Yoichiro Okubo

PURPOSE: Most thyroid cancers are initiated by alterations activating the mitogen-activated protein kinase (MAPK) pathway and progress via additional genomic events. Because papillary thyroid carcinoma (PTC) generally has a favorable prognosis and rarely advances, knowledge about later-acquired genomic alterations and their impact on prognosis is limited. MATERIALS AND METHODS: This study is a real-world database study using a nationwide database that contains clinical data and comprehensive genomic profiling (CGP) test results. We investigated gene alterations and their impact on prognosis in advanced PTC. RESULTS: The study included 322 patients with advanced papillary carcinoma who underwent CGP tests for drug selection between June 2019 and April 2024. Metastases were present in 96% of cases, and 70% received systemic therapy. The most common genomic abnormalities were mutations in the TERT promoter and BRAF . BRAF alterations were mutually exclusive with RBM10 and other MAPK pathway genes such as RET, NRAS, and NTRK1 , but co-occurred with TERT and AKT1 . The MAPK pathway had the highest frequency of alterations (96%), followed by the phosphoinositide 3-kinase (PI3K; 23%), cell cycle (13%), and p53 (11%) pathways. Survival analysis showed that alterations in PTEN and CDKN2A were independent poor prognostic factors. Patients harboring alterations in the PI3K or cell cycle pathway showed significantly shorter overall survival. CONCLUSION: Our study clarified the frequency, co-occurrence, and exclusivity of gene alterations in advanced PTC. Alterations in the PI3K or cell cycle pathways are linked to poor prognosis, and therapies targeting these pathways may warrant further investigation.

Invasive stratified mucin-producing carcinoma (ISMC) of the uterine cervix can masquerade as non-keratinizing squamous cell carcinoma (SCC) on small biopsies because it often grows as solid nests with minimal gland formation and little or no keratinization, and may show patchy cytokeratin 5/6 (CK5/6) positivity. We report a 44-year-old woman whose outside cervical biopsy was interpreted as SCC. Repeat biopsy showed SCC-like solid nests without keratinization and patchy CK5/6 positivity, but p40 and p63 were negative and periodic acid-Schiff with diastase (D-PAS) demonstrated diastase-resistant intracytoplasmic mucin within tumor nests. Radical hysterectomy revealed a human papillomavirus (HPV)-associated endocervical adenocarcinoma with a predominant ISMC component, lymphovascular invasion, and nodal metastases. This case highlights a practical diagnostic pitfall and supports a minimal, reproducible workup for p16 block-positive, SCC-like biopsies: p40/p63 plus a mucin stain (D-PAS and/or Alcian blue), with PAX8 as needed. Funding: Japan Society for the Promotion of Science (JSPS) KAKENHI [25 K10294].

Molecular testing in thyroid nodules and papillary thyroid carcinoma (PTC) is not required for every case, but it becomes clinically important when the result may influence diagnostic confidence, surgical planning, including the extent of surgery, or systemic therapy options. Representative scenarios include indeterminate thyroid cytology, clinically advanced or metastatic disease, and recurrent or progressive PTC. In these settings, the key question is not simply whether a common hotspot mutation is present, but whether clinically relevant drivers, including RET and NTRK fusions, have been adequately assessed. Fusion-inclusive molecular testing is preferable when molecular information is required for thyroid nodules or PTC, particularly when the clinical question includes the possibility of a fusion-driven tumor. However, in routine practice, limited or mutation-focused assays, such as BRAF V600E testing or hotspot DNA panels, may already have been performed because of limitations in access, reimbursement, specimen availability, or institutional workflow. Negative results from such assays can be misread as definitive exclusion of clinically relevant fusions, despite pre-analytic constraints and incomplete fusion coverage. This Correspondence does not advocate a hotspot-first workflow, nor does it propose serial add-on testing as a preferred strategy. Rather, we propose a pragmatic “panel-negative” communication and decision-making framework for situations in which limited testing has already been performed and morphologic or clinical suspicion for fusion-driven PTC persists. The approach emphasizes (i) selecting a thyroid-appropriate molecular assay from the outset whenever feasible, (ii) explicitly documenting residual suspicion and the scope of the performed assay in pathology reports, (iii) using pan-TRK immunohistochemistry only as an optional triage tool rather than a rule-out test, and (iv) considering RNA-based or other fusion-optimized assays only when the original clinical question remains unresolved and the result is clinically relevant. This framework is intended to reduce false reassurance from negative limited panels while reinforcing the need for appropriate molecular testing in the correct clinical scenario.

Cribriform pattern and intraductal carcinoma of the prostate are recognized adverse histological features, yet their prognostic value in treatment‐naïve metastatic disease remains uncertain. We conducted a single‐center retrospective study of 183 biopsy‐proven prostate carcinomas (105 with metastatic castration‐sensitive prostate carcinoma and 78 non‐metastatic high‐grade cases) diagnosed between 2017 and 2024. Cribriform pattern, intraductal carcinoma of the prostate, and coagulative tumor necrosis were recorded per core and summarized as patient‐level binary status and as semiquantitative proportions per cancer‐positive core. Two multivariable logistic regression models (binary and semiquantitative) were fitted, and receiver operating characteristic (ROC) analysis evaluated the discriminatory performance of the cribriform proportion. Cribriform pattern and intraductal carcinoma of the prostate were more frequent in metastatic castration‐sensitive prostate carcinoma. In the semiquantitative model, the cribriform proportion remained independently associated with metastatic status [odds ratio (OR) 1.29, 95% CI 1.07–1.55, p = 0.008; per 1.0 increase in the proportion, equivalent to OR 1.03 per 10%‐point increase], whereas necrosis remained significant only in the binary model. The cancer‐positive core rate and a lower total number of biopsy cores were predictive in both models, whereas prostate‐specific antigen, intraductal carcinoma of the prostate, and Grade Group composition were not independent predictors. ROC analysis for the cribriform proportion yielded an area under the curve of 0.704, with a Youden Index cut‐off of 0.445 (approximately half of cancer‐positive cores), corresponding to a sensitivity of 57.1% and a specificity of 75.6%. These findings indicate that semiquantitative reporting of cribriform pattern – expressed as the proportion of cancer‐positive cores – adds discriminatory information for metastatic status at presentation and could complement binary reporting in high‐grade disease. From a clinical perspective, such evaluation may refine risk stratification at diagnosis and support treatment intensification strategies in very‐high‐risk patients.

A 65‐year‐old male presented to our hospital with a complaint of a left cervical mass. The left supraclavicular lymph node was enlarged, measuring 77 mm, and biopsy results confirmed metastasis of papillary thyroid carcinoma (PTC). The left supraclavicular lymph node extended to the upper mediastinum and invaded the internal jugular and subclavian veins, with suspicion of common carotid and subclavian artery invasion. Surgical resection was deemed infeasible. The Oncomine Dx Target Test system, a gene panel test using a next‐generation sequencer, of the metastatic lymph node was positive for RET fusion ( CCDC6-RET ), and selpercatinib treatment was initiated. After 4 months, the tumor reduced in size, and surgery was performed. The postoperative course was uneventful, with ongoing follow‐up. This case is a successful case of neoadjuvant chemotherapy for RET fusion‐positive PTC with local regional progression.