BASICS
- Rare, highly aggressive, cutaneous neuroendocrine carcinoma classically found on the head and neck of elderly individuals.
- System(s) affected: skin
- Synonym(s): primary neuroendocrine carcinoma of the skin; trabecular carcinoma; anaplastic carcinoma of the skin; primary small cell carcinoma of the skin, cutaneous apudoma
EPIDEMIOLOGY
Incidence
- Age-adjusted incidence estimated to be 0.24/100,000 person-years in the United States (1).
- Incidence has tripled since 1986, with an average annual increase of 8% (2).
- Highest in the elderly: Median age at diagnosis is 71 years in immunocompetent and 60 years in immunosuppressed (3).
- Increased incidence likely secondary to aging population, increased sun exposure, and number of immunocompromised individuals (2)
- Rare, <1% of all skin cancers in the United States
- 1,500 cases diagnosed in 2007 (2).
ETIOLOGY AND PATHOPHYSIOLOGY
- Tumor shares several ultrastructural, morphologic, and immunohistologic features with Merkel cells, (slowly adapting fine-touch mechanoreceptors in the basal epidermis), as well as with other extracutaneous neuroendocrine tumors. Despite these shared features from which the tumor was originally named, there is little evidence for direct relationship between Merkel cells and MCC. As such, the term "primary cutaneous neuroendocrine tumor " has been suggested but not yet widely adopted (4).
- Some suggest derivation from immature pluripotent cells in dermis.
- Merkel cell polyomavirus (MCPyV) likely contributes to development of MCC and has been detected in 80% of tumors tested (5,6,7).
RISK FACTORS
- UV exposure (natural or artificial)
- History of prior skin cancer
- Fair skin
- Age >65
- Chronic immune suppression (HIV, leukemia, organ transplantation)
- Merkel cell polyomavirus (MCPyV)
GENERAL PREVENTION
Avoid sun exposure; early biopsy of suspicious rapidly growing lesion; early referral for further management
COMMONLY ASSOCIATED CONDITIONS
Increased risk for developing other malignancies, including lymphomas and other skin cancers
DIAGNOSIS
Complete examination of skin and regional lymph nodes, followed by biopsy. Sentinel lymph node biopsy should be considered for all patients as even small tumors have been shown to have ≥15% risk of lymph node disease.
HISTORY
Rapidly growing, painless nodule
PHYSICAL EXAM
- Distribution:
- Favors chronically sun-exposed skin such as head and neck, followed by extremities, buttocks
- Morphology:
- Nonspecific appearance; may be mistaken for more common skin lesions, including BCC, cyst, or abscess
- Classically presents as a rapidly enlarging red-pink to violaceous solitary dome-shaped nodule or firm plaque
- May be shiny, and have telangiectasias similar to BCC
- Associated signs:
- Grows rapidly, rarely can ulcerate
DIFFERENTIAL DIAGNOSIS
Clinical DDx:
- Cyst
- Basal cell carcinoma (BCC)
- Abscess
- Squamous cell carcinoma
- Amelanotic melanoma
- Lymphoma cutis
- Kaposi sarcoma
- Pyogenic granuloma
- Adnexal tumor
- Dermatofibrosarcoma protuberans
- Angiosarcoma
- Lymphoma
Histologic DDx:
- Small cell/oat cell carcinoma of the lung
- Metastatic neuroblastoma
- Primary peripheral primitive neuroectodermal tumor
- Ewing sarcoma
- Melanoma
- Poorly differentiated SCC
DIAGNOSTIC TESTS & INTERPRETATION
- Biopsy with histologic stains (see below) (2)[C]
- In cases of confirmed Merkel cell carcinoma (MCC), evaluate for metastatic disease. This includes clinical lymph node examination evaluating for gross lymph node disease and sentinel lymph node biopsy to evaluate for microscopic lymph node disease. Radiologic imaging can be used to evaluate for distant metastases if indicated.
- CT/MRI/PET scans are most valuable in cases of confirmed lymph node disease to evaluate for visceral or bone metastases. Imaging may also be utilized to evaluate patients with primary lesions >2 cm who are known to have a higher risk of metastasis and/or to monitor for disease progression.
