Staging and treatment of Merkel cell carcinoma
- Patricia Tai, MB, BS, DABR, FRCR, FRCPC
Patricia Tai, MB, BS, DABR, FRCR, FRCPC
- Clinical Oncologist
- Clinical Professor
- University of Saskatchewan
- Canada Department of Radiation Oncology
- Allan Blair Cancer Center
- Section Editors
- Robert S Stern, MD
Robert S Stern, MD
- Section Editor — Nonmelanoma Skin Cancer
- Professor of Dermatology
- Harvard Medical School
- June K Robinson, MD
June K Robinson, MD
- Section Editor — Nonmelanoma Skin Cancer
- Professor of Clinical Dermatology
- Northwestern University Feinberg School of Medicine
- Michael B Atkins, MD
Michael B Atkins, MD
- Section Editor — Malignant Melanoma and Other Cutaneous Neoplasms; Cancer of the Kidney
- Deputy Director
- Georgetown Lombardi Comprehensive Cancer Center
Merkel cell carcinoma (MCC) of the skin is a rare, aggressive cutaneous malignancy that predominantly affects elderly Caucasians and has a propensity for local recurrence and regional lymph node metastases. Other terms used to describe this tumor include neuroendocrine or primary small cell carcinoma of the skin, trabecular cell carcinoma, and anaplastic cancer of the skin.
The staging and treatment of MCC are discussed here. The clinical features and initial diagnosis of MCC are reviewed separately. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)
TNM STAGING SYSTEM
The 2010 tumor (T) node (N) metastasis (M) staging system provides important information for both patient management and prognosis. The TNM system is recommended by both the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC) (table 1) .
●Stage I – Primary tumors ≤2 cm maximum tumor dimension, without evidence of regional lymph node involvement
●Stage II – Primary tumors >2 cm (T2 or T3) or a primary tumor with invasion into bone, muscle, fascia, or cartilage (T4), without evidence of lymph node involvement
- Merkel Cell Carcinoma. In: AJCC Staging Manual, Springer, New York 2010. p.315.
- Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol 2010; 63:751.
- Iyer JG, Storer BE, Paulson KG, et al. Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma. J Am Acad Dermatol 2014; 70:637.
- Treglia G, Kakhki VR, Giovanella L, Sadeghi R. Diagnostic performance of fluorine-18-fluorodeoxyglucose positron emission tomography in patients with Merkel cell carcinoma: a systematic review and meta-analysis. Am J Clin Dermatol 2013; 14:437.
- Harrington C, Kwan W. Outcomes of Merkel cell carcinoma treated with radiotherapy without radical surgical excision. Ann Surg Oncol 2014; 21:3401.
- Veness M, Howle J. Radiotherapy alone in patients with Merkel cell carcinoma: the Westmead Hospital experience of 41 patients. Australas J Dermatol 2015; 56:19.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
- Lebbe C, Becker JC, Grob JJ, et al. Diagnosis and treatment of Merkel Cell Carcinoma. European consensus-based interdisciplinary guideline. Eur J Cancer 2015; 51:2396.
- Tai PT, Yu E, Tonita J, Gilchrist J. Merkel cell carcinoma of the skin. J Cutan Med Surg 2000; 4:186.
- Howle JR, Hughes TM, Gebski V, Veness MJ. Merkel cell carcinoma: an Australian perspective and the importance of addressing the regional lymph nodes in clinically node-negative patients. J Am Acad Dermatol 2012; 67:33.
- Jabbour J, Cumming R, Scolyer RA, et al. Merkel cell carcinoma: assessing the effect of wide local excision, lymph node dissection, and radiotherapy on recurrence and survival in early-stage disease--results from a review of 82 consecutive cases diagnosed between 1992 and 2004. Ann Surg Oncol 2007; 14:1943.
- O'Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg 1997; 23:929.
- Gollard R, Weber R, Kosty MP, et al. Merkel cell carcinoma: review of 22 cases with surgical, pathologic, and therapeutic considerations. Cancer 2000; 88:1842.
- Senchenkov A, Barnes SA, Moran SL. Predictors of survival and recurrence in the surgical treatment of merkel cell carcinoma of the extremities. J Surg Oncol 2007; 95:229.
- Boyer JD, Zitelli JA, Brodland DG, D'Angelo G. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol 2002; 47:885.
- Snow SN, Larson PO, Hardy S, et al. Merkel cell carcinoma of the skin and mucosa: report of 12 cutaneous cases with 2 cases arising from the nasal mucosa. Dermatol Surg 2001; 27:165.
- Veness M, Foote M, Gebski V, Poulsen M. The role of radiotherapy alone in patients with merkel cell carcinoma: reporting the Australian experience of 43 patients. Int J Radiat Oncol Biol Phys 2010; 78:703.
- Pape E, Rezvoy N, Penel N, et al. Radiotherapy alone for Merkel cell carcinoma: a comparative and retrospective study of 25 patients. J Am Acad Dermatol 2011; 65:983.
