Multifocality in Sporadic Medullary Thyroid Carcinoma: An International Multicenter Study

Introduction

Medullary thyroid carcinoma (MTC) accounted for 2.2% of all thyroid cancer in a database of 43,644 thyroid cancer cases from 1992 to 2006 in the United States (1), and historically is observed sporadically in approximately 75–80% of patients while the remainder have a hereditary form (multiple endocrine neoplasia type 2 [MEN2], including the familial MTC variant) (2) transmitted with autosomal dominant patterns of inheritance by mutation of the REarranged during Transfection (RET) proto-oncogene (3 –7).

Surgery is the only curative treatment for both hereditary and sporadic forms of MTC, and its chance of success is greatest when the disease is confined to the thyroid, or when minimal lymph node metastatic disease is present (8). Total thyroidectomy, central neck dissection, and therapeutic dissection of involved lateral neck compartments, with or without prophylactic dissection of clinically uninvolved compartments (levels II–V), is the current recommended treatment for patients with MTC (2,9). Because the hereditary form of MTC is due to an oncogenic germline mutation in the RET proto-oncogene, virtually all patients are at risk for bilateral and multifocal disease (10 –12), which justifies the need for total thyroidectomy, whether prophylactic (ideal) or therapeutic. Therapeutic total thyroidectomy in addition to lymph node dissection has also been generally recommended for patients with sporadic MTC (sMTC). However, it has been noted that tumor multifocality and bilaterality occurs less frequently compared with the hereditary form (12). Based upon these findings, the argument has been made for unilateral thyroidectomy (lobectomy and isthmusectomy) with a lymph node dissection for sMTC that is confined to one lobe (13), shortening operating time and potentially lowering the risks of hypoparathyroidism, hypothyroidism, recurrent laryngeal nerve injury, voice changes, and other surgical complications compared with total thyroidectomy (14 –21).

The prevalence of bilateral foci in sMTC has been reported to range widely from 0% to 66.7% (13,22 –37), though these reports were not all based upon germline DNA testing to exclude MEN2. Several studies from single institutions have more systematically applied RET mutation testing and standardized pathological analyses to investigate the occurrence of multifocal or bilateral disease more accurately among sMTC patients. Still, most of these patient cohorts were small, and some inconsistent results were seen (Table 1). The objective of this investigation was to evaluate the prevalence, and possible correlation, of multifocality and bilaterality in sMTC. A large, international, multi-institutional retrospective investigation was conducted to quantify this occurrence in a large and diverse population to limit random or biased findings from small cohorts and to test the impact of geography. These analyses allow the role of alternative surgical approaches in the current treatment of sMTC to be considered.

Methods

Results

Subject recruitment

Of the 53 institutions invited, 13 agreed to participate, and 11 ultimately submitted data. Responding institutions represented seven nations and four continents. From these centers presenting for management from 1983 to 2011, 313 patients with biopsy-proven sMTC were identified. One patient elected for nonoperative management of biopsy-proven sMTC and was excluded from this analysis. The remaining 312 operated patients were included in analyses of multifocality. Average age at first surgical intervention was 52 ± 15 years (range 19–101 years). While 81.2% of patients had negative RET proto-oncogene testing supporting sMTC, the remaining 18.8% were untested and classified as sMTC based upon negative family history and absence of other findings of MEN syndromes. Six patients underwent thyroid lobectomy alone and were excluded from analysis of bilateral disease (n = 306; Fig. 1).

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FIG 1.

Schematic accounting for all patients identified in this retrospective multicenter study.

