Vascular anomalies can be divided into two broad groups: vascular malformations being congenital defects in vascular morphogenesis that tend to grow with age, and vascular tumors, neoplastic proliferations that tend to regress with age when benign. These two categories have long imposed immense confusion among both clinicians and pathologists due to their overlapping clinical presentation and histopathology. The erroneous use of the term hemangioma for etiopathologically different entities is a common phenomenon. This poses a major risk to patients’ safety, as vascular malformations and tumors have different therapeutic approaches. From the pathological point of view, previous studies have focused on the histomorphological, immunohistochemical, and lately the genetic characterization of these lesions. The International Society for the Study of Vascular Anomalies (ISSVA) proposed a multidisciplinary approach, including the most recent discovered genetics. In this comprehensive review we consider the current etiopathological classification of vascular anomalies in correlation with their clinical and radiological characteristics.
Some thyroid follicular lesions are morphologically bland but still contain clues to an underlying tumour-predisposition syndrome. We present two thyroidectomy cases illustrating how molecular results can alter patient management when interpreted with the histological features. The first was a macrofollicular follicular adenoma with papillary hyperplasia and atrophic change; next-generation sequencing identified a DICER1 mutation and prompted germline testing, which was negative. The second patient had thyroid follicular nodular disease, multiple papillary thyroid carcinomas and a near-heterozygous truncating PTEN variant, with germline testing confirming PTEN-hamartoma tumour syndrome. These cases emphasise the value of sequencing in thyroid pathology when the clinical and morphological features are suggestive of an underlying predisposition syndrome.
Pancreatic neuroendocrine neoplasms (PanNEN) encompass a biologically and clinically heterogeneous group of epithelial tumours with divergent natural histories, therapeutic implications, and prognostic trajectories. The 2022 WHO Classification stratifies PanNEN into well-differentiated neuroendocrine tumours (NET) of Grades 1–3 and poorly differentiated neuroendocrine carcinomas (NEC). A critical and practically challenging diagnostic conundrum exists at the high-grade boundary, where Grade 3 well-differentiated NET (G3 NET) and poorly differentiated NEC share overlapping mitotic indices and Ki-67 proliferation indices yet are morphologically, molecularly, and clinically distinct entities with fundamentally different management pathways. In this review, the current WHO classification criteria for PanNEN is discussed and a structured, four-step diagnostic algorithm integrating morphological assessment, immunohistochemical profiling, molecular characterisation, and clinical correlation to guide the distinction between G3 NET and high-grade NEC, is highlighted. The diagnostic utility of chromatin remodelling biomarker, specifically ATRX and DAX-1, is important in the context of their mutually exclusive loss-of-function mutation patterns in well-differentiated NET. Characteristic morphological, immunophenotypic, and molecular features reliably distinguish G3 NET from NEC in most cases. In a minority of diagnostically indeterminate cases (those with intermediate proliferative indices, ambiguous morphology, or conflicting ancillary data), a diagnosis of "Grade 3 neuroendocrine neoplasm, uncertain differentiation" is appropriate and clinically actionable.
Secretory carcinoma is a rare tumour that can arise within, or metastasise to, the thyroid gland. Its overlap of features with papillary thyroid carcinoma is a recognised difficulty in thyroid pathology, with a papillary architecture, colloid or colloid-like secretions, and nuclear irregularities common to both. We present a case in which molecular testing and identification of the ETV6::NTRK3 gene fusion was crucial to the identification of this rare thyroid pathology, however, recommend caution in its interpretation as both secretory carcinoma and papillary thyroid carcinoma can harbour this translocation. Correlation between the morphological features, immunohistochemical prolife, and molecular testing is essential.
Kaposi sarcoma (KS) is a vascular neoplasm classically associated with immunosuppression and HIV infection. We report a rare case of classic KS presenting as isolated cervical lymphadenopathy in a 57-year-old immunocompetent, HIV-negative male with no cutaneous lesions or systemic symptoms. Imaging suggested a schwannoma or fibrous tumour. Core biopsy demonstrated atypical spindle cells with positivity for HHV-8, confirming KS. Extensive immunodeficiency workup was negative. The disease was localised, and surgical excision was performed with curative intent. This case highlights the diagnostic challenge of KS in immunocompetent patients and the importance of including KS in the differential diagnosis of isolated lymphadenopathy.
