Acinic cell carcinoma (ACC) is a low grade salivary gland malignancy characterized by serous acinar differentiation. Most ACCs arise in the parotid gland, but ACCs have been reported to originate in non-parotid salivary glands where where serous acini are less abundant. Given the recent discovery of mammary analogue secretory carcinoma (MASC) – a salivary malignancy that histologically mimics ACC – a retrospective re-evaluation of non-parotid ACCs is warranted. The surgical pathology archives of The Johns Hopkins Hospital were searched for all ACCs arising outside of the parotid gland. For each case, the histologic slides were reviewed; immunohistochemistry (mammaglobin, S100 protein) was performed; and confirmatory ETV6 break-apart FISH assay was completed. Demographic and clinical data was obtained from the medical records. Fourteen extra-parotid tumors diagnosed as ACC were identified. Eleven of 14 (79%) tumors harbored the ETV6 translocation (oral cavity = 9 of 11; submandibular gland = 2 of 2). The translocation positive tumors occurred in 7 women and 4 men ranging in age from 20–86 years (mean, 56), and usually presented as painless masses. Immunohistochemistry for mammaglobin and S100 was positive in all 11 translocation positive tumors, but negative in the 3 translocation negative tumors. Histologically, the translocation positive tumors exhibited uniform cells with vacuolated cytoplasm, microcystic/cystic and papillary architecture, and intraluminal secretions; but the presence of basophilic cytoplasmic granules was conspicuously absent. Basophilic cytoplasmic granules, indicative of true serous acinar differentiation, were present in the 3 translocation negative tumors. Of the translocation positive tumors, only one locally recurred, and none metastasized. Most alleged ACCs of non-parotid origin actually represent misclassified MASCs. The impact of diagnostic error is mitigated by the low grade nature of MASC that, like ACCs, do not appear to be clinically aggressive.

BACKGROUND Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland neoplasm that is defined by ETV6-NTRK3 gene fusion. To the best of the authors’ knowledge, only rare case reports of the cytopathologic features of MASC have been published to date. METHODS A wide variety of archival salivary gland tumors were tested for ETV6 translocation by break-apart fluorescent in situ hybridization. Positive cases with preoperative fine-needle aspiration (FNA) specimens or intraoperative touch preparations were retrieved from the archives of The Johns Hopkins Hospital. All smears were reviewed and the cytologic characteristics were described. RESULTS Five cases of MASC with cytopathologic material (4 FNA specimens and 1 touch preparation) were identified. The cases occurred in 3 men and 2 women ranging in age from 21 years to 78 years (mean, 52 years). On the cytologic smears, the MASCs were variably cellular and exhibited 2 different architectural patterns: 1) intact tissue fragments with isomorphic cells arranged in a sheet-like or papillary configuration; and 2) dispersed and dissociated cells with a mostly “histiocyte-like” appearance with large cells containing abundant vacuolated cytoplasm. No matrix tissue or stromal spindled cells were present. The cells did not display acinic differentiation in the form of cytoplasmic zymogen granules. In each case, the preoperative FNA correctly identified a neoplasm, and the most frequent diagnostic considerations were acinic cell carcinoma, mucoepidermoid carcinoma, and pleomorphic adenoma. CONCLUSIONS MASC is a newly described salivary gland tumor that should be considered in the differential diagnosis of low-grade salivary gland neoplasms. Its cytologic features overlap considerably with those of other tumors, especially acinic cell carcinoma and mucoepidermoid carcinoma.

Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland neoplasm defined by ETV6-NTRK3 gene fusion. MASC’s morphologyis not entirely specific and overlaps with other salivary gland tumors. Documenting ETV6 rearrangement is confirmatory, but most laboratories are not equipped to perform this test. As MASCs are positive for mammaglobin, immunohistochemistry could potentially replace molecular testing as a confirmatory test, but the specificity of mammaglobin has not been evaluated across a large and diverse group of salivary gland tumors. One hundred-thirty-one salivary gland neoplasms were evaluated by routine microscopy, mammaglobin immunohistochemistry, and ETV6 break-apart fluorescent in situ hybridization. The cases included 15 MASCs, 44 adenoid cystic carcinomas, 33 pleomorphic adenomas (PAs), 18 mucoepidermoid carcinomas, 10 acinic cell carcinomas, 4 adenocarcinomas not otherwise specified, 3 polymorphous low-grade adenocarcinomas, 3 salivary duct carcinomas, and 1 low-grade cribriform cystadenocarcinoma. All 15 MASCs harbored the ETV6 translocation and were strongly mammaglobin-positive. None of the 116 other tumors carried the ETV6 translocation, however mammaglobin staining was present in 1 of 1 (100%) low-grade cribriform cystadenocarcinoma, 2 of 3 (67%) polymorphous low-grade adenocarcinomas, 2 of 3 (67%) salivary duct carcinomas, 2 of 18 (11%) mucoepidermoid carcinomas, and 2 of 33 (6%) pleomorphic adenomas. Mammaglobin is highly sensitive for MASC, but immunostaining can occur in a variety of tumors that do not harbor the ETV6 translocation. Strategic use of mammaglobin immunostaining has a role in the differential diagnosis of salivary gland neoplasms, but it should not be indiscriminately used as a confirmatory test for MASC.

A complex chromosome rearrangement (CCR) involving chromosomes 7, 8, and 13 was detected in a phenotypically normal woman ascertained through her mentally retarded son with abnormal phenotype. He had a karyotype with 47 chromosomes including an extra der(13). In initial banding studies the CCR in the mother was interpreted as a three-way translocation. Fluorescence in situ hybridization with whole chromosome libraries and a telomere-specific probe was used to better characterize the rearrangement. Combined data allowed us to reinterpret the CCR as a translocation and an insertion. A review of 35 familial CCRs involving at least three chromosomes led to the following observations: 1) familial CCRs tend to have fewer chromosomes involved and fewer break-points than do de novo CCRs; 2) familial transmission is mainly observed through female carriers although the origin of de novo cases is paternal; 3) an apparent excess of balanced female carriers among the offspring of index carriers was noted; and 4) meiotic segregation resulting in malformed liveborn infants is most frequently due to adjacent-1 segregation, followed by 4:2 segregation; no adjacent-2 segregation was observed.

Animal models of Down syndrome (DS), trisomic for human chromosome 21 (HSA21) genes or orthologs, provide insights into better understanding and treatment options. The only existing transchromosomic (Tc) mouse DS model, Tc1, carries a HSA21 with over 50 protein coding genes (PCGs) disrupted. Tc1 is mosaic, compromising interpretation of results. Here, we “clone” the 34 MB long arm of HSA21 (HSA21q) as a mouse artificial chromosome (MAC). Through multiple steps of microcell-mediated chromosome transfer, we created a new Tc DS mouse model, Tc(HSA21q;MAC)1Yakaz (“TcMAC21”). TcMAC21 is not mosaic and contains 93% of HSA21q PCGs that are expressed and regulatable. TcMAC21 recapitulates many DS phenotypes including anomalies in heart, craniofacial skeleton and brain, molecular/cellular pathologies, and impairments in learning, memory and synaptic plasticity. TcMAC21 is the most complete genetic mouse model of DS extant and has potential for supporting a wide range of basic and preclinical research.