LETTERS AND COMMUNICATIONS Polydactylous Bowen's Disease in an Immunocompromised Patient: Resolution of All Lesions After Mohs Surgery on a Single Lesion The patient is a 21-year-old man with congenital renal dysplasia, status postrenal transplant in 1998, who has been immunosuppressed since that time. At the age of 20, he developed numerous dark lesions around all of the nail folds on his hands (Figure 1A). Multiple biopsies showed changes consistent with Bowen disease. Pathology demonstrated fullthickness keratinocyte atypia which supported a diagnosis of squamous cell carcinoma in situ and argued against a verruca vulgaris, which would not show that amount of keratinocyte atypia. He was treated with imiquimod cream, 5-fluorouracil cream, and then 3 rounds of photodynamic therapy with no response. It is important to note that full skin examination was performed and there was no evidence of any other verrucous lesions or condyloma (perianal or penile). He was subsequently lost to follow-up for 9 months because he was diagnosed with diffuse large B-cell lymphoma and underwent 4 cycles of chemotherapy over the course of 7 months. He has continued to have no evidence of disease since that time. He also has remained on the same doses of prednisone and tacrolimus, respectively, as his immunosuppressive
regimen. In early June of 2014, 2 months after his last cycle of chemotherapy, he presented with worsening periungual lesions. Biopsy of a tender lesion on his left fourth nail fold showed Bowen disease “at least”, extending to the base of the biopsy (Figure 1B,C). At that point, the patient was referred for Mohs excision of this one lesion. His tumor demonstrated clear margins after one stage and was repaired using a porcine xenograft. He returned for follow-up 1 month later and showed significant improvement in both texture and color of all his lesions (all nail folds), including the Mohstreated lesion. At that point, we decided to monitor the lesions with serial photographs over several months and finally performed a biopsy on a previously active lesion different from the Mohs site to confirm clearance 4 months after his Mohs procedure. Pathology showed no evidence of Bowen disease (Figure 2A,B). He continues to be doing well over 2 years after his Mohs procedure and has not developed any new lesions or any recurrent lesions and remains on the same doses of prednisone and tacrolimus.
Figure 1. Clinical and histological images of the periungual lesions. (A) Hyperpigmented thin plaques involving the proximal nail folds of multiple digits on both hands. (B) Clinical image of lesion on left fourth digit after being lost to followup. (C) Histology showing epidermal hyperplasia with abundant atypical keratinocytes and full-thickness atypica extending to the base of the biopsy. © 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1076-0512 Dermatol Surg 2017;0:1–3
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© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
LETTERS AND COMMUNICATIONS
Figure 2. Clinical images of both hands 4 months after Mohs to treat lesion on the left fourth digit. (A) Right hand. (B) Left hand.
Discussion Periungual squamous cell carcinoma (SCC) and squamous cell carcinoma in situ (SCCis) are uncommonly reported diagnoses in current medical literature. The first case of polydactylous Bowen’s disease (BD) of the fingernails was cited by Baran in 1987.1 As of 2003, the estimated incidence for SCC of the nail ranged from 3 cases in 250,000 hospital admissions to 14 cases in 50,000 dermatologic consultations. BD is present in 2/3 of patients with periungual tumors, whereas invasive SCC is present in the remaining 1/3 of patients.2 Diagnosis of periungual SCC and SCCis is often delayed because of the broad differential in clinical presentation which includes most commonly verruca vulgaris, longitudinal melanonychia, onychomycosis, eczema, and melanoma. Biopsy of SCC demonstrates acanthosis, marked hyperkeratosis, and thick columns of parakeratosis. BD may show epidermal involvement with atypical keratinocytes, disorderly maturation, mitoses at varying stages, and dyskeratotic cells. Greater than 90% of digital SCC lesions are human papilloma virus (HPV)-associated.2 Of the HPV subtypes, HPV16 is more commonly associated with periungual SCC and SCCis. Numerous treatments have been described for periungual BD including cryotherapy, topical 5-fluorouracil, imiquimod and photodynamic therapy, and radiotherapy, but Mohs surgery remains the gold standard for treatment. This report is the first to describe a case of polydactylous periungual BD showing resolution of all
2
