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PubMed1985

Electron microscope study of the Grandry and Herbst corpuscles in the palatine mucosa, gingival mucosa and beak skin of the duck.

Grandry and Herbst corpuscles of the palatine mucosa, gingival mucosa and beak skin were studied with the electron microscope. Typical Grandry corpuscles are surrounded by thick bundles of collagen fibers and composed of a terminal axon sandwiched between Grandry cells. Occasionally, two or three nerve endings are found within one corpuscle. The Grandry cell contains numerous electron-dense granules similar to those of a Merkel cell. The cell extends protrusions at the poles and the opposing faces. Desmosome-like attachments are noted between interdigitated protrusions, and between the axon and Grandry cell. Herbst corpuscles are composed of an outer capsule, inner core and central nerve ending. The outer capsule consists of 15 to 20 concentric lamellae, while the inner core possesses 60 to 70 sheets of cytoplasmic extensions. Under the scanning electron microscope, the corpuscles appeared as an elongated oval form surrounded by dense fibrous connective tissue, and each lamella of the outer capsule was composed of a dense network of thick and thin fibrils. These were seen under the transmission electron microscope as thick fibrils about 50 nm in diameter and peripheral thin fibrils about 10 nm in diameter. In some portions, a periodic increase of cytoplasmic density about 20 nm in width located in neighboring sheets was noted. The terminal axons of both corpuscles contain numerous neurofilaments, slender mitochondria, neurotubules, smooth endoplasmic reticulum and vesicles. Both corpuscles are limited by several flat cells which are arranged in parallel and probably correspond to the perineural cells of the peripheral nerve. Tight junctions were observed between these cells.

Animals↗
PubMed2007

[Skin tumors in organ-transplant recipients].

Skin cancers are a significant medical problem for organ-transplant recipients. Squamous cell carcinoma and basal cell carcinoma are most common tumors. An increasing incidence of melanoma, Kaposi sarcoma, Merkel cell carcinoma, as well as uncommon skin malignancies, is also seen. Predisposing factors include cumulative sun exposure, cumulative immunosuppression, age, gender, skin type, virus detection and genetic alterations. Skin tumors grow rapidly and their number continues to increase in the years following transplantation. Large numbers of tumors, aggressive courses and appearance in young patients are other characteristics of these skin tumors. More general awareness of the need for preventive measures and regular dermatological examinations is desirable. In addition standardized registries are needed to assure the comparability of data, to better correlate immunosuppression with skin tumors and to plan therapeutic studies.

Carcinoma↗
PubMed1995

Ber-EP4 immunoreactivity in normal skin and cutaneous neoplasms.

Ber-EP4 is an antibody raised against a cell membrane glycoprotein of, as yet, unknown function. In the skin, the ability to distinguish basal cell carcinoma from squamous cell carcinoma has been emphasized. Immunoreactivity in apocrine and eccrine secretory coil epithelium, Merkel cell carcinoma, and cutaneous mixed tumor has been reported. Having observed more widespread staining than previously reported, we sought to characterize further Ber-EP4 immunoreactivity by examining 76 formalin-fixed and paraffin-embedded proliferative epithelial skin lesions, 2 sections of fetal skin with developing adnexa, and frozen sections of skin from Mohs surgery procedures, using hematoxylin and eosin and Ber-EP4 immunostaining. In paraffin-embedded skin, matrical and outer sheath epithelium of vellus anagen follicles, inferior segment epithelium of vellus telogen follicles, and secretory coils of sweat glands stain with Ber-EP4, but anagen terminal follicle epithelium and eccrine and apocrine sweat ducts are negative. On frozen section, additional staining of eccrine ducts and cells in the outer sheath and matrix of the inferior segment of terminal follicles is noted. Basaloid epithelium of trichoepitheliomas, follicular induction over dermatofibromas, mammary Paget's disease, and selected other neoplasms showing eccrine or apocrine differentiation stain with Ber-EP4. These data indicate that in addition to basal cell carcinoma, Ber-EP4 staining may be seen in a variety of proliferative epidermal and adnexal lesions.

Adenoma, Sweat Gland↗
PubMed2006

The management of skin malignancy: to what extent should we rely on clinical diagnosis?