Three unusual primary tumours of the adrenal gland are highlighted. Awareness of these unusual entities will prevent misdiagnosis and allow proper work-up to achieve the correct diagnosis. The first case is an adrenal angiomyolipma which is usually sporadic but can occur in tuberous sclerosis as well. Often times this can be mistaken for a smooth muscle tumour or an angio/myelolipoma or even a lipoma. Search for all three components will achieve the correct diagnosis together with confirmatory immunohistochemistry. Primary adrenal solitary fibrous tumour can masquerade as other spindle cell fibrous appearing tumours. Search for the haemangiopericytic vasculature or even amianthoid-like foci are useful. Staining for STAT-6 is diagnostic. Lastly, combined phaeochromocytoma-ganglioneuroma can be missed with inadequate sampling and not paying attention for the background Schwannian component, and the presence of ganglion cells.
Thyroid follicular and papillary neoplasms are the most frequently encountered endocrine tumours, with incidence rising markedly over recent decades. Advances in molecular biology have fundamentally transformed their nosological classification, moving beyond purely morphological criteria toward molecular-directed diagnostic and prognostic frameworks. Two overarching oncogenic programmes, the BRAF-like and RAS-like molecular axes, organise the biological spectrum of thyroid epithelial neoplasia, each conferring distinct histological phenotypes, clinical behaviour and therapeutic opportunities. Follicular neoplasms are anchored by RAS mutations and PAX8::PPARγ fusions, which initiate a multi-step tumourigenesis sequence from follicular adenoma through carcinoma to anaplastic transformation, gated critically by clonal TERT promoter mutation and TP53 inactivation. Hürthle cell carcinoma emerges as a molecularly distinct entity defined by mitochondrial genomic instability. Papillary thyroid carcinoma is driven predominantly by BRAF V600E and, less commonly, by RAS mutations and kinase fusions involving RET, NTRK, and ALK — alterations with directly actionable therapeutic implications. Epigenetic dysregulation, immune microenvironment remodelling, and non-coding RNA perturbation add further layers of oncogenic complexity. Molecular platforms now enable refined risk stratification, resolution of cytologically indeterminate nodules, and personalised therapeutic selection in advanced and radioiodine-refractory disease.
Osteosarcomas are the most common primary bone malignancy, typically affecting the long bones. Rarely are they found within the jaw, but when they do so, they present with paraesthesia, swelling and tooth loss. Herein we present a case of primary osteosarcoma of the mandible in a 76-year-old man, similarly, presenting to clinicians with paraesthesia, jaw swelling and loss of his back molar tooth. Computed tomography (CT) showed a spiculated lesion arising from bone, with overlying soft tissue infiltration, confirmed by Histopathology as a high-grade osteoblastic osteosarcoma. The patient underwent a hemi-mandibulectomy and lymph node dissection, with reconstructive surgery. A focused literature view highlights the; presentation, investigation, and management of jaw osteosarcomas, and touches on how immunohistochemical and genetic factors are hoping to effectively aid in the treatment and prognostication of patients, ultimately aiming to provide a more personalised and precision-based care for this rare entity.
Acute invasive fungal sinusitis (AIFS) is a rapidly progressive fungal infection commonly affecting immunocompromised individuals and patients with poorly controlled diabetes mellitus. Clinical presentation is often nonspecific, including fever, facial pain, nasal congestion, or purulent discharge, which may delay diagnosis. Prompt recognition is essential, as delayed treatment is associated with substantial morbidity and mortality. Definitive diagnosis of AIFS relies on histologic demonstration of fungal hyphae with associated tissue invasion and damage. Intraoperative frozen section consultation plays a critical role in guiding urgent surgical and medical management but can be challenging due to frozen section artifact and limitations, as well as morphologic mimics. We explore representative clinical and histopathologic vignettes spanning from AIFS to non-invasive and chronic fungal infections and illustrate common pitfalls that may lead to diagnostic uncertainty and error. Given the potential consequences of both false-negative and false-positive diagnoses (including delayed therapy or inappropriately extensive surgical debridement) standardized specimen handling, careful histologic evaluation, and clear communication with multidisciplinary teams are essential. This review provides a practical histopathologic framework to support accurate diagnosis and effective intraoperative consultation.
