Merkel cell carcinoma

Approximate 2000 cases diagnosed in the US annually.

An aggressive lesion with local recurrence rates of an infiltrating skin cancer and regional and distant metastatic rates of a thick melanoma.

Thought to arise from Merkel cells in the basal layer of the dermis.

Typically presents as an integrated nodule on sun-exposed areas of the head and neck in the white population.

It has no definitive physical characteristics.

Typically is rapid growing and presents as a red-violet firm, and painless cutaneous nodule in sun exposed areas of the head and neck or upper limbs.

On immmunohistchemistry Merkel cells express both epithelial and neuroendocrine markers.

CK20 consistently positive with a paranuclear staining pattern.

CK20 and thyroid transcription factor 1 (TTF-1) provide the greatest sensitivity and specificity to diagnose MCC.

CK20 with its classic para-nuclear diet like pattern is positive and 89 to 100% of MCC cases.

TTF-1 expressed in small cell lung cancer, but is consistently negative in MCC.

Biopsy reveals three histological subtypes: A, intermediate type, which is the most common type B, the small cell type and differentiate, and C the trabecula type which is well differentiated.

Disproportionally affects elderly or immunocompromised individuals.

Its incidence among white patients and ultraviolet light radiation are correlated.

Hawaii’s population has the highest incidence of US states.

Risk factors for MCC are predominately linked to immunodeficiency conditions such as organ transplantation, the use of immunosuppressive therapy, HIV infection, and malignancies such as chronic lymphocytic leukemia, with a 34-48 fold increase risk of developing MCC.

About 90% of patients with MCC are immunocompetent.

Male:female ratio, 1.4:1.0.

Major risk factors include: immunosuppression, UV light exposure, and advanced age.

MCC lesions are commonly located on sun expose skin, and chronic UV exposure is likely involved in the increased incidence observed in people of advanced age.

Approximately 2488 cases per year in the U.S. with a mortality rate of approximately 33%.

The number of new cases per year of Merkel cell carcinoma (MCC) increased by 95% during 2000-2013, according to a review of Surveillance, Epidemiology, and End Results (SEER) data.

Its incidence is dramatically increasing by about 2.5-fold over 10 years, 3-fold over 15 years, and 5.4-fold over 18 years.

Between 2000 and 2013 alone, rates of MCC increased by 95%.

The increasing incidence of this skin cancer type has been attributed to the aging population.

Incidence increasing rapidly.

Almost exclusively in Caucasians and causally associated with excessive sun exposure.

Risk factors include: advanced age, chronic ultraviolet exposure, and immunosuppression.

Carcinogenesis is strongly associate with immune mechanisms.

Predominantly affects individuals with light skin.

43%of cases occur in the head and neck area.

Lesions can vary from flesh colored to red or bluish colored.

Mean age for men 74 years and for women 76 years.

The number of cases has been steadily growing over last few decades.

In the US approximately 2500 new cases are diagnosed per year.

MCC has a mortality rate three times greater than melanoma and the overall survival at five years ranges from 30-64%.

The great majority of tumors harbor a species of polyomavirus (Feng H et al).

Up to 80% of patients with MCC are associated with Merkel cell Polyomavirus.

It is presently suspected that Merkel cell polyomavirus is the causal of factor that underlies most cases.

Polyomavirus is a double-stranded DNA virus that has oncogenic potential and induces latent infections in immunocompetent hosts that may turn into Merkel cell tumors.

The risk of Merkel cell carcinoma is greatly increased in elderly people and in younger adults with who are infected with HIV or are immunosuppressed for other reasons. 

Infection does not generally cause symptoms, and there are no treatments for MCPyV.

Merkell cell polyoma is a ubiquitous double stranded DNA virus.

Patient with a virus-negative MCC have a significantly increased risk of disease progression in death relative to patients with MCC with virus-positive tumors.

MCC’s not driven by Polyomavirus represents a more aggressive subtype.

Prior to diagnosis, 63% of the primary lesions grew rapidly in the preceding 3 months, and 26% to 36% of cases have lymph node involvement on presentation, with up to half eventually developing metastases.

Histologically it has nests of basil epithelioid cells,  indistinct nuclei, scant cytoplasm  and numerous mitotic figures.

The lesion typically stains strongly for cytokeratin 20.

Differential diagnosis: basal cell carcinoma, metastatic small cell lung cancer come melanoma, Ewings sarcoma, and neuroblastoma.

About 50% of patients have a localized disease and surgical resection radiotherapy is generally indicated management.

Adjuvant radiation therapy improves the overall survival in patients with early stage Merkel cell cancer.

