Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from the parafollicular calcitonin producing cells of the thyroid [1]. Representing about 2-3% of all thyroid cancer diagnoses, the rarity of disease has limited understanding of the disease and hindered advances in developing optimal therapy for patients. As a result, surgical resection has remained the cornerstone of management for MTC patients with disease recurrence occurring in 23-47% of patients [2-4]. More recently, efforts to improve our understanding of the biologic underpinnings and factors associated with poor disease outcomes led to an evaluation of MTC tumors based on pathologic characteristics [5]. Through a multi-institutional, international approach, the International Medullary Thyroid Cancer Grading System (IMTCGS) was developed that stratified MTC into high and low grade based on Ki-67 proliferation index, presence of necrosis, and mitotic index [6]. High-grade MTC patients in the study were associated with significantly worse recurrence and survival outcomes. While the IMTCGS enabled clinicians to predict disease outcomes based on objective histologic factors, its effect on the management of patient remained to be elucidated.

In our study, Tumor Grade Predicts for Calcitonin Doubling Times and Disease-Specific Outcomes After Resection of Medullary Thyroid Carcinoma, we aimed to evaluate the role of the IMTCGS on the clinical management of patient- focusing on the potential impact of post resection surveillance and outcomes [7]. Consistent with its significantly greater recurrence, high grade tumors demonstrated significantly more rapid calcitonin doubling times occurring on average every 8 months compared to low-grade tumors occurring every 35 months. In addition, high-grade tumors with calcitonin doubling times less than two years demonstrated significant worse local recurrence-free survival and overall survival compared to low-grade patients. The study not only further supported the prognostic predictability of the IMTCGS but also further demonstrated that MTC grading could be used to stratify patients requiring close clinical and diagnostic follow-up. In this commentary, we aimed to expand on the observations found in the study by evaluating the factors associated with MTC recurrence and the role of calcitonin doubling times in surveillance in the setting of the IMTCGS. In addition, we aimed to further extrapolate these findings in its application to the clinical evaluation of patients diagnosed with neuroendocrine carcinomas of the breast (NECB).

Our study demonstrated that grading MTC patients according to pathologic characteristics was strongly associated with disease-specific outcomes. In particular, high-grade patients were characterized by a Ki-67 proliferation ≥ 5%, mitotic index ≥ 5 per 2 mm2, or the presence of necrosis within the tumor [6]. The association of these parameters as the basis for histologic grading with prognosis has been mirrored in other neuroendocrine tumors of the body [8]. However, the impact of grade on management remains pending further investigation, but encouraging given its prognostic predictability in the setting of the tumor rarity. For example, increasing studies have evaluated the use of optimal adjuvant therapy use in small bowel neuroendocrine tumors with somatostatin analogs used for patients with lower grade tumors (Ki-67 <10%) and chemotherapy for higher grade tumors (Ki-67 >20%) with poor differentiation [9]. Similarly, for gastrointestinal stromal tumors (GISTs), the use of size and mitotic index has been the basis of guiding the use of adjuvant therapy [10,11].

The use of adjuvant therapy in MTC patients is limited by a lack of large cohort randomized trials and approved drugs. Historically, the use of multikinase inhibitors in the setting of MTC lost favor due to variable efficacy of the drugs combined with the drug-related toxicities and development resistance [12-15]. The advancement of selective RET-inhibitors, including Selpercatinib and Pralsetinib, has shown promise in RET-mutant non-squamous cell lung cancer [16] and has recently been approved for evaluation in RET-mutant thyroid cancers [17,18]. While its clinical benefit in MTC remains pending further evaluation, the high risk for poor disease-specific outcomes associated with high-grade MTC may identify a cohort of patients that would benefit from multimodal therapy.

Prior to the establishment of the IMTCGS, factors associated with poor outcomes and worse survival in MTC included older age at diagnosis, female gender, high postoperative calcitonin levels, the presence of perivascular invasion or extrathyroidal extension, and disease stage [19]. While these factors were evaluated in our study, multivariate analysis demonstrated that high grade tumors and tumors with calcitonin doubling times <2 years were associated with higher risk of recurrence and poor survival. While these findings do not undermine the importance of considering additional factors in determining prognosis, they demonstrated the importance of recognizing the grade and trending the postoperative calcitonin levels as important clinical parameters after curative resection in our cohort of patients. In particular, based on our study findings, it is suggested that histologic grading could represent the overall aggressiveness of disease while postoperative calcitonin doubling times could be a surrogate for persistent or recurrent disease.

To build on this concept, while the IMTCGS gives clinicians the ability to stratify patients and predict for recurrence/survival, the additional prognostic factors provide the overall status of the patient’s current disease state. Specifically, disease stage at presentation remains an important factor for consideration for patients [20]. Prior studies have demonstrated the strong association of nodal status with recurrence in MTC patients with locoregional and distant metastasis [21]. While we excluded patients in our study that demonstrated distant metastasis, an important observation in our cohort was that 50% of high-grade patients had lymph node disease at time of presentation compared to 35% of low-grade patients. Although surgery remains the only current treatment option for patients that develop recurrence, these findings demonstrate the importance of considering several factors in the management of MTC patients.

