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Neuron-specific enolase and serotonin in the Merkel cells of conger-eel (Conger conger) epidermis. An immunohistochemical study.

Immunocytochemical techniques were used to investigate the distribution and co-localization of neuron-specific enolase (NSE) and serotonin (5-HT) in the skin of the conger eel, Conger conger. NSE and 5-HT immunoreactivity were found in Merkel cells; these cells were also identified at the electron-microscope level by the presence of characteristic granules and their association with an intraepithelial nerve ending. For the first time, it was demonstrated that Merkel-cell granules of vertebrate skin exhibit an immunoreaction with 5-HT. The production of amines may indicate that the Merkel cells of C. conger have both secretory capabilities and transduction functions. However, immunocytochemical investigation of the synaptic zones at the electron microscope level will be necessary to confirm this hypothesis. The present histochemical results suggest that NSE and 5-HT may be marker substances for Merkel cells, and that immunocytochemistry is a useful tool for the light-microscopic localization of these cells.

Animals↗

Primary neuroendocrine (Merkel cell) carcinoma of the skin: morphologic diversity and implications thereof.

A significant proportion of primary neuroendocrine cell carcinomas of the skin (Merkel cell carcinomas [MCCs]) have been reported to occur in intimate association with malignant epithelial neoplasms, mainly squamous cell carcinomas. In addition, divergent differentiation within these tumors, particularly of squamous and eccrine types, is not infrequent. This expanded morphologic spectrum of MCC calls for evaluation of potential biologic implications of the phenotypic diversity and begs reconsideration of the histogenesis of the lesion. The current retrospective review of 29 cases of primary cutaneous neuroendocrine cell carcinoma aims to address these issues by integrating new information with that which is extant. Eleven tumors were associated with evolving or established cutaneous carcinomas: 2 actinic keratoses, 5 Bowen's disease, 3 superficial squamous cell carcinomas, and 1 basal cell carcinoma. Two combined squamous-neuroendocrine tumors occurred in recipients of solid organ transplants, and another developed in a Marjolin's ulcer at the site of a previous burn. Squamous and/or adnexal differentiation within the dermal component of the tumor was observed in 4 instances and was significantly associated with MCCs in intimate association with another cutaneous carcinoma. The outcome of the group as a whole is similar to that recorded in previous series of MCC, with local recurrence in 32% of cases and death caused by the neoplasm in 28%. Only 52% of the patients were alive with no history of metastasis at follow-up. No significant difference in outcome was observed between the patients with pure MCCs and those with MCCs in combination with another cutaneous carcinoma.

Aged↗

Immunohistochemical examination of 25 cases of Merkel cell carcinoma: a comparison with small cell carcinoma of the lung and oesophagus, and a review of the literature.

Merkel cell carcinomas (MCC) were compared to small cell carcinomas of the lung (SCCL) and oesophagus (SCCO). Most MCC were of the intermediate cell type while SCCL and SCCO were usually of the small cell type. Only MCC of trabecular type could be separated from SCCL and SCCO by means of histopathological examination alone. All MCC (25) stained with cytokeratin CAM 5.2, 20 of which in a "paranuclear globular" or combined "paranuclear globular"/diffuse pattern while 17 MCC stained with cytokeratin AE1/AE3. Cytokeratin CAM 5.2 reacted with 60 percent of the SCCL and 86 percent of the SCCO, and cytokeratin AE1/AE3 with 33 and 28 percent respectively. Neurofilament stained 17 MCC in a "paranuclear globular" pattern but none of the SCCL and SCCO. All MCC with a diffuse staining pattern for cytokeratin CAM 5.2 were negative for neurofilament. The results of this study and review of the literature indicate that in most instances Merkel cell carcinoma can be separated from other SCC, pulmonary as well as extrapulmonary, by means of histopathological and, above all, immunohistochemical examinations.

Antigens, CD↗

[Merkel cell carcinoma: a report of two cases].

The Authors report two cases of Merkel cell carcinoma and describe their diagnostic and therapeutic difficulties in the management of these tumours. The main therapeutic problem consists in establishing the size of the excision margins in relation to the neoplastic aggressiveness. The first case was characterised by major lymphophilia and by a tendency to relapse. Radical excision was achieved by low invasive surgery using a radioguided technique to search for microscopic disease. The radioguided technique takes the place of the intra-operative anatomo-pathological examination. After adjuvant ra- diotherapy and chemotherapy the patienthas remained in remission for three years. The second case is characterized by a rapid haematic diffusion with metastasis and exitus after one year. Radiotherapy and chemotherapy were ineffective. In this case surgery was limited to a bioptic approach since extirpative surgery would have been inappropriate. Our experience shows the wide biological variability of Merkel cell carcinoma and the importance of eclectic treatment to avoid ineffective extirpative surgery.

