MOLECULAR PROFILE AND CLINICAL OUTCOMES IN DIFFERENTIATED THYROID CANCER PATIENTS PRESENTING WITH BONE METASTASIS

Objective: Differentiated thyroid cancer patients uncommonly present with bone metastasis as the initial manifestation. Their molecular profile is largely unknown. The aim of this study was to evaluate the histopathology, molecular profiles, and response to radioactive iodine therapy in these patients. Methods: Eight patients presented with symptomatic bone metastasis from an unknown primary tumor. We identified these patients by performing a retrospective chart review. Pathology slides were reviewed and the molecular analysis of 112 thyroid cancer-related genes was performed on bone metastasis specimens using targeted next-generation sequencing. Results: These patients presented with long bone fractures, spinal cord compression, or intractable bone pain. Histopathologic analysis of the bone and thyroid tumor specimens revealed follicular variant of papillary carcinoma in 7 patients and tall cell variant papillary carcinoma in 1 patient. Primary tumor size ranged from 0.4 to 7.5 cm. All patients received high dose radioiodine therapy following thyroidectomy. Molecular analysis revealed telomerase reverse transcriptase ( TERT) mutations in 7 (88%) tumors, 4 (50%) contained co-occurring TERT and RAS GTPase gene ( RAS) mutations, 2 had isolated TERT mutations, and 1 had TERT and proto-oncogene B-Raf ( BRAF) V600E mutations, respectively. Tumors carrying RAS, TERT, or a combination of these mutations were radioiodine-avid, with predictable tumor response and reduction in serum thyroglobulin levels. One patient with radioiodine-refractory disease harbored BRAF and TERT mutations. Conclusion: These results demonstrate that differentiated thyroid cancers presenting with bone metastasis independent of the primary tumor size have a high prevalence of TERT mutations, frequently coexisting with RAS mutations. This molecular signature may predict a favorable response to radioiodine therapy. Abbreviations: BRAF = proto-oncogene B-Raf; DNA = deoxyribonucleic acid; DTC = differentiated thyroid cancer; FV = follicular variant; PTC = papillary thyroid carcinoma; RAI = radioactive iodine; RAS = Ras GTPase gene; TERT = telomerase reverse transcriptase; TG = thyroglobulin

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Pattern analysis for prognosis of differentiated thyroid cancer according to preoperative serum thyrotropin levels

Scientific Reports ◽

10.1038/s41598-021-01898-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hosu Kim ◽

Jaehoon Jung ◽

Young-Seok Cho ◽

Joon Young Choi ◽

Hyunju Park ◽

...

Keyword(s):

Thyroid Cancer ◽

Distant Metastasis ◽

Tumor Size ◽

Primary Tumor ◽

Differentiated Thyroid Cancer ◽

Pattern Analysis ◽

Primary Tumor Size ◽

Preoperative Serum ◽

Serum Tsh ◽

Tsh Levels

AbstractSerum thyrotropin (TSH) level after thyroid surgery affects the prognosis of differentiated thyroid cancer (DTC). However, the effects of preoperative serum TSH levels on the prognosis of DTC remain contradictory. In this study, to better understand the relationship between preoperative TSH levels and the prognosis of DTC, we performed pattern analysis of prognostic factors of DTC according to preoperative serum TSH levels. We retrospectively reviewed the clinical records of patients who were diagnosed and treated for DTC at the Samsung Medical Center, between 1994 and 2016. We reviewed preoperative serum TSH levels and performed a pattern analysis with prognostic risk factors for DTC. For pattern analysis, TSH was divided into 10 groups of equal fractions (TSH decile). We found a linear association between preoperative TSH levels and extra-thyroidal extension and lymph node metastasis. However, primary tumor size and initial distant metastasis showed a bimodal peak, which was similar to the pattern of overall and disease-specific death. We found that preoperative TSH range which showed the lowest mortality rate was about 0.8 to 1.59 mIU/L, which are slightly lower normal TSH levels. Although there was no linear trend, the primary tumor size, initial distant metastasis, and mortality of DTC were closely related with preoperative TSH decile and they showed a bimodal pattern. The results obtained in this study provide additional information for understanding the association between preoperative TSH levels and DTC prognosis.

