Search Results (739)

Background and Clincal significance: Esophageal squamous cell carcinoma (ESCC) classically presents with progressive dysphagia and weight loss, but atypical presentations may redirect the diagnostic workup before the esophageal primary is identified. We report a case illustrating the simultaneous convergence of three diagnostic pitfalls: absence of dysphagia, bone-predominant metastatic presentation initially managed as carcinoma of unknown primary (CUP), and negative p40 staining in a vertebral biopsy in a patient subsequently confirmed to have invasive mid-esophageal squamous cell carcinoma. CasePresentation: A 66-year-old African American man with dementia, active tobacco exposure, and prior alcohol use disorder presented with constipation, abdominal pain, melena, fever, nausea, vomiting, and progressive back pain. Dysphagia or odynophagia was not documented. CT of the abdomen and pelvis demonstrated diffuse lytic osseous metastases. During evaluation and palliation of symptomatic L2 disease, kyphoplasty and radiofrequency ablation were performed, and bilateral core biopsies showed poorly differentiated carcinoma that was AE1/AE3-positive but negative for p40, CK7, CK20, TTF-1, S100, GATA-3, PAX8, and NKX3.1, yielding an initial diagnosis of CUP. Subsequent chest CT revealed esophageal wall thickening with intraluminal debris. Esophagogastroduodenoscopy (EGD) identified a non-obstructive ulcerated mid-esophageal lesion, and biopsy confirmed invasive squamous cell carcinoma. Poor performance status precluded systemic therapy; palliative external-beam radiation was initiated after diagnosis but discontinued because of clinical deterioration, and the patient transitioned to hospice before passing several weeks after diagnosis. Melena is a gastrointestinal alarm feature, and the combination of gastrointestinal bleeding and an esophageal imaging abnormality warrants timely endoscopic evaluation even when dysphagia is not reported or the symptom history is unreliable. Negative p40 staining in a poorly differentiated, potentially decalcified bone specimen may reflect loss of lineage-marker expression, technical antigen degradation, or both. Tissue or plasma genomic profiling and emerging cell-free DNA methylation classifiers could complement the workup but would not replace direct biopsy of a radiographically suspicious esophageal lesion. Conclusions: In metastatic poorly differentiated carcinoma, lack of documented dysphagia should not exclude an esophageal primary, particularly in patients with cognitive impairment. A p40-negative bone biopsy does not rule out squamous lineage. Timely EGD and integrated clinicopathologic assessment are essential when clinical or imaging findings suggest esophageal involvement. Full article

Malaria pathogenesis involves complex immunopathological mechanisms that hinder early diagnosis and effective treatment. This study integrates multi-omics data and experimental models to identify host-derived biomarkers and elucidate their functional roles. By combining human transcriptomic datasets, weighted gene co-expression network analysis (WGCNA), and machine learning (LASSO, SVM, RF), we identified C1QB as a key hub gene. In human data, C1QB was significantly upregulated in both training and validation cohorts (AUC 0.983 and 0.970). Single-gene GSEA and immune infiltration analyses linked C1QB to apoptosis, inflammation, and altered immune cell composition, including increased activated dendritic cells and neutrophils, and decreased naïve B cells and CD8⁺ T cells. In a murine malaria model (Plasmodium berghei ANKA), C1QB expression rose as early as day one post-infection, preceding detectable parasitemia. Immunohistochemistry revealed C1QB accumulation in the liver and spleen. Single-cell RNA sequencing in the murine model confirmed monocyte-predominant expression, and scTenifoldKnk analysis suggested its role in immune regulation. Crucially, inhibiting C1q in mice via antibody intervention alleviated malaria-induced inflammation, tissue damage, and apoptosis, indicating that C1QB/C1q actively contributes to immunopathology. AI-based drug prediction and molecular docking further supported its therapeutic potential. Collectively, our findings establish C1QB as a dual biomarker and pathogenic driver in malaria, with diagnostic and therapeutic implications. Further studies are required to validate direct target engagement and clarify upstream regulatory mechanisms. Full article

