"Pancreatic Mucoepidermoid Carcinoma" Is not a Pancreatic Counterpart of CRTC1/3-MAML2 Fusion Gene-related Mucoepidermoid Carcinoma of the Salivary Gland, and May More Appropriately be Termed Pancreatic Adenosquamous Carcinoma With Mucoepidermoid Carcinoma-like Features.

"Mucoepidermoid carcinoma (MEC)" has been accepted as a synonym for pancreatic adenosquamous carcinoma (ASC). Pancreatic ASC can show salivary gland-type MEC-like morphology. CRTC1/3-MAML2 fusion gene is a characteristic molecular feature of MEC of the salivary gland. We conducted this study to clarify whether the pancreatic ASC with salivary gland-type MEC-like morphology (Pan-MEC) is a pancreatic counterpart of salivary gland-type MEC (Sal-MEC). We retrospectively analyzed 37 pancreatic ASCs including 16 Pan-MECs and 21 tumors without MEC-like features (ASC-NOS [not otherwise specified]), and we investigated (1) clinicopathologic features, (2) the presence of CRTC1/3-MAML2 fusion gene by reverse transcription polymerase chain reaction, (3) the presence of rearrangement of MAML2 gene by fluorescence in situ hybridization, and (4) mucin core proteins by immunohistochemistry. We also compared 16 Pan-MECs with 20 Sal-MECs by immunohistochemistry for mucin core protein. There were no significant differences of any clinicopathologic characteristics and survival analysis between the Pan-MECs and ASCs-NOS. Of note, the pancreatic ASCs (including Pan-MEC and ASC-NOS) were significantly more aggressive than conventional pancreatic ductal adenocarcinoma. In addition, all Pan-MECs were histologically high-grade. CRTC1/3-MAML2 fusion gene and MAML2 gene rearrangement were not detected in any ASCs including Pan-MECs. There were significant differences of MUC5AC and MUC6 between the Pan-MECs and Sal-MECs, but no significant differences of mucin core protein between the Pan-MECs and pancreatic ASCs-NOS. Pan-MEC is histologically and biologically high-grade and unrelated to CRTC1/3-MAML2 fusion gene, unlike Sal-MEC which is related to CRTC1/3-MAML2 fusion gene. Pan-MEC is not a pancreatic counterpart of CRTC1/3-MAML2 fusion gene-related Sal-MEC.

Reevaluation of MAML2 fusion-negative mucoepidermoid carcinoma: a subgroup being actually hyalinizing clear cell carcinoma of the salivary gland with EWSR1 translocation.

Hyalinizing clear cell carcinoma (HCCC) is a rare salivary gland tumor with a specific EWSR1-ATF1 fusion gene and can have mucin production. Mucoepidermoid carcinoma (MEC) with a clear cell component is its morphologic mimic. Using MAML2 fluorescence in situ hybridization (FISH), a total of 49 MEC cases were separated into MAML2 fusion-positive (32 cases) and MAML2 fusion-negative groups (17 cases). This study used EWSR1 FISH to investigate MAML2 fusion-negative cases to identify previously unrecognized HCCC. Among 17 MAML2 fusion-negative cases, 3 had rearrangement of the EWSR1 gene and were reclassified as HCCC. Including 5 previously diagnosed HCCC cases, these 8 HCCC cases had a male-to-female ratio of 1:7, and most (7/8) tumors arose from oral minor salivary glands in the oral cavity (tongue base and palate). EWSR1-ATF1 fusion was confirmed by FISH in all 8 HCCC cases. The histologic features between genetically confirmed HCCC and MEC were compared. HCCC was significantly associated with minor salivary gland involvement, a discrepancy between low-grade cytology and intermediate- to high-grade histology using the MEC grading system, and absence of both epidermoid cells with abundant cytoplasm and goblet cells lining cysts or forming clusters. Clear cells and a hyalinized stroma were not specific for HCCC. HCCC may be erroneously classified as MEC because clear cells may be a minor histologic component and mucin production is not uncommon. Previously diagnosed MEC cases should be reevaluated, especially those arising from minor salivary glands or without MAML2 fusion. Careful histologic evaluation with supporting molecular testing can facilitate pathologic diagnoses.

[Salivary gland-type lung tumor: An update]. / Tumeurs de type glandes salivaires du poumon.

