Oral epithelial dysplasia (OED) is the principal histopathological marker for malignant risk stratification in oral potentially malignant disorders (OPMDs). Current World Health Organisation (WHO) three-tier and other binary grading systems are limited by modest inter-observer reproducibility and suboptimal prognostic discrimination, particularly for architecture-predominant lesions where cytological atypia is inconspicuous. The most clinically consequential failure of current practice is not mis-grading but non-recognition of dysplasia altogether, with direct implications for patient surveillance and management. This position paper, arising from Working Group 2 of COST Action CA21140 INTERCEPTOR, synthesises evidence from inter-observer reproducibility studies, feature-based prognostic models, under-recognition studies, outcome data and computational pathology analyses to propose and contextualise a pattern-anchored, grade-retaining diagnostic framework for OED. Five recognisable histological patterns are proposed: conventional/basaloid, keratinising/differentiated, verrucous, papillomatous, and HPV-associated, functioning as diagnostic anchors that capture the full morphological spectrum of OED, including architecture-predominant phenotypes that are disproportionately under-recognised in routine practice. Feature-based prognostic models demonstrate that architectural traits characterising these patterns (bulbous rete ridges, AUROC 0.74; cohesion loss, AUROC 0.73) predict malignant transformation more effectively than grade alone. Independent computational pathology analyses identify corresponding immune microenvironment and architectural signals as the strongest prognostic variables, providing convergent support. A two-step approach i.e. first identifying the dominant morphological pattern and then assigning grade within that pattern using existing WHO or binary criteria, offers a pragmatic, grade-retaining refinement compatible with current diagnostic frameworks and clinical pathways. The proposal is hypothesis-driven and requires prospective multicentre validation before wider adoption.
Inflammatory rhabdomyoblastic tumors (IRMT) are newly described entities characterized by a near-haploid karyotype. Most IRMTs exhibit indolent behavior; however, rare malignant transformation has been reported. We report a case of IRMT with malignant progression. A 67-year-old man presented with a painless mass in the left neck. Radiology revealed a 40-mm tumor in the left sternocleidomastoid muscle, with no evidence of distant metastasis. Core needle biopsy showed densely proliferating polygonal cells with pleomorphic nuclei, necrosis, and atypical mitoses. Based on histology, a preliminary diagnosis of pleomorphic rhabdomyosarcomas was made, although the clinical behavior seemed atypical. Nanopore DNA sequencing was subsequently performed and, within days, revealed characteristic molecular features, including relative gains of chromosomes 5, 7, and 22, a TP53 mutation, and DNA methylation profiling consistent with IRMT with malignant progression. The tumor was surgically resected, and pathological examination of the resected specimen confirmed a minor conventional IRMT component. Furthermore, infiltration of CD163-positive histiocytes was prominent, and fluorescence in situ hybridization analysis revealed two red signals (COL1A1 on chromosome 17) and four green signals (PDGFB on chromosome 22) in most tumor cells. Collectively, these histopathological, immunohistochemical, cytogenetic, and epigenetic findings established a final diagnosis of IRMT with malignant progression. Given the small tumor size, chemotherapy and radiotherapy were not administered. Nevertheless, the long-term behavior of IRMT with malignant progression remains unclear; thus, careful follow-up is warranted.
