1. Embryology. The development of follicles (or more correctly, the folliculosebaceous-apocrine unit) differs from the development of eccrine units in that mesenchymal cells, precursors of the follicular papilla, descend jointly into the dermis with developing epithelial elements. Sebaceous and apocrine glands and their ducts begin to arise in the third and fourth months, elaborating from bulges on the side of the developing follicle. If ontogeny reflects phylogeny, it is reasonable to expect that ontogenetic relationships reflect relationships in clinical disease. Based on ontogeny, logic predicts that follicular, sebaceous, and apocrine elements might "hang together," and that combinations of eccrine and folliculosebaceous differentiation might be nonexistent!
   
   
2. "Combined" neoplasms. Biphasic or multiphasic lesions can be encountered, and with the exception of rare "collision" lesions between proliferations of disparate biology, the elements that occur conjointly in "combined" adnexal neoplasms should be assumed to be related. When we seen spiradenoma commingling with cylindroma, or spiradenoma commingling with trichoepithelioma, or shadow cells and follicular germs in a mixed tumor, or even trichoblastoma commingling with basal cell carcinoma, it suggests there is an interrelationship.
   
   
3. Associations of neoplasms. When adnexal neoplasms are linked in the context of a genetic disorder, such as Brooke-Spiegler syndrome, it suggests a relationship. The fact that spiradenoma and cylindroma and trichoepithelioma all occur in patients with this disease suggests an interrelationship of these entities.
   
   
4. Anatomic distribution. There is striking variation in anatomic distribution among adnexal neoplasms. Syringoma, reputedly eccrine, almost never develops at glabrous sites that are replete with eccrine elements. Acral syringomata are a rarity! Rather, syringomata are found almost exclusively on the face and genitalia, where apocrine elements abound. While this type of analysis is admittedly simplistic, there are a number of inconsistencies out there!
   
   
5. Microscopy and special stains.
   • Microscopy. The significance of some cytological findings is indisputable. Cells with coarsely vacuolated cytoplasm and scalloped nuclei are unequivocally indicatative of sebaceous differentiation. Follicular differentiation can be assumed if a proliferation contains bulbar follicular germinative cells and adjacent mesenchymal cells resembling the papilla, or follicular differentiation can be assumed from the presence of matrical corneocytes ("shadow" cells). There are also traits of dubious specificity. Decapitation secretion is held as pathognomonic of apocrine differentiation, yet a virtually indistinguishable pattern can be encountered in occluded eccrine glands or in some neoplasms of eccrine lineage. Ducts with a cuticle have been regarded as the sine qua non of eccrine differentiation, yet identical structures are readily found in apocrine or sebaceous structures. Herein lies the problem, or at least part of the problem. There are no reliable light microscopic clues to permit distinction of eccrine and apocrine structures.
     
     
   • Histochemistry. Although histochemical stains have achieved the status of gospel, a return to the original references reveals findings that are less than compelling. Phosphorylase, the archetypal eccrine enzyme, is expressed in eccrine glands and ducts, and serves as the basis for the ongoing misconception that phosphorylase positivity indicates eccrine lineage. Unfortunately for the true believers, the apocrine duct contains phosphorylase in greater abundance than the eccrine unit, and thus phosphorylase cannot be used as a global discriminator of eccrine and apocrine differentiation. If anything, phosphorylase is merely an indicator of ductal or tubular differentiation.
     
     
   • Immunohistochemistry. Immunoperoxidase staining has clarified the classification and lineage of lymphomas and a variety of other lesions. Unfortunately, immunohistochemistry has proved not much better than enzyme histochemistry in the context of adnexal neoplasms, and the fundamental problem is a lack of specificity. Carcinoembryonic antigen (CEA), S100 protein, GCDFP-15 (gross cystic disease fluid protein), epithelial membrane antigen (EMA), and various anti-keratins all have been found at times to stain both eccrine and apocrine elements, whether normal or neoplastic.
     
