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Home , Sebaceoma, Sebaceous adenoma, Sebaceous carcinoma, Spiradenoma

ORIGINAL ARTICLE

Cutaneous Sebaceous With a Focal Glandular Pattern (Seboapocrine Lesions): A Clinicopathological Study of Three Cases Dmitry V. Kazakov, MD, PhD,* Eduardo Calonje, MD,† Dip RCPath, Arno Ru¨tten, MD,‡ Kathrin Glatz, MD,§ and Michal Michal, MD*

sebaceous differentiation and different architectural and Abstract: Presented here are three cutaneous sebaceous tumors cytological features, usually allowing clear histopathological (one carcinoma and two ), each demonstrating a focal separation, although some histopathological overlap exists. glandular pattern representing apocrine differentiation. The patients, The tumor cells in these sebaceous neoplasms grow mainly in two males and one female, each clinically presented with a small a cohesive fashion, although rare tumors manifest distinctive solitary or tumor on the scalp. None of the patients had growth patterns such as the rippled, labyrinthine/sinusoidal, features of Muir–Torre syndrome. Surgical removal of the lesions was and carcinoid-like ones that are apparently specific for lesions performed in all cases. None of the patients developed recurrence or with sebaceous differentiation and are encountered either sin- after (follow-up ranged from 18 to 24 months). gly or in combination in cutaneous tumors with sebaceous The glandular areas represented a minor but significant component of differentiation.2–6 So-called adenoid and acinar patterns have the lesions and appeared as of various complexity, mostly as been recorded in some examples of ocular sebaceus carcinoma,7 simple round or elongated tubular structures lined by a row of and rare sebaceous neoplasms have been reported to focally cuboidal to columnar cells with eosinophilic cytoplasm and round exhibit apocrine differentiation.8,9 Presented here are three nuclei, with or without a distinct nucleolus. Decapitation secretion further cutaneous sebaceous tumors with a focal glandular was evident but not prominent. In both sebaceomas, at least a portion pattern representing apocrine differentiation. of the glands had a peripheral small-cell layer that appeared similar to the basal/myoepithelial cells of normal eccrine and apocrine ducts. In some glands, the basal/myoepithelial cells seemed to have undergone hyperplasia, resulting in two or more rows of cells that even formed MATERIALS AND METHODS small islands, with an overall appearance reminiscent of basal cell Histological slides from approximately 200 malignant hyperplasia in the prostate, arising in the basal layer of the prostatic and benign cutaneous sebaceous tumors (ocular and extra- glands. The descriptive terms seboapocrine carcinoma or seboapo- ocular carcinomas, sebaceomas, sebaceous , basal crine are proposed for such lesions. These tumors may be cell carcinoma with sebaceous differentiation, cystic seba- ceous tumor10), including those associated with the Muir– viewed as rare histopathological variants of and 11 sebaceoma, with a second type of differentiation along the lines of the Torre syndrome, were evaluated. Cases of organoid nevus folliculosebaceous–apocrine unit. (nevus sebaceus of Jadassohn) and secondary tumors arising in it were not studied and, when recognized histologically as Key Words: adnexal tumors, sebaceous neoplasms, apocrine such, were excluded. Eight sebaceous tumors manifesting differentiation, multidirectional differentiation, myoepithelial cells a glandular pattern were found. The term glandular is used to (Am J Dermatopathol 2007;29:359–364) describe structures containing lumina surrounded by epithelial cells, with or without evidence of decapitation secretion. Multiple sections were reviewed to exclude the possibility that these glandular areas might represent preexisting ducts or ebaceous tumors of the are most commonly classified represent a pseudoglandular pattern attributable to various Sinto carcinoma (ocular and extraocular), sebaceoma, and causes (holocrine secretion, cell discohesive arrangement 1 sebaceous . These show different degrees of attributable to necrosis, acantholysis, or myxoid degeneration), as was the case in five tumors that were subsequently excluded from the study. Clinical information and follow-up on the three From the *Sikl’s Department of Pathology, Charles University, Medical included cases were obtained from pathology reports, sub- Faculty Hospital, Pilsen, Czech Republic (D.V.K.,M.M.); †Department of Dermatopathology, St John’s Institute of , St Thomas’s mitting pathologists, patients, and their clinicians. Hospital, London, England, UK (E.C.); ‡Dermatohistopathologische Paraffin blocks or reserved unstained slides were Gemeinschaftspraxis, Friedrichshafen, Germany (A.R.); and §Institute of available in two cases for immunohistochemical study. Pathology, University of Basel, Basel, Switzerland (K.G.). Immunohistochemical stains were performed on 5-mM-thick, Reprints: Dmitry V. Kazakov, MD, PhD, Sikl’s Department of Pathology, Charles University Medical Faculty Hospital, Alej Svobody 80, 304 60 formalin-fixed, paraffin-embedded tissue sections, and appro- PILSEN, Czech Republic (e-mail: [email protected]). priate controls were applied using the monoclonal and poly- Copyright Ó 2007 by Lippincott Williams & Wilkins clonal antisera listed in Table 1. The avidin–biotin complex or