BACKGROUND: Cutaneous malignancy forms a major part of the dermatologist's workload. Clinical diagnosis is an important factor in facilitating the urgent excision of squamous cell carcinomas (SCC) and malignant melanomas. OBJECTIVES: To identify the numbers and types of malignant skin tumours managed in an NHS teaching hospital and to assess the diagnostic accuracy. METHODS: Data were collected on every histologically proven malignant skin lesion over a 6-month period. RESULTS: One thousand one hundred and ninety-five malignant skin tumours were identified: 78% were basal cell carcinomas, 14% were SCC, 6% were malignant melanomas and the remaining 2% included Merkel cell tumours, malignant adnexal tumours and lentigo maligna. Eighty-one per cent of the tumours were managed by dermatologists. The correct clinical diagnosis had been made by the secondary care clinician in 84% of cases but an incorrect clinical diagnosis was given in 32% of SCC. Of the 1195 tumours, 916 (77%) had a primary excision and 92% (843 of 916) of these were completely excised. CONCLUSIONS: The majority of skin malignancies (968 of 1195, 81%) were managed by dermatologists. Where primary excision was attempted, this was complete in 91% (767 of 916) of cases. The correct clinical diagnosis was made in 84% of all tumours, but 32% of SCC were not correctly diagnosed prior to surgery.

Biopsy↗
PubMed2006

Functional redundancy of NSCL-1 and NeuroD during development of the petrosal and vestibulocochlear ganglia.

To study the role of different members of the bHLH gene family for sensory organ development we have generated NSCL-1 and NeuroD compound-mutant mice. Double homozygous animals were characterized by a more severe reduction of the petrosal and vestibulocochlear ganglia than NeuroD-knockout mice. The more severe reduction of the petrosal and vestibulocochlear ganglia in double-knockout mice indicates overlapping functions of the two genes during neuronal development. Interestingly, we also found that the two genes are jointly regulated by thyroid hormone during sensory hair cell development. We further present a detailed expression analysis of NSCL-1 and NSCL-2 during sensory neuron development. NSCL-1 expression was detected in all developing cranial ganglia including the petrosal and vestibulocochlear ganglion, in inner and outer hair cells of the organ of Corti and in hair cells of the vestibular system. Expression domains in other sensory structures include the retina, Merkel cells of the developing skin and sensory cells of the tongue. The expression of NSCL-2 was restricted to developing cranial ganglia, the retina and the vestibular nerve. Both NSCL-1 and NSCL-2 genes are active only in postmitotic neurons, indicating a role for neuronal cell migration and/or differentiation within the sensory system.

Animals↗
PubMed1984

An ultrastructural cytochemical stain specific for neuroendocrine neoplasms.

Previous work from our laboratory has indicated that the uranaffin reaction, when run under specific conditions, will stain neurosecretory granules. In this ultrastructural cytochemical study, we analyzed the granule-staining properties of 13 normal, 10 abnormal (non-neoplastic), and 138 neoplastic tissues in an attempt to evaluate the specificity of the uranaffin reaction for diagnostic purposes when compared with routinely processed specimens. For the uranaffin reaction, previously fixed tissue stored in buffer was rinsed with 0.9% NaCl and reacted with a 4% aqueous solution of uranyl acetate (pH 3.9) for 48 hours. After three NaCl rinses, the tissue was dehydrated and processed for electron microscopy. The granules of normal or non-neoplastic neuroendocrine cells that stained positively with the uranaffin reaction included pancreatic islet cells, thyroid C cells, adrenal medullary cells, parathyroid chief cells, and the neuroendocrine cells of the intestine. All 42 neuroendocrine neoplasms studied possessed abundant uranaffin-positive granules and included carcinoids, oat cell carcinomas, islet cell neoplasms, medullary carcinomas of the thyroid, pheochromocytomas, carotid body paragangliomas, a pituitary adenoma, Merkel cell carcinomas, parathyroid adenomas, and a neuroblastoma. All 96 control neoplasms that were not classified as neuroendocrine in nature were negative for neurosecretory granules when studied with the uranaffin reaction and included 13 neoplasms derived from endocrine glands, 57 neoplasms from secretory epithelium, 10 of hematopoietic origin, and 16 miscellaneous neoplasms. It was determined that the uranaffin reaction is a useful ultrastructural cytochemical marker for neuroendocrine granules and helped distinguish these cytoplasmic organelles from ultrastructurally similar granules derived from non-neuroendocrine cells.

