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National Cancer Institute
Ultima Vez Modificado: 16 de julio del 2012
Merkel cell carcinoma (MCC) was originally described by Toker in 1972 as trabecular carcinoma of the skin. 1 Other names include Toker tumor, primary small cell carcinoma of the skin, primary cutaneous neuroendocrine tumor, and malignant trichodiscoma. 2
MCC is an aggressive neuroendocrine carcinoma arising in the dermoepidermal junction. (See Figure 1.) Although the exact origin and function of the Merkel cell remains under investigation, it is thought to have features of both epithelial and neuroendocrine origin and arise in cells with touch-sensitivity function (mechanoreceptors). 3 4 5 6 7 8 9Figure 1. Merkel Cell Anatomy.
In Surveillance, Epidemiology and End Results (SEER) Program data from 1986 to 2001, the age-adjusted U.S. annual incidence of MCC tripled from 0.15 to 0.44 per 100,000, an increase of 8.08% per year. Although this rate of increase is faster than any other skin cancer including melanoma, the absolute number of U.S. cases per year is small. About 1,500 new cases of MCC were expected in the United States in 2007. 10 11 12 13 14 15
MCC incidence increases progressively with age. There are few cases in patients younger than 50 years, and the median age at diagnosis is about 65 years (see Figure 2). 11 Incidence is considerably greater in whites than blacks and slightly greater in males than females. 10 11 12 13 15 Figure 2. . Frequency of MCC by age and sex of men (square) and women (circle). Reprinted from Journal of the American Academy of Dermatology, 49 (5), Agelli M and Clegg L, Epidemiology of primary Merkel cell carcinoma in the United States, pp. 83241, Copyright (2003), with permission from Elsevier.
The apparent increase in incidence may reflect an actual increase and/or more accurate diagnostic pathology tools, improved clinical awareness of MCC, an aging population, increased sun exposure in susceptible populations, and improved registry tools.
MCC occurs most frequently in sun-exposed areas of skin, particularly the head and neck, followed by the extremities, and then the trunk. 3 13 16 Incidence has been reported to be greater in geographic regions with higher levels of ultraviolet B sunlight. 13
|Anatomic Site||Cases (%)|
|Skin, face||1,041 (26.9)|
|Skin of upper limb and shoulder||853 (22.0)|
|Skin of lower limb and hip||578 (14.9)|
|Skin of trunk||410 (10.6)|
|Skin of scalp and neck||348 (9.0)|
|Skin, NOS||234 (6.0)|
|External ear||120 (3.1)|
|Skin of lip||91 (2.4)|
|Unknown primary site||31 (0.8)|
|NOS = not otherwise specified|
In various cases series, up to 97% of MCCs arise in skin. Primaries in other sites were very rare, as are MCCs from unknown primary sites. 15
SEER registry data have shown excess risk of MCC as a first or second cancer in patients with several primary cancers. 17 National cancer registries from three Scandinavian countries have identified a variety of second cancers diagnosed after MCC. 18
Increased incidence of MCC has also been seen in people treated heavily with methoxsalen (psoralen) and ultraviolet A (PUVA) for psoriasis (3 of 1,380 patients, 0.2%), and those with chronic immune suppression, especially from chronic lymphocytic leukemia, human immunodeficiency virus, and prior solid organ transplant. 13 19
In 2008, a novel polyomavirus (Merkel cell polyoma virus, MCPyV) was first reported in MCC tumor specimens 20, a finding subsequently confirmed in other laboratories. 21 22 23 High levels of viral DNA and clonal integration of the virus in MCC tumors have also been reported 24 along with expression of certain viral antigens in MCC cells and the presence of antiviral antibodies. Not all cases of MCC appear to be associated with Merkel cell polyomavirus infection. 25
MCPyV has been detected at very low levels in normal skin distant from the MCC primary, in a significant percentage of patients with non-MCC cutaneous disorders, in normal appearing skin in healthy individuals, and in nonmelanoma skin cancers in immune-suppressed individuals. 8 26 27 28 Various methods have been used to identify and quantify the presence of MCPyV in MCC tumor specimens, other non-MCC tumors, blood, urine, and other tissues. 29 30
The significance of the new MCPyV findings remains uncertain. The prognostic significance of viral load, antibody titer levels, and the role of underlying immunosuppression in hosts (from disease and medications) are under investigation.
