The Ethical Implications of the Reclassification of Noninvasive Follicular Variant Papillary Thyroid Carcinoma

Abstract

Background:

Several studies have highlighted the lack of consensus in the diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC). An international multidisciplinary panel to address the controversy was assembled at the annual meeting of the Endocrine Pathology Society in March of 2015, leading to the recent publication reclassifying encapsulated (or noninvasive) FVPTC (EFVPTC) as a benign neoplasm. Does this change in histologic taxonomy warrant a change in clinical practice, and how should it affect those who have been given this diagnosis in the past? We consider the financial and psychological impact of this reclassification and discuss the ethical, legal, and practical issues involved with sharing this information with the patients who are affected.

Summary:

The total direct and indirect cost of thyroid cancer surveillance in patients is significant. High levels of clinically relevant distress affect up to 43% of patients with papillary thyroid carcinoma, as estimated by the Distress Thermometer developed by the National Comprehensive Cancer Network for detecting distress in cancer patients. Although there are currently no legal opinions that establish a precedent for recontacting patients whose clinical status is altered by a change in nomenclature, the prudent course would be to attend to the requirements of medical ethics.

Conclusion:

Informing patients with a previous diagnosis of EFVPTC that the disease has been reclassified as benign is expected to have a dramatic effect on their surveillance needs and to alleviate the psychological impact of living with a diagnosis of cancer. It is important to re-evaluate the pathologic slides of those patients at risk to ensure that the invasive nature of the tumor is comprehensively evaluated before notifying a patient of a change in diagnosis. The availability of the entire tumor for evaluation of the capsule may prove to be a challenge for a portion of the population at risk. We believe that it is the clinician's professional duty to make a sincere and reasonable effort to convey the information to the affected patients. We also believe that the cost savings with respect to the need for additional surgery, radioactive iodine, and rigorous surveillance associated with a misinterpretation of the biology of the diagnosis of EFVPTC in less experienced hands will likely more than offset the cost incurred in histologic review and patient notification.

Introduction

The diagnosis of follicular-pattern lesions showing nuclear features of papillary thyroid carcinoma (PTC) is challenging and has been the subject of much debate over the last 50 years (1). Several papers have highlighted the lack of consensus in the diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC) even by pathologists who are experts in interpreting thyroid cancer histology (2). Lloyd et al. (3) reported 87 cases of FVPTC that were reviewed by 10 thyroid pathology experts with a 39% cumulative frequency of diagnostic concordance. Owing to the lack of diagnostic agreement, treatment guidelines and prognosis for individuals with these thyroid lesions are varied. The challenge is that the minimal histological criteria for the diagnosis of FVPTC, particularly in encapsulated neoplasms, are subjective. The clinical behavior of FVPTC with an invasive growth pattern is different from its encapsulated noninvasive counterpart (4). The metastatic potential of encapsulated, also known as noninvasive, FVPTCs has been cited as low or nonexistent in most publications (5,6), and the reclassification of this neoplasm as indolent or benign has been on the horizon for some time (7 –10). An international multidisciplinary panel to address the controversy was assembled at the annual meeting of the Endocrine Pathology Society in March of 2015. This led to the recent publication reclassifying encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) as a benign neoplasm, specifically termed “noninvasive follicular thyroid neoplasms with papillary-like nuclear features” (NIFTP) (11). Does this change in histologic taxonomy warrant a change in clinical practice, and how should it affect those who have been given this diagnosis in the past? Here, we consider the financial and psychological impact of this reclassification. Further, we discuss the ethical, legal, and practical issues involved in sharing the information with the affected patients. In this manuscript we will be referring to the entity previously known as EFVPTC, which has now been reclassified as NIFTP.

Review

Costs of EFVPTC surveillance

A recent search of the Surveillance, Epidemiology, and End Results database reveals that the prevalence of PTC in the United States population was 601,789 cases in 2012 (12). A large study by Strickland et al. (13) showed that EFVPTC accounts for 24.6% of PTC cases, or 148,040 Americans. In 2015 alone, 62,450 new cases of PTC were diagnosed in the United States (12), approximately 15,363 of which were EFVPTC. The review of our institutional database yielded 775 patients with PTC. Twelve percent of these were FVPTC. Review of the pathology reports confirmed that 64 patients (9%) had encapsulated tumors without evidence of invasion. The impact of the reclassification of this condition, from being previously identified as a cancer to now being classified as a benign tumor, is significant. The financial burden of cancer surveillance for patients with the diagnosis of EFVPTC includes the direct expenses of diagnostic testing and indirect costs.