This case report describes the investigation of two cases of cutaneous vasculitis in sows following vaccination. The herd was porcine reproductive and respiratory syndrome virus (PRRSV)-stable, with routine PRRSV-1 and porcine circovirus type 2 (PCV2) sows’ vaccination. Two sows developed red-to-purple macules on the udder, flanks, and hind limbs, occurring two and three days after vaccination, respectively. Diagnostic investigations included biochemistry, complete blood count, PCR, immunohistochemistry (IHC), serology, histopathology, Gram staining, and immunofluorescence (IF) to assess the involvement of type III hypersensitivity. Clinical examination and herd evaluation revealed no significant abnormalities. Both sows showed biochemistry results within the reference intervals. One sow had lymphocytosis. All PCR PCV2, PCV3 and PRRSV-1/2 on serum and IHC PCV2 conducted on skin biopsies were negative, although both animals were seropositive for PCV2. Histopathology revealed necrotizing leukocytoclastic vasculitis, and Gram staining detected no bacteria. IF failed to identify immune complex or complement deposition. However, type III hypersensitivity could not be excluded, as immune complexes are transient and biopsies were collected about 48 h after lesion onset. Overall, the findings support a vaccine-related adverse reaction. Vaccine adverse effects should therefore be considered in the differential diagnosis of cutaneous vasculitis in swine. Full article

The recent introduction of “molecularly defined renal cell carcinomas” in the World Health Organization classification has significantly expanded the diagnostic spectrum of renal neoplasia, highlighting entities characterized by specific genetic alterations with potential clinical and therapeutic relevance. However, the recognition of these tumors in routine practice remains challenging due to overlapping morphological features and variable access to molecular testing. In this context, immunohistochemistry (IHC) has emerged as a practical and widely available tool that can act as a surrogate for underlying molecular alterations. Depending on the biological context, IHC may reflect genetic events either through protein overexpression, as in fusion-driven tumors, or through loss of expression associated with gene inactivation in metabolically or chromatin remodeling-deficient neoplasms. Accordingly, IHC plays a central role as a screening and triage method within the diagnostic workflow of these entities. Overall, IHC remains an indispensable component in the evaluation of molecularly defined renal cell carcinomas, but its optimal use requires integration with morphological assessment and, in most cases, confirmatory molecular testing. The aim of this review is to provide a comprehensive and evidence-based overview of the main immunohistochemical surrogates used in molecularly defined renal cell carcinomas, including TFE3-, TFEB-, and ALK-rearranged tumors, as well as SDH-, FH-, and SMARCB1-deficient neoplasms, highlighting their diagnostic applications, strengths, pitfalls, and role within an integrated diagnostic workflow. For each marker, the biological rationale, expected staining patterns, diagnostic applications, and major pitfalls are discussed, with particular emphasis on variability across studies and technical limitations. Full article

Background/Objectives: Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by multisystem infiltration of foamy histiocytes, leading to chronic inflammation, fibrosis, and organ dysfunction. Breast involvement in ECD is extremely uncommon, and the sonographic features of ECD involving the breast remain poorly described. Case Presentation: We report the case of a 59-year-old woman with chronic bone pain and multisystem disease who experienced an extended diagnostic course despite undergoing renal biopsy, biopsy of a right elbow lesion, bone marrow examination, and multidisciplinary evaluation. Breast ultrasound revealed bilateral infiltrative hypoechoic lesions involving the breasts and axillae. These were classified as BI-RADS 4C and were highly suspicious for breast malignancy. Subsequently, an ultrasound-guided core needle biopsy was performed on the breast and axillary lesions. Results: Histopathology showed fibroadipose tissue infiltrated by numerous foamy histiocytes, scattered epithelioid cells, and occasional Touton giant cells. Immunohistochemistry showed positivity for CD68, CD163, CD4, and Cyclin D1, partial positivity for OCT2 and CD30, and negativity for S100, CD1a, Langerin, ALK, CK (Pan), and GATA3. The Ki-67 index was approximately 3%. Molecular testing detected the BRAF V600E mutation, supporting the diagnosis of ECD. A review of reported cases showed that breast involvement in ECD lacks specific ultrasound findings and may closely mimic primary breast malignancy. Conclusions: Breast involvement in ECD is rare and may present as bilateral infiltrative hypoechoic lesions with axillary involvement on ultrasound. In patients with chronic bone pain, symmetric osteosclerosis, or multisystem disease, ECD should be considered in the differential diagnosis. Ultrasound-detected superficial lesions may provide accessible biopsy targets, helping to establish a timely diagnosis and reduce diagnostic delay. Full article

