American Journal of Surgical Pathology最新文献

Gastric-type endocervical adenocarcinomas (GAS) are aggressive HPV-independent neoplasms with molecular alterations in TP53 , STK11 , CDKN2A , and SMAD4 . Claudin-18 (CLDN18) has emerged as a useful marker to distinguish GAS from HPV-associated neoplasia. Its role in separating GAS from benign proliferations and exuberant endocervical glands is unknown. We studied the utility of immunohistochemistry for CLDN18, progesterone receptor (PR), and mutation surrogate stains (P53, STK11/LKB1, MTAP, SMAD4/DPC4) in 46 GAS, 12 benign gastric-type endocervical lesions, 54 benign Mullerian endocervical populations, and 11 HPV-associated endocervical adenocarcinomas. PD-L1 and HER2 immunostains were evaluated in GAS. Gastric-type lesions were more often positive for CLDN18 (100% benign, 78% GAS, most often well to moderately differentiated) compared to benign Mullerian endocervical specimens (all negative) and HPV-associated neoplasia (18%, always focal). Conversely, PR was negative in all gastric-type lesions and positive in 92% of benign Mullerian endocervical populations. GAS revealed aberrant/mutant expression of P53 in 35%, STK11/LKB1 in 25%, MTAP in 23%, and SMAD4/DPC4 in 9% of cases. Abnormal staining in at least one of these 4 mutation surrogate markers was present in 63% of GAS. HER2 score of 3+ was seen in 25% of GAS, and PD-L1 was positive in 37% based on a combined positive score. CLDN18 is a sensitive and highly specific marker of gastric-type benign and malignant endocervical lesions. Once a gastric-type phenotype is confirmed, mutation surrogate immunostains can be used to support a diagnosis of GAS. PD-L1 and HER2 expression is seen in a subset of GAS offering therapeutic options for this aggressive tumor.

Juxtaglomerular cell tumor (JxGCT) is a rare type of renal neoplasm demonstrating morphologic overlap with some mesenchymal tumors such as glomus tumor (GT) and solitary fibrous tumor (SFT). Its oncogenic drivers remain elusive, and only a few cases have been analyzed with modern molecular techniques. In prior studies, loss of chromosomes 9 and 11 appeared to be recurrent. Recently, whole-genome analysis identified alterations involving genes of MAPK-RAS pathway in a subset, but no major pathogenic alterations have been discovered in prior whole transcriptome analyses. Considering the limited understanding of the molecular features of JxGCTs, we sought to assess a collaborative series with a multiomic approach to further define the molecular characteristics of this entity. Fifteen tumors morphologically compatible with JxGCTs were evaluated using immunohistochemistry for renin, single-nucleotide polymorphism array (SNP), low-pass whole-genome sequencing, and RNA sequencing (fusion assay). In addition, methylation analysis comparing JxGCT, GT, and SFT was performed. All cases tested with renin (n=11) showed positive staining. Multiple chromosomal abnormalities were identified in all cases analyzed (n=8), with gains of chromosomes 1p, 10, 17, and 19 and losses of chromosomes 9, 11, and 21 being recurrent. A pathogenic HRAS mutation was identified in one case as part of the SNP array analysis. Thirteen tumors were analyzed by RNA sequencing, with 2 revealing in-frame gene fusions: TFG::GPR128 (interpreted as stochastic) and NAB2::STAT6 . The latter, originally diagnosed as JxGCT, was reclassified as SFT and excluded from the series. No fusions were detected in the remaining 11 cases; of note, no case harbored NOTCH fusions previously described in GT. Genomic methylation analysis showed that JxGCT, GT, and SFT form separate clusters, confirming that JxGCT represents a distinct entity (ie, different from GT). The results of our study show that JxGCTs are a distinct tumor type with a recurrent pattern of chromosomal imbalances that may play a role in oncogenesis, with MAPK-RAS pathway activation being likely a driver in a relatively small subset.

