Low-grade Cribriform Cystadenocarcinoma Research Articles

Mammary Analog Secretory Carcinoma (MASC) of the oral mucosa with proven ETV6- NTRK3 fusion gene as the gold standard for diagnosis – A case series and literature review

Abstract Introduction/Objective Mammary Analog Secretory Carcinoma (MASC) is a rare type of cancer that occurs in the salivary glands. It is named after its similarity in appearance and behavior to secretory carcinoma of the breast. The incidence of MASC is estimated at 0.3%, with less tha 500 cases reported. The diagnosis of MASC is based on a combination of clinical, radiographic, and histopathologic features. Prognosis is generally good, with a low risk of recurrence and metastasis; its differential diagnosis includes: acinic cell carcinoma, adenocarcinoma (primary or metastatic), mucoepidermoid carcinoma, and low-grade cribriform cystadenocarcinoma. MASC is characterized by ETV6-NTRK3 fusion gene, a translocation between the ETV6 gene on chromosome 12 and the NTRK3 gene on chromosome 15, leading to the fusion of these two genes and the production of a chimeric protein. FISH testing can detect the presence of the ETV6-NTRK3 fusion gene. The detection of the ETV6-NTRK3 fusion gene is highly specific for MASC and can aid in the diagnosis and management of this tumor. In addition, the presence of this gene fusion can have implications for targeted therapy, as drugs that target the NTRK3 gene may be effective in the treatment of MASC. Methods/Case Report This review aims to compare the characteristics of MASC in cases we diagnosed since 2015. Results (if a Case Study enter NA) Cases Case 1 (2015) 68yo Female Right Lower Lip, Biopsy Positive: S100, PAS with and without diastase and mammaglobin Negative: Mucicarmine ETV6 + Case 2 (2016) 54yo Female Right Buccal Mucosa, Biopsy Positive: S100, Mammaglobin Weakly positive: p63 ETV6 + Case 3 (2016) 42yo Male Right Buccal Mucosa, Biopsy Positive: S100, Ck7, Ck5/6, Vimentin Weakly positive: GFAP, p63 Negative: SMA, MSA, Calponin ETV6 + Case 4 (2018) 60yo Female Left Soft Palate, Biopsy Positive: CK7 Weakly positive: GATA-3 Negative: CK20, TTF-1, CDX-2, Napsin A ETV6 + Case 5 (2019) 57yo Female Right Palatal Mucosa, Biopsy Positive: S100, Ck7, Ck5/6, Vimentin Negative: p63, GFAP, Calponin, SMA ETV6 + Conclusion MASC is a very rare salivary gland tumor and the gold standard for its diagnosis is FISH for ETV6 gene rearrangement. All our cases showed ETV6- NTRK3 fusion gene, while 80% (4/5) of the patients were females. S100, mammaglobin and PAS were positive in all tested cases, consistent with previous reports. The histopathological diagnosis of MASC on a biopsy can be challenging; although immunohistochemical stains and morphology may be helpful hints, FISH testing should be considered when MASC is suspected.

Low Grade Intraductal Carcinoma of Palate: An Extremely Rare Entity with Review of Literature.

Low-grade intraductal carcinoma (LG-IDC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma". LG-IDC is a rare low grade malignant salivary gland neoplasm. A 56-year old woman presented with a painless swelling on the right posterior part of palate of 2months duration. Radiographic examination revealed heterogenously enhancing soft tissue mass on right side of palate. A provisional diagnosis of pleomorphic adenoma was executed and local excision was done. The tumor had a typical feature of intraductal growth pattern composed of low grade ductal epithelial cells with cribriform and micropapillary patterns forming true "Roman bridges". Immunohistochemically myoepithelial cells displayed p63 around all tumor islands. The case was diagnosed as LG-IDC. LG-IDC is an extremely rare entity and awareness of this entity is important to avoid erroneous diagnosis and inappropriate treatment.

Low-grade Apocrine Intraductal Carcinoma: Expanding the Morphologic and Molecular Spectrum of an Enigmatic Salivary Gland Tumor.

