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PubMed2005

Tenascin-C in primary Merkel cell carcinoma.

BACKGROUND/AIMS: Merkel cell carcinoma (MCC) is a rare malignant cutaneous neuroendocrine tumour that mostly affects the elderly. It shows rapid progression of the primary tumour, together with a vertical growth pattern into the underlying subcutaneous tissue. Metastatic dissemination to regional lymph nodes is early and frequent. Tenascin-C (Tn-C) is a large extracellular matrix glycoprotein that is expressed in various benign and malignant processes. Expression of Tn-C is also associated with invasion and cellular proliferation, and is often downregulated in fully evolved advanced carcinomas. In previous studies, Tn-C expression correlated with prognosis in tumours of different origin. METHODS: Immunohistochemistry was used to investigate the expression of Tn-C in 25 MCC specimens and to evaluate the prognostic importance of this glycoprotein. RESULTS: Seventeen samples expressed Tn-C. Staining was mainly seen in the invasion borders and within the connective tissue septae inside the tumours. The expression of Tn-C correlated significantly with large tumour size. There was also frequent expression of Tn-C in primary tumours with metastatic dissemination. Most of the Tn-C negative samples were of small size. CONCLUSIONS: Tn-C expression seems to increase with tumour size and malignant behaviour. Expression was slightly enhanced in tumours with high proliferative indices. Expression is seen mainly in areas of invasive growth and, in this respect, resembles that of other invasive tumours.

Aged↗
PubMed1999

Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a highly malignant skin neoplasm. Regional lymph node and distant metastasis occur in 20-52% of patients. The role of chemotherapy in the treatment of patients with this rare tumor is unclear. METHODS: An exhaustive analysis of the literature (1980-1995) describing chemotherapy for patients with locally advanced or metastatic MCC was performed. All available published medical records (n = 101 patients) were entered in a database. In addition, data on six additional patients given chemotherapy during this time frame in Lyon, France, were included in the database. RESULTS: For the 107 patients, the overall objective response rate to first-line chemotherapy was 61% (61 of 101 evaluable patients). The response rate was 57 % (41 of 72) for patients with metastasis and 69% (20 of 29) for patients with locally advanced tumors. No clinical parameter was found to be correlated to response to chemotherapy. A high rate of toxic death during first-line treatment (n = 7.7%) was reported for these patients. The median overall survival from the date of chemotherapy initiation was 9 months for patients with metastasis and 24 months for patients with locally advanced tumors. The projected overall survival at 3 years was 17% for patients with metastasis and 35% for patients with locally advanced tumors. Progression after first-line chemotherapy was associated with significantly worse survival for patients with metastasis. Rates of response to second-line (n = 33) and third-line (n = 10) chemotherapy were 45% and 20%, respectively. CONCLUSIONS: MCC is chemosensitive but rarely chemocurable in patients with metastasis or locally advanced tumors. A high incidence of toxic death due to chemotherapy is reported in the literature.

Aged↗
PubMed2001

Scanning electron microscopic observation of Merkel cells in the lamprey epidermis.

The Merkel cell in the epidermis has generally been regarded as a mechanoreceptor which detects tissue deformations with its microvilli, and subsequently releases certain transmitters to nerve endings. In order to analyze the mechanism of mechanoreception, the fine structure of lamprey Merkel cells and their relationships with surrounding tissue were examined by scanning electron microscopy (SEM) after exposure of the cells by NaOH maceration, as well as by transmission electron microscopy (TEM) according to a conventional method. By SEM, lamprey Merkel cells revealed small round cell bodies bearing numerous microvilli on the upper and lower poles in accord with previous TEM reports. Combined SEM and TEM observations showed that the Merkel cell bodies were tightly held in corresponding concavities of other epidermal cells, with some desmosomes connecting the cells with each other. On the other hand, microvilli of the Merkel cells extended freely in intercellular spaces bound with complex microplicae of epidermal cells. The regional difference in mechanical anchorage of the Merkel cells probably leads to transient deflection and subsequent recovery of their microvilli during a given mechanical stimulation, suggesting rapidly adapting mechanoreception by the cells.

Animals↗
PubMed2002

Spatial relationship between Merkel cells and Langerhans cells in human hair follicles.

