What type of receptors are found at the terminals of SA1 neurons

Merkel cells

Merkel cells are epithelial neuroendocrine cells. Although their origin is unclear, they are thought to arise from epidermal ectoderm rather than neural crest. Merkel cells are rare and are found in the basal layer of the epidermis and around the bulge region of hair follicles. They are not visualized on hematoxylin–eosin-stained preparations, but can be seen in silver-impregnated sections or by using immunohistochemical markers such as cytokeratin 20. While some Merkel cells are associated with a nerve axon forming a synapse-like contact zone, others are not.

The function of Merkel cells is not completely understood. An established function of Merkel cells is that of a slowly adapting mechanoreceptor. Merkel cells also may play a role in touch perception as part of ‘Haarscheiben,’ which are disklike structures spatially associated with hair follicles that contain arrays of Merkel cells and a dermal nerve. Merkel cells also contain neuroendocrine markers such as chromogranin A and a variety of neurosecretory substances such as neuropeptides. While some of these substances work as neurotransmitters, others promote growth and differentiation of cutaneous cell types. Combined with the fact that some Merkel cells are not associated with a nerve, it has been suggested that Merkel cells may have endocrine and paracrine functions.

Although Merkel cells have traditionally been thought to be the cell of origin in Merkel cell carcinoma, recent evidence has questioned whether these malignancies may instead arise from pluripotent cutaneous stem cells.

Merkel cells

Merkel cells (see Commentary 1.4

The plasma membrane of a Merkel cell has short, stiff processes that interdigitate with the adjacent basal keratinocytes to which it is attached by small desmosomes. The cytoplasm contains numerous closely packed intermediate filaments (mostly K8 and K18, but also K19 and K20) and characteristic 80–110 μm dense-core granules. The basal plasma membranes of many Merkel cells are closely opposed to the membrane of an axonal terminal that conveys the sensation of touch. They are slowly adapting mechanoreceptors that respond to directional deformations of the epidermis and the direction of hair movement by releasing a transmitter from their dense-core cytoplasmic granules. There is evidence that a subpopulation of Merkel cells lacks axonal contact and may serve a neuroendocrine function locally.

Merkel cells can undergo malignant transformation and give rise to a rare and aggressive tumour called a Merkel cell carcinoma (see Commentary 1.4

Merkel Cells

Merkel cell–neurite complexes mediate the mechanosensing function of the epidermis—the discrimination of touch, shape and texture of objects. Merkel cells are named after Friedrich S. Merkel who discovered them back in 1875. These cells cluster and physically contact intra-epidermal sensory nerve endings in a structure referred to as the touch-dome (Niu et al., 2014).

Their close association with nerve endings and production of neurotransmitters led researchers to believe that Merkel cells originated from neural crest cells, migrating to the epidermis during embryogenesis as melanoblasts do (Szeder et al., 2003). But we now know that Merkel cells appear in the epidermis before nerve endings innervate the epidermis. And, recent studies using lineage tracing and conditional knockout mouse models show that Merkel cells originate from basal stem cells in the developing epidermis (Van Keymeulen et al., 2009). Thus, in addition to periderm and differentiated keratinocytes, basal stem cells give rise to a distinct cell population, Merkel cells.

Transcriptome analysis of epidermal Merkel cells indicate the expression of Merkel-specific genes that are not found in differentiated keratinocytes (Perdigoto et al., 2014a). Atoh1, a basic helix-loop-helix transcription factor and a unique marker of Merkel cells, is required for Merkel cell specification (Ostrowski et al., 2015). Conditional deletion of Atoh1 in Krt14-expressing epidermal cells resulted in the loss of epidermal Merkel cells (Van Keymeulen et al., 2009). Atoh1-positive cells are first detected in the developing epidermis at E15.5 (Fig. 3B).

Mature Merkel cells found in the neonatal epidermis express Merkel-specific differentiation markers such as Krt8, Krt18, and Krt20 that are not found in differentiated epidermal keratinocytes (Moll and Moll, 1992). Maturation of Atoh1-positive Merkel cells is induced by Sox2 that is expressed in all Atoh1-positive Merkel cells at E15.5; Sox2 is an upstream regulator of Atoh1, sustaining Atoh1 expression in differentiated Merkel cells. Loss of epidermal Sox2 results in complete absence of mature Merkel cells in the newborn epidermis with loss of Krt18 and Krt20 expression (Perdigoto et al., 2014a). The LIM-homeodomain transcription factor Isl1 is also expressed during mid-stage of Merkel cells maturation; it physically interact with Sox2 to sustain the transcription of Atoh1 during Merkel cells differentiation (Perdigoto et al., 2014a).

