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PubMed1984

The sensorineural apparatus of the human eyelid.

The present study describes a complex array of sensory nerve terminals in the human eyelid. In many respects this pattern of innervation resembles that previously described in the rhesus monkey, but in other respects it is unique to man. The most prominent nerve terminals are a complex array of lanceolate and circular Ruffini and free nerve endings that envelop the eyelashes. In addition, Merkel cells have not been conclusively identified to date in other nonhuman primate nonsinus hairs. The external root sheath collar contains Merkel cells, and dermal Merkel cells have also been identified close to the collar. The anterior cutaneous surface of the eyelid contains small vellus hairs with typical lanceolate, Ruffini, and free nerve endings resembling those of primate facial skin. Scattered Meissner and scant simple corpuscles as well as scattered free nerve endings (FNEs) can be identified on the occlusal surface of the eyelid. Intraepithelial as well as dermal FNEs were most easily identified in this region in areas lacking other corpuscular receptors. Corpuscular receptors are especially common at the occlusal/conjunctival angle. The inner or conjunctival surface of the eyelid appears to be a glandular epithelium, whereas in the rhesus monkey it is stratified squamous epithelium. This epithelium needs additional study. In summary, the present study confirms the unique sensory neural status of the human eyelid and verifies the presence of Ruffini nerve terminals by light and electron microscopy and of free nerve ending terminals at least by light microscopy, as well as a unique pattern of innervation of the human eyelash.

Adolescent↗
PubMed1987

The effects of hypoxia on slowly adapting type I (SAI) cutaneous mechanoreceptors in the cat and rat.

In whatever mammalian receptor system Merkel cells are found, they are always associated with a characteristic slowly adapting response. The role of Merkel cells in the transduction process of slowly adapting Type I cutaneous mechanoreceptors (SAI receptors or touch domes) of rats and cats was investigated by mechanical and electrical stimulation of SAI receptors and their afferent fibers in an O2-depleted environment. Circulatory hypoxia was produced either by ventilating animals with N2 or by recirculating venous blood around a limb. In both these experimental preparations, the results obtained were identical. For receptor failure to occur, it was found necessary to have an O2-depleted environment on the limb surface. This was achieved by passing N2 into a gas-tight polythene sock placed over the limb. Replacement of N2 within the polythene sock with O2 was sufficient to bring about receptor recovery, irrespective of arterial blood PO2 levels. There was an inverse linear relationship between receptor response and time when touch domes were stimulated with N2 around the limb. In contrast, the replacement of N2 around the limb with O2 produced an exponential increase in the response with time. Correlated with receptor failure was a significant reduction in the number of dense-cored vesicles normally found in the Merkel cell cytoplasm adjacent to the nerve ending innervating the cell. Receptor recovery was associated with a return in the number of dense-cored vesicles back to that found in control cells. Hypoxia had no effect on the level of electrical stimulation necessary to initiate an action potential in the afferent fiber, even though the response of SAI receptors to mechanical stimulation had ceased. The results indicate that Merkel cell dense-cored vesicles are necessary for the characteristic slowly adapting response of SAI mechanoreceptors and that this may be due to the secretion of a transmitter substance stored within the vesicles.

Animals↗
PubMed2004

The application of sentinel node radiolocalization to solid tumors of the head and neck: a 10-year experience.