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Role of Radioactive Iodine for Adjuvant Therapy and Treatment of Metastases

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2007.0054 ◽

2007 ◽

Vol 5 (6) ◽

pp. 631-640 ◽

Cited By ~ 3

Author(s):

Jacqueline Jonklaas

Keyword(s):

Thyroid Cancer ◽

Side Effects ◽

Adjuvant Therapy ◽

Cancer Cells ◽

Differentiated Thyroid Cancer ◽

Sodium Iodide ◽

Radioactive Iodine ◽

Radioiodine Therapy ◽

Sodium Iodide Symporter ◽

Thyroid Cancer Cells

Normal thyrocytes and thyroid cancer cells are characterized by possession of a sodium iodide symporter. Radioiodine administration is a unique and powerful means of treating differentiated thyroid cancer because of the ability of thyroid cancer cells to concentrate beta-emitting radiolabeled iodine. Several manipulations, such as iodine depletion and thyroid hormone-stimulating hormone elevation, are used to enhance uptake of radiolabeled iodine by tumor cells. Adjuvant radioiodine therapy, given to patients without evidence of residual disease, enhances the sensitivity of subsequent surveillance and may decrease recurrence rates and mortality. However, its exact role in the management of low-risk patients merits further investigation. In contrast, radioactive iodine therapy used in patients with residual or metastatic disease clearly improves outcomes. Several studies show decreased recurrence and mortality rates in patients treated with radioiodine compared with those not receiving radioactive iodine. Adverse events from radioiodine therapy include salivary gland dysfunction, bone marrow suppression, and reproductive disturbances. Side effects of radioiodine therapy are generally greater when higher activities of radioiodine are used and may be transient or permanent. Secondary malignancies also may occur after radioiodine therapy. These side effects must be weighed against potential benefits, especially when radioactive iodine is used as adjuvant therapy. Stimulation of the expression of the sodium iodide symporter, or its introduction de novo into nonthyroid cells, is promising in treating poorly differentiated thyroid cancer and nonthyroid malignancies, respectively.

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Do Molecular Profiles of Primary Versus Metastatic Radioiodine Refractory Differentiated Thyroid Cancer Differ?

Frontiers in Endocrinology ◽

10.3389/fendo.2021.623182 ◽

2021 ◽

Vol 12 ◽

Author(s):

Cristiane J. Gomes-Lima ◽

Leila Shobab ◽

Di Wu ◽

Dorina Ylli ◽

Athanasios Bikas ◽

...

Keyword(s):

Thyroid Cancer ◽

Primary Tumor ◽

Differentiated Thyroid Cancer ◽

Distant Metastases ◽

Molecular Profile ◽

Mutation Burden ◽

Genetic Landscape ◽

Digital Microfluidic ◽

Metastatic Sites ◽

Promoter Mutations

Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25–82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigate TERT promoter mutations. The genetic landscape of all paired sites comprised BRAF, NRAS, HRAS, TP53, ATM, MUTYH, POLE, and NTRK genes, including BRAF and NTRK fusions. BRAF V600E was the most common point mutation in the paired specimens (5/12). TERT promoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention.

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2022 ETA Consensus Statement: What are the indications for post-surgical radioiodine therapy in differentiated thyroid cancer?

European Thyroid Journal ◽

10.1530/etj-21-0046 ◽

2022 ◽

Vol 11 (1) ◽

Author(s):

Furio Pacini ◽

Dagmar Fuhrer ◽

Rossella Elisei ◽

Daria Handkiewicz-Junak ◽

Sophie Leboulleux ◽

...

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Randomized Trials ◽

Radioactive Iodine ◽

Consensus Statement ◽

Radioiodine Therapy ◽

Beneficial Effects ◽

Risk Patients ◽

Patient Preparation ◽

Pre Treatment

Modern use of post-operative radioactive iodine (RAI) treatment for differentiated thyroid cancer (DTC) should be implemented in line with patients’ risk stratification. Although beneficial effects of radioiodine are undisputed in high-risk patients, controversy remains in intermediate-risk and some low-risk patients. Since the last consensus on post-surgical use of RAI in DTC patients, new retrospective data and results of prospective randomized trials have been published, which have allowed the development of a new European Thyroid Association (ETA) statement for the indications of post-surgical RAI therapy in DTC. Questions about which patients are candidates for RAI therapy, which activities of RAI can be used, and which modalities of pre-treatment patient preparation should be used are addressed in the present guidelines.

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