Creating a frozen section slide and crafting an interpretation is a multistep process with multiple possible points of failure. Head and neck frozen section pathology presents particular technical and diagnostic challenges. The aim of our study was to identify discrepancies between head/neck intraoperative and final diagnoses, determine the site of process failure, and assess the potential causes. Concordance data from head and neck intraoperative and final diagnoses (2020–2023) were queried from our LIS-embedded quality assurance system. Discrepancies were categorized as major and minor, with major defined as those that would have altered the surgical procedure. We found 71 total discrepancies out of 1844 head and neck cases (3.9
This systematic review with functional meta-synthesis and exploratory meta-analysis evaluated the clinical utility of molecular testing in ameloblastoma, focusing on diagnostic, genotype–phenotype, prognostic, liquid-biopsy, and precision-therapy implications. PubMed/MEDLINE, Scopus, and Embase were searched from inception to April 2026. Eligible studies were full original articles evaluating direct molecular or molecularly interpretable testing in human ameloblastoma. Data were synthesized using functional meta-synthesis. Exploratory random-effects meta-analyses were performed when sufficient study-level data were available. Twenty-nine studies met the inclusion criteria. Molecular testing was most consistently informative for defining the molecular landscape and supporting diagnosis. BRAF V600E was the dominant alteration across the evidence base, but additional alterations in SMO, FGFR2, RAS-family genes, CTNNB1, PIK3CA, EGFR, and ROS1 were reported, particularly in selected or BRAF-wild-type tumors. Exploratory meta-analysis of 19 studies showed a pooled BRAF V600E prevalence of 69.1
This study aimed to compare the clinicopathological features of stage I–II oral squamous cell carcinoma (OSCC) between adolescents and young adults (AYAs) and older patients, and to identify prognostic factors in AYA OSCC. Forty-eight AYA patients aged 15–39 years and 69 older patients aged ≥ 65 years with surgically treated stage I–II OSCC were retrospectively analyzed. Histological evaluation, survival analysis, immunohistochemistry for p53, p16, and MTAP, high-risk HPV RNA in situ hybridization, and fluorescence in situ hybridization for CDKN2A and MTAP were performed. Compared with older patients, OSCCs in AYAs were more frequently located on the tongue (93.7
Lenalidomide is an immunomodulatory agent widely used in the treatment of multiple myeloma and is generally associated with a favorable safety profile. Although pigmentary alterations such as cutaneous hyperpigmentation and hair repigmentation have been reported, oral mucosal involvement remains poorly documented. An 80-year-old Black female with multiple myeloma undergoing lenalidomide therapy presented with asymptomatic brown macules on the tongue, hard palate, bilateral buccal mucosa and gingiva. Histopathological examination of an incisional biopsy on the tongue revealed many fine granular, brownish pigmentation of approximately the same size throughout all epithelial layers, as well as collagen fibers, vascular walls, neural tissue, and skeletal striated muscle. These findings represent an unusual pattern of pigment distribution not previously described in patients under lenalidomide therapy. This case emphasizes the need for thorough oral examination in patients undergoing lenalidomide therapy, as early recognition of drug-induced pigmentation is essential for proper diagnosis and management.
This study aimed to investigate the clinicopathological features of malignant odontogenic tumors (MOTs) and to provide a comprehensive characterization that enhances the current understanding of this disease group. MOTs were retrieved from six Brazilian oral pathology services between 2007 and 2025. Demographic, clinical and radiographic data were collected from the charts, and the histological H E-stained sections were revised by two blinded pathologists; previously available immunohistochemical and molecular findings were retrieved and reviewed in selected cases and the diagnosis was established according to the 2022 World Health Organization classification. A total of 53 malignant odontogenic tumors were identified, predominantly affecting the mandible (83
This study aims to evaluate the effectiveness of deep learning AI model in the diagnosis and grading of mucoepidermoid carcinoma. We developed a multiple instance learning based-deep learning model which consisted of two modules. One to perform slide-level classification of whole slide images into mucoepidermoid carcinoma and non-mucoepidermoid carcinoma classes and the second one to perform grading into low, intermediate, and high grades. A total of 194 whole slide images were included in the study. Of these, 92 corresponded to mucoepidermoid carcinoma, while the remaining 102 represented non-mucoepidermoid carcinoma cases. Our results showed that the classification model achieved 90.62
Calcified chondroid mesenchymal neoplasm (CCMN) is a recently described and evolving entity that predominantly arises in the distal extremities andtemporomandibular joint (TMJ) region. CCMN is characterized by FN1 and PDGFRA gene fusions. In the TMJ region, most cases previously described as tophaceous pseudogout (i.e., mass-forming calcium pyrophosphate deposition disease) are now being increasingly recognized as CCMN. There is considerable morphologic overlap between CCMN and tophaceous pseudogout (TPG), and the detection of FN1 and PDGFRA gene rearrangements is critical in distinguishing CCMN from TPG. We aim to identify, from our archival records, cases of CCMN that were previously diagnosed as TPG. We retrospectively reviewed clinical history and histopathology slides of three cases of TMJ region masses initially diagnosed as TPG, and submitted all three cases for targeted RNA sequencing. Results: Case 1 harbored a canonical FN1::FGFR2 fusion. Case 2 failed targeted RNA sequencing. Case 3 harbored a canonical PDGFRA::USP8 fusion. None of the three cases had clinical history of pseudogout. All three cases were subsequently reclassified as CCMN on review. CCMN should be considered as a differential diagnosis in first presentations of ‘tophaceous pseudogout’ associated with chondroid metaplasia, with targeted molecular testing done as part of the diagnostic process.
