Nonmelanoma Skin Cancer

In the late 19th century, Brooke and Spiegler described the familial occurrence of multiple tumors of the skin appendages. Synonyms have included familial cylindromatosis, turban tumor syndrome, and Brooke-Spiegler syndrome (BSS).1 In this report, we describe a patient with pegged teeth and BSS. We discuss the pathogenesis, diagnosis, genetic testing, and treatment options for this interesting syndrome.

Case Report
A 40-year-old white woman presented in 1997 for evaluation of numerous flesh-colored papules on her face. One of the lesions was biopsied in 1999 and diagnosed as a trichoepithelioma (Figure 1). These particular lesions had been present since she was 13 years of age, increasing in size and number with time. Subsequently, in December 2003, she presented with a 0.8-cm pink papule in the left preauricular area; a biopsy was performed and a spiradenoma in association with a trichoepithelioma was diagnosed. In January 2006, she presented with enlarging "bumps" on her scalp. She denied any substantial pain, pruritus, or other symptoms, but was rather concerned about the recent growth of lesions, both in size and number. Her medical history was noncontributory. However, there was a family history of similar lesions on the face and scalp of a great-aunt and uncle. No workup or genetic testing was ever performed.

Physical examination revealed a healthy, well-nourished, middle-aged woman. There were numerous symmetrically distributed flesh-colored to off-white firm papules involving the bilateral nasolabial folds, coalescing in areas to form plaques (Figure 2). There were 3 pink, firm, smooth, well-circumscribed nodules with overlying telangiectases involving the vertex and crown of the scalp, measuring 0.7X0.7 cm, 1.4X1.1 cm, and 1.4X1.4 cm in size. There was mild tenderness to palpation of all 3 lesions. Most interestingly, examination of the oral cavity revealed pegged (conical) teeth (Figure 3). It was not clear if they were primary or secondary teeth. There was no history of incontinentia pigmenti or any other ectodermal dysplasia in the patient or family members. Further evaluation of the hair and nails revealed no additional abnormalities.

The differential diagnoses for the scalp lesions included pilar cysts, basal or squamous cell carcinomas, spiradenomas, cylindromas, trichoblastomas, neurofibromas, and keloids or hypertrophic scars. The patient underwent an excisional biopsy of the smallest lesion in February 2006. Subsequently, excisional biopsies were performed on the other 2 lesions in April and July 2006. The first specimen revealed variably sized discrete aggregations of cuboidal epithelial cells with a rim of thickened eosinophilic basement membrane material surrounding tumor islands. There were 2 types of epithelial cells: cells with small, dark-staining nuclei present at the periphery in a palisading fashion, and light-staining nuclei lying in the center of the aggregations. Sweat duct lumina were appreciated within the tumor islands, and a diagnosis of cylindroma was made. The second biopsy showed a single, large, well-demarcated nodule of cuboidal epithelial cells arranged in interweaving cords present in the dermis. Again, there were 2 types of epithelial cells: smaller cells with dark nuclei lying at the periphery of the cords, and cells with larger pale nuclei in the center of the cords, associated with lumina. A diagnosis of spiradenoma was rendered. Based on the clinical findings and histopathologic diagnoses of trichoepithelioma, cylindroma, and spiradenoma, the patient received a diagnosis of BSS. Treatment for the trichoepitheliomas consisted of several glycolic acid peels, and the patient was pleased with the results. Furthermore, complete excisional biopsies were performed for all tumors on the scalp. The patient considered genetic testing for herself and family members.

Comment
Brooke-Spiegler syndrome is inherited in an autosomal dominant fashion with complete penetrance and variable expression. Both interfamilial and intrafamilial phenotypic variability have been well-documented in BSS; thus, a correlation between genotype and phenotype is lacking.2 Brooke-Spiegler syndrome is uncommon, with a female to male ratio of 2 to 1.1 Characteristically, patients present with the classic triad of cylindromas, trichoepitheliomas, and spiradenomas. Often, other adnexal tumors are observed, including but not limited to trichoblastomas, basal cell carcinomas, milia, organoid nevi, and syringomas.3 It was initially believed that cylindromas and spiradenomas showed sweat gland differentiation and trichoepitheliomas showed follicular differentiation.4 This combination represents an unusual inherited tumor diathesis involving neoplasms derived from pluripotential basal cells with adnexal differentiation along both sweat gland and follicular lineages.5-7 Typically, these tumors are located in the head and neck region, appear in puberty to early adulthood, and gradually increase in size and number throughout life.8 Malignant transformation of cylindromas in particular is quite rare, but metastasis in the event of malignancy is not infrequent.9-11 Malignancy is more frequent in patients with BSS rather than solitary cylindroma.10-12 Patients also are at risk for developing benign and malignant tumors of the salivary glands, particularly the parotid, including adenocarcinoma.4,6,8,13 In affected families, mutations have been demonstrated in the cylindromatosis gene, CYLD, located on band 16q12-13.¹⁴ This gene consists of 20 exons and reveals the characteristic attributes of a tumor suppressor gene with loss of heterozygosity.1,15,16 CYLD plays a role in governing cell cycle and apoptosis.9 Mutational changes in the CYLD gene could affect the normal regulation of the stem cell population of the folliculosebaceousapocrine unit. In turn, mutations in the genes that regulate proliferation and differentiation of the putative stem cells, possibly located in the bulge region of the hair follicle,3 could give rise to different combinations of adnexal skin tumors.1,2,17-19 More recently, spiradenomas have been proposed to be apocrine tumors on the basis of adnexal morphogenesis and their close association with follicular and apocrine tumors in BSS.10 The morphogenesis of both apocrine and sebaceous glands is dependent on the hair follicle because the glands develop from epithelial buds arising directly above the isthmus. However, eccrine glands develop from the base of the interfollicular rete ridges of embryonic skin. Cylindromas and spiradenomas are not eccrine tumors but neoplasms of the folliculosebaceousapocrine unit, as demonstrated by the occurrence of sebaceous and trichoblastic differentiation in spiradenocylindromas. It is hypothesized that cylindromas and spiradenomas may be polar extremes of a spectrum of adnexal neoplasms with apocrine differentiation.13 Since the initial observation of mutations in the CYLD1 gene as cause for BSS,15 a host of different mutations have been reported, including frameshift mutations,1,20 splice site mutations,1 small deletions and insertions,1,15,21 and novel missense mutations.8 Most mutations lead to a premature translational stop, which disrupts the protein function.21 The CYLD gene interacts with several members of the nuclear factor-κΒ signaling pathway, which play important roles in inflammation, immune response, and oncogenesis. Inhibition of the CYLD gene enhances activation of the transcription factor nuclear factor-κΒ and leads to increased resistance to apoptosis and advanced carcinogenesis,21 which also results in compromise of the early steps in the development of epidermal appendages, including hair follicles and sweat glands.22 The exact mechanisms of CYLD-dependent tumorigenesis in the skin remain to be established. Cylindromas located on the head and neck region may eventually cover the entire scalp, resulting in so-called turban tumors.8 Mutational screening for the CYLD gene is beneficial to patients with multiple cylindromas and/or trichoepitheliomas as well as their family members. Physicians caring for patients and family members affected with BSS should contact the medical genetics department of their respective local medical school or academic medical center. Early identification of mutation carriers and appropriate genetic counseling may improve the therapeutic management to avoid complications such as disfigurement (turban tumor) or malignant transformation.21 Excision of all cylindromas and spiradenomas is recommended due to the low risk for malignant potential (cylindrocarcinoma and spiradenocarcinoma).8 If untreated, BSS can cause considerable disfigurement and discomfort, and severely neglected cases may require scalp surgery and reconstruction.23 Additionally, laser treatments, such as CO2 and erbium:YAG lasers, have been used for surgical destruction of several of the adnexal tumors (cylindromas and trichoepitheliomas), though the former ideally should be excised for histology because of the low risk for malignant transformation.5,9 Dermabrasion, chemical peels, electrodesiccation, and cryotherapy also may be considered as alternative treatment modalities.9 Brummelkamp et al24 demonstrated that inhibitory effects caused by CYLD gene mutations potentially can be reversed by application of salicylates or prostaglandin A. This discovery may give hope for novel therapeutic approaches in the future. The presence of pegged (conical) teeth in our patient is unusual, as this finding has not been described in BSS. The question remains, are these truly pegged teeth, and if so, is it merely an incidental (idiopathic) finding or rather part of an altogether new syndrome? As a result, genetic testing is extremely inviting.

