American Journal of Surgical Pathology最新文献

Working Group 1 at ISUP's Cancer Precursors meeting (September 2024) evaluated 5 putative precursors of invasive prostate cancer: high-grade prostatic intraepithelial neoplasia (HGPIN), intraductal carcinoma (IDC), atypical intraductal proliferation (AIP), atypical adenomatous hyperplasia (AAH)/adenosis, and proliferative inflammatory atrophy (PIA). Objectives were to compile recent evidence, interrogate current practices, and vote on recommendations, with 67% approval defined as consensus. Consensus was reached against the reporting of the low-grade form of PIN. HGPIN need not be reported when concomitant cancer or atypical small acinar proliferation suspicious for cancer exists adjacent to it, for biopsy or prostatectomy specimens. Finally, while the clinical significance of unifocal HGPIN in biopsies remains uncertain, there is stronger evidence for multifocal isolated HGPIN as a predictor of subsequent cancer detection. By consensus, multifocal HGPIN should continue being reported. Slight refinement was achieved regarding IDC criteria. The consensus opinion was that a dense cribriform to solid proliferation need not demonstrate marked nuclear atypia/ pleomorphism to qualify as IDC. The inverse scenario of marked atypia without dense cribriform/solid proliferation fell just short (65%) of consensus for IDC. Redesignating cribriform HGPIN as AIP achieved consensus. AIP found alone or with grade group 1 cancer warrants an explanatory comment. However, agreement was not attained to report AIP in the presence of invasive cancer, in either needle biopsy or prostatectomy. Finally, the optional reporting of PIA or AAH/adenosis in biopsies as pertinent negatives both fell short of consensus. This guidance should help pathologists standardize reporting, staying focused on the clinically actionable aspects of these lesions.

Neoadjuvant chemotherapy plays a vital role in the treatment of pancreatic ductal adenocarcinoma (PDAC), but treatment effect complicates pathologic examination of postneoadjuvant Whipple resections. Institutional practice is variable but current Pancreatobiliary Pathology Society (PBPS) guidelines suggest extensive microscopic examination of the tumor bed (TB). In practice, gross identification of TB is challenging and may lead to an inaccurate assessment of tumor size. The purpose of this study is to evaluate the adequacy of current practice in postneoadjuvant Whipple resections for pathologic staging. A single institutional prospective cohort was assessed, including 29 entirely submitted (ES) specimens and 10 current PBPS guideline-based (CG) specimens. Cases were evaluated for TB gross measurement, TB microscopic tumor, nontumor bed (N-TB) microscopic tumor, overall size assessment by microscopic evaluation, and presence of lymph nodes with metastases. ES and CG specimens showed similar overall residual tumor size measurements under the current PBPS guidelines protocol, but with the entire submission, tumor size increased by an average of 0.5 cm (range: 0.0 to 2.1 cm). Twenty-eight percent had an upstaged ypT due to a significant N-TB tumor. These findings delineate the limitations of gross TB assessment in postneoadjuvant Whipple resections for adequate pathologic staging and appropriate prognostication.

A significant subset of well-differentiated prostatic acinar neoplasms with invasive histologic features will not spread outside of the prostate, become symptomatic, or shorten a patient's life even if the tumor is left untreated. Overdiagnosis and overtreatment of these indolent prostate cancers (PCa) remain a significant health care problem despite the improved risk assessment and uptake in acceptance of conservative management. While detection of indolent PCa on an entirely resected prostate is possible, recognition of indolent PCa on a needle biopsy (NBX) cannot be reliably made as Grade Group 1 (GG1) PCa diagnosis on NBX is not always identical to one from radical prostatectomy due to a variety of reasons. Further, some of the initially diagnosed GG1 PCas on NBX and carefully monitored on active surveillance (AS) are later reclassified with higher grades. At the same time, other GG1 PCas never progressed on long-term follow-up while receiving no therapy. The overarching goal of this white paper by the 2 leading uropathology organizations, Genitourinary Pathology Society (GUPS) and International Society of Urological Pathology (ISUP), is to help identify a path toward a more meaningful multidisciplinary solution addressing the pervasive problem of overdiagnosis of indolent PCa and its downstream negative effects. Herein, GUPS and ISUP jointly release statements that address why recognition of indolent PCa cannot be reliably made in NBX and why various contemporary multidisciplinary approaches are needed to help improve the detection of indolent PCa in NBX.

