Richard Miller, DO

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

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

The Diagnosis: Phacomatosis Cesioflammea  

Phacomatosis pigmentovascularis (PPV) encompasses a group of diseases that have a vascular nevus coupled with a pigmented nevus.¹ It is divided into 5 types: Type I is defined by the presence of a vascular malformation and epidermal nevus; type II by a vascular malformation and dermal melanosis with or without nevus anemicus; type III by a vascular malformation and nevus spilus with or without nevus anemicus; type IV by a vascular malformation, dermal melanosis, and nevus spilus with or without nevus anemicus; and type V as cutis marmorata telangiectatica congenita and dermal melanosis.¹  

Happle² proposed a descriptive classification system in 2005 that eliminated type I PPV because neither linear epidermal nevus nor Becker nevus are derived from pigmentary cells. An appended "a" denotes a subtype with isolated cutaneous findings, while "b" is associated with extracutaneous manifestations. Phacomatosis cesioflammea (type IIa/b) refers to blue-hued dermal melanocytosis and nevus flammeus. Phacomatosis spilorosea (type IIIa/b) refers to nevus spilus and rose-colored nevus flammeus. Phacomatosis cesiomarmorata (type Va/b) refers to dermal melanocytosis and cutis marmorata telangiectasia congenita. The last group (type IVa/b) is unclassifiable phacomatosis pigmentovascularis.^2,3  

Phacomatosis pigmentovascularis can be isolated to the skin or have associated extracutaneous findings, including ocular melanocytosis, seizures, or cognitive delay due to intracerebral vascular malformations. Patients also can develop limb and soft-tissue overgrowth.⁴ Phacomatosis pigmentovascularis has been found to be associated with mutations in the GNA11 and GNAQ genes. The theory behind PPV is twin spotting, resulting from a somatic mutation that leads to mosaic proliferation of 2 different cell lines.⁵ Phacomatosis pigmentovascularis can occur in isolation or can demonstrate the phenotype of Sturge-Weber syndrome or Klippel-Trenaunay syndrome. In Sturge-Weber syndrome, capillary malformations involve the face and underlying leptomeninges and cerebral cortex. Glaucoma and epilepsy also may be present. In Klippel-Trenaunay syndrome, capillary malformations involve the extremities (usually the legs) in association with varicose veins, soft-tissue hypertrophy, and skeletal overgrowth.^6-9 Tuberous sclerosis is an autosomal-dominant neurocutaneous disease in which patients develop hamartomas throughout the body, including the brain, skin, eyes, kidneys, heart, and lungs. Cutaneous manifestations include facial angiofibromas, ungual fibromas, hypomelanotic macules (ash leaf spots, confetti-like lesions), shagreen patches or connective tissue hamartomas, and fibrous plaques on the forehead. Tuberous sclerosis does not include vascular malformations.¹⁰  

Our patient was diagnosed with PPV type IIb, or phacomatosis cesioflammea. He had a large port-wine stain involving the right upper arm, back (Figure, A), and chest (Figure, B) with involvement of the bilateral conjunctivae (Figure, C). Our case is unique because our patient did not have dermal melanocytosis, only ocular melanocytosis.  

Once underlying neurologic and vascular anomalies have been ruled out, port-wine stains can be treated cosmetically. Pulsed dye laser is the gold standard therapy for capillary malformations, especially when instituted early. Follow-up with ophthalmology is advised to monitor ocular involvement. Shields et al¹¹ suggested dilated fundoscopy for patients with port-wine stains because choroidal pigmentation often is the only ocular change seen. Ocular melanocytosis can progress to pigmented glaucoma or choroidal melanoma. 

The Diagnosis: Phacomatosis Cesioflammea  

Phacomatosis pigmentovascularis (PPV) encompasses a group of diseases that have a vascular nevus coupled with a pigmented nevus.¹ It is divided into 5 types: Type I is defined by the presence of a vascular malformation and epidermal nevus; type II by a vascular malformation and dermal melanosis with or without nevus anemicus; type III by a vascular malformation and nevus spilus with or without nevus anemicus; type IV by a vascular malformation, dermal melanosis, and nevus spilus with or without nevus anemicus; and type V as cutis marmorata telangiectatica congenita and dermal melanosis.¹  

Happle² proposed a descriptive classification system in 2005 that eliminated type I PPV because neither linear epidermal nevus nor Becker nevus are derived from pigmentary cells. An appended "a" denotes a subtype with isolated cutaneous findings, while "b" is associated with extracutaneous manifestations. Phacomatosis cesioflammea (type IIa/b) refers to blue-hued dermal melanocytosis and nevus flammeus. Phacomatosis spilorosea (type IIIa/b) refers to nevus spilus and rose-colored nevus flammeus. Phacomatosis cesiomarmorata (type Va/b) refers to dermal melanocytosis and cutis marmorata telangiectasia congenita. The last group (type IVa/b) is unclassifiable phacomatosis pigmentovascularis.^2,3  

