Overdiagnosis of Thyroid Cancer: Is This Not an Ethical Issue for Pathologists As Well As Radiologists and Clinicians?

Abstract

In 1993, Black and Welch1 published a prophetic article that foretold the diagnostic imaging-induced conundrum now known as overdiagnosis. Overdiagnosis is defined as detection of a medical condition that, if left undiagnosed, would cause no harm.2 Compelled by the above-cited authors and my own experiences,3 I advocate discussions of cancer overdiagnosis with medical students, house officers, and faculty. The potential harms of cancer overdiagnosis include not only unnecessary surgery and complications, but also the emotional and financial tribulations incurred by cancer diagnosis and indefinite follow-up.4 Cancer diagnosis, especially thyroid, contributes significantly to bankruptcy in parts of the United States.5 Should not thyroid cancer overdiagnosis be considered a public health ethics issue?4Is there an epidemic of fear for profit, and are pathologists aiding and abetting the epidemic? There has been a 3- to 15-fold increase in thyroid carcinoma in developed countries. Nearly 90% of this increase is due to computed tomography or ultrasound (US) detection of small, asymptomatic papillary carcinoma (PTC) for which mortality rates remain essentially nil.6–8 Whether reported miniscule increases in total thyroid cancer deaths are real or due to attribution bias is unknown.6 Thyroid nodule detection commonly leads to fine-needle aspiration (FNA) and either surgery or follow-up studies. Ancillary molecular studies add to the expense. Deaths from thyroid cancer remain at or below 0.5/100,000, and there is no evidence that US and FNA seek-and-destroy missions are beneficial. Is this explosion of US and FNA procedures driven by beneficence or by access to funding and diagnostic imaging? Thyroid cancer diagnosis has been positively correlated with Medicare and private health insurance access as well as higher levels of patient education, affluence, and amount of radiologic imaging performed.9–12 We must address whether or not we are advocating potentially harmful testing to the funded while limiting care to the unfunded.3Physician cognizance of overdiagnosis and public education can reduce thyroid cancer diagnosis and surgery; however, one must battle resistance. The South Korean universal health care program initiated cancer screening in 1999. Touting that early diagnosis is good for you, fee-for-service thyroid US screening was also offered. The incidence of thyroid cancer increased 15-fold between 1993 and 2011. All of the increase was due to PTC, and thyroid surgery rates soared.13–15 Concerned physicians resolved to educate the public. Both screening and surgery decreased.14 Should we not follow the Korean example and promote education rather than procedures? There may be backlash from marketers of screening, FNA, and ancillary studies, who, like some Korean surgeons and endocrinologists, may protest that screening and treatment are "basic human rights."14 American radiologists and clinicians are initiating efforts to curb our overdiagnosis epidemic. The United States Preventive Services Task Force now recommends against screening, by either US or palpation, for thyroid cancer in asymptomatic adults and acknowledges the potential harms of US and follow-up FNA.16,17 Radiologists propose limits on US and FNA performed for thyroid incidentalomas found by computed tomography.18 Pathologists and trainees should be aware of these recommendations and the rationale behind them.Most patients, especially children, with metastatic PTC do not die of PTC.19 Takano20 offers an interesting theory about the natural history of thyroid cancer, and Japanese studies give evidence that PTC is a common childhood phenomenon.21 Baseline US studies performed on children following the 2011 Fukushima nuclear plant accident revealed a prevalence of thyroid cancer of 37.3/100,000. Nearly all were PTCs and all deemed unrelated to radiation. Important information was bestowed, but an "epidemic of fear" followed.21,22 Autopsy data from Japan have shown increasing prevalence of PTC from ages 15 through 34 years with no increase thereafter.20 Papillary carcinoma may arise from thyroblasts, grow during childhood and early adulthood, then either regress, nonlethally progress, or persist as an indolent lesion in adulthood. Lethal thyroid tumors are rare, arise in older adults, and may be of a different origin.20 The annual incidence of anaplastic thyroid carcinoma is approximately 1 to 2 cases/million. Some anaplastic carcinomas are found to be associated with differentiated thyroid carcinomas and, hence, assumed to have arisen within the more differentiated tumors. This belief can generate fear that neglect of incidental PTC may lead to dedifferentiation later in life. Takano20 has recently challenged