Diagnostic challenges in calcitonin negative medullary thyroid carcinoma: a systematic review of 101 cases

Introduction

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor (NET) that originates from the malignant proliferation of parafollicular C cells (1). It accounts for only 1–2% of all thyroid cancers (2), the majority of cases arise sporadically, while 25% of MTC cases arise from hereditary factors stemming from germline variants in the RET proto-oncogene as a component of the type 2 multiple endocrine neoplasia (MEN) syndromes (3). Calcitonin-negative MTC (CNMTC) is a rare and poorly understood primary neuroendocrine carcinoma of the thyroid that is characterized by classic MTC morphology with normal serum calcitonin. In 1989, the first case of MTC with normal or low serum calcitonin was reported (4). This entity of normal serum calcitonin and typical MTC histopathology has been referred to by several names, including “atypical MTC”, “calcitonin-negative MTC”, “C-cell-derived calcitonin-free neuroendocrine carcinoma of thyroid”, and “calcitonin-negative neuroendocrine tumor of thyroid” (5-9). Alternative biochemical markers such as procalcitonin (PCT) and carcinoembryonic antigen (CEA) have been suggested as adjuncts in the diagnosis of CNMTC (10). The aim of this systematic review is to comprehensively examine and summarize the existing literature on CNMTC, with a particular focus on its clinical and pathological features. This study will also evaluate the potential utility of alternative biochemical markers in diagnosing and monitoring this rare form of MTC. We present this article in accordance with the PRISMA reporting checklist (11) (available at https://gs.amegroups.com/article/view/10.21037/gs-24-292/rc).

Methods

The systematic review was carried out following the Cochrane Collaboration guidelines for conducting systematic reviews (12). The protocol for this study was registered in PROSPERO (registration No. CRD42023413564).

Eligibility criteria

This systematic review included studies that have reported a confirmed histopathological diagnosis of MTC, normal preoperative serum calcitonin levels, or negative immunohistochemical (IHC) stain for calcitonin and included patients who are 18 years of age or older. To maintain the integrity of the review, studies that are not published in English, non-peer-reviewed articles, systematic reviews, and books were excluded from the review. As CNMTC is a rare entity, this review has considered all study designs for inclusion, including case reports, case series, cross-sectional studies, case-control studies, and clinical prospective, retrospective cohort, or randomized/non-randomized clinical trials.

Information sources

The present systematic review utilized a comprehensive electronic search strategy starting from January 1^st, 1950, until March 9^th, 2023. A concept-by-concept approach was employed to retrieve all relevant scholarly articles from PubMed, Scopus, and Embase databases for CNMTC studies. The research topic was divided into three concepts, including “medullary thyroid carcinoma”, “calcitonin-negative neuroendocrine tumor”, and “calcitonin-negative medullary thyroid carcinoma”. The search field of each database was populated with Medical Subject Headings (MeSH) search terms and keywords related to each concept, and Boolean operators such as “AND” and “OR” were used to refine the search results. The entries for each concept were recorded and then combined using “AND” to eliminate duplicate entries. The retrieved entries from these databases and the references cited in the retrieved articles were combined as shown in the PRISMA flow diagram (Figure 1). Articles that did not meet the eligibility criteria, such as systematic reviews, books, and non-peer-reviewed articles, were excluded from the review list. No language, country, or publication date filters were applied to the search results. Advanced data tools in each of the database platforms were used to eliminate the ineligible materials. Furthermore, the bibliography of each included study in the final review was scanned, and non-original data articles not included in the final review were evaluated to identify any additional relevant studies.

Figure 1 PRISMA flow diagram.

Study selection

The retrieved search results underwent an initial blinded review for abstracts and titles, with each study being screened by two independent authors. The studies were divided among four authors (M.A., O.A., A.A., J.A.). Initial screening was based on the title, with a brief abstract review conducted if there was uncertainty. Following title and abstract screening, the authors met and discussed all studies with conflict decisions. The full texts of the subsequent selections were retrieved and subjected to blind review against eligibility criteria. Each study was reviewed by two independent authors, with five authors (M.A., O.A., J.A., A.A., N.A.) being involved in the review process. Studies were excluded if they were deemed irrelevant. Additionally, studies that referred to their case as CNMTC but did not report either the preoperative level of serum calcitonin or the IHC stain were also excluded.

