IN BRIEF

Merkel Cell Carcinoma of the Hand Alexis L. Parcells, MD, Edward S. Lee, MD, Earl J. Fleegler, MD

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(MCC) is a rare, aggressive neuroendocrine malignancy arising from the dermoepidermal junction of the skin. First described as trabecular carcinoma by Toker1 in 1972, it is currently the most malignant of all skin tumors and has an exceptionally high rate of recurrence and mortality. The incidence of MCC has tripled since 1986, likely owing to our aging population and increasing diagnostic sensitivity. However, MCC remains relatively uncommon, with approximately 1,500 newly diagnosed cases annually, compared with other skin cancers of the hand. The Surveillance, Epidemiology, and End Result database (SEER) was established to identify all patients with MCC of the skin from 1986 to 2009.2 Of the 5,211 cases reported, the mean age of patients at diagnosis was 70 years, and analysis revealed that the groups at highest risk are Caucasian males.3 The SEER database found 20% of MCC tumors originated in the hand and upper extremity.4 MCC has a predilection for sun-exposed areas, and in a study of 195 cases, the tumor was found to arise in ultraviolet-exposed regions in 81% of cases, with 98% occurring on fair-skinned individuals.5 In addition to ultraviolet exposure, a nonenveloped, doublestranded DNA polyomavirus has been causally linked to the development of MCC. In 2008, Feng et al6 identified its presence in 8 of 10 MCC tumors. The prevalence of Merkel cell polyomavirus in MCC does not differ among countries and regions, which indicates that the virus is widespread and its genome is stable. Patients with MCC typically present with a rapidly growing, painless, firm purple nodule on sun-exposed ERKEL CELL CARCINOMA

From the Division of Plastic Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ. Received for publication February 3, 2014; accepted in revised form February 14, 2014. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Corresponding author: Alexis Lanteri Parcells, MD, Division of Plastic Surgery, Department of Surgery, Rutgers New Jersey Medical School, 140 Bergen Street, Suite E1620, Newark, NJ 07103; e-mail: [email protected]. 0363-5023/14/---0001$36.00/0 http://dx.doi.org/10.1016/j.jhsa.2014.02.014

skin (Fig. 1). The early course of MCC is symptomfree and the lesion may resemble basal cell carcinoma clinically and histologically, which often delays diagnosis. Therefore, a high index of suspicion is required, because most of these tumors are rapidly expanding. Initial patient evaluation should include a complete history and physical examination of the skin and regional lymph nodes, with further workup of any abnormalities detected. Confirmation of diagnosis is based on tissue biopsy revealing pathologic histology and immunohistochemistry. Microscopically, the tumor is composed of small cells with round, uniform, acytoplasmic features. Vascular invasion, tumor necrosis, perineural invasion, and high mitotic rates can be seen. Immunohistochemical staining for cytokeratin 20 is pathognomonic in differentiating MCC from histologically similar tumors such as small cell lung carcinoma, melanoma, neuroectodermal tumor, and cutaneous lymphoma (Fig. 2).8 The American Joint Committee on Cancer supports the tumor (T) node (N) metastasis (M) staging system for MCC. Stage I consists of primary tumors 2 cm or less without evidence of regional lymph node involvement. Stage II includes primary tumors greater than 2 cm (T2 or T3) or a primary tumor with invasion into bone, muscle, fascia, or cartilage (T4). Stage III is defined as any primary tumor with regional lymph node disease, and stage IV is metastasis beyond the regional lymph nodes. TREATMENT Most research regarding the treatment of MCC is from small case series, which are subject to many confounding factors. Therefore, the management of MCC must be individualized based on tumor location and the presence of lymph node involvement. Current National Comprehensive Care Network guidelines advocate surgery as the mainstay of therapy for localized disease and radiotherapy for local and regional spread.8 The role of chemotherapy for systemic disease has not been studied systematically. Wide local excision Recommendations regarding the optimal minimum width and depth of excision differ among various retrospective

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Sentinel lymph node biopsy The most important prognostic factor for survival and development of metastasis in patients with MCC is the presence of lymph node involvement.13,14 MCC spreads to regional lymph nodes, and sentinel lymph node biopsy is important for the diagnosis and treatment of localized tumors. For patients with regional node involvement, definitive treatment with radiation therapy is indicated. Radiation therapy MCC is a radiosensitive tumor, and adjuvant radiotherapy is associated with markedly reduced risk of local recurrence.15 National Comprehensive Care Network guidelines recommend a total radiation dose of 50 to 55 Gy in patients with clinically negative margins, 56 to 60 Gy for those with microscopically positive margins, and 60 to 66 Gy for patients with grossly positive margins or an unresectable lesion.8 In patients with regional node metastasis, there is no consensus regarding complete lymph node dissection versus adjuvant radiotherapy, or the use of both.

