Bethesda System Research Articles

BackgroundThe widespread use of high-resolution ultrasonography (US) imaging has led to an increased detection of thyroid nodules, which are common in the general population.PurposeTo evaluate the correlation between ultrasonographic and pathological findings of thyroid nodules undergoing US-guided fine-needle aspiration (FNA) and assess the contribution of US features to malignancy prediction.Material and MethodsA total of 573 patients (137 men, 436 women; age range = 20-88 years) who underwent US-guided FNA were included. Nodule characteristics were recorded using the British Thyroid Association (BTA) U classification, and cytological results were assessed according to the Bethesda system. Logistic regression analysis (LRA) was performed to determine the relationship between US features and malignancy.ResultsThe distribution of nodules in U2, U3, U4, and U5 categories was 212, 171, 84, and 36, respectively, with corresponding Bethesda (2-6) classifications of 287, 159, 18, 27, and 12. Malignancy rates (Bethesda 4-6) were 0%, 10%, 28.6%, and 44.5%, respectively. Hypoechogenicity (relative to muscle), internal vascularization, and microcalcifications were significantly associated with malignancy (P <0.05). LRA achieved an 85.5% accuracy in malignancy prediction.ConclusionUS features in the BTA U classification align with pathological findings. Hypoechoic solid nodules, central vascularization, and microcalcifications should raise suspicion for malignancy in the differential diagnosis of thyroid nodules. These study findings highlight the strong association between vascularity in the BTA classification and malignancy, suggesting its potential role in risk stratification.

As the first vaccinated cohorts are gradually becoming eligible for cervical cancer screening (CCS), changes in the distribution of high-risk human papillomavirus (hrHPV) infection and associated disease endpoints are expected to occur. We aimed to describe the clinical outcomes of the Regional CCS Program of the North of Portugal in the latest years and to estimate the impact of different hrHPV genotypes on the occurrence of cervical neoplasia. Secondary data collected from the Regional CCS Program of the North of Portugal between January 2019 and December 2024 was used. Descriptive analysis was performed, and the proportion of high-grade squamous intraepithelial lesion (≥HSIL) attributable to different hrHPV genotypes was estimated. Between January 2022 and December 2024, the prevalence of hrHPV infection was 14.1%, and multiple infections accounted for 28.4% of the cases. Overall, the most prevalent genotypes were HPV-68 (16.6%), HPV-52 (14.5%), and HPV-31 (13.3%). Among the samples that underwent cytological analysis, 14.8% were atypical squamous cells of undetermined significance, 7.2% were low-grade squamous intraepithelial lesion, and 3.9% were ≥HSIL. Between 2019 and 2024, there was a decrease in the prevalence of the hrHPV genotypes included in the quadrivalent vaccine (17.5%-11.4%), especially in the youngest females, who also experienced a decrease in the frequency of ≥HSIL (6.0%-2.4%). The proportion of ≥HSIL attributable to these hrHPV types decreased from 38.5% to 23.5% in the youngest females, and no significant variations were found for the remaining. This study highlights the considerable reduction of the prevalence of both hrHPV infection and associated cervical abnormalities among the youngest and presumably vaccinated cohorts.

People living with HIV, especially gay, bisexual, and other men who have sex with men, are at increased risk of anal cancer. A recent randomized controlled trial showed treating anal high-grade squamous intraepithelial lesions (HSIL) reduces anal cancer incidence, supporting development of screening programs. Given the transition from cytological to HPV testing in cervical cancer screening, HPV testing for anal cancer is worth investigating. However, because of its low specificity, additional biomarkers like the p16/Ki67 dual stain may improve specificity. In this multicenter pilot study, people living with HIV aged 35+ years were recruited from sexual health centers and a general practice. Participants underwent digital anorectal examination and anal swab collection for HPV and p16/Ki67 dual stain testing. High-resolution anoscopy (HRA) referrals were based on screening results at baseline and 12 months, with immediate HRA referral for HPV16-positive participants. The primary objective was to assess adherence to the screening program. From October 2019 to July 2021, 136 participants (median age 54 years) were recruited. Overall, 85.3% completed all screening and HRA steps, with 92.8% attending HRA referrals. At baseline, 71.4% had anal high-risk HPV (HRHPV), with 40 testing positive for HPV16. Of those with HRHPV, 42.1% had a positive p16/Ki67 dual stain, whereas 37.9% had unsatisfactory results. Among 37 HRA attendees, 73.0% had composite cytological/histological HSIL. At 12 months, 81.4% tested positive for HRHPV, and 25.9% had composite HSIL. Adherence to the screening algorithm was 85.3%, with >90% attendance at HRA referrals. Screening identified composite HSIL in 53.1% of participants. Utility of the p16/Ki67 dual stain remains undetermined because of high rates of unsatisfactory samples.

