Meghana Anika Varde
Meghana Anika Varde received her medical degree from the University of Frankfurt am Main, Germany, and did her residency in ophthalmology at the Universities of Tübingen, Erlangen and Kiel. She completed a fellowship in Oculoplastics and Trauma at Sankara Nethralaya Eye Hospital in Chennai, India.
Dr. Varde has been working as a consultant at the KlinikumNordstadt in Hannover, Germany, for the past 6 years. Her main interests are Oculoplastics as well as Traumatology and globe reconstruction.
She is a full member of the European Society of Ophthalmic Plastic and Reconstructive Surgery and teaches Oculoplastic Surgery at Acha Eye Hospital in Cameroon. She is also examiner for the European Board of Ophthalmology.
Introduction and Epidemiology
Merkel cell carcinoma (MCC) is a rare, highly aggressive malignant tumour of the skin. The tumour is fast growing and tends to metastasize regionally and systemically. It usually presents in the white, elderly population, especially in immunosuppressed individuals. More than half of the MCCs are found in light-exposed areas of the head and neck.
The face is involved in about 27 % and the eyelids in 2.5–10 % of all cases [1, 2]. The upper eyelid seems to be more often affected than the lower lid . MCC represents an uncommon tumour in the eyelid. In a population-based study from Florida, it represented only 2.9 % of all non-basal cell and non-squamous cell carcinomas of the lid (both accounting for about 90 % of eyelid malignancies) .
Incidence of MCC is stated at 0.1–0.3 per 100,000 per year  although in the last years, an increase in incidence to 0.44/100,000 has been recorded in the USA . Ninety-three percent of the tumours arise in white-skinned patients and only 1.2 % in blacks. Male preponderance for MCC in general has been reported, although in the periocular region, females seem to be affected more often . The tumour is mainly found in patients above 65 years of age .
Aetiology and Pathogenesis
MCC is thought to be derived from Merkel cells, which are touch-sensitivity-associated cells located in the dermo-epidermal junction of the skin. In the eyelid, these cells are mainly found near the lashes, associated with touch receptors . The origin of the cells has been unclear until recently, since they exhibit neuroendocrine and epidermal properties. However, a recent study suggests the development of Merkel cells from epidermal stem cells rather than neural crest progenitors . Interestingly, MCC is located almost exclusively in the dermis and subcutis, although Merkel cells are epithelial cells. This might suggest the cellular origin of this tumour being in dermal progenitor cells rather than in the cell itself .
Recent research suggests a DNA virus named Merkel cell polyomavirus (MCV) to be a causative factor for the development of MCC. Integration of a part of the viral genome has been found in 80 % of MCC .
MCC is found mainly in whites on UV-exposed skin and incidence is higher in Australia. Moreover, patients receiving PUVA therapy (psoralen + UVA) for psoriasis have been found to present with a higher incidence of MCC . MCC incidence is also higher, and age of onset is lower in immunocompromised individuals following organ transplants, HIV infection or haematolymphoid diseases . Complete regression of metastatic Merkel cell carcinoma has been described . MCC is a dermal tumour and might not be directly related to UV skin damage, but rather to UV-induced downregulation of immune responses .
Clinical Presentation and Macroscopic Differential Diagnosis
Merkel cell carcinoma presents commonly as red or violaceous firm, painless nodule that can grow rapidly within weeks to months (Fig. 48.1). The surface is often smooth and shiny and ulceration is uncommon . Necrosis can occur in very fast-growing tumours. If the eyelid is involved, the margin is predisposed for the development of these tumours corresponding to the distribution of Merkel cells in the lid in the outer root layer of the cilia . Growth is usually as a nodule, inducing a variable amount of cilia loss and exhibiting telangiectasia. Satellite lesions can occur.
Merkel cell carcinoma of the left upper lid in an 87-year-old patient. Nodular appearance, shiny, red surface and dilated vessels
Histopathology and Microscopic Differential Diagnosis
Histopathology shows a solid, sometimes septate tumour in the dermis with uniform, small, monomorphous cells with basophilic cytoplasm and large, round, clear nuclei with prominent nucleoli. Many mitoses can be seen throughout. The tumour is characteristically separated from the overlying epidermis by a free zone of uninvolved dermis . Sometimes there are pseudorosettes and signs of high cell turnover such as necrosis and apoptosis. Lymphocytic and plasmacellular infiltrates commonly surround the lesion  (Fig. 48.2).
Merkel cell carcinoma H&E staining. Large monomorphous cells with basophilic cytoplasm and lymphocytic infiltrate. Arrow showing mitosis
Microscopic differential diagnoses are mainly lymphoma, metastasis of small cell (neuroendocrine) carcinoma of the lung and amelanotic melanoma. As discussed above, the tumour cells exhibit epithelial and neuroendocrine histologic properties, which are represented in the positive immunohistochemical (IHC) staining which is usually positive for low-molecular-weight cytokeratin (cytokeratin 20), neuroendocrine markers (neuron-specific enolase, synaptophysin) and neurofilament protein. Differentiation from amelanotic melanoma is with S100 and HMB-45 stains and from metastatic small cell carcinoma is with thyroid transcription factor-1 for which MCC is usually negative . Differentiation from cutaneous non-Hodgkin lymphoma can be made through the positive staining for cytokeratin and negative CD45 staining .
