Merkel cell cancer

9 Interesting Facts of Merkel cell cancer

1. Merkel cell cancer is a rare and aggressive cutaneous neuroendocrine carcinoma that primarily arises on skin of head and neck, followed by lower limbs and upper extremities; it also may develop at extracutaneous sites (eg, lymph nodes, oral cavity, breast tissue, vaginal walls, salivary glands) 
2. Carcinogenesis is not completely understood but is thought to be linked to Merkel cell polyomavirus infection and exposure to UV radiation
3. Most patients present with a firm, nontender nodular lesion, variable in color, on sun-exposed skin; patient may have history of immunosuppression or excessive sun exposure
4. Diagnosis is confirmed by distinct histopathologic and immunohistochemical features of primary lesion biopsy
5. Sentinel node biopsy and imaging modalities (eg, PET-CT, CT scan, MRI) are used to determine stage and tumor burden
6. Resection of primary lesion is first line therapy for stage I and II disease; in select patients at risk of regional or distant metastasis, radiotherapy also may be implemented
7. Positive nodal disease is treated by surgical removal of primary lesions and/or positive lymph nodes, followed by radiotherapy; in select patients, a cisplatin- or carboplatin-based chemotherapeutic regimen may be used
8. Metastatic or recurrent disease may be treated with surgery, radiotherapy, chemotherapy, or a combination to slow progression of cancer and provide symptomatic relief
9. Overall 10-year survival rate for Merkel cell cancer is 57.3% but varies widely depending on age at diagnosis and anatomic site, stage, and size of tumor 

Merkel cell cancer is a rare and aggressive cutaneous neuroendocrine carcinoma that primarily arises on skin of head and neck, followed by lower limbs and upper extremities; it also may develop at extracutaneous sites (eg, lymph nodes, oral cavity, breast tissue, vaginal walls, salivary glands) 

Incidence is increasing in the United States 

Develops at the dermal-epidermal junction and displays both neuroendocrine and epithelial differentiation 

Classification of Merkel cell cancer

• American Joint Committee on Cancer TNM staging classification for Merkel cell cancer 
  • Tumor status 
    • TX: primary tumor cannot be assessed
    • T0: no evidence of primary tumor
    • Tis: in situ primary tumor
    • T1: primary tumor is no larger than 2 cm in its maximum dimension
    • T2: primary tumor is larger than 2 cm but not more than 5 cm in its maximum dimension
    • T3: primary tumor is larger than 5 cm in its maximum dimension
    • T4: primary tumor invades bone, muscle, fascia, or cartilage
  • Lymph node status (clinical) 
    • NX: regional lymph nodes cannot be assessed
    • N0: no regional lymph node metastasis
    • N1: regional lymph node metastasis
    • N2: in transit metastasis (tumor that is distinct from the primary lesion and located either between the primary lesion and draining regional lymph nodes or distal to the primary lesion) without lymph node metastasis
    • N3: in transit metastasis (tumor that is distinct from the primary lesion and located either between the primary lesion and draining regional lymph nodes or distal to the primary lesion) with lymph node metastasis
  • Metastasis (clinical) 
    • M0: no distant metastasis
    • M1: distant metastasis detected
    • M1a: metastasis to distant skin, distant subcutaneous tissues, or distant lymph nodes
    • M1b: metastasis to lung
    • M1c: metastasis to all other visceral sites
  • Clinical stage group 
    • Stage 0: TisN0M0
    • Stage I: T1N0M0
    • Stage IIA: T2-3N0M0
    • Stage IIB: T4N0M0
    • Stage III: T0-4N1-3M0
    • Stage IV: T0-4, any N, M1

Symptoms of Merkel cell cancer

• Most patients affected with Merkel cell cancer presents with a firm, nontender nodular lesion on sun-exposed skin 
  • Most common on head and neck skin, followed by lower limbs and upper extremities 
  • Nodule may be red or pink, blue or violaceous, flesh colored, or, rarely, yellow or white
  • Often develops and enlarges rapidly over weeks to months; however, more gradual progression may be noted 
• Constitutional symptoms are typically not present
• Patient may have history of other cancers, immunosuppression (eg, HIV-positive status, previous organ transplant), or excessive exposure to UV radiation (eg, sunlight) 

