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Andreas Machens and Henning Dralle

Objective

Time trends of the extent of disease at first diagnosis and biochemical cure remain ill-defined for sporadic medullary thyroid cancer (MTC). This investigation aimed to delineate time trends and biochemical cure rates for sporadic MTC.

Design

This was an observational study of consecutive patients operated on for sporadic MTC between 1995 and 2015.

Methods

Time trends of clinical and histopathological variables indicative of the extent of disease and biochemical cure were calculated for 600 patients with sporadic MTC, 322 of whom had initial neck surgery and 278 of whom had neck reoperation at a tertiary surgical center in Germany.

Results

From 1995–2000 to 2011–2015, significant declines (all P<0.001) were noted in the percentage of node-positive tumors (from 73 to 49%), mediastinal lymph node metastasis (from 21 to 6%) and distant metastasis (from 23 to 6%). These changes were paralleled by significant increases (all P<0.001) in mean patient age (from 49.1 to 57.3years) and the percentage of MTC ≤10mm (from 19 to 39%) and biochemical cure (from 28 to 62%). When only patients with primary tumors >10mm were considered, the decreasing percentage of mediastinal lymph node metastasis and distant metastasis, and rising mean patient age and biochemical cure rates remained statistically significant.

Conclusions

Significant reductions in the extent of the disease and improved biochemical cure rates pointed toward increasing therapeutic control of sporadic MTC. The independent contribution of routine calcitonin screening to these time-dependent changes warrants more research.

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Andreas Machens and Henning Dralle

Objective

Decreasing tumor size in a population over time is widely interpreted as a measure of effectiveness of cancer screening programs. Nonetheless, thyroid cancer size is rarely analyzed as a function of time. This study aimed to explore secular trends of thyroid cancer diameter in Germany.

Design

Retrospective analysis of 1644 thyroid cancer patients from a large referral center for thyroid cancer (1995–2009).

Methods

Calculation of largest tumor diameters for each type of cancer as a function of time periods and birth cohorts.

Results

Over the past 25 years, subdivided into 5-year periods by year of thyroidectomy (1985–1989; 1990–1994; 1995–1999; 2000–2004; 2005–2009), tumor diameters diminished from 25 to 16 mm (P=0.025) for medullary thyroid cancer and from 28 to 18 mm (P=0.017) for papillary thyroid cancer. This reduction was greater for hereditary medullary thyroid cancer (from 27 to 11 mm; P=0.088) than sporadic medullary thyroid cancer (from 23 to 19 mm; P=0.11). No decline was observed for follicular thyroid cancer (means of 45 to 42 mm; P=0.52). From the first (1921–1940) to the most recent birth cohort (1981–2000), tumor size fell from 22 to 10 mm (P<0.001) for medullary thyroid cancer, from 24 to 22 mm (P<0.001) for papillary thyroid cancer, and from 49 to 38 mm (P=0.011) for follicular thyroid cancer. The reduction of medullary thyroid cancers affected exclusively patients with hereditary disease (from 20 to 7 mm; P<0.001).

Conclusion

The consistency and robustness of these data signify powerful secular trends toward smaller papillary, follicular, and medullary thyroid cancers. The causes and consequences of these trends warrant further investigation.

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Andreas Machens, Christine Hofmann, Steffen Hauptmann and Henning Dralle

Objective: Studies of outcome in patients with medullary thyroid carcinoma require long follow-ups to accrue enough cancer-specific events. Owing to time-dependent changes in diagnosis and therapy, long observation periods render studies susceptible to ‘time bias’ which can yield spurious results. This study was designed to investigate cancer-specific event rates after initial neck resection in contemporaneous patients recruited within less than a decade.

Design: Institutional cohort study of 128 consecutive patients who underwent compartment-oriented neck surgery between 1994 and 2002 at a tertiary surgical center for hitherto untreated medullary thyroid carcinoma.

Methods: The Kaplan–Meier method was used in conjunction with the log-rank test for analysis of time-dependent outcomes.

Results: Follow-up was available for 120 patients (94%) including 63 rearranged during transfection (RET) carriers. There were six locoregional recurrences in the 110 patients with clear surgical margins at initial neck resection, and 12 cancer-specific deaths in the 120 patients with available follow-up. On Kaplan–Meier analysis, most clinicopathological variables were significantly associated with recurrence-free survival and cancer-specific survival. Within the median observation period of 64.5 months, patients with node-negative tumors did not develop locoregional recurrence or die from their malignancies. The low event rates precluded multivariate analyses with all clinicopathological variables. With our extensive surgical approach, median recurrence-free survival and cancer-specific survival at 5 years were 95.2 and 89.3% respectively.

Discussion: Compared with literature data, our 5-year locoregional recurrence rate of 4.8% appeared very favorable, and our 5-year cancer-specific mortality rate of 10.7% was among the lowest ever reported. The growing proportion of localized medullary thyroid carcinomas among contemporaneous patients can be expected to ultimately lower the event rates, complicating future studies of outcome.

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Andreas Machens, Kerstin Lorenz, Carsten Sekulla, Wolfgang Höppner, Karin Frank-Raue, Friedhelm Raue and Henning Dralle

Objective

Twenty years ago, the groundbreaking discovery that rearranged during transfection (RET) mutations underlie multiple endocrine neoplasia 2 (MEN2) and familial medullary thyroid cancer (FMTC) ushered in the era of personalized medicine. MEN2-associated signs, taking time to manifest, can be subtle. This study sought to clarify to what extent conventional estimates of 1:200 000–500 000 underestimate the incidence of RET mutations in the population.

Design

Included in this retrospective investigation were 333 RET carriers born between 1951 and 2000 and operated on at the largest German surgical referral center (286 carriers) or elsewhere (47 carriers).

Methods

To estimate the incidence of RET mutations, the number of RET carriers born in Germany in five decades (1951–1960, 1961–1970, 1971–1980, 1981–1990, and 1991–2000) was divided by the corresponding number of German live births.

Results

Owing to improved diagnosis and capture of FMTC and MEN2 patients, minimum incidence estimates increased over time: overall from 5.0 (1951–1960) to 9.9 (1991–2000) per million live births and year (P=0.008), and by American Thyroid Association/ATA class from 1.7 to 3.7 for ATA class C (P=0.008); from 1.8 to 2.7 for ATA class A (P=0.017); from 1.5 to 2.2 for ATA class B (P=0.20); and from 0 to 1.4 for ATA class D mutations per million live births and year (P=0.008). Based on 1991–2000 incidence estimates the prevalence in Germany is ∼1:80 000 inhabitants.

Conclusions

The molecular minimum incidence estimate of ≈1:100 000 was two- to fivefold greater than conventional estimates of 1:200 000–500 000.