Distinct Patterns of GLUT1 Expression in Human Papillomavirus Associated and Human Papillomavirus Independent Vulvar Intraepithelial Neoplasia and Squamous Cell Carcinoma.

Pediatric thyroid nodules and cancer are uncommon but have significant challenges in clinical management due to potential malignancy. Understanding the genotype-phenotype correlation helps in enhancing patient care and personalized treatment strategies. Our study aimed to determine the molecular characterization of thyroid nodules and cancer in childhood and investigate the genotype-phenotype relationship. The Bethesda Category (BC) is a standardized framework for classifying thyroid fine-needle aspiration (FNA) results. We conducted a retrospective analysis of clinical data, including next-generation sequencing (NGS), from pediatric thyroid nodule and cancer patients. Analysis was conducted using samples from a pathology archive and follow-up clinical data from a tertiary care center. A cohort of 62 pediatric patients (50 female, 12 male) aged 2.67-19.61 years (mean 14.18 ± 3.45 years), evaluated over a mean follow-up period of 5.06 ± 3.99 years. NGS analysis of 34 genes for DNA variants and RNA sequencing for gene fusions in BC II-VI samples. Of 62 patients, 37 (59.7%) had differentiated thyroid cancer (DTC), 14 (22.6%) had benign findings, and 9 (14.5%) were categorized as other. Pathogenic variants were found in 80% of DTC patients, with BRAFV600E being the most common (37%). RET, NTRK, and ALK fusions were present in 32% of DTC patients. In the benign group, variants in DICER1, TSHR, and PTEN were noted. Pathogenic variants were also identified in BC-II to BC-IV patients that later developed DTC. High-risk DTC patients included those with BRAFV600E and NCOA4-RET fusions. BRAFV600E and gene fusions involving RET, NTRK, and ALK were the most frequent pathogenic findings in pediatric DTC, with implications for risk stratification and tailored management. Early molecular analysis can guide prognosis and treatment in patients with initial benign or indeterminate diagnoses.

Fine-needle aspiration cytology (FNAC) is the cornerstone of thyroid nodule evaluation, standardized by the Bethesda System. However, indeterminate categories (Bethesda III–IV) remain a major challenge, often leading to unnecessary surgery or delayed molecular testing. Deep learning (DL) has recently emerged as a promising adjunct in thyroid cytopathology, with applications spanning triage support, Bethesda category classification, and integration with molecular data. Yet, routine adoption is limited by preanalytical variability (staining, slide preparation, Z-stack acquisition, scanner heterogeneity), annotation bias, and domain shift, which reduce generalizability across centers. Most studies remain retrospective and single-institution, with limited external validation. This article provides a technical overview of DL in thyroid cytology, emphasizing preanalytical sources of variability, architectural choices, and potential clinical applications. We argue that standardized datasets, multicenter prospective trials, and robust explainability frameworks are essential prerequisites for safe clinical deployment. Looking forward, DL systems are most likely to enter practice as diagnostic co-pilots, Bethesda classifiers, and multimodal risk-stratification tools. With rigorous validation and ethical oversight, these technologies may augment cytopathologists, reduce interobserver variability, and help transform thyroid cytology into a more standardized and data-driven discipline.

