Cutis

Linear porokeratosis refers to 1 of 5 variants of porokeratosis. Porokeratosis is a keratinization disorder of multiple etiologies including genetic aberrancy, trauma, and infection. We review a case of a 35-year-old man with a chronic history of linear porokeratosis and conduct a review of porokeratosis subtypes, etiology, histology, pathology, differential diagnosis, and treatment.

Case Report
A 35-year-old man presented to the dermatology clinic for medical clearance to receive smallpox vaccination. The patient was diagnosed with eczema that first appeared on the left lower leg at 6 months of age. The rash was asymptomatic and unresponsive to antifungal creams and topical steroids. Over the course of 20 years, there was an increase in the number of lesions that developed up his calf, upper leg, scrotum, and penis. He denied trauma to any of the lesion sites, immunosuppression, viral exposure, or sunburn that may have led to new lesions. He admitted that the lesions were more sensitive to sunburn and mosquito bites. More recently, the patient noticed a similar lesion on his right lower leg. There was no family history of similar rash or hepatic or internal malignancy. His only medication was atenolol for hypertension. Results of a physical examination revealed a linear, deep red, atrophic plaque on the left leg with single lesions coalescing into a larger plaque on the lower leg (Figure 1A). The lesions had a prominent peripheral hyperkeratotic ridge (Figure 1B). The plaque appeared to follow the Blaschko lines with extension onto the foot and terminating with pterygium of the proximal nail folds of the second and third toes. Linear porokeratosis was suspected and a biopsy specimen of the peripheral ridge and the central atrophic areas revealed cornoid lamellae with loss of the granular layer with focal lymphocytic infiltrate (Figure 2). The patient was given a trial of fluorouracil cream 5% applied topically to a test spot for 2 weeks. There was no response and the medication was discontinued. He elected not to pursue alternative treatments.

Comment
Classically described by Mibelli1 and Respighi2 in 1893, porokeratosis is a keratinization disorder involving a sharply demarcated annular lesion, peripheral hyperkeratotic ridge with a longitudinal furrow, and central atrophic crater. The following 5 clinical variants are currently recognized: classic porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, porokeratosis palmaris et plantaris disseminata, linear porokeratosis, and punctate porokeratosis (Table).3 Linear porokeratosis is the unilateral linear variant with identical Mibelli morphology; however, these lesions are found grouped along the distal portion of the extremities in a linear distribution. Linear porokeratosis is strictly unilateral and may involve the entire side of the body (ie, arm, leg, trunk, face). Lesions vary in size (0.5–1.0 cm), height (≥1 mm), and number (few to many). The lesions are characterized by small, brownish, keratotic papules that slowly enlarge from childhood to form irregular annular plaques with well-demarcated 1-mm raised borders. The center generally is atrophic with anhidrosis and alopecia.3

Classic porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, porokeratosis palmaris et plantaris disseminata, and punctate porokeratosis are characterized by autosomal dominant inheritance. Some reports suggest mosaicism may give rise to aberrant hyperkeratotic events for linear porokeratosis.4,5 Because coexistent observations have been made regarding the disseminated superficial actinic and linear variants of porokeratosis, a conclusion of a common genetic aberration at chromosome 12, 15, or 18 may be postulated.6-10 There seems to be multiple etiologies. Porokeratosis has been observed in skin tissue that has been burned11 or damaged by UVA/UVB radiation from artificial light12,13 and irradiation sources.14 Herpes simplex virus type 115,16 and hepatitis C virus infections also have been observed in patients with porokeratosis.17,18 Transplants and concurrent immunosuppression have led to disseminated and fatal malignant degeneration.19-24 The cornoid lamella, a thick column of parakeratotic cells extending outward from a notch in the malpighian layer of the epidermis, is the basis for the ridgelike border in all variants. This classic finding is believed to be a peripheral clonal expansion of aberrant keratinocytes,25 which is supported by the presence of helper T cells, suppressor T cells, and Langerhans cells approximating the cornoid lamella, perhaps providing a stimulatory signal.26 The cornoid lamella arises in the interfollicular epidermis and consists of a tightly packed column extending through the entire stratum corneum. The granular layer is missing below the cornoid lamella and vacuolated keratinocytes are found at its base. The center of the lesion is atrophic, with possible liquefaction or colloid body formation and flattening of the rete ridges. The dermis may be edematous with telangiectasia. Both classic porokeratosis of Mibelli and the linear variant share histologic features. Disseminated superficial actinic porokeratosis lesions are small and uniformly distributed. They tend to present as discrete keratotic papules with a less than prominent ridge (1–3 mm in diameter) that spreads over sun-exposed skin or extensor surfaces of the extremities.3 Porokeratosis palmaris et plantaris disseminata begins on the palms and soles and disseminates across the body. The keratotic ridge is more pronounced and these lesions tend to be pruritic.3 Punctate porokeratosis lesions are discrete, punctate, hyperkeratotic, and seedlike, and are surrounded by a thin peripheral ridge.27 Diagnosis of all variants usually is confirmed clinically with visualization of a continuous ridge and furrow and histopathologically with demonstration of cornoid lamellae. Based on presentation, the differential diagnosis would include entities of similar location and morphologic features or those expressing linearity. The differential diagnosis for a plaque of the extremity of similar description may include elastosis perforans serpiginosa, lichen sclerosus et atrophicus, lichen planus, plaque stage of cutaneous T-cell lymphoma, or punctate keratoderma.28,29 Treatment includes destruction using cryotherapy, electrodesiccation, dermabrasion, or CO2 laser.30,31 Successful treatment also has been observed by inducing a cell-mediated/cytotoxic response using 5-fluorouracil and imiquimod cream 5%.32,33 Retinoid therapy has yielded inconsistent results.34,35 All porokeratosis variants tend to increase in size and number with accelerated growth with UV exposure or decreased immune status.12 To date, no study has determined the frequency of porokeratosis that degenerates to malignancy, yet squamous cell carcinoma has been observed in linear porokeratosis as well as other variants.36-38 Interestingly, the protein p53 has been considered as a possible marker of malignant degeneration in patients with confirmed porokeratosis.39-41 Aside from malignant degeneration, it has been observed that porokeratosis palmaris et plantaris disseminata and linear porokeratosis may rarely cause bone and nail dystrophy.42-45