Intraductal carcinoma (IDC) is the current designation for a salivary gland neoplasm previously referred to as "low-grade salivary duct carcinoma" and "low-grade cribriform cystadenocarcinoma," among others. IDC is conceptually believed to be similar to ductal carcinoma in-situ of the breast. Although IDC is one entity in the current WHO Classification of Head and Neck Tumors, recent studies have suggested that at least three subtypes exist: a low-grade, intercalated duct-like variant with frequent RET rearrangements; a high-grade apocrine variant with complex, salivary duct carcinoma-like genetics; and a mixed variant. We sought to characterize an unusual form of low-grade, purely apocrine IDC. Three cases of apocrine-type IDC with low-grade histology were retrieved from the authors' consultation files. Immunohistochemistry for androgen receptor, GCDFP-15, S100, smooth muscle actin, and p40 was performed. A custom, targeted next generation sequencing (NGS) panel including 1425 cancer-related genes was also done on all cases. All three cases developed in the parotid glands of men, aged 51, 63, and 73years (mean, 62years). All cases consisted of large, rounded macrocysts surrounded by smaller nests which were lined by cells with abundant granular eosinophilic cytoplasm and large round nuclei with prominent nucleoli. Pleomorphism was mild, the mitotic rate was low, and necrosis was absent. No cases had any invasive foci or areas of intercalated duct-like morphology. By immunohistochemistry, all cases were diffusely positive for androgen receptor and GCDFP-15, surrounded entirely by an intact layer of small myoepithelial cells positive for S100, smooth muscle actin, and p40. Targeted NGS results were obtained from two cases: both harbored HRAS mutations and copy number losses in TP53, while one case each harbored mutations in PIK3CA, SPEN, and ATM. Fusions were absent in both cases. All three patients were treated by surgery alone, and are currently free of disease (follow up 12-190months). This study confirms the existence of a low-grade, purely apocrine form of IDC. In its pure form, i.e., without an intercalated duct-type component, low-grade apocrine IDC is genetically similar to high-grade salivary duct carcinoma, with frequent HRAS and PI3K pathway mutations. Despite its molecular similarities to the aggressive salivary duct carcinoma, low-grade apocrine IDC appears to behave in a very indolent manner, supporting is classification as a non-invasive neoplasm, and underscoring the need to distinguish these tumors from each other.

NCOA4-RET and TRIM27-RET Are Characteristic Gene Fusions in Salivary Intraductal Carcinoma, Including Invasive and Metastatic Tumors: Is "Intraductal" Correct?

Intraductal carcinoma (IC) is the new WHO designation for tumors previously encompassed by "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma (SDC) is controversial, even though they are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with histopathological features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast, showing diffuse S100 protein and mammaglobin positivity, while it is partially defined genetically. Recently, RET rearrangements including NCOA4-RET and TRIM27-RET have been described in IC. Here, we genetically characterize the largest cohort of IC to date (33 cases) including 8 cases with focal or widespread invasive growth and 1 case with lymph node metastasis. Thirty-three cases of IC were analyzed by next-generation sequencing (NGS) using the FusionPlex Solid Tumor kit (ArcherDX). Identified gene fusions were confirmed using fluorescence in situ hybridization break-apart and fusion probes and an reverse transcription polymerase chain reaction designed specifically for the detected breakpoints. Ten cases of SDC were analyzed for comparison using NGS panels that detect mutations and fusion transcripts. NGS analysis detected an NCOA4-RET fusion transcript in 11 cases of intercalated duct-type IC joining exon 7 or 8 of NCOA4 gene and exon 12 of the RET gene. Eight cases of IC had an invasive growth pattern, including one with widespread invasion and lymph node metastasis. Three invasive ICs harbored an NCOA4-RET fusion transcript, while 1 case was negative, and 2 cases were not analyzable. In addition, a novel TRIM27-RET fusion transcript between exon 3 of TRIM27 and exon 12 of RET was identified in 2 cases of IC with apocrine features, and one of them displayed invasive growth. Two IC cases with invasive growth harbored novel fusions TUT1-ETV5 and KIAA1217-RET, respectively. A total of 42.4% of the cases in this series of IC harbored fusions involving RET. Such fusion transcripts were not detected in any of the 10 SDC cases. We have confirmed NCOA4-RET as a predominant fusion in intercalated duct-type IC, including 3 cases with invasive growth pattern. A novel finding in our series was a case of widely invasive intercalated duct-type IC, with a single lymph node metastasis that revealed an NCOA4-RET fusion transcript. We also demonstrated that a subset of apocrine ICs harbored a TRIM27-RET gene fusion, including one case with invasive growth. In contrast, neither NCOA4-RET nor TRIM27-RET fusions were detected in any tested SDCs. Thus, the distinct molecular findings in IC and SDC support that the tumors are separate malignant salivary tumor entities. The presence of tumor-type-specific NCOA4-RET or TRIM27-RET translocations in a subset of widely invasive carcinomas with intercalated duct-like immunoprofiles suggests that a recharacterization of IC including its redesignation as "intercalated duct carcinoma, invasive or noninvasive" may be appropriate.

Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions: A Report of 17 cases.

Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.

Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland.

Intraductal carcinoma (IC) is the World Health Organization designation for lesions previously called low-grade cribriform cystadenocarcinoma. The relationship of IC to salivary duct carcinoma (SDC) is controversial, but currently these are considered distinct entities. It is hypothesized that IC and SDC should have different genomic signatures that may be identifiable by next-generation sequencing. A total of 23 ICs were identified: 14 pure IC and 9 invasive carcinomas with an intraductal component. Five invasive carcinomas were subjected to next-generation paired-end RNA sequencing. Data analysis was performed using FusionSeq and Mutation detection algorithms (MuTect and VarScan) for variant callers. Gene fusion candidates were validated by fluorescence in situ hybridization and reverse transcription polymerase chain reaction, and mutations by Sanger sequencing. Among the 9 invasive carcinomas, all except 1 were apocrine SDCs with an intraductal component. The remaining case showed typical intercalated duct type IC with invasive adenocarcinoma. The 14 pure ICs had typical intercalated duct features (2 showed hybrid intercalated/apocrine features). RNA sequencing predicted a NCOA4-RET fusion, confirmed by reverse transcription polymerase chain reaction, in the intercalated duct type IC invasive component. Six additional cases of pure IC showed RET rearrangement by fluorescence in situ hybridization (7/15=47%). No apocrine carcinomas showed RET rearrangement. RNA sequencing and Sanger sequencing identified PIK3CA (p.E545K/p.H1047R) and/or HRAS (p.Q61R) hotspot mutations in 6 of 8 (75%) apocrine carcinomas. In conclusion, 2 distinctive types of intraductal lesions are emerging based on molecular analysis. Classic intercalated type ICs commonly harbor fusions involving RET and rarely show widespread invasion. Apocrine intraductal lesions are typically associated with widespread invasion with no pure examples and show similar PIK3CA and HRAS mutations to SDC.

Salivary Duct Carcinoma: An Update on Morphologic Mimics and Diagnostic Use of Androgen Receptor Immunohistochemistry.

More than 15 years ago, seminal studies by Dr. E. Leon Barnes and colleagues transformed our understanding of salivary duct carcinoma (SDC) and, in doing so, paved the way for contemporary diagnostic and therapeutic approaches to this aggressive salivary adenocarcinoma. In particular, attention to the apocrine phenotype of SDC and expression of androgen receptor (AR) by immunohistochemistry has improved the diagnostic accuracy and showed how SDC can be reliably distinguished from its morphologic mimics (i.e., other salivary gland carcinomas with high grade transformation, low grade cribriform cystadenocarcinoma, and squamous cell carcinomas involving parotid). Furthermore, the observation that SDC shares AR expression with prostate cancer and apocrine breast cancer foresaw the discovery of common molecular alterations between SDC and these tumor types and draw attention to androgen deprivation therapy for SDC patients.

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Tumors of the Salivary Gland.

The salivary gland section in the 4th edition of the World Health Organization classification of head and neck tumors features the description and inclusion of several entities, the most significant of which is represented by (mammary analogue) secretory carcinoma. This entity was extracted mainly from acinic cell carcinoma based on recapitulation of breast secretory carcinoma and a shared ETV6-NTRK3 gene fusion. Also new is the subsection of "Other epithelial lesions," for which key entities include sclerosing polycystic adenosis and intercalated duct hyperplasia. Many entities have been compressed into their broader categories given clinical and morphologic similarities, or transitioned to a different grouping as was the case with low-grade cribriform cystadenocarcinoma reclassified as intraductal carcinoma (with the applied qualifier of low-grade). Specific grade has been removed from the names of the salivary gland entities such as polymorphous adenocarcinoma, providing pathologists flexibility in assigning grade and allowing for recognition of a broader spectrum within an entity. Cribriform adenocarcinoma of (minor) salivary gland origin continues to be divisive in terms of whether it should be recognized as a distinct category. This chapter also features new key concepts such as high-grade transformation. The new paradigm of translocations and gene fusions being common in salivary gland tumors is featured heavily in this chapter.