"Salivary gland-type" tumors arising from the bronchi and lung are rare but not exceptional entities. They are mostly represented by malignant entities such as cystic adenoid carcinoma, mucoepidermoid carcinoma and epithelial/myoepithelial carcinoma. Benign tumors are rare, mainly encompassing pleomorphic adenomas, which are to differentiate from mucous gland adenomas, another entity arising specifically from the peri-bronchial glands. These tumours develop in the proximal bronchi and are not associated with smoke abuse. Their main treatment is surgery. It is important to differentiate them from other broncho-pulmonary tumours as they do not share the same prognosis and therapeutic. This article will review the WHO 2015 classification of these tumours as well as recent updates from the literature to help define diagnosis criteria for these uncommon entities.

Warthin-like Mucoepidermoid Carcinoma: A Combined Study of Fluorescence In Situ Hybridization and Whole-slide Imaging.

There has been some debate as to whether a subset of metaplastic Warthin tumors (mWTs) harbor the mucoepidermoid carcinoma (MEC)-associated CRTC1-MAML2 fusion. We analyzed 15 tumors originally diagnosed as mWT (mWT-like tumors), 2 of which had concurrent MECs. We looked for the CRTC1/3-MAML2 fusion transcripts and performed immunohistochemistry for p63 and fluorescence in situ hybridization (FISH) for the MAML2 split. To localize MAML2 split-positive cells at the cellular level, whole tumor tissue sections were digitalized (whole-slide imaging [WSI]). The CRTC1-MAML2, but not CRTC3-MAML2 was detected in 5/15 mWT-like tumors. FISH-WSI results showed that all epithelial cells harbored the MAML2 split in fusion-positive mWT-like tumors and were totally negative in fusion-negative mWT-like tumors. A review of the hematoxylin and eosin-stained slides showed that morphology of the "metaplastic" epithelium was virtually indistinguishable between fusion-positive and fusion-negative tumors. However, oncocytic bilayered tumor epithelium, characteristic to typical WT, was always found somewhere in the fusion-negative tumors but not in the fusion-positive tumors. This distinguishing histologic finding enabled 5 pathologists to easily differentiate the 2 tumor groups with 100% accuracy. The age and sex distribution of fusion-positive mWT-like tumor cases was similar to that of fusion-positive MEC cases and significantly different from those of fusion-negative mWT-like tumor and typical WT cases. In addition, only fusion-positive mWT-like tumors possessed concurrent low-grade MECs. In conclusion, a subset of mWT-like tumors were positive for the CRTC1-MAML2 fusion and had many features that are more in accord with MEC than with WT. The term Warthin-like MEC should be considered for fusion-positive mWT-like tumors.

Mammaglobin and S-100 immunoreactivity in salivary gland carcinomas other than mammary analogue secretory carcinoma.

Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that has morphologic features similar to secretory carcinoma of the breast and that also harbors the same ETV6 translocation. Diffuse mammaglobin and S-100 immunoreactivity are used to differentiate MASC from its morphologic mimics, especially acinic cell carcinoma and adenocarcinoma, not otherwise specified. However, the combination of mammaglobin and S-100 immunoreactivity has not been well studied in other types of salivary gland carcinomas that may have focal areas reminiscent of MASC. Here we evaluated mammaglobin and S-100 immunoreactivity in 15 cases each of polymorphous low-grade adenocarcinoma, adenoid cystic carcinoma and mucoepidermoid carcinoma, and also in 2 cases of adenocarcinoma, not otherwise specified, and 1 mucinous adenocarcinoma. Cases with significant co-expression of mammaglobin and S-100 (moderate or strong immunoreactivity in >25% of tumor cells) were further analyzed by fluorescence in situ hybridization using the ETV6 (12p13) break-apart probe. Nine cases (60%) of polymorphous low-grade adenocarcinoma and two (13.3%) of adenoid cystic carcinoma met the criteria for significant co-expression of mammaglobin and S-100. All were negative for the ETV6 translocation by fluorescence in situ hybridization. Although mammaglobin and S-100 positivity was seen in the majority of polymorphous low-grade adenocarcinomas and a minority of adenoid cystic carcinomas, none were positive for the ETV6 translocation characteristic of MASC. This indicates a need for caution in the use of immunohistochemistry for diagnosing MASC, especially in the absence of cytogenetic confirmation.

Salivary mucoepidermoid carcinoma: a multi-institutional review of 76 patients.

