Present status of prophylactic thyroidectomy in pediatric multiple endocrine neoplasia 2: a nationwide survey in Japan 1997–2017

Introduction

Medullary thyroid carcinoma (MTC) arises from C cells and occurs in almost all patients with multiple endocrine neoplasia type 2 (MEN2) caused by germline mutations in the RET gene. Because lymph node metastasis starting during the early stage of tumorigenesis is common, patients with MTC are at increased risk of postoperative recurrence [1]. Moreover, in hereditary MTC, the rate of progression from C cell hyperplasia (CCH) to MTC increases with age [2].

For hereditary MTC, prophylactic total thyroidectomy in early childhood is recommended by a consensus statement by Brandi et al. and the guidelines established by the American Thyroid Association (ATA), according to the estimated recurrence risk [3], [4], [5], and is an important treatment option for recurrence-free survival in all carriers of RET gene mutations [3], [4], [5]. Based on genotype-phenotype correlations, ATA classified the risks of hereditary MTC as highest (RET M918T mutation, phenotype MEN2B), high (codon 634 mutations, phenotype MEN2A and RET A883F mutation, phenotype MEN2B), and moderate (RET codon mutations other than M918T, C634, and A883F, phenotype MEN2A) in the 2015 revised guidelines for the diagnosis and management of patients with MTC [5].

However, the ATA also reports that thyroid surgery frequently causes postoperative complications in children, particularly in infants [5], [6]; the most common postoperative complications are hypoparathyroidism [7], [8], [9] and recurrent laryngeal nerve (RLN) palsy.

Due to concerns about balancing the need for prophylactic resection and overtreatment/postoperative complications, thyroid surgery is often performed at age >10 years in Japan [10], [11]. Moreover, in Japan, RET gene testing during screening of patients with MTC is covered by insurance, but RET screening test before onset in the proband’s family and prophylactic thyroidectomy are out-of-pocket expenses. Surgery at a higher age than the ATA-recommended age may be the cause of the 39% recurrence at age 10–20 years among Japanese pediatric hereditary MTC patients [10], [11].

It remains unclear whether the low rate of complications from thyroid surgery in early childhood reported in large facilities is also true when a smaller number of pediatric patients with thyroid cancer are treated. Thyroid cancer rarely occurs in children, with an incidence of 0.54 per 100,000 person-years. Furthermore, MTC accounts for only 5% of all pediatric thyroid cancer patients [12]. Therefore, few studies concerning postoperative complications of prophylactic thyroidectomy in children with MEN2 have been reported from large facilities [7], [8], [9].

The introduction of a sensitive diagnostic assay using calcitonin as a tumor marker for MTC has increased the accuracy of predicting malignancy [13]. Electrochemiluminescence immunoassay (ECLIA) is currently considered the most sensitive diagnostic test for MTC [14] and has been used to measure calcitonin in all medical facilities in Japan since April 2015. Herein, we aimed to identify the pathological onset or timing of increased calcitonin levels among Japanese children, the frequency of prophylactic thyroidectomy, prognosis, complications and rate of recurrence in patients with hereditary MTC. Toward this goal, the Japanese Society for Pediatric Endocrinology (JSPE) conducted a nationwide survey of young patients with RET gene mutations or MEN2.

Subjects and methods

Results

Of the 26 patients registered by the Thyroid Committee of the JSPE, 21 patients with MEN2 were enrolled (highest risk, n=5; high risk, n=5; and moderate risk, n=11) (Figure 1). Patient characteristics are shown in Table 1. All 16 patients with MEN2A, i.e. those with a high or moderate risk, had a family history of MEN2 and had undergone genetic testing at a young age (median, 3 years; range, 0–8 years). All patients with MEN2B, i.e. those with the highest risk, had a de novo mutation and had been diagnosed at an older age, after the MTC clinically occurred. Of the five patients with MEN2B, four (80%) underwent a detailed examination for refractory diarrhea or constipation before being diagnosed with MTC (data not shown).

Figure 1:

Inclusion and exclusion criteria.

Pre-symptomatic thyroidectomy was performed in seven of 16 patients with MEN2A (44%); five patients were awaiting surgery after disease onset possibility (median, 1.0 [range, 0.5–1.8] year), and four patients in the same family were lost to follow-up. Five of the seven patients (71%) with MEN2A who underwent surgery received prophylactic thyroidectomy as defined by the ATA. No thyroid lesion was detected preoperatively in any patient with MEN2A.