Prevalence of MCPyV appears to differ between MCC patients in the the United States and Europe versus Australia. It has been suggested that there may be two independent pathways for the development of MCC: one driven by the presence of MCPyV, and the other driven primarily by sun damage, especially as noted in patient series from Australia. 21 25 31
MCC usually presents as a painless, indurated, solitary dermal nodule with a slightly erythematous to deeply violaceous color, and rarely, an ulcer. MCC can infiltrate locally via dermal lymphatics, resulting in multiple satellite lesions. Because of its nonspecific clinical appearance, MCC is rarely suspected prior to biopsy. 3 Photographs of MCC skin lesions illustrate its clinical variability. 32
A mnemonic 16 summarizing typical clinical characteristics of MCC has been proposed:
Not all patients have every element in this mnemonic; however, in this study, 89% of patients met three or more criteria, 52% met four or more criteria, and 7% met all five criteria. 16
Because local-regional spread is common, newly diagnosed MCC patients require a careful clinical examination that includes looking for satellite lesions and regional nodal involvement.
An imaging work-up should be tailored to the clinical presentation as well as any relevant signs and symptoms. There has been no systematic study of the optimal imaging work-up for newly diagnosed patients, and it is not clear if all newly diagnosed patients, especially those with the smallest primaries, benefit from a detailed imaging work-up.
If an imaging work-up is performed, it may include a computed tomography (CT) scan of the chest and abdomen to rule out primary small cell lung cancer as well as distant and regional metastases. Imaging studies designed to evaluate suspicious signs and symptoms may also be recommended. In one series, CT scans had an 80% false-negative rate for regional metastases. 33 Head and neck presentations may require additional imaging. Magnetic resonance imaging has been used to evaluate MCC but has not been studied systematically. 34 Fluorodeoxyglucose-positron emission tomography results have been reported only in selected cases. 35 36 Routine blood work as a baseline has been recommended but has not been studied systematically. There are no known circulating tumor markers specifically for MCC.
The results of initial clinical staging of MCC vary widely in the literature, based on retrospective case series reported over decades. In 2009, 3,870 MCC cases were reported from the SEER Program registry. For invasive cancers, 48.6% were localized, 31.1% were regional, and 8.2% were distant. 15
MCC that presents in regional nodes without an identifiable primary lesion is found in a minority of patients, with the percent of these cases varying among the reported series. Tumors without an identifiable primary lesion have been attributed to either spontaneous regression of the primary or metastatic neuroendocrine carcinoma from a clinically occult site. 6 15 16 37 38
In a review of patients from 18 case series, 279 of 926 patients (30.1%) developed local recurrence during follow-up, excluding those presenting with distant metastatic disease. These events have been typically attributed to inadequate surgical margins and/or a lack of adjuvant radiation therapy. In addition, 545 of 982 patients (55.5%) had lymph node metastases at diagnosis or during follow-up. 6
In the same review of 18 case series, the most common sites of distant metastases were distant lymph nodes (60.1%), distant skin (30.3%), lung (23.4%), central nervous system (18.4%), and bone (15.2%). 6 Many other sites of disease have also been reported, and the distribution of metastatic sites varies among case series.
