Low-grade Salivary Gland Tumors Research Articles

Tumor budding -a potential biomarker in low grade salivary gland carcinomas?

Low-grade salivary gland carcinoma is regularly treated with surgical therapy of the salivary gland without elective neck dissection in T1/2 carcinomas, either alone or with adjuvant radiation therapy. However, occult metastasis and locoregional recurrence influence therapy and outcome. Tumor budding is an emerging prognostic pathological factor in many carcinomas, but has not yet been adequately considered in salivary gland carcinomas. We conducted a retrospective single-center study of 64 patients diagnosed with low-grade carcinoma of the major salivary glands treated between 2003 and 2017. Pathological risk factors and TNM classification were thoroughly assessed for each case. All hematoxylin and eosin (HE)-stained histological specimens underwent careful examination, and tumor budding was identified following the guidelines set forth by the International Tumor Budding Consensus Conference in 2016. Tumor budding was not statistically significant concerning 5-year survival rate (5-YSR) (p=0.969) and mean overall survival (log-rank p=0.315). Whereas 5-year disease-free survival rate (5-YDFSR) was 87% in the low tumor budding group and 61.1% in the intermediate and high tumor budding group (p=0.021). Mean disease-free survival accounted for 100.2 months (CI: 88.6;111.9) in the low budding score group and 58.7 months (CI: 42.8;74.6) in the other group (log-rank p=0.032). Notably, pT1/2 showed significantly lower tumor buds than pT3/4 stages (2.43 tumor buds/0.785 mm2 vs. 4.19 tumor buds/0.785 mm2, p=0.034). Similar findings were noted comparing nodal-positive and nodal-negative patients, as well as patients with and without lymphovascular invasion and perineural invasion (each p<0.05). Tumor budding might be used as an additional prognostic factor for recurrence in low-grade salivary gland carcinoma, seemingly associated with a higher nodal metastasis rate and advanced tumor stages and a worse 5-YDFSR. Consequently, the evaluation of tumor budding in resection specimens of low-grade salivary gland tumor may prove valuable in decision-making for neck dissection and follow-up strategy.

Microsecretory adenocarcinoma: Cutaneous counterpart of a newly described salivary gland tumor with recurrent MEF2C::SS18 fusion.

Microsecretory adenocarcinoma (MSA) is a distinctive low-grade salivary gland tumor with a novel MEF2C::SS18 fusion. Although MSA most commonly occurs in the oral cavity, cases of MSA involving skin have been described recently. Histopathologically, MSA is characterized by microcystic tubules with basophilic luminal secretions, a fibromyxoid stroma and cells with eosinophilic or clear cytoplasm, and a unique immunohistochemical profile (S100+, SOX10+, p63+, and p40-). Cutaneous MSA may rarely demonstrate high-grade features. Follow-up studies have shown MSA to be an indolent tumor, without local recurrence or metastasis after complete surgical excision in the vast majority of cases. It is important to recognize the histopathological features of this unique tumor with a novel MEF2C::SS18 fusion that may occur in skin and to utilize appropriate molecular studies for accurate diagnosis.

Intraductal carcinoma of the retromolar trigone found with elevated serum CEA and CA19-9 levels: a case report

Intraductal carcinoma (IDC) is a rare salivary gland tumor, classified according to the 4th WHO Classification of Head and Neck Tumors in 2017. The tumor affects the parotid gland much more frequently than the minor salivary glands. It’s often asymptomatic. We report a case of IDC of the left retromolar trigon occurring in an 81-year-old woman. She was diagnosed with high serum CEA and CA19-9 at a medical examination. Examinations of her gastrointestinal tract, lungs, and mammary glands were conducted, resulting in no abnormal findings. FDG-PET showed abnormal uptake only in the left retromolar trigon, and a painless mass was observed. A biopsy of this tumor indicated it was likely a low-grade salivary gland tumor. The tumor was completely removed, along with sufficient margins. Histological examination revealed that the lesion was composed of alveolar nests showing an expanded duct-like structure surrounded by an intact myoepithelial layer, with no evidence of infiltration. The final diagnosis was IDC. The postoperative course was uneventful and the patient’s serum CEA and CA19-9 levels decreased to within normal range. We believe that serum CEA and CA19-9 levels could be used for the diagnosis and evaluation of therapeutic effect for this tumor.