Data extraction

To extract data in a consistent manner, a standardized datasheet was utilized during the data extraction process. Five authors (M.A., O.A., J.A., A.A., N.A.) were involved in this process, with each study being extracted by two authors independently. Any discrepancies that arose during the data extraction process were resolved through discussion within the review team. The datasheet contained various parameters, such as the first author, title, year of publication, study location, study design, objective, number of cases, incidence, gender, age, preoperative assessment, intraoperative and postoperative assessment, nomenclature, follow-up time, and recurrence.

Risk of bias

A formal bias assessment was not carried out in this systematic review, given that it primarily comprised case reports and case series. Nonetheless, the team conducted a comprehensive evaluation of the quality of the included studies and disclosed any limitations or potential sources of bias in the review.

Results

A database search revealed 326,744 records which, after removal by automation tools and removing duplicates, were reduced to 140, with further screening excluding 118 studies and adding 11 manually via citation searching, this systematic review consists of 32 studies listed in Table 1.

Demographics and preoperative findings

One hundred and one patients were identified, the gender was reported in 99 patients, 66 were females (66.6%), 33 were males (33.3%), and the remaining two cases did not specify the gender. The mean age among the patients was approximately 52.2 years. However, it is important to acknowledge that the studies conducted by Zhou et al. and Chambon et al. were not considered in the calculation. Chambon et al.’s study (20) did not specify the ages of its participants, and in the Zhou et al.’s study (26), it was reported that 16 patients were under 30 years old, while three patients were 30 years old or older. Out of 101 patients, the location of CTNMTC was reported in a total of 24 patients. Of these, 11 patients (45.8%) exhibited CTNMTC on the right side, while 8 patients (33.3%) on the left side. In addition, CTNMTC involved both lobes in 4 patients (16.6%) and was detected in ectopic thyroid tissue in a single patient (4.1%). In all included patients, the preoperative serum calcitonin levels were below the upper reference limit specified in each study, except for two cases in which serologic calcitonin was slightly elevated but presented with negative IHC staining for calcitonin. Notably, multiple immunoassays were employed for measuring the calcitonin levels, as summarized in Table 2. Out of 101 patients, only seven underwent the Pentagastrin Stimulation Test (PST), only two patients had relative elevated calcitonin levels after stimulation (100 and 372 pg/mL), while the remaining patients reported normal levels. A total of 59 patients were tested for CEA levels, and the results revealed that 8 of them had elevated CEA levels (13.6%) and 51 had normal CEA levels (86.4%). The serum CEA levels varied from 0.5 to 56 ng/mL. PCT level was measured in only two patients, with one patient showing mildly elevated levels, while the other had normal levels. Among the nine patients, serum chromogranin A (CgA) levels were measured, of whom five had normal values, and four had increased levels, including Murphy et al.’s study (10) that initially showed a negative result, but when repeated, demonstrated high levels.

Fine needle aspiration (FNA) and cytological findings

Among the 101 patients included in this review, only 21 reported performing FNA for diagnosis, summarized in Table 3. Ten out of the 21 patients who underwent FNA had immunostaining done for markers. Of the 10 patients, five were positive for calcitonin while four patients were negative for calcitonin but positive for other neuroendocrine markers, including CgA and synaptophysin. CEA immunostaining was performed in three patients only and was negative in all of them. Thyroid transcription factor-1 (TTF-1) staining was performed in two patients, and both had positive results. Cytokeratin-20 (CK-20) was done in only one patient and showed a negative result.