The dates of pathological disease onset or first increased calcitonin timing, surgical pathological diagnosis, prognosis, and rate of recurrence or residual disease or residual thyroid tissues in patients with MEN2A are shown in Figure 2.

Figure 2:

Cumulative incidence of first serum calcitonin increased timing, C cell hyperplasia (CCH) or medullary thyroid carcinoma (MTC) in patients with multiple endocrine neoplasia type 2A (MEN2A) (n=16).

The solid line indicates high-risk patients (n=5), whereas the dotted line indicates moderate-risk patients (n=11). Each curve represents adjustments for competing risks for high- and moderate-risk patients. The onset in patients with pathological MTC or CCH and the adjusted onset in pathologically normal patients undergoing surgery are shown as follows:●: MTC, ○: CCH, and □: normal. ∆ Patients with increased calcitonin levels who did not undergo surgery. ¶ The need for prophylactic thyroidectomy was determined according to the American Thyroid Association (ATA) definition: high risk, before or at 5 years of age based on serum calcitonin levels; moderate risk, serum calcitonin level increase or children of parents who refused long-term treatment. ^*Increased serum calcitonin levels after total thyroidectomy was defined as an increase in baseline calcitonin levels of >0.5 pg/mL after total thyroidectomy, as measured via the electrochemiluminescence immunoassay (ECLIA). The baseline level of this patient was 1.33 pg/mL.

Surgical and postoperative complications

Postoperative complications are shown in Tables 2 and 3. Transient RLN palsy occurred in a moderate-risk patient aged 17 years (patient no. 6) and a high-risk patient aged 10 years (patient no. 3). Two high-risk patients (aged 5 and 9 years; no. 1 and 2, respectively) experienced transient hypoparathyroidism (Table 2). Hypoparathyroidism was the only permanent complication (n=4; patients no. 17, 19, 20, and 21); it occurred only in the highest-risk patients who required lymphadenectomy (Table 3). No permanent complications were observed in patients who did not undergo cervical lymphadenectomy or were aged 5–6 years. The incidence of permanent complications increased with age and as the area of the neck lymphadenectomy widened. As shown in Figure 3, patients were referred to many different surgeons by the physician in charge. The surgery department showed no correlation with postoperative complications.

Table 2:

Incidence of any complications after thyroidectomy according to age.

Type of complication	Children with any postoperative complications
		Age (years)
	Total (%)	3–6	7–12	13–18
Transient RLN palsy	2 of 12 (17)	0 of 3 (0)	1 of 7 (14)¶	1 of 2 (50)§
Transient hypoparathyroidism	2 of 12 (17)	1 of 3 (33)§	1 of 7 (14)¶	0 of 2 (0)
Permanent hypoparathyroidism	4 of 12 (33)	0 of 3 (0)	3 of 7 (43)¶,*	1 of 2 (50)*
Any complication	8 of 12 (67)	1 of 3 (33)	5 of 7 (71)	2 of 2 (100)

1. ¶With central dissection.

2. *With central and lateral dissection.

3. ^§Thyroidectomy.

4. Abbreviations: RLN, recurrent laryngeal nerve.

Table 3:

Permanent complications after surgery by extent of surgery according to age.

Extent of surgery	Children with permanent postoperative hypoparathyroidism
		Age, years
	Total (%)	3–6	7–12	13–18
Thyroidectomy	0 of 3 (0)	0 of 1 (0)	0 of 1 (0)	0 of 1 (0)
With central dissection	1 of 6 (17)	0 of 2 (0)	1 of 4 (25)
With central and lateral dissection	3 of 3 (100)		2 of 2 (100)	1 of 1 (100)
Any surgery	4 of 12 (33)	0 of 3 (0)	3 of 7 (43)	1 of 2 (50)

Figure 3:

Types of referrals from physicians in charge to surgeons and postoperative complications.

Own: Surgery was performed at the same institution (the physician in charge referred the patient to a surgeon within the same facility for surgery). Other: Patient was referred to a surgeon at another facility.

