Familial medullary thyroid cancer: clinical aspects and prognosis

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Abstract

Objective

To assess clinical features and long-term results of treatment of familial medullary thyroid carcinoma (FMTC).

Design

Retrospective analysis of all patients with familial forms of MTC diagnosed between 1949–2000 and treated in our unit.

Results

Fifty five patients (25 males, 30 females) were identified with at least two first-degree relatives affected by medullary thyroid cancer; 26 were classified as MEN 2A, 1 as MEN 2B and 28 as FMTC. Median age at diagnosis was 35 years (MEN 2A), 25 (MEN 2B) and 47.5 (FMTC). Median follow-up was 9 years (range: 4–24). Total or near-total thyroidectomy was performed in all patients and 11 received adjuvant external beam radiotherapy. Cause specific survival was 89% at 10 years and 77% at 20 years for MEN patients, 51% and 32% for those with sporadic MTC, and 46% and 26% for those with FMTC. In multivariate analysis, factors predicting survival were presence of metastases, nodal status and age at diagnosis.

Conclusions

Improved survival rates associated with familial types of MTC can be accounted for by the earlier stage at which disease is detected and the younger age at presentation. These observations emphasize the need for early detection in those at risk.

Introduction

Medullary thyroid carcinoma (MTC) is a rare tumour derived from the parafollicular C cells of the thyroid, accounting for 5–10% of all thyroid malignancies.1, 2 Although the majority are sporadic, as many as 20–25% are inherited.3, 4 Early observations by Sipple5 identified an association between inherited MTC and neoplasia of the adrenal glands. Later, associations with mucosal and skeletal abnormalities were described. These clinical entities are now known as the multiple endocrine neoplasia (MEN) type 2 syndromes.6 Three phenotypes are described: (i) MEN 2A is characterized by the development of MTC, phaeochromocytoma and parathyroid hyperplasia/adenoma (ii) MEN 2B by MTC, marfanoid habitus and mucosal neuromas and (iii) familial MTC (FMTC) where inheritance is of MTC alone.

Phaeochromocytoma and parathyroid hyperplasia/adenoma develop in 50 and 20% of patients with MEN 2A, respectively.7, 8 Consequently, small MEN 2A families or late onset of clinical associations could result in some MEN 2A individuals being misclassified as having FMTC. The distinction between familial MTC and MEN 2A can be reliably made only after long follow-up.

All MEN subtypes are inherited in an autosomal dominant manner. In the past decade the molecular basis of the MEN 2 syndromes has been elucidated and are now known to be due to inherited mutations in the ret proto-oncogene located on chromosome 10.9 An identifiable ret mutation can be detected in about 85% of FMTC families.10

The natural history of FMTC is unclear based mainly from data from relatively few families. There is evidence that MTC occurs later in life in FMTC families and may have a more indolent course.11 Guidelines for management based on the natural history of MEN 2A and 2B patients may not be applicable to FMTC families.

We have previously reported our experience with sporadic medullary thyroid cancer.12 Here, we review all patients with inherited MTC treated in our unit between 1949 and 2000 to analyse their clinical features and prognosis.

Section snippets

Patients and methods

The Royal Marsden Hospital serves as a tertiary referral unit for patients with thyroid disease and maintains a tumour registry of all thyroid cancer patients based on a confirmed report of thyroid malignancy. All clinical information at presentation and at follow-up was entered at the time of the consultation. Clinical evaluation consisted of history and examination with particular attention to features of MEN 2 syndromes. Patients were followed until death and cause of death was recorded.

Statistical methods

Actuarial survival was calculated from the date of diagnosis by the Kaplan–Meier method. The effect of patient and tumour characteristics on survival was evaluated in univariate analysis by the log-rank method and the variables found to be significant at p<0.01 were put into a stepwise Cox proportional hazard model in a multivariate analysis to establish which had significant influence on survival.

Results

Clinical characteristics of patients with familial forms of MTC are shown in Table 1. Compared to other groups, MEN 2A patients were more likely to have less advanced disease at presentation (more likely to be M0 or N0); Table 2, Table 3. Within the MEN 2A group, the 12 patients detected by screening had smaller tumours compared to the 14 who presented with symptoms although there was no difference in their nodal status.

Median age (range) at presentation of clinical disease was 35 (8–66) for

Discussion

The outcome of familial forms of MTC is generally considered to be favourable although published series are often based on data from relatively few families. Whilst the number of hereditary MTC cases in this study is comparable with previous studies4, 13 our results are based on a prolonged period of follow-up performed at a single institution using standardised diagnostic criteria.

The distinction between FMTC and MEN 2A can be difficult particularly in small families with inadequate follow-up

Conclusion

This study provides additional evidence to support previous reports that patients with FMTC have an intermediate prognosis compared with MEN 2A patients and those with sporadic disease. MTC developed at a later age in FMTC families compared with MEN kindred. In this study, MEN clinical status was not found to be an independent risk factor and the differing prognosis between the patient groups relates to the less advanced disease and younger age at presentation in the MEN 2A patients. This

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