Conclusion
Brooke-Spiegler syndrome consists of the classic triad of cylindromas, trichoepitheliomas, and spiradenomas. Mutations occur in the CYLD gene on band 16q12-13. Brooke-Spiegler syndrome is theorized as reflecting genetic dysfunction in the regulation of the folliculosebaceousapocrine unit. Early diagnosis is important with confirmatory genetic testing of the patient and family members. Further studies including genetic testing will need to be conducted to determine the relationship between pegged (conical) teeth and BSS.

In the late 19th century, Brooke and Spiegler described the familial occurrence of multiple tumors of the skin appendages. Synonyms have included familial cylindromatosis, turban tumor syndrome, and Brooke-Spiegler syndrome (BSS).1 In this report, we describe a patient with pegged teeth and BSS. We discuss the pathogenesis, diagnosis, genetic testing, and treatment options for this interesting syndrome.

Case Report
A 40-year-old white woman presented in 1997 for evaluation of numerous flesh-colored papules on her face. One of the lesions was biopsied in 1999 and diagnosed as a trichoepithelioma (Figure 1). These particular lesions had been present since she was 13 years of age, increasing in size and number with time. Subsequently, in December 2003, she presented with a 0.8-cm pink papule in the left preauricular area; a biopsy was performed and a spiradenoma in association with a trichoepithelioma was diagnosed. In January 2006, she presented with enlarging "bumps" on her scalp. She denied any substantial pain, pruritus, or other symptoms, but was rather concerned about the recent growth of lesions, both in size and number. Her medical history was noncontributory. However, there was a family history of similar lesions on the face and scalp of a great-aunt and uncle. No workup or genetic testing was ever performed.

Physical examination revealed a healthy, well-nourished, middle-aged woman. There were numerous symmetrically distributed flesh-colored to off-white firm papules involving the bilateral nasolabial folds, coalescing in areas to form plaques (Figure 2). There were 3 pink, firm, smooth, well-circumscribed nodules with overlying telangiectases involving the vertex and crown of the scalp, measuring 0.7X0.7 cm, 1.4X1.1 cm, and 1.4X1.4 cm in size. There was mild tenderness to palpation of all 3 lesions. Most interestingly, examination of the oral cavity revealed pegged (conical) teeth (Figure 3). It was not clear if they were primary or secondary teeth. There was no history of incontinentia pigmenti or any other ectodermal dysplasia in the patient or family members. Further evaluation of the hair and nails revealed no additional abnormalities.

The differential diagnoses for the scalp lesions included pilar cysts, basal or squamous cell carcinomas, spiradenomas, cylindromas, trichoblastomas, neurofibromas, and keloids or hypertrophic scars. The patient underwent an excisional biopsy of the smallest lesion in February 2006. Subsequently, excisional biopsies were performed on the other 2 lesions in April and July 2006. The first specimen revealed variably sized discrete aggregations of cuboidal epithelial cells with a rim of thickened eosinophilic basement membrane material surrounding tumor islands. There were 2 types of epithelial cells: cells with small, dark-staining nuclei present at the periphery in a palisading fashion, and light-staining nuclei lying in the center of the aggregations. Sweat duct lumina were appreciated within the tumor islands, and a diagnosis of cylindroma was made. The second biopsy showed a single, large, well-demarcated nodule of cuboidal epithelial cells arranged in interweaving cords present in the dermis. Again, there were 2 types of epithelial cells: smaller cells with dark nuclei lying at the periphery of the cords, and cells with larger pale nuclei in the center of the cords, associated with lumina. A diagnosis of spiradenoma was rendered. Based on the clinical findings and histopathologic diagnoses of trichoepithelioma, cylindroma, and spiradenoma, the patient received a diagnosis of BSS. Treatment for the trichoepitheliomas consisted of several glycolic acid peels, and the patient was pleased with the results. Furthermore, complete excisional biopsies were performed for all tumors on the scalp. The patient considered genetic testing for herself and family members.

