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Study Type: Review article (narrative/synthesis)

Key Question: What are the clinicopathological, immunohistochemical, and molecular features of perivascular epithelioid cell tumours (PEComas) arising in the genitourinary tract, and how should they be classified and risk-stratified?

Key Findings:

• Renal AML represents the most common and best-characterised GU PEComa, serving as the reference model for understanding the broader PEComa family
• Extrarenal GU PEComas are rare, morphologically heterogeneous, and diagnostically challenging—particularly on limited biopsy material
• The authors advocate molecular driver-based classification over organ-site or legacy terminology to guide diagnosis and risk stratification

Clinical Relevance: For UK pathologists encountering unusual mesenchymal GU tumours, this review offers a practical framework for diagnosis and malignant risk assessment, particularly relevant when evaluating small biopsies where morphology alone is insufficient.

Limitations: As a narrative review without systematic methodology or original data, conclusions reflect expert synthesis rather than evidence-graded analysis.

Study Type: Retrospective analysis

Key Question: How accurately can low-grade spindle cell lesions of the breast (LGSCL-B) be classified on core needle biopsy (CNB), and what diagnostic pitfalls arise?

Key Findings:

• Desmoid-type fibromatosis was the most common subtype (28/68 cases; 41%); 6 resections were β-catenin negative, including 3 cases already diagnosed as DF on CNB, highlighting IHC unreliability.
• 13/68 CNBs (19%) yielded indeterminate results, with reclassification occurring at resection in several cases (e.g., malignant phyllodes tumour misclassified as fibromatosis-like metaplastic carcinoma).
• Myofibroblastoma showed a male predominance (58%) and morphological variants warranting awareness; one case was reclassified from solitary fibrous tumour to palisaded myofibroblastoma.

Clinical Relevance: These findings directly inform UK breast pathology MDT decision-making, particularly given evolving non-surgical management of desmoid fibromatosis and the risk of overtreatment from misclassification.

Limitations: Single-institution retrospective design over 24 years limits generalisability and introduces selection bias.

Study Type: Systematic review and meta-analysis

Key Question: What clinicopathological features and risk factors are associated with neoplastic transformation in sporadic gastric hyperplastic polyps (GHP)?

Key Findings:

• Overall neoplastic transformation rate was 6.0%; progression to adenocarcinoma occurred in 1.5% of GHPs
• Significant risk factors: age ≥65 years (OR 2.60; 95% CI 1.88–3.59), size ≥20 mm (OR 4.63; 95% CI 1.82–11.77), and intestinal metaplasia in background mucosa (OR 3.65; 95% CI 1.68–7.97)
• Immunophenotypic analysis demonstrated a shift from gastric to hybrid gastric-intestinal phenotype with increasing dysplastic progression; TP53 alterations and chromosomal instability were the predominant molecular events

Clinical Relevance: GI pathologists reporting gastric polyp resections should systematically assess polyp size, patient age, and background mucosal status (intestinal metaplasia, dysplasia) to stratify malignant risk and inform endoscopic surveillance decisions.

Limitations: Quantitative synthesis included only 11 of 58 studies, limiting statistical power and potentially introducing selection bias.

Study Type: Retrospective case series

Key Question: How does malignant adenomyoepithelioma (M-AME) of the breast present histologically, and what diagnostic criteria support accurate classification?

Key Findings:

• Seven cases in women aged 45–74 years demonstrated marked architectural heterogeneity, including metaplastic carcinoma arising within AME, invasive AME with aberrant IHC profiles, adenomyoepithelial adenosis pattern, and M-AME in situ
• Molecular findings in one case included *HRAS* p.G13R mutation and *PIK3R1* in-frame deletion, associated with late lung metastasis, highlighting malignant potential even in morphologically atypical lesions
• Classification into in situ vs invasive M-AME vs conventional carcinoma arising in AME requires integration of morphology, IHC, and molecular data, given significant overlap with metaplastic breast carcinoma and infiltrative-pattern classic AME

Clinical Relevance: For UK breast pathologists, accurate subclassification of M-AME has direct management implications; misclassification risks inappropriate surgical or systemic treatment decisions.

Limitations: Seven-case series limits generalisability; no outcome data beyond individual case descriptions.

Study Type: Retrospective cohort analysis (case series with comparative cohort)

Key Question: What are the clinicopathological, immunohistochemical, and survival characteristics of neuroendocrine carcinomas of the gallbladder (GBNECs)?

Key Findings:

• GBNECs constitute <5% of gallbladder cancers (31/636); two-thirds are mixed with adenocarcinoma, and 72% present at pT3/T4 stage versus 26% in ordinary gallbladder carcinomas (p=0.001)
• Median survival was 6.1 months, markedly worse than ordinary gallbladder carcinoma; pRB/p16 pathway inactivation was present in 83%, predominantly through pRB loss (67%)
• Standard neuroendocrine markers are reliable (synaptophysin 95%, CD56 90%, chromogranin 75%); TTF-1 positivity in 25% does not indicate pulmonary origin in this context

Clinical Relevance: Pathologists reporting gallbladder resections should recognise GBNECs as a distinct aggressive entity requiring specific IHC workup, with implications for staging documentation and oncological referral pathways.

Limitations: Small case numbers with incomplete lymph node data limit survival analysis generalisability.

Study Type: Retrospective analysis (diagnostic accuracy study)

Key Question: Can NF2/Merlin immunohistochemistry reliably distinguish collecting duct carcinoma (CDC) from upper tract urothelial carcinoma (UTUC)?

Key Findings:

• NF2/Merlin loss was identified in 10/16 CDC cases (63%) versus 0/35 UTUC cases (0%; P<0.000001), indicating high specificity for CDC in this differential.
• IHC loss correlated with confirmed NF2 mutations in 6/6 sequenced cases; however, 2/7 CDC cases without detectable NF2 mutations also showed protein loss, indicating imperfect IHC–molecular concordance.
• NF2/Merlin loss is not sensitive enough to exclude CDC when absent, but its presence strongly favours CDC over UTUC.

Clinical Relevance: CDC and UTUC require different treatment strategies; this marker offers an objective IHC adjunct for pathologists encountering diagnostically challenging infiltrative renal carcinomas with tubular architecture.

Limitations: Small CDC cohort (n=16) limits precision of sensitivity estimates and generalisability.