According to the National Comprehensive Cancer Network (NCCN), postthyroidectomy follow-up for patients with PTC includes ultrasonographic surveillance and testing of blood levels of thyroglobulin, anti-thyroglobulin antibodies, and thyrotropin at 6 and 12 months postoperatively and then annually (14). Recurrence of PTC can occur up to 30 years after diagnosis, warranting lifetime surveillance (15). These tests are not indicated for benign tumors of the thyroid because there is no risk of recurrence or metastases. An approximation of the direct costs can be obtained using the Medicare cost associations as per the Centers for Medicare and Medicaid Services reimbursement schedules. The costs of surveillance for the first year after treatment are presented in Table 1, and the costs for the subsequent years are presented in Table 2. The only way to make the diagnosis of an EFVPTC versus an invasive form is by surgical removal of the nodule, usually via a hemithyroidectomy. The costs of surgery and thyroid hormone level measurements are not included in the calculation because they will not be affected by the reclassification. Prior to the reclassification, the management of patients with EFVPTC ranged from a diagnostic lobectomy alone to a completion thyroidectomy and in some cases adjuvant radioactive iodine.

Table 1.

Thyroid Cancer Surveillance Direct and Indirect Costs for the Year After Treatment

	Cost per patient	Cost for all incident patients in 2015 (15,363)
Direct costs
Ultrasound ( × 1)	$123	$1,889,649
Tg test ( × 2)	$60	$921,780
Tg Ab test ( × 2)	$58	$891,054
Office visit ( × 2)	$146	$2,242,998
Total direct costs	$387	$5,945,481
Indirect costs
Out-of-pocket expenses	$2,400	$36,871,200
Productivity loss	$1,601	$24,596,163
Psychosocial distress	N/A	N/A
Total indirect costs	$4,001	$61,467,363
Total direct and indirect costs	$4,388	$67,412,844

All costs are in US dollars.

Tg, thyroglobulin; Tg Ab, thyroglobulin antibody; TSH, thyrotropin.

Table 2.

Thyroid Cancer Surveillance Direct and Indirect Costs for Each Subsequent Year After the First Posttreatment Year

Test	Cost per patient	Cost for all prevalent patients in 2015 minus incident cases (132,677)
Direct costs
Ultrasound	$123	$16,319,271
Tg test	$30	$3,980,310
Tg Ab test	$29	$3,847,633
Office visit	$73	$9,685,421
Total direct costs	$255	$33,832,635
Indirect costs
Out-of-pocket expenses	$2,028	$269,068,956
Productivity loss	$1,601	$212,415,877
Psychosocial distress	N/A	N/A
Total indirect costs	$3,629	$481,484,833
Total direct and indirect costs	$3,884	$515,317,468

All costs are in US dollars.

Indirect costs encompass a wide array of burdens, including out-of-pocket expenses, work days lost, as well as psychosocial sequelae. Out-of-pocket costs associated with routine follow-up can include transportation, restaurant meals, telephone calls, housekeeping and laundry services, childcare, and hotel stays (16). Though data specific to thyroid cancer is not available, the financial burden for a breast cancer patient, which is likely to be similar, is estimated at an average of $2,400 per year. In the same population, the cost of work days lost has been estimated to be approximately $1,601 per year per patient (17).

High levels of clinically relevant distress affect up to 43% of PTC patients, as estimated by the Distress Thermometer developed by the NCCN for detecting distress in cancer patients (18). Despite early-stage disease and excellent prognosis, the diagnosis of cancer itself carries a significant psychological impact on patients (19). Treatment of anxiety is certainly associated with a financial cost, however, because of the multifactorial nature of the psychosocial impact of living with a cancer diagnosis, this cost is difficult to quantify. The symptoms of emotional distress might be further exacerbated by the short-term hormone imbalance in the immediate posttreatment period (20).

Physician obligations

Physicians are obligated to provide clinically relevant information to patients under their care, and providing that information is the essential requirement of showing respect for patient autonomy. Since medicine has rejected a paternalistic model of care, society and the medical profession have embraced the view that patients must be provided with all of the data relevant to their medical care decision-making (21). For that reason, information that is likely to be relevant to patient choices must be conveyed to the patient. While this may be fairly straightforward in an ongoing clinical relationship, questions arise about what needs to be done for patients who are no longer under the care of the physician who performed the initial treatment or diagnostic procedure.

