Initial Evaluation of Thyroid Nodules Suspicious of MTC

Presenter: Anupam Kotwal, MD

Summary

• Progress in staging of MTC.
• Germline RET mutations (MEN2A) should be classified based on age and not risk.
• Optimal imaging for high calcitonin: Dopa PET/CT + liver MRI + neck US.
• Advanced disease: NGS and RET inhibitors when appropriate.

Background

• Significant morbidity and mortality in advanced cases of medullary thyroid cancer.
• Strongest poor prognosis in MTC include older age and higher stage at the time of diagnosis.
• There is prognostic value in tumor marking, however, progression has already occurred by the time that markers increase rapidly.
• Therefore it is important to evaluate perioperative factors for prognostication.
• Some studies do not stratify sporadic and hereditary MTC patients.

Study Aim: Identification of perioperative factors to predict outcomes (disease free survival, local regional recurrence or persistence and regional metastasis).

Methods: Retrospective Cohort Study

• N = 163 followed for a median 5.5 years until the most recent visit or death.
• Exclusion criteria: c-cell hyperplasia only, no research authorization, or no follow-up after surgery.
• Preoperative assessment: Comprehensive neck US; Serum calcitonin (n = 152); Biopsy of suspicious neck LN.
• Postoperative assessment: Neck US and CT neck every 6 – 12 months; Additional imaging if labs discordant with neck US.
• Outcomes: Overall survival (OS); Disease specific survival (DSS); Locoregional recurrence/persistent disease (LR); Distant metastasis (DM).

MTC Cohort Characteristics

• Balanced sex distribution.
• 44% had palpable neck mass.
• Mean age 48 years at time of surgery.
• Hereditary MTC: N = 61 or 38% of cohort (higher than average, perhaps because study conducted at Mayo); Approximately ⅔ had MEN2A, most diagnosed by screening; Patients with hereditary MTC were more likely to have bilateral disease and multifocal disease as compared with sporadic; 95% underwent at least total thyroidectomy and central neck dissection; 44% with multifocal and/or bilateral MTC; 35% with N1b, 8% with M1.

Survival Rates

• 5 year overall survival (OS) was 81.2%; 5 year disease specific survival (DSS) was 91.9%.
• No difference by decade (1995 – 2005 versus 2006-2015) in OS and DSS.
• However, did find better survival rates compared to the previous cohort (1964–70).
• Possibly due to more extensive surgery in more recent years; availability of tumor markers; higher resolution imaging modalities.

Outcomes in Hereditary vs. Sporadic MTC

• Sporadic n = 102; hereditary (clinical/radiographic) n = 15; hereditary (screening) n = 46.
• Patients with sporadic disease were actually more likely to have distant metastasis but non-significant differences.
• We think some of the favorable outcomes in hereditary outcomes could be due to the young age of diagnosis and treatment for hereditary MTC patients (diagnosed by family screening).
• Hereditary MTC Cohort: More bilateral and multifocal disease but underwent surgery at a younger age (36-38 years) as compared with sporadic (56 years); 75% diagnosed by family screening; Stage 1 or 2 in 85% (versus 36% for sporadic).

Multivariable Analysis for Predictors of Outcomes

• Gross ETE and the presence of distant metastasis at initial surgery were the strongest predictors of disease-specific survival.
• Lateral neck LN involvement, gross ETE, high postoperative calcitonin were highest predictors of local regional recurrence or persistence and distant metastasis in the cohort.

Limitations

• Retrospective chart review.
• Limited number of outcome events did not allow for evaluation of predictors within different MTC types or more robust multivariable analysis.
• Potential selection bias due to collection of data from a referral center (more aggressive cancer) but still favorable outcomes.
• Calcitonin & CEA doubling times were not the focus of this study (not analyzed).
• Most cases of recurrence were actually persistence (this category was combined in the study).

Conclusions

• M1 status and gross ETE of the tumor were the strongest predictors of worse DSS.
• Lateral neck LN involvement, gross ETE, and high postoperative Calcitonin were the strongest predictors of both LR and DM.
• Demographic factors were not predictive of DSS, LR, and DM when adjusted for other variables, except age >55 years predictive for worse OS.
• Disease burden at the time of initial surgery as well as biochemical response to surgery appear to be more important than demographic factors for MTC prognosis.
• This highlights the importance of rigorous perioperative assessment to better predict MTC outcomes.

Medullary Thyroid Cancer: What’s New?

TNM Staging vs. Calcitonin Doubling Time

• Calcitonin and CEA doubling time are powerful prognostic indicators; superior to initial AJCC 6th edition.
• In the AJCC 8th edition, MTC has its own staging, but the stages are only moderately predictive for 10 year outcomes.
• This new data contributes meaningful conclusions: N1b is not significant after accounting for M1; Worse OS associated with gross ETE, age > 55 years, male sex, high Calcitonin; Worse DSS associated with gross ETE and M1.

New Data about Germline RET Mutations

• The different mutations are classified as moderate and high risk.
• But a study from MD Anderson in 2017 demonstrated that ATA moderate or high-risk RET mutations did not predict disease aggressiveness among MTC in MEN2A.
• Patients with high and moderate risk RET mutation have similar overall survival, so the guidelines need to be changed.
• Future guidelines should consider RET mutation classification by disease onset (early vs. late) rather than risk of aggressiveness (high vs. moderate).

Best Imaging Modality

• The guidelines from 2015, if the patient has high calcitonin, you have to do US and CT of the head and neck, enhanced MRI of the liver, axial MRI, and bone scan.
• The next guidelines do not recommend FDG or F dopa PET CT; these are no longer our guiding conclusions.
• Gustave-Roussy found that the combination of Dopa PET/CT with liver MRI and neck US detected all lesions in their study.

New Era of RET Inhibitors

• The FDA approved two drugs in 2020 (selpercatinib and pralsetinib).
• Multikinase inhibitors had been approved (vandetanib or cabozantinib) but the new drugs are more specific.
• RET inhibitors: Require next-generation sequencing; They are effective; They may be used with or without previous vendetanib/cabozantinib; They penetrate the blood brain barrier so are effective for brain metastasis; Most adverse events are only grade 1 or 2.
• Now among patients with advanced MTC, we start with local therapy, if that’s not enough, we will get next generation sequencing (NGS), then start RET inhibitor if RET positive (multikinase otherwise).