Post-operative histopathology and immunohistochemistry

Among the 101 patients, 93 patients underwent IHC staining for calcitonin, the results revealed 57 patients (61.2%) stained positive for calcitonin on IHC staining, while 36 patients (38.7%) had negative staining. Staining for calcitonin gene-related peptide (CGRP)-IHC was performed in three cases, with two patients showing positive results and one patient stained negative for it. CgA-IHC staining was performed in 93 patients and was positive in 58 (62.3%) cases, but negative in 36 patients (37.6%). CEA-IHC staining was performed in 83 patients, with 43 cases (51.8%) showing positive results and 40 cases (48.2%) showing negative results. A total of 40 patients had IHC staining for synacthen, of which 39 (97.5%) had positive staining, and one had negative staining. A thyroglobin (TG) IHC stain was performed on 44 patients, of whom 39 (88.6%) had negative results and 5 (11.4%) had positive results. TTF-1 staining was performed in 18 patients, it was found to be positive in 15 patients and negative in three patients. Of the 101 patients, 37 were genetically tested for the RET mutation, with six testing positive, but 28 test negative. Meanwhile, Frank-Raue et al. (21) reported RET mutations of 39%, 60%, and 22% in three of their patients. Among the 24 patients evaluated histopathologically, 17 showed the presence of amyloid substance while seven showed no evidence of amyloid. Diverse tumor cell morphologies were observed in the study population, ranging from round to elongated spindle-shaped forms, displaying varying cytoplasmic features. The findings are summarized in Table 2.

Operative findings, diagnosis & follow-up

The majority of cases (n=33, 33%) underwent total thyroidectomy with central lymph node dissection. Additionally, bilateral neck dissection was performed in 10 cases (10%). Meanwhile, only 20 (19.8%) out of the 101 cases described in Table 4 had a lobectomy. Two cases that were deemed unresectable utilized palliative radiation and chemotherapy as alternative treatments. Among the cases reviewed, 14 patients (13.9%) had lymph node metastasis, and 5 (4.9%) had distant metastasis. Of those with distant metastasis, lung metastasis was noted in 4 cases (3.9%), while the other case developed metastasis to the liver. The follow-up period ranged from 1 week to 6 years with a mean of 2.6 years. The majority of cases did not experience recurrence, including those who underwent a partial thyroidectomy. However, 10 patients (9.9%) experienced recurrence, which was detected by either imaging or serum CEA and PCT monitoring. Unfortunately, 3 patients (2.9%) in this review died during the follow-up period due to various causes, including respiratory failure from distant metastasis, as reported by Frank-Raue et al. (21), or central lung emboli and multiple lung and intracerebral metastases, as seen in Sand et al. report (16). Vascular thrombus formation was positive in 5 cases (4.9%). Multiple names were reported in the final diagnosis, including MTC, Non-secretory MTC, CNMTC, and Triple-negative MTC.

Discussion

The diagnosis of MTC and other NETs is often challenging. Since both MTC and NET have amyloid and spindle-shaped or spherical cells in trabecular arrangements, it is often challenging to differentiate between them. Both cells are usually positive for CgA, neuron-specific enolase (NSE), and CEA-IHC staining. Therefore, it is crucial to assess the calcitonin serum level and IHC staining. In CNMTC cases where the diagnosis of a primary or secondary thyroidal NET is unclear, there exists a possibility of erroneous interpretation of treatment options and prognosis (5). MTC may have a similar histopathological appearance to other tumors, therefore confirming the diagnosis requires additional tests such as immunohistochemistry, electron microscopy, and in situ hybridization. Among the differentials for CNMTC is primary oat cell carcinoma of the thyroid gland. These tumors usually show cytoplasmic CEA positivity. Additionally, tumor cells are usually smaller in size; paragangliomas, which display S100 protein and GATA3 with negative CKs with IHC positivity; hyalinizing trabecular tumors that have a characteristic thyroglobulin positivity which indicate follicular origin (39-43). Another differential diagnosis is calcitonin-negative NET, which is also characterized by normal levels of calcitonin and CEA, yet positive IHC staining for thyroglobulin, accompanied by histopathological characteristics typical of a neuroendocrine origin (6).

