Bone and soft tissue pathology - perhaps more than in any other surgical pathology subspecialty - has been profoundly shaped by a cadre of trailblazing female pathologists who have seamlessly integrated morphologic expertise, molecular innovation, and educational leadership. While no single review can capture the full breadth of contributions made by women in this field, this article highlights the remarkable achievements of six such leaders - Drs. Sharon W. Weiss, Adrienne M. Flanagan, Julia A. Bridge, Cristina R. Antonescu, Judith V.M.G. Bovée, and Jeanne M. Meis - whose careers collectively mirror the evolution of musculoskeletal pathology from morphology-centered diagnoses to an era of integrative molecular precision. Through their work, we trace a historical journey encompassing seminal tumor descriptions, transformative advances in immunohistochemistry and molecular cytogenetics, and parallel improvements in classification and clinical management.
The term "adenoid ameloblastoma" (AA) was formally introduced as an aggressive subtype of conventional ameloblastoma, and the name remains today despite controversies surrounding its nomenclature. As additional cases accumulated, the 2022 WHO Classification of odontogenic tumors classified AA as a distinct entity, and not a subtype of ameloblastoma. Although AA shares microscopic features with other odontogenic tumors, including adenomatoid odontogenic tumor (AOT), dentinogenic ghost cell tumor (DGCT), and odontogenic carcinoma with dentinoid (OCD), recent genetic investigations have shed light on the pathogenesis and molecular characterization of AA, confirming CTNNB1 mutations in 25% to 67% of cases. Due to the increasing histopathologic and molecular similarities between AA and DGCT, we recommend that consideration be given to renaming AA as adenoid dentinogenic ghost cell tumor to more closely reflect its biological aggressiveness and pathogenesis.
Odontogenic lesions can present the diagnostic pathologist with uncertainty due to the range of clinical presentations and histological features. Whilst most of the tooth-forming apparatus involutes on completion of tooth formation, small remnants of both the epithelial and mesenchymal components remain in many individuals, both within the jaws and the overlying gingival mucosa. These developmental remnants can give rise to a range of lesions which span from reactive/inflammatory lesions through hamartomata to those which are neoplastic in nature. This varied etio-pathogenesis does not result in discrete diagnostic entities, but rather a range of overlapping clinical presentations and histological features, which makes definitive diagnosis challenging. This spectrum of lesions and their interrelationships have long been the subject of discussion in the oral pathology literature, and because many of the issues raised regarding our understanding of the biological potential of these lesions remain unresolved, this has contributed to persistent ambiguity in their diagnostic features. In this paper, we will outline the literature published relating to two poorly defined and understood epithelial and mesenchymal odontogenic lesions, which commonly arise in the gingiva and in relation to the crown of unerupted teeth, respectively. We aim to provide clearer diagnostic criteria for two poorly described entities, the odontogenic gingival epithelial hamartoma (OGEH) and the odontogenic follicular hamartoma (OFH), whilst acknowledging the spectrum of lesions which exist and where diagnostic certainty cannot be assured. Additionally, we briefly review the recent progress in understanding the inter-relationship of developing odontoma and ameloblastic fibro-odontoma with a view to suggesting helpful features which will allow for greater diagnostic certainty in this area.
Gross examination of surgical pathology specimens is a foundational component of pathology training and remains essential for the accurate evaluation of resection specimens. Bone and soft tissue tumors represent a rare and diagnostically challenging group of neoplasms that often require specialized expertise and subspecialty training for proper classification. Although definitive diagnosis typically relies on the careful integration of clinical, radiologic, histologic, immunophenotypic, and molecular findings; gross (macroscopic) features can provide valuable early diagnostic clues regarding tumor type, surgical adequacy, and biologic behavior. Despite their diagnostic value, the gross features of bone and soft tissue tumors are often underappreciated, in part due to the relative rarity of these neoplasms. In this review, we highlight selected bone and soft tissue tumors to emphasize the practical importance of careful gross examination in the evaluation and diagnosis of musculoskeletal neoplasia.
