Salivary gland secretory carcinoma (SGSC) represents a rare malignant tumor of the salivary glands. Despite being regarded as low-grade tumors, they may manifest with metastases and a high-grade aggressive clinical behaviour. The literature on this subject is limited, and there is currently no standardized approach to treatment.

We report a rare case of SGSC in the palate of a 14-year-old female patient. The patient underwent excision, bilateral tonsillectomy and adjuvant radiotherapy.

A critical review of the literature was conducted with the objective of analysing the cases of intraoral SGSC that have been previously reported. A total of 23 articles, published between 2010 and 2024, were identified as being directly pertinent to the review, resulting in a total of 58 patients being included.

SGSC on the hard palate in a 14-year-old child is an exceedingly rare occurrence. These tumors can mimic other pathologies of the salivary glands clinically and microscopically, which can result in misdiagnosis and a delay in treatment.

Gene rearrangements or fusions have emerged as critical oncogenic drivers in various cutaneous adnexal neoplasms. This review offers a comprehensive overview of both established and recently identified molecular alterations, with a specific focus on gene fusions. Key alterations discussed include YAP1 rearrangements, CRTC1::MAML2 fusions, BRD3 rearrangements, MYB::NFIB fusions, ETV6::NTRK3 fusions, and PLAG1 rearrangements, alongside rarer fusion transcripts, such as MEF2C::SS18 , FOXK1::GRHL1/2 , GPS2::GRHL , and RARA::NPEPPS . The article highlights the significance of these genetic changes in tumor biology and their potential therapeutic implications for locally advanced and metastatic skin adnexal tumors. It also addresses diagnostic challenges and molecular distinctions, providing updated insights into adnexal tumors driven by these gene fusions.

The increasingly widespread availability of next-generation sequencing has led to its incorporation as a diagnostic tool in pathology and a modality for identifying targetable alterations. However, sequencing is still a somewhat expensive and time-consuming. Here, we discuss tumor types for which (1) molecular testing is not generally indicated, (2) surrogate immunohistochemical markers have rendered molecular testing unnecessary, or (3) sequencing is important for diagnostic and therapeutic purposes. We also provide a practical framework to assist in decision-making for molecular testing of both classified and unclassified mesenchymal neoplasms, reflecting our practice in a tertiary sarcoma referral center.

Infantile fibrosarcoma (IFS) is a rare pediatric tumor of intermediate malignancy with high local aggressiveness that typically presents in young infants. Its occurrence in the head and neck region is rare. Complete non-mutilating surgical resection is often not possible, requiring multimodal treatment. IFS frequently harbors neurotrophic receptor tyrosine kinase (NTRK) fusions. Targeted therapy with NTRK inhibitors is modifying treatment paradigms of IFS.

Herein, we report the case of a neonate with a giant unresectable congenital ETV6::NTRK3 (+) IFS of the head and neck region without rapid response to chemotherapy who was treated with larotrectinib oral suspension.

Larotrectinib was well tolerated and induced an impressive clinical and radiologic response.

This case illustrates an example of pediatric precision oncology in a neonate with an ETV6::NTRK3 (+) congenital IFS of the head and neck region and provides further reference for the use of larotrectinib in the neonatal period.

Spitz lesions display a set of genetic alterations that differ from classical melanocytic lesions: examples include mutations in HRAS and fusions involving ALK, ROS1, MET, MAP3K8, BRAF, and the NTRK genes. We present a Spitz spindle cell/Reed nevus with atypical junctional features and an NTRK2 translocation in a patient of unusual age. The patient was a 61-year-old man with a pigmented brown flat 6 mm lesion growing on the skin over the left scapula. The lesion was composed of spindled and epithelioid melanocytes and was arranged in nests with some scattered focal pagetoid cells as well as intraepidermal nests at the center of the lesion and occasional mitotic figures. The melanocytes showed diffuse staining for pan-Trk antibodies. p16 staining was focally and weakly positive. The cells showed staining for HMB-45, MART-1, and tyrosinase, whereas they were negative for PRAME, ALK-1, and ROS-1 immunostaining. BAP-1 was preserved. Next-generation sequencing detected a SQSTM1::NTRK2 fusion and showed no alterations of ALK, ROS1, RET, NTRK1, and NTRK3 genes, as well as no pathogenic variants of BRAF. Fluorescent in situ hybridization showed NTRK2 translocation in all melanocytes evaluated. This case presents a Spitz nevus with a rare translocation in an older patient.

There is an ongoing explosion of new information regarding the underlying molecular alterations driving a variety of salivary gland neoplasms. The volume of this emerging data makes it difficult to keep up with and may cause pathologists to believe that salivary gland neoplasms cannot be diagnosed without genetic analysis. This review focuses on the practical diagnostic applications of molecular tools in surgical pathology specimens.

Juvenile Xanthogranuloma (JXG) is a rare form of non-Langerhans cell histiocytosis. The most common known gene mutations affect the mitogen-activated protein (MAP) kinase, phosphoinositide 3-kinase (PI3K), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. We present a case of congenital JXG in a premature newborn from a dicygotic twin pregnancy with subdermal infiltrates on the chest, hepatosplenomegaly, ascites, pancytopenia, and petechiae on the abdomen and extremities. Next-generation sequencing of tissue from a subdermal infiltrate revealed a tropomyosin 3::neurotrophic tyrosine kinase receptor (TPM3::NTRK1) gene fusion. Therefore, a retrospective analysis of 34 additional non-Langerhans cell histiocytoses (16 JXG, 3 adult xanthogranuloma and 1 benign cephalic histiocytosis, both clinical subtypes of JXG, as well as 13 Rosai-Dorfman and 1 Erdheim-Chester disease) for NTRK1, 2 and 3 aberrations was performed. This analysis revealed an NTRK1 gene fusion in 4 additional JXGs and 1 adult xanthogranuloma. In conclusion, NTRK1 gene fusions are moderately common in JXG (6/21; 28.6% in our series). This finding places JXG in the category of proliferative diseases with one of the highest frequencies of NTRK gene rearrangements. Therefore, NTRK gene fusions should be included in a gene panel test for difficult-to-treat JXG. Given the potential of NTRK gene fusions as a therapeutic target, NTRK inhibitors may represent a novel effective treatment for JXG with a challenging clinical course.

