Pamela C. Martin, M.D., Donald R. Pulitzer, M.D., and
Richard J. Reed, M.D.
The skin appendage tumors are morphologically diverse. In most examples, the histologic features are distorted expressions of normal, adnexal patterns. For some examples in the follicular group, the distortions, in part, recapitulate the spectrum of cellular differentiation as manifested during cyclic growth. The neoplastic counterparts of hair matrix, inner root sheath, and even trichogenesis are manifested in some follicular neoplasms. In a second broad category, neoplastic squamous cells are preponderant: the patterns are comparable to those of the follicular infundibulum or the outer root sheath. In the histologic spectrum, overlaps are common. At one extreme, distinctions between a lesion of the follicular infundibulum and the epidermis are based on patterns in which cells are arranged rather than on specific patterns of cellular differentiation.
Follicular neoplasms showing hair matrix differentiation generally have basaloid or basal cell qualities.The patterns in basal cell carcinomas with rare exceptions are expressions of follicular differentiation. In well differentiated variants, a distinctive mucinous stroma recapitulates the inductive influence of the primordial germ on mesenchyme. The blastomatous qualities of a developing hair germ (primordial bud) are recapitulated in some examples: the inherent potential for divergent differentiation as both hair follicle and sweat gland (including sweat duct) is expressed. In such examples, both follicular and adenomatous (sweat gland apparatus) patterns are expressed.
In the basaloid category, a group of benign expansile tumors with variable expressions of hair matrix differentiation includes trichoepithelioma, giant trichoepithelioma, and trichoblastoma. If the common, basal cell variant of trichoepithelioma is selected as a model, its most distinctive feature is manifested in abortive patterns of hair bulb differentiation with induction of a hair papilla. The cells of the common trichoepithelioma more closely resemble cells of a well differentiated basal cell carcinoma than normal hair matrix cells. Hair bulb differentiation also should be a requisite for the recognition of giant trichoepithelioma.
The requisites for the diagnosis of trichoblastoma remain nebulous. The concept was an earnest effort to relate patterns of epithelial - stroma reactions as seen in odontogenic lesions to patterns of differentiation in adnexal tumors. Some examples may represent a cellular phase of pilomatrixoma. Others represent the ameloblastic variant (with expression of stellate reticulum) of basal cell carcinoma. The trichogenic variants are organoid and distinctive.
Distorted patterns of hair matrix differentiation with recapitulation of the patterns of the inner root sheath are manifested in pilomatrixoma but are additionally characterized by accelerated cell death (ghost cells).
Some of the follicular neoplasms in the basaloid category are related sequentially to distinctive follicular dysplasias. If represented, the related dysplasias are irregularly spaced in the dermis in close proximity to a follicular neoplasm. They are distortions of normal follicles in form and usually are basaloid.
Hair matrix lesions lacking distinctive patterns of differentiation are uncommon, difficult to classify, and likely to be confused with expansile, well differentiated basal cell carcinoma. Herein, several patterns of cellular aggregation are grouped under the designation of hair matrix adenoma. This economy is justified by overlaps in patterns and in clinical presentation and behavior. In contrast to the detailed studies and complex classification of Headington, the approach herein emphasizes follicular dysplasias as a common precursor of benign, expansile basaloid tumors, commonly affecting the scalp (8). The lesions have morphologic features indicative of hair matrix differentiation. They are notable in that they are histologically "basaloid", often large and expansile, mitotically active, yet biologically indolent. The clinical and pathologic features of eleven cases of hair matrix adenoma (HMA) are presented.
MATERIALS AND METHODS
Cases from the histopathology files of Charity Hospital of Louisiana in New Orleans, the surgical pathology files of the Department of Pathology, Tulane University School of Medicine and from the private consultation files of one of us (RJR) were reviewed. Our familiarity with the cases is the sole basis for their inclusion in this study.
Microscopic slides stained with hematoxylin and eosin were available for examination in all cases. Periodic acid-Schiff (PAS) stain for glycogen was performed in one case in which material was available.
Patients ranged in age from 18 to 72 years, with a mean of 36.6 and a median of 52 years (Table 1.). The two youngest patients were male, aged 18 and 24 years. The youngest female patient was 62 years old. The average age difference between male and female patients was 30.4 years (37.6 vs. 68.0 years). Although this difference is remarkable, its significance is questionable, in view of the small number of patients in the study.
Approximately half of the lesions were on the scalp. The remainder occurred on the face, with the exceptions of one lesion of the axilla and one lesion involving the knee.
