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Dermatologic Manifestations of Merkel Cell Carcinoma

  • Author: Christopher R Shea, MD; Chief Editor: William D James, MD  more...
 
Updated: Sep 14, 2015
 

Background

Merkel cell carcinoma is a rare, aggressive, primary skin cancer exhibiting neuroendocrine differentiation. Several synonyms exist; however, the term Merkel cell carcinoma is still most commonly used in view of the many similarities of the constituent tumor cell to the normal Merkel cell of the skin. In 1875, Friedrich Sigmund Merkel described Tastzellen (touch cells) in the skin of the snouts of moles and pigs and proposed that they had a mechanoreceptor function.

Merkel cells are present in high numbers on the lip, hard palate, palms, finger pads, proximal nail folds, and dorsa of the feet. They have a predilection for perifollicular areas in the skin; confirmed reports exist of Merkel cells free in the dermis, but they are most easily identified in the basal layer of the epidermis. Recent elegant studies of conditionally deleted transcription factor Atoh1 from truncal skin and foot pads of mice have clarified that Merkel cells are responsible for light touch and are likely an indispensible part of the somatosensory system. In Atoh1CKO mice, skin areas lacking Merkel cells exhibit a complete loss of characteristic neurophysiologic responses normally mediated by MC-neurite complexes.[1]

In human development, Merkel cells appear by the eighth gestational week. Lineage-tracing experiments have shown that Merkel cells arise through differentiation of epidermal progenitors during embryonic development. In adults, Merkel cells undergo slow turnover and are replaced by cells originating from epidermal stem cells, not through the proliferation of differentiated Merkel cells.[2]

Also see Merkel Cell Tumors of the Head and Neck and Skin Malignancies, Merkel Cell Carcinoma and Rare Appendageal Tumors.

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Pathophysiology

The histogenesis of Merkel cell carcinoma is controversial. Possible cells of origin include the epidermal Merkel cell, a dermal Merkel cell equivalent, a neural-crest–derived cell of the amine precursor uptake and decarboxylation (APUD) system, and a residual epidermal stem cell.

Cytogenetic abnormalities are present in 30-47% of Merkel cell carcinomas. The most frequent change is loss of heterozygosity due to translocations or deletions of chromosome 1; specifically, 2 distinct regions in the most distal band 1p36 on the short arm of chromosome 1 are implicated in Merkel cell carcinoma. Similar abnormalities near this site occur in several neurocristic tumors, including melanoma, neuroblastoma, and pheochromocytoma. Other abnormalities described in Merkel cell carcinoma include losses at chromosomes 3, 13, and 22 and partial trisomy of chromosomes 1, 11, 18, and X.[3, 4, 5, 6, 7] Unlike neuroendocrine (small cell) carcinoma of the lung, gene amplifications are rare in cutaneous Merkel cell carcinoma.

Recent studies of Merkel cell carcinoma using high-resolution comparative genomic hybridization confirm that Merkel cell carcinomas frequently carry extra copies of chromosomes 1, 3q, 5p, and 6, with loss of chromosomes 3p, 4, 5q, 7, 10, and 13; tumors with less genomic aberration are associated with improved survival. The patterns of cytogenetic alterations suggest the possible involvement of the tumor suppressor RB1, as well as L-Myc, which is related to the c-Myc proto-oncogene, has transforming activity, and is amplified in small-cell lung cancer, a closely related neuroendocrine tumor.[8]

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Epidemiology

Frequency

United States

Merkel cell carcinoma is a rare tumor, accounting for less than 1% of cutaneous malignancies. In Rochester, Minnesota, the annual incidence of Merkel cell carcinoma was reported to be 0.2 cases per 100,000 residents. The incidence appears to be rising, however. In a study of 1,124 cases identified in the Surveillance, Epidemiology, and End Results database, the incidence increased over a 15-year period (from 0.15 case per 100,000 in 1986 to 0.44 case per 100,000 in 2001).[9] In 2009, the Centers for Disease Control and Prevention announced specific International Classification of Disease (ICD) codes for Merkel cell carcinoma.[10] The use of such codes should facilitate more precise epidemiologic studies in the future.

