diagnosis of neurofibromatosis type 1. Histologically, neurofibromas present as dermal or subcutaneous nodules composed of randomly arranged spindle cells with wavy tapered nuclei within a loose collagenous stroma (Figure 4).¹⁶ The spindle cells in neurofibromas will stain positively for S-100 protein and SOX-10 and negatively for SMA and desmin.  

Angiolipoma is a benign tumor composed of adipocytes that also contains vasculature.¹⁷ The majority of cases are of unknown etiology, though familial cases have been described. They typically present as multiple painful or tender (differentiating from lipomas) subcutaneous swellings over the forearms in individuals aged 20 to 30 years.¹⁸ On histopathology, angiolipomas appear as well-circumscribed subcutaneous tumors containing mature adipocytes intermixed with small capillary vessels, some of which contain luminal fibrin thrombi (Figure 5).  

The Diagnosis: Piloleiomyoma 

Leiomyoma cutis, also known as cutaneous leiomyoma, is a benign smooth muscle tumor first described in 1854.¹ Cutaneous leiomyoma is comprised of 3 distinct types that depend on the origin of smooth muscle tumor: piloleiomyoma (arrector pili muscle), angioleiomyoma (tunica media of arteries/veins), and genital leiomyoma (dartos muscle of the scrotum and labia majora, erectile muscle of nipple).² It affects both sexes equally, though some reports have noted an increased prevalence in females. Piloleiomyomas commonly present on the extensor surfaces of the extremities (solitary) and trunk (multiple).¹ Tumors most often present as firm flesh-colored or pink-brown papulonodules. They can be linear, dermatomal, segmental, or diffuse, and often are painful. Clinical differential diagnosis for painful skin tumors is aided by the acronym "BLEND AN EGG": blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor.³ For isolated lesions, surgical excision is the treatment of choice. For numerous lesions in which excision would not be feasible, intralesional corticosteroids, medications (eg, calcium channel blockers, alpha blockers, nitroglycerin), and botulinum toxin have been used for pain relief.⁴  

Notably, multiple cutaneous leiomyomas can be seen in association with uterine leiomyomas in Reed syndrome due to an autosomal-dominant or de novo mutation in the fumarate hydratase gene, FH. Reed syndrome is associated with a lifetime risk for renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer) in 15% of cases with FH mutations.⁵ In our patient, both immunohistochemical staining and blood testing for FH were performed. Immunohistochemistry revealed notably diminished staining with only weak patchy granular cytoplasmic staining present (Figure 1). Genetic testing revealed heterozygosity for a pathogenic variant of the FH gene, consistent with a diagnosis of Reed syndrome.  

Histologically, the differential diagnosis includes other spindle cell tumors, such as dermatofibroma, neurofibroma, and dermatomyofibroma. The histologic appearance varies depending on the type, with piloleiomyoma typically located within the reticular dermis with possible subcutaneous extension. Fascicles of eosinophilic smooth muscle cells in an interlacing arrangement often ramify between neighboring dermal collagen; these smooth muscle cells contain cigar-shaped, blunt-ended nuclei with a perinuclear clear vacuole. Marked epidermal hyperplasia is possible.⁶ A close association with a nearby hair follicle frequently is noted. Although differentiated smooth muscle cells usually are evident on hematoxylin and eosin, positive staining for smooth muscle actin (SMA) and desmin can aid in diagnosis.⁷ Immunohistochemical staining for FH has proven to be highly specific (97.6%) with moderate sensitivity (70.0%).⁸ Angioleiomyomas appear as well-demarcated dermal to subcutaneous tumors composed of smooth muscle cells surrounding thick-walled vaculature.⁹ Scrotal and vulvar leiomyomas are composed of eosinophilic spindle cells, though vulvar leiomyomas have shown epithelioid differentiation.¹⁰ Nipple leiomyomas appear similar to piloleiomyomas on histology with interlacing smooth muscle fiber bundles.  

Eccrine spiradenoma is a relatively uncommon adnexal tumor derived from eccrine sweat glands. It most often presents as a small, painful or tender, intradermal nodule (or rarely as nodules) on the head or ventral trunk.¹¹ There is no sexual predilection. It affects adults at any age but most often from 15 to 35 years. Although rare, malignant transformation is possible. Histologically, eccrine spiradenomas appear as a well-demarcated dermal tumor composed of bland basaloid cells with minimal cytoplasm, often with numerous admixed lymphocytes and variably prominent vasculature (Figure 2). Eosinophilic basement membrane material can be seen within or surrounding the nodules of tumor cells. Multiple spiradenomas can occur in the setting of Brooke-Spiegler syndrome, which is an autosomal-dominant disorder due to an inherited mutation in the CYLD gene. Spiradenomas are benign neoplasms, and surgical excision with clear margins is the treatment of choice.¹²  

Dermatofibroma, also known as cutaneous benign fibrous histiocytoma, is a firm, flesh-colored papule or nodule that most often presents on the lower extremities. It typically is seen in women aged 20 to 40 years.¹³ The etiology is uncertain, and dermatofibromas often spontaneously develop, though there are inconsistent reports of development with local trauma including insect bites and puncture wounds. The dimple sign refers to skin dimpling with lateral pressure.¹³ Most commonly, dermatofibromas consist of a dermal proliferation of bland fibroblastic cells with entrapment of dermal collagen bundles at the periphery of the tumors (Figure 3). The fibroblastic cells often are paler and less eosinophilic than smooth muscle cells seen in cutaneous leiomyomas, with tapered nuclei that lack a perinuclear vacuole. Admixed histocytes and other inflammatory cells often are present. Overlying epidermal hyperplasia and/or hyperpigmentation also may be present. Numerous histologic variants have been described, including cellular, epithelioid, aneurysmal, atypical, and hemosiderotic types.¹⁴ Immunohistochemical stains may show patchy positive staining for SMA, but h-caldesmon and desmin typically are negative.  

Neurofibroma is a tumor derived from neuromesenchymal tissue with nerve axons. They form through neuromesenchyme (eg, Schwann cells, mast cells, perineural cells, endoneural fibroblast) proliferation. Solitary neurofibromas occur most commonly in adults and have no gender predilection. The most common presentation is an asymptomatic, solitary, soft, flesh-colored papulonodule.¹⁵ Clinical variants include pigmented, diffuse, and plexiform, with plexiform neurofibromas almost always being consistent with a diagnosis of neurofibromatosis type 1. Histologically, neurofibromas present as dermal or subcutaneous nodules composed of randomly arranged spindle cells with wavy tapered nuclei within a loose collagenous stroma (Figure 4).¹⁶ The spindle cells in neurofibromas will stain positively for S-100 protein and SOX-10 and negatively for SMA and desmin.  

Angiolipoma is a benign tumor composed of adipocytes that also contains vasculature.¹⁷ The majority of cases are of unknown etiology, though familial cases have been described. They typically present as multiple painful or tender (differentiating from lipomas) subcutaneous swellings over the forearms in individuals aged 20 to 30 years.¹⁸ On histopathology, angiolipomas appear as well-circumscribed subcutaneous tumors containing mature adipocytes intermixed with small capillary vessels, some of which contain luminal fibrin thrombi (Figure 5).  

The Diagnosis: Clonal Melanoacanthoma 

Melanoacanthoma (MA) is an extremely rare, benign, epidermal tumor histologically characterized by keratinocytes and large, pigmented, dendritic melanocytes. These lesions are loosely related to seborrheic keratoses, and the term was first coined by Mishima and Pinkus¹ in 1960. It is estimated that the lesion occurs in only 5 of 500,000 individuals and tends to occur in older, light-skinned individuals.² The majority are slow growing and are present on the head, neck, or upper extremities; however, similar lesions also have been reported on the oral mucosa.³ Melanoacanthomas range in size from 2×2 to 15×15 cm; are clinically pigmented; and present as either a papule, plaque, nodule, or horn.² 

Classic histologic findings of MA include papillomatosis, acanthosis, and hyperkeratosis with heavily pigmented dendritic melanocytes diffusely dispersed throughout all layers of the seborrheic keratosis-like epidermis.³ Other features include keratin-filled pseudocysts, Langerhans cells, reactive spindling of keratinocytes, and an inflammatory infiltrate. In our case, the classic histologic findings also were architecturally arranged in oval to round clones within the epidermis (quiz images 1 and 2). A MART-1 (melanoma antigen recognized by T cells) immunostain was obtained that highlighted the numerous but benign-appearing, dendritic melanocytes (quiz image 2 [inset]). A dual MART-1/Ki67 immunostain later was obtained and demonstrated a negligible proliferation index within the dendritic melanocytes. Therefore, the diagnosis of clonal MA was rendered. This formation of epidermal clones also is called the Borst-Jadassohn phenomenon, which rarely occurs in MAs. This subtype is important to recognize because the clonal pattern can more closely mimic malignant neoplasms such as melanoma.  

