American Journal of Surgical Pathology最新文献

{"title":"Nondiffuse p16 Expression in HPV-Associated and HPV-Independent Cervical Squamous Cell Carcinomas: A Single-Institution Case Series With Emphasis on Histopathologic Features and Molecular Alterations.","authors":"Delaram Shakiba, Alice Dobi, Henrietta C Eugene, Hiro Nonogaki, Tricia A Numan, T-C Wu, Deyin Xing","doi":"10.1097/PAS.0000000000002600","DOIUrl":"10.1097/PAS.0000000000002600","url":null,"abstract":"<p><p>Negative or focal p16 expression may occur in cervical squamous cell carcinomas (SCCs) associated with high-risk or low-risk human papillomavirus (HPV), as well as in HPV-independent SCCs. However, this phenomenon is uncommon, and its pathologic and molecular characteristics remain poorly defined. In this single-institution study, we identified 11 cases (11/201 [5.5%]) with negative or focal p16 expression, including 4 (2.0%) associated with high-risk HPV, 6 (3.0%) HPV-independent, and 1 (0.5%) associated with low-risk HPV. Among the 4 high-risk HPV-associated SCCs with complete loss of p16 expression, 3 showed complete loss of the methylthioadenosine phosphorylase (MTAP). Notably, MTAP loss was also observed in 2 p16-negative high-grade squamous intraepithelial lesions (HSILs), suggesting that p16/MTAP codeletion may occur at both precursor and invasive stages. In contrast, all 6 HPV-independent SCCs retained MTAP expression. Two HPV-independent SCCs were associated with precursor lesions: 1 resembled verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN), while the other was analogous to HSIL. Consistent with high-risk HPV infection, all 4 HPV-associated SCCs demonstrated partial or complete loss of RB1 expression. In comparison, only 2 of 6 HPV-independent SCCs showed partial RB1 loss, likely through HPV-independent mechanisms. A wild-type p53 immunostaining pattern was observed in all cases except 1 HPV-independent SCC (case 7), which exhibited a null pattern and harbored a TP53 nonsense mutation (c.430C>T; p.Gln144Ter). p16 promoter methylation was detected in case 9 (HPV-independent SCC). Somatic TERT promoter mutations were identified in 2 of 4 (50%) HPV-associated SCCs, including c.-131C>T, c.-148C>T, and c.-150C>T. Among HPV-independent SCCs, 4 of 6 cases (66.7%) harbored pathogenic TERT promoter mutations, including c.-138C>T (n=1) and c.-124C>T (n=3). No PIK3CA hotspot mutations were detected in p16-negative, high-risk HPV-associated SCCs. In contrast, 2 HPV-independent SCCs harbored PIK3CA hotspot mutations (p.E545K and p.H1047R), supporting a role for PI3K-AKT-mTOR signaling in this setting. Because nondiffuse p16 expression can occur in both HPV-associated (high-risk and low-risk HPV) and HPV-independent cervical SCCs, which may have different clinical outcomes, awareness of this phenomenon is important when interpreting negative p16 immunostaining. Although data are limited, routine assessment of both p16 immunohistochemistry and HPV status, or correlation with prior liquid-based HPV test results when available, is recommended.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1294-1306"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kinase Fusions Define a Distinct Subset of BRAF V600E‑Negative Metanephric Adenomas : A Multi-Institutional Study of 7 Cases.","authors":"Ming Zhao, Xiaoqun Yang, Qifeng Wang, Wenjuan Yu, Rong Fang, Jiayun Xu, Yimiao Qiu, Ping Zhang, Huiying He","doi":"10.1097/PAS.0000000000002604","DOIUrl":"10.1097/PAS.0000000000002604","url":null,"abstract":"<p><p>Metanephric adenoma (MA) is a rare benign renal neoplasm characterized by recurrent BRAF V600E mutations in ∼80% to 90% of cases. The molecular drivers in BRAF V600E‑negative MAs remain poorly understood, although rare kinase fusions have been reported. Here, we present a multi‑institutional series of 7 BRAF V600E‑negative MAs with confirmed