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Skin Cancer – Merkel Cell Carcinoma

Skin Cancer – Merkel Cell Carcinoma

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Merkel cell carcinoma (MCC) is the eponym for primary cutaneous neuroendocrine carcinoma, a dermal neoplasm with cytoplasmic, dense-core neuroendocrine granules and keratin filaments. Merkel cell carcinoma (MCC) is an uncommon and aggressive cutaneous neoplasm that lacks distinguishing clinical features. More than half of Merkel cell carcinomas (MCCs) occur in the head and neck of elderly people in areas of actinically damaged skin. The most common site of occurrence is the periorbital region. Merkel cell carcinoma (MCC) has a propensity to recur and to cause local and distant metastases. Distant metastases indicate a condition that is nearly always fatal. [1]

The diagnosis is based on a combination of light microscopy, electron microscopy, and immunohistochemistry. Current treatment consists of wide local excision with adjuvant irradiation. Neck dissection is used for clinically positive nodes, and chemotherapy is given for advanced disease. [2]

If the prognosis of patients with (MCC) is to be improved, early diagnoses are needed, and further understanding of the roles of neck dissection, radiation therapy, and chemotherapy must be attained. [3]

Freidrich Sigmund Merkel, a German histopathologist, first described the Merkel cell in 1875. He fixed and stained the skin of geese and ducks and demonstrated touch cells in the snouts of pigs. These clear-staining cells at the dermoepidermal junction were near myelinated nerve fibers. Merkel postulated that these cells acted as mechanoreceptors in all animals.

Cyril Toker first described Merkel cell carcinoma (MCC) in 1972. [4] On the basis of the histologic characteristics of the tumor, he named it trabecular cell carcinoma of the skin.

Subsequent studies involving immunohistochemistry and electron microscopy revealed that these tumors originate from the Merkel cell.

Merkel cell carcinoma (MCC) is a deadly disease with a poor likelihood for survival. Local recurrence occurs in 44% of patients; multiple local recurrences occur in 15%. These tumors appear as rapidly growing, painless nodules in elderly Caucasian individuals or in young adults with ectodermal dysplasia syndromes. The mean age at presentation is 68 years, and no sex bias is observed. Merkel cell carcinomas (MCCs) usually appear as indurated plaques or violaceous (red or deep purple) solitary and dome-shaped nodules. The surface is typically shiny, with telangiectasias and possibly ulceration. Most tumors measure 0.7-1.2 cm in diameter.

Merkel cell carcinomas (MCCs) usually occur in sun-damaged skin. They are often found near other lesions of actinically damaged skin, including skin involved with Bowen disease, squamous cell carcinoma, basal cell carcinoma, solar keratoses, or lentigo maligna. Merkel cell carcinoma (MCC) has also been linked to previous radiation exposure and B-cell lymphoma.

Approximately 53% of Merkel cell carcinomas (MCCs) occur in the head and neck; 35% occur in the extremities. In the head and neck, 46% of tumors occur in the periorbital region; 29%, on the cheek; 18%, on the eyelid; and 17%, on the forehead. Other sites in the head and neck include the lips (9%), ears (7%), nose and neck (5.4%), and scalp (4%). Common distribution of Merkel cell carcinoma in the head and neck is shown in the image below.

Tumors have also been reported in areas not exposed to sun, such as the nasal cavity, buccal mucosa, gingiva, hard palate, and postauricular skin.

About 3% of patients with Merkel cell carcinoma (MCC) have tumors at several sites. Approximately 11-15% of patients present with clinically positive nodes. About 75-83% of patients eventually develop regional nodal and distant metastases during their illness.

The nonspecific characteristics of Merkel cell carcinoma (MCC) lead to a lengthy differential diagnosis that includes basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, epidermal cysts, lymphoma, and metastatic carcinoma of the skin. As a result, Merkel cell carcinoma (MCC) is rarely diagnosed until biopsy is performed.

Since Merkel cell carcinomas (MCCs) were first described in 1972, more than 600 cases have been reported in the literature; 321 of these cases have involved the head and neck.

The reported annual incidence of Merkel cell carcinoma (MCC) is 0.2-0.45 case per 100,000 population. Merkel cell carcinoma (MCC) is 100 times rarer than melanoma.

