Dermatologic Manifestations of Merkel Cell Carcinoma

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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 Merkel Cell Carcinoma and Rare Appendageal Tumors.

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, most of them related to ultraviolet-light damage. The most frequent change is loss of heterozygosity due to translocations or deletions of chromosome 1; specifically, two 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.

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]

Merkel cell polyomavirus (MCPyV) is present in approximately 70-80% of Merkel cell carcinomas. The integration of the genomic material of this virus in the tumor DNA was reported in 2008[9] and likely represents a key driver in the pathogenesis of this tumor. Presence or absence of genomic material of MCPyV is strongly associated with the type of molecular signature seen in this tumor; as such, patients from countries with a relatively low level of ultraviolet exposure tend to be positive for MCPyV.[10] Probably related to the participation of a virus in the pathogenesis of this tumor, immunosuppression is associated with an increased risk, as seen in patients with chronic lymphocytic leukemia or solid organ transplantation.[11]

Etiology

An etiologic role for chronic exposure to solar ultraviolet radiation (UVR) is proposed, mainly due to the markedly increased risk for white patients versus black patients and the predominant location of Merkel cell carcinoma on sites of maximal cumulative UVR exposure (head and neck). The regional incidence rate of Merkel cell carcinoma increases with increasing sun exposure, measured by the UVB solar index. Recent studies indicate that Merkel cell carcinomas occurring on non–sun-exposed sites tend to be larger, have an increased female predominance, and carry a higher risk of death from Merkel cell carcinoma.[12] Both the frequency and the aggressiveness of Merkel cell carcinoma increase after immunosuppression,[13, 11] organ transplantation, and B-cell neoplasia.

Other potential risk factors for Merkel cell carcinoma include erythema ab igne and congenital ectodermal dysplasia. Merkel cell carcinoma is not associated with Epstein-Barr virus or human papillomavirus.[14] However, DNA sequences of a previously unknown polyomavirus (Merkel cell polyomavirus, MCV or MCPyV) have been detected in 80% of Merkel cell carcinomas but only 16% of healthy skin.[9] The frequent finding of clonal integration of viral DNA within the Merkel cell carcinoma genome suggests that viral infection and integration may contribute to the pathogenesis of Merkel cell carcinoma. Recent studies show that the MCV small T antigen is oncogenic in transgenic mice[15] and that MCV small T antigen mediates microtubule destabilization, thereby promoting cell motility and migration.[16]

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,[17] and up to 7.9 cases per million in 2011.[18] In 2009, the Centers for Disease Control and Prevention announced specific International Classification of Disease (ICD) codes for Merkel cell carcinoma.[19] 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.[20]

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.[21]

Age

The mean patient age at diagnosis is about 75 years[22] ; only 5% of cases occur before age 50 years.

Prognosis

Partial or complete spontaneous regression (reminiscent of that sometimes seen in melanoma) is a well documented but rare phenomenon in Merkel cell carcinoma and may be more common in women than in men.[23] Even some metastases may remit spontaneously. Regression is accompanied by dense lymphocytic infiltrates, primarily of the CD8 phenotype, and proceeds via apoptosis (as documented ultrastructurally and by the in situ DNA nick end labeling [TUNEL] technique).

Local cutaneous recurrence occurs after wide excision in 30-40% of patients with clinical stage I Merkel cell carcinoma; local invasion of contiguous organs (eg, intracranial) is also possible. Regional lymph node metastasis occurs in 50-79% of patients, and distant metastasis occurs in more than 30% of patients; major sites include liver, bone, central nervous system, lung, and skin.

Overall, the mortality rate is 30-50% in 2 years; few studies include longer-term follow-up. Women appear to have a better survival rate than men. Histopathologic features associated with a lower survival rate include small cell size, high mitotic rate, subcutaneous invasion, diffuse growth pattern, heavy lymphocytic infiltrates, increased vascular density, lymphovascular invasion, mast cell count, and tumor size greater than 5 mm.[22, 24]  

Patient Education

For patient education resources, see the Cancer and Tumors Center, as well as Skin Cancer and Skin Biopsy.

History

Merkel cell carcinoma generally presents as cutaneous disease only, but some patients present with evidence of regional or distant metastasis. The primary skin lesion is generally asymptomatic. Patients with disseminated disease may have constitutional symptoms (eg, fatigue), localizing signs (eg, hemoptysis, neurologic defect, adenopathy secondary to metastasis), or both.

Physical Examination

Skin/primary lesion

Merkel cell carcinoma usually presents as a solitary, dome-shaped nodule or firm plaque (see image below).



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Large, violaceous nodule of Merkel cell carcinoma on the antecubital fossa. Courtesy of Dr. Jonathan Cook.

