Journal of Clinical Pathology最新文献

Aims: The prognostic impact of programmed death-ligand 1 (PD-L1) cells in classic Hodgkin lymphoma (cHL) tumour microenvironment remains undefined.

Methods: Model development via Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines were followed. PD-L1+ and CD30+ tumoral Reed-Sternberg cells were quantified through whole slide imaging and digital image analysis in 155 digital histopathological slides of cHL. Univariate and multivariate survival analyses were performed. The analyses were reproduced for patients with advanced stages (IIB, III and IV) using the Advanced-stage cHL International Prognostic Index.

Results: The PD-L1/CD30 ratio was statistically significantly associated with survival outcomes. Patients with a PD-L1/CD30 ratio above 47.1 presented a shorter overall survival (mean OS: 53.7 months; 95% CI: 28.7 to 78.7) in comparison with patients below this threshold (mean OS: 105.4 months; 95% CI: 89.6 to 121.3) (p=0.04). When adjusted for covariates, the PD-L1/CD30 ratio retained prognostic impact, both for the OS (HR: 1.005; 95% CI: 1.002 to 1.008; p=0.000) and the progression-free survival (HR: 3.442; 95% CI: 1.045 to 11.340; p=0.04) in a clinical and histopathological multivariate model including the male sex (HR: 3.551; 95% CI: 0.986 to 12.786; p=0.05), a percentage of tumoral cells ≥10.1% (HR: 1.044; 95% CI: 1.003 to 1.087; p=0.03) and high risk International Prognostic Score (≥3 points) (HR: 6.453; 95% CI: 1.970 to 21.134; p=0.002).

Conclusions: The PD-L1/CD30 ratio identifies a group of cHL patients with an increased risk of treatment failure. Its clinical application can be performed as it constitutes an easy to implement pathological information in the diagnostic work-up of patients with cHL.

Aims: Von Willebrand disease (VWD) is an inherited haemostatic disorder with a wide range of bleeding phenotypes based on von Willebrand factor (VWF) levels. Multiple assays including VWF gene analysis are employed to correctly diagnose VWD and its subtypes. However, data on VWF mutations among Southeast Asian populations are lacking. We, therefore, aimed to explore genetic variations in Thai patients with type 2 and type 3 VWD by whole exome sequencing (WES).

Methods: In this multicentre study, Thai patients with type 2 and type 3 VWD, according to the definitions and VWF levels recommended by the international guidelines, were recruited. WES was performed using DNA extracted from peripheral blood in all cases. The novel variants were verified by Sanger sequencing.

Results: Fifteen patients (73% females; median age at diagnosis 3.0 years) with type 2 (n=12) and type 3 VWD (n=3) from 14 families were enrolled. All patients harboured at least one VWF variant. Six missense (p.Arg1374Cys, p.Arg1374His, p.Arg1399Cys, p.Arg1597Trp, p.Ser1613Pro, p.Pro1648Arg) and one splice-site (c.3379+1G>A) variants in the VWF gene were formerly described. Notably, six VWF variants, including three missense (p.Met814Ile, p.Trp856Cys, p.Pro2032Leu), one deletion (c.2251delG) and two splice-site (c.7729+4A>C, c.8115+2delT) mutations were novelly identified. Compound heterozygosity contributed to type 2 and type 3 VWD phenotypes in two and one patients, respectively.

Conclusions: Type 2 and type 3 VWD in Thailand demonstrate the mutational variations among VWF exons/introns with several unique variants. The WES-based approach potentially provides helpful information to verify VWD diagnosis and facilitate genetic counselling in clinical practice.

Aims: In routine diagnosis of lymphoma, initial non-specialist triage is carried out when the sample is biopsied to determine if referral to specialised haematopathology services is needed. This places a heavy burden on pathology services, causes delays and often results in over-referral of benign cases. We aimed to develop an automated triage system using artificial intelligence (AI) to enable more accurate and rapid referral of cases, thereby addressing these issues.