Comment
Brooke-Spiegler syndrome is inherited in an autosomal dominant fashion with complete penetrance and variable expression. Both interfamilial and intrafamilial phenotypic variability have been well-documented in BSS; thus, a correlation between genotype and phenotype is lacking.2 Brooke-Spiegler syndrome is uncommon, with a female to male ratio of 2 to 1.1 Characteristically, patients present with the classic triad of cylindromas, trichoepitheliomas, and spiradenomas. Often, other adnexal tumors are observed, including but not limited to trichoblastomas, basal cell carcinomas, milia, organoid nevi, and syringomas.3 It was initially believed that cylindromas and spiradenomas showed sweat gland differentiation and trichoepitheliomas showed follicular differentiation.4 This combination represents an unusual inherited tumor diathesis involving neoplasms derived from pluripotential basal cells with adnexal differentiation along both sweat gland and follicular lineages.5-7 Typically, these tumors are located in the head and neck region, appear in puberty to early adulthood, and gradually increase in size and number throughout life.8 Malignant transformation of cylindromas in particular is quite rare, but metastasis in the event of malignancy is not infrequent.9-11 Malignancy is more frequent in patients with BSS rather than solitary cylindroma.10-12 Patients also are at risk for developing benign and malignant tumors of the salivary glands, particularly the parotid, including adenocarcinoma.4,6,8,13 In affected families, mutations have been demonstrated in the cylindromatosis gene, CYLD, located on band 16q12-13.¹⁴ This gene consists of 20 exons and reveals the characteristic attributes of a tumor suppressor gene with loss of heterozygosity.1,15,16 CYLD plays a role in governing cell cycle and apoptosis.9 Mutational changes in the CYLD gene could affect the normal regulation of the stem cell population of the folliculosebaceousapocrine unit. In turn, mutations in the genes that regulate proliferation and differentiation of the putative stem cells, possibly located in the bulge region of the hair follicle,3 could give rise to different combinations of adnexal skin tumors.1,2,17-19 More recently, spiradenomas have been proposed to be apocrine tumors on the basis of adnexal morphogenesis and their close association with follicular and apocrine tumors in BSS.10 The morphogenesis of both apocrine and sebaceous glands is dependent on the hair follicle because the glands develop from epithelial buds arising directly above the isthmus. However, eccrine glands develop from the base of the interfollicular rete ridges of embryonic skin. Cylindromas and spiradenomas are not eccrine tumors but neoplasms of the folliculosebaceousapocrine unit, as demonstrated by the occurrence of sebaceous and trichoblastic differentiation in spiradenocylindromas. It is hypothesized that cylindromas and spiradenomas may be polar extremes of a spectrum of adnexal neoplasms with apocrine differentiation.13 Since the initial observation of mutations in the CYLD1 gene as cause for BSS,15 a host of different mutations have been reported, including frameshift mutations,1,20 splice site mutations,1 small deletions and insertions,1,15,21 and novel missense mutations.8 Most mutations lead to a premature translational stop, which disrupts the protein function.21 The CYLD gene interacts with several members of the nuclear factor-κΒ signaling pathway, which play important roles in inflammation, immune response, and oncogenesis. Inhibition of the CYLD gene enhances activation of the transcription factor nuclear factor-κΒ and leads to increased resistance to apoptosis and advanced carcinogenesis,21 which also results in compromise of the early steps in the development of epidermal appendages, including hair follicles and sweat glands.22 The exact mechanisms of CYLD-dependent tumorigenesis in the skin remain to be established. Cylindromas located on the head and neck region may eventually cover the entire scalp, resulting in so-called turban tumors.8 Mutational screening for the CYLD gene is beneficial to patients with multiple cylindromas and/or trichoepitheliomas as well as their family members. Physicians caring for patients and family members affected with BSS should contact the medical genetics department of their respective local medical school or academic medical center. Early identification of mutation carriers and appropriate genetic counseling may improve the therapeutic management to avoid complications such as disfigurement (turban tumor) or malignant transformation.21 Excision of all cylindromas and spiradenomas is recommended due to the low risk for malignant potential (cylindrocarcinoma and spiradenocarcinoma).8 If untreated, BSS can cause considerable disfigurement and discomfort, and severely neglected cases may require scalp surgery and reconstruction.23 Additionally, laser treatments, such as CO2 and erbium:YAG lasers, have been used for surgical destruction of several of the adnexal tumors (cylindromas and trichoepitheliomas), though the former ideally should be excised for histology because of the low risk for malignant transformation.5,9 Dermabrasion, chemical peels, electrodesiccation, and cryotherapy also may be considered as alternative treatment modalities.9 Brummelkamp et al24 demonstrated that inhibitory effects caused by CYLD gene mutations potentially can be reversed by application of salicylates or prostaglandin A. This discovery may give hope for novel therapeutic approaches in the future. The presence of pegged (conical) teeth in our patient is unusual, as this finding has not been described in BSS. The question remains, are these truly pegged teeth, and if so, is it merely an incidental (idiopathic) finding or rather part of an altogether new syndrome? As a result, genetic testing is extremely inviting.

Conclusion
Brooke-Spiegler syndrome consists of the classic triad of cylindromas, trichoepitheliomas, and spiradenomas. Mutations occur in the CYLD gene on band 16q12-13. Brooke-Spiegler syndrome is theorized as reflecting genetic dysfunction in the regulation of the folliculosebaceousapocrine unit. Early diagnosis is important with confirmatory genetic testing of the patient and family members. Further studies including genetic testing will need to be conducted to determine the relationship between pegged (conical) teeth and BSS.

In the late 19th century, Brooke and Spiegler described the familial occurrence of multiple tumors of the skin appendages. Synonyms have included familial cylindromatosis, turban tumor syndrome, and Brooke-Spiegler syndrome (BSS).1 In this report, we describe a patient with pegged teeth and BSS. We discuss the pathogenesis, diagnosis, genetic testing, and treatment options for this interesting syndrome.

Case Report
A 40-year-old white woman presented in 1997 for evaluation of numerous flesh-colored papules on her face. One of the lesions was biopsied in 1999 and diagnosed as a trichoepithelioma (Figure 1). These particular lesions had been present since she was 13 years of age, increasing in size and number with time. Subsequently, in December 2003, she presented with a 0.8-cm pink papule in the left preauricular area; a biopsy was performed and a spiradenoma in association with a trichoepithelioma was diagnosed. In January 2006, she presented with enlarging "bumps" on her scalp. She denied any substantial pain, pruritus, or other symptoms, but was rather concerned about the recent growth of lesions, both in size and number. Her medical history was noncontributory. However, there was a family history of similar lesions on the face and scalp of a great-aunt and uncle. No workup or genetic testing was ever performed.

Physical examination revealed a healthy, well-nourished, middle-aged woman. There were numerous symmetrically distributed flesh-colored to off-white firm papules involving the bilateral nasolabial folds, coalescing in areas to form plaques (Figure 2). There were 3 pink, firm, smooth, well-circumscribed nodules with overlying telangiectases involving the vertex and crown of the scalp, measuring 0.7X0.7 cm, 1.4X1.1 cm, and 1.4X1.4 cm in size. There was mild tenderness to palpation of all 3 lesions. Most interestingly, examination of the oral cavity revealed pegged (conical) teeth (Figure 3). It was not clear if they were primary or secondary teeth. There was no history of incontinentia pigmenti or any other ectodermal dysplasia in the patient or family members. Further evaluation of the hair and nails revealed no additional abnormalities.