this concept. Based on some recent theories regarding cell origins of thyroid cancer and molecular studies, the converse may occur. Anaplastic tumors may arise from stem cells and later undergo PTC or follicular differentiation.20 While one cannot discount dedifferentiation of PTC in the genesis of some lethal thyroid tumors, one must consider the extremely low and stable incidence of anaplastic carcinoma relative to the burgeoning rates of incidentaloma PTC. There is yet no evidence that neglect of asymptomatic, incidentaloma thyroid nodules leads to deaths from anaplastic carcinoma. Is it not cruel to inject fear of anaplastic carcinoma transformation into thousands of people with asymptomatic, incidentaloma PTC, and would this not contribute to soaring rates of surgery, surgical complications, and possibly bankruptcy?Many PTCs, attributed to radiation, actually may be childhood normalomas. Intensive screening, false positives, and detection of previously neglected tumors may have led to overestimation of Chernobyl-associated PTC and tumor aggressivity.23 Increases in neither anaplastic nor poorly differentiated carcinomas are found in elderly adults who underwent childhood tonsillar or thymic irradiation. Most studies have not found thyroid cancer following external beam irradiation to be more aggressive.24 Should the term indolent lesion of epithelial origin (IDLE)25 be considered for incidentaloma PTC regardless of radiation exposure?Indisputably, variables in diagnosis and technology obfuscate our understanding of PTC and the utility of mutation testing (MT). Standardization is desirable. Nonetheless, there is evidence that most asymptomatic PTCs are stable or indolent lesions and that lethal PTCs are rare and present de novo as macrometastases.26–31 Why just angst over noninvasive follicular thyroid neoplasm with papillary-like nuclear features? Pathologists, as physicians, must acknowledge that cancer diagnosis and condemnation to follow-up studies can cause emotional stress and financial burdens. Should we indiscriminately insert the "risk for malignancy" into indeterminate or suspicious FNA reports from asymptomatic incidentalomas? A 5-cm mass with extrathyroidal extension or macrometastasis is certainly a real malignancy, while a 1.3-cm, asymptomatic incidentaloma in a 50-year-old woman is far more likely to be benign or an IDLE. Do these comments needlessly scare patients and clinicians?Mutation testing should be justified by proof of improvement in patient outcomes and well-being. Proof is still lacking.32 Some laud MT as a means of reducing surgery, but a positive test result often predicts presence of an IDLE called papillary carcinoma. A negative test result precludes neither patient nodule-awareness anxiety nor the expense of required follow-up. The value of BRAFv600e and other gene MT for predicting aggressive behavior in asymptomatic PTC is controversial.20,33–35 The verdict regarding the benefits or lack thereof of MT is still pending.A small percentage of PTCs are aggressive and cause morbidity. This editorial does not focus on clinically evident PTC or aggressive variants or non-PTC tumors. Aggressive tumors typically present as clinically evident neoplasms. Small (<2 cm) PTCs are responsible for nearly all of today's massive increase in thyroid cancer incidence.31 Tumors that present with clinical signs or symptoms must be biopsied and treated appropriately.Aggressive PTCs are most commonly found in adolescents and young adults, but these are rarely fatal.19 Lethal thyroid carcinomas usually occur in older adults but are very rare in comparison to the myriad harmless incidentalomas currently being diagnosed. Selective US follow-up of incidentalomas in elderly adults to assess for rapid growth has been considered.20 It has also been recommended that patients with serious comorbidities be eliminated from follow-up.18This is a litigious era dominated by Internet babble and indiscriminate, sometimes draconian, enforcement of one guideline fits all patients. Thus, one can blame neither all physicians nor frightened patients for our overdiagnosis epidemic; however, when it comes to management of thyroid nodules, "neither monetary rewards nor professional advancement should be part of the equation."3 Pathologists must consider the effects of commercial advertising and monetary support from companies that benefit from radiologic, cytologic, and surgical procedures. As is being done in radiology and endocrinology,16–18 pathology societies should address these problems as members of a community of physicians who have vowed to do no harm. My personal atonement is to discuss cancer overdiagnosis with medical students and pathology and endocrinology house officers and to avoid commenting on incidentaloma "risk for malignancy."

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