Follow-Up Tests & Special Considerations
MRI may help plan target volume for radiation therapy.
Diagnostic Procedures/Other
Skin biopsy
Test Interpretation
- Morphology:
- Small, uniformly round, blue cells; 2 to 3 times larger than lymphocytes; basophilic nuclei; minimal cytoplasm; finely dispersed chromatin; frequent mitoses; extensive necrosis, high apoptotic index
- Dermal tumor nodule frequently extending into subcutaneous fat, fascia, and muscle usually sparing papillary dermis and adnexa
- Similar histologic appearance as small cell lung cancer, small cell melanoma, lymphoma
- Immunohistochemistry:
- Stains positive for epithelial and neuroendocrine markers, negative for lymphoid and melanoma markers including S-100 (differentiates melanoma from MCC) and leukocyte common antigen
- CK20 staining in perinuclear dot pattern (low-molecular-weight intermediate filament), is highly sensitive for MCC and can help differentiate from BCC
- TTF-1 negativity (thyroid transcription factor-1) differentiates MCC from small cell carcinoma of the lung (2)[C].
TREATMENT
Primary: wide local excision followed by local/regional radiation, including affected lymph node basin (2)[C]
GENERAL MEASURES
- Wide local excision (>1 cm for lesions <2 cm in size and 2 cm for lesions >2 cm) with pathologically clear margins and sentinel lymph node biopsy (2)[C]
- Adjuvant radiation to primary site ± draining regional nodes decreases locoregional recurrence and improves survival.
- Radiation may be used as monotherapy in inoperable disease and has been used alone to control local disease.
- Metastatic disease treated with mono- or polychemotherapy has high remission rates; however, responses are usually short-lived (8).
- Treatment with clinical trials is considered standard of care for disseminated disease (8).
ISSUES FOR REFERRAL
Early referral to dermatologist if MCC is suspected. Recommend multidisciplinary tumor board with surgeon and radiation oncologist.
ADDITIONAL THERAPIES
- Chemotherapy reserved for palliative care for patients with stage IV disease; can shrink advanced metastatic disease, but may not increase survival.
- The discovery of MCPyV has led to the investigation of antivirals including interferon as well as other potential immunotherapeutic agents in the treatment of MCC.
SURGERY/OTHER PROCEDURES
Mohs surgery may be indicated for MCC on the head, where it may not be possible to obtain a margin of at least 2 cm (2)[C].
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Regular follow-up appointments with dermatologist every 1 to 3 months for the first year, every 3 to 6 months in second year, and annually thereafter (2)[C].
- CT scans every 6 months after a high-risk diagnosis.
Patient Monitoring
Patients should perform routine skin checks for any new nodules or pigmentary changes at surgical site to suggest local recurrence or distant cutaneous metastasis.
PATIENT EDUCATION
- http://www.merkelcell.org
- http://www.cancer.gov/types/skin/patient/merkel-cell-treatment-pdq#section/all
PROGNOSIS
- 70 " 80% of patients with MCC present with localized disease (3)
- Locoregional recurrence usually develops within 8 months of diagnosis and is associated with distant metastasis in the future (2).
- 2- and 5-year mortality rate is 30-50%, respectively (2).
- Distant metastasis found at mean of 18 months: mean survival <6 months (2)
COMPLICATIONS
Metastasizes via lymphatics, commonly to skin, liver, lung, bone, and brain
REFERENCES
11 Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol. 2003;49(5):832 " 841.22 Nicolaidou E, Mikrova A, Antoniou C, et al. Advances in Merkel cell carcinoma pathogenesis and management: a recently discovered virus, a new international consensus staging system and new diagnostic codes. Br J Dermatol. 2012;166(1):16 " 21.33 Swartz JL, Bichakjian CK, Lowe L, et al. Clinicopathologic features of primary Merkel cell carcinoma: a detailed descriptive analysis of a large contemporary cohort. Dermatol Surg. 2013;39(7):1009 " 1016.44 Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkel cell?) carcinoma of the skin. I. A clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol. 1985;9(2):95 " 108.55 Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866):1096 " 1100.66 Faust H, Andersson K, Ekstr Άm J, et al. Prospective study of Merkel cell polyomavirus and risk of Merkel cell carcinoma. Int J Cancer. 2014;134(4):844 " 848.77 Santos-Juanes J, Fern ‘ndez-Vega I, Fuentes N, et al. Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis. Br J Dermatol. 2015;173(1):42 " 49.88 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(16):2396 " 2403.