The differential diagnoses for the scalp lesions included pilar cysts, basal or squamous cell carcinomas, spiradenomas, cylindromas, trichoblastomas, neurofibromas, and keloids or hypertrophic scars. The patient underwent an excisional biopsy of the smallest lesion in February 2006. Subsequently, excisional biopsies were performed on the other 2 lesions in April and July 2006. The first specimen revealed variably sized discrete aggregations of cuboidal epithelial cells with a rim of thickened eosinophilic basement membrane material surrounding tumor islands. There were 2 types of epithelial cells: cells with small, dark-staining nuclei present at the periphery in a palisading fashion, and light-staining nuclei lying in the center of the aggregations. Sweat duct lumina were appreciated within the tumor islands, and a diagnosis of cylindroma was made. The second biopsy showed a single, large, well-demarcated nodule of cuboidal epithelial cells arranged in interweaving cords present in the dermis. Again, there were 2 types of epithelial cells: smaller cells with dark nuclei lying at the periphery of the cords, and cells with larger pale nuclei in the center of the cords, associated with lumina. A diagnosis of spiradenoma was rendered. Based on the clinical findings and histopathologic diagnoses of trichoepithelioma, cylindroma, and spiradenoma, the patient received a diagnosis of BSS. Treatment for the trichoepitheliomas consisted of several glycolic acid peels, and the patient was pleased with the results. Furthermore, complete excisional biopsies were performed for all tumors on the scalp. The patient considered genetic testing for herself and family members.

Comment
Brooke-Spiegler syndrome is inherited in an autosomal dominant fashion with complete penetrance and variable expression. Both interfamilial and intrafamilial phenotypic variability have been well-documented in BSS; thus, a correlation between genotype and phenotype is lacking.2 Brooke-Spiegler syndrome is uncommon, with a female to male ratio of 2 to 1.1 Characteristically, patients present with the classic triad of cylindromas, trichoepitheliomas, and spiradenomas. Often, other adnexal tumors are observed, including but not limited to trichoblastomas, basal cell carcinomas, milia, organoid nevi, and syringomas.3 It was initially believed that cylindromas and spiradenomas showed sweat gland differentiation and trichoepitheliomas showed follicular differentiation.4 This combination represents an unusual inherited tumor diathesis involving neoplasms derived from pluripotential basal cells with adnexal differentiation along both sweat gland and follicular lineages.5-7 Typically, these tumors are located in the head and neck region, appear in puberty to early adulthood, and gradually increase in size and number throughout life.8 Malignant transformation of cylindromas in particular is quite rare, but metastasis in the event of malignancy is not infrequent.9-11 Malignancy is more frequent in patients with BSS rather than solitary cylindroma.10-12 Patients also are at risk for developing benign and malignant tumors of the salivary glands, particularly the parotid, including adenocarcinoma.4,6,8,13 In affected families, mutations have been demonstrated in the cylindromatosis gene, CYLD, located on band 16q12-13.¹⁴ This gene consists of 20 exons and reveals the characteristic attributes of a tumor suppressor gene with loss of heterozygosity.1,15,16 CYLD plays a role in governing cell cycle and apoptosis.9 Mutational changes in the CYLD gene could affect the normal regulation of the stem cell population of the folliculosebaceousapocrine unit. In turn, mutations in the genes that regulate proliferation and differentiation of the putative stem cells, possibly located in the bulge region of the hair follicle,3 could give rise to different combinations of adnexal skin tumors.1,2,17-19 More recently, spiradenomas have been proposed to be apocrine tumors on the basis of adnexal morphogenesis and their close association with follicular and apocrine tumors in BSS.10 The morphogenesis of both apocrine and sebaceous glands is dependent on the hair follicle because the glands develop from epithelial buds arising directly above the isthmus. However, eccrine glands develop from the base of the interfollicular rete ridges of embryonic skin. Cylindromas and spiradenomas are not eccrine tumors but neoplasms of the folliculosebaceousapocrine unit, as demonstrated by the occurrence of sebaceous and trichoblastic differentiation in spiradenocylindromas. It is hypothesized that cylindromas and spiradenomas may be polar extremes of a spectrum of adnexal neoplasms with apocrine differentiation.13 Since the initial observation of mutations in the CYLD1 gene as cause for BSS,15 a host of different mutations have been reported, including frameshift mutations,1,20 splice site mutations,1 small deletions and insertions,1,15,21 and novel missense mutations.8 Most mutations lead to a premature translational stop, which disrupts the protein function.21 The CYLD gene interacts with several members of the nuclear factor-κΒ signaling pathway, which play important roles in inflammation, immune response, and oncogenesis. Inhibition of the CYLD gene enhances activation of the transcription factor nuclear factor-κΒ and leads to increased resistance to apoptosis and advanced carcinogenesis,21 which also results in compromise of the early steps in the development of epidermal appendages, including hair follicles and sweat glands.22 The exact mechanisms of CYLD-dependent tumorigenesis in the skin remain to be established. Cylindromas located on the head and neck region may eventually cover the entire scalp, resulting in so-called turban tumors.8 Mutational screening for the CYLD gene is beneficial to patients with multiple cylindromas and/or trichoepitheliomas as well as their family members. Physicians caring for patients and family members affected with BSS should contact the medical genetics department of their respective local medical school or academic medical center. Early identification of mutation carriers and appropriate genetic counseling may improve the therapeutic management to avoid complications such as disfigurement (turban tumor) or malignant transformation.21 Excision of all cylindromas and spiradenomas is recommended due to the low risk for malignant potential (cylindrocarcinoma and spiradenocarcinoma).8 If untreated, BSS can cause considerable disfigurement and discomfort, and severely neglected cases may require scalp surgery and reconstruction.23 Additionally, laser treatments, such as CO2 and erbium:YAG lasers, have been used for surgical destruction of several of the adnexal tumors (cylindromas and trichoepitheliomas), though the former ideally should be excised for histology because of the low risk for malignant transformation.5,9 Dermabrasion, chemical peels, electrodesiccation, and cryotherapy also may be considered as alternative treatment modalities.9 Brummelkamp et al24 demonstrated that inhibitory effects caused by CYLD gene mutations potentially can be reversed by application of salicylates or prostaglandin A. This discovery may give hope for novel therapeutic approaches in the future. The presence of pegged (conical) teeth in our patient is unusual, as this finding has not been described in BSS. The question remains, are these truly pegged teeth, and if so, is it merely an incidental (idiopathic) finding or rather part of an altogether new syndrome? As a result, genetic testing is extremely inviting.

Conclusion
Brooke-Spiegler syndrome consists of the classic triad of cylindromas, trichoepitheliomas, and spiradenomas. Mutations occur in the CYLD gene on band 16q12-13. Brooke-Spiegler syndrome is theorized as reflecting genetic dysfunction in the regulation of the folliculosebaceousapocrine unit. Early diagnosis is important with confirmatory genetic testing of the patient and family members. Further studies including genetic testing will need to be conducted to determine the relationship between pegged (conical) teeth and BSS.