Molecular Profiling of Salivary Oncocytic Mucoepidermoid Carcinomas Helps to Resolve Differential Diagnostic Dilemma With Low-grade Oncocytic Lesions.

Oncocytic mucoepidermoid carcinoma (OMEC) is a rare but diagnostically challenging variant of mucoepidermoid carcinoma (MEC). OMEC is notable for differential diagnostic considerations that are raised as a result of overlap with other benign and low-grade oncocytic salivary gland tumors. Diffuse and strong immunoreactivity of p63 protein may be useful in distinguishing OMEC from its mimics. However, focal p63 staining can be present in benign oncytomas. Presence of mucin-containing cells, mucinous cystic formation, and foci of extravasated mucin are considered a hallmark of MEC. True mucocytes may be, however, very few and hardly discernable in OMECs. Recent evidence has shown that most MECs harbor gene fusions involving MAML2. A retrospective review of archived pathology files and the authors' own files was conducted to search for "low-grade/uncertain oncocytic tumor," "oncocytoma," and "oncocytic carcinoma" in the period from 1996 to 2019. The tumors with IHC positivity for p63 and/or p40, and S100 negativity, irrespective of mucicarmine staining, were tested by next-generation sequencing using fusion-detecting panels to detect MAML2 gene rearrangements. Two index cases from consultation practice (A.S. and A.A.) of purely oncocytic low-grade neoplasms without discernible mucinous cells showed a CRTC1-MAML2 fusion using next-generation sequencing, and were reclassified as OMEC. In total, 22 cases of oncocytic tumors, retrieved from the authors' files, and from the Salivary Gland Tumor Registry, harbored the MAML2 gene rearrangements. Presence of mucocytes, the patterns of p63 and SOX10 immunopositivity, and mucicarmine staining were inconsistent findings. Distinguishing OMEC devoid of true mucinous cells from oncocytoma can be very challenging, but it is critical for proper clinical management. Diffuse and strong positivity for p63 and visualization of hidden mucocytes by mucicarmine staining may be misleading and does not always suffice for correct diagnosis. Our experience suggests that ancillary studies for the detection of MAML2 rearrangement may provide useful evidence in difficult cases.

EPITHELIAL MYOEPITHELIAL CARCINOMA: A RARE CAUSE OF ENDOBRONCHIAL OBSTRUCTION

SESSION TITLE: Monday Fellow Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Endobronchial tumors have been reported in numerous benign and malignant conditions. Epithelial myoepithelial carcinoma is a rare malignant cause of endobronchial obstruction for which guidelines for management are lacking. CASE PRESENTATION: A 74 y/o female presented with a complaints of wheezing and hemoptysis. A CT chest revealed an 8 mm obstructing lesion in the distal left main stem bronchus. A bronchoscopy with endobronchial biopsy was performed by the patient's general pulmonologist which showed a low grade salivary gland tumor. She was then referred to Interventional Pulmonology for further removal and management of the tumor. Rigid and flexible bronchoscopy were performed with debridement of the tumor using the bevel of the rigid bronchoscope followed by mechanical debridement with forceps. Due to residual tumor which appeared embedded within the bronchial wall, laser debridement was performed using a 600 nm diode laser fiber at 14W, pulse 1, 0.7s. Additional endobronchial biopsy specimens were consistent with an epithelial myoepithelial carcinoma. The case was reviewed by our institution's Tumor Board with recommendations for additional imaging including CT head and neck which were negative for further evidence of malignancy. Symptoms resolved following resection of the tumor. DISCUSSION: Epithelial myoepithelial carcinoma is a rare malignant tumor seen most frequently in the salivary glands. There are a small number of case reports of primary lung tumors consistent with the same pathology as these salivary gland tumors which are believed to originate from the submucosal bronchial glands. As additional imaging in our patient was negative for malignancy, this is presumed to be a rare, primary lung malignancy. Following local resection and laser debridement, our patient will be monitored closely with surveillance bronchoscopy and imaging for evidence of recurrence. CONCLUSIONS: Given the rarity of epithelial myoepithelial carcinoma, long term follow up is required in order to provide improved recommendations regarding both management and prognosis. Reference #1: Latife Doganay, Selcuk Bilgi, Asli Ozdil, Yener Yoruk, Semsi Altaner, and Kemal Kutlu (2003) Epithelial-Myoepithelial Carcinoma of the Lung. Archives of Pathology & Laboratory Medicine: April 2003, Vol. 127, No. 4, pp. e177-e180. DISCLOSURES: No relevant relationships by Sara Greenhill, source=Web Response No relevant relationships by Jessica Johnson, source=Web Response

