May 2022 – Surgical Pathology

A 53-year-old man presents with left neck fullness. An ultrasound was performed demonstrating a 1.8 cm left thyroid nodule. The nodule appeared solid and hypoechoic, with macrocalcifications. His thyroid function tests were normal. This prompted an FNA of the nodule, which demonstrated cytologic features suggestive of papillary thyroid carcinoma. The patient underwent left thyroid lobectomy and isthmusectomy.

Image A
Image B
Image C
Image D
Image E

What is the most likely diagnosis?

  • Medullary thyroid carcinoma
  • Papillary thyroid carcinoma
  • Hyalinizing trabecular tumor
  • Paraganglioma

The correct answer is ...

Hyalinizing trabecular tumor.

Hyalinizing trabecular tumor (HTT) is a rare, follicular, cell-derived thyroid neoplasm with a characteristic trabecular growth pattern and hyalinization. The tumor is solid and circumscribed with a thin, irregular and uneven fibrous connective tissue capsule. Capsular, vascular, or thyroid parenchymal invasion is almost always absent. The tumor has scant to absent colloid. The neoplastic cells are medium to large, polygonal to fusiform. The oval to elongated shaped nuclei are arranged perpendicular to the long axis of the trabeculae and fibrovascular stroma. Prominent nuclear grooves, irregular nuclear contour, and numerous intranuclear cytoplasmic inclusions are usually present. Perinucleolar halos are also common (arrows in image E). Mitotic figures are uncommon. Other findings such as calcospherites (psammoma or calcific bodies) may be present. Chronic lymphocytic thyroiditis may be seen in the surrounding thyroid parenchyma.

HTT is known to share morphological and architectural similarities with paraganglioma and medullary thyroid carcinoma. It also shares the nuclear features of papillary thyroid carcinoma (PTC). By immunohistochemistry, HTT neoplastic cells are positive for TTF-1, thyroglobulin, PXA-8, CK-PAN, and CK7. Although HTT and PTC may show overlapping immunoreactivity for TTF-1, thyroglobulin and PXA-8, the distinctive cell membrane and cytoplasmic reactivity for Ki-67 (MIB-1) (compared to nuclear staining in PTC), and the lack of diffuse positivity for HBME-1 and galectin-3 staining favor HTT. Furthermore, HTT is shown to harbor recurrent PAX8-GLIS1 or PAX8-GLIS3 gene fusions, while negative for BRAF and RAS gene mutations which may be seen in PTC. HTT neoplastic cells show negative immunoreactivity to calcitonin, chromogranin, pCEA, and S100 protein aiding in its differentiation from medullary thyroid carcinoma and paragangliomas (see below).

Medullary thyroid carcinoma is an invasive tumor, often with multiple growth patterns. It lacks colloid. Amyloid can mimic hyalinization but will be Congo red positive. Medullary thyroid carcinoma is positive for calcitonin, chromogranin, keratin, and pCEA, while negative for thyroglobulin.

Papillary thyroid carcinoma has an invasive papillary and possibly follicular growth pattern. Extensive intratrabecular stromal hyalinization is very rare. Overlapping nuclear features such as nuclear grooves and intranuclear cytoplasmic inclusions can be present in both PTC and HTT.  PTC is strongly and diffusely immunoreactive with keratin, CK7, thyroglobulin, TTF-1, CK19, HBME-1, galectin-3, and MSG1 (CITED-1). BRAF gene mutations are the most common genetic alterations. PAX8-GLIS3 seen in HTT is not present in PTC.

Paraganglioma: Histology alone may overlap extensively with HTT, although hyalinization is not usually seen in paragangliomas. By immunohistochemistry, paragangliomas are positive for chromogranin, synaptophysin, and S100 protein (sustentacular cells), while the neoplastic cells are negative for keratin.


  1. Carney, J. Aidan MD, PhD, FRCPI, FRCP*; Hirokawa, Mitsuyoshi MD, PhD†; Lloyd, Ricardo V. MD, PhD*; Papotti, Mauro MD‡; Sebo, Thomas J. MD, PhD* Hyalinizing Trabecular Tumors of the Thyroid Gland are Almost all Benign, The American Journal of Surgical Pathology December 2008; Volume 32, Issue 12, pages 1877-1889 doi:10.1097/PAS.0b013e31817a8f1b
  2. 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;14(3):778-784. doi:10.1007/s12105-019-01083-5
  3. Howard BE, Gnagi SH, Ocal IT, Hinni ML. Hyalinizing trabecular tumor masquerading as papillary thyroid carcinoma on fine-needle aspiration. ORL J Otorhinolaryngol Relat Spec. 2013;75(6):309-13. doi: 10.1159/000355291. Epub 2013 Oct 2. PMID: 24107636.
  4. Gowrishankar, S., Pai, S.A. and Carney, J.A. (2008), Hyalinizing trabecular carcinoma of the thyroid gland. Histopathology, 52: 529-531.
  5. Nosé V, Volante M, Papotti M. Hyalinizing trabecular tumor of the thyroid: an update. Endocr Pathol. 2008;19(1):1-8. doi:10.1007/s12022-007-9002-2
  6. Marchiò C, Da Cruz Paula A, Gularte-Merida R, et al. PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid. Mod Pathol. 2019;32(12):1734-1743. doi:10.1038/s41379-019-0313-x

Mazen Osman, M.B., B.Ch.
Resident, Anatomic and Clinical Pathology
Mayo Clinic

Anja Roden Profile

Anja Roden, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education

This post was developed by our Education and Technical Publications Team.