kinase fusions. The patients included 5 women and 2 men, with a median age of 43 years (range: 24 to 62 y). All tumors were uncapsulated and exhibited typical MA histology. Notably, leaf‑like structures formed by branching dilated tubules surrounding dense small acini were observed in 4 of 7 cases, and thyroid follicle‑like structures and/or microcystic/reticular patterns were observed in 3 of 7 cases. The majority of cases showed marked paucity of edematous or fibrous stroma. By immunohistochemistry, all cases were diffusely positive for WT1 and CD57, negative for BRAF V600E (clone VE1), and largely negative for CK7 and AMACR. Targeted RNA sequencing identified fusions involving RET ( CCDC6 :: RET in 2 cases, ANKRD26 :: RET in 1), ALK ( STRN :: ALK in 2), ROS1 ( RDX :: ROS1 in 1), and BRAF ( CUX1 :: BRAF in 1). All fusions preserved the kinase domain of the respective genes. Fluorescence in situ hybridization or reverse‑transcriptase PCR confirmed the rearrangements in available cases. In contrast, targeted RNA sequencing of 7 BRAF V600E‑mutant MAs revealed no kinase fusions. All patients underwent partial nephrectomy and remained disease‑free during follow‑up (median: 18 mo, range: 14 to 115 mo). Our findings demonstrate that kinase fusions, including RET , ALK , ROS1 , and BRAF , represent alternative drivers in BRAF V600E‑negative MAs, expanding the molecular spectrum of MA. In VE1-negative cases with classic MA histology, targeted RNA sequencing for these fusions may serve as a useful diagnostic adjunct.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1342-1351"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Tumor Microenvironment Score and Its Subsite-Specific Relevance in Colon Cancer.","authors":"Mari J Jawad, Vilja V Tapiainen, Ville K Äijälä, Päivi H Sirniö, Anne E Tuomisto, Hanna Elomaa, Maarit Ahtiainen, Olli Helminen, Erkki-Ville Wirta, Toni T Seppälä, Jan Böhm, Jukka-Pekka Mecklin, Henna Karjalainen, Meeri Kastinen, Timo Väisänen, Vesa-Matti J Pohjanen, Markus J Mäkinen, Jukka M Rintala, Heikki Huhta, Juha P Väyrynen","doi":"10.1097/PAS.0000000000002599","DOIUrl":"10.1097/PAS.0000000000002599","url":null,"abstract":"<p><p>Colon cancer is a major global malignancy with significant mortality. Right-sided (RCC) and left-sided colon cancers (LCC) exhibit distinct clinicopathological characteristics. Tumor microenvironment score (TMS) combines Klintrup-Mäkinen grade, tumor stroma percentage, and tumor budding, classifying cases into 4 groups (TMS 0-3). Evaluation of TMS is an integrative method for prognostic classification; however, further validation is needed, and differences between RCC and LCC remain unclear. A discovery cohort (n=940) and a validation cohort (n=613) were retrospectively included. TMS was evaluated from hematoxylin-eosin-stained slides. Five-year disease-specific survival (DSS) was analyzed using life-table methods and Cox regression. Associations with clinicopathological variables were assessed. In both the discovery and validation cohorts, higher TMS was associated with worse 5-year DSS in univariable analyses for both RCC and LCC. In multivariable analysis, high TMS (TMS3 vs. TMS0) remained independently associated with survival in the discovery cohort (RCC-HR: 2.47, 95% CI: 1.36-4.46, P =0.003; LCC-HR: 3.08, 95% CI: 1.46-6.45, P =0.003). In the validation cohort, the prognostic impact of TMS was more pronounced in RCC (HR: 4.35, 95% CI: 2.32-8.14, P <0.001) than in LCC (HR: 2.21, 95% CI: 0.81-6.03, P =0.12). TMS also appeared to provide improved prognostic stratification compared with the Glasgow microenvironment score (combination of Klintrup-Mäkinen grade and tumor stroma percentage). In conclusion, TMS serves as an integrative histopathological marker with potential to improve prognostic stratification in colon cancer, particularly in right-sided tumors.