Adult↗
PubMed1993

Ultrastructure of the taste disc in the red-bellied toad Bombina orientalis (Discoglossidae, Salientia).

The taste disc of the red-bellied toad Bombina orientalis (Discoglossidae) has been investigated by light and electron microscopy and compared with that of Rana pipiens (Ranidae). Unlike the frog, B. orientalis possesses a disc-shaped tongue that cannot be ejected for capture of prey. The taste discs are located on the top of fungiform papillae. They are smaller than those in Ranidae, and are not surrounded by a ring of ciliated cells. Ultrastructurally, five types of cells can be identified (mucus cells, wing cells, sensory cells, and both Merkel cell-like basal cells and undifferentiated basal cells). Mucus cells are the main secretory cells of the taste disc and occupy most of the surface area. Their basal processes do not synapse on nerve fibers. Wing cells have sheet-like apical processes and envelop the mucus cells. They contain lysosomes and multivesicular bodies. Two types of sensory cells reach the surface of the taste disc; apically, they are distinguished by either a brush-like arrangement of microvilli or a rod-like protrusion. They are invaginated into lateral folds of mucus cells and wing cells. In contrast to the situation in R. pipiens, sensory cells of B. orientalis do not contain dark secretory granules in the perinuclear region. Synaptic connections occur between sensory cells (presynaptic sites) and nerve fibers. Merkel cell-like basal cells do not synapse onto sensory cells, but synapse-like connections exist between Merkel cell-like basal cells (presynaptic site) and nerve fibers.

Animals↗
PubMed1990

Human oral epithelial cell culture. II. Keratin expression in fetal and adult gingival cells.

Epithelial cells from human fetal and adult gingiva were cultured in keratinocyte growth medium (KGM), a serum-free medium. The expression of keratin proteins in these cells was evaluated using immunohistochemistry and SDS-PAGE-immunoblot analysis and compared with expression in the tissue. Keratins 5, 6, 14, 16, and 19 were identified in cells cultured from both fetal and adult tissues. K19 was localized in basal cells of fetal oral tissue but was not seen in adult gingiva (except for scattered Merkel cells). K1 and K10 were expressed in tissue, but not in cultured cells. The keratin profiles of cultured epithelial cells from several adult donors were similar and were identical in cultures from primary through Passage 5. K13, a differentiation-specific keratin, was expressed in all suprabasal cells of fetal oral epithelium, but shows only spotty expression in adult gingival tissue. K13 was expressed in cultures of fetal cells, but very weakly or not at all in cultures of adult cells. K13 expression was greater in cultures grown with physiologic calcium concentrations (1.2 mM) than in those grown at 0.15 mM or less. Our findings are consistent with basal-like characters of these cells in 0.15 mM calcium growth conditions. Differentiation of fetal oral cells in culture to the suprabasal basal cell stage in 1.2 mM Ca2+ is shown by the expression of K13.

Adult↗
PubMed1985

Small cell carcinoma of skin: a report of two cases.

We present two cases of small cell carcinoma of skin and review the evidence for the origin of these tumours from Merkel cells situated in the basal layers of the epidermis. The aggressive behaviour of these tumours makes their initial histological diagnosis important if careful follow-up is to be instituted and we suggest that more radical primary treatment might improve results. We emphasise the need to exclude an origin from other sites apart from skin and the role of electron microscopy and immunohistochemistry in identifying these tumours as being distinct from other poorly differentiated carcinomas.

Aged↗
PubMed2006

Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: a Hoosier Oncology Group phase II trial.