Salivary gland carcinomas (SGCs) represent a rare and heterogeneous group of malignancies accounting for 3-6% of all head and neck cancers. While surgical resection and radiotherapy remain the standard for locoregional control, systemic treatment is indicated for recurrent or metastatic disease. Advances in molecular profiling have identified actionable targets such as NTRK gene fusions, HER2, immune checkpoint regulators, androgen receptors, and RET receptors. These have facilitated the development of targeted therapies, including TRK inhibitors, HER2-directed agents, and androgen receptor modulators, as well as emerging combinations of immunotherapy and chemotherapy. Despite these advancements, challenges such as resistance mechanisms and limited therapeutic efficacy persist. Overall response rates remain relatively low across most systemic therapies, reflecting a persistent unmet clinical need. This review discusses the current landscape of treatment options and explores promising clinical trials and future directions to enhance outcomes for patients with SGCs.

The present study reports the case of a 25-year-old male patient with salivary gland secretory carcinoma (SC) with the ETV6::RET gene fusion. The patient presented with a left parotid mass and was treated using a superficial parotidectomy. Histological analysis of the tumor demonstrated a combination of cystic, follicular and trabecular patterns in cells, with eosinophilic secretions and a vacuolated cytoplasm. Tumor cells exhibited infiltrative growth into muscle and nerve tissues, accompanied by central stromal hyalinized sclerosis. Immunohistochemically, the tumor cells were positive for S-100, mammaglobin and GATA binding protein 3, and negative for DOG1. The results of the present case demonstrated that the patient possessed SC with the ETV6::RET gene fusion. Following the operation, the patient underwent radiotherapy, leading to a disease-free state at the last follow-up at 1 year and 3 months following surgery. A comprehensive review of 21 SC cases with this gene fusion, including the case reported in the present study, demonstrated that invasive growth, neural and lymphovascular invasion and hyalinized sclerosis were frequently seen on histology, and 11 cases (52%) exhibited advanced-stage disease (>T3 or M1). Thus, salivary gland SC with an ETV6::RET fusion may show infiltrative growth and may be more aggressive compared with salivary gland SC with an ETV6::NTRK3 fusion, which is often associated with an indolent clinical course. Therefore, confirmation of the genetic profile of SC is crucial for the prediction of patient prognosis and administration of an effective therapeutic course.

Over the past two decades, an increased understanding of molecular alterations has greatly refined salivary gland tumor classification. Many tumors that were previously difficult or impossible to classify have been recognized to represent emerging entities based on shared histologic, immunophenotypic and molecular characteristics. While initial attention was given to carcinomas, more recently molecular discoveries have shed light on salivary gland adenomas as well. We present a series of biphasic salivary gland tumors characterized by striking bizarre myoepithelial atypia, unified at the genetic level by evidence of 12q amplification.

Salivary gland tumors demonstrating bizarre but degenerative-appearing atypia were identified. Immunohistochemistry, MDM2 and HMGA2 fluorescence in situ hybridization (FISH), and/or targeted next-generation sequencing (NGS) were attempted on the cases.

Seven cases were identified. The tumors arose in the parotid gland (3 of 7), oral cavity (3 of 7) and submandibular gland (1 of 7). The patients were 5 women and 2 men, ranging from 53 to 83 years (mean, 65.7 years). Histologically, the tumors appeared well-circumscribed and partially encapsulated. They were highly cellular and solid, with no chondromyxoid stromal component. The tumors were biphasic, with a population of eosinophilic ducts in a background of basaloid cells with variable clear cell change and spindling. The most striking feature in all cases was the presence of scattered cells with bizarrely atypical nuclei with smudgy chromatin. These bizarre cells maintained low nuclear:cytoplasmic ratios and lacked mitotic activity. The biphasic nature of the tumors was demonstrated by the basaloid cells staining with S100, p63 and p40, while the ducts were positive for CD117 and AE1/AE3 (strong). The bizarre cells had a myoepithelial immunophenotype. The Ki67 index ranged from 1 to 10%, with most of the markedly atypical cells not labeling. DNA NGS was successful in 4 cases, demonstrating 12q copy number increase and 5q copy number loss in all 4 cases. RNA sequencing was able to identify increased MDM2 and HMGA2 expression in one additional case, while amplification of MDM2 and/or HMGA2 was also demonstrated in 6 of 7 cases by FISH. In summary, all 7 cases exhibited evidence of 12q amplification by at least one technique.

Salivary gland neoplasms with bizarre myoepithelial atypia are consistently associated with evidence of 12q amplification. Although this histologic alteration may be alarming, the smudgy nature of the chromatin and paucity of mitotic activity and Ki67 labeling suggest that this finding may not necessarily be indicative of malignancy.