Background and Clinical Significance: Solitary fibrous tumor (SFT), historically termed hemangiopericytoma (HPC), is a rare fibroblastic mesenchymal neoplasm with variable biological behavior. Pulmonary involvement is uncommon and may represent either a primary thoracic tumor or metastatic disease from an extrapulmonary site. Its clinical course ranges from indolent, surgically curable disease to aggressive malignancy with local recurrence and distant dissemination. In this retrospective case, confirmatory STAT6 immunohistochemistry was unavailable; therefore, the tumor is described as a hemangiopericytoma/solitary fibrous tumor spectrum neoplasm. Case Presentation: We report the case of a 33-year-old woman who presented with sudden-onset hemoptysis and was found to have two large, well-defined bilateral pulmonary masses. Initial clinical and radiological evaluation raised suspicion of primary pulmonary tumors or other benign lesions. Because both lesions were considered resectable, staged pulmonary resections were performed. Subsequent reassessment of the patient’s medical history revealed previous surgeries for a poorly documented recurrent thigh tumor, later confirmed to represent the primary malignant hemangiopericytoma/solitary fibrous tumor spectrum neoplasm. Despite staged pulmonary resections, systemic chemotherapy, and further oncologic management, the disease progressed rapidly, with cerebral, bilateral pulmonary, mediastinal, and subcutaneous metastases. The patient died within 18 months of the initial pulmonary diagnosis. Conclusions: This case highlights the diagnostic difficulty of metastatic pulmonary hemangiopericytoma, particularly when the primary soft tissue tumor is inadequately documented. It emphasizes the importance of detailed clinical history, retrieval of previous histopathological reports, and long-term surveillance in patients with soft tissue tumors, even when initially considered benign. Full article

Background and Clinical Significance: Proliferative fasciitis (PF) is an infrequent benign fibroblastic/myofibroblastic proliferation that may closely resemble a soft tissue sarcoma, creating a diagnostic dilemma out of proportion to its biological behaviour. Because no single clinical, histological or immunohistochemical feature is diagnostic, accurate classification depends on the integration of complementary findings. We describe a challenging case of PF involving the lower leg and present a practical clinicopathological approach to its evaluation. Case Presentation: A 34-year-old man presented with a painless subcutaneous nodule on the lateral aspect of the left lower leg, discovered incidentally. Clinical examination suggested a benign superficial soft-tissue lesion, and because no features raised suspicion for malignancy, complete excision was performed without preoperative imaging. Gross examination revealed a 1.9 × 1.6 × 0.7 cm fascial-based lesion composed of spindle cells and scattered ganglion-like cells within a variably myxoid stroma. Focal nuclear pleomorphism, typical mitotic activity (2 mitoses/10 high-power fields), and limited extension into adjacent adipose tissue broadened the differential diagnosis. Immunohistochemistry demonstrated focal SMA positivity, weak focal desmin and S100 expression, absence of CD31 and CD34 staining, and a low Ki-67 proliferative index (approximately 2–3%). Negative surgical margins, together with integration of the clinical presentation, gross findings, histomorphology, and immunophenotype, supported the diagnosis of proliferative fasciitis. The patient remains free of local recurrence four months after surgery. Conclusions: PF should be considered in the differential diagnosis of superficial spindle-cell proliferations showing deceptively aggressive histological features. Careful clinicopathological correlation remains the cornerstone of diagnosis and helps distinguish this benign entity from its malignant mimics. The clinicopathological framework proposed in this report may assist pathologists in the systematic evaluation of similar diagnostically challenging lesions. Full article