Linear porokeratosis refers to 1 of 5 variants of porokeratosis. Porokeratosis is a keratinization disorder of multiple etiologies including genetic aberrancy, trauma, and infection. We review a case of a 35-year-old man with a chronic history of linear porokeratosis and conduct a review of porokeratosis subtypes, etiology, histology, pathology, differential diagnosis, and treatment.

Case Report
A 35-year-old man presented to the dermatology clinic for medical clearance to receive smallpox vaccination. The patient was diagnosed with eczema that first appeared on the left lower leg at 6 months of age. The rash was asymptomatic and unresponsive to antifungal creams and topical steroids. Over the course of 20 years, there was an increase in the number of lesions that developed up his calf, upper leg, scrotum, and penis. He denied trauma to any of the lesion sites, immunosuppression, viral exposure, or sunburn that may have led to new lesions. He admitted that the lesions were more sensitive to sunburn and mosquito bites. More recently, the patient noticed a similar lesion on his right lower leg. There was no family history of similar rash or hepatic or internal malignancy. His only medication was atenolol for hypertension. Results of a physical examination revealed a linear, deep red, atrophic plaque on the left leg with single lesions coalescing into a larger plaque on the lower leg (Figure 1A). The lesions had a prominent peripheral hyperkeratotic ridge (Figure 1B). The plaque appeared to follow the Blaschko lines with extension onto the foot and terminating with pterygium of the proximal nail folds of the second and third toes. Linear porokeratosis was suspected and a biopsy specimen of the peripheral ridge and the central atrophic areas revealed cornoid lamellae with loss of the granular layer with focal lymphocytic infiltrate (Figure 2). The patient was given a trial of fluorouracil cream 5% applied topically to a test spot for 2 weeks. There was no response and the medication was discontinued. He elected not to pursue alternative treatments.

Comment
Classically described by Mibelli1 and Respighi2 in 1893, porokeratosis is a keratinization disorder involving a sharply demarcated annular lesion, peripheral hyperkeratotic ridge with a longitudinal furrow, and central atrophic crater. The following 5 clinical variants are currently recognized: classic porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, porokeratosis palmaris et plantaris disseminata, linear porokeratosis, and punctate porokeratosis (Table).3 Linear porokeratosis is the unilateral linear variant with identical Mibelli morphology; however, these lesions are found grouped along the distal portion of the extremities in a linear distribution. Linear porokeratosis is strictly unilateral and may involve the entire side of the body (ie, arm, leg, trunk, face). Lesions vary in size (0.5–1.0 cm), height (≥1 mm), and number (few to many). The lesions are characterized by small, brownish, keratotic papules that slowly enlarge from childhood to form irregular annular plaques with well-demarcated 1-mm raised borders. The center generally is atrophic with anhidrosis and alopecia.3