Aged↗

[Primary neuroendocrine Merkel cell carcinoma of the skin].

A 78-year-old woman noticed a nodule on the dorsal aspect of the left lower leg which caused no symptoms but gradually increased in size. The raised, brown-red nodule, about 1.5 cm in diameter, was widely excised because malignancy was suspected. Light and electronmicroscopy revealed changes typical of Merkel-cell carcinoma. Immunohistochemistry demonstrated neuron-specific enolase and cytokeratin. No metastases were found. Together with Langerhans cells and melanocytes, Merkel cells belong to the three non-keratinocyte cell types of the epidermis.

Aged↗

Involvement of chromosome 22 in a Merkel cell carcinoma in a patient with a previous meningioma.

The relatively simple cytogenetic findings in an aggressive metastatic Merkel cell carcinoma are reported. Deletion 2p was found in 100% of the cells. Nevertheless, this was considered a secondary (metastatic?) change because the same aberration has been found in several other kinds of malignancy. The involvement of chromosome 22 [del(22q) and -22] in 85% of the cells seemed more intriguing, considering the fact that the Merkel cell carcinoma followed a previous meningioma.

Carcinoma, Merkel Cell↗

Merkel cells do not require trophic maintenance from the nerves in adult human skin.

A 34-year-old Japanese man with hereditary sensory neuropathy was examined to evaluate the distribution, density and inter-relationship between Merkel cells and peripheral nerves in the skin. An epidermal sheet of affected plantar skin showed numerous CAM 5.2-reactive Merkel cells, whereas PGP 9.5-reactive peripheral nerves were completely absent in the epidermis and dermis. These findings strongly suggest that Merkel cells do not require trophic maintenance from nerves in adult human skin.

Adult↗

[Merkel cell tumor].

Two cases of skin carcinoma which display endocrine differentiation are reported. In the relevant literature, these neoplasms are considered to be of Merkel cells lineage. These two carcinomas demonstrated salient morphological features. The first tumor contained small aggregates of cells with a deeply indented nucleus. It is postulated that these formations represent foci of Merkel cells maturation. It is suggested that this distinctive focal histological feature may permit recognition of these neoplasms. The second tumor exhibited an admixture of endocrine and epidermoid differentiation. Such observations prompt us to postulate that Merkel cells and keratinocytes originate from the same stem cell.

Aged↗

Merkel cells and the mechanosensitivity of normal and regenerating nerves in Xenopus skin.

We have investigated some of the physiological, morphological and trophic characteristics of the Merkel cell-neurite complexes in the skin of Xenopus laevis. The Merkel cells, which are specialized sensory cells, occur in groups of 2-4 around the openings of the cutaneous gland ducts. A voltage-controlled mechanical stimulator was used to determine the distribution of mechanosensory thresholds across the skin; an analysis of the results revealed the presence of a single population of rapidly adapting, low threshold mechanoreceptors, whose locations coincided with those of the epidermal Merkel cell-neurite complexes. The possible role of the Merkel cell in the mechanosensory process, and its trophic interactions with the sensory nerve, were examined (i) by following the development of mechanosensitivity when sensory nerves regenerated into denervated, or newly regenerated, skin; (ii) by looking for possible correlations between the expression of physiological function and the appearance of morphological features characteristic of the Merkel cell-neurite complex; and (iii) by investigating the mechanosensitivity that remained after elimination of the Merkel cells. Not only did Merkel cells survive denervation without obvious changes in their fine structure, but they developed with normal morphology in new skin that had regenerated in nerve free limbs. Ingrowing sensory nerves contacted these Merkel cells, and eventually normal mechanosensory function was established; thus the Merkel cells act as targets for these nerves. The full recovery of the normal pattern of mechanosensitivity in the skin following nerve regeneration was correlated with the redevelopment of the specialized contacts between the nerve endings and Merkel cells, that eventually included reciprocal synapses. However, following the mechanical removal of the epidermis by enzymatic treatment, or the selective elimination of the Merkel cells by irradiation after they had taken up the fluorescent dye quinacrine, essentially normal mechanosensory responses could be initiated, though with somewhat increased thresholds. The results indicate that the Merkel cells are not involved in mechanosensory transduction; they do, however, act as targets for the growing nerves, thereby ensuring the appropriate distribution of low threshold mechanosensitivity, and they may have a role in enhancing and even inducing the excitability of the mechanosensitive nerve endings.

