Thyroid Follicular Cell-derived Carcinomas in a Background of Multiple Adenomatous Nodules Leading to a Diagnosis of PTEN Hamartoma Tumor Syndrome in an Adult Patient With a Novel RECQL4 Mutation

Case Report

The patient was a 31-year-old male with a long-standing history of thyroid enlargement. At 14 years old, he had thyroid gland enlargement and was sent for a thyroid gland fine needle aspiration (FNA). It was diagnosed as benign. He presented for evaluation of difficulty breathing at rest in certain positions and an inability to rotate his neck in certain positions. Physical exam documented an enlarged left thyroid gland lobe and macrocephaly. No penile freckling, generalized skin pigmentation or papillomas were identified. Ultrasound examination and computed tomography scans of the neck showed an enlarged left thyroid gland lobe containing a 10 cm hypervascular, heterogeneous appearing mass (Figure 1A and B). Serologies showed normal T4 free (1.2 ng/dl) and TSH (1.6 mIU/ml) levels. FNA of the left thyroid gland mass was interpreted as Bethesda II (benign thyroid nodule). For symptomatic relief, a left hemithyroidectomy was performed.

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Figure 1.

Minimally invasive follicular thyroid carcinoma. A and B) Computer tomography scans show a 10 cm left thyroid gland mass (T) (A, Axial; B, Sagittal). C) Grossly, the left hemithyroidectomy specimen shows an encapsulated mass with heterogeneous cut surface. D) Microscopically, H&E stained section shows tumor capsular invasion (arrow) (100×).

The macroscopic hemithyroidectomy showed a 10 cm encapsulated mass with a heterogeneous and hemorrhagic cut surface, along with a calcified center (Figure 1C). The tumor-to-capsule-to-adjacent parenchymal interface was entirely submitted for microscopic evaluation in 93 blocks. Microscopically, a well-formed tumor capsule was identified, with smooth muscle-walled vessels within the fibrous connective tissue, helping to support the presence of a true capsule. No areas of lymphatic or vascular invasion were identified, with only capsular invasion (Figure 1D) identified in four areas. The tumor was arranged in a follicular architecture with easily identified colloid throughout. There were no nuclear features of PTC. There was no tumor necrosis and no increased mitoses. These changes supported a diagnosis of minimally invasive FTC. In addition, there was a microscopic focus (0.2 mm) of classical PTC (on slide 78), showing all of the characteristic nuclear and architectural features of PTC. The margins were free from tumor. It was the background non-neoplastic thyroid gland parenchyma that was of note for about 50 adenomatous (hamartomatous) nodules that ranged from 0.2 to 5 mm. These nodules were cellular, showing a monotonous follicular architecture with nuclei that were round and regular with nuclear hyperchromasia. These nodules were quite different from the surrounding parenchyma. With such tight, well-formed nodules lacking any fibrous connective tissue capsules and having a general monotony to them, raised the possibility of a PTEN or DICER1 abnormality. Immunohistochemistry for PTEN was performed, and showed nuclear loss of PTEN in the FTC (Figure 2A) and in the hamartomatous nodules randomly tested from the submitted parenchyma (Figure 2B-D). The PTC was not identified in the immunohistochemistry slide as it was so small. The pathology diagnoses included a minimally invasive FTC, which based on a tumor size of 10×8×4.7 cm, was placed in the pT3a AJCC stage, with “M” used to designated multifocal tumors (the PTC), along with loss of PTEN suggested a germline alteration in this gene and possible association with PHTS. Further genetic consultation and counselling resulted in molecular testing and completion thyroidectomy. The completion thyroidectomy specimen showed no additional malignancy, but demonstrated about 60 adenomatous/hamartomatous nodules, similar to the contralateral side. The patient recovered well after surgery and was without evidence of disease 6 months after surgery.

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Figure 2.

PTEN immunohistochemistry in the follicular thyroid carcinoma and adenomatous nodules. A) PTEN immunohistochemical loss in the follicular carcinoma cells. B and C) H&E stained sections show multiple adenomatous nodules, some with fibrosis (B, 100×; C, 200×). D) PTEN immunohistochemical loss in the adenomatous nodule, while the adjacent thyroid parenchyma shows an intact reaction (arrows indicating the transition, 200×; inset at 400×).

Molecular characteristics and genetic consultation. A PCR test for Invitae KPNC Hereditary Cancer Panel, which included 62 genes, was performed. In addition to the pathogenic PTEN mutation [PTEN c.388C>T (p.Arg130)], two mutations in RECQL4 [RECQL4 c.2755G>A (p.Ala919Thr); RECQL4 c.940C>T (p.Pro314Ser)] of uncertain significance were also identified.

A genetics consultation developed a family pedigree. The patient’s family was of Hispanic ancestry. The patient’s mother was diagnosed with breast cancer at 40 years old and died of disease 2 years later. The patient’s father is currently cancer free. The patient’s son has macrocephaly with speech delay. The histological findings, molecular testing and family pedigree supported Cowden syndrome (CS), one of the subtypes within PHTS.