Mucoepidermoid carcinoma (MEC) is a relatively common salivary tumor with varying potential for aggressive behavior. Mucoepidermoid carcinoma grading has evolved from descriptive two-tiered schemata to more objective three-tiered systems. In 2001, we published a grading system Brandwein et al. in Am J Surg Pathol 25:835-845, (2001) which modified the prevailing criteria of Auclair et al. in Cancer 69:2021-2030 (1992), and included additional features of aggressive MEC. Here we seek to validate our modified grading system in a new multicenter cohort. The retrospective cohort consisted of 76 patients with confirmed MEC and known outcome data. The resection specimens were reviewed and uniformly graded according to our modified criteria Brandwein et al. in Am J Surg Pathol 25:835-845 (2001), and the Auclair criteria Auclair et al. in Cancer 69:2021-2030, (1992), Goode et al. in Cancer 82:1217-1224, (1998). Case distribution was as follows: Montefiore Medical Center: 41 (1977-2009), University of Alabama at Birmingham: 21 (1999-2010), and Rhode Island Hospital: 14, (1995-2011). Patient age ranged from 7 to 81 years (mean 51 years). The female to male ratio was 3:1. The most commonly involved sites were: parotid: n = 39 (51%), palate: n = 10 (13%), retromolar trigone: n = 6 (8%), buccal: n = 5 (7%), and submandibular gland: n = 5 (7%). The modified criteria upgraded 41% MEC; 20/25 MEC from AFIP Grade 1 to Grade 2 and 5/25 from AFIP grade 1 to grade 3. Eleven patients had positive lymph nodes; the AFIP MEC grade for cases were: grade 1-3/11, Grade 2-1/11, and grade 3-7/11; the modified grading criteria distribution for these cases were Grade 1: 0/11, grade 2: 1/11, and grade 3: 10/11. Nine patients developed disease progression after definitive treatment. High-stage and positive lymph node status were significantly associated with disease progression (p = 0.0003 and p < 0.0001, respectively). For the nine patients with disease progression, the modified grading schema classified eight MEC as grade 3 and one as grade 2. By comparison, the AFIP grading schema classified three of these MEC as grade 1, and the remaining six as grade 3. Despite the fact that this multicenter retrospective study accrued 76 patients with outcome, the predictive performance of the two grading schema could not be compared due to the few patients who experienced disease progression and were also reclassified with respect to grade (n = 3).

Mucoepidermoid carcinoma: a five-decade journey.

Several decades after a comprehensive description of mucoepidermoid carcinoma (MEC), there is no uniformly accepted grading system. The most recent debate regarding the histologic grading of MECs, centers on the wide range of reported prevalence of cyclic AMP response element-binding protein (CREB)-regulated transcription coactivator (CRTC1-MAML2) rearrangement in high-grade (HG) MECs. We hypothesize that difficulties in morphologic classification may partially explain problems in grading MECs. We believe that HG MECs, as diagnosed over the last several decades, represent a blend of true MECs with unrelated clinicopathologic entities. To examine the historic aspects of this problem, and to identify neoplasms that most commonly mimic "high-grade" MEC, we reviewed 46 cases of alleged MEC diagnosed in our department from 1956 to 1974. The diagnosis of MEC was confirmed in 22 cases and was changed in 24 cases. Compared to cases of confirmed MEC, cases with changed diagnoses had higher incidence of lymph node metastases, perineural invasion, and shorter overall survival. Adenosquamous carcinoma, squamous cell carcinoma, and salivary duct carcinoma emerged as the most common mimics of HG MEC. The single most common diagnostic issue in these cases is the level of keratinization acceptable for MEC. Twenty cases of confirmed MEC were tested for CRTC1-MAML2 rearrangement and 5 low-grade MECs, 7 intermediate grade MECs, and 2 cases of HG MEC were translocation-positive.

Patterns of malignant salivary gland tumours in Jos University Teaching Hospital (JUTH), Jos: a ten-year retrospective study.