ADDITIONAL READING
- Albores-Saavedra J, Batich K, Chable-Montero F, et al. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 2010;37(1): 20 " 27.
- Coursaget P, Samimi M, Nicol JT, et al. Human Merkel cell polyomavirus: virological background and clinical implications. APMIS. 2013;121(8):755 " 769.
- Miller SJ, Alam M, Andersen J, et al. Merkel cell carcinoma. J Natl Compr Canc Netw. 2009;7(3):322 " 332.
- Schrama D, Ugurel S, Becker JC. Merkel cell carcinoma: recent insights and new treatment options. Curr Opin Oncol. 2012;24(2):141 " 149.
- Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol. 2011;29(8):1036 " 1041.
- Schwartz JL, Wong SL, McLean SA, et al. NCCN guidelines implementation in the multidisciplinary Merkel Cell Carcinoma Program at the University of Michigan. J Natl Compr Canc Netw. 2014;12(3):434 " 441.
CODES
ICD10
- C4A.9 Merkel cell carcinoma, unspecified
- C4A.30 Merkel cell carcinoma of unspecified part of face
- C4A.4 Merkel cell carcinoma of scalp and neck
- C4A.60 Merkel cell carcinoma of unsp upper limb, including shoulder
- C4A.8 Merkel cell carcinoma of overlapping sites
- C4A.72 Merkel cell carcinoma of left lower limb, including hip
- C4A.71 Merkel cell carcinoma of right lower limb, including hip
- C4A.70 Merkel cell carcinoma of unsp lower limb, including hip
- C4A.62 Merkel cell carcinoma of left upper limb, including shoulder
- C4A.59 Merkel cell carcinoma of other part of trunk
- C4A.52 Merkel cell carcinoma of skin of breast
- C4A.0 Merkel cell carcinoma of lip
- C4A.39 Merkel cell carcinoma of other parts of face
- C4A.31 Merkel cell carcinoma of nose
- C4A.22 Merkel cell carcinoma of left ear and external auric canal
- C4A.21 Merkel cell carcinoma of right ear and external auric canal
- C4A.12 Merkel cell carcinoma of left eyelid, including canthus
- C4A.11 Merkel cell carcinoma of right eyelid, including canthus
- C4A.10 Merkel cell carcinoma of unsp eyelid, including canthus
- C4A.51 Merkel cell carcinoma of anal skin
- C4A.61 Merkel cell carcinoma of right upper limb, inc shoulder
ICD9
- 209.36 Merkel cell carcinoma of other sites
- 209.31 Merkel cell carcinoma of the face
- 209.32 Merkel cell carcinoma of the scalp and neck
- 209.33 Merkel cell carcinoma of the upper limb
- 209.35 Merkel cell carcinoma of the trunk
- 209.34 Merkel cell carcinoma of the lower limb
- 209.30 Malignant poorly differentiated neuroendocrine carcinoma, any site
SNOMED
Merkel cell carcinoma (disorder)
CLINICAL PEARLS
- MCC is a rare, cutaneous neuroendocrine carcinoma that classically presents as a rapidly enlarging red-pink to violaceous solitary dome-shaped nodule or firm plaque on the head and neck of elderly individuals.
- Clinically, MCC may be mistaken for less aggressive or even benign skin lesions; however, MCC is a highly aggressive tumor with a 5-year disease-specific survival rate of approximately 50% portending a poorer prognosis than melanoma.
- Disease recurrence ranges from 40% (extremities) to 77% (head and neck) typically within 2 years of diagnosis.
- Early detection is critical " biopsy any rapidly growing suspicious lesion.
- Optimal management often requires involvement of multiple specialists, including pathologists, dermatologists, surgeons, and radiation and medical oncologists.