Pure Apocrine Intraductal Carcinoma of Salivary Glands: Reassessment of Molecular Underpinnings and Behavior.

BACKGROUND: Intraductal carcinoma (IDC) of the salivary glands is a confounding entity, our understanding of which continues to evolve. At least four forms have been elucidated based on histomorphology, immunophenotype, and molecular profile: (1) intercalated duct-like, S100/SOX10+ with frequent NCOA4::RET fusions; (2) oncocytic, S100/SOX10+ with TRIM33::RET, NCOA4::RET, and BRAF V600E; (3) apocrine, AR+ with PI3 kinase pathway mutations; and (4) mixed/hybrid intercalated duct-like/apocrine, with S100/SOX10+ and AR+ areas and frequent TRIM27::RET. The revelation that myoepithelial cells harbor the same fusion as luminal cells suggested that fusion-positive cases are not in situ carcinomas as previously believed. To this point, purely apocrine IDC with entirely intraductal growth has not been found to harbor fusions, but very few cases have been tested. METHODS: IDCs with pure apocrine morphology, entirely intraductal growth, and no precursor lesion (pleomorphic adenoma or sclerosing polycystic adenoma) were retrieved from the authors' archives. Several immunostains (S100, SOX10, GCDFP-15, AR, p40/SMA) and targeted next generation sequencing (NGS) panel including 1425 cancer-related genes were performed. RESULTS: Seven entirely IDC with pure apocrine type were collected. The cases arose in the parotid glands (mean, 1.9 cm) of 5 men and 2 women ranging from 51 to 84 years (mean, 69.7 years). Histologically, tumors consisted of rounded to angulated ductal cysts lined by epithelial cells with abundant finely granular eosinophilic cytoplasm and large nuclei with prominent nucleoli. Pleomorphism was mild to moderate, the mitotic rate was low, and necrosis was absent. Conventionally invasive foci or areas of intercalated duct-like morphology were not identified. In all cases, luminal cells were diffusely positive for AR and GCDFP-15 while negative for S100/SOX10, and the ducts were completely surrounded by myoepithelial cells highlighted by p40 and SMA. Molecular analysis was successful in 6 cases. Three harbored fusions: one with NCOA4::RET, another with STRN::ALK and one with both CDKN2A::CNTRL and TANC1::YY1AP1. The three fusion-negative cases all harbored HRAS mutations; additional mutations (PIK3CA, SPEN, ATM) were found in 2 of 3 cases. All patients were treated by surgery alone. Six of them are currently free of disease (follow up 12-190 months), but the case harboring NCOA4::RET developed lymph nodes metastasis in the form of a fusion-positive invasive salivary duct carcinoma. CONCLUSIONS: Purely apocrine IDC is a heterogeneous disease. A subset seems to be genetically similar to salivary duct carcinoma and may indeed represent carcinoma in situ. The other group harbors fusions, similar to other forms of IDC. Moreover, the occurrence of lymph node metastasis discredits the idea that any fusion-positive IDC with a complete myoepithelial cell layer has no metastatic potential. With the wide use of RET-and ALK-based targeted therapies, our findings further underscore the importance of fusion analysis for IDC.

Adenoid Cystic carcinoma of minor salivary glands (AdCCmSG): a multidisciplinary update.

INTRODUCTION: Adenoid cystic carcinoma of minor salivary glands (AdCCmSG) represents a 'rarity in the rarity,' posing a clinical challenge in lack of standardized, evidence-based recommendations. At present, AdCCmSG management is mostly translated from major salivary gland cancers (MSGCs). Ideally, AdCCmSG diagnostic-therapeutic workup should be discussed and carried out within a multidisciplinary, high-expertise setting, including pathologists, surgeons, radiation oncologists and medical oncologists. AREAS COVERED: The present review provides an overview of epidemiology and pathologic classification. Moreover, the most recent, clinically relevant updates in the treatment of AdCCmSG (Pubmed searches, specific guidelines) are critically discussed, aiming to a better understanding of this rare pathologic entity, potentially optimizing the care process, and offering a starting point for reflection on future therapeutic developments. EXPERT OPINION: The management of rare cancers is often hindered by limited data and clinical trials, lack of evidence-based guidelines, and hardly represented disease heterogeneity, which cannot be successfully tackled with a 'one-size-fits-all' approach. Our goal is to address these potential pitfalls, providing an easy-to-use, updated, multidisciplinary collection of expert opinions concerning AdCCmSG management as of today's clinical practice. We will also cover the most promising future perspectives, based on the potential therapeutic targets highlighted within AdCCmSG's molecular background.