Low-grade cribriform cystadenocarcinoma of the palatal gland: A case report.

Low-grade cribriform cystadenocarcinoma (LGCCC) is a malignant salivary gland tumor. LGCCC occurs rarely, with the parotid gland being the most commonly afflicted site. Few cases arise in other sites. The present study reports a case of LGCCC that occurred at the palatal gland of the hard palate. A 56-year-old female was referred to Saitama Medical University Hospital (Moroyama, Saitama, Japan) due to an intraoral mass. Since cytological examination and biopsy led to a diagnosis favoring a neoplasm, but with uncertain malignant potential, the tumor was resected with a safe surgical margin. The specimen was thoroughly examined. Microscopically, there was a well-demarcated, unilocular cyst with the lumen lined by tumor cells. The tumor cells were arranged in tubular, cribriform and solid structures in the area of the intracystic mass lesions. Nuclear atypia was inconspicuous, although mitotic figures were observed throughout the tumor. Neither local nor perineural invasion was present. On immunohistochemistry, the tumor cells were diffusely positive for S-100 protein. Myoepithelial markers, calponin and p63, highlighted the cells rimming the cystic mass. The final histopathological diagnosis was of LGCCC. The tumor was completely resected. At 1 year post-resection, the patient exhibited no recurrence or distant metastasis. LGCCC is regarded as clinically indolent. However, there is little literature available to aid with prognosis prediction due to the rarity of LGCCC cases. Thus, greater experience and longer follow-up periods are necessary to find the optimal/curative treatment for patients with LGCCC and to clarify the pathophysiology.

Carcinome salivaire sécrétoire, analogue des carcinomes sécrétoires mammaires

Mammary analog secretory carcinoma (MASC) of the parotid gland is a rare and recently described lesion. We report the case of a 46-year-old man with a tumor of the parotid gland which was carried to the diagnosis of MASC. Diagnostic was confirmed by highlighting the ETV6-NTRK3 gene translocation. However, some morphologic and immunohistochemical features are suggestive of this entity. This carcinoma should be distinguished from its main differential diagnoses: acinic cell carcinoma and low grade cribriform cystadenocarcinoma.

A comparative immunohistochemistry study of diagnostic tools in salivary gland tumors: usefulness of mammaglobin, gross cystic disease fluid protein 15, and p63 cytoplasmic staining for the diagnosis of mammary analog secretory carcinoma?

Mammary analog secretory carcinoma (MASC) of the salivary gland has been recently described according to morphological, immunohistochemical, and molecular (ETV6-NTRK3 translocation) similarities with the mammary secretory carcinoma. The most important differential diagnostic considerations of MASC are low-grade adenocarcinoma not otherwise specified (NOS), cystadenocarcinoma, and acinic cell carcinoma (AciCC). These tumors may share an overlapping morphology with MASC, and additional immunohistochemical studies are required to reinforce the diagnosis. Mammaglobin, GCDFP-15, and p63 staining have been reported in MASC. Our study was designed to check the specificity of these antibodies in MASC compared to other frequent tumors of salivary glands. A series of 62 salivary gland tumors [10 MASCs, 5 adenocarcinomas NOS and 2 cystadenocarcinomas with MASC features and without ETV6 rearrangement, one low-grade cribriform cystadenocarcinoma (LGCCC), 9 AciCCs, 10 MECs, 10 adenoid cystic carcinomas (AdeCCs), 5 polymorphous low-grade adenocarcinomas (PLGAs), and 10 pleomorphic adenomas (PAs)] was analyzed by immunohistochemistry with mammaglobin, GCDFP-15, and p63 antibodies. Positivity for mammaglobin was observed in all MASCs, cystadenocarcinomas, LGCCC, and PLGAs, in some adenocarcinomas NOS, PAs, and MECs, rarely in AciCCs and never in AdeCCs. Positivity for GCDFP-15 was observed in most of the tumor types except in AdeCCs. Interestingly, cytoplasmic positivity for p63 was observed in most of MASCs and PLGAs while rarely in adenocarcinomas NOS and PAs, and never in the other tumor types. Our study revealed the usefulness of mammaglobin and p63 cytoplasmic staining to define which tumors are worth to be screened for ETV6 rearrangement.