     
   • Ultrastructure. Electron microscopy (EM) was a valued technique in the early exploration of adnexal lineage, but has not permitted definitive resolution of the problem, because the ultrastructural characteristics of apocrine and eccrine cells, whether normal or neoplastic, are not unique.

Adnexal Neoplasms with Conspicuous Ducts
When viewing an adnexal neoplasm, the presence of lumina (ducts or glands) clearly implies an element of glandular differentiation. However, the presence of lumina does not dictate the lineage of the neoplasm at hand; such structures can be found in eccrine, apocrine, and sebaceous proliferations. Sometimes it is unclear whether a lumen represents a duct or a gland. Generally speaking, ductal differentiation is hallmarked by the presence of a dense eosinophilic cuticle, which can be highlighted by PAS-D staining. Ducts are also generally highlighted by CEA. The inexperienced eye can sometimes find it difficult to discern if a structure is a duct or a small cornifying cyst. Generally, ducts are lined by a cuticle, highlighted by CEA, and may contain amorphous secretion. In contrast, small cornifying cysts generally lack these attributes, with lumens that generally contain laminated orthokeratin.

Our "ductal" differential diagnosis includes a wide spectrum of glandular adnexal proliferations:

Syringoma. Syringomata present most commonly as small facial papules but sometimes present at extrafacial locales. The lesions are typically small and well circumscribed, composed of closely apposed nests of pale keratinocytes arrayed within sclerotic stroma. Ducts are typically obvious and conspicuous, and can contribute to diagnostic difficulty if lacking. Syringomatous carcinoma. The malignant analogue of syringoma, syringomatous carcinoma has also been referred to as sclerosing sweat duct carcinoma. Syringomatous carcinoma can be considered on the spectrum of microcystic adnexal carcinoma, distinctive for its lack of "microcysts" (lack of infundibular follicular differentiation). Lesions are poorly circumscribed with pale nests of keratinocytes in infiltrative array within sclerotic stroma. Nuclear atypicality is typically modest and rarely marked. Ducts are usually obvious but can be highlighted by CEA if inconspicuous. Poroma. Once considered the prototypical "eccrine" neoplasm, most authorities now view poroma as a lesion of either eccrine or apocrine lineage. Microscopically, poromata have a "solid" microscopical appearance, composed of "poroid" cells with monomorphous round or ovoid nuclei and scant compact cytoplasm. Ducts are typically prominent. Poromata may present in intraepidermal, juxtaepidermal, or wholly dermal fashion. Porocarcinoma. The malignant analogue of poroma, porocarcinoma may arise de novo or in association with a pre-existent poroma. The degree of nuclear atypicality is highly variable, but typically there is substantial nuclear pleomorphism coupled with an increase in mitotic figures in a carcinoma. Much like poroma, porocarcinoma is composed of "poroid" cells and ductal differentiation is typically prominent. Importantly, necrosis en masse is an unreliable sign for the discrimination of poroma from porocarcinoma, as necrosis is common in the spectrum of poroma. Hidradenoma. Hidradenoma is a close relative of poroma, composed of somewhat larger cells with ample cytoplasm that is often pallid (e.g. "clear cell" Hidradenoma). Ductal differentiation is generally less than that observed in poroma, but may be pronounced. Some view poroma and hidradenoma as a spectrum, known as "acrospiroma", rather than as distinct entities. Hidradenocarcinoma is a rarity but can show pronounced ductal differentiation. Sebaceous adenoma and carcinoma may show pronounced ductal differentiation in an occasional case but typically such lesions also show prominent sebocytic differentiation as well, and thus the diagnosis is often obvious.

Adnexal Neoplasms with Small Cornifying Cysts
As noted previously, sometimes it is unclear whether a lumen within a given neoplasm represents a duct or a gland. Generally speaking, small cornifying cysts lack a cuticle, fail to label with PAS-D or CEA, and contain laminated orthokeratin rather than inspissated secretion. Small cornifying cysts are usually an indicator of superficial follicular differentiation, typically representing either infundibular or isthmic differentiation. Sometimes, squamous metaplasia of eccrine ducts can yield a similar microscopical pattern. In most instances, when there are small cornifying cysts present, the lesion at hand represents a follicular neoplasm, or a neoplasm with differentiation that is in part follicular.

Our "cornifying cystic" differential diagnosis is largely centered on two important entities:

Desmoplastic trichoepithelioma/trichoblastoma. Trichoepithelioma is of course a benign follicular neoplasm that mostly displays follicular germinative differentiation. In the past, trichoepithelioma and trichoblastoma were designations used independently, but increasingly in recent years the two terms have been used interchangeably. Trichoblastoma is an overarching term that refers to the entire spectrum of benign follicular germinative proliferations, while trichoepithelioma is generally utilized to designate superficial trichoblastomas with prominent superficial follicular differentiation. Desmoplastic trichoepithelioma/trichoblastoma is an entity common to the face in which slender strands of follicular germinative ("basaloid") cells are enmeshed within coarse fibrocytic (sclerotic) stroma. Commonly, there is an element of superficial follicular differentiation, much like conventional trichoepithelioma, with small cornifying cysts as a conspicuous feature. The laminated keratin within these small cystic spaces may extrude into the surrounding stroma and dermis, eliciting an accompanying granulomatous reaction that sometimes eventuates with microcalcification. Desmoplastic trichoepitheliomata tend to show relatively good circumscription and tend to be confined to the upper half of the reticular dermis, although these attributes can be difficult to appreciate in biopsies en parte. Much like any follicular proliferation, desmoplastic trichoepithelioma may show focal ductal (presumably apocrine) or sebaceous differentiation, although the majority show strictly follicular differentiation. The term trichoadenoma refers to a superficial follicular neoplasm that consists solely of small cornifying cysts. In my view, trichoadenoma is merely a desmoplastic trichoepithelioma in which basaloid (follicular germinative) cells are inconspicuous or absent. Microcystic adnexal carcinoma. Basal cell (trichoblastic) carcinoma aside, MAC is among the most common forms of adnexal carcinoma, although it remains an uncommon lesion in the experience of most. MAC is a type of adnexal carcinoma that typically shows "dual" differentiation, with both follicular and glandular/ductular attributes evident. The differentiation in both respects tends to be distal in nature. Follicular differentiation is commonly manifest as small cornifying cysts, lined by infundibular and isthmic keratinocytes, and small pink collections of isthmic keratinocytes or pale collections of glycogenated outer sheath keratinocytes may also be seen. As a rule, follicular germinative differentiation is not found within MAC, and the lesions generally do not assume a basaloid appearance. The ductular component of MAC is essentially identical to that observed within syringomatous carcinoma, with nests of pale keratinocytes that commonly display central ductules. Both populations are enmeshed in abundant sclerotic stroma. The overall lesion tends to show deep extension, with involvement of the lower half of the reticular dermis commonly and with subcutaneous or perineural involvement on occasion. There may be an interstitial infiltrate of lymphocytes and eosinophils present, especially in proximity to neoplastic cells with clear cytoplasm. Digression regarding cytokeratin-20 staining. CK20 is an immunostain that is currently in vogue (rightly so) in surgical pathology and dermatopathology. This low-molecular-weight keratin is useful in the recognition of adenocarcinomas of gastrointestinal origin, and also in the recognition of cutaneous neuroendocrine carcinoma. In light of the latter reactivity, it comes as no surprise that CK20 labels normal Merkel cells that populate the epidermis and adnexal epithelium. Merkel cells are unrecognizable in conventional microscopical sections, but are avidly labeled in low density by CK20-staining of normal skin. Several investigators have also documented that CK20 staining also labels scattered Merkel cells that "colonize" trichoepithelioma and trichoblastoma, while basal cell carcinomas (and other adnexal carcinomas) generally lack these colonizing cells. The follicular germinative cells of the underlying trichoblastoma completely lack CK20 immunoreactivity, but scattered CK20-positive cells can be found throughout the proliferation. CK20 labeling of colonizing Merkel cells is perhaps most useful in the recognition of desmoplastic trichoepithelioma. Desmoplastic trichoepitheliomas pose difficulties in diagnosis because they are composed of thin strands of basaloid cells, a configuration shared by infiltrative or morpheaform basal cell carcinoma. Scattered CK20-positive cells are common in desmoplastic trichoepithelioma, but are generally absent from the basaloid strands of desmoplastic (morpheaform) basal cell carcinoma. Importantly, microcystic adnexal carcinoma has been evaluated and has been found to lack colonizing Merkel cells as well. It seems that the affinity of the Merkel cells is for follicular germinative differentiation, which is generally lacking in MAC. Since desmoplastic trichoepithelioma and basal cell carcinoma represent a diagnostic continuum, it seems likely that CK20 staining does not fully separate benignancy from malignancy, but rather corresponds to the degree of differentiation of a given case. Thus, desmoplastic trichoepitheliomas contain many colonizing Merkel cells because they are well-differentiated lesions with pronounced follicular germinative differentiation, while basal cell carcinomas contain few because they are poorly differentiated (and show less pronounced germinative features). If one evaluates a basal cell carcinoma with pronounced follicular germinative differentiation, then one might expect to find many colonizing Merkel cells. We have limited proof that this is the case, as most examples of fibroepithelioma of Pinkus contain many colonizing Merkel cells. Is a Pinkus tumor a basal cell carcinoma or a trichoblastoma? I consider it the former, but the issue remains in some debate.