Discussion

Total thyroidectomy with central neck dissection, with or without lateral neck dissection, is a well-established treatment for patients with MTC (2). This is well supported in patients with hereditary MTC who present with clinical disease or significantly elevated serum calcitonin levels, as there is a high prevalence of tumor bilaterality and multifocality, necessitating removal of the thyroid gland in its entirety (2). Total thyroidectomy is also recommended in sMTC, despite the fact that the disease tends to be a unicentric process confined to one lobe. This is historically justified by the possibilities of bilateral primary disease or intraglandular metastases, the possibility of inherited disease when RET proto-oncogene testing has not been performed or was negative, and to optimize surgical access for bilateral central neck lymph node dissection (10 –12). Still, some authors have recommended hemithyroidectomy (lobectomy with isthmusectomy) with central and ipsilateral lateral neck dissection based on the absence of RET proto-oncogene mutation and on the macroscopic extent of the primary tumor (13,41). Ito et al. managed a series of patients with this approach in Japan, and reported clinical outcomes better than those from Western countries, and none of their patients showed disease recurrence in the thyroid remnant (41). These authors noted that previous treatment recommendations focused more on the debate of using central and lateral nodal dissection, while their approach instead focused on the extent of thyroidectomy (while all patients underwent ipsilateral central and lateral neck dissections). Total thyroidectomy (as well as bilateral central neck dissection) places the bilateral recurrent and superior laryngeal nerves and all parathyroid glands at risk. In comparison, hemithyroidectomy (lobectomy with isthmusectomy) and ipsilateral central neck dissection places only the ipsilateral nerves at risk and lowers the risk of permanent hypoparathyroidism by leaving undisturbed parathyroid tissue on the contralateral side. Further, hemithyroidectomy significantly reduces the risk of long-term hypothyroidism requiring thyroid hormone replacement compared with bilateral thyroidectomy (21). In the surgical treatment for sMTC, these surgical risks must be weighed against the risk of persistent disease. Regarding the currently recommended extent of thyroid surgery according to guidelines, the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) recommend total thyroidectomy as opposed to hemithyroidectomy (2,9). In patients diagnosed with apparent sMTC following a hemithyroidectomy, these guidelines indicate that RET germline mutation status, serum calcitonin, and the results of imaging studies should determine the role of completion thyroidectomy (2,9). It is important to note that this approach does not include tumor focality in this consideration. This may be particularly relevant for patients with multifocal disease in the ipsilateral lobe or isthmus, as 21.6% of them were found to be harboring disease in the contralateral lobe. While serum calcitonin and ultrasonography may safely indicate the need for completion thyroidectomy (immediately or subsequently) in similar patients treated with a hemithyroidectomy, especially those with macroscopic MTC in the remaining lobe, it is unknown if patient outcomes are impaired by not including tumor multifocality as an independent clinical factor to guide the completion thyroidectomy decision. In the present cohort, the median size of the largest contralateral MTC focus was 8 mm (range 0.6–48 mm), suggesting that a significant fraction of patients with bilateral disease would have had negative or inconclusive preoperative ultrasound findings of the contralateral lobe. It is also important to recognize that bilateral disease did occur, even in sMTC patients with unifocal disease in the ipsilateral lobe and isthmus, suggesting that all patients who chose to be treated with an initial lobectomy require at least ongoing careful surveillance.

The consequences of persistent disease are believed to be significant. Complete surgical resection when the disease is confined to the neck is currently the only curative treatment of MTC (sporadic or hereditary) (11,42). Residual primary tumor in a remaining thyroid lobe could potentially give rise to metastatic foci, a disease state associated with a significantly reduced rate of biochemical cure. Duh et al. reported that patients who underwent less surgery than routine total thyroidectomy and central neck dissection have been shown to require more reoperations (43). In a study evaluating prognostic factors in sMTC, Gulben et al. reported in a multivariate analysis that the extent of the primary surgical resection was an independent risk for survival (25). Patients with incomplete resection had a 4.8 times higher risk of death than those who had a complete resection. In their sample, 28% of tumors were noted to be bilateral. Panigrahi et al. reported that patients receiving surgery discordant with ATA guideline recommendations had shorter survival than those receiving surgery according to recommendations (44). Still, not all studies support these findings. Esfandiari et al. reported that for tumors ≤2 cm without distant metastases, overall survival was not altered by surgical intervention, while all surgical interventions similarly improved survival compared to no surgery for tumors >2 cm without distant metastases (45).

The frequency of bilateral disease in sMTC varies widely from 0% to 66.7%, as illustrated in Table 1, although the frequency was lower in series with more thorough germline RET proto-oncogene testing (13,22 –36). The present findings show that 17/306 (5.6%) patients had bilateral disease, which is comparable to the median value of 7.2% among the previous reports shown in Table 1. To account for any geographical variances in focality and bilaterality, 313 patients with biopsy proven sMTC were identified from 11 centers within seven nations and four continents. The prevalence of bilateral sMTC among the sites surveyed ranged broadly (0–18%; Table 4). There were no statistically significant differences in prevalence among the geographic locations. Although there was no linear association with increasing T stage and prevalence of bilateral disease, there was a statistically significant increase in the prevalence of bilateral sMTC when comparing advanced T stage lesions with T2 tumors. Still, among T2 and lower tumors, the prevalence of bilaterality was 4.5%.