Sox2 expression in basal stem cells is regulated by PRC2 subunits Ezh1 and Ezh2 (Bardot et al., 2013). Ezh1/2 null mice exhibit an increase in epidermal Merkel cells, a phenotype that is attenuated by ablation of Sox2, indicating that PRC2 represses Sox2 expression in epidermal basal stem cells to maintain their epidermal fate.

Mature Merkel cells are detected within the basal layer of the epidermis at E17. They account for 2%–5% of total epidermal cells although their abundance varies between anatomical locations. They are mainly located at touch-sensitive areas of the skin such as human fingertips, and mouse whiskers and paw pads (Maksimovic et al., 2014). Merkel cell–neurite complexes are formed when Merkel cells are innervated by sensory neurons. At the epidermal-dermal junction, Merkel cells physically contact Aβ sensory neurons, specifically the slowly adapting I (SAI) mechanoreceptors, which express neural filament heavy chain (NFH) (Niu et al., 2014). Neurogenic factors such as neurotrophins (NTF3) and nerve growth factors (NRG) secreted by Merkel cells and epidermal keratinocytes bind to tyrosine kinase receptors found on the sensory nerve fibers. These interactions are required for epidermal innervation and formation of Merkel cell–neurite complexes.

Merkel Cell (Primary Cutaneous Neuroendocrine) Carcinoma

Primary cutaneous neuroendocrine tumors have been thought to show differentiation toward the Merkel cell, a neurotactile element in normal skin. However, that conceptual linkage is probably not altogether valid. Merkel cell carcinoma (MCC) appears as an erythematous or violaceous nodule (Fig. 34.16), which is ulcerated in 20% of cases.18

The original examples of MCC had a trabecular growth pattern (trabecular carcinoma), but growth in solid sheets or nests of cells is more common (Fig. 34.17). Focal epidermal involvement is seen in approximately 10% of cases.19–21 Subcuticular infiltration is frequent and adipocytes are entrapped by MCC cells, as seen in lymphoproliferative disorders. Cytologic features of MCC include finely stippled chromatin, high nuclear-to-cytoplasmic ratios, inconspicuous nucleoli, and extremely numerous mitoses (Fig. 34.18). As many as 15 division figures may be seen in each high-power (×400) field, along with apoptosis and necrosis. The stroma may be sclerotic or delicately fibrovascular, and a lymphoplasmacytic infiltrate is present in many examples of MCC.22 A distinction from metastatic small cell carcinoma of the lung may be difficult in selected cases.However, if one observes DNA encrustation around intratumoral blood vessels (the Azzopardi phenomenon), metastasisto the skin from a visceral neoplasm must be strongly considered.23

Immunoreactivity of MCCs for CK may be diffuse in the cytoplasm or take the form of paranuclear dots. CK20 is present in approximately 90% of cases24,25; chromogranin-A has been reported in 33% to 100% of cases.26 Synaptophysin is demonstrable in 40%.27 Other markers that are helpful in diagnosis include CD56 (probably the best screening determinant for neuroendocrine lesions), CD57, and PAX5. CD99 and FLI-1 (Friend leukemia virus–related nuclear antigen) expression is potentially shared by both MCC and primitive neuroectodermal tumors (PNETs) of the subcutis,28 but only the latter lesions contain vimentin.

MCC is an aggressive cutaneous neoplasm, second in that regard only to melanoma. It is prone to local recurrence and has a high incidence (approximately 50% of cases) of lymph node metastasis.29 Complete surgical excision provides the best chance of cure; irradiation and chemotherapy are largely palliative, producing only rare instances of long-term remission.

Key Diagnostic Points

Superficial Cutaneous Carcinomas of the Breast

Basal cell carcinoma and Bowen disease are most common.

Mammary Paget is in the differential diagnosis with Bowen, and is CK7+, but Bowen disease is CK7(−), CK5/6+.

Merkel cell carcinoma is positive for neuroendocrine markers, CD56, synaptophysin, chromogranin, and typically, CK20.