A smaller portion, 6% to 16%, have distant metastases on presentation, with up to one-third subsequently spreading.

Approximately 25% to 50% of patients with MCC experience disease recurrence.

Recurrent rates are high with overall poor prognosis and mortality rate of 33-46%.

Depending on the stage at presentation, the 5-year relative or MCC-specific survival rates are 41% to 77%.7,8 For patients with MCC who receive chemotherapy, prognosis is poor, with about 10% surviving 3 years after systemic treatment initiation.

MCC is a chemotherapy sensitive disease, but responses in advanced setting are seldom durable and not associated with improved survival.

Avelumab is a fully human IgG1 antibody, acting as a PD-L1 inhibitor elicits a response from the innate immune system to induce antibody-dependent cell-mediated cytotoxicity.

The efficacy of PD-1/PD-L1 inhibition in MCC may be related to the Merkel cell polyomavirus (MCPyV).

Most adults are infected with MCPyV, with transmission most likely occurring through casual direct, as by skin-to-skin, or indirect by touching a surface that an infected person has touched in early childhood. 

The Merkel cell polyomavirus (MCPyV) drives approximately 80% of cases.

Approximately 88% of older individuals with Markell cell tumor have positive antibody tigers specific to the capsid viral protein.

MCPyV-specific T-cells are present in up to 67% of patients with MCC.

MCPyV-specific T-cells represents a PD-1+ and Tim-3+ exhausted T cell phenotype.

PD-L1 is expressed in about 55% of these tumors.

Merkel cell polyomavirus detected in 43-100% of cases.

Average diameter of presenting lesions 7-10 mm.

Primary lesions generally appear as painless, rapidly growing, and no tender lesions.

Tumor diameter is the only pathological feature that predicts risk of local recurrence and likelihood of distant metastases.

Local recurrences of 25-30% of cases, regional disease in 52-59% an distant metastases in 34-36% of cases (Gillenwater).

The most common sites for distant metastasis or skin, lymph nodes, bone, and liver.

The five-year survival rates range from greater than 60% in patients with stage I disease to 13% in patients with stage IV disease.

Mortality exceeds that of melanoma with an overall 5 year survival of 30-64%(Allen PJ).

Patients with Stage I or II disease have a 5-year disease specific survival of 78%, while those with stage III disease have only a 54% survival.

Patients with metastatic disease have an overall 5-years survival rate of 0-18%.

Disease specific mortality rates of 28% by 2 years and 46% by 5 years after initial diagnosis have been reported (Lemos BD et al).

Frequently associated with solar keratoses, squamous cell and basal cell cancers.

Tends to occur on sun exposed skin.

Extensive sun exposure a major risk factor.

Nearly 15% of cases associated with immunosuppressive therapy.

Occurs in immunocompromised solid organ transplant patients 20 years younger than immunocompetent patients.

Higher incidence in HIV, or other malignancies.

Immunocompromised patients have a more aggressive disease with approximately 68% of transplant recipients presenting with lymph node metastases and 56% of such patients die of disease.

Associated with HIV infections.

Usually affects elderly white individuals with a mean age of 69 years, and manifests mainly in sun-exposed areas.

Most common sites of presentation are the head and neck, the extremities and the trunk.

Usually presents as a solitary, painless nodule in sun-exposed skin.

Usually presents with a fast growing violet colored skin nodule often on the face or extremity which are sun exposed.

Rarely presents with a classic clinical finding and diagnosis rests with biopsy.

Difficult to differentiate from metastatic small cell carcinoma of the lung histologically.

Most lesions are thick, deeply invasive, associated with regional nodal metastases and subclinical distant dissemination is present in many patients at diagnosis.

Lacks the ability to be recognized early in diagnosis.

Associated with delay in diagnosis.

Lesions are frequently asymptomatic, extending, associated with immunosuppression,, usually in patients older than 60 years, and located on the ultraviolet exposed site.

There should be a low threshold for performing a biopsy.

Sentinel lymph node biopsy is the most sensitive staging test for the detection of lymph node metastasis.

If sentinel lymph node biopsy is negative local treatment with radiotherapy and/or lymph node dissection is only indicated if there is a high risk of recurrence related to anatomic location or previous recurrence.

Sentinel lymph node biopsy is questionable when the primary tumor size is greater than 2cm, as radiotherapy is generally recommend regardless of nodal status.

Imaging testing, as clinically indicated, may be useful to identify distant metastasis because of the metastatic potential of MCC.

PET/CT scanning is increasingly used for diagnostic imaging, while CT or MRI may be used as well.

PET/CT scans have been known to change the stage and primary treatment in up to 22% of cases (Siva S et al).

