American Journal of Surgical Pathology最新文献

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.

Gestational alloimmune liver disease (GALD) is a leading cause of neonatal acute liver failure (ALF) with unique histologic features but no established histologic scoring criteria. This study aimed to develop an accurate histologic scoring system to distinguish GALD from non-GALD neonatal ALF. A preliminary system using 6 histologic features characteristic of GALD was created. Four pathologists from 2 institutions applied this system to GALD (n=11) and non-GALD (n=20) neonatal ALF cases from 2008 to 2020. Four cases of Trisomy 21-associated transient myeloproliferative disorder were analyzed separately, as these patients can present with neonatal ALF and display GALD histologic features but are clinically distinguishable. Area under the receiver operating curve (AUROC) was fitted for stepwise combinations of features to determine the most accurate scoring system. GALD histologic features included extensive parenchymal fibrosis and neotubules, and a paucity of healthy hepatocytes, portal tract involvement, extramedullary hematopoiesis, and inflammation. A revised 3-feature system including parenchymal fibrosis, neotubules, and hepatocyte characterization established highest accuracy with an AUROC of 0.891 ( P <0.001). Importantly, there were no significant interinstitutional differences in scores assigned to GALD versus non-GALD cases. A 3-factor score of <2 had 100% sensitivity (95% CI: 74%-100%) to exclude GALD and a score >5 had 95% specificity (95% CI: 76%-100%) to diagnose GALD. This study establishes a highly accurate histologic scoring system to differentiate GALD from non-GALD neonatal ALF. Findings may aid in accurate diagnosis of index cases, reducing recurrence risk in subsequent pregnancies and lowering morbidity and mortality associated with GALD.

Dendritic cell neurofibroma with pseudorosettes is an uncommon but distinctive variant of neurofibroma. The pseudorosette structures are formed by the circumferential arrangement of small, dark cells around an eosinophilic core at the center of which there is often a single larger and paler cell with slender dendrite-like projections. Dendritic cell neurofibroma often shows a multinodular architecture, which can cause confusion with plexiform neurofibroma. Since plexiform neurofibroma is essentially pathognomonic of Neurofibromatosis type I, such confusion could lead to unnecessary and costly clinical work-up. Since its description in 2001, there has been controversy as to whether dendritic cell neurofibroma represents a true subtype of neurofibroma, whose defining molecular feature is loss-of-function mutation in NF1 . Here we show in a series of 9 cases that dendritic cell neurofibroma harbors recurrent gene fusions involving protein kinase c-alpha ( PRKCA ), including SLC44A1::PRKCA . Identical gene fusions are known to occur in a rare brain tumor known as papillary glioneuronal tumor, although this entity appears to be morphologically and clinically distinct from dendritic cell neurofibroma. Our results distinguish dendritic cell neurofibroma from conventional types of neurofibroma and raise consideration that dendritic cell neurofibroma may be better classified as a unique type of benign neural tumor.

Preneoplastic and precursor lesions are important to recognize and report, as they can influence clinical management decisions. The International Society of Urological Pathology (ISUP) organized a consensus meeting in Florence, Italy, in September 2024 focused on preneoplastic and precursor lesions of the genitourinary organs. Working group 2 was assigned the topic of bladder and a group of pathologists and clinicians was convened. They developed a 46 question premeeting survey for the ISUP membership assessing flat, papillary, squamous, and glandular entities and clinical issues to determine use of terminology, reporting practices, and areas that needed to be addressed at the consensus meeting. The premeeting survey results showed consistency in the terminology used by pathologists, similarities in reporting practices, and highlighted areas of uncertainty with respect to whether certain entities could be classified as precursors/preneoplastic. The results enabled the working group to conduct focused literature reviews and to develop a presentation and set of in-meeting polling questions to address the problematic topics from the survey results. Overall, 14/18 in-meeting polling questions achieved consensus. The surveys and in-person voting demonstrated a strong preference to use existing terminology such as dysplasia, verrucous squamous, and papillary hyperplasia, to grade glandular and squamous dysplasia and to judiciously use immunohistochemistry to classify lesions. Pathologists expressed highly variable opinions with respect to questions about quantification, management recommendations, and inclusion of newer entities as precursors/preneoplastic lesions.

Perinephric myxoid pseudotumor of fat (PMPTF) is a recently characterized lesion typically associated with non-neoplastic renal disease. Its pathogenesis is thought to result from chronic renal "irritation," either due to mass effect from renal carcinoma or inflammation related to benign renal conditions. Prompted by several cases arising in the absence of underlying renal pathology, we conducted a multi-institutional study of 29 mass-forming cases with detailed clinical, histologic, and molecular characterization. We also reviewed 79 published cases to place our findings in a broader context. Histologic slides were reviewed for morphologic and immunohistochemical features. Clinical and follow-up data were obtained through retrospective chart review. The mean age was 67 years (range: 35 to 82), with a strong male predominance (M:F=13.5:1). The average tumor size was 10.3 cm. Liposarcoma was the most common initial diagnosis (n=20). Twelve patients (42%) had non-neoplastic renal disease, 7 (24%) had both non-neoplastic disease and renal cell carcinoma, one (3%) had renal cell carcinoma only, and 9 (31%) had no renal pathology. Histologically, lesions showed mature fat with scattered bland spindle to stellate cells, chronic inflammation, lymphoid aggregates, myxoid change, fat necrosis, hemosiderin, and prominent vasculature; extramedullary hematopoiesis was rare. All tested 28 cases were negative for MDM2 amplification by FISH. Comprehensive targeted NGS (Oncomine) and whole transcriptome sequencing (n=4) did not reveal any pathogenic alterations. Follow-up (n=28; mean, 20 months) showed stable or no disease in 24 cases; 3 patients died of unrelated causes, and one from postoperative complications. PMPTF is a benign, mass-forming lesion that mimics malignancy, particularly well-differentiated liposarcoma. Its occurrence in patients without identifiable renal pathology suggests alternative etiologies. Lack of genomic alterations supports its non-neoplastic nature. Accurate recognition is critical to prevent overtreatment. PMPTF may represent an early-stage reactive process within a broader spectrum of adipose tissue remodeling that includes renal replacement lipomatosis.