Diagnosis and Discussion - Case 1128

Final Diagnosis

HYALINIZING TRABECULAR TUMOR

Discussion

Hyalinizing trabecular tumor (HTT) is a follicular cell-derived neoplasm composed of large trabeculae of elongated/polygonal cells with hyaline cytoplasm admixed with intra-trabecular hyaline material (1). HTTs represent <1% of all thyroid neoplasms. HTTs have a female predominance with a mean age of 50 years (2). In a case series of 119 HTTs, only 1 developed metastasis (2).

HTTs can be difficult to diagnose by morphology alone and because some of the features may resemble thyroid tumors, including papillary thyroid carcinoma (PTC), follicular adenoma (FA), medullary thyroid carcinoma (MTC) and paragangliomas (2,3). Because of the overlapping features of nuclear grooves, intranuclear cytoplasmic inclusions and vesicular chromatin, HTTs must be separated from PTC. However, intratrabecular hyalinization is extremely rare in PTC. In addition, PTCs often show invasive growth, have a papillary or follicular architecture and have psammoma bodies. Follicular adenomas show intertrabecular, perivascular stromal hyalinization, but lack the perpendicular arrangement of nuclei, grooves and pseudoinclusions more common in HTT. MTCs can have a multitude of growth patterns but will have amyloid rather than hyalinization and can be confirmed with calcitonin, chromogranin and CEA staining. Paragangliomas overlap with HTTs, but can be separated using chromogranin, synaptophysin and S100 immunohistochemical staining.

Table 1
Table 1. Rossi et al; Head Neck Pathology, 2020.
Figure 1
Figure 1. Nikiforova et al; Thyroid, 2019.

Nikiforova et al. was the first to investigate 14 cases of HTT by next generation sequencing and other techniques and revealed that 13 out of the 14 cases were positive for a PAX8-GLIS3 fusion and one was positive for a PAX8-GLIS1 fusion by RNA sequencing (4). Of the 14 samples, no BRAF, RAS, or RET/PTC mutations or other driver fusions were identified. In the case of the PAX8-GLIS1 fusion, the fusion point of the chimeric transcript was between exon 2 of the PAX8 gene and exon 2 of GLIS1 (Fig. 1A). PAX8 is located on chromosome 2q14.1 and GLIS1 on chromosome 1p32.3, indicating that the fusion is a result of an inter-chromosomal rearrangement. The fusion was confirmed by RT-PCR and Sanger sequencing (Fig. 1C). Next, to confirm the fusions at the chromosomal level, fluorescence in situ hybridization (FISH) was performed with DNA probes corresponding to the PAX8 and GLIS3 and PAX8 and GLIS1 chromosomal regions. The hybridized tumor cell nuclei demonstrated one pair of fused signals in the majority of cells, confirming the occurrence of interchromosomal rearrangements leading to PAX8–GLIS3 and PAX8–GLIS1 fusions. (Fig. 1D and E) Marchiò et al confirmed that the PAX8-GLIS3 fusions were pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid by either RNA-sequencing, whole-exome sequencing or targeted massively parallel sequencing the 16 cases of HTTs they found. Conversely, no PAX8-GLIS gene fusions were detected in a cohort of 237 control thyroid neoplasms, including 15 highly resembling HTTs from a morphology standpoint (5).

PAX8 is a paired box transcription factor, which is highly expressed indifferentiated thyroid follicular cells and required for normal thyroid development and function. GLI-similar 1 and 3 (GLIS1 and GLIS3) belong to a family of the GLI-similar zinc finger transcription factors that can act either as activators or repressors of gene transcription, and in thyroid, GLIS3 is known to be an important regulator of thyroid hormone biosynthesis. GLIS1 and GLIS3 share a highly homologous DNA-binding domain that consists of five zinc finger motifs. The DNA-binding domain is coded by exons 4–6 of GLIS3 and exons 3–5 of GLIS1. The PAX8– GLIS3 and PAX8–GLIS1 fusions juxtapose exon 3 of GLIS3 or exon 2 of GLIS1 in-frame and downstream of exon 2 of PAX8. As a result, the chimeric transcripts should be regulated by the PAX8 gene promoter and preserve the zinc-finger containing DNA-binding domains of both GLIS genes. The predicted structure of PAX8–GLIS3 and PAX8–GLIS1 transcripts was confirmed by RNA-Seq data.

References

  1. Volante M, Erickson LA, Tallini G, et al. Hyalinizing trabecular tumor. In: WHO Classification of Tumours Editorial Board. Endocrine and neuroendocrine tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 2024 03 15]. (WHO classification of tumours series, 5th ed.; vol. 10). Available from: https://tumourclassification.iarc.who.int/chapters/53.
  2. Carney JA, Hirokawa M, Lloyd RV, Papotti M, Sebo TJ. Hyalinizing trabecular tumors of the thyroid gland are almost all benign. Am J Surg Pathol. 2008 Dec;32(12):1877-89. doi: 10.1097/PAS.0b013e31817a8f1b. PMID: 18813121.
  3. Rossi ED, Papotti M, Faquin W, Larocca LM, Pantanowitz L. The Diagnosis of Hyalinizing Trabecular Tumor: A Difficult and Controversial Thyroid Entity. Head Neck Pathol. 2020 Sep;14(3):778-784. doi: 10.1007/s12105-019-01083-5. Epub 2019 Sep 30. PMID: 31571046; PMCID: PMC7413943.
  4. Nikiforova MN, Nikitski AV, Panebianco F, Kaya C, Yip L, Williams M, Chiosea SI, Seethala RR, Roy S, Condello V, Santana-Santos L, Wald AI, Carty SE, Ferris RL, El-Naggar AK, Nikiforov YE. GLIS Rearrangement is a Genomic Hallmark of Hyalinizing Trabecular Tumor of the Thyroid Gland. Thyroid. 2019 Feb;29(2):161-173. doi: 10.1089/thy.2018.0791. PMID: 30648929; PMCID: PMC6389773.
  5. Marchiò C, Da Cruz Paula A, Gularte-Merida R, Basili T, Brandes A, da Silva EM, Silveira C, Ferrando L, Metovic J, Maletta F, Annaratone L, Pareja F, Rubin BP, Hoschar AP, De Rosa G, La Rosa S, Bongiovanni M, Purgina B, Piana S, Volante M, Weigelt B, Reis-Filho JS, Papotti M. PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid. Mod Pathol. 2019 Dec;32(12):1734-1743. doi: 10.1038/s41379-019-0313-x. Epub 2019 Jul 4. PMID: 31273314; PMCID: PMC7442035.