American Journal of Surgical Pathology最新文献

POLE-mutated endometrial carcinomas (POLEmut EC) have the most favorable prognosis among all TCGA molecular subgroups. Though the consequent "ultramutated" phenotype is recognized as a trademark feature, hypermutated tumors (10-100 mutations/megabase), as well as those that are histologically low-grade, have been described. Herein, we investigate 19 POLEmut ECs from a single institution to determine whether morphologic and genomic differences exist between tumors with high tumor mutational burden (TMB-H: 10-100 mutations/megabase) and ultra-high TMB (TMB-UH: >100 mutations/megabase). All tumors were FIGO stage I, of endometrioid histotype, and no patients recurred (median follow-up of 90 mo). Six previously described POLE exonuclease domain mutations were detected, with the 2 most common being P286R (n=7) and V411L (n=6). Seven ECs were TMB-H (median 76 mutations/megabase), and 12 TMB-UH (median 187 mutations/megabase). TMB-UH tumors were more frequently high-grade, with intratumoral heterogeneity, serous-like nuclei, and bizarre nuclei. Using an integrated approach, multiple classifiers were observed in both cohorts (53% of all tumors); however, those associated with MMRd were exclusive to TMB-UH ECs. All TMB-H ECs had a dominant (>50%) POLE mutational signature, in contrast to only 5 TMB-UH tumors. The remaining TMB-UH ECs demonstrated mixed signatures associated with mismatch repair deficiency (MMRd, n=4) or nonspecific signatures (n=3). All POLEmut tumors were enriched in single-nucleotide variants, while insertions-deletions were rare (maximum of 1.7%). In both groups, all harbored PTEN mutations, with other commonly recurring mutations including PIK3CA, ATRX, BRCA2, FBXW7, and NF1. ARID1A mutations were not identified in any TMB-H ECs. Although our cohort is small, the morphology of POLEmut ECs appears to be influenced by TMB, a phenomenon not yet described in the evolving landscape of these tumors. Taken in combination with differences in underlying genomic signatures, these findings provide an interesting springboard for better understanding POLEmut EC pathobiology.

Patients undergoing periods of starvation or malnutrition may develop degenerative and/or atrophic changes of various organs. These findings may manifest histologically and may cause confusion when first encountered, raising a differential that includes benign and malignant tumor entities. Herein, we report 16 cases of incidentally identified degenerative changes within abdominal-site fatty tissues that caused diagnostic difficulties. The patients were 11 males and 5 females, aged from 1 day to 82 years (mean: 58 years). The degenerative changes were all incidentally identified within adipose tissue of the abdominal cavity or adjacent to organs contained within the abdominal cavity in procedures done for unrelated reasons such as cancer, infection, or perforation. Cases were identified in the colon (n=6), small intestine (n=4), omentum (n=3), inguinal hernia sac (n=1), peritoneum (n=1), and retroperitoneal soft tissue (n=1). Patients had variable past medical histories with multiple comorbidities. Ten patients presented with some form of malnutrition and/or cachexia. Histologically, the lesions demonstrated lobules of atrophic-appearing fat with small signet-ring-like adipocytes that were sometimes bilobed. The nodules varied in size and were characterized in some cases by a variably myxoid stromal background, often with a prominent delicate capillary network. Immunohistochemistry was performed and was uniformly positive for S100 protein and negative for cytokeratins. The lesions were generally recognized as degenerative, but various differential diagnoses proposed at the time of sign-out included signet-ring cell carcinoma, liposarcoma, and vascular lesions, among others. Nomenclature to describe this phenomenon has been inconsistent in the literature, and thus, we suggest the term "pseudoneoplastic fat atrophy."