To assess the efficacy of prior 9-valent human papillomavirus (9vHPV) vaccination on risk of subsequent cervical, vaginal, and vulvar disease after a cervical excisional procedure for cervical squamous intraepithelial lesion (SIL) in a retrospective clinical trial analysis. Women aged 16-26 years were randomized to three-dose regimens of 9vHPV vaccine, quadrivalent HPV (4vHPV) vaccine, or placebo in three double-blind efficacy trials: a study of 9vHPV vaccine compared with 4vHPV vaccine (ClinicalTrials.gov, NCT00543543) and two historic placebo-controlled 4vHPV vaccine studies (ClinicalTrials.gov, NCT00092521 and NCT00092534). Incidence of subsequent condyloma, cervical, vulvar, or vaginal SIL was compared between 9vHPV vaccine and controls in women who underwent cervical excisional surgery after vaccination and had 6 months or more of follow-up after surgery. For HPV31/33/45/52/58-related endpoints, the control group was 4vHPV vaccine (from 9vHPV vaccine trial); for HPV6/11/16/18 analysis, the control group was historic placebo (from 4vHPV vaccine trials). This analysis included 295 9vHPV vaccine, 722 4vHPV vaccine, and 493 historic placebo recipients who underwent cervical surgery after a median of 1.7 years (range 0.1-4.4 years) after dose 1. Subsequent to surgery, HPV6/11/16/18-related SIL incidence was reduced by 95.4% (95% CI, 74.7-99.8%) with prior 9vHPV vaccine relative to historic placebo (1.3 vs 29.0/1,000 person-years, respectively); HPV31/33/45/52/58-related SIL incidence was reduced by 86.3% (95% CI, 47.5-97.8%) with 9vHPV vaccine compared with 4vHPV vaccine (2.7 vs 19.4/1,000 person-years, respectively). The incidence of high-grade SIL was numerically lower in the 9vHPV vaccine group relative to control, but this was not statistically significant (HPV6/11/16/18 related 69.6% reduction [95% CI, -133.5% to 98.7%]; HPV31/33/45/52/58 related 82.7% [95% CI, -29.2% to 99.2%]). Among female trial participants who underwent cervical excisional surgery, prior vaccination with 9vHPV vaccine (ie, 0.1-4.4 years before surgery) reduced the incidence of subsequent cervical and lower genital tract dysplasia. ClinicalTrials.gov, NCT00543543, NCT00092521, NCT00092534.

A 36-year-old lady presented with convincing symptoms of hyperthyroidism with a swelling in front of her neck for the last 3 months, but she denied any fever, flu-like illness, or pain over it. On examination, there was a non-tender (2 X 2) cm2 nodule in the left lobe of the thyroid, firm in consistency, not fixed to the surrounding structure, and no cervical lymphadenopathy. Investigations showed suppressed TSH, normal FT4 and FT3, and positive TRAb. USG of the thyroid showed a nodule (2.2 x 1.3 x 2 cm3) with a TIRADS score of 4 in the lower pole of the left lobe of the thyroid; thyroid scan revealed a warm nodule in the left lobe. FNAC showed Bethesda category VI. Total thyroidectomy was safely performed. Histopathology confirmed the case as a well-differentiated, classical variety of papillary thyroid cancer. One month later, she visited the endocrinologist with TSH 73.3 mU/L, thyroglobulin 3.52 ng/mL, negative anti-thyroglobulin antibody, USG of the neck showing no remnant, thyroid scan showing a small remnant in the thyroid bed. So, the patient was categorized into the American Thyroid Association-defined “indeterminate response” category. Levothyroxine was started again, and she was kept under regular follow-up. [J Assoc Clin Endocrinol Diabetol Bangladesh, 2025;4(Suppl 1): S52]

A 51-year-old woman presented with two years of postmenopausal spotting, mainly postcoital. Although vaginal atrophy was considered, prior use of vaginal estrogen at another center had not improved her symptoms. She had a history of persistent human papillomavirus (HPV) 16 infection and abnormal cytology. Initial colposcopy showed CIN 1 but one year later, a biopsy revealed CIN 2, and loop electrosurgical excision procedure (LEEP) was performed with negative margins. At 6-month follow-up, HPV positivity and low-grade squamous intraepithelial lesion persisted, with CIN 2 on colposcopy. Despite being offered repeat LEEP, the patient opted for definitive surgery. Due to a family history of ovarian cancer, she also requested bilateral salpingo-oophorectomy. This case highlights an individualized approach to recurrent cervical dysplasia and postmenopausal bleeding. Despite long-term follow-up, cervical dysplasia persisted, necessitating surgical intervention. The procedure was completed laparoscopically without complications. Cervical stump excision is a rare but important option in patients experiencing persistent symptoms or premalignant lesions after subtotal hysterectomy (SH). This case highlights careful patient selection and thorough counseling regarding potential long-term risks, including bleeding, dysplasia, and cervical malignancy, following SH.

