Follicular Neoplasms 

FOLLICULAR NEOPLASMS (with emphasis on lesions of the inconstant portion of the hair follicle, particularly the follicular sheaths):

Hair follicles are subject to a remarkable number of both inflammatory diseases, and an array of distinctive neoplasms. Follicles are epithelial structures whose histologic patterns patterns can be correlated with inherent cyclic phenomena; such correlations are a must in attempts to meaningfully classify follicular neoplasms. At regular intervals, with the phenomena of an individual follicle mostly independent of the activity of neighboring follicles, an immature follicle matures and, after an interval of generative activity, regresses to then assume a resting state; after an interval of rest, the phenomena are repeated. Inflammatory diseases, and trauma can alter the cyclic phenomena.

A resting follicle is small. It composed of uniform squamous cells. Small cords of small squamous cells often project from the surface of such a structure (F5Ch12); a limited domain is defined among each neighboring pair of cords. The development of a papilla, and an initiation of a new cycle of growth may depend upon an encounter between the epithelial component and a special portion of the dermal domain. Each limited domain, as defined by the epithelial protrusions of a resting follicle may be representative of a search for the special components. A developing (anagen) follicle shows varying patterns along its length. A pore on the surface of the skin communicates with a channel that is lined by squamous epithelium (F1Ch13a). The channel (the infundibulum) is lined by squamous epithelium having the same basic characteristics as those of the adjacent epidermis. For a mature anagen follicle, a hair shaft courses through this channel and protrudes through the pore. The epithelium does not tightly embrace the hair shaft in this portion of the follicle. About the hair, but in the same channel, keratinized debris is loosely laminated. The next (deeper) segment is a conduit for both a segment of the hair and for sebum that is secreted into the channel (F1Ch13). In descending order, the isthmus, a short segment that is lined by squamous epithelium, is next. Below this level, the epithelium is specialized. It closely adheres to the developing hair. This portion of the hair is the “root.” There are three basic divisions of the epithelium of the inconstant portion: an outer root sheath, an inner root sheath, and a bulb (F1-4Ch9). The bulb, in turn, is divisible into a central, trichogenic, germinative portion, and a non-trichogenic, germinative portion (F1Ch9 & F4Ch9) The non-trichogenic portion gives rise to a tri-laminar inner root sheath (comprised of a “cuticle,” a trichohyalin-rich zone (Huxley’s layer), and outer row of keratinizing cells (Henle’s layer) (F3Ch9). The outer root sheath consists of rounded, or polygonal squamous cells that have distinctive, clear cytoplasm (F2Ch10). These cells seem to be resistant to the process of keratinization in anagen phases; only near the proximal extremity of an anagen follicle do the cells of the outer root sheath keratinize (F4, F5, & 6Ch10, F5Ch13); in this process, the newly keratinized cells from the outer root sheath seem to have a role in promoting the detachment and desquamation of hard keratinized debris that is a product of the inner root sheath at its upper extremity. At the interface with perifollicular connective tissue, a hyaline membrane (glassy membrane) (F1Ch12) defines the boundary between the basal layer of the outer root sheath, and perifollicular connective tissue sheath (characterized by cells that are CD34 +).

A hair follicle can be divided into a constant portion, and an inconstant portion. The constant portion is comprised of the infundibulum, sebaceous glands, and a common duct between the infundibulum and the so-called isthmus. The epithelium of the common duct differs from the epithelium of the infundibulum (F1Ch13). The features of the constant portion of a hair follicle are variably represented in a variety of follicular tumors of the skin. The most common example is seborrheic keratosis; the keratin-filled cysts of such a lesion display the histologic features of the infundibular portion of a follicle. A seborrheic keratosis is characterized by a dual population of keratinocytes: a small cell component (the germinative basal unit) includes the basal layer of the epithelium; the large cell component has a role in the formation of pores that open to the surface of the skin. In the development of patterns in a seborrheic keratosis, large cells first form a whorl; cells, that are centrally placed in the whorls, keratinize; the keratin lamellae separate from their neighbors. In this process, a keratin-filled lumen is the result. The epithelial lining of an epidermoid cyst can be compared with that of the infundibulum. The lining of a steatocystoma shares features with the epithelial lining of the common-duct portion of a follicle

