UPDATE ON MALIGNANT ADNEXAL NEOPLASMS

David S. Cassarino, M.D., Ph.D. Los Angeles Medical Center, Southern California Permanente Medical Group, Department of Pathology University of California, Irvine, Department of Dermatology CLASSIFICATION OF ADNEXAL TUMORS

• Older classifications based on questionable morphologic and histochemical observations - Most of these are not specific for apocrine vs. eccrine diff’nt • Many tumors designated as eccrine or apocrine have features of the other category or features of adnexal ducts - Ducts of apocrine and eccrine nature show similar features and are essentially indistinguishable • Benign versus malignant determination is crucial for treatment and prognosis • Features such as asymmetry, infiltrative borders, increased mitoses, and necrosis favor malignancy • Atypical adnexal tumors show some, but not all, of these features • In many cases, due to limited sampling of the tumor (i.e., shave or punch biopsy), a definitive classification is not possible ◼ Such cases should be signed out descriptively, with a differential diagnosis, and complete excision recommended to obtain a definitive diagnosis • Newer immunohistochemical and molecular findings associated with particular tumors: • SOX10 in apocrine and some eccrine tumors • GATA3 in follicular, sebaceous, and apocrine tumors • MYB in adenoid cystic carcinoma, apocrine tumors • Beta-catenin overexpression in pilomatrical tumors • FXIIIa (nuclear) in sebaceous tumors • CYLD mutations in cylindroma, spiradenoma, trichoblastomas, and adenoid cystic carcinoma • HRAS, p53, RB1, APC, CDKN2A, and PTEN mutations in porocarcinoma • t(11;19) translocation in hidradenomas and hidradenocarcinomas • ETV6-NTRK3 translocation in primary cutaneous mammary analog secretory carcinoma CD117 and SOX-10 had similar overall positivity rates in benign apocrine and eccrine tumors (45% and 68% respectively), and were generally negative in other benign and malignant adnexal tumors. 16% (23/140) of benign adnexal tumors significantly expressed MYB, mostly in cylindromas and to a lesser extent, spiradenomas. SOX10 showed positivity in spiradenomas (13/13), cylindromas (9/10), hidradenoma papilliferum (10/10), syringocystadenoma papilliferum (8/10), apocrine adenomas (8/10), and negativity in poromas (0/12), syringomas (0/10), and basal cell carcinomas (0/13). • Nuclear GATA3 expression was seen in 70% (153/220) of cases, including sebaceous carcinoma (93%), apocrine carcinoma (93%), follicular neoplasms (100%), and predominantly apocrine neoplasms (69%), but only 38% of predominantly eccrine neoplasms. MICROCYSTIC ADNEXAL CARCINOMA (MAC) Clinical: - Occurs on face, usually lip and nasolabial area, followed by chin and cheeks, slowly enlarging firm plaque - Locally aggressive tumor, high recurrence rate, but only rare mets Molecular: - Rare mutations in p53 and CDKN2A genes Histology: - Large, poorly-circumscribed dermal tumor deeply infiltrating into subcutis (even muscle) - Consists of bland adnexal (likely apocrine) cells forming cords and small ducts infiltrating a desmoplastic stroma - Superficial horn cysts and abortive follicles (FSAU-diff’nt) - Mitoses rare, perineural invasion frequent

CEA IHC: + for EMA and CEA (luminal), CK7 (diffuse), low Ki67 and p53 (versus high in Perineural invasion sBCC) • Diff’nt diagnosis: 1. Infiltrative/sclerosing BCC: - Lacks superficial follicular cysts and ductal diff’nt, only rare perineural invasion; EMA, CEA, CK7- 2. Desmoplastic trichoepithelioma: - Lacks deep and perineural invasion, has calcifications, follicular but no ductal diff’nt; EMA, CEA, CK7-; CK20+ Merkel cells 3. Syringoma: - Bland ductal structures containing proteinaceous secretions (not keratin or hair material), lacks the deep infiltration, keratinocysts, and perineural invasion of MAC SCLEROSING BCC DesmoTE

