Dr. Murad Alam MD (editor) - Merkel Cell Carcinoma

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Book:
Merkel Cell Carcinoma
Author:
Dr Murad Alam MD editor / Jeremy S Bordeaux editor / Siegrid S Yu editor
Publisher:
Springer-Verlag New York Inc.
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Books / Detective and thriller
Year:
2013
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Merkel Cell Carcinoma: summary, description and annotation

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Merkel Cell Carcinoma is one of the first comprehensive, single-source clinical texts on the subject. Although not as common as melanoma, Merkel cell carcinoma is not rare - and it is both more deadly than melanoma and increasing at an epidemic rate. The book is clinical in focus and emphasizes treatment of this poorly understood cancer. Contributing authors include dermatologists, surgical oncologists, radiation oncologists, and medical oncologists from the US and around the world.

Features:

- Comprehensive single-source clinical reference

- Treatment focus

- Written for practitioners, with emphasis on clinical relevance and quick retrieval of information

- Contributing authors represent all disciplines involved in treatment of Merkel cell carcinoma: dermatology, surgical oncology, radiation oncology, and medical oncology

- International in perspective, with contributors from US and abroad

- Members of active Merkel Cell Carcinoma Multicenter Interest Group have authored some of the chapters

Dr. Murad Alam MD (editor): author's other books

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Part 1
Basic Science and Epidemiology

Murad Alam , Jeremy S. Bordeaux and Siegrid S. Yu (eds.) Merkel Cell Carcinoma 2013 10.1007/978-1-4614-6608-6_1 Springer Science+Business Media New York 2013

1. Basic Science of the Merkel Cell

Stephen M. Ostrowski 1

(1)

Department of Dermatology, University Hospitals Case Medical Center, 11100 Euclid Avenue, 44106 Cleveland, OH, USA

(2)

Department of Pediatrics, Division of Neurology, University of Pittsburgh School of Medicine, Childrens Hospital of Pittsburgh of UPMC, Rangos Research Building Room 8129, One Childrens Hospital Drive, Pittsburgh, 15224, PA, USA

Stephen M. Ostrowski

Email:

Stephen Michael Maricich (Corresponding author)

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Abstract

In 1875, Friedrich Sigmund Merkel identified a unique epidermal cell type closely associated with sensory nerve endings. These Tastzallen or touch cells have subsequently been renamed Merkel cells in his honor. Recent genetic and electrophysiological studies offer conclusive evidence that Merkel cells play a critical role in mechanoreception. Based on expression of bioactive peptides, it has also been suggested that Merkel cells may participate in skin homeostasis.

The most direct link between Merkel cells and human disease comes in the form of Merkel cell carcinoma (MCC), a rare and deadly carcinoma of the skin. Several lines of evidence indicate that Merkel cells and MCC arise from the same cellular lineage, but the molecular and genetic pathways that control disease pathogenesis are unknown. The recent discovery of Merkel cell polyomavirus (MCPyV), which appears to be involved in MCC initiation, and increased insight into pathways that control normal Merkel cell specification and development offer exciting new avenues for understanding and treating this devastating disorder.

Merkel Cell Structure

Ultrastructure

Merkel cells are a distinct epidermal cell type found at the dermal/epidermal junction just below the basal layer of the epidermis. They are roughly the same size as keratinocytes, with oval or round cell somata 10 m in diameter and large, lobulated nuclei (Fig. ].

