Clinical and Morphologic Features of ETV6-NTRK3 Translocated Papillary Thyroid Carcinoma in an Adult Population Without Radiation Exposure

Abstract

The ETV6-NTRK3 translocation characterizes a subset of radiation associated and pediatric papillary thyroid carcinomas (PTCs). We now describe the clinicopathologic features of ETV6-NTRK3 translocated PTC in an adult population without radiation exposure. Twelve cases were identified by next-generation sequencing (ThyroSeq version 2). The mean patient age was 37 years with a female predilection (10:2). Preoperative fine needle aspiration was performed on 6 patients of which 4 were classified as "malignant," whereas 2 were classified as "follicular lesion of undetermined significance." One third (4/12) of patients demonstrated extrathyroidal extension and one half of patients (5/10) demonstrated lymph node metastases. One patient presented with brain metastasis. Tumors typically (8/12) demonstrated an admixture of follicular and papillary patterns and were usually infiltrative and multinodular (6/12 cases). Tumors often showed clear cell or oncocytic foci and demonstrated overt nuclear features of PTC, though characteristically, interspersed bland areas were common, even in metastases. Cytoplasmic vacuolization resembling that of mammary analog secretory carcinoma was also common but focal. TTF-1 was positive and S100 was negative in all tested cases confirming a thyroid phenotype. Unique morphologies included glomeruloid follicles, reverse polarization of nuclei. Survey of the TCGA datasets revealed similar findings. Thus, ETV6-NTRK3 translocated PTC are locoregionally aggressive and can metastasize distantly. They are characterized by mixture of papillary and follicular architecture and may show cytoplasmic vacuolization akin to other ETV6 translocated carcinomas. Although nuclear features are typically overt, interspersed bland regions may cause diagnostic difficulty in metastatic sites, and may explain discordance on fine needle aspiration.

Figure 1

Typical growth pattern and architecture in ETV6-NTRK3 translocated PTC. a) Tumors are permeative in a multinodular fashion (H&E, 40×). b) Tumors typically demonstrate a mixture of papillary (bottom) and follicular (top) growth patterns (H&E, 200×).

Figure 2

ETV6-NTRK3 translocated PTC with a predominant papillary growth pattern. a) Papillae are arborizing and tightly packed (H&E, 40×). b) This tumor also demonstrates psammoma bodies (H&E, 200×).

Figure 3

Encapsulated predominantly follicular patterned tumors were rare. a) This encapsulated tumor shows only a sprinkling of foci, mainly underneath the capsule, with nuclear features of papillary thyroid carcinoma (H&E, 40×). b) Follicles with diagnostic nuclear features are interspersed between bland follicles with attenuated epithelium (H&E, 200×).

Figure 4

In two cases follicles coalesced into glomeruloid/anastomosing foci (H&E, 100×).

Figure 5

Discordant morphology in between primary and metastasis in Case 7. a) Primary tumor shows fairly obvious nuclear enlargement, clearing and membrane irregularities (H&E, 200×). b) The metastasis to the brain, on the other hand, shows bland nuclei (H&E, 200×).

Figure 6

Additional characteristic cytonuclear features in ETV6-NTRK3 translocated PTC. a, b) Scattered clear cell foci are noted within all tumors (H&E, 20×, 200×). c) Oncocytic change was fairly common as well, and in some cases tumor nuclei lining follicles demonstrated a “reverse polarization.” (H&E, 400×).

Figure 7

Other features in ETV6-NTRK3 translocated PTC. a) These tumors bear superficial resemblance to salivary mammary analog secretory carcinomas (H&E, 100×). b) However, TTF-1 is uniformly positive (100×), and c) S100 is uniformly negative (100×). d) Though most patients were euthyroid, chronic lymphocytic thyroiditis was common in the background thyroid parenchyma (H&E, 40×).

Figure 8

HBME-1 and Galectin-3 staining profile in Case 7. a) HBME-1 staining is heterogeneous and attenuated to negative in areas without overt nuclear features of papillary thyroid carcinoma (200×). b) Galectin-3 however shows diffuse staining, both cytoplasmic and nuclear (200×).

Figure 9

TCGA case morphology. a) Despite limited review of a representative virtual slide reverse polarization of nuclei was noted in two cases with an ETV6-NTRK3 translocation (case TCGA-E8-A438-01 shown here). b) NTRK3-RBPMS translocated case showing no significant unique morphology with perhaps the exception of vaguely anastomosing follicles (case TCGA-ET-A39L-01).