The distributions of Merkel cells and Langerhans cells within human hair follicles have been reported. However, there has been no description of the relationship between Merkel cells and Langerhans cells, which were discovered by 19th century German pathologists. Merkel cells and Langerhans cells share some similar characteristics such as the localization of human hair follicles, a close association with peripheral nerves and the expression of several neuropeptides. Merkel cells were stained with CK20 or CAM5.2, while Langerhans cells were stained with CD1a or S-100 protein. We thus immunohistochemically confirmed the preferential localization of Merkel cells and Langerhans cells in normal human hair follicles. Using a double staining technique, two- and three-dimensional observations demonstrated that a small proportion of Merkel cells were closely contacted with Langerhans cells below the sebaceous gland level, presumably indicating the bulge area. Merkel cells and Langerhans cells connected directly or approached each dendrite within the basal layer of the outer root sheath. For the first time, we demonstrated a close anatomical relationship between Merkel cells and Langerhans cells within the bulge area of human hair follicles where follicular stem cells may be present. These morphological observations suggest a functional interaction between follicular Merkel cells and Langerhans cells. We herein hypothesize that Merkel cells communicate with Langerhans cells by characteristic dendrites in which some neuropeptides or cytokines may be stored.

Hair Follicle↗
PubMedDate not supplied

Merkel cells, normal and neoplastic: an update.

Merkel cells (MC) occur in the basal epidermal layer, hair follicles, and oral mucosa, as complexes with sensory axons. The axons transduce slowly adapting type I mechanoreception, and MC modulate their sensitivity. MC also determine and maintain the 3-dimensional epidermal structure. They have neuroendocrine granules, rigid spinous processes, and desmosomal junctions with each other and with keratinocytes. Rare MC are dermaWl. Current evidence supports a basal cell origin. Merkel cell carcinomas (MCC) occur mostly in sun-exposed skin in old age. Trabecular, intermediate, or small cell in pattern, MCC have neuroendocrine granules, intercellular junctions, rigid spinous processes, and a paranuclear collection of intermediate filaments staining for cytokeratin 20. Most MCC behave indolently, but those with the small cell pattern, and some with the intermediate pattern, are aggressive and rapidly fatal.

Animals↗
PubMed1998

Merkel cell carcinoma of the skin.

Merkel cell carcinoma is a rare, aggressive neuroendocrine tumor of the skin with a predisposition for local regional and distant spread. Radiotherapy after wide local excision has improved local control, but distant spread continues to be a significant problem. This is an update of our experience in the treatment of Merkel cell carcinoma at the University of Florida. Of 24 patients who were treated for Merkel cell carcinoma between 1984 and 1996, 18 patients were treated at the time of the initial diagnosis, and six were treated after local-regional recurrence. Of the 18 previously untreated patients, 13 had primary sites in the head and neck region, and five had primary sites elsewhere. Minimum follow-up was 1 year; no patient was lost to follow-up. The 5-year absolute survival, cause-specific survival, and local-regional control rates for the entire group were 27%, 31%, and 78%, respectively. Patients who were treated with radiotherapy at the time of initial presentation had 5-year absolute survival, cause-specific survival, and local-regional control rates of 38%, 44%, and 73%, respectively. Most deaths were due to distant metastasis. Site of the primary tumor (head and neck versus other) was not associated with any difference in the outcome. Of six patients who were treated at the time of local-regional recurrence, five developed distant metastasis at 3-19 months (median 8 months) from the time of treatment. One patient was alive and without evidence of disease 13 months after treatment. All patients who were treated at the time of local-regional recurrence had local-regional control after radiotherapy at 3-30 months (median 8 months). Wide local excision and radiotherapy is effective local-regional treatment for Merkel cell carcinoma of the skin, but distant metastasis remains a significant problem in this disease. The role and effectiveness of chemotherapy as part of the initial treatment remains to be defined.

Aged↗
PubMed1983

Immunostaining of neuron-specific enolase as a diagnostic tool for Merkel cell tumors.

Conventional histologic examination of Merkel cell tumors may result in misdiagnosis because of the close similarities these tumors bear to either malignant lymphomas or certain undifferentiated carcinomas. The authors have previously reported that neuron-specific enolase (NSE), a specific marker for neuroendocrine cells, is present in normal Merkel cells and can be used as a marker to identify this cell type. In this study, 11 Merkel cell tumors, identified employing electron microscopy, were studied using immunostaining of NSE by the peroxidase-antiperoxidase method. Varying intensities of NSE immunoreactivity were found in the cytoplasm of all the neoplastic cells in the different cases. The uniformly stained cytoplasm formed a small rim surrounding the large, unstained nucleus. Immunostaining of NSE thus provides a simple and reliable method for the differential diagnosis of Merkel cell tumors from other primary skin tumors which, with the exception of some malignant melanomas, have been shown not to contain NSE immunoreactivity.

