Modern Pathology最新文献

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications.

Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is recognized as a distinct entity in the 2026 WHO classification, defined by characteristic morphology and frequent SMARCB1 (INI1) loss, which differentiates it from conventional MPNST. Limited data suggest EMPNST may have a more favorable prognosis, but prognostic markers remain undefined. We studied 78 primary EMPNSTs and compared them to 60 conventional MPNSTs. EMPNST patients included 41 females and 37 males, with a median age of 45 years (range 6-84). Necrosis was observed in 20% of cases, cytologic atypia was mild (25%), moderate (57%) or severe (18%), and mitoses ranged from 0-42/10 high-power fields (HPF) (median 7/10). SMARCB1 loss was observed in 81% of EMPNSTs and correlated with prominent nucleoli (64%, P <0.001). EMPNSTs predominantly arose in the lower extremities, with 32% superficial, whereas conventional MPNSTs were mostly truncal. Targeted sequencing in 34 EMPNSTs identified SMARCB1 inactivation in 77% of cases, which was associated with SMARCB1 loss (P <0.001), and recurrent alterations targeting 2q35/XRCC5 in 59% of cases. Among 34 patients with follow-up (median 43 months, range 0-225), 9 developed local recurrence, 15 metastases, and 10 died of disease. Compared to conventional MPNST, EMPNST demonstrated longer median progression-free survival (34 vs. 19 months, P-value for global difference of survival curves = 0.35); overall survival was not reached in EMPNST (vs. 85 months in conventional MPNST, P-value for global difference of survival curves = 0.16). In multivariable analysis, tumor size and mitotic rate were independently associated with poor prognosis (HR, 5.2; 95% CI, 1.5-17.7; HR, 1.1; 95% CI, 1.01-1.2, respectively). A risk score integrating tumor size >5 cm, mitoses >7/10 HPF, and necrosis predicted poor outcomes (HR, 4.1; 95% CI, 1.4-12). In conclusion, EMPNST tumor size and mitotic activity are key prognostic factors, supporting a simple risk stratification model. SMARCB1 inactivation is the most frequent genomic event, followed by gains at 2q35 potentially targeting XRCC5, highlighting molecular underpinnings for this distinct sarcoma subtype.

Chimeric antigen receptor T-cell (CAR-T) therapy is a type of immunotherapy that utilizes genetically engineered T-cells with synthetic receptors targeting malignant cells that express specific antigens. CAR-T cell therapy primarily targets B-cell maturation antigen expressed by multiple myeloma and CD19 expressed in several lymphoid malignancies. Data regarding patterns of gastrointestinal injury associated with CAR-T cell therapy are limited and, thus, we conducted this study to characterize the changes observed in biopsy samples from patients who have received this treatment. We retrospectively reviewed 14 cases from 8 patients who received CAR-T cell therapy, including 43 sets of mucosal biopsies and three surgical resection specimens. Information regarding symptoms, endoscopic findings, medications, and infections was recorded. The study patients were adults (mean age: 63 years, median: 62.5 years) and included five men and three women. Seven had refractory/relapsed multiple myeloma, and one had diffuse large B-cell lymphoma. Gastrointestinal symptoms included diarrhea (88%) or nausea and/or vomiting (22%), which developed a mean of 294 days (range: 41-700) post-CAR-T cell therapy. Endoscopic findings were variable; a minority of patients had normal examinations or only mild erythema, while others had mucosal granularity and ulcers in the upper and lower gastrointestinal tract. Five patients underwent evaluation for gastrointestinal infection; enteropathogenic Escherichia coli was detected in one. None of the patients received any medications known to cause gastrointestinal injury for at least three months prior to the endoscopic procedure. Tissue samples contained regenerative-appearing glands and/or crypts lined by cells with attenuated cytoplasm; apoptotic epithelial cells and intraepithelial lymphocytosis were uniformly present, being most pronounced in the deep mucosa. Inflammation was minimal; the lamina propria was mostly hypocellular to normocellular with decreased or absent plasma cells. Immunohistochemical stains were negative for cytomegalovirus and adenovirus. Our findings suggest that CAR-T cell therapy causes gastrointestinal injury characterized by epithelial cell apoptosis and intraepithelial lymphocytosis and predominantly affects crypts and glands in the deep mucosa. Recognizing this pattern may help pathologists suggest the presence of CAR-T cell therapy-induced injury in the appropriate clinical context.

Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer, and its clinical presentations and outcome are not clear. This multi-institutional study comprehensively evaluated the clinicopathologic features, treatment patterns and outcomes of 149 MBC cases. In total, 149 MBC cases diagnosed from 2005-2023 were included and compared with 350 non-MBC triple negative breast cancer (TNBC) diagnosed from 2004-2019: 62 MBCs and 174 TNBCs were treated with neoadjuvant chemotherapy (NACT); and 87 MBCs and 176 TNBCs with adjuvant chemotherapy (ACT). We evaluated pathologic variables including necrosis, lymph vascular invasion (LVI), tumor infiltrating lymphocytes (TILs), tumor nuclear grade, Nottingham grade, tumor size, presence of DCIS, and the presence and percentage of different metaplastic components. Clinical data including age, race, estrogen receptor, progesterone receptor and HER2 status, local recurrence-free survival (LRFS) and metastasis-free survival (MFS), were retrieved. The median follow-up time was 58.9 months for all patients. Only 5 (8.1%) MBC patients achieved pCR when treated with NACT, compared with 37.9% of TNBC patients (P<0.0001). None of the MBC patients who achieved pCR developed metastasis. No clinicopathologic variables were associated with the pCR rate in MBC. The proportion of metaplastic components was not associated with pCR rate or MFS in the MBC cases. MBC patients treated with NACT had significantly shorter MFS than MBC patients treated with ACT (P=0.011). In MBC patients who did not achieve pCR after NACT, larger tumor size was associated with shorter MFS (P<0.001). In MBC patients who received ACT, higher TILs level was associated with longer MFS (P=0.016). This study with large cohorts showed patients with MBC had a low pCR rate to NACT, but these patients who achieved pCR had excellent prognosis. Therefore it is important to identify which patients benefit from NACT. The proportion of metaplastic component was not associated with pCR rate or MFS, supporting the current recommendation that breast carcinoma with any metaplastic component should be diagnosed as MBC. Finally, higher TILs levels were associated with improved MFS in MBC patients treated with ACT. Further investigation is warranted to define biomarkers and patient selection for NACT vs ACT in MBC.

Diagnosing ovarian sex cord-stromal tumors can be difficult in some cases due to the overlapping morphological and immunohistochemical features, especially for adult granulosa cell tumors (AGCTs), juvenile granulosa cell tumors (JGCT), Sertoli-Leydig cell tumors (SLCT), and thecomas. In such situations, molecular testing can be helpful, as these tumors are often associated with specific genetic alterations. SLCTs, for instance, are known to be associated with DICER1 mutations. However, expression of DICER1 has not yet been systematically investigated in sex cord-stromal tumors. We evaluated the potential use of DICER1 immunohistochemistry for detecting DICER1 mutations in ovarian sex cord-stromal tumors, including 267 AGCT, 38 SLCT, 5 JGCT, and 21 Leydig cell tumors/steroid cell tumors (SCT). Specifically, DICER1 positivity was found in 21/38 (55.3%) of SLCTs, and 16/21 (76.2%) SCT. All DICER1-positive moderately differentiated SLCTs harbored DICER1 mutation. One DICER1-negative moderately differentiated SLCT carried two DICER1 mutations. Additionally, 3/10 well differentiated SLCTs showed immunohistochemical positivity. No SCT harbored DICER1 mutation. Among AGCTs, 4/267 (1.5%) were DICER1-positive, one of these cases harbored two DICER1 mutations. No JGCT demonstrated DICER1 mutation or expression. In cases with both analyses available, DICER1 expression was found in 39/273 (14.3%), while 21/273 (7.7%) harbored DICER1 mutation. Using an optimal cut-off of ≥ 10 % positive tumor cells, immunohistochemistry closely matched mutational status (sensitivity of 90.5%, specificity 92.1%). Our study found substantial concordance between DICER1 immunohistochemistry and mutation status in subset of sex cord-stromal tumors, suggesting that immunohistochemical detection of DICER1 protein may serve as a useful surrogate marker of DICER1 mutation, especially in SLCTs and AGCT. This could be particularly valuable in settings where molecular testing is limited by cost and/or availability. However, in SCT the DICER1 expression is common, but unrelated to DICER1 mutation. This suggests that alternative mechanisms, potentially involving androgen-related pathways, may contribute to DICER1 expression in these tumors.