The inconstant portion of a follicle, as classically defined, is basically a unique expression of anagen phenomena. Its components, in classical terms, consist of a glassy membrane, an outer root sheath, Henle’s layer, Huxley’s layer, the “cuticle of the inner root sheath, the “cuticle” of the hair shaft, and the hair shaft (more specifically the “root”) (F1-4Ch9)). The common anatomic approach has a stifling effect on the interpretation of anagen patterns. The glassy membrane, in extent, is peculiarly restricted to the interface between the fibrous sheath, and the glycogen rich component of the outer root sheath. Henle’s layer, at its deeper reaches, is a single-cell layer that adheres closely to the sheath of trichohyalin-rich cells (Huxley’s layer) (F2 & 3Ch9, F1-3CH10, & F2Ch11); it seems appropriate to include this layer as a component of the inner root sheath. In an irregular fashion, as the cells of Henle’s layer move upward, they keratinize; in this change, the nucleus of the keratinizing cells undergoes lysis; the keratinized cells tend to retain a cuboidal configuration with margins that overlap those of the neighbors. Huxley’s layer is a sheath in which the component cells form 2 or 3 layers along the horizontal axis (F1-3Ch10). This sheath terminates at about the level where the hair root separates from the inner root sheath (F1 & 2, 6Ch10); it is at this same level that a true cuticle can be recognized at the surface of the hair shaft; the cellular precursor of the “cuticle” loses its identity in the cap of keratinized debris that marks the terminus of Huxley’s layer. At this level, Huxley’s layer terminates in keratinized debris that is indistinguishable from that contributed by the cellular component of the inner root “cuticle,” and Henle’ layer (F6Ch10). Huxley’s layer, in keratinizing, has, as intermediate phenomena, a zone (a cap) of parakeratosis. Henle’s layer, Huxleys’s layer, and the “cuticle” of the inner root sheath can be characterized as the three components of the inner root sheath (F2Ch10).

Only in the anagen phase does the outer root sheath have a well defined morphology. The outer root sheath appears to be phenotypically independent of the complicated phenomena of an anagen hair bulb. The hair bulb, as it differentiates and grows, sends a multi-layered wedge of cells upward (F1Ch11). In a sense, this wedge invades a separate column for which growth is downward, and in pace, with the downward migration of the bulb (F1 & 2Ch11, F2Ch13, & F3Ch13). As the wedge from the bulb extends upward into the column, the penetrated column differentiates to become the outer root sheath. The wedge of cells extends upward; the developing hair root initially keeps pace with the other components of the wedge; the “root” becomes the shaft once it is freed from its association with the inner root sheath (at about the level where the inner root sheath undergoes keratinization and then terminates) (F1, 2, & 6Ch10). Just above this level, the cells of the outer root sheath keratinize (F4Ch10); in this act, the uppermost portion of the hard keratin cap of the inner root sheath desquamates into the newly formed lumen. A short expanse of squamous epithelium below the ostia of the sebaceous ducts has been characterized as the isthmus (F2Ch13).