A Possible Association of Salivary Gland Tumors and Oral Lesions with Birt-Hogg-Dube Syndrome: A Systematic Review.

BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) is an autosomal dominant syndrome with different skin, lung, and renal manifestations. It is diagnosed commonly in the third decade of life, and patients have an increased risk for pneumothorax and renal carcinomas. METHODS: Articles published in PubMed, and Medline from 1977 to September 2023, were included in the systematic review. Inclusion criteria were applied to case reports, case series, and a retrospective cohort study, describing clinical, histopathological, and genetic findings in patients with BHDS with oral and/or parotid lesions. RESULTS: Sixteen families/individuals with BHDS were identified for analysis. Patients ranged in age from 20 to 74 years, with an average of 49.4 years. Males were affected 52.2% of the time and females, 39.1%. Skin fibrofolliculomas were reported in 87% of cases, and oral lesions were documented in 47.8%. Parotid tumors were documented in 43.5% of patients, 30.4% of which were oncocytomas, 4.3% bilateral oncocytomas, and 4.3% "oncocytic carcinoma". CONCLUSIONS: Because BHDS is uncommon, its spectrum of clinical manifestations may be underrecognized, especially as the disease is mostly reported at advanced stage. And some of the patients with BHDS may have oncocytic parotid tumors and oral lesions. In this regard, patients presenting these lesions and other indications of BHDS should be considered for renal screening.

Mucin-rich salivary gland tumors.

Salivary gland neoplasms characterized by abundant mucin production are rare but have long been recognized. Due to their scarcity, precise classification has long eluded these mucin-rich tumors. Recent molecular discoveries, however, have shed considerable light on the genetic underpinnings of mucin-rich salivary gland neoplasms. This manuscript will review the most up-to-date information on this fascinating group of salivary gland neoplasms.

The basaloid-spectrum of salivary gland tumors: A focused review with practical diagnostic considerations.

Basaloid salivary gland neoplasms are a diverse and varied group of benign and malignant tumors. The term 'basaloid' is broadly used in reference to cells with elevated nuclear to cytoplasmic ratio, sparse cytoplasm, and hyperchromatic nuclei. However, a subset may also fit within the "small round blue cell tumor" morphologic category or the "biphasic" salivary gland tumor category. Furthermore, there are no established thresholds for the proportion of basaloid tumor cells needed to consider a tumor within the basaloid spectrum. Given the implicit variability in what is considered a basaloid salivary gland tumor, one may question the inclusion of certain entities (canalicular adenoma, HMGA2::WIF1 pleomorphic adenoma, polymorphous adenocarcinoma) in this review based on classic morphologic features. However, salivary gland tumors with even minor basaloid components may appear 'basaloid' in small biopsy specimens and, thus, a choice was made to focus on common and uncommon diagnostic differentials with this in mind. Entities that will be covered in this review also include basal cell adenoma and basal cell adenocarcinoma, adenoid cystic carcinoma, lymphoepithelial carcinoma, sialoblastoma, adamantinoma-like Ewing Sarcoma, NUT carcinoma, and carcinoma showing thymus-like differentiation.

Intraoral Salivary Gland Cystadenomas: A Case Series Study and Literature Review.

BACKGROUND: Salivary gland cystadenoma (SGCA) is a rare benign tumor that predominantly occurs in the parotid gland. SGCAs affecting the minor salivary glands are uncommon and often resemble, clinically and histopathologically, other salivary gland lesions. METHODS: This study aimed to describe a series of four cases of SGCA affecting intraoral sites and performed a literature review of well-reported SGCA published in the English-language literature. RESULTS: SGCA cases included in this series were diagnosed in the buccal mucosa, lip, and hard palate of female patients aged between 19 and 78 years. All cases underwent excisional biopsy and were histologically characterized by a multicystic growth with variable degrees of capsule formation and were lined by several types of epithelium, including some cell types that are infrequently reported in SGCA. In some cases, a small collection of lymphocytes was observed adjacent to cystic formations. All SGCA were positive for periodic acid-Schiff, and immunohistochemical reactions were positive for CK7 and p63. The follow-up time ranged widely from 3 to 53 months, and to date, no recurrence has been observed. CONCLUSION: The literature review revealed a total of 33 published studies accounting for 55 SGCA cases.