Classic porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, porokeratosis palmaris et plantaris disseminata, and punctate porokeratosis are characterized by autosomal dominant inheritance. Some reports suggest mosaicism may give rise to aberrant hyperkeratotic events for linear porokeratosis.4,5 Because coexistent observations have been made regarding the disseminated superficial actinic and linear variants of porokeratosis, a conclusion of a common genetic aberration at chromosome 12, 15, or 18 may be postulated.6-10 There seems to be multiple etiologies. Porokeratosis has been observed in skin tissue that has been burned11 or damaged by UVA/UVB radiation from artificial light12,13 and irradiation sources.14 Herpes simplex virus type 115,16 and hepatitis C virus infections also have been observed in patients with porokeratosis.17,18 Transplants and concurrent immunosuppression have led to disseminated and fatal malignant degeneration.19-24 The cornoid lamella, a thick column of parakeratotic cells extending outward from a notch in the malpighian layer of the epidermis, is the basis for the ridgelike border in all variants. This classic finding is believed to be a peripheral clonal expansion of aberrant keratinocytes,25 which is supported by the presence of helper T cells, suppressor T cells, and Langerhans cells approximating the cornoid lamella, perhaps providing a stimulatory signal.26 The cornoid lamella arises in the interfollicular epidermis and consists of a tightly packed column extending through the entire stratum corneum. The granular layer is missing below the cornoid lamella and vacuolated keratinocytes are found at its base. The center of the lesion is atrophic, with possible liquefaction or colloid body formation and flattening of the rete ridges. The dermis may be edematous with telangiectasia. Both classic porokeratosis of Mibelli and the linear variant share histologic features. Disseminated superficial actinic porokeratosis lesions are small and uniformly distributed. They tend to present as discrete keratotic papules with a less than prominent ridge (1–3 mm in diameter) that spreads over sun-exposed skin or extensor surfaces of the extremities.3 Porokeratosis palmaris et plantaris disseminata begins on the palms and soles and disseminates across the body. The keratotic ridge is more pronounced and these lesions tend to be pruritic.3 Punctate porokeratosis lesions are discrete, punctate, hyperkeratotic, and seedlike, and are surrounded by a thin peripheral ridge.27 Diagnosis of all variants usually is confirmed clinically with visualization of a continuous ridge and furrow and histopathologically with demonstration of cornoid lamellae. Based on presentation, the differential diagnosis would include entities of similar location and morphologic features or those expressing linearity. The differential diagnosis for a plaque of the extremity of similar description may include elastosis perforans serpiginosa, lichen sclerosus et atrophicus, lichen planus, plaque stage of cutaneous T-cell lymphoma, or punctate keratoderma.28,29 Treatment includes destruction using cryotherapy, electrodesiccation, dermabrasion, or CO2 laser.30,31 Successful treatment also has been observed by inducing a cell-mediated/cytotoxic response using 5-fluorouracil and imiquimod cream 5%.32,33 Retinoid therapy has yielded inconsistent results.34,35 All porokeratosis variants tend to increase in size and number with accelerated growth with UV exposure or decreased immune status.12 To date, no study has determined the frequency of porokeratosis that degenerates to malignancy, yet squamous cell carcinoma has been observed in linear porokeratosis as well as other variants.36-38 Interestingly, the protein p53 has been considered as a possible marker of malignant degeneration in patients with confirmed porokeratosis.39-41 Aside from malignant degeneration, it has been observed that porokeratosis palmaris et plantaris disseminata and linear porokeratosis may rarely cause bone and nail dystrophy.42-45

Linear porokeratosis refers to 1 of 5 variants of porokeratosis. Porokeratosis is a keratinization disorder of multiple etiologies including genetic aberrancy, trauma, and infection. We review a case of a 35-year-old man with a chronic history of linear porokeratosis and conduct a review of porokeratosis subtypes, etiology, histology, pathology, differential diagnosis, and treatment.

Case Report
A 35-year-old man presented to the dermatology clinic for medical clearance to receive smallpox vaccination. The patient was diagnosed with eczema that first appeared on the left lower leg at 6 months of age. The rash was asymptomatic and unresponsive to antifungal creams and topical steroids. Over the course of 20 years, there was an increase in the number of lesions that developed up his calf, upper leg, scrotum, and penis. He denied trauma to any of the lesion sites, immunosuppression, viral exposure, or sunburn that may have led to new lesions. He admitted that the lesions were more sensitive to sunburn and mosquito bites. More recently, the patient noticed a similar lesion on his right lower leg. There was no family history of similar rash or hepatic or internal malignancy. His only medication was atenolol for hypertension. Results of a physical examination revealed a linear, deep red, atrophic plaque on the left leg with single lesions coalescing into a larger plaque on the lower leg (Figure 1A). The lesions had a prominent peripheral hyperkeratotic ridge (Figure 1B). The plaque appeared to follow the Blaschko lines with extension onto the foot and terminating with pterygium of the proximal nail folds of the second and third toes. Linear porokeratosis was suspected and a biopsy specimen of the peripheral ridge and the central atrophic areas revealed cornoid lamellae with loss of the granular layer with focal lymphocytic infiltrate (Figure 2). The patient was given a trial of fluorouracil cream 5% applied topically to a test spot for 2 weeks. There was no response and the medication was discontinued. He elected not to pursue alternative treatments.