In this study, we used optical genome mapping (OGM), conventional karyotyping, and next-generation sequencing (NGS) to analyze cytogenomic alterations in 91 cases of T-lymphoblastic leukemia/lymphoma (T-ALL). While karyotyping detected abnormal karyotypes in 55% of cases, OGM identified cytogenetic abnormalities in 97.8% of the cases and provided clinically relevant information beyond karyotyping in approximately 70% of cases. OGM detected gene rearrangements in 80% of cases, including 24 recurrent gene fusions and 21 previously unreported putative gene fusions in T-ALL. Copy number variants were detected in 93% of cases, with interstitial deletions the most common. Gene mutations were detected in 93% of cases, with NOTCH1 being most frequent (in 57% cases). Combining all data, most T-ALL cases harbored three or more cytogenomic aberrations. Specific cytogenomic alterations differed among T-ALL subtypes: rearrangements of BCL11B and PICALM::MLLT10, deletions of 7p and mutations involving DNMT3A, WT1, TET2, IDH2 and FLT3 were common in early T-precursor (ETP) and near-ETP subtypes. Rearrangements of TLX1, KMT2A, STIL::TAL1 and NUP214::ABL1, deletions of 9p, and FBXW7 mutations were frequently associated with the cortical subtype. We conclude that integration of OGM and NGS with karyotyping enables comprehensive cytogenomic profiling of T-ALL that improves detection of clinically relevant genomic alterations and may inform disease classification and future studies of risk stratification.

Sinusoidal obstruction syndrome (SOS) is a known adverse effect of oxaliplatin, causing significant morbidity and cessation of chemotherapy. Recent studies suggest single nucleotide polymorphisms (SNPs) of certain genes may predispose carriers to oxaliplatin-induced liver toxicity. This study aims to evaluate candidate SOS-predisposing SNPs by correlating routinely available next-generation sequencing (NGS) data with clinical and histologic evidence of SOS. Seventy-nine colorectal cancer (CRC) cases with liver metastases and clinical NGS data were identified. A combination of clinical, biochemical, and histologic criteria was used to identify 12 cases with confirmed SOS. Additionally, 10 control cases were selected with no clinical or histological evidence of SOS. Clinical data and SOS-related findings were collected. For each patient, the expanded panel NGS data obtained for clinical management was reanalyzed to assess 12 polymorphisms in ERCC1, ERCC2, ABCB1, GSTP1, DPYD, MTHFR, ABCC2, UGT1A1, GSTT1, and GSTM1 known to be associated with oxaliplatin toxicity, as identified in the PharmGKB database. Statistical analyses, including Fisher's exact test and odds ratios were performed. The strongest nominal signal was observed in the prevalence of ERCC1 rs11615 (A>G) in SOS and control groups (allelic p-value=0.006, false discovery rate [FDR] q=0.072). The odds ratio for developing SOS associated with rs11615 (A>G) was 0.15 (95% confidence interval: 0.04-0.59), indicating a protective effect of the ERCC1 rs11615 (A>G). There was a noticeable numerical increase in ascites frequency, levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and frequency of neuropathy in the SOS group, albeit not statistically significant. These findings highlight the utility of expanded analysis of routinely obtained NGS panel results at the time of CRC diagnosis at many medical centers to personalize the chemotherapy regimen. Our data suggest that patients who carry the ERCC1 rs11615 (A>G) variant may be protected from developing oxaliplatin-induced SOS and those lacking the G allele should be monitored more carefully after oxaliplatin use.