International

Data from the Danish Cancer Registry indicate that the nationwide incidence rate of Merkel cell carcinoma increased 5.4-fold between 1986 and 2003 and was highest in people older than age 65 years.[11]

Race

Whites have a 20-fold increased age-adjusted relative risk of developing Merkel cell carcinoma compared with blacks.

Sex

The incidence reported in most studies is approximately equal for males and females, although some authors report an elevated female-to-male ratio of up to 4:1. Survival is greater in women.[12]

Age

The mean patient age at diagnosis is about 75 years[13] ; only 5% of cases occur before age 50 years.

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Contributor Information and Disclosures
Author

Christopher R Shea, MD Professor and Chief, Section of Dermatology, Department of Medicine, University of Chicago, The Pritzker School of Medicine

Christopher R Shea, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology, Association of Professors of Dermatology, International Society of Dermatopathology, Arthur Purdy Stout Society, Chicago Dermatological Society, Dermatology Foundation, Illinois Dermatological Society

Disclosure: Nothing to disclose.

Coauthor(s)

Victor G Prieto, MD, PhD Director of Dermatopathology, Professor, Departments of Pathology and Dermatology, University of Texas MD Anderson Cancer Center

Victor G Prieto, MD, PhD is a member of the following medical societies: American Society of Dermatopathology, College of American Pathologists, American Association for the Advancement of Science, International Society of Dermatopathology, European Society of Pathology, American Medical Association, American Society for Clinical Pathology, Society for Investigative Dermatology, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Specialty Editor Board

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

John G Albertini, MD Private Practice, The Skin Surgery Center; Clinical Associate Professor (Volunteer), Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine; President-Elect, American College of Mohs Surgery

John G Albertini, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery

Disclosure: Received grant/research funds from Genentech for investigator.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Susan M Swetter, MD Director, Pigmented Lesion and Melanoma Program, Professor, Department of Dermatology, Stanford University Medical Center and Cancer Institute, Veterans Affairs Palo Alto Health Care System

Susan M Swetter, MD is a member of the following medical societies: American Academy of Dermatology, Women's Dermatologic Society, American Society of Clinical Oncology, Society for Melanoma Research, Eastern Cooperative Oncology Group, American Medical Association, Pacific Dermatologic Association, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

References
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Large, violaceous nodule of Merkel cell carcinoma on the antecubital fossa. Courtesy of Dr. Jonathan Cook.
Histologic appearance of nodular Merkel cell carcinoma. Dermal nodule with a cohesive, expansile growth of basophilic cells.
High-power view demonstrates an open chromatin pattern and a high mitotic index.
Pseudorosette formation in Merkel cell carcinoma.
Merkel cell carcinoma with a focus of squamous differentiation.
Prominent in situ nested component of Merkel cell carcinoma, simulating malignant melanoma.
Electron micrograph of Merkel cell carcinoma showing a dense core granule (arrow).
Electron micrograph of Merkel cell carcinoma showing whorled bundles of intermediate filaments (arrow) near nucleus in Merkel cell carcinoma.
Dotlike paranuclear pattern of cytokeratin immunolocalization.
Table 1. Tumor Status
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis In situ primary tumor
T1 Primary tumor 2 cm or less in greatest dimension
T2 Primary tumor >2 cm but not >5 cm in greatest dimension
T3 Primary tumor >5 cm in greatest dimension
T4 Primary tumor invades bone, muscle, fascia, or cartilage
Table 2. Node Status
Nx Regional nodes cannot be assessed
N0 No regional node metastasis
cN0 Nodes not clinically detectable
cN1 Nodes clinically detectable
pN0 Nodes negative by pathologic examination
pNx Nodes not examined pathologically
N1a Micrometastasis
N1b Macrometastasis
N2 In-transit metastasis
Table 3. Metastasis Status
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
M1a Distant skin, distant subcutaneous tissues, or distant lymph nodes
M1b Lung
M1c All other visceral sites
Table 4. Stage Grouping
Stage Stage grouping
0 Tis N0 M0
IA T1 pN0 M0
IB T1 cN0 M0
IIA T2/T3 pN0 M0
IIB T2/T3 cN0 M0
IIC T4 N0 M0
IIIA Any T N1a M0
IIIB Any T N1b/N2 M0
IV Any T Any N M1
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