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Three hundred and five normal Merkel cells (MC) were studied in rabbit lip specimens by a double indirect immunofluorescence technique using both neurofilament (NF) antiserum and a monoclonal antibody to rabbit MC. NF proteins were not found to be expressed in MC. This suggests that MC are not neural cells and that NF-positive neuroendocrine carcinomas of the skin do not derive from MC.
Although epidermal Merkel cells (MC) are able to form synapses and synthetize neuromediators, they can be considered as being of epithelial nature because of the presence of cytokeratins in their cytoskeleton and desmosomes on their membranes. Since epidermis is an epithelium undergoing permanent renewal, it was important to determine whether MC were able to renew, as neighbouring keratinocytes do. This was investigated by studying whether S phase nuclei could be found in cells bearing a specific MC marker. The technique consisted of injecting rabbits with bromodeoxyuridine (BrdUrd) and performing double immunofluorescence on skin sections with the antikeratin number 8 monoclonal antibody (MAb) TROMA-I and anti-BrdUrd MAb. The results show that, in contrast to the neighbouring epidermal cells, the great majority of MC were found to be devoid of BrdUrd labelling, indicating that most of these cells are unable to divide, or divide very rarely.
Since its original description in 1972, we have seen and personally treated a group of 15 patients with Merkel cell carcinoma at the Vanderbilt Medical Center and the Nashville VA Hospital. We will review the demographics, management, and clinical course of this extremely lethal but initially benign appearing cutaneous malignancy. The majority of lesions occur on the head and neck, followed by the extremities and trunk. Location of the primary tumor has no effect on outcome. Despite a high mortality in our series (10 of 15), early recognition and aggressive surgical therapy may be the only way to prolong survival. No other adjuvant therapy has proved effective.
The role of radiotherapy in treating local and regional disease in patients with clinically localized Merkel cell carcinoma remains controversial. Given the lack of randomized evidence and patient and treatment heterogeneity in published retrospective series, sound clinical judgment is required to assess individual patient risk factors. Although many single-institution series have shown that adjuvant radiation to the primary tumor site decreases the risk for local and regional failure, evidence is emerging that there is a cohort of patients at relatively low risk for local recurrence after wide local excision alone. Node dissection, radiotherapy, and combined modality treatment may all play a role in managing occult or clinically evident nodal disease, depending on the anatomic location of draining lymphatics and the extent of microscopic or macroscopic disease. For select patients, primary radiotherapy is a reasonable option with a low risk for local or regional recurrence.
Four patients with primary neuroendocrine carcinoma of the skin (Merkel cell or trabecular carcinoma) are reported to document their response to radiotheraphy. In three patients there was complete response following radiation treatment, with no local recurrence, whilst the other patient died later with distant metastases. In one patient, post-operative irradiation after excision of an involved local node prevented the growth of further tumour in this nodal group but the unirradiated primary site recurred after initial wide local excision only. This rare tumour appears to be radioresponsive, and although more clinical data are required, we would advocate a wider study of radiotherapy to the primary lesion after biopsy or excision biopsy, in association with prophylactic nodal irradiation. These tumours occur predominantly in elderly people in whom the avoidance of extensive surgery is particularly desirable.
Some Merkel cell carcinomas (MCC) have been reported to regress spontaneously. To clarify the mechanisms of spontaneous regression (SR) of MCC, we analyzed the TUNEL index, the labeling index of proliferating cell nuclear antigen (PCNA), the labeling index of bcl-2 protein, and the expression of p53 of the tumor cells. We also evaluated the number of infiltrating lymphocytes surrounding the tumor in the tissue specimens. Among seven patients with MCC (SR: n=4; non-regression (NR): n=3), the TUNEL index in the SR group was significantly higher than that in NR group (5.2 and 2.0%, respectively). In addition, the number of lymphocytes around the tumor nests was also significantly increased in the SR group compared to NR group (1576 and 663 cells/mm(2), respectively). Most of the infiltrating lymphocytes were UCHL-1 positive T-cells. There were no significant differences of the PCNA labeling index, the bcl-2 protein labeling index, and the expression p53 between SR and NR group. These results indicate that apoptosis and local T-cell mediated immune response might be involved in spontaneous regression of MCC.
