Nonmelanoma Skin Cancer

The Diagnosis: Irritated Seborrheic Keratosis

Biopsies of one of the protruding papules and the underlying plaque were performed. The specimen from the papule showed hyperkeratosis, acanthosis, papillomatosis, and a flattened dermoepidermal junction with demarcated horizontal margin, which demonstrated apparent upward growth of the epidermis. Moderate lymphocytic infiltration in the upper dermis also was observed (Figure, A). The histologic findings of the plaque showed acanthosis, several pseudohorn cysts, hyperpigmentation of the basal layer, and a horizontal demarcation of the dermoepidermal junction (Figure, B).

Seborrheic keratosis is the most common benign epidermal tumor of the skin with variable appearance.¹ It usually begins with well-circumscribed, dull, flat, tan or brown patches that then grow into waxy verrucous papules.¹ There are many clinicopathologic variants of SK such as common SK, stucco keratosis, and dermatosis papulosa nigra in clinical variation, as well as acanthotic, hyperkeratotic, clonal, reticulated, irritated, and melanoacanthoma subtypes based on histological variation.^2,3

Seborrheic keratosis is a tumor of keratinocytic origin. Although genetics, sun exposure,⁴ and human papillomavirus infection⁵ are thought to be causative factors, the precise etiology of SK is unknown.¹

The histology of SK shows monotonous basaloid tumor cells without atypia. It generally is comprised of focal acanthosis and papillomatosis with a sharp flat base. Intraepithelial horn pseudocysts are notable features of SK and increased melanin often is seen.^2,6

Irritated SK is a histologic variant of SK that has been mechanically or chemically irritated or is involved in immunologic responses. Histologically, the dermis underlying an SK lesion filled with a dense lymphocytic infiltration is characteristic.^1,2

For symptomatic or cosmetically undesirable lesions, complete removal of the lesion is the preferred treatment. Cryotherapy, electrodesiccation followed by curettage, curettage followed by desiccation, laser ablation, and surgical excision are effective treatments.¹

The Diagnosis: Irritated Seborrheic Keratosis

Biopsies of one of the protruding papules and the underlying plaque were performed. The specimen from the papule showed hyperkeratosis, acanthosis, papillomatosis, and a flattened dermoepidermal junction with demarcated horizontal margin, which demonstrated apparent upward growth of the epidermis. Moderate lymphocytic infiltration in the upper dermis also was observed (Figure, A). The histologic findings of the plaque showed acanthosis, several pseudohorn cysts, hyperpigmentation of the basal layer, and a horizontal demarcation of the dermoepidermal junction (Figure, B).

Seborrheic keratosis is the most common benign epidermal tumor of the skin with variable appearance.¹ It usually begins with well-circumscribed, dull, flat, tan or brown patches that then grow into waxy verrucous papules.¹ There are many clinicopathologic variants of SK such as common SK, stucco keratosis, and dermatosis papulosa nigra in clinical variation, as well as acanthotic, hyperkeratotic, clonal, reticulated, irritated, and melanoacanthoma subtypes based on histological variation.^2,3

Seborrheic keratosis is a tumor of keratinocytic origin. Although genetics, sun exposure,⁴ and human papillomavirus infection⁵ are thought to be causative factors, the precise etiology of SK is unknown.¹

The histology of SK shows monotonous basaloid tumor cells without atypia. It generally is comprised of focal acanthosis and papillomatosis with a sharp flat base. Intraepithelial horn pseudocysts are notable features of SK and increased melanin often is seen.^2,6

Irritated SK is a histologic variant of SK that has been mechanically or chemically irritated or is involved in immunologic responses. Histologically, the dermis underlying an SK lesion filled with a dense lymphocytic infiltration is characteristic.^1,2

For symptomatic or cosmetically undesirable lesions, complete removal of the lesion is the preferred treatment. Cryotherapy, electrodesiccation followed by curettage, curettage followed by desiccation, laser ablation, and surgical excision are effective treatments.¹

The Diagnosis: Irritated Seborrheic Keratosis

Biopsies of one of the protruding papules and the underlying plaque were performed. The specimen from the papule showed hyperkeratosis, acanthosis, papillomatosis, and a flattened dermoepidermal junction with demarcated horizontal margin, which demonstrated apparent upward growth of the epidermis. Moderate lymphocytic infiltration in the upper dermis also was observed (Figure, A). The histologic findings of the plaque showed acanthosis, several pseudohorn cysts, hyperpigmentation of the basal layer, and a horizontal demarcation of the dermoepidermal junction (Figure, B).

Seborrheic keratosis is the most common benign epidermal tumor of the skin with variable appearance.¹ It usually begins with well-circumscribed, dull, flat, tan or brown patches that then grow into waxy verrucous papules.¹ There are many clinicopathologic variants of SK such as common SK, stucco keratosis, and dermatosis papulosa nigra in clinical variation, as well as acanthotic, hyperkeratotic, clonal, reticulated, irritated, and melanoacanthoma subtypes based on histological variation.^2,3

Seborrheic keratosis is a tumor of keratinocytic origin. Although genetics, sun exposure,⁴ and human papillomavirus infection⁵ are thought to be causative factors, the precise etiology of SK is unknown.¹

The histology of SK shows monotonous basaloid tumor cells without atypia. It generally is comprised of focal acanthosis and papillomatosis with a sharp flat base. Intraepithelial horn pseudocysts are notable features of SK and increased melanin often is seen.^2,6

Irritated SK is a histologic variant of SK that has been mechanically or chemically irritated or is involved in immunologic responses. Histologically, the dermis underlying an SK lesion filled with a dense lymphocytic infiltration is characteristic.^1,2

For symptomatic or cosmetically undesirable lesions, complete removal of the lesion is the preferred treatment. Cryotherapy, electrodesiccation followed by curettage, curettage followed by desiccation, laser ablation, and surgical excision are effective treatments.¹

Granular Cell Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common human epithelial malignancy. There are several histologic variants, the rarest being granular cell BCC (GBCC).¹ Granular cell BCC is reported most commonly in men with a mean age of 63 years. Sixty-four percent of cases develop on the face, with the remainder arising on the chest or trunk. Granular cell BCC has distinct histologic features but has no specific epidemiologic or clinical features that differentiate it from more common forms of BCC. Treatment of GBCC is identical to BCC and demonstrates similar outcomes. The presence of granular cells can make GBCC difficult to differentiate from other benign and malignant lesions that display similar granular histologic changes.^1,2 Rarely, tumors that are histologically similar to human GBCC have been reported in animals.¹

Histologically, GBCC commonly demonstrates the architecture of a nodular BCC or may extend from an existing nodular BCC (quiz images A and B). Granular cell BCC is comprised of large islands of basaloid cells extending from the epidermis with rare mitotic activity. Certain variants showing no epidermal attachments have been described,^1,3 as in the current case. Classically, BCC and GBCC both demonstrate a peripheral palisade of blue basal cells; however, GBCC may lack this palisading feature in some cases. Therefore, GBCC may be comprised of granular cells only, which may be more easily confused with other tumors with granular cell differentiation. Even when GBCC retains the traditional peripheral palisade of blue basal cells, the central cells are filled with eosinophilic granules.^1,2

Electron microscopy of GBCC usually reveals bundles of cytoplasmic tonofilaments and desmosomes in both granular cells and the peripherally palisaded cells. Electron microscopy imaging also demonstrates 0.1- to 0.5-µm membrane-bound lysosomelike structures. In certain reports, these structures show focal positivity for lysozymes.^1,2 The etiology of the granules is unclear; however, they are thought to represent degenerative changes related to metabolic alteration and accumulation of lysosomelike structures. These lysosomelike structures have been highlighted with CD68 staining, which was negative in our case.^1,2 The lesional cells in GBCC stain positively for cytokeratins, p63, and Ber-EP4, and negatively for S-100 protein, epithelial membrane antigen, and carcinoembryonic antigen. The granules in GBCC generally are positive on periodic acid–Schiff staining.^1-4

The histologic differential diagnosis for GBCC includes granular cell tumor as well as other tumors that can present with granular cell changes such as ameloblastoma, leiomyoma, leiomyosarcoma, angiosarcoma, malignant peripheral nerve sheath tumor, and granular cell trichoblastoma. Granular cell ameloblastomas have histologic features and staining patterns that are identical to GBCC; however, ameloblastomas are distinguished by their location within the oral cavity. Granular cell tumors and malignant peripheral nerve sheath tumors stain positive for S-100 protein, and angiosarcomas stain positive for D2-40 and CD31. Leiomyomas and leiomyosarcomas can be differentiated by staining with smooth muscle actin or desmin.¹ Granular cell trichoblastomas can be differentiated by the follicular stem cell marker protein PHLDA1 positivity.⁵

Desmoplastic trichilemmoma is difficult to distinguish from BCC. These tumors are comprised of superficial lobules of basaloid cells with a perilobular hyaline mantel surrounding a central desmoplastic stroma (Figure 1). The basaloid cells in desmoplastic trichoepithelioma demonstrate clear cell change; however, granular features are not seen. The cells within the desmoplastic areas are arranged haphazardly in cords and nests and can mimic an invasive carcinoma; however, nuclear atypia and mitotic activity generally are absent in desmoplastic trichilemmoma.⁶

Granular cell tumors generally are poorly circumscribed dermal nodules comprised of large polygonal cells with an eosinophilic granular cytoplasm (Figure 2). The nuclei are generally small and round, and cytological atypia, necrosis, and mitotic activity are uncommon. The cells are positive for S-100 protein and neuron-specific enolase but negative for CD68. The granules are positive for periodic acid–Schiff stain and are diastase resistant. Rarely, these tumors can be malignant.⁷

Sebaceous adenoma is a well-circumscribed tumor comprised of lobules of characteristic mature sebocytes with bubbly or multivacuolated cytoplasm and crenated nuclei (Figure 3). There is an expansion and increased prominence of the peripherally located basaloid cells; however, in contrast to sebaceous epithelioma, less than 50% of the tumor usually is comprised of these basaloid cells.⁸

Xanthogranuloma demonstrates a dense collection of histiocytes in the dermis, commonly with Touton giant cell formation (Figure 4). The cells often have a foamy cytoplasm and cytoplasmic vacuoles are observed. The histiocytes are positive for factor XIIIa and CD68, and generally negative for S-100 protein and CD1a, which allows for differentiation from Langerhans cells.⁹

Granular Cell Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common human epithelial malignancy. There are several histologic variants, the rarest being granular cell BCC (GBCC).¹ Granular cell BCC is reported most commonly in men with a mean age of 63 years. Sixty-four percent of cases develop on the face, with the remainder arising on the chest or trunk. Granular cell BCC has distinct histologic features but has no specific epidemiologic or clinical features that differentiate it from more common forms of BCC. Treatment of GBCC is identical to BCC and demonstrates similar outcomes. The presence of granular cells can make GBCC difficult to differentiate from other benign and malignant lesions that display similar granular histologic changes.^1,2 Rarely, tumors that are histologically similar to human GBCC have been reported in animals.¹

Histologically, GBCC commonly demonstrates the architecture of a nodular BCC or may extend from an existing nodular BCC (quiz images A and B). Granular cell BCC is comprised of large islands of basaloid cells extending from the epidermis with rare mitotic activity. Certain variants showing no epidermal attachments have been described,^1,3 as in the current case. Classically, BCC and GBCC both demonstrate a peripheral palisade of blue basal cells; however, GBCC may lack this palisading feature in some cases. Therefore, GBCC may be comprised of granular cells only, which may be more easily confused with other tumors with granular cell differentiation. Even when GBCC retains the traditional peripheral palisade of blue basal cells, the central cells are filled with eosinophilic granules.^1,2

Electron microscopy of GBCC usually reveals bundles of cytoplasmic tonofilaments and desmosomes in both granular cells and the peripherally palisaded cells. Electron microscopy imaging also demonstrates 0.1- to 0.5-µm membrane-bound lysosomelike structures. In certain reports, these structures show focal positivity for lysozymes.^1,2 The etiology of the granules is unclear; however, they are thought to represent degenerative changes related to metabolic alteration and accumulation of lysosomelike structures. These lysosomelike structures have been highlighted with CD68 staining, which was negative in our case.^1,2 The lesional cells in GBCC stain positively for cytokeratins, p63, and Ber-EP4, and negatively for S-100 protein, epithelial membrane antigen, and carcinoembryonic antigen. The granules in GBCC generally are positive on periodic acid–Schiff staining.^1-4

The histologic differential diagnosis for GBCC includes granular cell tumor as well as other tumors that can present with granular cell changes such as ameloblastoma, leiomyoma, leiomyosarcoma, angiosarcoma, malignant peripheral nerve sheath tumor, and granular cell trichoblastoma. Granular cell ameloblastomas have histologic features and staining patterns that are identical to GBCC; however, ameloblastomas are distinguished by their location within the oral cavity. Granular cell tumors and malignant peripheral nerve sheath tumors stain positive for S-100 protein, and angiosarcomas stain positive for D2-40 and CD31. Leiomyomas and leiomyosarcomas can be differentiated by staining with smooth muscle actin or desmin.¹ Granular cell trichoblastomas can be differentiated by the follicular stem cell marker protein PHLDA1 positivity.⁵

Desmoplastic trichilemmoma is difficult to distinguish from BCC. These tumors are comprised of superficial lobules of basaloid cells with a perilobular hyaline mantel surrounding a central desmoplastic stroma (Figure 1). The basaloid cells in desmoplastic trichoepithelioma demonstrate clear cell change; however, granular features are not seen. The cells within the desmoplastic areas are arranged haphazardly in cords and nests and can mimic an invasive carcinoma; however, nuclear atypia and mitotic activity generally are absent in desmoplastic trichilemmoma.⁶

Granular cell tumors generally are poorly circumscribed dermal nodules comprised of large polygonal cells with an eosinophilic granular cytoplasm (Figure 2). The nuclei are generally small and round, and cytological atypia, necrosis, and mitotic activity are uncommon. The cells are positive for S-100 protein and neuron-specific enolase but negative for CD68. The granules are positive for periodic acid–Schiff stain and are diastase resistant. Rarely, these tumors can be malignant.⁷

Sebaceous adenoma is a well-circumscribed tumor comprised of lobules of characteristic mature sebocytes with bubbly or multivacuolated cytoplasm and crenated nuclei (Figure 3). There is an expansion and increased prominence of the peripherally located basaloid cells; however, in contrast to sebaceous epithelioma, less than 50% of the tumor usually is comprised of these basaloid cells.⁸

Xanthogranuloma demonstrates a dense collection of histiocytes in the dermis, commonly with Touton giant cell formation (Figure 4). The cells often have a foamy cytoplasm and cytoplasmic vacuoles are observed. The histiocytes are positive for factor XIIIa and CD68, and generally negative for S-100 protein and CD1a, which allows for differentiation from Langerhans cells.⁹

Granular Cell Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common human epithelial malignancy. There are several histologic variants, the rarest being granular cell BCC (GBCC).¹ Granular cell BCC is reported most commonly in men with a mean age of 63 years. Sixty-four percent of cases develop on the face, with the remainder arising on the chest or trunk. Granular cell BCC has distinct histologic features but has no specific epidemiologic or clinical features that differentiate it from more common forms of BCC. Treatment of GBCC is identical to BCC and demonstrates similar outcomes. The presence of granular cells can make GBCC difficult to differentiate from other benign and malignant lesions that display similar granular histologic changes.^1,2 Rarely, tumors that are histologically similar to human GBCC have been reported in animals.¹

