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PubMed1994

Establishment and characterization of two Merkel cell tumor cultures.

Two Merkel cell tumor cultures (MC-MA1, MC-MA2) have been established from metastases of typical Merkel cell tumors. The mestastases in vivo were characterized by co-expression of cytokeratins 8, 18, 19, 20 and neurofilaments, presence of intermediate filament whirls, expression of synaptophysin, neuron-specific enolase, and chromogranin A, rare and weak immunostaining for plakoglobin but absence of cadherins and desmoplakins. Both cultures grow, using supplemented RPMI medium on human irradiated fibroblast feeder layers, as loosely arranged floating small aggregates. Their karyotypes are mostly hyperdiploid. The mean doubling times were about 84 h in the first 8 months and later increased. Ultrastructural and immunoelectron microscopic studies of the Merkel cell tumor cells in vitro (MC-MA1, MC-MA2) revealed sparse membrane-bound neuroendocrine granules and typical IFs that were partly arranged in paranuclear whirls and were labeled by antibodies against cytokeratins and neurofilaments. In immunocytochemical studies using antibodies to cytokeratins 8, 18, 19, and 20 and neurofilament protein NF-L, Merkel cell tumor cells in vitro showed a uniform staining appearing as paranuclear whirls and cytoplasmic fibrils as well. Double-labeling experiments showed a co-localization of both intermediate filament types in most cells. Biochemically we found cytokeratins 8, 18, 19, and 20, and NF-L in tumor cells in vitro. Immunocytochemical staining was negative for desmoplakins, various cadherins, and cell adhesion molecules, whereas plakoglobin was only rarely detectable in some Merkel cell tumor cells in vitro. By immunoluminometric assay chromogranin A was detected in cell homogenates and culture supernatants as well. Immunocytochemically, synaptophysin and neuron-specific enolase were detectable additionally in some of the cells. These established cell cultures will allow further studies devoted to the biology, differentiation, and hormone secretion of Merkel cell tumors that may also increase our knowledge about normal Merkel cells.

Aged↗
PubMed1991

Merkel cells in vitro: production of nerve growth factor and selective interactions with sensory neurons.

A method has been developed for obtaining mixed primary cultures of dissociated epidermis enriched in Merkel cells. Merkel cells obtained from embryonic rat buccal pads were grown in serum-free medium and identified in vitro using a variety of histological and immunohistochemical markers. Quinacrine, a fluorescent amine, which has been used to identify Merkel cells in situ, labeled a morphologically distinct population of cells in vitro. Cells labeled with quinacrine had a large, phase bright nucleus with prominent nucleoli, surrounded by a phase dark perinuclear ring. Antibodies directed against neuron-specific enolase, another marker for Merkel cells in situ, and antibodies against a well-characterized neuroendocrine vesicle antigen also labeled this population of quinacrine fluorescent cells. Electron microscopic examination of our cultures indicated that cells containing characteristic features of Merkel cells including cytoplasmic dense-cored granules were present. A small but significant increase in the number of Merkel cells was observed over time in culture. Merkel cells supported the survival and outgrowth of both trigeminal ganglion sensory neurons and sympathetic neurons from the superior cervical ganglion in serum-free medium in the absence of exogenous nerve growth factor (NGF). Immunoblots probed with antibodies directed against NGF demonstrated that NGF was present in the medium taken from these cultures. NGF-like immunoreactivity colocalized to cells containing quinacrine fluorescence in situ and in vitro. Addition of antibodies directed against NGF to cocultures of Merkel cells and neurons decreased survival of sympathetic neurons by 90% and decreased survival of sensory neurons by 60%. These results suggest that Merkel cells are capable of providing trophic support for their normal complement of sensory neurons by producing NGF. Selective recognition of these targets was studied in vitro by characterizing the interactions between Merkel cells and growth cones from sensory or sympathetic neurons using both time-lapse videomicroscopy and standard morphometry of fixed cocultures. The majority of trigeminal ganglion sensory neurons (approximately 60%) extended growth cones onto clusters of Merkel cells. Neurites which contacted clusters of Merkel cells were significantly more highly branched than those growing on collagen. In contrast, the majority of sympathetic neurons (greater than 90%) failed to grow onto Merkel cells. Growth cones of sympathetic neurons often "collapsed" and retracted when contact was made with a cluster of Merkel cells. Fixation of Merkel cells with paraformaldehyde prior to coculture did not affect this difference between sensory and sympathetic neurite extension onto the Merkel cells. However, prior fixation of Merkel cells eradicated the apparent Merkel ce-induced branching of sensory neurites.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1977

The Merkel cell system and a comparison between it and the neurosecretory or APUD cell system.

