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A tumour, a cell, a misunderstanding: trabecular (Merkel cell) carcinoma of the skin.

Trabecular carcinoma has been renamed as Merkel cell carcinoma because, ultrastructurally, tumour cells resemble Merkel cells of the skin. Recently, evidence of exocrine (sweat gland) differentiation in some trabecular carcinomas has been reported. These findings raise two possibilities: (1) trabecular carcinomas are a heterogeneous group of lesions; or (2) that trabecular carcinomas are glandular tumours, in which exocrine features are rarely detected.

Carcinoma, Merkel Cell↗

Evidence of turnover of mammalian Merkel cells.

The Merkel cells in the snout of the pig and the lips of the sheep were studied by transmission electron microscopy. They were subdivided into three main subgroups that are believed to represent different stages in the life cycle of the cells. A final dermal disintegration of the cells is proposed. The observations are discussed in relation to earlier reports on the avian Merkel cells.

Animals↗

[Melanocytes, Langerhans and Merkel cells in oral epithelium].

The fine structural morphology of melanocytes, Langerhans cells and Merkel cells in the normal dorsal epithelium of the human tongue has been studied by electron microscopy. Melanocytes were regularly found in normal papillary epithelium, even in the absence of clinical signs of pigmentation. The basal epithelial melanocyte contains individual pigment organelles at different stages of maturation and rudimentary half-desmosomes were found between the melanocyte and the basal membrane. The suprabasal Langerhans cells can be identified by their specific organelles and by the lack of tonofilaments and desmosomes. The morphological features of these cells suggest functional relations to cell structures of the keratinocytes and to the epithelial keratinization process. The Merkel cell is characterized by a horizontal orientation in the basal epithelial layer, the development of desmosomal attachments to keratinocytes, the lack of tonofilaments, the typical Merkel cell granules and an associated axon terminal. The observation of Merkel cell granules in relation to the Merkel cell plasmalemma and the morphological similarity of these granules to the monoamine-storing granules in certain types of chromaffin cell system suggest a symbiotic union between the specialized Merkel cell and the associated neurite with a neuroepithelial tactile receptor function. Because of their specific ultrastructure, the Merkel cells are thought to constitute a self-maintaining cell population, independent of keratinocytes and dendritic cells, in the oral epithelium.

Basement Membrane↗

Cutaneous undifferentiated small (Merkel) cell carcinoma, that developed synchronously with multiple actinic keratoses, squamous cell carcinomas and basal cell carcinoma.

Merkel Cell Carcinoma (MCC) is an uncommon undifferentiated neuroendocrine tumor, arising in skin mainly on sun-exposed areas. We present an unusual case of primary cutaneous undifferentiated small cell carcinoma that co-existed with six other lesions; 2 actinic keratoses, 3 squamous-cell carcinomas and a basal-cell carcinoma. HE stained sections revealed MCC located in the mid-dermis, co-existing with severe actinic keratosis. Immunohistochemically, the tumor cells reacted to cytokeratin 20, epithelial membrane antigen, chromogranin and neuron specific enolase. This is an unusual case of cutaneous MCC co-existing with six other different lesions. The concurrent development of MCC, squamous-cell and basal-cell carcinoma in the same patient indicates the pluripotent epidermal stem cell origin of these tumors. Further research is needed to enlighten the factors inducing this divergent differentiation.

Aged↗

Early development of human Merkel cells.

Human fetal Merkel cells are now generally considered to be epidermal derivatives. Previous studies using antibodies against the simple epithelial cytokeratins (CKs), 8 and 18, have demonstrated the presence of these cells in the epidermis at as early as fetal week 10 to 12. Using antibodies against CK 20 whose expression within the skin is restricted to Merkel cells, we applied immunofluorescence and immunoperoxidase microscopy to analyze earlier embryonic and fetal human skin (wk 7 to 9). We were able to demonstrate the first Merkel cells at as early as fetal wk 8, i.e., at the same time as the epidermis starts to develop an intermediate, third layer, characterized by the expression of CKs 1, 10, and 11. Most of these early Merkel cells were localized above the basal layer. Their shape was round to oval, dendrites being infrequent and short. At fetal wk 9, Merkel cells were considerably more numerous. These results persuasively argue for a much earlier fetal development of Merkel cells within the epidermis than previously thought. A hypothesis concerning the differentiation of Merkel cells from embryonic basal keratinocytes is discussed.