Fascioliasis and echinococcosis are both parasitic diseases that present a significant threat to public health worldwide. These helminthic diseases are classified as neglected by the World Health Organization (WHO). Due to increased travel and migration, diagnostic challenges can be presented for physicians especially in areas where they are not endemic. While diagnoses are made using imaging and microbiological, serological and molecular methods, the lack of diagnostic algorithms can complicate matters. Both diseases can occur ectopically outside the liver, where they are most commonly found, and sometimes both can be confused with tumors in terms of clinical features, and alveolar echinococcosis can even metastasize. Although Fasciola spp. rarely seen directly in histopathologic specimens, they can be distinguished from other liver flukes by their morphology, such as spinous tegument, highly branched ceca, and their relatively bigger size, leading to diagnosis. The multilayered structure of the metacestode of Echinococcus spp. and/or the presence of protoscoleces/hooklets are also important in differential diagnosis. When both diseases are histopathologically evident, familiarity with their findings helps prevent a prolonged diagnostic process. This article aims to give insights on histopathology of these parasites and their host reactions for training and practicing pathologists.
Calcified chondroid mesenchymal neoplasms (CCMNs) are a heterogeneous tumours of bone and soft tissue characterised by the presence of fibronectin 1 (FN1) gene rearrangements, plasmacytoid mononuclear cells, multinucleated cells and extracellular matrix production. Classically presenting as enlarging masses within the distal extremities or temporomandibular joint, CCMNs exhibit a benign radiological appearance. CCMNs are commonly characterised by fusions between the FN1 gene and genes of the fibroblast growth factor receptor (FGFR) family, but more novel fusions such as PDGFRA::USP8 and COL1A2::MIR29B have also been described. Herein we present a case of CCMN arising within the proximal phalanx, with a FN1:FGFR2 fusion identified on RNA sequencing and review the clinicopathological, radiological and molecular findings associated with this newly described and often challenging entity.
In the diagnostic histopathology of infectious diseases, histological examination may, in addition to demonstrating inflammation - reveal structures in clinical specimen that are morphologically compatible with microorganisms. However, it is often difficult to ascertain whether those structures indeed represent bacteria or fungal pathogens and to determine their exact identity. In addition, findings from histopathology and medical microbiology are not always congruent, since different areas of a specimen are typically investigated by the respective disciplines. Here, we present FISHseq – the combination of Fluorescence in situ hybridization in combination with PCR and sequencing – as a tool to bridge the gap between histopathology, microbiology and molecular pathogen detection. FISHseq visualizes and identifies microorganisms in situ, even on the identical sample slide to be used for histopathology. Moreover, FISH reveals the living mode of the microorganisms, i.e. if they grow in hard-to-detect and hard-to-treat biofilms. This review describes how the method has been translated from a research technique in environmental microbiology into an accredited, quality-controlled diagnostic tool in medical microbiology and highlights recent developments. In the future, FISHseq may galvanize traditionally separate disciplines such as histopathology and microbiology by enabling integrated interpretation of tissue specimens and advancing tissue-based diagnostics of infectious diseases.
Chronic filamentous and non-filamentous bacterial granulomatous diseases, including actinomycosis, nocardiosis, and botryomycosis, are uncommon and rarely fatal diseases. Diagnosis is supported by microbiological and molecular evaluation; however, histological diagnosis enables precise conclusions to be reached, thereby facilitating the initiation of appropriate and timely treatment. A common tissue reaction seen in the three clinical entities under review is the Splendore-Hoeppli phenomenon. This reaction is characterized by the presence of radiant, eosinophilic material in the form of an asteroid or mace around infectious and non-infectious agents. The objective of this article is to offer a comprehensive yet concise approach to the histo-morphological evaluation of chronic filamentous and non-filamentous bacterial granulomatous diseases.