TRICHOADENOMA SYRINGOMA - Superficial, noninfiltrative ductal structures - Tadpole shapes - No follicular diff ’nt INFILTRATING ECCRINE (SYRINOGOID) CARCINOMA Clinical: - Older patients, often head and neck, upper extremities Histology: - Infiltrating ductal - but no follicular - structures in a sclerotic stroma - Small to moderately enlarged, basophilic to pale/clear cells with marked atypia, nuclear hyperchromasia, mitoses - Diffuse dermal and subQ invasion often present Prognosis: - Locally aggressive tumors, reportedly high rates of recurrence, low metastasis

TRICHOBLASTIC CARCINOMA Clinical: - Rare malignant tumors of hair germ, likely arise from trichoblastomas (can be a/w/Brook-Spiegler syndrome, CYLD mutations) - Usually large tumors, > 1 cm, on the head, esp. scalp Histology: - Large, poorly circumscribed basaloid tumor w/out epidermal connections, located in deep dermis, often w/subcutis extension - Show evidence of pilar differentiation - Cells are basaloid, and show mitoses and apoptoses, but lack prominent peripheral palisading, mucoid stroma typical of BCC

Ki-67 p53 TRICHOBLASTIC CARCINOMA: DIFFERENTIAL DIAGNOSIS 1. BCC: - Tumor-stroma retraction artifact, mucinous stroma, prominent palisading, and mitoses and apoptoses are abundant 2. TRICHOBLASTOMA: - Large, nodular basaloid tumor composed of relatively small, bland-appearing basaloid cells - Lacks atypia and increased mitoses, apoptoses of BCC and trichoblastic carcinoma BCC, Nodular and micronodular types TRICHOBLASTOMA CUTANEOUS LYMPHADENOMA SEBACEOUS TUMORS

• Tumors of definite sebaceous differentiation: - Sebaceous adenoma - Sebaceoma (“sebaceous epithelioma”/basal cell carcinoma with sebaceous differentiation) - Sebaceous carcinoma • Tumors of questionable/partial sebaceous differentiation: - Superficial epithelioma with sebaceous diff’nt - Mantleoma (likely fibrofolliculoma) SEBACEOUS CARCINOMA Clinical: - Most on eyelids, followed by head and neck, presents as a nodule ± ulceration and hemorrhage - Often misdiagnosed (> 80% in some studies!), usually as BCC, SCC, Paget disease, other adnexal tumors - May be a/w/Muir Torre Syndrome (MLH1, MSH2, MSH6, PMS2 mutations) – less aggressive Histology: - Irregular, fusing lobules, nodules and sheet-like collections of pale/clear cells with infiltrative features - Cytologic atypia, nuclear pleomorphism, multi mitoses, often see areas of comedonecrosis - IHC: AR+, adipophilin+, FXIIIa+, EMA±, CD10±, CK7±, p53+, ↑ Ki-67, oil red O (frozens)

Squamoid (left) and clear cell areas (right)

EMA Androgen receptor (AR) DIFFERENTIAL DIAGNOSIS Benign sebaceous tumors - Sebaceous adenoma: Circumscribed growth of well-differentiated sebocytes surrounded by layer of small basaloid cells, > 50% well-differentiated sebocytes - Sebaceoma (“sebaceous epithelioma”): Circumscribed growth, < 50% well-differentiated sebocytes, > 50% bland basaloid cells; may see mitoses in basaloid cells, but lack atypia, mucinous stroma or retraction artifact

MTS: cystic sebaceous neoplasms MLH1 MSH2

Ki-67

ADENOMA CARCINOMA Cabral et al., Amer J. Dermatopathol 2006; 28:465-71 - Clear cell BCC: Rare variant, usually has areas of more typical BCC with palisading, retraction-artifact, mucinous stroma - Clear cell SCC: Should see areas of squamous diff’nt, often w/overlying AK or SCC in situ; lack of cytoplasmic vacuoles and nuclear scalloping - Metastatic renal cell carcinoma: Usually well-circumscribed dermal nodule w/prominent vascularity; clear cells with often bland cytologic features; CK7-; CD10 & RCA+ DIFFERENTIAL DIAGNOSIS - Tricholemmal carcinoma: Peripheral palisading, uniformly clear cytoplasm lacking multivacuolar change, areas of squamoid diff, PAS+/PAS-D- (glycogen) - Clear cell hidradenoma/hidradenocarcinoma: Large nodular or cystic dermal-based lesion, usually lacks epidermal or follicular connections, lacks vacuoles, PAS+/PAS-D-; CEA & EMA highlight ductal structures CLEAR CELL BCC APOCRINE ADENOCARCINOMA