Antibodies, Monoclonal↗

[Merkel cell carcinoma].

Merkel cell carcinoma is a rare disease. During the last five years we have treated two patients at the Cancer Department, University Hospital Tromsø. These two cases are reported. Immunohistochemical analysis and electron microscopy are important for a precise diagnosis. The primary treatment is surgery. There is usually a need for supportive radiotherapy. The disease is also sensitive to chemotherapy.

Aged↗

Transient complete remission of metastasized Merkel cell carcinoma by high-dose polychemotherapy and autologous peripheral blood stem cell transplantation.

Merkel cell carcinoma (MCC) is a rare cutaneous tumour with neuroendocrine differentiation. Metastasis occurs preferentially to regional lymph nodes but distant and multiple visceral metastases may occur. Chemotherapy has been performed with a variety of protocols based largely on agents active in small-cell lung cancer. Owing to the rarity of MCC, there is no standard protocol for the treatment of metastatic disease. We report a 59-year-old patient with systemic metastatic MCC. After diagnosis of distant metastases, first-line polychemotherapy (cisplatin 80 mg m(-2), doxorubicin 50 mg m(-2), etoposide 300 mg m(-2) and bleomycin 30 mg) was administered four times at 3-weekly intervals and resulted in partial remission of metastases. Subsequently, high-dose chemotherapy according to the PEI regimen (ifosfamide 12 g m(-2), carboplatin 900 mg m(-2) and etoposide 1500 mg m(-2)) was applied, followed by autologous blood stem cell transplantation (ABSCT). This protocol resulted in a complete remission that lasted for 6 months. This is the first report on a complete remission of metastatic MCC after high-dose polychemotherapy and ABSCT. High-dose chemotherapy might be a therapeutic option in chemosensitive metastatic MCC, and further evaluation is warranted.

Antineoplastic Combined Chemotherapy Protocols↗

Expression of cyclin A in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare and aggressive primary neuroendocrine carcinoma of the skin. Large tumours, in particular, show rapid progression and metastatic dissemination, while smaller tumours show less aggressive behaviour. Cyclin A is considered to play a central role in cell cycle control. Its overexpression has been found to correlate with prognosis in many types of carcinomas and sarcomas. Twenty-six MCC patients with complete clinical data were selected. Formalin-fixed paraffin-embedded primary tumour samples were immunohistochemically stained for cyclin A. Correlation between expression of cyclin A and primary tumour size, invasion of subcutaneous tissue, local recurrence, metastasis and survival was statistically analysed. Twenty-five samples expressed cyclin A, and the mean value of positive cells was 25%. Our findings demonstrate that even small and superficial MCC show overexpression of cyclin A. There was no statistical correlation between cyclin A expression and the above-mentioned variables. Cyclin A does not seem to be useful as a prognostic tool. Consequently, size of the primary tumour (>/=2 cm) remains the primary prognostic tool. As a result every tumour, even those small in size, should be considered aggressive and treated radically and rapidly.

Aged↗

[Merkel cell carcinoma].

Merkel cell carcinoma is a rare form of skin cancer of likely neuroendocrine origin wich affects mainly white population in sun-exposed areas. It is an aggressive tumor and survival is dependent on stage at the time of diagnosis. The staging evaluation include CT imaging and recently PET scan. Surgical excision with or without lymph node dissection, followed by postoperative radiotherapy in stage II disease, is the standard treatment of non metastatic disease. The role of adjuvant chemotherapy is still controversial. In patients with metastatic disease, chemotherapy regimens active in small cell lung cancer are generally used. The combination of cyclophosphamide, doxorubicin and vincristine (CAV) has an overall response rate of 75%, whereas the response rate of etoposide in combination with cisplatin or carboplatin is 60%. Experience with other therapeutic agents, such as tumor necrosis factor, interferon and octreotide is scanty. Recently, encouraging preliminary results with targeted agents have been reported. Our experience in 14 patients, four of whom treated with chemotherapy for advanced disease, is in agreement with literature