BACKGROUND: Gefitinib has demonstrated activity in patients with non-small cell lung cancer (NSCLC). Clinical trials have not demonstrated a relationship between response to gefitinib and over-expression of the epidermal growth factor receptor (EGFR). Although, EGFR is not over-expressed in small cell lung cancer (SCLC), we postulated that gefitinib might affect tumor growth through other mechanisms. Agents that are active in NSCLC usually are also effective in SCLC. METHODS: The primary objective was to assess the clinical control rate: complete response (CR) partial response (PR) and stable disease (SD > 90 days), of gefitinib in patients with chemo-resistant and chemo-sensitive small cell cancers. Eligibility criteria included pathologic proof of a neuroendocrine tumor, especially small cell cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, prior treatment with one or two prior chemotherapy regimens and adequate end-organ function. Patients received gefitinib, 250 mg p.o. daily until disease progression or intolerable side effects. RESULTS: From April 2003 to March 2004, 19 patients were enrolled. Small cell lung cancer accounted for 18 of the 19 patients and one patient had metastatic Merkel cell carcinoma. Twelve patients (63%) had chemo-sensitive disease, defined as progression greater than three months from completion of prior chemotherapy; 7 (37%) had chemo-refractory disease; 13 (68%) had one prior chemotherapy regimen. Other patient characteristics: mean age 64 years (range 52-79 years); ECOG PS 0/1/2 = 7/9/3, M:F = 9:10. Grade 3 toxicities included: fatigue in three patients (15.8%), pulmonary toxicities in three (15.8%) and one patient (5.3%) each with hyperglycemia or pain. Four patients had grade four toxicities: one patient (5.3%) with fatigue and three patients (15.8%) with dyspnea. There were no patients with grade 3 or 4 rash or diarrhea. Two patients had stable disease (<90 days) and 17 had progressive disease as their best response. This study was a two-stage design and because the continuing criterion for stage one was not met, stage 2 was not performed. Median time to progression (TTP) was 50 days (95% CI = 21-58 days). One year overall survival (OS) was 21% (95% CI = 6-45.6%). CONCLUSION: Although gefitinib has activity in select patients with NSCLC, this study failed to demonstrate benefit in patients with small cell lung cancer.

Aged↗
PubMed1997

The intermediate filament peripherin is expressed in cutaneous melanocytic lesions.

Peripherin is an intermediate filament involved in growth and development of the peripheral nervous system and is localized to neurons, some other cells derived from neural tube and neural crest, and some neuroendocrine cells (e.g. beta cells of islets of Langerhans). Peripherin also has been demonstrated in neuroblastomas and cutaneous neuroendocrine (Merkel cell) carcinomas. The expression of peripherin by other cells derived from the neural crest is unknown. We evaluated by immunohistochemistry 74 cutaneous melanocytic lesions including primary invasive malignant melanoma (IMM), melanoma in situ (MIS), atypical nevus (nevus with architectural disorder and cytologic atypia of melanocytes) (AN), spindle and epithelioid cell nevus (Spitz nevus) (SN), blue nevus (BN), and common intradermal benign melanocytic nevus (BMN) for expression of peripherin. Peripherin was detected in a cytoplasmic distribution within tumor cells in 14/14 IMM and 8/10 MIS. For IMM, peripherin localized to both the intraepidermal and invasive dermal components. Peripherin was detected in 10/10 AN and 9/9 SN, being localized to the intraepidermal component and, focally, to the superficial dermal component of the lesions. The dendritic nevus cells in 15/15 BN also expressed peripherin. For most of the BMN, expression of peripherin was absent or limited to rare, scattered cells in the superficial portion of the lesions. Melanocytes in adjacent normal skin were not labeled in any of the lesions studied. These results indicate that expression of peripherin is common in both benign and malignant melanocytic lesions, but not in normal resting adult melanocytes. Among benign lesions, expression of peripherin in the dermal component is rare except in the dendritic cells of BN. These findings provide evidence that the expression of peripherin, a marker of neuronal differentiation, is maintained by IMM, MIS, and BN, but is lost in the normal maturational sequence of the dermal component of other melanocytic lesions.

Adult↗
PubMed2004

Cdx2 as a marker for neuroendocrine tumors of unknown primary sites.