Methods: A retrospective dataset of H&E-stained whole slide images (WSI) of lymph nodes was taken from Newcastle University Hospital (302 cases) and Manchester Royal Infirmary Hospital (339 cases) with approximately equal representation of the 3 most prevalent lymphoma subtypes: follicular lymphoma, diffuse large B-cell and classic Hodgkin's lymphoma, as well as reactive controls. A subset (80%) of the data was used for training, a further validation subset (10%) for model selection and a final non-overlapping test subset (10%) for clinical evaluation.

Results: AI triage achieved multiclass accuracy of 0.828±0.041 and overall accuracy of 0.932±0.024 when discriminating between reactive and malignant cases. Its ability to detect lymphoma was equivalent to that of two haematopathologists (0.925, 0.950) and higher than a non-specialist pathologist (0.75) repeating the same task. To aid explainability, the AI tool also provides uncertainty estimation and attention heatmaps.

Conclusions: Automated triage using AI holds great promise in contributing to the accurate and timely diagnosis of lymphoma, ultimately benefiting patient care and outcomes.

Aims: Adjuvant chemotherapy after radical cystectomy can reduce the risk of recurrence and death in advanced muscle-invasive urothelial bladder cancer (MIBC). Molecular subtypes have been shown to be associated with survival. However, their predictive value to guide treatment decisions is controversial and data to use subtypes as guidance for adjuvant chemotherapy is sparse. We aimed to assess survival rates based on MIBC consensus molecular subtypes with and without adjuvant chemotherapy.

Methods: Gene expression profiles of 143 patients with MIBC undergoing radical cystectomy were determined from formalin-fixed, paraffin-embedded specimen to assign consensus molecular subtypes. Expression of programmed cell death ligand-1 (PD-L1) and immune cell infiltration were determined using multiplex immunofluorescence. Matched-pair analysis was performed to evaluate the effect of adjuvant chemotherapy on overall survival (OS) for molecular subtypes applying Kaplan-Meier and Cox regression survival analyses.

Results: Samples were luminal papillary: 9.1% (n=13), luminal non-specified: 6.3% (n=9), luminal unstable: 4.9% (n=7), stroma-rich: 27.9% (n=40), basal/squamous (Ba/Sq): 48.9% (n=70) and neuroendocrine-like (NE-like): 2.8% (n=4). Ba/Sq tumours had the highest concentration of PD-L1+ tumour and immune cells. Patients with luminal subtypes had better OS than those with NE-like (HR 0.2, 95% CI 0.1 to 0.7, p<0.05) and Ba/Sq (HR 0.5, 95% CI 0.2 to 0.9, p<0.05). No survival benefit with adjuvant chemotherapy was observed for luminal tumours, whereas Ba/Sq had significantly improved survival rates with adjuvant chemotherapy. Retrospective design and sample size are the main limitations.

Conclusion: Consensus molecular subtypes can be used to stratify patients with MIBC. Luminal tumours have the best prognosis and less benefit when receiving adjuvant chemotherapy compared with Ba/Sq tumours.

The most recent WHO classification of endocrine and neuroendocrine tumours has brought about significant changes in the diagnosis and grading of these lesions. For instance, pathologists now have the ability to stratify subsets of thyroid and adrenal neoplasms using various histological features and composite risk assessment models. Moreover, novel recommendations on how to approach endocrine neoplasia involve additional immunohistochemical analyses, and the recognition and implementation of these key markers is essential for modernising diagnostic capabilities. Additionally, an improved understanding of tumour origin has led to the renaming of several entities, resulting in the emergence of terminology not yet universally recognised. The adjustments in nomenclature and prognostication may pose a challenge for the clinical team, and care providers might be eager to engage in a dialogue with the diagnosing pathologist, as treatment guidelines have not fully caught up with these recent changes. Therefore, it is crucial for a surgical pathologist to be aware of the knowledge behind the implementation of changes in the WHO classification scheme. This review article will delve into the most significant diagnostic and prognostic changes related to lesions in the parathyroid, thyroid, adrenal glands and the gastroenteropancreatic neuroendocrine system. Additionally, the author will briefly share his personal reflections on the clinical implementation, drawing from a couple of years of experience with these new algorithms.