Adult↗

Absence of classical MAP kinase pathway signalling in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a highly metastatic skin tumor. To assess the relevance of the Ras/Raf/MEK/MAP kinase pathway, we analyzed for activating B-Raf mutations and we elucidated the presence of the Raf Kinase Inhibitor Protein (RKIP) and extracellular signal-regulated kinase (ERK) as well as the phosphorylation status of ERK. All MCC samples were negative for the B-Raf(V600E) mutation. Remarkably, RKIP, which was shown to interfere with the activation of MEK by Raf, was highly expressed in primary as well as in metastatic MCC. Immunohistochemical analysis of the phosphorylation status of ERK revealed in 42 out of 44 samples a complete lack of activated ERK in the tumor cells although ERK is expressed; in the two positive cases phosphorylated ERK was restricted to a minor fraction of the tumor cells. Western blot analysis of three MCC-derived cell lines revealed in one case the pattern present in situ (i.e. high RKIP expression and complete absence of phosphorylated ERK). In summary, our data demonstrate the inactivity of the classical MAP kinase signal transduction pathway in MCC, which seems to be because of lack of activation as well as active deactivation. These findings should be accounted for in future therapeutic approaches for this tumor.

Androgen-Binding Protein↗

Molecular analysis of 1p36 breakpoints in two Merkel cell carcinomas.

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin. Only little information is available on the genetic alterations occurring in this tumor. Cytogenetic studies thus far have not shown recurrent chromosomal changes, although various structural chromosome 1 rearrangements, including deletions, often leading to loss of distal 1p material appear to be frequent. We report on fluorescence in situ hybridization and loss of heterozygosity analyses of an MCC tumor and MCC cell line UISO. The present study has shown that two distinct regions in the most distal band 1p36 on the short arm of chromosome 1 can be implicated in MCC. One region at 1p36.3 was delineated by a distal deletion in the MCC tumor as a result of an unbalanced translocation, resulting in loss of all markers distal to ENO1. This region was previously shown to be deleted in different tumor types including neuroblastoma. In cell line UISO an insertion in 1p36.2 was identified. The insertion breakpoint indicates a second, more proximal, region on 1p involved in MCC. The insertion breakpoint was mapped within a cluster of repetitive tRNA and snRNA genes and thus could coincide with the constitutional 1p36 breakpoint previously reported in a patient with neuroblastoma.

Aged↗

Nine cases of Merkel cell tumour.

Merkel cell tumour is an aggressive neuroendocrine neoplasm arising in the dermis. Although only a few hundred cases have been reported worldwide, nine were seen in Nottingham between 1985 and early 1994. The patients were five women and four men age 63-88. One was the first Afro-Caribbean reported to have such a tumour. In no case was the diagnosis made clinically; histological and histochemical examination was necessary. Three of the patients died quickly with metastatic disease. The primary treatment is surgical excision. For advanced disease, radiotherapy is commonly beneficial.

Aged↗

Unusual presentation of a Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an uncommon, potentially lethal, cutaneous tumor that mainly occurs in sun-exposed skin of the head and neck area of the elderly. We report a case of MCC presenting as a 2-mm crusted erosion on the nose of an elderly patient, the smallest MCC reported thus far in the literature. The optimal management of MCC has not been clearly established. In view of its high local recurrence rate, predilection to metastasis, and significant mortality, aggressive treatment has been advocated. Identification of this tumor at such a small size posed a management dilemma because of lack of prospective treatment data involving biologic markers of prognostic significance for MCC.

Aged↗

Imaging of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, highly malignant cutaneous tumor, primarily of the head and neck, that requires timely diagnosis, adequate staging, and aggressive therapy. MCC tends to be overlooked in the early stage, has a high propensity for invading local and regional nodal basins, and exhibits a high postoperative recurrence rate, with distant thoracic, abdominal, and central nervous system metastases. Conventional radiography and cross-sectional imaging show lesions similar to those originating from other small cell carcinomas. Nuclear medicine procedures such as sentinel node scintigraphy, somatostatin receptor scintigraphy, and positron emission tomography may be used to supplement judicious cross-sectional imaging evaluation, thereby adding diagnostic value in staging and providing therapeutic guidance. Ultimately, however, the diagnosis relies exclusively on pathologic findings at immunohistochemical staining and electron microscopy. The rarity of MCC and the resulting insufficient awareness of this neoplasm often delay correct identification and treatment, which essentially consists of wide-margin surgical excision of the primary tumor and local and regional radiation therapy. To date, clinical information is still insufficient to fully appreciate the role of imaging in MCC management. A better imaging algorithm is expected with increased awareness and improved clinical understanding of this uncommon skin neoplasm.