lesions after Mohs surgery to only a single lesion. We considered periungual verruca as the principal alternative diagnosis, but 3 different biopsies read by 2 separate dermatopathologists confirmed a diagnosis of periungual BD given the degree of keratinocytic atypia, mitoses, and necrosis. There are several reports of this type of “distant bystander” or abscopal effect in patients with numerous cutaneous metastatic melanoma lesions that resolve after radiation therapy or even surgery to the primary lesion. There are a number of proposed mechanisms but most common is the hypothesis that tumor antigens are released due to radiation/surgery, which in turn mediates an antitumor response. In a case report, combined treatment with ipilimumab (immune response augmenter anti-CTLA4 antibody) and palliative stereotactic radiosurgery (SRS) to a brain metastasis resulted in intracranial disease control and resolution of nodal metastases. Serology testing following SRS revealed augmentation of the patient’s autoantibody titer against melanoma antigen A3 (MAGEA3) and a new response against the antigen cancer antigen PAS domain containing 1.3 Mouse studies have demonstrated the need for CD8 cells to produce this effect. Along similar lines, stereotactic body radiotherapy to a target lesion combined with IL2 was associated with a treatment response in nonradiated melanoma metastatic sites higher than predicted based on historic data regarding IL2 alone. Interestingly, a proof of principal trial was conducted at NYU and about one quarter of patients with metastatic solid tumors demonstrated an abscopal effect after treatment with radiation and granulocyte-monocyte-colony stimulating factor.4
DERMATOLOGIC SURGERY
© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
LETTERS AND COMMUNICATIONS
There are several reports of similar phenomena occurring during treatment of molluscum and warts. Immunotherapy using candida antigen can result in resolution of both treated and untreated warts. The proposed mechanism of action is the generation of HPV-specific mononuclear cells that mediate an attack against distant warts as well as the treated lesion. A recent report described a similar phenomenon after local hyperthermia was applied to a single wart and resulted in resolution of the treated wart but also of several other untreated lesions.5 Since periungual BD is known to be associated with distinct HPV subtypes, it is plausible that Mohs surgery to the single site elicited a local and distal immune reaction which allowed for the resolution of our patient’s lesions. Although gross and microscopic tumor was cleared, it is plausible that residual surrounding HPV served as the immunological target which led to this immune phenomenon. This underscores the importance of the immune response in combatting skin cancer and offers a potential therapeutic option in addressing similar types of polydactylous lesions of BD.
References 1. Baran RL, Gormley DE. Polydactylous Bowen’s disease of the nail. J Am Acad Dermatol 1987;17(2 Pt 1):201–4. 2. Alam M, Caldwell JB, Eliezri YD. Human papillomavirus-associated digital squamous cell carcinoma: literature review and report of 21 new cases. J Am Acad Dermatol 2003;48:385–93.
3. Stamell EF, Wolchok JD, Gnjatic S, Lee NY, et al. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys 2013;85:293–5. 4. Golden EB, Chhabra A, Chachoua A, Adams S, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-ofprinciple trial. Lancet Oncol 2015;16:795–803. 5. Hu L, Qi R, Hong Y, Huo W, et al. One stone, two birds: managing multiple common warts on hands and face by local hyperthermia. Dermatol Ther 2015;28:32–5.
Nikita S. Goel, MD Brody School of Medicine East Carolina University Greenville, North Carolina Rajat Varma, MD Department of Dermatology University of North Carolina School of Medicine Chapel Hill, North Carolina Daniel C. Zedek Coastal Carolina Pathology Wilmington, North Carolina Puneet S. Jolly, MD, PhD Department of Dermatology University of North Carolina School of Medicine Chapel Hill, North Carolina The authors have indicated no significant interest with commercial supporters.
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© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
regimen. In early June of 2014, 2 months after his last cycle of chemotherapy, he presented with worsening periungual lesions. Biopsy of a tender lesion on his left fourth nail fold showed Bowen disease “at least”, extending to the base of the biopsy (Figure 1B,C). At that point, the patient was referred for Mohs excision of this one lesion. His tumor demonstrated clear margins after one stage and was repaired using a porcine xenograft. He returned for follow-up 1 month later and showed significant improvement in both texture and color of all his lesions (all nail folds), including the Mohstreated lesion. At that point, we decided to monitor the lesions with serial photographs over several months and finally performed a biopsy on a previously active lesion different from the Mohs site to confirm clearance 4 months after his Mohs procedure. Pathology showed no evidence of Bowen disease (Figure 2A,B). He continues to be doing well over 2 years after his Mohs procedure and has not developed any new lesions or any recurrent lesions and remains on the same doses of prednisone and tacrolimus.
Figure 1. Clinical and histological images of the periungual lesions. (A) Hyperpigmented thin plaques involving the proximal nail folds of multiple digits on both hands. (B) Clinical image of lesion on left fourth digit after being lost to followup. (C) Histology showing epidermal hyperplasia with abundant atypical keratinocytes and full-thickness atypica extending to the base of the biopsy. © 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1076-0512 Dermatol Surg 2017;0:1–3
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·
1
© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
LETTERS AND COMMUNICATIONS
Figure 2. Clinical images of both hands 4 months after Mohs to treat lesion on the left fourth digit. (A) Right hand. (B) Left hand.