A Novel Algorithmic Diagnostic Approach to Secretory Carcinoma of Salivary Gland

Background: Secretory carcinoma (SC) is a recently recognized tumour of salivary gland with characteristic t (12; 15) (q13; q25) translocation with ETV6-NTRK3 fusion. SC were misdiagnosed as Acinic cell carcinoma (AciCC), especially Papillary cystic variant (PCV) in the past. Primary objective of the study was to devise diagnostic algorithm to distinguish SC from other low grade salivary gland tumors especially AciCC. Methods: Surgical pathology archives was searched for cases diagnosed as PCV-AciCC from 2005 to 2017 and as SC from 2012-2017. The H&E, IHC and FISH results were studied. Results: Parotid and oral cavity were involved in 74.3% and 14.2% cases. HE b) solid pattern showing multivacuolated bubbly cytoplasm; c) follicular pattern with dense colloid like secretions. A diagnostic algorithm was devised. Of 35 cases, upfront diagnosis of SC was offered in 22 cases. 13 Cases of PCV-AciCC were reclassified as SC based on morphology and confirmed by IHC (diffuse co-expression of mammaglobin, S100 and lack of DOG1 positivity) and molecular study. 65.7% cases showed ETV6 translocation by FISH. Conclusion: SC is a new entity, which was misdiagnosed as PCV-AciCC in the past. SC can originate in minor salivary gland. Awareness of morphological indicators and high index of suspicion is necessary for diagnosis. IHC markers further facilitate the diagnosis. The translocation study can thus be limited to cases with unusual histology and planning of targeted therapy in future. A novel diagnostic algorithm is suggested for recognition of this new entity.

Newly Described Entities in Salivary Gland Pathology.

Salivary glands may give rise to a wide spectrum of different tumors. This review concentrates on 4 salivary gland tumors that have been accepted in the recent literature as new neoplastic entities: mammary analog secretory carcinoma, cribriform adenocarcinoma of minor salivary glands (CASG), sclerosing polycystic adenosis/adenoma (SPA), and the mucinous/secretory variant of myoepithelioma. Mammary analog secretory carcinoma is a distinctive low-grade malignant salivary cancer that harbors a characteristic chromosomal translocation, t(12;15) (p13;q25), resulting in an ETV6-NTRK3 fusion. Cribriform adenocarcinoma (CASG) is a distinct tumor entity that differs from polymorphous low-grade adenocarcinoma by location (ie, most often arising on the tongue), by prominent nuclear clearing, differing alterations of the PRKD gene family, and clinical behavior with frequent metastases at the time of presentation of the primary tumor. Early nodal metastatic disease is seen in most cases of CASG; yet, they are still associated with indolent clinical behavior, making it a unique neoplasm among all low-grade salivary gland tumors. SPA is a rare sclerosing tumor of the salivary glands characterized by the combination of cystic ductal structures with variable cell lining including vacuolated, apocrine, mucinous, squamous, and foamy cells, by prominent large acinar cells with coarse eosinophilic cytoplasmic zymogen-like granules, and by closely packed ductal structures, surrounded by a peripheral myoepithelial layer and stromal fibrosis with focal inflammatory infiltrates. SPA frequently harbors intraductal epithelial dysplastic proliferations ranging from mild dysplasia to severe dysplasia/carcinoma in situ. Moreover, SPA has been proven to be a clonal process by HUMARA assay and is associated with considerable risk of recurrence. Therefore, on the basis of all these newly recognized findings, we believe that SPA is likely a neoplasm, and we suggest the name "sclerosing polycystic adenoma." The mucinous variant of myoepithelioma is a myoepithelial tumor with foci of prominent cytoplasmic clearing frequently containing intracellular mucin material and having signet-ring morphology.

