Journal of Pathology and Translational Medicine

Original Article

Mutational status of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): molecular analysis should be performed for NIFTPs with nuclear score 3: Ayaka Sako, Mitsuyoshi Hirokawa, Michiko Matsuse, Miyoko Higuchi, Akira Miyauchi, Takashi Akamizu, Atsushi Kawakami, Norisato Mitsutake; Received October 14, 2025 Accepted December 6, 2025 Published online February 23, 2026; DOI: https://doi.org/10.4132/jptm.2025.12.06 [Epub ahead of print]

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Abstract PDF: Background
The classification of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced to prevent the overtreatment of indolent tumors that were formerly diagnosed as non-invasive encapsulated follicular variant papillary thyroid carcinomas (NIEFV-PTCs). Although NIFTP was initially estimated to account for 10%–20% of papillary thyroid carcinomas in Western populations, its incidence is substantially lower in Asian cohorts. However, a multi-institutional Japanese study revealed that 31.0% of tumors previously diagnosed as follicular adenomas (FAs) were reclassified as NIFTPs. NIFTP diagnosis requires a nuclear score (NS) of 2–3, and according to the recent World Health Organization criteria, molecular analysis is recommended, but not mandatory, to exclude high-risk subtypes, namely cases with the BRAFV600E mutation, particularly for NS3 tumors. Methods: We performed genetic analysis on 92 archival thyroid tumor samples, including 69 previously diagnosed as FA, of which 34 remained as FA upon re-evaluation (group A) and 35 were reclassified as NIFTP with NS2 (group B). Additional 23 tumors previously diagnosed as NIEFV-PTC were reclassified as NIFTP with NS3 (group C). Results: RAS mutations were detected in 8.8%, 34.3%, and 21.7% of the tumor samples in groups A, B, and C, respectively, whereas BRAF mutations were present in 43.5% of the tumor samples in group C only. Conclusions: These findings suggest the presence of two distinct tumor subsets within NIFTP-NS3, underscoring the need for routine molecular diagnostics in NIFTP-NS3 to facilitate appropriate clinical management.

Case Study

Encapsulated Papillary Thyroid Tumor with Delicate Nuclear Changes and a KRAS Mutation as a Possible Novel Subtype of Borderline Tumor: Kenji Ohba, Norisato Mitsutake, Michiko Matsuse, Tatiana Rogounovitch, Nobuhiko Nishino, Yutaka Oki, Yoshie Goto, Kennichi Kakudo; J Pathol Transl Med. 2019;53(2):136-141. Published online January 14, 2019; DOI: https://doi.org/10.4132/jptm.2018.12.07

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10 Web of Science
6 Crossref

Although papillary thyroid carcinoma (PTC)–type nuclear changes are the most reliable morphological feature in the diagnosis of PTC, the nuclear assessment used to identify these changes is highly subjective. Here, we report a noninvasive encapsulated thyroid tumor with a papillary growth pattern measuring 23 mm at its largest diameter with a nuclear score of 2 in a 26-year-old man. After undergoing left lobectomy, the patient was diagnosed with an encapsulated PTC. However, a second opinion consultation suggested an alternative diagnosis of follicular adenoma with papillary hyperplasia. When providing a third opinion, we identified a low MIB-1 labeling index and a heterozygous point mutation in the KRAS gene but not the BRAF gene. We speculated that this case is an example of a novel borderline tumor with a papillary structure. Introduction of the new terminology “noninvasive encapsulated papillary RAS-like thyroid tumor (NEPRAS)” without the word “cancer” might relieve the psychological burden of patients in a way similar to the phrase “noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).”

Citations

Citations to this article as recorded by

The Asian Thyroid Working Group, from 2017 to 2023
Kennichi Kakudo, Chan Kwon Jung, Zhiyan Liu, Mitsuyoshi Hirokawa, Andrey Bychkov, Huy Gia Vuong, Somboon Keelawat, Radhika Srinivasan, Jen-Fan Hang, Chiung-Ru Lai
Journal of Pathology and Translational Medicine.2023; 57(6): 289. CrossRef
Whole Tumor Capsule Is Prognostic of Very Good Outcome in the Classical Variant of Papillary Thyroid Cancer
Carlotta Giani, Liborio Torregrossa, Teresa Ramone, Cristina Romei, Antonio Matrone, Eleonora Molinaro, Laura Agate, Gabriele Materazzi, Paolo Piaggi, Clara Ugolini, Fulvio Basolo, Raffaele Ciampi, Rossella Elisei
The Journal of Clinical Endocrinology & Metabolism.2021; 106(10): e4072. CrossRef
Evidence of Cooperation between Hippo Pathway and RAS Mutation in Thyroid Carcinomas
Thaise Nayane Ribeiro Carneiro, Larissa Valdemarin Bim, Vanessa Candiotti Buzatto, Vanessa Galdeno, Paula Fontes Asprino, Eunjung Alice Lee, Pedro Alexandre Favoretto Galante, Janete Maria Cerutti
Cancers.2021; 13(10): 2306. CrossRef
Capsular Invasion Matters Also in “Papillary Patterned” Tumors: A Study on 121 Cases of Encapsulated Conventional Variant of Papillary Thyroid Carcinoma
Dilara Akbulut, Ezgi Dicle Kuz, Nazmiye Kursun, Serpil Dizbay Sak
Endocrine Pathology.2021; 32(3): 357. CrossRef
Noninvasive encapsulated papillary RAS-like thyroid tumor (NEPRAS) or encapsulated papillary thyroid carcinoma (PTC)
Pedro Weslley Rosario
Journal of Pathology and Translational Medicine.2020; 54(3): 263. CrossRef
Updates in the Pathologic Classification of Thyroid Neoplasms: A Review of the World Health Organization Classification
Yanhua Bai, Kennichi Kakudo, Chan Kwon Jung
Endocrinology and Metabolism.2020; 35(4): 696. CrossRef

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