Aged↗
PubMed1984

Identification of Merkel cells in human skin by specific cytokeratin antibodies: changes of cell density and distribution in fetal and adult plantar epidermis.

Merkel cells are special neurosecretory cells which, in adult human skin, are usually very scarce. By immunofluorescence microscopy using antibodies to human cytokeratin polypeptide no. 18, we localized distinct non-keratinocyte cells in the glandular ridges of human fetal and adult plantar epidermis. Using electron and immunofluorescence microscopy, these cells were identified as Merkel cells containing typical neurosecretory granules as well as bundles of intermediate-sized filaments and desmosomes. Two-dimensional gel electrophoresis of the cytoskeletal fractions of microdissected epidermal preparations highly enriched in Merkel cells indicated the presence of cytokeratin polypeptides nos. 8, 18 and 19 which are typical of diverse simple epithelia of the human body. Double immunofluorescence microscopy showed that these human Merkel cells contain neither neurofilaments nor vimentin filaments. In human fetuses of 18-24 weeks of age, conspicuously high concentrations of Merkel cells, reaching a density of approximately 1,700 Merkel cells/mm2 skin, were found in the glandular ridges of plantar skin. The concentration decreased considerably at newborn and adult stages. Thin cell processes (up to 20 microns long) were observed in many fetal epidermal Merkel cells. In addition, we detected isolated Merkel cells deeper in the dermis (i.e. at distances of, at most, 100 microns from the epidermis) in fetal and newborn plantar skin. Our results show that Merkel cells are true epithelial cells which, however, differ profoundly from epidermal keratinocytes in their cytokeratin expression. The findings are discussed in relation to the much disputed question of the origin of Merkel cells. The present data speak against the immigration of Merkel cells from the neural crest, but rather suggest that they originate from epithelial cells of the skin, although most probably not from differentiated keratinocytes.

Aging↗
PubMed1989

Merkel cells in lower vertebrates.

In lower vertebrates, Merkel cells are widely distributed in the epidermis. Dense-cored specific granules similar to those in mammalian Merkel cells are found in amphibians, dipnoans and lampreys, but only in some species of teleosts, others having few and small-cored vesicles. The characteristic microvilli are found in all these groups, but their number and disposition vary. In amphibians a Merkel cell is associated with a single nerve fibre, known to be mechanoreceptive, which forms reciprocal synapses at a varicosity against the cell and continues on in the epidermis. In lampreys most of the specific granules are grouped around spur-like processes of a nerve fibre which has other branches in the epidermis. In teleosts, one or more nerve fibres wind around a Merkel cell; synaptic modifications are variable. Fluorescence histochemistry shows the presence of quinacrine, neuron-specific enolase, met-enkephalin and serotonin in Merkel cells of some species that have been investigated, but experimental results from amphibians suggest that the receptive element may be the nerve fibre. The Merkel cell can act as a target for growing nerve fibres, but other functions, especially connected with the synapses, most of which are morphologically afferent, remain unknown. Merkel cells do not require trophic maintenance from the nerve. The basal cells of taste buds in teleosts and amphibians have been compared to Merkel cells, but are not identical, although in frogs the basal cells have dense-cored vesicles. In teleosts, both cell types qualify as paraneurons, but there are considerable differences in their cytology especially in the form of the synaptic specializations.

Amphibians↗
PubMedDate not supplied

Cell cycle control by p21, p27 and p53 in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive dermal tumour of neuroendocrine origin with poor prognosis. The role of cell cycle-regulatory proteins (p53/p21/p27) in MCC pathogenesis and their prognostic importance were evaluated. Twenty-four primary MCC specimens with corresponding clinical data were analysed by immunohistochemistry for p21, p27 and p53 antibodies. The stainings were evaluated semi-quantitatively and the results analysed statistically. p53 was negative in 80% and p21 in 71% of the samples. Positive staining for p27 was evident in 92% of the samples. However, the expression of these antibodies did not correlate with the outcome of the patient. The proportion of p53- and p21-negative samples seems to indicate that correction processes after DNA damage are not activated during MCC pathogenesis, a supposition that is supported by the aggressive nature of this tumour. Therefore, the expressions of the three studied cell cycle regulators cannot serve as prognostic markers for survival.