Infectious diseases remain a major global cause of morbidity and mortality, yet timely and definitive diagnosis is often delayed by overlapping clinical presentations, pathogen diversity, and host-dependent variability in disease progression. Although conventional diagnostics (culture, serology, targeted polymerase chain reaction) have transformed clinical microbiology, they are limited by predefined targets, restricted multiplexing capacity, and reduced sensitivity in complex or pre-treated cases. These limitations have accelerated the development of high-resolution molecular approaches. Single-cell transcriptomics enables the identification of infection-specific immune states and cell-type transcriptional profiles linked to disease severity. Co-transcriptomics capture host and pathogen gene expression within individual cells, revealing co-regulatory programs. Spatial transcriptomics adds tissue context by mapping inflammatory niches and infection microenvironments. Meanwhile, shotgun-metagenomics and long-read sequencing support pathogen-agnostic detection and antimicrobial resistance profiling. Artificial intelligence-driven analytical frameworks integrate these multimodal datasets into clinically interpretable signatures. Collectively, these technologies are redefining infectious disease diagnostics by shifting from isolated pathogen identification to comprehensive molecular phenotyping, paving the way for more precise prognosis and personalized therapeutic strategies. This review aims to summarize current advances in these emerging technologies, discuss their strengths and limitations, and evaluate their translational potential for clinical implementation in infectious disease diagnostics.
In this review, we discuss classic and recently described fibroblastic tumors, emphasizing practical aspects of their diagnostic approach in routine practice. The fibroblastic lineage is a fuzzy term that refers to a bland cytomorphology of small cells with small elongated, monotonous nuclei and inconspicuous cytoplasm, arranged in short fascicles frequently associated with a collagenous stroma. These morphological features are hardly specific; for many of these entities, there is limited evidence to definitively assert a fibroblastic lineage. To illustrate the complexity of assigning a definitive fibroblastic lineage to a neoplasm, recent studies have speculated on the fibroblastic lineage of atypical fibroxanthomas based on their proteomic profiles and expression analysis. The list of fibroblastic tumors keeps evolving. We will mention the various clinical, morphological, phenotypic, and molecular aspects of fibroblastic tumors that occur exclusively in children—lipofibromatosis and calcifying aponeurotic fibroma—as well as fibroblastic tumors found at any age or sometimes exclusively in adults: superficial CD34-positive pleomorphic fibroblastic tumors and PRDM10-rearranged tumors; EWSR1::SMAD3-rearranged fibroblastic tumors; nodular necrotizing fibroblastic sarcoma associated with MAML2 fusions; sclerosing epithelioid fibrosarcoma; KMT2A-rearranged tumor; MUC4-positive fibroblastoma; PRRX1-rearranged fibroblastic tumors and acral fibrochondromyxoid tumors.
Understanding the molecular underpinnings of oncogenesis has led to an expansion of the spectrum of superficial mesenchymal neoplasms. The present review aims to provide an overview of the clinicopathologic and molecular characteristics of emerging entities with disease-defining molecular alterations. These include benign and indolent tumors such as hemangioma with epithelioid features harboring TPM3/4::ALK fusions, OGT-rearranged mesenchymal neoplasm, acral fibrochondromyxoid tumor, superficial FET::ETS neurocristic tumor, as well as hybrid peripheral nerve sheath tumors (hPNSTs), a subset of which harbor recurrent VGLL3 rearrangements or alternative rare and unique fusions. A concise review of the main characteristics of recently described biologically aggressive to overtly malignant tumors is also presented, including nodular necrotizing fibroblastic tumor, superficial GLI1-altered mesenchymal tumor, CRTC1::TRIM11 cutaneous tumor, and TFCP2-rearranged rhabdomyosarcoma. The review concludes with an update on dermatofibrosarcoma protuberans (DFSP). A subset of DFSPs harbor PDGFD rearrangements, and approximately 5% of both PDGFB- and PDGFD-rearranged DFSPs show S100 expression, which may pose a diagnostic challenge for practicing pathologists. These findings have further elucidated the molecular background and associated morphologic characteristics of superficial mesenchymal tumors, leading to the recognition of novel entities and further subclassification of existing ones, with important implications for diagnosis and patient management.
