American Journal of Surgical Pathology最新文献

Canalicular tumors of the salivary glands have recently emerged as an entity characterized by distinct morphology and recurrent HMGA2 gene rearrangement. In this study, we analyzed 40 cases intending to elucidate their features further. The monophasic or biphasic tumors exhibited a growth pattern of interconnected anastomosing trabeculae and canaliculi, accompanied by a classical pleomorphic adenoma in one-third of the cases. Invasive growth into surrounding adipose tissue was revealed in one case which was, therefore, diagnosed as epithelial-myoepithelial carcinoma. Although the tumor cells uniformly expressed HMGA2 protein in all cases, cytokeratin 7, S100 protein, and SOX10 displayed either diffuse positivity or highlighted the luminal and abluminal cell populations, respectively. Areas with morphological oncocytoid change and AR-immunopositivity of luminal cells were seen in 13/14 (93%) of tested biphasic cases. HMGA2 rearrangement was detected by RNA-sequencing in 30 cases. The most common alteration was an HMGA1::WIF1 fusion, but several novel or rare fusion partners were identified, including ARID2, FHIT, MSRB3 and its antisense variant MSRB3-AS1, IFNG-AS1, and the long intergenic region LINC02389. In addition, FISH revealed HGMA2 break-apart in the remaining 10 cases where targeted sequencing failed to detect any alteration or where RNA sequencing could not be performed. Notably, the loss of the 3'-untranslated region of HMGA2 emerges as the common denominator for the described rearrangements, possibly disrupting its negative regulation by small regulatory RNAs. Awareness of this lesion ensures appropriate diagnosis and clinical management, especially with regard to the possibility of malignant transformation described in this and previous studies.

Programmed death-ligand 1 (PD-L1/CD274) structural variation (SV) disrupting the 3'-untranslated region has been highlighted as being associated with PD-L1 overexpression. In the present study, we evaluated lymphoma tissue samples to investigate the applicability of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for detecting the PD-L1 SV involving the 3'-untranslated region. In total, 1052 lymphoma samples were screened using IHC, and 99 IHC screening-positive samples were evaluated with FISH (non-Hodgkin lymphoma [NHL, n=58] and Hodgkin lymphoma [HL, n=41]). Of these, 92 samples showed strong PD-L1 expression with 2 PD-L1 antibodies (E1J2J and SP142) (concordant PD-L1 IHC), whereas 7 samples showed strong PD-L1 expression only with E1J2J (discordant PD-L1 IHC). Abnormal FISH findings for PD-L1 were detected in all evaluated samples (51 NHLs and 41 HLs). A structural abnormality pattern was observed in 17 of the 51 evaluated NHL samples (33%). In contrast, all 41 HL samples showed a copy number abnormality pattern, with 1 exhibiting a structural abnormality pattern. Target-capture sequencing of the PD-L1 gene was performed on 73 of the 99 IHC screening-positive samples, comprising 41 NHLs and 32 HLs. PD-L1 SVs were detected in 16 (39%) of the 41 NHL samples and in only one of the 32 HL samples (3%). Samples exhibiting discordant PD-L1 IHC and/or FISH structural abnormality patterns were shown to harbor PD-L1 SV by target-capture sequencing, with positive and negative predictive values of 94% and 96%, respectively. Our approach is an alternative to target-capture sequencing for evaluating PD-L1 gene abnormalities.

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.

To survey and characterize intraductal polypoid neoplasms in the intrahepatic large bile ducts of small duct-type intrahepatic cholangiocarcinoma (small duct-iCCA), a total of 121 cases of small duct-iCCA presenting mass-forming growth were surveyed for intraductal polypoid neoplasms that were compared with mass-forming tumors in individual cases and with intraductal papillary neoplasm of bile duct (IPNB) (20 cases). Polypoid neoplasms were found in intrahepatic bile ducts in 8 (6.6%) of 121 cases of small duct-iCCA. They showed cast-like growth involving several adjoining bile ducts adjacent to or in the peripheries of mass-forming tumors as well as well-differentiated papillary or tubular/cribriform patterns and no stromal invasion. Intraductal polypoid neoplasms were histologically and immunohistochemically similar to mass-forming tumors in individual cases, and both components were of biliary subtype. There was an abrupt transition between these polypoid neoplasms and normal lining epithelia in the affected bile ducts, suggesting that intraductal polypoid neoplasms reflect the cancerization of ducts. IPNB presented with biliary (5 cases), intestinal (8 cases), gastric (5 cases), and oncocytic subtypes (2 cases), and about half of IPNBs were noninvasive, thus differing from intraductal polypoid neoplasms of small duct-iCCA. In conclusion, small duct-iCCA occasionally presents as intraductal polypoid neoplasms in adjoining bile ducts, reflecting the cancerization of ducts. These intraductal polypoid neoplasms should be considered in the differential diagnosis of heterogeneous intraductal tumors of bile ducts.

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.

Immature PIT1-lineage pituitary neuroendocrine tumors (PitNETs)/adenomas (Immature PIT1-lineage tumors) are a rare and underrecognized subtype of PitNETs that exhibits distinct cytologic atypia features and aggressive clinical potential. This study characterizes the clinical, radiological, histologic, and immunohistochemical features of 15 immature PIT1-lineage tumors identified from 1084 PitNETs patients over 5 years. Our cohort of 6 males and 9 females had a median age of 37.00 years (range: 23 to 68 y). All patients presented with pituitary macrotumors with an average size of 27.13×22.60×22.13 mm (length×width×height). The invasive growth pattern was identifiable, with 40.00% of tumors presenting with advanced stage (Knosp type 3 and 4) disease, followed by 20.00% Knosp type 2, 26.67% type 1, and 13.33% type 0. Clinical follow-up in 11 patients (median duration: 10.91 mo) revealed local recurrence in 1 case (9.09%). Microscopically, immature PIT1-lineage tumors comprised epithelioid (n=14) or spindle-shaped (n=1) chromophobic or weak basophilic cells with marked cytologic atypia, macronucleoli, and nuclear pseudoinclusions. By immunohistochemistry, most cases showed a consistent stain for PIT1 but limited expression of PIT1 family hormones in conjunction with diffuse or focal expression of CK8/18 (Cam 5.2), whereas none of the mimics showed a similar stain pattern in such a distinct way. We corroborate that immature PIT1-lineage tumors are rare, aggressive, and morphologically unique PitNETs/adenomas with cytologic atypia features. Immunohistochemistry may facilitate diagnosis in the distinction from histologic mimics.

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.