Concomitant Thyroid Cancer in Patients with Multiple Endocrine Neoplasia Type 1 Undergoing Surgery for Primary Hyperparathyroidism

Introduction

Primary hyperparathyroidism (PHP) is a common endocrine disorder that results from autonomous hypersecretion of parathyroid hormone. Histologically, PHP can arise from a hyper-functioning single adenoma, double adenomata, hyperplasia, or parathyroid carcinoma. Surgical management is the only definitive treatment (1).

While most PHP cases are classified as sporadic, the disorder can also result from inherited syndromes in 3–18% (1,2). A sizable proportion of inherited PHP is due to multiple endocrine neoplasia type 1 (MEN1). One series reported that 12/19 (63%) cases of inherited PHP were associated with MEN1, and among patients found to have multi-glandular hyperplasia for presumed sporadic disease, up to 26% may have undiagnosed MEN1 (3 –5). MEN1 is caused by a loss of function alteration in the menin (MEN1) gene, but not all genetic changes are identifiable by conventional testing methods. The diagnosis can be reached by clinical or familial criteria, in addition to genetic testing (2,6,7). PHP is seen in 90% of patients with MEN1, and other common clinical manifestations of MEN1 include pancreatic neuroendocrine tumors, particularly gastrinoma (30–70%), pituitary tumors (30–40%) as well as benign adrenal tumors (40%), lipomas (30%), and other soft-tissue tumors such as collagenomas and angiofibromas (70–80%) (8). PHP presents at a younger age in MEN1 than in sporadic PHP (SPHP) and has a more equal sex distribution (2,9). Multi-glandular parathyroid disease is expected in MEN1 patients, and they typically require more extensive dissection. Today, the standard initial approach is subtotal parathyroidectomy (1,2). In MEN1, there is a high lifelong likelihood of recurrence, and parathyroidectomy is rarely or never curative (1,2,8).

For all patients with PHP, current management recommendations include routine preoperative evaluation of the thyroid due to a significant risk of concomitant thyroid disease (12–67%). Current estimates of concomitant thyroid cancer rates among SPHP patients range from 2% to 18% (1,10,11), but up to 58% of these are papillary microcarcinomas (PTMC) defined as <1 cm in diameter (10,12). Identified thyroid nodules should be fully evaluated according to the current guidelines (12), and if indicated, concurrent thyroid resection is recommended at the time of parathyroidectomy (1).

However, little is known about thyroid nodules and thyroid cancer in MEN1. After noting an anecdotally high rate of differentiated thyroid cancer in MEN1 patients and in order to assess whether MEN1 patients should undergo specific preoperative counseling about thyroid carcinoma, a study was designed to examine objectively the thyroid cancer rates in patients undergoing parathyroid exploration for MEN1-related parathyroid disease compared to those with SPHP.

Methods

Results

Among 87 patients with MPHP, 29 had concurrent thyroidectomy. As described above, a 2:1 age- and sex-matched cohort (n = 58) was selected from 745 patients with SPHP who met the inclusion criteria (i.e., who had concurrent thyroidectomy during parathyroid exploration). Sex and age distributions for both cohorts are included in Table 1. Three MPHP patients and one SPHP patient had more than one thyroid operation. Thyroidectomy was performed for 45% of the MEN1 cohort during initial parathyroid surgery and in 66% at reoperation. Again, this distribution differs significantly from that of SPHP patients, 93% of whom underwent thyroidectomy at initial parathyroid operation compared to only 9% at reoperation (p < 0.01). Unsurprisingly, the MEN1 group had significantly more operations for hyperparathyroidism (M = 2.55 vs. 1.07, p < 0.01) and a higher rate of multi-glandular disease than the SPHP cohort (100% vs. 7%, p < 0.01). Prior to MEN1 diagnosis, three MPHP patients had an initial unilateral parathyroid operation with removal of a single abnormal gland and subsequent recurrent PHP, but they have not been reexplored to date.

The indications for and extent of thyroidectomy are detailed in Table 1 and were found to differ by cohort. Thyroidectomy was more often unplanned in MPHP than in SPHP (83% vs. 34%, p < 0.01). In particular, more MPHP patients required thyroidectomy combined with parathyroidectomy than did SPHP patients (83% vs. 29%, p < 0.01), while more SPHP patients required thyroidectomy for a preoperatively evaluated thyroid nodule than did MPHP patients (59% vs. 10%, p < 0.01). Altogether, 7/29 (24%) MPHP patients and 6/58 (14%) SPHP patients had an intrathyroidal parathyroid gland (p = 0.24).

In comparing the two cohorts, MPHP patients were not more likely to have histologic thyroid cancer (28% vs. 47%, p = 0.11), although the sample size may have been underpowered for this parameter. Even when limiting the analysis to unplanned thyroidectomies, there was no difference in prevalence of thyroid cancer in MPHP versus SPHP patients (13% vs. 25%, p = 0.44). Because imaging tests, particularly the routine use of ultrasound, differed over the course of the study period (above), the year of surgery was evaluated in relation to the extant type of parathyroid imaging. After routine ultrasound was added to the preoperative evaluation in 2005, 12/29 (41.4%) MPHP patients underwent thyroidectomy compared to 44/58 (75.9%) SPHP patients (p < 0.01). In addition, the median date of thyroidectomy in the SPHP matched cohort was September 2, 2011, compared to May 30, 2000, for the MPHP cohort.