Newly described salivary gland tumors

This review concentrates on three salivary gland tumors that have been accepted in the recent literature as new neoplastic entities: mammary analog secretory carcinoma (MASC), sclerosing polycystic adenoma (SPA) and cribriform adenocarcinoma of tongue and other minor salivary glands (CAMSGs). MASC is a distinctive low-grade malignant salivary cancer that harbors a characteristic chromosomal translocation, t(12;15) (p13;q25) resulting in an ETV6–NTRK3 fusion. SPA is a rare lesion often mistaken histologically for low-grade salivary carcinoma. Previously thought to be a reactive fibroinflammatory process, but recent evidence of clonality, recurrences in up 30%, and dysplastic foci suggest it may be truly neoplastic. CAMSG is a distinct tumor entity that differs from polymorphous low-grade adenocarcinoma (PLGA) by location (ie, most often arising on the tongue), by prominent nuclear clearing, alterations of the PRKD gene family and clinical behavior with frequent metastases at the time of presentation of the primary tumor. Early metastatic disease seen in most cases of CAMSG associated with indolent behavior makes it a unique neoplasm among all low-grade salivary gland tumors. Salivary glands may give rise to a wide spectrum of different tumors. They are often diagnostically challenging as morphological features often overlap between different entities. Although conventional morphology in combination with immunohistochemical findings still provide the most important clues for diagnosis, recent advances in molecular pathology offer new diagnostic tools in investigating the differential diagnosis, as well as providing potentially valuable prognostic indicators. In the last two decades, several new salivary gland tumor entities have been described, namely MASC, SPA and CAMSGs.

Cribriform adenocarcinoma of the tongue and minor salivary glands: a review.

Cribriform adenocarcinoma of the tongue and minor salivary glands (CATMSG) is a tumor occurring mostly, but not exclusively, in the base of the tongue. Other locations are minor salivary glands of the oral cavity. Histopathologically, CATMSG resembles papillary carcinoma of the thyroid gland. It usually reveals a solid growth devoid of colloid, and eosinophilic material present in follicular areas is rather pale in contrast to metastatic foci seen in papillary thyroid carcinoma that shows typical deeply eosinophilic colloid with "moth-eaten peripheries" and cystic configuration. In addition, giant multinucleated cells are not observed in CATMSG and psammoma bodies are found only exceptionally. Unlike papillary thyroid carcinoma, CATMSG is composed of hybrid secretory-myoepithelial cells. Most importantly, CATMSG is consistently negative with both thyroglobulin and TTF-1. CATMSG is a distinct tumor entity that also differs from polymorphous low-grade adenocarcinoma by location, cytology, histological architecture, and behavior, with frequent metastases at the time of presentation. Paradoxically, early metastatic disease seen in most cases of CATMSG is associated with an indolent behavior. It makes CATMSG a unique neoplasm among all low-grade salivary gland tumors.