We present the clinical and pathological features of two cases of facial Merkel cell carcinoma (MCC) and a critical reappraisal of the literature on this subject. Among patients with this presentation of a rare neoplasm, the disease is very often localized (local or locoregional growth, without distant metastases). Radiotherapy seems to be highly effective in obtaining local control and possibly cure, even when used as the sole treatment method; prompt regression of the neoplastic masses has been observed in both the cases we treated. One of them, and many of those reported in the literature and treated with radiotherapy alone or combined with surgery, achieved long-term survival.
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Neuroendocrine carcinoma of the skin, Merkel cell carcinoma, is an aggressive malignancy with a high incidence of local recurrence and metastasis. We describe a case of neuroendocrine carcinoma of the skin with unusual metastatic spread to the bone marrow in a 55-year-old man with systemic lupus erythematosus. Following resection of a left temporal subcutaneous nodule and complete left parotidectomy and radical lymph node dissection, the patient presented with pancytopenia. Although focal bony metastatic disease was not identified, his bone marrow was diffusely replaced by metastatic carcinoma. High-dose chemotherapy allowed a brief remission; however, the patient subsequently died with central nervous system metastases.
BACKGROUND: Optimal treatment of primary Merkel cell carcinoma (MCC) is unknown. High local recurrence rates after excision alone compel some physicians to advocate postoperative radiation therapy to improve local control. OBJECTIVE: We wondered whether marginal recurrence and survival rates differed between patients with primary MCC treated with Mohs surgery alone and those treated with Mohs surgery and adjuvant postoperative radiation. METHODS: A collaborative retrospective study was performed; the study group consisted of 45 patients with stage I MCC who were histologically and clinically free of disease after Mohs excision. Twenty patients subsequently received elective postoperative radiation to the primary site, and 25 patients had no adjuvant radiation therapy. RESULTS: One marginal recurrence (4%) and 3 in-transit metastases were observed in the Mohs surgery alone group, whereas none were observed in the Mohs surgery and radiation group. The proportion of patients with these events was not significantly different between treatment groups. Overall survival, relapse-free survival, and disease-free survival were not significantly different between treatment groups. CONCLUSION: Adjuvant radiation appears unessential to secure local control of primary MCC lesions completely excised with Mohs micrographic surgery. Adjuvant radiation is recommended for patients unable to have complete excision or if complete histologic margin control is unavailable and should be considered for patients with large or recurrent tumors.
Histopathologically, 18 of our patients had classical Merkel-cell carcinomas (MCC); seven had neuroendocrine (NE) carcinomas with features different from MCC, here called "aberrant MCC". These patients showed a progressive neoplastic disease with a fatal outcome in four of them. The cytometric DNA distribution pattern of the tumor cell nuclei of all the aberrant MCCs was found to be of the aneuploid type. By contrast, the neoplastic disease of the majority of patients with classical MCC ran a milder course; a fatal outcome occurred in only one of them. Here, the DNA ploidy pattern was of the euploid (diploid or tetraploid) type in eight cases and of the aneuploid type in another eight. Our recently described "proliferation cell index" (PCI), based on nuclear immunoreactivity (IR) with the proliferation "marker" antigen Ki-67, was significantly lower in those five MCCs of the classical "DNA-diploid" type than in the seven "DNA-aneuploid" ones. These five patients presented a mild neoplastic disease; only one had a local recurrence and none had metastases. Otherwise, neither the PCI values nor the NCAM IR of the MCC cells were found to be of any prognostic significance.
A new case of primary Merkel cell carcinoma (MCC) of the vulva is reported and the literature reviewed for noting its clinical presentation, microscopic, immunohistochemical and ultrastructural features, as well as for establishing the role of immunohistochemistry in the ultimate diagnosis of this uncommon and aggressive tumor. The lesion occurred in a 79 year old patient. Histologically, the tumor was composed of intradermal small cells with high mitotic index and frequent apoptosis. The immunohistochemical study showed positivity for wide spectrum and low molecular weight cytokeratins, epithelial membrane antigen, neurofilaments, neuron specific enolase and chromogranin A. Electron microscopy revealed intermediate filaments in a typical globular paranuclear arrangement. The coexpression of cytokeratins (including cytokeratin 20) and neurofilaments, both in typical globular paranuclear arrangement, made possible the diagnosis of MCC, differentiating it from other malignant small cell tumors such as neuroendocrine metastatic carcinoma.