Angiosarcoma is a rare malignant vascular tumor that is localized to the skin or superficial soft tissue in 60% of cases.1,2 More than half of cutaneous angiosarcomas arise on the head or neck.2,3 Skin lesions may be difficult to diagnose early because of their highly variable and often seemingly innocuous appearance1-4; it is not uncommon for there to be extensive local spread and/or distant metastases by the time angiosarcoma is diagnosed. Cutaneous angiosarcoma typically affects elderly patients and is more common in men.1-4 It is relatively rare in black individuals.1,3 Classic presentation is an erythematous or violaceous lesion arising on the scalp of an elderly white man.1-4 Cutaneous angiosarcoma has well-documented associations with a number of conditions and factors, including chronic lymphedema, prior radiation therapy, and exposure to chemicals such as thorotrast and vinyl chloride.1-4 In addition, there are several reported cases of malignant transformation to angiosarcoma of otherwise benign vascular lesions such as hemangiomas.5 To date, there is only one reported case of cutaneous angiosarcoma arising in association with scleroderma on the face of a 77-year-old white woman with systemic sclerosis (SSc).6 We report the case of a 40-year-old black man with SSc who developed a cutaneous angiosarcoma in an area of sclerodermatous scalp. back to top

Case Report
A 40-year-old black man with a 5-year history of SSc involving the skin, lungs, and esophagus developed a painful nodule in a sclerodermatous plaque on the scalp (Figure 1). The patient's medical history was remarkable for Raynaud phenomenon, with recurrent digital ulcerations, a restrictive ventilatory defect, chronic dysphagia, and gastroesophageal reflux disease, as well as diffuse thickening and tightening of the skin, all related to his SSc. Serologic tests revealed antinuclear antibodies (titer ≥640) with a homogeneous nucleolar pattern and high levels of anti–Scl-70 antibodies. Anticentromere and anti-DNA antibodies were absent. His only medications were esomeprazole magnesium (40 mg daily) and amlodipine besylate (5 mg daily).

On physical examination, there was a 1.8-cm faintly erythematous nodule with overlying excoriations and crust on the right anterior parietal scalp. The remainder of the physical examination was notable for diffusely tight, firm, shiny skin involving the scalp, face, neck, chest, arms, hands, and groin. There were areas of depigmentation in several of the scleroderma plaques as well as multiple fingertip ulcerations. On initial evaluation, the scalp lesion was diagnosed as a skin abscess not requiring further intervention. It continued to grow and cause discomfort, eventually necessitating surgical excision. Because of its anatomic position and the extremely taut nature of the surrounding sclerodermatous scalp, the mass was excised only partially so that primary closure would be possible. Histologic evaluation of the 2.5X1.5-cm surgical specimen revealed an epithelioid-type high-grade angiosarcoma composed of cells that were positive for CD31 and CD34 (endothelial cell markers) on immunohistochemical stain (Figure 2). A wide excision of the lesion was then performed. Intraoperatively, the tumor was observed to have involved the galea and pericranium, necessitating removal of full-thickness soft tissue and adjacent bone (Figure 3). The scalp excision defect was closed with a split-thickness skin graft.

 Microscopic examination of the excised tissue revealed extensive invasion of the dermis, perineural tissue, and deep skeletal muscle by angiosarcoma. Both circumferential and deep margins of the surgical specimen were involved by tumor. Tumor size was estimated at 9.5 cm. Computed tomographic (CT) scans of the chest, abdomen, and pelvis revealed a moderately dilated esophagus and moderate diffuse, hazy, ground glass pattern radiodensities of the bilateral lung bases consistent with SSc but no lesions suggestive of metastasis. The extensive local tissue involvement by tumor dictated radiation therapy to the area. Treatment was delayed, however, by failure of the skin graft to completely heal. The open wound was subsequently surgically debrided and closed with an allograft. This second graft began to successfully heal, but an enlarging subcutaneous mass at its anterior border soon developed. Results of a biopsy revealed recurrent angiosarcoma. This lesion grew quickly to encompass over half of the patient's forehead, as well as the nasal root, causing severe periorbital edema and conjunctival congestion. Daily radiation therapy totaling 5000 cGy to the upper face and frontal, parietal, and occipital scalp was initiated. Soon after, the patient was hospitalized for methicillin-resistant Staphylococcus aureus bacteremia thought to have originated from a skin infection near the tumor. He also complained of worsening sharp right retroauricular and left hip pains. Results of a punch biopsy of the right posterior auricular scalp revealed recurrent angiosarcoma, and a CT-guided biopsy specimen of the left iliac bone revealed metastatic angiosarcoma. Magnetic resonance imaging of the pelvis and lower extremities showed bone marrow lesions involving the left ischium, left anterior superior iliac spine, and femoral necks of both legs. Palliative radiation therapy to the left iliac bone was initiated for symptom control. Given the extensive metastatic spread, systemic paclitaxel chemotherapy (100 mg/m2 weekly [3 of 4 weeks]) was administered through a central venous port. Soon after completing the first round of chemotherapy, the patient was hospitalized with a polymicrobial infection of his partially healed scalp wound including Klebsiella pneumoniae, Pseudomonas aeruginosa, and group B streptococci. He was treated with levofloxacin (500 mg daily for 10 days). An abdominal CT scan showed that the patient had a lesion in the right posterior inferior lobe of the liver suggestive of metastatic angiosarcoma. Several weeks after discharge, he presented to the emergency department of an outside hospital complaining of worsening dysphagia and purulent material draining from his central venous port. Shortly thereafter, he died, with sepsis as the presumed cause of death. At autopsy, there were multiple large scalp ulcerations extending to bone. The skin was diffusely firm and taut. Serial sectioning of the liver demonstrated a somewhat hemorrhagic-appearing dark red–brown lesion measuring 3 cm in the right posterior lobe, composed microscopically of diffusely infiltrating metastatic angiosarcoma confirmed by CD31 immunostain. Additionally, there were multifocal microabscesses of the heart, lungs, kidneys, spleen, and skin of the face and neck. 