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complexity, mostly as simple round or elongated tubular TABLE 1. Antibodies Used for Immunohistochemical Study structures lined by rows of cuboidal to columnar cells with Antibody Specificity Clone Dilution Source eosinophilic cytoplasm and round nuclei, with or without a CK7 OV-TL 12/30 1:200 DakoCytomation distinct nucleolus (Fig. 1E and F and Fig. 2D–F). Decapitation CK 14 Ll002 1:1000 NeoMarkers secretion was evident but not prominent (Fig. 2E). In one EMA E29 1:700 DakoCytomation sebaceoma (case 3), the cytoplasm of the luminal cells in CK 8 &18 CAM5.2 1:200 Becton Dickinson glandular structures contained zymogen granules (Fig. 2F). ASMA 1A4 1:200 DakoCytomation In both sebaceomas, at least a portion of the glands had a MSA HHF-35 1:5000 DakoCytomation peripheral small-cell layer that seemed similar to the basal/ GCDFP-15 BRST-2 1:1000 Signet Laboratories myoepithelial cells of normal eccrine and apocrine ducts. The p63 4A4 1:500 Biotex structures were numerous and were distributed some- CK, cytokeratin; EMA, epithelial membrane antigen; ASMA, a-smooth muscle what haphazardly. In some glands, the basal/myoepithelial actin; MSA, muscle-specific actin; GCDFP-15, gross cystic disease fluid protein-15. cells seemed to have undergone hyperplasia, resulting in two or more rows of cells that even formed small islands, with an overall appearance reminiscent of basal cell hyperplasia in streptavidin–biotin complex, labeled with peroxidase or the prostate, arising in the basal layer of the prostatic glands. alkaline phosphatase, were employed as the detection systems. (Fig. 2G). Glands with basal/myoepithelilal cells and those Automated immunostaining employing the Lab Vision lacking them were intermingled. automatic stainer was used. In one sebaceoma (case 2), there were foci of immature squamous metaplasia and areas composed of basaloid cells, devoid of sebaceous differentiation, that housed scattered RESULTS lymphocytes, with the resulting picture vaguely resembling a . In both sebaceomas, differentiation toward Clinical Data sebaceous ducts was seen. No other metaplastic phenomena or The patients, two males and one female, each clinically adnexal-type differentiations were observed, nor were there presented with a small solitary nodule or tumor on the scalp any recognizable microscopic features of nevus sebaceus of (Table 2). Ulceration was seen in case 1, which represented Jadassohn. sebaceous carcinoma. None of the patients had features of Muir–Torre syndrome. Surgical removal of the lesions was Immunohistochemical Findings performed in all cases. None of the patients developed Immunohistochemical studies were performed on the recurrence or metastasis after surgery (follow-up ranged from sebaceomas. The glandular areas were positive for CAM5.2 18 to 24 months). and CK7 (Fig. 2H). Stains for CK7 also highlighted sebocytes with multivacuolated cytoplasm, as did the stains for EMA Histopathological Findings (Fig. 2I). CK14 stained the entire tumors, including the One case was classified as sebaceous carcinoma because glandular parts and basaloid cells; GCDFP-15 was tested in of the presence of architectural (asymmetry, infiltrative case 3 and proved positive in the glandular luminal cells. The growth) and cytological atypia (cellular and nuclear pleomor- peripheral basal/myoepithelial-like cells in the glandular areas phism, cell necrosis, atypical mitoses; Fig. 1A–D). Two were positive for p63 in both cases; they tested negative for lesions were classified as sebaceomas (Fig. 2A–C). All three actins in case 3. neoplasms manifested a multinodular architecture and were predominantly composed of basaloid cells and cells with vacuolated cytoplasm and scalloped nuclei. The DISCUSSION cells grew mainly in a cohesive fashion, but in both seba- We have presented three sebaceous cutaneous neo- ceomas, labyrinthine/sinusoidal, poorly developed carcinoid- plasms with a focal glandular pattern. The detection of this like, and rippled patterns, as previously reported,2–4 were feature in an otherwise typical sebaceous tumor seems to have identified (Fig. 2B). no clinical or prognostic implication, but this microscopic The glandular areas represented a minor but significant finding may be confusing. Two of the presented cases were component of the lesions; they appeared as glands of various consultations, and the submitting pathologists specifically