Papillary ductal proliferations of the salivary glands encompass a spectrum of benign neoplasms and reactive conditions. The present review will focus on the sialadenoma papilliferum (SP) family of tumors and inverted ductal papillomas (IDP). Intraductal papilloma is a rare salivary gland lesion with poorly defined diagnostic criteria, significant overlap with more reproducible entities, and histologic features distinct from SP and IDP, and is therefore excluded from this review. The SP family of tumors comprises conventional SP, SP-like intraductal papillary tumor, and tubulopapillary hidradenoma-like tumor of the mandible, is characterized by a consistent small ductal proliferation and a variable exophytic component, and is often driven by BRAF p.V600E mutations. Inverted ductal papillomas exhibit a distinct endophytic growth pattern reminiscent of their sinonasal counterparts but are restricted to the salivary ducts. While generally indolent, these tumors can mimic malignant entities such as intraductal carcinoma, mucoepidermoid carcinoma, or squamous cell carcinoma. Accurate diagnosis is essential to ensure appropriate conservative management and avoid unnecessary treatment. This review provides an overview of the clinical, histopathological, and molecular features of these papillary ductal proliferations, outlining key diagnostic criteria to distinguish them from their mimics.
Gynecologic pathology is undergoing major changes in classification and diagnosis with recent advances in molecular pathology. Not only have advances allowed for refinement of diagnostic algorithms, but they have also translated into more targeted therapies for many patient groups. Molecular pathology is an area which necessitates ongoing review by the practicing pathologist, especially those in a multi-disciplinary setting. While the field of gynecologic pathology has many areas which are showing developments, a comprehensive review would span the length of a textbook. In this review article, the authors focus on two of the most common and therefore most applicable categories, endometrial and ovarian carcinoma. A review of the molecular underpinnings of recent developments is presented alongside new testing which is available to translate these findings into therapies for patients.
Pleomorphic sarcomas represent a heterogenous group of sarcomas characterized by marked nuclear anaplasia and overlapping high-grade morphology, often requiring ancillary studies for accurate subclassification. This category includes undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and pleomorphic variants of rhabdomyosarcoma, leiomyosarcoma, and liposarcoma, as well as dedifferentiated liposarcoma and malignant PEComa, among others. Equally important are several non-sarcoma mimics, including superficial CD34-positive pleomorphic fibroblastic tumor and, perhaps most importantly, non-mesenchymal malignancies, such as undifferentiated / dedifferentiated or transdifferentiated melanoma and sarcomatoid carcinoma, which can closely resemble pleomorphic sarcomas, but require fundamentally different management. In this review, we summarize key diagnostic pearls of these entities and present a practical, algorithmic approach integrating clinical, radiologic, gross, histologic, immunohistochemical, and molecular findings to facilitate accurate classification, minimize diagnostic pitfalls, and reduce clinically significant diagnostic errors.
In the 5th edition World Health Organisation (WHO) classification of head and neck tumours, lesions that are distinctive in the jaws for reasons of presentation, behaviour or molecular changes are separated from the bone tumour classification and listed with head and neck tumours in a section on odontogenic and maxillofacial bone tumours. The molecular characterisation of these lesions has advanced recently and this narrative review discusses critically the genetic alterations in the odontogenic tumours that form bone/cementum (variable findings), giant cell-rich lesions of the jaws (sporadic giant cell granulomas with mutually exclusive TRPV4, KRAS or FGFR1 mutations, brown tumours with KRAS mutations and cherubism with SH3BP2 mutations), and bone cysts (aneurysmal bone cyst with USP6 rearrangements and simple bone cyst lacking NFATC2 rearrangement). Additionally, fibro-osseous lesions are discussed, with fibrous dysplasia harbouring GNAS mutations, familial florid cemento-osseous dysplasia, familial gigantiform cementoma and gnathodiaphyseal dysplasia sharing ANO5 mutations and psammomatoid ossifying fibroma showing SATB2 rearrangements. In most cases the changes support the current classification, but areas of uncertainty are described and differences between jaw lesions and similar lesions elsewhere in the skeleton are highlighted.
