Nonmelanoma Skin Cancer

To the Editor:

I read with interest the informative Cutis case report by Krooks and Weatherall¹ in which the authors not only described the case of a 66-year-old man whose diagnosis of bone marrow biopsy–confirmed acute myeloid leukemia (AML) presented concurrently with skin biopsy–confirmed leukemia cutis but also discussed the poor prognosis of individuals with acute myelogenous leukemia cutis. Their patient died within 5 weeks of establishing the diagnosis. In addition, lateral and frontal photographs of the patient’s face demonstrated diffuse infiltrative plaques of leukemia cutis; he had swollen eyelids and lips with distortion of the nose secondary to dermal infiltration of leukemic myeloid cells.¹ Although not emphasized by the authors, the patient appeared to have a leonine facies and at least partial loss of the lateral eyebrows.

Malignancy-associated leonine facies resulting from infiltration of the skin by neoplastic cells has been reported in a patient with metastatic breast carcinoma.^2,3 However, it predominantly occurs in patients with hematologic dyscrasias such as leukemia cutis, lymphoma (ie, cutaneous B cell, cutaneous T cell, Hodgkin), plasmacytoma, and systemic mastocytosis.^3,4 The report by Krooks and Weatherall¹ adds AML-associated leukemia cutis to the previously observed types of leukemia cutis–related leonine facies in patients with acute lymphocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.^3,4

Partial or complete loss of eyebrows in the setting of leonine facies has a limited differential diagnosis.^3,5 In addition to cancer, the associated disorders include adnexal mucin deposition (alopecia mucinosis), granulomatous conditions (sarcoidosis), infectious diseases (leprosy), inherited syndromes (Setleis syndrome), photoallergic dermatoses (actinic reticuloid), and viral conditions (viral-associated trichodysplasia).^3-9 Neoplasms associated with leonine facies and eyebrow loss include lymphomas (mycosis fungoides and unspecified cutaneous T-cell lymphoma), systemic mastocytosis and leukemia cutis secondary to acute lymphocytic leukemia, acute myelomonocytic leukemia, and now AML.^1,3-5

The eyebrow loss associated with leonine facies often is not reversible once the causative cell of the associated condition (eg, granulomas of mycobacteria-infected histiocytes in leprosy, neoplastic lymphocytes in cutaneous T-cell lymphoma) has infiltrated the area of the eyebrows and abolished the preexisting hair follicles; however, follow-up descriptions of patients after treatment of other conditions that cause eyebrow loss usually are not reported. Indeed, there was partial reappearance of the eyebrows in a woman with systemic mastocytosis–associated loss of the eyebrows after malignancy-related treatment was reinitiated and the infiltrative facial plaques that had created her leonine facies had decreased in size.⁵ It is reasonable to speculate that the eyebrows may have reappeared in the patient reported by Krooks and Weatherall¹ and his leonine facies–associated facial plaques may have resolved if he had underwent and responded to treatment with antineoplastic chemotherapy.

To the Editor:

I read with interest the informative Cutis case report by Krooks and Weatherall¹ in which the authors not only described the case of a 66-year-old man whose diagnosis of bone marrow biopsy–confirmed acute myeloid leukemia (AML) presented concurrently with skin biopsy–confirmed leukemia cutis but also discussed the poor prognosis of individuals with acute myelogenous leukemia cutis. Their patient died within 5 weeks of establishing the diagnosis. In addition, lateral and frontal photographs of the patient’s face demonstrated diffuse infiltrative plaques of leukemia cutis; he had swollen eyelids and lips with distortion of the nose secondary to dermal infiltration of leukemic myeloid cells.¹ Although not emphasized by the authors, the patient appeared to have a leonine facies and at least partial loss of the lateral eyebrows.

Malignancy-associated leonine facies resulting from infiltration of the skin by neoplastic cells has been reported in a patient with metastatic breast carcinoma.^2,3 However, it predominantly occurs in patients with hematologic dyscrasias such as leukemia cutis, lymphoma (ie, cutaneous B cell, cutaneous T cell, Hodgkin), plasmacytoma, and systemic mastocytosis.^3,4 The report by Krooks and Weatherall¹ adds AML-associated leukemia cutis to the previously observed types of leukemia cutis–related leonine facies in patients with acute lymphocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.^3,4

Partial or complete loss of eyebrows in the setting of leonine facies has a limited differential diagnosis.^3,5 In addition to cancer, the associated disorders include adnexal mucin deposition (alopecia mucinosis), granulomatous conditions (sarcoidosis), infectious diseases (leprosy), inherited syndromes (Setleis syndrome), photoallergic dermatoses (actinic reticuloid), and viral conditions (viral-associated trichodysplasia).^3-9 Neoplasms associated with leonine facies and eyebrow loss include lymphomas (mycosis fungoides and unspecified cutaneous T-cell lymphoma), systemic mastocytosis and leukemia cutis secondary to acute lymphocytic leukemia, acute myelomonocytic leukemia, and now AML.^1,3-5

The eyebrow loss associated with leonine facies often is not reversible once the causative cell of the associated condition (eg, granulomas of mycobacteria-infected histiocytes in leprosy, neoplastic lymphocytes in cutaneous T-cell lymphoma) has infiltrated the area of the eyebrows and abolished the preexisting hair follicles; however, follow-up descriptions of patients after treatment of other conditions that cause eyebrow loss usually are not reported. Indeed, there was partial reappearance of the eyebrows in a woman with systemic mastocytosis–associated loss of the eyebrows after malignancy-related treatment was reinitiated and the infiltrative facial plaques that had created her leonine facies had decreased in size.⁵ It is reasonable to speculate that the eyebrows may have reappeared in the patient reported by Krooks and Weatherall¹ and his leonine facies–associated facial plaques may have resolved if he had underwent and responded to treatment with antineoplastic chemotherapy.

To the Editor:

I read with interest the informative Cutis case report by Krooks and Weatherall¹ in which the authors not only described the case of a 66-year-old man whose diagnosis of bone marrow biopsy–confirmed acute myeloid leukemia (AML) presented concurrently with skin biopsy–confirmed leukemia cutis but also discussed the poor prognosis of individuals with acute myelogenous leukemia cutis. Their patient died within 5 weeks of establishing the diagnosis. In addition, lateral and frontal photographs of the patient’s face demonstrated diffuse infiltrative plaques of leukemia cutis; he had swollen eyelids and lips with distortion of the nose secondary to dermal infiltration of leukemic myeloid cells.¹ Although not emphasized by the authors, the patient appeared to have a leonine facies and at least partial loss of the lateral eyebrows.

Malignancy-associated leonine facies resulting from infiltration of the skin by neoplastic cells has been reported in a patient with metastatic breast carcinoma.^2,3 However, it predominantly occurs in patients with hematologic dyscrasias such as leukemia cutis, lymphoma (ie, cutaneous B cell, cutaneous T cell, Hodgkin), plasmacytoma, and systemic mastocytosis.^3,4 The report by Krooks and Weatherall¹ adds AML-associated leukemia cutis to the previously observed types of leukemia cutis–related leonine facies in patients with acute lymphocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.^3,4

Partial or complete loss of eyebrows in the setting of leonine facies has a limited differential diagnosis.^3,5 In addition to cancer, the associated disorders include adnexal mucin deposition (alopecia mucinosis), granulomatous conditions (sarcoidosis), infectious diseases (leprosy), inherited syndromes (Setleis syndrome), photoallergic dermatoses (actinic reticuloid), and viral conditions (viral-associated trichodysplasia).^3-9 Neoplasms associated with leonine facies and eyebrow loss include lymphomas (mycosis fungoides and unspecified cutaneous T-cell lymphoma), systemic mastocytosis and leukemia cutis secondary to acute lymphocytic leukemia, acute myelomonocytic leukemia, and now AML.^1,3-5

The eyebrow loss associated with leonine facies often is not reversible once the causative cell of the associated condition (eg, granulomas of mycobacteria-infected histiocytes in leprosy, neoplastic lymphocytes in cutaneous T-cell lymphoma) has infiltrated the area of the eyebrows and abolished the preexisting hair follicles; however, follow-up descriptions of patients after treatment of other conditions that cause eyebrow loss usually are not reported. Indeed, there was partial reappearance of the eyebrows in a woman with systemic mastocytosis–associated loss of the eyebrows after malignancy-related treatment was reinitiated and the infiltrative facial plaques that had created her leonine facies had decreased in size.⁵ It is reasonable to speculate that the eyebrows may have reappeared in the patient reported by Krooks and Weatherall¹ and his leonine facies–associated facial plaques may have resolved if he had underwent and responded to treatment with antineoplastic chemotherapy.

WASHINGTON – Psoriasis induced by tumor necrosis factor (TNF) therapy is among the treatment-associated effects that involve the skin in patients with inflammatory bowel disease (IBD), Sophia Delano, MD, said during a session on the cutaneous effects of IBD at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

This is a paradoxical reaction, which can happen “weeks to years after starting a TNF blocker,” with about 70% of cases occurring during the first year of therapy, said Dr. Delano, an attending physician in the dermatology program at Boston Children’s Hospital.

Those receiving infliximab are more likely to develop TNF inhibitor–induced psoriasis, compared with those on adalimumab or etanercept. TNF inhibitor–induced psoriasis may not track with gastrointestinal activity, and some patients whose gastrointestinal disease is responding to treatment can begin to develop psoriasis, she noted.

The clinical presentation of TNF inhibitor–induced psoriasis can also vary. In one study of 216 cases, 26.9% of patients had a mixed morphology, with the most common presentations including plaque psoriasis (44.8%) and palmoplantar pustular psoriasis (36.3%). Other presentations were psoriasiform dermatitis (19.9%), scalp involvement with alopecia (7.5%), and generalized pustular psoriasis (10.9%). Locations affected were the soles of the feet (45.8%), extremities (45.4%), palms (44.9%), scalp (36.1%), and trunk (32.4%), Dr. Delano said.


TNF inhibitor–induced psoriasis is likely a class effect, she said, noting that, in the same review, symptoms resolved in 47.7% of patients who discontinued TNF inhibitors, in 36.7% of patients who switched to another TNF inhibitor, and in 32.9% of patients who continued their original therapy (J Am Acad Dermatol. 2017 Feb;76[2]:334-41). In the study, Crohn’s disease and RA were the most common diseases, in 40.7% and 37.0% of the patients, respectively.

There have been case reports of TNF antagonist–induced lupus-like syndrome (TAILS), which is more common in patients with RA and ulcerative colitis. TAILS occurs more often in women than in men; can present similarly to systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus; and resolves by stopping TNF inhibitor treatment, Dr. Delano said.

Skin cancer risk, infections, and injection site reactions

Both adult and pediatric patients treated with TNF inhibitors for IBD may be at increased risk for lymphoma, visceral tumors, melanoma, and nonmelanoma skin cancers. Dr. Delano referred to a study published in 2014, which identified 972 reports of melanoma in the Food and Drug Administration’s Adverse Event Reporting System database associated with TNF inhibitor use; of these, 69 cases involved patients using more than one TNF inhibitor. Infliximab, golimumab, etanercept, and adalimumab were associated with a safety signal for melanoma, but not certolizumab (Br J Dermatol. 2014 May;170[5]:1170-2).

Dr. Delano observed that thiopurines such as azathioprine are also associated with an increased cancer risk, as noted in one retrospective study that found that the risk of nonmelanoma skin cancer was 2.1 times higher in a mostly white male cohort with ulcerative colitis during treatment with thiopurines, compared with patients not treated with thiopurines (Am J Gastroenterol. 2014 Nov;109[11]:1781-93). A greater duration of treatment (more than 6 months) and higher doses were associated with higher risks.

Adalimumab, golimumab, and certolizumab can also cause injection site reactions, typically within 1- 2 days of injection, said Dr. Delano. In these cases, symptoms of erythema, warmth, burning, or pruritus are worse at the beginning of treatment and can be relieved by rotating the injection site as well as providing cool compresses, topical steroids, antihistamines, and supportive care.

“If you have a patient with a worsening reaction, consider it may represent the type 1 IgE-related hypersensitivity requiring desensitization to continue that systemic,” she noted.

Cutaneous bacterial, fungal, and viral infections such as molluscum contagiosum, verruca vulgaris, herpes simplex, and varicella zoster can occur as a result of TNF inhibition as well, and can be difficult to clear because of immunosuppression, she added.

Dr. Delano reported no relevant conflicts of interest.

WASHINGTON – Psoriasis induced by tumor necrosis factor (TNF) therapy is among the treatment-associated effects that involve the skin in patients with inflammatory bowel disease (IBD), Sophia Delano, MD, said during a session on the cutaneous effects of IBD at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

This is a paradoxical reaction, which can happen “weeks to years after starting a TNF blocker,” with about 70% of cases occurring during the first year of therapy, said Dr. Delano, an attending physician in the dermatology program at Boston Children’s Hospital.

Those receiving infliximab are more likely to develop TNF inhibitor–induced psoriasis, compared with those on adalimumab or etanercept. TNF inhibitor–induced psoriasis may not track with gastrointestinal activity, and some patients whose gastrointestinal disease is responding to treatment can begin to develop psoriasis, she noted.

The clinical presentation of TNF inhibitor–induced psoriasis can also vary. In one study of 216 cases, 26.9% of patients had a mixed morphology, with the most common presentations including plaque psoriasis (44.8%) and palmoplantar pustular psoriasis (36.3%). Other presentations were psoriasiform dermatitis (19.9%), scalp involvement with alopecia (7.5%), and generalized pustular psoriasis (10.9%). Locations affected were the soles of the feet (45.8%), extremities (45.4%), palms (44.9%), scalp (36.1%), and trunk (32.4%), Dr. Delano said.