The Merkel cell, a neural crest migrant to the skin, possesses a characteristic intranuclear rodlet, cytoplasmic membrane-bound granules, and horn projections and is usually associated with nerve terminations. It is also associated with all types of known organizations of sensory nerve endings in the skin and possesses characteristic enzyme reactions in relation to the ending. The Merkel cell is found in the skin and the oral mucous membranes, and similar cells are observed in the taste buds and pulmonary tissue. A comparison between the Merkel cell and the APUD cell system of polypeptide hormone and amine-producing cells reveals many structural and chemical similarities.

Animals↗
PubMed1992

Voltage-dependent currents in isolated single Merkel cells of rats.

1. Merkel cells were dissociated enzymatically from the footpad epidermis of 10- to 20-day-old rats pretreated with fluorescent dye, quinacrine, for purposes of staining. The fluorescent Merkel cells had an elongated or elliptic shape in situ, yet the dissociated ones were round (7-12 microns in diameter). 2. Electrical recordings were performed in the whole-cell configuration using a conventional patch-clamp technique. The mean resting membrane potential of fluorescent Merkel cells was -54.0 mV, the value being greater than the -26.1 mV of non-fluorescent epidermal cells. No voltage-dependent channel was observed in non-fluorescent cells. 3. The Merkel cells had no Na+ spike in an external standard solution, but tetrodotoxin-resistant long-lasting action potentials were evoked by depolarization with injection of constant currents in an external solution containing Ba2+. 4. In Merkel cells under voltage clamp, depolarizing step pulses (800 ms) from a holding potential (VH) of -80 mV elicited predominantly outward K+ currents composed of transient and sustained components: the former was selectively inhibited by 4-aminopyridine (4-AP), while the latter was inhibited by both tetraethylammonium (TEA) and quinacrine. Quinacrine was more effective and selective than TEA in blocking the sustained K+ current but had no effect on the current at the low concentration (10(-7) or 3 x 10(-6) M) used for staining the Merkel cells. 5. The sustained outward K+ current (IKD) was activated at potentials more positive than -20 or -10 mV at a VH of -50 mV, at which potential the transient outward K+ channel was completely inactivated. The potential for half-inactivation in the steady-state inactivation curve for IKD was -33 mV. 6. The transient outward K+ current (IA) was activated at potentials more positive than -50 mV at a VH of -80 mV. The potential for half-inactivation in the steady-state inactivation curve for IA was -64 mV. 7. When the outward K+ currents were blocked by adding both TEA and 4-AP, only a sustained inward Ca2+ current was observed. In an external solution containing 10 mM-Ca2+, ICa was evoked by potentials more positive than -20 mV at a VH of -80 mV, and the maximum inward current appeared around +10 mV. Increases in external Ca2+ concentration ([Ca2+]o) induced a hyperbolic increase in ICa and shifted the current-voltage (I-V) relationship along the voltage axis in a more positive direction. Saturation of ICa occurred at about 25 mM [Ca2+]o.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

[False Merkel cell tumor of the gingival mucosa disclosed by small cell bronchial carcinoma].

Merkel cell tumours are exceptional and usually occur in exposed areas of the face or limbs. These tumours are related to small-cell bronchogenic cancer. The case reported here demonstrates the relationship between these two cancers since the diagnosis of Merkel cell tumour of the gingival mucosa, initially made in a patient with no other presenting signs other than the stomatological lesions, was corrected six weeks later when the buccal lesion was found to be a metastasis of small-cell bronchogenic cancer. This observation is in agreement with the retrospective study reported by the Institute of Stomatology of the Salpêtrière hospital published in 1992 and presented at the XXIVth congress of the French Society of Cervicofacial Cancerology.

Carcinoma, Bronchogenic↗
PubMed2000

Analysis of thyroid transcription factor-1 and cytokeratin 20 separates merkel cell carcinoma from small cell carcinoma of lung.

Merkel cell carcinoma needs to be separated from small cell carcinoma metastatic from visceral sites to skin. Pulmonary small cell carcinoma is the most common primary site of small cell carcinoma. We evaluated the immunophenotypic characteristics of 21 Merkel cell carcinomas and 33 small cell carcinomas of lung using thyroid transcription factor-1 and cytokeratin 20. Thyroid transcription factor-1 was 100% specific for the diagnosis of small cell carcinoma of lung associated with a diagnostic sensitivity of 85%. Cytokeratin 20 was present in 95% of Merkel cell carcinomas; however, 33% of small cell carcinoma of lung were also positive. Both antibodies typically demonstrate diffuse and intense staining of their respective tumor cells. We conclude that thyroid transcription factor-1 is a sensitive and specific marker for small cell carcinomas of lung and that a combination of thyroid transcription factor-1 and cytokeratin 20 is indicated to assist in the differentiation of metastatic small cell carcinoma of lung from merkel cell carcinoma.