Several hypotheses have been proposed to explain the pathophysiology of CNMTC. One hypothesis, presented by Cipri et al., suggests the “hook effect”, where calcitonin assay interference can occur. Various immunoassay techniques, including enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoradiometric assay (IRMA), and immunofluorometric assay (IFMA), can measure serum calcitonin levels (29). The hook effect occurs in one-step IRMA when the serum antigen level is excessively high, causing the signal antibodies to be washed out, resulting in inaccurate or lower measurements. Repeated dilutions of the same serum sample by 1:10 and 1:100 can be done to eliminate the hook effect, particularly in cases with advanced, poorly differentiated CNMTC (29,32). Frank-Raue et al. proposed the production of complex isoforms of calcitonin in CNMTC, which may not be detected by commonly used immunoassays (21). Another hypothesis suggests that the poor differentiation of tumor cells leads to lack of calcitonin production and poor prognosis (22). Additionally, a mutation in the CGRP may disrupt the synthesis and secretion capabilities of C-cells, affecting the production of modified forms of calcitonin (28). In cases of CNMTC where abnormal cellular processing of calcitonin occurs, serum PCT levels are expected to rise. However, if the pathogenesis involves defective cellular secretory mechanisms, both serum calcitonin and PCT levels may remain within the normal range. This suggests that the underlying cellular dysfunction primarily affects the secretion of calcitonin and does not significantly impact PCT production. The measurement of PCT levels can be helpful in distinguishing between these different mechanisms involved in CNMTC pathogenesis (10).

Elevated serum calcitonin levels can potentially serve as an early indication of MTC. As serum calcitonin, sensitivity ranges between 83% and 100%, and its specificity ranges between 94% and 100%. Stimulating tests such as pentagastrin or calcium have also been shown to increase the sensitivity and specificity of serum calcitonin (43). However, a few points must be considered when using calcitonin as an MTC marker. Firstly, an increased calcitonin serum level is suggestive of MTC but is not pathognomonic, and the possibility of false positives or other calcitonin-secreting NET should be considered (44). Secondly, slightly or moderately elevated levels could be attributable to various confounding factors. Thirdly, elevated calcitonin levels can be seen in C-cell hyperplasia (CCH), which is also commonly associated with chronic lymphocytic thyroiditis (45). Fourthly, the sensitivity of serum calcitonin measurement is limited in patients with small MTCs. Fifthly, the diagnostic accuracy of routine calcitonin measurements in patients with nodular thyroid disease remains controversial (46,47). Lastly, some MTCs may not secrete calcitonin, leading to false-negative results. Therefore, serum calcitonin measurement should be used in conjunction with other diagnostic tools, such as FNA and imaging studies, to improve the accuracy of MTC diagnosis and surveillance (48,49).

Pentagastrin and calcium stimulation tests are utilized to enhance the diagnostic accuracy of MTC by distinguishing it from other conditions with elevated calcitonin levels, such as CCH and non-thyroidal NET (50). These tests are also used for planning preventive thyroidectomy in RET-mutation carriers and for postoperative monitoring of MTC. Pentagastrin stimulation involves administering pentagastrin and measuring the peak calcitonin level, with a peak calcitonin of 275 ng/L after pentagastrin effectively differentiating MTC from CCH with 100% sensitivity and 89% specificity (51). On the other hand, calcium-stimulated calcitonin has varying cut-off values to distinguish MTC from CCH and normal cases. A recent paper suggests a threshold of 611 pg/mL for males and 445 pg/mL for females to differentiate MTC from normal or CCH cases (52). Calcium stimulation tests are increasingly preferred over pentagastrin due to their cost-effectiveness and widespread availability. However, variability in cut-off values across studies complicates standardization.

Calcium stimulation tests are increasingly preferred over pentagastrin due to their cost-effectiveness and widespread availability. However, variability in cut-off values across studies complicates standardization, with different thresholds reported for genders.

