The World Health Organization's (WHO) Reporting System for Liver Cytopathology aims to standardize communication with clinicians globally to improve patient management. Our study reclassifies liver cytology reports based on the WHO classification and assesses the risk of malignancy (ROM) in each category. Liver cytology reports from 2019 to 2023 were retrieved to obtain demographic details, clinical data, cytology, and surgical follow-up (SFU). Cytology diagnoses were reclassified using the WHO classification. ROM was analyzed based on SFU. Our study had 976 cases, age ranged from 1-96 years, with an average age of 67 years. Male: female ratio was 1:1. Majority of lesions (400/525, 76%) were less than 5 cm. Location of the lesion was available in 595 cases, with right lobe being the most common (64%; n = 383), followed by left lobe (36%, n = 212). 883 cases (90%) underwent rapid onsite evaluation. Reclassification using the WHO classification system into 5 categories included non-diagnostic (n = 79), benign (n = 117), atypical (n = 25), suspicious for malignancy (n = 6) and malignant (n = 749). Thirty-one cases (3%) had cytology follow up, 71(7.3%) had SFU. The ROM in the SFU cohort was 17% (1/6; 95% CI: 10%-76%) in non-diagnostic, 23% (3/13, 95% CI: 15.4%-30.6%) in benign and 100% in atypical (3/3, 95% CI: 88%-100%), suspicious for malignancy (2/2, 95% CI: 50%-100%) and malignant(47/47, 95% CI: 99.5%-100%) categories. Repeat FNA yielded malignant upgrade rates of 80% (4 out of 5) in non-diagnostic and 75% (3 out of 4) in atypical categories. We present the values of ROM in the various categories of the WHO Reporting System for Liver Cytopathology using a large cohort of cases. Repeat sampling is recommended in non-diagnostic and atypical categories based on an increase in malignant upgrades in these categories.

Lung adenocarcinoma, the most common subtype of non-small cell lung cancer (NSCLC), exhibits diverse histopathological and vascular patterns influencing prognosis and therapeutic response. Angiogenesis, the process of new blood vessel formation, has historically been regarded as the predominant mechanism of tumor vascularization in solid cancers. However, vessel co-option, a non-angiogenic process, has emerged as an alternative strategy, involving the hijacking of pre-existing blood vessels by cancer cells rather than the induction of new ones. Furthermore, vessel co-option has been observed in both primary and metastatic cancers. The aim of this study was to determine the vascular patterns of different human adenocarcinoma samples and establish potential correlations between histological subtypes and microvascular growth patterns. Seventy lung adenocarcinoma samples were classified according to the 2021 WHO classification system, and their vascularization patterns were analyzed using CD31 immunohistochemistry and Weigert-Van Gieson staining. A substantial correlation was observed between histological subtypes and vascularization strategies, with solid basal and diffuse tumors exhibiting angiogenesis, and solid alveolar and lepidic tumors associated with vessel co-option. Additionally, papillary and micropapillary patterns exhibited mixed vascularization, while acinar tumors displayed the highest heterogeneity. The combination of staining techniques improved classification accuracy, achieving successful identification in 92.5% of cases. In conclusion, we present a powerful tool that can be used in lung cancer diagnostics to analyze tumor vascularization based on CD31 and elastic fibers staining. The observed correlations highlight the significance of histopathological assessment in determining vascularization mechanisms, which may optimize therapeutic strategies for NSCLC.

Rare cancers are usually defined as an incidence of <6/100,000 persons per year. Gynecological oncology is characterized by a paradoxical high prevalence of rare cancer subtypes, especially in ovarian tumors. Ovarian germ cell tumors, clear cell ovarian cancer and gestational trophoblastic disease encompass this set of gynecologic tumors. The WHO classification distinguishes epithelial cell tumors (85% of malignant tumors) from non-epithelial tumors, sex cord stromal tumors (8% of malignant tumors), and germ cell tumors (6% of malignant tumors). The current treatment for these tumors is similar to that for ovarian cancer but advancing quickly to incorporate targeted therapy. Gestational trophoblastic tumors are usually curable, even when widely metastatic disease is present. Ovarian clear-cell carcinoma (OCCC) remains a challenging disease characterized by intrinsic chemoresistance and distinct molecular features. A more biologically aligned treatment strategy has emerged. Continued integration of molecular selection and microenvironmental modulation will likely define the next phase of therapeutic development in OCCC. The clinical features, staging, and current treatment of each of these tumors is reviewed.

