Merkel cell carcinoma is a rare and aggressive form of skin cancer that can grow rapidly and has a high risk of local recurrence and metastasis at an early stage. The disease most commonly occurs on areas of the skin exposed to the sun. At the time of diagnosis, one third of patients have regional lymph node involvement and one in ten patients has distant metastases.
The incidence of Merkel cell carcinoma is increasing. Sun exposure is a predisposing factor. Other factors are advanced age, light skin type, immunosuppression, and Merkel cell polyomavirus infection.
The disease is rare and prospective randomized studies of treatment and follow-up are lacking. In terms of treatment and prognosis, Merkel cell carcinoma has many similarities to malignant melanoma, but unlike malignant melanoma, Merkel cell carcinoma is very sensitive to radiation. Additionally, tumor diameter is an important factor for staging. Correct initial evaluation and treatment are critical for prognosis.
The purpose of this article is to provide a brief overview of the diagnosis and treatment of Merkel cell carcinoma. It is aimed at primary and specialty care physicians and is based on Scandinavian and international guidelines as well as the clinical experience of the authors.
| Initial diagnostic work |
Clinically, Merkel cell carcinoma is often misinterpreted as squamous cell carcinoma, basal cell carcinoma, or a benign condition such as a cyst, lipoma, or fibroma.
A rapidly growing, painless, reddish-purple skin nodule on sun-exposed skin areas in elderly or immunocompromised patients should raise suspicion of Merkel cell carcinoma.
If Merkel cell carcinoma is suspected, a diagnostic excisional biopsy of the entire tumor is recommended. Margins are not specified in the guidelines, but in our opinion, excisional biopsy should be performed in the same manner as for skin lesions suspicious for melanoma, with a margin of 2 to 5 mm on normal skin and with an underlying cuff. of subcutaneous fat.
In the case of lesions located in sites where scarring may be aesthetically disfiguring or lesions that cannot be completely removed, punch biopsies can be taken where the tumor is thickest, but not from the ulcerated areas. The clinical diameter of the tumor is crucial for staging. It should be measured before excision because shrinkage of formalin-fixed tissue can lead to underestimation of tumor diameter.
When resected tissue is sent to pathology, the referral should indicate that Merkel cell carcinoma is suspected, as well as the location and clinical diameter of the tumor. Immunohistochemical examination is necessary to differentiate Merkel cell carcinoma from primary and secondary undifferentiated small cell carcinoma, lymphoma, melanoma, sarcoma, and cutaneous metastasis from small cell lung cancer. Most Merkel cell carcinomas are positive for the marker CK20 and negative for TTF-1 . It can be challenging to reach a diagnosis, particularly if there are divergent results from immunohistochemical examination.
It is necessary to combine the case history, clinical, radiological and pathological findings to make the correct diagnosis. Satellite tumors and micrometastases are often seen adjacent to the primary tumor. Tumor thrombi are present in a high proportion of patients and it may be difficult to achieve clear margins, even if the tumor is removed with clinically good margins.
The main parameters for the correct management of the patient are the diameter of the tumor, the depth of the invasion and the status of the peripheral and deep margins. Other parameters to report are tumor thickness, vascular infiltration, local satellite metastases, mitoses, tumor-infiltrating lymphocytes, and Merkel cell polyomavirus status. One or more of the following characteristics identify a patient as high risk: primary head/neck site, immunosuppression, tumor diameter > 2 cm, or lymphovascular invasion.
Following a diagnosis of Merkel cell carcinoma, further investigation and treatment should be carried out in a hospital where there are surgeons, pathologists and oncologists with experience in this type of cancer and where the oncology department has experience in radical radiotherapy in the region of head/neck.
| Surgical treatment |
The goal of surgical treatment is radical excision of the primary lesion. International guidelines recommend excision of the tumor with margins of 1 to 2 cm, including tissue to the underlying muscle fascia, perichondrium, or periosteum.
On the face, adjacent vital structures and cosmetic considerations determine the limits of excision margins. Reconstruction requiring tissue undermining or flap surgery is not recommended until free margins are verified. Adjuvant radiation therapy to the tumor site is usually appropriate.
Clinical evaluation of regional lymph nodes should be performed as part of the preoperative examination of all patients with suspected or confirmed Merkel cell carcinoma. Patients with palpable regional lymph nodes should undergo ultrasound-guided fine-needle aspiration biopsy. One-third of patients without palpable lymph nodes have microscopic lymph node metastases, and sentinel lymph node biopsy is recommended.
| Radiotherapy |
US guidelines recommend observation of nonimmunocompromised patients with primary lesions less than 1 cm in diameter without lymphovascular infiltration who have undergone wide excision with clear margins. Adjuvant radiation therapy to the tumor site should be considered for all other patients.
Oslo University Hospital recommends adjuvant radiation of the tumor site for primary lesions with a diameter of more than 2 cm and for primary lesions with a diameter of less than 2 cm that were removed with positive or unclear margins, and where a new split is not possible.
| Pharmacotherapy |
Chemotherapy usually has a high response rate in metastatic Merkel cell carcinoma.
The duration of response is short, with a median duration of two to nine months. Treatment is associated with a high risk of serious adverse events, such as hematologic or gastrointestinal toxicity, renal failure, sepsis, and death. Patients with metastatic disease without significant comorbidities should be considered for chemotherapy.
Electrochemotherapy is a local palliative treatment that combines chemotherapy with electrical pulses. Electrical pulses are delivered through electrodes placed on the tumor. Electrochemotherapy is mainly used to relieve symptoms in exudative or foul-smelling skin lesions.
Isolated extremity perfusion may be an alternative for in-transit metastases or unresectable recurrence in extremities. Both electrochemotherapy and isolated limb perfusion are performed under general anesthesia.
| Follow-up |
Patients with Merkel cell carcinoma have a high risk of local and regional recurrence and distant metastasis. They should receive regular follow-up, mainly in an oncology department. The median time to recurrence is 8 to 9 months and 90% of recurrences occur within 2 years.
Follow-up should include inspection of the skin and palpation of lymph nodes. Imaging should be used on an individual basis, based on clinical findings and risk profile. For patients with Merkel cell polyomavirus antibodies, increasing antibody titer may be an early indicator of recurrence.
Radiological examination with CT or PET/CT is recommended annually for the first two years or as indicated. Patients with many sun-induced skin changes may be referred to a dermatologist.