TNF inhibitor–induced psoriasis is likely a class effect, she said, noting that, in the same review, symptoms resolved in 47.7% of patients who discontinued TNF inhibitors, in 36.7% of patients who switched to another TNF inhibitor, and in 32.9% of patients who continued their original therapy (J Am Acad Dermatol. 2017 Feb;76[2]:334-41). In the study, Crohn’s disease and RA were the most common diseases, in 40.7% and 37.0% of the patients, respectively.

There have been case reports of TNF antagonist–induced lupus-like syndrome (TAILS), which is more common in patients with RA and ulcerative colitis. TAILS occurs more often in women than in men; can present similarly to systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus; and resolves by stopping TNF inhibitor treatment, Dr. Delano said.

Skin cancer risk, infections, and injection site reactions

Both adult and pediatric patients treated with TNF inhibitors for IBD may be at increased risk for lymphoma, visceral tumors, melanoma, and nonmelanoma skin cancers. Dr. Delano referred to a study published in 2014, which identified 972 reports of melanoma in the Food and Drug Administration’s Adverse Event Reporting System database associated with TNF inhibitor use; of these, 69 cases involved patients using more than one TNF inhibitor. Infliximab, golimumab, etanercept, and adalimumab were associated with a safety signal for melanoma, but not certolizumab (Br J Dermatol. 2014 May;170[5]:1170-2).

Dr. Delano observed that thiopurines such as azathioprine are also associated with an increased cancer risk, as noted in one retrospective study that found that the risk of nonmelanoma skin cancer was 2.1 times higher in a mostly white male cohort with ulcerative colitis during treatment with thiopurines, compared with patients not treated with thiopurines (Am J Gastroenterol. 2014 Nov;109[11]:1781-93). A greater duration of treatment (more than 6 months) and higher doses were associated with higher risks.

Adalimumab, golimumab, and certolizumab can also cause injection site reactions, typically within 1- 2 days of injection, said Dr. Delano. In these cases, symptoms of erythema, warmth, burning, or pruritus are worse at the beginning of treatment and can be relieved by rotating the injection site as well as providing cool compresses, topical steroids, antihistamines, and supportive care.

“If you have a patient with a worsening reaction, consider it may represent the type 1 IgE-related hypersensitivity requiring desensitization to continue that systemic,” she noted.

Cutaneous bacterial, fungal, and viral infections such as molluscum contagiosum, verruca vulgaris, herpes simplex, and varicella zoster can occur as a result of TNF inhibition as well, and can be difficult to clear because of immunosuppression, she added.

Dr. Delano reported no relevant conflicts of interest.

WASHINGTON – Psoriasis induced by tumor necrosis factor (TNF) therapy is among the treatment-associated effects that involve the skin in patients with inflammatory bowel disease (IBD), Sophia Delano, MD, said during a session on the cutaneous effects of IBD at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

This is a paradoxical reaction, which can happen “weeks to years after starting a TNF blocker,” with about 70% of cases occurring during the first year of therapy, said Dr. Delano, an attending physician in the dermatology program at Boston Children’s Hospital.

Those receiving infliximab are more likely to develop TNF inhibitor–induced psoriasis, compared with those on adalimumab or etanercept. TNF inhibitor–induced psoriasis may not track with gastrointestinal activity, and some patients whose gastrointestinal disease is responding to treatment can begin to develop psoriasis, she noted.

The clinical presentation of TNF inhibitor–induced psoriasis can also vary. In one study of 216 cases, 26.9% of patients had a mixed morphology, with the most common presentations including plaque psoriasis (44.8%) and palmoplantar pustular psoriasis (36.3%). Other presentations were psoriasiform dermatitis (19.9%), scalp involvement with alopecia (7.5%), and generalized pustular psoriasis (10.9%). Locations affected were the soles of the feet (45.8%), extremities (45.4%), palms (44.9%), scalp (36.1%), and trunk (32.4%), Dr. Delano said.


TNF inhibitor–induced psoriasis is likely a class effect, she said, noting that, in the same review, symptoms resolved in 47.7% of patients who discontinued TNF inhibitors, in 36.7% of patients who switched to another TNF inhibitor, and in 32.9% of patients who continued their original therapy (J Am Acad Dermatol. 2017 Feb;76[2]:334-41). In the study, Crohn’s disease and RA were the most common diseases, in 40.7% and 37.0% of the patients, respectively.

There have been case reports of TNF antagonist–induced lupus-like syndrome (TAILS), which is more common in patients with RA and ulcerative colitis. TAILS occurs more often in women than in men; can present similarly to systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus; and resolves by stopping TNF inhibitor treatment, Dr. Delano said.

Skin cancer risk, infections, and injection site reactions

Both adult and pediatric patients treated with TNF inhibitors for IBD may be at increased risk for lymphoma, visceral tumors, melanoma, and nonmelanoma skin cancers. Dr. Delano referred to a study published in 2014, which identified 972 reports of melanoma in the Food and Drug Administration’s Adverse Event Reporting System database associated with TNF inhibitor use; of these, 69 cases involved patients using more than one TNF inhibitor. Infliximab, golimumab, etanercept, and adalimumab were associated with a safety signal for melanoma, but not certolizumab (Br J Dermatol. 2014 May;170[5]:1170-2).

Dr. Delano observed that thiopurines such as azathioprine are also associated with an increased cancer risk, as noted in one retrospective study that found that the risk of nonmelanoma skin cancer was 2.1 times higher in a mostly white male cohort with ulcerative colitis during treatment with thiopurines, compared with patients not treated with thiopurines (Am J Gastroenterol. 2014 Nov;109[11]:1781-93). A greater duration of treatment (more than 6 months) and higher doses were associated with higher risks.

Adalimumab, golimumab, and certolizumab can also cause injection site reactions, typically within 1- 2 days of injection, said Dr. Delano. In these cases, symptoms of erythema, warmth, burning, or pruritus are worse at the beginning of treatment and can be relieved by rotating the injection site as well as providing cool compresses, topical steroids, antihistamines, and supportive care.

“If you have a patient with a worsening reaction, consider it may represent the type 1 IgE-related hypersensitivity requiring desensitization to continue that systemic,” she noted.

Cutaneous bacterial, fungal, and viral infections such as molluscum contagiosum, verruca vulgaris, herpes simplex, and varicella zoster can occur as a result of TNF inhibition as well, and can be difficult to clear because of immunosuppression, she added.

Dr. Delano reported no relevant conflicts of interest.

Microcystic lymphatic malformations, also known as lymphangioma circumscriptum, are rare hamar­tomatous lesions comprised of dilated lymphatic channels that can be both congenital and acquired.¹ They often present as translucent or hemorrhagic ves­icles of varying sizes that may contain lymphatic fluid and often can cluster together and appear verrucous (Figure 1). The differential diagnosis for microcystic lym­phatic malformations commonly includes molluscum contagiosum, squamous cell carcinoma, verruca vulgaris, or condylomas, as well as atypical vascular lesions. They most often are found in children as congenital lesions but also may be acquired. Most acquired cases are due to chronic inflammatory and scarring processes that damage lymphatic structures, including surgery, radiation, infec­tions, and even Crohn disease.^2,3 Because the differential diagnosis is so broad and the disease can clinically mimic other common disease processes, biopsies often are per­formed to determine the diagnosis. On biopsy, pathologic examination revealed well-circumscribed nodular lesions with large lymphatic channels often in a background of connective tissue stroma. Increased eosinophilic mate­rial, including mast cells, also was seen (Figure 2A). On immunohistochemistry, staining showed D2-40 posi­tivity (Figure 2B). 

Damage to lymphatics from radiation and postsurgi­cal excision of tumors are well-described causes of micro­cystic lymphatic malformations, as in our patient, with most instances in the literature occurring secondary to treatment of breast or cervical cancer.^4-6 In these acquired cases, the pathogenesis is thought to be due to destruc­tion and fibrosis at the layer of the reticular dermis, which causes lymphatic obstruction and subsequent dilation of superficial lymphatic channels.⁶ 

Microcystic lymphatic malformations can be difficult to distinguish from atypical vascular lesions, another common postradiation lesion. Both are benign well-circumscribed lesions that histologically do not extend into surrounding subcutaneous tissues and do not have multilayering of cells, mitosis, or hemorrhage.⁷ Although lymphatic lesions tend to form vesicles, atypical vas­cular lesions arising after radiation treatment present as erythematous or flesh-colored patches or papules. They also tend to be fairly superficial and often only involve the superficial to mid dermis. On histology they show thin-walled channels without erythrocytes that are lined by typical endothelial cells.⁷ Despite these differ­ences, both clinically and histopathologically these lesions can appear similar to acquired microcystic lymphatic malformations. It is important to differentiate between these two entities, as atypical vascular lesions have a slightly higher rate of transformation into malignant tumors such as angiosarcomas. 

Although angiosarcomas clinically may present as ery­thematous patches, plaques, or nodules similar to benign postradiation lesions, they tend to be more edematous than their benign counterparts.^7,8 Two other clinical fac­tors that can help determine if a postradiation lesion is benign or malignant are the size and time of onset of the lesion. Angiosarcomas tend to be much larger than benign postradiation lesions (median size, 7.5 cm) and tend to be more multifocal in nature.^8,9 They also tend to arise on average 5 to 7 years after the initial radiation treatment, while benign lesions arise sooner.⁹ 

Small, asymptomatic, acquired microcystic lymphatic malformations can be followed clinically without treat­ment, but these lesions do not commonly regress spon­taneously. Even when asymptomatic, many clinicians will opt for treatment to prevent secondary complications such as infections, drainage, and pain. Moreover, these lesions can have notable psychosocial impacts on patients due to poor cosmetic appearance. Unfortunately, there is no gold standard of treatment, and recurrence is com­mon, even after treatment. Historically, surgical excision was the treatment of choice, but this option carries a high risk for scarring, invasiveness, and recurrence. Recurrence rates of up to 23.1% have been reported with decreased effectiveness of resection, particularly in areas of deeper involvement.¹⁰ For these deeper lesions, CO2 laser therapy is a promising evolving therapy. It can penetrate up to the mid dermis and seems to destroy the lymphatic chan­nels between deep and surface lymphatics, preventing the cutaneous manifestations of the disease. It has the added benefit of minimal invasiveness and fewer side effects than complete excision, with most studies report­ing hyperpigmentation and scarring as the most common side effects.¹¹ Additional emerging therapies including sclerotherapy and isotretinoin have shown benefits in case studies. Sclerotherapy causes local tissue destruction and thrombosis leading to destruction of vessel lumens and fibrosis that halts disease progression and clears existing lesions.¹² Oral therapy with isotretinoin appears to work by inhibiting certain cytokines and acting as an antiangiogenic factor.¹³ Given the rarity of microcystic lymphatic malformations, further research must be done to determine definitive treatment. 

Acquired microcystic lymphatic malformation is an important sequela of radiation therapy and surgical exci­sion of malignancy. Despite its striking clinical appear­ance, it is sometimes difficult to diagnose given its rarity. It is important that clinicians are able to recognize it clini­cally and understand common treatment options to pre­vent both the mental stigma and complications, including secondary infections, drainage, and pain. 

Microcystic lymphatic malformations, also known as lymphangioma circumscriptum, are rare hamar­tomatous lesions comprised of dilated lymphatic channels that can be both congenital and acquired.¹ They often present as translucent or hemorrhagic ves­icles of varying sizes that may contain lymphatic fluid and often can cluster together and appear verrucous (Figure 1). The differential diagnosis for microcystic lym­phatic malformations commonly includes molluscum contagiosum, squamous cell carcinoma, verruca vulgaris, or condylomas, as well as atypical vascular lesions. They most often are found in children as congenital lesions but also may be acquired. Most acquired cases are due to chronic inflammatory and scarring processes that damage lymphatic structures, including surgery, radiation, infec­tions, and even Crohn disease.^2,3 Because the differential diagnosis is so broad and the disease can clinically mimic other common disease processes, biopsies often are per­formed to determine the diagnosis. On biopsy, pathologic examination revealed well-circumscribed nodular lesions with large lymphatic channels often in a background of connective tissue stroma. Increased eosinophilic mate­rial, including mast cells, also was seen (Figure 2A). On immunohistochemistry, staining showed D2-40 posi­tivity (Figure 2B). 

Damage to lymphatics from radiation and postsurgi­cal excision of tumors are well-described causes of micro­cystic lymphatic malformations, as in our patient, with most instances in the literature occurring secondary to treatment of breast or cervical cancer.^4-6 In these acquired cases, the pathogenesis is thought to be due to destruc­tion and fibrosis at the layer of the reticular dermis, which causes lymphatic obstruction and subsequent dilation of superficial lymphatic channels.⁶ 

Microcystic lymphatic malformations can be difficult to distinguish from atypical vascular lesions, another common postradiation lesion. Both are benign well-circumscribed lesions that histologically do not extend into surrounding subcutaneous tissues and do not have multilayering of cells, mitosis, or hemorrhage.⁷ Although lymphatic lesions tend to form vesicles, atypical vas­cular lesions arising after radiation treatment present as erythematous or flesh-colored patches or papules. They also tend to be fairly superficial and often only involve the superficial to mid dermis. On histology they show thin-walled channels without erythrocytes that are lined by typical endothelial cells.⁷ Despite these differ­ences, both clinically and histopathologically these lesions can appear similar to acquired microcystic lymphatic malformations. It is important to differentiate between these two entities, as atypical vascular lesions have a slightly higher rate of transformation into malignant tumors such as angiosarcomas. 