Phacomatosis pigmentovascularis can be isolated to the skin or have associated extracutaneous findings, including ocular melanocytosis, seizures, or cognitive delay due to intracerebral vascular malformations. Patients also can develop limb and soft-tissue overgrowth.⁴ Phacomatosis pigmentovascularis has been found to be associated with mutations in the GNA11 and GNAQ genes. The theory behind PPV is twin spotting, resulting from a somatic mutation that leads to mosaic proliferation of 2 different cell lines.⁵ Phacomatosis pigmentovascularis can occur in isolation or can demonstrate the phenotype of Sturge-Weber syndrome or Klippel-Trenaunay syndrome. In Sturge-Weber syndrome, capillary malformations involve the face and underlying leptomeninges and cerebral cortex. Glaucoma and epilepsy also may be present. In Klippel-Trenaunay syndrome, capillary malformations involve the extremities (usually the legs) in association with varicose veins, soft-tissue hypertrophy, and skeletal overgrowth.^6-9 Tuberous sclerosis is an autosomal-dominant neurocutaneous disease in which patients develop hamartomas throughout the body, including the brain, skin, eyes, kidneys, heart, and lungs. Cutaneous manifestations include facial angiofibromas, ungual fibromas, hypomelanotic macules (ash leaf spots, confetti-like lesions), shagreen patches or connective tissue hamartomas, and fibrous plaques on the forehead. Tuberous sclerosis does not include vascular malformations.¹⁰  

Our patient was diagnosed with PPV type IIb, or phacomatosis cesioflammea. He had a large port-wine stain involving the right upper arm, back (Figure, A), and chest (Figure, B) with involvement of the bilateral conjunctivae (Figure, C). Our case is unique because our patient did not have dermal melanocytosis, only ocular melanocytosis.  

Once underlying neurologic and vascular anomalies have been ruled out, port-wine stains can be treated cosmetically. Pulsed dye laser is the gold standard therapy for capillary malformations, especially when instituted early. Follow-up with ophthalmology is advised to monitor ocular involvement. Shields et al¹¹ suggested dilated fundoscopy for patients with port-wine stains because choroidal pigmentation often is the only ocular change seen. Ocular melanocytosis can progress to pigmented glaucoma or choroidal melanoma. 

The Diagnosis: Phacomatosis Cesioflammea  

Phacomatosis pigmentovascularis (PPV) encompasses a group of diseases that have a vascular nevus coupled with a pigmented nevus.¹ It is divided into 5 types: Type I is defined by the presence of a vascular malformation and epidermal nevus; type II by a vascular malformation and dermal melanosis with or without nevus anemicus; type III by a vascular malformation and nevus spilus with or without nevus anemicus; type IV by a vascular malformation, dermal melanosis, and nevus spilus with or without nevus anemicus; and type V as cutis marmorata telangiectatica congenita and dermal melanosis.¹  

Happle² proposed a descriptive classification system in 2005 that eliminated type I PPV because neither linear epidermal nevus nor Becker nevus are derived from pigmentary cells. An appended "a" denotes a subtype with isolated cutaneous findings, while "b" is associated with extracutaneous manifestations. Phacomatosis cesioflammea (type IIa/b) refers to blue-hued dermal melanocytosis and nevus flammeus. Phacomatosis spilorosea (type IIIa/b) refers to nevus spilus and rose-colored nevus flammeus. Phacomatosis cesiomarmorata (type Va/b) refers to dermal melanocytosis and cutis marmorata telangiectasia congenita. The last group (type IVa/b) is unclassifiable phacomatosis pigmentovascularis.^2,3  

Phacomatosis pigmentovascularis can be isolated to the skin or have associated extracutaneous findings, including ocular melanocytosis, seizures, or cognitive delay due to intracerebral vascular malformations. Patients also can develop limb and soft-tissue overgrowth.⁴ Phacomatosis pigmentovascularis has been found to be associated with mutations in the GNA11 and GNAQ genes. The theory behind PPV is twin spotting, resulting from a somatic mutation that leads to mosaic proliferation of 2 different cell lines.⁵ Phacomatosis pigmentovascularis can occur in isolation or can demonstrate the phenotype of Sturge-Weber syndrome or Klippel-Trenaunay syndrome. In Sturge-Weber syndrome, capillary malformations involve the face and underlying leptomeninges and cerebral cortex. Glaucoma and epilepsy also may be present. In Klippel-Trenaunay syndrome, capillary malformations involve the extremities (usually the legs) in association with varicose veins, soft-tissue hypertrophy, and skeletal overgrowth.^6-9 Tuberous sclerosis is an autosomal-dominant neurocutaneous disease in which patients develop hamartomas throughout the body, including the brain, skin, eyes, kidneys, heart, and lungs. Cutaneous manifestations include facial angiofibromas, ungual fibromas, hypomelanotic macules (ash leaf spots, confetti-like lesions), shagreen patches or connective tissue hamartomas, and fibrous plaques on the forehead. Tuberous sclerosis does not include vascular malformations.¹⁰  

Our patient was diagnosed with PPV type IIb, or phacomatosis cesioflammea. He had a large port-wine stain involving the right upper arm, back (Figure, A), and chest (Figure, B) with involvement of the bilateral conjunctivae (Figure, C). Our case is unique because our patient did not have dermal melanocytosis, only ocular melanocytosis.  

Once underlying neurologic and vascular anomalies have been ruled out, port-wine stains can be treated cosmetically. Pulsed dye laser is the gold standard therapy for capillary malformations, especially when instituted early. Follow-up with ophthalmology is advised to monitor ocular involvement. Shields et al¹¹ suggested dilated fundoscopy for patients with port-wine stains because choroidal pigmentation often is the only ocular change seen. Ocular melanocytosis can progress to pigmented glaucoma or choroidal melanoma.