Biomarkers, Tumor↗
PubMed1998

Evidence for polymorphism of Merkel cells in the adult human oral mucosa.

We recently reported that Merkel cells in the normal palatine mucosa of adult rodents are highly polymorphic. In order to ascertain whether or not this polymorphism is also evident in the human oral mucosa, palatine mucosae from cadavers without oral diseases and perilesional palatine mucosae of patients with pleomorphic adenoma were examined by immunohistochemistry using an antibody against cytokeratin 20. Findings showed that Merkel cells in the human normal palatine mucosa were polymorphic, and a number of irregular-shaped Merkel cells (dendritic Merkel cells) with apparent cytoplasmic projections were present among typical oval to round Merkel cells. The mucosa usually contained a small number of oval to round Merkel cells residing in ectopic places such as prickle and granular cell layers. On the other hand, the slightly inflamed perilesional palatine mucosa contained an increased incidence of dendritic Merkel cells. Ectopic Merkel cells were rare in the perilesional palatine mucosa. Characteristics of dendritic Merkel cells were examined using specimens from perilesional palatine mucosae by means of immunohistochemistry and electron microscopy. It was shown that every dendritic Merkel cell and most roundish Merkel cells in the perilesional mucosa lacked innervation. Electron microscopy suggested that dendritic Merkel cells release secretory granules from the tip of the cytoplasmic process and the basal cytoplasm towards the lamina propria mucosae, in a manner resembling the case of similar cells in rodents.

Adenoma↗
PubMed1996

A pure, monolayer culture of Merkel cells from sinus hair follicles of the rat.

Merkel cells, mechanoreceptor cells in the skin, were dissociated from sinus hair follicles of the whisker pads of newborn rats, and cultured in a serum-free medium. Based on the uptake of quinacrine, a specific fluorescence marking dye, more than 90% of the cells in culture were identified as Merkel cells. During monolayer culture on a poly-L-lysine-coated coverglass surface, Merkel cells exhibited a flat round morphology and often extended thin lamellae on their fringe. Small particles eliciting quinacrine fluorescence were present throughout these cells, with the exception of the lamellae or nuclei. Most Merkel cells died in 48-72 h in the serum-free medium. Fetal calf serum added to the medium protected Merkel cells from the cell death, and the Merkel cells had a fibroblast-like morphology in the serum-containing medium.

Animals↗
PubMed1999

Merkel cells are responsible for the initiation of taste organ morphogenesis in the frog.

Taste organs in the frog have a distinctive cell type located exclusively in the basal portion. In the same fashion as type III cells in mammalian taste buds, these basal cells show immunoreactivity for serotonin antibody. Further, these cells are morphologically similar to epidermal Merkel cells. To determine the significance of these serotonergic basal cells, we examined the early development of taste organs during metamorphosis of the frog by focusing on the origin and possible roles of serotonergic basal cells. For convenience of description, five stages of development (metamorphic stage to climax stages A-D) are defined. In the metamorphic stage, a few noninnervated Merkel cells appear at the upper layer of the lingual epithelium. No neuronal elements are seen in the epithelium at this stage. At climax stages A-B, immature fungiform papillae become discernible in the dorsal surface of the tongue, where the Merkel cells are located. Merkel cells then move downward and extend their cytoplasmic processes toward the basal lamina. These cells are identified by their intense immunoreactivity for serotonin. During the later stages, many nerve fibers in the subepithelial connective tissue approach the epithelium containing Merkel cells. At climax stages C-D, Merkel cells extend cytoplasmic processes along the basal lamina toward the center of the newly forming fungiform papillae. The morphology of these Merkel cells exactly coincides with that of serotonergic basal cells in adult taste organs. Profuse exocytotic release of dense-cored granules of Merkel cells toward the nerve fibers through the basal lamina is frequently seen in these stages. The present study indicates that serotonergic basal cells are derived from intraepithelial Merkel cells, which act as target sites for growing nerves and may be responsible for the initiation of taste organ morphogenesis.

Animals↗
PubMed1986

Formation of epidermal and dermal Merkel cells during human fetal skin development.