Animals↗

Neuroendocrine (Merkel-cell) carcinoma of the skin: immunocytochemical and cytomorphologic analysis on fine-needle aspirates.

Cytomorphologic and immunocytochemical characteristics of tumor cells from fine-needle aspirates of four neuroendocrine (Merkel-cell) carcinomas of the skin are described. All aspirates were cellular with dispersed small to medium sized tumor cells with scanty cytoplasm. Many mitoses were observed. Careful scrutiny revealed a tendency of the tumor cells to form microacinar and pseudorosette formations as well as small clusters of molding cells. Immunocytochemical analysis of cytospin preparations showed a peculiar dot-like cytokeratin positivity, while neuron-specific enolase staining was more diffuse. A weak S-100 positivity was observed. This staining pattern is highly suggestive of Merkel-cell tumor. It can thus be concluded that immunocytochemical analysis in conjunction with cytomorphology on fine-needle aspirates will allow the identification of neuroendocrine carcinoma of the skin and its differentiation from other small-cell neoplasias of the skin.

Aged↗

Gingival metastasis of merkel cell carcinoma: a case report.

An 82-year-old Caucasian man developed an ulcerated mass on the anterior mandibular gingiva. Five years previously he had been treated for a Merkel cell carcinoma (MCC) on his right cheek. Histopathologic examination showed small tumor cells with scanty cytoplasm, suggestive of malignancy. Immunohistochemical studies were performed with the use of nine antibodies. S-100 protein and leukocyte common antigen were helpful in ruling out melanoma and lymphoma. Pronounced reaction was shown for cytokeratin 20, a new histodiagnostic marker whose expression is almost entirely confined to Merkel cells, the gastric epithelium, and urothelium. The tentative diagnosis of metastasis of MCC was confirmed. Immunohistochemical studies are useful diagnostic aids in the establishment of the diagnosis of Merkel cell carcinoma.

Aged↗

Trisomy 6 in Merkel cell carcinoma: a recurrent chromosomal aberration.

UNLABELLED: We retrospectively investigated 17 cases of primary and metastasizing Merkel cell carcinomas (MCC) from 14 patients using chromosomal in-situ hybridization (CISH) to study the occurrence of trisomy 6 in these lesions. METHODS AND RESULTS: Histological diagnosis on all tumour samples was obtained on haematoxylin and eosin stained sections. Immunohistochemistry was performed with antibodies against pancytokeratin (CAM 5.2), cytokeratin 20 (CK20), MIC2 antigen (CD99), neuron-specific enolase (NSE), and chromogranin A (chrA). Sections (4 microm) of the paraffin-embedded tumours were analysed with alpha-satellite centromeric probes for chromosome 6 or 17 using CISH. The signal was amplified by the Tyramide Signal Amplification (TSA) assay. Immunohistochemically, the tumours showed the same general epithelial neuro-endocrine pattern: 11/13 expressed cytokeratin 20, and 47% exhibited trisomy 6, with no significant difference between primary and metastatic lesions. Incomplete follow-up data did not allow us to establish a prognostic value of trisomy 6, however, this aberration might be an additional diagnostic tool in distinguishing MCC from other small round blue cell tumours. CONCLUSIONS: CISH seems to be a promising adjunctive method to diagnose Merkel cell carcinoma. Trisomy 6 should be investigated more closely in these cases, as has been done for chromosomes 1 and 11. Of particular interest would be identification of modifications in proto-oncogene(s) located on chromosome 6.

Aged↗

F-18 FDG Accumulation in an Octreotide Negative Merkel Cell Tumor.

Regional positron emission tomography (PET) imaging with F-18 Fluorodeoxyglucose (FDG) was performed in a patient with pathologically proven Merkel cell tumor around the right knee region. Prior to the PET imaging, whole-body Indium-111 octreotide scan was performed in this patient but was negative. F-18 FDG was offered as an attempt to image this somatostatin-receptor negative Merkel cell tumor. The PET images delineate a series of focal abnormal uptake along the right lower extremity without evidence of distant metastasis. Patient was treated locally. The positive accumulation of F-18 FDG in Merkel cells may offer a tool for defining the extent of this rare neuroendocrine tumor.