Histologically, GBCC commonly demonstrates the architecture of a nodular BCC or may extend from an existing nodular BCC (quiz images A and B). Granular cell BCC is comprised of large islands of basaloid cells extending from the epidermis with rare mitotic activity. Certain variants showing no epidermal attachments have been described,^1,3 as in the current case. Classically, BCC and GBCC both demonstrate a peripheral palisade of blue basal cells; however, GBCC may lack this palisading feature in some cases. Therefore, GBCC may be comprised of granular cells only, which may be more easily confused with other tumors with granular cell differentiation. Even when GBCC retains the traditional peripheral palisade of blue basal cells, the central cells are filled with eosinophilic granules.^1,2

Electron microscopy of GBCC usually reveals bundles of cytoplasmic tonofilaments and desmosomes in both granular cells and the peripherally palisaded cells. Electron microscopy imaging also demonstrates 0.1- to 0.5-µm membrane-bound lysosomelike structures. In certain reports, these structures show focal positivity for lysozymes.^1,2 The etiology of the granules is unclear; however, they are thought to represent degenerative changes related to metabolic alteration and accumulation of lysosomelike structures. These lysosomelike structures have been highlighted with CD68 staining, which was negative in our case.^1,2 The lesional cells in GBCC stain positively for cytokeratins, p63, and Ber-EP4, and negatively for S-100 protein, epithelial membrane antigen, and carcinoembryonic antigen. The granules in GBCC generally are positive on periodic acid–Schiff staining.^1-4

The histologic differential diagnosis for GBCC includes granular cell tumor as well as other tumors that can present with granular cell changes such as ameloblastoma, leiomyoma, leiomyosarcoma, angiosarcoma, malignant peripheral nerve sheath tumor, and granular cell trichoblastoma. Granular cell ameloblastomas have histologic features and staining patterns that are identical to GBCC; however, ameloblastomas are distinguished by their location within the oral cavity. Granular cell tumors and malignant peripheral nerve sheath tumors stain positive for S-100 protein, and angiosarcomas stain positive for D2-40 and CD31. Leiomyomas and leiomyosarcomas can be differentiated by staining with smooth muscle actin or desmin.¹ Granular cell trichoblastomas can be differentiated by the follicular stem cell marker protein PHLDA1 positivity.⁵

Desmoplastic trichilemmoma is difficult to distinguish from BCC. These tumors are comprised of superficial lobules of basaloid cells with a perilobular hyaline mantel surrounding a central desmoplastic stroma (Figure 1). The basaloid cells in desmoplastic trichoepithelioma demonstrate clear cell change; however, granular features are not seen. The cells within the desmoplastic areas are arranged haphazardly in cords and nests and can mimic an invasive carcinoma; however, nuclear atypia and mitotic activity generally are absent in desmoplastic trichilemmoma.⁶

Granular cell tumors generally are poorly circumscribed dermal nodules comprised of large polygonal cells with an eosinophilic granular cytoplasm (Figure 2). The nuclei are generally small and round, and cytological atypia, necrosis, and mitotic activity are uncommon. The cells are positive for S-100 protein and neuron-specific enolase but negative for CD68. The granules are positive for periodic acid–Schiff stain and are diastase resistant. Rarely, these tumors can be malignant.⁷

Sebaceous adenoma is a well-circumscribed tumor comprised of lobules of characteristic mature sebocytes with bubbly or multivacuolated cytoplasm and crenated nuclei (Figure 3). There is an expansion and increased prominence of the peripherally located basaloid cells; however, in contrast to sebaceous epithelioma, less than 50% of the tumor usually is comprised of these basaloid cells.⁸

Xanthogranuloma demonstrates a dense collection of histiocytes in the dermis, commonly with Touton giant cell formation (Figure 4). The cells often have a foamy cytoplasm and cytoplasmic vacuoles are observed. The histiocytes are positive for factor XIIIa and CD68, and generally negative for S-100 protein and CD1a, which allows for differentiation from Langerhans cells.⁹

Linear Basal Cell Carcinoma

On examination, the lesion was suspected to be a nevocellular nevus, foreign body granuloma, or venous lake; however, a skin biopsy specimen from the lesion on the left wrist revealed a tumor mass of basaloid cells, peripheral palisading arrangement, and scattered pigment granules (Figure 1). Tumor cells were negative for S-100 protein staining. These findings were consistent with a diagnosis of linear basal cell carcinoma (BCC). The lesion was removed by simple excision with primary closure of the wound. The surgical margins were free of tumor cells. The lesion had not recurred at 6-month follow-up. The patient was subsequently lost to follow-up.

Basal cell carcinoma presents with diverse clinical features, and several morphologic and histologic variants have been reported.¹ Linear BCC was described as a distinct clinical entity in 1985 by Lewis² in a 73-year-old man with a 20-mm linear pigmented lesion on the left cheek. Linear BCC often is not recognized or categorized as such by clinicians, as some may think that linear BCC is not a distinct entity but rather is one of the diverse clinical features of BCC.³ Linear BCC is believed to have specific clinical and histologic features and can be regarded as a distinct entity.⁴ Mavrikakis et al⁵ objectively defined linear BCC as a lesion that appeared to extend preferentially in one direction, resulting in a lesion with relatively straight borders and a length much greater than the width (3:1 ratio). Our patient presented with a linearly curved lesion, which is a rare feature of BCC.

Linear BCC occurs in equal proportions in men and women aged 40 to 87 years. More than 92% of reported patients were older than 60 years.⁶ The most common site for linear BCC is the periocular area, with the majority of lesions occurring on the cheek or lower eyelid. The second most common site is the neck, followed by the trunk, lower face, and inguinal skin fold.^3,5

The mechanism of linearity has been speculated. The majority of the reported cases of linear BCC have no history of trauma.⁷ However, focal trauma has been assumed to be a risk factor for the development of linear BCC, so the possibility that the Köbner phenomenon may be related to its linear pattern has been proposed.⁸ The Köbner phenomenon can be implicated in our case, as there was a history of surgery, which resulted in a scar.

Menzies⁹ described dermoscopic features of pigmented BCC and stated that the diagnosis of pigmented BCC required the presence of 1 or more of the following 6 positive features: large blue-gray ovoid nests; multiple blue-gray globules; maple leaf–like areas; spoke wheel areas; ulceration; and arborizing treelike vessels. In our case, there were multiple blue-gray globules and a streak that resembled ginseng (Figure 2).

Linear BCC is an uncommon morphological variant that requires clinical recognition. Our case was unique because of the ginsenglike streak on dermoscopy and possible association with a prior trauma.

Linear Basal Cell Carcinoma

On examination, the lesion was suspected to be a nevocellular nevus, foreign body granuloma, or venous lake; however, a skin biopsy specimen from the lesion on the left wrist revealed a tumor mass of basaloid cells, peripheral palisading arrangement, and scattered pigment granules (Figure 1). Tumor cells were negative for S-100 protein staining. These findings were consistent with a diagnosis of linear basal cell carcinoma (BCC). The lesion was removed by simple excision with primary closure of the wound. The surgical margins were free of tumor cells. The lesion had not recurred at 6-month follow-up. The patient was subsequently lost to follow-up.

Basal cell carcinoma presents with diverse clinical features, and several morphologic and histologic variants have been reported.¹ Linear BCC was described as a distinct clinical entity in 1985 by Lewis² in a 73-year-old man with a 20-mm linear pigmented lesion on the left cheek. Linear BCC often is not recognized or categorized as such by clinicians, as some may think that linear BCC is not a distinct entity but rather is one of the diverse clinical features of BCC.³ Linear BCC is believed to have specific clinical and histologic features and can be regarded as a distinct entity.⁴ Mavrikakis et al⁵ objectively defined linear BCC as a lesion that appeared to extend preferentially in one direction, resulting in a lesion with relatively straight borders and a length much greater than the width (3:1 ratio). Our patient presented with a linearly curved lesion, which is a rare feature of BCC.

Linear BCC occurs in equal proportions in men and women aged 40 to 87 years. More than 92% of reported patients were older than 60 years.⁶ The most common site for linear BCC is the periocular area, with the majority of lesions occurring on the cheek or lower eyelid. The second most common site is the neck, followed by the trunk, lower face, and inguinal skin fold.^3,5

The mechanism of linearity has been speculated. The majority of the reported cases of linear BCC have no history of trauma.⁷ However, focal trauma has been assumed to be a risk factor for the development of linear BCC, so the possibility that the Köbner phenomenon may be related to its linear pattern has been proposed.⁸ The Köbner phenomenon can be implicated in our case, as there was a history of surgery, which resulted in a scar.

Menzies⁹ described dermoscopic features of pigmented BCC and stated that the diagnosis of pigmented BCC required the presence of 1 or more of the following 6 positive features: large blue-gray ovoid nests; multiple blue-gray globules; maple leaf–like areas; spoke wheel areas; ulceration; and arborizing treelike vessels. In our case, there were multiple blue-gray globules and a streak that resembled ginseng (Figure 2).

Linear BCC is an uncommon morphological variant that requires clinical recognition. Our case was unique because of the ginsenglike streak on dermoscopy and possible association with a prior trauma.

Linear Basal Cell Carcinoma

On examination, the lesion was suspected to be a nevocellular nevus, foreign body granuloma, or venous lake; however, a skin biopsy specimen from the lesion on the left wrist revealed a tumor mass of basaloid cells, peripheral palisading arrangement, and scattered pigment granules (Figure 1). Tumor cells were negative for S-100 protein staining. These findings were consistent with a diagnosis of linear basal cell carcinoma (BCC). The lesion was removed by simple excision with primary closure of the wound. The surgical margins were free of tumor cells. The lesion had not recurred at 6-month follow-up. The patient was subsequently lost to follow-up.

Basal cell carcinoma presents with diverse clinical features, and several morphologic and histologic variants have been reported.¹ Linear BCC was described as a distinct clinical entity in 1985 by Lewis² in a 73-year-old man with a 20-mm linear pigmented lesion on the left cheek. Linear BCC often is not recognized or categorized as such by clinicians, as some may think that linear BCC is not a distinct entity but rather is one of the diverse clinical features of BCC.³ Linear BCC is believed to have specific clinical and histologic features and can be regarded as a distinct entity.⁴ Mavrikakis et al⁵ objectively defined linear BCC as a lesion that appeared to extend preferentially in one direction, resulting in a lesion with relatively straight borders and a length much greater than the width (3:1 ratio). Our patient presented with a linearly curved lesion, which is a rare feature of BCC.

Linear BCC occurs in equal proportions in men and women aged 40 to 87 years. More than 92% of reported patients were older than 60 years.⁶ The most common site for linear BCC is the periocular area, with the majority of lesions occurring on the cheek or lower eyelid. The second most common site is the neck, followed by the trunk, lower face, and inguinal skin fold.^3,5

The mechanism of linearity has been speculated. The majority of the reported cases of linear BCC have no history of trauma.⁷ However, focal trauma has been assumed to be a risk factor for the development of linear BCC, so the possibility that the Köbner phenomenon may be related to its linear pattern has been proposed.⁸ The Köbner phenomenon can be implicated in our case, as there was a history of surgery, which resulted in a scar.

Menzies⁹ described dermoscopic features of pigmented BCC and stated that the diagnosis of pigmented BCC required the presence of 1 or more of the following 6 positive features: large blue-gray ovoid nests; multiple blue-gray globules; maple leaf–like areas; spoke wheel areas; ulceration; and arborizing treelike vessels. In our case, there were multiple blue-gray globules and a streak that resembled ginseng (Figure 2).

Linear BCC is an uncommon morphological variant that requires clinical recognition. Our case was unique because of the ginsenglike streak on dermoscopy and possible association with a prior trauma.

Imatinib mesylate (IM) represents the first-line treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). Its pharmacological activity is related to a specific action on several tyrosine kinases in different tumors, including Bcr-Abl in CML, c-Kit (CD117) in GIST, and platelet-derived growth factor receptor in dermatofibrosarcoma protuberans.^1,2

Imatinib mesylate has been shown to improve progression-free survival and overall survival²; however, it also has several side effects. Among the adverse effects (AEs), less than 10% are nonhematologic, such as nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions.^3,4

We followed patients who were treated with IM for 5 years to identify AEs of therapy.

Methods

The aim of this prospective study was to identify and collect data regarding IM cutaneous side effects so that clinicians can detect AEs early and differentiate them from AEs caused by other medications. All patients were subjected to a median of 5 years’ follow-up. We included all the patients treated with IM and excluded patients who had a history of eczematous dermatitis, psoriasis, renal impairment, or dyshidrosis palmoplantar. Before starting IM, all patients presented for a dermatologic visit. They were subsequently evaluated every 3 months.

The incidence rate was defined as the ratio of patients with cutaneous side effects and the total patients treated with IM. Furthermore, we calculated the ratio between each class of patient with a specific cutaneous manifestation and the entire cohort of patients with cutaneous side effects related to IM.

When necessary, microbiological, serological, and histopathological analyses were performed.

Results

In 60 months, we followed 220 patients treated with IM. Among them, 55 (25%) developed cutaneous side effects (35 males; 20 females). The incidence rate of the patients with cutaneous side effects was 1:4. The median age of the entire cohort was 52.5 years. Fifty patients were being treated for CML and 5 for GISTs. All patients received IM at a dosage of 400 mg daily.

The following skin diseases were observed in patients treated with IM (Table): 19 patients with maculopapular rash with pruritus (no maculopapular rash without pruritus was detected), 7 patients with eczematous dermatitis such as stasis dermatitis and seborrheic dermatitis, 6 patients with onychodystrophy melanonychia (Figure 1), 5 patients with psoriasis, 5 patients with skin cancers including basal cell carcinoma (BCC)(Figure 2), 3 patients with periorbital edema (Figure 3), 3 patients with mycosis, 3 patients with dermatofibromas, 2 patients with dyshidrosis palmoplantar, 1 patient with pityriasis rosea–like eruption (Figure 4), and 1 patient with actinic keratoses on the face. No hypopigmentation or hyperpigmentation, excluding the individual case of melanonychia, was observed.

All cutaneous diseases reported in this study appeared after IM therapy (median, 3.8 months). The median time to onset for each cutaneous disorder is reported in the Table. During the first dermatologic visit before starting IM therapy, none of the patients showed any of these cutaneous diseases.

The adverse cutaneous reactions were treated with appropriate drugs. Generally, eczematous dermatitis was treated using topical steroids, emollients, and oral antihistamines. In patients with maculopapular rash with pruritus, oral corticosteroids (eg, betamethasone 3 mg daily or prednisolone 1 mg/kg) in association with antihistamine was necessary. Psoriasis was completely improved with topical betamethasone 0.5 mg and calcipotriol 50 µg. Skin cancers were treated with surgical excision with histologic examination. All treatments are outlined in the Table.

Imatinib mesylate therapy was suspended in 2 patients with maculopapular rash with moderate to severe pruritus; however, despite the temporary suspension of the drug and the appropriate therapies (corticosteroids and antihistamines), cutaneous side effects reappeared 7 to 10 days after therapy resumed. Therefore, the treatment was permanently suspended in these 2 cases and IM was replaced with erlotinib, a second-generation Bcr-Abl tyrosine kinase inhibitor.