Astroblastoma, MN1 -altered, is a newly recognized entity in the 5th edition of the WHO Classification of CNS Tumors. Its genetic definition is the presence of an alteration, most commonly gene fusions, in the MN1 gene, with BEND2 being the most frequent fusion partner. However, some astroblastomas and astroblastoma-like tumors with fusion of non- MN1 to BEND2 have been reported recently. These tumors exhibit epigenetic profiles similar to those of astroblastomas with MN1 :: BEND2 , suggesting that BEND2 may play a more important role than MN1 in tumorigenesis. Therefore, investigation of BEND2 fusion will be essential to make an accurate diagnosis of astroblastomas in the near future. In this study, we aimed to explore the diagnostic utility of BEND2 immunohistochemistry using a commercially available rabbit polyclonal antibody. As a result, nuclear expression of BEND2 was observed in all 15 cases of astroblastomas with BEND2 fusion (9 with MN1 :: BEND2 , 4 with EWSR1 :: BEND2 , 1 with MAMLD1 :: BEND2 , and 1 with TCF3 :: BEND2 ), whereas it was not found in 147 cases of other CNS tumors from 48 different entities. In contrast, negative nuclear staining for BEND2 was observed in a previously reported case of spindle cell sarcoma with MN1 :: BEND2 , whose fusion junction differed from those of the astroblastomas analyzed in this study. In conclusion, we demonstrated that BEND2 immunohistochemistry has extremely high sensitivity and specificity, suggesting its utility as a reliable marker for the diagnosis of astroblastoma with BEND2 fusion.

Soft tissue-RADS scoring system for musculoskeletal (MSK) tumor and tumor-like lesions is recently published. The system includes diagnostic MRI flowcharts and algorithms for lipomatous masses, cyst-like or high-water content masses, and indeterminate-solid appearing masses with consistent and standardized management recommendations. MSK radiology and cancer imaging training commonly provides the essential skills needed to render appropriate prospective diagnosis for many non-neoplastic tumor-like lesions and various commonly encountered sarcomas. Such trained readers may benefit from additional advanced algorithms to accurately identify and categorize different benign tumors and sarcomas and correctly input them in the soft tissue-RADS scoring system. These algorithms are built from a comprehensive literature search to establish an evidence-based composite and are supported by the expert opinions of the multidisciplinary ACR-soft tissue-RADS team. In this article we provide (1) a literature review of multimodality imaging, immunopathology, and clinical findings of soft tissue tumors and tumor-like lesions, presented in 7 tables (condensed from the 12 tables published in the WHO classification of soft tissue tumors) with respective table summaries; (2) a suggested modality-based lexicon; and (3) advanced diagnostic algorithms for trained readers based on published evidence and expert opinion that feed into the soft tissue-RADS scoring system (categories 1-6). The purpose of this work is to provide comprehensive guidance on soft tissue-RADS scoring to help streamline care for soft tissue tumors and tumor-like lesions and optimize patient outcomes.

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2 :: NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases ( NFATC2::NUTM2A , n=2; NFATC2::NUTM2E , n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24mo; range: 9 to 41mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2 -associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

Basaloid squamous cell carcinoma of the cervix (BSCC) is an extremely rare subtype. In the 2020 WHO classification, BSCC is considered a subtype within HPV-associated squamous cell carcinoma. We report a case wherein liquid-based cytology (LBC) initially suggested a high-grade squamous intraepithelial lesion (HSIL). Retrospective review, prompted by the histologic diagnosis of BSCC, revealed diffuse sheets of monotonous basaloid and parabasaloid cells. Key cytologic features included three-dimensional clusters with occasional papillary architecture, palisading, and cord-like arrangements-findings that can be misleading. This case underscored that BSCC's deceptively bland cytology often overlaps with HSIL, contributing to diagnostic under-call. Increased awareness of these subtle yet distinctive patterns is crucial for accurate identification and appropriate clinical management of this rare variant.