Evidence suggests that the incidence of Merkel cell carcinoma (MCC) is increasing. In an analysis of the Surveillance, Epidemiology and End Results (SEER) database, Hodgson (2005) reported that the incidence of Merkel cell carcinoma (MCC) increased 3-fold between 1986 and 2001. [5]  Moreover, a study by Uitentuis et al reported that in the Netherlands, between 1993 and 2016, the incidence of Merkel cell carcinoma (MCC) rose from 0.17 per 100,000 person-years to 0.59 per 100,000 person-years. [6]

The Merkel cell is found in the skin of fish, amphibians, reptilians, avians, and mammals. It is an ovoid or round cell in the basal layer of the epidermis, lying parallel to the surface. The cell has scant cytoplasm and a round or oval nucleus with fine, evenly dispersed chromatin. The cells cluster in areas of sensory perception, such as fingertips, the tip of the nose, and tactile hair follicles.

Ultrastructural evaluation of the Merkel cell reveals desmosomal connections with surrounding keratinocytes; intracytoplasmic aggregates of intermediate filaments; and numerous, membrane-bound, dense core granules located in short, spinous, cytoplasmic processes that synapse with adjacent terminal nerve endings.

Immunohistochemical studies of the Merkel cell have demonstrated the presence of neuron-specific enolase (NSE), an amine precursor uptake and decarboxylation (APUD) cell marker. Studies have also shown staining for cytokeratins 8, 18, and 19.

The origin of the Merkel cell is still controversial. The cell has both epithelial and neuroendocrine elements. This finding has led some to hypothesize that the cell is derived from an epidermal stem cell in the basal layer of the epidermis that is capable of differentiation along either lineage. An alternative hypothesis, one stimulated by the presence of calcitonin and other hormones, suggests that the cell may be of neural crest origin.

The exact function of the Merkel cell has yet to be delineated, but most believe that it acts to modulate mechanoreception.

Recently, a polyomavirus was found to be integrated into the genome of MCC and has been postulated to play a role in the pathogenesis and progression of this disease. [7, 8, 9, 10, 11]

Merkel cell carcinoma (MCC) commonly appears as a painless mass on or just under the skin surface. Appropriate clinical diagnosis is often delayed because of a lack of symptoms. The tumor may take on an erythematous or violaceous appearance. Bleeding and superficial ulceration are late findings suggestive of advanced disease. Regional lymph node metastasis is common, even with tumors smaller than 2 cm.

In a representative case that demonstrates common findings, a patient was an 89-year-old Caucasian woman with a 6-month history of an enlarging painless mass involving the right side of her nose. No pain or bleeding was associated with this mass. Her medical history included no previous cutaneous malignancies or sun exposure.

Physical examination revealed a smooth violaceous discolored mass measuring 2 X 3 cm involving the right nasal ala. The mass deeply invaded the full thickness of the nasal skin, with evidence of right nasal obstruction as seen in the image below. The rest of her facial skin contained no additional lesions. The bilateral intraparotid and jugulodigastric nodes were normally sized.

The patient underwent right-sided partial rhinectomy, with at least 5-mm margins from the visible borders of the tumor. Frozen sections revealed that all margins were free of disease. Reconstruction was accomplished immediately with a nasolabial flap. The patient’s postoperative treatment included radiation therapy of 45 Gy for 5 weeks. The patient was free from recurrence at 2 years after surgery, when she died from causes unrelated to this mass.

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Kim JA, Choi AH. Effect of radiation therapy on survival in patients with resected Merkel cell carcinoma: a propensity score surveillance, epidemiology, and end results database analysis. JAMA Dermatol. 2013 Jul. 149(7):831-8. [Medline].

Toker C. Trabecular carcinoma of the skin. Arch Dermatol. 1972 Jan. 105(1):107-10. [Medline].

Hodgson NC. Merkel cell carcinoma: changing incidence trends. J Surg Oncol. 2005 Jan 1. 89(1):1-4. [Medline].

Uitentuis SE, Louwman MWJ, van Akkooi ACJ, Bekkenk M. Treatment and survival of Merkel cell carcinoma since 1993: a population-based cohort study in the Netherlands. J Am Acad Dermatol. 2019 Jan 28. [Medline].

Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008 Feb 22. 319(5866):1096-100. [Medline]. [Full Text].

Busam KJ, Jungbluth AA, Rekthman N, et al. Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am J Surg Pathol. 2009 Sep. 33(9):1378-85. [Medline]. [Full Text].

Xie H, Lee L, Caramuta S, Höög A, Browaldh N, Björnhagen V, et al. MicroRNA Expression Patterns Related to Merkel Cell Polyomavirus Infection in Human Merkel Cell Carcinoma. J Invest Dermatol. 2013 Aug 20. [Medline].

Kwun HJ, Shuda M, Feng H, Camacho CJ, Moore PS, Chang Y. Merkel cell polyomavirus small T antigen controls viral replication and oncoprotein expression by targeting the cellular ubiquitin ligase SCFFbw7. Cell Host Microbe. 2013 Aug 14. 14(2):125-35. [Medline]. [Full Text].

Faust H, Andersson K, Ekström J, Hortlund M, Robsahm TE, Dillner J. Prospective study of Merkel cell polyomavirus and risk of Merkel cell carcinoma. Int J Cancer. 2013 Aug 7. [Medline].

Lebbe C, Becker JC, Grob JJ, et al. Diagnosis and treatment of Merkel cell carcinoma. European consensus-based interdisciplinary guideline. Eur J Cancer. 2015 Aug 6. [Medline].

Yao M, Smith RB, Hoffman HT, et al. Merkel cell carcinoma: two case reports focusing on the role of fluorodeoxyglucose positron emission tomography imaging in staging and surveillance. Am J Clin Oncol. 2005 Apr. 28(2):205-10. [Medline].

Gould VE, Moll R, Moll I, et al. Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms. Lab Invest. 1985 Apr. 52(4):334-53. [Medline].

Yiengpruksawan A, Coit DG, Thaler HT, et al. Merkel cell carcinoma. Prognosis and management. Arch Surg. 1991 Dec. 126(12):1514-9. [Medline].

Bishop AJ, Garden AS, Gunn GB, et al. Merkel cell carcinoma of the head and neck: Favorable outcomes with radiotherapy. Head Neck. 2015 Feb 2. [Medline].

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 Feb. 141 (2):137-41. [Medline].

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 Oct. 17 (10):1374-1385. [Medline].

FDA. FDA approves pembrolizumab for Merkel cell carcinoma. US Food and Drug Administration. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm628867.htm. 2018 Dec 19; Accessed: 2018 Dec 20.

Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med. 2016 Jun 30. 374 (26):2542-52. [Medline]. [Full Text].

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Hitchcock CL, Bland KI, Laney RG 3d, et al. Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural history, diagnosis, and treatment. Ann Surg. 1988 Feb. 207(2):201-7. [Medline].

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James M Pearson, MD Private Practice, Beverly Hills/Hermosa Beach, CA

James M Pearson, MD is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, California Medical Association, Los Angeles County Medical Association

Disclosure: Nothing to disclose.

Michael J Pitman, MD Associate Professor of Otolaryngology-Head and Neck Surgery, Columbia University College of Physicians and Surgeons; Chief, Division of Laryngology, Director, Voice and Swallowing Institute, ColumbiaDoctors, Columbia University Medical Center

Michael J Pitman, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, Voice Foundation

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

M Sherif Said, MD, PhD Associate Professor, Department of Pathology, University of Colorado School of Medicine; Associate Director of Pathology Department, Denver Health Medical Center

M Sherif Said, MD, PhD is a member of the following medical societies: American Society for Clinical Pathology, College of American Pathologists

Disclosure: Nothing to disclose.

Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine

Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;Preacute Population Health Management;The Physicians Edge<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; for: Rxblockchain;Bridge Health.

M Abraham Kuriakose, MD, DDS, FRCS Chairman, Head and Neck Institute, Amrita Institute of Medical Sciences

M Abraham Kuriakose, MD, DDS, FRCS is a member of the following medical societies: American Association for Cancer Research, American Head and Neck Society, British Association of Oral and Maxillofacial Surgeons, Royal College of Surgeons of England

Disclosure: Nothing to disclose.

Skin Cancer – Merkel Cell Carcinoma

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