Fine-needle aspiration cytology (FNAC) is a preferred method for evaluation of thyroid nodules. Under The Bethesda System for Reporting Thyroid Cytopathology, approximately 15%-30% of FNAC results fall into an indeterminate category: atypia of undetermined significance (AUS), follicular neoplasm (FN), and suspicious for malignancy (SFM), Bethesda classes III, IV, and V respectively. Molecular testing of indeterminate nodules helps evaluate the risk of malignancy and guide management decisions. This retrospective study assesses the impact of molecular testing on thyroid nodule classification in our institution, with an emphasis on indeterminate results. A 9-year retrospective analysis (January 2015-December 2023) was conducted at the University of North Carolina Health System. FNAC cases were classified per The Bethesda System. Molecular testing results and, when available, surgical pathology outcomes were reviewed. The study compared pre- and post-implementation data of routine reflex molecular testing of thyroid nodule diagnosis. A total of 3992 thyroid aspirates were evaluated: 490 (12.3%) nondiagnostic (class I), 2096 (52.5%) benign (class II), 1041 (26.1%) AUS (class III), 136 (3.4%) FN (class IV), 89 (2.2%) SFM (class V), and 140 (3.5%) malignant (class VI). Indeterminate cytology (classes III-V) accounted for 32% of all aspirates (n=1266). Before molecular testing, the AUS rate was 19.8% with an AUS:malignant ratio of 5.4. Post-implementation, the AUS rate rose to 30.1%, with a ratio of 8.9. This increase was statistically significant (p=.029). Implementation of molecular testing was associated with a significant rise in indeterminate cytologic diagnoses, particularly AUS.

Persistent infection with high-risk human papillomavirus (hrHPV) is recognized as the primary cause of cervical cancer and its precancerous lesions. However, most HPV infections are transient and naturally clear. Currently effective triage tools for distinguishing between transient HPV infections and clinically relevant hrHPV-induced diseases are lacking, leading to excessive referrals and overtreatment. This is the first large-scale, prospective, multicenter study to evaluate the triage performance of host DNA six-methylation marker assay (ASTN1, DLX1, ITGA4, RXFP3, SOX17, and ZNF671) in women who are hrHPV-positive in China. Compared with HPV genotyping and cytology [≥ atypical squamous cells of undetermined significance (ASCUS)] screening, the six-methylation marker assay demonstrated superior triage performance, with sensitivities of 82.2% and 90.3% and specificities of 92.4% and 84.1% for cervical intraepithelial grade II/III and worse (CIN2+ and CIN3+), respectively. Further subgroup analysis of women <30 years of age revealed its efficacy. The methylation positivity rate increased with the severity of cervical lesions, and the most significant marker was ZNF671. Moreover, the six-methylation marker assay required the fewest colposcopy referrals, with only 1.32 and 2.39 per CIN2+ and CIN3+ cases, respectively, highlighting its strong health and economic advantages. The large number of women with HPV infections in China each year has led to excessive cytological screenings and colposcopy referrals. A feasible triage tool for women who are hrHPV-positive significantly reduces unnecessary medical resource utilization and offers substantial health and economic benefits.