The origin of Merkel cells is still a matter of debate, specifically the question of whether they are derived from epithelial cells of the epidermis or from immigrated neural crest cells. As an argument for the latter hypothesis the occurrence of dermal, nerve-associated Merkel cells in human fetal skin has often been mentioned. Therefore, we analyzed the distribution of Merkel cells in epidermis and dermis of plantar skin of human embryos and fetuses, ranging in gestational age between 7 and 17 weeks. Merkel cells were identified by immunocytochemistry on frozen sections using antibodies against simple epithelium-type cytokeratins and by electron microscopy. In the 17-week-old fetus, 17% of the total cutaneous (epidermal and dermal) Merkel cells were located in the upper dermal compartment, whereas in the 14-week-old fetus only 3.9% of the Merkel cells were dermal, including some cells that seemed to be in the process of traversing the dermal-epidermal junction. Thirteen-week-old fetuses showed even fewer dermal Merkel cells. Twelve-week-old fetuses exhibited 660 epidermal Merkel cells per 100 mm total section length, but none in the upper or deep dermis. In 7- to 9-week embryos, no Merkel cells were recognized. However, at this stage, but not in later stages, the basal cells of the plantar epidermis expressed certain simple epithelium-type cytokeratin polypeptides. These results speak against an invasion of Merkel cells or putative neural crest-derived precursor cells into the epidermis via a dermal passage. They suggest that in plantar skin Merkel cells arise, between weeks 8-12, from precursor stages of epithelial cells of the early fetal epidermis which still express simple epithelium-type cytokeratins. The results further suggest that in subsequent stages of skin development some epidermal Merkel cells detach from the epithelium and migrate into the upper dermis where some of them may associate with small nerves.

Embryonic and Fetal Development↗
PubMed1995

Metastatic merkel cell tumour to the bladder.

Merkel cell tumour is becoming increasingly recognized. A case of Merkel cell tumour metastatic to the urinary bladder is presented. The primary site was a cutaneous lesion of the left hand which later metastasized to the axillary and supraclavicular lymph nodes before metastasizing to the bladder. This is believed to be the first reported case of metastatic Merkel cell tumour to the bladder.

Aged↗
PubMed1993

Merkel cell carcinoma of the eyelid.

The Merkel cell is part of the dendritic cell population of the epidermis, and studies suggest it has a role as a slowly adapting mechanoreceptor involved with mediating the sense of touch. Merkel cells can give rise to malignant neoplasms, one tenth of which occur in the eyelid and periocular area, and manifest as painless erythematous nodules, with overlying telangiectatic blood vessels. Merkel cell carcinoma can mimic other malignant lesions, and the diagnosis can be difficult. One third of the tumors recur, and there is a high rate of metastasis. The estimated 5-year survival rate is 38%. Initial treatment should be aggressive, including surgical resection, with consideration of postoperative radiation. Merkel cell carcinoma responds to chemotherapy, but routinely recurs on cessation of treatment. Two cases are presented to illustrate the typical presentation of Merkel cell carcinoma and the importance of electron microscopy and immunohistochemical studies.

Aged↗
PubMed2006

Merkel cell carcinoma metastatic to testis.

Merkel cell carcinoma is an uncommon, highly aggressive, neuroendocrine tumor that derives from cutaneous Merkel cells involved in proprioception. It is an extremely aggressive and rapidly fatal cancer. We report a rare case of Merkel cell carcinoma metastatic to the testis with prolonged survival.

Carcinoma, Merkel Cell↗
PubMed1989

Cytologic and immunohistochemical diagnosis of neuroendocrine (Merkel cell) carcinoma in cerebrospinal fluid.

Neuroendocrine (Merkel cell) carcinoma of the skin is a rare entity. Often locally aggressive, this lesion may also metastasize to organ systems, including bone, liver, and brain. The authors report a case of a 64-year-old male who presented with hoarseness and dysphagia 17 months after resection of a primary Merkel cell carcinoma of the nose. Additional studies revealed bilateral vocal cord paralysis secondary to central nervous system dysfunction. Cytologic evaluation of the cerebrospinal fluid revealed malignant tumor cells consistent with metastatic Merkel cell carcinoma. Presented are the cytologic and immunohistochemical findings in a case of metastatic Merkel cell carcinoma involving the central nervous system.

Carcinoma, Merkel Cell↗