Biomarkers, Tumor↗
PubMed2006

No evidence of Epstein-Barr virus association with Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive tumor of cutaneous neuroendocrine cells with a reported 13-fold increased incidence in immunocompromised patients, raising the possibility that it is driven by an oncogenic virus. Additionally, Merkel cell hyperplasia is seen in the Epstein-Barr virus (EBV)-driven process oral hairy leukoplakia, and EBV is known to be involved in the pathogenesis of several other malignancies. OBJECTIVE: We tested the hypothesis that EBV is involved in MCC. METHODS: We employed EBV-encoded RNA in situ hybridization (ISH), lytic EBV ISH, latent membrane protein 1 immunohistochemistry, and BamH1Z leftward reading frame 1 immunohistochemistry to detect and localize EBV in paraffin sections of MCC from five patients as well as seven other cutaneous tumors and positive controls for EBV infection. RESULTS: Positive controls reacted appropriately. However, there was no evidence of latent or lytic EBV in any of the MCC biopsies or other cutaneous tumors. CONCLUSION: Our findings suggest that EBV is not associated with MCC.

Adult↗
PubMed2000

Bcl-2 antisense oligonucleotides (G3139) inhibit Merkel cell carcinoma growth in SCID mice.

Merkel cell carcinoma was first described in 1972 by Toker and is an aggressive neuroendocrine skin tumor with a high metastatic potential. Merkel cell carcinoma is thought to derive from the neuroendocrine (Merkel) cells of the skin, although in contrast to fetal and especially adult Merkel cells, Merkel cell carcinomas express high levels of the Bcl-2 oncoprotein. Bcl-2 is capable of blocking programmed cell death and has been shown to play an important role in normal cell turnover, tumor biology, and chemoresistance. High Bcl-2 expression leading to prolonged survival of cells may therefore be of importance in the biological and clinical characteristics of Merkel cell carcinoma. In a SCID mouse xenotransplantation model for human Merkel cell carcinoma, we investigated the influence of the bcl-2 antisense oligonucleotide G3139 (Genta) on tumor growth in comparison with control oligonucleotides or cisplatin. Bcl-2 antisense treatment, targeting the first six codons of the bcl-2 mRNA, resulted in either a dramatic reduction of tumor growth or complete remission, whereas reverse sequence and two-base mismatch control oligonucleotides or cisplatin had no significant antitumor effects compared with saline-treated controls. Apoptosis was enhanced 2.4-fold in the bcl-2 antisense treated tumors compared with the saline-treated group, and no other treatment showed a comparable increase in apoptosis. Our findings suggest that bcl-2 antisense treatment may be a novel approach to improve treatment outcome of human Merkel cell carcinoma.

Animals↗
PubMed1994

Merkel cells in neurofibromas and neurilemomas.

Merkel cells are an integral component of the cutaneous nervous system. They are commonly associated with dermal nerves under normal physiological conditions. We postulated that Merkel cells may be present in increased numbers within the epidermis overlying benign peripheral nerve sheath tumours such as neurilemomas and neurofibromas. Paraffin-embedded skin biopsy specimens from 21 patients with neurilemomas and 26 with neurofibromas, were analysed for the presence of Merkel cells using a standard immunohistochemical assay (avidin-biotin-peroxidase complex system) with an antibody to cytokeratin 8 (CAM 5.2). Ten cases of leiomyomas were examined as controls. Merkel cells were identified in the interfollicular area of the basal cell layer overlying 14 of 21 (67%) neurilemomas and nine of 26 (35%) neurofibromas. Merkel cells were more frequently observed in increased numbers in a linear array within the basal cell layer in neurilemomas than in neurofibromas, where they were found as individual cells. No Merkel cells were found in the epidermis overlying leiomyomas. The results of this study suggest that Merkel cells are quantitatively increased in the basal cell layer of the epidermis overlying benign peripheral nerve sheath tumours, particularly neurilemomas.

Humans↗
PubMed1987

Merkel cell tumor.