Aged↗

Combined karyotyping, CGH and M-FISH analysis allows detailed characterization of unidentified chromosomal rearrangements in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin. Cytogenetic studies have indicated that deletions and unbalanced translocations involving chromosome 1 short arm material occur in 40% of the investigated cases. Recurrent chromosomal imbalances detected by comparative genomic hybridization (CGH) analysis were loss of 3p, 10q, 13q and 17p and gains of 1q, 3q, 5p and 8q. In order to study genomic aberrations occurring in MCC in further detail, we combined karyotyping, CGH and multiplex-fluorescence in situ hybridization (M-FISH), a strategy that proved to be successful in the analysis of other malignancies. Analysis of 6 MCC cell lines and 1 MCC tumor revealed mostly near-diploid karyotypes with an average of 5 chromosomal rearrangements. The observed karyotypic changes were heterogeneous, with 3-27 breakpoints per case, leading to imbalance of the involved chromosomal regions that was confirmed by CGH. Chromosomal rearrangements involving the short arm of chromosome 1, the long arm of chromosome 3 and gain of 5p material were the most frequently observed abnormalities in our study. In keeping with previous observations, this series of MCCs showed no evidence for high-level amplification. We provid a detailed description of chromosomal translocations occurring in MCC that could be useful to direct future intensive investigation of these chromosomal regions.

Aged↗

Merkel cell carcinoma.

Merkel cell carcinoma is an unusual cutaneous malignancy with a propensity for spreading to regional lymph nodes, either at presentation or as a first site of relapse. Complete surgical resection is the mainstay of treatment of the primary tumor. Because the nodotrophic behavior of the tumor is recognized, lymphatic mapping with sentinel lymph node biopsy is becoming increasingly popular in the initial surgical staging of these patients. The role of elective lymphadenectomy in patients with clinically negative regional nodal basins is unknown. The role of adjuvant radiotherapy, either to the primary site or regional nodal basin, remains undefined. The role of adjuvant chemotherapy in diminishing the risk of subsequent systemic recurrence in patients with positive nodes remains undefined. Overall response rates to combination chemotherapy for surgically unresectable distant metastatic disease are generally high, although responses are transient.

Carcinoma, Merkel Cell↗

[Merkel cell carcinoma].

Merkel cell carcinoma (Mcc) is a very rare, malignant, neuroendocrine tumour. Mcc has an aggressive behavior, local recurrence, and regional or distant metastasis generally develop within a short period of time. At the Oral Medicine Department 158,056 patients were treated between 1970 and 2004. A single case of Mcc was diagnosed, in a 79-year-old woman. The tumour was localized to the upper lip. After successful cryosurgery and a 7-year tumour-free period, a new tumour developed in her palatine tonsil. It was an anaplastic carcinoma with neuroendocrine features, raising the possibility of a late haematogenous metastasis, a second field tumour, or a second primary tumour. The clinical, histological, immunohistochemical and genetic findings suggested that the tumour of the palatine tonsil is a second field tumour.

Aged↗

Proliferation markers and prognosis in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a frequently aggressive primary cutaneous neuroendocrine malignancy. We investigated 3 cell proliferation markers which may be useful in predicting the aggressiveness of MCC: 1) p53, a tumor suppressor protein, 2) Ki-67, a marker of cell cycling, and 3) proliferating cell nuclear antigen (PCNA). Twenty patients with MCC were studied. The 3 cell proliferation markers were studied by immunoperoxidase. Clinical and immunoperoxidase results were tabulated according to recurrence or death from disease. Of the 20 patients, 10 experienced recurrence, and 10 did not. Seven tumors were positive for p53. We found correlations between recurrence and death in MCC patients, between p53 positivity and recurrence/death, and between p53 positivity and head/neck primary sites. We found no correlation with recurrence by gender or primary site. PCNA was positive in only 1 patient, while Ki-67 was positive in all patients, making these 2 markers unsuitable for predicting recurrence. Further clinical studies will be helpful to confirm and refine the application of this test. Prognostic information from such studies may be useful in planning observation and treatment for patients in the future.

Aged↗