Hidroacanthoma simplex is an intraepidermal variant of eccrine poroma. It is a rare entity that typically occurs in the extremities of women as a hyperkeratotic plaque. These typically clonal epidermal tumors may be heavily pigmented and rarely contain dendritic melanocytes; therefore, they may be confused with MA. However, classic histology will reveal an intraepidermal clonal proliferation of bland, monotonous, cuboidal cells with ample pink cytoplasm, as well as occasional cuticle-lined ducts (Figure 1).⁴ These ducts will highlight with carcinoembryonic antigen and epithelial membrane antigen immunostaining.  

Malignant melanoma typically presents as a growing pigmented lesion and therefore can clinically mimic MA. Histologically, MA could be confused with melanoma due to the increased number of melanocytes plus the appearance of pagetoid spread resulting from the diffuse presence of melanocytes throughout the neoplasm. However, histologic assessment of melanoma should reveal cytologic atypia such as nuclear enlargement, hyperchromasia, molding, pleomorphism, and mitotic activity (Figure 2). Architectural atypia such as poor lateral circumscription of melanocytes, confluence and pagetoid spread of nondendritic atypical junctional melanocytes, production of pigment in deep dermal nests of melanocytes, and lack of maturation and dispersion of dermal melanocytes also should be seen.⁵ Unlike a melanocytic neoplasm, true melanocytic nests are not seen in MA, and the melanocytes are bland, normal-appearing but heavily pigmented, dendritic melanocytes. Electron microscopy has shown a defect in the transfer of melanin from these highly dendritic melanocytes to the keratinocytes.⁶  

Similar to melanoma, seborrheic keratosis presents as a pigmented growing lesion; therefore, definitive diagnosis often is achieved via skin biopsy. Classic histologic findings include acanthotic or exophytic epidermal growth with a dome-shaped configuration containing multiple cornified hornlike cysts (Figure 3).⁷ Multiple keratin plugs and variably sized concentric keratin islands are common features. There may be varying degrees of melanin pigment deposition among the proliferating cells, and clonal formation may occur. Melanocyte-specific special stains and immunostains can be used to differentiate MA from seborrheic keratosis by highlighting numerous dendritic melanocytes diffusely spread throughout the epidermis in MA vs a normal distribution of occasional junctional melanocytes in seborrheic keratosis.^2,8  

Squamous cell carcinoma in situ presents histologically with cytologically atypical keratinocytes encompassing the full thickness of the epidermis and sometimes crushing the basement membrane zone (Figure 4). There is a loss of the granular layer and overlying parakeratosis that often spares the adnexal ostial epithelium.⁹ Clonal formation can occur as well as increased pigment production. In comparison, bland keratinocytes are seen in MA.  

Establishing the diagnosis of MA based on clinical features alone can be difficult. Dermoscopy can prove to be useful and typically will show a sunburst pattern with ridges and fissures.² However, seborrheic keratoses and melanomas can have similar dermoscopic findings¹⁰; therefore, a biopsy often is necessary to establish the diagnosis. 

The Diagnosis: Clonal Melanoacanthoma 

Melanoacanthoma (MA) is an extremely rare, benign, epidermal tumor histologically characterized by keratinocytes and large, pigmented, dendritic melanocytes. These lesions are loosely related to seborrheic keratoses, and the term was first coined by Mishima and Pinkus¹ in 1960. It is estimated that the lesion occurs in only 5 of 500,000 individuals and tends to occur in older, light-skinned individuals.² The majority are slow growing and are present on the head, neck, or upper extremities; however, similar lesions also have been reported on the oral mucosa.³ Melanoacanthomas range in size from 2×2 to 15×15 cm; are clinically pigmented; and present as either a papule, plaque, nodule, or horn.² 

Classic histologic findings of MA include papillomatosis, acanthosis, and hyperkeratosis with heavily pigmented dendritic melanocytes diffusely dispersed throughout all layers of the seborrheic keratosis-like epidermis.³ Other features include keratin-filled pseudocysts, Langerhans cells, reactive spindling of keratinocytes, and an inflammatory infiltrate. In our case, the classic histologic findings also were architecturally arranged in oval to round clones within the epidermis (quiz images 1 and 2). A MART-1 (melanoma antigen recognized by T cells) immunostain was obtained that highlighted the numerous but benign-appearing, dendritic melanocytes (quiz image 2 [inset]). A dual MART-1/Ki67 immunostain later was obtained and demonstrated a negligible proliferation index within the dendritic melanocytes. Therefore, the diagnosis of clonal MA was rendered. This formation of epidermal clones also is called the Borst-Jadassohn phenomenon, which rarely occurs in MAs. This subtype is important to recognize because the clonal pattern can more closely mimic malignant neoplasms such as melanoma.  

Hidroacanthoma simplex is an intraepidermal variant of eccrine poroma. It is a rare entity that typically occurs in the extremities of women as a hyperkeratotic plaque. These typically clonal epidermal tumors may be heavily pigmented and rarely contain dendritic melanocytes; therefore, they may be confused with MA. However, classic histology will reveal an intraepidermal clonal proliferation of bland, monotonous, cuboidal cells with ample pink cytoplasm, as well as occasional cuticle-lined ducts (Figure 1).⁴ These ducts will highlight with carcinoembryonic antigen and epithelial membrane antigen immunostaining.  

Malignant melanoma typically presents as a growing pigmented lesion and therefore can clinically mimic MA. Histologically, MA could be confused with melanoma due to the increased number of melanocytes plus the appearance of pagetoid spread resulting from the diffuse presence of melanocytes throughout the neoplasm. However, histologic assessment of melanoma should reveal cytologic atypia such as nuclear enlargement, hyperchromasia, molding, pleomorphism, and mitotic activity (Figure 2). Architectural atypia such as poor lateral circumscription of melanocytes, confluence and pagetoid spread of nondendritic atypical junctional melanocytes, production of pigment in deep dermal nests of melanocytes, and lack of maturation and dispersion of dermal melanocytes also should be seen.⁵ Unlike a melanocytic neoplasm, true melanocytic nests are not seen in MA, and the melanocytes are bland, normal-appearing but heavily pigmented, dendritic melanocytes. Electron microscopy has shown a defect in the transfer of melanin from these highly dendritic melanocytes to the keratinocytes.⁶  

Similar to melanoma, seborrheic keratosis presents as a pigmented growing lesion; therefore, definitive diagnosis often is achieved via skin biopsy. Classic histologic findings include acanthotic or exophytic epidermal growth with a dome-shaped configuration containing multiple cornified hornlike cysts (Figure 3).⁷ Multiple keratin plugs and variably sized concentric keratin islands are common features. There may be varying degrees of melanin pigment deposition among the proliferating cells, and clonal formation may occur. Melanocyte-specific special stains and immunostains can be used to differentiate MA from seborrheic keratosis by highlighting numerous dendritic melanocytes diffusely spread throughout the epidermis in MA vs a normal distribution of occasional junctional melanocytes in seborrheic keratosis.^2,8  

Squamous cell carcinoma in situ presents histologically with cytologically atypical keratinocytes encompassing the full thickness of the epidermis and sometimes crushing the basement membrane zone (Figure 4). There is a loss of the granular layer and overlying parakeratosis that often spares the adnexal ostial epithelium.⁹ Clonal formation can occur as well as increased pigment production. In comparison, bland keratinocytes are seen in MA.  

Establishing the diagnosis of MA based on clinical features alone can be difficult. Dermoscopy can prove to be useful and typically will show a sunburst pattern with ridges and fissures.² However, seborrheic keratoses and melanomas can have similar dermoscopic findings¹⁰; therefore, a biopsy often is necessary to establish the diagnosis. 

The Diagnosis: Clonal Melanoacanthoma 

Melanoacanthoma (MA) is an extremely rare, benign, epidermal tumor histologically characterized by keratinocytes and large, pigmented, dendritic melanocytes. These lesions are loosely related to seborrheic keratoses, and the term was first coined by Mishima and Pinkus¹ in 1960. It is estimated that the lesion occurs in only 5 of 500,000 individuals and tends to occur in older, light-skinned individuals.² The majority are slow growing and are present on the head, neck, or upper extremities; however, similar lesions also have been reported on the oral mucosa.³ Melanoacanthomas range in size from 2×2 to 15×15 cm; are clinically pigmented; and present as either a papule, plaque, nodule, or horn.² 

Classic histologic findings of MA include papillomatosis, acanthosis, and hyperkeratosis with heavily pigmented dendritic melanocytes diffusely dispersed throughout all layers of the seborrheic keratosis-like epidermis.³ Other features include keratin-filled pseudocysts, Langerhans cells, reactive spindling of keratinocytes, and an inflammatory infiltrate. In our case, the classic histologic findings also were architecturally arranged in oval to round clones within the epidermis (quiz images 1 and 2). A MART-1 (melanoma antigen recognized by T cells) immunostain was obtained that highlighted the numerous but benign-appearing, dendritic melanocytes (quiz image 2 [inset]). A dual MART-1/Ki67 immunostain later was obtained and demonstrated a negligible proliferation index within the dendritic melanocytes. Therefore, the diagnosis of clonal MA was rendered. This formation of epidermal clones also is called the Borst-Jadassohn phenomenon, which rarely occurs in MAs. This subtype is important to recognize because the clonal pattern can more closely mimic malignant neoplasms such as melanoma.  