Adnexal Neoplasms with Conspicuous Clear Cell Change
Clear cell change is a relatively routine incidental finding in adnexal neoplasms, especially those with glandular differentiation. Clear cell change may also be found as a specific indicator (jointly with other attributres) of follicular outer sheath (trichilemmal) differentiation. Commonly, pale cells are a consequence of glycogen accumulation, which can be proved by histochemical staining with PAS, with and without diastase. Clear cell alteration may also be a consequence of intracellular degeneration; this is especially true of basal cell carcinomas. It is important not to lump clear cell change with sebaceous differentiation, which is discussed in the section below. Mature sebocytes are of course cells with clear or pale cytoplasm, but are distinguishable because of coarse vacuolization.

Our "clear cell" differential is broad, including lesions of disparate lineage:

Syringoma with clear cell change. Marked clear cell change is not uncommon in syringoma; in some instances, ductal differentiation may seem inconspicuous in the face of collections of cells with ample pale cytoplasm, which resemble nests. It has been suggested that clear cell change may be an indicator of diabetes mellitus, although it has been my experience that this finding has little or no predictive value. Syringomatous carcinoma and microcystic adnexal carcinoma. As discussed in a prior section, syringomatous and microcystic adnexal carcinomas are closely related lesions; the former can be thought of as MAC with exclusively ductular differentiation, in contrast to the follicular and ductular differentiation that typifies conventional MAC. Clear cell change may occur in either the follicular or ductular component of MAC. Follicular clear cells probably represent outer sheath (trichilemmal) differentiation. Ductular clear cells are a consequence of glycogen accumulation, much like the clear cells in poroid and hidradenoid lesions. Poroma and porocarcinoma with clear cell change. Clear cells are common in association with poroid differentiation. The diagnostic approach to such lesions is otherwise identical to that employed for conventional poroma and porocarcinoma. Hidradenoma and hidradenocarcinoma with clear cell change. Pale cells are especially common in "hidradenoid" lesions, whether benign or malignant. Renal cell carcinoma. Obviously, renal carcinoma is not an adnexal lesion. However, it is an important consideration in the differential of adnexal lesions, including those with clear cell change and those of sebaceous lineage. There is overlap in both conventional microscopical and immunoperoxidase findings. Typically, metastatic renal carcinoma shows only modest cytological atypicality, contributing to the overlap with benign lesions. Commonly, increased vascularity and subtle evidence of necrosis (either of single cells or en masse) are the best clues to malignancy. Immunophenotypically, renal carcinoma expresses both EMA and CD10, a combination that is also typical of sebaceous lesions. EMA expression is of course a relatively non-specific finding that can be observed in a wide spectrum of glandular lesions, including neoplasms with sebaceous differentiation, as well as the spectrum of poroma and hidradenoma. Trichilemmoma and trichilemmal carcinoma. As noted above, clear cell change is a specific attribute of trichilemmal (outer sheath) differentiation, occurring in combination with slight peripheral palisading and a surrounding thickened basement membrane. Most trichilemmomas have a lobular or verrucous pattern, but a "desmoplastic" variant that can closely simulate carcinoma has also been described. Trichilemmal carcinoma is a bit of a theoretical entity. Many authorities (including this author) believe it exists, yet it may be unrecognizable because of extensive overlap with clear-cell squamous-cell carcinoma. Basal cell carcinoma with clear cell change. In contrast to the entities above, basal cell carcinoma shows clear cell change due to degenerative influences, rather than intracellular glycogen accumulation. In most instances, clear cell change is only focal, and thus a traditional approach to the diagnosis can be employed. In lesions with extensive clear cell change, the pattern may resemble some other type of clear cell carcinoma, or perhaps a benign adnexal neoplasm with clear cell change.

