Sclerosing Polycystic Adenoma: Conclusive Clinical and Molecular Evidence of Its Neoplastic Nature

Abstract

Sclerosing polycystic adenosis, initially considered a non-neoplastic salivary gland lesion and classified as such in the 2017 WHO Classification of Head and Neck Tumors, has been the subject of controversy regarding its possible neoplastic nature. The reporting of recurrent PI3K pathway alteration represents evidence to support these lesions as being neoplastic and more appropriately referred to as sclerosing polycystic adenoma (SPA). Herein, we provide additional evidence that supports the classification of SPA as a true neoplasm. Eight cases of SPA were identified in our database and consultation files. All cases were subjected to PTEN immunohistochemistry (IHC) and next-generation sequencing (NGS). In addition, one patient underwent genetic counseling and germline testing. The cases included 5 men and 3 women with a mean age of 41 years (range 11-78) and all tumors arose in the parotid gland. One patient had multiple recurrences over a period of 2 years. Morphologically the tumors were circumscribed and characterized by an admixture of acini, ducts and cysts embedded in a fibrotic/sclerotic stroma. The cells lining the ducts and cysts showed variable granular, vacuolated, foamy and apocrine cytoplasmic features, as well as acinar cells contained intracytoplasmic brightly eosinophilic granules. The apocrine intraductal proliferations showed mild to moderate atypia in 6 cases. One case showed overt malignant morphology that ranged from intraductal carcinoma to invasive salivary duct carcinoma. Seven cases tested for PTEN IHC showed loss of nuclear expression in the acinar and ductal cells with retained PTEN expression in the myoepithelial cell and stroma. NGS detected PIK3CA or PIK3R1 genetic alterations in 7 cases, including a novel TFG-PIK3CA fusion. Coexisting PTEN mutations were seen in 4 cases, including in a patient with clinical stigmata of Cowden syndrome and confirmed by germline genetic testing. Our findings herein documented including recurrence of tumor, malignant transformation, high prevalence of PI3K pathway oncogenic alterations and the possible heretofore undescribed association with Cowden syndrome add support to classifying SPA as true neoplasms justifying their designation as adenoma, rather than adenosis.

Keywords: Cowden syndrome; PI3K pathway; PTEN; Sclerosing polycystic adenoma; Sclerosing polycystic adenosis.

Fig. 1

Sclerosing polycystic adenoma of patient #1. A Well-circumscribed tumor separated from the surrounding uninvolved parotid parenchyma (lower right) showing an admixture of cystic structures and ducts embedded in a fibrotic stroma (H&E, 2 × 10 magnification). B Cysts and ducts lined by epithelial cells with variable granular, foamy, and apocrine morphology, the latter including cells with apical snouting (H&E, 4 × 10 magnification). C Acinar-type structures containing intracytoplasmic bright eosinophilic granules (H&E, 20 × 10 magnification)

Fig. 2

Sclerosing polycystic adenoma of patient #2. A The overall histological features of sclerosing polycystic adenoma can be identified on a core biopsy (H&E, 2 × 10 magnification), including B the acinar-type structures containing intracytoplasmic brightly eosinophilic granules and C the cystic structures with a cell lining with variable morphology (H&E, 10 × 10 magnification). D The loss of nuclear expression of PTEN immunohistochemistry in the acinar and ductal cells with retain reactivity in the myoepithelial and stromal cells is a useful diagnostic aid (H&E, 20 × 10 magnification)

Fig. 3

Spectrum of the apocrine intraductal epithelial proliferation in sclerosing polycystic adenoma of patient #1 showing: A Solid, B cribriform, and C micropapillary patterns (H&E, 10 × 10 magnification)

Fig. 4

Carcinoma ex-sclerosing polycystic adenoma of patient #3. A Portions of the tumor show classical morphological features of sclerosing polycystic adenoma including: A Well-circumscribed tumor borders, admixture of cystic and ductal structures, and a fibrotic stroma (H&E, 2 × 10 magnification), as well as B acinar-type structures containing intracytoplasmic brightly eosinophilic granules (H&E, 4 × 10 magnification). C Intraductal epithelial proliferation with rigid cribriform architecture (H&E, 4 × 10 magnification) highlighted by D peripheral layer of myoepithelial cells positive for CK5/6) (4 × 10 magnification). E Another portion of the tumor shows a frankly invasive component associated with a prominent desmoplastic reaction. (H&E, 2 × 10 magnification). F The invasive carcinoma had features of a salivary duct carcinoma including abundant eosinophilic cytoplasm and large pleomorphic nuclei with prominent nucleoli (H&E, 10 × 10 magnification). G The invasive carcinoma showed loss of PTEN expression and H diffuse and strong reactivity for androgen receptor that in conjunction with the histologic features support a diagnosis of salivary duct carcinoma. (10 × 10 magnification)

Fig. 5

Schematic diagram of TFG-PIK3CA fusion in the sclerosing polycystic adenoma of patient #4. TFG is located on 3q12.2 and PIK3CA on3q26.3. The break points were mapped exon 5 of TFG and exon 3 of PIK3CA