Molecular characterisation of odontogenic cysts and tumours has advanced recently and molecular pathogenesis for several tumour types is included in the 5th edition World Health Organisation (WHO) classification of head and neck tumours. This narrative review examines critically the genetic and signalling alterations reported in odontogenic cysts and tumours and groups them by the signalling pathways affected: MAPK/ERK (mostly BRAF and KRAS mutations), Wnt/beta-catenin (mostly CTNNB1 mutations) and HH (PTCH1 mutations). Odontogenic tumours characterized by gene rearrangements are also discussed. Apparent negative results and areas requiring further analysis are included. These genetic signatures illustrate the successes and limitations in interpreting molecular data for classification, diagnosis, pathogenesis, and targeted therapies for odontogenic tumours.
Sarcomas are rare connective tissue malignancies characterized by striking histological and molecular heterogeneity. Advances in molecular diagnostics have increasingly identified recurrent genetic alterations that aid in tumor classification and may carry important clinical implications. Among these, amplification and overexpression of MDM2 - a cell-cycle-associated oncogene that negatively regulates p53- represent a characteristic molecular signature of several tumor types, including atypical lipomatous tumor / well-differentiated liposarcoma (ALT/WDL), dedifferentiated liposarcoma (DDLPS), intimal sarcoma, low-grade osteosarcoma variants, and GLI1-altered mesenchymal tumors. However, MDM2 amplification may also occur in non-mesenchymal neoplasms and can arise as a secondary alteration in other sarcoma subtypes, underscoring the importance of careful clinicopathologic correlation when interpretating this finding. In this review, we discuss the biology of MDM2 as an oncogene and summarize the current literature on MDM2 gene amplification in surgical pathology. We further outline the available diagnostic methods for assessing MDM2 status and highlight the potential diagnostic, prognostic, and therapeutic implications of this alteration.
While triple-negative breast cancer (TNBC) traditionally describes an aggressive group of high-grade cancers, a rare subset of TNBC have more favorable prognoses with emerging therapeutic targets. In this article, we review the clinicopathologic and molecular advancements of select TNBC: salivary gland-type carcinomas (secretory breast carcinoma, adenoid cystic carcinoma, and low-grade mucoepidermoid carcinoma), metaplastic carcinomas (low-grade adenosquamous carcinoma and fibromatosis-like metaplastic carcinoma), and other rare triple-negative breast carcinoma subtypes (tall cell carcinoma with reverse polarity and apocrine carcinoma).
Histologic evaluation has long been a cornerstone of prostate cancer diagnosis and management. While the Gleason grading system has significantly improved prognostic stratification, the full potential of histomorphology remains underrecognized—particularly in an era increasingly shaped by molecular diagnostics.This review explores the evolution of prostate cancer grading, emphasizing recent advances in histologic subclassification and the prognostic significance of specific architectural patterns. Features such as cribriform growth and intraductal carcinoma have emerged as critical markers of aggressive disease, emphasizing the diagnostic and prognostic value embedded in detailed morphologic assessment.As precision oncology continues to evolve, integrating refined histologic features into routine pathology reporting offers a practical, cost-effective, and universally accessible strategy to improve risk stratification. Recent evidence suggests that nuanced histologic interpretation can complement—and in some cases rival—the prognostic utility of genomic and AI-based platforms. Incorporating these refinements into diagnostic workflows enhances prognostic precision, supports personalized treatment planning, and facilitates clearer communication across multidisciplinary teams. Reaffirming the prognostic relevance of histomorphology in the modern era not only strengthens diagnostic accuracy but also reinforces the enduring role of pathology in the landscape of precision oncology.