Physical examination

• Note location, size, and characteristics of presenting lesion
  • Typically appears as a firm and hemispherical nodule with smooth, shiny surface that is stretching the intact epidermis 
    • Rarely, plaquelike variants occur on the trunk
    • Ulcerations are rare
  • Lesion color varies 
    • Red or pink: 55.6%
    • Blue or violaceous: 25.9%
    • Skin colored: 16%
    • Yellowish or white: 2.5%
  • Most lesions are 1 to 2 cm in diameter at diagnosis 
  • Most common sites are skin of the head and neck, followed by lower limbs and upper extremities 
• Conduct a full body skin examination to check for any other suspicious lesions; satellite metastases may occur 
• Examine lymph nodes to check for suspicious size, shape, or texture that is associated with nodal disease 

Causes of Merkel cell cancer

• Pathogenesis of Merkel cell cancer is not completely understood, but it is clear that cutaneous infection with Merkel cell polyomavirus plays a role in most cases 
  • Merkel cell polyomavirus is found in 80% of patients with Merkel cell cancer; it is the only polyomavirus known to cause disease in both immunocompromised and immunocompetent (typically elderly) people 
  • Merkel cell polyomavirus large T antigen is found in the cancer cells of Merkel cell polyomavirus–positive patients, and interactions between that antigen and a certain cellular tumor suppressor—retinoblastoma protein—are considered essential for Merkel cell carcinogenesis 
  • UV radiation also has been shown to promote Merkel cell polyomavirus small T antigen expression and thus may facilitate tumor development 
• In cases without Merkel cell polyomavirus, UV radiation (via sun exposure) may be primary cause 
  • Most polyomavirus-negative cases occur in Australia 
    • Merkel cell polyomavirus DNA has been detected in only 24% of patients from Australia, compared with 69% of patients from the United States
  • Somatic mutations in polyomavirus-negative Merkel cell cancer were shown to lead to retinoblastoma dysregulation independent of Merkel cell polyomavirus large T antigen expression 

Risk factors of Merkel cell cancer

Age

• Predominantly occurs in elderly patients 
  • Mean age of diagnosis for women: 76.2 years 
  • Mean age of diagnosis for men: 73.6 years 
• In the Surveillance, Epidemiology, and End Results program from 1973 to 2006, a study of 3870 patients found that only 4% of patients with the diagnosis were younger than 49 years 

Sex

• In the Surveillance, Epidemiology, and End Results program from 1973 to 2006, a study of 3870 patients found that incidence was higher in men (61.5%) than in women (38.5%) 

Genetics

• In a whole exome sequencing study, gene RB1 (encoding the retinoblastoma protein) was found to have nonsense mutations, producing truncated protein, in patients with polyomavirus-negative disease 
  • Mutations: chr13:g.48916767G>A (exon 3), chr13:g.49027222C>T (exon 18), chr13:g.48923137G>A (exon 6) 
• None of the polyomavirus-positive cases had a nonsense mutation in RB1  

Ethnicity/race

• In the Surveillance, Epidemiology, and End Results program from 1973 to 2006, a study of 3870 patients found that most patients with the diagnosis were white (94.9%) 

Other risk factors/associations

• Immunosuppression increases risk
  • Patients who are HIV-positive have a 13-fold increased risk compared with general population 
    • Linkage study of a registry of 500,000 patients with AIDS found that the standardized incidence ratio was 11.95 relative to general population 
• Merkel cell cancer is often seen in association with other skin malignancies (eg, squamous cell carcinoma, basal cell carcinoma, Bowen disease) and internal and hematologic malignancies 

How is Merkel cell cancer diagnosed

Primary diagnostic tools

• Rarely clinically suspected; primary tumor lacks distinguishing characteristics 
• Diagnosis is based on history and complete examination of skin and lymph nodes followed by biopsy of suspicious lesion with or without sentinel lymph nodes 
• Imaging studies may be needed to identify nodal and distant metastatic sites 
  • If cytokeratin 20 is negative, imaging may help exclude skin metastasis from noncutaneous carcinoma 
  • Either whole body PET with fused axial imaging (either CT or MRI) or CT of neck, chest, abdomen, and pelvis (with contrast) and MRI of brain may be obtained 
  • Somatostatin receptor scintigraphy with radiolabeled octreotide or newer somatostatin analogues such as gallium dotatate may play a role in identifying involved lymph nodes and other metastatic sites 

Laboratory

• Merkel cell polyomavirus oncoprotein antibodies 
  • May be measured as part of initial evaluation
  • Seronegative patients may have higher risk for recurrence