Pelvicalyceal invasion (PCI) is a relatively novel pT3a staging parameter for renal cell carcinoma (RCC) nephrectomies. While interobserver reproducibility staging studies of sinus/vascular invasion in RCC exist, a similar evaluation for PCI has not been performed. Moreover, in our experience, there is also diagnostic variability in how pathologists interpret PCI. Herein, we explore interobserver reproducibility among genitourinary (GU) pathologists. Twenty hematoxylin and eosin-stained digitized slides from RCCs (all grossly approaching the renal pelvis) were distributed to 31 GU pathologists to classify each as PCI or not PCI based on their respective clinical practices; slides with concomitant sinus/fat/vascular invasion were excluded. Slides were then evaluated for the following 4 morphologic features: tumor abutting renal pelvis, tumor pushing/indenting into the renal pelvis, polypoid configuration of tumor into the renal pelvis, and tumor eroding through renal pelvic urothelium. Interobserver reproducibility was assessed, and the morphologic features were correlated with PCI. Relationships between pathologists' interpretations, morphologic features, and PCI were evaluated using hierarchical clustering. Although the diagnosis of PCI was relatively uniform with a majority agreement (>67%) reached in 16/20 slides, overall interobserver reproducibility was only moderate (kappa=0.601). While all 4 morphologic features were sensitive for PCI, polypoid configuration of the tumor into the renal pelvis and the tumor eroding through the renal pelvic urothelium were most specific (90%, 100%, respectively). Although we show general consensus among genitourinary pathologists on PCI assessment, clarifying the diagnostic guidelines with specific criteria should be included in pathologic staging systems.

Tubulocystic renal cell carcinoma is a rare neoplasm, first adopted into the WHO classification of kidney tumors in 2016. The diagnostic criteria were refined in the 2022 WHO classification, requiring "pure morphology" and exclusion of other renal cell carcinoma subtypes with overlapping features. We identified 31 tubulocystic renal cell carcinomas from 30 patients. Median age was 60 years (30 to 77 y) with male:female ratio of 13.5:1. Race was known for 26 patients, and the majority were African American (n = 16/26,62%), followed by white/Caucasian (10/26, 38%). Eleven patients (37%) had a history of chronic or end-stage renal disease. Median tumor size was 2.3 cm (range: 0.4 to 6.3 cm). All tumors were characterized by cysts and tubules, surrounded by fibrotic stroma. Lining epithelial cells had eosinophilic cytoplasm, ranging from flattened to cuboidal to hobnail in arrangement. By definition, solid epithelial nodules and destructive invasion were absent. In addition, all tumors had a normal pattern of FH and 2SC expression by immunohistochemistry. AJCC stage was pT1 for all 31 tumors: 30 pT1a and 1 pT1b. All patients had no evidence of disease at last follow-up (median: 35 mo; range: 1 to 294 mo). We report a large series of tubulocystic renal cell carcinomas with pure morphology and confirmed normal/"wild type" FH/2SC immunophenotype. When these strict definitions are applied, our findings confirm an indolent clinical behavior.

Biomarker-driven therapies have led to several recent advances in treating gastric and gastroesophageal junction (GEJ) cancers, but the overlap of these biomarkers remains unclear. We analyzed coexpression of Claudin 18.2 (CLDN18.2), HER2, PD-L1, and mismatch repair (MMR), focusing on CLDN18.2 staining extent and clinicopathologic correlations in gastric and GEJ adenocarcinomas. A total of 145 cases from 2023 to 2024 were identified from pathology archives. Following published clinical trial criteria, tumors were considered CLDN18.2-positive if ≥75% of tumor cells showed moderate-to-strong membranous staining. CLDN18.2 positivity was observed in 70 cases (48%) and was enriched in tumors with signet-ring-cell features ( P =0.0391, univariate; P =0.0113, multivariate). No significant correlation was found with other clinicopathologic features or HER2, PD-L1, or MMR status. The inclusion of CLDN18.2 increased the proportion of cases with at least one actionable biomarker to 92%. Among triple-negative (HER2-negative, PD-L1-negative, and MMR-proficient) tumors, CLDN18.2 was positive in 52% overall and 50% of cases with metastasis, suggesting its potential utility in expanding treatment options. CLDN18.2 appeared to demonstrate relatively low intratumoral heterogeneity, with most tumors (72%) demonstrating either no staining (<10% tumor cells staining) or diffuse staining (≥90% of tumor cells staining). Among tumors classified as CLDN18.2-positive on the above criteria, 84% displayed homogeneous positivity. Nevertheless, heterogeneous expression was observed in a small percentage of tumors (28% of all tumors), indicating that sampling-related misclassification remains a potential concern. Our study provides detailed insights into CLDN18.2 expression and sheds light on the biomarker landscape in gastric and GEJ cancers.

