Section 3 -

Hyalinizing Trabecular Tumor Vânia Nosé Brigham and Women's Hospital, Harvard Medical School Boston , MA

Hyalinizing Trabecular Tumor Hyalinizing trabecular tumour (HTT) of the thyroid is a unique neoplasm of follicular derivation, exhibiting prominent trabecular architecture and hyaline appearance. This tumor does share some morphological and architectural similarities with paraganglioma and medullary thyroid carcinoma (MTC) as well as some nuclear features of papillary thyroid carcinoma (PTC). HTT displays a curious histologic appearance of elongated tumor cells arranged in a trabecular growth pattern, interspersed with dense, hyalinized basement membrane (BM) material. This material is present in the stroma, and electron microscopy shows characteristic accumulation that is discernible from other histologic types of BM-producing tumors. None of the PTC variants have these BM findings. Tumor cells may contain nuclei with some features of PTC, including elongation, grooves, and pseudoinclusions. In addition, rare calcifications/psammoma bodies may be present. However, these HTT cells have the characteristic staining of the cell membranes and cytoplasm for MIB-1; all HTT are strongly positive for MIB-1. There is no cell membrane or cytoplasmic MIB-1 positivity in MTC or PTC and its variants. Many round, pale-yellow, cytoplasmic inclusion bodies are present in HTT. The bodies are refractile and frequently have a microvacuolated or granular substructure. They are usually located close to the nucleus. Ultrastructurally, the inclusions are consistent with giant lysosomes, so-called "fingerprint" bodies. Descriptions exist of rare PTC with the presence of occasional yellow bodies. There are contradictory results in the literature regarding cytokeratin in HTT. The absence of immunostaining for cytokeratin 19 and high molecular weight keratins in HTT does not support the relationship between HTT and PTC. However, further confirmation of these findings is needed. Most often, the relation between HTT and PTC is that HTT can coexist with PC. Based on morphological observations, some authors hypothesize that these two entities are related. Indeed, HTT may share focal histologic features of PTC, such as psammoma body formation (rare), and nuclear features; however, these findings are not enough to postulate that HTT are a subtype of PTC. The term "hyalinizing trabecular carcinoma" has been mistakenly used in a few reports in the literature since it was there was believed that these HTT had metastasized, showed vascular invasion or invaded into the surrounding thyroid. Subsequently, the metastases appear more likely to have been PTC and not HTT. Also, some photographs and descriptions of these tumors seem more consistent with papillary carcinoma, than HTT. HTT may not have a real fibrous capsule, and therefore capsular invasion is not sufficient evidence to call these neoplasms carcinomas. RET proto-oncogene rearrangements are common in papillary thyroid carcinoma. In thyroid RET/PTC gene rearrangements are believed to be specific for PTC. However, RET/PTC rearrangement is also occasionally reported in HTT, as well as in other benign entities, including Hashimoto's thyroiditis, follicular adenomas, and hyperplastic nodules. Mixed HTT-PTC tumors were studied by RET immunohistochemistry by Papotti et al, 2000. Expression of RET was restricted to the PTC component, most likely indicating RET rearrangement as part of a progression, rather than as an initiating event. In face of these results, we do not believe that RET/PTC rearrangements found in HTT would put these tumors in the category of PTCs. In a study by Gaffney et al, 2003, galectin-3 expression was compared in a number of different thyroid neoplasms to gain insight into the biologic behavior of HTT. Galectin-3 immunostaining showed that 60% of the HTT were negative or had weak staining and 40% had strong staining. The immunophenotype of HTT, as characterized by galectin-3 expression, is intermediate between that of benign and malignant thyroid tumors. Follow-up studies revealed absence of metastatic disease in all 58 patients with HTT. These authors suggest that the variable pattern of galectin-3 expression may reflect a difference in biologic behavior between HTT and papillary thyroid carcinoma. Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions, with a particularly high prevalence in PTC. The hot-spot mutation in BRAF (V599E) is frequently detected in PTC and its variants (36-69%) in contrast to its absence in other benign or malignant thyroid lesions. Although Salvatori et al, 2005, found a 47% prevalence of RET/PTC rearrangements in 28 cases of HTT, neither BRAF nor N-ras mutations were found in any of the 28 cases studied. Moreover, no BRAF mutations were detected in 10 cases of HTT studied by Trovisco et al, 2004. Although RET/PTC, N-ras, and BRAF proteins may act along the same signaling cascade, the biological and morphological outcome of their oncogenic activation is not completely overlapping. This tumor is controversial regarding its nature and prognostic features. Is this a distinct entity? Is this a pattern of growth of a neuroendocrine neoplasm or PTC? The relationship of HTT to PTC is still to be determined, and the classification and biologic behavior of HTT is still to be clarified. In summary, HTT of the thyroid are most likely benign neoplasms or at most, a neoplasm of extremely low malignant potential, since there is no convincing evidence of malignancy. Feature Benign HTT PTC MTC Circumscription + + + + Predominant trabecular growth pattern - + - - Elongated nuclei + + + + Nuclear groove + + + Rare Intranuclear pseudo-inclusion + + + Rare Hyaline material - + - + Cytoplasmic yellow bodies - + + - Calcification/psammoma bodies - Rare + Rare Eccentric nuclear position - + - + Giant cells - + - MIB-1 membranous and cytoplasmic - + - - CK 19 +/- - or ?+ + - Galectin 3 - - to intermediate + - RET/PTC +/- +/- (2.8 - 47%) + (< 40%) - RAS - - + - BRAF - - + (30-70%) - Metastatic potential - Unknown + + Lymph node metastases - - + + Table: Comparison of morphological and molecular features of some benign thyroid lesions such as Hashimoto thyroiditis, nodular hyperplasia and adenomas, HTT, PTC and MTC Conclusions: HTT share some similarities with PTC and MTC; however, these similarities do not support a relationship between these entities nor the idea of HTT as a variant of PTC. The detection of B-RAF mutations in a thyroid follicular tumor may prove to be a valuable tool, supplementing histological examination, and allowing a differential diagnosis between PTC and HTT. From a practical standpoint, HTT fulfilling the classical morphological characteristics listed in the original paper by Carney, 1987, will behave in a benign fashion, and should be considered a benign tumor. References: LiVolsi VA. Hyalinizing trabecular tumor of the thyroid: adenoma, carcinoma, or neoplasm of uncertain malignant potential? Am J Surg Pathol. 2000;24(12):1683-4 Cheung CC, Boemner SL, MacMillan CM, Ramyar L, Asa SL. Hyalinizing trabecular tumor of the thyroid: a variant of papillary carcinoma proved by molecular genetics. Am J Surg Pathol. 2000;24(12):1622-6 Papotti M, Volante M, Giuliano A, Fassina A, Fusco A, Bussolati G, Santoro M, Chiappetta G. RET/PTC activation in hyalinizing trabecular tumors of the thyroid. Am J Surg Pathol. 2000;24(12):1615-21 Hirokawa M, Carney JA, Ohtsuki Y. Hyalinizing trabecular adenoma and papillary carcinoma of the thyroid gland express different cytokeratin patterns. Am J Surg Pathol. 2000;24(6):877-81 Hirokawa M, Carney JA. Cell membrane and cytoplasmic staining for MIB-1 in hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Pathol. 2000;24(4):575-8 Katoh R, Kakudo K, Kawaoi A. Accumulated basement membrane material in hyalinizing trabecular tumors of the thyroid. Mod Pathol. 1999 Nov;12(11):1057-61 Trovisco V, Vieira de Castro I, Soares P et al.BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol. 2004 Feb;202(2):247-51 Gaffney RL, Carney JA, Sebo TJ, et al. Galectin-3 expression in hyalinizing trabecular tumors of the thyroid gland. Am J Surg Pathol. 2003 Apr;27(4):494-8 Nakamura N, Carney JA, Jin L, et al. RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors. Lab Invest. 2005 Sep;85(9):1065-75 Salvatori G, Chiappetta G, Nikiforov YE, et al. Molecular profile of hyalinizing trabecular tumours of the thyroid: high prevalence of RET/PTC rearrangements and absence of B-raf and N-ras point mutations. Eur J Cancer. 2005;41(5):816-21