Imaging

• PET with fused axial imaging (CT or MRI)
  • Indicated to evaluate for distant metastases and guide treatment planning 
  • Metastatic tissue has higher uptake of fludeoxyglucose F 18 
    • Uptake of fludeoxyglucose F 18 that is within reference range does not exclude Merkel cell cancer that has low proliferative activity 
• CT
  • Alternative to PET to evaluate for distant metastases 
  • Primarily used for initial staging as it is very effective in imaging lymph nodes of head and neck and detecting metastases (ie, nodular metastases in subcutaneous fat, visceral metastases) 
  • Primary skin lesions appear from isodense to slightly hyperdense compared with muscle; they also appear as cutaneous rounded nodules that extend below the skin 
  • Metastases of abdominal organs appear as hypervascular lesions with ringlike enhancement 
  • Contrast-enhanced CT can demonstrate high-attenuation lymphadenopathy and high-attenuation tissue nodules, which are suggestive of focal metastases 
• MRI
  • Alternative to PET to evaluate for distant metastases 
  • Highly accurate for evaluating soft tissue metastases and brain and bone marrow involvement 
  • Primary lesions appear as inhomogeneous in signal intensity on T1- and T2-weighted images 
  • Lymphatic satellite lesions appear as reticular stranding and subcutaneous masses 
  • Large lymph node metastases appear as lesions and retained fatty tissue that is compressed and fine

Procedures

Skin biopsy 

General explanation

• Sample taken of cutaneous lesion for histopathologic examination
• Obtain sample with tangential, punch, incisional, or excisional biopsy 

Indication

• Indicated as part of work-up for all patients with suspected Merkel cell cancer

Contraindications

• No absolute contraindications

Complications 

• Bruising
• Local bleeding
• Pain

Interpretation of results

• Definitive diagnosis is based on histopathologic assessment of biopsy specimen
• Specific morphologic characteristics of primary lesion biopsy must be evaluated 
  • Tumor size
  • Peripheral and deep margin status
  • Lymphovascular invasion
  • Extracutaneous extension (eg, bone, cartilage)
• Additional clinical features must be evaluated 
  • Tumor depth (eg, millimeters of Breslow thickness)
  • Mitotic rate: number of cells undergoing mitosis divided by millimeters squared is preferred method
  • Tumor growth pattern
  • Presence of tumor-infiltrating lymphocytes
  • Presence of secondary malignancies
• Initial diagnosis is made with hematoxylin-eosin staining and confirmed with immunohistochemical staining
  • Immunopanel includes cytokeratin 20 and thyroid transcription factor 1 for primary lesion biopsy 
    • Majority of tumor cells are consistently and strongly positive for cytokeratin 20 (75%-100%) and stain in a paranuclear dot pattern 
    • Tumor cells stain negatively for thyroid transcription factor 1 
  • For ambiguous cases, additional immunohistochemical stains include neuroendocrine markers (eg, neurofilament, neuron-specific enolase, chromogranin, synaptophysin, CD56)
    • Neurofilament protein stains positively in primary tumor 
    • Neuron-specific enolase stains positively in primary tumor 
    • Chromogranin A stains both positively and negatively, depending on case, in primary tumor 
    • CD56 stains positively in primary tumor; sensitive but not specific 
    • Synaptophysin stains positively in primary tumor

Sentinel lymph node biopsy

General explanation

• First lymph node(s) involved in lymphatic drainage are biopsied to detect metastasis and to predict potential for metastasis in associated nodal drainage area 
• Blue dye and radioactive tracer are injected around skin lesion to allow lymphatic drainage path to be mapped and the first draining node (ie, sentinel node) to be identified via lymphoscintigraphy
• Identified lymph node(s) are surgically excised for histologic analysis

Indication

• Staging tool for patients with clinically negative nodes and no apparent evidence of distant metastasis 
• Performed to verify negative margins before therapeutic lymph node excision and reconstruction 

Contraindications

• No absolute contraindications
• In rare situations, a prior excision can affect lymph drainage and lead to false-negatives