Hidroacanthoma simplex is an intraepidermal variant of eccrine poroma. It is a rare entity that typically occurs in the extremities of women as a hyperkeratotic plaque. These typically clonal epidermal tumors may be heavily pigmented and rarely contain dendritic melanocytes; therefore, they may be confused with MA. However, classic histology will reveal an intraepidermal clonal proliferation of bland, monotonous, cuboidal cells with ample pink cytoplasm, as well as occasional cuticle-lined ducts (Figure 1).⁴ These ducts will highlight with carcinoembryonic antigen and epithelial membrane antigen immunostaining.  

Malignant melanoma typically presents as a growing pigmented lesion and therefore can clinically mimic MA. Histologically, MA could be confused with melanoma due to the increased number of melanocytes plus the appearance of pagetoid spread resulting from the diffuse presence of melanocytes throughout the neoplasm. However, histologic assessment of melanoma should reveal cytologic atypia such as nuclear enlargement, hyperchromasia, molding, pleomorphism, and mitotic activity (Figure 2). Architectural atypia such as poor lateral circumscription of melanocytes, confluence and pagetoid spread of nondendritic atypical junctional melanocytes, production of pigment in deep dermal nests of melanocytes, and lack of maturation and dispersion of dermal melanocytes also should be seen.⁵ Unlike a melanocytic neoplasm, true melanocytic nests are not seen in MA, and the melanocytes are bland, normal-appearing but heavily pigmented, dendritic melanocytes. Electron microscopy has shown a defect in the transfer of melanin from these highly dendritic melanocytes to the keratinocytes.⁶  

Similar to melanoma, seborrheic keratosis presents as a pigmented growing lesion; therefore, definitive diagnosis often is achieved via skin biopsy. Classic histologic findings include acanthotic or exophytic epidermal growth with a dome-shaped configuration containing multiple cornified hornlike cysts (Figure 3).⁷ Multiple keratin plugs and variably sized concentric keratin islands are common features. There may be varying degrees of melanin pigment deposition among the proliferating cells, and clonal formation may occur. Melanocyte-specific special stains and immunostains can be used to differentiate MA from seborrheic keratosis by highlighting numerous dendritic melanocytes diffusely spread throughout the epidermis in MA vs a normal distribution of occasional junctional melanocytes in seborrheic keratosis.^2,8  

Squamous cell carcinoma in situ presents histologically with cytologically atypical keratinocytes encompassing the full thickness of the epidermis and sometimes crushing the basement membrane zone (Figure 4). There is a loss of the granular layer and overlying parakeratosis that often spares the adnexal ostial epithelium.⁹ Clonal formation can occur as well as increased pigment production. In comparison, bland keratinocytes are seen in MA.  

Establishing the diagnosis of MA based on clinical features alone can be difficult. Dermoscopy can prove to be useful and typically will show a sunburst pattern with ridges and fissures.² However, seborrheic keratoses and melanomas can have similar dermoscopic findings¹⁰; therefore, a biopsy often is necessary to establish the diagnosis. 

The Diagnosis: Primary Cutaneous γδ T-cell Lymphoma

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a distinct entity that can be confused with other types of cutaneous T-cell lymphomas. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal.¹ Primary cutaneous γδ T-cell lymphoma represents less than 1% of all cutaneous T-cell lymphomas.² Diagnosis and treatment remain challenging. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection on clinical examination; biopsy establishes the diagnosis. Typical findings include a cytotoxic phenotype, variable epidermotropism, dermal and subcutaneous involvement, and loss of CD4 and often CD8 expression. Testing for Epstein-Barr virus expression yields negative results. The neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are T-cell intracellular antigen-1 (TIA-1) and granzyme positive.¹

Immunohistochemistry failed to reveal CD8, CD56, granzyme, or T-cell intracellular antigen-1 staining of neoplastic cells in our patient but stained diffusely positive with CD3 and CD4. A CD20 stain decorated only a few dermal cells. The patient’s skin lesions continued to enlarge, and the massive lymphadenopathy made breathing difficult. Computed tomography revealed diffuse systemic involvement. An axillary lymph node biopsy revealed sinusoids with complete diffuse effacement of architecture as well as frequent mitotic figures and karyorrhectic debris (Figure 1A). Negative staining for T-cell receptor beta-F1 of the axillary lymph node biopsy and clonal rearrangement of the T-cell receptor gamma chain supported the diagnosis of PCGDTL. Nuclear staining for Epstein-Barr virus–encoded RNA was negative. Human T-cell leukemia virus type 1 antibodies and polymerase chain reaction also were negative. Flow cytometry demonstrated an atypical population of CD3⁺, CD4⁺, and CD7− γδ T lymphocytes, further supporting the diagnosis of lymphoma.

The median life expectancy for patients with dermal or subcutaneous PCGDTL is 10 to 15 months after diagnosis.³ The 5-year life expectancy for PCGDTL is approximately 11%.² Limited treatment options contribute to the poor outcome. Chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and EPOCH (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) have yielded inconsistent results. Stem cell transplant has been tried in progressive disease and also has yielded mixed results.² Brentuximab is indicated for individuals whose tumors express CD30.⁴ Associated hemophagic lymphohistiocytosis portends a poor prognosis.⁵

Despite treatment with etoposide, vincristine, doxorubicin, and high-dose oral steroids, our patient developed progressive difficulty breathing, stridor, kidney injury, and anemia. Our patient died less than 1 month after diagnosis—after only 1 round of chemotherapy—secondary to progressive disease and an uncontrollable gastrointestinal tract bleed. The leonine facies (Figure 1B) encountered in our patient can raise a differential diagnosis that includes infectious as well as neoplastic etiologies; however, most infectious etiologies associated with leonine facies manifest in a chronic fashion rather than with a sudden eruption, as noted in our patient.

Leprosy is caused by Mycobacterium leprae, a grampositive bacillus. The condition manifests across a spectrum, with the poles being tuberculoid and lepromatous, and borderline variants in between.^6-8 Lepromatous leprosy arises in individuals who are unable to mount cellular immunity against M leprae secondary to anergy.⁶ Lepromatous leprosy often presents with numerous papules and nodules. Aside from cutaneous manifestations, lepromatous leprosy has a predilection for peripheral nerves and specifically Schwann cells. Histologically, biopsy reveals a flat epidermis and a cell-free subepidermal grenz zone. Within the dermis, there is a diffuse histiocytic infiltrate that typically is not centered around nerves (Figure 2).^6,7 Mycobacterium leprae can appear scattered throughout or clustered in globi. Mycobacterium leprae stains red with Ziehl-Neelsen or Wade-Fite stains.^6,7 Immunohistochemistry reveals a CD4⁺ helper T cell (TH2) predominance, supported by the increased expression of type 2 reaction cytokines such as IL-4, IL-5, IL-10, and IL-13.⁸

Diffuse large B-cell lymphoma (DLBCL) embodies 10% to 20% of all primary cutaneous lymphomas; it is more prevalent in older adults (age range, 70–82 years) and women. Clinically, DLBCL presents as either single or multiple rapidly progressing nodules or plaques, usually violaceous or blue-red in color.^9,10 The most common area of presentation is on the legs, though it also can surface at other sites.⁹ On histology, DLBCL has clearly malignant features including frequent mitotic figures, large immunoblasts, and involvement throughout the dermis as well as perivascularly (Figure 3). Spindle-shaped cells and anaplastic features can be present. Immunohistochemically, DLBCL stains strongly positive for CD20 and B-cell lymphoma 2 (Bcl-2) along with other pan–B-cell markers.^9-11 The aggressive leg type of DLBCL stains positively for multiple myeloma oncogene 1 (MUM-1).^9,11