Aims: A new molecular subtype classification was proposed for small-cell lung carcinoma (SCLC). We aimed to further validate the classification in various SCLC patient samples using immunohistochemistry (IHC) to highlight its clinical significance.

Methods: We analysed the protein expression of four subtype (achaete-scute family BHLH transcription factor 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3) and Yes1-associated transcriptional regulator (YAP1)) and two predictive markers (delta-like ligand 3 (DLL3) and MYC) using IHC in 216 specimens from 195 SCLC patients, including 21 pairs of resected biopsy tumours. Associations among molecular subtypes, clinicopathological features and prognostic implications were also explored.

Results: The ASCL1, NEUROD1, POU2F3, YAP1, DLL3 and MYC-positive expression rates were 70.3%, 56.9%, 14.9%, 19.0%, 75.4% and 22.6%, respectively. DLL3 expression had positive and negative associations with that of ASCL1 and POU2F3/YAP1, respectively, whereas MYC had the opposite effect. Strong associations of ASCL1 (Ρ=0.8603, p<0.0001), NEUROD1 (Ρ=0.8326, p<0.0001), POU2F3 (Ρ=0.6950, p<0.0001) and YAP1 (Ρ=0.7466, p<0.0001) expressions were detected between paired resected biopsy tumours. In addition to SCLC-A (ASCL1-dominant), SCLC-N (NEUROD1-dominant) and SCLC-P (POU2F3-dominant), unsupervised hierarchical cluster analyses identified a fourth, quadruple-negative SCLC subtype (SCLC-QN) characterised by the low expression of all four subtype-specific proteins, and 55.4% (n=108), 27.2% (n=53), 11.8% (n=23) and 5.6% (n=11) were categorised as SCLC-A, SCLC-N, SCLC-P and SCLC-QN, respectively. Significant enrichment of SCLC-P in the combined SCLC cohort was observed, and adenocarcinoma was more prevalent in SCLC-A, while large-cell neuroendocrine carcinoma was more commonly seen in SCLC-P. No survival difference was found among molecular subtypes.

Conclusions: Our results provide clinical insights into the diagnostic, prognostic and predictive significance of SCLC molecular subtype classifications.

Aims: Light chain proximal tubulopathy (LCPT) is a rare complication of paraprotein-related diseases. We report a case series to present the clinicopathological characteristics and outcomes of LCPT.

Methods: A multicentre retrospective case series of 47 patients with LCPT, consisting of 36 crystalline, three non-crystalline, and eight mixed LCPTs, was studied between January 2007 and December 2023.

Results: The median age at diagnosis was 57 years. Presentations included proteinuria (100%), renal insufficiency (62%) and Fanconi syndrome (68%). The underlying haematological diagnoses were monoclonal gammopathy of renal significance in 81% and multiple myeloma in 19%. Monoclonal light chain (LC) was detected in all cases using serum/urine-free LC assays or immunofixation electrophoresis. Among 36 crystalline LCPTs, 34 were κ-restricted and 2 λ-restricted. Three non-crystalline LCPTs were all λ-restricted. In mixed LCPTs, seven were κ-restricted and one was λ-restricted. Notably, 66% frozen-section immunofluorescence failed to reveal restricted LC, requiring paraffin-immunofluorescence or immunoelectron microscopy. The appearance of inclusions displayed intraindividual homogeneity but interindividual heterogeneity in 42 patients and notable intraindividual heterogeneity in the remaining 5 patients. Haematological complete response, very good partial response and partial response occurred in 61%. Kidney function improved or remained stable in 84%, worsened in 8% and progressed to end-stage renal disease in 8%.

Conclusions: Proteinuria and kidney dysfunction are the most common but less-specific renal manifestations of LCPTs, with most featuring Fanconi syndrome. Crystalline LCPT, primarily associated with κ-LC, is the predominant form. Most inclusions displayed intraindividual homogeneity and interindividual heterogeneity by electron microscopy. Most achieved haematological responses and favourable renal outcomes.