In what appears to be a constant, but morphologically poorly defined, portion of each resting follicle, there are thought to be progenitor cells. They are assumed to have the capacity to express phenotypic diversity. Phenotypic diversity characterizes anagen phenomena; it finds expression in distinctive cytologic features; these cytologic components can be correlated with unique functional expressions. The outer root sheath appears to resist keratinization for as long as the hair shaft retains an intimate attachment between the “cuticle” of the hair shaft, and the “cuticle” of the inner root sheath. Perhaps, the glycogen-rich nature of cells of the outer root sheath may be a correlate of a resistance to keratinization. On the other hand, I suspect that the glycogen-rich cells have a role in formation of mucinous interstitium. In turn, a mucinous interstitium would, perhaps, facilitate the upperward migration of the inner root sheath along the inner surface of the outer root sheath. It seems to me that there must be at least one, and most likely two, moveable cell populations, to accommodate the growth of a hair along the course of the inconstant portion of a follicle. If this is not the case, there must be a remarkable synchronization of cellular phenomena in the outer root sheath, the inner root sheath, and the root of the hair. The outer root sheath, at its deep limits, terminates at about the level where the bulbous contour of the bulb first distorts the outline of a follicle. As it approaches its limits, the outer root sheath becomes progressively thinner, and the individual cells smaller. The glassy membrane also is thinner. With a properly oriented section, the glassy membrane appears to wrap around the deep extremity of the outer root sheath, and then extends a short distance upward along the inner surface of this sheath; at about the level where a Henle’s layer can first be defined, the glassy membrane then terminates.

Concepts of “follicular bulge” and “follicular mantle” give recognition to proposed reserves of germinative cells.

In catagen phases, the complex of distinctive cell types (the diversity of phenotypes) give way; the cell types revert to what is basically a squamous cell of a rather undistinguished type. The outer root sheath progressively gives up the domain it had acquired during the anagen phase. It persists for awhile as thin and short, lateral protrusions (as seen in a central section along the long axis of a follicle); the clear cell quality gives way to peri-nuclear vacuoles; finally, the cells appear as common squamous cells (F3Ch13a). In all these changes of catagen type, dyskeratosis and cytolysis are markers for regressive phenomena. Similarly, a bulbous component, devoid of distinctive cells, may be a marker for what was once the trichogenic portion of a hair bulb (F5Ch11). The central core - that population of cells which, during anagen phase, had the trichogenic role - reverts to a population of small squamous cells with peri-nuclear vacuoles. Distinctive keratinization, with streaming of the keratinizing cells, may persist for a period but is inadequate for the formation of a root (F2Ch11); the keratinized product probably has a role in promoting the detachment of the hair shaft.

It is tempting to characterize an “ inverted follicular keratosis” as a tumor in which patterns of the constant portion of a follicle are recapitulated; in the expression of patterns, whorls of squamous cells are a histologic feature by which the lesion is defined (F3-6Ch30, F1-6Ch31); these whorls keratinize centrally. The whorls of squamous epithelium have been cited as evidence of infundibular differentiation, but other patterns in such lesions - features that mostly seem to be ignored - are better characterized as having the qualities of catagen-like tricholemma.

A tricholemmoma is often cast as a distinctive lesion in which glycogen-rich, vacuolated cells are basic to the histologic definition. Although overlaps are mostly ignored, lesions with features of both inverted follicular keratosis and tricholemmoma are sufficiently common to make a precise categorization of individual lesions a most arbitrary endeavor. The cells of some tricholemmomas retain prominent squamous cells qualities with thick cell membranes; the cells of other examples are mostly clear cells with less distinct squamoid qualities. A glassy membrane is more characteristic of a classic tricholemmoma; the basement membrane of an inverted follicular keratosis generally would not qualify as a glassy membrane. Whorls of squamous cells are encountered in both lesions. For lesions with prominent overlap patterns, the overlaps can be accepted as evidence of phenotypic diversity in which patterns of both anagen and catagen phenomena are expressed (i.e., mixed pattern).

As an introduction, phenotypic variations, as expressed in the normal cycles of hair follicles - and as manifested histologically - are documented; some of the problems presented by the classical discussion of the histology of hair follicle are considered. This presentation primarily is limited to patterns in which the basic requisites include patterns of inverted follicular keratosis and/or tricholemmoma. Additional patterns, that are acceptable but secondary, include sebaceous differentiation (a follicular component), basal cell differentiation (a correspondent of a primitive hair bulb), hair matrical patterns (generally to the exclusion of trichogenic components), and cytopathic patterns that might be compared to those expressed in a catagen follicle. Patterns of cytologic atypia, including carcinomas, have been included. Molluscum contagiosum is included as an example of virus-induced follicular neogenesis.


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