Complications

• Lymphedema 
• Infection 
• Bleeding

Interpretation of results

• Histopathologic assessment of biopsy specimen detects macroscopic or microscopic metastasis
  • Micrometastatic involvement is found in about 25% of patients 
• Parameters reported should include tumor burden (ie, percentage of node), tumor location (eg, parenchyma, subcapsular sinus), and whether or not extracapsular extension is present 
• Diagnosed via hematoxylin-eosin and immunohistochemical staining
  • Merkel cell cancer micrometastases are more cohesive than lymphocytes and display larger nuclei and hypodense chromatin without nucleoli 
    • Very difficult to identify single or small groups of cancerous Merkel cells on hematoxylin-eosin stain 
  • For sentinel lymph nodes, immunopanel includes cytokeratin 20 and pancytokeratins (AE1/AE2) 
    • Cytokeratin 20 immunostaining shows a diffuse, paranuclear dot pattern, and background lymph node cells are nonreactive 
    • Pancytokeratin immunostaining shows a paranuclear dot pattern and stains smaller and spindled nontumor lymph node reticulum cells 
      • Pancytokeratin stains also consistently demonstrate cytoplasmic staining of nontumor cells, deemed nonspecific 

Differential Diagnosis of Merkel cell cancer

Most common

• Basal Cell Carcinoma
• Nodular melanoma
• Epidermoid cyst

How is Merkel Cell Cancer treated?

Treatment Goals of Merkel cell cancer

• Resect tumor
• Prevent local recurrence and regional and distant metastasis

Admission criteria

• Admit to hospital for surgical resection of primary tumor or lesion and/or lymphadenectomy, radiotherapy, and chemotherapy

Recommendations for specialist referral

• Refer to dermatologist for comprehensive skin examination and biopsy of cutaneous lesions 
• Refer to surgical, medical, or radiation oncologist, preferably for multidisciplinary panel review, to develop and implement an appropriate therapeutic strategy 

Treatment Options

Overview

• Treatment of Merkel cell cancer is highly dependent on microstaging and accurate histopathologic interpretation of lesion; also, lack of prospective clinical trials results in lack of agreement among clinicians regarding management 
• Localized primary tumors: primarily treated with complete surgical excision 
  • Wide local excision with intraoperative lymph node biopsy is standard technique 
  • Radiotherapy is commonly used to prevent local recurrence of primary tumor 
  • Follow surgical excision with complete lymph node dissection and/or radiotherapy to the draining lymph nodes if micrometastases are found in sentinel node 
• Clinical node-positive disease: treated with lymph node dissection and radiotherapy 
  • Primary tumor is treated with wide local excision with lymph node dissection and/or radiotherapy to the draining lymph node basin 
  • In select cases, adjuvant chemotherapy may be considered; however, no survival benefit has been reported 
    • Cisplatin with or without etoposide
    • Carboplatin with or without etoposide
• Metastatic disease of Merkel cell cancer: treated with chemotherapy, radiotherapy, or surgery, alone or in combination 
  • Immunotherapy or systemic chemotherapy is the most commonly used treatment strategy; regimens include: 
    • PD-1/PD-L1 blockers (preferred) 
      • Pembrolizumab 
      • Avelumab 
      • Nivolumab 
    • Cisplatin or carboplatin with or without etoposide 
    • Topotecan 
    • Cyclophosphamide, doxorubicin, and vincristine 
  • Enrollment in clinical trial is preferred, if available 

Rationale

• Wide surgical resection of Merkel cell cancer is recommended for stage I and II disease because subclinical satellite metastases are responsible for high rate of local recurrence 
• Postoperative radiotherapy is commonly used as part of treatment strategy, to serve the following goals: 
  • Prevent recurrence of primary tumor
  • Prevent further regional and metastatic spread
  • Provide optimal palliative care

Outcomes

• Rarity of Merkel cell cancer results in paucity of randomized clinical trials to guide treatment 
• Merkel cell cancer tumors are usually radiosensitive; adjuvant radiotherapy for primary tumor site and regional lymphatic drainage basin can significantly reduce local recurrence rate 
  • Adjuvant radiotherapy should be started immediately after surgery; delay has been associated with worse outcomes 
• Studies suggest that Merkel cell cancer tumors are chemosensitive; however, there are currently no evidence-based chemotherapy regimens
  • Chemotherapy regimens used for small cell lung cancer have achieved a high rate of short-term remission but do not generally prolong survival 

Drug therapy

• Chemotherapeutic agents
  • Alkylating agents 
    • Cisplatin
    • Carboplatin
    • Cyclophosphamide
  • Topoisomerase inhibitors 
    • Topotecan
    • Etoposide
  • Anthracycline antibiotics 
    • Doxorubicin 
  • Plant alkaloids 
    • Vincristine
  • Biologic agent
    • Pembrolizumab 
    • Avelumab 
    • Nivolumab 