Although angiosarcomas clinically may present as ery­thematous patches, plaques, or nodules similar to benign postradiation lesions, they tend to be more edematous than their benign counterparts.^7,8 Two other clinical fac­tors that can help determine if a postradiation lesion is benign or malignant are the size and time of onset of the lesion. Angiosarcomas tend to be much larger than benign postradiation lesions (median size, 7.5 cm) and tend to be more multifocal in nature.^8,9 They also tend to arise on average 5 to 7 years after the initial radiation treatment, while benign lesions arise sooner.⁹ 

Small, asymptomatic, acquired microcystic lymphatic malformations can be followed clinically without treat­ment, but these lesions do not commonly regress spon­taneously. Even when asymptomatic, many clinicians will opt for treatment to prevent secondary complications such as infections, drainage, and pain. Moreover, these lesions can have notable psychosocial impacts on patients due to poor cosmetic appearance. Unfortunately, there is no gold standard of treatment, and recurrence is com­mon, even after treatment. Historically, surgical excision was the treatment of choice, but this option carries a high risk for scarring, invasiveness, and recurrence. Recurrence rates of up to 23.1% have been reported with decreased effectiveness of resection, particularly in areas of deeper involvement.¹⁰ For these deeper lesions, CO2 laser therapy is a promising evolving therapy. It can penetrate up to the mid dermis and seems to destroy the lymphatic chan­nels between deep and surface lymphatics, preventing the cutaneous manifestations of the disease. It has the added benefit of minimal invasiveness and fewer side effects than complete excision, with most studies report­ing hyperpigmentation and scarring as the most common side effects.¹¹ Additional emerging therapies including sclerotherapy and isotretinoin have shown benefits in case studies. Sclerotherapy causes local tissue destruction and thrombosis leading to destruction of vessel lumens and fibrosis that halts disease progression and clears existing lesions.¹² Oral therapy with isotretinoin appears to work by inhibiting certain cytokines and acting as an antiangiogenic factor.¹³ Given the rarity of microcystic lymphatic malformations, further research must be done to determine definitive treatment. 

Acquired microcystic lymphatic malformation is an important sequela of radiation therapy and surgical exci­sion of malignancy. Despite its striking clinical appear­ance, it is sometimes difficult to diagnose given its rarity. It is important that clinicians are able to recognize it clini­cally and understand common treatment options to pre­vent both the mental stigma and complications, including secondary infections, drainage, and pain. 

Microcystic lymphatic malformations, also known as lymphangioma circumscriptum, are rare hamar­tomatous lesions comprised of dilated lymphatic channels that can be both congenital and acquired.¹ They often present as translucent or hemorrhagic ves­icles of varying sizes that may contain lymphatic fluid and often can cluster together and appear verrucous (Figure 1). The differential diagnosis for microcystic lym­phatic malformations commonly includes molluscum contagiosum, squamous cell carcinoma, verruca vulgaris, or condylomas, as well as atypical vascular lesions. They most often are found in children as congenital lesions but also may be acquired. Most acquired cases are due to chronic inflammatory and scarring processes that damage lymphatic structures, including surgery, radiation, infec­tions, and even Crohn disease.^2,3 Because the differential diagnosis is so broad and the disease can clinically mimic other common disease processes, biopsies often are per­formed to determine the diagnosis. On biopsy, pathologic examination revealed well-circumscribed nodular lesions with large lymphatic channels often in a background of connective tissue stroma. Increased eosinophilic mate­rial, including mast cells, also was seen (Figure 2A). On immunohistochemistry, staining showed D2-40 posi­tivity (Figure 2B). 

Damage to lymphatics from radiation and postsurgi­cal excision of tumors are well-described causes of micro­cystic lymphatic malformations, as in our patient, with most instances in the literature occurring secondary to treatment of breast or cervical cancer.^4-6 In these acquired cases, the pathogenesis is thought to be due to destruc­tion and fibrosis at the layer of the reticular dermis, which causes lymphatic obstruction and subsequent dilation of superficial lymphatic channels.⁶ 

Microcystic lymphatic malformations can be difficult to distinguish from atypical vascular lesions, another common postradiation lesion. Both are benign well-circumscribed lesions that histologically do not extend into surrounding subcutaneous tissues and do not have multilayering of cells, mitosis, or hemorrhage.⁷ Although lymphatic lesions tend to form vesicles, atypical vas­cular lesions arising after radiation treatment present as erythematous or flesh-colored patches or papules. They also tend to be fairly superficial and often only involve the superficial to mid dermis. On histology they show thin-walled channels without erythrocytes that are lined by typical endothelial cells.⁷ Despite these differ­ences, both clinically and histopathologically these lesions can appear similar to acquired microcystic lymphatic malformations. It is important to differentiate between these two entities, as atypical vascular lesions have a slightly higher rate of transformation into malignant tumors such as angiosarcomas. 

Although angiosarcomas clinically may present as ery­thematous patches, plaques, or nodules similar to benign postradiation lesions, they tend to be more edematous than their benign counterparts.^7,8 Two other clinical fac­tors that can help determine if a postradiation lesion is benign or malignant are the size and time of onset of the lesion. Angiosarcomas tend to be much larger than benign postradiation lesions (median size, 7.5 cm) and tend to be more multifocal in nature.^8,9 They also tend to arise on average 5 to 7 years after the initial radiation treatment, while benign lesions arise sooner.⁹ 

Small, asymptomatic, acquired microcystic lymphatic malformations can be followed clinically without treat­ment, but these lesions do not commonly regress spon­taneously. Even when asymptomatic, many clinicians will opt for treatment to prevent secondary complications such as infections, drainage, and pain. Moreover, these lesions can have notable psychosocial impacts on patients due to poor cosmetic appearance. Unfortunately, there is no gold standard of treatment, and recurrence is com­mon, even after treatment. Historically, surgical excision was the treatment of choice, but this option carries a high risk for scarring, invasiveness, and recurrence. Recurrence rates of up to 23.1% have been reported with decreased effectiveness of resection, particularly in areas of deeper involvement.¹⁰ For these deeper lesions, CO2 laser therapy is a promising evolving therapy. It can penetrate up to the mid dermis and seems to destroy the lymphatic chan­nels between deep and surface lymphatics, preventing the cutaneous manifestations of the disease. It has the added benefit of minimal invasiveness and fewer side effects than complete excision, with most studies report­ing hyperpigmentation and scarring as the most common side effects.¹¹ Additional emerging therapies including sclerotherapy and isotretinoin have shown benefits in case studies. Sclerotherapy causes local tissue destruction and thrombosis leading to destruction of vessel lumens and fibrosis that halts disease progression and clears existing lesions.¹² Oral therapy with isotretinoin appears to work by inhibiting certain cytokines and acting as an antiangiogenic factor.¹³ Given the rarity of microcystic lymphatic malformations, further research must be done to determine definitive treatment. 

Acquired microcystic lymphatic malformation is an important sequela of radiation therapy and surgical exci­sion of malignancy. Despite its striking clinical appear­ance, it is sometimes difficult to diagnose given its rarity. It is important that clinicians are able to recognize it clini­cally and understand common treatment options to pre­vent both the mental stigma and complications, including secondary infections, drainage, and pain. 

Eccrine porocarcinoma (EPC), originally described by Pinkus and Mehregan¹ in 1963, is an exceedingly rare sweat gland tumor most commonly seen in older patients. Fewer than 300 cases have been reported in the literature, and it is believed to represent only 0.005% to 0.01% of cutaneous malignancies.² In the absence of established guidelines, wide local excision (WLE) has traditionally been considered the standard of treatment; however, local recurrence and nodal metastasis rates associated with WLE have been reported as high as 20%.³ More recently, a number of case reports and small case series have demonstrated higher cure rates with Mohs micrographic surgery (MMS), though follow-up is limited.^3-5 We describe a case of EPC presenting as a recurrent wart in a 36-year-old man that was successfully treated with MMS.

Case Report

A 36-year-old man with no notable medical history presented with a 0.5×0.5-cm, asymptomatic, flesh-colored, hyperkeratotic, polypoid papule on the right medial thigh (Figure 1). The lesion was diagnosed as a wart and treated with cryotherapy by another dermatologist several years prior to presentation. Dermatoscopic examination at the current presentation showed a homogenous yellow center with a few peripheral vessels and a faint pink-tan halo (Figure 2). Our differential diagnosis included a recurrent wart, fibrosed pyogenic granuloma, irritated intradermal nevus, skin tag, and adnexal neoplasm. A shave biopsy was performed. Histopathologic analysis revealed multiple aggregations of mildly pleomorphic epithelial cells emanating from the epidermis, with many aggregations containing ductal structures (Figure 3). Rare necrotic and pyknotic cells were present, but no mitotic figures or lymphovascular invasion were identified. Immunohistochemical staining was positive for carcinoembryonic antigen and epithelial membrane antigen but negative for Ber-EP4. These findings were consistent with a well-differentiated EPC.

The patient was offered MMS or WLE, with or without sentinel lymph node biopsy (SLNB). He opted for MMS. The initial 1-cm margin taken during MMS was sufficient to achieve complete tumor extirpation, and the final 3.7×2.5-cm defect was closed primarily. The MMS debulking specimen was sent for permanent sectioning and showed a small focus of residual tumor cells, but no mitoses or lymphovascular invasion were seen. The patient was referred to surgical oncology to discuss the option of SLNB, which he ultimately declined. He also was offered regional or whole-body positron emission tomography–computed tomography (PET-CT) to rule out metastatic disease, which he also declined. There was no evidence of recurrence or lymphadenopathy 19 months postoperatively.

Comment

Eccrine porocarcinoma is an exceptionally rare adnexal neoplasm that most commonly affects older adults. The average age at diagnosis is 71 years in men and 75 years in women.² Our case is rare because of the patient’s age. Benign eccrine poromas occur most frequently on the palms, soles, axillae, and forehead where eccrine density is highest; EPC occurs most frequently on the lower extremities.⁶ It may arise de novo or from malignant transformation of a preexisting benign poroma. Clinically, EPC may present as an asymptomatic pink-brown papule, plaque, or nodule and may have a polypoid or verrucous appearance, as in our patient. Ulceration is common.⁷ The differential diagnosis often includes nodular basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, and seborrheic keratosis.

Histologically, EPCs are characterized by aggregations of cohesive basaloid epithelial cells forming eccrine ductal structures.² Cellular atypia may be extremely subtle but, if present, can be helpful in differentiating malignant from benign lesions. Features of basal and squamous cell carcinoma also may be present. Definitive diagnosis is frequently based on the overall invasive architectural pattern.⁵ Robson et al² examined 69 cases of EPC for high-risk histologic features and concluded that tumor depth greater than 7 mm, mitoses greater than 14 per high-power field, and the presence of lymphovascular invasion were independently predictive of mortality. Moreover, after adjusting for mitosis and depth, an infiltrative border vs a pushing border was strongly predictive of local recurrence.² Immunohistochemical stains, although not necessary for diagnosis, may have utility as adjunctive tools. Cells lining the ducts within EPCs commonly stain positive for carcinoembryonic antigen, though glandular myoepithelial cells stain positive for S-100. Negative Ber-EP4 staining helps to differentiate EPC from basal cell carcinoma. Abnormal expression of p53 and overexpression of p16 also has been described.⁴

The rarity of EPC has precluded the development of any evidence-based management guidelines. Historically, the standard of care has been WLE with 2- to 3-cm margins. A review of 105 cases of EPC treated with WLE showed 20% local recurrence, 20% regional metastases, and 12% distant metastasis rates.⁸ Mohs micrographic surgery, which allows examination of 100% of the surgical margin vs less than 1% for WLE with the standard bread-loafing technique, might be expected to achieve higher cure rates. A review of 29 cases treated with MMS monotherapy demonstrated no local recurrences, distant metastasis, or disease-specific deaths with follow-up ranging from 19 months to 6 years.⁵ One case was associated with regional lymph node metastases that were treated with completion lymphadenectomy and adjuvant radiation therapy.⁷ The high mortality rate of patients with nodal disease has led some to recommend PET-CT and SLNB for patients with EPC. However, the prognostic value of such procedures has not been clearly defined and there is no demonstrated survival benefit for treatment of widespread disease. Our patient declined both SLNB and PET-CT, and our plan was to follow him clinically with symptom-directed imaging only.

Conclusion

Patients with EPC generally have a favorable prognosis with prompt diagnosis and complete surgical excision. Although most commonly seen in elderly patients, EPC may present in younger patients and may be clinically and histologically nondescript with little cytologic atypia. Based on a small but growing body of literature, MMS appears to be at least as effective as WLE as a primary treatment modality for EPC, while offering the advantage of tissue sparing in cosmetically or functionally important areas.

Eccrine porocarcinoma (EPC), originally described by Pinkus and Mehregan¹ in 1963, is an exceedingly rare sweat gland tumor most commonly seen in older patients. Fewer than 300 cases have been reported in the literature, and it is believed to represent only 0.005% to 0.01% of cutaneous malignancies.² In the absence of established guidelines, wide local excision (WLE) has traditionally been considered the standard of treatment; however, local recurrence and nodal metastasis rates associated with WLE have been reported as high as 20%.³ More recently, a number of case reports and small case series have demonstrated higher cure rates with Mohs micrographic surgery (MMS), though follow-up is limited.^3-5 We describe a case of EPC presenting as a recurrent wart in a 36-year-old man that was successfully treated with MMS.

