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PubMed2006

Lymphatic mapping and sentinel node biopsy in Merkel's cell carcinoma.

AIM: The purpose of this study was to determine the predictive value of lymphatic mapping with selective lymphadenectomy in patients with Merkel's cell carcinoma. METHODS: Eight patients with biopsy proven Merkel's cell carcinoma underwent sentinel node biopsy. Lymphoscintigraphy was performed the day before surgery following intradermal injection of 74-111MBq of 99mTc-nanocolloid divided into four doses around the biopsy scar. Dynamic and static images were obtained. RESULTS: At least one sentinel node was visualized in all patients. The sentinel node was intra-operatively identified with the aid of a hand-held gamma probe in all cases and patent blue dye in six out of eight cases. During surgery, all sentinel nodes were successfully harvested. Metastatic cell deposits were subsequently identified in three patients (37.5%) and they underwent regional lymphadenectomy. No additional involved lymph nodes were identified. No recurrence has been reported in a median follow-up of 4.6 years (range: 8 months-10 years). CONCLUSIONS: In conclusion, sentinel node biopsy in patients with Merkel's cell carcinoma appears to be a reliable staging technique.

Adult↗
PubMed2002

Merkel-like cells in Malassez epithelium in the periodontal ligament of cats: an immunohistochemical, confocal-laser scanning and immuno electron-microscopic investigation.

The cellular heterogeneity of Malassez epithelium (ME) residing in the periodontal ligament has recently been reported, and the presence and coexistence of the neuropeptides calcitonin gene-related peptide (CGRP), substance P (SP) and vasoactive intestinal peptide (VIP) in single cells in ME has been shown (1). However, the identity of these neuroendocrine cells has so far not been verified. This study was undertaken in order to elucidate the identity of the neuroendocrine cells in ME by means of transmission electron microscopy, confocal scanning microscopy and immunohistochemistry using antibodies to protein gene product (PGP) 9.5 and cytokeratin 20 (CK). Gingival tissue was included in the study as a positive control for identification of Merkel-like cells in oral epithelium. CK 20 immunopositive cells were present in both Malassez epithelium and in basal cell layers of gingival epithelium showing a distribution consistent with PGP 9.5 labelled cells in both epithelia. The results from PGP 9.5 immuno electron microscopy clearly evidenced the presence of single, intensely labelled cells and some nerve fibres invested between the Malassez epithelial cells. The conformity of the immunopositive cells in Malassez and gingival epithelium verified by double immunolabelling with PGP 9.5 and CK 20, indicates that the labelled neuroendocrine cells are identical in ME and in gingival epithelium. This demonstrates that Malassez epithelium not only exhibits neuroendocrine cells, but additionally that the neuroendocrine cells represent Merkel-like cells.

Animals↗
PubMedDate not supplied

Oral hairy leukoplakia with ultrastructural evidence of Merkel-like cells in human tongue epithelium.

The purpose of this investigation was to examine cells in the stratum basale and subjacent lamina propria of oral hairy leukoplakia (OHL) specimens for previously unreported morphological changes. Tongue biopsy specimens were obtained from ten HIV-positive and five healthy male patients and examined by light (LM) and transmission electron microscopy (TEM). Observations made during the investigation revealed the following: (1) LM comparisons of control and OHL specimens indicated that clear cells in the stratum basale ranged from 3 to 7 per 100 basal epithelial cells in healthy tongue mucosa vs. 6 to 15 in OHL. (2) Merkel-like cells were noted in the stratum basale of control biopsies from the dorsal-lateral tongue surface. However, the frequency of observation was so rare as to imply that their presence was an exception rather than the norm. (3) In contrast, Merkel-like cells in OHL specimens were commonly encountered, indicating a possible unique relationship to the pathology. (4) Merkel-like cells associated with OHL lesions were morphologically similar, in all respects, to that of control specimens except for the presence of large, membrane bound, dense granules that ranged in size from 150-300 nm. (5) All biopsies of OHL exhibited evidence of Epstein Barr virus in the stratum corneum and superficial layers of the stratum spinosum. (6) A mild inflammatory infiltrate associated with OHL specimens revealed cytopathic changes in fibroblasts that appeared related to the presence of lymphoid cell types; indicating a possible cytolytic lymphocyte-mediated degradation of antigen altered host cells.