Recently, PCT has emerged as a valuable diagnostic and monitoring marker for MTC (53). PCT has several advantages over calcitonin, including its exclusive production by thyroid C cells, lower blood concentration, temperature stability, and accessibility for measurement. It is an extremely stable protein with a 25–35-hour in vivo half-life (54). Previous research has shown that the sensitivity and specificity of PCT for diagnosis vary depending on the threshold used, with a threshold of 0.95 ng/mL providing a specificity of 95.8% and a sensitivity of 100%. Moreover, the mean PCT values in active disease were higher than those in cured MTC (53,55,56). In this systematic review, PCT levels were measured preoperatively in two cases. In Brutsaert et al.’s case, the PCT level was elevated prior to surgery, but it normalized after operation. On the other hand, in Kim et al. case, the PCT level was within the normal range before the surgery (22,32). PCT shows promise as a diagnostic and monitoring marker for CNMTC. However, drawing a definitive conclusion is premature, as it was applied to only two out of 101 patients and yielded conflicting results.

CNMTC nomenclature

In 1989, the first case of MTC with normal serum calcitonin was reported (4). It was referred to as “calcitonin-negative, chromogranin A-positive endocrine tumor”. Since then, several different names such as “atypical MTC”, “non-secretory MTC”, and finally “CNMTC” have been used for such cases. We identified a significant level of variability in the nomenclature of the final diagnosis across the different studies that were included in the review.

For instance, Schmid et al. used the terms “atypical MTC” and “neuroendocrine tumors of the thyroid” to describe thyroid tumors that lack calcitonin but possess neuroendocrinological markers. They concluded that although such tumors display an obvious dilemma; calcitonin absence represents an atypical form (8). Wang et al. used the term “calcitonin negative MTC”, since tumor cells were positive for CEA and CgA, although minimally positive for calcitonin, with serum calcitonin being slightly above the upper limit (9). Ismi et al. used the term “calcitonin negative NET of thyroid”, patient’s serum calcitonin was in normal limits and IHC was negative for calcitonin, thyroglobulin, and amyloid staining (6). They preferred to use this term since all MTCs should be confirmed by calcitonin immunopositivity (57). Nakazawa et al. employed the term “C-cell-derived calcitonin free neuroendocrine carcinoma of thyroid” to describe tumor cells that were negative for calcitonin but positive for neuroendocrine markers. The diagnosis of atypical MTC was made through the use of IHC staining that demonstrated CGRP positivity (7).

Surveillance of CNMTC

Determining the best approach for postoperative surveillance of patients with CNMTC remains a daunting challenge. This is because serum biomarkers, which are commonly used to monitor cancer recurrence, have limited reliability in the context of CNMTC. This lack of dependable serum biomarkers for CNMTC adds to the complexity of the issue and makes it challenging to determine the most effective method for postoperative surveillance.

Although PCT was only measured in two patients preoperatively, several studies in this systematic review have used it for surveillance. In a case report by Baptista et al., PCT successfully identified a relapse even when all neuroendocrine markers yielded negative results (35). Nevertheless, akin to the diagnostic potential of PCT, its use for surveillance shows promising results, but the scarcity of studies makes it challenging to arrive at a definitive conclusion.

Interestingly, Frank-Raue et al. reported that in patients with CNMTC, an increase in calcitonin levels is commonly observed during relapse (21). This finding is consistent with the results of a study by Zhou et al. which also demonstrated an association between elevated calcitonin levels and recurrence (26). These findings suggest that monitoring calcitonin levels may be an important tool for detecting recurrence and guiding appropriate clinical management, even when calcitonin levels are normal at diagnosis.

While the overexpression of CGRP is not necessarily linked to tumor growth, it is a consistent feature of C-cell origin, particularly when expressed alongside TTF-1 and PAX-8. As reported by Brutsaert et al., a study involving 18 CNMTC patients showed that CGRP was expressed in 66% of primary tumor sites and 73% of metastases (22). CgA, a protein belonging to the granin family of neuroendocrine secretory proteins (58), has been implicated in various malignant and non-malignant conditions (59). In regard to CNMTC, CgA’s reliability as a marker of recurrence is questionable, as it was not elevated in any of the cases included in this literature. However, CgA was found to be elevated mainly in advanced stages of MTC (60), and failed to prove to be a reliable marker for MTC recurrence or metastasis (61).

