Histopathology最新文献

Background and objective: Occult germ cell neoplasia in situ (GCNIS) can occur in testicular biopsies prompted by male infertility with or without concomitant contralateral tumour. Immunohistochemistry can improve the diagnostic yield of GCNIS. The objective of this long-spanned retrospective single institutional series is to assess the value of OCT3/4 reflex testing on the detection of GCNIS.

Methods: Through a search of the pathology medical system, we included all men who underwent testicular biopsy for infertility, including cases with a known or suspected germ cell tumour (GCT) between 2010 and 2025. The detection of GCNIS was performed through histology and reflex use of OCT3/4 immunohistochemistry for all cases.

Results: The detection frequency of GCNIS was 48/3353 (1.4%) testicular biopsies from 42/1870 (2.2%) patients. Subtle interstitial seminoma was diagnosed in 3 patients adjacent to GCNIS. Patients with a concern for GCT were 6x more likely to be diagnosed with GCNIS on biopsy. Among patients with concern for GCT, no difference in GCNIS rate was found between patients with unilateral or bilateral sampling (P = 0.600). GCNIS was sometimes found adjacent to and even within tubuli with normal spermatogenesis. The frequency of GCNIS was similar (P = 0.277) among biopsies with no spermatogenesis, diminished spermatogenesis and intact spermatogenesis.

Conclusions: This study assessed the diagnostic yield of OCT3/4 reflex testing in testicular infertility biopsies with a GCNIS rate of 1.4% and interstitial seminoma frequency of 0.2%. While a history of GCT or clinical suspicion of GCNIS was associated with a 6x higher risk of finding GCNIS, the level of spermatogenesis was not.

Background: Epstein-Barr virus (EBV)-positive small cell neuroendocrine carcinoma of the nasopharynx (SCNEC-nasopharynx) is exceptionally rare and aggressive, with poorly characterized molecular features.

Methods: Clinicopathological, immunohistochemical (synaptophysin, INSM1, chromogranin A, CK-pan, EGFR, NUT, INI1), and molecular profiles of 15 EBV-positive SCNEC-nasopharynx cases (2012-2025) were analysed. EBV status was confirmed by EBER-ISH. Exploratory next-generation sequencing compared nine SCNEC with five EBV-positive nasopharyngeal non-keratinizing carcinomas (NKUC).

Results: Patients (median age 51; male:female = 2:1) presented with advanced-stage disease and cervical lymphadenopathy. Histology showed solid nests of small cells with high-grade features. All tumours were diffusely positive for synaptophysin and EBER, showed perinuclear dot-like CK-pan staining, and were negative for squamous markers and EGFR. NUT was negative and INI1 retained. Comparative genomics revealed greater mutational burden and unique alterations enriched in cell cycle/DNA damage pathways in SCNEC versus NKUC. After multimodal therapy, median overall survival was 33 months.

Conclusion: This largest integrated study defines the distinct clinicopathological and molecular profile of EBV-positive SCNEC-nasopharynx. The identified diagnostic immunophenotype and potential oncogenic pathways provide a foundation for precise diagnosis and future targeted therapy development.

Aims: Human papillomavirus (HPV) is the most common sexually transmitted disease in the United States. HPV-associated invasive anorectal adenocarcinoma has been previously described. In this study, we report the clinicopathological features of three HPV-associated anorectal adenomas.

Methods and results: A retrospective review of anorectal adenomas identified 46 in-house cases. Chromogenic in situ hybridization (CISH) for low- and high-risk HPV subtypes was performed, and high-risk HPV was detected in one (2.1%) case. Additionally, two consultation cases of HPV-positive anorectal adenomas were included, yielding a total of three cases (two females and one male, ages 58-63). All three tumours were located in the surgical anal canal and exhibited similar histologic features, characterized by a predominantly villous or villoglandular architecture with slit-like serrations. The tumour cells exhibited eosinophilic to mucinous cytoplasm with apical mucin cups. The nuclei were crowded and oval- to cigar-shaped. The chromatin was mostly smooth and delicate without prominent nucleoli. Additional immunohistochemistry performed on these HPV-positive adenomas revealed diffuse positivity for p16, CK7 and MUC5AC, with variable CDX2 expression.