Immature PIT-1 lineage tumors are classified as high-risk pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) under the 2022 WHO Classification, yet clinical outcome data remain scarce. This study aimed to characterize clinicopathological features and treatment outcomes of this rare entity. We retrospectively analyzed 13 patients with pathologically confirmed immature PIT-1 lineage tumors who underwent surgery at our tertiary center between January 2022 and December 2024. Diagnoses were established according to WHO 2022 criteria using comprehensive transcription factor (TF) immunohistochemistry. Clinical, radiological, histopathological, treatment, and follow-up data were evaluated. Immature PIT-1 lineage tumors accounted for 4% (21/525) of surgically treated pituitary adenomas, of whom 13 with complete follow-up data constituted the primary analysis cohort. Median age was 37 years (range: 25-73), with female predominance (61.5%). Notably, 61.5% presented with hormonal hypersecretion: acromegaly (38.5%), TSH-secreting tumors (15.4%), and GH-PRL co-secretion (7.7%). All patients had macroadenomas (median diameter 28mm (range: 15-59mm)); 38.5% demonstrated cavernous sinus invasion (Knosp grades 3-4). Immunohistochemically defined plurihormonal phenotype was present in 77% of cases; cytologic atypia was identified in all cases. Despite maximal surgical resection, residual disease persisted in 46% and 31% required reoperation at 16-month follow-up (range: 4-51 months). The median Ki-67 proliferation index was 4% (IQR: 2-10%; range: 1-35%), and the median mitotic count was 4 per 2mm² (IQR: 1-8; range: 1-20). Immature PIT-1 lineage tumors exhibit aggressive behavior with high residual disease rates, with 31% of patients requiring reoperation, 23% receiving adjuvant radiotherapy, and somatostatin analogue resistance observed in two patients. Routine TF immunohistochemistry is essential for accurate diagnosis; management requires maximal safe surgical resection and intensive long-term surveillance.

Acoustic schwannomas are a highly prevalent yet poorly studied class of benign brain tumors impacting neuropsychological functioning, clinical, and functional outcomes. The study aims to assess neurocognitive functions and emotional processing in right-handed adults of Indian origin with acoustic schwannomas and identify neuropsychological impairments and relevant correlates. A prospective cross-sectional research design with consecutive sampling was employed. The sample (n = 44) was screened according to the WHO Classification of Tumors of the Central Nervous System (2021) and recruited by consecutive sampling from a referral and tertiary care medical center in South India. Selected neuropsychological tests from the Post-Graduate Institute Battery of Brain Dysfunction, Wechsler Memory Scale III, and National Institute of Mental Health and Neurosciences Neuropsychology Battery were administered along with a task developed for the assessment of emotion processing. The data was statistically analyzed using Statistical Analysis System (SAS) for descriptive analysis and non-parametric inferential statistics. The cohort had a mean age of 43.86 (±11.09) years, with a median of 12 (±3.02) years of education and right hemispheric (54.5%) cerebellar-pontine angle lesions. Our results demonstrate impairment in multiple neurocognitive domains, including visuospatial construction, visual/verbal memory, attention, executive functions, and difficulty in emotional processing in acoustic schwannoma patients, consistent with cerebellar contributions to higher-order functions. These deficits correlated with sociodemographic and clinical factors, potentially implicating networks such as the default mode network, cerebello-thalamo-cortical, and fronto-cerebellar pathways. The study highlights the need for comprehensive neuropsychological assessments in acoustic schwannomas and implications for functional outcomes.

Precursor flat urothelial lesions: Molecular landscape, pathogenesis, and biological insights.

