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EscoP Courses in Pathology Belgrade 2011, Serbia Head and neck Pathology, 7-9 April 2011 New entities and recent developments in salivary gland pathology Alena Skálová, MD, PhD Charles University in Prague Medical Faculty in Pilsen The review describes the new findings on salivary gland pathology. Newly recognized entities include sclerosing polycystic adenosis (SPA) initially believed to be reactive/inflammatory lesion similar to fibrocystic disease of breast (1). Recent molecular study using the HUMARA (human androgen receptor assay) for clonality analysis demonstrated that SPA is clonal, and thus most likely neoplastic process (2). Mammary analogue secretory carcinoma (MASC) of salivary glands was recently described as a new entity characterized histologically by resemblance to secretory breast cancer (3). It was demonstrated that MASCs harbour a recurrent balanced chromosomal translocation t(12;15)(p13;q25), which leads to a fusion gene between the ETV6 gene from chromosome 12 and the NTRK3 gene from chromosome 15, exactly as in secretory breast cancer (3). Cribriform adenocarcinoma of the tongue (CAT) is an infiltrative tumor that occurs almost exclusively in the base of the tongue characterized by synchronous metastases in lateral neck lymph nodes, but no distant spread (4). In 1999, we published a series of this distinctive type of adenocarcinoma occurring typically in the posterior tongue and retromolar region (4). These tumors were designated cribriform adenocarcinoma of the tongue (CAT) (4). The tumor was recognized by the latest issue of the WHO classification as a possible variant of PLGA, but it was noted that it was not yet clear whether this represented a genuine separate entity (5). Therefore, over the subsequent years, we have collected a new series of 23 cases of these tumors, some of which arose in minor salivary glands other than in the tongue (6). All the patients in our latest series were adults with a mean age at diagnosis of 55.8 years (range 25-85). Fourteen of the 23 tumors were localized in the tongue, three in the soft palate, two in the retromolar buccal mucosa, three in the lingual tonsils, and one in the upper lip. Fifteen patients out of 23 had synchronous metastases in the cervical lymph nodes at the time of diagnosis, bilateral in three cases; in 3 patients, the nodal metastasis was the first evidence of disease, later investigation revealing primary neoplasms in the base of tongue and tonsil, respectively. In addition, one patient developed a cervical lymph node metastasis 8 years after excision of a primary tumor of the tongue. Data on treatment and follow-up were available in 14 cases. The patients were treated by radical excision with clear margins (12 cases) or by simple excision (2 cases). Neck dissection was performed in 10 patients; nine received radiotherapy, but none was treated by chemotherapy. Twelve patients are alive with no evidence of recurrent or metastatic disease after treatment, one patient died two years after surgery without evidence of tumor, and one patient is alive with recurrent tumor of the palate (6). In short, we believe the present study shows that CATS is a distinct tumor entity that differs from PLGA by location (i.e. most often arising on the tongue), cytology, histological architecture, and behavior, with frequent metastases at the time of presentation of the primary tumor (6). In addition, old salivary gland tumor entities with new findings were included, such as salivary duct carcinoma (SDC) with newly recognized morphological variants (7,8), and a proposal of molecular classification (9). SDC and invasive breast ductal carcinomas have remarkably similar morphological features. Microarray studies have demonstrated that the latter can be subclassified into biologically and clinically meaningful molecular subgroups: luminal, molecular apocrine, HER2 and basal-like cancers. In our recent study of forty-three pure salivary duct carcinomas (10), the immunohistochemical panel previously validated for breast cancer was applied in order to determine whether SDC could likewise be classified into analogous molecular groups. SDC cases were stained with antibodies for estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), HER2, epidermal growth factor receptor (EGFR) and cytokeratin 5/6. HER2 status was assessed by immunohistochemistry and silver in situ hybridisation. Cases were classified as HER2 positive if they expressed HER2 protein and harboured the HER2 gene amplification, regardless of the expression of other markers. Tumors lacking HER2 expression which expressed either ER, PR or AR were considered of ‘luminal’/molecular apocrine phenotype, again regardless of the expression of other markers. Cases negative for HER2, ER, PR or AR which expressed either EGFR or Ck 5/6 were considered of ‘basal-like’ phenotype. Carcinomas which were negative for all markers were considered of indeterminate phenotype. Analysis revealed that 16.3% of the tumours were of HER2 phenotype, 67.4% were of ‘luminal’/molecular apocrine phenotype, 7% were of basal-like phenotype and 9.3% were of indeterminate phenotype. Interestingly, the in situ and invasive components displayed the same molecular subtype in all but one case. Our results demonstrate that SDC can be classified into molecular subgroups approximately equivalent to those in the breast. Understanding the phenotypic complexity of SDCs may help expedite the development of novel therapeutic targets for these usually very aggressive tumors (10). Selected References: 1. Skálová A, Michal M, Simpson RHW, Stárek I, Přádná J, Pfaltz M. Sclerosing polycystic adenosis of parotid gland with focal dysplasia and ductal carcinoma in situ. Report of three cases with immunohistochemical and ultrastructural examination. Virchows Arch 2002:440:29-35. 2. Skalova A, Gnepp DR, Simpson RH, et al. Clonal nature of sclerosing polycystic adenosis of salivary glands demonstrated by using the polymorphism of the human androgen receptor (HUMARA) as a marker. Am J Surg Pathol 2006: 30:939-944. 3. Skálová A, Vaneček T, Šíma R, Laco J, Weinreb I, Perez-Ordonez B, Stárek I, Geierová M, Simpson RHW, Passador-Santos F, Ryska A, Leivo I, Kinkor Z, Michal M. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 2010:34:599-608. 4. Michal M, Skalova A, Simpson RH, et al Cribriform adenocarcinoma of the tongue: a hitherto unrecognized type of adenocarcinoma characteristically occurring in the tongue. Histopathology 1999: 35:495-501. 5. Luna MA, Wenig BM. Polymorphous low-grade adenocarcinoma. In: Barnes EL, Eveson JW, Reichart P, et al, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. Lyon, IARC Press, 2005, pp. 223-224. 6. Skalova A, Sima R, Kaspirkova-Nemcova J, Simpson RHW, Elmberger G, Leivo I, Di Palma S, Jirasek T, Gnepp RD, Weinreb I, Perez-Ordoñez B, Mukensnabl P, Rychly B, Michal M. Cribriform Adenocarcinoma of the Tongue and Other Minor Salivary Glands: Characterization of New Entity. Am J Surg Pathol 2011- accepted. 7. Simpson RH, Prasad AR, Lewis JE, Skalova A, David L. Mucin rich variant of salivary duct carcinoma: a clinicopathologic and immunohistochemical study of four cases. Am J Surg Pathol 2003:27:1070-1079. 8. Nagao T, Gaffey TA, Visscher DW, et al. Invasive micropapillary salivary duct carcinoma: a distinct histologic variant with biologic significance. Am J Surg Pathol 2004: 28:319-326. 9. Di Palma S, Skalova A, Ungari M, et al. Pure salivary duct carcinoma can be classified into luminal, HER2 and basal-like phenotypes. (Abstract). Mod Pathol 2008:21 (Suppl 1):234A. 10. Di Palma S, Simpson RHW, Skálová A, Ungari M, Sandison A, Whitaker S, Parry S, Marchiò C, Reis-Filho JS. Pure salivary duct carcinomas can be classified into luminal/ molecular apocrine, HER2 and basal-like phenotypes. Submitted in Histopathology 2011.