FIGURE 1: A 60-year-old Caucasian man with MCC on the dorsum of the right hand.

Chemotherapy To date, chemotherapy has no standardized role in the treatment of local or regional MCC. Its use has been described in patients with metastatic disease, and cytostatic drug regimens used in MCC are adapted from those for small cell carcinoma of the lung. However, no randomized trials evaluating the efficacy of adjuvant chemotherapy have been conducted in patients with MCC. SURVIVAL MCC recurrence rates range from 55% to 79%.7 Agelli and Clegg4 reported that patients diagnosed with localized, regional, and metastatic MCC have a 5-year relative survival rate of 75%, 59%, and 25%. Local recurrences usually occur within 1 year of initial therapy.5 The SEER database found that patients with MCC of the hand and upper extremity had a significantly higher survival rate than MCC at other anatomic sites. This is thought to result from earlier diagnosis while tumors were still confined to the dermis. However, no difference in overall mean size was found between hand and upper extremity tumors and other areas, which suggests that different factors contribute to this observed survival difference. Future basic research is important to further the understanding of the pathophysiology of MCC and

FIGURE 2: CK20 stain exhibits paranuclear globules characteristic of MCC.

reports; this has not yet been studied systematically. In addition, no definitive data suggest that extremely wide margins improve overall survival.9 Mohs microsurgery relapse rates have been comparable to wide local excision in small case series only.10 For a tumor on the dorsum of the hand, Dancey et al11 recommended wide local excision with 2- to 3-cm margins down to the underlying fascia. For a tumor localized to a digit with no metastatic disease, ray resection is recommended.12 J Hand Surg Am.

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introduce novel therapeutic approaches for management to improve patient outcomes. Because MCC has a high propensity for recurrence, patients benefit from frequent follow-up and combined modality therapy when feasible.

7. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: Merkel cell carcinoma. Version 1. http://www.nccn.org/ professionals/physician_gls/fguidelines.asp. Accessed January 2014. 8. Goessling W, McKee P, Mayer R. Merkel cell carcinoma. J Clin Oncol. 2002;20(2):588e598. 9. Nghiem P, James N. Merkel cell carcinoma. In: Wolff K, Goldsmith LA, Katz SI, et al., eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGraw-Hill; 2008:1087e1094. 10. O’Connor WJ, Roenigk KR, Brodland DG. Merkel cell carcinoma: comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg. 1997;23(10):929e933. 11. Dancey AL, Rayatt SS, Soon C, et al. Merkel cell carcinoma: a report of 34 cases and literature review. J Plast Reconstr Aesth Surg. 2006;59(12):1294e1299. 12. Mikolyzk DK, Bednar MS. Merkel cell tumor of the hand: report of two cases. J Hand Surg Am. 2008;33(3):404e406. 13. Bichakjian CK, Lowe L, Lao CD, et al. Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer. 2007;110(1):1e12. 14. Gupta SG, Want LC, Penas PF, et al. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: the Dana-Faber experience and meta-analysis of the literature. Arch Dermatol. 2006;142(6):685e690. 15. Venes M, Pere L, McCourt J, et al. Merkel cell carcinoma: improved outcome with adjuvant radiotherapy. ANZ J Surg. 2005;75(5): 275e281.

REFERENCES 1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol. 1972;105(1):107e110. 2. National Cancer Institute. Surveillance, epidemiology and end results program. Available at: http://seer.cancer.gov. Accessed January 2014. 3. Albores-Saavedra J, Batich K, Chable-Montero F, et al. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 2010;37(1):20e27. 4. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol. 2003;49(4): 832e841. 5. Health M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol. 2008;58(3):375e381. 6. Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866): 1096e1100.

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