Traditional anatomic pathologic classification of cancer is based on tissue of origin and morphologic and immunohistochemical characterization of the malignant cells. With the technological improvements of massively parallel or next-generation sequencing, oncogenic drivers that are shared across different tumor types are increasingly being identified and used as pan-cancer biomarkers. This approach is reflected in the growing list of Food and Drug Administration-approved tumor-agnostic therapies, including pembrolizumab in the setting of microsatellite instability and high tumor mutational burden, larotrectinib and entrectinib for solid tumors with NTRK fusions, and combined dabrafenib-trametinib for BRAF V600E-mutated neoplasms. Several other biomarkers are currently under investigation, including fibroblast growth factor receptor (FGFR), RET, and ROS1 fusions; ERBB2 amplification; and mutations in the AKT1/2/3, NF1, RAS pathway and (mitogen-activated protein kinase (MAPK) pathway. As molecular assays are increasingly incorporated into routine tumor workup, the emergence of additional pan-cancer biomarkers is likely to be a matter more of "when" than "if." In this review, we first explore some of the conceptual and technical considerations at the intersection of surgical and molecular pathology, followed by a brief overview of both established and emerging molecular pan-cancer biomarkers and their diagnostic and clinical applications.

Malignancy of parotid glands is uncommon in the pediatric age group. Among the various subtypes, mammary analogue secretory carcinoma (MASC) of parotid is an unusual variant that mimics pathologically those of mammary secretory carcinoma of the breast. It usually presents as a slow-growing, painless parotid mass.

We had a 17-year-old female patient who presented with recurrent swelling in her right parotid region, which was adherent to the skin focally. Contrast-enhanced MR showed a solid multi-cystic lesion in her right parotid region. Pre-operative cytopathology was inconclusive. She underwent total parotidectomy with level II nodal clearance, and the histopathology was suggestive of mammary analogue secretory carcinoma.

MASC is considered to be a low-grade, slow-growing malignancy when presented at an earlier stage. Our patient was kept under close follow-up, and she is disease-free at nearly thirty months post-operatively.

Background: Salivary gland cancers (SGCs) are a rare and heterogeneous group of malignancies, accounting for approximately 5% of head and neck cancers. Despite their rarity, advances in molecular profiling have revealed a variety of genetic and molecular pathways, many of which are potentially actionable with targeted therapies. Methods: We reviewed the current literature involving the molecular landscape of SGCs, encompassing the diagnostic and prognostic value of tissue and liquid biomarkers and the potential therapeutic targets across various histological subtypes. Results: Our review highlights key molecular diagnostic findings such as the CRTC1-MAML2 fusion in mucoepidermoid carcinoma and MYB-NFIB rearrangements in adenoid cystic carcinoma, but also targetable alterations such as HER2 and AR positivity in salivary duct carcinoma and ETV6-NTRK3 fusion in secretory carcinoma. Liquid biopsy (both blood- or salivary-based), including circulating tumor DNA, circulating tumor cells, and miRNAs, offers novel, noninvasive approaches for disease monitoring and personalized treatment. Emerging therapies such as HER2 inhibitors, androgen deprivation therapy, and TRK inhibitors underscore the shift towards precision oncology in managing these malignancies. Conclusions: Despite promising advances, challenges remain due to the rarity and phenotypic heterogeneity of SGCs, emphasizing the need for molecularly stratified clinical trials. This review presents an overview of tissue and liquid biomarkers, focusing on molecular targets and therapeutic innovations that lay the foundation for improved diagnostic and treatment strategies for SGCs.

Paiva-Correia A, Hellquist H, Apolónio J, Castelo-Branco P. Role of ancillary techniques in the differential diagnosis of salivary gland carcinomas. The diagnosis of salivary gland carcinomas (SGC) rests mainly on histology, but immunohistochemical and molecular investigations are often necessary for differential diagnosis. This review is primarily aimed as a tool for pathologists in non-specialised head and neck hospitals who encounter a limited number of SGC annually. The use of testing an initial antibody panel, which may comprise both positive and negative expression for a suspected entity, and examples of different panels are outlined. We also focused on acinic cell carcinoma (AcCC), which is positive for DOG1 and negative for mammaglobin, whilst secretory carcinoma (SC) is positive for mammaglobin and negative for DOG1. In addition, the exclusive expression of androgen and HER2 in salivary duct carcinoma (SDC) and its use for differential diagnosis are also addressed. This review also highlights the particularities of mucoepidermoid carcinoma (MEC) and its negativity for S100 and SOX10, which distinguishes it from some of its mimics. In laboratories with limited access to antibodies for SGC, we recommend inclusion of mammaglobin. The use of molecular techniques for the diagnosis of MEC (MAML2), SC (ETV6), adenoid cystic carcinoma (MYB), and AcCC (NR4A3) is discussed. We highlight the role of commonly available antibodies for the histological classification of SGC.

Salivary gland carcinomas are a rare and heterogeneous group of malignant tumors, accounting for 3-6% of all malignant tumors in the head and neck region. The 1-, 3- and 5-year survival rates are 83%, 69% and 63% respectively. Due to new molecular pathological and genetic findings, new entities are constantly being defined as part of the recurring WHO classification of salivary gland carcinomas, so that the incidence rates of the entities are subject to constant change. The only certain risk factor for the development of salivary gland carcinomas is ionizing radiation. In addition, large tumors, cervical lymph node involvement and perineural sheath involvement significantly worsen the prognosis. Today, molecular pathology is coming to the fore, with which potential targets have been identified that can offer prognosis-improving treatment options, particularly in recurrent or distant metastatic stages. Entity-specific tyrosine kinase inhibitors such as axitinib in adenoid cystic carcinoma or larotrectinib in secretory carcinoma and cross-entity therapies such as HER2 inhibition and androgen deprivation can prolong median and progression-free survival with a favorable side effect profile.

Secretory carcinoma (SC) of the salivary glands, previously termed mammary analog secretory carcinoma (MASC), is a rare, low-grade malignant tumor of the salivary glands that closely resembles SC of the breast. This case report discusses parotid SC in a 40-year-old female patient who presented with recurrent parotid swelling. The report aims to demonstrate the importance of recognizing this rare tumor, raising awareness, and adding this case to world literature.