ELOC -mutated renal cell carcinoma ( ELOC -RCC), a newly recognized tumor entity in the fifth edition of the WHO Classification of Tumors of Urinary and Male Genital Organ Tumors (5th WHO Classification), presents morphologic and immunohistochemical (IHC) features overlapping those of clear cell RCC (ccRCC), RCC with fibromyomatous stroma (RCC-FMS), and clear cell papillary renal cell tumor (ccPRCT). Confirmation of an ELOC mutation is required for a definitive diagnosis. This study aims to enhance the understanding of ELOC -RCC's morphologic and molecular characteristics and to develop an affordable and practical panel for its preliminary differentiation based on morphologic and IHC features. Representing one of the largest cohorts of ELOC -RCC, this research involved a retrospective analysis of 56 suspected cases at Shanghai Ruijin Hospital from January 2022 to March 2024, identifying 15 cases through next-generation sequencing (NGS). We report an ELOC mutation site (c.274G>A, p.Glu92Lys), which has not been previously reported in the literature. NGS analysis also showed recurrent mutations in MAP2K4 and HRAS in ELOC -RCC, though their implications are not yet clear. In addition, we describe a case of ELOC -RCC with a PARP4 mutation. Our findings indicate that the "basally polarized" nuclear arrangement and the "apical/apicolateral polarized" staining patterns of CD10 and EMA offer valuable diagnostic clues for differentiating ELOC -RCC from low-grade ccRCC. Furthermore, the immunophenotypic profile of CD10+/AMACR+/GPNMB- appears helpful for differentiating ELOC -RCC from both ccPRCT and mTOR pathway-mutated RCC-FMS ( mTOR -RCC-FMS). However, genetic testing remains indispensable, as evidenced by one CK7-negative ELOC -RCC case.

RAS/RAF/MAPK signaling pathway is one of the best-defined cancer signaling pathways but its role in renal tumorigenesis is unknown outside of papillary renal neoplasm with reverse polarity (PRNRP), which harbors recurrent KRAS alteration. In 383 renal tumors with NGS performed at the University of Chicago and 406 tumors from the available TCGA PRCC/chromophobe RCC data sets, 6 and 9 renal tumors with RAS/RAF/MAPK pathway alteration were identified, respectively. KRAS was the most common gene to be altered (11/15) but alterations in BRAF (2/15), RAF1 (1/15), and NRAS (1/15) were also present. On the basis of morphology, the tumors were separated into 3 groups: classic PRNRPs (group 1), predominantly tubulocystic (group 2), and papillary with high-grade features (group 3). Although morphologically different, groups 1 and 2 shared many similarities in having (1) low-grade appearing eosinophilic tumor cells, (2) identical IHC profile (GATA3+/CK7+/CD117-/Vimentin-), (3) isolated KRAS alteration with no copy number variations, and (4) no proven metastatic potential. Group 3 showed predominantly papillary architecture composed of tumor cells with clear-to-eosinophilic cytoplasm and high-grade cytologic features. Unlike Group 1/2, 57% (4/7) of group 3 tumors showed additional gene alterations on top of RAS/RAF/MAPK pathway alteration and all group 3 tumors (7/7) showed significant copy number variations. On follow-up, 2 of the 7 (2/7) group 3 tumors have metastasized. One tumor with NRAS alteration showed unique morphology unlike any other tumors, composed of mixed tubulocystic and solid architecture with eosinophilic tumor cells. This tumor also showed significant copy number variations. The tumor was staged as pT4N1, displaying metastatic potential. This study shows that renal tumors with RAS/RAF/MAPK pathway alteration are heterogeneous morphologically, immunohistochemically, and molecularly. Although rare, recognition of this novel mechanism in renal tumorigenesis may be clinically important, as there are FDA-approved therapies that can target the RAS/RAF/MAPK pathway hyperactivation.

Early onset prostate cancer (EOPC; defined herein as prostate cancer [PCa] affecting men ≤ 55 years-old) tends to show low histologic grade, likely representing early detection of indolent tumors that would otherwise be diagnosed later in life. A small subset of EOPC exhibits Gleason scores consistent with high-risk disease (Grade Groups 4 to 5; high-grade EOPC [HG-EOPC] hereafter). In this study, we assess the clinicopathologic features of HG-EOPC, with genomic analysis of ERG-negative cases. We assessed HG-EOPC using immunohistochemistry for ERG (as a surrogate marker of TMPRSS2::ERG ), PMS2 (as a surrogate marker of MLH1/PMS2 inactivation), and MSH6 (as a surrogate marker of MSH2/MSH6 inactivation). Selected ERG negative cases were assessed using Oncopanel, which interrogates 447 genes, including PCa-relevant genes. Ninety-six samples from 96 individual patients (median age: 52 y; range: 40 to 55 y) were included in the study. Immunohistochemical staining with ERG was performed in 95 cases, 52 (54%) of which showed negative staining. PMS2 was performed in 93 cases, being retained in 92 (98.9%) and lost in 1 (1.1%). MSH6 was performed in 96 cases, being retained in 92 (95.8%), lost in 2 (2.1%), and equivocal in 2 (2.1%). Sequencing of 23 ERG-negative primary tumors showed enrichment for alterations that are typically associated with castration resistance, including loss of 8p (>50%), gains of 8q (>50%), and inactivation of CDK12 (n=4). The cohort also showed a relatively high frequency of pathogenic TP53 (n=7) and SPOP (n=4) variants. Pathogenic BRCA2 variants and mismatch repair deficiency were identified in 1 case each. Interestingly, >50% of the tumors showed HOXB13 amplification. In conclusion, TMPRSS2::ERG fusion-negative HG-EOPC shows a high frequency of genomic alterations typically enriched in castration-resistant neoplasms but variants of potential germline origin (including those in mismatch repair genes) are rare. These results demonstrate that HG-EOPC is driven largely by somatic events.