Abstract
KEY POINTS
Multifocal and bilateral disease differ markedly between sporadic and hereditary medullary thyroid cancer (MTC).
In this prospective analysis of 389 patients with MTC treated with total thyroidectomy, multifocality was observed more frequently in hereditary MTC (56.4%) than in sporadic disease (14.5%) and was associated with more aggressive clinicopathological features.
Selective lobectomy may be feasible in carefully chosen sporadic MTC cases but not in hereditary disease.
SUMMARY
Background
Surgery remains the standard initial treatment for medullary thyroid cancer (MTC), with current guidelines recommending total thyroidectomy and routine central neck dissection, with lateral neck dissection when nodal disease is suspected (e.g., high calcitonin or suspicious nodes on ultrasound evaluation). 1 Unlike with differentiated thyroid cancer (DTC), this extensive surgical approach is advised irrespective of tumor size, focality, patient age, or other clinicopathological factors. However, mirroring the evolution seen in DTC, some authors have proposed less aggressive surgery in selected patients with sporadic MTC (sMTC).2,3 This approach is supported by evidence suggesting that the extent of initial surgery does not influence biochemical cure in carefully selected cases and by the assumption that sMTC is less frequently multifocal or bilateral than hereditary MTC (hMTC), given the absence of germline RET mutations. 4 Reported rates of multifocality and bilaterality in sMTC vary across studies, and data correlating these features with clinicopathological outcomes remain limited. This study aimed to define the prevalence of multifocality in sMTC and hMTC and explore its relationship to aggressive pathological features. 5
Methods
This study analyzed a prospectively collected cohort of 389 consecutive patients with MTC treated at Pisa University Hospital between 2005 and 2018. All patients underwent total thyroidectomy with at least prophylactic central neck dissection, while lateral neck dissection was reserved for cases with suspected nodal metastases. RET germline mutation testing was performed routinely. Comprehensive preoperative and postoperative histological, molecular, and clinical data were evaluated. Follow-up included serial clinical assessment, calcitonin measurement, and neck ultrasonography. Outcomes were classified as cured, biochemically persistent, or structurally persistent based on biomarker levels and imaging findings. Multifocality was defined as the presence of two or more tumor foci within one or both thyroid lobes, with bilateral disease considered multifocal.
Results
This analysis of 389 patients with MTC included 311 sporadic and 78 hereditary cases; all were treated with total thyroidectomy and central neck dissection. Multifocality was observed in 22.9% of cases and was markedly more frequent in hMTC (56.4%) than in sporadic disease (14.5%). Bilaterality was uncommon in sMTC, occurring in only 8.7% of this cohort. Most tumors were early stage (I–II), small in size, and confined to the thyroid, with more than two-thirds of patients determined to be cured during follow-up. hMTC was characterized by younger age at diagnosis, smaller tumors, and higher rates of multifocality, bilaterality, and C-cell hyperplasia. Across the entire cohort, multifocality correlated with more aggressive pathological features, including advanced stage, extrathyroidal extension, nodal metastases, and higher preoperative calcitonin levels. Multivariate analysis of the sMTC cohort showed that multifocality was associated with extrathyroidal extension and N1 status, while in hMTC, it was associated with N1 status and persistent disease. No preoperative factors predicted multifocality or bilaterality.
Conclusions
Multifocality and bilaterality are demonstrated to be uncommon in sMTC but frequent in hereditary disease, where they correlated with nodal involvement and persistence. No preoperative factors predicted bilateral disease. These findings support consideration of lobectomy in carefully selected cases of sMTC, but not in cases of hMTC.
COMMENTARY
This study addresses a question that many clinicians managing MTC encounter in daily practice: whether the historical requirement for total thyroidectomy should apply uniformly to all patients. By analyzing a large, well-characterized single-center cohort, the authors show that multifocality and bilaterality are uncommon in sMTC but frequent in hereditary disease, where they remain strongly linked to nodal involvement and persistent disease. These findings reinforce the biological distinction between germline RET-driven hMTC and sporadic tumors and provide data that are directly relevant to surgical decision-making.
From a clinical standpoint, the dilemma is familiar. Surgery remains the only opportunity for a true cure in MTC, and this imperative is particularly strong in patients without a targetable driver. Although the therapeutic landscape has improved for those with metastatic, RET-driven disease, access to highly selective RET inhibitors is variable, and their use generally commits patients to lifelong systemic therapy. 6 For RET-wild-type tumors, effective systemic options are limited and largely confined to multikinase inhibitors, which offer modest benefit at the cost of substantial toxicity. 7 This creates a natural bias toward more extensive surgery. At the same time, total thyroidectomy is not without consequences, carrying well-recognized risks of hypoparathyroidism, recurrent laryngeal-nerve injury, and permanent dependence on thyroid hormone replacement—outcomes that may be avoidable in carefully selected patients undergoing lobectomy.
The study is particularly useful in the not-uncommon scenario of incidental MTC discovered after hemithyroidectomy, and the authors highlight this, suggesting follow-up with calcitonin and ultrasonography. However, interpretation of calcitonin values requires caution, as values may fluctuate even when measured within the same laboratory, underscoring the importance of longitudinal trends rather than isolated results.
A last observation from this study is, frustratingly, the ongoing inability to reliably predict contralateral bilaterality. Preoperative ultrasonography showed limited sensitivity, missing more than half of bilateral cases, and even in this large, comprehensive cohort, no preoperative or pathological features were identified that could consistently predict bilateral disease. Complete certainty is, as always in medicine, unattainable. Despite this, these findings provide reassurance that in sMTC with no adverse pathological features, completion thyroidectomy need not be automatic and instead support a more considered, individualized discussion regarding the necessity of further surgery.