Breast cancer (BC) is a profoundly heterogenous disease, with diverse molecular, histological, and clinical variations. The intricate molecular landscape of BC is evident even at early stages, illustrated by the complexity of the evolution from precursor lesions to invasive carcinoma. The key for therapeutic decision-making is the dynamic assessment of BC receptor status and clinical subtyping. Hereditary BC adds an additional layer of complexity to the disease, given that different cancer susceptibility genes contribute to distinct phenotypes and genomic features. Furthermore, the various BC subtypes display distinct metabolic demands and immune microenvironments. Finally, genotypic-phenotypic correlations in special histologic subtypes of BC inform diagnostic and therapeutic approaches, highlighting the significance of thoroughly comprehending BC heterogeneity.

Salivary gland tumors represent a diagnostic challenge for pathologists due to their rarity, their very wide histopathological and immuno-phenotypic spectrum, and the recent identification of new entities. This article presents the main molecular characteristics of these tumors in order to allow any pathologist to perceive the diagnostic tracks of these ENT tumors and to better guide the molecular approach to establish the diagnosis and guide therapy.

Background and Objectives: Salivary gland tumors (SGTs) are diverse lesions with varying morphological and clinical characteristics. Limited data exist on the distribution of SGTs in Saudi Arabia. We aimed to fill this gap by examining the distribution of SGTs across four tertiary hospitals in Riyadh. Materials and Methods: A retrospective analysis was conducted on SGT cases diagnosed from January 2010 to December 2022 to investigate the clinicopathological features (tumor location, patient sex, and age). Histological slides were evaluated by two independent certified oral pathologists and classified based on the latest 2022 World Health Organization classification (WHO). Results: There were 796 SGTs. Most cases occur in individuals in their 4th to 5th decades of life. The parotid gland was the predominant site (79.4%), followed by the submandibular gland (9.3%). More than half of the tumors (527, 66.2%) were benign, involving major and minor salivary glands. Pleomorphic adenoma was the most common benign tumor, accounting for 354 cases (44.5%), followed by Warthin tumor with 117 cases (14.7%). Mucoepidermoid carcinoma was the most prevalent malignant tumor, identified in 98 patients (12.3%). Additionally, 36 (4.5%) mesenchymal and 30 (3.8%) hematolymphoid non-epithelial SGTs were reported. Conclusions: This multicenter study is the largest of its kind in Saudi Arabia, identifying pleomorphic adenoma and mucoepidermoid carcinoma as the most commonly reported benign and malignant tumors, respectively. These findings offer valuable insights into the understanding of salivary gland tumors globally.

Salivary gland Secretory Carcinoma (SC), characterized by Skalova in 2010 is a rare tumor studied within the REFCOR (French Network of experts on Rare Head and Neck Cancers). We conducted a prospective multicentric cohort study of 108 SC cases in the REFCOR database up to July 2021, analyzing diagnostic, therapeutic, and survival data.

Data was collected prospectively from diagnosis to the last update. Each patient had two histological readings including one by a REFCORpath pathologist, and all cases underwent molecular testing to confirm diagnosis. Statistical analyses were performed using R software.

MRI was not contributive to malignancy diagnosis. After 2 histological readings, 79 % of patients were diagnosed, with 21 % requiring molecular testing to confirm diagnosis. Surgical treatment typically involved tumor excision and lymph node dissection. The tumor exhibited low lymph node involvement, with 95 % of patients being cN0, and no nodal metastases post-dissection. Five-year overall survival and recurrence-free survival were 91.4 % {95 % CI (0.84-1)} and 89 % {95 % CI (0.81; 0.98)} respectively, indicating a favorable prognosis.

SC is a rare and newly recognized tumor, with generally favorable outcomes. Our cohort, among the largest to date, provides valuable insights. Future research should refine treatment guidelines.

Low-grade non-intestinal-type sinonasal adenocarcinoma (LGSNAC) is a rare heterogeneous and poorly characterised group of tumours, distinct from intestinal- and salivary-type neoplasms. Therefore, further characterisation is needed for clearer biological understanding and classification.

Clinical, histological and molecular characterisation of four cases of biphasic, low-grade adenocarcinomas of the sinonasal tract was performed. All patients were male, aged between 48 and 78 years, who presented with polypoid masses in the nasal cavity. Microscopically, virtually all tumours were dominated by tubulo-glandular biphasic patterns, microcystic, focal (micro)papillary, oncocytic or basaloid features. Immunohistochemical staining confirmed biphasic differentiation with an outer layer of myoepithelial cells. Molecular profiling revealed HRAS (p.G13R, p.Q61R) mutations, and concomitant AKT1 (p.E17K, p.Q79R) mutations in two cases. Two cases showed potential in-situ/precursor lesions adjacent to the tumour. Follow-up periods ranged from 1 to 30 months, with one case relapsing locally after 12 and > 20 years.

This study further corroborates a distinct biphasic low-grade neoplasm of the sinonasal tract with seromucinous differentiation. Although morphological and molecular features overlap with salivary gland epithelial-myoepithelial carcinoma, several arguments favour categorising these tumours within the spectrum of LGSNAC.

