Primary Thyroid NUT Carcinoma With High PD-L1 Expression and Novel Massive IGKV Gene Fusions: A Case Report With Treatment Implications and Literature Review

Abstract

BackgroundNuclear protein in testis (NUT) carcinoma (NC) is a rare and aggressive undifferentiated carcinoma that typically arises from midline supradiaphragmatic structures. It is uniquely driven by a NUT gene rearrangement on chromosome 15q14. Few thyroid NCs have been reported and there are no established treatment guidelines for NUT carcinoma.MethodUltrasound-guided fine needle aspiration smear was performed for the preoperative diagnosis of thyroid lesions. Cytopathology, histology, and immunochemical staining all indicated NC. Fluorescence in situ hybridization (FISH), qRT-PCR, and next-generation sequencing (NGS) were used to analyze the genetic characteristics of NC.ResultsWe describe a rare case of thyrogenic NC in a 38-year-old male with cytological, histological, immunohistochemical, and genetic features. Cytological smears and histopathological specimens showed typical features of NC. Immunohistochemistry confirmed strong immunoreactivity with NUT, EMA, P63, TTF-1, and c-myc. CK19 was positive exclusively in sudden keratosis. No immunoreactivity was found for neuroendocrine markers. FISH was applied to isolate the NUT gene on chromosome 15q14. The NGS results revealed a BRD4-NUT gene fusion, which was further confirmed by RT-qPCR. Structural variation (SV) of NUTM1 occurred in the exon region, and the mutation site was 15q14. Moreover, BRD4 single-nucleotide variation (SNV) occurs in the 3′ UTR at mutation site 19p13.12. The PD-L1 combined predictive score was over 30%. The patient received chemotherapy, followed by programmed cell death 1 (PD-1) inhibition with camrelizumab, and died 10 months after surgery.ConclusionThyroid NC is an extremely rare and fatal malignant tumor. It is necessary to consider NC when squamous differentiation is observed cytologically or histologically. NGS is an effective tool for obtaining the final diagnosis and obtaining a better understanding of tumor pathogenesis. A large number of IGKV gene fusions in addition to the BRD4-NUT fusion may play a role in the pathogenesis and immunotherapy response of NC. Immunotherapy for NC remains to be explored due to the rarity of this aggressive malignancy.

Thyroblastoma: A DICER1‐associated embryonal neoplasm and fine needle aspiration diagnostic criteria

“…In cases with borderline features, the presence of a DICER1 hotspot mutation on molecular testing would favor thyroblastoma 19 . Other primitive neoplasms, such as Ewing sarcoma, rhabdomyosarcoma, or NUT carcinoma can have histologic overlap with the small round cell blastemal elements of thyroblastoma 43–46 . Notably, all of these primitive tumor types have specific non‐ DICER1 molecular alterations that are diagnostic.…”

“…19 Other primitive neoplasms, such as Ewing sarcoma, rhabdomyosarcoma, or NUT carcinoma can have histologic overlap with the small round cell blastemal elements of thyroblastoma. [43][44][45][46] Notably, all of these primitive tumor types have specific non-DICER1 molecular alterations that are diagnostic. As such, molecular testing will often play an important role in evaluation of thyroblastoma.…”

Drug repositioning in thyroid cancer: from point mutations to gene fusions

“…Bromodomain-containing protein 4 ( BDR4 ) binds to the chromatin, while NUT midline carcinoma family member 1 ( NUT ) recruits histone acetyltransferase ( HAT ), promoting the expression of several associated oncogenes ( 95 ). This rare fusion has also been described in some TC cases, and it is associated with high expression of CD274 ( 96 ). The prognosis is low, with an estimated overall survival of 10 months, while therapy consists of radiotherapy and standard chemotherapy for large tumors.…”

From Malignant Thyroid Teratoma to Thyroblastoma: Evolution of a Newly-recognized DICER1-associated Malignancy

“…[68][69][70][71] NUT carcinoma of the thyroid gland is also characterized by primitive high grade cells that may parallel blastema and even rarely show thyroid follicular cell differentiation. 72,73 Notably, all of these sarcomas or other primitive tumor types have specific non-DICER1 molecular alterations or lack well-developed multilineage differentiation, allowing for definitive differentiation from thyroblastoma.…”