Case Report

A 36-year-old man with no notable medical history presented with a 0.5×0.5-cm, asymptomatic, flesh-colored, hyperkeratotic, polypoid papule on the right medial thigh (Figure 1). The lesion was diagnosed as a wart and treated with cryotherapy by another dermatologist several years prior to presentation. Dermatoscopic examination at the current presentation showed a homogenous yellow center with a few peripheral vessels and a faint pink-tan halo (Figure 2). Our differential diagnosis included a recurrent wart, fibrosed pyogenic granuloma, irritated intradermal nevus, skin tag, and adnexal neoplasm. A shave biopsy was performed. Histopathologic analysis revealed multiple aggregations of mildly pleomorphic epithelial cells emanating from the epidermis, with many aggregations containing ductal structures (Figure 3). Rare necrotic and pyknotic cells were present, but no mitotic figures or lymphovascular invasion were identified. Immunohistochemical staining was positive for carcinoembryonic antigen and epithelial membrane antigen but negative for Ber-EP4. These findings were consistent with a well-differentiated EPC.

The patient was offered MMS or WLE, with or without sentinel lymph node biopsy (SLNB). He opted for MMS. The initial 1-cm margin taken during MMS was sufficient to achieve complete tumor extirpation, and the final 3.7×2.5-cm defect was closed primarily. The MMS debulking specimen was sent for permanent sectioning and showed a small focus of residual tumor cells, but no mitoses or lymphovascular invasion were seen. The patient was referred to surgical oncology to discuss the option of SLNB, which he ultimately declined. He also was offered regional or whole-body positron emission tomography–computed tomography (PET-CT) to rule out metastatic disease, which he also declined. There was no evidence of recurrence or lymphadenopathy 19 months postoperatively.

Comment

Eccrine porocarcinoma is an exceptionally rare adnexal neoplasm that most commonly affects older adults. The average age at diagnosis is 71 years in men and 75 years in women.² Our case is rare because of the patient’s age. Benign eccrine poromas occur most frequently on the palms, soles, axillae, and forehead where eccrine density is highest; EPC occurs most frequently on the lower extremities.⁶ It may arise de novo or from malignant transformation of a preexisting benign poroma. Clinically, EPC may present as an asymptomatic pink-brown papule, plaque, or nodule and may have a polypoid or verrucous appearance, as in our patient. Ulceration is common.⁷ The differential diagnosis often includes nodular basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, and seborrheic keratosis.

Histologically, EPCs are characterized by aggregations of cohesive basaloid epithelial cells forming eccrine ductal structures.² Cellular atypia may be extremely subtle but, if present, can be helpful in differentiating malignant from benign lesions. Features of basal and squamous cell carcinoma also may be present. Definitive diagnosis is frequently based on the overall invasive architectural pattern.⁵ Robson et al² examined 69 cases of EPC for high-risk histologic features and concluded that tumor depth greater than 7 mm, mitoses greater than 14 per high-power field, and the presence of lymphovascular invasion were independently predictive of mortality. Moreover, after adjusting for mitosis and depth, an infiltrative border vs a pushing border was strongly predictive of local recurrence.² Immunohistochemical stains, although not necessary for diagnosis, may have utility as adjunctive tools. Cells lining the ducts within EPCs commonly stain positive for carcinoembryonic antigen, though glandular myoepithelial cells stain positive for S-100. Negative Ber-EP4 staining helps to differentiate EPC from basal cell carcinoma. Abnormal expression of p53 and overexpression of p16 also has been described.⁴

The rarity of EPC has precluded the development of any evidence-based management guidelines. Historically, the standard of care has been WLE with 2- to 3-cm margins. A review of 105 cases of EPC treated with WLE showed 20% local recurrence, 20% regional metastases, and 12% distant metastasis rates.⁸ Mohs micrographic surgery, which allows examination of 100% of the surgical margin vs less than 1% for WLE with the standard bread-loafing technique, might be expected to achieve higher cure rates. A review of 29 cases treated with MMS monotherapy demonstrated no local recurrences, distant metastasis, or disease-specific deaths with follow-up ranging from 19 months to 6 years.⁵ One case was associated with regional lymph node metastases that were treated with completion lymphadenectomy and adjuvant radiation therapy.⁷ The high mortality rate of patients with nodal disease has led some to recommend PET-CT and SLNB for patients with EPC. However, the prognostic value of such procedures has not been clearly defined and there is no demonstrated survival benefit for treatment of widespread disease. Our patient declined both SLNB and PET-CT, and our plan was to follow him clinically with symptom-directed imaging only.

Conclusion

Patients with EPC generally have a favorable prognosis with prompt diagnosis and complete surgical excision. Although most commonly seen in elderly patients, EPC may present in younger patients and may be clinically and histologically nondescript with little cytologic atypia. Based on a small but growing body of literature, MMS appears to be at least as effective as WLE as a primary treatment modality for EPC, while offering the advantage of tissue sparing in cosmetically or functionally important areas.

Eccrine porocarcinoma (EPC), originally described by Pinkus and Mehregan¹ in 1963, is an exceedingly rare sweat gland tumor most commonly seen in older patients. Fewer than 300 cases have been reported in the literature, and it is believed to represent only 0.005% to 0.01% of cutaneous malignancies.² In the absence of established guidelines, wide local excision (WLE) has traditionally been considered the standard of treatment; however, local recurrence and nodal metastasis rates associated with WLE have been reported as high as 20%.³ More recently, a number of case reports and small case series have demonstrated higher cure rates with Mohs micrographic surgery (MMS), though follow-up is limited.^3-5 We describe a case of EPC presenting as a recurrent wart in a 36-year-old man that was successfully treated with MMS.

Case Report

A 36-year-old man with no notable medical history presented with a 0.5×0.5-cm, asymptomatic, flesh-colored, hyperkeratotic, polypoid papule on the right medial thigh (Figure 1). The lesion was diagnosed as a wart and treated with cryotherapy by another dermatologist several years prior to presentation. Dermatoscopic examination at the current presentation showed a homogenous yellow center with a few peripheral vessels and a faint pink-tan halo (Figure 2). Our differential diagnosis included a recurrent wart, fibrosed pyogenic granuloma, irritated intradermal nevus, skin tag, and adnexal neoplasm. A shave biopsy was performed. Histopathologic analysis revealed multiple aggregations of mildly pleomorphic epithelial cells emanating from the epidermis, with many aggregations containing ductal structures (Figure 3). Rare necrotic and pyknotic cells were present, but no mitotic figures or lymphovascular invasion were identified. Immunohistochemical staining was positive for carcinoembryonic antigen and epithelial membrane antigen but negative for Ber-EP4. These findings were consistent with a well-differentiated EPC.

The patient was offered MMS or WLE, with or without sentinel lymph node biopsy (SLNB). He opted for MMS. The initial 1-cm margin taken during MMS was sufficient to achieve complete tumor extirpation, and the final 3.7×2.5-cm defect was closed primarily. The MMS debulking specimen was sent for permanent sectioning and showed a small focus of residual tumor cells, but no mitoses or lymphovascular invasion were seen. The patient was referred to surgical oncology to discuss the option of SLNB, which he ultimately declined. He also was offered regional or whole-body positron emission tomography–computed tomography (PET-CT) to rule out metastatic disease, which he also declined. There was no evidence of recurrence or lymphadenopathy 19 months postoperatively.

Comment

Eccrine porocarcinoma is an exceptionally rare adnexal neoplasm that most commonly affects older adults. The average age at diagnosis is 71 years in men and 75 years in women.² Our case is rare because of the patient’s age. Benign eccrine poromas occur most frequently on the palms, soles, axillae, and forehead where eccrine density is highest; EPC occurs most frequently on the lower extremities.⁶ It may arise de novo or from malignant transformation of a preexisting benign poroma. Clinically, EPC may present as an asymptomatic pink-brown papule, plaque, or nodule and may have a polypoid or verrucous appearance, as in our patient. Ulceration is common.⁷ The differential diagnosis often includes nodular basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, and seborrheic keratosis.

Histologically, EPCs are characterized by aggregations of cohesive basaloid epithelial cells forming eccrine ductal structures.² Cellular atypia may be extremely subtle but, if present, can be helpful in differentiating malignant from benign lesions. Features of basal and squamous cell carcinoma also may be present. Definitive diagnosis is frequently based on the overall invasive architectural pattern.⁵ Robson et al² examined 69 cases of EPC for high-risk histologic features and concluded that tumor depth greater than 7 mm, mitoses greater than 14 per high-power field, and the presence of lymphovascular invasion were independently predictive of mortality. Moreover, after adjusting for mitosis and depth, an infiltrative border vs a pushing border was strongly predictive of local recurrence.² Immunohistochemical stains, although not necessary for diagnosis, may have utility as adjunctive tools. Cells lining the ducts within EPCs commonly stain positive for carcinoembryonic antigen, though glandular myoepithelial cells stain positive for S-100. Negative Ber-EP4 staining helps to differentiate EPC from basal cell carcinoma. Abnormal expression of p53 and overexpression of p16 also has been described.⁴

The rarity of EPC has precluded the development of any evidence-based management guidelines. Historically, the standard of care has been WLE with 2- to 3-cm margins. A review of 105 cases of EPC treated with WLE showed 20% local recurrence, 20% regional metastases, and 12% distant metastasis rates.⁸ Mohs micrographic surgery, which allows examination of 100% of the surgical margin vs less than 1% for WLE with the standard bread-loafing technique, might be expected to achieve higher cure rates. A review of 29 cases treated with MMS monotherapy demonstrated no local recurrences, distant metastasis, or disease-specific deaths with follow-up ranging from 19 months to 6 years.⁵ One case was associated with regional lymph node metastases that were treated with completion lymphadenectomy and adjuvant radiation therapy.⁷ The high mortality rate of patients with nodal disease has led some to recommend PET-CT and SLNB for patients with EPC. However, the prognostic value of such procedures has not been clearly defined and there is no demonstrated survival benefit for treatment of widespread disease. Our patient declined both SLNB and PET-CT, and our plan was to follow him clinically with symptom-directed imaging only.

Conclusion

Patients with EPC generally have a favorable prognosis with prompt diagnosis and complete surgical excision. Although most commonly seen in elderly patients, EPC may present in younger patients and may be clinically and histologically nondescript with little cytologic atypia. Based on a small but growing body of literature, MMS appears to be at least as effective as WLE as a primary treatment modality for EPC, while offering the advantage of tissue sparing in cosmetically or functionally important areas.

Previously unknown risk factors for secondary skin cancer linked with allogeneic hematopoietic cell transplantation (HCT) have been identified, researchers report after a retrospective analysis.

“We confirmed [graft-versus-host disease] as a risk factor, identified [chronic lymphocytic leukemia] as an additional risk factor, and found that patients who received myeloablative transplants in adulthood had fewer [basal cell carcinomas] than their counterparts,” Peggy A. Wu, MD, of the Beth Israel Deaconess Medical Center in Boston, and her colleagues wrote in the Journal of Investigative Dermatology.

The team analyzed 1,974 patients who underwent transplantation for various types of hematologic cancer and survived for a minimum of 100 days following transplant. Among this cohort, 119 patients developed various forms of skin cancer, including basal and squamous cell carcinoma.

Reports of skin malignancy were confirmed using physician records and pathology reports. Dr. Wu and her colleagues excluded patients whose indication for transplant was a primary immunodeficiency or Fanconi anemia.

“Reflecting advances that allow older patients to be eligible for HCT, the median age at transplantation of our cohort was one of the oldest (51.1 years) in the literature,” the researchers wrote.

In univariable models, the researchers found that prior chronic lymphocytic leukemia (CLL) (hazard ratio, 2.2; 95% CI, 1.3-3.7), chronic graft-versus-host disease (GVHD) (HR, 3.1; 95% CI, 1.7-5.4), and age at transplant of more than 60 years (HR, 10.8; 95% CI, 3.3-35.6) were all linked to an increased risk for squamous cell carcinomas. A multivariable analysis found that these factors continued as significant risk factors.

For basal cell carcinomas, the risk factors identified were prior CLL (HR, 3.5; 95% CI, 2.0-6.4), acute GVHD (HR, 1.9; 95% CI, 1.1-3.3), and chronic GVHD (HR, 3.2; 95% CI, 1.6-6.5) using univariable models. These factors all continued to be significant in multivariable analysis.

Additionally, the researchers found that a myeloablative conditioning regimen and total body irradiation were protective against development of basal cell carcinomas in univariable models. However, the protective effect continued for myeloablative condition in the multivariable model only.

“To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma,” the researchers wrote.

The study was supported by the Skin Cancer Foundation, Women’s Dermatologic Society, Harvard Catalyst, and Harvard University. The authors reported having no conflicts of interest.
 

SOURCE: Wu PA et al. J Invest Dermatol. 2019 Mar;139(3):591-9.

Previously unknown risk factors for secondary skin cancer linked with allogeneic hematopoietic cell transplantation (HCT) have been identified, researchers report after a retrospective analysis.

“We confirmed [graft-versus-host disease] as a risk factor, identified [chronic lymphocytic leukemia] as an additional risk factor, and found that patients who received myeloablative transplants in adulthood had fewer [basal cell carcinomas] than their counterparts,” Peggy A. Wu, MD, of the Beth Israel Deaconess Medical Center in Boston, and her colleagues wrote in the Journal of Investigative Dermatology.

The team analyzed 1,974 patients who underwent transplantation for various types of hematologic cancer and survived for a minimum of 100 days following transplant. Among this cohort, 119 patients developed various forms of skin cancer, including basal and squamous cell carcinoma.

Reports of skin malignancy were confirmed using physician records and pathology reports. Dr. Wu and her colleagues excluded patients whose indication for transplant was a primary immunodeficiency or Fanconi anemia.

“Reflecting advances that allow older patients to be eligible for HCT, the median age at transplantation of our cohort was one of the oldest (51.1 years) in the literature,” the researchers wrote.

In univariable models, the researchers found that prior chronic lymphocytic leukemia (CLL) (hazard ratio, 2.2; 95% CI, 1.3-3.7), chronic graft-versus-host disease (GVHD) (HR, 3.1; 95% CI, 1.7-5.4), and age at transplant of more than 60 years (HR, 10.8; 95% CI, 3.3-35.6) were all linked to an increased risk for squamous cell carcinomas. A multivariable analysis found that these factors continued as significant risk factors.