Comment
Systemic sclerosis, or scleroderma, is a chronic systemic disease characterized by widespread fibrosis of the skin and internal organs, vasculopathy, and autoimmunity.7,8 Black individuals are affected more frequently than white individuals and tend to have an earlier age of disease onset, greater tendency for severe disease, and overall worse prognosis.9 Patients with SSc have a 2.6% to 8.7% risk of malignancy in general, with lung cancer and squamous cell carcinoma (arising in affected pulmonary or skin tissue) among the most commonly associated neoplasms.10,11 To our knowledge, we describe the second reported case of SSc-associated angiosarcoma. Systemic sclerosis is thought to arise from altered endothelial cell function and blood vessel reactivity occurring in association with inflammation and autoimmunity. The earliest disease manifestations are generally vasculature related, with most patients developing Raynaud phenomenon before manifesting signs and symptoms of overt sclerosis.7,8 Characteristic nail fold capillaroscopy findings in patients with SSc include enlarged capillaries, busy capillary formations, microhemorrhages, and variable capillary loss.7 Patients with SSc have increased serum and skin levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis that induces differentiation, proliferation, and migration of endothelial cells.7 Endothelial cell VEGF receptors are up-regulated in SSc as well. This chronic overexpression of VEGF is thought to account for the chaotic vessel morphology observed on nail fold capillaroscopy.7 We hypothesize that elevated levels of VEGF in sclerodermatous skin may also predispose one to the development of angiosarcoma. Studies have shown that the proliferating cells in angiosarcoma overexpress VEGF messenger RNA, VEGF protein, and VEGF receptors, suggesting that VEGF may spur the development and invasion of neoplasia.12-14 Furthermore, Arbiser et al13 found that overexpression of human VEGF in immortalized endothelial cells was sufficient to convert them from benign hemangiomas to malignant angiosarcomas. Cutaneous angiosarcoma can assume a variety of clinical appearances, including bruiselike lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, infectious-appearing lesions, and scarring alopecia.1-4 Tumor tissue usually extends far beyond the apparent borders of the lesion and frequently invades underlying soft tissue and bone. Thus, patients often have advanced disease at the time of diagnosis.1-4 Angiosarcoma prognosis is generally poor, with reported 5-year survival rates ranging from 10% to 35%.1,2 Surgical excision, extended-field radiotherapy, and/or paclitaxel chemotherapy are commonly employed modes of treatment,1,4,15,16 though even with these interventions, local tumor recurrence and distant metastases are common. Importantly, early diagnosis positively correlates with prolonged survival.3,4

Conclusion
We present a case of cutaneous angiosarcoma arising in an area of SSc-affected skin. We suspect that the co-occurrence of these 2 diseases may be related to interconnected underlying pathophysiology. Because early diagnosis can positively impact prognosis, physicians should maintain a high index of clinical suspicion and low threshold for performing a biopsy when suspicious lesions are present on sclerodermatous skin.

Acknowledgment—We thank Frederick M. Wigley, MD, for his detailed clinic and procedure notes. 

Angiosarcoma is a rare malignant vascular tumor that is localized to the skin or superficial soft tissue in 60% of cases.1,2 More than half of cutaneous angiosarcomas arise on the head or neck.2,3 Skin lesions may be difficult to diagnose early because of their highly variable and often seemingly innocuous appearance1-4; it is not uncommon for there to be extensive local spread and/or distant metastases by the time angiosarcoma is diagnosed. Cutaneous angiosarcoma typically affects elderly patients and is more common in men.1-4 It is relatively rare in black individuals.1,3 Classic presentation is an erythematous or violaceous lesion arising on the scalp of an elderly white man.1-4 Cutaneous angiosarcoma has well-documented associations with a number of conditions and factors, including chronic lymphedema, prior radiation therapy, and exposure to chemicals such as thorotrast and vinyl chloride.1-4 In addition, there are several reported cases of malignant transformation to angiosarcoma of otherwise benign vascular lesions such as hemangiomas.5 To date, there is only one reported case of cutaneous angiosarcoma arising in association with scleroderma on the face of a 77-year-old white woman with systemic sclerosis (SSc).6 We report the case of a 40-year-old black man with SSc who developed a cutaneous angiosarcoma in an area of sclerodermatous scalp. back to top

Case Report
A 40-year-old black man with a 5-year history of SSc involving the skin, lungs, and esophagus developed a painful nodule in a sclerodermatous plaque on the scalp (Figure 1). The patient's medical history was remarkable for Raynaud phenomenon, with recurrent digital ulcerations, a restrictive ventilatory defect, chronic dysphagia, and gastroesophageal reflux disease, as well as diffuse thickening and tightening of the skin, all related to his SSc. Serologic tests revealed antinuclear antibodies (titer ≥640) with a homogeneous nucleolar pattern and high levels of anti–Scl-70 antibodies. Anticentromere and anti-DNA antibodies were absent. His only medications were esomeprazole magnesium (40 mg daily) and amlodipine besylate (5 mg daily).

On physical examination, there was a 1.8-cm faintly erythematous nodule with overlying excoriations and crust on the right anterior parietal scalp. The remainder of the physical examination was notable for diffusely tight, firm, shiny skin involving the scalp, face, neck, chest, arms, hands, and groin. There were areas of depigmentation in several of the scleroderma plaques as well as multiple fingertip ulcerations. On initial evaluation, the scalp lesion was diagnosed as a skin abscess not requiring further intervention. It continued to grow and cause discomfort, eventually necessitating surgical excision. Because of its anatomic position and the extremely taut nature of the surrounding sclerodermatous scalp, the mass was excised only partially so that primary closure would be possible. Histologic evaluation of the 2.5X1.5-cm surgical specimen revealed an epithelioid-type high-grade angiosarcoma composed of cells that were positive for CD31 and CD34 (endothelial cell markers) on immunohistochemical stain (Figure 2). A wide excision of the lesion was then performed. Intraoperatively, the tumor was observed to have involved the galea and pericranium, necessitating removal of full-thickness soft tissue and adjacent bone (Figure 3). The scalp excision defect was closed with a split-thickness skin graft.

 Microscopic examination of the excised tissue revealed extensive invasion of the dermis, perineural tissue, and deep skeletal muscle by angiosarcoma. Both circumferential and deep margins of the surgical specimen were involved by tumor. Tumor size was estimated at 9.5 cm. Computed tomographic (CT) scans of the chest, abdomen, and pelvis revealed a moderately dilated esophagus and moderate diffuse, hazy, ground glass pattern radiodensities of the bilateral lung bases consistent with SSc but no lesions suggestive of metastasis. The extensive local tissue involvement by tumor dictated radiation therapy to the area. Treatment was delayed, however, by failure of the skin graft to completely heal. The open wound was subsequently surgically debrided and closed with an allograft. This second graft began to successfully heal, but an enlarging subcutaneous mass at its anterior border soon developed. Results of a biopsy revealed recurrent angiosarcoma. This lesion grew quickly to encompass over half of the patient's forehead, as well as the nasal root, causing severe periorbital edema and conjunctival congestion. Daily radiation therapy totaling 5000 cGy to the upper face and frontal, parietal, and occipital scalp was initiated. Soon after, the patient was hospitalized for methicillin-resistant Staphylococcus aureus bacteremia thought to have originated from a skin infection near the tumor. He also complained of worsening sharp right retroauricular and left hip pains. Results of a punch biopsy of the right posterior auricular scalp revealed recurrent angiosarcoma, and a CT-guided biopsy specimen of the left iliac bone revealed metastatic angiosarcoma. Magnetic resonance imaging of the pelvis and lower extremities showed bone marrow lesions involving the left ischium, left anterior superior iliac spine, and femoral necks of both legs. Palliative radiation therapy to the left iliac bone was initiated for symptom control. Given the extensive metastatic spread, systemic paclitaxel chemotherapy (100 mg/m2 weekly [3 of 4 weeks]) was administered through a central venous port. Soon after completing the first round of chemotherapy, the patient was hospitalized with a polymicrobial infection of his partially healed scalp wound including Klebsiella pneumoniae, Pseudomonas aeruginosa, and group B streptococci. He was treated with levofloxacin (500 mg daily for 10 days). An abdominal CT scan showed that the patient had a lesion in the right posterior inferior lobe of the liver suggestive of metastatic angiosarcoma. Several weeks after discharge, he presented to the emergency department of an outside hospital complaining of worsening dysphagia and purulent material draining from his central venous port. Shortly thereafter, he died, with sepsis as the presumed cause of death. At autopsy, there were multiple large scalp ulcerations extending to bone. The skin was diffusely firm and taut. Serial sectioning of the liver demonstrated a somewhat hemorrhagic-appearing dark red–brown lesion measuring 3 cm in the right posterior lobe, composed microscopically of diffusely infiltrating metastatic angiosarcoma confirmed by CD31 immunostain. Additionally, there were multifocal microabscesses of the heart, lungs, kidneys, spleen, and skin of the face and neck. 