The transcription factors CDX1 and CDX2 are homeobox genes that regulate development of the epithelium of the small and large intestine. A few studies have shown that Cdx2 protein expression is useful in the diagnosis of adenocarcinomas as well as neuroendocrine tumors of the small and large intestine. To examine the utility of Cdx2 in recognizing neuroendocrine tumors of unknown primary sites, we analyzed 224 primary and metastatic neuroendocrine tumors by immunohistochemistry. The specificity of the antibody reaction was confirmed by Western blotting. Cdx2 antibody stained all primary and most metastatic midgut carcinoid tumors. A few rectal and pulmonary carcinoids were positive, while gastric carcinoids were negative for Cdx2. One of five small cell carcinomas (20%) of the colon was positive for Cdx2, while all pulmonary small cell carcinomas were negative. Neuroendocrine tumors of the pituitary, parathyroid, medullary thyroid carcinomas, paragangliomas, pheochromocytomas and Merkel cell carcinomas were all negative for Cdx2. Western blot analysis of seven cases showed a 40 kDa band in both primary and metastatic midgut carcinoid tumors. These results indicate that Cdx2 can be very useful in recognizing metastatic neuroendocrine carcinomas of unknown primary sites, especially when they are derived from the small intestine.

Biomarkers, Tumor↗
PubMed1990

[The association of neuro-endocrine carcinoma of the skin and Bowen's disease. Review of the literature apropos of 4 cases].

Four cases of neuroendocrine carcinoma following Bowen's disease are presented. An immunohistochemical study was performed. The four patients, 3 men and a woman, ranging from seventy to eighty-seven years of age, developed a nodular tumor on a preexisting cutaneous lesion. In one of those cases the diagnosis of Bowen's disease was confirmed histologically before the apparition of the nodular tumor. The tumors were localized on the scalp, thorax, dorsum of the hand, and the scrotum. The four tumors were immunohistologically typical of neuro-endocrine carcinoma: there was a positivity for neurofilaments, cytokeratins and neurone-specific enolase. The clinico-pathological characteristics of those 4 neuro-endocrine carcinomas associated with a Bowen's disease, when compared with the 15 similar described in the literature, are identical to the isolated neuroendocrine carcinoma, from a clinical, morphological and evolutional point of view. The majority are seen in patients older than 60 years old and one third of the cases described survived at least 5 years. The coexistence of Bowen's disease and neuroendocrine carcinoma, the association of neuroendocrine and epidermoid cells in other cutaneous tumors, reactivate the controversy concerning the histogenesis of the so-called Merkel cell carcinoma. In fact, the histogenesis of the tumor is still not fully understood.

Aged↗
PubMed1990

[Immunohistochemical examination of olfactory neuroblastoma].

The results of the immunohistochemical examinations by means of PAP method in 3 olfactory neuroblastomas were described. In the neoplastic cells there were cytokeratin as well as neuronal enolase. The same was recently encountered in the merkel cell tumor, which have the analogous histogenesis. The usefulness of the immunohistochemical method of examinations are essential in correct diagnosis.

Adult↗
PubMed1985

Gastrin releasing peptide in human neuroendocrine tumours.

Neuroendocrine tumours of the lung and gut are known to possess bombesin-like immunoreactivity. The recent observation that gastrin releasing peptide (GRP), a 27 amino acid peptide isolated from the porcine intestine, may be the mammalian analogue of bombesin led us to look for this peptide in a variety of human neoplasms. Formalin-fixed tissues from 85 tumours were examined by the immunoperoxidase technique, using specific antisera to the GRP molecule (1-27) and the GRP fragment (1-16). Intense cytoplasmic GRP immunoreactivity was seen in thyroid medullary carcinomas (3/3), carcinoids of lung, pancreas, and intestine (22/36), and paragangliomas (2/3). Less frequent staining was present in pulmonary small cell (oat cell) carcinomas (1/8) and pituitary adenomas (1/6). Complete absence of immunoreactivity was observed in three phaeochromocytomas, five Merkel cell tumours, six neuroblastomas and 15 non-neuroendocrine tumours. Normal neuroendocrine cells of the thyroid (C-cells) and bronchial mucosa (Kulchitsky cells) exhibited GRP immunoreactivity; nerve fibres from all sites failed to demonstrate staining for GRP. In each positive case, the pattern of staining for GRP (1-27) and GRP (1-16) was identical, although the GRP (1-16) immunostaining was weaker. These findings indicate that bombesin immunoreactivity in human neuroendocrine cells and tumours is attributable to GRP-like molecules and that GRP is a useful marker of neuroendocrine differentiation in many tumours.