Biopsy↗
PubMed1993

Fine structure of Merkel corpuscles in the lingual mucosa of Japanese quail, Coturnix coturnix japonica.

By electron microscopy, these corpuscles were found exclusively in the connective tissue just beneath the dorsal epithelium near the lateral margin of the tongue. Each consisted of 4-8 Merkel cells and flattened nerve terminals arranged alternately. The Merkel cell was characterized by dense-cored granules, with a diameter ranging from 120 to 180 nm, throughout the cytoplasm. The functional significance of the avian Merkel cell, i.e. a mechanoreceptor cell or a trophic cell with the axon, still remains enigmatic, as is the case with Merkel cells of other vertebrates.

Animals↗
PubMed2000

Divergent differentiation in endocrine and nonendocrine tumors of the skin.

In the skin, endocrine tumors showing areas with nonendocrine features and nonendocrine tumors showing endocrine differentiation are present. (1) Neuroendocrine carcinomas with nonendocrine differentiation: Merkel cell carcinoma (MCC) of the skin has been frequently described in association with squamous cells carcinoma (SCC) which can arise separately (as synchronous or metachronous lesions) from MCC as well as closely intermixed. In the first event the possibility that the lesions are sustained by same causative factors (among which sun exposure is the most probable) is suggested. In cases of lesions closely intermixed the possibility of an origin from a common precursor is suggested. Furthermore, cases of MCC have been described to contain glandular, melanocytic, striated muscle, and lymphoepithelioma-like features. These latter findings further support the hypothesis of tumors showing divergent differentiations. (2) Nonendocrine tumors showing endocrine differentiation: Basal cell carcinoma (BCC) was the first cutaneous nonendocrine tumor described to contain neuroendocrine granules. Presence of endocrine features were subsequently confirmed with immunohistochemical studies. Endocrine features were then described in sweat gland apocrine and eccrine carcinomas. Endocrine elements present in BCC and in sweat gland carcinomas do not show morphological and immunohistochemical features of Merkel cells. Thus the possibility that these tumors develop an immature Merkel cell or a new type of endocrine cell of the skin is suggested. Tumors with follicular differentiation such as trichoblastomas and trichofolliculomas contain a high number of Merkel cells. As Merkel cells are numerous in hair follicles of human fetal skin, the possibility that these tumors recapitulate the human skin embryogenesis is suggested.

Aged↗
PubMed1989

Chemoreceptive and mechanoreceptive paraneurons in the tongue.

Chemoreceptive and mechanoreceptive paraneurons in the tongue include gustatory cells and basal cells of the taste buds, Merkel cells in the lingual epithelium and Merkel or Grandry corpuscles in avian subepithelial connective tissue. Neuron-specific enolase immunoreactivity is recognized in the basal cells, a type of Merkel cells, in the taste buds of teleost fishes and amphibia, certain taste bud cells of mammals and the Merkel cells in birds. The present study also concerns itself with the ultrastructural features of the gustatory cells of the rabbit taste buds, and the Merkel cells of the finch tongue. The functional significance of the dense-cored granules in the gustatory cell is still enigmatic. On the other hand, the dense-cored granules in the Merkel cells may have dual functions storing both neurotransmitters and local hormones. Shortly after giving a mechanical stimulus to the finch tongue, we could demonstrate massive exocytotic changes of the Merkel cell granules.

Amphibians↗
PubMed1984

Primary neuroendocrine carcinoma of the skin (Merkel's cell carcinoma).

Primary neuroendocrine carcinoma of the skin (Merkel's cell carcinoma) is a rare tumor. Until recently 86 patients with this tumor have been described. Two cases of this tumor are presented. This neoplasm has a high propensity for lymphatic as well as hematogenous metastases. It presents as a dermal or subcutaneous nodule. Awareness of this condition may lead to earlier diagnosis and improved survival.

Aged↗
PubMed2000

Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites.