Because thyroidectomy (lobectomy or total thyroidectomy) was more likely in the MPHP cohort prior to the use of routine ultrasound, multivariate analysis was performed to assess the effect of these potentially confounding factors that can be associated with thyroid cancer. Despite observed differences in the extent or timing of surgery, MPHP patients did not have an increased likelihood of thyroid cancer (surgery before 2005: odds ratio [OR] = 2.57, p = 0.09; total thyroidectomy: OR = 5.47, p < 0.01; MPHP: OR = 1.14, p = 0.83). However, compared to lobectomy, total thyroidectomy was independently associated with a 5.5-fold increase in the likelihood of thyroid cancer.

Histologically, all cancers in MEN1 patients were conventional PTC, while the thyroid cancers in the SPHP cohort were PTC (66%) and FVPTC (34%, p = 0.08). Interestingly, none of the thyroid cancers identified in MPHP patients were >1 cm in diameter, that is, all would be considered, by current definitions, to be PTMCs (12), and none required completion thyroidectomy or ablation. Conversely, 15 clinically significant cancers >1 cm in diameter were identified in SPHP patients (0% vs. 26%, p < 0.01; Table 2), all of whom underwent total thyroidectomy, and 67% had radioactive iodine ablation.

Discussion

As expected, the demographic findings of this study are in keeping with the unique epidemiology and etiology of hyperparathyroidism in MEN1, with a significantly younger age and more equal sex distribution for MPHP than for sporadic disease, which occurs predominantly in older women (1). Since it is well studied that thyroid nodules increase in prevalence with age (12,16 –18), the 2:1 age- and sex-matched study design allowed a direct comparison of thyroid cancer rates.

With the characteristic multi-glandular parathyroid disease of MEN1, the observed higher reoperative rates of MPHP substantiate the higher risk of recurrent or persistent hyperparathyroidism reported in the literature (1,2,19 –22). Due to the natural history of their parathyroid disease, MEN1 patients also require more extensive cervical surgery, and to this point, when the reasons for thyroid resection were examined, the MEN1 patients predominantly underwent unplanned thyroidectomy (i.e., thyroid resection that was intraoperatively necessary during the requisite four-gland parathyroid exploration; 89%) and their thyroid resections also occurred primarily in the reoperative setting (66%). Conversely, concurrent thyroidectomy in sporadic hyperparathyroidism more often resulted from a preoperatively identified thyroid lesion (59%).

The recommended gold standard approach for evaluating thyroid nodules prior to parathyroid exploration includes routine ultrasound (1), for which the features of microcalcifications, irregular margins, and taller-than-wide shape have specificities of >90% for thyroid cancer (12). Such suspicious sonographic features should prompt ultrasound-guided fine-needle thyroid aspiration, with malignant Bethesda cytology associated with a 97–99% risk of thyroid malignancy (12). The two cohorts differed in the rate of routine preoperative ultrasound use, since surgery prior to 2005 was more common in the MPHP cohort. However, when controlling for this variable, the observed cancer rates were not different. Similarly, MPHP patients disproportionately underwent lobectomy, so that small cancers in the remaining thyroid lobe could not be fully excluded—yet, cancer rates did not differ between cohorts when accounting for extent of thyroidectomy in multivariate analysis. Cohort-related differences in thyroid cancer type were identified. First, histologic FVPTC was a cancer type that was only observed in the SPHP group, although this finding may relate to changing diagnostic histology criteria during the study period. Second, the cancers identified in MPHP patients were all microcarcinomas, while those found in SPHP patients were clinically significant in more than half of cases. Outcomes following surgery for PTMCs are excellent, with disease-specific mortality rates of <1% (12). On aggregate, the study findings suggest a natural history effect of thyroid cancer disease progression, that is, the finding that clinically significant thyroid cancer is rare in MEN1 is likely because thyroidectomy in MEN1 often occurs before a cancer grows large enough to be clinically apparent.

Preoperative counseling for parathyroid exploration for PHP today often includes a discussion about potential thyroidectomy, but this is not always the case. It is particularly necessary for MEN1 patients, who of course have multi-glandular parathyroid disease that typically requires reoperative parathyroid surgery over decades. However, the findings reported here indicate that the preoperative evaluation and management of thyroid nodules in MEN1 patients do not need to be any more extensive than the evaluation in SPHP patients.

This study has several limitations, including its retrospective nature. While the database is prospectively maintained, patients were treated according to standard practice at the time of surgery, which has evolved over time, including changing histology criteria and molecular advances in the evaluation and management of thyroid nodules (23,24). Imaging resolution has also advanced, leading to the identification of more and smaller thyroid nodules than in prior years (12,25). Thus, chronological bias may exist, as the rarity of MEN1 necessitates a long study period (1967–2014). In addition, thyroid US was not routinely employed in this population prior to 2005, and hence small cancers may have been missed. After the addition of routine US to the evaluation of all patients with PHP, any missed cancers in the unresected lobe would be quite small and likely not clinically relevant. Further, the extent of thyroidectomy was based largely on preoperative results, and small cancers in the remaining lobe of those who had only thyroid lobectomy cannot be excluded. Finally, while the matched design improves the ability to compare SPHP to MEN1 patients, matching also makes the results from the SPHP cohort less generalizable to all patients with SPHP, and because the matched groups are small, the results may suffer from type 2 error.

Conclusions

When compared to those with SPHP, MEN1 patients require more parathyroid operations and more unplanned thyroidectomies. While occult thyroid cancers are about as common in MEN1 as in sporadic hyperparathyroidism, clinically significant cancer is rare in MEN1 patients, who are also generally younger at the time of thyroidectomy. The results suggest that MEN1 is not associated with a higher risk of thyroid cancer. Surgeons and other providers involved in the care of patients with MEN1-associated hyperparathyroidism should continue to adhere to current guidelines for preoperative thyroid screening in this population.