In one series of 237 patients presenting with local or regional disease, the median time-to-recurrence was 9 months (range, 270 months). Ninety-one percent of recurrences occurred within 2 years of diagnosis. 39
The extent of disease at presentation appears to provide the most useful estimate of prognosis. 5
Diagnostic procedures, such as sentinel lymph node biopsy, may help distinguish between local and regional disease at presentation. One-third of patients who lack clinically palpable or radiologically visible nodes will have microscopically evident regional disease. 33 The likelihood is that nodal positivity may be substantially lower among patients with small tumors (e.g., 1.0 cm). 40
Many retrospective studies have evaluated the relationship of a wide variety of biological and histological factors to survival and local-regional control. 5 6 15 33 39 41 42 43 44 45 46 47 48 49 50 51 52[Level of evidence: 3iiiDiii] Many of these reports are confounded by small numbers, potential selection bias, referral bias, short follow-up, no uniform clinical protocol for both staging and treatment, and are underpowered to detect modest differences.
A large, single-institution, retrospective study of 156 MCC patients, with a median follow-up of 51 months (range 2224 months), evaluated histologic factors potentially associated with prognosis. 50[Level of evidence: 3iiiB] Although this report is subject to potential selection and referral bias, both univariate and multivariate analyses demonstrated a relationship between improved cause-specific survival and circumscribed growth pattern versus infiltrative pattern, shallow-tumor depth versus deep-tumor depth, and absence of lymphovascular invasion versus presence of lymphovascular invasion. Adoption of these findings into a global prognostic algorithm awaits independent confirmation by adequately powered studies.
A 2009 study investigated whether the presence of newly identified MCPyV in MCC tumor specimens influenced clinical outcome among 114 Finnish patients with MCC. In this small study, patients whose tumors were MCPyV+ appeared to have better survival than patients whose tumors were MCPyV-. 53[Level of evidence: 3iiiDiii] Standardization of procedures to identify and quantify MCPyV and relevant antibodies is needed to improve understanding of both prognostic and epidemiologic questions. 8
The bulk of MCC literature is from small case series, which are subject to many confounding factors (refer to the Prognostic Factors section of this summary). For this reason, the relapse and survival rates reported by stage vary widely in the literature. In general, lower-stage disease is associated with better overall survival. 54
Outcomes from patients presenting with small volume local disease and pathologically confirmed cancer-negative lymph nodes report a cause-specific 5-year survival exceeding 90% in one report. 39 50[Level of evidence: 3iiiDiii]
A tabular summary of treatment results of MCC from 12 series illustrates the difficulty in comparing outcome data among series. 5
Using the SEER Program registry MCC staging system adopted in 1973, MCC survival data (19732006) by stage is summarized below: 15Figure 3. Relative ten-year survival rates for Merkel Cell Carcinoma by stage (SEER 19732006). Albores-Saavedra J et al: Merkel cell carcinoma demographics, morphology, and survival based on 3,870 cases: A population-based study. J Cutan Pathol. Reprinted with permission 2009. Published by Wiley-Blackwell. All rights reserved.
Although the exact origin and function of the Merkel cell remains under investigation, it is thought to have features of both epithelial and neuroendocrine origin and arise in cells with touch-sensitivity function (mechanoreceptors). 1 2 3 4
A panel of immunoreagents (see Figure 4) helps to distinguish Merkel cell carcinoma (MCC) from other similar-appearing tumors including neuroendocrine carcinoma of the lung (i.e., small cell carcinoma), lymphoma, peripheral primitive neuroectodermal tumor, metastatic carcinoid tumor, and small cell melanoma. 5Figure 4. Merkel - Immunohistochemical differential diagnosis of Merkel-Cell Carcinoma (Typical Staining Pattern).
Mixtures of variants are common. 6 7 8 Although some small, retrospective case series have suggested correlations between certain histologic features and outcome, the evidence remains uncertain. 10 11 12
One group has suggested a list of 12 elements that should be described in pathology reports of resected primary lesions and nine elements to be described in pathology reports of sentinel lymph nodes. The prognostic significance of these elements has not been validated prospectively. 13
The College of American Pathologists has published a protocol for the examination of specimens from patients with MCC of the skin. 14
(Refer to the Stage Information section of this summary for more information.)