Reclassification of a malignant pathology to benign disease has been described in the case of urothelial papilloma and grade 1 carcinoma being renamed papillary urothelial neoplasia of low malignant potential (22). The ethical implications for physicians with patients who were previously diagnosed with conditions that have been subsequently reclassified, have not been explored in the literature.

Related issues have been encountered in rapidly developing fields such as genetics. The dramatic speed of the evolution of genetic testing and interpretation techniques has elevated the issue of recontacting patients as new information becomes available. The literature on the subject can be used as a platform for discussion of the ethical and legal obligations of physicians involved in the care of patients with the diagnosis of EFVPTC. The genetics community has taken the stand that actionable information must be communicated. They have even gone so far as to recommend that research involving whole exome and whole genome analysis specifically identify and communicate information about identifiable conditions that are actionable (23,24).

Similarly, problematic aspects of FVPTC diagnosis have forced the issue of how to manage changes in pathologic disease designation in the past. Widder et al. (25) reported a review of an institutional database of thyroid malignancies that yielded a 25% change in diagnosis. The majority of these were reclassified from a benign diagnosis to a malignant diagnosis. The authors concluded that patients must be informed of the change in diagnosis, even though the review was done as part of a research study. Presumably, the justification for that recommendation was that patients were at risk of harm from disease progression. Physicians’ commitment to “regard responsibility to the patient as paramount” (21) requires that they extend themselves to help patients by informing them of the risk. Both examples suggest that physicians should communicate the reclassification to their patients because it is their fiduciary responsibility.

We expect that learning the cancer diagnosis has been revised will have a positive psychological impact on patients. Nevertheless, some may express anger at having been overtreated and living with unnecessary anxiety. It is important to convey to patients that the diagnosis previously rendered was appropriate and based on the medical knowledge at the time. The recommendations previously given to patients were the standard of care until the most recent update. The news must be conveyed because patients with EFVPTC will ultimately benefit from learning it and they are likely to be harmed financially, socially, and psychologically by having the information withheld.

One final point relates to the interpretation of the diagnosis of EFVPTC by an insurance company, in comparison to the change in designation to NIFTP. One can expect that the insurability of a patient with the diagnosis of EFVPTC will be positively influenced by the change in nomenclature to a benign condition. The ability of a patient to obtain life insurance and disability insurance can have a far-reaching impact on the financial well-being of a patient and their family.

Legal Considerations

At present, no clear legal obligation exists for informing patients of any new medically relevant information (25). In situations in which no direct physical harm can be expected to ensue from information that is not shared, the legal requirements are not defined. Because there are currently no legal opinions that establish a precedent on this issue, the prudent course would be to attend to the requirements of medical ethics. If and when such matters come before a court, it is likely that professional standards of behavior will guide the ruling. Although the legal duty to recontact patients is unlikely to extend in perpetuity or to require more than reasonable effort, a sincere effort to inform patients is likely to become the legal standard.

Some discussants have voiced concerns about legal liability as a reason for not sharing the reclassification information. They postulate that patients who are informed may bring a suit for a wrongful diagnosis or unnecessary surveillance and treatment. It is hard to imagine that such a claim could be successful because the diagnosis was correct according to the standard of care at the time when it was offered. Furthermore, it is far more likely that patients who were deliberately kept in the dark would sue for damages compared with those who received honest communication from their doctors.

Implementation

The practical matter of contacting patients may be complicated. For those practices that maintain effective and current patient databases, the process should not be especially burdensome. However, contacting patients who are no longer under surveillance will be more of a challenge. We acknowledge that some clinicians may have already interpreted the biology of this tumor as being very indolent and advised their patients of this and thereby may not require a change in management strategy. However, the change in terminology will certainly be meaningful for those clinicians who have not already made this transition and are following this population of patients with the same degree of rigor as other variants of thyroid cancer. We also acknowledge that there may be patients who are difficult or impossible to contact because of insurmountable logistical factors.