Comment
Classically described by Mibelli1 and Respighi2 in 1893, porokeratosis is a keratinization disorder involving a sharply demarcated annular lesion, peripheral hyperkeratotic ridge with a longitudinal furrow, and central atrophic crater. The following 5 clinical variants are currently recognized: classic porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, porokeratosis palmaris et plantaris disseminata, linear porokeratosis, and punctate porokeratosis (Table).3 Linear porokeratosis is the unilateral linear variant with identical Mibelli morphology; however, these lesions are found grouped along the distal portion of the extremities in a linear distribution. Linear porokeratosis is strictly unilateral and may involve the entire side of the body (ie, arm, leg, trunk, face). Lesions vary in size (0.5–1.0 cm), height (≥1 mm), and number (few to many). The lesions are characterized by small, brownish, keratotic papules that slowly enlarge from childhood to form irregular annular plaques with well-demarcated 1-mm raised borders. The center generally is atrophic with anhidrosis and alopecia.3

Classic porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, porokeratosis palmaris et plantaris disseminata, and punctate porokeratosis are characterized by autosomal dominant inheritance. Some reports suggest mosaicism may give rise to aberrant hyperkeratotic events for linear porokeratosis.4,5 Because coexistent observations have been made regarding the disseminated superficial actinic and linear variants of porokeratosis, a conclusion of a common genetic aberration at chromosome 12, 15, or 18 may be postulated.6-10 There seems to be multiple etiologies. Porokeratosis has been observed in skin tissue that has been burned11 or damaged by UVA/UVB radiation from artificial light12,13 and irradiation sources.14 Herpes simplex virus type 115,16 and hepatitis C virus infections also have been observed in patients with porokeratosis.17,18 Transplants and concurrent immunosuppression have led to disseminated and fatal malignant degeneration.19-24 The cornoid lamella, a thick column of parakeratotic cells extending outward from a notch in the malpighian layer of the epidermis, is the basis for the ridgelike border in all variants. This classic finding is believed to be a peripheral clonal expansion of aberrant keratinocytes,25 which is supported by the presence of helper T cells, suppressor T cells, and Langerhans cells approximating the cornoid lamella, perhaps providing a stimulatory signal.26 The cornoid lamella arises in the interfollicular epidermis and consists of a tightly packed column extending through the entire stratum corneum. The granular layer is missing below the cornoid lamella and vacuolated keratinocytes are found at its base. The center of the lesion is atrophic, with possible liquefaction or colloid body formation and flattening of the rete ridges. The dermis may be edematous with telangiectasia. Both classic porokeratosis of Mibelli and the linear variant share histologic features. Disseminated superficial actinic porokeratosis lesions are small and uniformly distributed. They tend to present as discrete keratotic papules with a less than prominent ridge (1–3 mm in diameter) that spreads over sun-exposed skin or extensor surfaces of the extremities.3 Porokeratosis palmaris et plantaris disseminata begins on the palms and soles and disseminates across the body. The keratotic ridge is more pronounced and these lesions tend to be pruritic.3 Punctate porokeratosis lesions are discrete, punctate, hyperkeratotic, and seedlike, and are surrounded by a thin peripheral ridge.27 Diagnosis of all variants usually is confirmed clinically with visualization of a continuous ridge and furrow and histopathologically with demonstration of cornoid lamellae. Based on presentation, the differential diagnosis would include entities of similar location and morphologic features or those expressing linearity. The differential diagnosis for a plaque of the extremity of similar description may include elastosis perforans serpiginosa, lichen sclerosus et atrophicus, lichen planus, plaque stage of cutaneous T-cell lymphoma, or punctate keratoderma.28,29 Treatment includes destruction using cryotherapy, electrodesiccation, dermabrasion, or CO2 laser.30,31 Successful treatment also has been observed by inducing a cell-mediated/cytotoxic response using 5-fluorouracil and imiquimod cream 5%.32,33 Retinoid therapy has yielded inconsistent results.34,35 All porokeratosis variants tend to increase in size and number with accelerated growth with UV exposure or decreased immune status.12 To date, no study has determined the frequency of porokeratosis that degenerates to malignancy, yet squamous cell carcinoma has been observed in linear porokeratosis as well as other variants.36-38 Interestingly, the protein p53 has been considered as a possible marker of malignant degeneration in patients with confirmed porokeratosis.39-41 Aside from malignant degeneration, it has been observed that porokeratosis palmaris et plantaris disseminata and linear porokeratosis may rarely cause bone and nail dystrophy.42-45

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.