Glioblastoma (GBM) remains the most common and lethal primary malignant brain tumor in adults, with a median survival of approximately 15months despite maximal multimodal therapy. The 2021 WHO classification has improved diagnostic precision by incorporating key molecular features, including EGFR amplification, TERT promoter mutation, PTEN loss, and MGMT promoter methylation. However, current standard of care treatments such as surgical resection, radiotherapy, temozolomide, and tumor treating fields have reached a therapeutic plateau, highlighting the urgent need for new therapeutic strategies. Although immunotherapy has transformed the treatment of several solid tumors, its clinical benefit in GBM remains limited. This limitation reflects not only low tumor mutational burden or blood brain barrier constraints, but also the profound spatial and temporal heterogeneity of the tumor. Distinct tumor regions exhibit diverse immune states, while ongoing clonal evolution dynamically reshapes antigenicity, immune recognition, and therapeutic response. In this review, we provide a comprehensive overview of glioblastoma, including epidemiology, molecular pathogenesis, diagnostic approaches, tumor microenvironment, intratumoral heterogeneity, and current therapeutic strategies. We further synthesize recent advances in spatial and longitudinal profiling technologies to describe the dynamic tumor immune ecosystem. We discuss how spatial compartmentalization and evolutionary processes collectively drive immune escape and therapeutic resistance, and highlight emerging strategies including adaptive immunotherapy, precision targeted delivery, and multimodal monitoring to overcome these challenges.

Activated cancer-associated fibroblasts (aCAFs), characterized by distinct histological features including fibroblast proliferation and extensive desmoplasia, play a key role in tumor progression induced by cancer cell infiltration and may serve as important predictive and prognostic factors in gastric cancer (GC). This study investigated the relationship between aCAFs and clinicopathologic factors and their impact on survival outcomes in 691 GC patients across two independent cohorts. aCAFs were identified based on histological features on H&E-stained slides, and clinicopathological parameters, survival outcomes, immune cell composition, and transcriptomic features were comprehensively evaluated. Publicly available transcriptomic datasets were also analyzed for translational insights. aCAFs were significantly associated with advanced T and N stages, vascular/lymphatic/perineural invasion, and necrosis. Higher histological grade tended to correlate with increased aCAF frequency (P = 0.061). Notably, aCAFs were less frequently observed in diffuse-type GC according to Lauren classification and in poorly cohesive carcinoma according to WHO classification compared to other subtypes (all P < 0.05). The presence of aCAFs was significantly associated with poor survival in diffuse-subtype GC and WHO-defined poorly cohesive carcinoma on univariate and multivariate analyses (all P < 0.05). aCAFs correlated with immune dysfunction but were not related to CD4 + and CD8 + T cell counts. Incorporating aCAF status modestly but consistently improved survival prediction in machine learning-based prognostic models. Histologically identifiable aCAFs on routine H&E slides represent a clinically accessible prognostic biomarker in diffuse-subtype GC, highlighting the importance of stromal morphology in risk stratification and providing a translational framework for future therapeutic studies targeting the tumor microenvironment.

Lymphoid neoplasms are a diverse group of cancers derived from lymphocytes, with classification recently updated by the 5th edition of the WHO Classification of Haematolymphoid Tumours (WHO-HAEM5). Benzene, a well-known carcinogen, is widely used in industries and environmental exposures vary; however, its association with specific lymphoid neoplasm subtypes remains unclear due to historical classification challenges. This study aimed to clarify the risk of lymphoid neoplasms related to benzene exposure using the updated WHO-HAEM5 framework.A systematic review and meta-analysis were conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eligible studies were comparative human studies evaluating benzene exposure and lymphoid neoplasm risk, with sufficient data for risk estimates. Inclusion criteria specified study designs, participants, exposures and outcomes based on clinical diagnoses. Data were independently extracted by multiple reviewers. The main outcome was risk of lymphoid neoplasms and subtypes analysed by random-effects meta-analysis with heterogeneity and bias assessments.From 1488 records, 95 studies met criteria (65 occupational and 30 environmental exposure). Benzene exposure significantly increased overall lymphoid neoplasm risk (RR 1.26; 95% CI 1.18 to 1.35). B-cell neoplasms showed elevated risk (RR 1.26; 95% CI 1.16 to 1.37), including mature B-cell neoplasms, Hodgkin lymphoma and plasma cell neoplasms. T-cell and natural killer cell neoplasm risk was not significantly increased overall. Occupational exposures conferred higher risks with lower heterogeneity than environmental exposures.Benzene exposure is strongly associated with increased risk of lymphoid neoplasms, particularly B-cell subtypes, supported by the refined WHO-HAEM5 classification reducing heterogeneity. This study underscores the importance of biologically informed disease classification and the need for targeted occupational safety and environmental health policies.The review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (Registration ID: CRD420251063844).

