Contributed by Oscar F. Lopez Nunez, MD; Jennifer Picarsic, MD.FINAL DIAGNOSIS
Eccrine Spiradenoma
DISCUSSION
The histologic sections show a well circumscribed, thinly encapsulated, multilobulated basaloid nodule in the deep dermis, unattached to the dermis, composed of oval cells with dispersed chromatin and inconspicuous nucleoli. The cells show a variable palisading pattern around globules of dense eosinophilic basement membrane material. There is evidence of sweat duct differentiation, including a few cystically dilated ducts lined by low cuboidal cells with luminal frothy "sweat" secretions. There are numerous small lymphocytes throughout the specimen. A distinct subcapsular sinus is not appreciated. There are occasional mitotic figures but no significant nuclear pleomorphic or atypia is noted. No Hassall's corpuscles are identified. The larger oval cells are variably reactive for cytokeratins with a lace-like pattern whereas the p63 immunostain highlights the majority of cells. Scattered aggregates of CD1a positive spindled Langerhans cells are noted. The TdT is predominately negative. The lymphoid population shows few scattered CD20 positive B-cells but with more numerous intervening CD3 and CD5 positive T-cells. The synaptophysin, CD31, and EBER probe were negative.
This case represents a spiradenoma, which is a benign adnexal tumor occasionally seen in young patients as an often painful cutaneous lesion. Microscopically, it is arranged as an intradermal nodule or group of basophilic nodules, often pushing down into the subcutis. These lesions are often composed of groups of "blue cells" in a trabecular arrangement with variable cords, islands, or sheets. The individual groups of tumor cells are composed of two epithelial cell types: small, dark, basaloid cells with hyperchromatic nuclei (recapitulating the basal/myoepithelial cell layer) and larger cells with pale, vesicular, and ovoid nuclei (recapitulating apical/inner lining layer) more in center of islands. Both cell types have very little cytoplasm, thus giving a "blue cell" appearance. In pediatric cases, especially in infancy, the two cell types may be more difficult to discern without a clear distinction between dark and pale cells, as compared to adult cases. These lesions are peppered with lymphocytes and reactive Langerhans cells. A helpful diagnostic clue in spiradenoma are the little globules of dense pink basement membrane material made up of type IV collagen, which is present throughout the lesion and can be highlighted by a PAS stain. Often one can recognize sweat duct differentiation by spotting small ducts with a low-cuboidal lining. Sometimes the ducts will be cystically dilated with intraluminal pink frothy secretions (i.e. sweat) or there may only be tiny holes and an inner pink cuticle layer rimming the luminal margin, recapitulating a small sweat duct. Mitotic figures are rare in spiradenomas , and their presence, along with central necrosis and other atypical features, should be concerning for malignant transformation.
Of the other skin adnexal tumors, hidradenoma will have more prominent cystic dilated spaces. Trichoepitheliomas share the same basaloid appearance; however, they usually show characteristic papillary mesenchymal bodies and lack the biphasic cell population seen in spiradenomas, albeit more commonly seen in adult type spiradenomas. Cylindroma is a closely related lesion to spiradenoma and is diagnostically differentiated based on its low power appearance displaying larger islands of basophilic cells with a more prominent pink layer of basement membrane material separating or outlining each individual nest. This architectural pattern resembles the so-called "jigsaw puzzle" pattern. They also show a biphasic cell population, with cylindromas having more prominent globules of pink basement membrane around individual cells and have less infiltrating lymphocytes compared to spiradenoma, although histologic overlap in a single lesion can be seen.