Comment

The introduction of IM for the treatment of GIST and CML has changed the history of these diseases. The drug typically is well tolerated and few patients have reported severe AEs. Mild skin reactions are relatively frequent, ranging from 7% to 21% of patients treated.³ In our case, the percentage was relatively higher (25%), likely because of close monitoring of patients, with an increase in the incidence rate.

Imatinib mesylate cutaneous reactions are dose dependent.⁴ Indeed, in all our cases, the cutaneous reactions arose with an IM dosage of 400 mg daily, which is compatible with the definition of dose-independent cutaneous AEs.

The most common cutaneous AEs reported in the literature were swelling/edema and maculopapular rash. Swelling is the most common AE described during therapy with IM with an incidence of 63% to 84%.⁵ Swelling often involves the periorbital area and occurs approximately 6 weeks after starting IM. Although its pathogenesis is uncertain, it has been shown that IM blocks the platelet-derived growth factor receptor expressed on blood vessels that regulates the transportation transcapillary. The inhibition of this receptor can lead to increased pore pressure, resulting in edema and erythema. Maculopapular eruptions (50% of cases) often affect the trunk and the limbs and are accompanied by pruritus. Commonly, these rashes arise after 9 weeks of IM therapy. These eruptions are self-limiting and only topical emollients and steroids are required, without any change in IM schedule. To treat maculopapular eruptions with pruritus, oral steroids and antihistamines may be helpful, without suspending IM treatment. When grade 2 or 3 pruriginous maculopapular eruptions arise, the suspension of IM combined with steroids and antihistamines may be necessary. When the readministration of IM is required, it is mandatory to start IM at a lower dose (50–100 mg/d), administering prednisolone 0.5 to 1.0 mg/kg daily. Then, the steroid gradually can be tapered.⁶ Critical cutaneous AEs that are resistant to supportive measures warrant suspension of IM therapy. However, the incidence of this event is small (<1% of all patients).⁷

Regarding severe cutaneous AEs from IM therapy, Hsiao et al⁸ reported the case of Stevens-Johnson syndrome. In this case, IM was immediately stopped and systemic steroids were started. Rarely, erythroderma (grade 4 toxicity) can develop for which a prompt and perpetual suspension of IM is necessary and supportive care therapy with oral and topical steroids is recommended.⁹

Hyperpigmentation induced by IM, mostly in patients with Fitzpatrick skin types V to VI and with a general prevalence of 16% to 40% in treated patients, often is related to a mutation of c-Kit or other kinases that are activated rather than inhibited by the drug, resulting in overstimulation of melanogenesis.¹⁰ The prevalence of Fitzpatrick skin types I to III determined the absence of pigmentation changes in our cohort, excluding melanonychia. Hyperpigmentation was observed in the skin as well as the appendages such as nails, resulting in melanonychia (Figure 1). However, Brazzelli et al¹¹ reported hypopigmentation in 5 white patients treated with IM; furthermore, they found a direct correlation between hypopigmentation and development of skin cancers in these patients. The susceptibility to develop skin cancers may persist, even without a clear manifestation of hypopigmentation, as reported in the current analysis. We documented BCC in 5 patients, 1 patient developed actinic keratoses, and 3 patients developed dermatofibromas. However, these neoplasms probably were not provoked by IM. On the contrary, we did not note squamous cell carcinoma, which was reported by Baskaynak et al¹² in 2 CML patients treated with IM.

The administration of IM can be associated with exacerbation of psoriasis. Paradoxically, in genetically predisposed individuals, tumor necrosis factor α (TNF-α) antagonists, such as IM, seem to induce psoriasis, producing IFN-α rather than TNF-α and increasing inflammation.¹³ In fact, some research shows induction of psoriasis by anti–TNF-α drugs.^14-16 Two cases of IM associated with psoriasis have been reported, and both cases represented an exacerbation of previously diagnosed psoriasis.^13,17 On the contrary, in our analysis we reported 5 cases of psoriasis vulgaris induced by IM administration. Our patients developed cutaneous psoriatic lesions approximately 1.7 months after the start of IM therapy.

The pityriasis rosea–like eruption (Figure 4) presented as nonpruritic, erythematous, scaly patches on the trunk and extremities, and arose 3.6 months after the start of treatment. This particular cutaneous AE is rare. In 3 case reports, the IM dosage also was 400 mg daily.^18-20 The pathophysiology of this rare skin reaction stems from the pharmacological effect of IM rather than a hypersensitivity reaction.¹⁸

Deininger et al⁷ reported that patients with a high basophil count (>20%) rarely show urticarial eruptions after IM due to histamine release from basophils. Premedication with an antihistamine was helpful and the urticarial eruption resolved after normalization in basophil count.⁷

Given the importance of IM for patients who have limited therapeutic alternatives for their disease and the ability to safely treat the cutaneous AEs, as demonstrated in our analysis, the suspension of IM for dermatological complications is necessary only in rare cases, as shown by the low number of patients (n=2) who had to discontinue therapy. The cutaneous AEs should be diagnosed and treated early with less impact on chemotherapy treatments. The administration of IM should involve a coordinated effort among oncologists and dermatologists to prevent important complications.

Imatinib mesylate (IM) represents the first-line treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). Its pharmacological activity is related to a specific action on several tyrosine kinases in different tumors, including Bcr-Abl in CML, c-Kit (CD117) in GIST, and platelet-derived growth factor receptor in dermatofibrosarcoma protuberans.^1,2

Imatinib mesylate has been shown to improve progression-free survival and overall survival²; however, it also has several side effects. Among the adverse effects (AEs), less than 10% are nonhematologic, such as nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions.^3,4

We followed patients who were treated with IM for 5 years to identify AEs of therapy.

Methods

The aim of this prospective study was to identify and collect data regarding IM cutaneous side effects so that clinicians can detect AEs early and differentiate them from AEs caused by other medications. All patients were subjected to a median of 5 years’ follow-up. We included all the patients treated with IM and excluded patients who had a history of eczematous dermatitis, psoriasis, renal impairment, or dyshidrosis palmoplantar. Before starting IM, all patients presented for a dermatologic visit. They were subsequently evaluated every 3 months.

The incidence rate was defined as the ratio of patients with cutaneous side effects and the total patients treated with IM. Furthermore, we calculated the ratio between each class of patient with a specific cutaneous manifestation and the entire cohort of patients with cutaneous side effects related to IM.

When necessary, microbiological, serological, and histopathological analyses were performed.

Results

In 60 months, we followed 220 patients treated with IM. Among them, 55 (25%) developed cutaneous side effects (35 males; 20 females). The incidence rate of the patients with cutaneous side effects was 1:4. The median age of the entire cohort was 52.5 years. Fifty patients were being treated for CML and 5 for GISTs. All patients received IM at a dosage of 400 mg daily.

The following skin diseases were observed in patients treated with IM (Table): 19 patients with maculopapular rash with pruritus (no maculopapular rash without pruritus was detected), 7 patients with eczematous dermatitis such as stasis dermatitis and seborrheic dermatitis, 6 patients with onychodystrophy melanonychia (Figure 1), 5 patients with psoriasis, 5 patients with skin cancers including basal cell carcinoma (BCC)(Figure 2), 3 patients with periorbital edema (Figure 3), 3 patients with mycosis, 3 patients with dermatofibromas, 2 patients with dyshidrosis palmoplantar, 1 patient with pityriasis rosea–like eruption (Figure 4), and 1 patient with actinic keratoses on the face. No hypopigmentation or hyperpigmentation, excluding the individual case of melanonychia, was observed.

All cutaneous diseases reported in this study appeared after IM therapy (median, 3.8 months). The median time to onset for each cutaneous disorder is reported in the Table. During the first dermatologic visit before starting IM therapy, none of the patients showed any of these cutaneous diseases.

The adverse cutaneous reactions were treated with appropriate drugs. Generally, eczematous dermatitis was treated using topical steroids, emollients, and oral antihistamines. In patients with maculopapular rash with pruritus, oral corticosteroids (eg, betamethasone 3 mg daily or prednisolone 1 mg/kg) in association with antihistamine was necessary. Psoriasis was completely improved with topical betamethasone 0.5 mg and calcipotriol 50 µg. Skin cancers were treated with surgical excision with histologic examination. All treatments are outlined in the Table.

Imatinib mesylate therapy was suspended in 2 patients with maculopapular rash with moderate to severe pruritus; however, despite the temporary suspension of the drug and the appropriate therapies (corticosteroids and antihistamines), cutaneous side effects reappeared 7 to 10 days after therapy resumed. Therefore, the treatment was permanently suspended in these 2 cases and IM was replaced with erlotinib, a second-generation Bcr-Abl tyrosine kinase inhibitor.

Comment

The introduction of IM for the treatment of GIST and CML has changed the history of these diseases. The drug typically is well tolerated and few patients have reported severe AEs. Mild skin reactions are relatively frequent, ranging from 7% to 21% of patients treated.³ In our case, the percentage was relatively higher (25%), likely because of close monitoring of patients, with an increase in the incidence rate.

Imatinib mesylate cutaneous reactions are dose dependent.⁴ Indeed, in all our cases, the cutaneous reactions arose with an IM dosage of 400 mg daily, which is compatible with the definition of dose-independent cutaneous AEs.

The most common cutaneous AEs reported in the literature were swelling/edema and maculopapular rash. Swelling is the most common AE described during therapy with IM with an incidence of 63% to 84%.⁵ Swelling often involves the periorbital area and occurs approximately 6 weeks after starting IM. Although its pathogenesis is uncertain, it has been shown that IM blocks the platelet-derived growth factor receptor expressed on blood vessels that regulates the transportation transcapillary. The inhibition of this receptor can lead to increased pore pressure, resulting in edema and erythema. Maculopapular eruptions (50% of cases) often affect the trunk and the limbs and are accompanied by pruritus. Commonly, these rashes arise after 9 weeks of IM therapy. These eruptions are self-limiting and only topical emollients and steroids are required, without any change in IM schedule. To treat maculopapular eruptions with pruritus, oral steroids and antihistamines may be helpful, without suspending IM treatment. When grade 2 or 3 pruriginous maculopapular eruptions arise, the suspension of IM combined with steroids and antihistamines may be necessary. When the readministration of IM is required, it is mandatory to start IM at a lower dose (50–100 mg/d), administering prednisolone 0.5 to 1.0 mg/kg daily. Then, the steroid gradually can be tapered.⁶ Critical cutaneous AEs that are resistant to supportive measures warrant suspension of IM therapy. However, the incidence of this event is small (<1% of all patients).⁷

Regarding severe cutaneous AEs from IM therapy, Hsiao et al⁸ reported the case of Stevens-Johnson syndrome. In this case, IM was immediately stopped and systemic steroids were started. Rarely, erythroderma (grade 4 toxicity) can develop for which a prompt and perpetual suspension of IM is necessary and supportive care therapy with oral and topical steroids is recommended.⁹

Hyperpigmentation induced by IM, mostly in patients with Fitzpatrick skin types V to VI and with a general prevalence of 16% to 40% in treated patients, often is related to a mutation of c-Kit or other kinases that are activated rather than inhibited by the drug, resulting in overstimulation of melanogenesis.¹⁰ The prevalence of Fitzpatrick skin types I to III determined the absence of pigmentation changes in our cohort, excluding melanonychia. Hyperpigmentation was observed in the skin as well as the appendages such as nails, resulting in melanonychia (Figure 1). However, Brazzelli et al¹¹ reported hypopigmentation in 5 white patients treated with IM; furthermore, they found a direct correlation between hypopigmentation and development of skin cancers in these patients. The susceptibility to develop skin cancers may persist, even without a clear manifestation of hypopigmentation, as reported in the current analysis. We documented BCC in 5 patients, 1 patient developed actinic keratoses, and 3 patients developed dermatofibromas. However, these neoplasms probably were not provoked by IM. On the contrary, we did not note squamous cell carcinoma, which was reported by Baskaynak et al¹² in 2 CML patients treated with IM.

The administration of IM can be associated with exacerbation of psoriasis. Paradoxically, in genetically predisposed individuals, tumor necrosis factor α (TNF-α) antagonists, such as IM, seem to induce psoriasis, producing IFN-α rather than TNF-α and increasing inflammation.¹³ In fact, some research shows induction of psoriasis by anti–TNF-α drugs.^14-16 Two cases of IM associated with psoriasis have been reported, and both cases represented an exacerbation of previously diagnosed psoriasis.^13,17 On the contrary, in our analysis we reported 5 cases of psoriasis vulgaris induced by IM administration. Our patients developed cutaneous psoriatic lesions approximately 1.7 months after the start of IM therapy.

The pityriasis rosea–like eruption (Figure 4) presented as nonpruritic, erythematous, scaly patches on the trunk and extremities, and arose 3.6 months after the start of treatment. This particular cutaneous AE is rare. In 3 case reports, the IM dosage also was 400 mg daily.^18-20 The pathophysiology of this rare skin reaction stems from the pharmacological effect of IM rather than a hypersensitivity reaction.¹⁸

Deininger et al⁷ reported that patients with a high basophil count (>20%) rarely show urticarial eruptions after IM due to histamine release from basophils. Premedication with an antihistamine was helpful and the urticarial eruption resolved after normalization in basophil count.⁷

Given the importance of IM for patients who have limited therapeutic alternatives for their disease and the ability to safely treat the cutaneous AEs, as demonstrated in our analysis, the suspension of IM for dermatological complications is necessary only in rare cases, as shown by the low number of patients (n=2) who had to discontinue therapy. The cutaneous AEs should be diagnosed and treated early with less impact on chemotherapy treatments. The administration of IM should involve a coordinated effort among oncologists and dermatologists to prevent important complications.

Imatinib mesylate (IM) represents the first-line treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). Its pharmacological activity is related to a specific action on several tyrosine kinases in different tumors, including Bcr-Abl in CML, c-Kit (CD117) in GIST, and platelet-derived growth factor receptor in dermatofibrosarcoma protuberans.^1,2

Imatinib mesylate has been shown to improve progression-free survival and overall survival²; however, it also has several side effects. Among the adverse effects (AEs), less than 10% are nonhematologic, such as nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions.^3,4

We followed patients who were treated with IM for 5 years to identify AEs of therapy.

Methods

The aim of this prospective study was to identify and collect data regarding IM cutaneous side effects so that clinicians can detect AEs early and differentiate them from AEs caused by other medications. All patients were subjected to a median of 5 years’ follow-up. We included all the patients treated with IM and excluded patients who had a history of eczematous dermatitis, psoriasis, renal impairment, or dyshidrosis palmoplantar. Before starting IM, all patients presented for a dermatologic visit. They were subsequently evaluated every 3 months.

The incidence rate was defined as the ratio of patients with cutaneous side effects and the total patients treated with IM. Furthermore, we calculated the ratio between each class of patient with a specific cutaneous manifestation and the entire cohort of patients with cutaneous side effects related to IM.

When necessary, microbiological, serological, and histopathological analyses were performed.

Results

In 60 months, we followed 220 patients treated with IM. Among them, 55 (25%) developed cutaneous side effects (35 males; 20 females). The incidence rate of the patients with cutaneous side effects was 1:4. The median age of the entire cohort was 52.5 years. Fifty patients were being treated for CML and 5 for GISTs. All patients received IM at a dosage of 400 mg daily.