AIMS: The thyroid transcription factor-1 (TTF-1) is a highly specific immunohistochemical marker for the identification of pulmonary adenocarcinomas and non-neuroendocrine large cell carcinomas, especially in patients presenting with metastatic carcinomas of unknown primary site. In this study we tested if anti-TTF-1 can also be used to verify a pulmonary origin of neuroendocrine carcinomas, placing emphasis on the discrimination of pulmonary small cell carcinomas (SCCs) from extrapulmonary SCCs and the distinction of SCCs from Merkel cell carcinomas of the skin. METHODS AND RESULTS: We studied 37 pulmonary SCCs, 15 SCCs of extrapulmonary origin, 4 pulmonary large cell neuroendocrine carcinomas (LCNECs), four extrapulmonary LCNECs, six medullary thyroid carcinomas, 16 Merkel cell carcinomas, and a total of 32 carcinoids/low-grade neuroendocrine carcinomas of pulmonary (12 cases) and extrapulmonary (20 cases) origin. Using the commercially available monoclonal antibody 8G7G3/1, TTF-1 was immunohistochemically detectable in 81% of pulmonary SCCs but also in 80% of extrapulmonary SCCs. Furthermore, anti-TTF-1 showed a positive staining in 50% of all pulmonary carcinoids, in one gastric carcinoid, in 2/4 of pulmonary, and 1/4 of extrapulmonary LCNECs. All medullary thyroid carcinomas were also TTF-1-positive. Merkel cell carcinomas were consistently TTF-1-negative. CONCLUSIONS: Our results suggest that in contrast to non-neuroendocrine carcinomas, anti-TTF-1 cannot be used to prove or to exclude a pulmonary origin of SCCs or LCNECs of unknown or uncertain primary site. Therefore, before using anti-TTF-1 as a marker for pulmonary carcinomas one should be sure to have excluded SCC and LCNEC. On the other hand, anti-TTF-1 might be used to specifically discriminate SCCs of various origin from Merkel cell carcinomas.

Antibodies, Monoclonal↗
PubMed1992

Distribution and coexistence of chromogranin A-, serotonin- and pancreastatin-like immunoreactivity in endocrine-like cells of the human anal canal.

The comparative distribution and coexistence of chromogranin A (CGA)-, serotonin (5-hydroxytryptamine; 5-HT)- and pancreastatin (PST)-like immunoreactivity in endocrine-like cells of the human anal canal was investigated by light-microscopic immunocytochemistry. The largest population of colorectal endocrine-like cells consisted of CGA-immunoreactive (ir) cells, followed by the 5-HT-ir and PST-ir cell population. In the anal transitional zone (ATZ), CGA- and 5-HT-immunoreactivity was equally distributed; ir-PST was confined to a smaller endocrine-like cell population. In the squamous zone and the perianal skin, Merkel cells in the basal layer of the epidermis and hair follicles exhibited ir-CGA and ir-PST but no ir-5-HT. Double immunofluorescence on identical sections revealed distinct coexistence patterns. In the colorectal zone, about 2/3 of the CGA-ir endocrine-like cells also stained for 5-HT, whereas in the ATZ epithelium, CGA- and 5-HT-immunoreactivity completely overlapped. No 5-HT-immunoreactivity could be detected in CGA-ir Merkel cells of the squamous zone of the anal canal and the perianal skin. PST-immunoreactivity was present in about 1/3 of the CGA-ir colorectal and anal transitional endocrine-like cells and in about 1/4 of the Merkel-cell population staining for CGA. These chemically heterogeneous phenotypes of the anal endocrine-like and Merkel cells may reflect a specific regulatory role of these cells in the various epithelial linings of the human anal canal and the perianal skin.

Anal Canal↗
PubMed1999

Merkel's cell carcinoma in organ recipients: report of 41 cases.

