Microanatomical And Embryological Considerations

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Although we often think of hair follicles, sebaceous glands, and apocrine glands as distinct elements, all three components actually stem from the same structure, which has been termed the folliculosebaceous-apocrine unit. For practical purposes, the terms "follicle," "hair follicle," "folliculosebaceous unit," and "folliculosebaceous-apocrine unit" are used interchangeably. The folliculosebaceous-apocrine unit is a structure that provides insulatory, cosmetic, and pheromonic functions to the mammalian organism. The eccrine unit is a completely independent structure that serves as a thermoregulatory device via secretion of sweat.

The follicle proper consists of an infundibulum, an isthmus, and an underlying stem and bulb. The infundibu-lum is the superficial most segment, in continuity with the surface epithelium, and is composed mostly of keratinocytes that are microscopically identical to epidermal keratinocytes. Infundibular keratinocytes display pink cytoplasm within a conspicuous layer analogous to the stratum spinosum and mature via a stratum granulosum to form orthokeratin that envelops a hair. The infundibulum forms a tunnel that harbors and shields the projecting hair shaft. The apocrine duct emanates from the lower infundibulum and spirals downward through the dermis to the apocrine secretory unit. Subjacent to the infundibulum, the follicular isthmus is defined superiorly by the origin of the sebaceous duct and inferiorly by the insertion of the leiomyocytes of the arrectores pilorum musculature. The follicular isthmus is characterized microscopically by keratinocytes with dense pink cytoplasm that display abrupt cornification with little intervening stratum granulosum, forming compact ortho-keratin that is tightly arrayed around the hair shaft.

Sebaceous and apocrine glands emanate from the primary follicle and reside within the adjacent dermis. Virtually, all follicles sport sebaceous glands, whereas apocrine glands usually involute at most body sites, remaining detectable in genital and axillary sites, in periorbital and periauri-cular skin, and sometimes in skin of the scalp. The sebaceous duct, distinctive for the corrugated luminal border and compact eosinophilic cuticle lining its canal, courses a short distance through the adventitial dermis and links to the adjacent sebaceous gland. The sebaceous gland proper consists of a thin peripheral layer of seboblasts with a basaloid appearance, with the bulk of the gland composed of mature sebocytes, characterized by a scalloped nuclear border because of the presence of abundant surrounding coarsely vacuolated cytoplasm.

In areas in which apocrine glands are preserved, the apocrine duct juts from the lower infundibulum just superior to the insertion of the sebaceous duct and spirals downward to join the secretory portion of the apocrine gland, which is situated in the deep reticular dermis and subjacent subcutis. The secretory elements are arranged as tubules lined by cuboidal and columnar cells with ample eosinophilic cytoplasm that often appears finely granular in conventional sections. At the luminal border, a papillated or "decapitation" pattern is often present, reflecting holo-crine secretion.

A crucial principle to keep in mind when considering adnexal lesions is the fact that the development of the eccrine apparatus is completely distinct from that of the folliculose-baceous-apocrine unit. In fully developed human skin, eccrine glands and folliculosebaceous-apocrine units are unrelated structures, and their embryogenesis is completely independent. Eccrine glands develop directly from the embryonic epidermis in the early months of fetal development, projecting as a cord of cells that subsequently entubu-lates to form a gland. Folliculosebaceous units develop directly from the epidermis at much the same time, but the development of follicles differs from the development of eccrine glands in that mesenchymal cells, precursors of the follicular papilla, induce a follicular germ and descend jointly into the dermis with the developing epithelial structure. Subsequently, sebaceous and apocrine glands and their ducts elaborate as secondary structures. The folliculo-sebaceous unit is a hamartoma-like structure from the start, eventuating with a combination of epithelial cells of different types and perifollicular fibrocytes, whereas the eccrine gland is a strictly epithelial structure.

This ontogenetic principle reflects relationships that can be observed repetitively in dermatological diseases. As one might predict from ontogeny, follicular, sebaceous, and apocrine differentiations are frequently observed conjointly, and combinations of eccrine and folliculosebaceous differentiations probably do not exist. Certainly, authors in the past have described proliferations of putative mixed eccrine and folliculosebaceous differentiation, but in the view of most current authorities, these claims are baseless.

Combinations of adnexal neoplasms also shed light on lineage and provide insight into the development of a logical classification scheme. Although most adnexal neoplasms display a relatively uniform microscopical pattern, it is not uncommon to encounter lesions with biphasic or multipha-sic patterns. Excepting the identification of a coincidental "collision" between proliferations of disparate biology, such as syringoma combined with basal cell carcinoma or a melanocytic nevus juxtaposed on desmoplastic trichoe-pithelioma, the elements that occur conjointly in "combined" adnexal neoplasms can be assumed to be of related lineage. For example, the commingling of spiradenoma and cylin-droma is commonplace and suggests a close relationship. Indeed, it has been suggested by some observers that these two separately described lesions represent different patterns of the same entity. Spiradenoma or cylindroma is occasionally captured with trichoepithelioma. Adnexal neoplasms also develop, singly or in combination, in association with nevus sebaceus, which is not an adnexal neoplasm itself but rather a folliculosebaceous-apocrine hamartoma.