TABLE 2. The Main Clinical Features of Patients With Seboapocrine Carcinoma (Case 1) and Seboapocrine Sebaceomas (Cases 2 and 3) Case Sex Age Location Clinical Presentation Size (cm) Treatment Follow-Up MTS Case 1 Female 76 Scalp Solitary tumor 3 3 1.7 Excision NED at 29 months No Case 2 Male 36 Scalp Solitary grey nodule. 1.2 3 0.8 Excision NED at 18 months No Atheroma? Fibroma? Case 3 Male 84 Scalp Solitary tumor. BCC? 1 3 0.8 Excision NED at 24 months No

NED, no evidence of disease; MTS, Muir–Torre syndrome; BCC, basal cell carcinoma.

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FIGURE 1. Sebaceous carcinoma. A and B, Asymmetric multinodular neoplasm with an infiltrative growth pattern. C and D, Cytological details: cohesive growth of cells with pleomorphic round nuclei and prominent nucleolus. The cytoplasm of some cells contained tiny vacuoles and a mature sebocyte can be seen in the center. Note atypical mitotic figures. E and F, A glandular structure with decapitation secretion. asked for the meaning of this feature and the precise Combined folliculosebaceous–apocrine differentiation is quite classification of the lesions. We suggest that the descriptive often seen in apocrine mixed tumors12,24–26 and nevus sebaceus terms seboapocrine carcinoma, seboapocrine sebaceoma,or of Jadassohn.27–31 In the classification of cutaneous adnexal sebaceous carcinoma (or sebaceoma) with focal apocrine neoplasms proposed by McCalmont,32 the lesions that are differentiation can be used in such situations. The term reported herein can be added to the apocrine–sebaceous seboapocrine sebaceoma should not be mistaken for the term category to join apocrine poroma33–37 and may be viewed as sebocrine adenoma, which has been used by Zaim8 to describe examples of adnexal tumors with divergent (multidirectional) two lesions that were regarded later as apocrine poroma. differentiation.32,38–40 Parenthetically, a sebaceoma in one of Conjoint apocrine, sebaceous and follicular differentiation in our patients manifested small areas resembling those seen a cutaneous appendageal tumor, is not an unexpected finding in a spiradenoma, the entity that some authorities now con- given the embryological derivation of the apocrine gland, sider an apocrine neoplasm.12,41 Evidence supporting this , and follicle from the common issue is provided by the reported cases of spiradenoma folliculosebaceous–apocrine unit.12–14 The simultaneous occur- associated with areas of sebaceous and/or follicular differen- rence of two or three types of differentiation along the lines of tiation in adnexal lesions or simultaneous occurrence of the folliculosebaceous–apocrine unit in cutaneous adnexal spiradenoma and other follicular, sebaceous, or apocrine tumors15–23 is not rare; it may, in fact, be underrecognized. neoplasms in patients with Brooke–Spiegler syndrome, or q 2007 Lippincott Williams & Wilkins 361 Kazakov et al Am J Dermatopathol Volume 29, Number 4, August 2007