Fig. 1.1

Merkel cell structure. ( a ) Electron microscopic image of a Merkel cell (M). Note the lobulated nucleus ( arrow ) and numerous electron dense granules ( arrowheads ) positioned across from an adjacent nerve terminal (T). ( b ) Diagram showing relationship of a Merkel cell (M) to surrounding keratinocytes (K) and sensory nerve (N). Desmosomes ( dark rectangles ) attach adjacent cells. ( c ) Electron micrograph of a desmosome ( bracket ) and intermediate filaments in a keratinocyte ( arrow ) and Merkel cell ( arrowhead ). ( d ) 3D confocal microscopic reconstruction of a Merkel cell stained with an antibody against villin, demonstrating numerous spike-like villi projecting from the cell surface. ( e ) Merkel cell in the mouse footpad stained with an antibody against cytokeratin 8. Villous projections ( arrows ) intercalate with surrounding keratinocytes ( a : Reprinted from Halata Z, Grim M, Bauman KI. Friedrich Sigmund Merkel and his Merkel cell, morphology, development, and physiology: review and new results. The anatomical record. 2003;271, 225239. With permission from John Wiley & Sons.). ( c : Reprinted from Rickelt S, Moll I, Franke WW. Intercellular adhering junctions with an asymmetric molecular composition: desmosomes connecting Merkel cells and keratinocytes. Cell and tissue research 2011;346, 6577. With permission from Springer Science + Business Media.). ( d : Reprinted from Toyoshima K, Seta Y, Takeda S, Harada H. Identification of Merkel Cells by an Antibody to Villin. Journal of Histochemistry & Cytochemistry 1998;46, 13291334. With permission from Sage Publications)

A defining feature of Merkel cells across species is the presence of electron dense granules unlike any others seen in the epidermis. These structures, 80120 nm in size, are concentrated at the basal surface opposite to Merkel cell-associated nerve termini (see below) (Fig. ]. The physical location and appearance of these granules suggest that they may function as key mediators of Merkel cellnerve interactions.

Organization and Anatomic Distribution

Using basic histochemical staining methods, Merkel and others identified expanded nerve endings associated with the majority of Merkel cells (Fig. ], suggesting a potential mechanism by which Merkel cells communicate with the neurons that contact them.

Fig. 1.2

Organization of Merkel cells in the touch dome. ( a ) One of Merkels original touch dome illustrations. ( b ) Mouse touch dome viewed under fluorescence. Merkel cells, immunostained with anti-CK8 ( red ), are innervated by branching sensory nerves immunostained with NF200 ( green ); nerve terminals are shown by arrowheads . Brackets mark thickened touch dome epidermis. A single guard hair follicle (GH) sits in the middle of the touch dome. Cell nuclei are stained with TOTO-3 ( blue ) ( a : Reprinted from Halata Z, Grim M, Bauman KI. Friedrich Sigmund Merkel and his Merkel cell, morphology, development, and physiology: review and new results. The anatomical record. 2003;271, 225239. With permission from John Wiley & Sons, Inc.)

The best characterized Merkel cellneurite complexes are found in epidermal structures of the hairy skin first described by Pinkus as Haarschibe and subsequently termed touch domes [].

Large numbers of Merkel cells are also found in glabrous (hairless) skin of the plantar and palmar surfaces, being most highly concentrated at the fingertips []. These Merkel cells are not associated with nerve endings, and their function is unknown.

Merkel Cell Function

The Sense of Touch

Merkel himself first proposed that Merkel cells must be involved in cutaneous mechanosensation based on their intimate association with cutaneous nerves. The accuracy of this claim has been debated for over 130 years, with various lines of evidence either supporting or refuting his hypothesis.

Several types of electrophysiological responses are elicited from cutaneous nerves following mechanical deformation of the skin surface. The slowly adapting type I (SAI) response was among the first to be associated with a defined anatomical structure. Nerve fibers that exhibit SAI responses have small receptive fields that center around small, distinct areas of the skin originally termed touch spots []. However, the question remained as to whether the SAI nerve fibers that innervate touch domes were sufficient to detect these stimuli or whether Merkel cells were required for mechanotransduction (transformation of mechanical to electrical stimuli).

Recently, this question was definitively addressed in genetically engineered mice. The gene encoding the transcription factor Atoh1 , which is required for specification of Merkel cells, was conditionally (specifically) deleted from the skin of transgenic mice []. Touch dome ultrastructure and innervation were preserved in these animals, allowing the opportunity to test peripheral nerve responses to mechanical stimulation in the absence of Merkel cells. These mice completely lacked SAI responses to light touch stimuli, demonstrating that Merkel cells are necessary for the generation of these signals. These data also demonstrate that Merkel cells are not required for general development or maintenance of touch dome innervation and structure but instead play a direct role in mechanotransduction.

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