Parotid cystadenoma is an uncommon benign epithelial salivary gland neoplasm. Rarely, it may present with recurrent inflammatory episodes, creating diagnostic uncertainty and operative complexity. To the authors’ knowledge, this represents the largest reported case series specifically focused on histologically confirmed parotid cystadenoma presenting with recurrent parotitis. This case series describes five such patients and outlines preliminary clinicopathological features that may support recognition of this presentation, while acknowledging the exploratory nature of the observations. We performed a retrospective descriptive case series from a specialist parotid surgical practice. Five consecutive patients managed by the primary author with histologically confirmed parotid cystadenoma and a clinical history of recurrent parotitis were included. Clinical presentation, imaging, tissue sampling, operative findings, histopathology, facial nerve status and 12-month follow-up were reviewed from clinical records. No formal diagnostic criteria were developed or validated. All patients had unilateral cystic parotid lesions with recurrent inflammatory symptoms. Imaging demonstrated benign-appearing cystic lesions, varying from well-circumscribed superficial-lobe cysts to multiloculated lesions extending into the deep lobe. Preoperative core biopsy was non-diagnostic in all cases, usually yielding cyst fluid, inflammatory debris or degenerate cells. Surgical excision established the diagnosis in each patient. Histology confirmed cystadenoma, predominantly oncocytic; intraluminal crystalloids were identified in two cases, both associated with suppurative or inflammatory change. No patient had preoperative facial nerve dysfunction. At 12-month follow-up, no recurrence or persistent postoperative facial nerve deficit was recorded in any case. Parotid cystadenoma should be included in the differential diagnosis of recurrent parotitis associated with a cystic parotid lesion, particularly when tissue sampling is inconclusive. The proposed clinicopathological features are preliminary observations from a small retrospective series and require validation in larger cohorts before use as diagnostic criteria.
BACKGROUND:Biphenotypic sinonasal sarcoma (BSNS) typically demonstrates expression of both neural and myogenic markers while harboring PAX3 gene fusions. Reported fusion partners include MAML3, NCOA1, NCOA2, FOXO1, FOXO6, WWTR1, and YAP1. Herein, we report two additional cases of BSNS harboring PAX3::FOXO6 gene fusions to aid in variant classification. CASE PRESENTATION:Patient 1 was a 37-year-old female and patient 2 was 56-year-old male with BSNS involving the right nasal cavity and left middle turbinate, respectively. Both sarcomas were unencapsulated infiltrative spindle cell neoplasms that demonstrated morphologic features of BSNS. Case 1 demonstrated variable aberrant nuclear accumulation of beta-catenin protein and lacked expression of SMA and S100 protein. Positive reactions were observed with SMA and S100 protein in case 2. RNA sequencing identified PAX3::FOXO6 (exon 7::exon 2) in both cases. CONCLUSION:The sinonasal location, morphology, and immunophenotype allow for discrimination against competing entities in most cases. In select cases genetic evaluation becomes necessary and to further aid in variant classification and to provide additional support for this rare finding we provide two examples of BSNS harboring PAX3::FOXO6.
BackgroundLeprosy is a chronic infectious disease caused by Mycobacterium leprae that primarily affects the skin and peripheral nerves. Oral manifestations are rare and typically occur in advanced cases of multibacillary lepromatous leprosy.Case PresentationAn 18-year-old male from Tocantins, a hyperendemic region of Brazil, presented with widespread mucocutaneous papulonodular lesions affecting the face and extremities, as well as nodular and ulcerative lesions of the hard and soft palates and the uvula. Histopathological analysis revealed a diffuse subepithelial inflammatory infiltrate predominantly consisting of foamy macrophages exhibiting Virchow-like characteristics. Immunohistochemistry showed diffuse CD68 positivity. Fite-Faraco and Ziehl-Neelsen staining revealed numerous intracytoplasmic acid-fast bacilli. These findings, together with clinical features, established the diagnosis of lepromatous leprosy.ConclusionAlthough oral manifestations of leprosy are uncommon, they may represent important diagnostic indicators of advanced multibacillary disease. Oral biopsy, combined with histopathological examination and special stains, remains essential for definitive diagnosis, particularly in hyperendemic regions where other granulomatous infectious diseases may coexist.
Intraductal carcinoma (IDC) of the salivary gland is an uncommon epithelial neoplasm characterized by a predominantly intraductal or intracystic proliferation rimmed by a myoepithelial cell layer. Advances in molecular profiling have revealed recurrent gene fusions in IDC, most frequently involving RET, although fusions implicating other kinase genes have also been described. Among these, ALK rearrangements are rare and remain poorly characterized. Herein, we report a case of oncocytic IDC of the parotid gland harboring a STRN::ALK fusion, further expanding the molecular landscape of this tumor. Although this fusion has been previously reported in intercalated duct IDC, to our knowledge, this is the first report of this specific fusion in oncocytic IDC.