For basal cell carcinomas, the risk factors identified were prior CLL (HR, 3.5; 95% CI, 2.0-6.4), acute GVHD (HR, 1.9; 95% CI, 1.1-3.3), and chronic GVHD (HR, 3.2; 95% CI, 1.6-6.5) using univariable models. These factors all continued to be significant in multivariable analysis.

Additionally, the researchers found that a myeloablative conditioning regimen and total body irradiation were protective against development of basal cell carcinomas in univariable models. However, the protective effect continued for myeloablative condition in the multivariable model only.

“To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma,” the researchers wrote.

The study was supported by the Skin Cancer Foundation, Women’s Dermatologic Society, Harvard Catalyst, and Harvard University. The authors reported having no conflicts of interest.
 

SOURCE: Wu PA et al. J Invest Dermatol. 2019 Mar;139(3):591-9.

Previously unknown risk factors for secondary skin cancer linked with allogeneic hematopoietic cell transplantation (HCT) have been identified, researchers report after a retrospective analysis.

“We confirmed [graft-versus-host disease] as a risk factor, identified [chronic lymphocytic leukemia] as an additional risk factor, and found that patients who received myeloablative transplants in adulthood had fewer [basal cell carcinomas] than their counterparts,” Peggy A. Wu, MD, of the Beth Israel Deaconess Medical Center in Boston, and her colleagues wrote in the Journal of Investigative Dermatology.

The team analyzed 1,974 patients who underwent transplantation for various types of hematologic cancer and survived for a minimum of 100 days following transplant. Among this cohort, 119 patients developed various forms of skin cancer, including basal and squamous cell carcinoma.

Reports of skin malignancy were confirmed using physician records and pathology reports. Dr. Wu and her colleagues excluded patients whose indication for transplant was a primary immunodeficiency or Fanconi anemia.

“Reflecting advances that allow older patients to be eligible for HCT, the median age at transplantation of our cohort was one of the oldest (51.1 years) in the literature,” the researchers wrote.

In univariable models, the researchers found that prior chronic lymphocytic leukemia (CLL) (hazard ratio, 2.2; 95% CI, 1.3-3.7), chronic graft-versus-host disease (GVHD) (HR, 3.1; 95% CI, 1.7-5.4), and age at transplant of more than 60 years (HR, 10.8; 95% CI, 3.3-35.6) were all linked to an increased risk for squamous cell carcinomas. A multivariable analysis found that these factors continued as significant risk factors.

For basal cell carcinomas, the risk factors identified were prior CLL (HR, 3.5; 95% CI, 2.0-6.4), acute GVHD (HR, 1.9; 95% CI, 1.1-3.3), and chronic GVHD (HR, 3.2; 95% CI, 1.6-6.5) using univariable models. These factors all continued to be significant in multivariable analysis.

Additionally, the researchers found that a myeloablative conditioning regimen and total body irradiation were protective against development of basal cell carcinomas in univariable models. However, the protective effect continued for myeloablative condition in the multivariable model only.

“To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma,” the researchers wrote.

The study was supported by the Skin Cancer Foundation, Women’s Dermatologic Society, Harvard Catalyst, and Harvard University. The authors reported having no conflicts of interest.
 

SOURCE: Wu PA et al. J Invest Dermatol. 2019 Mar;139(3):591-9.

The Diagnosis: Verrucous Carcinoma

An excisional biopsy revealed an endophytic and exophytic squamous proliferation with a papillomatous growth pattern, bulbous pushing border, and confluent parakeratosis (Figure). No fungal organisms were seen. Due to clinical and histological findings, a diagnosis of verrucous carcinoma (VC) was made.

Verrucous carcinoma is a rare variant of squamous cell carcinoma (SCC) with specific clinical and histological features.¹ These tumors have a slow and localized growth pattern but can be locally aggressive. Metastasis of VC is rare, giving VC an overall good prognosis, with a 5-year survival rate greater than 75%.² Verrucous carcinoma typically occurs in 1 of 3 locations: the oropharynx, genitals, or soles of the feet. Depending on the site of involvement, various names have been used in the literature to describe this entity, including Ackerman tumor (solitary oral mucosal lesion), Buschke-Lowenstein tumor (genital involvement), florid oral papillomatosis (multiple oral lesions), and carcinoma cuniculatum (sole of the foot).³ The most common sites for VC in the oral cavity are the buccal mucosa and gingiva.⁴

Verrucous carcinoma occurs more often among men in the sixth decade of life.³ The etiology of oral VC remains unclear; however, use of chewing tobacco, chemical carcinogens, chronic irritation, human papillomavirus (HPV), and poor oral hygiene have been reported as predisposing risk factors.^4,5 The role of HPV in the pathogenesis of VC remains controversial, but both low-risk types HPV-6 and HPV-11 and high-risk types HPV-16 and HPV-18 have been found in association with VC.^5,6

Clinically, oral VC lesions most often present as pink-white erythematous papules or plaques with exophytic cauliflowerlike surface alterations. Although the tumors are slow growing with little risk for metastasis, they may be locally invasive with deep involvement of the surrounding
structures.¹ Histopathologically, VC displays proliferation of the epithelium with downward growth into the connective tissue but usually without a pattern of true invasion. The epithelium is well differentiated and displays little pleomorphism or mitoses.^5,7 Obtaining a generous biopsy specimen is essential to view the diagnostic architecture of VC and rule out other entities, such as viral verruca, blastomycosis, SCC, and verruciform xanthoma. Squamous cell carcinoma characteristically has a more infiltrative border as opposed to the bulbous border of VC. In addition, the distribution of p53 and Ki-67 staining differs between SCC and VC. Squamous cell carcinoma shows positive p53 and Ki-67 staining for the full thickness of the epidermis, while VC has positive staining only in the lower third of the epidermis.⁵

Surgical resection is considered the first-line treatment of VC through excision or Mohs micrographic surgery. Radiation therapy is controversial due to the risk for anaplastic transformation. When surgery is not ideal due to the tumor size or location or the patient’s preference, other treatment modalities with reported success include intralesional interferon alfa; cryosurgery; topical imiquimod; and topical or systemic cytostatic agents such as bleomycin, 5-fluorouracil, cisplatin, or methotrexate.^1,2

The Diagnosis: Verrucous Carcinoma

An excisional biopsy revealed an endophytic and exophytic squamous proliferation with a papillomatous growth pattern, bulbous pushing border, and confluent parakeratosis (Figure). No fungal organisms were seen. Due to clinical and histological findings, a diagnosis of verrucous carcinoma (VC) was made.

Verrucous carcinoma is a rare variant of squamous cell carcinoma (SCC) with specific clinical and histological features.¹ These tumors have a slow and localized growth pattern but can be locally aggressive. Metastasis of VC is rare, giving VC an overall good prognosis, with a 5-year survival rate greater than 75%.² Verrucous carcinoma typically occurs in 1 of 3 locations: the oropharynx, genitals, or soles of the feet. Depending on the site of involvement, various names have been used in the literature to describe this entity, including Ackerman tumor (solitary oral mucosal lesion), Buschke-Lowenstein tumor (genital involvement), florid oral papillomatosis (multiple oral lesions), and carcinoma cuniculatum (sole of the foot).³ The most common sites for VC in the oral cavity are the buccal mucosa and gingiva.⁴

Verrucous carcinoma occurs more often among men in the sixth decade of life.³ The etiology of oral VC remains unclear; however, use of chewing tobacco, chemical carcinogens, chronic irritation, human papillomavirus (HPV), and poor oral hygiene have been reported as predisposing risk factors.^4,5 The role of HPV in the pathogenesis of VC remains controversial, but both low-risk types HPV-6 and HPV-11 and high-risk types HPV-16 and HPV-18 have been found in association with VC.^5,6

Clinically, oral VC lesions most often present as pink-white erythematous papules or plaques with exophytic cauliflowerlike surface alterations. Although the tumors are slow growing with little risk for metastasis, they may be locally invasive with deep involvement of the surrounding
structures.¹ Histopathologically, VC displays proliferation of the epithelium with downward growth into the connective tissue but usually without a pattern of true invasion. The epithelium is well differentiated and displays little pleomorphism or mitoses.^5,7 Obtaining a generous biopsy specimen is essential to view the diagnostic architecture of VC and rule out other entities, such as viral verruca, blastomycosis, SCC, and verruciform xanthoma. Squamous cell carcinoma characteristically has a more infiltrative border as opposed to the bulbous border of VC. In addition, the distribution of p53 and Ki-67 staining differs between SCC and VC. Squamous cell carcinoma shows positive p53 and Ki-67 staining for the full thickness of the epidermis, while VC has positive staining only in the lower third of the epidermis.⁵

Surgical resection is considered the first-line treatment of VC through excision or Mohs micrographic surgery. Radiation therapy is controversial due to the risk for anaplastic transformation. When surgery is not ideal due to the tumor size or location or the patient’s preference, other treatment modalities with reported success include intralesional interferon alfa; cryosurgery; topical imiquimod; and topical or systemic cytostatic agents such as bleomycin, 5-fluorouracil, cisplatin, or methotrexate.^1,2

The Diagnosis: Verrucous Carcinoma

An excisional biopsy revealed an endophytic and exophytic squamous proliferation with a papillomatous growth pattern, bulbous pushing border, and confluent parakeratosis (Figure). No fungal organisms were seen. Due to clinical and histological findings, a diagnosis of verrucous carcinoma (VC) was made.

Verrucous carcinoma is a rare variant of squamous cell carcinoma (SCC) with specific clinical and histological features.¹ These tumors have a slow and localized growth pattern but can be locally aggressive. Metastasis of VC is rare, giving VC an overall good prognosis, with a 5-year survival rate greater than 75%.² Verrucous carcinoma typically occurs in 1 of 3 locations: the oropharynx, genitals, or soles of the feet. Depending on the site of involvement, various names have been used in the literature to describe this entity, including Ackerman tumor (solitary oral mucosal lesion), Buschke-Lowenstein tumor (genital involvement), florid oral papillomatosis (multiple oral lesions), and carcinoma cuniculatum (sole of the foot).³ The most common sites for VC in the oral cavity are the buccal mucosa and gingiva.⁴

Verrucous carcinoma occurs more often among men in the sixth decade of life.³ The etiology of oral VC remains unclear; however, use of chewing tobacco, chemical carcinogens, chronic irritation, human papillomavirus (HPV), and poor oral hygiene have been reported as predisposing risk factors.^4,5 The role of HPV in the pathogenesis of VC remains controversial, but both low-risk types HPV-6 and HPV-11 and high-risk types HPV-16 and HPV-18 have been found in association with VC.^5,6

Clinically, oral VC lesions most often present as pink-white erythematous papules or plaques with exophytic cauliflowerlike surface alterations. Although the tumors are slow growing with little risk for metastasis, they may be locally invasive with deep involvement of the surrounding
structures.¹ Histopathologically, VC displays proliferation of the epithelium with downward growth into the connective tissue but usually without a pattern of true invasion. The epithelium is well differentiated and displays little pleomorphism or mitoses.^5,7 Obtaining a generous biopsy specimen is essential to view the diagnostic architecture of VC and rule out other entities, such as viral verruca, blastomycosis, SCC, and verruciform xanthoma. Squamous cell carcinoma characteristically has a more infiltrative border as opposed to the bulbous border of VC. In addition, the distribution of p53 and Ki-67 staining differs between SCC and VC. Squamous cell carcinoma shows positive p53 and Ki-67 staining for the full thickness of the epidermis, while VC has positive staining only in the lower third of the epidermis.⁵

Surgical resection is considered the first-line treatment of VC through excision or Mohs micrographic surgery. Radiation therapy is controversial due to the risk for anaplastic transformation. When surgery is not ideal due to the tumor size or location or the patient’s preference, other treatment modalities with reported success include intralesional interferon alfa; cryosurgery; topical imiquimod; and topical or systemic cytostatic agents such as bleomycin, 5-fluorouracil, cisplatin, or methotrexate.^1,2

Patients with the aggressive skin cancer Merkel cell carcinoma who were treated with the immune checkpoint inhibitor pembrolizumab (Keytruda) in the first line had higher complete response rates, better progression-free survival, and longer overall survival than historical controls treated with cytotoxic chemotherapy.

Among 50 adults with advanced Merkel cell carcinoma (MCC) with no prior systemic therapy who received pembrolizumab 2 mg/kg every 3 weeks for up to 2 years in a phase 2 clinical trial (NCT02267603), 24% had a complete response and 32% a partial response, for an overall response rate of 56%.

The 24-month overall survival rate was 68.7%, with median overall survival not reached after a median follow-up time of 14.9 months. In contrast, a retrospective study of 67 patients with MCC treated with first-line chemotherapy showed an ORR of 29.4%, a median OS of 10.5 months, and a 24-month OS of 24.5% (Future Oncol. 2017 Aug;13(19):1699-1710).

Similarly, a second retrospective study showed that, among 62 patients treated with first-line chemotherapy, the ORR was 55%, median OS was 9.5 months, and 24-month OS was 20% (Cancer Med. 2016 Sep;5(9):2294-2301), reported Paul Nghiem, MD, PhD, from the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, and his colleagues.

The rationale for using a checkpoint inhibitor for advanced MCC is that “[m]ultiple lines of evidence support the notion that MCC is an immunogenic cancer, including the fact that MCC incidence is greater than 10-fold higher in chronically immunosuppressed persons,” they wrote in the Journal of Clinical Oncology.