Cutaneous metastatic adenocarcinoma from internal malignancies occurs in approximately 5% of cancer patients with metastatic spread.¹² Most of these cutaneous lesions develop in close proximity to the primary tumor such as on the trunk, head, or neck. All cutaneous metastases carry a poor prognosis. Clinical presentation can vary greatly, ranging from painless, firm, or elastic nodules to lesions that mimic inflammatory skin conditions such as erysipelas or scleroderma. The majority of these metastases develop as painless firm nodules that are flesh colored, pink, red-brown, or purple.^12,13 The histopathology of metastatic adenocarcinoma demonstrates an infiltrative nodular appearance, though there rarely are well-circumscribed nodules found.¹³ The lesion originates in the dermis or subcutaneous tissue. It is a glandulartype lesion that may reflect the tissue of the primary tumor (Figure 4).^12,14 Immunohistochemical stains likely will remain consistent with those of the primary tumor, which is not always the case.¹⁴

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy of epithelial and neuroendocrine origin, first described as trabecular carcinoma due to the arrangement of tumor resembling cancellous bone.^15,16 Merkel cells are mechanoreceptors found near nerve terminals.¹⁷ Approximately 80% of MCCs are associated with Merkel cell polyomavirus, which is a small, double-stranded DNA virus with an icosahedral capsid.^17,18 Merkel cell polyomavirus–positive cases of MCC tend to have a better prognosis. In Merkel cell polyomavirus–negative MCC, there is an association with UV damage and increased chromosomal aberrations.¹⁸ Merkel cell carcinoma is known for its high rate of recurrence as well as local and distant metastasis. Nodal involvement is the most important prognostic indicator.¹⁵ Clinically, MCC is associated with the AEIOU mnemonic (asymptomatic, expanding rapidly, immunosuppression, older than 50 years, UV exposed/fair skin).^15-17 Lesions appear as red-blue papules on sun-exposed skin and usually are smaller than 2 cm by their greatest dimension. On histopathology, MCC demonstrates small, round, blue cells arranged in sheets or nests originating in the dermis and occasionally can infiltrate the subcutis and lymphovascular surroundings (Figure 5).^16-19 Cells have scant eosinophilic cytoplasm and may have fine granular chromatin. Numerous mitotic figures and apoptotic cells also are present. On immunohistochemistry, these cells will stain positive for cytokeratin AE1/AE3, anticytokeratin (CAM 5.2), CK20, and CD56. Due to their neuroendocrine derivation, they also are commonly synaptophysin, neuron-specific enolase, and chromogranin A positive. Notably, MCC will stain negative for leukocyte common antigen, CD20, CD3, CD34, and thyroid transcription factor 1 (TTF-1).^16,17

Primary cutaneous γδ T-cell lymphoma can be difficult to diagnose and requires urgent treatment. Clinicians and dermatopathologists need to work together to establish the diagnosis. There is a high mortality rate associated with PCGDTL, making prompt recognition and timely treatment critical. Acknowledgments—Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

Acknowledgments
Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

The Diagnosis: Primary Cutaneous γδ T-cell Lymphoma

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a distinct entity that can be confused with other types of cutaneous T-cell lymphomas. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal.¹ Primary cutaneous γδ T-cell lymphoma represents less than 1% of all cutaneous T-cell lymphomas.² Diagnosis and treatment remain challenging. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection on clinical examination; biopsy establishes the diagnosis. Typical findings include a cytotoxic phenotype, variable epidermotropism, dermal and subcutaneous involvement, and loss of CD4 and often CD8 expression. Testing for Epstein-Barr virus expression yields negative results. The neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are T-cell intracellular antigen-1 (TIA-1) and granzyme positive.¹

Immunohistochemistry failed to reveal CD8, CD56, granzyme, or T-cell intracellular antigen-1 staining of neoplastic cells in our patient but stained diffusely positive with CD3 and CD4. A CD20 stain decorated only a few dermal cells. The patient’s skin lesions continued to enlarge, and the massive lymphadenopathy made breathing difficult. Computed tomography revealed diffuse systemic involvement. An axillary lymph node biopsy revealed sinusoids with complete diffuse effacement of architecture as well as frequent mitotic figures and karyorrhectic debris (Figure 1A). Negative staining for T-cell receptor beta-F1 of the axillary lymph node biopsy and clonal rearrangement of the T-cell receptor gamma chain supported the diagnosis of PCGDTL. Nuclear staining for Epstein-Barr virus–encoded RNA was negative. Human T-cell leukemia virus type 1 antibodies and polymerase chain reaction also were negative. Flow cytometry demonstrated an atypical population of CD3⁺, CD4⁺, and CD7− γδ T lymphocytes, further supporting the diagnosis of lymphoma.

The median life expectancy for patients with dermal or subcutaneous PCGDTL is 10 to 15 months after diagnosis.³ The 5-year life expectancy for PCGDTL is approximately 11%.² Limited treatment options contribute to the poor outcome. Chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and EPOCH (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) have yielded inconsistent results. Stem cell transplant has been tried in progressive disease and also has yielded mixed results.² Brentuximab is indicated for individuals whose tumors express CD30.⁴ Associated hemophagic lymphohistiocytosis portends a poor prognosis.⁵

Despite treatment with etoposide, vincristine, doxorubicin, and high-dose oral steroids, our patient developed progressive difficulty breathing, stridor, kidney injury, and anemia. Our patient died less than 1 month after diagnosis—after only 1 round of chemotherapy—secondary to progressive disease and an uncontrollable gastrointestinal tract bleed. The leonine facies (Figure 1B) encountered in our patient can raise a differential diagnosis that includes infectious as well as neoplastic etiologies; however, most infectious etiologies associated with leonine facies manifest in a chronic fashion rather than with a sudden eruption, as noted in our patient.

Leprosy is caused by Mycobacterium leprae, a grampositive bacillus. The condition manifests across a spectrum, with the poles being tuberculoid and lepromatous, and borderline variants in between.^6-8 Lepromatous leprosy arises in individuals who are unable to mount cellular immunity against M leprae secondary to anergy.⁶ Lepromatous leprosy often presents with numerous papules and nodules. Aside from cutaneous manifestations, lepromatous leprosy has a predilection for peripheral nerves and specifically Schwann cells. Histologically, biopsy reveals a flat epidermis and a cell-free subepidermal grenz zone. Within the dermis, there is a diffuse histiocytic infiltrate that typically is not centered around nerves (Figure 2).^6,7 Mycobacterium leprae can appear scattered throughout or clustered in globi. Mycobacterium leprae stains red with Ziehl-Neelsen or Wade-Fite stains.^6,7 Immunohistochemistry reveals a CD4⁺ helper T cell (TH2) predominance, supported by the increased expression of type 2 reaction cytokines such as IL-4, IL-5, IL-10, and IL-13.⁸

Diffuse large B-cell lymphoma (DLBCL) embodies 10% to 20% of all primary cutaneous lymphomas; it is more prevalent in older adults (age range, 70–82 years) and women. Clinically, DLBCL presents as either single or multiple rapidly progressing nodules or plaques, usually violaceous or blue-red in color.^9,10 The most common area of presentation is on the legs, though it also can surface at other sites.⁹ On histology, DLBCL has clearly malignant features including frequent mitotic figures, large immunoblasts, and involvement throughout the dermis as well as perivascularly (Figure 3). Spindle-shaped cells and anaplastic features can be present. Immunohistochemically, DLBCL stains strongly positive for CD20 and B-cell lymphoma 2 (Bcl-2) along with other pan–B-cell markers.^9-11 The aggressive leg type of DLBCL stains positively for multiple myeloma oncogene 1 (MUM-1).^9,11

Cutaneous metastatic adenocarcinoma from internal malignancies occurs in approximately 5% of cancer patients with metastatic spread.¹² Most of these cutaneous lesions develop in close proximity to the primary tumor such as on the trunk, head, or neck. All cutaneous metastases carry a poor prognosis. Clinical presentation can vary greatly, ranging from painless, firm, or elastic nodules to lesions that mimic inflammatory skin conditions such as erysipelas or scleroderma. The majority of these metastases develop as painless firm nodules that are flesh colored, pink, red-brown, or purple.^12,13 The histopathology of metastatic adenocarcinoma demonstrates an infiltrative nodular appearance, though there rarely are well-circumscribed nodules found.¹³ The lesion originates in the dermis or subcutaneous tissue. It is a glandulartype lesion that may reflect the tissue of the primary tumor (Figure 4).^12,14 Immunohistochemical stains likely will remain consistent with those of the primary tumor, which is not always the case.¹⁴