BACKGROUND:NUT carcinoma is a rare and aggressive malignancy defined by rearrangements of NUTM1, most commonly with partner BRD4 or BRD3, and carries a dismal prognosis. Carcinoma arising from Stensen's (parotid excretory) duct is itself an exceedingly rare entity, with only 30 previously reported cases spanning diverse morphologies. CASE PRESENTATION:We report the first case of NUT carcinoma arising from Stensen's duct in a 37-year-old female who presented with an enlarging right buccal submucosal mass, initially favored on imaging to represent a chronic inflammatory process. Punch biopsy was originally interpreted as invasive squamous cell carcinoma. Surgical resection revealed a high-grade basaloid carcinoma with abrupt keratinization centered at the parotid papilla with retrograde ductal spread. Immunohistochemistry demonstrated NUT positivity, and fluorescence in situ hybridization confirmed NUTM1 translocation. RNA sequencing identified a BRD4::NUTM1 fusion, establishing the diagnosis of NUT carcinoma. Incidentally, next-generation sequencing identified a BRCA1 mutation, confirmed to be germline on subsequent germline testing. The patient was treated with surgical resection, adjuvant cisplatin chemotherapy, and external beam radiation, with no evidence of disease on PET-CT two months after diagnosis. CONCLUSION:This case expands the morphologic spectrum of Stensen's duct carcinoma, underscores the challenges in clinical, radiologic, and pathologic interpretation of masses at this site, and suggests a potential association between homologous recombination deficiency and this translocation-associated malignancy.
Sinonasal squamous cell carcinoma (SNSCC) comprises a heterogeneous group of tumors with emerging molecular subtypes. Human papillomavirus (HPV)-associated SNSCC is a distinct entity, although actionable genomic alterations beyond HPV-driven pathways remain underexplored. Distinguishing HPV-associated SNSCC from carcinoma ex inverted papilloma can be particularly challenging in limited biopsy specimens, as these lesions may appear morphologically similar. We report a case of HPV-associated SNSCC with concurrent FGFR3::TACC3 fusion and NOTCH1 p.C1416 stop-gain mutation.
PURPOSE:Because of their relative rarity, bone and soft tissue lesions of the head and neck region can present a diagnostic challenge to anatomic pathologists who practice in a general surgical pathology model-while novel lesions may be unfamiliar to subspecialty head and neck pathologists. METHODS:This review focuses on a diagnostically confounding neoplasm that arises in the bone (primary intraosseous rhabdomyosarcoma / FUS::TFCP2-rearranged spindle cell rhabdomyosarcoma) and soft tissue (trans-/de-/undifferentiated melanoma) of the head and neck region-each of which can easily be mistaken for more common entities. RESULTS:The clinical, radiological, and histopathologic findings (including the molecular pathogenesis) of each neoplasm is discussed-along with selected differential diagnoses. CONCLUSION:The accurate recognition of these neoplasms ensures that patients are reviewed, treated, and followed at the appropriate multidisciplinary meeting.
Artificial intelligence (AI) has emerged as a promising tool for digital pathology, with potential applications in the histopathologic evaluation of oral epithelial dysplasia (OED). This systematic review synthesized current evidence on AI-assisted histopathologic diagnosis and grading of OED, focusing on diagnostic performance, methodological quality, certainty of evidence, and functional roles of AI systems in the diagnostic workflow. A systematic search of PubMed/MEDLINE, Scopus, and Embase was conducted. Eligible studies evaluated AI, machine learning, deep learning, convolutional neural network (CNN), Transformer-based, or computational pathology methods applied to microscopic or digital histopathologic images of OED or oral potentially malignant disorders with dysplasia. Data on study characteristics, image format, analytical level, model architecture, reference standard, validation strategy, and diagnostic performance were extracted. Thirteen studies published between 2017 and 2026 met the inclusion criteria. AI applications were grouped into three functional domains: detection of dysplastic epithelium, grading of dysplasia severity, and diagnostic assistance through enhanced image interpretation. Included studies used heterogeneous analytical approaches, ranging from handcrafted-feature machine-learning pipelines and CNN-based cellular or tissue-level classifiers to whole-slide image segmentation, DenseNet, Vision Transformer, and hybrid computational pathology pipelines. Several studies reported high experimental performance, including accuracy above 90