Conclusions: HPV-associated anorectal adenomas are a distinct and rare entity. To the best of our knowledge, this is the first clinicopathological report of well-documented high-risk-HPV-associated anorectal adenomas. Increased awareness of this entity among pathologists will enable larger scale studies to further understand the pathogenesis of HPV-associated anorectal adenocarcinoma.

Malignant struma ovarii (MSO) is an extremely rare ovarian teratoma containing malignant thyroid tissue, typically presenting in middle-aged women. Molecularly and histologically, MSO mirrors thyroid carcinoma and includes analogous subtypes as defined in the 2022 WHO classification: 'BRAF-like' tumours (commonly driven by BRAF^V600E mutations or kinase fusions) and 'RAS-like' tumours (driven by mutations in the RAS pathway), along with rare high-grade variants with aggressive behaviour. Next-generation sequencing shows that MSO harbours a mutational spectrum closely matching primary thyroid cancers. Genotype-guided targeted therapies (e.g. BRAF/MEK inhibitors, selective RET or NTRK inhibitors and multikinase inhibitors) are emerging as promising options for advanced or radioiodine-refractory cases. Surgical excision of the ovarian tumour is typically curative for localized disease. Thyroidectomy followed by radioactive iodine (RAI) is reserved for high-risk tumours. Long-term surveillance is essential, as late recurrences can occur. In this first comprehensive review of MSO, we integrate our own case series findings with published data to provide an up-to-date synthesis of its clinicopathologic spectrum and management.

The cover image is based on the article The OLGIMA system for gastric cancer risk assessment. A useful method based on the histological Sydney consensus by Miriam Cuatrecasas et al., https://doi.org/10.1111/his.70042.

Aims: Oncotype DX has played a critical role in guiding treatment decisions for hormone receptor (HR)-positive, HER2-negative early-stage breast cancer. Clinically, a subset of patients with low Oncotype recurrent score (RS) will still progress on standard therapy and ultimately develop metastasis. Our goal was to explore potential molecular mechanisms, including specific genetic alterations and pathway activity associated with disease progression.

Methods and results: We retrospectively reviewed a small series of low RS breast cancers with subsequent metastasis and analysed the clinicopathological characteristics and comprehensive genomic profiling (CGP) data from tumour tissue and circulating tumour DNA (ctDNA) by liquid biopsy.

Results: These tumours demonstrated a range of histopathologic features and molecular profiles. Common findings included enrichment of PIK3CA and TP53 mutations and treatment-emergent ESR1 mutations, observed in both tissue and ctDNA. CDKN2A, SPEN, KIT, CTNNB1, MYC, EMSY, KMT2C, MAP3K1 gene alterations were only found in low RS group in low frequency. Copy number amplifications events were less common in low RS group. In cases with both tissue and ctDNA data, tissue CGP proved useful baseline for identifying driver mutations such as PIK3CA and for contextualizing ctDNA findings, and ctDNA analysis was adequate for disease monitoring and tracking molecular evolution over time.

Conclusions: Using real-world CGP of tumour tissue and ctDNA, we identified key molecular features associated with endocrine resistance in patients with low RS who later developed metastases. PIK3CA mutation and other ER group-related mutations contributed to the low RS. Tissue CGP provides baseline for interpreting ctDNA, and ctDNA monitoring PIK3CA, TP53, ESR1 and other pathogenic or driver mutations in the early course of low RS cases may represent an excellent non-invasive option for identifying targets and early intervention to prevent disease progression, though a large validation study is needed.

The cover image is based on the article The OLGIMA system for gastric cancer risk assessment. A useful method based on the histological Sydney consensus by Miriam Cuatrecasas et al., https://doi.org/10.1111/his.70042.