The current National Comprehensive Cancer Network guideline on Merkel cell carcinoma recommends the use of the programmed death–1/programmed death–ligand 1 (PD-1/PD-L1) inhibitors pembrolizumab, avelumab (Bavencio), or nivolumab (Opdivo) as preferred first-line systemic therapy for patients with disseminated disease, Dr. Nghiem and his colleagues noted.

In the current report, they presented data on the longest follow-up to date of patients with advance MCC who received a PD-1 inhibitor in the first line.

In the multicenter, phase 2 trial, 50 patients with a median age of 70.5 years were treated. Of this group, 64% had tumors positive for the Merkel cell polyomavirus and 49% had PD-L1 expression on tumor cells.

Of the 50 total patients, 28 had an objective response according to Response Evaluation Criteria in Solid Tumors version 1.1, including 12 with a complete response and 16 with a partial response. A total of 5 patients had stable disease, 16 had progressive disease, and 1 patient died before the first on-treatment scan for assessment.

After a median follow-up of 4.9 months, the 24-month progression-free survival rate (PFS) was 48.3% months, with a median PFS of 16.8 months.

As noted before, the 24-month OS rate was 68.7% and the median OS had not been reached at the time of the analysis.

There were no significant differences in PFS or OS between patients with tumors positive or negative for the Merkel polyomavirus, and there was a nonsignificant trend toward better PFS and OS for patients whose tumors had PD-L1 expression greater than 1%.

In all, 48 of the 50 patients had a treatment-related adverse event of any kind, and 14 had grade 3 or greater events. Treatment-related events led to discontinuation of pembrolizumab for seven patients, and one patient, a 73-year-old man with metastatic MCC and atrial fibrillation, developed pericardial and pleural effusions 1 day after receiving a single pembrolizumab infusion. The patient died 10 days after receiving pembrolizumab, and his death was deemed to be related to the drug.

The investigators noted that the drug’s efficacy in patients with both polyomavirus- and UV-induced subtypes of MCC “provides compelling evidence that both the quality and quantity of tumor antigens are important factors driving antitumor immunity and tumor rejection.”

The study was supported by grants from the National Cancer Institute, the Merkel cell carcinoma (MCC) patient gift fund at University of Washington, the Kelsey Dickson MCC Challenge Grant from the Prostate Cancer Foundation, and Merck, which provided pembrolizumab and partial funding. Dr. Nghiem reported receiving honoraria, travel expenses, and a consulting or advisory role from/for Merck and others. Multiple coauthors reported similar relations with Merck and/or other companies.

SOURCE: Nghiem P et al. J Clin Oncol. 2019 Feb 6. doi: 10.1200/JCO.18.01896.

Patients with the aggressive skin cancer Merkel cell carcinoma who were treated with the immune checkpoint inhibitor pembrolizumab (Keytruda) in the first line had higher complete response rates, better progression-free survival, and longer overall survival than historical controls treated with cytotoxic chemotherapy.

Among 50 adults with advanced Merkel cell carcinoma (MCC) with no prior systemic therapy who received pembrolizumab 2 mg/kg every 3 weeks for up to 2 years in a phase 2 clinical trial (NCT02267603), 24% had a complete response and 32% a partial response, for an overall response rate of 56%.

The 24-month overall survival rate was 68.7%, with median overall survival not reached after a median follow-up time of 14.9 months. In contrast, a retrospective study of 67 patients with MCC treated with first-line chemotherapy showed an ORR of 29.4%, a median OS of 10.5 months, and a 24-month OS of 24.5% (Future Oncol. 2017 Aug;13(19):1699-1710).

Similarly, a second retrospective study showed that, among 62 patients treated with first-line chemotherapy, the ORR was 55%, median OS was 9.5 months, and 24-month OS was 20% (Cancer Med. 2016 Sep;5(9):2294-2301), reported Paul Nghiem, MD, PhD, from the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, and his colleagues.

The rationale for using a checkpoint inhibitor for advanced MCC is that “[m]ultiple lines of evidence support the notion that MCC is an immunogenic cancer, including the fact that MCC incidence is greater than 10-fold higher in chronically immunosuppressed persons,” they wrote in the Journal of Clinical Oncology.

The current National Comprehensive Cancer Network guideline on Merkel cell carcinoma recommends the use of the programmed death–1/programmed death–ligand 1 (PD-1/PD-L1) inhibitors pembrolizumab, avelumab (Bavencio), or nivolumab (Opdivo) as preferred first-line systemic therapy for patients with disseminated disease, Dr. Nghiem and his colleagues noted.

In the current report, they presented data on the longest follow-up to date of patients with advance MCC who received a PD-1 inhibitor in the first line.

In the multicenter, phase 2 trial, 50 patients with a median age of 70.5 years were treated. Of this group, 64% had tumors positive for the Merkel cell polyomavirus and 49% had PD-L1 expression on tumor cells.

Of the 50 total patients, 28 had an objective response according to Response Evaluation Criteria in Solid Tumors version 1.1, including 12 with a complete response and 16 with a partial response. A total of 5 patients had stable disease, 16 had progressive disease, and 1 patient died before the first on-treatment scan for assessment.

After a median follow-up of 4.9 months, the 24-month progression-free survival rate (PFS) was 48.3% months, with a median PFS of 16.8 months.

As noted before, the 24-month OS rate was 68.7% and the median OS had not been reached at the time of the analysis.

There were no significant differences in PFS or OS between patients with tumors positive or negative for the Merkel polyomavirus, and there was a nonsignificant trend toward better PFS and OS for patients whose tumors had PD-L1 expression greater than 1%.

In all, 48 of the 50 patients had a treatment-related adverse event of any kind, and 14 had grade 3 or greater events. Treatment-related events led to discontinuation of pembrolizumab for seven patients, and one patient, a 73-year-old man with metastatic MCC and atrial fibrillation, developed pericardial and pleural effusions 1 day after receiving a single pembrolizumab infusion. The patient died 10 days after receiving pembrolizumab, and his death was deemed to be related to the drug.

The investigators noted that the drug’s efficacy in patients with both polyomavirus- and UV-induced subtypes of MCC “provides compelling evidence that both the quality and quantity of tumor antigens are important factors driving antitumor immunity and tumor rejection.”

The study was supported by grants from the National Cancer Institute, the Merkel cell carcinoma (MCC) patient gift fund at University of Washington, the Kelsey Dickson MCC Challenge Grant from the Prostate Cancer Foundation, and Merck, which provided pembrolizumab and partial funding. Dr. Nghiem reported receiving honoraria, travel expenses, and a consulting or advisory role from/for Merck and others. Multiple coauthors reported similar relations with Merck and/or other companies.

SOURCE: Nghiem P et al. J Clin Oncol. 2019 Feb 6. doi: 10.1200/JCO.18.01896.

Patients with the aggressive skin cancer Merkel cell carcinoma who were treated with the immune checkpoint inhibitor pembrolizumab (Keytruda) in the first line had higher complete response rates, better progression-free survival, and longer overall survival than historical controls treated with cytotoxic chemotherapy.

Among 50 adults with advanced Merkel cell carcinoma (MCC) with no prior systemic therapy who received pembrolizumab 2 mg/kg every 3 weeks for up to 2 years in a phase 2 clinical trial (NCT02267603), 24% had a complete response and 32% a partial response, for an overall response rate of 56%.

The 24-month overall survival rate was 68.7%, with median overall survival not reached after a median follow-up time of 14.9 months. In contrast, a retrospective study of 67 patients with MCC treated with first-line chemotherapy showed an ORR of 29.4%, a median OS of 10.5 months, and a 24-month OS of 24.5% (Future Oncol. 2017 Aug;13(19):1699-1710).

Similarly, a second retrospective study showed that, among 62 patients treated with first-line chemotherapy, the ORR was 55%, median OS was 9.5 months, and 24-month OS was 20% (Cancer Med. 2016 Sep;5(9):2294-2301), reported Paul Nghiem, MD, PhD, from the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, and his colleagues.

The rationale for using a checkpoint inhibitor for advanced MCC is that “[m]ultiple lines of evidence support the notion that MCC is an immunogenic cancer, including the fact that MCC incidence is greater than 10-fold higher in chronically immunosuppressed persons,” they wrote in the Journal of Clinical Oncology.

The current National Comprehensive Cancer Network guideline on Merkel cell carcinoma recommends the use of the programmed death–1/programmed death–ligand 1 (PD-1/PD-L1) inhibitors pembrolizumab, avelumab (Bavencio), or nivolumab (Opdivo) as preferred first-line systemic therapy for patients with disseminated disease, Dr. Nghiem and his colleagues noted.

In the current report, they presented data on the longest follow-up to date of patients with advance MCC who received a PD-1 inhibitor in the first line.

In the multicenter, phase 2 trial, 50 patients with a median age of 70.5 years were treated. Of this group, 64% had tumors positive for the Merkel cell polyomavirus and 49% had PD-L1 expression on tumor cells.

Of the 50 total patients, 28 had an objective response according to Response Evaluation Criteria in Solid Tumors version 1.1, including 12 with a complete response and 16 with a partial response. A total of 5 patients had stable disease, 16 had progressive disease, and 1 patient died before the first on-treatment scan for assessment.

After a median follow-up of 4.9 months, the 24-month progression-free survival rate (PFS) was 48.3% months, with a median PFS of 16.8 months.

As noted before, the 24-month OS rate was 68.7% and the median OS had not been reached at the time of the analysis.

There were no significant differences in PFS or OS between patients with tumors positive or negative for the Merkel polyomavirus, and there was a nonsignificant trend toward better PFS and OS for patients whose tumors had PD-L1 expression greater than 1%.

In all, 48 of the 50 patients had a treatment-related adverse event of any kind, and 14 had grade 3 or greater events. Treatment-related events led to discontinuation of pembrolizumab for seven patients, and one patient, a 73-year-old man with metastatic MCC and atrial fibrillation, developed pericardial and pleural effusions 1 day after receiving a single pembrolizumab infusion. The patient died 10 days after receiving pembrolizumab, and his death was deemed to be related to the drug.

The investigators noted that the drug’s efficacy in patients with both polyomavirus- and UV-induced subtypes of MCC “provides compelling evidence that both the quality and quantity of tumor antigens are important factors driving antitumor immunity and tumor rejection.”

The study was supported by grants from the National Cancer Institute, the Merkel cell carcinoma (MCC) patient gift fund at University of Washington, the Kelsey Dickson MCC Challenge Grant from the Prostate Cancer Foundation, and Merck, which provided pembrolizumab and partial funding. Dr. Nghiem reported receiving honoraria, travel expenses, and a consulting or advisory role from/for Merck and others. Multiple coauthors reported similar relations with Merck and/or other companies.

SOURCE: Nghiem P et al. J Clin Oncol. 2019 Feb 6. doi: 10.1200/JCO.18.01896.

Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.

Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.

The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.

“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.

One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.

Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.

While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.

Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.

Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).

The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).

Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.

“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.

The investigators did not report disclosures related to the research.

SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.

Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.

Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.

The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.

“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.

One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.

Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.

While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.

Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.

Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).

The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).

Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.

“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.

The investigators did not report disclosures related to the research.

SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.

Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.

Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.

The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.

“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.

One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.

Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.

While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.

Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.

Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).

The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).

Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.

“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.

The investigators did not report disclosures related to the research.

SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.

ORLANDO – When caring for individuals with sun-damaged skin, dermatologists need comfort with the full spectrum of photo-related skin disease. From assessment and treatment of actinic keratoses (AKs) and field cancerization, to long-term follow-up of cutaneous squamous cell carcinomas (SCCs), appropriate treatment and staging can improve patient quality of life and reduce health care costs, Vishal Patel, MD, said at the Orlando Dermatology Aesthetic and Clinical Conference.

Kari Oakes/MDedge News

“Actinic keratosis/squamous cell carcinoma in situ is not a disease; it’s a symptom of cutaneous carcinogenesis or field cancerization,” said Dr. Patel, director of cutaneous oncology at George Washington University Cancer Center, Washington. On the other hand, he added, “field disease can be a marker for invasive squamous cell carcinoma risk, and it requires field treatment.” Treatment that reduces field disease is primary prevention because it decreases the formation of invasive SCC, he noted.

“But this level of disease – AKs and SCC in situ – doesn’t kill people,” he emphasized. “I want to leave you with an ability to stage this disease,” said Dr. Patel, noting that SCC mortality may eventually surpass melanoma mortality as deaths from the latter decline and numbers of older Americans with high ultraviolet light exposure and other risk factors climb.

While the majority of AKs regress within 5 years, he looks at the total burden of AKs as a marker for field cancerization “because having less than five in situ or actinic lesions puts you at less than a 1% risk of squamous cell carcinoma formation. Having more than 20 increases that risk 20-fold to 20%,” he said. “That’s the way we need to start thinking about this: Is this a disease – or a symptom?”

Rather than thinking of each AK or SCC in situ as a separate disease event, “the disease we need to be focusing on and treating is field cancerization,” he continued. Within this context, “we should not be thinking that … we need to be aggressive in our management,” which is what results in high costs.

“The reality is that this is a big quality of life issue for our patients. So what do we do?” Field treatment is appropriate for field disease, he said. Dr. Patel said that at GW only field treatment is used; destructive treatment for AKs and SCC in situ is not used. In the absence of patient and lesion characteristics that elevate risk,“surgery is really not the standard of care for in situ lesions for us,” he commented.

“We start by discerning the field disease from the invasive disease” with an initial round of field treatment and, if needed, adjunctive oral chemoprophylaxis. “We lather, rinse, and repeat” the field therapy, continuously if needed, Dr. Patel said.

“We like to do that because we can then identify those specific lesions we want to go after. No cryosurgery, no destructive therapy, because we run the risk of burying those tumors under the scar. They may recur and make it more difficult to accurately stage them in the future,” he noted.