Lesions are most often smaller than 2 cm in greatest dimension, but may exceed 15 cm in diameter. They are typically red, violaceous, or purple. The epidermal surface is often shiny, and telangiectases may be seen, suggesting atrophy. Ulceration is uncommon.

Skin/distribution

Lesions characteristically appear on the head or the neck (about half of cases). Any mucosal or cutaneous site may be affected.

Metastases

Regional nodal metastases are usually the first site of dissemination. They may be detectable by palpation. Sentinel lymph node biopsy is effective in predicting the risk of regional recurrence; however, lymph node dissection does not appear to convey a survival advantage.[25, 26, 27, 28] Cutaneous metastatic deposits also occur.

Complications

Complications secondary to metastasis depend on the anatomic sites of involvement.

Imaging Studies

Radiography of the chest is indicated in Merkel cell carcinoma (MCC) to rule out the alternative diagnosis of cutaneous metastasis from a primary small cell neuroendocrine carcinoma (oat cell carcinoma) of the lung.

Staging CT or MRI studies are needed to assess the possibility of dissemination of primary Merkel cell carcinoma to the lymph nodes or the viscera.

Procedures

Fine-needle aspiration may be helpful to assess recurrence or metastatic spread.

Histologic Findings

Tumors cells are usually located intradermally; an intraepidermal component may also be present, and a purely intraepidermal (in situ) Merkel cell carcinoma rarely may be encountered. Reactive epidermal hyperplasia is frequent.

Several architectural patterns of intradermal tumor are recognized. The classic trabecular pattern consists of interconnecting strands of tumor cells in the dermis, with formation of cellular aggregates resembling glands or neural rosettes.[29] The intermediate pattern is the most common, and it exhibits large, solid nests of neoplastic cells. The least common, diffuse pattern consists of an infiltration of tumor cells among dermal collagen bundles, without the more distinctive organoid appearance of the trabecular pattern. A particular tumor often contains elements of all architectural patterns, with individual variation in the proportions represented.



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Histologic appearance of nodular Merkel cell carcinoma. Dermal nodule with a cohesive, expansile growth of basophilic cells.



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High-power view demonstrates an open chromatin pattern and a high mitotic index.

The tumor is usually composed of round, small, dark cells with conspicuous nucleoli and open chromatin with peripheral heterochromatin (salt-and-pepper pattern). Less commonly, Merkel cell carcinoma cells may simulate lymphoma, or may exhibit plasmacytoid, clear cell, anaplastic, or spindle-cell features. Mitotic figures and apoptotic bodies are often numerous. Vascular or lymphatic invasion is not uncommon. Histologic variants of Merkel cell carcinoma include the desmoplastic, epidermotropic (resembling mycosis fungoides), and pagetoid (resembling Paget disease[30] or melanoma) types, and tumors with focal true glandular or squamous differentiation.[31, 32, 33] Merkel cell carcinoma has been associated with squamous cell carcinoma, basal cell carcinoma, adnexal tumors, and trichilemmal cyst.



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Merkel cell carcinoma with a focus of squamous differentiation.



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Prominent in situ nested component of Merkel cell carcinoma, simulating malignant melanoma.

Immunohistochemistry is very helpful. Cytokeratin 20 is expressed in a dotlike paranuclear or crescentic pattern; other low molecular weight (MW) cytokeratin antibodies (eg, CAM5.2, MNF116), while less specific, react in a similar localization pattern. Neurofilament is also expressed in the cytoplasm of most Merkel cell carcinoma. The above findings support the diagnosis of primary Merkel cell carcinoma of the skin and tend to rule out metastatic neuroendocrine carcinoma, as from a pulmonary primary. The CK20 expression is so sensitive and specific that it has largely replaced traditional markers of neuroendocrine differentiation (ie, synaptophysin, chromogranin) as the initial antibody panel of choice; however, the latter may be helpful adjuncts in difficult cases.[34]

Fluorescence in-situ hybridization studies of MCV in the tumors can differentiate a punctate pattern, indicating viral integration, correlated with moderate viral load, versus a combined punctate and diffuse pattern, associated with very high viral load.[35]



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Dotlike paranuclear pattern of cytokeratin immunolocalization.

Electron microscopic findings are characteristic, revealing a lobulated nucleus that may contain rodlets. The cytoplasm is electron-lucent and contains a prominent Golgi apparatus and numerous ribosomes. Intermediate filaments are numerous and often assume a parallel or whorled arrangement near the nucleus, accounting for the dotlike pattern of cytokeratin distribution visualized by immunohistochemistry.[36] Desmosomes may be present. Most diagnostic is the dense core granule (80-120 nm in diameter), the source, and the locus of the neuroendocrine peptides.