OBJECTIVES/HYPOTHESIS: The goals of the research study were to develop an easily mastered, accurate, minimally invasive technique of sentinel node radiolocalization with biopsy (SNRLB) in the feline model; to compare it with blue-dye mapping techniques; and to test the applicability of sentinel node radiolocalization biopsy in three head and neck tumor types: N0 malignant melanoma, N0 Merkel cell carcinoma, and N0 squamous cell carcinoma. STUDY DESIGN: Prospective consecutive series studies were performed in the feline model and in three head and neck tumor types: N0 malignant melanoma (43 patients), N0 Merkel cell carcinoma (8 patients), and N0 squamous cell carcinoma (20 patients). METHODS: The technique of sentinel node radiolocalization with biopsy was analyzed in eight felines and compared with blue-dye mapping. Patterns of sentinel node gamma emissions were recorded. Localization success rates were determined for blue dye and sentinel node with radiolocalization biopsy. In the human studies, all patients had sentinel node radiolocalization biopsy performed in a similar manner. On the morning of surgery, each patient had sentinel node radiolocalization biopsy of the sentinel lymph node performed using an intradermal or peritumoral injection of technetium Tc 99m sulfur colloid. Sentinel nodes were localized on the skin surface using a handheld gamma detector. Gamma count measurements were obtained for the following: 1) the "hot" spot/node in vivo before incision, 2) the hot spot/node in vivo during dissection, 3) the hot spot/node ex vivo, 4) the lymphatic bed after hot spot/node removal, and 5) the background in the operating room. The first draining lymph node(s) was identified, and biopsy of the node was performed. The radioactive sentinel lymph node(s) was submitted separately for routine histopathological evaluation. Preoperative lymphoscintigrams were performed in patients with melanoma and patients with Merkel cell carcinoma. In patients with head and neck squamous cell carcinoma, the relationship between the sentinel node and the remaining lymphatic basin was studied and all patients received complete neck dissections. The accuracy of sentinel node radiolocalization with biopsy, the micrometastatic rate, the false-negative rate, and long-term recurrence rates were reported for each of the head and neck tumor types. In the melanoma study, the success of sentinel node localization was compared for sentinel node radiolocalization biopsy, blue-dye mapping, and lymphoscintigraphy. In the Merkel cell carcinoma study, localization rates were evaluated for sentinel node radiolocalization biopsy and lymphoscintigraphy. In the head and neck squamous cell carcinoma study, the localization rate of sentinel node radiolocalization biopsy and the predictive value of the sentinel node relative to the remaining lymphatic bed were determined. All results were analyzed statistically. RESULTS: Across the different head and neck tumor types studied, sentinel node radiolocalization biopsy had a success rate approaching 95%. Sentinel node radiolocalization biopsy was more successful than blue-dye mapping or lymphoscintigraphy at identifying the sentinel node, although all three techniques were complementary. There was no instance of a sentinel node-negative patient developing regional lymphatic recurrence. In the head and neck squamous cell carcinoma study, there was no instance in which the sentinel node was negative and the remaining lymphadenectomy specimen was positive. CONCLUSION: In head and neck tumors that spread via the lymphatics, it appears that sentinel node radiolocalization biopsy can be performed with a high success rate. This technique has a low false-negative rate and can be performed through a small incision. In head and neck squamous cell carcinoma, the histological appearance of the sentinel node does appear to reflect the regional nodal status of the patient.

Adult↗
PubMed2003

Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma from other small blue round cell tumors.

Over the last decade, a number of "master regulator" genes that control distinct pathways of mesenchymal differentiation have been discovered. These genes are expressed early during embryogenesis and initiate a cascade of gene expression responsible for specific cell lineage commitment. Thus, identification of their products may allow the classification of seemingly primitive, morphologically uncommitted tumors such as small blue round cell tumors. The transcription factor Sox9 has been demonstrated to be a master regulator of the differentiation of mesenchymal cells into chondrocytes. For this reason, we examined the utility of Sox9 in distinguishing mesenchymal chondrosarcoma (a small cell malignancy thought to be derived from primitive chondroprogenitor cells) from other primitive small cell malignancies. Representative sections from 90 cases of small blue round cell tumors (22 mesenchymal chodrosarcoma, 10 neuroblastomas, 11 rhabdomyosarcomas, 9 Ewing's sarcomas/primitive neuroectodermal tumors, 5 desmoplastic small round cell tumors, 7 small cell carcinomas, 6 Merkel cell carcinomas, 6 small cell osteosarcomas, 7 diffuse large B-cell lymphomas, 7 lymphoblastic leukemias/lymphomas, and 5 extraskeletal myxoid chondrosarcomas) were immunohistochemically stained with antibodies to Sox9 protein. All but 1 mesenchymal chondrosarcoma showed positive nuclear staining in both primitive mesenchymal and cartilaginous components of the tumor. All other types of small blue round cell tumors, as well as the lymphomas and leukemias, were negative for Sox9 protein. These findings confirm that mesenchymal chondrosarcoma has phenotypic features corresponding to the early condensational phase of cartilaginous differentiation. More important, Sox9 may serve as a useful tool in the differentiation of small cell malignancies.

