An 84-years old man, with a history of systemic hypertension, type II diabetes mellitus, ischemic cardiomyopathy and atrial fibrillation (AF) sought medical attention after two months exertional dyspnea and throat tightness. Thus, in August 2020 diagnostic investigations were performed. Neck ultrasonography showed a worrisome highly vascular nodule in the right thyroid lobe (45.5 x 41.1 x 58 mm) and right latero-cervical lymph nodes at III and IV levels (26.1 x 16.1 x 24.6 mm). Thyroid and nodal fine needle aspiration (FNA) cytology identified malignant cells (Bethesda VI) compatible with papillary thyroid carcinoma (Figure 1A). Basal levels of thyroid-stimulating hormone (TSH) and thyroglobulin (Tg) were 0.7 mcU/ml and 1026 ng/ml, respectively. A fibrobronchoscopy was performed due to patient's symptoms, revealing ab estrinseco stenosis of the trachea with vegetating neoplastic tissue within the lumen. An endotracheal stent was placed, and the tumor was biopsied. The diagnosis was PTC with high grade features due to the presence of mitotic activity and necrosis (Figures 1B-D). Neoplastic cells were positive for Thyroid Transcription Factor- 1 (TTF-1) and Tg (Figures 1E, F).
Next-generation sequencing (NGS) analysis - performed on the thyroid cytology specimen using a laboratory-developed multi-gene panel and the Oncomine Focus panel assay - demonstrated RET:CCDC6 rearrangement with three additional co-occurring mutations involving PI3KCA (p.N1044K c.3132T>A, Exon 21), TP53 (p.Y163C c.488A>G, Exon 5), and hTERT (C228T, Promoter).
Total-body computed tomography (TB-CT) scan demonstrated the tumor of the right thyroid lobe dislodging and infiltrating cervical esophagus and trachea, a partially necrotic confluent right latero-cervical lymph node metastases (maximum diameter of 5.8 cm), bilateral non-calcified pulmonary nodules, mediastinal lymph nodes, and a 12 mm liver lesion at V segment (Figure 2).
Total thyroidectomy and laryngectomy were not performed due to the extent of the disease, the patient's age and his multiple comorbidities. Thus, in November 2020 systemic therapy with lenvatinib at personalized dose of 14 mg daily was started. The patient experienced several side-effects, such as asthenia grade 2 (G2), stomatitis G2, diarrhea G2, leading to transient treatment interruption and further dose reduction to 10 mg daily. At the first CT-scan evaluation, performed in March 2021, a dimensional reduction of latero-cervical lymphadenopathies (maximum diameter of 2x3 cm), and of left thyroid lobe was obtained, while a mild increase of the hepatic lesion was documented (17 mm vs 12 mm) (Figure 3). Thus, lenvatinib was continued until June 2021 when it was stopped due to the onset of severe anemia G4 (Hb 6 gr/dL, MCV 94 fL) from a gastrointestinal bleeding probably related to the concomitant anticoagulant therapy for AF.
However, as a consequence of this treatment period-off, in August 2021, a CT-scan was performed due to markedly increased Tg levels (2495 vs 749 ng/ml), reveling disease progression with the onset of at least six bilateral brain and two cerebellar lesions, all with hemorrhagic features (Figure 4). Subsequent 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) showed high glucose uptake in the right thyroid lobe (SUVmax = 23.7), together with intense uptake at a very large right latero-cervical adenopathy (SUVmax = 44.5), and at several additional lymph nodal and visceral sites, including lung, bone and pancreas (Figure 5A).
Given the tumor molecular profile, taking into account the patient's good performance status and the gastrointestinal bleeding, a second line of treatment with pralsetinib within a compassionate use protocol (AG43388 - Roche) was considered. The study was approved by the local Ethic Committee of S. Orsola-Malpighi Hospital, Bologna (208/2021/Compass/AOUBo) and the patient provided informed consent. Pralsetinib was started in September 2021 at the standard dose of 400 mg daily, and subsequently personalized to 200 mg daily, due to the onset of G3 diarrhea and G2 asthenia. Noteworthy, the 18F-FDG-PET performed after one month of therapy for early treatment response evaluation, reported a complete metabolic response in almost all sites and a relevant partial response in the others (Figure 5B). CT-scan performed four months after the beginning of therapy showed dramatic tumor shrinkage of both primary tumor and of all metastatic lesions, including the brain metastases, for which an almost complete radiological response was obtained, with a consequent patient's clinical benefit especially on dyspnea and throat tightness, and an important drop of Tg levels from 2495 to 485 ng/ml.
At present the patient is still in treatment with pralsetinib at the personalized dose of 200 mg daily, with an overall good tolerance. The last CT-scan performed in October 2022, 13 months after the beginning of treatment, showed a further tumor volume reduction and Tg levels have drop to 378 ng/ml (Figure 6).