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In Response to "Overdiagnosis of Thyroid Cancer: Is This Not an Ethical Issue for Pathologists As Well As Radiologists and Clinicians?".

To the Editor.--We read with interest Dr Schnadig's (1) article on overdiagnosis of thyroid carcinoma. Pathologists have recognized this problem for at least a decade, (2) and have actively worked to reduce this incidence by a variety of means, including the introduction of noninvasive follicular tumor with papillary-like features (NIFTP). (3) Preliminary data suggest that these efforts are succeeding. (4) We agree by all means that pathologists and cytologists should be actively engaged in trying to educate clinicians and patients alike about the true risks associated with the lesions they are treating.

However, we strongly disagree with the suggestion that reporting the risk of malignancy (ROM) in an indeterminate thyroid fine-needle aspiration report should be discouraged. (1) Reporting ROM was introduced (5) around the time of the original description of the Bethesda System for Reporting Thyroid Cytopathology (6) as a way to allow more accurate comparison of the performance of individual cytopathologists and laboratories for both quality assurance and research purposes. In our view, reporting the ROM along with the standardized terminology of the Bethesda System has been wildly successful. It is certainly much more effective than trying to figure out what a diagnosis of atypical or indeterminate might mean from a cytopathologist or laboratory that uses nonstandardized terminology for which the risks have not been documented. Indeed, the evidence that pathologists are actually succeeding at reducing the overdiagnosis of thyroid carcinoma is strongly supported by data that explicitly use ROM. (4) The only limitation we see with its current use is that it would be much more informative if individual laboratories reported the ROM calculated with data from their own individual laboratories rather than the ROM from published national studies. Either way, however, is much better than reducing the information we provide for our clinicians and patients by not reporting ROM at all.

However, what really seems to bother Dr Schnadig is that the ROMs that are reported are too high. In this regard we agree. The most recent version of the Bethesda System continues to report ROMs for indeterminate aspirates that are similar to those in the first edition and do not account for NIFTP. These data are no longer relevant and are actively misleading. The second edition of the Bethesda System7 does, however, also include a table in which NIFTP is taken into account. Our experience with more than 15 000 aspirates and 2000 resections (8) is that the ROM for indeterminate aspirates in our laboratory is at the very lowest end of the range reported in the Bethesda System. We believe that as pathologists continue to become more comfortable diagnosing NIFTP, the reported ROMs for indeterminate thyroid aspirates will continue to decrease, and the difference in risk between an indeterminate and a benign aspirate will continue to shrink.

As a result, defining exactly what the ROM of a benign aspirate actually is (9-11) turns out to be crucial. Both clinicians and cytologists often confuse the risk of clinically significant disease (ROCSD, however one wishes to define it) with the ROM. The data clearly show that the ROM of a benign aspirate is about 3% (even when NIFTP is taken into account, because most of these cases are the result of inadequate sampling of classical malignancies), whereas the ROCSD based on clinical follow-up of patients with benign aspirates approaches zero. The difference between 0 and 3% may be very important to both patients and researchers. Most, if not all, of the current molecular tests do not achieve sensitivities of 100% for their benign category.

Given the confusion between ROM and ROCSD, our preference would be to report both of them for our indeterminate thyroid aspirates, and thus give both patients and clinicians more rather than less information about their tests. However, we believe defining the ROCSD is much harder than Dr Schnadig implies. Dr Schnadig states, "A 5-cm mass with extrathyroidal extension or a macrometastasis is certainly a real malignancy, while a 1.3-cm, asymptomatic incidentaloma ... is far more likely to be benign ..." Sure, but with appropriate therapy the risk of clinical progression or death for both patients is very low and may not be very different. That is the whole point of therapy, after all. In addition, in order to report ROCSD for an indeterminate thyroid aspirate, one would need to know the risk of a lesion for a patient who does not get any surgical or medical therapy, and whose tumor type, pathologic stage, and other pathologic risk factors will not be known because their nodules will be followed rather than excised. These data may be very difficult to collect and calculate, and would require long-term follow-up of patients with indeterminate thyroid aspirates who choose not to have resection. In addition, given the overall very low pretest probability of progression for all patients with thyroid malignancies, whether the ROCSD for patients with an indeterminate aspirate could be shown to be significantly different from that of a patient with either a benign or a malignant aspirate is not at all clear. Ideally, the ROCSD should be defined by clinicians rather than pathologists, because they have access to the appropriate follow-up information and the best feel for exactly which ROCSD would be most useful to both the patients and themselves. Nevertheless, if the ROCSD (however a clinician wants to define it) could be measured for patients with indeterminate thyroid aspirates, providing it in the cytology report might lead to improved patient care.