Integrins are heterodimeric transmembrane receptors that mediate bidirectional signaling and regulate cell–cell and cell–extracellular matrix interactions. Integrin αvβ6 is an epithelial-associated integrin that has emerged as a promising molecular target for PET/CT imaging using integrin αvβ6-directed radiotracers such as ⁶⁸Ga-Trivehexin, and, most recently, for antibody–drug conjugate therapy in epithelial malignancies. Unexpected physiological and incidental uptake within the pituitary gland has been reported in integrin αvβ6-targeted PET studies, including uptake in morphologically normal pituitary glands and pituitary neuroendocrine tumors (PitNETs). However, the histological basis of integrin αvβ6 expression in the human pituitary gland remains poorly understood. The aim of this study is to characterize the immunohistochemical expression of integrin αvβ6 in normal human pituitary tissue and PitNETs and to evaluate its potential implications for integrin αvβ6-targeted imaging and theranostic applications. Five complete adult pituitary glands obtained at autopsy and 28 PitNETs were examined by immunohistochemistry for integrin αvβ6. Staining distribution, intensity, and cellular localization were assessed in the adenohypophysis, neurohypophysis, and Rathke’s cleft remnants. PitNETs were classified according to transcription factor expression (PIT1, TPIT, and SF1). Among the 28 PitNETs, 17 were SF1-lineage (60.7%), three were PIT1-lineage (10.7), two were TPIT-lineage (7.1%), three lacked a dominant transcription factor (10.7%), and three showed plurilineage expression (10.7%). Integrin αvβ6 expression was evaluated semiquantitatively according to staining intensity and the percentage of positive tumor cells. In normal pituitary glands, integrin αvβ6 immunoreactivity was predominantly membranous and localized to larger adenohypophyseal cells irrespective of transcription factor lineage or hormone phenotype. Strong expression was also observed in the epithelial lining cells of Rathke’s cleft remnants, whereas the neurohypophysis lacked detectable integrin αvβ6 expression. Among the 28 PitNETs, integrin αvβ6 expression was detected in 20 cases (71.4%). Positive tumors demonstrated variable staining intensity and extent, ranging from 20% to 100% positive tumor cells. By lineage, integrin αvβ6 expression was detected in 13 of 17 SF1-lineage tumors (76.5%), one of three PIT1-lineage tumors (33.3%), and zero of two TPIT-lineage tumors (0%). Additionally, all three tumors lacking a dominant transcription factor (100%) and all three plurilineage tumors (100%) demonstrated integrin αvβ6 expression. Eleven integrin αvβ6-positive tumors showed expression in ≥50% of tumor cells, and six exhibited strong or diffuse immunoreactivity. Integrin αvβ6 expression in adenohypophyseal cells and Rathke’s cleft remnants provides a histological explanation for physiological pituitary uptake observed on αvβ6-targeted PET/CT imaging. The high prevalence of integrin αvβ6 expression in PitNETs, particularly in a subset demonstrating strong and diffuse immunoreactivity, suggests potential applicability of integrin αvβ6-targeted molecular imaging and theranostic approaches, including both radioligand- and antibody-based strategies. However, these applications remain investigational and require further validation in preclinical and clinical studies. At the same time, physiological integrin αvβ6 expression in normal anterior pituitary tissue may limit imaging specificity and should be considered when developing integrin αvβ6-targeted radioligand therapies. Further clinicopathological and imaging correlation studies are warranted to define the diagnostic and therapeutic role of integrin αvβ6-targeted approaches in PitNETs. Full article