Envisioning the Next WHO Head and Neck Classification

The next WHO classification should abandon "salivary duct carcinoma"; conventional salivary duct carcinoma should be classified as "high-grade salivary duct carcinoma". Low-grade salivary duct carcinoma should replace the current nosology of "low-grade cribriform cystadenocarcinoma". Cystadenocarcinoma should be classified with the descriptor "Not Otherwise Specified" and should be considered an exclusionary diagnostic category. On the other hand, "Not Otherwise Specified" does not fit for hyalinizing clear cell carcinoma (HCCC). The EWSR1-ATF1 fusion is specific for HCCC within the context of salivary neoplasia. We recommend adding "hyalinizing" even though this feature is not present in all cases; the benefit of which is the mental association with a salivary clear cell malignancy. Sinonasal Renal Cell-like Adenocarcinoma (SNRCLA) is a distinct clear cell neoplasm and should be added to the next WHO classification. Future studies will bear out whether SNRCLA is even a low-grade carcinoma, or may be reclassified as "adenoma". Lastly, the next WHO monograph should include the Risk Model in the general introductory statements on oral squamous cell carcinoma, under a subheading of "Histological Prognosticators". The positive predictive value for developing locoregional recurrence in patients with low-stage oral cavity squamous carcinoma (OSCC) and "worst pattern of invasion type-5" (WPOI-5) is 42 %. Low-stage high-risk OSCC with a combination of features other than WPOI-5 is associated with 32 % likelihood for locoregional progression. WPOI-5 also predicts occult metastatic disease (p = 0.0001, Chi squared, 2 DF). Thus the Risk Model can also be used to make decisions regarding staged elective neck dissections.

43. Low grade cribriform cystadenocarcinoma: the cytology and histology of a rare salivary gland tumour

Low grade cribriform cystadenocarcinoma (LGCCC) is a rare low grade malignant neoplasm which occurs almost exclusively in the parotid gland. The lesion is also known as low grade intraductal carcinoma of the salivary gland, coined by Delgado et al. in 1996, due to its resemblance to atypical ductal hyperplasia or low grade ductal carcinoma in situ of the breast. The majority of patients are elderly and have a female predominance of 2:1. While there have been several case series and case reports in the literature about its histological and immunohistochemical features, only two studies in the English language literature have given any cytolomorpho-logical description. We present a case of a 62-year-old female with a right parotid mass. A fine needle aspiration showed a hypercelllular smear, with sheet-like and branching architecture, composed of fairly uniform cells with atypical features, in a mucoid/myxoid background. A diagnosis suggestive of a pleomorphic adenoma was given. Five months later, an excision of a 1.5 cm, solid-cystic mass was performed. Histological examination showed an intraductal proliferation of tumour cells akin to a breast low grade ductal carcinoma in situ with papillary and cribriform pattern. A focal area of microinvasion was present. Immunohistochemically, the luminal cells showed strong and diffuse positive cytokeratin and S-100 staining. The myoepithelial marker, calponin, highlighted the basal cells. Hence, a diagnosis of low grade cribriform cystadenocarcinoma was favoured. The characteristic features of this lesion are discussed, with focus given to the cytological findings and the diagnostic difficulties in fine needle aspirates, particularly due to lack in the current literature of definitive diagnostic criteria.

Mammary Analogue Secretory Carcinoma of Salivary Gland Origin: An Update and Expanded Morphologic and Immunohistochemical Spectrum of Recently Described Entity

Mammary analogue secretory carcinoma of salivary gland origin (MASC) is a recently described tumor with ETV6 translocation. Akin to secretory breast cancer, MASC expresses S-100 protein, mammaglobin, vimentin, and harbors a t(12;15) (p13;q25) translocation which leads to ETV6-NTRK3 fusion product. Histologically, MASC displays a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogeneous or bubbly secretions. Colloid-like secretory material stains positive for periodic acid-Schiff (PAS) with and without diastase and for Alcian blue. The cells of MASC are devoid of PAS-positive secretory zymogen granules. These features help to exclude the most important differential diagnostic considerations, namely acinic cell carcinoma, low-grade cribriform cystadenocarcinoma, cystadenocarcinoma (not otherwise specified), and low-grade mucoepidermoid carcinoma. To date the presence of the ETV6-NTRK3 fusion gene has not been demonstrated in any other salivary gland tumor than MASC. It is likely that MASC is more common than currently recognized and with further studies, the clinical need for molecular studies of the ETV6-NTRK3 fusion may diminish. However, molecular testing is recommended at this time to arrive at the diagnosis of MASC.