Andrew A. Renshaw, MD; Edwin W. Gould, MD

Department of Pathology, Baptist Hospital, and the Miami Cancer Institute, Miami, Florida

(1.) Schnadig VJ. Overdiagnosis of thyroid cancer: is this not an ethical issue for pathologists as well as radiologists and clinicians? Arch Pathol Lab Med. 2018;142(9):1018-1020.

(2.) Renshaw AA, Gould EW. Why there is the tendency to "overdiagnose" the follicular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002; 117(1):19-21.

(3.) Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2(8):1023-1029.

(4.) Strickland KC, Howitt BE, Marqusee E, et al. The impact of noninvasive follicular variant of papillary thyroid carcinoma on rates of malignancy for fine-needle aspiration diagnostic categories. Thyroid. 2015;25(9):987-992.

(5.) Renshaw AA. Reporting risk of malignancy/ dysplasia in cytology: a potential way to improve communication, if not reputation. Cancer. 2007; 111(6):465-466.

(6.) Ali SZ, Cibas ES. The Bethesda System for Reporting Thyroid Cytopathology. New York, NY: Springer; 2010.

(7.) Ali SZ, Cibas ES. The Bethesda System for Reporting Thyroid Cytopathology. 2nd ed. Cham, Switzerland; Springer; 2018.

(8.) Renshaw AA, Gould EW. Adequate sampling of multiple thyroid nodules by fine-needle aspiration. Cancer Cytopathol. 2017;125(11):848-853.

(9.) Renshaw A. An estimate of risk of malignancy for a benign diagnosis in thyroid fine-needle aspirates. Cancer Cytopathol. 2010;118(4):190-195.

(10.) Renshaw AA. Accuracy of thyroid fine-needle aspiration using receiver operator characteristic curves. Am J Clin Pathol. 2001;116(4):477-482.

(11.) Renshaw AA. Sensitivity of fine-needle aspiration for papillary carcinoma of the thyroid correlates with tumor size. Diagn Cytopathol. 2011; 39(7):471-474.

Accepted for publication February 13, 2019.

The authors have no relevant financial interest in the products or companies described in this article.

doi: 10.5858/arpa.2018-0452-LE

In Reply.--Incorporated into the neoplasia lectures that I give to first-year medical students is discussion of overdiagnosis and the need to update our definition of cancer. There is increasing evidence that many small, nonmetastatic or micrometastatic cancers are Dr H. G. Welch's "turtles." (1) Turtles are slow-growing neoplasms that will not become clinically evident during patients' lifetimes. Some of these could even be called lemmings because they self-destruct. I do not deny that the Bethesda System's risk of malignancy is an accurate method for assessing the risk of finding histologically defined cancers; however, malignancy is a scary word. Malignant implies evil intent and a harbinger of death. D'Agostino et al (2) found that fear generated by the word cancer affects patients' approach to decision-making in regard to nonintervention versus surgical intervention for papillary thyroid carcinoma (PTC). A hypothetical context study by Nickel et al (3) suggests that the word cancer can induce anxiety and cause patients to favor surgery over active surveillance. As Kakudo and Bychkov note, clinicians and patients may be confused by indeterminate reports, and most thyroid nodules with indeterminate cytology are benign or indolent.

Use of decision aids and implementation of shared decision-making for management of thyroid nodules are currently under investigation. (4) The result could be less unnecessary surgery and fewer fine-needle aspirates in favor of limited ultrasound studies or just plain old-fashioned clinical follow-up. However, we must heed patients' reactions to our vocabulary.