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1333-1341"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unique Thyroid Carcinoma With Somatic Inactivating TSC2 Mutations, Follicular and Melanocytic Differentiation and Distinct Morphologic Features.","authors":"Chatchanan Ausavarungnirun, Muhammad Usama, Daniel Ngov, Ami U Badami, Amanda S Karcioglu, Todd G Kroll","doi":"10.1097/PAS.0000000000002608","DOIUrl":"10.1097/PAS.0000000000002608","url":null,"abstract":"<p><p>Thyroid carcinomas with mutations in the TSC2 gene have been described rarely. Here, we report a unique thyroid carcinoma that has somatic mutations in TSC2 , follicular and melanocytic differentiation and distinct morphologic features, supported by a comprehensive molecular-genetic analyses. No other known pathogenic driver mutations were identified. The TSC2 mutations are predicted to be truncating and result in constitutive activation of mammalian target of rapamycin (mTOR) signaling that was confirmed by transcriptome expression profiling. This is the first demonstration of a thyroid follicular tumor with melanocytic differentiation and corresponding Melan-A expression may be a biomarker for this thyroid cancer. Its diffuse papillary architecture, macronuclei, multinuclear aggregates and intratumoral T lymphocytes are morphologic features not yet described in other TSC2 -mutated thyroid carcinomas. Morphologic overlap with classic thyroid papillary carcinoma and known technical difficulties in sequencing the large TSC2 gene make it likely that TSC2 -mutated thyroid carcinomas have been underdiagnosed so far. We suggest that TSC2 -mutated thyroid carcinoma should be considered in the differential diagnosis of any thyroid tumor that has unusual morphologic and immunohistochemical features or lacks known driver mutations in thyroid cancer.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1398-1405"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diversion-Associated Rectal Pathology in Patients With and Without Inflammatory Bowel Disease: A Rectum-Exclusive, Blinded Histologic Comparison and Practical Reporting Approach.","authors":"Mengxue Zhang, Hongzhang Mei, Yueying Li, Shu-Yuan Xiao","doi":"10.1097/PAS.0000000000002606","DOIUrl":"10.1097/PAS.0000000000002606","url":null,"abstract":"<p><p>Diversion colitis is an established clinicopathologic complication of fecal stream diversion and may mimic inflammatory bowel disease (IBD) histologically, creating diagnostic and management challenges in the diverted rectum or rectosigmoid colon. We aim to clarify the histologic spectrum of diversion-associated pathology in patients with and without IBD, emphasizing de novo diversion colitis in non-IBD patients and interpretation of chronic colitis patterns in established IBD. We conducted a blinded, rectum‑exclusive histologic comparison of 63 diverted rectal resections (17 non‑IBD, 46 IBD), using a 5‑domain semiquantitative scheme for lymphoid follicles, activity, chronicity, mucosal atrophy, and surface integrity. Reproducibility was assessed by a blinded rereview after a 6-month washout. Ulcerative colitis versus Crohn's disease subgroups were compared by diversion interval-adjusted proportional-odds models with false-discovery rate correction. Available prediversion slides from the IBD group (31/46) were also reviewed for distal margin involvement. Diversion colitis occurred in 3/17 (18%) non‑IBD diverted rectum specimens, while most non‑IBD cases showed diversion change only. In contrast, 43/46 (93%) IBD cases exhibited a chronic colitis pattern, with or without activity, and also higher grades across all 5 parameters than non‑IBD cases. Higher rate of moderate-to-marked chronic active colitis in IBD, together with frequent prediversion distal margin involvement, favors persistent IBD as a likely interpretation in most cases, although severe diversion colitis cannot be definitively excluded by histology alone. Ulcerative colitis cases presented more severe histologic changes of chronic active colitis than those with Crohn's disease. These findings support a context-aware spectrum and practical reporting terminology after clinicopathologic correlation: (i) diversion change, (ii) diversion colitis, and (iii) IBD with superimposed diversion changes.