Adolescent↗
PubMed1990

Primary culture of cells arising from a neuroendocrine skin carcinoma.

A carcinoma arising in the skin of the lip metastasized to the lymph nodes in the neck of a 53-year-old white man. Electron microscopy of the initial excisional biopsy specimen revealed that the tumor cells contained dense-cored vesicles (100 nm in diameter) in their cytoplasm and were joined by simple junctions. Cells from the nodal metastases were found to be immunoreactive for neuronspecific enolase, keratin intermediate filaments, and chromogranin A, but not for neurofilaments. The tumor was thus classified as a neuroendocrine skin carcinoma. In addition, its metastatic cells shared immunoreactive and ultrastructural characteristics of Merkel cells, which are situated in the basal epidermis of normal skin. Primary cultures from a nodal metastasis were established and characterized. The cells attached and proliferated on culture flask surfaces. The population-doubling time was 2 days. This is the first report where cells from a neuroendocrine skin carcinoma have been demonstrated to retain their characteristic ultrastructure in an in vitro environment (10 days). Studies of cells cultured from neuroendocrine skin carcinomas may prove useful in understanding the pathobiology of this disease and help define the in vitro growth requirements of nontransformed Merkel cells as well.

Carcinoma↗
PubMed1990

Some special skin tumours in the elderly.

A review of uncommon skin tumours, all of which characteristically arise in elderly patients, is presented. Angiosarcoma of the face and scalp is a highly progressive tumour with a poor prognosis, but initially it may be misdiagnosed as a simple bruise or cellulitis. In well-differentiated tumours a characteristic feature is interlacing endothelial cell-lined channels showing considerable nuclear atypia. Merkel cell tumours, which develop as deep-seated nodules in the skin, occur most frequently in photodamaged areas, especially on the head and neck. The prognosis of Merkel cell tumours is generally poor; histological evidence suggests that some of these tumours may be a special type of poorly differentiated squamous cell carcinoma. Atypical fibroxanthoma, which is normally benign, occurs most frequently in elderly, fair-skinned males, especially around the face. It is typically a polypoid lesion with a vascular appearance. Acantholytic squamous cell carcinomas, also known as adenoid squamous cell carcinomas, are most common in fair-skinned men with a history of keratoses. They also occur in the female genital region and the oral mucosa. Histologically, these tumours differ from squamous cell carcinomas because of their tendency to form duct-like areas in tumour lobules.

Aged↗
PubMed2004

New fields of application of the sentinel lymph node biopsy in the pathologic staging of solid neoplasms: review of literature and surgical perspectives.

Sentinel lymph node (sN) biopsy has gained special attention among surgical and medical oncologists as it represents an accepted technique for detecting occult nodal disease in regional lymph nodes of patients with melanoma and breast cancer. The histopathologic examination of the sN may well predict regional lymph node status in order to define the most suitable loco-regional and systemic treatment. Recently, this technique has also been applied to other solid tumor types such as gynecologic and urologic malignancies, squamous head and neck cancer, thyroid cancer, non-small-cell lung cancer, Merkel cell carcinoma, and gastric cancer. The aim of this literature review is to define the rationale of sN biopsy in these tumor sites, the most effective procedure for sN detection, and the accuracy of the sN in predicting regional nodal status, as well as the surgical perspectives of sN biopsy application.

Carcinoma, Merkel Cell↗
PubMed1988

The structure and function of cutaneous sensory receptors.

