Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution's experience over 20 years.

OBJECTIVE: Many patients with medullary thyroid carcinomas (MTC) have reoperative surgery in different hospitals, which makes their follow-up difficult. To comprehend these complex courses and to find relevant prognostic factors we report a 20-year single center experience of 289 patients with MTC or precursor C-cell-hyperplasias. PATIENTS AND METHODS: Between April 1986 and May 2006, 289 consecutive patients with MTC or MEN2 gene carriers were treated at the Department of Surgery at the University Hospital Düsseldorf. Tumor stages were documented according to the classification of the International Union against Cancer 5th edition, 1997 (Schott. Endocr Relat Cancer. 2006;13:779-795). A system to easily comprehend operative procedures is suggested. RESULTS: There were 159 female and 130 male patients (f/m ratio 1.22). Mean age at time of diagnosis was 32 years (4-77) in the familial cases and 53 years (23-84) years in the sporadic cases. Sixty-six patients (23%) had multifocal disease. Twelve MEN2-patients had only C-cell-hyperplasia (pT0). Tumor stage was pT1 in 86 patients, pT2 in 106 patients, pT3 in 25 patients, pT4 in 52 patients and unclear in 8 patients. In the 289 patients 648 operations were performed. One hundred seventy patients had more than 1 operation (59%). Ninety-nine patients (34%) are calcitonin-negative and 91 patients (31%) live with elevated calcitonin. Median follow-up time of the surviving 211 patients was 8.9 years (range, 0.3-30.7 years). The 5- and 10-year survival of all tumor patients was 86% and 68%, respectively. CONCLUSION: The chance to achieve biochemical cure in MTC is clearly dependent on the primary tumor size. The chance for long-term biochemical cure in a pT4-tumor is almost nil even after multiple and extended reoperations, whereas a pT1 tumor can be cured in up to 67% of the patients. Long-term survival, however, can be achieved even in pT4 tumor patients in almost 50%.

Mitochondrial DNA mutations in differentiated thyroid cancer with respect to the age factor.

INTRODUCTION: Increased numbers of mitochondria in differentiated thyroid cancer and, most strikingly, mutations in human mitochondrial DNA (mtDNA) in older people have led to speculation that mtDNA mutations might contribute to aging or accumulate in postmitotic tissues with age. Mutation analyses of mtDNA in papillary (PTCs) and follicular (FTCs) thyroid carcinomas have been limited to date. The significance and frequency of mtDNA mutations in PTC and FTC are therefore controversial, as is age dependence. METHODS: We analyzed eight sample pairs of PTC and six of FTC tissue with the corresponding normal thyroid tissue. DNA was extracted from frozen and formaldehyde-fixed tissue using the QIAmp Tissue Kit. Sequence differences in the mtDNA between tumor and normal tissue were detected using appropriate polymerase chain reaction (PCR) products for heteroduplex analysis in a denaturing high performance liquid chromatography (HPLC) Wave System (Transgenomic). Mutations were confirmed and identified by sequencing the PCR products of conspicuous chromatograms. The samples were obtained from 346 patients with PTC and 105 patients with FTC. We analyzed the whole mitochondrial genome from seven PTC and three FTC tumors along with the corresponding normal thyroid tissue. 3/7 PTC samples showed two heteroplasmic mutations and one polymorphism; all 3 FTCs showed homoplasmic and/or heteroplasmic mutations. RESULTS: All but one of these tumors are well documented in the mitochondrial database MITOMAP. MtDNA mutations were found in all three patients aged 45 years and older. There was no correlation, however, in this small group to clinical prognostic factors for recurrence and especially for survival in differentiated thyroid carcinomas, such as histology, tumor size, lymph node metastases, distant metastases, and gender, most likely because of the short follow-up. While univariate analysis of the findings in the whole cohort of 346 patients with PTC suggested that age is a significant prognostic factor for survival (P = 0.0237) but not for recurrence (P = 0.65), this was not the case in the 105 patients with FTC. CONCLUSIONS: Although we found accumulation of mutations in two older patients with PTC and one patient with FTC (all three patients older than 45 years had mtDNA mutations), the low frequency of these mutations in the small group of 10 analyzed patients did not correlate with statistically validated clinical prognosticators for recurrence or survival, especially not with age. The low power of our data are therefore not able to support or refute the hypothesis that these mtDNA mutations are related to age-dependent tumor progression in the thyroid or that they "may be involved in thyroid tumorigenesis."

Importance of lymph node metastases in follicular thyroid cancer.

There are many concepts of risk and prognostic factor analysis for differentiated thyroid cancer. The prognostic role of lymph node metastases in follicular thyroid cancer (FTC), however, is still controversial. We performed a retrospective trial in 186 patients with FTC (124 women, 62 men; mean follow-up 5.5 years) questioning whether lymph node metastases and radical thyroid surgery with neck dissection contribute to the prognosis of FTC. Univariate analysis demonstrated that lymph node metastasesp <0.005), tumor size (p <0.005), tumor stage (p <0.005), distant metastases p = 0.0063), and gender (p = 0.003) are significant prognostic factors for recurrence (Kaplan-Meier). Tumor size (p = 0.004), lymph node metastases p = 0.0478), and distant metastases p = 0.0064) influenced mortality. Age and extent of surgery were not significant for recurrence nor was gender for mortality. Multivariate analysis (Cox regression test) characterized tumor size (p <0.005) and lymph node metastases p = 0.004) as prognostic factors for recurrence of FTC. No significant difference was detected between patients being treated by thyroidectomy when compared to patients treated by thyroidectomy plus neck dissection in relation to recurrence. Our data demonstrate lymph node metastases to be a significant prognostic factor for recurrence of FTC and the patient's survival. We advocate thyroidectomy plus central lymph node dissection as the basic surgical strategy. For T3 and T4 tumors, unilateral modified neck dissection is an all but optional procedure. Whether radical surgery with thyroidectomy plus neck dissection has an impact on survival remains questionable.

Adrenal involvement in multiple endocrine neoplasia type 1.

Adrenal lesions belong to the spectrum of multiple endocrine neoplasia type 1 (MEN-1) syndrome. However, the prevalence of adrenal involvement, the characteristics, and the clinical management of adrenal lesions have not yet been clearly defined. A total of 66 patients with confirmed MEN1 germline mutations and 1 additional patient with typical manifestations in three organ systems were monitored in a regular screening program that included evaluation of the adrenals (median follow-up 96 months; range 12 to 300 months). Age at the diagnosis of MEN-1 and of adrenal tumors and the clinical characteristics, genotype, treatment, and follow-up of adrenal disease were analyzed. Adrenal lesions were identified in 18 of 67 (26.8%) MEN-1 patients and were diagnosed 5 years later than MEN-1. The median tumor diameter at diagnosis was 3.0 cm (range 1.2-15.0 cm), with most tumors being 3 cm or smaller. Eight patients had bilateral tumors. Ten patients had nonfunctional benign tumors, three had benign adrenal Cushing syndrome, and one patient had a pheochromocytoma. Four patients developed adrenocortical carcinomas (ACCs), three of which were functional. Nine adrenalectomies and one subtotal adrenalectomy were performed in six patients. Three patients with ACC died owing to the tumor. Patients with mutations in exons 2 and 10 developed adrenal tumors significantly more often than patients with other mutations (p <0.01). Adrenal tumors are a common feature of MEN-1 but occur later in the course of the disease. The lesions are often small and nonfunctional and can therefore be managed by close surveillance; others have significant malignant potential and should be considered for surgery when they are 3 cm or larger.