Pathology departments should initiate retrospective reviews of their databases and alert clinicians as to which patients had the diagnosis reclassified. When available, clinicians should analyze their individual or institutional databases to identify patients affected by the change in disease designation. Since patients with the diagnosis of FVPTC are under thyroid cancer surveillance indefinitely, the review of the records should go as far back as is logistically feasible for each particular institution. It is important to highlight the fact that the reclassification will also be limited by the completeness of the pathology specimen available for review, which may depend on how old the slides are as well as the conditions under which the specimens were stored. The Clinical Laboratory Improvement Amendments of 1988 mandates laboratories retain glass slides for at least 10 years and paraffin blocks for at least 2 years (26). However, some states have individual regulations, such as New York, which requires laboratories to store both glass slides and paraffin blocks for at least 20 years (26). Once this time period has elapsed, institutions may continue to store or discard specimens at their own discretion. Therefore, reclassification may indeed prove to be a significant challenge for patients who were operated upon a considerable time ago because their slides have been discarded. It is also possible that the entire capsule of the tumor is not available to exclude invasion; without that a thorough review is not possible. While these efforts will involve costs and time, medicine's commitment to the welfare of patients requires that this responsibility be discharged. Once the obligation to inform patients is acknowledged, means have to be found to overcome the practical barriers (27). Searchable medical records, up-to-date contact information, and available staffing would all help to facilitate the effort. It appears that the added costs of unnecessary completion thyroidectomies, radioactive iodine therapy, and lifelong surveillance would more than offset the costs of histologic review and patient notification, although those cost savings may have to be shifted to the pathology department.

Up-to-date digital storage and electronic health systems in which patients are in control of their own data over time has been proposed as a solution in the genetic research literature (28,29). The Thyroid Care Collaborative is an example of such a system, dedicated to patients with thyroid disease (30,31). In a similar vein, Fitzpatrick et al. (32) proposed the use of the media, patient support groups, and primary care physician organizations to disseminate the information. Orchestration of this type of outreach is beyond the responsibility of the individual clinicians and falls on organizations such as the American Thyroid Association, the American Association of Endocrine Surgeons, American Head and Neck Society, the American College of Endocrinology, and the American Society for Clinical Pathology. Such information broadcast is especially important in light of the most recent American Thyroid Association guidelines, which continue to list FVPTC in the low-risk category for recurrence (33).

All tools are useful for communicating with patients, but they do not absolve physicians of their responsibilities. The extent of the effort to inform patients of a reclassification of a medical condition has not been defined. The surgeon who made the diagnosis has the primary responsibility for the communication. A personal phone call or a letter with a signed return receipt is probably sufficient. When another clinician is following the patient for cancer surveillance (endocrinologist or primary care provider), perhaps that physician who has regular interaction with the patient should be contacted and asked to take on the responsibility for conveying the change in the diagnosis. Choosing that route may be questionable because the clinician in question may be faced with a financial conflict of interest in recommending discontinuation of routine surveillance.

The financial responsibility of reviewing the pathology slides to ensure an accurate diagnosis prior to contacting patients is a very important consideration. It is expected that the diagnosis will not be changed in a significant number of cases; however, any potential error must be avoided. Although the insurance provider stands to benefit from this reclassification, the cost may fall on the hospital system or on the pathology department. An upfront agreement between the pathology department, the managing clinician, and the hospital administration must be established. All members of the patient care team must be informed and participate in this initiative to make certain that the patient does not receive mixed messages.

Summary

The recently published reclassification of EFVPTC as a benign neoplasm will affect not only patients diagnosed with this pathology in the future, but those living with the diagnosis as well. The direct and the indirect costs of thyroid cancer surveillance are significant and continue to accrue through years of surveillance. Although there are currently no mandates to recontact patients when their diagnosis is changed as a result of advancement in medical knowledge, the prudent course would be to attend to the requirements of medical ethics. In a perfect world, this course would be possible for all patients, but the realities of having to review the entire pathology of the specimen may prove to be an insurmountable challenge, particularly in patients who were operated upon a number of years ago. Up-to-date electronic health systems in which patients are in control of their own data, such as the Thyroid Care Collaborative, are media through which to tackle the logistical barriers of recontacting patients as new medical information emerges.

Conclusion

Informing patients with a previous diagnosis of EFVPTC that the disease has been reclassified as benign is expected to have a dramatic effect on their surveillance needs and on the psychological impact of living with a diagnosis of cancer. We believe that it is the clinician's professional duty to make a sincere and reasonable effort to convey the information to the affected patients.

The reclassification of EFVPTC to NIFTP is most certainly not an isolated event, and similar changes in the clinical implications of a pathologic diagnosis will likely be seen with implementation of genetic fingerprinting and other new technologies. Thus, the discussion on how such developments are handled is timely and important. As a profession, medicine has to prepare itself for the conversations that medical advances are likely to require.

Footnotes

Acknowledgment

The authors would like to acknowledge the generous support of the Mount Sinai Health System in support of this research project.

Author Disclosure Statement

No competing financial interests exist.

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