Although the preoperative diagnoses varied, they were of two basic categories: skin appendage tumors and melanocytic lesions. Diagnoses included trichoepithelioma, "skin appendage tumor," blue nevus and "possible melanoma". Two other cases in which a clinical diagnosis was available were less specific: "cyst" and "mole." None of the lesions is known to have recurred in a follow up period of 1 to 37 years.
The lesions consisted of polypoid, circumscribed, unen-capsulated nodules ranging in size (diameter) from 0.9 to 1.5 cm., with a mean of 1.2 cm (median 1.3 cm.). The overlying skin was intact and select tumors showed hyperpigmentation. Cut section demonstrated a lobulated, solid and focally cystic dermal tumor. Tumor lobules were separated by fibrous septa. In some tumors, brown pigmentation was prominent both within tumor nodules and within the adjacent dermis (Fig. 1).
The lesions all shared certain features. The histologic appearance was that of expansile, multilobate dermal tumors arising in hair-bearing skin. A laminated, fibrous pseudocapsule composed of compressed dermal collagen fibers was present at the periphery. Rounded nests of closely aggregated, basophilic cells composed individual tumor lobules. The nests varied in size and were occasionally centrally cystic. Often, bud-like projections of stroma impinged upon the periphery of tumor cell aggregates. The outermost cells in each nest were radially oriented, having a characteristic "palisaded" appearance. They had plump oval nuclei, with finely granular, marginated chromatin and one to two small pink nucleoli. Cytoplasm was scanty and basophilic, and intercellular borders were not prominent. Mitotic figures were abundant in all lesions, but abnormal mitoses were not observed. Individual cells varied little in size, configuration or chromatin content. The boundary between the peripheral cell layer and the surrounding dermis consisted of a narrow eosinophilic membrane. The characteristic mucin-filled cleft seen at the tumor-stroma interface in basal cell carcinomas, was notably absent. Often abortive follicles were present in the adjacent stroma.
The aggregates of epithelial cells were supported by a specialized stroma. Stromal cells were slender and spindle-shaped.Nuclei were elongated and oval with finely divided chromatin and a single, small pink nucleolus. The cytoplasm of each tumor cell was amphophilic, and tapered to slender dendritic processes at either end. Cytoplasmic melanin was present, the quantity of which varied, both from lesion to lesion, and regionally within individual lesions. Cytoplasmic processes of the stromal cells interdigitated with cells of the outer layers of the epithelial nests. Melanin was also present within the cytoplasm of the latter, in amounts roughly proportional to that within cells of the adjoining stroma. For some lesions, that were otherwise indistinguishable from their pigmented counterparts, pigmentation of stromal cells was imperceptible.
Within the confines of the multilobular framework, some variation was observed. An intraepithelial trabecular pattern, wherein tumor cells were arranged in broad intersecting bands separated by a specialized intercellular matrix, was most common. Individual trabeculae were 8-14 cells wide, and had palisaded basaloid cells along one border. At the opposite edge, small, polygonal squamoid cells with scanty basophilic cytoplasm were seen. Cells in between were morphologically intermediate between these two cell types. There was no evidence of keratinization. Trabeculae were gently contoured and appeared to intermingle randomly. Occasionally they assumed an annular configuration, and focally exhibited the "indented cup" formation of the normal hair bulb.
In another less common intraepithelial histologic pattern, broad trabeculae were present at the edges of lobules, but dissociated centrally into columns one cell in width. Cells were arranged single file in a pale mucinous matrix. These "subtrabeculae" were parallel to one another and exhibited gentle undulations. PAS stain for glycogen was performed in one of the lesions. The proliferating tumor cells failed to show positive staining.
The histologic differential diagnosis for hair matrix adenoma is complicated. The clinical impression is usually that of a dermal tumor or of a pigmented lesion and is seldom helpful in the differential diagnosis.
Pigmented basal cell carcinomas, like their non-pigmented counterparts, are characterized by mucin-filled clefts at the tumor-stromal interface. HMA may be distinguished from basal cell carcinoma by its delicate uniform stroma. The cellular constituents of HMA, while distinctly basaloid, lack anaplasia. Follicular dysplasias are commonly represented at the margins of HMA. They are rare in the dermis adjacent to basal cell carcinomas. Basal cell carcinomas are divisible into well differentiated and poorly differentiated categories. In the well differentiated category, the cells are small with uniform nuclear characteristics. Most examples are associated with a delicate mucinous stroma which is uniformly cellular. The stroma often ensheaths isolated nests of tumor cells at the advancing margin. The poorly differentiated variants are composed of larger cells with cytologic atypia and usually with evidence of squamous cell differentiation in many of the nests (basosquamous qualities). It is usually associated with a cellular inflamed stroma. The stromal cells are arranged with their long axes parallel to the perimeter of each nests. The stroma is indistinguishable from common tumor stroma manifested in many carcinomas in other organ systems and from the stroma usually associated with the common actinic carcinoma of the skin. Other features of basal cell carcinomas, namely, origin from the overlying epidermis, surface ulceration, infiltrative growth are not features of hair matrix adenomas. Actinic damage of dermal connective tissue is a regular feature of actinic basal carcinoma but is variable in the clinical setting of most HMA.