Aims: PAX8 immunohistochemistry (IHC) is often used to distinguish urothelial carcinomas (UCs) from tumours of renal and Mullerian origin. However, some UCs have been shown to be PAX8-positive. This study investigates the frequency of PAX8-positive conventional UCs of the urinary bladder without subtype morphology and/or divergent differentiation and their molecular profiles.

Methods: One hundred and one consecutive transurethral resections of the urinary bladder from 2019 to 2022 with a diagnosis of conventional urothelial carcinoma (UC) without subtype morphology and/or divergent differentiation were retrospectively reviewed. Representative sections were selected for whole-slide PAX8 IHC (10336-1-AP; polyclonal). Next-generation sequencing (NGS) was performed on all PAX8-positive cases and on a subset of PAX8-negative cases.

Results: PAX8 IHC was positive in 10% (10/101) of cases. Twenty cases underwent NGS, including all 10 PAX8-positive UCs. All PAX8-positive UCs had TERT promoter mutations. TSC1 alterations, NOTCH1 loss and WT1 loss were more frequent in the PAX8-positive cases compared with the PAX8-negative cases. RB1 loss was not seen in the PAX8-positive UCs, while it was present in 40% of the PAX8-negative UCs.

Conclusions: A subset of conventional UCs of the urinary bladder without subtype morphology and/or divergent differentiation are PAX8-positive and have frequent alterations in TERT promoter, TSC1, NOTCH1, and WT1, with an absence of RB1 loss. PAX8 positivity should be interpreted with caution if UC is in the differential, and NGS could be helpful in diagnostic workups as this study shows PAX8-positive UCs may have a distinct molecular profile.

Aim: The aim of this study was to evaluate whether the utility of cytokeratin (AE1/AE3) rapid immunohistochemistry (IHC) in combination with haematoxylin-eosin (H&E) staining improves the intraoperative diagnosis of spread through air spaces (STAS) on frozen sections (FS).

Methods and results: This study included 153 patients. Three pathologists independently evaluated STAS on FS using either HE staining alone or in combination with rapid IHC, with postoperative paraffin sections serving as the gold standard. Sensitivity and specificity were compared, along with interobserver and intraobserver agreement (κ values), diagnostic time, and causes of misdiagnosis. Compared with HE alone, HE combined with rapid IHC staining increased mean diagnostic sensitivity from 73.7% to 87.8% and specificity from 85.5% to 89.9% across pathologists with varying levels of experience. Mean intraobserver agreement improved from κ = 0.644 (83.9%) to κ = 0.907 (95.9%), and mean interobserver agreement improved from κ = 0.485 (65.0%) to κ = 0.671 (77.2%). Average diagnostic time decreased from 2 min 53-23 s. Misdiagnoses were primarily attributable to a limited number of STAS clusters, confusion with macrophages, and artefacts.

Conclusions: Intraoperative H&E combined with rapid IHC enhanced the sensitivity and specificity of STAS detection, improved interobserver/intraobserver agreement and reduced diagnostic time during FS evaluation without significantly extending the overall intraoperative FS processing time. Nevertheless, additional multicenter validation is required.

In the era of immune checkpoint inhibitors for cancers, the need for prognostic biomarkers to identify patients most likely to achieve a durable response has become increasingly more relevant. Tumour-infiltrating lymphocytes (TILs) have gained significant interest, as they can be evaluated using standard haematoxylin and eosin-stained slides, making it a widely accessible and cost-effective biomarker. In addition to their practicality, TILs provide prognostic insights into the interplay between the immune system and tumour cells. While the morphological assessment of TILs has been standardised in breast cancer, comprehensive guidelines for their evaluation in gastro-oesophageal carcinomas (GEC) are still lacking. This narrative review examines the current literature on the composition, clinical implications and therapeutic utility of TILs in GEC. These insights are used to propose a framework with recommendations for standardised evaluation and reporting of TILs in GEC, while also highlighting pitfalls specific to GEC pathology. These recommendations serve as a vital first step towards the widespread use and validation of TILs as a biomarker.