Journal Article↗

Merkel cell carcinoma--a retrospective analysis of 17 cases.

OBJECTIVE: To report clinical experience with the rare neuroendocrine Merkel cell carcinoma of the skin. SUBJECTS AND SETTING: Seventeen patients with Merkel cell carcinoma of the skin treated at the Departments of Dermatology and ENT, Krankenhaus Dresden-Friedrichstadt, Dresden, Germany, during the years 1984-2000 were evaluated. METHODS: A retrospective analysis was performed. Age and sex distribution, clinical data and therapy were collected. Outcome measures including overall survival, tumour-free survival and relapse-free survival were determined. RESULTS: Six male and 11 female patients with an age range of 68-90 years (mean age 73.3 years) were identified. The primary tumour localization was head and neck region (n = 8), upper limbs (8), lower limbs (1). Twelve patients presented in tumour stage I, three in stage II and one in stage III. First line therapy was complete surgical excision with wide margins in 16 patients followed by loco-regional radiation in 12 of 16 cases. In 16 patients follow up data were available. After primary treatment complete response was achieved in 14 of 16 patients (87.5%), two patients had a partial response. The median of relapse-free survival was 44 weeks [mean +/- standard deviation: (44 +/- 118) weeks]. The median of overall survival was 102 weeks [mean +/- standard deviation: (137 +/- 94) weeks]. Three patients with a PR after primary treatment had a median overall survival of only 48 weeks [mean +/- standard deviation: (51 +/- 20) weeks]. CONCLUSIONS: Primary surgical treatment with wide excision combined with radiotherapy seems to be a reasonable first-line treatment but prospective controlled multicentre trials are necessary for validation.

Aged↗

Merkel cell tumor of the skin. Ultrastructural and immunohistochemical studies.

A skin tumor of a 66-year-old female was investigated morphologically and immunohistochemically. The tumor was located within the dermis and comprised of rounded cells with scanty cytoplasm, which proliferated forming a small nest or trabecular arrangement. Electron microscopic observation indicated the presence of dense-core granules within the tumor cell cytoplasm suggesting that the tumor was derived from Merkel cells. Occasionally clusters or bundles of the intermediate filaments were found in the perinuclear cytoplasm of the tumor cells. Each tumor cell was connected with desmosomes. Immunohistochemical staining with anti-keratin antiserum showed positive reaction at the perinuclear cytoplasm of the tumor cells indicating that the cluster of the microfilaments presumably contains keratin. Conversely S-100 protein was negative in the tumor cells. The results obtained strongly suggest that the tumor or Merkel cell was considered to be derived from the epidermal immature cells rather than from the neural crest.

Aged↗

Merkel cells, corpuscular nerve endings and free nerve endings in the mouse palatine mucosa express three subtypes of vesicular glutamate transporters.

The hard palate of rodents is a mucous membrane covered by a keratinized epithelium that typically contains Merkel cell (MC)-neurite complexes. MCs have engendered considerable research activity because of their involvement in mechanoreception and possibly also Merkel cell carcinomas. MCs derive from the neural crest, differentiate under control of peripheral nerve factors, are enriched in large dense core vesicles, and secrete neuropeptides and other neuroactive molecules. Upon stimulation, MC-neurite complexes produce slowly adapting type I responses. Here we emphasize that the murine hard palate is a highly differentiated sensory region, as shown by intravital staining with a styryl dye and immunocytochemistry with antibodies to vesicular glutamate transporters (VGLUTs). The entire palate contained densities of sensory endings and MC-neurite complexes, that nearly paralleled in abundance the vibrissal pads. MCs were differentially distributed in the murine palate; clusters of MCs were most abundant in the antemolar and intermolar rugae, while individual MCs were particularly enriched in the rugae at the mid-portion of the palate and in the postrugal field. VGLUT1, VGLUT2 and VGLUT3 were expressed in MCs throughout, although immunostained MCs were most frequently encountered in intermolar than antemolar rugae. The same transporters were also present in corpuscular endings at the summit of the rugae and in intraepithelial free nerve endings throughout the palate. VGLUTs presumably load glutamate into large dense core vesicles in MCs and into small clear vesicles in corpuscular and free nerve endings. The data suggest that glutamate release, or co-release, is likely to represent an important functional aspect of palatine Merkel cells and neighboring corpuscular and free nerve endings.

Amino Acid Transport Systems, Acidic↗