Adenoid cystic carcinomas (AdCC) of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost universal presence of the gene fusion MYB::NFIB , or less commonly MYBL1::NFIB. Sinonasal AdCC is an aggressive salivary gland malignancy with no effective systemic therapy. Therefore, it is urgent to search for potentially targetable genetic alterations associated with AdCC. We have searched the authors' registries and selected all AdCCs arising in the sinonasal tract. The tumors were examined histologically, immunohistochemically, by next generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) looking for MYB/MYBL1 and/or NFIB gene fusions or any novel gene fusions and/or mutations. In addition, all tumors were tested for HPV by genotyping using (q)PCR. Our cohort comprised 88 cases of sinonasal AdCC, predominantly characterized by canonical MYB::NFIB (49 cases) and MYBL1::NFIB (9 cases) fusions. In addition, noncanonical fusions EWSR1::MYB ; ACTB::MYB; ESRRG::DNM3 , and ACTN4::MYB were identified by NGS, each of them in 1 case. Among nine fusion-negative AdCCs, FISH detected rearrangements in MYB (7 cases) , NFIB (1 case), and EWSR1 (1 case). Six AdCCs lacked fusions or gene rearrangements, while 11 cases were unanalyzable. Mutational analysis was performed by NGS in 31/88 (35%) AdCCs. Mutations in genes with established roles in oncogenesis were identified in 21/31 tumors (68%), including BCOR (4/21; 19%), NOTCH1 (3/21; 14%), EP300 (3/21; 14%), SMARCA4 (2/21; 9%), RUNX1 (2/21; 9%), KDM6A (2/21; 9%), SPEN (2/21; 9%), and RIT1, MGA, RB1, PHF6, PTEN, CREBBP, DDX41, CHD2, ROS1, TAF1, CCD1, NF1, PALB2, AVCR1B, ARID1A, PPM1D, LZTR1, GEN1 , PDGFRA , each in 1 case (1/21; 5%). Additional 24 cases exhibited a spectrum of gene mutations of uncertain pathogenetic significance. No morphologic differences were observed between AdCCs with MYBL1::NFIB and MYB::NFIB fusions. Interestingly, mutations in the NOTCH genes were seen in connection with both canonical and noncanonical fusions, and often associated with high-grade histology or metatypical phenotype, as well as with poorer clinical outcome. Noncanonical fusions were predominantly observed in metatypical AdCCs. These findings emphasize the value of comprehensive molecular profiling in correlating morphologic characteristics, genetic landscape, and clinical behavior in AdCC.

Determining whether an ipsilateral breast carcinoma recurrence is a true recurrence or a new primary remains challenging based solely on clinicopathologic features. Algorithms based on these features have estimated that up to 68% of recurrences might be new primaries. However, few studies have analyzed the clonal relationship between primary and secondary carcinomas to establish the true nature of recurrences. This study analyzed 70 breast carcinomas from 33 patients using immunohistochemistry, FISH, and massive parallel sequencing. We compared 35 primary carcinomas with the associated recurrences, identifying 24 (68.6%) as true recurrences, 7 (20%) as new primaries, and 4 (11%) as undetermined. Twenty-eight primary carcinomas were invasive carcinomas (22 of no special type, 5 invasive lobular, and 1 invasive micropapillary carcinoma), and 7 were in situ (6 ductal and 1 lobular). Time to recurrence was longer for new primaries (median 12.8 y) than for true recurrences (median 6.8 y). Among the new primary cases, 6 of 7 (85%) patients had undergone mastectomy as their initial treatment. Clinicopathologic classifications of invasive carcinomas overestimated the number of new primaries (41.6% to 68.6%), partially due to phenotype conversion in 14% of true recurrences. Although 41.7% of recurrences showed private mutations or amplifications relevant to tumor progression, such as PIK3CA, PIK3R1, MAP3K1, AKT1, GATA3, CCND1, MDM4 , or T P 5 3 ; a common mutational progression pattern was not identified. Further studies, including larger series, are necessary to evaluate the prognostic significance of the molecular classification of recurrences.

