American Journal of Surgical Pathology最新文献

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.

POLE -mutated endometrial carcinomas ( POLE mut 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 POLE mut 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 POLE mut 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 POLE mut 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 POLE mut EC pathobiology.

The aim of this study was to perform a detailed clinical and pathologic analysis of biopsies from 180 BE patients with the goal of understanding the clinical significance and outcome of patients diagnosed with crypt dysplasia (CD). Biopsies from 58 progressors and 122 nonprogressors (372 biopsies) were graded by 3 gastrointestinal pathologists. A consensus biopsy diagnosis (agreement by ≥2 pathologists) was used for outcome analysis. The overall diagnostic agreement among all 3 observers was high (0.75) and was observed in 83.9% cases, with a moderate level of agreement (0.44) noted for CD. BE progressors had a significantly higher proportion of index biopsies with CD (17% vs. 2%) and LGD (9% vs. 0%; overall P <0.0001) compared with nonprogressors. Compared with an index consensus biopsy diagnosis of NDBE, a consensus biopsy diagnosis of IND, CD, and LGD had significantly increased odds of developing HGD/EAC by univariable (OR: 4.05; P <0.0001) as well as multivariable analysis (OR: 10.3; P =0.01). Furthermore, Kaplan-Meier analysis showed that patients diagnosed with CD or LGD on an index biopsy had a higher probability of developing HGD/EAC than those with NDBE ( P <0.0001), and the timeline for progression among patients with CD was found to be intermediate between those diagnosed with NDBE and LGD. BE patients with an index biopsy diagnosis of CD are more likely to develop HGD/EAC compared with those without dysplasia, and these patients may benefit from surveillance and management strategies, similar to LGD.

Erdheim-Chester disease (ECD) is a rare disease characterized by the accumulation of neoplastic histiocytes in various extra-nodal tissues. Tissue biopsies involved by ECD are difficult to distinguish from reactive inflammatory infiltrates given the bland appearance of the neoplastic histiocytes. Confirmation of the ECD diagnosis often relies on molecular studies to confirm BRAF V600E mutation or other activating mutations involving MAPK pathway genes. In this study, we examined the diagnostic utility of cyclin D1 and pERK as immunohistochemical markers of MAPK pathway activation in ECD compared with its histopathologic mimics. The cohort included 41 clinically confirmed ECD patients, most with known genetic alterations in MAPK pathway genes (n=38). In 3 cases no mutation was identified. 37 of 41 (90%) of ECD cases showed cyclin D1 overexpression, with frequent staining in the cytoplasm as well as the nucleus. pERK expression was observed in 32 of 39 (82%) cases. Cyclin D1 staining was negative in histopathologic mimics of ECD, apart from weak patchy staining in fat necrosis and uniform staining in a subset of cases of juvenile/adult xanthogranuloma. While not entirely sensitive or specific, in the proper clinical and radiologic context strong nuclear and cytoplasmic cyclin D1 expression within histiocytic infiltrates helps to support a diagnosis of ECD.

The 5th edition of the WHO classification of haematolymphoid tumours introduces the concept of hyperplasias arising in immune deficiency and dysregulation (IDD), which are frequently associated with Epstein-Barr virus (EBV). These lesions can be histologically classified as follicular hyperplasia (FH), infectious mononucleosis-like hyperplasia (IMH), or plasmacytic hyperplasia. Although EBV-associated reactive lymphoid hyperplasia (EBV-RLH) has been recognized in various IDD settings, comprehensive clinicopathologic analyses remain limited. We analyzed 34 Japanese patients with EBV-RLH. The IDD settings primarily included autoimmune diseases (with or without immunosuppressive therapy), chemotherapy for prior malignancies, aging, post-hematopoietic stem cell transplantation, and HIV infection. No patient exhibited histologic transformation or died due to EBV-RLH. Three patients had concurrent hematologic malignancies, and 12 had immune dysregulation related to prior chemotherapy. Histologically, 20 cases showed FH, 6 IMH, and 8 nonspecific patterns. EBER-positive cells were distributed in both interfollicular areas and germinal centers (GCs) in 27 cases (79%) and confined to interfollicular areas in 7. Six cases exhibited intensive aggregation of EBER-positive cells in one or a few GCs. Double staining confirmed that most EBER-positive cells expressed CD79a but not CD3. IGH and TCRG PCR analyses were successful in 24 cases: 21 were negative for both rearrangements, and 3 showed clonal rearrangements (1 double, 1 IGH-only, and 1 TCRG-only). EBV-RLH generally followed an indolent course; however, it may coexist with hematologic malignancies or develop after multichemotherapy. Careful histopathologic evaluation is essential to avoid overlooking concurrent malignancy or unnecessary treatment.

The College of American Pathologists recognizes "intraductal papillary neoplasm of the bile ducts (IPNB) with an associated invasive carcinoma" in its protocols for the pancreas and intrahepatic bile ducts, but not for the perihilar or distal bile ducts. We aimed to investigate the clinicopathologic and molecular features of 27 surgically resected perihilar IPNB cases. The cohort included 14 males and 13 females, with a median age of 70 years. Six IPNBs were noninvasive, while 21 had associated invasive carcinoma. The median overall tumor size was 2.8 cm, and the median invasive tumor size was 1.2 cm. Eight of 16 patients had elevated CA19-9. Immunohistochemistry as a surrogate of molecular analysis was performed in 19 cases with invasive carcinoma. Among them, positive PD-L1 expression was found in 3 cases (15.8%, all had low expression, CPS<5). DNA mismatch repair deficiency (loss of MSH2 and MSH6) and p53 overexpression were each identified in 1 case (5.3%). All cases were negative for HER2 and pan-TRK. After a median follow-up of 38 months, 11 patients died of disease. Next-generation sequencing revealed genetic alterations impacting multiple signaling pathways, including MAPK/ERK, WNT/β-catenin, TGF-β, DNA damage response, and PI3K/AKT. Our case series suggests that IPNB with associated invasive carcinoma may be included in CAP protocols as one of the carcinoma types of perihilar bile ducts. Future studies are warranted to compare perihilar IPNB with those originating in other biliary tract sites. We expect our molecular findings to help guide the selection of potential therapeutic targets.