Comment
Systemic sclerosis, or scleroderma, is a chronic systemic disease characterized by widespread fibrosis of the skin and internal organs, vasculopathy, and autoimmunity.7,8 Black individuals are affected more frequently than white individuals and tend to have an earlier age of disease onset, greater tendency for severe disease, and overall worse prognosis.9 Patients with SSc have a 2.6% to 8.7% risk of malignancy in general, with lung cancer and squamous cell carcinoma (arising in affected pulmonary or skin tissue) among the most commonly associated neoplasms.10,11 To our knowledge, we describe the second reported case of SSc-associated angiosarcoma. Systemic sclerosis is thought to arise from altered endothelial cell function and blood vessel reactivity occurring in association with inflammation and autoimmunity. The earliest disease manifestations are generally vasculature related, with most patients developing Raynaud phenomenon before manifesting signs and symptoms of overt sclerosis.7,8 Characteristic nail fold capillaroscopy findings in patients with SSc include enlarged capillaries, busy capillary formations, microhemorrhages, and variable capillary loss.7 Patients with SSc have increased serum and skin levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis that induces differentiation, proliferation, and migration of endothelial cells.7 Endothelial cell VEGF receptors are up-regulated in SSc as well. This chronic overexpression of VEGF is thought to account for the chaotic vessel morphology observed on nail fold capillaroscopy.7 We hypothesize that elevated levels of VEGF in sclerodermatous skin may also predispose one to the development of angiosarcoma. Studies have shown that the proliferating cells in angiosarcoma overexpress VEGF messenger RNA, VEGF protein, and VEGF receptors, suggesting that VEGF may spur the development and invasion of neoplasia.12-14 Furthermore, Arbiser et al13 found that overexpression of human VEGF in immortalized endothelial cells was sufficient to convert them from benign hemangiomas to malignant angiosarcomas. Cutaneous angiosarcoma can assume a variety of clinical appearances, including bruiselike lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, infectious-appearing lesions, and scarring alopecia.1-4 Tumor tissue usually extends far beyond the apparent borders of the lesion and frequently invades underlying soft tissue and bone. Thus, patients often have advanced disease at the time of diagnosis.1-4 Angiosarcoma prognosis is generally poor, with reported 5-year survival rates ranging from 10% to 35%.1,2 Surgical excision, extended-field radiotherapy, and/or paclitaxel chemotherapy are commonly employed modes of treatment,1,4,15,16 though even with these interventions, local tumor recurrence and distant metastases are common. Importantly, early diagnosis positively correlates with prolonged survival.3,4

Conclusion
We present a case of cutaneous angiosarcoma arising in an area of SSc-affected skin. We suspect that the co-occurrence of these 2 diseases may be related to interconnected underlying pathophysiology. Because early diagnosis can positively impact prognosis, physicians should maintain a high index of clinical suspicion and low threshold for performing a biopsy when suspicious lesions are present on sclerodermatous skin.

Acknowledgment—We thank Frederick M. Wigley, MD, for his detailed clinic and procedure notes. 

Angiosarcoma is a rare malignant vascular tumor that is localized to the skin or superficial soft tissue in 60% of cases.1,2 More than half of cutaneous angiosarcomas arise on the head or neck.2,3 Skin lesions may be difficult to diagnose early because of their highly variable and often seemingly innocuous appearance1-4; it is not uncommon for there to be extensive local spread and/or distant metastases by the time angiosarcoma is diagnosed. Cutaneous angiosarcoma typically affects elderly patients and is more common in men.1-4 It is relatively rare in black individuals.1,3 Classic presentation is an erythematous or violaceous lesion arising on the scalp of an elderly white man.1-4 Cutaneous angiosarcoma has well-documented associations with a number of conditions and factors, including chronic lymphedema, prior radiation therapy, and exposure to chemicals such as thorotrast and vinyl chloride.1-4 In addition, there are several reported cases of malignant transformation to angiosarcoma of otherwise benign vascular lesions such as hemangiomas.5 To date, there is only one reported case of cutaneous angiosarcoma arising in association with scleroderma on the face of a 77-year-old white woman with systemic sclerosis (SSc).6 We report the case of a 40-year-old black man with SSc who developed a cutaneous angiosarcoma in an area of sclerodermatous scalp. back to top

Case Report
A 40-year-old black man with a 5-year history of SSc involving the skin, lungs, and esophagus developed a painful nodule in a sclerodermatous plaque on the scalp (Figure 1). The patient's medical history was remarkable for Raynaud phenomenon, with recurrent digital ulcerations, a restrictive ventilatory defect, chronic dysphagia, and gastroesophageal reflux disease, as well as diffuse thickening and tightening of the skin, all related to his SSc. Serologic tests revealed antinuclear antibodies (titer ≥640) with a homogeneous nucleolar pattern and high levels of anti–Scl-70 antibodies. Anticentromere and anti-DNA antibodies were absent. His only medications were esomeprazole magnesium (40 mg daily) and amlodipine besylate (5 mg daily).