FIGURE 2. Sebaceoma. A, Whole-mount view of the vertically oriented multinodular lesion. B, Labyrinth-like /sinusoidal pattern. C, Cytological detail: monomorphous basaloid cells admixed with mature sebocytes. D–G, Glandular areas. Numerous elongated tubules and small round lumens can be seen (D). Note rare vacuolated sebocytes in the adjacent areas (D, lower left). Glands of more complex architecture surrounded by a distinct peripheral basal/myoepithelial cell layer and decapitation secretion in the luminal cells (E). Zymogen granules in the luminal cells of the glands (F). In some glands, the basal/myoepithelial cell layer appears hyperplastic resulting in two or more rows of cells that even form small islands (G, arrows). This appearance can be linked to basal cell hyperplasia in the prostate. H and I, Immunohistochemical staining. The glandular structures are positive for CAM5.2, whereas the rest of the tumor reacted negatively (H). Both scattered sebocytes with vacuolated cytoplasm and glandular structures are positive for CK7 (I).

362 q 2007 Lippincott Williams & Wilkins Am J Dermatopathol Volume 29, Number 4, August 2007 Seboapocrine Skin Tumors folliculosebaceous–apocrine tumors manifesting spiradenom- if benign and sebaceous carcinoma if malignant]. Dermatopathol Pract atous areas.12,40,42–51 Conc. [serial online]. 2001;7:355–362. Available at: http://www.derm101. com/dynaweb/resources/dpc/130926/@Generic_BookTextView/130926; The glandular patterns described above should be dis- cs¼pr. Accessed October 2006. tinguished from a pseudoglandular pattern, in which the 4. Kazakov DV, Kutzner H, Rutten A, et al. Carcinoid-like pattern in formation of structures resembling glands is caused by the loss sebaceous neoplasms: another distinctive, previously unrecognized of integrity of solid epithelial structures attributable to cell pattern in extraocular sebaceous carcinoma and sebaceoma. Am J necrosis, acantholysis, or myxoid degeneration. Holocrine Dermatopathol. 2005;27:195–203. 5. Requena L, Barat A. Giant on the scalp. Am J secretion may sometimes impart a pseudoglandular appear- Dermatopathol. 1993;15:497–502. ance to a sebaceous tumor. Further, small aggregations of 6. Graham BS, Barr RJ. Rippled-pattern sebaceous trichoblastoma. J Cutan neoplastic sebaceous cells with vacuolated cytoplasm may Pathol. 2000;27:455–459. produce cleftlike spaces resembling tubules. Glandular 7. Ni C, Searl SS, Kuo PK, et al. Sebaceous cell carcinomas of the ocular adnexa. Int Ophthalmol Clin. 1982;22:23–61. patterns, especially simple, small, round, tubular ones, should 8. Zaim MT. Sebocrine adenoma. An adnexal adenoma with sebaceous and also be distinguished from preexisting adnexal structures that apocrine poroma-like differentiation. Am J Dermatopathol. 1988;10:311–318. became entrapped by the tumor. Clues to the latter situation 9. Okuda C, Ito M, Fujiwara H, et al. Sebaceous epithelioma with sweat include a small number of tubular elements in the lesion, the gland differentiation. Am J Dermatopathol. 1995;17:523–528. location of tubular/ductal structures near the preexisting hair 10. Rutten A, Burgdorf W, Hugel H, et al. Cystic sebaceous tumors as marker lesions for the Muir-Torre syndrome: a histopathologic and molecular follicle, or a traceable vertical arrangement suggesting involv- genetic study. Am J Dermatopathol. 