Utility of mammaglobin immunohistochemistry as a proxy marker for the ETV6-NTRK3 translocation in the diagnosis of salivary mammary analogue secretory carcinoma

Mammary analogue secretory carcinoma is a recently described salivary gland neoplasm defined by ETV6-NTRK3 gene fusion. Mammary analogue secretory carcinoma's morphology is 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 mammary analogue secretory carcinomas 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 mammary analogue secretory carcinomas, 44 adenoid cystic carcinomas, 33 pleomorphic adenomas, 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 mammary analogue secretory carcinomas 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 (100%) of 1 low-grade cribriform cystadenocarcinoma, 2 (67%) of 3 polymorphous low-grade adenocarcinomas, 2 (67%) of 3 salivary duct carcinomas, 2 (11%) of 18 mucoepidermoid carcinomas, and 2 (6%) of 33 pleomorphic adenomas. Mammaglobin is highly sensitive for mammary analogue secretory carcinoma, 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 mammary analogue secretory carcinoma.

An analysis of PLAG1 and HMGA2 rearrangements in salivary duct carcinoma and examination of the role of precursor lesions

Salivary duct carcinoma (SDC) often arises in pleomorphic adenoma (PA). Putative precursors, including low-grade cribriform cystadenocarcinoma (LGCCC) and ductal carcinoma in-situ (DCIS), are more controversial. Rearrangement of PLAG1 or HMGA2 is seen in 50-70% of PAs, but this has not been investigated in SDC. Using a large collection of SDCs from a single institution, we aimed to study these genes by fluorescence in-situ hybridization (FISH), and to correlate the presence of precursor lesions/intraductal proliferations with gene alterations. Forty-four SDCs were stained for smooth muscle actin, CK14, and p63, and examined with PLAG1 and HMGA2 FISH. Eight cases were SDC ex-PA; ten had a hyalinized nodule (HN), which is suspicious for PA; six arose in association with LGCCC; and twenty were 'de-novo' SDCs. Ten cases had PLAG1 rearrangement/amplification (22.7%) and eight had HMGA2 (18.2%) rearrangement/amplification. The positive cases were four SDC ex-PAs, eight SDCs with an HN, and five 'de-novo' SDCs. Twenty-three SDC ex-PAs were present in total (52.3%). All six SDC ex-LGCCCs were FISH-negative. Myoepithelial staining surrounded all LGCCCs, and demonstrated DCIS in 17 cases. Eleven DCIS lesions were in SDC ex-PAs or FISH-positive 'de-novo' SDCs. These cases represent 'cancerization' of ducts. Only six FISH-negative 'de-novo' SDCs showed DCIS. A large proportion of SDCs arise in PAs (with or without residual evidence of a PA). A small proportion of SDCs arise in LGCCCs. Cases showing DCIS often represent cancerization.

GATA3 Immunohistochemical Expression in Salivary Gland Neoplasms

GATA3 is a zinc finger transcription factor that regulates the normal development of many tissues and cell types. Recent studies have shown that immunohistochemical nuclear staining for GATA3 among tumors is highly restricted to carcinomas of breast and urothelial origin; however salivary gland tumors have not been tested. Given that breast and salivary gland tissues are very similar with respect to embryologic development and structure, we performed GATA3 staining on a spectrum of salivary gland neoplasms. GATA3 immunohistochemistry was performed on a diverse collection of 180 benign and malignant salivary gland neoplasms including 10 acinic cell carcinomas, 2 adenocarcinomas not otherwise specified, 41 adenoid cystic carcinomas, 2 epithelial-myoepithelial carcinomas, 1 low grade cribriform cystadenocarcinoma, 15 mammary analogue secretory carcinomas, 7 metastatic squamous cell carcinomas, 27 mucoepidermoid carcinomas, 2 oncocytic carcinomas, 5 oncocytomas, 34 pleomorphic adenomas, 4 polymorphous low grade adenocarcinomas, 25 salivary duct carcinomas, and 5 Warthin tumors. Staining for GATA3 was observed in 92/180 (51%) of salivary gland tumors. GATA3 staining was observed in most of the tumor types, but diffuse immunolabeling was consistently seen in salivary duct carcinoma (25 of 25) and mammary analogue secretory carcinoma (15 of 15)-the two tumor types that most closely resemble breast neoplasia. Background benign salivary gland tissue was also usually weakly positive in both acini and ducts. GATA3 immunostaining is not restricted to tumors of breast and urothelial origin. Rather, it is expressed across many different types of salivary gland neoplasms. As a result, salivary gland origin should be considered in the differential diagnosis of a GATA3-positive carcinoma, particularly in the head and neck. Although GATA3 immunohistochemistry is not helpful in resolving the differential diagnosis between a primary salivary gland neoplasm and metastatic breast cancer, it may have some utility in subtyping salivary gland tumors, particularly salivary duct carcinoma and mammary analogue secretory carcinoma.