The differential diagnosis of lymphoepithelial lesion of the salivary gland.

The differential diagnosis of salivary gland lesions with epithelial components and lymphoid stroma is often challenging. Salivary gland carcinoma with tumor-associated lymphoid proliferation, tumors composed of both epithelial and lymphoid components, lymphoid neoplasms in the salivary gland, and inflammatory lesions are all included in this category. It encompasses inflammatory lesions and neoplastic lesions. With the exception of Warthin tumors, these lesions are rare, making them more difficult to diagnose. Carcinoma showing thymus-like elements has recently been reported in the salivary gland. Similar to thymic carcinoma, tumor cells are positive for CD5 and are accompanied by T lymphocytes.

Diagnostic clues and pitfalls in salivary gland fine-needle aspiration cytology.

Salivary gland tumors (SGT) display morphological diversity and pose diagnostic challenges. Preoperative fine needle aspiration cytology (FNAC) is a minimally invasive and efficient diagnostic test. However, due to the limited sample size, the final diagnosis may not be established based on FNAC alone. Although cytomorphology and architecture are usually preserved on FNAC, morphologic changes specific to FNAC can complicate the diagnosis. The Milan System for Reporting Salivary Gland Cytopathology categorizes complex FNAC interpretations. Because the cytological diagnosis is closely linked to the histological diagnosis, a multidimensional approach considering the possibility of several differential diagnoses is necessary. From the standpoint of treatment, distinguishing high-grade malignancy from low-grade malignancy is more important than distinguishing malignancy from benign tumors.

Uncovering the WWTR1::NCOA2 Gene fusion in low-grade myoepithelial-rich neoplasm with HMGA2 expression: A case report.

We describe a case of a pleomorphic adenoma (PA) arising from the para-tracheal accessory salivary gland in a 44-year-old male harboring a novel WWTR1::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in salivary gland tumors. The patient presented with hoarseness of voice. The radiological exam revealed a mass in the upper third of the trachea involving the larynx. Histologically, the tumor consisted of bland-looking monocellular eosinophilic epithelial cells arranged in cords and sheets separated by thin fibrous stroma, focally forming a pseudo-tubular pattern. In immunohistochemistry, the tumor cells demonstrated positivity for CK7, PS100, SOX10, and HMGA2; and negativity for CK5/6, p40 p63, and PLAG1. In addition, the clustering analysis clearly demonstrates a clustering of tumors within the PA group. In addition to reporting this novel fusion in the PA spectrum, we discuss the relevant differential diagnoses and briefly review of NCOA2 and WWTR1 gene functions in normal and neoplastic contexts.

Evolving Diagnostic Approach of Pulmonary Salivary Gland-type Tumors.

Pulmonary salivary gland-type, although bear resemblance to their salivary gland counterparts, present a diagnostic challenge due to their rarity. Clinical features overlap with lung carcinoma; however, management strategies and outcomes are distinct. Onus falls on the pathologist to avoid misinterpretation of small biopsies especially in young, nonsmokers with slow growing or circumscribed endobronchial growths. A combination of cytokeratin, myoepithelial immunohistochemical markers, and identification of signature molecular alteration is invaluable in differentiation from lung cancers and subtyping the pulmonary salivary gland-type tumor.

A Novel Gene Fusion YLPM1::PRKD1 Identified in a Cribriform Subtype of Polymorphous Adenocarcinoma.

Cribriform adenocarcinoma of the salivary gland (CASG) is an entity that is currently classified under polymorphous adenocarcinoma (PAC), cribriform subtype per the 2022 WHO classification of head and neck tumours. There is debate about whether CASG should be considered a separate diagnostic entity, as CASG differs from conventional PAC in anatomic site, clinical behaviors, and molecular patterns. Herein we describe a challenging and unique case which shares histologic and behavioral features between CASG and conventional PAC with a YLPM1::PRKD1 rearrangement not previously reported in the literature.

Secretory carcinoma of minor salivary glands.