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1362-1371"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Expression of RORγt and T-bet in ALK-Negative Anaplastic Large Cell Lymphoma: Implications for Biological Heterogeneity and Differential Diagnosis.","authors":"Aya Muramatsu, Daisuke Yamashita, Yuta Tsuyuki, Akira Satou, Naoko Asano, Waki Hosoda, Kennosuke Karube, Shigeo Nakamura, Seiichi Kato","doi":"10.1097/PAS.0000000000002602","DOIUrl":"10.1097/PAS.0000000000002602","url":null,"abstract":"<p><p>ALK-negative anaplastic large cell lymphoma (ALK-negative ALCL) frequently expresses cytotoxic molecules, which may complicate its distinction from peripheral T-cell lymphoma NOS (PTCL-NOS), particularly in cytotoxic molecule-positive cases. Among these, nodal EBV-negative cytotoxic T-cell lymphoma (CTL) represents an important diagnostic consideration. We evaluated the clinicopathological features of ALK-negative ALCL in comparison with nodal EBV-negative CTL and ALK-positive ALCL, with a focus on the immunohistochemical expression of master transcription factors (RORγt, T-bet, and GATA3). RORγt expression was significantly more frequent in ALK-negative ALCL than in nodal EBV-negative CTL (11/21 [52%] vs. 2/25 [8%]; P =0.001), and was uniformly present in ALK-positive ALCL (10/10 [100%]; P =0.012 vs. ALK-negative ALCL). In contrast, T-bet expression was less frequent in ALK-negative ALCL (2/21 [10%]) than in nodal EBV-negative CTL (9/25 [36%]; P =0.045), and was absent in all ALK-positive ALCL cases. RORγt and T-bet expression were largely mutually exclusive across the cohort, with only one overlapping case. GATA3 expression was absent in all evaluable cases of nodal EBV-negative CTL and ALK-positive ALCL, and was detected in only 2 of 19 ALK-negative ALCL cases (11%). These findings suggest that ALK-negative ALCL shows a distinct transcription factor profile characterized by frequent RORγt expression and infrequent T-bet expression, in contrast to nodal EBV-negative CTL. Assessment of these markers may provide a useful adjunct in the differential diagnosis of cytotoxic T-cell lymphomas, particularly in diagnostically challenging cases.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1307-1315"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reappraisal of Endobronchial Polypoid Adenocarcinoma of the Lung: A Clinicopathological Analysis of 11 Cases.","authors":"Miyuki Shimazu, Taishi Takahara, Risa Oishi, Masanori Seki, Akira Satou, Yuki Yamamoto, Nagako Maeda, Akana Hinokimoto, Naoki Kurita, Natsuki Taniguchi, Akiko Ohashi, Emiko Takahashi, Satoru Ito, Toyonori Tsuzuki","doi":"10.1097/PAS.0000000000002605","DOIUrl":"10.1097/PAS.0000000000002605","url":null,"abstract":"<p><p>Lung adenocarcinoma rarely presents as a grossly or bronchoscopically visible tumor protruding into the bronchial lumen. This multicenter retrospective study aimed to reappraise this unusual growth pattern, termed endobronchial polypoid adenocarcinoma, and to examine its clinicopathological characteristics. We retrospectively reviewed 2261 surgically resected primary lung adenocarcinomas from 4 institutions and identified 11 cases of endobronchial polypoid adenocarcinoma, accounting for ∼0.5% of the included cases. All tumors showed both pulmonary parenchymal and endobronchial components, and direct continuity between the 2 components through the bronchial wall was identified in 8 cases. A lepidic pattern was