The present review of cutaneous sensory receptors begins with a consideration of free nerve endings (FNEs) that can be considered as sensory terminals evidencing the least structural specialization of the axon and associated cells. Using the criteria established by Kruger et al (1981), FNEs of both A delta and C fibers can be identified on the basis of ultrastructural characteristics that include an intimate relationship between axons and the associated epithelium, the lack of a complete Schwann cell investment, the accumulation of numerous vesicles and other cytoplasmic organelles, and for A delta terminals a 1:1 relationship between axon and investing Schwann cell. Using these criteria, the so-called genital end bulbs of the human glans penis are merely a skein of FNEs based on the ultrastructural study of Halata and Munger (1986). Hair follicles of most species studied to date (the exception being the rabbit and to some extent the guinea pig) are multiply innervated with lanceolate, Ruffini and FNEs. The lanceolate terminals are the rapidly adapting terminals that are numerous in guard hairs. Ruffini terminals of hairs resemble those of the periodontal ligament or joint capsules and both are remarkably similar to Golgi tendon organs in terms of ultrastructural characteristics. The key ultrastructural characteristic is the encircling of collagen bundles by axons and associated Schwann and connective tissue cells. Axons frequently enter the epidermis either to terminate as FNEs or become associated with Merkel cells in glabrous skin at the base of the papillary ridges or in clusters of Merkel cells in hairy skin in touch domes or Haarscheiben. Merkel cells have clusters of apparent secretory granules polarized toward the axon and the axon is typically a slowly adapting mechanoreceptor. The function of the granules is not known. Pacinian corpuscles are the largest of the corpuscular receptors of the dermis and are characterized by an elaborate inner core of stacks of numerous thin lamellae arranged in a bilaterally symmetrical manner. Based on the fact that the lamellae are coupled with gap junctions and the outer core lamellae isolated by numerous tight junctions, the authors have proposed that the unique ionic environment may be in part responsible for the remarkable sensitivity of Pacinian corpuscles (Munger and Ide, 1987). Meissner corpuscles are a typical corpuscular receptor of murine (Ide, 1976, 1977), marsupial and primate glabrous skin (Munger, 1971). The axons typically weave back and forth between stacks of lamellae.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Are Merkel and Grandry cells two varieties of the same cell in birds?

For over a century it has been held that the Grandry corpuscle and the Merkel corpuscle are unique sensory organs in aquatic and nonaquatic birds, respectively. In other words, the Grandry and the Merkel cells are two varieties of the same receptor cell and never coexist together. Contrary to what has been believed, we found unmistakable Merkel cells in addition to Grandry cells in the lingual mucosa of the duck, Anas platyrhynchos var. domestica, an unprecedented observation in an aquatic bird. This study concerns the fine structure of these cells in the tongue of the duck. Although some ultrastructural features are shared by the Grandry and the Merkel cells, i.e., the presence of numerous dense-cored granules and microvillous projections at the cell surface, the morphology of these two types of cells clearly differ, especially in their size. Cells suggestive of stages intermediate between these two cells have never been recognizable. The present study indicates that the Grandry and the Merkel cells are not two varieties of the same cell in birds. It is suggested that the Merkel cell may exist in every vertebrate species, while the Grandry cell is unique to aquatic birds.

Animals↗
PubMed1974

Patterning in the regeneration of type I cutaneous receptors.

1. Type I sensory fibres in cat hairy skin innervate structures characterized by twenty to fifty specialized epithelial (Merkel) cells aggregated in a small dome-shaped elevation. Only one fibre enters each dome and it branches repeatedly to supply at least one terminal to each Merkel cell. After the nerve is cut, the Merkel cells and the dome ultimately disappear.2. The distribution of domes on the posterior thigh was mapped before interruption of the femoral cutaneous nerve and after its regeneration. Regeneration after nerve crush was apparently complete, producing a coincidence pattern similar to those seen in control studies where the nerve was not damaged. After cutting the nerve fewer domes returned, but coincidence of regenerated femoral cutaneous domes with old sites generally was significantly greater than would be expected by chance alone. Non-femoral cutaneous fibres sprouting into the denervated femoral cutaneous field tended to form domes at old sites. Domes were also reformed on scars where domes had been excised.3. Domes appearing at new locations and on excision scars were often small and close together (clustered). Individual domes in a cluster could be innervated by different Type I fibres.4. Type I fibres are directed by some mechanism to sites formerly occupied by domes and to sites where domes are being induced.