Secretory carcinoma is a malignant salivary gland tumor, which typically presents as an indolent painless mass within the parotid gland. Involvement of the minor gland is reported but less common. Secretory carcinoma was often misclassified as other salivary gland mimics, particularly acinic cell carcinoma, prior to 2010. It was first recognized as a molecularly distinct salivary gland tumor harboring the same fusion gene as well as histologic and cytogenetic features seen in juvenile breast cancer. Secretory carcinoma is generally managed in the same way as other low-grade salivary gland neoplasms and has a favorable prognosis; however, high-grade transformation requiring aggressive therapeutic interventions have been documented. Recent studies of biologic agents targeting products of this fusion gene offer the promise of a novel therapeutic option for treatment of this malignancy. Due to the limited number of reported cases, the spectrum of clinical behavior, best practices for management, and long-term treatment outcomes for secretory carcinoma remain unclear. A long-standing secretory carcinoma involving minor salivary glands of the mucobuccal fold, which was detected years after it was first noted by the patient, is reported. This case brings to light the importance of a thorough clinical exam during dental visits and reviews diagnostic differentiation of this malignancy from other mimics and discusses decision making for its management.

Prognosticators of Excision of Giant Intra-Oral Tumors in a Resource-Challenged Setting: A Case Report.

Minor salivary glands are widely distributed in the mucosal surface of the lips, palate, nasal cavity, pharynx, and larynx, thus can arise from any of these primary sites. Intra-oral minor salivary gland tumors (IMSGTs), while considered rare in the general population are relatively more common when compared to all the other extra-oral sites. Pleomorphic adenoma, as seen in the index patient, is the most commonly diagnosed benign IMSGT. Intra-oral minor salivary gland tumors are not uncommon and depending on their size, nature, and location can be associated with severe limitation of the Patient's ability to breathe, speak clearly, and/or swallow and consequent severe morbidity and even mortality. In addition to these deleterious effects, they present a major surgical challenge to the surgeon, who has to determine the safest, most feasible access to ensure complete, or near-complete excision, as well as to the anesthetist, who needs to secure a definitive airway through the nose or mouth, both of which could be significantly restricted by the presence of the tumor. The aim is to present our successful management of one of the largest intra-oral minor salivary gland tumors documented in the literature, highlighting the specific measures we undertook to tackle the peculiar surgical and anesthetic challenges we faced. It had been two years since surgery and the patient is thriving with a markedly improved quality of life and no features of recurrence. The patient is a 50-year-old male with a slowly growing painless, left palatal mass in the roof of the mouth of 10 years duration with recurrent spontaneous bloody discharge effluent and snoring. There was an associated history of dysphagia to solid with associated choking spells, a left-sided facial asymmetry with no cheek swelling, odynophagia, sore throat, or difficulty with breathing. There was ipsilateral loss of upper incisors and dental anarchy about two years before presentation. No other nasal, otologic, or ophthalmic symptoms were present. No neck swelling, stiffness, cough, or chest symptoms. The oropharyngeal physical examination was highly restricted due to the intra-oral size of the mass. Figure 1. There was facial asymmetry with a bulge of the left maxilla, left-sided levels 1b and 2 non-tender lymph node enlargements, freely mobile, not adhered to the skin. A craniofacial CT scan revealed extensive isodense heterogeneously enhancing intra-oral soft tissue mass occupying the entire palate/oral cavity and encroaching laterally on the masticator and the parapharyngeal space with erosion of the left maxillary floor and hyoid bone Figure 2. The patient had an excision biopsy of the palatal mass with a free margin. No frozen section at the time of surgery. Histology revealed Pleomorphic adenoma and was followed up for 2 years with no evidence of recurrence. Prognosticators are delay in presentation leading to an increase in size of the mass and severe limitation of the patient's ability to breathe, speak clearly, and/or swallow and consequent severe morbidity and even mortality, the surgeon not being overwhelmed, the skillful Anaesthesist that could maneuver the nasal cavity without us doing tracheostomy and the successful outcome of the surgery.