observed in the pulmonary parenchymal component in 8 cases. In the involved endobronchial mucosa, abrupt transitions between non-neoplastic ciliated epithelium and adenocarcinoma were identified in all cases. Spread through air spaces was observed in 10 of the 11 cases. EGFR mutations were detected in 3 of 9 examined cases. TTF-1 positivity and NKX3.1 negativity supported a terminal respiratory unit-type rather than bronchial gland-type origin. Postoperative recurrence was observed in 5 patients, with a median time to recurrence of 6 months. Two patients died of the disease. These findings suggest that endobronchial polypoid growth may represent a rare, macroscopically recognizable manifestation of airway-associated progression in lung adenocarcinoma, conceptually related to STAS and endobronchial spreading of adenocarcinoma (EBSA).</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1388-1397"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathologic Analysis of 138 Uterine Serous Carcinomas: Morphology Revisited.","authors":"Maximilian Lennartz, Lawrence Hsu Lin, Kyle M Devins, Esther Oliva, Gulisa Turashvili","doi":"10.1097/PAS.0000000000002603","DOIUrl":"10.1097/PAS.0000000000002603","url":null,"abstract":"<p><p>Serous carcinomas are copy-number-high (p53-abnormal) endometrial carcinomas with adverse outcomes. We aimed to assess the prognostic value of classic morphologic features in these tumors. Treatment-naive uterine serous carcinomas diagnosed from 1995 to 2022 were identified, and clinical-pathologic features were evaluated. The median age was 71 (52 to 95) years. Of 138 tumors, most (87 [63%]) were myoinvasive, and 51 (37%) were endometrium-confined, including 11 (21.6%) with only intraepithelial growth and 40 (78.4%) with stromal invasion within polyps and/or background endometrium. Predominant growth pattern was papillary in 63 tumors (45.6%), glandular in 60 (43.5%), and solid in 15 (10.9%). Lymphovascular invasion (LVI) was present in 49 (35.5%) cases, with nodal micro/macrometastases in 25/106 (23.6%) and isolated tumor cells in 3/106 (2.8%). Of 126 patients with follow-up (median: 38 mo, 0.9 to 230.7), 49 (38.9%) experienced recurrences and 27 (21.4%) died of disease. Both recurrence-free and disease-specific survival were associated with T category of pTNM staging, FIGO stage, endometrial stromal invasion, myoinvasion, margin status, cervical, lower uterine segment, and uterine serosal involvement (all P <0.0001), LVI ( P ≤0.002), predominant growth pattern, surrounding intraepithelial growth, and multinucleated tumor cells ( P ≤0.01). Patients with only intraepithelial growth experienced no recurrence or cancer-related death. LVI was associated with decreased recurrence-free ( P <0.0001) and disease-specific ( P <0.001) survival regardless of extent. T category ( P =0.0049) and uterine serosal involvement ( P =0.0514) were independent predictors of recurrence-free survival, with T category ( P =0.03) also predicting disease-specific survival. The presence of only intraepithelial growth portends a favorable prognosis in serous carcinoma, whereas the clinical significance of the extent of LVI is limited.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1352-1361"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sporadic Burkitt Lymphoma Lacking MYC Protein Expression: A Rare Entity With Diagnostic Pitfalls and Dismal Prognosis.","authors":"Xiaoying Lou, Keqi Chen, Mansi Yu, Cai Lei, Qingqing Cai, Xia Yang, Yuhua Huang","doi":"10.1097/PAS.0000000000002593","DOIUrl":"10.1097/PAS.0000000000002593","url":null,"abstract":"<p><p>The pathognomonic genetic alteration in Burkitt lymphoma (BL) is the immunoglobulin ( IG )- MYC translocation, causing intense nuclear MYC expression in almost all cases. Rare cases harbor MYC rearrangements yet lack detectable MYC protein expression. In this