The authors report a case of lymph node metastasis of a Merkel cell carcinoma with unknown primary localization. The definitive diagnosis was posed histologically since the FNA report was--in this case--only "coherent with a small malignant cells proliferation".
BACKGROUND: The purpose of the current study was to determine the outcomes of patients with previously untreated Merkel cell carcinoma of the skin who were treated with curative intent. METHODS: Between October 1984 and January 2002, 34 patients were treated with radiotherapy alone (2 patients) or combined with surgery (32 patients). Nine patients received adjuvant chemotherapy. Patients had follow-up for a median of 3.0 years (range, 0.3 to 18.5 yrs). Follow-up on living patients ranged from 2.2 to 18.5 years (median, 7.1 yrs). RESULTS: The 5-year outcomes were as follows: local control, 94%, locoregional control, 80%; freedom from distant metastases, 60%; cause-specific survival, 52%; and survival, 37%. No patient experienced a severe complication. CONCLUSIONS: Patients treated aggressively with surgery and locoregional radiotherapy have about a 50% chance of cure. Limited data suggest that definitive radiotherapy alone or after incomplete macroscopic resection may control locoregional disease in a significant subset of patients. The dominant site of failure was distant.
The authors report the case of an 81 year old woman with a Merkel cell tumor (trabecular carcinoma, cutaneous neuroendocrine carcinoma). A review of the literature is used to recall the principal clinical and pathological characteristics of this rare tumor and to define treatment modalities.
A high incidence of local recurrence, spread to regional lymph nodes, and distant metastases has been reported after surgical excision of Merkel cell tumors (MCT). The use of postoperative radiation therapy and/or chemotherapy is reviewed from the literature. Despite adjuvant treatment, local tumor recurrences frequently develop. Two patients are presented with metastatic MCT recurrent in previously irradiated sites who had excellent clinical responses and local control following retreatment with local hyperthermia in conjunction with low to moderate dose radiation therapy. These patients represent the first reported use of hyperthermia in the management of MCT. The encouraging local responses described suggest a potential role for the use of hyperthermia and concomitant radiation therapy in the treatment of recurrent MCT.
The clinical and pathological features of two Merkel cell carcinomas of the eyelid skin are reported. Both tumours occurred in the upper lid in elderly women and enlarged rapidly to form smooth, round nodules which projected from the lid surface anterior to the grey line. In one case the primary excision biopsy was followed by a wider excision in 1982, and the patient has been free from recurrence or metastases in the intervening period. In the second more recent case, the tumour was inadequately excised in 1984 and the lid was treated by radiotherapy: this patient is at present free from recurrence. Histological examination of each tumour revealed an identical morphology - characterised by the presence of uniform polyhedral cells with multiple nucleoli lying in nests and lobules within the dermis: mitotic figures were prominent. Immunohistochemical studies showed the cells to react positively with antisera against neurone-specific enolase, epithelial membrane antigen and met-enkephalin. Electron microscopy revealed only rare neuroendocrine granules in one tumour, and numerous granules in the other. Intranuclear rodlets were not identified and there was paucity of cell membrane attachment modifications.
Merkel cell carcinoma of the skin has only recently been described. From the literature 115 cases are analysed. This carcinoma is most probably far more common than would be assumed from the few publications presently available. Between 40 to 50% of tumours are found in the head and neck area. Clinically the tumour presents as a typical bluish red firm intracutaneous nodule with the overlying skin intact, and sometimes malignant melanoma-like intracutaneous satellites. Regional lymph node metastasis is frequent and the five year survival rate, although not yet available, may well be about 50% or less. Clinical diagnosis is of paramount importance, as final diagnosis is only confirmed by electron microscopy and routine light microscopy leaves a wide range of differential diagnoses. In our case all typical characteristics are present. A cervicofacial flap which utilizes the abundant cervical skin for direct closure of the secondary defect in a U-Y manner was used to cover the primary defect. The flap is based on the preauricular area. Advantages and indications for the cervicofacial as opposed to Esser's cheek rotation flap are discussed.