Tumors of the major and minor salivary glands histologically encompass a diverse and partly overlapping spectrum of frequent diagnostically challenging neoplasms. Despite recent advances in molecular testing and the identification of tumor-specific mutations or gene fusions, there is an unmet need to identify additional diagnostic biomarkers for entities lacking specific alterations. In this study, we collected a comprehensive cohort of 363 cases encompassing 20 different salivary gland tumor entities and explored the potential of DNA methylation to classify these tumors. We were able to show that most entities show specific epigenetic signatures and present a machine learning algorithm that achieved a mean balanced accuracy of 0.991. Of note, we showed that cribriform adenocarcinoma is epigenetically distinct from classical polymorphous adenocarcinoma, which could support risk stratification of these tumors. Myoepithelioma and pleomorphic adenoma form a uniform epigenetic class, supporting the theory of a single entity with a broad but continuous morphologic spectrum. Furthermore, we identified a histomorphologically heterogeneous but epigenetically distinct class that could represent a novel tumor entity. In conclusion, our study provides a comprehensive resource of the DNA methylation landscape of salivary gland tumors. Our data provide novel insight into disputed entities and show the potential of DNA methylation to identify new tumor classes. Furthermore, in future, our machine learning classifier could support the histopathologic diagnosis of salivary gland tumors.

Ceruminous glands are modified apocrine glands, situated in the external auditory canal (EAC) that, together with sebaceous glands, produce cerumen. The neoplastic transformation of these structures is exceedingly rare. We encounter two cases of EAC adenocarcinoma with ETV6::NTRK3 fusion. Despite this genetic overlap, the morphology and immunophenotype delineate its clear separation from secretory carcinoma. These cases demonstrate novel primary EAC adenocarcinoma with papillary morphology, which expands the ever-increasing list of ETV6::NTRK3-positive malignancies and which we would like to term ETV6::NTRK3-translocation associated papillary adenocarcinoma. We also advocate the use of molecular techniques in rare tumors of uncertain type or differentiation, to increase understanding and possibilities of reproducible classification of these rare neoplasms. Pathologists and oncologists should recognize this entity, which leads to a direct approach for detecting NTRK fusion for appropriate treatment.

A 56-year-old female was referred to our service for management of a malignant salivary gland neoplasm with compromised margins that had been biopsied previously at another service. The patient reported a twenty-year history of a lesion in the oral cavity with progressive and exuberant growth over the past two years, associated with local pain and dyspnea. Physical examination revealed an erythematous, ulcerated, and hemorrhagic lesion measuring approximately 3 cm on the left soft palate and tonsillar pillar. Computed tomography revealed an expansile lesion in the topography of the left soft palate, growing predominantly toward the lumen of the nasopharynx and partially invading the left wall of this region. The patient underwent surgery and histopathologic examination revealed an infiltrative and aggressive epithelial neoplasia with large vacuolated and eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. The neoplastic cells were arranged in a solid, microcystic, tubular, and follicular pattern with eosinophilic luminal secretion. Mitotic figures were frequent and all margins were affected by the neoplasia. Morphologic and immunohistochemical features supported the diagnosis of secretory carcinoma, and the patient is currently being followed for further therapeutic intervention.

High-grade transformation, previously known as dedifferentiation, in salivary gland carcinoma and carcinosarcoma ex pleomorphic adenoma is a rare phenomenon. It is, however, clinically relevant and affects treatment and prognosis.

To review the existing literature, describe the histologic and immunophenotypic features, and highlight the diagnostic criteria of high-grade transformation in various salivary gland carcinomas and carcinosarcomas; to review its effect on clinical presentation and prognosis; and to review relevant molecular characteristics and recent concepts and advances.

Literature search in PubMed using key words such as "high-grade transformation," "dedifferentiation," and "carcinosarcoma" in salivary gland. Relevant articles were reviewed, and additional articles were curated from the references of these articles.

High-grade transformation occurs rarely but has a significant impact on prognosis and management. By microscopy, the high-grade area is usually a distinct nodule and shows solid and nested architecture, cellular atypia, high mitotic count, and necrosis. The molecular features are not well established. Carcinosarcoma almost always arises in a pleomorphic adenoma and likely follows an adenoma-carcinoma-sarcoma pathway.

Salivary gland tumors are rare tumor types for which the molecular understanding has resulted in a rapid expansion and shuffling of entities. These changes are reflected in the 5th edition World Health Organization Classification of Head and Neck Tumours (WHO 5th edition), although many nuances still remain.

To review how molecular alterations have helped recategorize, justify, and reinstate entities into our lexicon as well as defining interrelationships between categories, new entities, and subtypes. Furthermore, newer theranostic applications to molecular phenotype will be summarized.

World Health Organization Classification of Head and Neck Tumours (WHO 3rd through 5th editions), literature review, and personal and institutional experience.

Molecular alterations have helped reclassify, retain, and create new categories by augmenting rather than replacing standard criteria. Key entities that have emerged include sclerosing polycystic adenoma, microsecretory adenocarcinoma, and mucinous adenocarcinoma. Molecular phenotypes solidify the range of morphology in established entities such as mucoepidermoid carcinoma and facilitate connectivity between entities. Molecular characteristics now allow for targeted therapeutic approaches for secretory carcinoma and adenoid cystic carcinoma.

Mammary analogue secretory carcinoma (MASC) is a rare salivary gland tumor which shares its histologic, immunohistochemical, and genetic features with the secretory carcinoma (SC) of breast. In this case report, we describe a case of MASC in a young adolescent male with swelling in the right angle of mandible which is a relatively rare site to present along with its correlation of cytological, histological, and immunohistochemical features. A 16-year-old male came with the complaint of swelling in the right angle of mandible since 2 years. Contrast-enhanced computed tomography (CECT) neck revealed differential diagnosis of nerve sheath tumor, pleomorphic adenoma, and adenoid cystic neoplasm was kept, and subsequently fine-needle aspiration cytology (FNAC) was done. FNAC was done in which differential diagnosis of myoepithelial neoplasm, acinic cell carcinoma, and SC was given. Surgical excision was done followed by histopathological examination. Immunohistochemistry panel was also applied, and final diagnosis of SC was rendered. SC has distinct cytological, histological, and immunohistochemical features which should be recognized by the pathologists for the appropriate management of the patient.