Discussion

We confirmed the several tendencies in Japanese pediatric MEN2: those of therapy policy variations in each facility and higher age at thyroidectomy than that recommended by the ATA. There were no permanent complications due to prophylactic thyroidectomy, but there were many transient surgical complications. Moreover, there was a high proportion of surgical complications among advanced MEN2B cases with lymphadenectomy. In order to solve these problems, it is necessary to discuss whether prophylactic thyroidectomy at low age will reduce surgical complications and improve the probability of recurrence. It is also necessary to consider whether there is merit in cost.

First, regarding operative complications, few studies have reported on postoperative complications of prophylactic thyroidectomy in children (Table 4) [7], [9], [23], [24], revealing a higher risk of postoperative complications when neck lymphadenectomy was performed at a young age. In those studies, and ours, permanent RLN palsy occurred in only a 1-year-old boy [7] out of 347 patients (0.3%). Permanent hypothyroidism occurred in 27/347 patients (7.8%). There was no surgery-related death. Generally, the parathyroid glands of children younger than 5 years are translucent and small; postoperative complications, including hypoparathyroidism, are more common with pediatric thyroid surgery when compared to those in adults [6]. However, adult Japanese MEN2 patients who underwent thyroidectomy with 94.9% neck lymphadenectomy also had a high operative complication rate: permanent RLN palsy 11/330 (3.3%), permanent hypothyroidism 74/327 (22.6%) [11]; 80% of MEN2B patients of higher age in our study had permanent hypoparathyroidism. These suggest that clinically apparent disease requiring aggressive surgery with neck lymphadenectomy is associated with a high rate of permanent complications.

The ATA guidelines recommend that patients should be referred to experienced surgeons to decrease the rate of postoperative complications [5], [6]. It is noteworthy that facilities with a high number of pediatric thyroid surgeries exhibited no permanent surgical complications [9]. The present study analyzed data from multiple facilities at which thyroid surgeries were not frequently performed in children. The incidence of transient RLN palsy was 1.8% in high-volume facilities; in contrast, it was 28.6% (2/7 patients with MEN2A) in our study [9]. Another nationwide report described a high proportion of permanent hypoparathyroidism in 15/79 patients (19.0%) [24].

Second, regarding recurrence, we believe that operations for children in high-volume facilities also reduce recurrence. In reports where the definition of prophylactic thyroidectomy was closest to that of the ATA and where age was considered in high-volume facilities, the rate of recurrence or residual disease was 0.7–5% [7], [9]. On the other hand, a nationwide survey that included cases with delayed surgery had 62% recurrence or residual disease proportion [24]. Of course, it was obvious that the definitions were different in that report. The data regarding prophylactic thyroidectomy among pediatric patients with MEN2 are shown in Table 4 [7], [9], [23], [24]. Patients with suspected recurrence or residual disease all had biochemical recurrence or were at the residual disease stage, except for one MEN2B patient with advanced MTC [24]. Notably, in hereditary MTC, recurrence was observed in both high- and moderate-risk patients aged >8 years, even if MTC was not in the advanced stage [23].

Our study included a patient with a high-risk C634Y mutation who had elevated serum calcitonin levels after undergoing total thyroidectomy at 5 years of age with CCH in pathology. Detectable thyroglobulin level may indicate remnant thyroid tissue in this patient. However, because micrometastases can occur during an early stage in MTC, recurrence or residual disease cannot also be denied. The recurrence proportion in hereditary MTC is 4% among cases with tumor size <2 mm and node negative at surgery [1]. Hereditary MTC has an estimated annual growth of 0.4–0.5 mm [25]. Accordingly, at least after the elevation of calcitonin, surgery should not be postponed. MTC-related death at 12 years has been reported in moderate-risk patients [26]. The ATA states that delaying surgery after disease onset increases the risk of recurrence. However, in patients aged ≤3 years, calcitonin levels are physiologically high; thus, an early determination of disease onset is challenging [20]. Moreover, unexpected postoperative complications can occur [7]. Thyroid hormones substantially affect an individual’s growth and development [27], particularly in children; thus, cautious judgment is necessary. Because metastatic MTC is extremely rare in patients with MEN2A aged ≤3 years, the ATA does not recommend surveillance in this patient population.

Lastly, we should solve the cost problem for children. In Japan, most medical expenses are covered by the universal healthcare insurance system. However, prophylactic surgery is not covered. This may be one reason why most children aged <10 years do not undergo prophylactic resection [10]. This may have influenced the mean age at MTC-related death in patients with MEN2, i.e. 53 years [28], causing economic loss.

