Jürgen Witte

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.”

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.