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy of epithelial and neuroendocrine origin, first described as trabecular carcinoma due to the arrangement of tumor resembling cancellous bone.^15,16 Merkel cells are mechanoreceptors found near nerve terminals.¹⁷ Approximately 80% of MCCs are associated with Merkel cell polyomavirus, which is a small, double-stranded DNA virus with an icosahedral capsid.^17,18 Merkel cell polyomavirus–positive cases of MCC tend to have a better prognosis. In Merkel cell polyomavirus–negative MCC, there is an association with UV damage and increased chromosomal aberrations.¹⁸ Merkel cell carcinoma is known for its high rate of recurrence as well as local and distant metastasis. Nodal involvement is the most important prognostic indicator.¹⁵ Clinically, MCC is associated with the AEIOU mnemonic (asymptomatic, expanding rapidly, immunosuppression, older than 50 years, UV exposed/fair skin).^15-17 Lesions appear as red-blue papules on sun-exposed skin and usually are smaller than 2 cm by their greatest dimension. On histopathology, MCC demonstrates small, round, blue cells arranged in sheets or nests originating in the dermis and occasionally can infiltrate the subcutis and lymphovascular surroundings (Figure 5).^16-19 Cells have scant eosinophilic cytoplasm and may have fine granular chromatin. Numerous mitotic figures and apoptotic cells also are present. On immunohistochemistry, these cells will stain positive for cytokeratin AE1/AE3, anticytokeratin (CAM 5.2), CK20, and CD56. Due to their neuroendocrine derivation, they also are commonly synaptophysin, neuron-specific enolase, and chromogranin A positive. Notably, MCC will stain negative for leukocyte common antigen, CD20, CD3, CD34, and thyroid transcription factor 1 (TTF-1).^16,17

Primary cutaneous γδ T-cell lymphoma can be difficult to diagnose and requires urgent treatment. Clinicians and dermatopathologists need to work together to establish the diagnosis. There is a high mortality rate associated with PCGDTL, making prompt recognition and timely treatment critical. Acknowledgments—Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

Acknowledgments
Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

The Diagnosis: Primary Cutaneous γδ T-cell Lymphoma

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a distinct entity that can be confused with other types of cutaneous T-cell lymphomas. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal.¹ Primary cutaneous γδ T-cell lymphoma represents less than 1% of all cutaneous T-cell lymphomas.² Diagnosis and treatment remain challenging. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection on clinical examination; biopsy establishes the diagnosis. Typical findings include a cytotoxic phenotype, variable epidermotropism, dermal and subcutaneous involvement, and loss of CD4 and often CD8 expression. Testing for Epstein-Barr virus expression yields negative results. The neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are T-cell intracellular antigen-1 (TIA-1) and granzyme positive.¹

Immunohistochemistry failed to reveal CD8, CD56, granzyme, or T-cell intracellular antigen-1 staining of neoplastic cells in our patient but stained diffusely positive with CD3 and CD4. A CD20 stain decorated only a few dermal cells. The patient’s skin lesions continued to enlarge, and the massive lymphadenopathy made breathing difficult. Computed tomography revealed diffuse systemic involvement. An axillary lymph node biopsy revealed sinusoids with complete diffuse effacement of architecture as well as frequent mitotic figures and karyorrhectic debris (Figure 1A). Negative staining for T-cell receptor beta-F1 of the axillary lymph node biopsy and clonal rearrangement of the T-cell receptor gamma chain supported the diagnosis of PCGDTL. Nuclear staining for Epstein-Barr virus–encoded RNA was negative. Human T-cell leukemia virus type 1 antibodies and polymerase chain reaction also were negative. Flow cytometry demonstrated an atypical population of CD3⁺, CD4⁺, and CD7− γδ T lymphocytes, further supporting the diagnosis of lymphoma.

The median life expectancy for patients with dermal or subcutaneous PCGDTL is 10 to 15 months after diagnosis.³ The 5-year life expectancy for PCGDTL is approximately 11%.² Limited treatment options contribute to the poor outcome. Chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and EPOCH (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) have yielded inconsistent results. Stem cell transplant has been tried in progressive disease and also has yielded mixed results.² Brentuximab is indicated for individuals whose tumors express CD30.⁴ Associated hemophagic lymphohistiocytosis portends a poor prognosis.⁵

Despite treatment with etoposide, vincristine, doxorubicin, and high-dose oral steroids, our patient developed progressive difficulty breathing, stridor, kidney injury, and anemia. Our patient died less than 1 month after diagnosis—after only 1 round of chemotherapy—secondary to progressive disease and an uncontrollable gastrointestinal tract bleed. The leonine facies (Figure 1B) encountered in our patient can raise a differential diagnosis that includes infectious as well as neoplastic etiologies; however, most infectious etiologies associated with leonine facies manifest in a chronic fashion rather than with a sudden eruption, as noted in our patient.

Leprosy is caused by Mycobacterium leprae, a grampositive bacillus. The condition manifests across a spectrum, with the poles being tuberculoid and lepromatous, and borderline variants in between.^6-8 Lepromatous leprosy arises in individuals who are unable to mount cellular immunity against M leprae secondary to anergy.⁶ Lepromatous leprosy often presents with numerous papules and nodules. Aside from cutaneous manifestations, lepromatous leprosy has a predilection for peripheral nerves and specifically Schwann cells. Histologically, biopsy reveals a flat epidermis and a cell-free subepidermal grenz zone. Within the dermis, there is a diffuse histiocytic infiltrate that typically is not centered around nerves (Figure 2).^6,7 Mycobacterium leprae can appear scattered throughout or clustered in globi. Mycobacterium leprae stains red with Ziehl-Neelsen or Wade-Fite stains.^6,7 Immunohistochemistry reveals a CD4⁺ helper T cell (TH2) predominance, supported by the increased expression of type 2 reaction cytokines such as IL-4, IL-5, IL-10, and IL-13.⁸

Diffuse large B-cell lymphoma (DLBCL) embodies 10% to 20% of all primary cutaneous lymphomas; it is more prevalent in older adults (age range, 70–82 years) and women. Clinically, DLBCL presents as either single or multiple rapidly progressing nodules or plaques, usually violaceous or blue-red in color.^9,10 The most common area of presentation is on the legs, though it also can surface at other sites.⁹ On histology, DLBCL has clearly malignant features including frequent mitotic figures, large immunoblasts, and involvement throughout the dermis as well as perivascularly (Figure 3). Spindle-shaped cells and anaplastic features can be present. Immunohistochemically, DLBCL stains strongly positive for CD20 and B-cell lymphoma 2 (Bcl-2) along with other pan–B-cell markers.^9-11 The aggressive leg type of DLBCL stains positively for multiple myeloma oncogene 1 (MUM-1).^9,11

Cutaneous metastatic adenocarcinoma from internal malignancies occurs in approximately 5% of cancer patients with metastatic spread.¹² Most of these cutaneous lesions develop in close proximity to the primary tumor such as on the trunk, head, or neck. All cutaneous metastases carry a poor prognosis. Clinical presentation can vary greatly, ranging from painless, firm, or elastic nodules to lesions that mimic inflammatory skin conditions such as erysipelas or scleroderma. The majority of these metastases develop as painless firm nodules that are flesh colored, pink, red-brown, or purple.^12,13 The histopathology of metastatic adenocarcinoma demonstrates an infiltrative nodular appearance, though there rarely are well-circumscribed nodules found.¹³ The lesion originates in the dermis or subcutaneous tissue. It is a glandulartype lesion that may reflect the tissue of the primary tumor (Figure 4).^12,14 Immunohistochemical stains likely will remain consistent with those of the primary tumor, which is not always the case.¹⁴

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy of epithelial and neuroendocrine origin, first described as trabecular carcinoma due to the arrangement of tumor resembling cancellous bone.^15,16 Merkel cells are mechanoreceptors found near nerve terminals.¹⁷ Approximately 80% of MCCs are associated with Merkel cell polyomavirus, which is a small, double-stranded DNA virus with an icosahedral capsid.^17,18 Merkel cell polyomavirus–positive cases of MCC tend to have a better prognosis. In Merkel cell polyomavirus–negative MCC, there is an association with UV damage and increased chromosomal aberrations.¹⁸ Merkel cell carcinoma is known for its high rate of recurrence as well as local and distant metastasis. Nodal involvement is the most important prognostic indicator.¹⁵ Clinically, MCC is associated with the AEIOU mnemonic (asymptomatic, expanding rapidly, immunosuppression, older than 50 years, UV exposed/fair skin).^15-17 Lesions appear as red-blue papules on sun-exposed skin and usually are smaller than 2 cm by their greatest dimension. On histopathology, MCC demonstrates small, round, blue cells arranged in sheets or nests originating in the dermis and occasionally can infiltrate the subcutis and lymphovascular surroundings (Figure 5).^16-19 Cells have scant eosinophilic cytoplasm and may have fine granular chromatin. Numerous mitotic figures and apoptotic cells also are present. On immunohistochemistry, these cells will stain positive for cytokeratin AE1/AE3, anticytokeratin (CAM 5.2), CK20, and CD56. Due to their neuroendocrine derivation, they also are commonly synaptophysin, neuron-specific enolase, and chromogranin A positive. Notably, MCC will stain negative for leukocyte common antigen, CD20, CD3, CD34, and thyroid transcription factor 1 (TTF-1).^16,17

Primary cutaneous γδ T-cell lymphoma can be difficult to diagnose and requires urgent treatment. Clinicians and dermatopathologists need to work together to establish the diagnosis. There is a high mortality rate associated with PCGDTL, making prompt recognition and timely treatment critical. Acknowledgments—Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

Acknowledgments
Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

The Diagnosis: Erythropoietic Protoporphyria 

Erythropoietic protoporphyria (EPP) is an autosomal-recessive photodermatosis that results from loss of activity of ferrochelatase, the last enzyme in the heme biosynthetic pathway.¹ Erythropoietic protoporphyria normally involves sun-exposed areas of the body. Skin that is exposed to sunlight develops intense burning and stinging pain followed by erythema, edema, crusting, and petechiae that develops into waxy scarring over time. In contrast to other porphyrias, blistering generally is not seen.² Accurate diagnosis often can be delayed by a decade or more following symptom onset due to the prominence of subjective pain as the presenting sign.  