“I like to be more sophisticated in thinking about our approach to the outcomes of these individual lesions,” he said. When it comes to excising lesions that have been biopsied and show invasive SCC, “disc excision may be a more cost-effective way to treat many low-risk SCCs,” he noted. In any case, “removal with clear surgical margins is key.”

Primary tumors with such low-risk attributes as diameter under a centimeter and thickness under 2 mm; well-defined borders; location on the trunk, neck, or extremities; well-differentiated histology; and lack of perineural invasion can all be considered for a disc technique, especially if the patient is immunocompetent without background chronic inflammation or a history of prior radiation therapy.

Staging SCCs, said Dr. Patel, is where things really get tricky. Older staging systems for SCC “led us to overtreat nonaggressive disease and undertreat aggressive disease. I think we have the responsibility to lead the charge to having a more sophisticated approach.” For example, patients whose tumors were staged T2 in the American Joint Commission on Cancer (AJCC) 7 classification system were most likely to have poor outcomes – in part because so few tumors were staged higher – which meant AJCC 7 didn’t provide adequate differentiation for useful risk prognostication.

A group of researchers at the Brigham and Women’s Hospital (BWH), Boston, “came up with a better system to better differentiate those T2 tumors into a high-risk and a low-risk subtype,” according to Dr. Patel.

With use of validated risk factors, the investigators applied a long list of risk factors to 2,000 tumors to see which risk factors, taken individually, were really contributing to poor outcomes. Eventually, four risk factors that made the most difference were identified: size greater than 2 cm, poor tumor differentiation, perineural invasion greater than 0.1 mm in diameter, and tumor invasion beyond subcutaneous fat. “I really want to highlight the size portion of those risk factors,” said Dr. Patel. “Something I’d like you to do in your clinical practice is to measure and document the size of the lesion. … That really, clearly helps” with risk prognostication.

These four factors were then used to break out a T2a stage for tumors with one risk factor and a T2b stage for tumors with two or three risk factors. Tumors with no risk factors are stage T1, and those with all four risk factors are stage T3. In situ SCC is T0.

Applying this new staging system to a 2,000-patient cohort with SCC yielded clear separation in outcomes including recurrence, nodal metastasis, disease-specific death, and overall survival between patients with the T2a and T2b tumors (P less than .001 for all; J Clin Oncol. 2014 Feb 1;32[4]:327-34).

While AJCC 8 is “significantly better” than AJCC 7 in its incorporation of meaningful risk factors into the SCC staging system, “it still underperforms in comparison” with the BWH staging system using the 2000 patient cohort, he said. Recent work has shown the BWH classification system to have superior specificity and positive predictive value in detecting nodal metastasis and disease-specific death in higher-grade tumors. But both BWH and AJCC 8 need further refinement.

“So what are the staging pearls to take home?” Dr. Patel asked. “First, utilize a staging system.” “Staging of SCC utilizing should be done routinely. Most data seems to suggest that the BWH system appears to outperform AJCC 8, and it is what we currently use routinely at GW,” he said.

Patients who are T1 by BWH criteria, with no risk factors, are at low or even no risk, he noted. He pointed out that of the nearly 1,400 patients who met T1 criteria, there were just eight local recurrences, one nodal metastasis, and no distant metastases or deaths. Knowing this should guide physicians on a treatment path that will reduce costs and provide patients with peace of mind, he said.

In the BWH schema, T2a patients fared almost as well, with a 2% risk of nodal metastasis and an overall 1% risk of disease-specific death. “T2a disease is low risk, in my mind. Most of these patients will go on to do well,” he said.

By contrast, “there may be a number of tumors that you are missing” that are candidates for close follow-up if the BWH criteria are not being used, said Dr. Patel. These are the T2b tumors. “For those patients, we want to aggressively follow them and think about a more aggressive management plan.”

The bottom line is that BWH T2b and T3 tumors are both high risk, and management needs to acknowledge this, he said. The current protocol in our cutaneous oncology program includes using routine radiologic nodal staging in patients with BWH stage 2b and above SCCs and considering sentinel lymph node biopsy for certain individuals.

For patients with BWH T2b and T3 tumors, dermatologists should give consideration to tertiary care or cancer center referrals so they have access to the full spectrum of diagnostic and therapeutic modalities and the opportunity to participate in clinical trials, Dr. Patel said.

Dr. Patel reported that he is a speaker for Regeneron/Sanofi and a cofounder of the Skin Cancer Outcomes (SCOUT) consortium.

This article was updated 2/9/2019

[email protected]

ORLANDO – When caring for individuals with sun-damaged skin, dermatologists need comfort with the full spectrum of photo-related skin disease. From assessment and treatment of actinic keratoses (AKs) and field cancerization, to long-term follow-up of cutaneous squamous cell carcinomas (SCCs), appropriate treatment and staging can improve patient quality of life and reduce health care costs, Vishal Patel, MD, said at the Orlando Dermatology Aesthetic and Clinical Conference.

Kari Oakes/MDedge News

“Actinic keratosis/squamous cell carcinoma in situ is not a disease; it’s a symptom of cutaneous carcinogenesis or field cancerization,” said Dr. Patel, director of cutaneous oncology at George Washington University Cancer Center, Washington. On the other hand, he added, “field disease can be a marker for invasive squamous cell carcinoma risk, and it requires field treatment.” Treatment that reduces field disease is primary prevention because it decreases the formation of invasive SCC, he noted.

“But this level of disease – AKs and SCC in situ – doesn’t kill people,” he emphasized. “I want to leave you with an ability to stage this disease,” said Dr. Patel, noting that SCC mortality may eventually surpass melanoma mortality as deaths from the latter decline and numbers of older Americans with high ultraviolet light exposure and other risk factors climb.

While the majority of AKs regress within 5 years, he looks at the total burden of AKs as a marker for field cancerization “because having less than five in situ or actinic lesions puts you at less than a 1% risk of squamous cell carcinoma formation. Having more than 20 increases that risk 20-fold to 20%,” he said. “That’s the way we need to start thinking about this: Is this a disease – or a symptom?”

Rather than thinking of each AK or SCC in situ as a separate disease event, “the disease we need to be focusing on and treating is field cancerization,” he continued. Within this context, “we should not be thinking that … we need to be aggressive in our management,” which is what results in high costs.

“The reality is that this is a big quality of life issue for our patients. So what do we do?” Field treatment is appropriate for field disease, he said. Dr. Patel said that at GW only field treatment is used; destructive treatment for AKs and SCC in situ is not used. In the absence of patient and lesion characteristics that elevate risk,“surgery is really not the standard of care for in situ lesions for us,” he commented.

“We start by discerning the field disease from the invasive disease” with an initial round of field treatment and, if needed, adjunctive oral chemoprophylaxis. “We lather, rinse, and repeat” the field therapy, continuously if needed, Dr. Patel said.

“We like to do that because we can then identify those specific lesions we want to go after. No cryosurgery, no destructive therapy, because we run the risk of burying those tumors under the scar. They may recur and make it more difficult to accurately stage them in the future,” he noted.

“I like to be more sophisticated in thinking about our approach to the outcomes of these individual lesions,” he said. When it comes to excising lesions that have been biopsied and show invasive SCC, “disc excision may be a more cost-effective way to treat many low-risk SCCs,” he noted. In any case, “removal with clear surgical margins is key.”

Primary tumors with such low-risk attributes as diameter under a centimeter and thickness under 2 mm; well-defined borders; location on the trunk, neck, or extremities; well-differentiated histology; and lack of perineural invasion can all be considered for a disc technique, especially if the patient is immunocompetent without background chronic inflammation or a history of prior radiation therapy.

Staging SCCs, said Dr. Patel, is where things really get tricky. Older staging systems for SCC “led us to overtreat nonaggressive disease and undertreat aggressive disease. I think we have the responsibility to lead the charge to having a more sophisticated approach.” For example, patients whose tumors were staged T2 in the American Joint Commission on Cancer (AJCC) 7 classification system were most likely to have poor outcomes – in part because so few tumors were staged higher – which meant AJCC 7 didn’t provide adequate differentiation for useful risk prognostication.

A group of researchers at the Brigham and Women’s Hospital (BWH), Boston, “came up with a better system to better differentiate those T2 tumors into a high-risk and a low-risk subtype,” according to Dr. Patel.

With use of validated risk factors, the investigators applied a long list of risk factors to 2,000 tumors to see which risk factors, taken individually, were really contributing to poor outcomes. Eventually, four risk factors that made the most difference were identified: size greater than 2 cm, poor tumor differentiation, perineural invasion greater than 0.1 mm in diameter, and tumor invasion beyond subcutaneous fat. “I really want to highlight the size portion of those risk factors,” said Dr. Patel. “Something I’d like you to do in your clinical practice is to measure and document the size of the lesion. … That really, clearly helps” with risk prognostication.

These four factors were then used to break out a T2a stage for tumors with one risk factor and a T2b stage for tumors with two or three risk factors. Tumors with no risk factors are stage T1, and those with all four risk factors are stage T3. In situ SCC is T0.

Applying this new staging system to a 2,000-patient cohort with SCC yielded clear separation in outcomes including recurrence, nodal metastasis, disease-specific death, and overall survival between patients with the T2a and T2b tumors (P less than .001 for all; J Clin Oncol. 2014 Feb 1;32[4]:327-34).

While AJCC 8 is “significantly better” than AJCC 7 in its incorporation of meaningful risk factors into the SCC staging system, “it still underperforms in comparison” with the BWH staging system using the 2000 patient cohort, he said. Recent work has shown the BWH classification system to have superior specificity and positive predictive value in detecting nodal metastasis and disease-specific death in higher-grade tumors. But both BWH and AJCC 8 need further refinement.

“So what are the staging pearls to take home?” Dr. Patel asked. “First, utilize a staging system.” “Staging of SCC utilizing should be done routinely. Most data seems to suggest that the BWH system appears to outperform AJCC 8, and it is what we currently use routinely at GW,” he said.

Patients who are T1 by BWH criteria, with no risk factors, are at low or even no risk, he noted. He pointed out that of the nearly 1,400 patients who met T1 criteria, there were just eight local recurrences, one nodal metastasis, and no distant metastases or deaths. Knowing this should guide physicians on a treatment path that will reduce costs and provide patients with peace of mind, he said.

In the BWH schema, T2a patients fared almost as well, with a 2% risk of nodal metastasis and an overall 1% risk of disease-specific death. “T2a disease is low risk, in my mind. Most of these patients will go on to do well,” he said.

By contrast, “there may be a number of tumors that you are missing” that are candidates for close follow-up if the BWH criteria are not being used, said Dr. Patel. These are the T2b tumors. “For those patients, we want to aggressively follow them and think about a more aggressive management plan.”

The bottom line is that BWH T2b and T3 tumors are both high risk, and management needs to acknowledge this, he said. The current protocol in our cutaneous oncology program includes using routine radiologic nodal staging in patients with BWH stage 2b and above SCCs and considering sentinel lymph node biopsy for certain individuals.

For patients with BWH T2b and T3 tumors, dermatologists should give consideration to tertiary care or cancer center referrals so they have access to the full spectrum of diagnostic and therapeutic modalities and the opportunity to participate in clinical trials, Dr. Patel said.

Dr. Patel reported that he is a speaker for Regeneron/Sanofi and a cofounder of the Skin Cancer Outcomes (SCOUT) consortium.

This article was updated 2/9/2019

[email protected]

ORLANDO – When caring for individuals with sun-damaged skin, dermatologists need comfort with the full spectrum of photo-related skin disease. From assessment and treatment of actinic keratoses (AKs) and field cancerization, to long-term follow-up of cutaneous squamous cell carcinomas (SCCs), appropriate treatment and staging can improve patient quality of life and reduce health care costs, Vishal Patel, MD, said at the Orlando Dermatology Aesthetic and Clinical Conference.

Kari Oakes/MDedge News

“Actinic keratosis/squamous cell carcinoma in situ is not a disease; it’s a symptom of cutaneous carcinogenesis or field cancerization,” said Dr. Patel, director of cutaneous oncology at George Washington University Cancer Center, Washington. On the other hand, he added, “field disease can be a marker for invasive squamous cell carcinoma risk, and it requires field treatment.” Treatment that reduces field disease is primary prevention because it decreases the formation of invasive SCC, he noted.

“But this level of disease – AKs and SCC in situ – doesn’t kill people,” he emphasized. “I want to leave you with an ability to stage this disease,” said Dr. Patel, noting that SCC mortality may eventually surpass melanoma mortality as deaths from the latter decline and numbers of older Americans with high ultraviolet light exposure and other risk factors climb.

While the majority of AKs regress within 5 years, he looks at the total burden of AKs as a marker for field cancerization “because having less than five in situ or actinic lesions puts you at less than a 1% risk of squamous cell carcinoma formation. Having more than 20 increases that risk 20-fold to 20%,” he said. “That’s the way we need to start thinking about this: Is this a disease – or a symptom?”

Rather than thinking of each AK or SCC in situ as a separate disease event, “the disease we need to be focusing on and treating is field cancerization,” he continued. Within this context, “we should not be thinking that … we need to be aggressive in our management,” which is what results in high costs.

“The reality is that this is a big quality of life issue for our patients. So what do we do?” Field treatment is appropriate for field disease, he said. Dr. Patel said that at GW only field treatment is used; destructive treatment for AKs and SCC in situ is not used. In the absence of patient and lesion characteristics that elevate risk,“surgery is really not the standard of care for in situ lesions for us,” he commented.

“We start by discerning the field disease from the invasive disease” with an initial round of field treatment and, if needed, adjunctive oral chemoprophylaxis. “We lather, rinse, and repeat” the field therapy, continuously if needed, Dr. Patel said.