Adenoma↗
PubMed1993

Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide.

Several observations suggest interactions between the immune and nervous systems. Psoriasis and atopic dermatitis may worsen with anxiety and have been associated with anomalous neuropeptide regulation. Neurotransmitters affect lymphocyte function and lymphoid organs are innervated. Calcitonin gene-related peptide (CGRP) is a neuropeptide and vasodilator that modulates some macrophage functions, including antigen presentation in vitro. CGRP is associated with Langerhans cells (LC) in oesophageal mucosa, particularly during inflammation, is present in epidermal nerves and is associated with Merkel cells. We examined the ability of CGRP to modulate LC antigen-presenting function and asked if CGRP-containing nerves impinge on LC. We report here that CGRP-containing nerve fibres are intimately associated with LC in human epidermis and CGRP is found at the surface of some LC. In three functional assays CGRP inhibited LC antigen presentation. These findings indicate that CGRP may have immunomodulatory effects in vivo and suggest a locus of interaction between the nervous system and immunological function.

Adult↗
PubMed2025

Defective but tumorigenic: the evolutionary and functional roles of mutated oncoviruses.

Human oncogenic viruses contribute significantly to the global health burden and include seven types: Epstein-Barr virus, hepatitis B virus, human T-cell leukemia virus type 1, human papillomavirus, hepatitis C virus, Kaposi's sarcoma-associated herpesvirus, and Merkel cell polyomavirus. While the roles of latent or integrated viral genomes in cancer have been documented, emerging evidence highlights the contribution of defective viruses-those carrying intragenic deletions or loss-of-function mutations-in promoting viral oncogenesis. These altered genomes often lack genes essential for lytic replication or immune recognition, which enhances their persistence and immune evasion. In virus-associated diseases, specific patterns of gene retention and deletion suggest that host-driven selective pressures drive the emergence of these altered genomes. This review examines the generation, prevalence, and functional impact of these viruses, reframing them as active participants in disease development and progression. Recognizing their role offers new insights into viral tumor evolution and creates opportunities for applications in viral diagnostics and targeted intervention strategies.

Humans↗
PubMed1987

Iodine-131 MIBG scintigraphy of neuroendocrine tumors other than pheochromocytoma and neuroblastoma.

Metaiodobenzylguanidine (MIBG) locates most pheochromocytomas and neuroblastomas. The tracer is concentrated in intracellular storage vesicles by an active process. Many other neuroendocrine tumors of the amine precursor uptake and decarboxylation (APUD) series have hormonal storage vesicles and, thus, the potential to take up [131I]MIBG. A variety of neuroendocrine tumors in 57 patients were studied 1, 2, and 3 days after 0.5 mCi [131I]MIBG. Views from skull to pelvis were obtained. Results of MIBG scans were compared with all available imaging modalities (including plain radiography, liver scan, ultrasound, computed tomography, and angiography) and surgical exploration. The neuroendocrine nature of the tumor was determined by histology, immunohistochemistry, electron microscopy, and the assay of appropriate biogenic amines and peptide hormones. Results were (positive/total cases): carcinoids (four of ten), nonsecreting paragangliomas (three of three), sporadic medullary carcinomas of the thyroid (MCT) (one of five), familial MCT (one of 26), chemodectomas (two of five), oat cell carcinomas (zero of four), choriocarcinoma (one of one), atypical schwannoma (with storage granules) (one of one), Merkel cell skin cancer (one of one), islet cell carcinoma (zero of one). We conclude that a wide range of neuroendocrine tumors show [131I]MIBG uptake; tumors other than pheochromocytomas and neuroblastomas are less often seen scintigraphically, but in certain cases (e.g., carcinoid and nonsecreting paragangliomas) scintigraphy may be useful in depicting the extent and location of disease and may indicate therapeutic potential. Iodine-131 MIBG shows promise in the diagnosis and staging of tumors of varied types.

3-Iodobenzylguanidine↗