Background: Acute kidney injury (AKI) is a severe clinical syndrome characterized by metabolic stress and profound inflammation. However, the landscape of lactylation-associated molecular alterations and their potential relevance in AKI remain incompletely understood. Methods: Bulk transcriptomes (GSE30718) were analyzed using the limma package, weighted gene co-expression network analysis (WGCNA), and consensus clustering to characterize AKI-associated molecular patterns linked to lactylation-associated signatures. Hub genes, prioritized through least absolute shrinkage and selection operator (LASSO) regression and the random forest algorithm, were integrated into a diagnostic nomogram and evaluated in an external cohort (GSE139061). Immune infiltration analysis was performed, and single-cell RNA sequencing data (GSE183276) were used to resolve cell-type-specific expression patterns of the hub genes. A cisplatin-induced murine AKI model validated global protein lactylation and hub gene expression by immunohistochemistry and Western blot. Results: Three hub genes (CKLF, ACLY, and SLC13A3) reliably discriminated AKI from controls (training AUC = 0.897). Their diagnostic performance varied in the external validation cohort. These genes correlated significantly with diverse immune infiltrates. Single-cell analysis localized CKLF predominantly to immune cells, ACLY broadly across renal populations, and SLC13A3 to proximal tubules. In vivo validation demonstrated increased global protein lysine lactylation levels in injured kidneys and confirmed expression alterations of CKLF, ACLY, and SLC13A3 consistent with transcriptomic observations. Conclusions: Integrating transcriptomic analysis with in vivo experimental validation, this study identified CKLF, ACLY, and SLC13A3 as candidate lactylation-associated signatures linked to immune and metabolic alterations in AKI. Full article

Background and Clinical Significance: Oropharyngeal squamous cell carcinoma (OPSCC) and small-cell neuroendocrine carcinoma (SCNEC) are biologically distinct entities with markedly different prognostic and therapeutic implications. While HPV-negative OPSCC carries worse outcomes than HPV-positive disease, SCNEC is exceedingly rare, highly aggressive, and prone to early systemic dissemination. Their synchronous occurrence in the head and neck (HN) is exceptional and poses major diagnostic and therapeutic challenges. Case Presentation: A 54-year-old male, smoker and alcohol consumer, presented with a left tonsillar lesion and cervical lymphadenopathy. Biopsy confirmed p16-negative OPSCC. He underwent transoral robotic surgery with modified radical neck dissection. Histopathology unexpectedly revealed two distinct malignancies: keratinizing OPSCC in the tonsil and high-grade SCNEC in a cervical lymph node, confirmed by immunohistochemistry (synaptophysin, CD56, Ki-67 80%). Postoperative FDG-PET/CT performed within two months showed rapid systemic spread, including paravertebral, pulmonary, and pelvic nodal metastases. Despite recommendation for systemic therapy, the patient deteriorated quickly and died shortly thereafter. Conclusions: This study reports coexistence of p16-negative OPSCC and high-grade SCNEC in the HN. It highlights the diagnostic complexity, staging limitations, and therapeutic dilemmas of discordant histologies, while illustrating the fulminant clinical course typical of SCNEC of unknown origin. Early recognition, comprehensive pathology, and multidisciplinary management are essential, although prognosis remains dominated by the aggressive neuroendocrine component. Full article

Incontinentia pigmenti (IP) is a rare, X-linked dominant genodermatosis caused by mutations in the IKBKG gene and characterized by sequential cutaneous stages following the lines of Blaschko. The highly inflammatory initial vesiculobullous stage frequently mimics severe neonatal infections, such as herpes simplex or bullous impetigo, leading to potentially dangerous diagnostic delays and unnecessary antimicrobial therapies. The objective of this report is to highlight the utility of multimodal medical imaging and clinico-pathologic correlation in the rapid diagnosis of early-stage IP. We present the case of a full-term female neonate presenting on the third day of life with a rapidly disseminating blistering eruption, initially treated as a widespread infectious process. A multimodal diagnostic approach was applied, incorporating bedside clinico-dermoscopic evaluation of the infant and her mother (who reported a history of early miscarriages), followed by neonatal skin biopsy, immunohistochemistry (S-100, MART-1), and subsequent genetic testing. Dermoscopy of the neonate’s transitional lesions revealed early dermal melanophage accumulation, while maternal evaluation exposed pathognomonic residual Blaschko-linear dyspigmentation featuring a distinct “pepper-like” dermoscopic pattern. Histopathology demonstrated classic eosinophilic spongiosis, intraepidermal vesicles, and early pigment incontinence. Genetic testing confirmed recurrent IKBKG exon 4–10 deletion. Crucially, this rapid diagnosis facilitated immediate targeted ophthalmologic screening, detecting asymptomatic stage 2B retinal vasculopathy. Integrating noninvasive dermoscopy with precise histopathologic correlation offers a rapid, highly effective framework to distinguish early IP from neonatal blistering infections. Timely multimodal imaging is crucial for triggering immediate multidisciplinary screening, effectively preventing severe, irreversible vision-threatening complications. Full article