“We like to do that because we can then identify those specific lesions we want to go after. No cryosurgery, no destructive therapy, because we run the risk of burying those tumors under the scar. They may recur and make it more difficult to accurately stage them in the future,” he noted.

“I like to be more sophisticated in thinking about our approach to the outcomes of these individual lesions,” he said. When it comes to excising lesions that have been biopsied and show invasive SCC, “disc excision may be a more cost-effective way to treat many low-risk SCCs,” he noted. In any case, “removal with clear surgical margins is key.”

Primary tumors with such low-risk attributes as diameter under a centimeter and thickness under 2 mm; well-defined borders; location on the trunk, neck, or extremities; well-differentiated histology; and lack of perineural invasion can all be considered for a disc technique, especially if the patient is immunocompetent without background chronic inflammation or a history of prior radiation therapy.

Staging SCCs, said Dr. Patel, is where things really get tricky. Older staging systems for SCC “led us to overtreat nonaggressive disease and undertreat aggressive disease. I think we have the responsibility to lead the charge to having a more sophisticated approach.” For example, patients whose tumors were staged T2 in the American Joint Commission on Cancer (AJCC) 7 classification system were most likely to have poor outcomes – in part because so few tumors were staged higher – which meant AJCC 7 didn’t provide adequate differentiation for useful risk prognostication.

A group of researchers at the Brigham and Women’s Hospital (BWH), Boston, “came up with a better system to better differentiate those T2 tumors into a high-risk and a low-risk subtype,” according to Dr. Patel.

With use of validated risk factors, the investigators applied a long list of risk factors to 2,000 tumors to see which risk factors, taken individually, were really contributing to poor outcomes. Eventually, four risk factors that made the most difference were identified: size greater than 2 cm, poor tumor differentiation, perineural invasion greater than 0.1 mm in diameter, and tumor invasion beyond subcutaneous fat. “I really want to highlight the size portion of those risk factors,” said Dr. Patel. “Something I’d like you to do in your clinical practice is to measure and document the size of the lesion. … That really, clearly helps” with risk prognostication.

These four factors were then used to break out a T2a stage for tumors with one risk factor and a T2b stage for tumors with two or three risk factors. Tumors with no risk factors are stage T1, and those with all four risk factors are stage T3. In situ SCC is T0.

Applying this new staging system to a 2,000-patient cohort with SCC yielded clear separation in outcomes including recurrence, nodal metastasis, disease-specific death, and overall survival between patients with the T2a and T2b tumors (P less than .001 for all; J Clin Oncol. 2014 Feb 1;32[4]:327-34).

While AJCC 8 is “significantly better” than AJCC 7 in its incorporation of meaningful risk factors into the SCC staging system, “it still underperforms in comparison” with the BWH staging system using the 2000 patient cohort, he said. Recent work has shown the BWH classification system to have superior specificity and positive predictive value in detecting nodal metastasis and disease-specific death in higher-grade tumors. But both BWH and AJCC 8 need further refinement.

“So what are the staging pearls to take home?” Dr. Patel asked. “First, utilize a staging system.” “Staging of SCC utilizing should be done routinely. Most data seems to suggest that the BWH system appears to outperform AJCC 8, and it is what we currently use routinely at GW,” he said.

Patients who are T1 by BWH criteria, with no risk factors, are at low or even no risk, he noted. He pointed out that of the nearly 1,400 patients who met T1 criteria, there were just eight local recurrences, one nodal metastasis, and no distant metastases or deaths. Knowing this should guide physicians on a treatment path that will reduce costs and provide patients with peace of mind, he said.

In the BWH schema, T2a patients fared almost as well, with a 2% risk of nodal metastasis and an overall 1% risk of disease-specific death. “T2a disease is low risk, in my mind. Most of these patients will go on to do well,” he said.

By contrast, “there may be a number of tumors that you are missing” that are candidates for close follow-up if the BWH criteria are not being used, said Dr. Patel. These are the T2b tumors. “For those patients, we want to aggressively follow them and think about a more aggressive management plan.”

The bottom line is that BWH T2b and T3 tumors are both high risk, and management needs to acknowledge this, he said. The current protocol in our cutaneous oncology program includes using routine radiologic nodal staging in patients with BWH stage 2b and above SCCs and considering sentinel lymph node biopsy for certain individuals.

For patients with BWH T2b and T3 tumors, dermatologists should give consideration to tertiary care or cancer center referrals so they have access to the full spectrum of diagnostic and therapeutic modalities and the opportunity to participate in clinical trials, Dr. Patel said.

Dr. Patel reported that he is a speaker for Regeneron/Sanofi and a cofounder of the Skin Cancer Outcomes (SCOUT) consortium.

This article was updated 2/9/2019

[email protected]

LA JOLLA, CALIF. – A retrospective study suggests patients with mycosis fungoides (MF) have an increased risk of developing hematologic and solid tumor malignancies.

Vidyard Video

Researchers found the risk of second malignancy was highest among MF patients aged 30 to 50 years and patients who had tumor stage or advanced stage MF.

The increased risk was present during the entire period after MF diagnosis, but it was greatest in the first 6 months after diagnosis and roughly a dozen years later.

Amrita Goyal, MD, of the University of Minnesota in Minneapolis, and her colleagues presented these findings at the annual T-cell Lymphoma Forum.

The researchers first assessed the risk of second malignancy in 172 MF patients treated at UMN from 2005 to 2017, comparing this cohort to a control group of 172 patients with seborrheic dermatitis.

Second malignancies occurred in 24 MF patients and three controls, which was a significant difference (P = .0045). The most common second malignancies among the MF patients were melanoma (n = 4), prostate cancer (n = 3), and renal cell carcinoma (n = 3).

Further analyses revealed that MF patients were more likely to develop a second malignancy if they had tumor stage disease (P = .0024) or stage IIB or higher disease (P = .03).

To corroborate and expand upon these results, Dr. Goyal and her colleagues analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database on patients diagnosed with MF from 2000 to 2014.

Among the 6,196 MF patients in this cohort, there were 514 second cancers.

“We found that MF patients were, overall, 10 times more likely to develop a second malignancy [compared with the general population],” Dr. Goyal said.

Specifically, the standardized incidence ratio was 10.15 for all malignancies, 7.33 for solid tumors, and 41.72 for hematologic malignancies.

Standardized incidence ratios for individual malignancies were:

• 69.8 for Hodgkin lymphoma.
• 46.5 for non-Hodgkin lymphoma.
• 8.6 for leukemia.
• 7.2 for melanoma.
• 6.2 for lung cancer.
• 7.9 for female breast cancer.
• 5.2 for colon cancer.
• 4.1 for prostate cancer.
• 3.9 for renal cell carcinoma.
• 3.8 for pancreatic cancer.
• 3.6 for bladder cancer.

“We found there is an increased risk [of second malignancy] during the first 6 months after diagnosis of MF, likely related to patients being in contact with the health care system more,” Dr. Goyal said. “Over time, patients have about a 7- to 10-fold increased risk over baseline, until they reach about 12 or 13 years after diagnosis, at which point, there is an increase in risk.”

The researchers found the greatest risk of second malignancy was among patients aged 30 to 50 years, although there was an increased risk for all age groups.

“The reason we think patients are experiencing an increased risk of cancers is we believe this may be due to immune suppression secondary to the mycosis fungoides, although further studies need to be performed to determine if that’s accurate,” Dr. Goyal said.

To that end, she and her colleagues are planning gene expression studies in patients from the UMN cohort. The researchers plan to examine genes involved in the pathogenesis of second malignancies and MF progression in tissue samples from 36 MF patients, 12 who developed second malignancies and 24 who did not.

The current research was funded by the American Society of Hematology. Dr. Goyal reported having no relevant financial disclosures. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – A retrospective study suggests patients with mycosis fungoides (MF) have an increased risk of developing hematologic and solid tumor malignancies.

Vidyard Video

Researchers found the risk of second malignancy was highest among MF patients aged 30 to 50 years and patients who had tumor stage or advanced stage MF.

The increased risk was present during the entire period after MF diagnosis, but it was greatest in the first 6 months after diagnosis and roughly a dozen years later.

Amrita Goyal, MD, of the University of Minnesota in Minneapolis, and her colleagues presented these findings at the annual T-cell Lymphoma Forum.

The researchers first assessed the risk of second malignancy in 172 MF patients treated at UMN from 2005 to 2017, comparing this cohort to a control group of 172 patients with seborrheic dermatitis.

Second malignancies occurred in 24 MF patients and three controls, which was a significant difference (P = .0045). The most common second malignancies among the MF patients were melanoma (n = 4), prostate cancer (n = 3), and renal cell carcinoma (n = 3).

Further analyses revealed that MF patients were more likely to develop a second malignancy if they had tumor stage disease (P = .0024) or stage IIB or higher disease (P = .03).

To corroborate and expand upon these results, Dr. Goyal and her colleagues analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database on patients diagnosed with MF from 2000 to 2014.

Among the 6,196 MF patients in this cohort, there were 514 second cancers.

“We found that MF patients were, overall, 10 times more likely to develop a second malignancy [compared with the general population],” Dr. Goyal said.

Specifically, the standardized incidence ratio was 10.15 for all malignancies, 7.33 for solid tumors, and 41.72 for hematologic malignancies.

Standardized incidence ratios for individual malignancies were:

• 69.8 for Hodgkin lymphoma.
• 46.5 for non-Hodgkin lymphoma.
• 8.6 for leukemia.
• 7.2 for melanoma.
• 6.2 for lung cancer.
• 7.9 for female breast cancer.
• 5.2 for colon cancer.
• 4.1 for prostate cancer.
• 3.9 for renal cell carcinoma.
• 3.8 for pancreatic cancer.
• 3.6 for bladder cancer.

“We found there is an increased risk [of second malignancy] during the first 6 months after diagnosis of MF, likely related to patients being in contact with the health care system more,” Dr. Goyal said. “Over time, patients have about a 7- to 10-fold increased risk over baseline, until they reach about 12 or 13 years after diagnosis, at which point, there is an increase in risk.”

The researchers found the greatest risk of second malignancy was among patients aged 30 to 50 years, although there was an increased risk for all age groups.

“The reason we think patients are experiencing an increased risk of cancers is we believe this may be due to immune suppression secondary to the mycosis fungoides, although further studies need to be performed to determine if that’s accurate,” Dr. Goyal said.

To that end, she and her colleagues are planning gene expression studies in patients from the UMN cohort. The researchers plan to examine genes involved in the pathogenesis of second malignancies and MF progression in tissue samples from 36 MF patients, 12 who developed second malignancies and 24 who did not.

The current research was funded by the American Society of Hematology. Dr. Goyal reported having no relevant financial disclosures. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – A retrospective study suggests patients with mycosis fungoides (MF) have an increased risk of developing hematologic and solid tumor malignancies.

Vidyard Video

Researchers found the risk of second malignancy was highest among MF patients aged 30 to 50 years and patients who had tumor stage or advanced stage MF.

The increased risk was present during the entire period after MF diagnosis, but it was greatest in the first 6 months after diagnosis and roughly a dozen years later.

Amrita Goyal, MD, of the University of Minnesota in Minneapolis, and her colleagues presented these findings at the annual T-cell Lymphoma Forum.

The researchers first assessed the risk of second malignancy in 172 MF patients treated at UMN from 2005 to 2017, comparing this cohort to a control group of 172 patients with seborrheic dermatitis.

Second malignancies occurred in 24 MF patients and three controls, which was a significant difference (P = .0045). The most common second malignancies among the MF patients were melanoma (n = 4), prostate cancer (n = 3), and renal cell carcinoma (n = 3).

Further analyses revealed that MF patients were more likely to develop a second malignancy if they had tumor stage disease (P = .0024) or stage IIB or higher disease (P = .03).

To corroborate and expand upon these results, Dr. Goyal and her colleagues analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database on patients diagnosed with MF from 2000 to 2014.

Among the 6,196 MF patients in this cohort, there were 514 second cancers.

“We found that MF patients were, overall, 10 times more likely to develop a second malignancy [compared with the general population],” Dr. Goyal said.

Specifically, the standardized incidence ratio was 10.15 for all malignancies, 7.33 for solid tumors, and 41.72 for hematologic malignancies.

Standardized incidence ratios for individual malignancies were:

• 69.8 for Hodgkin lymphoma.
• 46.5 for non-Hodgkin lymphoma.
• 8.6 for leukemia.
• 7.2 for melanoma.
• 6.2 for lung cancer.
• 7.9 for female breast cancer.
• 5.2 for colon cancer.
• 4.1 for prostate cancer.
• 3.9 for renal cell carcinoma.
• 3.8 for pancreatic cancer.
• 3.6 for bladder cancer.

“We found there is an increased risk [of second malignancy] during the first 6 months after diagnosis of MF, likely related to patients being in contact with the health care system more,” Dr. Goyal said. “Over time, patients have about a 7- to 10-fold increased risk over baseline, until they reach about 12 or 13 years after diagnosis, at which point, there is an increase in risk.”

The researchers found the greatest risk of second malignancy was among patients aged 30 to 50 years, although there was an increased risk for all age groups.

“The reason we think patients are experiencing an increased risk of cancers is we believe this may be due to immune suppression secondary to the mycosis fungoides, although further studies need to be performed to determine if that’s accurate,” Dr. Goyal said.

To that end, she and her colleagues are planning gene expression studies in patients from the UMN cohort. The researchers plan to examine genes involved in the pathogenesis of second malignancies and MF progression in tissue samples from 36 MF patients, 12 who developed second malignancies and 24 who did not.

The current research was funded by the American Society of Hematology. Dr. Goyal reported having no relevant financial disclosures. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]