Animals↗
PubMed1995

Primary cutaneous neuroendocrine tumors. Diagnostic use of cytogenetic and MIC2 analysis.

Merkel cell carcinoma (MCC) is a primary cutaneous neoplasm most commonly involving older adults. The cell of origin is thought to be the Merkel cell, a cutaneous neurosecretory cell. However, other neuroectodermal tumors may present in the skin and may be difficult to distinguish from MCC, including peripheral neuroectodermal tumors (PNET) and metastatic small cell carcinoma. We examined a primary cutaneous tumor of an 18-year-old which was strongly positive for cytokeratin (CK), neuron-specific enolase (NSE), and 12E7, an antibody to the protein determined by the MIC2 gene. Electron microscopy showed paranuclear aggregates of filaments and no cytoplasmic processes. These findings were considered to be consistent with MCC. Cytogenetic analysis demonstrated 46,XX,der(1)t(1;3;22)(1qter-->pa34::3q28-->q11::22q 12--> qter),der(3)t(1;3)(3pter-->q11::1p35-->pter), der(22)t(3;22)(22pter-->q11::?3q29-->qter). This was confirmed by chromosome painting using probes for chromosomes 1, 3, and 22. Peripheral neuroectodermal tumors (PNETs) show a characteristic translocation involving the same breakpoint on chromosome 22 that was present in this tumor. PNETs can also be CK and NSE positive. The MIC2 gene codes for a surface glycoprotein that has been shown to be very strongly and reliably expressed in PNETs, but not in other small round blue cell tumors and not in small cell carcinoma of the lung. However, MIC2 expression has not been studied in MCC. We investigated the use of MIC2 analysis in the distinction of MCC from PNET. Five additional MCCs were stained with the monoclonal 12E7 antibody, and one additional tumor showed the strong membranous positivity reported in PNETs. Our data suggest that MIC2 analysis may be useful in differentiating between MCC and PNET. However, cases will remain for which the distinction is elusive and cytogenetic analysis may be helpful.

Adolescent↗
PubMed1988

Axonal domains within shared touch domes in the rat: a comparison of their fate during conditions favoring collateral sprouting and following axonal regeneration.

Low-threshold mechanosensory nerves in the adult rat differ both from their counterparts in lower vertebrates and from high-threshold nociceptive nerves in mammals in that they appear not to undergo collateral sprouting into adjacent denervated skin, although they will clearly regenerate into it after they are damaged. We have now studied the growth capabilities of the low-threshold nerves supplying touch domes, the visible mechanosensory structures scattered throughout the hairy skin. Touch domes in the rat are often multiply innervated. A serendipitous observation on such domes allowed us to investigate the possibility that a functional collateral sprouting of their nerves can indeed occur, but only to a spatially very restricted extent, e.g., within the confines of a partially denervated dome. We used a "prodder" with a tip diameter of 16 micron to examine the mechanosensory profile across single domes that were preselected as being supplied by only two axons, one running in each of two adjacent dorsal cutaneous nerves (DCNs). Simultaneous recordings were made of the afferent discharges evoked in these nerves when the prodder was applied at about 17 or more locations on a selected dome; the spatial resolution was better than 55 micron. We found that within such a shared dome, one axon can supply a discrete territory (its "domain"), which may or may not overlap with the corresponding domain of the other axon. In a preliminary electron microscopic study, we found no evidence for a sharing of single Merkel cells, which are the specialized sensory cells in touch domes, even in the regions of a shared dome where two domains overlapped; each innervated Merkel cell appeared to be contacted by a single nerve ending, implying that in a shared dome each axon probably supplies an exclusive subpopulation of the Merkel cells. We tested for functional collateral sprouting by eliminating one nerve to a shared dome, and at a selected time thereafter mapping the domain of the remaining axon to see whether it had enlarged. The result was the same whether the two domains initially had a region of overlap or not; no expansion of the surviving domain occurred over postoperative periods up to 4 months (an expansion of the domain by 55 micron would have been detected). Thus functional collateral sprouting had failed to occur.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

The differentiation of the skin and its appendages. I. Normal development of papillary ridges.