BACKGROUND: Salivary gland tumours are common head and neck tumours and more common in western world than Africans. Most salivary gland tumours are benign but the morbidity and mortality as expected is higher with malignant tumours. This study is aimed at describing the histological pattern, age, sex and site distribution of malignant salivary gland tumours in Jos University Teaching Hospital (JUTH) Jos from January 1998 to December 2007. METHODS: This is a descriptive study of all histologically confirmed malignant salivary gland tumours over a period of ten years. Fresh sections of tissue blocks of these lesions were made using the microtome (3 micrones). They were made into slides and stained with Hematoxylin and Eosin (H and E) and Periodic Acid Schiff (PAS) stains. The slides were reported independently by four pathologists. Diagnosis was made and classification done according to the World Health Organisation (WHO) classification of salivary gland tumours 3. Information such as age, sex and-site of distribution of these tumours was gotten from the patient's case files. The data was analyzed manually. RESULTS: Muco-epidermoid carcinoma accounted for the highest (32 cases) histologic type. Malignant salivary gland tumours occurred more within the age range 40 to 69 years with the age group 50-59 years accounting for the highest frequency (36 cases). Most of these malignant salivary gland tumours occurred more in the parotid gland, the minor salivary being the least site of occurrence. CONCLUSION: Mucoeperdermiod carcinoma is the commonest salivary gland tumour and that malignant salivary gland tumours in this study and it occurred more after the 5th decade of life.

Juvenile intraoral mucoepidermoid carcinoma.

PURPOSE: The purpose of this study was to assess the clinicopathologic, treatment, and outcome features of a series of intraoral mucoepidermoid carcinomas (MECs) affecting children and adolescents. PATIENTS AND METHODS: Between 1953 and 2006, from 102 intraoral MECs, 9 (8.8%) affected patients under 18 years of age. Clinical data were retrieved from the medical records, the microscopical slides reviewed, and the tumors graded in low, intermediate, and high grades of malignancy. RESULTS: Five cases occurred in females and 4 in males, with a mean age of 14 years. Seven cases affected the palate, and the other 2 occurred in the buccal mucosa and retromolar area. Most patients presented in initial clinical stages and all cases were surgically treated. Microscopically, 7 tumors were classified as histologically low-grade malignancies. Eight patients did not show tumor recurrence after a mean follow-up of 98.4 months (range, 4 to 278 months), and 1 patient developed local and neck recurrences and died after 15 years of initial treatment. CONCLUSION: Juvenile MEC are rare tumors, most occur in the palate and present as a low-grade malignancy with excellent prognosis. Although rare, MEC should be considered in the differential diagnosis of intraoral submucous nodule in young patients.

Salivary mucoepidermoid carcinoma: revisited.

Mucoepidermoid carcinoma (MEC) is a malignant epithelial neoplasm composed of varying proportions of mucous, epidermoid, intermediate, columnar, and clear cells and often demonstrates prominent cystic growth. MEC is usually subclassified as low, intermediate, or high grade on the basis of its histologic features, including the presence of cystic spaces, cellular differentiation, proportion of mucous cells, growth pattern, type of invasion, and cytologic atypia. Because even low-grade neoplasms may metastasize, the term mucoepidermoid tumor is inappropriate. The 3-level grading approach to tumor classification has found general acceptance among pathologists; differences in biologic behavior can be demonstrated even though clinical stage has become a better prognosticator. However, in the case of MEC, no universal agreement exists regarding which histologic grading criteria are most the useful, and grading has varied. These issues have led to the investigation of more subjective systems. We describe these new schemes, the histologic variants of MEC, and the ancillary methods that allow for further stratification of patients with MEC, especially for patients with grade 2 tumors, which have a variable and unpredictable clinical course.

MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma.

PURPOSE: Mucoepidermoid carcinoma is the most common primary malignancy of the salivary gland. Mucoepidermoid carcinoma translocated gene 1-mastermind-like gene family (MECT1-MAML2) gene fusion was identified from a recurring t(11;19)(q21;p13) translocation, which is often the sole cytogenetic alteration in this disease. This fusion transcript has been frequently detected in mucoepidermoid carcinoma and shown to be involved in the transformation of epithelial cells. However, its clinicopathologic significance remains unclear. EXPERIMENTAL DESIGN: Seventy-one cases of mucoepidermoid carcinoma and 51 cases of nonmucoepidermoid carcinoma salivary gland tumors (including 26 Warthin tumor cases) were retrospectively analyzed. RNA was extracted from archival materials: histologic paraffin specimens in all cases and cytologic specimens in 10 mucoepidermoid carcinoma cases. The MECT1-MAML2 fusion transcript was detected by a reverse transcription-PCR assay, which can be applied to both histologic and cytologic specimens. The presence of the fusion transcript was correlated with relevant clinicopathologic and survival data of the mucoepidermoid carcinoma patients. RESULTS: The MECT1-MAML2 fusion transcript was detected in 27 of the 71 (38%) mucoepidermoid carcinoma cases but not in any case of nonmucoepidermoid carcinoma tumors. The reverse transcription-PCR results showed no difference between histologic and cytologic specimens. Detection of the MECT1-MAML2 fusion transcript was associated with a less advanced clinical stage and a low-grade tumor histology. The presence of the transcript was associated with longer disease-free and overall survivals on univariate analysis and emerged as an independent prognostic factor for longer overall survival on multivariate analysis. CONCLUSIONS: The MECT1-MAML2 fusion transcript may be specific to mucoepidermoid carcinoma and associated with a distinct mucoepidermoid carcinoma subset that exhibits favorable clinicopathologic features and an indolent clinical course.