Increased access to and utilization of molecular testing in recent years has resulted in rapid discovery of fusion-driven entities in mesenchymal neoplasia. A subset of these rare tumors are defined by cytokeratin expression, which can lead to diagnostic overlap with more common keratin-positive neoplasms (poorly differentiated carcinomas, mesothelioma, etc). Recent examples include spindle cell rhabdomyosarcomas with TFCP2 fusions, keratin-positive giant-cell rich tumors with HMGA2::NCOR2 fusions, NR1D1- rearranged sarcomas, malignant epithelioid neoplasms with FET::CREB fusions, and the very recently described ossifying spindled and epithelioid tumors (OSET). This review will address the unique clinical, histologic, and immunophenotypic characteristics of these rare neoplasms and provide practical considerations for molecular testing in challenging cases of keratin-positive mesenchymal neoplasia.
Intraductal neoplasms of the pancreas encompass a spectrum of epithelial proliferations within the pancreatic ductal system and are broadly classified into flat-type and mass-forming lesions. Flat-type neoplasms, such as pancreatic intraepithelial neoplasia (PanIN), consist of microscopic epithelial changes, whereas mass-forming intraductal neoplasms-including intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN)-produce clinically or radiologically detectable ductal dilatation or cystic masses. Both categories represent important precursors to invasive pancreatic carcinoma, and accurate classification, grading, and distinction between pseudo-invasion and true invasion remain critical for patient management and prognostication. Gastric-type IPMNs, most often arising in branch ducts, tend to exhibit indolent behavior. Intestinal-type IPMNs, typically involving the main duct and characterized by MUC2 and CDX2 expression, carry a higher risk of progression to invasive colloid carcinoma, which generally has a more favorable outcome. Pancreatobiliary-type IPMNs frequently involve the main duct, express MUC1 and MUC5AC, and more commonly progress to tubular invasive carcinoma resembling pancreatic ductal adenocarcinoma. IOPN and ITPN constitute distinct mass-forming intraductal neoplasms. IOPN typically presents as a large cystic lesion with complex papillary architecture and demonstrates recurrent PRKACA or PRKACB fusions. ITPN is defined by its predominantly tubular growth pattern, mucin-poor phenotype, and absence of MUC5AC expression. Both entities are associated with favorable outcomes following complete resection. Recognition of these intraductal neoplasms is essential, as they must be distinguished from other cystic pancreatic lesions such as mucinous cystic neoplasm (MCN), which is defined by its characteristic ovarian-type stroma.
The evolving landscape of renal neoplasms is a field that is simultaneously exciting and challenging. Next generation sequencing of renal neoplasms over the past decade has deepened our understanding of the biology underlying various entities and provided greater insight into the complexity and numerous subtypes of therein. These advancements have not only refined our comprehension but have also led to the identification of novel tumors driven by molecular alterations not previously known. This progress represents an exciting landmark moment in the field of renal oncology, but also brings its own set of challenges, such as the need to familiarize oneself with these rare subtypes and the ancillary diagnostic tools necessary for accurate diagnosis. A comprehensive understanding of the pathogenesis and molecular biology is essential for the diagnosis of all tumors, including renal neoplasms, especially when genomic findings play a pivotal role. In this review, we explore the role of molecular testing in the diagnosis of renal tumors, addressing the scope of contemporary diagnostic approaches and their limitations, considerations for molecular testing, and provide a guide to judicious and effective molecular testing in the context of renal neoplasms. Finally, we present clinical case-based scenarios that illustrate how molecular results are incorporated into pathology reports to achieve an integrated diagnosis. Key points for each section are summarized into tables for ease of reference.
Even for experts, the diagnosis of soft tissue tumors remains challenging, owing to their rarity, striking diversity, and sometimes subtle morphological differences. Over the past decade, however, significant advances have been made in our collective understanding of the molecular genetic pathogenesis of these rare lesions, especially with the discovery that many are characterized by the presence of characteristic gene fusions, which can be exploited for diagnostic purposes. This review article focuses on four fusion-driven soft tissue tumors which illustrate different aspects of our evolving understanding of these tumors: (1) NUTM1-rearranged sarcoma, a prototypical example of a novel, clinically significant entity defined almost entirely by molecular genetics; (2) SRF-rearranged myoid neoplasm, an entity whose recognition greatly clarifies our understanding of pediatric "leiomyosarcomas;" (3) superficial FET-ETS neurocristic tumor, a very recently described, clinically benign entity sharing identical fusion events with often-lethal Ewing sarcoma; and (4) an evolving family of glomoid/myoid neoplasms harboring EWSR1::WT1 fusions, but clearly differing from desmoplastic small round cell tumor. These examples illustrate the complexity of fusion-driven soft tissue tumors and the importance of integrating molecular genetic testing with other clinicopathological data, rather than viewing it in isolation.