Lung squamous cell carcinoma (LUSC) is the second most common subtype of non-small cell lung carcinoma (NSCLC), typically associated with a poor prognosis. Unlike lung adenocarcinoma (LUAD), the application of next-generation sequencing (NGS) in LUSC has lagged due to the long-standing perception of low therapeutic yield, primarily based on highly selected, resected cohorts. We sought to determine the real-world clinical utility of NGS in LUSC. We analyzed an institutional cohort of 576 tumors initially diagnosed as LUSC that underwent NGS profiling. We defined "clinical yield" as either diagnostic reclassification or the identification of a targetable mitogenic alteration. Twenty cases (3.5%) were reclassified, including re-diagnosis to cutaneous squamous cell carcinoma (SCC), transformed adenocarcinoma (post-targeted therapy), and rare entities like NUT carcinoma and lymphoepithelial carcinoma. Primary mitogenic drivers were identified in 83 cases (14.4% of the total cohort), of which 43 (7.5% of the total cohort) harbored alterations with currently FDA-approved therapies for NSCLC (including KRAS, EGFR, MET, ALK, and ROS1). Overall clinical yield - defined as the sum of diagnostic reclassifications and identification of NSCLC-specific targetable alterations - was 11.0% (63/576). Univariate and multivariate analysis demonstrated that never or light smoking history was the strongest independent predictor of clinical yield, with 57.3% of tumors in this subset being reclassified or harboring a strong driver. Our findings demonstrate that NGS provides significant diagnostic and therapeutic value in a real-world LUSC cohort, challenging the historical premise of low yield. While clinicodemographic features can help prioritize testing in resource-limited settings, the identification of targetable drivers across all smoking groups supports the universal application of comprehensive NGS for all patients diagnosed with LUSC.

Natural killer (NK) cell neoplasms are a diverse group of entities with often nonspecific clinical presentations, making immunophenotyping essential for diagnosis. Immunophenotyping by flow cytometry can identify clonal NK cell populations by detecting restricted expression patterns of NK cell receptors such as killer cell immunoglobulin-like receptors (KIRs). However, reactive NK cells may also demonstrate KIR restriction through expansion of self-KIR-expressing NK cells, leading to identification of NK clones of uncertain significance (NK-CUS). A well-described reactive NK subset, termed "adaptive" NK cells, arises in response to cytomegalovirus (CMV) infection or reactivation, often appears KIR-restricted, and is defined by coexpression of CD57 and the activating receptor NKG2C. Because CMV reactivation is common among patients undergoing evaluation for hematolymphoid malignancy, we hypothesized that NK-CUS may frequently correspond to this non-neoplastic adaptive NK cell subset. Here, we describe a flow cytometry panel for immunophenotypic characterization of cytotoxic lymphocytes that includes NKG2C, enabling detection of non-neoplastic adaptive NK cells. We show that NK-CUS frequently represent reactive NKG2C⁺ adaptive NK cells. We describe several cases that meet diagnostic criteria for NK-large granular lymphocytic leukemia (NK-LGLL) and demonstrate that the NK cell clones are non-neoplastic NKG2C⁺ adaptive NK cells arising in the setting of CMV viremia. Further, we show that NKG2C expression is uncommon by neoplastic NK cell proliferations with recurrent molecular or cytogenetic abnormalities. Collectively, we demonstrate that NKG2C has a high specificity for reactive NK cell populations, and its inclusion in NK cell immunophenotyping panels is a useful strategy to more reliably distinguish between neoplastic and reactive NK cell populations.