In the general population Merkel's cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. More than 600 cases have been reported. MCC seems to be common in transplant recipients, with 41 cases being reported to the Cincinnati Transplant Tumor Registry, and another 11 in the transplant literature. In the general population, it is a disease of older adults, with only 51% of cases occurring below the age of 50 years. In transplant patients, the mean age at diagnosis was 53 (range 33-78) years, and 29% of recipients were <50 years old. The tumor appeared from 5 to 286 (mean 91.5) months after the transplant. Of 44 lesions that occurred in 41 patients, the distribution was similar to that seen in the general population, with 36% occurring on the head and neck, 32% on the upper extremities, 16% on the trunk, 9% at unknown sites, and 7% on the lower extremities. Twenty of the patients (49%) had 22 other malignancies, the great majority of which (91%) were other skin cancers. Treatment depended on the stage of the disease and included wide surgical excision, radical lymph node dissection, radiation therapy, and chemotherapy. In transplant patients, MCC probably proved to be more aggressive than in the general population in that 68% of patients developed lymph node metastases and 56% died of their malignancies. Furthermore, one third of surviving patients still have active cancers from which they may die. Also, follow-up of survivors has been relatively short, with a mean of only 18 (range 0-135) months.

Adult↗
PubMed1996

Two- and three-dimensional demonstrations of morphological alterations of early anagen hair follicle with special reference to the bulge area.

During late telogen to early anagen secondary hair germ is newly formed by the downgrowth of a clubbed column which is indistinguishable from the bulge. Serial vertical sections demonstrated that the early anagen terminal hair follicle formed the new secondary hair germ associated with a lateral protuberance of basaloid cells which could be considered as the bulge of the new hair follicle. Interestingly, the arrector pili muscle bundle was divided into two branches, one inserted into the original clubbed end and the other into this protuberance of the secondary hair germ. CAM5.2-reactive Merkel cells were present not only in the clubbed ends of the old follicle but also in the protuberance of the new hair germ. The formation of the lateral protuberance of the new hair germ preceded the appearance of CAM5.2-reactive Merkel cells in this location. Ks19.1 immunoreactivity was observed from the clubbed end to the upper half of the new hair germ. These phenomena occurred in early anagen before the club hairs were shed. It is postulated that the early anagen hair follicle formed the area within the new hair germ equivalent to the bulge and Merkel cells either moved from the bulge of the old hair follicle or differentiated de novo from immature epithelial cells. Merkel cells or their products in the bulge may serve as attractants for the readjusting arrector pili muscle to anchor to the bulge of the new hair follicle.

Edetic Acid↗
PubMed1994

Ultrastructure of Merkel-like cells labeled with carbocyanine dye in the non-taste lingual epithelium of the axolotl.

Fluorescent carbocyanine dye (diI), applied to the glossopharyngeal (IX) nerve of the axolotl, transneuronally labeled solitary cells in the non-taste lingual epithelium. With diaminobenzidine (DAB), the diI was photoconverted to a dark, electron-dense product. The labeled cell had a large nucleus with invaginations, dense-cored vesicles in the cytoplasm, and finger-like processes. These are reminiscent of morphological features of cutaneous Merkel cells, suggesting that solitary cells innervated by the IX nerve are associated with mechanosensory function of the IX nerve system.

Ambystoma mexicanum↗
PubMed1985

Early differentiation of the afferent nervous system in glabrous snout skin of the opossum (Monodelphis domesticus).

Early differentiation of afferent fibers innervating the snout skin of Monodelphis domesticus was studied by electron microscopy and by light-microscopic silver staining techniques. This study was undertaken to investigate the relationship between dermal and epidermal innervation in the neonate opossum while correlating these findings with behavioral responses. The advantage of using this species is that the neonate is born in a very immature stage and has a rostrocaudal development of the peripheral nervous system. Glabrous snout skin from young opossums was studied at birth (0 day) and postnatal days 1, 3, and 5. Neurite bundles were seen within the dermis, with axons and growth cones approaching the epidermis. Some axons penetrated the dermal-epidermal junction in newborn pups. Merkel cells were consistently numerous during the time spanned by this study. Mature Merkel cells had granules polarized toward an associated neurite and were often located in the base of the rete pegs. Immature Merkel cells were characterized by a lack of polarization of granules and absence of an apposed neurite, suggesting that these cells can differentiate without an associated neurite. Contiguous Merkel cells had junctional complexes in 0- and 1-day animals. Schwann cells, identified by their contact with neurite bundles, were present in large numbers, especially in the superficial dermis. Melanocytes could be identified in the epidermis in 5-day pups only. Developing rete pegs could be recognized in 0-day animals and became prominent in 5-day pups. These observations suggest that afferent fibers are present at a very early age and that some of these fibers are anatomically mature. These findings support the concept that the ability of the neonate to locate a teat and suckle requires only the presence of mature epidermal innervation, while dermal receptors appear later during postpartum development.