The histologic appearance of EPP differs depending on the chronicity of lesions. Biopsies of acute lesions show vacuolization of epidermal cells with intercellular edema, vacuolization and cytolysis of endothelial cells in superficial blood vessels, and focal red blood cell extravasation.^3,4 A largely neutrophilic inflammatory infiltrate can be present.⁵ Hyaline cuffing develops over time in and around vessels in the papillary and superficial reticular dermis with notable sparing of adnexal structures. The perivascular deposits are strongly periodic acid-Schiff (PAS) positive and diastase resistant (Figure 1). Direct immunofluorescence shows mainly IgG and some IgM, fibrinogen, and C3 outlining characteristic donut-shaped blood vessels in the papillary dermis.⁶ The prominent thickness of the perivascular hyaline material depositions and the absence of subepidermal blistering can help differentiate EPP from porphyria cutanea tarda (PCT) and pseudoporphyria.^6,7 When the deposition is extensive and involves the surrounding dermis, EPP can mimic colloid milium. Additional histologic differential diagnoses of EPP include other dermal depositional diseases such as lipoid proteinosis and amyloidosis.  

Lipoid proteinosis is an autosomal-recessive multisystem genodermatosis caused by mutations in extracellular matrix gene 1, ECM1. The first clinical sign can be a hoarse cry in infancy due to infiltration of vocal cords.³ Development of papulonodular lesions along the eyelids can result in a string-of-beads appearance called moniliform blepharosis, which is pathognomonic for lipoid proteinosis.⁶ With chronicity, the involved skin can become yellow, waxy, and thickened, particularly in the flexures or areas of trauma. Histologically, the dermis in lipoid proteinosis becomes diffusely thickened due to deposition of PAS-positive eosinophilic hyaline material that stains weakly with Congo red and thioflavin T.⁶ Early lesions demonstrate pale pink, hyalinelike thickening of the papillary dermal capillaries. Chronic lesions reveal an acanthotic epidermis, occasional papillomatosis with overlying hyperkeratosis, and a thickened dermis where diffuse thick bundles of pink hyaline deposits are oriented perpendicularly to the dermoepidermal junction.^1,6 Lipoid proteinosis can be differentiated from EPP by the involvement of adnexal structures such as hair follicles, sebaceous glands, and arrector pili muscles (Figure 2), as opposed to EPP where adnexal structures are spared.¹ Additionally, depositions in lipoid proteinosis are centered around both superficial and deep vessels with an onion skin-like pattern, while EPP involves mainly superficial vessels with more mild and focal hyalinization.

Juvenile colloid milium (JCM) is a rare condition that presents before puberty with discrete, yellow-brown, translucent papules predominantly located on the cheeks and nose and around the mouth. A gelatinous material can be expressed after puncturing a lesion.⁶ Gingival deposits and ligneous conjunctivitis also can be present. On histopathology, JCM shows degeneration of epidermal keratinocytes that form colloid bodies within the superficial dermis following apoptosis.⁶ Hematoxylin and eosin staining shows amorphous, fissured, pale pink deposits completely filling and expanding the superficial to mid dermis with clefting and no inflammation (Figure 3). Spindle-shaped fibroblasts may be seen within the lines of colloid fissuring and dispersed throughout the deposits.¹ Histologically, JCM can be differentiated from EPP because deposits in EPP are distributed around and within superficial blood vessel walls, causing prominent vascular thickening not seen in JCM.⁶ The adult variant of colloid milium also can be distinguished from EPP by the presence of solar elastosis, which is absent in EPP due to a history of sun avoidance.^3,7  

Lichen amyloidosis presents with highly pruritic, red-brown, hyperkeratotic papules that commonly are found on the anterior lower legs and extensor forearms.¹ The calves, ankles, dorsal aspects of the feet, thighs, and trunk also may be affected. Excoriations, lichenification, and nodular prurigo-like lesions due to chronic scratching can be present.⁶ Lichen amyloidosis is characterized by large, pink, amorphous deposits in the papillary dermis with epidermal acanthosis, hypergranulosis, and hyperkeratosis (Figure 4).⁶ Perivascular deposits are not a feature of primary cutaneous localized amyloid lesions.⁶ The diagnosis can be confirmed with Congo red staining under polarized light, which classically demonstrates apple green birefringence.¹ For cases of amyloid that are not detected by Congo red or are not clear-cut, direct immunofluorescence and immunohistochemistry can be used as adjuncts for diagnosis. Amyloid deposits fluoresce positively for immunoglobulins or complements, particularly IgM and C3,⁸ and immunohistochemistry confirms the presence of keratin epitopes in deposits.⁹  

Porphyria cutanea tarda can appear histologically similar to EPP. Caterpillar bodies, or linearly arranged eosinophilic PAS-positive globules in the epidermis overlying subepidermal bullae, are a diagnostic histopathologic finding in both PCT and EPP but are seen in less than half of both cases.^7,10 Compared to EPP, the perivascular deposits in PCT typically are less pronounced and limited to the vessel wall with smaller hyaline cuffs (Figure 5).⁷ Additionally, solar elastosis can be seen in PCT lesions but not in EPP, as patients with PCT tend to be older and have increased cumulative sun damage.  

The Diagnosis: Erythropoietic Protoporphyria 

Erythropoietic protoporphyria (EPP) is an autosomal-recessive photodermatosis that results from loss of activity of ferrochelatase, the last enzyme in the heme biosynthetic pathway.¹ Erythropoietic protoporphyria normally involves sun-exposed areas of the body. Skin that is exposed to sunlight develops intense burning and stinging pain followed by erythema, edema, crusting, and petechiae that develops into waxy scarring over time. In contrast to other porphyrias, blistering generally is not seen.² Accurate diagnosis often can be delayed by a decade or more following symptom onset due to the prominence of subjective pain as the presenting sign.  

The histologic appearance of EPP differs depending on the chronicity of lesions. Biopsies of acute lesions show vacuolization of epidermal cells with intercellular edema, vacuolization and cytolysis of endothelial cells in superficial blood vessels, and focal red blood cell extravasation.^3,4 A largely neutrophilic inflammatory infiltrate can be present.⁵ Hyaline cuffing develops over time in and around vessels in the papillary and superficial reticular dermis with notable sparing of adnexal structures. The perivascular deposits are strongly periodic acid-Schiff (PAS) positive and diastase resistant (Figure 1). Direct immunofluorescence shows mainly IgG and some IgM, fibrinogen, and C3 outlining characteristic donut-shaped blood vessels in the papillary dermis.⁶ The prominent thickness of the perivascular hyaline material depositions and the absence of subepidermal blistering can help differentiate EPP from porphyria cutanea tarda (PCT) and pseudoporphyria.^6,7 When the deposition is extensive and involves the surrounding dermis, EPP can mimic colloid milium. Additional histologic differential diagnoses of EPP include other dermal depositional diseases such as lipoid proteinosis and amyloidosis.  

Lipoid proteinosis is an autosomal-recessive multisystem genodermatosis caused by mutations in extracellular matrix gene 1, ECM1. The first clinical sign can be a hoarse cry in infancy due to infiltration of vocal cords.³ Development of papulonodular lesions along the eyelids can result in a string-of-beads appearance called moniliform blepharosis, which is pathognomonic for lipoid proteinosis.⁶ With chronicity, the involved skin can become yellow, waxy, and thickened, particularly in the flexures or areas of trauma. Histologically, the dermis in lipoid proteinosis becomes diffusely thickened due to deposition of PAS-positive eosinophilic hyaline material that stains weakly with Congo red and thioflavin T.⁶ Early lesions demonstrate pale pink, hyalinelike thickening of the papillary dermal capillaries. Chronic lesions reveal an acanthotic epidermis, occasional papillomatosis with overlying hyperkeratosis, and a thickened dermis where diffuse thick bundles of pink hyaline deposits are oriented perpendicularly to the dermoepidermal junction.^1,6 Lipoid proteinosis can be differentiated from EPP by the involvement of adnexal structures such as hair follicles, sebaceous glands, and arrector pili muscles (Figure 2), as opposed to EPP where adnexal structures are spared.¹ Additionally, depositions in lipoid proteinosis are centered around both superficial and deep vessels with an onion skin-like pattern, while EPP involves mainly superficial vessels with more mild and focal hyalinization.