A Merkel cell tumor appeared on the left cheek of an 83-year-old female was reported. The tumor was located mainly in the dermis and infiltrated to the subcutaneous adipose tissue with an involvement of the blood vessels and lymphatics at the periphery. Electron-microscopically, few of the dense-cored granules and the single globular aggregates of intermediate filaments at the nuclear indentations were observed. Electron-microscopic uranaffin reaction proved positive reaction on the dense-cored granules. Half of the cytoplasmic border was smooth, while the rest had short projections. Desmosomes or junctional complexes were not detected among the tumor cells. Immunohistochemically, the cytoplasm of tumor cell showed positive reaction to both neuron-specific enolase (NSE) and keratin. The single globular positive spots of the latter were localized in accordance with the aggregates of intermediate filaments. These findings suggested a neurogenic origin with double differentiation, epithelial and neuroendocrine, of the Merkel cell tumor.

Adenocarcinoma↗
PubMedDate not supplied

Anemone cell tumor with neuroendocrine differentiation (presumed Merkel cell carcinoma).

A neuroendocrine tumor with ultrastructural "anemone cell" features in lymph nodes is reported. A primary tumor was not identified, but clinical and morphologic features suggested a metastatic Merkel cell carcinoma. The anemone cells were dissociated, lacked intercellular junctions, and contained cytoplasmic intermediate filament aggregates that immunohistochemically reacted with keratins, but they had only sparse neurosecretory granules. Where the tumor cells had infiltrated beyond the lymph nodes, however, they formed a trabecular pattern. A fine-needle aspirate from a later recurrence of the tumor lacked anemone cell features and was ultrastructurally typical of a Merkel cell carcinoma, with neurosecretory granules and intercellular junctions both being evident. The concept of anemone cell tumors and the morphologic variations determined by site are discussed.

Carcinoma, Merkel Cell↗
PubMedDate not supplied

Merkel cell tumor: two cases.

Merkel cell tumors are rare skin lesions that arise from the Merkel cell in the dermal layers. The two cases presented in this report are important in that they add more information to the literature than previously had been recognized. The first case discusses a collision tumor with a basal cell carcinoma. This is the first such report of this type of collision tumor. The second report is of a black female with a Merkel cell tumor of her finger. The case is unusual in that it is only the second time that a black female is reported to have this disease and the first time that it is reported on a digit. A review of the literature accompanies these case reports.

Aged↗
PubMed1993

Characterization of cell lines established from Merkel-cell ("small-cell") carcinoma of the skin.

Six cell lines have been established from different biopsies of the rare small-cell skin cancer of neuro-endocrine origin known as Merkel-cell carcinoma (MCC). These were established from metastatic lesions and have now been in culture for periods varying from 1 to 3 years. All lines grow as suspension cultures and exhibit typical MCC cytological features of small round cells with little cytoplasm, round nuclei and tight junctions. There was variation in the number and size of nucleoli and dense-core granules. We present details of their immunohistochemistry and growth characteristics in culture. The latter were similar to small-cell lung-cancer (SCLC) lines and can be subdivided, by their appearance, into type I, type II and type III in the same way as SCLC lines. This classification may be of significance for the prognosis and management of MCC.

Carcinoma, Merkel Cell↗
PubMed1991

Immunohistochemical demonstration of nerve-Merkel cell complex in fetal human skin.

Using Merkel cell specific antikeratin antibodies and neurofilament antibody the nerve-Merkel cell relationship was studied with a double staining method on frozen sections. Merkel cells were stained with monoclonal anti-cytokeratin CK-5 and CAM 5.2 which react against human cytokeratin polypeptide 45 kDa and 52.5 kDa, respectively. Peripheral nerves were stained with monoclonal murine antibody Neurofilament 70 and 200 kDa. Epidermal Merkel cells were recognized in 12-week fetuses in the plantar skin. In 15-week fetuses dermal Merkel cells were found. Most of the dermal Merkel cells initially lacked a close association with immunoreactive nerve fibers. In 16-week fetuses immunoreactive small nerves reached the epidermis and a few dermal Merkel cells became heavily entangled with the meshwork of nerve endings. Nerve-Merkel cell complex in the dermis was confirmed by electron microscopy. The appearance of epidermal Merkel cells preceded the attachment of immunoreactive nerve endings to the epidermis. In an analysis of 448 dermal Merkel cells the nerve-Merkel cell complex became more frequent as the age of fetus advanced. It was concluded that Merkel cells do not arrive at the epidermis with peripheral nerves. Rather, the peripheral nerves are attracted to the dermal Merkel cells which originated in the epidermis.

Fetus↗
PubMed2000

Merkel cells and sclerosing epithelial neoplasms.

