Merkel cell carcinoma is a frequently lethal cutaneous cancer that has a high propensity for lymphatic metastases and local recurrence, has poor prognosis. Several reports have described the association of MCC of the eyelids [17] with incidence between 5% and 20% of all cases of head and neck Merkel cell carcinoma [8,10,13]. Most commonly in the eyelid, the tumor affects the upper eyelid and develops near the eyelid margin, sometimes causing partial or complete eyelash loss. The skin covering the primary lesion is habitually hard, smooth-surfaced, and red, with hues ranging from pink to violaceous. Overlying telangiectasis is often present [13,19,20].

Clinical diagnosis of these tumors is difficult because they can present as benign lesions such as chalazion and keratoacanthoma.[12] or malignant tumors as basal cell carcinoma [9,21].

MCCs of eyelids tumors are usually treated initially as benign lesions, which leads to local recurrences. In addition, in many cases the histopathologic examination is not performed, resulting in a delay of the exact diagnosis.[12,19].

Merkel cell carcinoma requires aggressive and rapid initial therapy for a favorable outcome. Owing to the rarity of this tumor, it is difficult to conduct a randomized, prospective

study to define optimal treatment [22]. The standard of care for primary tumor is surgical resection with negative margins or Mohs micrographic surgery with or without adjuvant radiotherapy [14,15,22]. A wide excision with margins of 2,5 to 3 cm has been advocated and is based on studies showing a significant reduction in local recurrence rate by increasing the margins from 1 to 3 cm [12,22].

The role of radiotherapy in the management of eyelid MCC remains controversial. There is a decrease of local recurrence and improving survival rate after radiotherapy [23,24]. However, this has no effect on overall survival [25,26]. Currently, most eyelid MCCs are treated without irradiation. On the contrary, adjuvant chemotherapy for MCC has not shown benefits and has even been associated with increased morbidity and mortality. Even though patients may initially respond, resistance often develops [27]. Chemotherapy in MCCs  is used  in patients with metastasis or locally advanced tumors. Moreover, a high incidence of toxic death occurs due to chemotherapy.  [28].

MCC has demonstrated sensitivity to chemotherapeutic drugs such as cisplatin, cyclophosphamide, doxorubicin, vincristine, etoposide and 5-fluorouracil [22,28]. A retrospective review of 107 patients with locally advanced or metastatic MCC demonstrated overall clinical response rate to first-line chemotherapy of 61%, however, this study additionally demonstrated high toxicity-related mortality [28]. Combination chemotherapy is more effective than monochemotherapy [28].

Cisplatin plus etoposide, cyclophosphamide plus doxorubicin plus vincristine, or cyclophosphamide plus epirubicin plus vincristine are the most commonly used regimens [17]. The response rate is 70%, with a complete response in 35%. Interestingly, non-ocular MCC is reported to be a very aggressive tumor, lethal in 33% of patients.[17] Myelosuppression, sepsis, fatigue, alopecia, diarrhea, nausea and renal failure are the most common adverse events of chemotherapy reported in literature [29].

The development of new alternative therapies, such as immunotherapy with checkpoint inhibitors [CPIs], has shown good results in the treatment for advanced or metastatic diseases. and, consequently, CPIs are considered to be emerging immunotherapeutic options for these patients [29].

MCC of the head and neck has been shown to be particularly aggressive with higher likelihood of cartilage, bone, and skeletal muscle invasion when compared to MCC of other sites [10]. While eyelid and periocular lesions may arise earlier due to better visualization of the lesion in this location, MCC of the head and neck still demonstrates high incidence of spread to the regional lymph nodes with up to 2/3 of patients having regional lymph node metastasis and 1/3 of patients with distant metastasis within 18 months of diagnosis [13,14,21]. MCC of the eyelid has been reported to have an overall metastatic rate ranging from 10% to 30% [14,21,30], regional lymph node recurrence rate of 20%, and distant metastasis rate of 5%. The recent study by our group demonstrated a 22% metastatic rate overall which included an 11% nodal metastasis and 11% distant metastasis rate [14].

Distant metastasis from MCC regardless of anatomic sites most frequently occurs in the skin, bone, brain, liver, and lung [8,10,13]. The reported rate of distant metastasis is as high as 36% [21].