Recurrent Hyalinizing Clear Cell Carcinoma of the Base of Tongue with High-Grade Transformation and EWSR1 Gene Rearrangement by FISH

Hyalinizing clear cell carcinoma (HCCC) is a rare, low-grade salivary gland tumor with clear cells and hyalinized stroma. Prognosis of HCCC is excellent with few cases metastasizing to the lymph nodes and lung. We present a case of a 61-year-old male with recurrent HCCC on the base of tongue. Histologic examination revealed sheets of clear and eosinophilic cells with a background of a myxoid-like matrix. In addition, large, bizarre malignant cells, focal necrosis, and atypical mitotic figures were identified. By immunohistochemistry, the clear cells were positive for CK18, EMA and vimentin, focally positive for CK7 and CD10, but negative for p63, HMWK, SMA and calponin. A metastatic renal cell carcinoma was considered a possibility but the tumor was called "poorly-differentiated carcinoma, NOS". The patient underwent primary radiotherapy. A recurrence was identified at 10months follow-up. A biopsy of the recurrent tumor showed clear cell differentiation and a predominant cribriform pattern with focal cords of eosinophilic cells invading the stroma. In contrast to the original tumor, no mitotic figures, atypia or necrosis were identified. The combination of lower grade and different architectural patterns appeared markedly different than the previous biopsy and the immunohistochemical pattern was also different. The recurrent tumor showed diffuse positivity for p63 and HMWK. It was negative for CD10, vimentin, SMA and calponin. Fluorescence in situ hybridization (FISH) analysis was positive for rearrangement of the EWSR1 gene in both samples, confirming that this represented a recurrence of the same tumor. It also confirmed that the initial tumor was a HCCC with high-grade transformation.

Mammary Analog Secretory Carcinoma of Salivary Gland Origin With the ETV6 Gene Rearrangement by FISH

Mammary analog secretory carcinoma (MASC) is a recently described tumor predominantly arising in the parotid gland. These tumors represent locally invasive malignancies with microcystic architecture, low-grade nuclei, and granular pink vacuolated cytoplasm. They display strong vimentin and S100 positivity and harbor an identical t(12;15)(p13;q25) to their breast counterpart, leading to a ETV6-NTRK3 fusion oncogene. These features help exclude the most important differential diagnostic considerations, namely, acinic cell carcinoma (AciCC) and low-grade cystadenocarcinoma, not otherwise specified. Here we present a series of 7 recent examples of MASC, which showed features not previously described. These 7 cases were observed in patients ranging in age from 14 to 77 years (mean, 40 y), occurred almost exclusively in male patients (6:1), and showed >50% (4 of 7 cases) involvement of the oral cavity, with only 2 arising in the parotid. The remaining case is the first reported in the submandibular gland. The tumors showed a variety of patterns including single macrocysts, combined macrocystic and microcystic spaces, and solid architecture. They showed prominent hobnailing in the cystic areas. Secretions within the cysts and tubular areas tended to be positive for periodic acid schiff, periodic acid schiff diastage and mucicarmine, the latter also showing occasional intracytoplasmic mucin droplets, a feature not previously recognized. One case showed prominent mucinous differentiation, which, coupled with high-molecular-weight keratins (HMWK) positivity, mimicked mucoepidermoid carcinoma (MEC). The tumors were generally positive for HMWK (6 of 7), S100 (5 of 7), vimentin, CK19, and other epithelial markers. The finding of duct involvement, proven with an incomplete p63-positive basal layer surrounding a minority of tumor cell nests and cysts, raised the possibility of a ductal epithelial origin for MASC. Alternatively, this could represent secondary ductal involvement by tumor. All cases showed rearrangement of the ETV6 gene by fluorescence in situ hybridization, confirming the diagnosis of MASC. These findings reinforce MASC as a unique low-grade salivary gland tumor entity with morphologic overlap with AciCC, MEC, and cystadenocarcinoma.