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Electron micrograph of Merkel cell carcinoma showing a dense core granule (arrow).



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Electron micrograph of Merkel cell carcinoma showing whorled bundles of intermediate filaments (arrow) near nucleus in Merkel cell carcinoma.

Cytologic preparations from fine-needle aspirates (FNAs) demonstrate a loosely cohesive pattern of small to intermediate-sized cells with round nuclei, finely granular chromatin, a thin rim of cytoplasm, and (infrequently) pseudorosette formation. Immunocytochemistry may be helpful.[37]



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Pseudorosette formation in Merkel cell carcinoma.

Staging

A consensus staging system based on analysis of 5823 cases from the US National Cancer Database was been adopted for use by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer in 2010.[38] This staging scheme has been updated in the current classification of the AJCC (8th edition).[39] The 4-stage system is summarized in the Tables below.

Table 1.



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See Table

Table 2.



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See Table

Sentinel lymph nodes may be examined by breadloafing and subsequent analysis of keratin expression with an antikeratin cocktail. Because dendritic cells in the lymph nodes may express keratin, in case of doubt anti-CK20 antibodies may be useful to rule out metastatic Merkel cell carcinoma. As in other solid tumors, positive sentinel lymph nodes correlate with impaired prognosis.[38]

Medical Care

Various chemotherapeutic regimens have been used, but none has been proven to result in improved survival; the role of chemotherapy in the management of Merkel cell carcinoma (MCC) remains unclear. Merkel cell carcinoma is chemosensitive but only rarely chemocurable in patients with metastasis or locally advanced tumors. Moreover, chemotherapeutic toxicity leads to high mortality.[40]

Avelumab (Bavencio), an anti-PD-L1 IgG1 monoclonal antibody, was approved by the US Food and Drug Administration (FDA) in March 2017 for metastatic MCC in adults and pediatric patients aged 12 years or older.

Approval of avelumab was based on the JAVELIN Merkel 200 open-label, single-arm, multicenter study in 88 patients with histologically confirmed metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease.[41] The objective response rate was 33%, partial response was 22%, and complete response was 11%. Tumor responses were durable, with 86% of responses lasting at least 6 months (n=25) and 45% of responses lasting at least 12 months (n=13). Duration of response ranged from 2.8 to over 23.3 months.

Another PD1 inhibitor, pembrolizumab, has already shown efficacy in metastatic Merkel cell carcinoma.[42]

The role of radiation therapy (RT) in managing Merkel cell carcinoma remains controversial. RT may help control unresectable primary or metastatic lesions, and it may also be useful for local control when administered postoperatively to the primary site and the regional draining lymph node basin. Adjuvant RT reportedly reduces the local and regional recurrence rate but may not lead to improved overall survival.[43, 44, 45, 46]

Also see Guidelines.

Surgical Care

Wide local excision (eg, with margins of 3 cm) is usually indicated if clinically feasible. Some have recommended Mohs micrographic surgery for its tissue-sparing effects and possible superior control of local disease; however, tumor deposits may be noncontiguous histologically, rendering this modality less effective in such cases.[47]

Selective lymphadenectomy (sentinel lymph node procedure) is becoming a standard approach for patients with Merkel cell carcinoma. While any effect on survival remains unclear,[48] it does provide valuable prognostic information since the presence of metastasis is the dominant risk factor for death from disease. Prophylactic complete lymph node dissection, combined with wide local excision and adjuvant radiotherapy, reportedly may improve survival.[49]

Consultations

Early referral to a surgical oncologist, a medical oncologist, and a radiation therapist is indicated.

Prevention

Photoprotection (eg, sunscreen, behavioral prevention) may help prevent Merkel cell carcinoma (MCC), but this is not proven. Also see Sunscreens and Photoprotection.

Guidelines Summary

New guidelines on Merkel cell carcinoma have been issued by the European Dermatology Forum, European Association of Dermato-Oncology, and European Organization of Research and Treatment of Cancer.[50] A summary is as follows:

Medication Summary

Avelumab is the first drug approved by the US Food and Drug Administration for Merkel cell carcinoma. It is a programmed death 1 (PD-1) inhibitor. Another PD-1 inhibitor, pembrolizumab, has already been used, with promising results.

Platinum-based chemotherapy regimens have been also been used, but clinical efficacy is limited and brief.

Avelumab (Bavencio)

Clinical Context:  Avelumab is an anti-PD-L1 IgG1 monoclonal antibody. It is indicated for metastatic Merkel cell carcinoma in adults and pediatric patients aged 12 years or older.