Les glandes salivaires mineures sont largement réparties à la surface muqueuse des lèvres, du palais, de la cavité nasale, du pharynx et du larynx, et peuvent donc survenir à partir de l'un de ces sites primaires. Les tumeurs des glandes salivaires mineures intra-orales (TGSMIO), bien que considérées comme rares dans la population générale, sont relativement plus courantes par rapport à tous les autres sites extra-oraux. L'adénome pléomorphe, tel que celui observé chez le patient index, est la TGSMIO bénigne la plus fréquemment diagnostiquée. Les tumeurs des glandes salivaires mineures intra-orales ne sont pas rares et, en fonction de leur taille, de leur nature et de leur emplacement, peuvent être associées à une limitation sévère de la capacité du patient à respirer, à parler clairement et/ou à avaler, avec une morbidité sévère et même une mortalité. Outre ces effets délétères, elles présentent un défi chirurgical majeur pour le chirurgien, qui doit déterminer l'accès le plus sûr et le plus faisable pour assurer une excision complète ou presque complète, ainsi que pour l'anesthésiste, qui doit assurer une voie aérienne définitive par le nez ou la bouche, tous deux pouvant être significativement restreints par la présence de la tumeur. L'objectif est de présenter notre prise en charge réussie de l'une des plus grandes TGSMIO documentées dans la littérature, mettant en évidence les mesures spécifiques que nous avons prises pour relever les défis chirurgicaux et anesthésiques particuliers auxquels nous avons été confrontés. Deux ans après l'intervention, le patient se porte bien avec une nette amélioration de sa qualité de vie et aucune manifestation de récurrence. Le patient est un homme de 50 ans présentant une masse palatine gauche en croissance lente et indolore dans le palais depuis 10 ans, avec des écoulements sanguins spontanés récurrents et des ronflements. Il y avait une histoire associée de dysphagie aux solides avec des épisodes d'étouffement, une asymétrie faciale du côté gauche sans tuméfaction de la joue, une odynophagie, un mal de gorge ou des difficultés respiratoires. Il y avait une perte ipsilatérale des incisives supérieures et une anarchie entaire environ deux ans avant la présentation. Aucun autre symptôme nasal, otologique, ophtalmique n'était présent. Aucun gonflement du cou, raideur, toux ou symptômes thoraciques. L'examen physique de l'oropharynx était fortement limité en raison de la taille intra-orale de la masse. Figure 1. Il y avait une asymétrie faciale avec une bosse du maxillaire gauche, des ganglions lymphatiques non douloureux des niveaux 1b et 2 du côté gauche, mobiles librement, non adhérents à la peau. La tomodensitométrie craniofaciale a révélé une masse tissulaire molle intraorale extensive, hétérogène, rehaussée de manière isodense occupant l'ensemble du palais/cavité buccale et empiétant latéralement sur les muscles masticateurs et l'espace parapharyngé, avec érosion du plancher du maxillaire gauche et de l'os hyoïde. Figure 2. Le patient a subi une biopsie d'excision de la masse palatine avec une marge libre. Aucune section congelée n'a été réalisée lors de la chirurgie. L'histologie a révélé un adénome pléomorphe et un suivi de 2 ans n'a montré aucun signe de récurrence. Les facteurs pronostiques comprennent le retard de la présentation entraînant une augmentation de la taille de la masse et une limitation sévère de la capacité du patient à respirer, à parler clairement et/ou à avaler, avec une morbidité sévère voire une mortalité, le chirurgien ne se laissant pas dépasser, l'anesthésiste compétent pouvant manœuvrer dans la cavité nasale sans avoir recours à une trachéotomie, et le succès de l'intervention chirurgicale. MOTS-CLÉS: Intraoral; Glande salivaire mineure; Excision; Tumeur; Pronostiqueurs.

Acinic cell Carcinoma with high-grade Squamoglandular and Chondrosarcomatous Transformation Mimicking 'Carcinosarcoma ex-pleomorphic Adenoma': A Wrinkle in the Proposed Nomenclature Revision for Sarcomatoid Salivary Gland Neoplasms.