These suggestions draw many similarities to the management of patients with NECBs. The several pathologic, demographic, and genetic factors that contribute to recurrence of NECBs allow clinicians a global evaluation of patients [22]. The multifactorial approach to predict prognosis has been critical for the management of NECB patients in not only guiding the approach to patients but give clinicians a better ability to discuss optimal postoperative management. To develop and apply a comparable approach to MTC patients is still pending further study. While the establishment of the IMTCGS has provided a foundation to predict patient prognosis, we believe tumor biology be evaluated in the setting of additional risk factors associated with poor disease outcomes.

Calcitonin, a 32-amino acid monomeric peptide produced by the parafollicular cells of the thyroid, plays a role in regulating calcium homeostasis [23]. Its inherent specificity to the C-cells has led to it being used in the management of MTC patients as a diagnostic and surveillance tumor marker [24]. Previous studies have demonstrated the clinical utility of postoperative calcitonin levels as a drop in levels to <10 ng/mL has demonstrated prognostic benefit [25]. As a result, the American Thyroid Association advocate for the postoperative serial measurements of calcitonin levels after resection with rising levels a current indication for diagnostic evaluation [2]. Recently, the calculation of calcitonin doubling times has been promoted due to their association with disease outcomes. To calculate doubling times, serial calcitonin levels every 6-12 months is required for a minimum of at least four measurements [26]. Specifically, a calcitonin doubling times less than two years has been used as a prognostic cutoff point associated with worse outcomes [27]. Interestingly, in our cohort of patients, approximately 90% of high-grade patients demonstrated calcitonin doubling times less than two years compared to about 6% of low-grade patients. While this data further highlighted the likely aggressive biology of high-grade tumors it also reiterated the worse disease-free survival in patients.

Calculation of calcitonin doubling times in patients who have undergone surgical resection has been advocated as a prognostic indicator according to ATA guidelines, however its utility in guiding management stops short of identifying a cohort of patients that require close surveillance. Studies evaluating the use of adjuvant therapy in patients with rapid calcitonin doubling times have been suggested in Japanese cohorts but have thus remain theoretical [28]. For future drug trials we believe that determination of grade and calcitonin doubling time in patients may be important variables for consideration as our study demonstrated that high-grade patients with rapid calcitonin doubling times were a particularly high-risk cohort of patients who experienced worse local recurrence and overall survival.

Interestingly, the use of serial tumor markers to evaluate for tumor recurrence in NECBs and other invasive breast cancers remains controversial [29,30]. Despite recognition of several biomarkers sensitive to breast cancer recurrence including carcinoembryonic antigen (CEA), CA 15-3, and CA 27-29, historically, the American Society of Clinical Oncology (ASCO) guidelines did not support its use in the postoperative setting. Instead, monitoring for disease recurrence has focused on frequent clinical examination and routine mammograms. More recently, a shift in the potential clinical benefit of these tumor markers has demonstrated potential clinical utility and have led NCCN [31], ASCO [32], and ESMO [33] to now consider of its when clinical evidence of disease recurrence is present. While additional work is needed to validate the use of these lab values as surveillance markers, future investigations may consider evaluation of doubling times in respective biomarkers to determine its potential role as an independent prognostic factor as demonstrated in MTC patients.

Similar to MTC, thorough characterization and understanding of primary neuroendocrine carcinomas of the breast (NECB) have been limited due to its rarity and disease heterogeneity [34]. Per the WHO guidelines, NECB involve primary tumors of the breast that contain a significant component of neuroendocrine histology or biomarker expression [35]. However, clinical understanding and optimal management of patient remains less well-established and pending further evaluation. For example, the prognosis of NECB remains controversial with tumors historically recognized poor prognosis but subject to level of differentiation. In addition, while the cornerstone of management of NECB is surgical resection multimodal therapy often defers to primary breast cancer rather than neuroendocrine tumor regimens- relying predominantly on ER/PR status and platinum-/anthracycline-based chemotherapy. The use of PRRT in NECB remains under investigation [36].

We believe that the approach of patients with NECB could potentially parallel the current diagnostic and management approaches our group has been using to better understand MTC. The inherent controversy is NECB prognosis and response to therapy could be attributed to different grading or aggressiveness of the tumor biology. Previous studies have documented the poor survival in NECB patients with Ki-67 proliferation index >14% and a more thorough evaluation of other histologic markers including presence of necrosis and mitotic index may better predict prognosis [37]. As is currently being explored by our group, grading and pathologic grading of NECB patients could potentially guide surveillance and future management approaches to patients.

The development of a histologic grading system for patients diagnosed with MTC has led to better characterization of tumor prognosis and disease-specific outcomes. While further studies are currently underway to delineate the clinical utility of the IMTCGS in guiding optimal surveillance and management of patients, its association as a prognostic predictor is encouraging. High grade tumors with rapid calcitonin doubling times potentially identify a particularly high-risk cohort of patients that would benefit from close surveillance and consideration for adjuvant therapy. Regardless, the IMTCGS has established itself as an important variable to consider in all MTC patients and its use in guiding the future management and treatment of patients is encouraging. Despite disease rarity, the clinical understanding of MTC patients garnered from the establishment of the IMTCGS shows promise for better approaching future primary breast tumors- in particular neuroendocrine tumors of the breast.

The authors have no disclosures.