The following skin diseases were observed in patients treated with IM (Table): 19 patients with maculopapular rash with pruritus (no maculopapular rash without pruritus was detected), 7 patients with eczematous dermatitis such as stasis dermatitis and seborrheic dermatitis, 6 patients with onychodystrophy melanonychia (Figure 1), 5 patients with psoriasis, 5 patients with skin cancers including basal cell carcinoma (BCC)(Figure 2), 3 patients with periorbital edema (Figure 3), 3 patients with mycosis, 3 patients with dermatofibromas, 2 patients with dyshidrosis palmoplantar, 1 patient with pityriasis rosea–like eruption (Figure 4), and 1 patient with actinic keratoses on the face. No hypopigmentation or hyperpigmentation, excluding the individual case of melanonychia, was observed.

All cutaneous diseases reported in this study appeared after IM therapy (median, 3.8 months). The median time to onset for each cutaneous disorder is reported in the Table. During the first dermatologic visit before starting IM therapy, none of the patients showed any of these cutaneous diseases.

The adverse cutaneous reactions were treated with appropriate drugs. Generally, eczematous dermatitis was treated using topical steroids, emollients, and oral antihistamines. In patients with maculopapular rash with pruritus, oral corticosteroids (eg, betamethasone 3 mg daily or prednisolone 1 mg/kg) in association with antihistamine was necessary. Psoriasis was completely improved with topical betamethasone 0.5 mg and calcipotriol 50 µg. Skin cancers were treated with surgical excision with histologic examination. All treatments are outlined in the Table.

Imatinib mesylate therapy was suspended in 2 patients with maculopapular rash with moderate to severe pruritus; however, despite the temporary suspension of the drug and the appropriate therapies (corticosteroids and antihistamines), cutaneous side effects reappeared 7 to 10 days after therapy resumed. Therefore, the treatment was permanently suspended in these 2 cases and IM was replaced with erlotinib, a second-generation Bcr-Abl tyrosine kinase inhibitor.

Comment

The introduction of IM for the treatment of GIST and CML has changed the history of these diseases. The drug typically is well tolerated and few patients have reported severe AEs. Mild skin reactions are relatively frequent, ranging from 7% to 21% of patients treated.³ In our case, the percentage was relatively higher (25%), likely because of close monitoring of patients, with an increase in the incidence rate.

Imatinib mesylate cutaneous reactions are dose dependent.⁴ Indeed, in all our cases, the cutaneous reactions arose with an IM dosage of 400 mg daily, which is compatible with the definition of dose-independent cutaneous AEs.

The most common cutaneous AEs reported in the literature were swelling/edema and maculopapular rash. Swelling is the most common AE described during therapy with IM with an incidence of 63% to 84%.⁵ Swelling often involves the periorbital area and occurs approximately 6 weeks after starting IM. Although its pathogenesis is uncertain, it has been shown that IM blocks the platelet-derived growth factor receptor expressed on blood vessels that regulates the transportation transcapillary. The inhibition of this receptor can lead to increased pore pressure, resulting in edema and erythema. Maculopapular eruptions (50% of cases) often affect the trunk and the limbs and are accompanied by pruritus. Commonly, these rashes arise after 9 weeks of IM therapy. These eruptions are self-limiting and only topical emollients and steroids are required, without any change in IM schedule. To treat maculopapular eruptions with pruritus, oral steroids and antihistamines may be helpful, without suspending IM treatment. When grade 2 or 3 pruriginous maculopapular eruptions arise, the suspension of IM combined with steroids and antihistamines may be necessary. When the readministration of IM is required, it is mandatory to start IM at a lower dose (50–100 mg/d), administering prednisolone 0.5 to 1.0 mg/kg daily. Then, the steroid gradually can be tapered.⁶ Critical cutaneous AEs that are resistant to supportive measures warrant suspension of IM therapy. However, the incidence of this event is small (<1% of all patients).⁷

Regarding severe cutaneous AEs from IM therapy, Hsiao et al⁸ reported the case of Stevens-Johnson syndrome. In this case, IM was immediately stopped and systemic steroids were started. Rarely, erythroderma (grade 4 toxicity) can develop for which a prompt and perpetual suspension of IM is necessary and supportive care therapy with oral and topical steroids is recommended.⁹

Hyperpigmentation induced by IM, mostly in patients with Fitzpatrick skin types V to VI and with a general prevalence of 16% to 40% in treated patients, often is related to a mutation of c-Kit or other kinases that are activated rather than inhibited by the drug, resulting in overstimulation of melanogenesis.¹⁰ The prevalence of Fitzpatrick skin types I to III determined the absence of pigmentation changes in our cohort, excluding melanonychia. Hyperpigmentation was observed in the skin as well as the appendages such as nails, resulting in melanonychia (Figure 1). However, Brazzelli et al¹¹ reported hypopigmentation in 5 white patients treated with IM; furthermore, they found a direct correlation between hypopigmentation and development of skin cancers in these patients. The susceptibility to develop skin cancers may persist, even without a clear manifestation of hypopigmentation, as reported in the current analysis. We documented BCC in 5 patients, 1 patient developed actinic keratoses, and 3 patients developed dermatofibromas. However, these neoplasms probably were not provoked by IM. On the contrary, we did not note squamous cell carcinoma, which was reported by Baskaynak et al¹² in 2 CML patients treated with IM.

The administration of IM can be associated with exacerbation of psoriasis. Paradoxically, in genetically predisposed individuals, tumor necrosis factor α (TNF-α) antagonists, such as IM, seem to induce psoriasis, producing IFN-α rather than TNF-α and increasing inflammation.¹³ In fact, some research shows induction of psoriasis by anti–TNF-α drugs.^14-16 Two cases of IM associated with psoriasis have been reported, and both cases represented an exacerbation of previously diagnosed psoriasis.^13,17 On the contrary, in our analysis we reported 5 cases of psoriasis vulgaris induced by IM administration. Our patients developed cutaneous psoriatic lesions approximately 1.7 months after the start of IM therapy.

The pityriasis rosea–like eruption (Figure 4) presented as nonpruritic, erythematous, scaly patches on the trunk and extremities, and arose 3.6 months after the start of treatment. This particular cutaneous AE is rare. In 3 case reports, the IM dosage also was 400 mg daily.^18-20 The pathophysiology of this rare skin reaction stems from the pharmacological effect of IM rather than a hypersensitivity reaction.¹⁸

Deininger et al⁷ reported that patients with a high basophil count (>20%) rarely show urticarial eruptions after IM due to histamine release from basophils. Premedication with an antihistamine was helpful and the urticarial eruption resolved after normalization in basophil count.⁷

Given the importance of IM for patients who have limited therapeutic alternatives for their disease and the ability to safely treat the cutaneous AEs, as demonstrated in our analysis, the suspension of IM for dermatological complications is necessary only in rare cases, as shown by the low number of patients (n=2) who had to discontinue therapy. The cutaneous AEs should be diagnosed and treated early with less impact on chemotherapy treatments. The administration of IM should involve a coordinated effort among oncologists and dermatologists to prevent important complications.

The Diagnosis: Primary Cutaneous Mucinous Carcinoma

Primary cutaneous mucinous carcinoma is a rare tumor of the sweat glands that was first reported in 1952 by Lennox et al.¹ These tumors are slow growing and have a predilection for the head and neck, with the eyelid being the most commonly reported location.² In general, they present as erythematous asymptomatic nodules measuring less than 7 cm in diameter.^2-4 Primary cutaneous mucinous carcinoma tends to have a good prognosis with complete resection, but cases of metastasis and recurrence have been reported.² Although there is no standard of care, treatment typically consists of surgical management, as the tumors are nonresponsive to chemotherapy or radiation.⁴ Kamalpour et al² compared outcomes for Mohs micrographic surgery versus standard excision, the former showing a lower percentage of poor outcomes. Of note, there were fewer cases treated with Mohs surgery in this study; only more recently reported cases have been treated with Mohs surgery.

Histologically, primary cutaneous mucinous carcinoma is composed of cords, tubules, and lobules of epithelial cells floating in large pools of basophilic mucin, separated by thin fibrovascular septa.⁵ It can be difficult to distinguish a primary tumor from a mucinous carcinoma metastasis with histology alone, especially on the breasts and in the gastrointestinal tract. Immunohistochemistry can be helpful in determining the origin of the tumor. A homologue of p53, p63 expressed in basal and myoepithelial cells of the skin can aid in the confirmation of a primary tumor when present.^6,7 Negative staining for cytokeratin 20 and positive staining for cytokeratin 7 also are helpful in distinguishing a primary cutaneous mucinous carcinoma from a gastrointestinal tract metastasis.^4,8

In our patient, no other symptoms were present that raised concern for an internal malignancy. Findings that supported a primary versus metastatic tumor included the clinicopathologic findings (Figure) as well as positive p63, cytokeratin 7, and negative cytokeratin 20 staining. The initial standard excision had tumor cells within 1 mm of the specimen margin; thus, a subsequent wider reexcision was performed. Reexcision was negative for tumor cells. Close follow-up with a primary care physician was recommended, with emphasis on colon and breast cancer screening. A follow-up mammogram was negative for breast cancer.

The Diagnosis: Primary Cutaneous Mucinous Carcinoma

Primary cutaneous mucinous carcinoma is a rare tumor of the sweat glands that was first reported in 1952 by Lennox et al.¹ These tumors are slow growing and have a predilection for the head and neck, with the eyelid being the most commonly reported location.² In general, they present as erythematous asymptomatic nodules measuring less than 7 cm in diameter.^2-4 Primary cutaneous mucinous carcinoma tends to have a good prognosis with complete resection, but cases of metastasis and recurrence have been reported.² Although there is no standard of care, treatment typically consists of surgical management, as the tumors are nonresponsive to chemotherapy or radiation.⁴ Kamalpour et al² compared outcomes for Mohs micrographic surgery versus standard excision, the former showing a lower percentage of poor outcomes. Of note, there were fewer cases treated with Mohs surgery in this study; only more recently reported cases have been treated with Mohs surgery.

Histologically, primary cutaneous mucinous carcinoma is composed of cords, tubules, and lobules of epithelial cells floating in large pools of basophilic mucin, separated by thin fibrovascular septa.⁵ It can be difficult to distinguish a primary tumor from a mucinous carcinoma metastasis with histology alone, especially on the breasts and in the gastrointestinal tract. Immunohistochemistry can be helpful in determining the origin of the tumor. A homologue of p53, p63 expressed in basal and myoepithelial cells of the skin can aid in the confirmation of a primary tumor when present.^6,7 Negative staining for cytokeratin 20 and positive staining for cytokeratin 7 also are helpful in distinguishing a primary cutaneous mucinous carcinoma from a gastrointestinal tract metastasis.^4,8

In our patient, no other symptoms were present that raised concern for an internal malignancy. Findings that supported a primary versus metastatic tumor included the clinicopathologic findings (Figure) as well as positive p63, cytokeratin 7, and negative cytokeratin 20 staining. The initial standard excision had tumor cells within 1 mm of the specimen margin; thus, a subsequent wider reexcision was performed. Reexcision was negative for tumor cells. Close follow-up with a primary care physician was recommended, with emphasis on colon and breast cancer screening. A follow-up mammogram was negative for breast cancer.

The Diagnosis: Primary Cutaneous Mucinous Carcinoma

Primary cutaneous mucinous carcinoma is a rare tumor of the sweat glands that was first reported in 1952 by Lennox et al.¹ These tumors are slow growing and have a predilection for the head and neck, with the eyelid being the most commonly reported location.² In general, they present as erythematous asymptomatic nodules measuring less than 7 cm in diameter.^2-4 Primary cutaneous mucinous carcinoma tends to have a good prognosis with complete resection, but cases of metastasis and recurrence have been reported.² Although there is no standard of care, treatment typically consists of surgical management, as the tumors are nonresponsive to chemotherapy or radiation.⁴ Kamalpour et al² compared outcomes for Mohs micrographic surgery versus standard excision, the former showing a lower percentage of poor outcomes. Of note, there were fewer cases treated with Mohs surgery in this study; only more recently reported cases have been treated with Mohs surgery.

Histologically, primary cutaneous mucinous carcinoma is composed of cords, tubules, and lobules of epithelial cells floating in large pools of basophilic mucin, separated by thin fibrovascular septa.⁵ It can be difficult to distinguish a primary tumor from a mucinous carcinoma metastasis with histology alone, especially on the breasts and in the gastrointestinal tract. Immunohistochemistry can be helpful in determining the origin of the tumor. A homologue of p53, p63 expressed in basal and myoepithelial cells of the skin can aid in the confirmation of a primary tumor when present.^6,7 Negative staining for cytokeratin 20 and positive staining for cytokeratin 7 also are helpful in distinguishing a primary cutaneous mucinous carcinoma from a gastrointestinal tract metastasis.^4,8

In our patient, no other symptoms were present that raised concern for an internal malignancy. Findings that supported a primary versus metastatic tumor included the clinicopathologic findings (Figure) as well as positive p63, cytokeratin 7, and negative cytokeratin 20 staining. The initial standard excision had tumor cells within 1 mm of the specimen margin; thus, a subsequent wider reexcision was performed. Reexcision was negative for tumor cells. Close follow-up with a primary care physician was recommended, with emphasis on colon and breast cancer screening. A follow-up mammogram was negative for breast cancer.

In 2009, the US Preventive Services Task Force issued an I statement for routine skin cancer screening, noting a lack of evidence to support the balance of benefits and harms from screening,¹ a recommendation that is likely to be upheld this year. As dermatologists and melanoma specialists, we have abundant anecdotal evidence of the value of screening; however, population-based screening performed exclusively by dermatologists is not practical. There are approximately 170,000,000 adults 35 years and older and only 9600 practicing dermatologists in the United States, requiring each dermatologist to screen nearly 18,000 individuals per year to meet the needs of the population.

Only 8% to 15% of people in the United States report having received a recent skin examination by a physician.^2,3 Partnering with our primary care provider (PCP) colleagues has the potential to reach more patients and to improve skin cancer screening rates more rapidly. The workforce in primary care is substantially larger than dermatology by approximately 30-fold, and PCPs are more likely than dermatologists to practice in rural areas, thus reaching patients with limited access to dermatologists. Skin cancer screening can be included in the routine PCP visit, reducing the need for an additional physician visit for the patient. Patients visit their PCP more frequently as they age, which parallels the risk for developing and dying from melanoma and also provides an opportunity to introduce skin cancer education and screening to a population at higher risk who may not otherwise seek it on their own.⁴ Providing PCPs with the training and tools to perform melanoma screening shifts the responsibility of initiating screening from the patient alone to a shared responsibility of patient and provider. Dermatologists, in turn, need to be available to examine those patients found to have a suspicious lesion, treat newly diagnosed skin cancer, and follow those patients at highest risk of developing skin cancer, including those who are immunosuppressed, have multiple atypical moles, or have a personal or family history of melanoma.

Evidence from the SCREEN (Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany) project supports PCP-based screening. In the 5 years following a 1-year pilot screening program, there was nearly a 50% reduction in melanoma mortality.⁵ Unfortunately, these encouraging results were not confirmed once the pilot project was translated into a national skin cancer screening program.⁶ However, there are lessons to be learned from the German project and we propose that PCP-led screening is feasible and practical in the United States and we currently have a pilot program in our institution, the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania).