Juvenile colloid milium (JCM) is a rare condition that presents before puberty with discrete, yellow-brown, translucent papules predominantly located on the cheeks and nose and around the mouth. A gelatinous material can be expressed after puncturing a lesion.⁶ Gingival deposits and ligneous conjunctivitis also can be present. On histopathology, JCM shows degeneration of epidermal keratinocytes that form colloid bodies within the superficial dermis following apoptosis.⁶ Hematoxylin and eosin staining shows amorphous, fissured, pale pink deposits completely filling and expanding the superficial to mid dermis with clefting and no inflammation (Figure 3). Spindle-shaped fibroblasts may be seen within the lines of colloid fissuring and dispersed throughout the deposits.¹ Histologically, JCM can be differentiated from EPP because deposits in EPP are distributed around and within superficial blood vessel walls, causing prominent vascular thickening not seen in JCM.⁶ The adult variant of colloid milium also can be distinguished from EPP by the presence of solar elastosis, which is absent in EPP due to a history of sun avoidance.^3,7  

Lichen amyloidosis presents with highly pruritic, red-brown, hyperkeratotic papules that commonly are found on the anterior lower legs and extensor forearms.¹ The calves, ankles, dorsal aspects of the feet, thighs, and trunk also may be affected. Excoriations, lichenification, and nodular prurigo-like lesions due to chronic scratching can be present.⁶ Lichen amyloidosis is characterized by large, pink, amorphous deposits in the papillary dermis with epidermal acanthosis, hypergranulosis, and hyperkeratosis (Figure 4).⁶ Perivascular deposits are not a feature of primary cutaneous localized amyloid lesions.⁶ The diagnosis can be confirmed with Congo red staining under polarized light, which classically demonstrates apple green birefringence.¹ For cases of amyloid that are not detected by Congo red or are not clear-cut, direct immunofluorescence and immunohistochemistry can be used as adjuncts for diagnosis. Amyloid deposits fluoresce positively for immunoglobulins or complements, particularly IgM and C3,⁸ and immunohistochemistry confirms the presence of keratin epitopes in deposits.⁹  

Porphyria cutanea tarda can appear histologically similar to EPP. Caterpillar bodies, or linearly arranged eosinophilic PAS-positive globules in the epidermis overlying subepidermal bullae, are a diagnostic histopathologic finding in both PCT and EPP but are seen in less than half of both cases.^7,10 Compared to EPP, the perivascular deposits in PCT typically are less pronounced and limited to the vessel wall with smaller hyaline cuffs (Figure 5).⁷ Additionally, solar elastosis can be seen in PCT lesions but not in EPP, as patients with PCT tend to be older and have increased cumulative sun damage.  

The Diagnosis: Erythropoietic Protoporphyria 

Erythropoietic protoporphyria (EPP) is an autosomal-recessive photodermatosis that results from loss of activity of ferrochelatase, the last enzyme in the heme biosynthetic pathway.¹ Erythropoietic protoporphyria normally involves sun-exposed areas of the body. Skin that is exposed to sunlight develops intense burning and stinging pain followed by erythema, edema, crusting, and petechiae that develops into waxy scarring over time. In contrast to other porphyrias, blistering generally is not seen.² Accurate diagnosis often can be delayed by a decade or more following symptom onset due to the prominence of subjective pain as the presenting sign.  

The histologic appearance of EPP differs depending on the chronicity of lesions. Biopsies of acute lesions show vacuolization of epidermal cells with intercellular edema, vacuolization and cytolysis of endothelial cells in superficial blood vessels, and focal red blood cell extravasation.^3,4 A largely neutrophilic inflammatory infiltrate can be present.⁵ Hyaline cuffing develops over time in and around vessels in the papillary and superficial reticular dermis with notable sparing of adnexal structures. The perivascular deposits are strongly periodic acid-Schiff (PAS) positive and diastase resistant (Figure 1). Direct immunofluorescence shows mainly IgG and some IgM, fibrinogen, and C3 outlining characteristic donut-shaped blood vessels in the papillary dermis.⁶ The prominent thickness of the perivascular hyaline material depositions and the absence of subepidermal blistering can help differentiate EPP from porphyria cutanea tarda (PCT) and pseudoporphyria.^6,7 When the deposition is extensive and involves the surrounding dermis, EPP can mimic colloid milium. Additional histologic differential diagnoses of EPP include other dermal depositional diseases such as lipoid proteinosis and amyloidosis.  

Lipoid proteinosis is an autosomal-recessive multisystem genodermatosis caused by mutations in extracellular matrix gene 1, ECM1. The first clinical sign can be a hoarse cry in infancy due to infiltration of vocal cords.³ Development of papulonodular lesions along the eyelids can result in a string-of-beads appearance called moniliform blepharosis, which is pathognomonic for lipoid proteinosis.⁶ With chronicity, the involved skin can become yellow, waxy, and thickened, particularly in the flexures or areas of trauma. Histologically, the dermis in lipoid proteinosis becomes diffusely thickened due to deposition of PAS-positive eosinophilic hyaline material that stains weakly with Congo red and thioflavin T.⁶ Early lesions demonstrate pale pink, hyalinelike thickening of the papillary dermal capillaries. Chronic lesions reveal an acanthotic epidermis, occasional papillomatosis with overlying hyperkeratosis, and a thickened dermis where diffuse thick bundles of pink hyaline deposits are oriented perpendicularly to the dermoepidermal junction.^1,6 Lipoid proteinosis can be differentiated from EPP by the involvement of adnexal structures such as hair follicles, sebaceous glands, and arrector pili muscles (Figure 2), as opposed to EPP where adnexal structures are spared.¹ Additionally, depositions in lipoid proteinosis are centered around both superficial and deep vessels with an onion skin-like pattern, while EPP involves mainly superficial vessels with more mild and focal hyalinization.

Juvenile colloid milium (JCM) is a rare condition that presents before puberty with discrete, yellow-brown, translucent papules predominantly located on the cheeks and nose and around the mouth. A gelatinous material can be expressed after puncturing a lesion.⁶ Gingival deposits and ligneous conjunctivitis also can be present. On histopathology, JCM shows degeneration of epidermal keratinocytes that form colloid bodies within the superficial dermis following apoptosis.⁶ Hematoxylin and eosin staining shows amorphous, fissured, pale pink deposits completely filling and expanding the superficial to mid dermis with clefting and no inflammation (Figure 3). Spindle-shaped fibroblasts may be seen within the lines of colloid fissuring and dispersed throughout the deposits.¹ Histologically, JCM can be differentiated from EPP because deposits in EPP are distributed around and within superficial blood vessel walls, causing prominent vascular thickening not seen in JCM.⁶ The adult variant of colloid milium also can be distinguished from EPP by the presence of solar elastosis, which is absent in EPP due to a history of sun avoidance.^3,7  

Lichen amyloidosis presents with highly pruritic, red-brown, hyperkeratotic papules that commonly are found on the anterior lower legs and extensor forearms.¹ The calves, ankles, dorsal aspects of the feet, thighs, and trunk also may be affected. Excoriations, lichenification, and nodular prurigo-like lesions due to chronic scratching can be present.⁶ Lichen amyloidosis is characterized by large, pink, amorphous deposits in the papillary dermis with epidermal acanthosis, hypergranulosis, and hyperkeratosis (Figure 4).⁶ Perivascular deposits are not a feature of primary cutaneous localized amyloid lesions.⁶ The diagnosis can be confirmed with Congo red staining under polarized light, which classically demonstrates apple green birefringence.¹ For cases of amyloid that are not detected by Congo red or are not clear-cut, direct immunofluorescence and immunohistochemistry can be used as adjuncts for diagnosis. Amyloid deposits fluoresce positively for immunoglobulins or complements, particularly IgM and C3,⁸ and immunohistochemistry confirms the presence of keratin epitopes in deposits.⁹  

Porphyria cutanea tarda can appear histologically similar to EPP. Caterpillar bodies, or linearly arranged eosinophilic PAS-positive globules in the epidermis overlying subepidermal bullae, are a diagnostic histopathologic finding in both PCT and EPP but are seen in less than half of both cases.^7,10 Compared to EPP, the perivascular deposits in PCT typically are less pronounced and limited to the vessel wall with smaller hyaline cuffs (Figure 5).⁷ Additionally, solar elastosis can be seen in PCT lesions but not in EPP, as patients with PCT tend to be older and have increased cumulative sun damage.  