Afferent Pathways↗
PubMedDate not supplied

Aspiration cytology in the diagnosis of primary tumors of skin adnexa.

OBJECTIVE: To evaluate the cytologic features and pitfalls in the cytodiagnosis of certain tumors of skin adnexa. STUDY DESIGN: Smears from five nodular basal cell carcinomas, two chondroid syringomas and one case each of primary mucinous carcinoma, Merkel cell tumor, trichoepithelioma, pilomatrixoma and eccrine spiradenocarcinoma, all histologically confirmed, were evaluated with special attention to cytologic features that may aid the diagnoses. RESULTS: Ten of 12 (83.3%) adnexal tumors were correctly recognized on aspiration cytology. The five basal cell carcinomas were atypical in presentation and clinically unsuspected but were diagnosed on cytology. The chondroid syringomas and Merkel cell tumor could also be diagnosed due to awareness of the cytologic features and sound clinical correlation. The eccrine spiradenocarcinoma was diagnosed as spiradenoma because of improper assessment of local invasion and incorrect mitotic count in the aspirates. The diagnosis was inaccurate in primary mucinous carcinoma as the aspirate yielded mainly mucin. CONCLUSION: Although exact subtyping of tumors of skin adnexa may not always be essential, certain benign adnexal tumors have aggressive counterparts (e.g., eccrine spiradenomas), while others clinically mimic metastases or small round cell carcinomas (e.g., Merkel cell tumors). Thus, correct cytodiagnoses and awareness of the limitations of cytology (such as in the assessment of local invasion) in these instances help to outline surgical management.

Adenocarcinoma, Mucinous↗
PubMed2004

CD117, CK20, TTF-1, and DNA topoisomerase II-alpha antigen expression in small cell tumors.

BACKGROUND: Distinguishing merkel cell carcinoma (MCC), small cell lung carcinoma (SCLC) metastatic to the skin, and atypical basal cell carcinoma (BCC) can be problematic in some cases. Significant differences in the biology of these tumors necessitate that they need to be distinguished from one another. METHODS: We evaluated the immunophenotypic characteristics of 22 MCCs, nine SCLCs, and 19 BCCs using antibodies to cytokeratin 20 (CK20), thyroid transcription factor-1 (TTF-1), CD117, and DNA topoisomerase II-alpha (topo II). RESULTS: Nineteen of 22 MCCs stained with the antibody to CK20, none stained with anti-TTF-1, and 13 stained with anti-CD117. No SCLC stained with anti-CK20, all stained with anti-TTF-1, and eight stained with anti-CD117. No BCC stained with any of the three markers. The proliferative index (PI), determined by the expression of topo II, was similar for SLCLs (mean 58.5 +/- 9.0%) and MCCs (mean 45.2 +/- 12.4%) and was lowest in BCCs (mean 25.0 +/- 8.7%). CONCLUSIONS: CK20 and TTF-1 appear to be reliable in distinguishing MCC from SCLC. CD117 is expressed in both MCC and SCLC, limiting its diagnostic utility. CK20, TTF-1, and CD117 are not expressed in BCC. The high PI seen in MCCs suggests a role for topoisomerase II inhibitors in their treatment.

Antigens, Neoplasm↗
PubMed2006

Cytopathologic features of olfactory neuroblastoma.