In the SCREEN project and in routine practice across the United States, screening is primarily driven by patients. Generally, higher-risk patients such as men and the elderly are the least likely group to seek skin cancer screening. In our program, PCPs are offered training in skin cancer screening using a validated web-based program and alerted through the electronic health record to offer skin cancer screening annually to patients 35 years and older who present for routine primary care visits.⁷ This approach reduces self-referral bias by promoting physician initiation rather than patient initiation of screening, which can occur while the patient is already in the PCP’s office.

Melanoma thickness can be measured among screened patients, unscreened patients, and historic controls and compared to determine if this approach is effective. Health care utilization data can help to inform us if this approach leads to more skin biopsies and procedures or to an increased rate of dermatology referrals. As health care payment and delivery models evolve, there is greater emphasis on outcomes and team-based care. We believe that this approach will allow us to form effective teams of PCPs, dermatologists, and other experts in melanoma, public health, and informatics to reduce melanoma mortality in a cost-effective manner.

In 2009, the US Preventive Services Task Force issued an I statement for routine skin cancer screening, noting a lack of evidence to support the balance of benefits and harms from screening,¹ a recommendation that is likely to be upheld this year. As dermatologists and melanoma specialists, we have abundant anecdotal evidence of the value of screening; however, population-based screening performed exclusively by dermatologists is not practical. There are approximately 170,000,000 adults 35 years and older and only 9600 practicing dermatologists in the United States, requiring each dermatologist to screen nearly 18,000 individuals per year to meet the needs of the population.

Only 8% to 15% of people in the United States report having received a recent skin examination by a physician.^2,3 Partnering with our primary care provider (PCP) colleagues has the potential to reach more patients and to improve skin cancer screening rates more rapidly. The workforce in primary care is substantially larger than dermatology by approximately 30-fold, and PCPs are more likely than dermatologists to practice in rural areas, thus reaching patients with limited access to dermatologists. Skin cancer screening can be included in the routine PCP visit, reducing the need for an additional physician visit for the patient. Patients visit their PCP more frequently as they age, which parallels the risk for developing and dying from melanoma and also provides an opportunity to introduce skin cancer education and screening to a population at higher risk who may not otherwise seek it on their own.⁴ Providing PCPs with the training and tools to perform melanoma screening shifts the responsibility of initiating screening from the patient alone to a shared responsibility of patient and provider. Dermatologists, in turn, need to be available to examine those patients found to have a suspicious lesion, treat newly diagnosed skin cancer, and follow those patients at highest risk of developing skin cancer, including those who are immunosuppressed, have multiple atypical moles, or have a personal or family history of melanoma.

Evidence from the SCREEN (Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany) project supports PCP-based screening. In the 5 years following a 1-year pilot screening program, there was nearly a 50% reduction in melanoma mortality.⁵ Unfortunately, these encouraging results were not confirmed once the pilot project was translated into a national skin cancer screening program.⁶ However, there are lessons to be learned from the German project and we propose that PCP-led screening is feasible and practical in the United States and we currently have a pilot program in our institution, the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania).

In the SCREEN project and in routine practice across the United States, screening is primarily driven by patients. Generally, higher-risk patients such as men and the elderly are the least likely group to seek skin cancer screening. In our program, PCPs are offered training in skin cancer screening using a validated web-based program and alerted through the electronic health record to offer skin cancer screening annually to patients 35 years and older who present for routine primary care visits.⁷ This approach reduces self-referral bias by promoting physician initiation rather than patient initiation of screening, which can occur while the patient is already in the PCP’s office.

Melanoma thickness can be measured among screened patients, unscreened patients, and historic controls and compared to determine if this approach is effective. Health care utilization data can help to inform us if this approach leads to more skin biopsies and procedures or to an increased rate of dermatology referrals. As health care payment and delivery models evolve, there is greater emphasis on outcomes and team-based care. We believe that this approach will allow us to form effective teams of PCPs, dermatologists, and other experts in melanoma, public health, and informatics to reduce melanoma mortality in a cost-effective manner.

In 2009, the US Preventive Services Task Force issued an I statement for routine skin cancer screening, noting a lack of evidence to support the balance of benefits and harms from screening,¹ a recommendation that is likely to be upheld this year. As dermatologists and melanoma specialists, we have abundant anecdotal evidence of the value of screening; however, population-based screening performed exclusively by dermatologists is not practical. There are approximately 170,000,000 adults 35 years and older and only 9600 practicing dermatologists in the United States, requiring each dermatologist to screen nearly 18,000 individuals per year to meet the needs of the population.

Only 8% to 15% of people in the United States report having received a recent skin examination by a physician.^2,3 Partnering with our primary care provider (PCP) colleagues has the potential to reach more patients and to improve skin cancer screening rates more rapidly. The workforce in primary care is substantially larger than dermatology by approximately 30-fold, and PCPs are more likely than dermatologists to practice in rural areas, thus reaching patients with limited access to dermatologists. Skin cancer screening can be included in the routine PCP visit, reducing the need for an additional physician visit for the patient. Patients visit their PCP more frequently as they age, which parallels the risk for developing and dying from melanoma and also provides an opportunity to introduce skin cancer education and screening to a population at higher risk who may not otherwise seek it on their own.⁴ Providing PCPs with the training and tools to perform melanoma screening shifts the responsibility of initiating screening from the patient alone to a shared responsibility of patient and provider. Dermatologists, in turn, need to be available to examine those patients found to have a suspicious lesion, treat newly diagnosed skin cancer, and follow those patients at highest risk of developing skin cancer, including those who are immunosuppressed, have multiple atypical moles, or have a personal or family history of melanoma.

Evidence from the SCREEN (Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany) project supports PCP-based screening. In the 5 years following a 1-year pilot screening program, there was nearly a 50% reduction in melanoma mortality.⁵ Unfortunately, these encouraging results were not confirmed once the pilot project was translated into a national skin cancer screening program.⁶ However, there are lessons to be learned from the German project and we propose that PCP-led screening is feasible and practical in the United States and we currently have a pilot program in our institution, the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania).

In the SCREEN project and in routine practice across the United States, screening is primarily driven by patients. Generally, higher-risk patients such as men and the elderly are the least likely group to seek skin cancer screening. In our program, PCPs are offered training in skin cancer screening using a validated web-based program and alerted through the electronic health record to offer skin cancer screening annually to patients 35 years and older who present for routine primary care visits.⁷ This approach reduces self-referral bias by promoting physician initiation rather than patient initiation of screening, which can occur while the patient is already in the PCP’s office.

Melanoma thickness can be measured among screened patients, unscreened patients, and historic controls and compared to determine if this approach is effective. Health care utilization data can help to inform us if this approach leads to more skin biopsies and procedures or to an increased rate of dermatology referrals. As health care payment and delivery models evolve, there is greater emphasis on outcomes and team-based care. We believe that this approach will allow us to form effective teams of PCPs, dermatologists, and other experts in melanoma, public health, and informatics to reduce melanoma mortality in a cost-effective manner.

ORLANDO – Matrilin-2 – a matrix protein found in peritumoral stroma – reliably distinguished invasive basal cell carcinoma from the often difficult-to-distinguish basaloid follicular hamartoma (BFH), in a study that evaluated the protein as a marker in this setting.

The protein marked 41 of 42 cancers and none of the hamartomas, Dr. Renato Goreshi reported at the annual meeting of the American College of Mohs Surgery. The one cancer it failed to identify was a superficial basal cell tumor – a finding that makes sense, since dermal fibroblasts appear to secrete matrilin-2 as a response to invasive skin tumors, said Dr. Goreshi of the Roger Williams Cancer Center, Providence, R.I.

Mohs surgery typically employs hematoxylin and eosin staining to delineate tumor boundary. But, Dr. Goreshi said, that stain doesn’t always reliably differentiate adnexal tumors from basal cell carcinomas. “Basaloid follicular hamartoma can be particularly difficult to distinguish from basal cell carcinoma,” he said.

BFH typically presents as individual or linearly arranged, small skin-colored to brown papules or plaques, or as multiple lesions in a generalized distribution on the face, scalp, and occasionally, the trunk (Arch Pathol Lab Med. 2010 Aug;134[8]:1215-9). These are often stable for many years. The differential diagnosis includes basal cell carcinoma and trichoepithelioma.

BFH sometimes occurs near a BCC, although there are no data on how often this happens.

Dr. Goreshi cited a 2007 case report of a young woman that illustrates this problem. The patient presented with a basal cell carcinoma on the side of her nose. The adjacent BFH was unrecognized, however. She underwent a multiple-stage Mohs that was unnecessarily extended because tumor margins included sections of the BFH.

“The lesion was interpreted as malignancy by both the Mohs surgeon and the dermatopathologist, but was later determined to have been a hamartoma. This highlights the importance of finding an effective marker,” Dr. Goreshi said.

He and his fellowship director, Dr. Satori Iwamoto, chief of Mohs micrographic surgery at Roger Williams, looked for a reliable way to differentiate these tumors, capitalizing on the invasive nature of BCC. The peritumoral stroma plays a role in tumor growth and invasion. It involves fibroblasts, inflammatory and endothelial cells, and extracellular matrix proteins. Matrilin-2, which is involved in the formation of filamentous networks, was a promising candidate and the initial investigations looked good, said Dr. Goreshi said.

Their confirmatory study comprised 42 BCC and seven BFH sections that were obtained during Mohs surgery. All were stained for matrilin-2 and scored for location and intensity of staining by two reviewers. The investigators also conducted flow cytometry to determine the source of the protein.

The BCC set consisted of 11 morpheaform/infiltrative BCCs, 25 nodular BCCs, and 6 superficial BCCs. With the exception of one superficial lesion, all of these stained positive for matrilin-2 in the peritumoral stroma. None of the BFH sections stained positive for the protein, however. Flow cytometry determined that the protein was coming from dermal fibroblasts in the stroma.

This is actually a key point, Dr. Goreshi noted. “Matrilin-2 is not acting as a conventional tumor marker would, but as a marker of invasion.”

This was again played out in the variation of staining intensity in the tumor subtypes. It was most intense around the infiltrative subtypes. There was also adnexal staining, but it was significantly less than what was seen in the peritumoral stroma. There was virtually no staining in or around the hamartoma.

Staining was not as intense around the superficial BCC subtypes. In fact, it was not significantly different from what was seen in the adnexal structures. Again, however, there was no staining in or around the hamartoma.

“Now we are looking at the staining patterns of other lesions, including melanoma and squamous cell carcinoma, and trying to figure out why the dermal fibroblasts are secreting matrilin-2,” Dr. Goreshi said.

The study was the winner of the 2016 Theodore Tromovitch Award, presented for original research conducted by a fellow-in-training during his or her year of training.

Neither Dr. Goreshi nor Dr. Iwamoto had any relevant financial disclosures.

[email protected]

ORLANDO – Matrilin-2 – a matrix protein found in peritumoral stroma – reliably distinguished invasive basal cell carcinoma from the often difficult-to-distinguish basaloid follicular hamartoma (BFH), in a study that evaluated the protein as a marker in this setting.

The protein marked 41 of 42 cancers and none of the hamartomas, Dr. Renato Goreshi reported at the annual meeting of the American College of Mohs Surgery. The one cancer it failed to identify was a superficial basal cell tumor – a finding that makes sense, since dermal fibroblasts appear to secrete matrilin-2 as a response to invasive skin tumors, said Dr. Goreshi of the Roger Williams Cancer Center, Providence, R.I.

Mohs surgery typically employs hematoxylin and eosin staining to delineate tumor boundary. But, Dr. Goreshi said, that stain doesn’t always reliably differentiate adnexal tumors from basal cell carcinomas. “Basaloid follicular hamartoma can be particularly difficult to distinguish from basal cell carcinoma,” he said.

BFH typically presents as individual or linearly arranged, small skin-colored to brown papules or plaques, or as multiple lesions in a generalized distribution on the face, scalp, and occasionally, the trunk (Arch Pathol Lab Med. 2010 Aug;134[8]:1215-9). These are often stable for many years. The differential diagnosis includes basal cell carcinoma and trichoepithelioma.

BFH sometimes occurs near a BCC, although there are no data on how often this happens.

Dr. Goreshi cited a 2007 case report of a young woman that illustrates this problem. The patient presented with a basal cell carcinoma on the side of her nose. The adjacent BFH was unrecognized, however. She underwent a multiple-stage Mohs that was unnecessarily extended because tumor margins included sections of the BFH.

“The lesion was interpreted as malignancy by both the Mohs surgeon and the dermatopathologist, but was later determined to have been a hamartoma. This highlights the importance of finding an effective marker,” Dr. Goreshi said.

He and his fellowship director, Dr. Satori Iwamoto, chief of Mohs micrographic surgery at Roger Williams, looked for a reliable way to differentiate these tumors, capitalizing on the invasive nature of BCC. The peritumoral stroma plays a role in tumor growth and invasion. It involves fibroblasts, inflammatory and endothelial cells, and extracellular matrix proteins. Matrilin-2, which is involved in the formation of filamentous networks, was a promising candidate and the initial investigations looked good, said Dr. Goreshi said.

Their confirmatory study comprised 42 BCC and seven BFH sections that were obtained during Mohs surgery. All were stained for matrilin-2 and scored for location and intensity of staining by two reviewers. The investigators also conducted flow cytometry to determine the source of the protein.

The BCC set consisted of 11 morpheaform/infiltrative BCCs, 25 nodular BCCs, and 6 superficial BCCs. With the exception of one superficial lesion, all of these stained positive for matrilin-2 in the peritumoral stroma. None of the BFH sections stained positive for the protein, however. Flow cytometry determined that the protein was coming from dermal fibroblasts in the stroma.

This is actually a key point, Dr. Goreshi noted. “Matrilin-2 is not acting as a conventional tumor marker would, but as a marker of invasion.”

This was again played out in the variation of staining intensity in the tumor subtypes. It was most intense around the infiltrative subtypes. There was also adnexal staining, but it was significantly less than what was seen in the peritumoral stroma. There was virtually no staining in or around the hamartoma.

Staining was not as intense around the superficial BCC subtypes. In fact, it was not significantly different from what was seen in the adnexal structures. Again, however, there was no staining in or around the hamartoma.

“Now we are looking at the staining patterns of other lesions, including melanoma and squamous cell carcinoma, and trying to figure out why the dermal fibroblasts are secreting matrilin-2,” Dr. Goreshi said.

The study was the winner of the 2016 Theodore Tromovitch Award, presented for original research conducted by a fellow-in-training during his or her year of training.

Neither Dr. Goreshi nor Dr. Iwamoto had any relevant financial disclosures.

[email protected]

ORLANDO – Matrilin-2 – a matrix protein found in peritumoral stroma – reliably distinguished invasive basal cell carcinoma from the often difficult-to-distinguish basaloid follicular hamartoma (BFH), in a study that evaluated the protein as a marker in this setting.

The protein marked 41 of 42 cancers and none of the hamartomas, Dr. Renato Goreshi reported at the annual meeting of the American College of Mohs Surgery. The one cancer it failed to identify was a superficial basal cell tumor – a finding that makes sense, since dermal fibroblasts appear to secrete matrilin-2 as a response to invasive skin tumors, said Dr. Goreshi of the Roger Williams Cancer Center, Providence, R.I.