It is clear from such combinations that cylindroma and spiradenoma are of the same lineage. The nonsensical historical notion (present in most textbooks of dermatology and dermatopathology) that spiradenoma is "eccrine" and cylindroma is "apocrine" is pure poppycock. This conclusion can be based not only on the fact that the two neoplasms occur intertwined, but also on their relationship in common with both trichoepithelioma and nevus sebaceus.

Although not in direct combination, adnexal neoplasms can also occur jointly (in multiplicity) in the same patient in the context of a genetic disorder, typically a dom-inantly inherited syndrome. Multiple trichoepitheliomas occurring in concert with multiple cylindromas and/or spir-adenomas, the so-called Brooke-Spiegler syndrome, is a common connection. Spiradenoma and cylindroma have also been observed jointly in multiplicity, as has the triad of spiradenoma, cylindroma, and trichoepithelioma. These observations assert that the lineage of cylindroma, spirade-noma, and trichoepithelioma is linked and that cylindroma, spiradenoma, and trichoepithelioma are best classified as folliculosebaceous-apocrine neoplasms.

The topographic distribution of adnexal structures also offers insight into logical classification. There is striking variation in anatomic distribution among adnexal neoplasms, and some of these differences hold implications with respect to logical assignment of lineage. Historically, poroma has been considered so thoroughly eccrine that many dermatologists do not even refer to it as poroma. Rather, the designation "eccrine poroma" is used as its formal name. Poromas are routinely observed on the palms and soles, sites rife with eccrine structures, as one would expect of a neoplasm of eccrine lineage. However, the clinical presentation of poroma is broad and is not limited to glabrous lesions. Poromas present not uncommonly on the scalp and in axillary and inguinal skin, sites where apocrine elements are prominent. Poromas also develop as secondary neoplasms within nevus sebaceus, a folliculosebaceous-apocrine hamartoma. The most parsimonious explanation for the distribution of poroma is not that poroma is eccrine, but rather that poroma may be of either eccrine or apocrine lineage. Similarly, the distribution of syringoma is at odds with historical classification schemes. Purportedly an eccrine neoplasm, syringomata virtually never develop at sites replete with eccrine elements, such as the palm or sole. Acral syringomata are a rarity. Instead, syringomata are found almost exclusively on the periorbital face and genitalia, sites at which apocrine elements are identifiable. This topographic evidence suggests that syrin-gomas are probably apocrine in nature, most of the time.

Microscopy and other morphological tools, including the wide array of available special stains, also play a role in the assessment of lineage. However, if microscopists are to use their observations as the foundation for a system of classification, they must be certain that the microscopical features chosen for tabulation are determinate of a specific line of differentiation. For some lines of differentiation, the meanings attributed to specific microscopical findings are indisputable. The presence of cells with coarsely vacuolated cytoplasm and scalloped nuclei clearly indicates sebaceous differentiation. There is consensus that follicular (germina-tive) differentiation is established if a proliferation contains basaloid cells resembling the follicular bulb and adjacent mesenchymal cells resembling the papilla. Other unequivocal marks of follicular differentiation include anucleate matrical cells ("shadow" cells), a palisade of pallid cells with an adjacent thickened basement membrane, an attribute of the follicular outer sheath (trichilemma), and bright pink intracytoplasmic trichohyalin granules, typical of matrical corneocytes of the inner sheath. In contrast to these universally accepted attributes, the features that indicate glandular lineage lack specificity. Decapitation secretion is rightly held as the pathognomonic marker of apocrine differentiation, yet an essentially indistinguishable microscopical pattern can be encountered at times in occluded eccrine glands or in neoplasms of postulated eccrine lineage. Ducts with a compact eosinophilic cuticle have been wrongly interpreted as a specific indicator of eccrine differentiation, as identical structures can reflect apocrine or even sebaceous lineage in the ducts of the folliculosebaceous-apocrine unit.

What then are the specific microscopical features of eccrine glands that, when observed within a neoplasm, confirm eccrine lineage? There are none. Apocrine lineage can be suspected on the basis of recognition of decapitation secretion, but a judgment as to whether a process exhibits eccrine or apocrine differentiation cannot be based on the presence of ducts, as eccrine and apocrine ducts are indistinguishable. In short, microscopical assessment is invaluable in the specific recognition of follicular and sebaceous differentiation and is sometimes sufficient to suspect apocrine differentiation. Microscopy alone is insufficient to establish eccrine lineage, save for the exclusion of other modes of differentiation.

Other morphological tools for assessing lineage, such as electron microscopy and enzyme histochemistry, have been suggested but have been proven to be of little value and will not be addressed further. Immunoperoxidase staining has clarified the classification and lineage of many neoplasms, especially lymphomas, and still holds hope as an arbiter of adnexal lineage. To date, however, immuno-peroxidase stains have resolved few, if any, of the conundrums of adnexal classification owing to lack of specificity. Carcinoembryonic antigen (CEA) was among the earliest reagents assessed. Although CEA nimbly labels areas of luminal differentiation, the pattern observed in both eccrine and apocrine ducts (and in eccrine and apocrine lesions) is identical. The situation is much the same for other reagents, including gross cystic disease fluid protein (GCDFP-15), epithelial membrane antigen, and various anti-keratins, all of which have been found at times to stain both eccrine and apocrine elements, whether normal or neoplastic.

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