The Diagnosis: Scleredema Diabeticorum  

Histologically, scleredema is characterized by mucin deposition between collagen bundles in the deep dermis. Clinically, it is characterized by a progressive indurated plaque with associated stiffness of the involved area. It most commonly presents on the posterior aspect of the neck, though it can extend to involve the shoulders and upper torso.¹ Scleredema is divided into 3 subtypes based on clinical associations. Type 1 often is preceded by an infection, most commonly group A Streptococcus. This type occurs acutely and often resolves completely over a few months.² Type 2, which has progressive onset, is associated with monoclonal gammopathy.³ Type 3 is the most common type and is associated with diabetes mellitus. A study of 484 patients with type 2 diabetes mellitus demonstrated a prevalence of 2.5%.⁴ Although the exact pathogenesis has not been defined, it is hypothesized that irreversible glycosylation of collagen and alterations in collagenase activity may lead to accumulation of collagen and mucin in the dermis.⁵ Similar to type 2, type 3 scleredema appears subtly, progresses slowly, and tends to be chronic.^1,6 Scleredema is characterized by marked dermal thickening and enlarged collagen bundles separated by mucin deposition (Figure 1). Fibroblast proliferation is characteristically absent.¹ 

Clinically, tumid lupus erythematosus presents with erythematous edematous plaques on sun-exposed areas.⁷ Pretibial myxedema (PM) classically is associated with Graves disease; however, it can present in association with other types of thyroid dysfunction. Classically, PM presents on the pretibial regions as well-demarcated erythematous or hyperpigmented plaques.⁸ Similar to scleredema, histologic examination of tumid lupus erythematosus and PM reveals mucin deposition. Tumid lupus erythematosus also may demonstrate periadnexal and perivascular lymphocytic inflammation (Figure 2).⁷ The collagen bundles present in PM often are thin in comparison to scleredema (Figure 3).⁸ 

Scleroderma also presents with skin induration, erythema, and stiffening. However, unlike scleredema, scleroderma commonly involves the fingers, toes, and face. It presents with symptoms of Raynaud phenomenon, painful digital nonpitting edema, perioral skin tightening, mucocutaneous telangiectasia, and calcinosis cutis. Scleroderma also can involve organs such as the lungs, heart, kidneys, and gastrointestinal tract.⁹ Histologically, scleroderma is characterized by a compact dermis with closely packed collagen bundles. Other features of scleroderma can include perivascular mononuclear inflammatory cell infiltration, progressive atrophy of intradermal and perieccrine fat, and fibrosis (Figure 4).¹⁰ 

Scleromyxedema, also called papular mucinosis, is primary dermal mucinosis that often presents with waxy, dome-shaped papules that may coalesce into plaques. Similar to scleredema, scleromyxedema shows increased mucin deposition. However, scleromyxedema commonly is associated with fibroblast proliferation, which is characteristically absent in scleredema (Figure 5).¹¹

The Diagnosis: Scleredema Diabeticorum  

Histologically, scleredema is characterized by mucin deposition between collagen bundles in the deep dermis. Clinically, it is characterized by a progressive indurated plaque with associated stiffness of the involved area. It most commonly presents on the posterior aspect of the neck, though it can extend to involve the shoulders and upper torso.¹ Scleredema is divided into 3 subtypes based on clinical associations. Type 1 often is preceded by an infection, most commonly group A Streptococcus. This type occurs acutely and often resolves completely over a few months.² Type 2, which has progressive onset, is associated with monoclonal gammopathy.³ Type 3 is the most common type and is associated with diabetes mellitus. A study of 484 patients with type 2 diabetes mellitus demonstrated a prevalence of 2.5%.⁴ Although the exact pathogenesis has not been defined, it is hypothesized that irreversible glycosylation of collagen and alterations in collagenase activity may lead to accumulation of collagen and mucin in the dermis.⁵ Similar to type 2, type 3 scleredema appears subtly, progresses slowly, and tends to be chronic.^1,6 Scleredema is characterized by marked dermal thickening and enlarged collagen bundles separated by mucin deposition (Figure 1). Fibroblast proliferation is characteristically absent.¹ 

Clinically, tumid lupus erythematosus presents with erythematous edematous plaques on sun-exposed areas.⁷ Pretibial myxedema (PM) classically is associated with Graves disease; however, it can present in association with other types of thyroid dysfunction. Classically, PM presents on the pretibial regions as well-demarcated erythematous or hyperpigmented plaques.⁸ Similar to scleredema, histologic examination of tumid lupus erythematosus and PM reveals mucin deposition. Tumid lupus erythematosus also may demonstrate periadnexal and perivascular lymphocytic inflammation (Figure 2).⁷ The collagen bundles present in PM often are thin in comparison to scleredema (Figure 3).⁸ 

Scleroderma also presents with skin induration, erythema, and stiffening. However, unlike scleredema, scleroderma commonly involves the fingers, toes, and face. It presents with symptoms of Raynaud phenomenon, painful digital nonpitting edema, perioral skin tightening, mucocutaneous telangiectasia, and calcinosis cutis. Scleroderma also can involve organs such as the lungs, heart, kidneys, and gastrointestinal tract.⁹ Histologically, scleroderma is characterized by a compact dermis with closely packed collagen bundles. Other features of scleroderma can include perivascular mononuclear inflammatory cell infiltration, progressive atrophy of intradermal and perieccrine fat, and fibrosis (Figure 4).¹⁰ 

Scleromyxedema, also called papular mucinosis, is primary dermal mucinosis that often presents with waxy, dome-shaped papules that may coalesce into plaques. Similar to scleredema, scleromyxedema shows increased mucin deposition. However, scleromyxedema commonly is associated with fibroblast proliferation, which is characteristically absent in scleredema (Figure 5).¹¹

The Diagnosis: Scleredema Diabeticorum  

Histologically, scleredema is characterized by mucin deposition between collagen bundles in the deep dermis. Clinically, it is characterized by a progressive indurated plaque with associated stiffness of the involved area. It most commonly presents on the posterior aspect of the neck, though it can extend to involve the shoulders and upper torso.¹ Scleredema is divided into 3 subtypes based on clinical associations. Type 1 often is preceded by an infection, most commonly group A Streptococcus. This type occurs acutely and often resolves completely over a few months.² Type 2, which has progressive onset, is associated with monoclonal gammopathy.³ Type 3 is the most common type and is associated with diabetes mellitus. A study of 484 patients with type 2 diabetes mellitus demonstrated a prevalence of 2.5%.⁴ Although the exact pathogenesis has not been defined, it is hypothesized that irreversible glycosylation of collagen and alterations in collagenase activity may lead to accumulation of collagen and mucin in the dermis.⁵ Similar to type 2, type 3 scleredema appears subtly, progresses slowly, and tends to be chronic.^1,6 Scleredema is characterized by marked dermal thickening and enlarged collagen bundles separated by mucin deposition (Figure 1). Fibroblast proliferation is characteristically absent.¹ 

Clinically, tumid lupus erythematosus presents with erythematous edematous plaques on sun-exposed areas.⁷ Pretibial myxedema (PM) classically is associated with Graves disease; however, it can present in association with other types of thyroid dysfunction. Classically, PM presents on the pretibial regions as well-demarcated erythematous or hyperpigmented plaques.⁸ Similar to scleredema, histologic examination of tumid lupus erythematosus and PM reveals mucin deposition. Tumid lupus erythematosus also may demonstrate periadnexal and perivascular lymphocytic inflammation (Figure 2).⁷ The collagen bundles present in PM often are thin in comparison to scleredema (Figure 3).⁸ 

Scleroderma also presents with skin induration, erythema, and stiffening. However, unlike scleredema, scleroderma commonly involves the fingers, toes, and face. It presents with symptoms of Raynaud phenomenon, painful digital nonpitting edema, perioral skin tightening, mucocutaneous telangiectasia, and calcinosis cutis. Scleroderma also can involve organs such as the lungs, heart, kidneys, and gastrointestinal tract.⁹ Histologically, scleroderma is characterized by a compact dermis with closely packed collagen bundles. Other features of scleroderma can include perivascular mononuclear inflammatory cell infiltration, progressive atrophy of intradermal and perieccrine fat, and fibrosis (Figure 4).¹⁰ 

Scleromyxedema, also called papular mucinosis, is primary dermal mucinosis that often presents with waxy, dome-shaped papules that may coalesce into plaques. Similar to scleredema, scleromyxedema shows increased mucin deposition. However, scleromyxedema commonly is associated with fibroblast proliferation, which is characteristically absent in scleredema (Figure 5).¹¹