IntroductionHuman papillomavirus (HPV) infection is a significant public health concern globally, with its burden increasing in regions with limited access to screening and preventive measures. Understanding how HPV affects different populations is crucial, genetic background, behavioral factors, sexual health practices, co-infections, and access to screening and vaccination services significantly influence disease dynamics, prevalence of high-risk genotypes, and progression to malignancies such as cervical cancer. Such variations underscore the importance of region-specific epidemiological studies and serve as key predictors which can impact the well-being of the population. The study aims to investigate the prevalence and burden of HPV and its association with different risk factors among the indigenous Mizo women of Mizoram, Northeast India.MethodThis cross- sectional study was conducted among 1018 women age (20–73 years) from November 2023 to 2024 from different districts in Mizoram. Cervical swabs were collected in VTM after obtaining consent from the patients as well as the demographic and clinical data via a questionnaire. DNA-based HPV genotyping and Pap smear analysis were performed. Statistical analysis was performed by using SPSS version 22.0 software to determine the association between HPV and the risk factors.ResultsOut of the 1018 participants, findings revealed a 14.9% overall prevalence of HPV infection, with most participants being from the district capital, Aizawl (78.7%). Age group 51–60 years age group had a notable proportion of HPV-positive individuals (11.5%), they exhibited significantly lower odds of HPV infection compared to younger age groups (OR = 0.155, 95% CI: 0.038–0.632; p = 0.009). Most participants were married (93.3%) with 78.5% being housewives. Among different occupations, participants employed in government sectors have a higher odds ratio 1.898 of HPV infection suggesting potential occupational or lifestyle-related influence on infection risk. Key lifestyle factors such as betel nut consumption and early sexual debut are associated with increased infection risk. Cervicitis, chronic pelvic pain and multiple pregnancies were significant clinical indicators. Ingestion of oral contraceptives were less likely to be HPV positive than were those who did not ingest them (OR: 0.604, Cl: 0.399–0.915; p = 0.017). Pap smear results revealed associations with high-grade squamous intraepithelial lesions (p = 0.025). Genotypes HPV-16 (26.97%) and HPV-18 (17.11%) were the most prevalent genotypes. Approximately 23.4% of the patients presented with multiple genotype infections.ConclusionThis study underscores the importance of tailored public health strategies for high-risk regions such as Mizoram. These include promoting HPV vaccination, enhancing screening programs, and addressing sociocultural practices contributing to infection risk. While the cross-sectional design, female-only participation, and lack of follow-up limit causal interpretation and generalizability. Comprehensive interventions and awareness campaigns are crucial to mitigate the HPV burden and reduce the incidence of cervical cancer in this unique sociodemographic context.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12879-025-11529-7.

To develop Australian anal cancer screening guidelines for people living with HIV. In 2023, ASHM Health assembled a committee to create guidelines, based on existing international guidelines and utilizing data from the Study of the Prevention of Anal Cancer (SPANC). SPANC provided Australian-specific data on different screening methodologies for the detection of anal high-grade squamous intraepithelial lesions. The guidelines were released in March 2025. They recommend primary high-risk human papillomavirus (HRHPV) testing with cytology triage for high-resolution anoscopy. Gay, bisexual and other men who have sex with men (GBM) and trans-women living with HIV should be offered screening from 35 years of age. Cis-women, trans-men and other cis-men (not GBM) living with HIV should be offered screening from 45 years of age. All anal cancer screening should include annual digital ano-rectal examination, examination of the peri-anal region and a thorough medical history. Screening should be repeated every 3 years for those who screen negative. Screening should be discontinued, with shared decision-making, at age 75 years and/or in individuals with two consecutive negative screening visits who are not currently sexually active. These are the first guidelines to recommend primary HRHPV testing with cytology triage as the screening modality. They will assist clinicians in identifying and screening people living with HIV at higher risk of anal cancer and will enable screening and referral of people living with HIV at highest risk for high-resolution anoscopy, while screening and treatment services capacity are expanded in Australia.

The third edition of the Bethesda system for reporting thyroid cytopathology recommends a simplified two-tiered subclassification of atypia of undetermined significance (AUS), dividing cases into AUS with nuclear atypia (AUS-Nuclear) and other atypia (AUS-Other). This study aims to evaluate the performance of these subcategories in estimating the risk of malignancy (ROM) in a setting without routine molecular testing. A retrospective review was conducted on consecutive thyroid fine-needle aspiration (FNA) cases diagnosed as AUS between 2018 and 2023. Surgical pathology reports were matched with the FNA-targeted nodules to enable cyto-histologic correlation. ROM and risk of neoplasm (RON) were calculated for all AUS cases and for each subcategory. Among 16,030 thyroid FNA cases, 617 (3.8%) were diagnosed as AUS. Histologic follow-up was available in 190 cases. Final diagnoses included non-neoplastic lesions (42.6%), benign neoplasms (17.4%), low-risk neoplasms (5.3%), and malignant neoplasms (34.7%). The ROM for AUS-Nuclear was significantly higher at 54.7%, compared to 14.7% for AUS-Other (p < 0.001). Similarly, the RON was significantly higher in the AUS-Nuclear group (67.4%) than in the AUS-Other group (47.4%) (p = 0.005). AUS-Nuclear carries a substantially higher ROM than AUS-Other, with a ROM (54.7%) comparable to the reported positive predictive values of molecular assays such as Afirma GSC (47%, 95% CI: 36%-58%) and ThyroSeq v3 (66%, 95% CI: 56%-75%). These findings support the clinical utility of the two-tiered AUS subclassification in enhancing risk stratification, particularly in settings where molecular testing is not routinely available.

