Seven-case study maps the morphology of ETV6::NTRK3-fused thyroid cancer

Papillary thyroid carcinoma is the most common form of thyroid cancer, and its incidence is rising worldwide. Yet for one genetically defined subset of these tumors—those carrying an ETV6::NTRK3 gene fusion—large-scale data on microscopic appearance have been scarce.

The research team collected seven papillary thyroid carcinoma samples in which ETV6::NTRK3 gene fusion had been detected, and every case underwent both histopathological and cytopathological examination. The patients were young on average: the mean age in the study was 33 years, and women far outnumbered men, with a female-to-male ratio of 6:1. The tumors showed a slight preference for one side of the gland, with lesions located in the right lobe in 71.43 percent of cases.

Under the microscope, the tumors displayed a consistent architectural signature. All seven cases exhibited a multinodular infiltrative growth pattern, meaning the cancer spread through the thyroid as multiple nodules rather than a single circumscribed mass. In five cases, accounting for 71.43 percent of the series, follicular architectures dominated, though these were accompanied by papillary, solid, or hobnail structures. One case, designated Case 4, stood out by showing a purely follicular-like growth pattern, lacking the papillary formations that give classic papillary thyroid carcinoma its name.

The disease was not confined to the thyroid in most patients. Multifocal lymph node metastases were observed in four of the seven cases, or 57.14 percent, with the largest diameter of the metastatic foci ranging from 0.9 to 1.3 centimeters. The surrounding thyroid tissue also told a story: chronic lymphocytic thyroiditis was present in the background thyroid of five cases, while nodular goiter was seen in two.

The cytopathological findings, derived from cell samples rather than tissue sections, added a complementary layer of detail. Tumor cells were distributed in small sheets or clusters, and all cases showed nuclear elongation along with thickening or irregularity of the nuclear membrane—features that overlap with the nuclear changes pathologists rely on to diagnose papillary thyroid carcinoma in general.

Other cytological features appeared in most but not all cases. Intranuclear pseudoinclusions, a hallmark of papillary thyroid carcinoma, were observed in six cases, while nuclear grooves were present in five. Four cases showed cells with abundant cytoplasmic content, three of which displayed eosinophilic, or pink-staining, cytoplasm. The remaining three cases instead demonstrated an increased nuclear-to-cytoplasmic ratio, a feature that can push diagnosticians toward different considerations.

Cell-embedded paraffin sections, prepared from the cytology material, revealed additional architecture in individual cases: follicular-like structures were identified in Case 1 and papillary-like structures in Case 2, each representing one of the seven cases in the series.

The authors conclude that the study uncovered the histological and cytopathological features of papillary thyroid carcinoma with ETV6::NTRK3 gene fusion. While this subset shares some morphological characteristics with classic papillary thyroid carcinoma, it also exhibits distinct morphological alterations that could complicate diagnosis. Because the series comprises only seven patients, the team emphasizes that further analysis with larger sample sizes is warranted to enhance diagnostic accuracy and differentiation, thereby reducing the risk of misdiagnosis or missed diagnosis. As an early-shared, peer-reviewed accepted article, the findings are citable but subject to further editorial refinement before the final version of record appears.

Subject of Research: Morphological features of papillary thyroid carcinoma with ETV6::NTRK3 gene fusion

Article Title: Clinicopathological analysis of seven cases of papillary thyroid carcinoma with ETV6::NTRK3 gene fusion

Article References: Chen, H., Guo, C., Liu, S., & Chen, S. (2026). Clinicopathological analysis of seven cases of papillary thyroid carcinoma with ETV6::NTRK3 gene fusion. Diagnostic Pathology. https://doi.org/10.1186/s13000-026-01867-8

Image Credits: AI Generated

DOI: 10.1186/s13000-026-01867-8

Keywords: papillary thyroid carcinoma, ETV6::NTRK3, gene fusion, histopathology, cytopathology, thyroid cancer, lymph node metastasis, chronic lymphocytic thyroiditis, Diagnostic Pathology, diagnostic accuracy, Clinicopathological, analysis