In the present study, the normal development of papillary ridges was studied in the volar pads of both fore and hindpaws of the opossum, Monodelphis domesticus. At birth, the developmental state of the opossum's paws is equivalent to that of a six-week human embryo. The development of papillary ridges in the opossum occurs entirely postnatally and the hindpaw lags behind the forepaw by at least four days in most developmental parameters. Papillary ridge formation is preceded by four events: skin innervation, Merkel cell differentiation, mesenchymal condensation, and epidermal proliferation. The apical pads at the tips of the digits and the interdigital pads between the heads of the metacarpals (or metatarsals) have a unique pattern of innervation and mesenchymal content as compared to the non-pad skin. Each pad is innervated by a prominent nerve trunk and axons ascend towards the epidermis providing a density of innervation that exceeds that in the non-pad epidermis. Merkel cells are absent in non-pad epidermis but present in the pads prior to the onset of formation of papillary ridges. A loose aggregation of mesenchyme forms the core of the pads and the superficial dermis is more cellular in the pads as compared to the equivalent dermis in surrounding non-pad skin. Developing papillary ridges always contained Merkel cell-axon complexes. Merkel cell axon complexes serve as the anatomical substrate of slowly adapting (SA) mechanoreceptors. The presence of these complexes during early skin differentiation is consistent with the use of the opossum's forepaw in climbing to the nipple, but also suggests other possible functions. We hypothesize that the nervous system might play a role in the timing or patterning of the formation of papillary ridges.

Animals↗
PubMed2001

Evidence for glutamate receptor mediated transmission at mechanoreceptors in the skin.

The functional role of Merkel cells in the mechanosensitivity of the slowly adapting type I responses has been a controversial issue for many years. Here we show, for the first time, that glutamate receptor-mediated transmission is largely responsible for the static component of the slowly adapting type I response. An isolated sinus hair preparation was used to study the two types (I and II) of slowly adapting units. A broad spectrum ionotropic glutamate receptor antagonist kynurenate (1-10 mM) caused reliable and dose-dependent reductions in the static component of type I unit responses to mechanical stimulation. In addition, an amino acid transmitter candidate aspartate applied to the preparation selectively increased responses in type I units but not responses in type II units. This evidence establishes that the Merkel cell is a mechano-electric transducer, and challenges prevailing views that the Merkel cell acts merely as a support or target cell in the epidermis.

Action Potentials↗
PubMed1982

Comparative study of ultrastructures of the lateral-line organs and the palatal taste organs in the African clawed toad, Xenopus laevis.

The fine structure of the lateral-line organ and the palatal taste organ in the African clawed toad, Xenopus laevis, was examined by means of electron microscopy. The lateral-line organ consisted of hair and accessory cells. The apical surface of a hair cell was studded with one kinocilium and 20 to 40 stereocilia. Synaptic bodies and subsynaptic cisternae were found in the cytoplasm of a hair cell adjacent to the synaptic contacts with the afferent and the efferent nerve endings, respectively. Crystalline bodies were observed in both the nucleoplasm and the cytoplasm of almost all hair cells. The palatal taste organ consisted of three types of cells: the taste, sustentacular, and the Merkel cells. The taste cells contained numerous dense-cored vesicles which accumulated in close association with both the afferent synapses and the basal plasma membrane. The possibility was raised from the ultrastructural results that these vesicles had dual functions as both neurotransmitter and hormone. The existence of Merkel cells in the palatal taste organ suggested that this organ might function not only as a chemoreceptor but also as a mechanoreceptor. In spite of possible chemosensory function of the lateral-line organ in Xenopus, its ultrastructure was significantly different from that of the typical gustatory organ, the palatal taste organ, in this animal.

Animals↗