Previous studies have shown that serum CEA can detect relapse of MTC even with normal calcitonin levels (62). However, in this systematic review, only one patient presented with increased CEA during relapse (21).

Other potential biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have demonstrated some prognostic utility in various neoplasms (63). However, their relevance to MTC remains uncertain. These biomarkers are beneficial due to their low cost and wide availability, yet they are limited by their nonspecific nature (64,65). Given the conflicting results from previous studies, further research is necessary to establish their utility in secretory MTC before they can be considered for evaluating CNMTC.

Overall, the optimal approach for postoperative surveillance of patients with CNMTC is uncertain, as serum biomarkers have limited reliability in this context. Nevertheless, calcitonin serum levels remain the best surveillance marker even in CNMTC cases.

Several imaging techniques have been investigated, such as computed tomography scans, magnetic resonance imaging (MRI), and positron emission tomography (PET), for detecting recurrent MTC. However, it is still unclear what the best approach is for postoperative surveillance of patients with CNMTC, and combining imaging and serum biomarkers may be necessary to improve the accuracy of surveillance methods. Therefore, further research is needed to determine the most effective surveillance protocols for CNMTC cases.

Management of CNMTC

Most cases reviewed opted for central neck dissection alongside total thyroidectomy, paralleling the treatment strategies employed for secretory MTC, which characteristically involves central neck dissection regardless of the presence or absence of lymph node metastasis in the central compartment (2). This approach was based on the histopathological features typical of MTC, despite the absence of elevated serum calcitonin levels. Additionally, bilateral neck dissection is carried out when there is evidence of lateral compartment lymph node involvement. However, there are instances where neck dissection is deferred. Comparing outcomes between these varying strategies presents challenges due to the limited follow-up periods documented in the studies. Interestingly, several cases that opted for lobectomy instead of total thyroidectomy reported no recurrence during follow-up, suggesting favorable outcomes (7,33,36). In cases of unresectable CNMTC with distant metastases, Ismi et al. used chemotherapy, including cysplatin and etoposide (6). Nakazawa et al. reported a case of CNMTC on the left lobe with no evidence of cervical lymph node metastasis, which was treated with left hemithyroidectomy due to fixation revealed by an OctreoScan (7). Similarly, Kasajima et al. performed left hemithyroidectomy with lymph node dissection due to discrepancies between serum calcitonin/CEA levels and cytological findings (23). Skutnik et al. identified focal radiotracer activity in the right thyroid mid-lower pole in a PET/CT scan, leading to a right partial thyroidectomy with isthmusectomy (33). In cases where CNMTC was deemed inoperable due to vascular encasement, Rafaey et al. administered external radiation beam therapy (ERBT) (34). In a study of 24 cases of CNMTC, Yue et al. found that unilateral lobectomy with central lymph node dissection was adequate in 17 cases, while the rest underwent total thyroidectomy with central lymph node dissection. Interestingly, males had better outcomes compared to females (36). Overall, these varying approaches highlight the need for individualized treatment plans tailored to the unique characteristics of each case of CNMTC.

Prognosis of CNMTC

Several authors, as well as the guidelines proposed by the American Thyroid Association for managing MTC, propose that decreased calcitonin production might be linked to loss of cellular differentiation, which could indicate a poorer prognosis (2,15,66). In fact, low calcitonin serum levels and tumors with less than 25% of cells staining for calcitonin have been associated with a more aggressive form of MTC that presents with early metastasis (9). Supporting this hypothesis, Saad et al. found that weak immunostaining for calcitonin was linked to poorer prognosis (67). However, conflicting results have been reported in other studies. For example, one study reported that CNMTCs have a varied prognosis, ranging from long-term survival to rapid tumor progression based on RET gene mutations and Ki-67 expression (21). In this systematic review, it was observed that positive Ki-67 expression was linked to larger tumor size, distant metastases, higher recurrence rates, and increased likelihood of early mortality during follow-up. Moreover, a higher percentage of tumor cells expressing Ki-67 was associated with poorer outcomes. Therefore, Ki-67 proves to be a valuable prognostic marker for MTC.

