The patient was a healthy 43-year-old female without previous history of thyroid illness and no family history suggestive of thyroid-related disorders. She had no prescribed medications at the time of presentation. In 2021, she noticed a swelling at the right side of the neck. Ultrasound revealed a 2.9 × 2.3 × 2.1 cm nodule in the right thyroid lobe as well as an enlarged right-sided lymph node in region IV. The subsequent fine-needle aspiration cytology (FNAC) examination of the primary lesion showed epithelial cells with nuclear grooves and pseudo-inclusions, consistent with PTC (Bethesda VI). FNAC from the lateral lymph node displayed epithelial cells with nuclear grooves and pseudo-inclusions, positive for TTF-1, consistent with metastatic PTC. The patient was planned for a total thyroidectomy with central node resection (region VI) along with a right-sided region II-IV modified neck dissection.
The histological examination of the thyroid gland revealed a right-sided, multifocal tumor with predominant papillary growth, with the largest focus measuring 30 mm (Fig. 1A). The majority of tumor cells exhibited an eosinophilic cytoplasm with cells three times taller than wide, and tumor nuclei were enlarged, with crowding, nuclear folds and pseudo-inclusions. The tumor was positive for the V600 mutation-specific BRAF antibody (BRAF1) (Fig. 1B). Approximately 50% of tumor cells showed thyroglobulin immunoreactivity, and the Ki-67 proliferation index was 5.6%. No vascular invasion or extrathyroidal extension was noted. The final diagnosis was tall cell variant PTC (TCV-PTC). Intriguingly, a 12 mm follicular thyroid tumor was observed in the ipsilateral lobe containing areas with capsular invasion, and the lesion was diagnosed as a minimally invasive FTC (miFTC) (Fig. 1C-1D). This lesion was negative for BRAF1, and the Ki-67 index was 3%. Moreover, a 6 mm follicular hyperplastic nodule was seen, as well as a 3 mm non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (data not shown).
In the central compartment, 13 lymph nodes were identified, two of them containing metastatic PTC foci. The largest metastatic deposit measured 4 mm, and no extranodal extension was noted. Less than 5% of the cells expressed thyroglobulin. In the lateral compartment, 12 lymph nodes were found, of which one displayed a metastatic PTC focus measuring 1 mm (Fig. 2A). In a separate lymph node, a 15 mm area with micro-follicular patterned cells with central colloid was observed (Fig. 2B). No extranodal extension was observed. The nuclei were small, round and displayed evident nucleoli, but lacked PTC associated nuclear changes (Fig. 2C). Thyroglobulin immunoreactivity was widespread, and the BRAF1 staining was negative. The Ki-67 index was well below 1%.
Given the finding of thyroid-derived, non-PTC tissue in a lateral lymph node, two options were discussed. The finding could represent either ectopic thyroid tissue entrapped within a lymph node, or a lateral lymph node metastasis of the miFTC detected in the right thyroid lobe. However, to our knowledge, lateral aberrant thyroid tissue is a rarity and has only been described in single case reports, and a lateral lymph node metastasis from the 12 mm miFTC was thus favored, although this phenomenon is also acknowledged as an exceptional event. The findings were in contrast to the previous FNAC report suggestive of metastatic PTC, but following re-investigation of the cytological preparations, this former biopsy was considered to derive from the node exhibiting metastatic FTC. To determine the nature of this 15 mm focus and its relation to the miFTC from a molecular standpoint, we extracted DNA from representative paraffin blocks and performed a targeted next-generation sequencing (NGS) analysis using the Oncomine Childhood Cancer Research Assay (Thermo-Fisher Scientific, Waltham, MA, USA), which has been validated for clinical use in our department [6]. The NGS analysis pinpointed a p.Q61R missense NRAS mutation in both the primary miFTC as well as the lateral lymph node deposit (Fig. 2D). This variant is an oncogenic mutation in both papillary and follicular thyroid cancer, and given the shared molecular phenotype, the final diagnosis was a 15 mm lateral lymph node metastasis of FTC. We also investigated the primary miFTC for TERT promoter mutations using highly sensitive digital droplet PCR (ddPCR), an analysis that has proven superior to conventional Sanger sequencing in identifying these risk mutations in follicular thyroid tumors [7]. However, the miFTC was wildtype at both position C228 and C250 of the TERT promoter.
The final histopathology report was signed out as multifocal TCV-PTC, largest focus 30 mm with a synchronous 12 mm miFTC in the ipsilateral lobe, both with lateral lymph node metastases. The pTNM was pT2(m)N1b and pT1bN1b respectively, and surgical margins were negative for both lesions. The patient was post-operatively investigated for a remaining right-sided lymph node enlargement visualized via ultrasound investigation, but the ensuing cytological investigation was negative.
The patient was subsequently discussed at a postoperative multidisciplinary conference. According to the Swedish national guidelines for thyroid cancer, the patient should have been offered 3.7 GBq radioiodine (RAI) as an ablation dose, due to the N1b status. However, the conference suggested the patient to receive 5.4 Gbq RAI, which was based on the tall cell variant found, and the fact that both thyroid cancer components had shown ability to metastasize. The American Thyroid Association (ATA) guidelines would classify the FTC component in our case as “low to intermediate risk” given the current N1b staging, thus suggesting that RAI should be considered, and most often favored due to higher risk of persistent or recurrent disease [1]. Following RAI, an ensuing whole-body scan was negative, and both unstimulated and TSH-stimulated measurements of serum thyroglobulin were < 0.2 µgram/L (ref: < 1 µgram/L for thyroidectomized patients), and serum thyroglobulin antibody levels were < 20 kU/L (ref: < 40 kU/L). The patient is currently prescribed 125 µg levothyroxine daily, with free serum T4 levels at 25 pmol/L (ref: 12–22 pmol/L), T3 at 5.8 pmol/L (3.1–6.8 pmol/L) and TSH at 0.2 mU/L (ref: 0.3–4.2 mU/L). According to the ATA guidelines, our patient thus exhibits excellent response [1]. She is alive and well, although monitored by our endocrinologists.