Clinical: - Rare tumor, primarily axillary and anogenital, but occurs in other sites as well - Presents as nodular/multinodular mass - Aggressive, reportedly lethal in over 30% of cases History: - Unencapsulated, infiltrative nodular lesion with variable patterns including papillary, tubular, and cord-like arrangements - Atypical apocrine cells w/low to high grade cytological atypia and mitoses

APOCRINE ADENOCARCINOMA Differential Diagnosis: 1. Tubular apocrine adenoma: benign cytologic features and lack of infiltration or mitoses 2. Metastatic adenocarcinoma, especially breast: may be very difficult without clinical history, exams Immunohistochemistry: - Most cases are CK 5/6, p63, AR, mammaglobin, and GCDFGP positive - Often GATA3, ER/PR positive, so cannot distinguish from Breast CA - Variable S100 and CEA staining CK 5/6

p63 GCDFP (Brst-2) ER

ADENOID CYSTIC CARCINOMA Clinical: - Rare primary cutaneous tumor, often scalp or chest, may arise from apocrine glands Molecular: - CYLD mutations (aberrant fusion transcript MYB-NFIB) Histology: - Islands and nests of cells with cribiform spaces and tubules filled with mucinous and basement membrane material - Low grade histology, rare mitoses, but frequent perineural invasion Prognosis: - Indolent growth and high recurrence potential (up to 70%), but low metastatic rate

S100

MALIGNANT SPIRADENOMA Clinical: - Usually malignant transformation of large, untreated spiradenoma: history of sudden enlargement of long-standing lesion - Can be a/w/Brooke-Spiegler syndrome, CYLD mutations Histology: - Areas of benign-appearing spiradenoma associated with foci of malignant transformation with cellular atypia, nuclear hyperchromasia, and pleomorphism, many mitoses Prognosis: - Mets occur, usually LNs, but few reported deaths

SPIRADENOMA MALIGNANT CYLINDROMA

Clinical: - Usually malignant transformation of large (often multicentric tumors) - a/w/Brooke-Spiegler syndrome, CYLD mutations, upregulated MYB or fusion transcript MYB-NFIB Histology: - Areas of benign-appearing cylindroma, with foci of malignant transformation showing cellular atypia, nuclear hyperchromasia and pleomorphism, many mitoses Prognosis: - Mets occur, usually LNs, but few reported deaths

CYLINDROMA POROCARCINOMA Clinical: - Older patients, often on lower extremities, usually associated with longstanding poroma Molecular: - Mutant HRAS, p53, RB1, APC, CDKN2A, and PTEN Histology: - Elongated thickened cords and large islands with cystic structures and frequent central necrosis - Large, eosinophilic cells with squamoid diff’nt, marked atypia, nuclear hyperchromasia, mitoses - May be in situ, but dermal invasion often present Prognosis: - Local recurrences, local mets in up to 20%, visceral metastases and death in 11% cases

CK 5/6

CEAm DDX: POROMA Dermal duct tumor HIDRADENOCARCINOMA Clinical: - Older patients, any site, usually associated with longstanding hidradenoma Molecular: - t(11;19) translocation reported in both hidradenomas and carcinomas, p53 mutations Histology: - Large nodules and islands with cystic structures and frequent central necrosis - Large, eosinophilic to clear cells with marked atypia, nuclear hyperchromasia, mitoses - May rarely show overlying carcinoma in situ Prognosis: - Local recurrences, visceral metastases and death in 10-15%

DDX: HIDRADENOMA CLEAR CELL HIDRADENOMA Questions