Meta-analyses suggests the sensitivity and specificity of PET/CT are 90 and 98%, respectively (Treglia G et al).

Immunohistochemical staining is positive for cytokeratin 20 (CK-20) and negative for thyroid transcription factor 1(TTF-1) with cytokeratin-20 positive 83-100% positive for Merkel cell carcinoma and TTF-1 absent for this lesion.

Pathology reports sure describe tumor size, depth, mitotic rate, lymphovascular invasion, any extra cutaneous extension to muscle facia, carilage, or bone, and peripheral and deep margin status.

Primary treatment is stage I disease is surgical resection.

Excisional biopsy of the entire lesion with narrow clear margins is the management of choice to obtain diagnostic and micro staging information.

Definitive excision with or without sentinel lymph node biopsy is subsequently performed.

Sentinel lymph node biopsy is usually recommended with early-stage MCC and should be performed inttaoperatively during wide local excision, as surgery may alter lymphatic drainage.

When sentinel lymph node biopsy is positive, a lymph node dissection or definitive radiation therapy is indicated.

Immunohistochemistry analysis of the sentinel lymph nodes for cytokeratin 20 (CK-20) allows for identification of micro metastases.

Immunohistochemistry CK20 positive 89-100% of cases.

Immunochemistry TTF-1 positive 83-100% of cases of small cell lung cancer, but is absent in Merkel cell carcinoma, and helps differentiate the two.

70%-80% of patients have stage I disease.

10%-30% have stage II disease (regional lymph node involvement).

2%-4% present with stage III (metastatic disease).

Patients with head and neck have the highest rate of local recurrence but still the best overall 5-year survival rates (91%).

Radiosensitive tumor and the use of adjuvant radiation therapy to the primary site and regional lymph nodes reduces the risk of local regional recurrence from 10% with radiation to 52% without radiation.

Overall recurrence rate is 55%-79%.

Improved survival following relapse include recurrence after more than 8 months, lymph node metastases rather than local regional or distant metastases or head and neck primary.

The most common site of recurrence is in the regional lymph nodes.

Median time to recurrence is 8 months, with the majority of recurrences occurring within 24 months and rarely beyond 36 months.

Overall survival following local regional recurrence is 30-62%.

Although rare at presentation distant metastases develop in 30-70% of patients.

Once distant metastases occur median survival in 5-9 months.

Extent of disease at presentation is predictive of outcome.

Involves regional lymph nodes in up to 45% of patients at presentation.

Up to 75% of patients have regional lymph node involvement during the course of the cancer.

Most consistent reported adverse prognostic factors are tumor stage and tumor size.

Local wide excision is the recommended treatment for localized disease.

Wide excision is recommended to achieve 1-2 cm clear margins, when feasible.

Excision with wide margins and complete peripheral margin examination and Moh’s surgery are suggested techniques.

Elective lymph node dissection decreases regional recurrence rates and improved survival.

Sentinel lymph node biopsy is standard procedure for most institutions.

Sentinel lymph node biopsy should be accomplished before definitive local excision.

With a positive sentinel lymph node biopsy a completion nodal dissection and or radiation is appropriate care.

Post operative radiotherapy is administered to reduce the risk of local recurrence when risk factors such as: primary tumor greater than 1 cm, head and neck location, positive or limited surgical margins, lymphovascular invasion, multiple involve lymph nodes, extracapsular node involvement, or the presence of immunosuppression.

The addition of radiation following lymph node dissection is generally recommended if multiple nodes are involved or extracapsular extension is present.

Adjuvant chemotherapy after resection is not routinely recommended because of lack of survival benefit, and concern for chemotherapy’s immunosuppressive effects.

Adjuvant immunotherapy is presently being considered with pembrolizumab, nivolumab, or ipilimumab.

Frontline therapy consists of a platinum-based chemotherapy plus etoposide, which produces an initial response rate of approximately 50%, but most responses are not durable.

Management of chemotherapy for metastatic disease has benefits which are uncertain.

Response rates range from 29-75% with cytotoxic agents such as platinum, etoposide, cyclophosphamide, vincristine, doxorubicin, and topotecan, either alone or in combination.

Chemotherapy responses are generally of short duration of the median progression free survival of 3-4 months in a median overall survival of less than 10 months.

More than 90% of patients will progress on chemotherapy within 10 months on average, with approximately half of these events occurring within the first 3 months.

Approval for pembrolizumab and Avelumab for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma.

Retifanlimab-dlwr (Zynyz), is an intravenous programmed death receptor–1 (PD-1) inhibitor for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma.