Folliculosebaceous Proliferations Timothy McCalmont, MD University of California, San Francisco

For decades, conclusions regarding differentiation and lineage and classification of adnexal neoplasms have been largely based upon observations of unknown specificity and questionable reliability, largely performed by dermatopathologists who are retired or dead. And once classification schemes based upon questionable techniques became entrenched, much like "chart lore", they have show surprising durability. Rather than trusting the embryological and clinical milieu in which adnexal neoplasms arise (in essence, rather than trusting the patient), dermatopathologists have been inclined to blindly accept what they learned in their training as "truth". They told me that poroma is eccrine poroma, so I'll stick with that. They told me that spiradenoma is eccrine spiradenoma, so I won't challenge that. Unfortunately, this leads to a lot of reporting (and a lot of chapter writing) that doesn't make much sense. As an example, consider a simple notion: why don't some neoplasms of purported eccrine lineage, such as spiradenoma, ever occur on the palm or sole? If spiradenoma is truly eccrine in nature, as many have claimed, why would it fail to exist in the eccrine heartland? And while this is perhaps a small issue compared to world hunger or the importance of proper staging of melanoma, why doesn't this type of inconsistency bother more of us? This author has suggested several factors that might guide our thinking regarding the classification of adnexal neoplasms: embryological relationships; neoplastic combinations; neoplastic associations (usually in the context of a genetic disorder); anatomic distribution; and light microscopic, histochemical, immunohistochemical, and ultrastructural findings. 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! "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. 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. 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! Microscopy and special stains. Microscopy. The significance of some cytological findings is indisputable. Cells with coarsely vacuolated cytoplasm and scalloped nuclei are unequivocally indicative 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. For the purposes of today's session and the cases reviewed today, things will be simpler and more straightforward because the cases presented by this author are of follicular and sebaceous (or folliculosebaceous) lineage, a combination that can be clearly recognized by conventional microscopy. Within the spectrum of traditional or entrenched follicular categories, lesions are generally separated into those with germinative differentiation (the trichoblastic group), and a hodge-podge of other lesions. Within the spectrum of sebaceous lesions, lesions are generally categorized into adenoma and carcinoma, with few other layers of categorization. Because of the small number of cases presented in this session, no effort will be made to clearly present a comprehensive overall classification scheme. For additional information in this regard, the reader should refer to the references. Case 1-1 - Reticulate Acanthoma with Sebaceous Differentiation Reticulate acanthoma with sebaceous differentiation is an uncommon benign adnexal proliferation that was probably first described under the designation "superficial epithelioma with sebaceous differentiation", and similar cases have been characterized under designations such as "sebocrine adenoma", "poroma with sebaceous differentiation", and "seborrheic keratosis with sebaceous differentiation". The entity is a rarity. Lesions are acquired and develop on the trunk or extremity in adulthood. There is no established association with Muir-Torre syndrome. Clinical history: 69 year old man, renal transplant, with a one year history of a 2.5 cm ulcerated sessile tumor on the left buttock, excised. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Histopathological features: Papillated epidermal hyperplasia across a broad front, with collections of sebocytes that emanate from the epidermal undersurface or are incorporated within surface epithelium Interanastomosis of elongated rete Foci of ductal differentiation, presumably sebaceous, resembling poroma Differential diagnosis: Nevus sebaceus typically is limited to the head and neck area, and differs in that follicular (especially follicular germinative) differentiation is usually conspicuous Sebaceous epithelioma is a diagnosis that should be eschewed, as it is used by some to convey benign sebaceous lesions and by others to convey low-grade carcinoma In poroma with sebaceous differentiation, the predominant mode of differentiation is "poroid" (distal ductular), accompanied by subtle foci of sebaceous differentiation Case 1-2 - Adamantinoid Trichoblastoma Trichoblastoma represents a broad and heterogeneous category of benign adnexal proliferations with follicular germinative differentiation. Trichoblastoma is the benign analogue of basal cell carcinoma, an entity that is probably more appropriately thought of as trichoblastic carcinoma. Most commonly, trichoblastoma presents with a large nodular or small nodular pattern. However, many other types of trichoblastoma can also be defined, depending upon the stringency of one's definition. Conventional trichoepithelioma represents a trichoblastoma with concomitant superficial follicular differentiation in the form of small cornifying cysts. Desmoplastic trichoepithelioma represents a trichoblastoma with a strand-like distribution of follicular germinative cells and enveloping sclerosis. Trichoblastic fibroma represents a trichoblastoma with exaggerated fibrocytic stroma, creating a hamartoma-like configuration. And adamantinoid trichoblastoma represents a variant with microscopical resemblance to the dental tumor adamantinoma. Adamantinoid trichoblastoma was first described under the designation cutaneous lymphadenoma, a misnomer that aptly characterizes the infiltrate that is associated with this entity, but falsely gives the impression of a lesion of glandular lineage. Clinical history: 53 year old woman with lesion of the right eyebrow. Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Histopathological features: A largely dermal array of small, closely juxtaposed basaloid aggregations, some with angular outlines, generally with at least partial overall circumscription Central pallor within basaloid aggregations, often Surrounding desmoplasia/sclerosis An associated lymphohistiocytic infiltrate, arrayed both within the collections of basaloid cells and also within the sclerotic stroma that envelops them Differential diagnosis: Basal cell carcinoma is composed of similar basaloid aggregations, but differs in that the enveloping stroma is generally fibromyxoid rather than sclerotic. An associated lymphohistiocytic infiltrate is common in either entity, but the finding of lymphocytes and histiocytes positioned centrally within basaloid aggregations is relatively distinctive and is only rarely found in association with basal cell carcinoma. Lymphoepithelioma-like carcinoma of the skin represents an uncommon poorly-differentiated cutaneous carcinoma that probably represents poorly-differentiated squamous cell carcinoma. The possibility that LELCS represents a type of adnexal carcinoma has also been suggested. LELCS shows poor circumscription and deep extension, and thus is generally separable from adamantinoid trichoblastoma based upon assessment of architectural features. Case 1-3 - Desmoplastic Trichlemmoma, Arising in Nevus Sebaceus Trichilemmoma represents a common benign cutaneous neoplasm with follicular outer sheath differentiation, typified by lobules of pale keratinocytes disposed in a juxtaepidermal distribution. Although some authorities have alleged that trichilemmoma is merely a verruca rather than an authentic neoplasm, there is little dispute that such lesions are benign and the diagnosis is typically not challenging. In contrast, desmoplastic trichilemmoma represents a variant in which angular collections of benign outer sheath cells are enmeshed in sclerosis, a peculiar pattern that is commonly misconstrued as carcinoma, particularly by the uninitiated or in the assessment of superficial partial biopsies. It is well-documented that a variety of adnexal proliferations, generally those of folliculosebaceous or apocrine lineage, can occur secondarily within nevus sebaceus, which represents a hamartoma of folliculosebaceous-apocrine lineage. Historically, it has been suggested that syringocystadenoma is the most common secondary proliferation, although recent data indicates that secondary trichoblastoma is actually more common. Desmoplastic trichilemmoma represents a common secondary event in this milieu, as occurred in this case. Clinical history: 28 year old woman with questionable intradermal melanocytic nevus versus nevus sebaceus. Slide 3 Click to view with ImageScope Click to view with a Web-Based Viewer Histopathological features: A perijunctional array of small pale angular keratinocytes, generally with at least partial overall circumscription Superjacent verrucous epithelial hyperplasia and hyperkeratosis, commonly Enveloping sclerosis Focally thickened basement membrane (with PAS-D positivity), often When in association with nevus sebaceus, one may also observe characteristic changes such as papillomatosis of the surface epithelium, perijunctional collections of trichoblastic cells, enlarged perijunctional sebaceous glands, and "ectopic" apocrine glands Differential diagnosis: Infiltrative basal cell carcinoma is composed of similar aggregations, usually composed of compact basaloid rather than outer sheath cells, and generally the associated stroma is fibromyxoid rather than sclerotic, at least in part. Infiltrative squamous cell carcinoma is composed of similar aggregations but typically shows a convincing degree of cytological atypism, as well as clear evidence of cytoplasmic keratinization. In a biopsy of appropriate size, the lack of circumscription of a carcinoma can be recognized and conversely the relative circumscription of a trichilemmoma can be substantiated. References: Kato N, Ueno H. Superficial epithelioma with sebaceous differentiation. J Dermatol. 1992 Mar;19(3):190-4. Rothko K, Farmer ER, Zeligman I. Superficial epithelioma with sebaceous differentiation. Arch Dermatol. 1980 Mar;116(3):329-31. Kamiya H, Oyama Z, Kitajima Y. "Apocrine" poroma: review of the literature and case report. J Cutan Pathol. 2001 Feb;28(2):101-4. Akasaka T, Imamura Y, Tomichi N, Kon S. A case of superficial epithelioma with sebaceous differentiation. J Dermatol. 1994 Apr;21(4):264-7. Harvell JD, Kerschmann RL, LeBoit PE. Eccrine or apocrine poroma? Six poromas with divergent adnexal differentiation. Am J Dermatopathol. 1996 Feb;18(1):1-9. 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 Mar;26(3):119-24. Diaz-Cascajo C, Borghi S, Rey-Lopez A, Carretero-Hernandez G. Cutaneous lymphadenoma. A peculiar variant of nodular trichoblastoma. Am J Dermatopathol. 1996 Apr;18(2):186-91. Santa Cruz DJ, Barr RJ, Headington JT. Cutaneous lymphadenoma. Am J Surg Pathol. 1991 Feb;15(2):101-10. Roson E, Gomez Centeno P, Sanchez-Aguilar D, Peteiro C, Toribio J. Desmoplastic trichilemmoma arising within a nevus sebaceus. Am J Dermatopathol. 1998 Oct;20(5):495-7. Hunt SJ, Kilzer B, Santa Cruz DJ. Desmoplastic trichilemmoma: histologic variant resembling invasive carcinoma. J Cutan Pathol. 1990 Feb;17(1):45-52.