There is an obvious cost benefit for preventive removal. About 30 MEN2 patients were born yearly in Japan. If the gene mutation is already known, the cost of 1 exon is $350 (1$=110 JPY), and the total cost for 30 persons with autosomal dominant siblings without genetic mutation is about $10,820. This is not high considering unnecessary surveillance. In addition, the fee for levothyroxine 100 μg per day per year comes to $36 per person. When hypoparathyroidism occurs, the cost of 0.5 μg per day of alfacalcidol per year comes to $198 per person. The monthly per capita expenditure for one person using vandetanib in the event of a recurrence is $12,236.40 [29].

In countries similar to Japan that have cost problems with prophylactic thyroidectomy, early calcitonin level-based thyroidectomy not based on age is needed to reduce surgical delay and postoperative complications and improve prognosis in pediatric MEN2. This is because early thyroidectomy may improve the timing of surgery with a large heterogeneity in the age of onset and aggressiveness of MTC. A previous study reported that prognosis after disease onset is similar in high- and moderate-risk patients [30], even in MEN2B [31]. The penetration rate of MTC among individuals aged 50 years is 83% in high-risk patients [32], whereas it varies among those with a familial history of identical genetic mutations [22], [33].

Our study showed that, in patients with MEN2A, using ECLIA-based calcitonin measurements to speculate the onset allowed for earlier recognition of the disease when compared to the results of other studies. In our study, the cumulative incidence of CCH or MTC or first increased serum calcitonin reached 50% at the age of 5 years and 100% at the age of 9 years and reached 50% at the age of 8 years and 100% in moderate-risk patients aged ≥17 years. A study in high-risk MEN2A patients who underwent surgery reported that CCH and MTC occurred at the ages of 6.9 years and 10.1 years on average, respectively [2]. For moderate-risk, another report showed that the cumulative incidence of MTC reached 50% in moderate-risk patients aged 13–18 years [9]. Reasons potentially explaining these differences are as follows. First, our study could not distinguish CCH or MTC in patients who did not undergo surgery. Second, there were differences in patient risks that were included. In our study, moderate-risk included only extracellular RET mutations that were classified as level B in the previous ATA guideline [4]. However, there may not be a strong selection bias. For example, in the German series, the prevalence of risk was determined as level B, that is higher risk in moderate-risk 144/567 (25.4%) or level A 163/567 (28.7%) [34], whereas in the Japan series, risk was level B 144/505 (28.5%) and level A 45/505 (8.9%) [11]. Lastly, as this study included patients without surgery, there is a possibility of false positives.

A study of medullary thyroid microcarcinoma in adults reported that lymph node metastases in the neck were observed in patients with calcitonin levels of 10–40 pg/mL, measured via the solid two-site immunoradiometric calcitonin assay [13]. Meanwhile, no recurrence was observed among children whose preoperative calcitonin level was <30 pg/mL, as measured via immunoradiometric assays during long-term follow-up [35]. In our study, disease onset possibility was recognized starting at very low calcitonin levels (<10 pg/mL). Thus, even in cases in which total thyroidectomy was performed at a higher age, the indication for surgery, i.e. the prevention of recurrence was still within that stipulated by the ATA.

The present study has many limitations, including its retrospective design and the small number of included cases due to the rarity of the disease. Moreover, the data were only collected from pediatricians and pediatric surgeons; thus, selection bias was unavoidable. The degree of progression in patients who did not undergo surgery was unclear, and the number of cases in which preoperative calcitonin levels were measured via the ECLIA was small. The calcium stimulation test is the only test used in Japan that is nonspecific compared to the pentagastrin stimulation test. Our study also included patients whose detailed clinical histories and prognoses were unavailable, due to changing hospitals or for other reasons, and the follow-up period was short; thus, the long-term prognosis related to recurrence could not be analyzed.

In conclusion, prophylactic thyroidectomy may be advantageous in patients with MEN2 as it can achieve a balance between a reduction of postoperative complications and the risk of recurrence. However, considering the large heterogeneity in hereditary MTC, measuring calcitonin levels via the ECLIA can provide a clinical basis for early thyroidectomy in collaboration with various medical specialties and in consideration of the country’s medical system.