Classification and Staging
Staging and grouping of MCCs in general are done according to the ninth edition of the American Joint Committee on Cancer (AJCC) on the basis of Lemos et al.  wherein the eyelid is not included. Eyelid carcinomas are staged by the system designed by AJCC .
Tumours are grouped by their Tumour-node-metastasis (TNM) status into groups that define the treatment or enrolment into clinical studies as in cutaneous melanoma.
The staging of MCC in the eyelid and general skin differs to a significant extent because the proximity of the eyelid skin to other crucial structures (muscle, tarsal plate) renders it special treatment, and smaller tumours have greater impact on prognosis.
Although SLNB is generally recommended for skin MCCs, the use of it in eyelid Merkel cell carcinomas is still under debate. Histopathological evaluation of the lymph nodes (via SLNB or elective lymph node resection such as neck dissection or parotid gland dissection in case of eyelid tumours) has been shown to significantly improve prognostic accuracy in MCC  and that around one third of patients undergoing only clinical nodal evaluation are understaged because occult microscopic nodal involvement is overlooked . Currently, some authors recommend SLNB for Merkel cell carcinoma of any size, mainly for prognostic purposes [23, 24]. Distant metastases of MCCs have been found in node-negative patients, so that treatment of occult nodal disease might not necessarily mean a better prognosis in eyelid MCC.
Because of the rare occurrence, there is no consensus statement as to the preoperative metastatic workup of patients with MCC. In general, careful clinical examination and palpation of the regional lymph nodes (i.e. preauricular and parotid, cervical and submandibular) are recommended and as per clinical judgement ultrasonography of the lymph node basins and CT or MRI of the chest and abdomen. CT of the chest may be required to rule out neuroendocrine small cell carcinoma of the lung as differential diagnosis might be difficult even with IHC. Abdominal sonography and chest X-ray may be performed, although with limited sensitivity and specificity as discussed in the chapter for cutaneous melanoma. SLNB as stated above is currently controversial. PET/CT can accurately detect Merkel cell carcinoma and might be an adjunct in preoperative assessment . It is to be noted that in large prospective studies of MCC, 27–31 % of patients presented with nodal disease [1, 20]; hence primary nodal involvement has to be taken into account when evaluating this aggressive tumour.
There are no serum markers specific for MCC as of now.
Surgical excision is the standard treatment in Merkel cell carcinomas. In locations other than the face, surgical margins of 2–3 cm are recommended [26–28]. In the eyelid, margins are not specified, and some surgeons advocate micrographically controlled surgery, although this might miss some of the satellite lesions for which this tumour is known. Since MCC is radiosensitive, adjuvant treatment with radiotherapy might be advocated in cases that have undergone micrographic excision . Currently, most eyelid MCCs are treated without irradiation .
Local recurrences should be excised with the same curative concepts.
In case of lymph node involvement, resection of regional lymphatics is recommended , combined with adjuvant radiotherapy.
The excision of distant metastases can be considered if associated morbidity is acceptable, in combination with radiotherapy and chemotherapy and for palliative purposes.
Radiotherapy can be administered as adjuvant treatment for excised primary or recurrent tumours of the eyelid. The dose should be ≥50 Gy . A significant decrease in local recurrence following adjuvant radiotherapy has been demonstrated; unfortunately it does not seem to have an effect on overall survival [32–34].
Radiotherapy is recommended as adjuvant treatment following regional lymphadenectomy with a dose of 50 Gy.
In cases of macroscopic (residual) tumour or metastasis, the recommended radiation dose is ≥55 Gy .
Medical treatment has so far been limited to the treatment of systemic disease, adjuvant treatment in locally advanced disease and in palliative situations. The treatment is based on the chemotherapy used for small cell lung cancer, but a standardised chemotherapeutic regimen does not exist. Remission occurs partially in about 70–75 % of cases, and complete remission is seen in 40 %, although this does not seem to have an influence on survival [15, 35]. The significant toxicity of these substances has to be weighed against the expected benefit and the patient’s quality of life.
Future treatment strategies are targeted towards MCV-positive Merkel cell tumours. Immune response alteration might have a benefit in localised tumours. In one case report of an MCC treated with intralesional Interferon α– 2b , the tumour responded well , but in another report of two cases with MCV-positive disseminated disease, systemic treatment with interferon did not alter the course of the disease and had severe side effects . Nevertheless, further research regarding the role of MCV in the treatment of MCC is currently under way. Intralesional tumour necrosis factor alpha (TNF-α) showed regression of a tumour in one case report .