Pembrolizumab (Keytruda)

Clinical Context:  Pembrolizumab is a monoclonal antibody to programmed cell death-1 protein (PD-1). It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

Class Summary

PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound.

This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation.

What is Merkel cell carcinoma?What is the pathophysiology of Merkel cell carcinoma?What causes Merkel cell carcinoma?What is the prevalence of Merkel cell carcinoma in the US?What is the global prevalence of Merkel cell carcinoma?What are the racial predilections of Merkel cell carcinoma?What are the sexual predilections of Merkel cell carcinoma?Which age groups have the highest prevalence of Merkel cell carcinoma?What is the prognosis of Merkel cell carcinoma?Which clinical history findings are characteristic of Merkel cell carcinoma?Which physical findings are characteristic of Merkel cell carcinoma?Which physical findings suggest metastatic Merkel cell carcinoma?What are the possible complications of Merkel cell carcinoma?What are the differential diagnoses for Dermatologic Manifestations of Merkel Cell Carcinoma?What is the role of imaging studies in the workup of Merkel cell carcinoma?What is the role of fine-needle aspiration (FNA) in the workup of Merkel cell carcinoma?Which histologic findings are characteristic of Merkel cell carcinoma?How is Merkel cell carcinoma staged?How is Merkel cell carcinoma treated?What is the role of surgery in the treatment of Merkel cell carcinoma?Which specialist consultations are beneficial to patients with Merkel cell carcinoma?How is Merkel cell carcinoma prevented?What are the European Dermatology Forum, European Association of Dermato-Oncology, and European Organization of Research and Treatment of Cancer guidelines on Merkel cell carcinoma?What is the role of medications in the treatment of Merkel cell carcinoma?Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Dermatologic Manifestations of Merkel Cell Carcinoma?

Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

Victor G Prieto, MD, PhD, Ferenc and Phyllis Gyorkey Chair for Research and Education in Pathology, Professor, Departments of Pathology and Dermatology, University of Texas MD Anderson Cancer Center

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Myriad (consultant regarding MyPath test in melanocytic lesions).

Specialty Editors

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

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; Past President, American College of Mohs Surgery

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: QualDerm Partners; Novascan<br/>Have a 5% or greater equity interest in: QualDerm Partners - North Carolina.

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

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

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

Disclosure: Nothing to disclose.

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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.

Merkel cell carcinoma with a focus of squamous differentiation.

Prominent in situ nested component of Merkel cell carcinoma, simulating malignant melanoma.

Dotlike paranuclear pattern of cytokeratin immunolocalization.

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.

Pseudorosette formation in Merkel cell carcinoma.

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.

 

Clinical Stage Groups (cNM)

 

Pathological Stage Groups (pNM)

Tumor (T)

Node (N)

Metastasis (M)

Tumor (T)

Node (N)

Metastasis (M)

0TisN0M00TisN0M0
IT1N0M0IT1N0M0
IIAT2-3N0M0IIAT2-3N0M0
IIBT4N0M0IIBT4N0M0
IIIT0-4N1-3M0IIIAT1-4N1a(sn) or N1aM0
    T0N1bM0
   IIIBT1-4N1b–3M0
IVT0-4Any NM1IVT0-4Any NM1

Tumor (T)

Node (N)

Metastasis (M)

Tx, primary tumor cannot be assessed



T0, no primary tumor



Tis, in situ primary tumor



T1, primary tumor ≤2 cm



T2, primary tumor >2 cm but ≤5 cm



T3, primary tumor >5 cm



T4, primary tumor  invades fascia, muscle, cartilage, or bone



cNx, regional lymph  nodes cannot be clinically  assessed (eg, previously removed  for another reason, body habitus)



cN0, no regional lymph node metastasis by clinical or  radiological evaluation



cN1, clinically detected regional nodal metastasis



cN2, in-transit metastasis without lymph node  metastasis



cN3, in-transit metastasis with lymph node  metastasis



pNx, regional lymph nodes cannot be  assessed (eg, previously removed for another  reason) or not removed for pathological evaluation



pN0, no regional lymph node metastasis  detected on pathological evaluation



pN1a(sn), clinically occult nodal  metastasis identified only by sentinel lymph node biopsy



pN1a, clinically occult regional lymph  node metastasis following lymph node dissection



pN1b, clinically or radiologically detected regional lymph node metastasis, pathologically confirmed



pN2, in-transit metastasis without lymph  node metastasis



pN3, in-transit metastasis with lymph  node metastasis



M0, no distant  metastasis



M1, distant  metastasis



 M1a, metastasis to distant skin, distant subcutaneous  tissue, or distant lymph  nodes



 M1b, lung



 M1c, all other distant sites