Discussion Periungual squamous cell carcinoma (SCC) and squamous cell carcinoma in situ (SCCis) are uncommonly reported diagnoses in current medical literature. The first case of polydactylous Bowen’s disease (BD) of the fingernails was cited by Baran in 1987.1 As of 2003, the estimated incidence for SCC of the nail ranged from 3 cases in 250,000 hospital admissions to 14 cases in 50,000 dermatologic consultations. BD is present in 2/3 of patients with periungual tumors, whereas invasive SCC is present in the remaining 1/3 of patients.2 Diagnosis of periungual SCC and SCCis is often delayed because of the broad differential in clinical presentation which includes most commonly verruca vulgaris, longitudinal melanonychia, onychomycosis, eczema, and melanoma. Biopsy of SCC demonstrates acanthosis, marked hyperkeratosis, and thick columns of parakeratosis. BD may show epidermal involvement with atypical keratinocytes, disorderly maturation, mitoses at varying stages, and dyskeratotic cells. Greater than 90% of digital SCC lesions are human papilloma virus (HPV)-associated.2 Of the HPV subtypes, HPV16 is more commonly associated with periungual SCC and SCCis. Numerous treatments have been described for periungual BD including cryotherapy, topical 5-fluorouracil, imiquimod and photodynamic therapy, and radiotherapy, but Mohs surgery remains the gold standard for treatment. This report is the first to describe a case of polydactylous periungual BD showing resolution of all
2
lesions after Mohs surgery to only a single lesion. We considered periungual verruca as the principal alternative diagnosis, but 3 different biopsies read by 2 separate dermatopathologists confirmed a diagnosis of periungual BD given the degree of keratinocytic atypia, mitoses, and necrosis. There are several reports of this type of “distant bystander” or abscopal effect in patients with numerous cutaneous metastatic melanoma lesions that resolve after radiation therapy or even surgery to the primary lesion. There are a number of proposed mechanisms but most common is the hypothesis that tumor antigens are released due to radiation/surgery, which in turn mediates an antitumor response. In a case report, combined treatment with ipilimumab (immune response augmenter anti-CTLA4 antibody) and palliative stereotactic radiosurgery (SRS) to a brain metastasis resulted in intracranial disease control and resolution of nodal metastases. Serology testing following SRS revealed augmentation of the patient’s autoantibody titer against melanoma antigen A3 (MAGEA3) and a new response against the antigen cancer antigen PAS domain containing 1.3 Mouse studies have demonstrated the need for CD8 cells to produce this effect. Along similar lines, stereotactic body radiotherapy to a target lesion combined with IL2 was associated with a treatment response in nonradiated melanoma metastatic sites higher than predicted based on historic data regarding IL2 alone. Interestingly, a proof of principal trial was conducted at NYU and about one quarter of patients with metastatic solid tumors demonstrated an abscopal effect after treatment with radiation and granulocyte-monocyte-colony stimulating factor.4
DERMATOLOGIC SURGERY
© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
LETTERS AND COMMUNICATIONS
There are several reports of similar phenomena occurring during treatment of molluscum and warts. Immunotherapy using candida antigen can result in resolution of both treated and untreated warts. The proposed mechanism of action is the generation of HPV-specific mononuclear cells that mediate an attack against distant warts as well as the treated lesion. A recent report described a similar phenomenon after local hyperthermia was applied to a single wart and resulted in resolution of the treated wart but also of several other untreated lesions.5 Since periungual BD is known to be associated with distinct HPV subtypes, it is plausible that Mohs surgery to the single site elicited a local and distal immune reaction which allowed for the resolution of our patient’s lesions. Although gross and microscopic tumor was cleared, it is plausible that residual surrounding HPV served as the immunological target which led to this immune phenomenon. This underscores the importance of the immune response in combatting skin cancer and offers a potential therapeutic option in addressing similar types of polydactylous lesions of BD.
References 1. Baran RL, Gormley DE. Polydactylous Bowen’s disease of the nail. J Am Acad Dermatol 1987;17(2 Pt 1):201–4. 2. Alam M, Caldwell JB, Eliezri YD. Human papillomavirus-associated digital squamous cell carcinoma: literature review and report of 21 new cases. J Am Acad Dermatol 2003;48:385–93.
3. Stamell EF, Wolchok JD, Gnjatic S, Lee NY, et al. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys 2013;85:293–5. 4. Golden EB, Chhabra A, Chachoua A, Adams S, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-ofprinciple trial. Lancet Oncol 2015;16:795–803. 5. Hu L, Qi R, Hong Y, Huo W, et al. One stone, two birds: managing multiple common warts on hands and face by local hyperthermia. Dermatol Ther 2015;28:32–5.
Nikita S. Goel, MD Brody School of Medicine East Carolina University Greenville, North Carolina Rajat Varma, MD Department of Dermatology University of North Carolina School of Medicine Chapel Hill, North Carolina Daniel C. Zedek Coastal Carolina Pathology Wilmington, North Carolina Puneet S. Jolly, MD, PhD Department of Dermatology University of North Carolina School of Medicine Chapel Hill, North Carolina The authors have indicated no significant interest with commercial supporters.
0:0:MONTH 2017
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© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