HMA and cutaneous eccrine cylindroma may appear similar histologically, especially at low magnification. Most cylindromas are characterized by focal or diffuse patterns in which small nests of cells are irregularly spaced among the collagen bundles of the reticular dermis. Lobular components are common. In such lesions as in HMA, lobules of closely aggregated basophilic cells form an expansile dermal lesion. In addition, both HMA and cylindroma commonly arise in hair-bearing skin, and may show abortive hair follicles in adjacent dermis. Cell nests showing peripheral palisading of nuclei and surrounding basement membrane like material may be seen in both entities. HMA may show deposits of basement membrane material in the nests of cells but not in the pattern of "hyaline cylinders" as seen within lobules of cutaneous cylindromas. In our experience bone fide examples of cutaneous cylindroma rarely show areas suggestive of direct evolution from structures of the follicular apparatus. The association of cutaneous cylindromas and trichoepitheliomas in a rare hereditary condition provides further evidence of a follicular rather than sweat duct derivation (10). The combined patterns are better related to the primordial bud than to the eccrine apparatus.
Trichoepithelioma is a benign basaloid neoplasm presumed to be derived from the distal portion of the follicular apparatus (4,8). This lesion, like HMA, may consist of several cellular lobules with palisading of nuclei at their peripheries. Trichoepithelioma however, is not usually composed exclusively of basaloid cells. Squamous differentiation with the formation of a granular layer and keratin filled cysts is often present in the central portions of these lesions, representing infundibular differentiation. Solid nests of basal cells may be manifested but the characteristic pattern is that of thin interconnected cords which radiate from a central nidus. The diagnosis of trichoepithelioma is best documented in examples in which differentiation of both hair bulb and papilla is developed, albeit in a distorted fashion. In addition, the stroma of trichoepithelioma is characteristic. It is mucinous or fibrous and uniformly cellular. It condenses at the margin of each lobule to produce a sharp interface with the adjacent reticular dermis.
Giant trichoepithelioma and its variants are composed of basal cells. Clinically, the giant variants are large and expansile lesions with significant involvement of the subcutaneous fat and may even present as subcutaneous nodules. The histologic patterns overlap with those of HMA, making the distinction difficult (1,4) It may be considered that both lesions are basaloid proliferations in which abortive hair matrical differentiation is expressed. Giant trichoepithelioma is an organoid tumor in which abortive hair bulbs and papillae are formed. The pattern recapitulates those of the common trichoepithelioma but the lesion is large, expansile, and organoid.
The uncommon trichoblastoma is an epithelial tumor of the hair germ (3,4). It, like HMA, is a tumoral lesion and is composed predominantly of basaloid cells. The differentiated trichogenic trichoblastoma is extremely rare. The patterns in the undifferentiated variant have been compared to those of the odontogenic ameloblastic lesions. The comparisons include subdivisions with distinctions between those with and those without induced stroma. Some of the lesions with induced stroma show patterns which overlap with those of fibrofolliculomas. Fibrofolliculomas are grouped with the trichodiscomas and perifollicular myxomas (angiomyxomas).
Other tumors of the matrix include pilomatrixoma (Calcifying epithelioma of Malherbe), and matrical carcinoma (3,4,6,8,9). HMA, unlike pilomatrixomas fail to show significant amounts of cellular necrosis, host reaction and calcification. The intrinsic growth limiting mechanisms present in pilomatrixoma are absent in HMA. Unlike true carcinomas of the hair matrix, HMA does not show significant cytologic atypism nor an infiltrative pattern of growth. Some hair matrix carcinomas may even be associated with a lymphoid stroma. Proliferating pilar tumor (2,7) is most often an alteration of a pre-existing pilar cyst. In it patterns of inner root sheath differentiation may be expressed. In this context, the lesion in part expresses the patterns of matrical cell differentiation.
The pluripotential nature of the primary hair germ and the functional variations of follicular epithelium find expression in diverse patterns in the group of follicular neoplasms. A wide spectrum of differentiation and combinations of structures are manifested in hamartomas and neoplasms of the hair follicle. The categorizations of these lesions have been confusing and often contradictory (1-5, 7-10). Specialized studies such as electron microscopy and enzymatic analyses, while having made histogenetic contributions, have occasionally yielded results which conflict with sound histologic criteria.