The histologic variants of MCC are shown in Figure 5. 15Figure 5. (A) Intermediate variant of MCC showing vesicular, basophilic nuclei with prominent nucleoli and multiple mitoses. (B) Small-cell variant, histologically indistinguishable from bronchial small-cell carcinoma. (C) Trabecular variant is rare and normally only seen as a small component of a mixed variant. Goessling W et al: Merkel Cell Carcinoma, J Clin Oncol, 20 (2), pp. 58898. Reprinted with permission. 2009 American Society of Clinical Oncology. All rights reserved.
|First Author||Publication Date||Institution(s)||No. of Patients in Case Series||Dates of Cases|
|Yiengpruksawan et al.||1991||MSKCCa||77||19691989|
|Allen et al.||1999||MSKCCa||102||19691996|
|Allen et al.||2005||MSKCCa||250||19702002|
|American Joint Committee on Cancer||2002||N/A||N/A|
|Clark et al.||2007||Westmead Hospital, Sydney, Australia||110|
|Princess Margaret Hospital/University Health Network, Toronto, Canada|
|Sydney Head and Neck Cancer Institute/Royal Prince Alfred Hospital, Sydney, Australia|
|MSKCC = Memorial Sloan Kettering Cancer Center; N/A = Not applicable.|
These staging systems are highly inconsistent with each other. Indeed, stage III disease can mean anything from advanced local disease to nodal disease to distant metastatic disease. Furthermore, all MCC staging systems in use have been based on fewer than 300 patients.
To address these concerns, a new MCC-specific consensus staging system was developed by the American Joint Committee on Cancer (AJCC) to define Merkel cell carcinoma, as shown in tables 3, 4, 5, and 6. 7 Prior to the publication of this new system, the AJCC advocated using the nonmelanoma staging system.
|TX||Primary tumor cannot be assessed.|
|T0||No evidence of primary tumor (e.g., nodal/metastatic presentation without associated primary).|
|Tis||In situ primary tumor.|
|T1||2 cm maximum tumor dimension.|
|T2||>2 cm but 5 cm maximum tumor dimension.|
|T3||>5 cm maximum tumor dimension.|
|T4||Primary tumor invades bone, muscle, fascia, or cartilage.|
|NX||Regional lymph nodes cannot be assessed.|
|N0||No regional lymph nodes metastasis.|
|cN0||Nodes negative by clinical examb (no pathologic node exam performed).|
|pN0||Nodes negative by pathologic exam.|
|N1||Metastases in regional lymph node(s).|
|N2||In transit metastasis.e|
|M0||No distant metastasis.|
|M1||Metastases beyond regional lymph nodes.|
|M1a||Metastases to skin, subcutaneous tissues, or distant lymph nodes.|
|M1b||Metastasis to lung.|
|M1c||Metastases to all other visceral sites.|
|IV||Any T||Any N||M1|
Before the new AJCC consensus staging system was published, the most recent MSKCC four-stage system was favored because it was based on the largest number of patients and was the best validated. 1 The stages in the MSKCC system included:
One group has suggested a list of 12 elements that should be described in pathology reports of resected primary lesions and nine elements to be described in pathology reports of sentinel lymph nodes. The prognostic significance of these elements has not been validated prospectively. 8 The 2009 AJCC staging manual also specifies a variety of factors which should be collected prospectively on pathology reports.
Merkel cell carcinoma (MCC) is an uncommon tumor. Most clinical management recommendations in the literature are based on case series that describe a relatively small number of patients who were not entered on formal clinical trials, evaluated with uniform clinical staging procedures, treated with uniform treatment protocols, or provided with regular, prescribed follow-up. These reports are also confounded by potential selection bias, referral bias, and short follow-up; and they are underpowered to detect modest differences in outcome.
In addition, outcomes of patients with American Joint Committee on Cancer stage IA, stage IB, and stage II are often reported together. In the absence of results from clinical trials with prescribed work-up, treatments, and follow-up, most MCC patients have been treated using institutional or practitioner preferences that consider the specifics of each case as well
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