Background: Diffuse axonal brain injury (DABI) is a major component of traumatic brain injury, but the optimal timing of magnetic resonance imaging and histologic assessment after isolated DABI remains unclear. Because each method captures a different phase of injury, defining time-dependent diagnostic windows may improve experimental design and reduce animal use. Methods: Sixty-four Sprague-Dawley rats were randomized to moderate DABI or sham operation. Neurological Severity Score (NSS), 3 T diffusion tensor imaging (DTI), and histologic assessment were performed at early and late time points. Hippocampal fractional anisotropy (FA) was measured at 48 h and 1 month. β-amyloid precursor protein (β-APP) immunohistochemistry assessed acute axonal injury at 48 h, and hematoxylin and eosin (H&E) staining quantified hippocampal neuronal density at 1 month. Results: At 48 h, DABI rats had higher NSS, lower hippocampal FA, and greater β-APP-positive axonal accumulation than sham-operated rats. By 1 month, NSS and hippocampal FA no longer differed between groups, whereas hippocampal neuronal density remained significantly reduced in DABI rats, indicating persistent structural injury. Conclusions: In this rat model of isolated DABI, hippocampal FA and β-APP immunohistochemistry identified acute axonal pathology at 48 h, whereas conventional histology detected a persistent reduction in neuronal density at 1 month. These findings support a time-optimized diagnostic strategy using early DTI for noninvasive injury detection and late histology for long-term structural assessment. Full article

Background: Myeloid/lymphoid neoplasms with FGFR1 rearrangement (MLN-FGFR1), also known as 8p11 myeloproliferative syndrome, are rare and aggressive hematologic malignancies arising from pluripotent stem cells. The FGFR1::ZMYM2 fusion resulting from t(8;13)(p11.2;q12) characteristically co presents as T-lymphoblastic lymphoma in lymph nodes alongside a myeloproliferative neoplasm in the bone marrow. The disease is resistant to tyrosine kinase inhibitors and conventional chemotherapy, and carries a median survival of less than 12 months without allogeneic hematopoietic stem cell transplantation (allo-HSCT). Case Presentation: We report a 23-year-old female who presented with progressive cervical lymphadenopathy and hyperleukocytosis (WBC 186.6 K/μL). Excisional lymph node biopsy demonstrated T-cell acute lymphoblastic lymphoma (T-ALL) with eosinophilic infiltration; immunohistochemistry confirmed lymphoblasts positive for CD1a, CD2, CD3, CD4, CD5, CD7, CD8, and TdT. Concurrent bone marrow biopsy showed a myeloproliferative neoplasm without excess blasts. Chromosomal analysis confirmed t(8;13)(p11.2;q12) with FGFR1::ZMYM2 rearrangement, and NGS identified a concurrent CSF3R variant (Q741*). She received induction chemotherapy per the PEDS AALL1231 protocol (Arm A) followed by consolidation, with a course complicated by hyperleukocytosis, venous thromboembolism, E. coli bacteremia, and severe mucositis requiring PICU admission. Despite initial response, the disease progressed to acute myeloid leukemia (AML) with acquisition of a PTEN variant; the patient was offered but did not complete allo-HSCT and died of refractory AML approximately 10 months after diagnosis. Conclusions: This case highlights the aggressive clinical course and diagnostic challenges of MLN-FGFR1, a rare stem cell-derived myeloid/lymphoid neoplasm. To our knowledge, this appears to be the first reported case documenting sequential CSF3R and PTEN variant acquisition with complete follow-up through fatal AML transformation, and the first to describe treatment with a pediatric ALL induction protocol (PEDS AALL1231) in this setting. The characteristic histomorphologic pattern of eosinophil-rich T-ALL in lymph nodes with concurrent myeloproliferative neoplasm in bone marrow should prompt immediate molecular workup. Allo-HSCT must be pursued urgently at diagnosis, as complications rapidly narrow the transplant window and the disease is uniformly fatal without it. Full article