While acinic cell carcinoma (AciCC) can undergo high-grade transformation (HGT) to high-grade adenocarcinoma or poorly differentiated carcinoma, other morphologies such as spindle cell/sarcomatoid carcinoma are rare and not well-characterized. We herein report a novel case of AciCC with squamoglandular and chondrosarcomatous HGT mimicking a so-called 'carcinosarcoma ex-pleomorphic adenoma'. The patient is an 81-year-old male with a two-month history of neck swelling and referred otalgia who presented with a left parapharyngeal space mass extending into retropharyngeal space and pterygoid muscles. On resection, the tumor showed considerable morphologic diversity with high-grade serous and mucous acinar components as well as cribriform to solid apocrine-like components with comedonecrosis and squamous differentiation, all of which were embedded in a chondromyxoid background ranging from paucicellular and bland to a high-grade chondrosarcoma/pleomorphic sarcoma-like appearance. Only a minor conventional AciCC component was noted. Immunostains were negative for AR and only focally positive for GCDFP-15 arguing against a true apocrine phenotype, while PLAG1 and HMGA2 were negative arguing against an antecedent pleomorphic adenoma. On the other hand, SOX-10, DOG-1 and PAS after diastase highlighted serous acinar differentiation, and mucicarmine, and NKX3.1 highlighted mucous acinar differentiation. NR4A3 immunohistochemical staining and NR4A3 fluorescence in situ hybridization were positive in the carcinomatous and sarcomatoid components while sequencing analysis of both components revealed identical alterations involving TP53, PIK3CB, ARID1A, and STK11. This unique case warrants caution in designating all salivary sarcomatoid carcinomas with heterologous elements as part of the 'carcinoma ex-pleomorphic adenoma' family.

The extent of androgen receptor and HER2 expression allows for targeted therapy in most cases of salivary duct carcinoma: analysis of clinical and histopathological data in a tertiary care center.

PURPOSE: The incidence of salivary duct carcinoma (SDC) seems to be underestimated due to inaccurate classification. Further, the frequency of SDC patients with targeted therapy options according to current guidelines is unclear. Therefore, this study aimed at (a) describing the proportion of SDC among salivary gland carcinoma (SGC) before and after reclassification of cases initially classified as adenocarcinoma, not otherwise specified (ANOS); and (b) quantifying the frequency of SDC patients with targeted therapy options. METHODS: All patients with SDC or ANOS treated in a tertiary care center between 1996 and 2023 were identified. Histopathological diagnosis was verified for patients primarily diagnosed with SDC and reviewed for patients initially diagnosed with ANOS. Clinical data for SDC patients were retrieved from clinical charts. Immunohistochemical (IHC) androgen receptor (AR) and HER2 staining was performed. RESULTS: Among 46 SDC, 34 were primarily diagnosed as SDC and 12 had initially been classified as ANOS. The proportion of SDC among SGC was 12.1% and was rising when comparing the time periods 2000-2015 (7.1-11.5%) versus 2016-2023 (15.4-18.1%). Nuclear AR staining in > 70% of tumor cells was found in 56.8% and HER2 positivity (IHC 3 +) in 36.4% of cases. 70.5% of patients showed AR staining in > 70% of tumor cells and/or HER2 positivity and therefore at least one molecular target. 5-year overall and disease-free survival (DFS) were 62.8% and 41.0%. Multivariate Cox regression revealed positive resection margins (HR = 4.0, p = 0.03) as independent negative predictor for DFS. CONCLUSIONS: The results suggest a rising SDC incidence and show that the extent of the AR and HER2 expression allows for targeted therapy in most SDC cases.

Non-squamous Cancers of the Larynx.

PURPOSE OF REVIEW: Although non-squamous tumors of the larynx are really rare, they may not always be viewed from the same perspective in the multidisciplinary treatment approach once the diagnosis is made. In this review, non-squamous tumors of the larynx and current approaches in treatment will be discussed. RECENT FINDINGS: When the studies and meta-analyses presented in the last 5 years are evaluated, it is seen that these tumors usually show non-specific symptoms. Due to their submucosal location, the stage of the disease at the time of diagnosis is often advanced. In the literature, treatment may vary in these particular cases. The majority of non-squamous tumors of the larynx includes minor salivary gland tumors, neuroendocrine carcinomas, sarcomas, cartilage tumors, and malignant melanomas. Once treating a patient with these diagnoses, it should be kept in mind that the histopathological subtype is almost as important as the stage of the tumor.

Expanding the cytological and architectural spectrum of mucoepidermoid carcinoma: The key to solving diagnostic problems in morphological variants.