Amino acid positron emission tomography (PET) is increasingly utilized in the clinical workup of patients with glioma. To better understand the PET characteristics of IDH-mutant glioma according to the 2021 WHO classification of CNS tumours, this retrospective study explored the association between amino acid PET and magnetic resonance imaging (MRI) characteristics in patients with newly diagnosed IDH-mutant glioma. Patients with histologically verified IDH-mutant glioma who underwent [18F]FET PET/CT scans without prior treatment were included. PET parameters (PET-positivity according to PET RANO 1.0 criteria, maximal and mean tumour-to-background ratio (TBRmax, TBRmean), PET volume and uptake kinetics including minimal time-to-peak (TTPmin)) were assessed and compared with neuropathological findings and contrast-enhanced MRI including Dice similarity coefficients for spatial overlap between PET and MR signals. A total of 147 patients were included (79 astrocytomas, 68 oligodendrogliomas). Contrast enhancement was present in 44/147 tumours (29.9%), most frequently in astrocytoma WHO grade 4 (8/9, 88.9%). [¹⁸F]FET PET was positive in 62/68 oligodendrogliomas (91.2%) and 35/79 astrocytomas (44.3%), with significantly higher uptake intensities in oligodendrogliomas (median TBRmax 2.43 vs. 1.55; p < 0.001) and increasing values with WHO grade. PET–CE spatial overlap was generally low (median Dice 0.26 (range: 0.01–0.90)), whereas PET–FLAIR overlap was higher (median Dice 0.55 (range: 0.05–0.99)) and showed significant differences between histologies and grades. Dynamic [¹⁸F]FET PET data were available in 91/147 tumours (61.9%) and demonstrated predominantly increasing kinetics (61.5%). In the TTPmin analysis, WHO grade 4 astrocytomas clustered in the early 12.5-min group, whereas WHO grade 2–3 gliomas showed later peaks (17.5–35 min). [18F]FET PET uptake intensity correlates positively with the CNS WHO grade in IDH-mutant gliomas, but with marked overlap between tumour grades, and provides complementary information to contrast-enhanced MRI. [18F]FET PET may therefore add another layer of information on tumour characteristics and should be further investigated as a complementary biomarker.

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently recognized renal tumor characterized by papillary architecture lined by a single layer of low-grade eosinophilic cells with apically located nuclei. In the latest WHO classification, they are not recognized as a distinct entity but rather as a morphological pattern of papillary renal cell carcinoma. To date, limited studies have compared PRNRP with eosinophilic/oncocytic papillary renal cell carcinoma (E/OPRCC), which they are not infrequently confused with, although a few previous comparisons with classic papillary renal cell carcinoma have already identified several distinguishing features. A comparative analysis of 15 of PRNRPs and 16 of E/OPRCC cases was conducted, evaluating their histopathological, immunophenotypic, interphase cytogenetic, and molecular profiles. PRNRPs demonstrated distinctive morphological features, including consistent apical nuclear positioning, absence of foamy macrophages in the papillary cores (p = 0.0001), and a lower nucleolar grade compared to E/OPRCCs (p = < 0.0001). Immunohistochemically, PRNRPs exhibited strong and uniform GATA3 expression and were negative for vimentin, CD10, and CD13, in contrast to E/OPRCCs. Cytogenetically, PRNRPs lacked trisomies of chromosomes 7 and 17, which were present in ~ 40% of E/OPRCCs (p = 0.0262). Notably, all PRNRP cases harbored KRAS mutations, absent in E/OPRCCs (p < 0.0001). Our findings support the classification of PRNRP as a distinct renal tumor entity, separated from both classic papillary renal cell carcinoma and its eosinophilic/oncocytic morphological variant.

Revisiting parathyroid carcinoma through the lens of the 2022 WHO classification.

Morphology spectrum and molecular landscape in eosinophilic solid and cystic renal cell carcinoma.