On physical examination, there was a 1.8-cm faintly erythematous nodule with overlying excoriations and crust on the right anterior parietal scalp. The remainder of the physical examination was notable for diffusely tight, firm, shiny skin involving the scalp, face, neck, chest, arms, hands, and groin. There were areas of depigmentation in several of the scleroderma plaques as well as multiple fingertip ulcerations. On initial evaluation, the scalp lesion was diagnosed as a skin abscess not requiring further intervention. It continued to grow and cause discomfort, eventually necessitating surgical excision. Because of its anatomic position and the extremely taut nature of the surrounding sclerodermatous scalp, the mass was excised only partially so that primary closure would be possible. Histologic evaluation of the 2.5X1.5-cm surgical specimen revealed an epithelioid-type high-grade angiosarcoma composed of cells that were positive for CD31 and CD34 (endothelial cell markers) on immunohistochemical stain (Figure 2). A wide excision of the lesion was then performed. Intraoperatively, the tumor was observed to have involved the galea and pericranium, necessitating removal of full-thickness soft tissue and adjacent bone (Figure 3). The scalp excision defect was closed with a split-thickness skin graft.

 Microscopic examination of the excised tissue revealed extensive invasion of the dermis, perineural tissue, and deep skeletal muscle by angiosarcoma. Both circumferential and deep margins of the surgical specimen were involved by tumor. Tumor size was estimated at 9.5 cm. Computed tomographic (CT) scans of the chest, abdomen, and pelvis revealed a moderately dilated esophagus and moderate diffuse, hazy, ground glass pattern radiodensities of the bilateral lung bases consistent with SSc but no lesions suggestive of metastasis. The extensive local tissue involvement by tumor dictated radiation therapy to the area. Treatment was delayed, however, by failure of the skin graft to completely heal. The open wound was subsequently surgically debrided and closed with an allograft. This second graft began to successfully heal, but an enlarging subcutaneous mass at its anterior border soon developed. Results of a biopsy revealed recurrent angiosarcoma. This lesion grew quickly to encompass over half of the patient's forehead, as well as the nasal root, causing severe periorbital edema and conjunctival congestion. Daily radiation therapy totaling 5000 cGy to the upper face and frontal, parietal, and occipital scalp was initiated. Soon after, the patient was hospitalized for methicillin-resistant Staphylococcus aureus bacteremia thought to have originated from a skin infection near the tumor. He also complained of worsening sharp right retroauricular and left hip pains. Results of a punch biopsy of the right posterior auricular scalp revealed recurrent angiosarcoma, and a CT-guided biopsy specimen of the left iliac bone revealed metastatic angiosarcoma. Magnetic resonance imaging of the pelvis and lower extremities showed bone marrow lesions involving the left ischium, left anterior superior iliac spine, and femoral necks of both legs. Palliative radiation therapy to the left iliac bone was initiated for symptom control. Given the extensive metastatic spread, systemic paclitaxel chemotherapy (100 mg/m2 weekly [3 of 4 weeks]) was administered through a central venous port. Soon after completing the first round of chemotherapy, the patient was hospitalized with a polymicrobial infection of his partially healed scalp wound including Klebsiella pneumoniae, Pseudomonas aeruginosa, and group B streptococci. He was treated with levofloxacin (500 mg daily for 10 days). An abdominal CT scan showed that the patient had a lesion in the right posterior inferior lobe of the liver suggestive of metastatic angiosarcoma. Several weeks after discharge, he presented to the emergency department of an outside hospital complaining of worsening dysphagia and purulent material draining from his central venous port. Shortly thereafter, he died, with sepsis as the presumed cause of death. At autopsy, there were multiple large scalp ulcerations extending to bone. The skin was diffusely firm and taut. Serial sectioning of the liver demonstrated a somewhat hemorrhagic-appearing dark red–brown lesion measuring 3 cm in the right posterior lobe, composed microscopically of diffusely infiltrating metastatic angiosarcoma confirmed by CD31 immunostain. Additionally, there were multifocal microabscesses of the heart, lungs, kidneys, spleen, and skin of the face and neck. 

Comment
Systemic sclerosis, or scleroderma, is a chronic systemic disease characterized by widespread fibrosis of the skin and internal organs, vasculopathy, and autoimmunity.7,8 Black individuals are affected more frequently than white individuals and tend to have an earlier age of disease onset, greater tendency for severe disease, and overall worse prognosis.9 Patients with SSc have a 2.6% to 8.7% risk of malignancy in general, with lung cancer and squamous cell carcinoma (arising in affected pulmonary or skin tissue) among the most commonly associated neoplasms.10,11 To our knowledge, we describe the second reported case of SSc-associated angiosarcoma. Systemic sclerosis is thought to arise from altered endothelial cell function and blood vessel reactivity occurring in association with inflammation and autoimmunity. The earliest disease manifestations are generally vasculature related, with most patients developing Raynaud phenomenon before manifesting signs and symptoms of overt sclerosis.7,8 Characteristic nail fold capillaroscopy findings in patients with SSc include enlarged capillaries, busy capillary formations, microhemorrhages, and variable capillary loss.7 Patients with SSc have increased serum and skin levels of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis that induces differentiation, proliferation, and migration of endothelial cells.7 Endothelial cell VEGF receptors are up-regulated in SSc as well. This chronic overexpression of VEGF is thought to account for the chaotic vessel morphology observed on nail fold capillaroscopy.7 We hypothesize that elevated levels of VEGF in sclerodermatous skin may also predispose one to the development of angiosarcoma. Studies have shown that the proliferating cells in angiosarcoma overexpress VEGF messenger RNA, VEGF protein, and VEGF receptors, suggesting that VEGF may spur the development and invasion of neoplasia.12-14 Furthermore, Arbiser et al13 found that overexpression of human VEGF in immortalized endothelial cells was sufficient to convert them from benign hemangiomas to malignant angiosarcomas. Cutaneous angiosarcoma can assume a variety of clinical appearances, including bruiselike lesions, dusky plaques, chronic edema or cellulitis, ulcerated nodules, infectious-appearing lesions, and scarring alopecia.1-4 Tumor tissue usually extends far beyond the apparent borders of the lesion and frequently invades underlying soft tissue and bone. Thus, patients often have advanced disease at the time of diagnosis.1-4 Angiosarcoma prognosis is generally poor, with reported 5-year survival rates ranging from 10% to 35%.1,2 Surgical excision, extended-field radiotherapy, and/or paclitaxel chemotherapy are commonly employed modes of treatment,1,4,15,16 though even with these interventions, local tumor recurrence and distant metastases are common. Importantly, early diagnosis positively correlates with prolonged survival.3,4

Conclusion
We present a case of cutaneous angiosarcoma arising in an area of SSc-affected skin. We suspect that the co-occurrence of these 2 diseases may be related to interconnected underlying pathophysiology. Because early diagnosis can positively impact prognosis, physicians should maintain a high index of clinical suspicion and low threshold for performing a biopsy when suspicious lesions are present on sclerodermatous skin.

Acknowledgment—We thank Frederick M. Wigley, MD, for his detailed clinic and procedure notes.