Mohs surgery typically employs hematoxylin and eosin staining to delineate tumor boundary. But, Dr. Goreshi said, that stain doesn’t always reliably differentiate adnexal tumors from basal cell carcinomas. “Basaloid follicular hamartoma can be particularly difficult to distinguish from basal cell carcinoma,” he said.

BFH typically presents as individual or linearly arranged, small skin-colored to brown papules or plaques, or as multiple lesions in a generalized distribution on the face, scalp, and occasionally, the trunk (Arch Pathol Lab Med. 2010 Aug;134[8]:1215-9). These are often stable for many years. The differential diagnosis includes basal cell carcinoma and trichoepithelioma.

BFH sometimes occurs near a BCC, although there are no data on how often this happens.

Dr. Goreshi cited a 2007 case report of a young woman that illustrates this problem. The patient presented with a basal cell carcinoma on the side of her nose. The adjacent BFH was unrecognized, however. She underwent a multiple-stage Mohs that was unnecessarily extended because tumor margins included sections of the BFH.

“The lesion was interpreted as malignancy by both the Mohs surgeon and the dermatopathologist, but was later determined to have been a hamartoma. This highlights the importance of finding an effective marker,” Dr. Goreshi said.

He and his fellowship director, Dr. Satori Iwamoto, chief of Mohs micrographic surgery at Roger Williams, looked for a reliable way to differentiate these tumors, capitalizing on the invasive nature of BCC. The peritumoral stroma plays a role in tumor growth and invasion. It involves fibroblasts, inflammatory and endothelial cells, and extracellular matrix proteins. Matrilin-2, which is involved in the formation of filamentous networks, was a promising candidate and the initial investigations looked good, said Dr. Goreshi said.

Their confirmatory study comprised 42 BCC and seven BFH sections that were obtained during Mohs surgery. All were stained for matrilin-2 and scored for location and intensity of staining by two reviewers. The investigators also conducted flow cytometry to determine the source of the protein.

The BCC set consisted of 11 morpheaform/infiltrative BCCs, 25 nodular BCCs, and 6 superficial BCCs. With the exception of one superficial lesion, all of these stained positive for matrilin-2 in the peritumoral stroma. None of the BFH sections stained positive for the protein, however. Flow cytometry determined that the protein was coming from dermal fibroblasts in the stroma.

This is actually a key point, Dr. Goreshi noted. “Matrilin-2 is not acting as a conventional tumor marker would, but as a marker of invasion.”

This was again played out in the variation of staining intensity in the tumor subtypes. It was most intense around the infiltrative subtypes. There was also adnexal staining, but it was significantly less than what was seen in the peritumoral stroma. There was virtually no staining in or around the hamartoma.

Staining was not as intense around the superficial BCC subtypes. In fact, it was not significantly different from what was seen in the adnexal structures. Again, however, there was no staining in or around the hamartoma.

“Now we are looking at the staining patterns of other lesions, including melanoma and squamous cell carcinoma, and trying to figure out why the dermal fibroblasts are secreting matrilin-2,” Dr. Goreshi said.

The study was the winner of the 2016 Theodore Tromovitch Award, presented for original research conducted by a fellow-in-training during his or her year of training.

Neither Dr. Goreshi nor Dr. Iwamoto had any relevant financial disclosures.

[email protected]

Men do not know as much about skin cancer prevention and detection techniques as women, according to a recent survey conducted by the American Academy of Dermatology (AAD). This lack of knowledge may delay or prevent early diagnosis and treatment of melanoma and other nonmelanoma skin cancers in this patient population.

The survey results showed that only 56% of men versus 76% of women know there is no such thing as a healthy tan, and only 54% of men versus 70% of women know that getting a base tan is not a healthy way to protect skin from the sun. Furthermore, only 56% of men surveyed were aware that skin cancer could occur on areas of the skin not typically exposed to the sun compared to 65% of women.

“While our survey results indicate that men don’t know as much about skin cancer prevention and detection as women, men over 50 have a higher risk of developing melanoma, so it’s especially important for them to be vigilant about protecting and monitoring their skin,” said AAD President Abel Torres, MD, JD.

More resources on the diagnosis and treatment of melanoma.

May is skin cancer awareness month and the AAD is encouraging patients to make sure their skin is “Looking Good in 2016” by using sun protection and regularly examining skin for signs of skin cancer. The campaign features a public service announcement encouraging men to check their skin for signs of skin cancer and find a partner to help. The AAD also released a new infographic with tips on performing a skin cancer self-examination that dermatologists can share with patients to promote early detection of skin cancer.

More resources on nonmelanoma skin cancers. 

Dermatologist intervention in catching skin cancers when they are easier to treat also is key. At the 74th Annual Meeting of the American Academy of Dermatology in Washington, DC, Dr. Orit Markowitz discussed noninvasive imaging tools that can help dermatologists diagnose skin cancers earlier. She noted that even when a lesion looks very small, tools such as dermoscopy can reveal features that indicate it already has depth and therefore may progress to a more serious malignancy. Early detection is particularly crucial in cases of rare aggressive tumors such as amelanotic melanoma. “If something is very pink clinically and then suddenly has pigmentation dermoscopically, you really have to be considering biopsying that lesion because you may be looking at an early amelanotic melanoma,” Dr. Markowitz explained. By the time the lesion develops more obvious clinical features suggesting malignancy, the tumor progression may be far more advanced.

Men do not know as much about skin cancer prevention and detection techniques as women, according to a recent survey conducted by the American Academy of Dermatology (AAD). This lack of knowledge may delay or prevent early diagnosis and treatment of melanoma and other nonmelanoma skin cancers in this patient population.

The survey results showed that only 56% of men versus 76% of women know there is no such thing as a healthy tan, and only 54% of men versus 70% of women know that getting a base tan is not a healthy way to protect skin from the sun. Furthermore, only 56% of men surveyed were aware that skin cancer could occur on areas of the skin not typically exposed to the sun compared to 65% of women.

“While our survey results indicate that men don’t know as much about skin cancer prevention and detection as women, men over 50 have a higher risk of developing melanoma, so it’s especially important for them to be vigilant about protecting and monitoring their skin,” said AAD President Abel Torres, MD, JD.

More resources on the diagnosis and treatment of melanoma.

May is skin cancer awareness month and the AAD is encouraging patients to make sure their skin is “Looking Good in 2016” by using sun protection and regularly examining skin for signs of skin cancer. The campaign features a public service announcement encouraging men to check their skin for signs of skin cancer and find a partner to help. The AAD also released a new infographic with tips on performing a skin cancer self-examination that dermatologists can share with patients to promote early detection of skin cancer.

More resources on nonmelanoma skin cancers. 

Dermatologist intervention in catching skin cancers when they are easier to treat also is key. At the 74th Annual Meeting of the American Academy of Dermatology in Washington, DC, Dr. Orit Markowitz discussed noninvasive imaging tools that can help dermatologists diagnose skin cancers earlier. She noted that even when a lesion looks very small, tools such as dermoscopy can reveal features that indicate it already has depth and therefore may progress to a more serious malignancy. Early detection is particularly crucial in cases of rare aggressive tumors such as amelanotic melanoma. “If something is very pink clinically and then suddenly has pigmentation dermoscopically, you really have to be considering biopsying that lesion because you may be looking at an early amelanotic melanoma,” Dr. Markowitz explained. By the time the lesion develops more obvious clinical features suggesting malignancy, the tumor progression may be far more advanced.

Men do not know as much about skin cancer prevention and detection techniques as women, according to a recent survey conducted by the American Academy of Dermatology (AAD). This lack of knowledge may delay or prevent early diagnosis and treatment of melanoma and other nonmelanoma skin cancers in this patient population.

The survey results showed that only 56% of men versus 76% of women know there is no such thing as a healthy tan, and only 54% of men versus 70% of women know that getting a base tan is not a healthy way to protect skin from the sun. Furthermore, only 56% of men surveyed were aware that skin cancer could occur on areas of the skin not typically exposed to the sun compared to 65% of women.

“While our survey results indicate that men don’t know as much about skin cancer prevention and detection as women, men over 50 have a higher risk of developing melanoma, so it’s especially important for them to be vigilant about protecting and monitoring their skin,” said AAD President Abel Torres, MD, JD.

More resources on the diagnosis and treatment of melanoma.

May is skin cancer awareness month and the AAD is encouraging patients to make sure their skin is “Looking Good in 2016” by using sun protection and regularly examining skin for signs of skin cancer. The campaign features a public service announcement encouraging men to check their skin for signs of skin cancer and find a partner to help. The AAD also released a new infographic with tips on performing a skin cancer self-examination that dermatologists can share with patients to promote early detection of skin cancer.

More resources on nonmelanoma skin cancers. 

Dermatologist intervention in catching skin cancers when they are easier to treat also is key. At the 74th Annual Meeting of the American Academy of Dermatology in Washington, DC, Dr. Orit Markowitz discussed noninvasive imaging tools that can help dermatologists diagnose skin cancers earlier. She noted that even when a lesion looks very small, tools such as dermoscopy can reveal features that indicate it already has depth and therefore may progress to a more serious malignancy. Early detection is particularly crucial in cases of rare aggressive tumors such as amelanotic melanoma. “If something is very pink clinically and then suddenly has pigmentation dermoscopically, you really have to be considering biopsying that lesion because you may be looking at an early amelanotic melanoma,” Dr. Markowitz explained. By the time the lesion develops more obvious clinical features suggesting malignancy, the tumor progression may be far more advanced.

Case Report

A 70-year-old man with history of coronary artery disease presented with a growing lesion on the right leg of 1 year’s duration. The lesion developed at a vein graft donor site for a coronary artery bypass that had been performed 18 years prior to presentation. The patient reported that the lesion was sensitive to touch. Physical examination revealed a 27-mm, firm, violaceous plaque on the medial aspect of the right upper shin (Figure 1). Mild pitting edema also was noted on both lower legs but was more prominent on the right leg. A 6-mm punch biopsy was performed.

Histology showed diffuse infiltration of the dermis and subcutaneous fat by intermediate-sized atypical blue cells with scant cytoplasm (Figure 2). The tumor exhibited moderate cytologic atypia with occasional mitotic figures, and lymphovascular invasion was present. Staining for CD3 was negative within the tumor, but a few reactive lymphocytes were highlighted at the periphery. Staining for CD20 and CD30 was negative. Strong and diffuse staining for cyto-keratin 20 and pan-cytokeratin was noted within the tumor with the distinctive perinuclear pattern characteristic of Merkel cell carcinoma (MCC). Staining for cytokeratin 7 was negative. Synaptophysin and chromogranin were strongly and diffusely positive within the tumor, consistent with a diagnosis of MCC.

The patient was found to have stage IIA (T2N0M0) MCC. Computed tomography completed for staging showed no evidence of metastasis. Wide local excision of the lesion was performed. Margins were negative, as was a right inguinal sentinel lymph node dissection. Because of the size of the tumor and the presence of lymphovascular invasion, radiation therapy at the primary tumor site was recommended. Local radiation treatment (200 cGy daily) was administered for a total dose of 5000 cGy over 5 weeks. The patient currently is free of recurrence or metastases and is being followed by the oncology, surgery, and dermatology departments.

Comment

Merkel cell carcinoma is a rare aggressive cutaneous malignancy. The exact pathogenesis is unknown, but immunosuppression and UV radiation, possibly through its immunosuppressive effects, appear to be contributing factors. More recently, the Merkel cell polyomavirus has been linked to MCC in approximately 80% of cases.^1,2

Merkel cell carcinoma is more common in individuals with fair skin, and the average age at diagnosis is 69 years.¹ Patients typically present with an asymptomatic, firm, erythematous or violaceous, dome-shaped nodule or a small indurated plaque, most commonly on sun-exposed areas of the head and neck followed by the upper and lower extremities including the hands, feet, ankles, and wrists. Fifteen percent to 20% of MCCs develop on the legs and feet.¹ Our patient presented with an MCC that developed on the right shin at a vein graft donor site.

The development of a cutaneous malignancy in a chronic wound (also known as a Marjolin ulcer) is a rare but well-recognized process. These malignancies occur in previously traumatized or chronically inflamed wounds and have been found to occur most commonly in chronic burn wounds, especially in ungrafted full-thickness burns. Squamous cell carcinomas (SCCs) are the most common malignancies to arise in chronic wounds, but basal cell carcinomas, adenocarcinomas, melanomas, malignant fibrous histiocytomas, adenoacanthomas, liposarcomas, and osteosarcomas also have been reported.³ There also have been a few reports of MCC associated with Bowen disease that developed in burn wounds.⁴ These malignancies generally occur years after injury (average, 35.5 years), but there have been reports of keratoacanthomas developing as early as 3 weeks after injury.^5,6

In some reports, malignancies in skin graft donor sites are differentiated from Marjolin ulcers, as the former appear in healed surgical wounds rather than in chronic unstable wounds and tend to occur sooner (ie, in weeks to months after graft harvesting).^7,8 The development of these malignancies in graft donor sites is not as well recognized and has been reported in donor sites for split-thickness skin grafts (STSGs), full-thickness skin grafts, tendon grafts, and bone grafts. In addition to malignancies that arise de novo, some develop due to metastatic and iatrogenic spread. The majority of reported malignancies in tendon and bone graft donor sites have been due to metastasis or iatrogenic spread.^9-14

Iatrogenic implantation of tumor cells is a well-recognized phenomenon. Hussain et al¹⁰ reported a case of implantation of SCC in an STSG donor site, most likely due to direct seeding from a hollow needle used to infiltrate local anesthetic in the tumor area and the STSG. In this case, metastasis could not be completely ruled out.¹⁰ There also have been reports of osteosarcoma, ameloblastoma, scirrhous carcinoma of the breast, and malignant fibrous histiocytoma thought to be implanted at bone graft donor sites.^14-17 Iatrogenic spread of malignancies can occur through seeding from contaminated gloves or instruments such as hollow bore needles or trocar placement in laparoscopic surgery.¹¹ Airborne spread also may be possible, as viable melanoma cells have been detected in electrocautery plume in mice.¹³

Metastatic malignancies including metastases from SCC, adenocarcinoma, melanoma, malignant fibrous histiocytoma, angiosarcoma, and osteosarcoma also have been reported to develop in graft donor sites.^11,13,18,19 Many malignancies thought to have developed from iatrogenic seeding may actually be from metastasis either by hematogenous or lymphatic spread. A possible contributing factor may be surgery-induced immunosuppression, which has been linked to increased tumor metastasis formation.²⁰ Surgery or trauma have been shown to have an effect on cellular components of the immune system, causing changes such as a shift in T lymphocytes toward immune-suppressive T lymphocytes and impaired function of natural killer cells, neutrophils, and macrophages.²⁰ The suppression of cell-mediated immunity has been shown to decrease over days to weeks in the postoperative period.²¹ In addition to surgery- or trauma-induced immunosuppression, the risk for metastasis may increase due to increased vascular, including lymphatic, flow toward a skin graft donor site.^13,16 Furthermore, trauma predisposes areas to a hypercoagulable state with increased sludging as well as increased platelet counts and fibrinogen levels, which may lead to localization of metastatic lesions.²² All of these factors could potentially work simultaneously to induce the development of metastasis in graft donor sites.