Low-grade cribriform cystadenocarcinoma of salivary glands: report of two cases and review of the literature

Low-grade cribriform cystadenocarcinoma (LGCCC) is a recently described rare tumor of salivary gland which exhibits clinically indolent behavior. This tumor predominantly consists of intraductal components and frequently exhibits papillary-cystic or cribriform proliferation pattern. Considering the histological features of LGCCC, it should be distinguished with papillocystic variant of acinic cell carcinoma, conventional salivary duct carcinoma, cystadenocarcinoma, polymorphous low-grade adenocarcinoma, carcinoma ex pleomorphic adenoma and mammary analogue secretory carcinoma. Herein, we presented two cases of LGCCC. One arose in the left parotid region in a 48-year-old male, and the other one arose in the right parotid gland in a 59-year-old female. For both cases, immunohistochemically, the luminal tumor cells showed diffuse expression of CK and S100; p63 and smooth muscle actin displayed a continuous rim of myoepithelial cells around all tumor islets; no myoepithelial cells were admixed with the luminal cells. Both patients were alive with no tumor recurrence or metastasis at follow-up.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2593621568999135

Fine-Needle Aspiration Cytology of Low-Grade Cribriform Cystadenocarcinoma with Many Psammoma Bodies of the Salivary Gland

Low-grade cribriform cystadenocarcinoma (LGCCC) is a rare salivary gland tumor that was recently defined as a variant of cystadenocarcinoma by the 2005 World Health Orgazniation (WHO) classification system. We report cytologic findings of an unusual case of LGCCC with many psammoma bodies. A 90-year-old man presented a palpable mass on his left parotid gland. Fine-needle aspiration (FNA) cytology showed tumor cells that were arranged in clusters and dispersed individually. The tumor cells showed mild atypia and had clear or dense cytoplasm with some vacuoles. Numerous psammoma bodies were noted. After surgical resection, the histologic examination revealed a mixed solid and cystic mass showing intraductal growth with focal stromal invasion. The S-100 protein expressed in the tumor cells, but smooth muscle actin and p63 were positive only in myoepithelial cells. Although LGCCCs resemble other salivary gland tumors, differentiating LGCCC during preoperative FNA is important to avoid unnecessary overtreatment.

Cytomorphological Findings and Histological Correlation of Low-Grade Cribriform Cystadenocarcinoma of Salivary Gland in Fine-Needle Aspiration: A Case Study

Low-grade cribriform cystadenocarcinoma (LGCCC) of the salivary gland is a rare tumor. We report the cytologic features and histologic correlation of a patient with LGCCC. A 57-year-old man had a hardly palpable, nontender mass in the right cheek area followed over nine months. Radiologic analysis revealed a 1.2 cm multiseptated, cystic, solid nodule in an anterior superficial lobe of the right parotid gland. Fine-needle aspiration cytology revealed many irregular overlapping sheets or clusters of ductal epithelial cells forming solid, pseudopapillary, and cribriform architectures. Nuclei of the tumor cells revealed inconspicuous atypia with minimal size variation. On the basis of these findings, we confirmed a diagnosis of ductal epithelial proliferative lesion, favoring neoplasm, with uncertain malignant potential. Tumor excision was performed, revealing a tiny multicystic nodule (0.7 cm). Histopathologically, this tumor showed the characteristic morphology of LGCCC. This is the first report of cytomorphological findings of LGCCC in Korea.