Anaplastic thyroid carcinoma and foscarnet use in a multitarget treatment documented by 18F-FDG PET/CT: A case report

Abstract

Rationale: The case reported the rapid remission of disease recurrence achieved adding foscarnet, a DNA polymerase inhibitor that interacts with fibroblast growth factor 2, to low molecular weight heparin and sunitinib for the first time in a patient with an anaplastic thyroid cancer (ATC).

Patient concerns: A 65-year-old woman with a multinodular goiter referred for a rapid enlargement of a nodule. Histological examination revealed an ATC with a little area of papillary thyroid cancer (PTC). The patient was resistant to selective single-target treatment.

Diagnoses: Immunophenotyping and gene analyses found a significant increase in FGF2 and FGFR1 expression in the primary ATC area (FGF2 = 38.2 ± 6.2% in ATC vs 34.6 ± 6.0% in the differentiated area of PTC, P < 0.05; FGFR1: 41.7 ± 6.0% in ATC vs 34.4 ± 4.2% in PTC, P < 0.001) and in metastatic neck lymph nodes (P < 0.001 vs normal control tissues). Unlike conventional imaging, F-FDG PET/CT with PERCIST 1.0 criteria promptly and quantitatively detected disease recurrence and remission before and after multitarget therapy, combining anatomic, metabolic, and functional data.

Interventions: Foscarnet was administered given the positivity for FGF2, FGFR1 and FGFR4 in ATC. Low molecular wight heparin and Sunitinib were coadministere to limiti metastatic progression and on neck tumor masse, respectively.

Outcomes: The rationale for the clinical response to this innovative multitarget association with foscarnet is based on the histological and genetic finding that fibroblast growth factors and their receptor super-family are up-regulated in the primary anaplastic thyroid tumor and in the metastatic lymph node of our patient.

Lessons: We propose that fibroblast growth factors and their receptor super-family play a key role as potential therapeutic targets in anaplastic thyroid cancer and the positive relevance of this suggestion for patient care, especially for an individualized management.

Figure 1

Histologic analyses with immunophenotyping. Top: anaplastic thyroid carcinoma with a differentiated component of papillary thyroid carcinoma. ATC was composed of a mixture of spindle cells often with sarcomatoid appearance and epithelioid cells, frequently with squamoid features (H&E, A ×10, B ×40); in some areas the neoplastic cells were also arranged in an angiosarcoma-like pattern. There were areas of coagulative necrosis, hemorrhage, and frequent mitotic activity. The neoplastic cells showed high Ki67 (MIB-1) index (C ×20) and positivity for TP53 (D ×20). PTC was the well-differentiated, classic variant (H&E, E ×10, F ×40), and showed very low Ki67 index (G ×20) and negativity for TP53 (H ×20). Bottom: immunohistochemical evaluation of FGF2, FGFR1, and FGFR4 in anaplastic thyroid carcinoma and in well-differentiated associated component. We observed stronger staining for all 3 antibodies in ATC (×20). ATC = anaplastic thyroid cancer, FGFR = fibroblast growth factors receptor, PTC = papillary thyroid carcinoma.

Figure 2

Whole body ¹⁸F-FDG PET/CT before and after multitarget therapy. A, It shows on the left, from bottom to top: complex PET/CT hybrid imaging of recurrence of pathological lesion in the right paramedian cervical region and right scapula before (bottom) and after (top) systemic multi-target therapy (foscarnet+sunitinib+LMWH). On the right from bottom to top: whole-body PET/CT shows the extraordinary disappearance of pathological lesions 1 month after systemic multitarget therapy (foscarnet + sunitinib + LMWH). Black arrows indicate the main lesions in the right lung and kidney. B, Graphical and quantitative analysis of response to multitarget treatment according to PERCIST 1.0 criteria. On the right, a reduction in tumor standardized uptake value (SUV) over 200% from the starting value is detected 30 days after the start of multitarget therapy (foscarnet + sunitinib + LMWH). PERCIST 1.0 criteria defined a fractional change from the starting value of 20% in SUV of a region 1 cm or larger in diameter as statistically significant, and of 30% as clinically relevant. C, It shows, from bottom to center, the appearance of a pathological lesion in the right lung with central necrosis (visible on the right center of the image). At the top, 30 days after the start of multitarget therapy (foscarnet+sunitinib+LMWH): on the right, the pulmonary lesion appears completely functionally and metabolically silent on complex PET/CT imaging according to PERCIST 1.0 criteria, while on the left, anatomical imaging alone (according to RECIST criteria) is unable to measure the early response to the target therapy, showing a near identical mass to before. CT = computed tomography, LMWH = low molecular weight heparin, PERCIST = Positron Emission Tomography Response Criteria in Solid Tumors.

Figure 3

Genetic analyses. A (Top) shows sequence electropherogram for BRAFV600E mutation. The mutation found in the papillary thyroid cancer component is marked by an arrow, and the wild-type sequence of a control sample is shown below for comparison. B (Bottom) shows FGF and FGFR1 mRNA levels in a lymph node metastasis from anaplastic thyroid cancer. For each gene, the mRNA levels detected in the metastatic lymph-node tissue (LN met) of the patient (gray bars) are expressed as fold changes with respect to a calibrator, which has been assigned a value of 1. On the left, the calibrator is a commercial pool of normal thyroid tissues (THYN) and on the right it was the average of 5 normal thyroid tissues from our biobank (Normal Thyroid). Values are expressed as mean ± SD.