We found that SCCs and keratoacanthomas, which may be a variant of SCC, are among the only primary malignancies that have been reported to develop in skin graft donor sites.^6-8 Malignancies in these donor sites appear to develop sooner than those found in chronic wounds and are reported to develop within weeks to several months postoperatively, even in as few as 2 weeks.^6,8 Tamir et al⁶ reported 2 keratoacanthomas that developed simultaneously in a burn scar and STSG donor site. The investigators believed it could be a sign of reduced immune surveillance in the 2 affected areas.⁶ It has been hypothesized that one cause of local immune suppression in Marjolin ulcers could be due to poor lymphatic regeneration in scar tissue, which would prevent delivery of antigens and stimulated lymphocytes.²³ Haik et al⁷ considered this possibility when discussing a case of SCC that developed at the site of an STSG. The authors did not feel it applied, however, as the donor site had only undergone a single skin harvesting procedure.⁷ Ponnuvelu et al⁸ felt that inflammation was the underlying etiology behind the 2 cases they reported of SCCs that developed in STSG donor sites. The inflammation associated with tumors has many of the same processes involved in wound healing (eg, cellular proliferation, angiogenesis). Ponnuvelu et al⁸ hypothesized that the local inflammation caused by graft harvesting produced an ideal environment for early carcinogenesis. Although in chronic wounds it is believed that continual repair and regeneration in recurrent ulceration contributes to neoplastic initiation, it is thought that even a single injury may lead to malignant change, which may be because prior actinic damage or another cause has made the area more susceptible to these changes.^24,25 Surgery-induced immunosuppression also may play a role in development of primary malignancies in graft donor sites.

There have been a few reports of SCCs and basal cell carcinomas occurring in other surgical scars that healed without complications.^24,26-28 Similar to the malignancies in graft donor sites, some authors differentiate malignancies that occur in surgical scars that heal without complications from Marjolin ulcers, as they do not occur in chronically irritated wounds. These malignancies have been reported in scars from sternotomies, an infertility procedure, hair transplantation, thyroidectomy, colostomy, cleft lip repair, inguinal hernia repair, and paraumbilical laparoscopic port site. The time between surgery and diagnosis of malignancy ranged from 9 months to 67 years.^24,26-28 The development of malignancies in these surgical scars may be due to local immunosuppression, possibly from decreased lymphatic flow; additionally, the inflammation in wound healing may provide the ideal environment for carcinogenesis. Trauma in areas already susceptible to malignant change could be a contributing factor.

Conclusion

Our patient developed an MCC in a vein graft donor site 18 years after vein harvesting. It was likely a primary tumor, as vein harvesting was done for coronary artery bypass graft. There was no evidence of any other lesions on physical examination or computed tomography, making it doubtful that an MCC serving as a primary lesion for seeding or metastasis was present. If such a lesion had been present at that time, it would likely have spread well before the time of presentation to our clinic due to the fast doubling time and high rate of metastasis characteristic of MCCs, further lessening the possibility of metastasis or implantation.

The extended length of time from procedure to lesion development in our patient is much longer than for other reported malignancies in graft donor sites, but the reported time for malignancies in other postsurgical scars is more varied. Regardless of whether the MCC in our patient is classified as a Marjolin ulcer, the pathogenesis is unclear. It is thought that a single injury could lead to malignant change in predisposed skin. Our patient’s legs did not have any evidence of prior actinic damage; however, it is likely that he had local immune suppression, which may have made him more susceptible to these changes. It is unlikely that surgery-induced immunosuppression played a role in our patient, as specific cellular components of the immune system only appear to be affected over days to weeks in the postoperative period. Although poor lymphatic regeneration in scar tissue leading to decreased immune surveillance is not generally thought to contribute to malignancies in most surgical scars, our patient underwent vein harvesting. Chronic edema commonly occurs after vein harvesting and is believed to be due to trauma to the lymphatics. Local immune suppression also may have led to increased susceptibility to infection by the MCC polyomavirus, which has been found to be associated with many MCCs. In addition, the area may have been more susceptible to carcinogenesis due to changes from inflammation from wound healing. We suspect together these factors contributed to the development of our patient’s MCC. Although rare, graft donor sites should be examined periodically for the development of malignancy.

Case Report

A 70-year-old man with history of coronary artery disease presented with a growing lesion on the right leg of 1 year’s duration. The lesion developed at a vein graft donor site for a coronary artery bypass that had been performed 18 years prior to presentation. The patient reported that the lesion was sensitive to touch. Physical examination revealed a 27-mm, firm, violaceous plaque on the medial aspect of the right upper shin (Figure 1). Mild pitting edema also was noted on both lower legs but was more prominent on the right leg. A 6-mm punch biopsy was performed.

Histology showed diffuse infiltration of the dermis and subcutaneous fat by intermediate-sized atypical blue cells with scant cytoplasm (Figure 2). The tumor exhibited moderate cytologic atypia with occasional mitotic figures, and lymphovascular invasion was present. Staining for CD3 was negative within the tumor, but a few reactive lymphocytes were highlighted at the periphery. Staining for CD20 and CD30 was negative. Strong and diffuse staining for cyto-keratin 20 and pan-cytokeratin was noted within the tumor with the distinctive perinuclear pattern characteristic of Merkel cell carcinoma (MCC). Staining for cytokeratin 7 was negative. Synaptophysin and chromogranin were strongly and diffusely positive within the tumor, consistent with a diagnosis of MCC.

The patient was found to have stage IIA (T2N0M0) MCC. Computed tomography completed for staging showed no evidence of metastasis. Wide local excision of the lesion was performed. Margins were negative, as was a right inguinal sentinel lymph node dissection. Because of the size of the tumor and the presence of lymphovascular invasion, radiation therapy at the primary tumor site was recommended. Local radiation treatment (200 cGy daily) was administered for a total dose of 5000 cGy over 5 weeks. The patient currently is free of recurrence or metastases and is being followed by the oncology, surgery, and dermatology departments.

Comment

Merkel cell carcinoma is a rare aggressive cutaneous malignancy. The exact pathogenesis is unknown, but immunosuppression and UV radiation, possibly through its immunosuppressive effects, appear to be contributing factors. More recently, the Merkel cell polyomavirus has been linked to MCC in approximately 80% of cases.^1,2

Merkel cell carcinoma is more common in individuals with fair skin, and the average age at diagnosis is 69 years.¹ Patients typically present with an asymptomatic, firm, erythematous or violaceous, dome-shaped nodule or a small indurated plaque, most commonly on sun-exposed areas of the head and neck followed by the upper and lower extremities including the hands, feet, ankles, and wrists. Fifteen percent to 20% of MCCs develop on the legs and feet.¹ Our patient presented with an MCC that developed on the right shin at a vein graft donor site.

The development of a cutaneous malignancy in a chronic wound (also known as a Marjolin ulcer) is a rare but well-recognized process. These malignancies occur in previously traumatized or chronically inflamed wounds and have been found to occur most commonly in chronic burn wounds, especially in ungrafted full-thickness burns. Squamous cell carcinomas (SCCs) are the most common malignancies to arise in chronic wounds, but basal cell carcinomas, adenocarcinomas, melanomas, malignant fibrous histiocytomas, adenoacanthomas, liposarcomas, and osteosarcomas also have been reported.³ There also have been a few reports of MCC associated with Bowen disease that developed in burn wounds.⁴ These malignancies generally occur years after injury (average, 35.5 years), but there have been reports of keratoacanthomas developing as early as 3 weeks after injury.^5,6

In some reports, malignancies in skin graft donor sites are differentiated from Marjolin ulcers, as the former appear in healed surgical wounds rather than in chronic unstable wounds and tend to occur sooner (ie, in weeks to months after graft harvesting).^7,8 The development of these malignancies in graft donor sites is not as well recognized and has been reported in donor sites for split-thickness skin grafts (STSGs), full-thickness skin grafts, tendon grafts, and bone grafts. In addition to malignancies that arise de novo, some develop due to metastatic and iatrogenic spread. The majority of reported malignancies in tendon and bone graft donor sites have been due to metastasis or iatrogenic spread.^9-14

Iatrogenic implantation of tumor cells is a well-recognized phenomenon. Hussain et al¹⁰ reported a case of implantation of SCC in an STSG donor site, most likely due to direct seeding from a hollow needle used to infiltrate local anesthetic in the tumor area and the STSG. In this case, metastasis could not be completely ruled out.¹⁰ There also have been reports of osteosarcoma, ameloblastoma, scirrhous carcinoma of the breast, and malignant fibrous histiocytoma thought to be implanted at bone graft donor sites.^14-17 Iatrogenic spread of malignancies can occur through seeding from contaminated gloves or instruments such as hollow bore needles or trocar placement in laparoscopic surgery.¹¹ Airborne spread also may be possible, as viable melanoma cells have been detected in electrocautery plume in mice.¹³

Metastatic malignancies including metastases from SCC, adenocarcinoma, melanoma, malignant fibrous histiocytoma, angiosarcoma, and osteosarcoma also have been reported to develop in graft donor sites.^11,13,18,19 Many malignancies thought to have developed from iatrogenic seeding may actually be from metastasis either by hematogenous or lymphatic spread. A possible contributing factor may be surgery-induced immunosuppression, which has been linked to increased tumor metastasis formation.²⁰ Surgery or trauma have been shown to have an effect on cellular components of the immune system, causing changes such as a shift in T lymphocytes toward immune-suppressive T lymphocytes and impaired function of natural killer cells, neutrophils, and macrophages.²⁰ The suppression of cell-mediated immunity has been shown to decrease over days to weeks in the postoperative period.²¹ In addition to surgery- or trauma-induced immunosuppression, the risk for metastasis may increase due to increased vascular, including lymphatic, flow toward a skin graft donor site.^13,16 Furthermore, trauma predisposes areas to a hypercoagulable state with increased sludging as well as increased platelet counts and fibrinogen levels, which may lead to localization of metastatic lesions.²² All of these factors could potentially work simultaneously to induce the development of metastasis in graft donor sites.

We found that SCCs and keratoacanthomas, which may be a variant of SCC, are among the only primary malignancies that have been reported to develop in skin graft donor sites.^6-8 Malignancies in these donor sites appear to develop sooner than those found in chronic wounds and are reported to develop within weeks to several months postoperatively, even in as few as 2 weeks.^6,8 Tamir et al⁶ reported 2 keratoacanthomas that developed simultaneously in a burn scar and STSG donor site. The investigators believed it could be a sign of reduced immune surveillance in the 2 affected areas.⁶ It has been hypothesized that one cause of local immune suppression in Marjolin ulcers could be due to poor lymphatic regeneration in scar tissue, which would prevent delivery of antigens and stimulated lymphocytes.²³ Haik et al⁷ considered this possibility when discussing a case of SCC that developed at the site of an STSG. The authors did not feel it applied, however, as the donor site had only undergone a single skin harvesting procedure.⁷ Ponnuvelu et al⁸ felt that inflammation was the underlying etiology behind the 2 cases they reported of SCCs that developed in STSG donor sites. The inflammation associated with tumors has many of the same processes involved in wound healing (eg, cellular proliferation, angiogenesis). Ponnuvelu et al⁸ hypothesized that the local inflammation caused by graft harvesting produced an ideal environment for early carcinogenesis. Although in chronic wounds it is believed that continual repair and regeneration in recurrent ulceration contributes to neoplastic initiation, it is thought that even a single injury may lead to malignant change, which may be because prior actinic damage or another cause has made the area more susceptible to these changes.^24,25 Surgery-induced immunosuppression also may play a role in development of primary malignancies in graft donor sites.

There have been a few reports of SCCs and basal cell carcinomas occurring in other surgical scars that healed without complications.^24,26-28 Similar to the malignancies in graft donor sites, some authors differentiate malignancies that occur in surgical scars that heal without complications from Marjolin ulcers, as they do not occur in chronically irritated wounds. These malignancies have been reported in scars from sternotomies, an infertility procedure, hair transplantation, thyroidectomy, colostomy, cleft lip repair, inguinal hernia repair, and paraumbilical laparoscopic port site. The time between surgery and diagnosis of malignancy ranged from 9 months to 67 years.^24,26-28 The development of malignancies in these surgical scars may be due to local immunosuppression, possibly from decreased lymphatic flow; additionally, the inflammation in wound healing may provide the ideal environment for carcinogenesis. Trauma in areas already susceptible to malignant change could be a contributing factor.

Conclusion

Our patient developed an MCC in a vein graft donor site 18 years after vein harvesting. It was likely a primary tumor, as vein harvesting was done for coronary artery bypass graft. There was no evidence of any other lesions on physical examination or computed tomography, making it doubtful that an MCC serving as a primary lesion for seeding or metastasis was present. If such a lesion had been present at that time, it would likely have spread well before the time of presentation to our clinic due to the fast doubling time and high rate of metastasis characteristic of MCCs, further lessening the possibility of metastasis or implantation.

The extended length of time from procedure to lesion development in our patient is much longer than for other reported malignancies in graft donor sites, but the reported time for malignancies in other postsurgical scars is more varied. Regardless of whether the MCC in our patient is classified as a Marjolin ulcer, the pathogenesis is unclear. It is thought that a single injury could lead to malignant change in predisposed skin. Our patient’s legs did not have any evidence of prior actinic damage; however, it is likely that he had local immune suppression, which may have made him more susceptible to these changes. It is unlikely that surgery-induced immunosuppression played a role in our patient, as specific cellular components of the immune system only appear to be affected over days to weeks in the postoperative period. Although poor lymphatic regeneration in scar tissue leading to decreased immune surveillance is not generally thought to contribute to malignancies in most surgical scars, our patient underwent vein harvesting. Chronic edema commonly occurs after vein harvesting and is believed to be due to trauma to the lymphatics. Local immune suppression also may have led to increased susceptibility to infection by the MCC polyomavirus, which has been found to be associated with many MCCs. In addition, the area may have been more susceptible to carcinogenesis due to changes from inflammation from wound healing. We suspect together these factors contributed to the development of our patient’s MCC. Although rare, graft donor sites should be examined periodically for the development of malignancy.

Case Report

A 70-year-old man with history of coronary artery disease presented with a growing lesion on the right leg of 1 year’s duration. The lesion developed at a vein graft donor site for a coronary artery bypass that had been performed 18 years prior to presentation. The patient reported that the lesion was sensitive to touch. Physical examination revealed a 27-mm, firm, violaceous plaque on the medial aspect of the right upper shin (Figure 1). Mild pitting edema also was noted on both lower legs but was more prominent on the right leg. A 6-mm punch biopsy was performed.

Histology showed diffuse infiltration of the dermis and subcutaneous fat by intermediate-sized atypical blue cells with scant cytoplasm (Figure 2). The tumor exhibited moderate cytologic atypia with occasional mitotic figures, and lymphovascular invasion was present. Staining for CD3 was negative within the tumor, but a few reactive lymphocytes were highlighted at the periphery. Staining for CD20 and CD30 was negative. Strong and diffuse staining for cyto-keratin 20 and pan-cytokeratin was noted within the tumor with the distinctive perinuclear pattern characteristic of Merkel cell carcinoma (MCC). Staining for cytokeratin 7 was negative. Synaptophysin and chromogranin were strongly and diffusely positive within the tumor, consistent with a diagnosis of MCC.