Ontogeny provides the basis for an under understanding of tumors of the pilar unit. The embryonic stratum germinativum differentiates into the basal cell layer of the epidermis, the primary epithelial germ of the hair (hair germ) and the eccrine gland germ. The potential for the development of both hair follicle and the sweat gland apparatus resides in the primordial hair germ. In providing the ectodermal contribution to the hair follicle, a focal crowding of cells at the basal layer in the fetal epidermis is the first recognizable stage of the germinative phase of pilar development. This localized proliferation bulges downward into the papillary dermis where it is capped by specialized mesenchymal cells. Differentiation and subsequent canalization of this ectodermal bud continues within the epidermis and results in the formation of the acrotrichium. Concurrently, the root sheath is a product of differentiating mesodermal cells in the adjacent papillary dermis. Thus, the developing follicle is composed of the conical proliferation of epithelial cells (the matrix) and the specialized cellular connective tissue with the papilla at the extremity of the cone. The unique character of this association is often recapitulated in tumors of the pilar apparatus.
The development of both the ectodermal and mesodermal portions of the hair follicle is distinct from that of surrounding epidermis and dermis. Differences in pattern of epidermal keratinization is evidence to support the separate development of the acrotrichium and the adjacent epidermis (6).
Matrical cells are characterized by their undifferentiated appearance, lack of glycogen and paucity of organelles. They possess a high mitotic rate, most of which are contained in the lower portion of the bulb. As differentiation into specialized layers of the hair occurs, the cells are pushed upward. The border between the differentiating cells and the undifferentiated cells of the matrix was termed the "critical level" by Montagna (6). Above this level, highly dendritic melanocytes are intermingled with the proliferating epithelial cells. In the fetal state, melanocytes, unlike those of the adult, may also be found in the lower portion of the bulb in association with the proliferating cells of the matrix.
The tumors of this series occurred most often, yet not exclusively on the scalp and face. All were tumoral and were thought to represent an adnexal tumor or melanocytic lesion clinically. Each consisted of an expansile proliferation of basaloid cells with delicate chromatin, fine nucleoli and scanty cytoplasm. The stroma at the periphery was distinctly laminated. Abortive follicles adjacent to the neoplasm were characteristic. Melanocytes were prominent in some lesions, both within the stroma and between epithelial cells, accounting for the clinical impression of a melanocytic neoplasm. This complex interaction of tumor epithelial cells and melanocytes recapitulates structural and functional relationships observed in anagen hair bulbs.
The various cell types manifested during the cyclic growth of hair follicles are recapitulated in a distorted manner in the hair matrical tumors. In HMA, three patterns are recognizable. The pattern of small basal cells recapitulates the cytologic features of the proanagen stage. The pattern of large cells with plump round nuclei and scanty cytoplasm recapitulates the cytologic features of the anagen phase (those germinative cells below the level of the differentiating cells of the inner root sheath). In pilomatrixoma, both germinative cells and differentiating cells of the inner root sheath are represented. There is no block at the germinative level as in HMA. As a consequence, the cells of pilomatrixoma follow the course of those of the inner root sheath: they are committed to inexorable cell death with both lysis of cells and a distinctive form of keratinization. In trichogenic trichoblastoma, the process of trichogenesis is remarkably duplicated in multiple foci in a neoplasm. In trichoepithelioma of both the common and giant types, abortive hair bulbs are associated with distorted papillae. The nidi of squamous cell differentiation with the formation of keratin-filled cysts are evidence of follicular infundibular differentiation. Occasionally, sebaceous differentiation is manifested.
HMA as a generic designation embraces a group of basal cell and basaloid tumors in which hair matrical differentiation is expressed. It gives recognition to a group in which differentiation is arrested at the germinative level. Stroma changes as expressions of the induction of papillae and epithelial patterns of the inner root sheath are not represented. HMA is an uncommon tumor of the hair follicle with a distinct histologic pattern and indolent clinical behavior. It is an epithelial proliferation with a maturation arrest, most closely simulating the anagen hair bulb. The importance of its recognition rests in its distinction from basal cell carcinoma with which it may be confused.
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TABLE 1. Hair Matrix Adenoma: Age, Sex, Site
Case Age/Sex Site
1. 18 M scalp
2. 62 F cheek
3. 70 F scalp
4. 50 M axilla
5. 24 M scalp
6. 54 M cheek
7. 40 M knee