PurposeHigh-risk human papillomavirus (hr-HPV) types are the primary cause of cervical and anogenital cancers. Understanding patterns of persistence, clearance, and re-infection is essential, as persistent infections contribute to precancerous and invasive lesions. This study evaluated hr-HPV infection dynamics and genotype specific outcomes over two years among Ethiopian women.Patients and MethodsA cohort of 893 women aged 30–49 years was followed for two years using self-collected samples for multiplexed hr-HPV genotyping by BSGP5+/6+ PCR. Women testing positive were re-evaluated at 6 and 24 months with HPV genotyping, Visual Inspection with Acetic Acid (VIA) and cytology. Persistent infection was defined as continuous HPV DNA presence over consecutive visits, while clearance indicated no detectable virus. Re-infection occurred if a cleared HPV type reappeared, or a new type was detected.ResultsAfter six months, 26.3% had persistent infections, while 73.7% cleared the infection. After two years, 13.2% experienced persistence, and 86.8% cleared their infections. Among women who tested negative at baseline, 74 were re-tested and showed hr-HPV incidence of 4.05% after 24 months. Genotype persistence rates varied, with HPV68, 82, 53, 52, and 56 showing the highest persistence after six months. After 24 months, HPV59, 68, 66, 52, and 16 had the highest persistence. Additionally, 29.9% of women at six months had abnormal cytology, including Atypical squamous cells of undetermined significance (ASCUS) and High grade squamous intraepithelial lesion (HSIL), which was 10.3% of those tested.ConclusionThe findings show that most hr-HPV infections among rural Ethiopian women cleared within two years, with varying persistence and clearance rates across HPV types. This emphasizes the need for regular monitoring and targeted prevention in high HPV prevalence populations.

Disclosure: S. Puri: None. M.Y. Roth: None. K. Madani: None. T.A. Tylee: None. M. Endo: None.Background: The Bethesda scoring system is a standardized risk assessment for malignancy based on features of thyroid FNA results. Categories range from I (nondiagnostic) to VI (malignant). This project aims to compare the presence of aggressive features of medullary thyroid cancer (MTC) between Bethesda categories. Methods: A cohort of patients at The University of Washington with a history of MTC was identified using Epic LEAF tool. Relevant data including Bethesda category, presence of lymph node metastases, cancer staging information, pre-op carcinoembryonic antigen (CEA) and calcitonin levels, and CEA and calcitonin levels at last follow up were extracted via chart review. Data was analyzed using JMP Pro 17. Wilcoxon two sample t-tests were performed, comparing data between Bethesda II/III/IV and V/VI groups. N=73 (Bethesda II=1, III=14, IV=3, V=10, VI=45). Results: Lymph node metastasis was significantly higher in Bethesda V/VI than II/III/IV [II/III/IV (N0 vs N1A vs N1B= 44% vs 11 vs 17%); V/VI (N0 vs N1A vs N1B= 20% vs 9 vs 60%)], (p=0.01). Structural disease was higher in Bethesda V/VI than II/III/IV (56% vs 27%), but not statistically significant (p=0.1). The presence of germline mutations was significantly higher in Bethesda V/VI [II/III/IV: 0% germline, 100% somatic; V/VI: 28% germline, 72% somatic (p=0.04)]. There was no statistically significant difference in tumor grading, metastases, lymphovascular invasion (LVI), and extrathyroidal extension (ETE) between Bethesda groups. Pre-op calcitonin was significantly higher in Bethesda V/VI [II/III/IV vs V/VI= 506 vs 1550, median value (p=0.02)]. There was no statistically significant difference in pre-op CEA levels, but these were higher in V/VI [II/III/IV vs V/VI= 20 vs 35, median value (p=0.39)]. CEA at the last follow-up was significantly higher in Bethesda V/VI [II/II/IV vs V/VI = 1.3 vs 6.5, median value (p=0.03)]. However, there was no statistically significant difference in calcitonin at last follow-up between Bethesda categories [II/III/VI vs V/VI= 8 vs 78, median value (p=0.09)]. Conclusion: Patients with Bethesda V/VI cytology tended to have more aggressive features of MTC such as lymph node metastases and higher tumor marker levels than those with II/III/VI cytology. Thus, initial FNA cytology may play a role in risk stratification and guiding future management of MTC.Presentation: Sunday, July 13, 2025