Multifocal tumors have also been shown to be independent risk factors for nodal metastasis, and may explain why tumor size alone does not always predict lymph node metastasis (23,37). Multifocal disease was found to be significantly more common in N1b compared with N0 patients (p < 0.001). With respect to distant metastatic disease, there was a significantly greater prevalence of multifocality in those with metastatic disease compared with those without. The prevalence of multifocal sMTC in the youngest quartile of the sample (26%) was significantly greater than the third and fourth quartiles. One may speculate that this is due to unrecognized hereditary MTC, despite their negative family histories, or negative germline RET proto-oncogene analysis. Lindsey et al. studied 50 patients for this question (40), 45 of whom are included in this study. Their 50 patient cohort had been screened by sequencing exons 8, 10, 11, and 13–16 of the RET gene in their entirety. Still, 27 patients had one or more features suggesting familial disease, such as a young age of onset of MTC (<35 years of age; 16 patients), tumor multifocality (13 patients), or the presence of C cell hyperplasia (10 patients). Four patients had both young age at diagnosis (in these cases <30 years old) and multifocal disease. Those 50 patients underwent extended RET testing of exons 1–7, 9, 12, and 17–19 with the identification of no new causative mutations. The present study identified multifocal tumors in 50/312 (16%) patients, which is consistent with the median value of 18.3% among the prior studies shown in Table 1 (range 0–43%). There were no statistically significant differences in prevalence among the geographic locations. As with bilateral disease, there was no linear association with increasing T stage and prevalence of multifocal disease. As with bilateral disease, there was a statistically significant increase in the prevalence of multifocal sMTC when comparing advanced versus early T-staged tumors.

The strengths of the current study of the rate of multifocality and bilaterality for clinically sMTC include the large number of patients accrued from 11 centers across seven countries, most of whom had negative RET germline testing. To the authors' knowledge, this is the largest study of its kind. The geographic diversity of the patients provides balance to institutional discrepancies and establishes a broad benchmark for the prevalence of multifocal and bilateral disease in sMTC. Preoperative analysis of RET gene mutation is an important point of differentiation, as up to 17% of patients with apparent sMTC with no family history or diagnostic criteria for MEN2A have been found to harbor germline RET gene mutations (26). While separate results for the entire cohort and those with known negative analyses for germline RET mutations are provided, these results were not statistically different. Only 3/17 patients with bilateral disease did not undergo germline RET mutational analysis.

The limitations of the current study include its retrospective nature and the lack of standardized protocol in assessing surgical specimens (such as number of tissue sections examined or use of calcitonin immunohistochemistry) or extent of RET gene analysis (e.g., rare or newly identified variants associated with inherited MTC may not have been investigated). Most familial MTC cases are identified when testing the most commonly affected exons, so additional testing for rare mutations is unlikely to change the findings meaningfully. In Tables 4 and 7, it should be noted that the Sao Paulo site contributed the largest fraction of patients to this study and routinely sequenced exons 8, 10, 11, and 13–16 of the RET gene in their entirety, and 45 of these patients also underwent extended testing of exons 1–7, 9, 12, 17, 18, and 19 (40). The Sao Paulo rates of bilaterality and multifocality are consistent with those of the entire cohort, and add credibility and generalizability to the findings. Additional limitations include the lack of standardized use and extent of lymph node surgery in sMTC among the participating centers, and the N stage may have been underestimated in patients who did not undergo maximal lymph node dissection. Finally, 312 patients were included in the analyses of multifocality, and 306 patients in the analyses of bilaterality. The difference was that six patients underwent only hemithyroidectomy (Fig. 1). Unifocal disease was found in five of these patients, and multifocal disease in the remaining patient. These five (or six) patients could have been excluded from the multifocality analyses, since the status of the contralateral lobe was unknown, although it is unlikely that the findings would have changed significantly, as the unifocal patients would have required finding disease in the contralateral lobe to change their focality status, and the data demonstrate that the prevalence of this occurring is low.

Conclusion

On average, 1/18 patients with sMTC have bilateral tumor foci in the thyroid gland. This finding supports the ATA and NCCN guideline recommendations that total thyroidectomy should remain the initial standard of care as opposed to hemithyroidectomy. In patients diagnosed with apparent sMTC following a hemithyroidectomy, these guidelines indicate that RET germline mutation status, serum calcitonin, and the results of imaging studies should determine the role of completion thyroidectomy (2, 9). sMTC patients with multifocal MTC in the ipsilateral thyroid lobe or isthmus have a significant prevalence of MTC in the contralateral lobe. It remains unknown if ipsilateral tumor focality should be included as an independent factor when considering completion thyroidectomy.