study, we report 8 cases of MYC protein-negative sporadic BL (MYC⁻ sBL). These cases accounted for 1.4% (8/574) of all sporadic BL cases. The median age was 10 years (range: 5 to 77 y), with a male-to-female ratio of 3:1. The majority (62.5%, 5/8) presented with advanced-stage disease (III/IV), and 25.0% (2/8) had bone marrow involvement. Morphologically, all cases met the World Health Organization (WHO) diagnostic criteria for BL, characterized by monotonous medium-sized cells with a typical \"starry sky\" pattern. Immunophenotypically, all cases exhibited a germinal center B-cell phenotype with nearly 100% Ki-67 positivity. Notably, MUM1 was positive in 50.0% (4/8) of cases, while Epstein-Barr virus (EBV)-encoded RNA (EBER) was positive in only 25.0% (2/8). Despite fluorescence in situ hybridization (FISH)-confirmed MYC rearrangement and the absence of BCL2 or BCL6 abnormalities, MYC protein expression was undetectable. Furthermore, patients with MYC⁻ sBL exhibited significantly inferior overall survival (OS) compared with those with MYC protein-positive sporadic BL (MYC + sBL) ( P <0.0001, HR=404.1). These findings confirm that MYC⁻ sBL is a rare but distinct clinicopathological entity associated with poor clinical outcomes, despite lacking unique histologic features. The molecular mechanisms underlying the absence of MYC protein expression remain to be investigated.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1316-1323"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifocal Thyroid Follicular Cell-Derived Carcinomas With Discordant Molecular Drivers: Morphologic and Clinical Features in 63 Patients.","authors":"Eren Altun, Muhammer Ergenç, Sylvia L Asa","doi":"10.1097/PAS.0000000000002594","DOIUrl":"10.1097/PAS.0000000000002594","url":null,"abstract":"<p><p>Thyroid carcinomas of follicular-cell origin are divided into 2 distinct morphologic and molecular families, RAS-like and BRAF p.V600E-like. Multifocality is common, usually of a single type. We retrospectively examined thyroid specimens diagnosed between 2019 and 2025 at one institution to evaluate the prevalence, clinicopathologic features, and immunohistochemical profiles of multifocal thyroid carcinomas with discordant molecular drivers. Clinical, demographic, and pathologic data were collected. Tissue microarrays were constructed for immunohistochemistry to localize BRAF p.V600E, NRAS p.Q61R, HBME-1, CK19, and Galectin-3. Among 1778 thyroid specimens, 626 thyroidectomy cases contained follicular cell-derived carcinomas. Multifocal disease was identified in 245 patients (39.1%); 63 (25.7%) had coexisting RAS-like and BRAF p.V600E-like carcinomas within the same gland. Most cases had a dominant tumor >1 cm and a second tumor <1 cm; in 19 cases (7.8%), both tumors were ≥1 cm. RAS-like tumors were larger (mean 3.6 cm) than BRAF p.V600E-like tumors (mean 1.85 cm; median 2.30 vs. 0.60 cm, P <0.001). HBME-1, CK19 and galectin-3 expression was more frequent in BRAF p.V600E-like tumors (81.0%, 82.5%, and 74.6%) compared with RAS-like tumors (63.5%, 65.1%, and 28.6%) ( P =0.004, P =0.003 and P <0.001). Lymphatic invasion occurred in 14 cases and lymph node metastasis in 10, predominantly from BRAF p.V600E-like papillary thyroid carcinoma, including 9 metastases arising from the smaller tumor focus. Two collision tumors were identified. We conclude that RAS-like and BRAF p.V600E-like tumors commonly coexist within the same thyroid gland. BRAF p.V600E-like papillary thyroid carcinomas demonstrate greater metastatic potential regardless of size, highlighting the importance of comprehensive histopathologic, immunohistochemical, and molecular evaluation for accurate risk stratification and individualized management.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1324-1332"},"PeriodicalIF":4.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}