Guidelines for the diagnosis and treatment of Merkel cell carcinoma – Cutaneous Oncology Group of the French Society of Dermatology

ARTICLE

ejd.2012.1694

Auteur(s) : Olivia Boccara¹, Celine Girard², Laurent Mortier³, Guido Bens⁴, Philippe Saiag¹, Bernard Guillot² b-guillot@chu-montpellier.fr

¹ Dermatology Department, Hôpital Ambroise-Paré, 92100 Boulogne, France

² Dermatology Department, Hôpital Saint-Éloi, 80 rue A. Fliche, 34295 Montpellier, France,

³ Dermatology Department, CHU de Lille, 59037 Lille, France

⁴ Dermatology Department, Porte Madeleine Hospital, 45032 Orléans, France

Reprints: B. Guillot

Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm belonging to the group of neuroendocrine tumors. Its incidence in France is unknown. MCC is an aggressive disease, with frequent locoregional recurrences and visceral metastatic evolution. Local recurrence rates have been reported to be between 25 and 33% and the risk for visceral metastases is about 33% in recent series [1-3]. The mortality rate of MCC is higher than for melanoma and the five-year survival rate is 30 to 64% [4-6]. The main risk factors for MCC are age over 65 years, fair skin, sun exposure, and immunosuppression [7]. Recently, a new polyomavirus was identified which seems to play a role in the pathogenesis of the tumor [8].

The treatment guidelines are not well defined, mainly because of the rarity of the tumor, which also prohibits randomized clinical trials. The clinical practices in France are heterogeneous and only two sets of guidelines have been created for the management of MCC: the American and the German guidelines [9, 10]. However, as these guidelines disagree on several items, the Cutaneous Oncology Group of the French Society of Dermatology recently developed a set of guidelines, adapted to French clinical practice, with the goal of standardizing tumor management. The guidelines were recently published in French [11].

Methods

The guidelines were created in three steps. First, the American and German guidelines were compared one to the other and if consensus was shown on a specific point, the recommendation was retained. The second step was a systematic analysis of the literature data by a working group, with proposals retained if the level of evidence was judged to be sufficient. This step was of poor quality since controlled trials are very rare and strong evidence is lacking on many points. The third step was a formalized expert consensus achieved using the methodology published by the Haute autorité de santé in France (HAS) [12]. The guidelines were classified according to three levels of recommendation:

• (a). consensus expressed in the two sets of guidelines,
• (b). proposals based on the formalized expert consensus,
• (c). proposals from the working panel based on findings in the literature data.

Results

Diagnosis

MCC is diagnosed by histological examination of a biopsy sample or after tumor excision. Standard coloration (haematoxylin and eosin staining) should be completed by immunohistochemical markers, including at least the expression of cytokeratin 20 and thyroid transcription factor 1 (TTF1) [13-16] to differentiate MCC from small cell lung cancer (a). Other recommended markers are: CK7, PS100, CD45, synaptophysin, NSE, and chromogranin A for specific and differential diagnosis [17]. In terms of prognosis [18], the working group recommended measuring the tumor thickness and checking for evidence of neural invasion (c).

Initial workup

Examination of the whole body, with a full examination of the skin and nodes, is mandatory (a). Ultrasonography of the nodes in drainage areas is recommended (b). Thoracic and abdominal CT scans should be proposed, as well as brain imaging if the lesion is located on the head or neck (b). The usefulness of MRI or PET scans should be discussed by the multidisciplinary tumor board. Sentinel lymph node dissection is recommended if localization of the tumor permits it (a).

Classification

Many classification systems have been proposed in the literature, which may lead to confusion [1, 2, 19-25]. The working panel proposed that the American Joint Committee on Cancer (AJCC) classification, 7th edition, to be retained for staging [26, 27] (c). This classification is summarized in table 1.

Table 1 American Joint Committee on Cancer classification (AJCC) 2010: Cancer Staging Manual, 7th ed. New York, NY Springer; 2010: 318-9

Treatment

Surgery

Surgery is the first-line treatment for MCC primary tumor. The recommended excision margins are between 2 and 3 cm (b). Excision larger than 3 cm is not useful. If localization is not compatible with these margins, 1 centimeter can be used. In this case, two-step surgery or Mohs micrographic surgery should be considered [28, 29]. For clinically lymph node negative (cN0) patients, sentinel lymph node biopsy will need to be performed. Histological analysis of the node is performed, using haematoxylin and eosin staining [26, 30, 31] and the above mentioned immunohistochemical panel [32, 33] (a).

For N+ patients, radical lymph node dissection should be performed, even though an improvement in overall survival has not been demonstrated [20, 23, 24] (a).

Radiotherapy

External radiotherapy on the site of the primary tumor is recommended (a) since radiotherapy seems to decrease the risk of loco-regional recurrence and may increase overall survival [34-37]. If surgical excision cannot be done, radiotherapy alone should be proposed [38] (c).

If the sentinel lymph node procedure has not been performed, radiotherapy of the draining nodal area should be considered, based on age, comorbidity and the primary tumor characteristics: this treatment is advised if primary tumor size is greater than 2 cm in diameter (c).

If sentinel node biopsy has been performed and the nodes are negative, radiation of the nodal basin is not recommended but could be discussed in a multidisciplinary tumor board. Conversely, if the nodes are positive, radiotherapy should be proposed (a). The usual dose for the treatment of localized MCC is 50 Gy with 3-cm margins and a booster dose of 10 Gy to the tumoral bed (a).

Chemotherapy

In the absence of metastases, chemotherapy does not increase overall patient survival [39]. It should thus be reserved for metastatic disease, although it does not improve overall survival. The two regimens classically proposed are an association of carboplatin and etoposide and the combination of cyclophosphamide, doxorubicin and vincristine [40-43] (c). In elderly patients with advanced disease, palliative care should be considered (c).

Follow-up

Strict follow-up is important after treatment since the risk of relapse and metastases is high in MCC [21, 25, 28] (a). However, the literature shows no consensus. One recommendation could be to follow the patients every three months for the first two years and then every six months for the next three years. Ultrasonography of the regional lymph nodes is optional. CT scans, MRI and PET scans should be considered on the basis of the clinical examination results (c). All these propositions are summarized in figures 1 to 3.

Disclosure

Financial support: None. Conflict of interest: none.

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