To investigate the clinicopathologic characteristics, therapeutic methods, and prognosis of secretory carcinoma of salivary gland (SCSG).

The clinicopathologic data of 13 patients with SCSG admitted to Shanxi Cancer Hospital from January 2018 to June 2023 were retrospectively analyzed, and a literature review was performed.

A total of eight males and five females aged 22-78 years old were enrolled, and they commonly presented with painless masses in the parotid or submandibular gland. They all underwent surgical treatment, accompanied by typical pathological examinations postoperatively. Fluorescence in situ hybridization (FISH) was conducted in seven cases, the results were all positive, and no gene fusion other than ETV6-NTRK3 was found. Two patients developed local relapse during follow-up, both of which were in the surgical area. By the end of the follow-up, 12 patients survived and one patient died.

SCSG is a rare low-grade malignancy with a good prognosis. Pathological and immunohistochemical characteristics are the key to secretory carcinoma (SC) diagnosis, and surgical excision is the major treatment means for SCSG. Whether to perform simultaneous cervical lymph node dissection and other adjuvant therapies should be determined based on the pathological stage and the presence or absence of high-risk factors.

Heterotopia, the occurrence of specific tissues in ectopic sites during embryogenesis, includes the presence of salivary gland tissue in unusual locations. Salivary gland neoplasms arising from heterotopic sites are rare. Secretory Carcinoma (SC) is a rare salivary gland carcinoma characterized by ETV6-NTRK3 fusion gene, very rarely described in salivary gland heterotopia. Here a case of SC originating from salivary gland heterotopia in a neck lymph node is reported, together with a literature review.A 66-year-old male presented with a left neck mass. Imaging and fine needle aspiration cytology indicated a preliminary diagnosis of a benign/low-grade malignancy neoplasm.Following surgery (superficial parotidectomy and mass excision), histological examination revealed SC within an intranodal salivary heterotopia, confirmed by molecular analysis.Heterotopic salivary gland tissue (HSGT) is rare, and its association with neoplasms is even rarer. Tumours arising on HSGT, share histological similarities with those affecting orthotopic salivary glands. This unique case expands the understanding of SC occurrences on HSGT.

Secretory carcinoma of breast (SCB) typically harbours ETV6-NTRK3 gene fusion. Pan-Trk immunohistochemistry analysis (IHC) has been shown to be sensitive for SCB diagnosis. However, weak focal pan-Trk nuclear staining was previously found in 10% of non-secretory breast carcinomas. To further examine pan-Trk IHC specificity, we evaluated pan-Trk staining in various breast carcinoma subtypes.

The study cohort consisted of 346 invasive breast carcinomas (IBCs), including 8 SCBs and 48 triple-negative histological mimickers (36 metaplastic carcinomas, including 12 matrix-producing carcinomas; 5 adenoid cystic carcinomas; 5 apocrine carcinomas; 2 acinic cell carcinomas), 101 triple-negative IBCs of no special type, 101 estrogen receptor (ER)-positive/HER2-negative IBCs and 88 HER2-positive IBCs. Six salivary gland secretory carcinomas were also included. Pan-Trk IHC was performed on tumours using a rabbit monoclonal pan-Trk antibody. Any nuclear staining in the invasive carcinoma cells was considered positive.

All 14 secretory carcinomas from breast and salivary gland exhibited moderate to strong pan-Trk nuclear staining. In contrast, no pan-Trk nuclear staining was identified in any of the 338 non-secretory IBCs. Focal cytoplasmic pan-Trk staining was observed in nine non-secretory IBCs (2.7%), and was considered nonspecific and negative.

Our results indicate that pan-Trk nuclear staining is highly specific for SCB. In low-grade to intermediate-grade IBCs that share histological features with SCB, adding pan-Trk to a routing panel of estrogen receptor/progesterone receptor/HER2 is highly diagnostic. Our results also support using pan-Trk IHC to differentiate SCB from its triple-negative histological mimickers, such as adenoid cystic carcinoma, matrix-producing carcinoma, apocrine carcinoma and acinic cell carcinoma.

Acinic cell carcinoma (ACC) is a salivary gland malignancy most commonly arising in the parotid gland. It is the second most common salivary gland carcinoma in children. It is characterised by neoplastic cells with acinar morphology arranged in variably architectural features, including solid, cystic or follicular patterns. Conventional ACC typically has a low-grade clinical pattern, whereas high grade ACC exhibits a more aggressive clinical course with distant metastasis a high mortality rate. Most ACCs are characterised by gene rearrangements in the NR4A3 gene. Here, we present a case of high grade ACC lacking NR4A3 gene translocation but harbouring a hitherto undescribed SYN2::PPARG gene fusion of uncertain clinical significance. Clinical, radiological, histological and genomic features of the case are discussed alongside a brief review of the literature.