Penile squamous cell carcinoma (SSC) accounts for almost 10% of male cancers in high-incidence areas, although the incidence in Europe is below 1%. About half of penile SCCs arise from a precancerous high-grade squamous intraepithelial lesion (HSIL) caused by atransforming infection with human papillomavirus (HPV), most often high-risk HPV16. The HPV E6/E7 oncoproteins bind to proteins of the p53 and retinoblastoma pathways. This cell cycle disruption results in cellular accumulation/overexpression of p16, which serves as surrogate biomarker for HPV-associated carcinogenesis. The majority of HPV-independent SCCs arise in lesions of lichenoid dermatoses (lichen sclerosus and lichen planus) via rapidly progressing precancerous differentiated penile intraepithelial neoplasms (d-PeIN). These inflammation-associated, generally highly differentiated keratinized lesions commonly carry mutations in the tumor suppressor genes TP53 and CDKN2A. Missense TP53 mutations lead to accumulation of p53/agerrant p53 in the nuclei of proliferating tumor cells (nuclear overexpression), which serves as a surrogate marker for aTP53 missense mutation. About one third of HPV-independent penile SCCs arise in the absence of dermatoses and mutations in tumor suppressor genes and lack p16 and p53 overexpression. They arise via verrucous/verruciform PeIN. Correct identification of the etiology of precursor lesions is of clinical significance, as HPV-associated SCCs have better prognoses and survival rates. Moreover, the etiology is particularly relevant to the choice of treatment for the precancerous lesion. The slow progression of HSIL to invasive cancers allows time-intense surgical, destructive, or drug-based treatment options. In contrast, the precursor lesion of dermatoses-associated SCC, d‑PeIN, calls for immediate surgical resection to exclude early invasion. Guideline-conform treatment of lichenoid dermatoses reduces the cancer risk.

Disclosure: S.A. Marowa: None. S. Hossain: None. J. Delshad: None. T. Saikia: None. H. Liao: None. D. Rosenthal: None. S.C. Kumar: None.Background: The most common form of thyroid cancer is primary thyroid cancer, which includes: papillary, follicular, oncocytic (hurthle cell), anaplastic and medullary thyroid cancer. Among these, papillary thyroid cancer is the most common and metastatic disease to the thyroid is rare. Breast cancer, although one of the most commonly diagnosed malignancies, rarely metastasizes to the thyroid. The incidence of thyroid metastases identified through fine needle aspiration (FNA) is less than 0.2% (1). In this report, we present a case of metastatic mammary carcinoma to the thyroid that was initially misdiagnosed as papillary thyroid cancer in the FNA. Case Presentation: A 68 years old female with history of metastatic invasive ductal carcinoma of breast and lung cancer presented to the endocrinology clinic for evaluation of an incidental thyroid nodule identified on a chest CT scan. An ultrasound of the thyroid identified two nodules. Both categorized as TI-RADS category 2 (TR2). Typically, TR2 nodules are not considered suspicious and do not necessitate a biopsy; however, due to the size of the dominant nodule measuring 3.5 x 2.4 x 2.9 cm and the presence of underlying metastatic breast and lung cancer, further evaluation was warranted. A FNA was performed on the dominant nodule and the pathology report resulted as Bethesda category 5, indicating it was suspicious for papillary thyroid carcinoma. Following this, she was referred for total thyroidectomy. However, surgical pathology revealed metastatic mammary carcinoma. Immunohistochemical staining showed neoplastic cells that were positive for Gata-3, CK7, estrogen receptor, AE1/3, and CEA, while negative for calcitonin, TTF-1, thyroglobulin, P63, synaptophysin, and NSE. After surgery, patient was resumed on hormonal therapy and continued to be monitored by her oncology team. Conclusion: This case illustrates a significant discrepancy in outcomes between FNA and surgical pathology report where the initial FNA suggested primary thyroid cancer but surgical pathology confirmed metastatic mammary carcinoma. This indicates that a more comprehensive approach is needed regarding interpretation of FNA results in patients with complex oncological histories. Further genetic and molecular studies may provide additional insights into the behavior of such tumors and guide future management strategies. Additionally, TI-RADS may misclassify nodules that are metastatic to the thyroid rather than originating from thyroid cells, highlighting the need for clinicians to exercise caution when relying on TI-RADS in patients with known or suspected malignancies. Reference: 1.Wang Y,Zhou S,Y B,et al.Case Report and Review of Literature:Thyroid Metastases From Breast Carcinoma.Frontiers in Endocrinology.2021;12:631894.DOI: 10.3389/fendo.2021.631894.PMID: 33776925; PMCID: PMC7994513Presentation: Sunday, July 13, 2025