BACKGROUND: Olfactory neuroblastoma (ONB) is an uncommon neoplasm arising from the olfactory mucosa. Because its cytopathology is largely limited to case reports, the goal was to evaluate a series of ONB cases, compare them with previously reported cases, and with a control group of pulmonary and cutaneous small cell neuroendocrine carcinoma (NEC). METHODS: Six fine-needle aspiration (FNA) biopsies of metastatic ONB and one case with imprint smears of primary ONB were recovered from files. Aspirates from seven FNA cases of metastatic pulmonary small cell NEC and four cases of metastatic Merkel cell carcinoma to the head and neck functioned as a control group and were compared with those of ONB. RESULTS: Seven cases from 4 patients included 3 males (ages 33-39 yrs) and 1 female (age 58 yrs). Aspirates were acquired from soft tissues of the neck (three cases), cervical lymph nodes (two cases), parietal scalp (one case), and imprint of a nasal mass (one case). A correct cytologic diagnosis of metastatic ONB (five cases) or malignant small round cell tumor (one case) was made in six cases. One aspirate was misdiagnosed as a reactive lymph node. The single primary tumor and five of six metastatic tumors were histologically confirmed. Cytologic features were similar in all cases. These included high cellularity (seven of seven cases), distribution as single forms and cell clusters (seven of seven cases), a two-cell population of intact and apoptotic nuclei (seven of seven cases), nuclear molding (seven of seven cases), paranuclear 'blue bodies' (five of seven cases), necrosis (five of seven cases), and absence of lymphoglandular bodies (seven of seven cases). Unlike prior reports, no case exhibited rosettes or fibrillar neuropil on smears. All examples from the control group displayed nearly identical cytomorphologic features to those of the study group. CONCLUSIONS: The cytopathology of metastatic ONB is nonspecific unless fibrillar neuropil is identified. Nonetheless, a cytopathologic diagnosis of metastatic ONB can be made with confidence in nearly all patients if a well documented history of ONB exists. Minus such a clinical context, aspirates of metastatic ONB may be mistaken for metastatic pulmonary small cell NEC, cutaneous neuroendocrine (Merkel cell) carcinoma, and even small cell lymphoma.

Adult↗
PubMed2000

Thyroid transcription factor-1 is expressed in extrapulmonary small cell carcinomas but not in other extrapulmonary neuroendocrine tumors.

Thyroid transcription factor-1 (TTF-1) is a nuclear homeodomain transcription factor that is expressed in the developing thyroid, respiratory epithelium, and diencephalon. TTF-1 is thought to be expressed specifically in pulmonary or thyroid neoplasms, and it is expressed in a significant subset of pulmonary non-small cell carcinomas, small cell carcinomas, and carcinoids but not in nonpulmonary, non-small cell carcinomas. Neuroendocrine tumors from sites other than the lung have not been evaluated for TFF-1 expression. We examined TFF-1 expression using immunohistochemistry on formalin-fixed, paraffin-embedded sections of 49 gastrointestinal carcinoids; 15 pancreatic islet cell tumors; 21 paragangliomas; 8 medullary thyroid carcinomas; 7 small cell carcinomas of the uterine cervix; 4 prostate, 4 bladder, and 6 Merkel cell (primary cutaneous neuroendocrine) carcinomas; and 1 renal carcinoma No gastrointestinal carcinoid tumor, pancreatic islet cell tumor, paraganglioma, or Merkel cell carcinoma expressed TFF-1. All of the medullary thyroid carcinomas strongly expressed TTF-1. However, 44% of nonpulmonary small cell carcinomas were also TTF-1 positive, including four of four prostate, two of four bladder, and one of seven cervical small cell carcinomas. We conclude that TTF-1 expression is not specific for small cell carcinomas of pulmonary origin and should not be used to distinguish primary from metastatic small cell carcinomas in extrapulmonary sites. However, TTF-1 expression may be useful in distinguishing Merkel cell carcinomas and cutaneous metastasis of small cell carcinomas. Among well-differentiated neuroendocrine tumors, TTF-1 expression seems to be present only in carcinoid tumors of the lung and medullary carcinomas of the thyroid and may be of differential diagnostic value when dealing with a metastatic well-differentiated neuroendocrine tumor.

Biomarkers, Tumor↗