- Sundaresan P, Hruby G, Hamilton A, et al. Definitive radiotherapy or chemoradiotherapy in the treatment of Merkel cell carcinoma. Clin Oncol (R Coll Radiol) 2012; 24:e131.
- Hruby G, Scolyer RA, Thompson JF. The important role of radiation treatment in the management of Merkel cell carcinoma. Br J Dermatol 2013; 169:975.
- Kachare SD, Wong JH, Vohra NA, et al. Sentinel lymph node biopsy is associated with improved survival in Merkel cell carcinoma. Ann Surg Oncol 2014; 21:1624.
- Gunaratne DA, Howle JR, Veness MJ. Sentinel lymph node biopsy in Merkel cell carcinoma: a 15-year institutional experience and statistical analysis of 721 reported cases. Br J Dermatol 2016; 174:273.
- Fang LC, Lemos B, Douglas J, et al. Radiation monotherapy as regional treatment for lymph node-positive Merkel cell carcinoma. Cancer 2010; 116:1783.
- Allen PJ, Bowne WB, Jaques DP, et al. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 2005; 23:2300.
- Fenig E, Brenner B, Katz A, et al. The role of radiation therapy and chemotherapy in the treatment of Merkel cell carcinoma. Cancer 1997; 80:881.
- Fenig E, Lurie H, Sulkes A. The use of cyclophosphamide, methotrexate, and 5-fluorouracil in the treatment of Merkel cell carcinoma. Am J Clin Oncol 1993; 16:54.
- Eng TY, Naguib M, Fuller CD, et al. Treatment of recurrent Merkel cell carcinoma: an analysis of 46 cases. Am J Clin Oncol 2004; 27:576.
- Servy A, Maubec E, Sugier PE, et al. Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy. Ann Oncol 2016; 27:914.
- Chen MM, Roman SA, Sosa JA, Judson BL. The role of adjuvant therapy in the management of head and neck merkel cell carcinoma: an analysis of 4815 patients. JAMA Otolaryngol Head Neck Surg 2015; 141:137.
- Clark JR, Veness MJ, Gilbert R, et al. Merkel cell carcinoma of the head and neck: is adjuvant radiotherapy necessary? Head Neck 2007; 29:249.
- Lawenda BD, Arnold MG, Tokarz VA, et al. Analysis of radiation therapy for the control of Merkel cell carcinoma of the head and neck based on 36 cases and a literature review. Ear Nose Throat J 2008; 87:634.
- Gillenwater AM, Hessel AC, Morrison WH, et al. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg 2001; 127:149.
- Harrington C, Kwan W. Radiotherapy and Conservative Surgery in the Locoregional Management of Merkel Cell Carcinoma: The British Columbia Cancer Agency Experience. Ann Surg Oncol 2016; 23:573.
- Foote M, Harvey J, Porceddu S, et al. Effect of radiotherapy dose and volume on relapse in Merkel cell cancer of the skin. Int J Radiat Oncol Biol Phys 2010; 77:677.
- Poulsen MG, Rischin D, Porter I, et al. Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin? Int J Radiat Oncol Biol Phys 2006; 64:114.
- Poulsen M, Rischin D, Walpole E, et al. High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study--TROG 96:07. J Clin Oncol 2003; 21:4371.
- Poulsen M, Walpole E, Harvey J, et al. Weekly carboplatin reduces toxicity during synchronous chemoradiotherapy for Merkel cell carcinoma of skin. Int J Radiat Oncol Biol Phys 2008; 72:1070.
- Satpute SR, Ammakkanavar NR, Einhorn LH. Role of platinum-based chemotherapy for Merkel cell tumor in adjuvant and metastatic settings. ASCO Meeting Abstracts 2014; 32(15 suppl):9049.
- Nghiem P, Bhatia S, Daud A, et al. Activity of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell carcinoma. Abstract 22LBA, European Society of Medical Oncology 2015.
- Lipson EJ, Vincent JG, Loyo M, et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res 2013; 1:54.
- Morand GB, Madana J, Da Silva SD, et al. Merkel cell carcinoma of the head and neck: poorer prognosis than non-head and neck sites. J Laryngol Otol 2016; 130:393.
- Bishop AJ, Garden AS, Gunn GB, et al. Merkel cell carcinoma of the head and neck: Favorable outcomes with radiotherapy. Head Neck 2016; 38 Suppl 1:E452.
- Tarantola TI, Vallow LA, Halyard MY, et al. Unknown primary Merkel cell carcinoma: 23 new cases and a review. J Am Acad Dermatol 2013; 68:433.
- Chen KT, Papavasiliou P, Edwards K, et al. A better prognosis for Merkel cell carcinoma of unknown primary origin. Am J Surg 2013; 206:752.
- Güler-Nizam E, Leiter U, Metzler G, et al. Clinical course and prognostic factors of Merkel cell carcinoma of the skin. Br J Dermatol 2009; 161:90.