Peripheral nerve sheath tumors (PNSTs) of the head and neck (H N) show histopathological overlap. Although convolutional neural networks (CNNs) have demonstrated feasibility in soft tissue tumor classification, limited intra-class variability related to perineurioma remains a critical constraint for rare tumor subtypes. This retrospective diagnostic accuracy study with internal validation included 30 patients diagnosed with PNSTs. Whole-slide images were digitized at 20× magnification and partitioned using a strict patient-wise split. Synthetic perineurioma patches were generated using a modified Pix2Pix-based Generative Adversarial Network (GAN) incorporating a bottleneck architecture and self-attention modules. Two morphology-driven augmentation strategies were evaluated: (1) intra-phenotypic expansion by cross-patient patch pairing within the sclerosing subtype and (2) inter-phenotypic interpolation by cross-phenotype patch pairing between sclerosing and intraneural variants. EfficientNetV2-B0 pre-trained on ImageNet was trained under three configurations: original dataset only, original + Experiment A synthetic patches, and original + Experiment B synthetic patches. All performance metrics were computed exclusively on an independent yet internal test set composed of original images. GAN-based augmentation improved global classification performance compared with the baseline model trained on original images only (accuracy 0.733). Intra-phenotypic expansion increased accuracy to 0.767 and achieved the highest balanced accuracy (0.750) and macro-F1 (0.740). Inter-phenotypic interpolation yielded the highest overall accuracy and competitive multiclass agreement metrics. Perineurioma recall improved from 0.34 (baseline) to 0.51 with intra-phenotypic augmentation and 0.47 with inter-phenotypic interpolation, while specificity remained ≥ 0.999 across all strategies. Structured, pathology-informed GAN augmentation improved CNN classification of PNSTs, particularly for the morphologically heterogeneous perineurioma class. Intra-phenotypic expansion primarily improved rare-class sensitivity, whereas inter-phenotypic interpolation improved multiclass agreement and global robustness. These findings support morphology-driven synthetic enrichment as a clinically meaningful strategy to improve AI performance in underrepresented tumor entities and potentially support diagnostic decision-making in digital pathology environments.
BACKGROUND: Similar to other head and neck organs, thyroid pathology encompasses a broad spectrum of diagnostic entities. The significant overlap in architectural or cytological features across these entities presents a unique set of diagnostic challenges. METHODS: This review focuses on diagnostic pitfalls related to metastasis in thyroid pathology, with particular emphasis on morphologic assessment and differential diagnosis. RESULTS: Key scenarios discussed include (1) intranodal thyroid inclusions, which may closely mimic metastatic papillary thyroid carcinoma in cervical lymph nodes, and (2) metastatic tumors to the thyroid that can simulate primary thyroid neoplasms across the full histologic spectrum, from low-grade to high-grade malignancies, especially in the absence of a known concomitant primary malignancy or when the clinical history is not provided. Awareness that both benign thyroid tissue and metastatic tumors may exhibit atypical architectural or cytologic features is critical to avoiding overdiagnosis or misclassification. Rigorous morphological assessment remains the first step in the diagnostic workup. Immunohistochemistry serves as a valuable adjunct when used judiciously, particularly mutation-specific markers such as BRAF VE1 and lineage-associated markers including TTF-1, PAX8, and thyroglobulin, with careful consideration of their sensitivity and specificity. CONCLUSION: Integration of histologic findings with clinical history and radiologic information ultimately enables accurate distinction between metastatic and non-metastatic lesions in thyroid pathology.
Myxoid epithelioid sarcoma is a rare morphologic variant of epithelioid sarcoma characterized by abundant myxoid stroma and frequent loss of SMARCB1/INI1 expression. Orbital involvement is exceptionally uncommon. We report a case of a SMARCB1-deficient malignant orbital neoplasm with features overlapping myxoid epithelioid sarcoma in a 61-year-old man presenting with visual disturbance. Imaging studies revealed a 2.5-cm medial orbital mass without evidence of another primary lesion. The tumor was excised without prior biopsy. Histologically, the lesion was predominantly composed of abundant myxoid stroma containing scattered atypical epithelioid, signet ring-like, and spindle cells, with focal fascicular proliferation infiltrating skeletal muscle. Immunohistochemically, tumor cells were positive for pan-cytokeratin, EMA, vimentin, and CD34, while negative for S100, ΔNp63 (p40), p63, SS18-SSX, and TLE1. Complete loss of SMARCB1/INI1 expression was observed in tumor cells. The overall findings suggested a SMARCB1-deficient malignant neoplasm showing substantial morphologic and immunophenotypic overlap with myxoid epithelioid sarcoma. This case highlights the diagnostic challenges posed by SMARCB1-deficient tumors arising in unusual anatomical sites and expands the clinicopathological spectrum of myxoid epithelioid sarcoma-like neoplasms involving the orbit.