Prostate cancer is one of the most common cancers in men, and accurate pathology evaluation is crucial for risk stratification and treatment planning. Traditional approaches, such as Gleason grading, are limited by interobserver variability and restricted access to expert consultation and molecular testing worldwide. Advances in digital pathology and artificial intelligence (AI) present opportunities to overcome these challenges. Whole slide imaging (WSI) forms the foundation for AI research, enabling remote review, large-scale data sharing, and the development of automated tools for tumor detection, Gleason grading, and molecular prediction. AI applications now extend beyond diagnostic support to prognostic and predictive modeling, including risk of recurrence and treatment response. Despite rapid progress, limitations persist, including data size, ground truth variability, training sets predominantly sourced from high-resource settings, and the "black-box" nature of AI outputs. Pathologists generally view AI as supportive tools, emphasizing the need for transparency, explainability, standardization, and trust. Overall, AI in digital pathology shows strong potential to augment pathology expertise, improve diagnostic efficiency and accuracy, and expand access to advanced cancer care globally. Continued collaboration between pathologists, clinicians, and researchers will be essential to ensure safe, equitable adoption.
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths, accounting for over 90 % of pancreatic cancer cases. Accurate diagnosis is crucial, but often challenging. It typically relies on minimally invasive procedures, such as endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and small biopsy samples. These small biopsies may be the only tissue diagnosis made before embarking on neoadjuvant therapy, major surgery, or transition to comfort care, depending on clinicoradiologic factors. This paper reviews important diagnostic strategies and criteria for cytologic and small biopsy samples, highlighting cytomorphologic characteristics, histologic patterns, and the role of immunohistochemical and molecular diagnostics. PDAC cytology often shows hypercellular aspirates with disorganized glandular fragments, significant nuclear atypia, prominent nucleoli, and a necrotic background. In contrast, small biopsy samples typically reveal invasive glandular structures surrounded by desmoplastic stroma and nuclear pleomorphism. However, biopsies are often scant and there are a variety of difficult histologic subtypes and mimics that complicate these cases. Although there is a lack of sensitive or specific markers for PDAC, immunohistochemical markers, such as P53, and SMAD4, can be useful for supporting a diagnosis of PDAC over chronic pancreatitis/tumor mimics. Molecular alterations in KRAS, TP53, BRCA1/2, and others may aid in diagnosis, prognostication, and the selection of targeted therapeutic options. By systematically integrating clinicoradiologic, cytological, histological, immunophenotypic, and molecular data, pathologists can effectively differentiate PDAC from benign or reactive lesions and metastatic neoplasms, ensuring accurate diagnoses that are essential for optimal patient management.
Conventional urothelial carcinoma in its invasive form has a relatively nonspecific morphologic description, frequently described as nests of epithelial cells containing hyperchromatic and pleomorphic nuclei, with readily identified mitotic figures, and moderate amounts of eosinophilic cytoplasm, infiltrating as irregular nests, single cells or solid sheets. The presence of a noninvasive papillary or flat component (urothelial carcinoma in situ), combined with the clinical presentation of a urinary bladder mass, typically helps to make the diagnosis. However, morphologic mimics of urothelial carcinoma are not uncommon and they can mimic both invasive and noninvasive forms, range from benign to malignant, and therefore pose significant diagnostic pitfalls that have profound effect on a patient's treatment planning and prognostic implications. Herein, we discuss some of the diagnostic mimickers of urothelial carcinoma and the clinical, immunohistochemical and molecular approaches that can prove useful for making the correct diagnosis. We highlight both the most common and the most difficult diagnostic dilemmas and pitfalls that we have seen in our clinical practice.