Silicone granulomas can have histologic features that mimic xanthogranulomatous inflammation, particularly in small samples or when the diagnosis is unsuspected. Histochemical stains for microorganisms may be performed to assess for infection in such cases. After observing diffuse Fite staining in a specimen exhibiting histologic features of silicone granuloma, the frequency of Fite staining in a series of confirmed silicone granulomas was assessed. Modified acid-fast (Fite) staining was performed in 20 silicone granuloma cases. In a subset (n=5), Ziehl-Neelsen (Z-N), Grocott's methenamine silver (GMS), and Brown & Brenn (B&B) stains, as well as mycobacterial immunohistochemistry were also performed. All 20 cases (100%) demonstrated Fite staining, ranging from patchy (45%) to diffuse (55%). Finely vacuolated histiocytes exhibited reticular to granular Fite staining, some morphologically resembling bacteria, whereas larger vacuolar spaces showed globular to crescent-like staining at their peripheral edges. Focal Z-N staining in a pattern similar to Fite staining was observed in 4 of the 5 cases examined. GMS, B&B, and mycobacterial IHC were negative. Silicone granulomas consistently show Fite staining. While the reason for this is uncertain, it is postulated that the hydrophobicity of silicone polymers may simulate the hydrophobic barrier of mycolic acids, preventing entry of decolorizer and removal of the primary stain. Recognition of this phenomenon is important to avoid misinterpretation of silicone granulomas as infectious. Fite staining may also serve as a potential diagnostic aid in cases with histologic features of silicone granuloma in which a history of silicone injection or silicone implant use is not established.

Proteus syndrome is a rare mosaic overgrowth disorder caused by somatic activating variants in AKT1, most commonly the c.49G>A p.(Glu17Lys) variant. It predisposes individuals to asymmetric tissue proliferation and an elevated risk for both benign and malignant neoplasms. Among 64 males with genetically confirmed Proteus syndrome enrolled in a longitudinal natural history study, 12 (19%) underwent surgery for paratesticular masses. The average age at surgery was 9 years, most tumors were unilateral, small (median 1.6 cm), and slow growing, but 50% showed recurrence or metachronous tumor development, occasionally with progression to more atypical histology. Histologically, these tumors demonstrated a broad spectrum of differentiation. Eight reviewed cases included Müllerian-type papillary cystadenomas and low-grade papillary adenocarcinomas, a Brenner tumor, and one case of a papillary adenocarcinoma with spindle cell transformation. The epithelial components were typically arranged in papillary and glandular architectures, with variable degrees of cytologic atypia. Psammomatous calcifications were common. Immunohistochemistry showed consistent expression of PAX8(7/7), WT1(7/7), estrogen receptor (ER)(7/7), and progesterone receptor (PR)(6/7), supporting Müllerian lineage, while negative staining for germ cell and mesothelial markers excluded common paratesticular differential diagnoses. Four of the 7 tumors were positive for SF-1. All 7/7 sequenced tumors harbored the AKT1 c.49G>A variant with no additional oncogenic alterations identified by exome sequencing. This series is the largest series to date documenting the clinicopathologic features of paratesticular tumors, a poorly understood component of the Proteus syndrome phenotype.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting for B-cell maturation antigen (BCMA) is used to treat patients with multiple myeloma (MM). To investigate gastrointestinal changes associated with CAR-T therapy, we performed a retrospective study. A total of 10 patients with 26 gastrointestinal biopsy specimens who underwent CAR-T therapy for MM were identified. Except for one patient with residual multiple myeloma, all specimens demonstrated markedly reduced or absent plasma cells. The most prominent biopsy findings occurred in the small intestine, primarily the duodenum, and included lamina propria lymphocytic infiltration, villous atrophy, foveolar metaplasia, an absence of plasma cells, and an increase in intraepithelial lymphocytes. There was an average of 7 apoptotic bodies per 10 high-power fields (hpf). The terminal ileum was also notable for increase in apoptotic bodies (average of 9.5 apoptotic bodies/10 hpf), villous atrophy, and lamina propria lymphocytic infiltration. The stomach biopsies overall typically showed mild inflammation with no increase in apoptotic bodies. A few colonic specimens demonstrated active colitis and prominent apoptotic bodies, while the majority of the colonic biopsies did not have significant findings other than melanosis coli, and an absence or reduction of plasma cells. The disproportionately greater injury in the duodenum versus the colon highlights the importance of upper endoscopic evaluation in symptomatic patients after CAR-T therapy. The mechanisms for these patterns of injury and differential anatomic findings are unknown; however, an immune-mediated injury associated with CAR-T therapy is suspected. Our study identifies a unique pattern of intestinal injury in patients with MM who received BCMA-targeted CAR-T therapy; this encompasses histologic findings more profound in the small intestine, which include absence of plasma cells, an increase in apoptotic bodies, lymphocytic infiltration, and villous atrophy.

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.