Ameloblastomas are locally aggressive odontogenic tumors that most commonly arise in the mandible and maxilla and often harbor BRAF V600E mutations. While rare extragnathic ameloblastomas have been reported, primary pulmonary cases have not been documented. We identified 3 pulmonary neoplasms with features of ameloblastoma that were submitted for consultation between 2022 and 2025 at 3 academic institutions and performed detailed clinicopathologic and molecular analysis. The tumors presented as 5.4 to 7.3 cm peribronchial solitary lung masses. All resected tumors exhibited a predominant stellate reticulum-like component composed of loosely arranged p40-reactive bland squamoid-to-spindled cells with long intercellular bridges, and streaming and swirling architecture, surrounded by palisaded columnar cells with focal reverse nuclear polarity at the interface with myxoid stroma. All tumors were immunoreactive for BRAF V600E IHC, and BRAF V600E mutations were confirmed by molecular assays, including broad next-generation sequencing on 2 cases. Florid hyperplasia of entrapped pneumocytes initially suggested a biphasic neoplasm, but the absence of BRAF V600E IHC labeling confirmed pneumocyte entrapment. Occult gnathic primary tumors were excluded by subsequent clinical examination, including negative panoramic dental x-rays. No recurrences or metastases have been observed to date. This first series of primary pulmonary ameloblastomas highlights a distinctive tumor with histologic and molecular features identical to gnathic counterparts. We discuss the potential histogenesis of these unusual tumors.

High-grade serous-like carcinoma (HG-SL-Ca) of the breast is a newly recognized entity. We present the largest series with 34 cases. Inclusion criteria were breast carcinoma with ≥70% areas showing discordant well-formed tubules and high nuclear grade. Twenty-four (70.6%) were triple negative; 5 (14.7%) were ER+/HER2-; 2 (5.9%) were ER+/HER2+; and 3 (8.8%) were ER-/HER2+. Axillary lymph node metastasis was seen in 10 (31.3%) of 32 cases. Nine patients had neoadjuvant chemotherapy and 2 (22.2%) achieved pathologic complete response (pCR). Of the 32 patients with available follow-up data, 2 (6.3%) had local recurrence; 6 (18.8%) had distant metastasis; and 1 (3.1%) had both local recurrence and metastasis; 6 (18.8%) died of disease. Univariate analysis showed that only larger tumor size (P=0.04) was associated with shorter metastasis-free survival; and larger tumor size (P=0.003) and higher percentage of serous-like pattern (P=0.03) were associated with worse overall survival. 27 (81.8%) of 33 cases had aberrant p53 expression; 16 (64.0%) of 25 showed p16 block positivity; 26 (86.7%) of 30 showed at least focal GATA-3 staining; 25 (89.3%) of 28 were negative for nuclear WT1 (3 had focal staining); and 28 (96.6%) of 29 were negative for PAX-8 (1 had focal staining). HG-SL-Ca of the breast has distinct morphology and the majority show aberrant p53 expression. Patients showed a low pCR rate and poor outcomes. The distinct morphology, immunohistochemistry (IHC) profile and clinical presentations warrant classifying these tumors as a new entity. The morphologic features and IHC studies can help differentiate breast HG-SL-Ca from other carcinomas.

According to the current WHO classification, noninvasive germ cell neoplasia of the testis comprises germ cell neoplasia in situ (GCNIS), specific forms of intratubular germ cell neoplasia, and gonadoblastoma. Because type II germ cell tumors (GCT, type II) arise from GCNIS, accurate detection of precursor lesions is diagnostically important. In preparation for the 2024 International Society of Urological Pathology (ISUP) Consensus Conference on genitourinary precursor lesions, which took place in Florence, Italy, an anonymous survey was distributed to ISUP members to assess current diagnostic practices regarding testicular precursor lesions. The literature and current WHO classification affirm the significance of precursor lesions in testicular tumours. Working Group 4-Precursor Lesions of the Testis-focused on their practical application by individual pathologists rather than establishing consensus from scientific data. There is strong agreement that GCNIS is the preferred and appropriate term for GCT precursor lesions and that its presence should be reported in cases of invasive GCT. Respondents also agree that "seminoma with intratubular nonseminoma" is the appropriate terminology for seminoma with an associated noninvasive nonseminomatous (embryonal carcinoma, yolk sac tumor, trophoblasts, or teratoma) component. Most pathologists prefer to use OCT3/4 as the primary immunohistochemical marker, and a panel was generally not considered necessary. No consensus is reached regarding the requirement for immunohistochemistry to confirm GCT precursor lesions in the testis. Three questions remain open: the value of subtyping intratubular lesions, the immunohistochemical approach to gonadoblastoma, and the criteria distinguishing Sertoli cell nodules from Sertoli cell tumors.