Intracranial sarcomas can arise secondarily from primary brain tumors, including gliomas and meningiomas, either spontaneously or following radiotherapy. The current WHO classification recognizes sarcomatous transformation in several tumor entities; however, sarcomas arising from meningiomas remain poorly characterized and are regarded as a possible histological manifestation within the spectrum of anaplastic meningiomas. We analyzed nine matched meningioma-sarcoma pairs using integrated histopathological assessment and molecular profiling, including DNA methylation analysis, next-generation sequencing, copy number profiling, and proteomics. Although recurrent sarcomatous tumors were clonally related to their meningioma precursors-sharing identical NF2 alterations and overlapping chromosomal aberrations-they demonstrated pronounced divergence at the histological, immunophenotypic, and epigenetic levels. Importantly, sarcomatous transformation occurred in four cases without prior radiotherapy. Sarcomatous recurrences exhibited loss of meningothelial markers and acquired expression of cytokeratin and myogenic markers. DNA methylation profiling revealed a shift away from canonical meningioma signatures toward profiles resembling non-meningothelial mesenchymal tumors. Proteomic analysis showed consistent upregulation of SOX2 in sarcomatous tumors compared with their primary counterparts, suggesting acquisition of stem-like features during lineage divergence. Clinically, these tumors were associated with aggressive growth, early recurrence, and extracranial metastases, resembling malignant sarcomas more closely than anaplastic meningiomas. In addition, analysis of an institutional cohort of NF2-mutant intracranial tumors (n = 316) suggests that sarcomas with inactivating NF2 mutations may originate from meningiomas even in the absence of a clinically recognized precursor. Together, these findings suggest that sarcomatous transformation represents a rare evolutionary endpoint in NF2-mutant meningiomas, marked by clonal continuity but pronounced biological divergence. These results highlight limitations of morphology-based classification and emphasize the value of integrated molecular diagnostics in distinguishing these tumors from conventional high-grade meningiomas. Given their sarcoma-like behavior despite a meningioma ancestry, these tumors may not be adequately captured by current meningioma grading schemes.

Papillary thyroid carcinoma (PTC) is uncommon in children compared with adults. Studies have examined the significance of histologic subtype on outcomes in adults; less is known about its importance in pediatric PTC. We sought to examine the relationship between PTC histologic subtype and clinicopathologic factors in children. The LIS was queried for pediatric PTC thyroidectomy patients between 01/2000 and 12/2023. H&E slides were assessed by 2 pathologists for PTC histologic subtypes per the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. All patterns identified in each tumor were recorded. Relevant clinicopathologic data was collected and correlated with histology using 2-tailed heteroscedastic Student-t-tests. Forty-six pediatric PTC patients were identified during the study timeframe. 16 (34.8%) tumors showed at least focal high-risk subtype morphology. The presence of any high-risk histology in any quantity correlated with higher AJCC pT stage (P = .0471), high ATA Risk Classification (P = .049), disease recurrence (P = .0357), and distant metastatic disease (P = .0034). Our findings suggest that WHO-defined high-risk PTC histologic subtypes correlate with more aggressive disease in children. This correlation - observed regardless of the amount of high-risk subtype in a given tumor - suggests that these morphologic patterns may provide important prognostic insight for these children.

Squamous odontogenic tumor is a rare benign epithelial odontogenic neoplasm whose overlapping features with other odontogenic lesions may hinder diagnosis and management. This systematic review analyzed clinical, radiographic, histopathological characteristics and treatment outcomes of SOT. Comprehensive search was conducted in April 2025 across PubMed, Web of Science, Scopus, Embase, Cochrane Library, Livivo, BVS, SciELO, ProQuest, OpenGrey, IBICT/BDTD, and Google Scholar. Two independent reviewers performed study selection, data extraction, and risk-of-bias assessment. Only cases fulfilling diagnostic criteria established by the WHO Classification of Head and Neck Tumors (2024) were included. Cases descriptions and images were assessed by an experienced oral pathologist to confirm diagnostic consistency. A total of 65 SOT lesions were identified, including 59 intraosseous and 6 peripheral cases. Intraosseous lesions occurred across a wide age range with slight male predominance. Most lesions were solitary and located in the maxilla or posterior jaw regions. Radiographically, intraosseous lesions were predominantly unilocular, with triangular configuration most frequently reported. Most lesions were treated with conservative surgery, particularly surgical excision, and recurrence occurred in a minority of intraosseous cases. Peripheral lesions were solitary and showed a benign course without recurrence. SOT generally presents as a benign lesion with a favorable prognosis.