Adnexal Neoplasms with Small Collections of Sebocytes
Sebaceous differentiation can manifest with seboblastic or sebocytic differentiation. Typically, both are present in varying proportions in a given sebaceous neoplasm. Seboblastic cells generally cannot be specifically identified as sebaceous via conventional microscopy. Much like any "blastic" cell type, seboblasts are relatively undifferentiated cells and thus are not microscopically distinctive. For example, a sebaceous adenoma composed wholly of seboblastic cells closely resembles a trichoblastoma composed mostly of follicular germinative (trichoblastic) cells. In contrast, sebocytic cells are obviously sebaceous in nature, at least most of the time (rare other cells, including the cells of a balloon-cell nevus, may pose as look-a-likes). Sebocytes are of course recognizable as cells with coarsely vacuolated cytoplasm and scalloped nuclei.

It would seem that if one identifies small clusters of sebocytes within a given neoplasm, then the lesion is of sebaceous lineage. However, this view is overly simplistic, in light of the commonness of "hybrids" or lesions with "divergent" differentiation within the spectrum of folliculosebaceous-apocrine neoplasms. For example, a basal cell carcinoma with focal sebaceous differentiation is not a sebaceous neoplasm. Rather, if is more appropriately designated a follicular (trichoblastic) neoplasm, or a folliculosebaceous neoplasm. In short, a variety of adnexal proliferations may display focal sebocytic differentiation, and the identification of this light microscopical finding calls to mind a broad differential diagnosis that includes follicular, sebaceous, and even apocrine neoplasms.

Our "sebocytic" differential diagnosis is quite broad, covering the full spectrum of adnexal neoplasia:

1. Basaloid sebaceous adenoma (sebaceoma). Most sebaceous adenomas show a predominance of sebocytic differentiation, but some show only focal sebocytic differentiation, with a predominance of seboblastic differentiation that can be overwhelming. Such lesions can be difficult to distinguish from sebaceous carcinoma or basal cell carcinoma and have been commonly categorized under the rubric of "sebaceous epithelioma", a term referring to a poorly-defined disease category that should probably be abandoned. Recognizing this difficulty, Troy and Ackerman forwarded the term "sebaceoma" as an alternative. While I have no strong opposition to this designation, it seems somewhat arbitrary (and meaningless) to subdivide sebaceous adenomas based upon the proportion of seboblastic cells. Thus, I generally refer to all benign sebaceous neoplasms as sebaceous adenomas, irrespective of the proportion of seboblastic cells that are present. Histopathologically, basaloid sebaceous adenomas are nodular and well circumscribed lesions disposed in either the dermis or subcutis. Small foci of sebocytes with pale vacuolated cytoplasm can be found punctuating a background of basaloid cells. In contrast to trichoblastoma or basal cell carcinoma, very little stroma is usually apparent.
   