The management of epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after progression on osimertinib is becoming increasingly complex, particularly in Canada, where access to diagnostic testing and newer therapies remains uneven. Although treatment is evolving with regimens such as amivantamab−lazertinib (MARIPOSA/MARIPOSA-2) and osimertinib plus chemotherapy (FLAURA2), access to such treatments in first and second lines varies across provinces. This article provides a pragmatic Canadian perspective on post-osimertinib management informed by expert roundtable discussions, a focused clinician survey, and the contemporary literature. Key challenges identified include delays and barriers related to tissue biopsy, next-generation sequencing, timely immunohistochemistry in time to influence treatment decisions and access to novel therapies. These gaps reduce the ability to individualize care and often force clinicians to rely on platinum-pemetrexed therapy as the default systemic backbone, even when biologically relevant resistance mechanisms exist, highlighting that post-osimertinib care in Canada remains shaped as much by access and system constraints as by emerging evidence. Full article

Background and Clinical Significance: Steroid cell tumours of the ovary, not otherwise specified (SCT-NOSs), are rare sex cord–stromal neoplasms with a poorly characterised molecular landscape, in which only exceptional CTNNB1 mutations have so far been reported and no recurrent driver alteration is firmly established. A better characterisation of their molecular spectrum has clinical significance for accurate diagnostic categorisation of ovarian sex cord–stromal tumours and for the identification of potentially targetable pathway alterations in this rare entity. Case Presentation: We report two consecutive SCT-NOSs of the right ovary, retrieved from the archives of the Department of Pathology of the Hôpital Universitaire de Bruxelles and of Curepath. Both underwent comprehensive sex cord–stromal and differential immunohistochemistry and targeted next-generation sequencing on a 168-gene panel with a mean coverage of 2690× (Case 1) and a 17-gene panel (Case 2) (MGI DNBSEQ-T7 for Case 1; Ion GeneStudio S5 for Case 2). A 56-year-old post-menopausal woman (Case 1) and a 50-year-old immunosuppressed woman with a history of renal transplantation and lymphoma (Case 2) both presented with rapidly progressive virilisation. The two right ovarian tumours (20 to 25 mm, no Reinke crystals) displayed an unambiguous sex cord–stromal immunophenotype (α-inhibin, calretinin, SF-1 and Melan-A positive; CD10, WT1, EMA, AE1/AE3 and PAX8 negative), with aberrant nuclear and cytoplasmic β-catenin staining. Sequencing identified a pathogenic CTNNB1 c.133T>C p.(Ser45Pro) variant in Case 1 and a pathogenic CTNNB1 c.95A>T p.(Asp32Val) variant in Case 2, with wild-type FOXL2 in both. Conclusions: Three of the four molecularly characterised CTNNB1-mutated SCT-NOSs converge on the two principal GSK-3β phosphorylation residues of β-catenin, identifying Wnt/β-catenin-pathway dysregulation as a potentially recurrent event and providing additional evidence for the involvement of the Wnt/β-catenin pathway in an emerging molecular subset of SCT-NOS. In a tumour with the canonical sex cord–stromal immunophenotype, an exon 3 CTNNB1 hotspot mutation should not be regarded as evidence against the diagnosis of SCT-NOS and may help define a distinct molecular subset. Full article