Use of the new term noninvasive follicular thyroid neoplasm with papillary-like nuclear features does not address the evidence that most occult, low-risk classical PTCs are turtles, especially those found in middle-aged to elderly patients. (5,6) Deletion of the carcinoma label from thyroid neoplasms likely to be indolent is not a new concept. (7) Lethal thyroid cancers of all types, including microPTC, are very rarely discovered as incidentalomas and generally present with obvious metastasis or extrathyroid invasion. Takano8 points out that most PTCs stop growing by early adulthood. Childhood PTCs that do progress are curable. Takano (8) also discusses evidence that undifferentiated carcinomas and other lethal carcinomas may not evolve from dormant, differentiated tumor cells, but rather from fetal stem cells.

Cronan (9) once asked, "Is it time to turn off the ultrasound machines?" Recommendations against screening for thyroid cancers and attempts to limit the harms of overzealous use of ultrasonography and fine-needle aspiration have followed. (10,11) Is it now time to revise our neoplasia terminology and definition of cancer? Should we include patients' values and choices when deciding follow-up of thyroid neoplasms and desist from creating unwarranted fear? Should we explain to patients that not all cancers are malignant?

Although this is difficult in today's medical care system, I believe that it should be the responsibility of clinicians and pathologists to attempt to communicate with one another prior to reporting thyroid needle aspiration or biopsy results. This enables the generation of more patient-oriented reports. Perhaps the attitude of "send out report and let the clinician decide what to do with it" is not in the best interest of patients. Vicki J. Schnadig, MD

Department of Pathology, University of Texas Medical Branch, Galveston

(1.) Welch HG. Less Medicine, More Health: 7 Assumptions That Drive Too Much Medical Care. Boston, MA: Beacon Press; 2015.

(2.) D'Agostino TA, Shuk E, Maloney EK, Zeuren R, Tuttle RM, Bylund CL. Treatment decision-making in early-stage papillary thyroid cancer. Psychooncology. 2018;27(1):61-68.

(3.) Nickel B, BarrattA, McGeechan K, etal. Effect of a change in papillary thyroid cancer terminology on anxiety levels and treatment preferences: a randomized crossover trial. JAMA Otolaryngol Head Neck Surg. 2018;144(10):867-874.

(4.) Sawka AM, Ghai S, Tomlinson G, et al. A protocol for a Canadian prospective observational study of decision-making on active surveillance or surgery for low-risk papillary thyroid cancer. BMJ. 2018;8:e020298. doi:10.1136/bmjopen-2017020298

(5.) Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, Miya A. Patient age is significantly related to the progression of papillary microcarcinoma of the thyroid under observation. Thyroid. 2014;24(1):27-31.

(6.) Sugitani I, Toda K, Yamada K, Yamamoto N, Ikenaga M, Fujimoto Y. Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes. WorldJ Surg. 2010;34(6):1222-1231.

(7.) Rosai J, LiVolsi VA, Sobrinho-Simoes M, Williams ED. Renaming papillary microcarcinomas of the thyroid gland: the Porto proposal. Int J Surg Pathol. 2003;11(4):249-251.

(8.) Takano T. Natural history of thyroid cancer. Endocr J. 2017;64(3):237-244.

(9.) Cronan JJ. Thyroid nodules: is ittime to turn off the US machines? Radiology. 2008;247(3):602-604.

(10.) US Preventive Services Task Force; Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for thyroid cancer: US Preventive Services Task Force recommendation statement. JAMA. 2017;317(18):1882-1887

(11.) Tessler FN, Middleton WD, Grant EG, et al. ACR thyroid imaging, reporting data system (TIRADS): white paper of the ACR TI-RADS committee. J Am Coll Radiol. 2017;14(5):587-595.

Accepted for publication March 14, 2019.

The author has no relevant financial interest in the products or companies described in this article.

doi: 10.5858/arpa.2019-0146-LE

Caption: Figure 1. Flyer given to breast cancer patients.

Caption: Figure 2. Patient satisfaction survey.
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Title Annotation:Letters to the Editor
Author:Renshaw, Andrew A.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1U5MD
Date:Jul 1, 2019
Words:2093
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