Merkel cells are normal constituents of the basal layer of the epidermis and the follicular epithelium. They have been identified in benign neoplasms with follicular germinative differentiation but seem to be absent in basal cell carcinomas (BCCs). Because sclerosing epithelial neoplasms are often sampled by small biopsies, any method that enables distinction among them would be welcome. We used immunohistochemical staining for cytokeratin 20 to assess the presence of Merkel cells in 14 cases of desmoplastic trichoepithelioma (DTE), 12 specimens of syringoma, 11 samples of morpheiform BCC, and 8 specimens of microcystic adnexal carcinoma (MAC). Merkel cells were found in association with all 14 specimens of DTE and in 1 of 11 cases of morpheiform BCC (p < 0.005) but in none of the specimens of syringoma or MAC. Our study supports previous findings that Merkel cells are seen in association with cutaneous neoplasms that are benign and of a follicular germinative origin. Although MAC may differentiate along follicular-sebaceous-apocrine lines, the absence of Merkel cells within it is consistent with its malignancy. The identification of Merkel cells in a sclerosing epithelial neoplasm of the skin points to DTE as the most likely diagnosis.

Biomarkers, Tumor↗
PubMed1994

A nonconsensus octamer-recognition sequence (TAATGARAT-motif) identifies a novel DNA binding protein in human Merkel cell carcinoma cell lines.

We have established a number of cell lines from Merkel cell carcinoma (MCC) of the skin. In many respects these cell lines resemble those established from small cell lung cancer (SCLC) and it is difficult to differentiate between metastatic MCC and SCLC on morphological or histochemical criteria. Both are thought to be neuroendocrine tumours and may express a number of neuroendocrine markers. SCLC cell lines express the octamer-DNA binding transcription factor brn-2 gene products N-Oct3 and N-Oct5, which are restricted to the neuroectodermal cell lineage. In DNA binding studies using a consensus octamer recognition site we have found that 4 of 8 MCC cell lines examined expressed brn-2 in at least trace amounts compared with 3 SCLC cell lines which all expressed brn-2 proteins at high levels. Moreover, these DNA binding studies were extended by using a high-affinity brn-2 recognition site related to the degenerate octamer TAATGARAT-motif. This identified a novel DNA binding protein in a subset of MCC cell lines. The protein was absent from the three SCLC cell lines, melanoma cells and brain tissue. This binding activity, which we term Merkel cell DNA nuclear (MNF), was shown to be specific by competitive inhibition with oligonucleotide binding sites and was not inhibited by polyclonal antisera against the Oct-1, Oct-2 or Brn-2 proteins. This protein may serve as a unique marker for MCC compared with SCLC cells and may be involved in regulating the Merkel cell phenotype.

Base Sequence↗
PubMed1996

Merkel cell carcinoma in Israel.

Merkel cell carcinoma is a rare and highly malignant skin tumor. We present the first report on the clinical and epidemiologic characteristics of Merkel cell carcinoma in Israel. Our findings, including average age of 69 years at diagnosis, equal sex distribution, disease location on sun-exposed skin, and an overall 3 year survival of 58%, are consistent with the data reported in the literature. Unique findings in our study were the predominance of Ashkenazic Jews and the excessive rate of second malignancies. This initial report on Merkel cell carcinoma in Israel emphasizes the need for increased awareness of this aggressive and potentially lethal skin malignancy.

Adult↗
PubMed1995

Cytokeratin 20 is a general marker of cutaneous Merkel cells while certain neuronal proteins are absent.

Merkel cells are difficult to identify in tissue sections. Previous studies have used cytokeratins (CK) 8, 18, and 19 as histologic markers of Merkel cells. However, these CKs are also expressed in some outer root sheath keratinocytes and some early fetal epidermal cells and thus are not truly specific of Merkel cells in general. Using selective antibodies against a newly described CK, number 20--originally found in intestinal epithelium and Merkel cell carcinomas--in comparison to a key protein of neuroendocrine cells, chromogranin A, we established CK 20 as a specific Merkel cell marker in skin of humans, pigs, and mice. CK 20 seems to be an even more general and sensitive Merkel cell marker as compared to CgA. In double-labeling experiments with stratified-squamous epithelial CK (numbers 5 and 13-17) and simple epithelial CK (numbers 8, 18, and 20) antibodies evaluated by confocal laser scanning microscopy, no cell expressing CKs of both types (i.e., no cell of so-called "transitional" character between Merkel cells and keratinocytes) was identified in human skin. In addition, various neuronal markers present in Merkel cell carcinomas including neurofilaments, peripherin, nerve growth factor receptor, and neuronal cell adhesion molecule appear to be absent in normal Merkel cells. Thus, Merkel cells exhibit a distinct and unique marker profile, with CK 20 being of particularly high value in various species.

Adult↗