Another potential prognostic marker is TTF-1, which is a transcription factor that mainly regulates the expression of thyroid-specific genes such as thyroglobulin and thyroperoxidase in the thyroid gland. TTF-1 expression is indicative of a thyroid origin and is usually expressed in MTC (23). TTF-1 serves as a functional marker for C cells and medullary C cell carcinomas (68). Among the 15 patients who underwent TTF-1 IHC testing, only three of them exhibited negative TTF-1 expression. The absence of TTF-1 expression was found to correlate with larger tumor size exceeding 4 cm, poor differentiation, high-grade tumors, and the presence of distant metastasis. Unfavorable outcomes were observed in two specific cases: Ismi et al. reported a scenario involving unresectable thyroid cancer with intrathoracic and intraabdominal peritoneal metastasis, necessitating chemotherapy (6), while Ballal et al. reported a case of aggressive, rapidly growing high-grade MTC associated with recurrence and liver metastasis (37). Thus, TTF-1 expression can be a potential predictor of prognosis in MTC and CNMTC cases.

Tumor size is a crucial clinical characteristic in MTC and serves as an independent prognostic indicator (26). In particular, when the MTC tumor diameter exceeds 1 cm, lymph node metastasis becomes more likely, leading to a poorer prognosis. Moreover, for tumors greater than 4 cm in diameter, the survival time is significantly shortened and the prognosis is particularly poor. In comparison with MTC, the rate of lymph node metastasis in the CNMTC group is remarkably lower. This finding suggests that the prognosis of CNMTC may be more favorable than that of secretory MTC. Besides lymph node metastasis, thyroid capsular invasion is also an independent prognostic factor. Notably, the CNMTC group appears to have a lower incidence of thyroid capsular invasion, which may suggest a better prognosis for these patients.

Limitations

The systematic review has several limitations that should be acknowledged. First, given the rarity of CNMTC, most of the studies included were case reports and case series, which could introduce bias and limit the generalizability of the findings. Furthermore, there was a lack of standardization in the diagnosis and management of CNMTC, resulting in varied approaches taken by different authors. This heterogeneity could lead to inconsistencies in the data and make it challenging to draw definitive conclusions about the optimal diagnostic and treatment strategies for CNMTC. Finally, although the review provides a comprehensive overview of the biomarkers used in the diagnosis and surveillance of CNMTC, it does not provide a detailed analysis of the accuracy or reliability of these biomarkers. Therefore, additional studies are needed to determine the sensitivity and specificity of these biomarkers, as well as their usefulness in predicting disease progression and response to treatment.

Conclusions

Despite the rarity of CNMTC, it is important to have a high index of suspicion when investigating thyroid nodules. In cases of CNMTC, surgery remains the primary treatment modality, with total thyroidectomy and central neck dissection being the standard approach. The role of adjuvant therapies, such as chemotherapy and radiation therapy, are limited to inoperable CNMTC cases. There is uncertainty regarding the prognosis of CNMTC in comparison to secretory MTC. It appears that CNMTC has a lower incidence of lymph node metastasis and thyroid capsular invasion. However, the conflicting data about the importance of calcitonin production as a prognostic marker emphasizes the necessity for more research to identify the most effective management and prognostic indicators for CNMTC. The use of alternative biomarkers such as PCT, CgA, and CEA has shown promising results in several studies. Moreover, the combination of various biomarkers such as calcitonin, CEA, PCT, and CgA may improve the sensitivity and specificity of CNMTC diagnosis and surveillance. This multimarker approach could be particularly useful in cases where calcitonin and CEA levels are inconclusive.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-292/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-292/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-292/coif). The authors have no conflicts of interest to declare.

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