The patient was found to have stage IIA (T2N0M0) MCC. Computed tomography completed for staging showed no evidence of metastasis. Wide local excision of the lesion was performed. Margins were negative, as was a right inguinal sentinel lymph node dissection. Because of the size of the tumor and the presence of lymphovascular invasion, radiation therapy at the primary tumor site was recommended. Local radiation treatment (200 cGy daily) was administered for a total dose of 5000 cGy over 5 weeks. The patient currently is free of recurrence or metastases and is being followed by the oncology, surgery, and dermatology departments.

Comment

Merkel cell carcinoma is a rare aggressive cutaneous malignancy. The exact pathogenesis is unknown, but immunosuppression and UV radiation, possibly through its immunosuppressive effects, appear to be contributing factors. More recently, the Merkel cell polyomavirus has been linked to MCC in approximately 80% of cases.^1,2

Merkel cell carcinoma is more common in individuals with fair skin, and the average age at diagnosis is 69 years.¹ Patients typically present with an asymptomatic, firm, erythematous or violaceous, dome-shaped nodule or a small indurated plaque, most commonly on sun-exposed areas of the head and neck followed by the upper and lower extremities including the hands, feet, ankles, and wrists. Fifteen percent to 20% of MCCs develop on the legs and feet.¹ Our patient presented with an MCC that developed on the right shin at a vein graft donor site.

The development of a cutaneous malignancy in a chronic wound (also known as a Marjolin ulcer) is a rare but well-recognized process. These malignancies occur in previously traumatized or chronically inflamed wounds and have been found to occur most commonly in chronic burn wounds, especially in ungrafted full-thickness burns. Squamous cell carcinomas (SCCs) are the most common malignancies to arise in chronic wounds, but basal cell carcinomas, adenocarcinomas, melanomas, malignant fibrous histiocytomas, adenoacanthomas, liposarcomas, and osteosarcomas also have been reported.³ There also have been a few reports of MCC associated with Bowen disease that developed in burn wounds.⁴ These malignancies generally occur years after injury (average, 35.5 years), but there have been reports of keratoacanthomas developing as early as 3 weeks after injury.^5,6

In some reports, malignancies in skin graft donor sites are differentiated from Marjolin ulcers, as the former appear in healed surgical wounds rather than in chronic unstable wounds and tend to occur sooner (ie, in weeks to months after graft harvesting).^7,8 The development of these malignancies in graft donor sites is not as well recognized and has been reported in donor sites for split-thickness skin grafts (STSGs), full-thickness skin grafts, tendon grafts, and bone grafts. In addition to malignancies that arise de novo, some develop due to metastatic and iatrogenic spread. The majority of reported malignancies in tendon and bone graft donor sites have been due to metastasis or iatrogenic spread.^9-14

Iatrogenic implantation of tumor cells is a well-recognized phenomenon. Hussain et al¹⁰ reported a case of implantation of SCC in an STSG donor site, most likely due to direct seeding from a hollow needle used to infiltrate local anesthetic in the tumor area and the STSG. In this case, metastasis could not be completely ruled out.¹⁰ There also have been reports of osteosarcoma, ameloblastoma, scirrhous carcinoma of the breast, and malignant fibrous histiocytoma thought to be implanted at bone graft donor sites.^14-17 Iatrogenic spread of malignancies can occur through seeding from contaminated gloves or instruments such as hollow bore needles or trocar placement in laparoscopic surgery.¹¹ Airborne spread also may be possible, as viable melanoma cells have been detected in electrocautery plume in mice.¹³

Metastatic malignancies including metastases from SCC, adenocarcinoma, melanoma, malignant fibrous histiocytoma, angiosarcoma, and osteosarcoma also have been reported to develop in graft donor sites.^11,13,18,19 Many malignancies thought to have developed from iatrogenic seeding may actually be from metastasis either by hematogenous or lymphatic spread. A possible contributing factor may be surgery-induced immunosuppression, which has been linked to increased tumor metastasis formation.²⁰ Surgery or trauma have been shown to have an effect on cellular components of the immune system, causing changes such as a shift in T lymphocytes toward immune-suppressive T lymphocytes and impaired function of natural killer cells, neutrophils, and macrophages.²⁰ The suppression of cell-mediated immunity has been shown to decrease over days to weeks in the postoperative period.²¹ In addition to surgery- or trauma-induced immunosuppression, the risk for metastasis may increase due to increased vascular, including lymphatic, flow toward a skin graft donor site.^13,16 Furthermore, trauma predisposes areas to a hypercoagulable state with increased sludging as well as increased platelet counts and fibrinogen levels, which may lead to localization of metastatic lesions.²² All of these factors could potentially work simultaneously to induce the development of metastasis in graft donor sites.

We found that SCCs and keratoacanthomas, which may be a variant of SCC, are among the only primary malignancies that have been reported to develop in skin graft donor sites.^6-8 Malignancies in these donor sites appear to develop sooner than those found in chronic wounds and are reported to develop within weeks to several months postoperatively, even in as few as 2 weeks.^6,8 Tamir et al⁶ reported 2 keratoacanthomas that developed simultaneously in a burn scar and STSG donor site. The investigators believed it could be a sign of reduced immune surveillance in the 2 affected areas.⁶ It has been hypothesized that one cause of local immune suppression in Marjolin ulcers could be due to poor lymphatic regeneration in scar tissue, which would prevent delivery of antigens and stimulated lymphocytes.²³ Haik et al⁷ considered this possibility when discussing a case of SCC that developed at the site of an STSG. The authors did not feel it applied, however, as the donor site had only undergone a single skin harvesting procedure.⁷ Ponnuvelu et al⁸ felt that inflammation was the underlying etiology behind the 2 cases they reported of SCCs that developed in STSG donor sites. The inflammation associated with tumors has many of the same processes involved in wound healing (eg, cellular proliferation, angiogenesis). Ponnuvelu et al⁸ hypothesized that the local inflammation caused by graft harvesting produced an ideal environment for early carcinogenesis. Although in chronic wounds it is believed that continual repair and regeneration in recurrent ulceration contributes to neoplastic initiation, it is thought that even a single injury may lead to malignant change, which may be because prior actinic damage or another cause has made the area more susceptible to these changes.^24,25 Surgery-induced immunosuppression also may play a role in development of primary malignancies in graft donor sites.

There have been a few reports of SCCs and basal cell carcinomas occurring in other surgical scars that healed without complications.^24,26-28 Similar to the malignancies in graft donor sites, some authors differentiate malignancies that occur in surgical scars that heal without complications from Marjolin ulcers, as they do not occur in chronically irritated wounds. These malignancies have been reported in scars from sternotomies, an infertility procedure, hair transplantation, thyroidectomy, colostomy, cleft lip repair, inguinal hernia repair, and paraumbilical laparoscopic port site. The time between surgery and diagnosis of malignancy ranged from 9 months to 67 years.^24,26-28 The development of malignancies in these surgical scars may be due to local immunosuppression, possibly from decreased lymphatic flow; additionally, the inflammation in wound healing may provide the ideal environment for carcinogenesis. Trauma in areas already susceptible to malignant change could be a contributing factor.

Conclusion

Our patient developed an MCC in a vein graft donor site 18 years after vein harvesting. It was likely a primary tumor, as vein harvesting was done for coronary artery bypass graft. There was no evidence of any other lesions on physical examination or computed tomography, making it doubtful that an MCC serving as a primary lesion for seeding or metastasis was present. If such a lesion had been present at that time, it would likely have spread well before the time of presentation to our clinic due to the fast doubling time and high rate of metastasis characteristic of MCCs, further lessening the possibility of metastasis or implantation.

The extended length of time from procedure to lesion development in our patient is much longer than for other reported malignancies in graft donor sites, but the reported time for malignancies in other postsurgical scars is more varied. Regardless of whether the MCC in our patient is classified as a Marjolin ulcer, the pathogenesis is unclear. It is thought that a single injury could lead to malignant change in predisposed skin. Our patient’s legs did not have any evidence of prior actinic damage; however, it is likely that he had local immune suppression, which may have made him more susceptible to these changes. It is unlikely that surgery-induced immunosuppression played a role in our patient, as specific cellular components of the immune system only appear to be affected over days to weeks in the postoperative period. Although poor lymphatic regeneration in scar tissue leading to decreased immune surveillance is not generally thought to contribute to malignancies in most surgical scars, our patient underwent vein harvesting. Chronic edema commonly occurs after vein harvesting and is believed to be due to trauma to the lymphatics. Local immune suppression also may have led to increased susceptibility to infection by the MCC polyomavirus, which has been found to be associated with many MCCs. In addition, the area may have been more susceptible to carcinogenesis due to changes from inflammation from wound healing. We suspect together these factors contributed to the development of our patient’s MCC. Although rare, graft donor sites should be examined periodically for the development of malignancy.

The Diagnosis: Fibroepithelioma of Pinkus

Fibroepithelioma of Pinkus (FeP) was first described in 1953¹ and was thought to be premalignant as evidenced by the proposed name premalignant fibroepithelial tumor of the skin. This neoplasm now is largely believed to represent a rare form of basal cell carcinoma (BCC). Typical presentation is a smooth, flesh-colored or pink plaque or nodule.² Fibroepithelioma of Pinkus has a predilection for the lumbosacral back, though the groin also has been reported as a common site of incidence.^1,3 Similar to other BCCs, it is seen in older individuals, typically those older than 50 years.^3,4

Clinical diagnosis of FeP can be difficult. The differential diagnosis of FeP can include acrochordon, amelanotic melanoma, compound nevus, hemangioma, neurofibroma, nevus sebaceous, pyogenic granuloma, and seborrheic keratosis.⁵ Dermoscopic evaluation can aid in the diagnosis. A vascular network composed of fine arborizing vessels with or without dotted vessels and white streaks are characteristic findings of FeP. Patients with pigment also demonstrate structureless gray-brown areas and gray-blue dots.⁶

Biopsy with subsequent histopathologic evaluation confirms the diagnosis of FeP. The characteristic microscopic findings of thin eosinophilic epithelial strands with eccrine ducts anastomosing in an abundant fibromyxoid stroma with collections of basophilic cells located at the ends of the epithelial strands were demonstrated in our patient’s histopathologic specimen (Figure). The histologic appearance is similar to syringofibroadenoma of Mascaro. Recognition of basaloid nests, which often demonstrate retraction, and mitotic activity can differentiate FeP from syringofibroadenoma of Mascaro.⁷

Treatment of FeP is largely the same as other BCCs including destruction by electrodesiccation and curettage or complete removal by surgical excision. Several studies have demonstrated effective treatment of nonaggressive BCCs with curettage alone and subjectively reported improved cosmesis compared to electrodesiccation and curettage.^8-10 Although methyl aminolevulinate photodynamic therapy has demonstrated some therapeutic efficacy for superficial and nodular BCCs,¹¹ a case report utilizing the same modality for FeP did not provide adequate response.¹² However, adequate data are not available to assess potential use of this less invasive therapy.

The Diagnosis: Fibroepithelioma of Pinkus

Fibroepithelioma of Pinkus (FeP) was first described in 1953¹ and was thought to be premalignant as evidenced by the proposed name premalignant fibroepithelial tumor of the skin. This neoplasm now is largely believed to represent a rare form of basal cell carcinoma (BCC). Typical presentation is a smooth, flesh-colored or pink plaque or nodule.² Fibroepithelioma of Pinkus has a predilection for the lumbosacral back, though the groin also has been reported as a common site of incidence.^1,3 Similar to other BCCs, it is seen in older individuals, typically those older than 50 years.^3,4

Clinical diagnosis of FeP can be difficult. The differential diagnosis of FeP can include acrochordon, amelanotic melanoma, compound nevus, hemangioma, neurofibroma, nevus sebaceous, pyogenic granuloma, and seborrheic keratosis.⁵ Dermoscopic evaluation can aid in the diagnosis. A vascular network composed of fine arborizing vessels with or without dotted vessels and white streaks are characteristic findings of FeP. Patients with pigment also demonstrate structureless gray-brown areas and gray-blue dots.⁶

Biopsy with subsequent histopathologic evaluation confirms the diagnosis of FeP. The characteristic microscopic findings of thin eosinophilic epithelial strands with eccrine ducts anastomosing in an abundant fibromyxoid stroma with collections of basophilic cells located at the ends of the epithelial strands were demonstrated in our patient’s histopathologic specimen (Figure). The histologic appearance is similar to syringofibroadenoma of Mascaro. Recognition of basaloid nests, which often demonstrate retraction, and mitotic activity can differentiate FeP from syringofibroadenoma of Mascaro.⁷

Treatment of FeP is largely the same as other BCCs including destruction by electrodesiccation and curettage or complete removal by surgical excision. Several studies have demonstrated effective treatment of nonaggressive BCCs with curettage alone and subjectively reported improved cosmesis compared to electrodesiccation and curettage.^8-10 Although methyl aminolevulinate photodynamic therapy has demonstrated some therapeutic efficacy for superficial and nodular BCCs,¹¹ a case report utilizing the same modality for FeP did not provide adequate response.¹² However, adequate data are not available to assess potential use of this less invasive therapy.

The Diagnosis: Fibroepithelioma of Pinkus

Fibroepithelioma of Pinkus (FeP) was first described in 1953¹ and was thought to be premalignant as evidenced by the proposed name premalignant fibroepithelial tumor of the skin. This neoplasm now is largely believed to represent a rare form of basal cell carcinoma (BCC). Typical presentation is a smooth, flesh-colored or pink plaque or nodule.² Fibroepithelioma of Pinkus has a predilection for the lumbosacral back, though the groin also has been reported as a common site of incidence.^1,3 Similar to other BCCs, it is seen in older individuals, typically those older than 50 years.^3,4

Clinical diagnosis of FeP can be difficult. The differential diagnosis of FeP can include acrochordon, amelanotic melanoma, compound nevus, hemangioma, neurofibroma, nevus sebaceous, pyogenic granuloma, and seborrheic keratosis.⁵ Dermoscopic evaluation can aid in the diagnosis. A vascular network composed of fine arborizing vessels with or without dotted vessels and white streaks are characteristic findings of FeP. Patients with pigment also demonstrate structureless gray-brown areas and gray-blue dots.⁶

Biopsy with subsequent histopathologic evaluation confirms the diagnosis of FeP. The characteristic microscopic findings of thin eosinophilic epithelial strands with eccrine ducts anastomosing in an abundant fibromyxoid stroma with collections of basophilic cells located at the ends of the epithelial strands were demonstrated in our patient’s histopathologic specimen (Figure). The histologic appearance is similar to syringofibroadenoma of Mascaro. Recognition of basaloid nests, which often demonstrate retraction, and mitotic activity can differentiate FeP from syringofibroadenoma of Mascaro.⁷

Treatment of FeP is largely the same as other BCCs including destruction by electrodesiccation and curettage or complete removal by surgical excision. Several studies have demonstrated effective treatment of nonaggressive BCCs with curettage alone and subjectively reported improved cosmesis compared to electrodesiccation and curettage.^8-10 Although methyl aminolevulinate photodynamic therapy has demonstrated some therapeutic efficacy for superficial and nodular BCCs,¹¹ a case report utilizing the same modality for FeP did not provide adequate response.¹² However, adequate data are not available to assess potential use of this less invasive therapy.