Primary biliary cholangitis (PBC) with early cholestasis and extensive bile duct loss but no significant fibrosis or cirrhosis is rare and underrecognized. We aimed to clarify the clinicopathology features and prognosis of these variants of patients with early-stage PBC with ductopenia. From January 2009 to January 2023, we retrospectively collected the laboratory and pathologic data of patients with early-stage PBC and recorded their liver-related events with a median follow-up of 4.5 years. Finally, a total of 141 patients with PBC in the early stage were included and divided into 2 groups: one with ductopenia (n = 36) and the other without ductopenia (n = 105). The median age of the participants was 50 years, with 90.8% being female. The ductopenia group exhibited significantly elevated alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin, total bile acid, and total cholesterol (CHOL). Conversely, they showed a reduced biochemical response to ursodeoxycholic acid according to the Paris II, Barcelona, and Rotterdam criteria. A relatively poorer prognosis was observed in patients with early-stage PBC with ductopenia but with no statistical difference (11.8% vs 4.9%, P = 0.352). Baseline total CHOL levels were identified as an independent factor for the presence of ductopenia in early-stage PBC (odds ratio = 1.771, 95% CI: 1.264-2.479, P = 0.001). In conclusion, ductopenia was a significant risk factor for worse biochemical profiles and poor treatment response in patients with early-stage PBC. High levels of total CHOL at baseline are associated with the presence of ductopenia in early-stage PBC.

Lymphomas of T-follicular helper origin (T-follicular helper-cell lymphoma [TFHL]) are often accompanied by an expansion of B-immunoblasts, occasionally with Hodgkin/Reed-Sternberg-like (HRS-like) cells, making the differential diagnosis with classic Hodgkin lymphoma (CHL) difficult. We compared the morphologic, immunophenotypic, and molecular features of 15 TFHL and 12 CHL samples and discussed 4 challenging cases of uncertain diagnosis. Compared with CHL, TFHL disclosed more frequent sparing of subcortical sinuses, high-endothelium venule proliferation, dendritic cell meshwork expansion, T-cell atypia, and aberrant T-cell immunophenotype. HRS-like and HRS cells were CD30+, often CD15+ and EBV infected. There was a variable loss of B-cell markers in both diseases, with an expression of CD20, CD79a, CD19, or OCT-2 more frequently preserved in HRS-like cells of TFHL. The T-cell infiltrate was predominantly CD4+/CD8-, with expression of at least 2 TFH-markers in all TFHL and 75% of CHL. The most useful TFH marker was CD10 (positive in 86% TFHL and no CHL). Twelve/15 TFHL contained CD30+ neoplastic TFH cells, whereas CD30 expression was mostly restricted to HRS cells in CHL. We detected monoclonal TR rearrangements in 75% of TFHL and no CHL; and monoclonal IG rearrangements in 23% of TFHL and 42% of CHL. All TFHL had TET2 mutations; 13/14 presented RHOA mutations, 3 accompanied by DNMT3A and 1 DNMT3A + IDH2 mutations. Three CHL had TET2 mutations, likely attributable to clonal hematopoiesis. Our study further underlines that HRS(-like) cells are not pathognomonic of CHL. Since no single pathologic criterion distinguishes TFHL and CHL, an integrative approach ideally comprising molecular investigations is fundamental.

B-cell and plasma cell proliferations are frequently observed in nodal T follicular helper (nTfh) cell lymphomas and can present a diagnostic challenge. These proliferations can be monotypic or monoclonal and morphologically resemble lymphoma or plasmacytoma, but their clinical behavior is poorly defined. In this study, we reviewed 414 cases of nTfh lymphoma seen over the past decade at our institution. We identified 78 (19%) cases that exhibited B-cell or plasma cell proliferation detected by morphology, flow cytometry, immunohistochemistry, and/or molecular techniques. The B-cell/plasma cell proliferations occurred before (22%), concurrently with (50%), or after (28%) the diagnosis of nTfh lymphoma. We divided them into 3 categories: (1) focal or scattered B-immunoblastic proliferations recognized morphologically without a monotypic/monoclonal B-cell population (17%), (2) monotypic/monoclonal B-cell/plasma cells identified solely by flow cytometry or molecular clonality studies without morphologic confirmation (11%), and (3) unequivocal B-cell/plasma cell expansions recognized by morphologic assessment (72%). We further subdivided group 3 into proliferations associated with and possibly dependent on neoplastic Tfh cells versus those proliferations occurring in the absence of neoplastic Tfh cells and likely bona fide lymphomas. Follow-up biopsy specimens showed persistence of B-cell/plasma cell proliferations in various patient subcategories, with transformation to higher-grade B-cell proliferation or persistence without Tfh cells in some cases. In conclusion, our data support the notion that most B-cell and plasma cell proliferations associated with neoplastic Tfh clones have little impact on the clinical course of patients with nTfh lymphoma and likely do not constitute an independent B-cell lymphoma, especially those of small B cells of plasma cells. However, B-cell expansions exhibiting aggressive morphologic features may represent an independent B-cell lymphoma.