The pathological classification of skeletal muscle tumours has undergone substantial refinement in recent years, driven by rapid advances in molecular diagnostics and an improved understanding of tumour biology. While traditional classification relied predominantly on morphological and immunohistochemical features, contemporary diagnostic schemes integrate molecular genetic evidence to delineate more precise neoplastic entities. The evolving role of next-generation sequencing has facilitated the discovery of novel fusion transcripts, enabling the establishment of a more robust, biologically consistent nomenclature. These technological and conceptual advances not only improve diagnostic precision but also bear significant prognostic implications. This review summarizes the current state of skeletal muscle tumour classification as reflected in the forthcoming 6th edition of the World Health Organization (WHO) classification and recently published literature, with an emphasis on persistent diagnostic challenges and emerging research directions in this evolving field.
Adipocytic tumors are among the most common mesenchymal neoplasms in general surgical pathology. These tumors encompass a broad histological spectrum with variable degrees of adipocytic differentiation and a wide range of clinical behaviour, varying from entirely benign lipomas to aggressive pleomorphic liposarcomas. The World Health Organization (WHO) classification of adipocytic tumors has evolved considerably in the last decades, largely due to important advances in understanding their pathogenetic basis. Although classic examples of lipomas and liposarcomas are straightforward diagnoses, primarily distinguished by their morphological characteristics, several lipomatous tumors are now known to show unique, recurrent molecular genetic aberrations, identification of which can be used in the diagnostic work-up of distinct (uncommon) lipomatous tumor variants and histologically ambiguous adipocytic tumors. This article will provide a practical pattern-based approach to the histological diagnosis of benign, intermediate and malignant adipocytic neoplasms. We will focus on the currently known morphological, immunohistochemical and molecular features of the different adipocytic tumor entities, discuss their differential diagnoses and update on recently described adipocytic tumor entities (lipoblastoma-like tumor, atypical spindle cell/pleomorphic lipomatous tumor, and myxoid pleomorphic liposarcoma).
Anorexia nervosa may be associated with significant haematological abnormalities, including anaemia, leucopenia and pancytopenia. Histopathological findings within the bone marrow range from mild hypocellularity to extensive gelatinous transformation. We present a 47-year-old female with long-standing anorexia nervosa referred for investigation of persistent macrocytic anaemia and leucopenia despite nutritional and haematinic optimisation. Extensive laboratory investigations excluded nutritional deficiency, autoimmune disease, haemolysis, plasma cell dyscrasia, viral infection and paroxysmal nocturnal haemoglobinuria. Bone marrow aspirate was hypocellular and haemodiluted. Trephine biopsy demonstrated marked hypocellularity, stromal oedema, and myxoid change, consistent with gelatinous transformation. Vacuolated signet-ring-like cells showed weak staining for epithelial markers and S100 positivity, initially raising concern for metastatic malignancy. Correlation with morphology and immunophenotype supported atrophied adipocytes within serous atrophy of bone marrow secondary to anorexia nervosa. This case showcases the characteristic histomorphology of anorexia-associated marrow injury, which may be a potential diagnostic pitfall by mimicking marrow failure syndromes or metastatic carcinoma.
The lungs may be involved, either primarily or secondarily, by virtually any type of infection (bacterial, mycobacterial, fungal, viral, or parasitic). The type of infection present is often dependent on the immune status of the patient as well as the endemic organisms in a given geographic region. Pulmonary infections, particularly common bacterial pneumonias, are frequently diagnosed clinically based on a combination of clinical presentation and radiographic findings and culture results. Molecular techniques and mass spectrometry may enhance identification of organisms. Serologic testing and techniques such as direct fluorescent antibody testing may also be employed. From a surgical pathology standpoint, infections are most commonly encountered in biopsies or resections for pulmonary nodules or non-resolving infiltrates. Such specimens often exhibit granulomatous inflammation but other inflammatory patterns may be encountered depending on the organism or immune status of the patient. The aim of this article is to review the most common pulmonary infections and their histologic findings encountered in the setting of surgical pathology, with focus on mycobacterial infections and fungi, testing strategies, and review of differential diagnoses.