Low-grade mucoepidermoid carcinoma of the subglottis treated with organ-preservation surgery.

Mucoepidermoid carcinoma of the subglottis is infrequently reported in the literature. This tumor subtype is more commonly associated with the major and minor salivary glands. Mucoepidertoid carcinoma of the larynx can be difficult to diagnose, and there is no consensus as to appropriate management. We report a case of a low-grade mucoepidermoid carcinoma that was confined to the subglottis and treated with organ-preservation surgery. A conservative surgical approach was taken because of the tumor's low-grade histology and its location and in order to preserve the patient's laryngeal function. At follow-up 15 months postoperatively, the patient remained disease-free, and laryngeal function was intact.

Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene.

Mucoepidermoid carcinomas (MECs) of the salivary and bronchial glands are characterized by a recurrent t(11;19)(q21;p13) translocation resulting in a MECT1-MAML2 fusion in which the CREB-binding domain of the CREB coactivator MECT1 (also known as CRTC1, TORC1 or WAMTP1) is fused to the transactivation domain of the Notch coactivator MAML2. To gain further insights into the molecular pathogenesis of MECs, we cytogenetically and molecularly characterized a series of 29 MECs. A t(11;19) and/or an MECT1-MAML2 fusion was detected in more than 55% of the tumors. Several cases with cryptic rearrangements that resulted in gene fusions were detected. In fusion-negative MECs, the most common aberration was a single or multiple trisomies. Western blot and immunohistochemical studies demonstrated that the MECT1-MAML2 fusion protein was expressed in all MEC-specific cell types. In addition, cotransfection experiments showed that the fusion protein colocalized with CREB in homogeneously distributed nuclear granules. Analyses of potential downstream targets of the fusion revealed differential expression of the cAMP/CREB (FLT1 and NR4A2) and Notch (HES1 and HES5) target genes in fusion-positive and fusion-negative MECs. Moreover, clinical follow-up studies revealed that fusion-positive patients had a significantly lower risk of local recurrence, metastases, or tumor-related death compared to fusion-negative patients (P = 0.0012). When considering tumor-related deaths only, the estimated median survival for fusion-positive patients was greater than 10 years compared to 1.6 years for fusion-negative patients. These findings suggest that molecularly classifying MECs on the basis of an MECT1-MAML2 fusion is histopathologically and clinically relevant and that the fusion is a useful marker in predicting the biological behavior of MECs.

[Significance of molecular-cytogenetic findings in mucoepidermoid carcinoma as an example of salivary gland tumors]. / Bedeutung molekular-zytogenetischer Befunde bei Speicheldrüsentumoren am Beispiel des Mukoepidermoidkarzinoms.

Chromosome translocations in tumors frequently give rise to fusion genes encoding proteins with oncogenic activities. Mucoepidermoid carcinomas (MEC) are characterized by a t(11;19)(q21-22;p13) translocation found in approximately 60% of the tumors. This t(11;19) translocation results in a fusion gene consisting of exon 1 of the MECT 1 gene and exons 2-5 of the MAML 2 gene. As a result of the t(11;19) a fusion protein is generated which, independent of NOTCH-ligands, activates the transcription of the NOTCH target gene HES 1. The altered function of MAML 2 causes a disruption of NOTCH signalling which suggests a novel mechanism of tumorigenesis. Pending the elucidation of the t(11;19) at the molecular level of an apparently identical chromosomal translocation in Warthin's tumor, the identification of the translocation in MEC by FISH- and/or RT-PCR-analyses may become important in diagnosis and might have prognostic relevance. Warthin's tumors are benign salivary gland neoplasms with a distinctive histomorphology and histogenesis completely different from MEC.