We present one of the largest cohorts of TP53 -pathogenic germline variants (PGVs) associated with patients with Li-Fraumeni syndrome (n = 82) with breast tumors (19 to 76 y; median age: 35). Most had missense variants (77%), followed by large gene rearrangements (LGRs; 12%), truncating (6%), and splice-site (5%) variants. Twenty-one unique germline missense variants were found, with hotspots at codons 175, 181, 245, 248, 273, 334, and 337. Of 100 total breast tumors, 63% were invasive (mostly ductal), 30% pure ductal carcinoma in situ, 4% fibroepithelial lesions, and 3% with unknown histology. Unlike BRCA -associated tumors, approximately half of the breast cancers exhibited HER2 -positivity, of which ~50% showed estrogen receptor coexpression. Pathology slides were available for review for 61 tumors (44 patients), and no significant correlation between the type of TP53 PGVs and histologic features was noted. High p53 immunohistochemistry expression (>50%) was seen in 67% of tumors tested (mostly missense variant). Null pattern (<1% cells) was seen in 2 (LGR and splicing variants carriers). Surprisingly, 2 tumors from patients with an LGR and 1 tumor from a patient with a truncating variant showed p53 overexpression (>50%). The subset of patients with the Brazilian p.R337H variant presented at a higher age than those with non-p.R337H variant (46 vs 35 y) though statistically insignificant ( P = 0.071) due to an imbalance in the sample size, and were uniquely negative for HER2 -overexpressing tumors. To conclude, breast cancer in carriers of TP53 PGVs has some unique clinicopathological features that suggest differential mechanisms of tumor formation. p53 immunohistochemistry cannot be used as a surrogate marker to identify germline TP53 -mutated breast cancers.

Gastric-type adenocarcinoma (GAS) is the most common subtype of human papillomavirus (HPV)-independent cervical adenocarcinomas and is associated with a poor prognosis. We used a gross morphologic classification system and imaging analysis to compare the clinicopathological features of GAS and HPV-associated adenocarcinoma (HPVA) and identify factors contributing to the poor prognosis of GAS. This retrospective 2-center study analyzed 33 patients with GAS and 70 with HPVA (stages IB-IVB) who underwent surgery between 1997 and 2023. GAS had a higher rate of positive surgical margins (21.2% vs. 0%, respectively, P<0.001) and unclear tumor boundaries on gross morphologic findings (47.8% vs. 8.8%, respectively, P<0.001). Discrepancies between clinical and pathologic T classifications were more common in GAS, leading to frequent upstaging (51.5% vs. 28.6%, respectively, P=0.029). Imaging analysis revealed that GAS was associated with a smaller median tumor cell area (19.8% vs. 55.7%, respectively, P<0.001), which was significantly correlated with unclear tumor boundaries. Perineural invasion (PNI) was significantly more frequent in GAS (69.7% vs. 10.0%, respectively, P<0.001). A Kaplan-Meier analysis showed that patients with PNI had significantly poorer overall survival (P<0.001). A Cox multivariate analysis identified an advanced pathologic stage, positive peritoneal cytology, and positive surgical margins as independent risk factors. The present results indicate that GAS has a unique "stealth" invasion pattern, possibly caused by low tumor density, leading to undetectable tumor boundaries and positive surgical margins. This suggests a greater risk of incomplete resection than HPVA, leading to a poorer prognosis.