Occasionally, morphologic features of both spiradenomas and cylindromas can be identified within the same tumor (spiradenocylindromas), suggesting that they represent two ends of the same spectrum. This is particularly prominent in patients with Brooke-Spiegler syndrome (BSS), an uncommon autosomal dominant entity characterized by the presence of multiple spiradenomas, cylindromas, and trichoepitheliomas. The BSS is related to mutations in the CYLD gene, which normally acts as a tumor suppressor gene. The histogenesis of spiradenomas remains in question, but many lesions demonstrate apocrine differentiation. Thus the term "eccrine" spiradenoma may join the list of other misnomers in dermatology. The WHO classification of these benign adnexal tumors is simply as spiradenoma. Immunohistochemistry is not necessary for the diagnosis of spiradenoma, but a pancytokeratin will highlight the epithelial cells; p63 will stain the basaloid/myoepithelial cells. The non-epithelial cells infiltrating the stroma, including numerous T-lymphocytes, can be highlighted by CD3, while a CD1a will stain scattered reactive Langerhans cells. Claudin-4 has been recently noted to have a distinctive staining pattern in the ductal-type cells of spiradenomas as compared to other adnexal tumors.
Spiradenomas rarely (< 1%) occur in infancy and differ from the conventional spiradenomas by the presence of superficial dermal nodules. The nodules display a less distinct two-cell pattern of immature adnexal epithelial cells. Ductule formation is rare. In infants and young adults, these tumors may be mistaken for mesenchymal neoplasms involving the skin and the subcutis. Clinically, spiradenomas can also mimic other painful tumors, in particular angiolipomas. Spiradenomas are highly basophilic lesions, a feature that combined with an extensive lymphoid population prompts consideration of a lymphoproliferative disorder, thymoma, or even ectopic thymic tissue; as they can also present as solitary nodules in the neck region. A reactive lymph node and a lymphoproliferative lesion can be ruled out given the absence of a distinct capsular sinus and the presence of scattered polytypic lymphocytes, respectively. The architectural similarities between spiradenomas and thymomas can be dispelled by the demonstration of sweat duct differentiation and globules of basement membrane formation, along with presence of mature CD3 positive, CD5 positive and TdT negative lymphocytes. These same features, along with the absence of Hassall's corpuscles, also dismiss the possibility of an ectopic thymic tissue. In children, the epithelial neoplastic cells of spiradenoma may appear more immature without a clear distinction between dark and pale cells, such as in this case, making the distinction from other more primitive mesenchymal neoplasms also challenging on morphology alone. The variable palisading pattern around globules of dense eosinophilic PAS positive basement membrane material is a helpful diagnostic clue to the diagnosis. A basal cell carcinoma can be ruled out given the lack of cytologic atypia, retraction, mitotic figures, mucinous stroma, and attachment to the epidermis. The histologic distinction between Merkel cell carcinoma (MCC) and primary adnexal tumors with basaloid morphology can be challenging, especially in small biopsies. MCC is, however, typically seen in older adults, lacks the classic biphasic cell population seen in spiradenomas, shows more cytologic atypia, and it should be positive for cytokeratin 20 (paranuclear dot-like pattern) and neuroendocrine markers.
Ectopic thymic tissue, ectopic cervical thymoma, and T-lymphoblastic lymphoma (T-LBL), can show immunophenotypic overlap even when flow cytometry is performed, including expression of common T-cell antigens and terminal deoxynucleotidyl transferase (TDT). In such a scenario, careful morphologic assessment for thymic histologic features or aberrant marker expression characteristic of T-LBL is extremely important. Finally, recent evidence demonstrated that MCC has been associated with the Merkel cell polyomavirus infection in susceptible individuals inducing the expression of viral antigens by T-lymphocytes and leading to disruption of regulatory proteins such as Rb and p53, among others.
In conclusion, spiradenomas are primary benign adnexal tumors with an excellent prognosis that can be easily confused with lymphoproliferative disorders, thymic tissue, thymic neoplasms, and other primary basaloid skin tumors. In children, especially in infants, the epithelial neoplastic cells may appear more immature without a clear distinction between dark and pale cells, such as in this case, making the distinction from other more primitive mesenchymal neoplasms also challenging. The variable palisading pattern around globules of dense eosinophilic basement membrane material and demonstration of sweat duct differentiation are also helpful clues to the diagnosis.
REFERENCES
Contributed by Oscar F. Lopez Nunez, MD; Jennifer Picarsic, MD.
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