EWSR1‐ATF1 fusion is a novel and consistent finding in hyalinizing clear‐cell carcinoma of salivary gland

Hyalinizing clear-cell carcinoma (HCCC) is a rare, low-grade salivary gland tumor with distinctive clear-cell morphology and pattern of hyalinization as well as focal mucinous differentiation. However, histological overlap exists with other salivary gland tumors, such as epithelial-myoepithelial carcinoma (EMCa), salivary myoepithelial carcinoma, and mucoepidermoid carcinoma (MEC). The potential relationship between HCCC and its morphological mimics has not been yet investigated at the genetic level. In this study, we conducted a molecular analysis for the presence of rearrangements in MAML2, commonly seen in MECs, and EWSR1, involved in "soft tissue myoepithelial tumors" (SMET) by fusion with POU5F1, PBX1, or ZNF444. Fluorescence in situ hybridization (FISH) was performed on 23 HCCC cases for abnormalities in MAML2, EWSR1, FUS, POU5F1, PBX1, and ZNF444. FISH for MAML2 was negative in all cases (0 of 14), including those with mucinous differentiation (0 of 7). An EWSR1 rearrangement was identified in 18 of 22 HCCCs (82%), while no break-apart signals were seen in FUS, POU5F1, PBX1, or ZNF444. 3'RACE on an EWSR1 rearranged HCCC identified an EWSR1-ATF1 fusion, which was confirmed by RT-PCR. ATF1 involvement was further confirmed by FISH analysis in 13 of 14 EWSR1-rearranged HCCC cases (93%). In contrast, all control cases tested, including among others 5 EMCa and 3 MEC with clear cells, were negative for EWSR1 and ATF1 rearrangements. The presence of EWSR1-ATF1 fusion in most HCCCs reliably separates these tumors from its histological mimics. The distinction from MEC is particularly important, as conventional MEC grading schemes overgrade these indolent HCCCs, potentially impacting on treatment.

Aberrant PLAG1 expression in pleomorphic adenomas of the salivary gland: a molecular genetic and immunohistochemical study

The morphologic distinction of pleomorphic adenoma from other benign or low-grade salivary gland tumors is sometimes difficult and problematic because of their potentially overlapping histological patterns. A subset of pleomorphic adenoma harbors specific gene alterations involving PLAG1 or HMGA2, and the detection of these fusion genes and their products using formalin-fixed, paraffin-embedded (FFPE) tumor specimens may be a useful diagnostic adjunct. In the present study, gene fusions involving PLAG1 or HMGA2 were examined by reverse transcription-polymerase chain reaction (RT-PCR) analysis, with FFPE tumor tissues and immunohistochemical expression of PLAG1 in 45 pleomorphic adenomas, using a commercially available antibody. RT-PCR analyses identified the CTNNB1-PLAG1, LIFR-PLAG1, CHCHD7-PLAG1, and HMGA2-WIF1 fusion transcripts in eight, two, one, and one case, respectively. The TCEA1-PLAG1, HMGA2-FHIT, and HMGA2-NFIB fusion transcripts were not detected. Immunohistochemically, tumor cells in all 45 pleomorphic adenomas were positive for PLAG1, irrespective of PLAG1 rearrangements, even in the case with the HMGA2-WIF1 fusion transcript. Tumor cells displaying myoepithelial or cartilaginous differentiation were almost constantly positive for PLAG1, whereas a limited expression was observed in glandular or keratinizing cells. Among the 46 tumors other than pleomorphic adenoma, 4 carcinomatous components of carcinomas ex pleomorphic adenoma were positive for PLAG1, the other 39 were negative for PLAG1, and the remaining 3 were only faintly and/or focally stained, indicating that the immunohistochemical detection of PLAG1 is diagnostically useful. The present results also suggest that overexpression of PLAG1 is essential for the tumorigenesis of pleomorphic adenomas, although the mechanisms mediating PLAG1 overexpression seem to be variable.