- Foote M, Veness M, Zarate D, Poulsen M. Merkel cell carcinoma: the prognostic implications of an occult primary in stage IIIB (nodal) disease. J Am Acad Dermatol 2012; 67:395.
- Deneve JL, Messina JL, Marzban SS, et al. Merkel cell carcinoma of unknown primary origin. Ann Surg Oncol 2012; 19:2360.
- Tai PT, Yu E, Winquist E, et al. Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 2000; 18:2493.
- Grotz TE, Tarantola TI, Otley CC, et al. Natural history of merkel cell carcinoma following locoregional recurrence. Ann Surg Oncol 2012; 19:2556.
- Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 2016; 374:2542.
- Mantripragada K, Birnbaum A. Response to Anti-PD-1 Therapy in Metastatic Merkel Cell Carcinoma Metastatic to the Heart and Pancreas. Cureus 2015; 7:e403.
- Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016; 17:1374.
- Davids MS, Charlton A, Ng SS, et al. Response to a novel multitargeted tyrosine kinase inhibitor pazopanib in metastatic Merkel cell carcinoma. J Clin Oncol 2009; 27:e97.
- www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-pazopanib-for-merkel-cell-carcinoma-ukmcc-01 (Accessed on April 02, 2016).
- Meier G, Waldherr C, Herrmann R, et al. Successful targeted radiotherapy with 90Y-DOTATOC in a patient with Merkel cell carcinoma. A Case Report. Oncology 2004; 66:160.
- Kau R, Arnold W. Somatostatin receptor scintigraphy and therapy of neuroendocrine (APUD) tumors of the head and neck. Acta Otolaryngol 1996; 116:345.
- di Bartolomeo M, Bajetta E, Buzzoni R, et al. Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group. Cancer 1996; 77:402.
- Cirillo F, Filippini L, Lima GF, et al. [Merkel cell tumor. Report of case and treatment with octreotide]. Minerva Chir 1997; 52:1359.
- Salavati A, Prasad V, Schneider CP, et al. Peptide receptor radionuclide therapy of Merkel cell carcinoma using (177)lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: a potential novel treatment based on molecular pathology. Ann Nucl Med 2012; 26:365.
- Brunner M, Thurnher D, Pammer J, et al. Expression of hedgehog signaling molecules in Merkel cell carcinoma. Head Neck 2010; 32:333.
- Fakiha M, Letertre P, Vuillez JP, Lebeau J. Remission of Merkel cell tumor after somatostatin analog treatment. J Cancer Res Ther 2010; 6:382.
- Hitchcock CL, Bland KI, Laney RG 3rd, et al. Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural history, diagnosis, and treatment. Ann Surg 1988; 207:201.
- Savage P, Constenla D, Fisher C, et al. The natural history and management of Merkel cell carcinoma of the skin: a review of 22 patients treated at the Royal Marsden Hospital. Clin Oncol (R Coll Radiol) 1997; 9:164.
- Eng TY, Boersma MG, Fuller CD, et al. Treatment of merkel cell carcinoma. Am J Clin Oncol 2004; 27:510.
- Ott MJ, Tanabe KK, Gadd MA, et al. Multimodality management of Merkel cell carcinoma. Arch Surg 1999; 134:388.
- Poulsen M. Merkel-cell carcinoma of the skin. Lancet Oncol 2004; 5:593.
- Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Oncol 2002; 20:588.
- Yiengpruksawan A, Coit DG, Thaler HT, et al. Merkel cell carcinoma. Prognosis and management. Arch Surg 1991; 126:1514.
- Pitale M, Sessions RB, Husain S. An analysis of prognostic factors in cutaneous neuroendocrine carcinoma. Laryngoscope 1992; 102:244.
- Smith DE, Bielamowicz S, Kagan AR, et al. Cutaneous neuroendocrine (Merkel cell) carcinoma. A report of 35 cases. Am J Clin Oncol 1995; 18:199.
- Pilotti S, Rilke F, Bartoli C, Grisotti A. Clinicopathologic correlations of cutaneous neuroendocrine Merkel cell carcinoma. J Clin Oncol 1988; 6:1863.
- TNM STAGING SYSTEM
- APPROACH TO STAGING AND MANAGEMENT
- Initial staging procedures
- Initial management
- PRIMARY TUMOR
- Radiation therapy
- REGIONAL LYMPH NODES
- Clinically negative nodes
- Clinically positive nodes
- ADJUVANT THERAPY
- Radiation therapy
- Adjuvant immunotherapy
- HEAD AND NECK LESIONS
- UNKNOWN PRIMARY
- SURVEILLANCE AFTER INITIAL THERAPY
- Second primary cancers
- RECURRENT DISEASE
- METASTATIC DISEASE
- Targeted therapy
- Somatostatin receptor-based therapy
- Experimental approaches
- SUMMARY AND RECOMMENDATIONS
- Initial evaluation and management of locoregional disease
- Recurrent and metastatic disease