Disclosure: S. Saad-Omer: None. M. Stan: None. M.R. Castro: None. J. Brito: None. J.E. Hallanger-Johnson: None. M.M. Ryder: None.Background: Thyroid fine needle aspiration (FNA) is a widely utilized diagnostic tool for evaluating thyroid nodules. The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) provides a standardized framework for classifying cytologic findings and guiding management. This study retrospectively reviews thyroid FNA cases at a large academic institution to analyze the distribution of Bethesda classifications.Methods: A retrospective review was conducted of all thyroid FNA cases done in the department of Endocrinology at a large academic institution performed from January 1st 2019 to October 3rd 2023. Thyroid FNA results were divided into categories according to the Bethesda classification system, such as benign, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm (FN), suspicious for malignancy, malignancy and non-diagnostic. FNA results that were not able to be classified were labelled as other.Results: A total of 3,291 thyroid FNA cases were included in the analysis. The distribution of cases across the Bethesda categories revealed a significant proportion of benign findings, with 73.6% classified as benign. This was followed by 8.1% follicular neoplasm, 6.56% Papillary Thyroid Cancer, 6.62% Non-diagnostic, 2.4% Atypical, and 2.3% Suspicious. 0.5% of FNA results were classified as other.Conclusion: Overall our cohort was found to have similar findings in terms of benign and confirmed PTC nodules compared to recent literature; however, the rate of atypical and non-diagnostic nodules was found to be lower.Presentation: Monday, July 14, 2025

Abstract Disclosure: N. Bhuiya: None. F. Ziyadeh: None. P. Rao: None. Euglycemic diabetic ketoacidosis (EDKA) is a clinical syndrome comprised of euglycemia, ketonemia, and severe metabolic acidosis among individuals with type 1 or type 2 diabetes. With the rise of usage of sodium-glucose transporter 2 (SGLT2) inhibitors, the incidence of EDKA has increased. Without hyperglycemia at presentation, a hallmark sign of DKA, the diagnosis of EDKA can be delayed. We report a case of a 43-year-old female with a history of uncontrolled type 2 diabetes (T2D), hypertension, high-grade squamous intraepithelial lesion of the cervix status-post LEEP, and glaucoma who presented with palpitations, pleuritic chest pain, nausea, lower abdominal pain, back pain, chills and weakness for approximately 2-3 days. Of note, the patient had started empagliflozin 10mg 3 days prior to presenting to the hospital. The patient was previously on dulaglutide and metformin, however, she was only prescribed empagliflozin for current diabetes management. Laboratory tests revealed glucose 166 mg/dL, pH 7.20 on VBG, bicarbonate 9 mmol/L, anion gap 37 mmol/L, and beta-hydroxybutyrate 6.86 mmol/L, which were concerning for euglycemic DKA. Additional laboratory tests exhibited normal C-peptide levels and negative insulin antibody and glutamic acid decarboxylase (GAD). Treatment with IV insulin and IV fluids led to clinical improvement. The patient was discharged with Lantus 20 units and sliding scale insulin (SSI); empagliflozin was discontinued. This case highlights the importance of including EDKA in the differential diagnosis among patients who use SGLT2 inhibitors and present with signs and symptoms of DKA in the setting of euglycemia. Additionally, this case emphasizes that EDKA can develop within a few days of initiating a SGLT2 inhibitor even among individuals without type 1 diabetes or insulin deficiency. A delay in diagnosis and treatment of EDKA can lead to worse outcomes including death. Presentation: Monday, July 14, 2025