Nondrug and supportive care

Radiotherapy for Merkel cell cancer

• Dose is individualized according to risk and tumor stage
• Indications
  • Draining lymph node basin irradiation 
    • No sentinel lymph node biopsy and/or lymph node dissection and clinical evidence of adenopathy
    • Positive sentinel lymph node biopsy result but lymph node dissection not undertaken
    • Lymph node dissection completed and multiple involved nodes and/or extracapsular extension found
    • Clinically negative nodes but risk of subclinical disease
  • Primary site irradiation 
    • Resected primary tumor larger than 1 cm with negative margins
    • Resected primary tumor with microscopically positive resection margins
    • Where resection is not possible (eg, patient refuses surgery or risk of morbidity is significant)
    • Where grossly positive resection margins remain that cannot undergo additional resection

Procedures

Surgical excision of primary tumor 

General explanation

• Wide local excision to remove entire Merkel cell cancer lesion with small margin (1-2 cm) of healthy tissue is standard 
• Other surgical techniques (eg, Mohs surgery, modified Mohs surgery, complete circumferential and peripheral deep margin assessment) may be used if tissue sparing is necessary 
  • Mohs surgery ensures clearance of cutaneous tumors while maximizing healthy tissue conservation 
    • Thin layers of cancer-containing skin are progressively removed and examined by surgeon until only cancer-free tissue remains
  • Modified Mohs surgery is Mohs surgery with an additional final margin taken for permanent section assessment 
  • Complete circumferential and peripheral deep margin assessment is an advanced surgical procedure in which pathologist performs microscopic examination of removed layers during resection to ensure complete removal of tumor tissue 
• Wide excisions may require skin grafting
• Sentinel lymph node biopsy is usually performed intraoperatively

Indication

• Surgical resection is indicated for patients with stage I and II Merkel cell cancer and in limited cases for regional metastasis
• Mohs surgery or modified Mohs surgery is indicated for areas where tissue conservation is a goal (eg, face)

Contraindications

• No absolute contraindication

Complications

• Local bleeding
• Infection

Lymph node dissection (ie, lymphadenectomy)

General explanation

• Surgical removal of 1 or more lymph nodes 

Indication

• An option for initial therapy in patients with clinically evident lymph node involvement 

Contraindications

• No absolute contraindications

Complications

• Seroma
• Infection
• Paresthesia

Special populations

• Patients who are HIV-positive 
  • May receive highly active antiretroviral therapy concomitant with surgical resection, chemotherapy, and/or radiotherapy
  • May receive interleukin-2 to bolster T-cell immune response and prevent metastatic spread

Monitoring

• Perform complete skin and regional lymph node examination every 3 to 6 months for the first 3 years after diagnosis and every 6 to 12 months thereafter 
• Obtain imaging (eg, brain MRI; neck, chest, abdomen, pelvis CT) to identify and quantify regional and distant metastases as clinically indicated; routinely consider imaging for high-risk patients
• Individualize follow-up based on local recurrence risk, disease stage, and patient anxiety; immunosuppressed patients may require more frequent follow-up

Complications

• Tumor recurrence
• Regional or distant metastasis
• Secondary malignancy 
  • Most secondary cancers are extracutaneous; common sites include digestive tract, respiratory system, breast, and male genitourinary tract 

Prognosis of Merkel cell cancer

• Overall 10-year survival rate is 57.3% 
  • 10-year survival rate
    • Patient age 
      • 0 to 49 years: 59.1%
      • 50 to 69 years: 59.6%
      • 70 years or older: 52.7%
    • Anatomic site
      • Upper limb tumors: 60.7% 
      • Head tumors: 57.1% 
      • Lower limb tumors: 56.7% 
    • Tumor size 
      • Tumors up to 2 cm: 61%
      • Tumors larger than 2 cm: 39.6%
  • 5-year overall survival
    • Disease extent 
      • Local: 50.6%
      • Nodal: 35.4%
      • Distant metastatic: 13.5%
  • Unfavorable prognostic factors include male gender; head, neck, or trunk tumor; advanced tumor stage; and immunosuppression 

Screening

At-risk populations

• Patients who are immunodeficient (eg, those with HIV, those with a prior transplant)
• Patients with history of extensive UV exposure

Screening tests

• No specific screening; however, lesion may be detected during routine skin examination

Prevention

• Limiting sun exposure may reduce risk, particularly in people who are immunodeficient 

Sources

Albores-Saavedra J et al: Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 37(1):20-7, 2010 Reference