   
2. Sebaceous carcinoma. Many sebaceous carcinomas show relatively obvious sebaceous differentiation, with broad zones in which atypical sebocytes are apparent. However, much like sebaceous adenoma, a predominance of seboblastic (in this case, atypical seboblastic) cells may be encountered on occasion. Sebaceous carcinoma can of course be distinguished from its benign counterpart based upon architectural and cytological attributes, including circumscription, as well as the presence of necrosis, cytological atypicality, and/or mitotic figures.
   
   
3. Basal cell carcinoma with focal sebaceous differentiation. Basal cell carcinoma is a lesion of follicular germinative (trichoblastic) lineage that can show considerable cytological and architectural variation. At times, focal clear cell change can be encountered, and small collections of mature sebocytes may also be found. The presence of sebaceous differentiation within a follicular lesion is not surprising. It is an expected variation within the spectrum of folliculosebaceous-apocrine differentiation.
   
   
4. Trichoblastoma and desmoplastic trichoblastoma with focal sebaceous differentiation. Small collections of sebocytes can be found within an otherwise conventional trichoblastoma not uncommonly. As discussed in the paragraph above, this is an expected variation within the broad spectrum of folliculosebaceous-apocrine differentiation. The differential diagnosis of a trichoblastoma with sebaceous differentiation includes sebaceous adenoma/sebaceoma. Usually the distinction can be made based upon the fibrocytic stroma that characteristically envelops a trichoblastoma, as well as the presence of mature follicular differentiation (such as the presence of so-called papillary mesenchymal bodies, a neoplastic caricature of the follicular bulb and papilla).
   
   
5. Miscellaneous follicular neoplasms with focal sebaceous differentiation. Collections of sebocytes can be found in any of a variety of follicular lesions, including trichilemmoma, tumor of follicular infundibulum, proliferating follicular-cystic neoplasm, and microcystic adnexal carcinoma. In all of these entities, the presence of sebaceous differentiation is an expected attribute of folliculosebaceous or folliculosebaceous-apocrine differentiation.
   
   
6. Miscellaneous glandular adnexal neoplasms with focal sebaceous differentiation. Small collections of mature sebocytes can be found within a variety of glandular adnexal neoplasms/proliferations, including poroma and porocarcinoma, hidradenoma and hidradenocarcinoma, mixed tumor (chondroid syringoma), and microcystic adnexal carcinoma. In all instances, the glandular lesion at hand is presumably of apocrine lineage (with sebaceous and apocrine attributes of a lesion that is fundamentally of folliculosebaceous-apocrine lineage). For example, poroma with sebaceous differentiation is not likely to be of eccrine lineage. Rather, logic suggests that "sebaceous" poroma is actually "folliculosebaceous-apocrine" poroma. Similarly, MAC is not a carcinoma with "mixed" follicular and eccrine differentiation. Rather, MAC is commonly a carcinoma with follicular and apocrine ductular differentiation, and sometimes a carcinoma with follicular, sebaceous, and apocrine differentiation.

References

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2. McNiff JM, Eisen RN, Glusac EJ. Immunohistochemical comparison of cutaneous lymphadenoma, trichoblastoma, and basal cell carcinoma: support for classification of lymphadenoma as a variant of trichoblastoma. J Cutan Pathol. 1999; 26(3):119-24.
   
   
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6. Avery AK, Beckstead J, Renshaw AA, Corless CL. Use of antibodies to RCC and CD10 in the differential diagnosis of renal neoplasms. Am J Surg Pathol. 2000 Feb;24(2):203-10.
   
   
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8. Hunt SJ, Kilzer B, Santa Cruz DJ. Desmoplastic trichilemmoma: histologic variant resembling invasive carcinoma. J Cutan Pathol. 1990 Feb;17(1):45-52.
   
   
9. Oliver GF, Winkelmann RK. Clear-cell, basal cell carcinoma: histopathological, histochemical, and electron microscopic findings. J Cutan Pathol. 1988 Dec;15(6):404-8.