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. Varying sized cysts and sheets composed of three cell types (epidermoid, intermediate, and mucous cells) with varying degrees of atypia form the characteristic histological appearance of MEC. MEC frequently contains a wide variety of modified tumor cells and can be entirely cystic or completely solid. Under these circumstances, MEC requires critical differentiation from many mimickers, ranging from simple cysts and benign tumors to high-grade carcinomas. Tumor-associated lymphoid proliferation and sclerotic changes in the stroma also contribute to diagnostic difficulties. Several well-known diagnostically challenging variants (oncocytic, clear cell, spindle cell, and sclerosing) exist in MEC. With the advent of studies on specific CRTC1/3::MAML2 fusion genes in MEC, newly proposed subtypes have emerged, including Warthin-like and non-sebaceous lymphadenoma-like MECs. In addition to the recently defined mucoacinar variant with a serous cell phenotype, MEC devoid of squamous differentiation has also been reported, implying the need to reconsider this basic concept. In this article, we outline the general clinical features and MAML2 status of conventional MEC and review the cytoarchitectural subtypes, with an emphasis on a pitfall in the interpretation of this histologically diverse single entity.

PON3::LCN1 and HTN3::MSANTD3 Gene Fusions With NR4A3/NR4A2 Expression in Salivary Acinic Cell Carcinoma.

Acinic cell carcinoma of the salivary gland (AciCC) is a low-grade carcinoma characterized by the overexpression of the transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3). AciCC has been the subject of a few molecular research projects. This study delves into AciCC's molecular landscape to identify additional alterations and explore their clinical implications. RNA sequencing and immunohistochemical staining for markers NR4A3/NR4A2, DOG-1, S100, and mammaglobin were utilized on 41 AciCCs and 11 secretory carcinoma (SC) samples. NR4A3 was evident in 35 AciCCs, while the residual 6 were NR4A3-negative and NR4A2-positive; SC samples were consistently NR4A3-negative. A novel fusion, PON3 exon 1- LCN1 exon 5, was detected in 9/41 (21.9%) AciCCs, exhibiting a classical histologic pattern with serous cell components growing in solid sheets alongside the intercalated duct-like component. Clinical follow-up of 39 patients over a median of 59 months revealed diverse prognostic outcomes: 34 patients exhibited no disease evidence, whereas the remaining 5 experienced poorer prognosis, involving local recurrence, lymph node, and distant metastasis, and disease-associated death, 4 of which harbored the PON3::LCN1 fusion. In addition, the HTN3::MSANTD3 fusion was recurrently identified in 7/41 AciCC cases. SC patients lacked both fusions. Immunohistochemistry uncovered differential expression of DOG-1, S100, and mammaglobin across samples, providing nuanced insights into their roles in AciCC. This study accentuates PON3::LCN1 and HTN3::MSANTD3 fusions as recurrent molecular events in AciCC, offering potential diagnostic and prognostic utility and propelling further research into targeted therapeutic strategies.

Number of positive lymph nodes affects oncologic outcomes in cN0 mucoepidermoid carcinoma of the major salivary gland.

The survival significance of the number of positive lymph nodes in salivary gland carcinoma remains unclear. Thus, the current study aimed to determine the effect of the number of positive lymph nodes on disease-specific survival (DSS) and overall survival (OS) in cN0 mucoepidermoid carcinoma (MEC) of the major salivary gland. Patients surgically treated for MEC of the major salivary gland between 1975 and 2019 were retrospectively enrolled from the surveillance, epidemiology, and end results database. The total population was randomly divided into training and test groups (1:1). Primary outcome variables were DSS and OS. Prognostic models were constructed based on the independent prognostic factors determined using univariate and multivariate Cox analyses in the training group and were validated in the test group using C-index. A total of 3317 patients (1624 men and 1693 women) with a mean age of 55 ± 20 years were included. The number of positive lymph nodes was an independent prognostic factor for both DSS and OS, but the effect began when at least two positive lymph nodes for DSS and three positive lymph nodes for OS were found. Predictive models for DSS and OS in the training group had C-indexes of 0.873 (95% confidence interval [CI] 0.853-0.893) and 0.835 (95% CI 0.817-0.853), respectively. The validation of the test group showed C-indexes of 0.877 (95% CI 0.851-0.902) for DSS and 0.820 (95% CI 0.798-0.842) for OS. The number of positive lymph nodes was statistically associated with survival in cN0 major salivary gland MEC. The current prognostic model could provide individualized follow-up strategies for patients with high reliability.