Secretory carcinoma (SC) is an uncommon salivary gland tumor that has been recently conceptualized. The present report describes a case of SC that was diagnosed as a mucocele on preoperative examination. A 46-year-old man presented to the Department of Oral and Maxillofacial Surgery at Saiseikai Senri Hospital (Suita-shi, Japan) with a main complaint of swelling of the right buccal mucosa. A mobile, elastic, hard mass was found beneath the right normal-appearing buccal mucosa. T2-weighted magnetic resonance imaging revealed a well-defined, internally homogeneous high-signal area with a maximum diameter of 18 mm. Based on the clinical diagnosis of mucocele, the buccal lesion was excised. Histopathological, immunohistochemical and fluorescence in situ hybridization analyses revealed the cystic lesion to be a macrocystic SC of a minor salivary gland. SC may have a mucocele-like appearance on magnetic resonance imaging. Even if a non-neoplastic lesion is suspected, the possibility of a malignant lesion such as SC must be considered for salivary gland disease.

the study aimed to characterize the novel entity referred to as secretory carcinoma of the salivary glands.

we comprehensively evaluated 150 patients afflicted by malignant salivary gland tumors who had been under treatment at the University of Verona. Inclusion criteria primarily focused on the availability of paraffin block materials and adequate follow-up data. Subsequently, we conducted a comprehensive Fluorescent In Situ Hybridization (FISH) analysis, utilizing probes targeting NTRK-3, MALM-2, EWRS-1, HER-2, MDM-2, and NTRK1-2.

out of the initial cohort, 37 patients met the eligibility criteria for our study. We identified NTRK3 gene rearrangements in four patients (11%), two of whom had mucoepidermoid carcinoma, and the remaining two had acinic cell carcinoma. Notably, none of these patients had initially received a secretory carcinoma diagnosis. The primary treatment approach for all patients entailed surgical parotid gland resection. The overall survival (OS) for patients with NTRK3 rearrangements amounted to 78 months, with a corresponding progression-free survival (PFS) of 73 months.

in summary, our case series suggests that secretory carcinomas exhibit a favorable clinical course and underscores the pivotal importance of distinguishing secretory carcinomas from other histological subtypes.

To compare the clinicopathological, molecular, and immune features of conventional and high-grade transformation (HGT) secretory carcinoma (SC) in salivary glands.

The clinicopathological data of 88 cases including 74 conventional SCs and 14 SCs with HGT were reviewed. Targeted next-generation sequencing was performed in 11 SCs with HGT and 7 conventional SCs. The level of PD-L1 and CD8+ TILs was determined by immunohistochemistry.

Compared with the conventional group, the rates of nodal metastasis, local recurrence, distant metastasis and mortality were significantly higher in the HGT cohort. Mutations of ARID1A/B, KMT2A, HOXD13, NRG1 and ETV6 genes were identified in HGT SCs. A recurrent E307G mutation in GATA6 gene was also observed in two cases. Two deceased HGT patients with distant metastasis harboured NOTCH3 mutations. ETV6-RET translocation was prone to occur in the HGT SCs. Additionally, PD-L1 expression was low, and CD8+ TILs were sparse in most HGT cases.

Our findings reveal novel gene alterations involved in the progression of HGT in SCs. Most HGT SCs patients cannot benefit from PD-L1 blocking and may be approached with a distinct treatment strategy including the lymph node dissection and application of molecular target drugs in precision oncology.

Secretory carcinoma is a relatively recently discovered low-grade salivary gland carcinoma with morphological similarities to its breast counterpart. The histopathological features of this entity are well established; however, the cytomorphological features are not well evaluated, leading to diagnostic challenges and pitfalls. We report a case of secretory carcinoma (SC) of the parotid gland, which was misdiagnosed as acinic cell carcinoma (ACC) on fine-needle aspiration cytology, to describe the cytological features.

Carcinoma ex pleomorphic adenoma (CXPA) is an aggressive epithelial and/or myoepithelial neoplasm that arises in association with a pleomorphic adenoma (PA). Its etiopathogenesis remains poorly understood, but it is believed that the development of this tumor is due to the accumulation of genetic, protein, metabolic, and epigenetic alterations in a PA. A retrospective review of the Salivary Gland Tumor Registry in Pilsen yielded 84 CXPA, namely 25/84 salivary duct carcinoma (SDC), 15/84 myoepithelial carcinoma (MC), 1/84 epithelial-myoepithelial carcinoma (EMC), and 1/84 adenoid cystic carcinoma (AdCC). All 84 CXPA cases were analyzed by next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH). Forty-three tumors originally diagnosed as CXPA (43/84, 51.2%) showed some molecular alteration. Fusion transcripts were identified in 12/16 (75%) CXPA, including LIFR::PLAG1, CTNNB1::PLAG1, FGFR1::PLAG1, and a novel fusion, HMGA2::LINC02389. Most of the fusions were confirmed by FISH using PLAG1 (6/11) and HMGA2 (1/1) gene break probes. Split signals indicating gene break were identified by FISH for PLAG1 (12/17), HMGA2 (3/4), EWSR1 (7/22), and MYB (2/7). Concerning pathogenic mutations, only CXPA with epithelial differentiation (SDC) presented these alterations, including HRAS mutation (2/4), TP53 (1/4), PTEN (1/4), and ATK1 (1/4). In addition, amplifications in ERBB2 (17/35), MDM2 (1/4), and EWSR1 (1/7) were detected. A novel finding was the discovery of an HMGA2::LINC02389 fusion in 1 patient with EMC ex-PA. The present results indicate that molecular profiling of CXPA with myoepithelial differentiation (MC) tends to reveal chromosomal fusion events, whereas CXPA with epithelial differentiation (SDC) tends to have a higher frequency of pathogenic mutations and gene amplifications.

Aberrant activation of tropomyosin receptor kinases (TRKs) is a well-defined oncogenic driver for neurotrophic tropomyosin receptor kinase (NTRK)-fusion cancers, and acquired resistant mutations have emerged with clinical use of the first-generation TRK inhibitors. Here we present BPI-28592, a novel second-generation TRK inhibitor with efficacy against TRK fusion-positive cancers, including those with resistant mutations. Docking simulations indicated no steric hindrance between BPI-28592 and TRK mutants, suggesting its potential to overcome drug resistance. Biochemical assays showed strong inhibition and high selectivity against TRKA, TRKB, and TRKC. The inhibitor significantly reduced cell proliferation and blocked TRK signaling. In vivo studies demonstrated effective tumor suppression in xenograft models harboring TRK fusions with or without resistant mutations. Clinically, BPI-28592 achieved a complete response in a patient with malignant melanoma carrying an AP3S2-NTRK3 fusion (Clinicaltrials. gov identifier: NCT05302843).

Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs in all major and minor salivary gland and seromucous gland sites. AdCCs of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost consistent presence of fusion genes MYB::NFIB, or less commonly MYBL1::NFIB. We collected a cohort of 95 cases of AdCC, which were largely characterized by canonical fusions MYB::NFIB (49 cases) or MYBL1::NFIB (9 cases). In additional 11 cases of AdCC, rearrangements in MYB or NFIB genes were detected by FISH. In addition, NGS revealed novel noncanonical fusion transcripts EWSR1::MYB; ACTB::MYB; ESRRG::DNM3, MYB::TULP4, and ACTN4::MYB, each of them in 1 case. The tumors that showed noncanonical fusions had features of metatypical AdCC with a diverse architecture, lobulated multinodular growth pattern, and hypercellular peripheral palisading of nuclei (2 cases), tubular hypereosinophilia (2 cases), and pale eosinophilic to vacuolated (bubbly) cytoplasm (3 cases). Our study documented 3 cases of AdCC of salivary glands harboring novel gene fusions TULP4::MYB, ACTN4::MYB, and ACTB::MYB, in 1 case each, which have not been described before. A rare EWSR1::MYB fusion was detected in 1 case. Moreover, 1 case of sinonasal metatypical AdCC showed EWSR1 rearrangement detected by FISH. Also, 1 case with an ESRRG::DNM3 fusion of unknown significance is described in this study. These discoveries illustrate how broad molecular profiling will expand understanding of changes in known entities.

ETV6 gene rearrangement is the molecular hallmark of secretory carcinoma (SC), however; the nature, frequency, and clinical implications of atypical ETV6 signal patterns by fluorescence in situ hybridization (FISH) has not yet been systematically evaluated in salivary gland neoplasms.

The clinical, histopathologic, immunohistochemical and molecular features of seven salivary SCs, including four cases with atypical ETV6 FISH patterns, were retrospectively analyzed along with a critical appraisal of the literature on unbalanced ETV6 break-apart in SCs.

The patients were four males and three females (31-70 years-old). Five presented with a painless neck mass and two patients with recurrent disease had a history of a previously diagnosed acinic cell carcinoma of the buccal mucosa. Histologically, there were varied combinations of microcystic, papillary, tubular, and solid patterns. All tumors were diffusely positive for S100 and/or SOX10, while 2 cases also showed luminal DOG1 staining. Rearrangement of the ETV6 locus was confirmed in 5/7 cases, of which 3 cases showed classic break-apart signals, 1 case further demonstrated duplication of the ETV6 5`end and the other loss of one copy of ETV6. Two cases harbored ETV6 deletion without rearrangement. Two of the 4 cases with atypical ETV6 FISH patterns represented recurrent tumors, one with widespread skeletal muscle involvement, bone and lymphovascular invasion. Surgical treatment resulted in gross-total resection in all 7 cases, with a median follow up of 9.5 months post-surgery for primary (n = 3) and recurrent disease (n = 1).

Duplication of the distal/telomeric ETV6 probe represented the most common (26/40; 65%) variant ETV6 break-apart FISH pattern in salivary SC reported in the literature and appears indicative of an aggressive clinical course.

Acinic cell carcinoma (AciCC) of the breast is a rare subtype of breast cancer. It was considered a low-grade triple-negative breast cancer (TNBC) with the potential to progress or transform into a high-grade lesion because of the molecular similarities with conventional aggressive TNBC in several genetic studies. Microscopically, the coexistence of classical low-grade and high-grade triple-negative components in breast AciCC is not uncommon. However, there is a scarcity of research on the comparative histopathological and genetic aspects of both components.

A 34-year-old woman with a nontender mass in the upper outer quadrant of the left breast was initially diagnosed with a malignant small round cell tumor (undifferentiated or poorly differentiated carcinoma) based on a preoperative biopsy, which was later identified as breast AciCC with a high-grade solid component. Left breast-conserving surgery with sentinel lymph node biopsy was performed. Microscopically, the breast AciCC consisted of a classical acinic component and a high-grade component. The latter demonstrated a solid sheet-like pattern characterized by large, round, pleomorphic or vesicular nuclei, prominent nucleoli, and frequent mitotic activities. Classical acinic architectures focally merged together to form solid nests and transited into high-grade areas. Remarkably, in the high-grade lesion, conventional immunochemical markers for breast AciCC, such as α1-antitrypsin (AAT), Lysozyme (LYS), Epithelial membrane antigen (EMA), S100 protein (S100), and cytokeratin (CK) were negative, whereas cell cycle protein D1 (cyclin D1) and vimentin showed diffuse expression. Next‑generation sequencing (NGS) revealed that 43.5% of variants were identical in both components. Furthermore, PAK5 mutation; copy number (CN) loss of CDH1, CHEK1, and MLH1; and CN gains of CDK6, HGF, and FOXP1 were identified in the high-grade lesion. The patient was treated with eight cycles of adjuvant chemotherapy (epirubicin combined with cyclophosphamide) and radiotherapy after surgery, and she is currently alive for 43 months with no metastases or recurrences.

This case demonstrates a comparative analysis of the histopathological and genetic characteristics of classical low-grade and high-grade components of AciCC within the same breast. This information may serve as a morphological and molecular basis for further investigation into the molecular mechanisms underlying high-grade lesions in breast AciCC.