American Journal of Surgical Pathology最新文献

{"title":"Clinicopathologic Analysis of 43 Surgically Resected Lactotroph Pituitary Neuroendocrine Tumors Stratified by Surgical Indication: A Pathologic Reappraisal of Apparent Male Aggressiveness.","authors":"Noriaki Tanabe, Naoko Inoshita, Eri Kasuga, Go Matsuoka, Atsushi Ishida, Masataka Kato, Haruko Yoshimoto, Hideki Shiramizu, Hidetaka Suga, Toru Tateno, Terushige Toyooka, Kenichi Ohashi, Masami Ono, Nobuhiro Miki, Koji Takano, Shozo Yamada","doi":"10.1097/PAS.0000000000002577","DOIUrl":"10.1097/PAS.0000000000002577","url":null,"abstract":"<p><p>Male lactotroph pituitary neuroendocrine tumors (PitNETs) are often considered more aggressive than those in women, but surgically treated cohorts are highly selected and may reflect differences in presentation and indication for surgery. We examined whether advanced clinical presentation in surgically treated lactotroph PitNETs is accompanied by distinct pathologic features. We reviewed 43 patients who underwent surgery for lactotroph PitNETs between 2018 and 2023 at a high-volume referral center. Cases were classified by surgical indication as preference for surgery/intolerance to dopamine agonists (P/I, n=26), resistance with hormonal symptoms (R/H, n=10), and resistance with mass effect (R/M, n=7). Clinical, radiologic, and pathologic parameters, including Ki-67, cytokeratin (CAM5.2), estrogen receptor, somatostatin receptor 2/5, and O6-methylguanine-DNA methyltransferase, were compared. Postoperative endocrinological remission was assessed at the last follow-up (median: 34 mo). All tumors were prolactin-immunoreactive, confirming lactotroph differentiation. Patients in the R/M group were older (median: 56 y), predominantly male (71.4%), and had larger tumors (median: 26 mm) with more frequent cavernous sinus invasion (Knosp grade 4, 85.7%) than those in the other groups. Long-term endocrinological remission differed significantly by indication (P/I, 88.5%; R/H, 80.0%; and R/M, 0%). In contrast, Ki-67 labeling index did not differ significantly across groups (P/I, 1.3%; R/H, 1.5%; and R/M, 2.6%; P =0.598), and no clear between-group differences were identified in CAM5.2 pattern, estrogen receptor, somatostatin receptor 2/5, or O6-methylguanine-DNA methyltransferase status. These findings suggest that the clinically most advanced surgical cases are not matched by distinct pathologic differences in the markers assessed and that the apparent aggressiveness of male-predominant mass-effect cases should not be interpreted solely as reflecting intrinsically aggressive tumor biology.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1097-1105"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410194","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":"De Novo and Postradiation Adenocarcinoma of the Urethra: A Clinicopathologic and Radiologic Study of 55 Cases.","authors":"Miao Zhang, Raghu Vikram, Junhyoun Sung, Peng Wei, Kanishka Sircar, Patricia Troncoso, Curtis Pettaway, Pheroze Tamboli, Bogdan Czerniak","doi":"10.1097/PAS.0000000000002614","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002614","url":null,"abstract":"<p><p>Herein, we report the results of clinicopathologic and radiographic analyses of 55 patients with primary adenocarcinoma of the urethra. Their ages at diagnosis ranged from 42 to 88 years (mean: 66 y). Twenty-six patients were male and 29 were female (ratio: 1.0:1.1). We noted 2 distinct groups of cases: de novo urethral adenocarcinoma (n=45) and urethral adenocarcinoma in patients after radiation therapy for prostatic adenocarcinoma (n=10), defined as postradiation adenocarcinoma. Postradiation tumors developed 8 to 25 years (mean: 15.6 y) after radiation therapy. Eight patients underwent brachytherapy. Among the 45 patients with de novo adenocarcinoma, 29 were female, for a female-to-male ratio of 1.8 to 1.0. In 17 female patients with de novo urethral adenocarcinoma, tumors developed in a urethral diverticulum. Histologically, urethral adenocarcinomas exhibited adenocarcinoma not otherwise specified or clear cell, mucinous, enteric, and adenoid cystic carcinoma morphology. In 2 cases of de novo adenocarcinoma and 3 cases of postradiation adenocarcinoma, the tumors progressed to sarcomatoid carcinoma. The mean disease-specific survival time for the entire cohort was 100.35 months. As reflected by the Kaplan-Meier curves for these patients, the patterns of disease-specific survival were similar in the de novo and postradiation groups.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862897","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":"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":"https://doi.org/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":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-27","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":"Toward Improved Classification of Vulvar Smooth Muscle Tumors: A Clinicopathologic Study of 35 Cases.","authors":"Krisztina Z Lengyel, G Petur Nielsen, Kyle M Devins, Lawrence Hsu Lin, Esther Oliva, Gulisa Turashvili","doi":"10.1097/PAS.0000000000002607","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002607","url":null,"abstract":"<p><p>Vulvar smooth muscle tumors have been evaluated using site-specific (1979 and 1996 Vulvar Criteria) or Uterine Criteria. We compared the performance of 3 classification systems for predicting clinical behavior in the largest series of 35 such tumors to date. Follow-up was available for 30 patients (median: 63 mo, 1 to 346). Most presented as a painless mass in premenopausal patients and showed spindled or myxoid morphology. Diagnoses were concordant across all 3 classification systems in most cases (80%, 28/35), including 22 leiomyomas and 6 leiomyosarcomas. Of the 7 discordant tumors, 3 with ≥5 cm, moderate to marked cytologic atypia, 5 mitoses per 10 high-power fields (HPF), and no tumor cell necrosis or infiltrative borders were diagnosed as smooth muscle tumors of uncertain malignant potential (STUMP) by the Uterine Criteria but as leiomyosarcoma/low-grade leiomyosarcoma by the site-specific criteria. Two tumors (≥5 cm, 8 to 9 mitoses per 10 HPF, no cytologic atypia or tumor cell necrosis, and unevaluable borders) were classified as mitotically active leiomyoma by the Uterine Criteria and the 1996 Vulvar Criteria but as low-grade leiomyosarcoma by the 1979 Vulvar Criteria. Two tumors with tumor cell necrosis, moderate atypia, 9 and 66 mitoses per 10 HPF, but <5 cm and well-circumscribed borders were categorized as leiomyosarcoma by the Uterine Criteria but as leiomyoma by both site-specific criteria. Our findings support the validity of the Uterine Criteria relative to the site-specific criteria for vulvar smooth muscle tumors, although the applicability of these criteria to the STUMP category warrants further study.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823914","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":"https://doi.org/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":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-26","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":"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":"https://doi.org/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":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-25","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":"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":"https://doi.org/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":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-25","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":"Histopathologic Grading of Residual Tumor Predicts Survival of Intrahepatic Cholangiocarcinoma Patients Treated With Neoadjuvant Therapy: Erratum.","authors":"Gaohua Wu, Xiufen Chen, Rongkui Luo, Ye Xin Koh, Tony Kiat Hon Lim, Valerie Chew, Jian Zhou, Jia Fan, Qiang Gao, Kai Zhu, Ruoyu Shi","doi":"10.1097/PAS.0000000000002597","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002597","url":null,"abstract":"","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807843","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":"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 of 4 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":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}