Tumor Microenvironment Features as Predictive Biomarkers in Metastatic Differentiated Thyroid Cancer and Their Relationship With 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) Metabolic Parameters

Abstract

Objective: The role of the tumor microenvironment in tumor progression and treatment response is being investigated for different types of cancer. This study aimed to determine the relationships between tumor microenvironment, histopathology, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)-based metabolic parameters, treatment response, and overall survival (OS) in metastatic differentiated thyroid cancer (DTC). Methods: Metastatic DTC patients who underwent 18F-FDG PET/CT between 2015-2019 were evaluated. Clinicopathological, histopathological features and PET/CT parameters of patients were recorded. Microenvironmental characteristics of the primary tumor, such as mitosis, intratumoral and peritumoral lymphocytosis, intratumoral and peritumoral fibrosis, were evaluated from the tissue samples. The relationships between these factors were statistically analyzed.

Results: Sixty-five patients (38 females, 27 males, age: 49±15 years) were included. Mitosis, intra/peritumoral lymphocytosis, and intra/peritumoral fibrosis were frequent; however, none of them had a statistically significant association with PET-positive metastases, treatment response, or OS. Univariate analysis showed that gender, size, thyroglobulin values, residual thyroid tissue, PET-positive metastases, and maximum standardized uptake value (SUVmax) were significant predictors of OS. At multivariate analysis, PET-positive metastases (HR=-2.65, 95%CI 0.007-0.707, p=0.024) and SUVmax (HR=-2.74, 95%CI 0.006-0.687, p=0.023) were the only independent predictors for OS. Conclusion: Our study revealed that microenvironmental characteristics of the primary tumor did not show prognostic significance in metastatic DTC. PET-positive metastases and SUVmax levels were the only significant factors that predicted overall survival in DTC. Supporting the results of our study with further studies with a larger sample size may be necessary to determine the relationship between the tumor microenvironment and prognosis in DTC.

Keywords: fibrosis; lymphocytosis; pet/ct; prognosis; thyroid cancer; tumor microenvironment.

Figure 1. Pathology and PET/CT findings of a patient

A 70-year-old male with no intratumoral but peritumoral grade 3 lymphocytosis (A, black arrow) and fibrosis (A, red arrow). PET/CT showed cervical lymph node (B, arrow), lung (C, arrow), and bone metastases (D, arrow). The patient died of DTC one year after diagnosis. PET/CT: positron emission tomography/computed tomography, DTC: differentiated thyroid cancer

Figure 2. Pathology and PET/CT findings of an another patient

A 52-year-old male with moderate intratumoral and peritumoral fibrosis without intratumoral or peritumoral lymphocytosis (A). PET/CT showed bone (B, arrow), mediastinal lymph node (C, arrows), and abdominal lymph node metastases (D, arrow). The patient died of DTC seven years after diagnosis. PET/CT: positron emission tomography/computed tomography, DTC: differentiated thyroid cancer

Figure 3. Kaplan Meier curves for overall survival based on gender (A), size (B).

Figure 4. Kaplan Meier curves for overall survival based on residual disease after RAI treatment (C), FDG avid distant metastases (D).

PET/CT: positron emission tomography/computed tomography, WBS: whole body scan, RAI: radioactive iodine

Figure 5. Kaplan Meier curves for overall survival based on SUVmax values (E), and Tg values (F).

PET: positron emission tomography, SUVmax: maximum standardized uptake value, Tg: thyroglobulin