Ethical issues raised by thyroid cancer overdiagnosis: A matter for public health?

Current practices of identifying and treating small indolent thyroid cancers constitute an important but in some ways unusual form of overdiagnosis. Overdiagnosis refers to diagnoses that generally harm rather than benefit patients, primarily because the diagnosed condition is not a harmful form of disease. Patients who are overdiagnosed with thyroid cancer are harmed by the psycho-social impact of a cancer diagnosis, as well as treatment interventions such partial or total thyroidectomy, lifelong thyroid replacement hormone, monitoring, surgical complications and other side effects. These harms seem to outweigh any putative benefit of knowing about a cancer that would not have caused problems if left undiscovered. In addition to harms to patients, thyroid cancer overdiagnosis leads to significant opportunity costs at a societal level, due to costs of diagnosis and treatment. Unlike many other overdiagnosed cancers, accurate risk stratification is possible with thyroid cancer. At the individual patient level, use of this risk information might support informed choice and/or shared decision-making, as mandated by clinical ethics frameworks. And this approach might, to some extent, help to reduce rates of diagnosis and intervention. In practice, however, it is unlikely to stem the rising incidence and associated harms and costs of overdiagnosed thyroid cancer, especially in situations where health professionals have conflicts of interest. We argue in this article that thyroid cancer overdiagnosis may be usefully understood as a public health problem, and that some public health approaches will be readily justifiable and are more likely to be effective in minimising its harms.

Cellular turnover of normal gastrointestinal epithelium assessed by changes in telomeric: total DNA signal ratios.

OBJECTIVES: The reasons why different areas of gastrointestinal mucosa exhibit widely different rates of malignant change are still poorly understood. Malignancy rates rise markedly with age. We therefore hypothesised that rates of malignant change might correlate with rates of ageing as judged by stem cell turnover. Telomeric DNA is lost with each cell division and so acts as a measure of the number of cell divisions undergone by stem cells. We measured telomeric:total DNA signal ratios in normal gastric (Helicobacter pylori-positive and H. pylori-negative), duodenal and colonic mucosa to see whether ratios correlated with propensity to malignancy. PATIENTS: Subjects undergoing diagnostic upper (n = 93) or lower (n = 45) gastrointestinal endoscopy, whose mucosa appeared macroscopically normal, sampled over a wide age range. METHODS: DNA was extracted from paired blood and mucosal samples (colonic or gastric and duodenal). Telomere length was assessed by dot blot hybridisation with an oligonucleotide-containing telomeric sequence compared with the signal obtained from total genomic DNA. Helicobacter status was assessed by Campylobacter-like organism (CLO) test and serologically. RESULTS: Telomeric signal ratios were scattered, but correlated within individuals. The ratios tended to decrease with age but the rates of decrease did not correlate with rates of malignant change. Gastric tissue had the shortest ratios and duodenal ratios decreased fastest. CONCLUSIONS: The telomeric signal ratios did not suggest any obvious basis for differential rates of disease especially malignancy. Infection with H. pylori was not associated with lower gastric telomere ratios.

Changing trends in surgery for Graves' disease: a cohort comparison of those having surgery intended to preserve thyroid function with those having ablative surgery.

BACKGROUND: Surgery for Graves' disease may be performed with the intent of preserving thyroid function (subtotal thyroidectomy) or ablating thyroid function (total thyroidectomy). This study examines the evolving practice in a specialist endocrine surgical unit. METHOD: Longitudinal cohort study of patients undergoing surgery for Graves' disease between 1986 and 2008. Outcome measures were thyroid failure, recurrent toxicity, recurrent laryngeal nerve (RLN) palsy, early reoperation and hypocalcaemia. Time to thyroid failure was analysed by potential predictors. RESULTS: Of 149 patients (129 female), 78 (52.3 percent) underwent subtotal thyroidectomy with the intention to preserve function (PF) and 71 (47.6 percent) total thyroidectomy with the intention to ablate thyroid function (AF). Mean duration of follow-up was 11.1 years; 14.8 years and 7.0 years respectively. Of 78 PF procedures: six (7.7 percent) patients suffered recurrent toxicity; 68 (87.2 percent) developed thyroid failure (four after treatment for recurrent toxicity); and eight (10 percent) remained euthyroid without replacement. Male gender and remnant gland weight were significant predictors of failure (P = 0.021 and 0.022 respectively). One patient developed permanent RLN palsy and one permanent hypocalcaemia. Of 71 AF procedures: one developed acute airway obstruction; one permanent RLN palsy; four permanent hypocalcaemia; and none developed recurrent toxicity. There were no deaths within a year of surgery. There was no statistically significant difference in complication rates. CONCLUSION: Most PF resections resulted in eventual thyroid failure. The shift to ablative surgery virtually eliminated the need for lifelong specialist follow-up, albeit with an insignificant rise in permanent hypocalcaemia.

X inactivation patterns of closely, but not distantly, related cells are highly correlated: little evidence for stem cell plasticity in normal females.

The early, random nature of X inactivation should cause related cells to have similar, but distinctive, active X chromosomes. We assessed the frequency of stem cell plasticity using X inactivation proportions (XIPs), determined at the human androgen receptor locus, in paired tissue samples from healthy individuals. Tissues sampled were stomach (n = 18 informative females), duodenum (n = 18), colon (n = 10) with corresponding peripheral blood samples (n = 33), and varicose veins (n = 28) with corresponding T cells (n = 26) and peripheral blood granulocytes (n = 25). XIPs from samples thought to have common stem cell origins were highly correlated: multiple samples from single vein, r = .80 (n = 24); T cells versus granulocytes, r = .67 (n = 23); duodenum versus stomach, r = .63 (n = 12). Blood cells and vessels are derived from a common hemangioblast, but XIP correlations were moderate or poor: vein versus T cells, r = .42 (n = 26); vein versus granulocytes, r = .11 (n = 25). X inactivation is believed to be a late process in gut, especially hind-gut, with corresponding independence from blood precursors. Correlations with blood cells were low: stomach, r = .23 (18); duodenum, r = .21 (18); colon, r = .034 (10). Any crossover of stem cells between different organs during adult life should increase correlations with age; no such increase was seen. This study confirms that XIPs can be used to track stem cell populations, provides a theoretical basis for the power of such studies, and indicates that hemopoietic stem cell plasticity is, at most, uncommon in normal humans.