NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States

Abstract

Fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population. The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation.

A Case of Primary Mammary Analog Secretory Carcinoma (MASC) of the Thyroid Masquerading as Papillary Thyroid Carcinoma: Potentially More than a One Off

“…In sporadic papillary thyroid carcinoma, the incidence of EVT6-NTRK3 gene fusion ranges from approximately 1.2-4 % [19][20][21]. However, the prevalence may be higher in children and adolescents based on a recent small series of 28 patients aged 6-18 years with no history of radiation exposure and with ''papillary thyroid carcinoma'' whose tumors were assessed by a targeted next-generation sequencing panel (ThyroSeq version 2) revealing a 26 % rate of NTRK fusions (7/27 cases; 5 comprising the ETV6-NTRK3 fusion) [22]. Notably, the ETV6-NTRK3 fusion in the radiation and sporadic papillary thyroid carcinomas differs from the ETV6-NTRK3 fusion reported in most MASC in the exon breakpoint in the NTRK3 gene (exon 14 in thyroid tumors and exon 13 in MASC of salivary glands) [1,20,21].…”

“…Intriguingly, the MASC-like immunohistochemical findings in our patient's tumor but with breakpoints in ETV6 and NTRK3 as reported in ''papillary thyroid carcinoma'' suggest that at least some ETV6-NTRK3 ''papillary thyroid carcinomas'' may represent mammary analog secretory carcinoma of the thyroid. Although the fusion partner in NTRK fusion positive ''papillary thyroid carcinoma'' is predominantly ETV6, other fusions have been described including TPR-NTRK1 and NTRK3-unknown fusion partner [22]. Due to the low number of NTRK fusion positive ''papillary thyroid carcinomas'', it is not possible to determine the definitive relative incidence of the various NTRK fusions in these papillary appearing thyroid carcinomas.…”

“…Further descriptions of the histomorphology of these tumors are generally not provided other than to note a solid component in some cases, especially those associated with radiation exposure. Descriptions of five examples of pediatric ETV6-NTRK3 fusion positive ''papillary thyroid carcinoma'' noted a mixture of architectures typically including solid growth (present in 6/7 cases with NTRK fusion ''PTC''), sclerotic background and follicle formation (including 2/7 cases with ''diffuse follicular variant PTC''), nodular growth (4/5 cases with ETV6-NTRK3 fusions) with uncommon psammoma bodies and papillae [22]. Importantly, the studies of ETV6-NTRK3 fusion positive PTC do not provide immunohistochemical staining results of the tumors with the antibodies we used and which would be expected to distinguish true PTC from MASC (e.g.…”

“…Importantly, the studies of ETV6-NTRK3 fusion positive PTC do not provide immunohistochemical staining results of the tumors with the antibodies we used and which would be expected to distinguish true PTC from MASC (e.g. antibodies to thyroglobulin, TTF-1, mammoglobin, GATA3, or S-100 protein) [18][19][20][21][22].…”

“…Importantly, MASC originating in the thyroid, as it is not differentiating to follicular thyroid cells, would not be expected to respond to radioactive iodine therapy. Intriguingly, among five pediatric patients with ETV6-NTRK3 fusion positive ''papillary thyroid carcinomas'', Prasad and co-workers reported one patient who developed recurrent tumor in the bed of the thyroid 2 years after initial resection despite radioactive iodine therapy [22]. Possibly, NTRK fusion positve ''papillary thyroid carcinomas'', whether immunophenotypically PTC or immunophenotypically MASC, may be better treated by a specific targeted therapy, especially in aggressively behaving and/or high stage cases.…”