1999;21:405–413. ed excretory ducts. The glands in both sebaceomas in our 11. Mathiak M, Rutten A, Mangold E, et al. Loss of DNA mismatch repair series were numerous—exceeding the number that one would proteins in skin tumors from patients with Muir-Torre syndrome and expect to see with the preexisting ducts—and were haphaz- MSH2 or MLH1 germline mutations: establishment of immunohisto- chemical analysis as a screening test. Am J Surg Pathol. 2002;26:338–343. ardly distributed. Still, we had the impression that the 12. Requena L, Kiryu H, Ackerman AB. Neoplasms with Apocrine neoplastic tubules may have indeed originated from the Differentiation. Philadelphia, Pa: Lippincott-Raven; 1998. preexisting ducts, because some glands were surrounded in 13. Ackerman AB, Reddy VB, Soyer HP. Neoplasms with Follicular part by a preserved basal/myoepithelial layer. On the other Differentiation. 2nd ed. New York,NY: Ardor Scribendi Publishers; 2001. hand, one cannot fully discard the fact that the ducts with 14. Requena L. Neoplasias Anexiales Cutaneas. Madrid, Spain: Aulo Medico Ediciones; 2004. basal/myoepithelial cells may represent newly formed neo- 15. Hanau D, Grosshans E, Laplanche G. A complex poroma-like adnexal plastic ducts. Three lines of evidence may indirectly support adenoma. Am J Dermatopathol. 1984;6:567–572. this preposition. First, the glands containing a peripheral 16. Sanchez Yus E, Requena L, Simon P, et al. Complex adnexal tumor of the basal/myoepithelial cell layer and those lacking it were primary epithelial germ with distinct patterns of superficial epithelioma with sebaceous differentiation, immature , and apocrine intermingled, as if they belonged to the same origin. Second, adenocarcinoma. Am J Dermatopathol. 1992;14:245–252. they showed decapitation secretion, which is normally seen 17. Boyd AS, Rapini RP. Cutaneous collision tumors. An analysis of 69 cases only in the secretory part, and never in the ducts (hence, and review of the literature. Am J Dermatopathol. 1994;16:253–257. apocrine and eccrine ducts cannot be distinguished morpho- 18. Pujol RM, LeBoit PE, Su WP. Microcystic adnexal carcinoma with exten- logically). Third, some glands showed focal hyperplasia of sive sebaceous differentiation. Am J Dermatopathol. 1997;19:358–362. 19. Gianotti R, Alessi E. Clear cell associated with the folliculo- cells comprising the peripheral layer, resulting in an appear- sebaceous-apocrine unit. Histologic study of five cases. Am J ance reminiscent of basal cell hyperplasia of the prostate. To Dermatopathol. 1997;19:351–357. our knowledge, this feature has not been described in normal 20. Gianotti R, Coggi A, Alessi E. Cutaneous apocrine mixed tumor: derived eccrine or apocrine ducts, but we have seen a similar phe- from the apocrine duct of the folliculo-sebaceous-apocrine unit? Am J Dermatopathol. 1998;20:323–325. nomenon in rare examples of cutaneous tubular adenoma and 21. Heenan PJ. Sebaceous differentiation in microcystic adnexal carcinoma. syringocystadenoma papilliferum (Kazakov et al, unpublished Am J Dermatopathol. 1998;20:537–538. observations, 2006). 22. Usmani AS, Rofagha R, Hessel AB. Trichoblastic neoplasm with apocrine In summary, we have described three sebaceous differentiation. 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