Thyroidologists on both sides of the Atlantic and their patients with papillary thyroid carcinoma (PTC) are living in interesting times, since during the past decade the topic of thyroid malignancy has emerged from being, formerly, a lesser topic for discussion at the annual gatherings of both the American (ATA) and the European Thyroid Associations (ETA) to now being the number one topic for submitted abstracts.  How has this change come about so recently?

The emergence of thyroid cancer as a “hot topic” in thyroidology

With the explosion of information derived from genomic unraveling and the increased emphasis of international funding bodies on awarding research grants almost exclusively to projects of a cell biologic and molecular genetic nature, we live in a time when goitrogenesis, deiodination and thyroid hormone metabolism have reluctantly accepted a shift of the spotlight to studies of thyroid cancer. Consequently, acknowledged authorities in those former fields now espouse a great interest, and are fast acquiring a recent experience, in the management of thyroid cancer patients. Moreover,  the  desks of  busy clinical thyroidologists are cluttered with, often largely unread, endocrine journals which  overflow with preliminary communications related to new insights into the pathogenesis of sporadic and radiation-associated PTC, aided and abetted by the intellectual fallout from the Chernobyl reactor  accident,  studies touting the value of novel  markers for the diagnosis  and outcome prediction of follicular cell–derived cancers (FCDC), others defining yet more prognostic scoring and staging  systems, in addition to  both  in vitro and in vivo animal studies of potentially new pharmacologic agents, that appear active in cell culture and could theoretically in future years be used in the management of advanced (recurrent and metastatic) FCDC.
Additionally, the recognition that kinase inhibitors may play a role in the pathogenesis of PTC has led for the first time to increasing interest by the powerful multinational pharmaceutical companies to conduct, in centers of academic endocrinology on both sides of the Atlantic, therapeutic trials in FCDC patients of novel agents that have shown promise in patients with non-thyroid cancers. In my own life, after more than three decades of treating FCDC patients with rarely a meaningful conversation with a medical oncologist, I was amazed to be approached within the past year by one of the most senior oncologists in our institution to enquire about the numbers of thyroid cancer patients I personally saw per year. When asked why he sought for the first time such information, I was told that, after recent discussions with a number of pharmaceutical consortia, the ascertainment of such numbers would be an essential prerequisite to determine whether our institution could be eligible to participate in the lucrative pursuit of future clinical trials, especially now that our medical oncology group had decided to become enthusiastically involved in "the business" of thyroid cancer!

Influence of rhTSH and sonography in contemporary clinical thyroidology

   It is well recognized that the role of a clinical thyroidologist is often to order appropriate studies of thyroid structure and function and to interpret the results “for the benefit of the individual thyroid patient”. In the management of patients with FCDC, the role of the endocrinologist in the multidisciplinary team (MDT) appears now in both European and American settings to be pivotal. Obviously, in the politics of internal medicine the powerful “nations” of cardiology and gastroenterology in part owe their power base to the financial impact of procedures. The cardiologists have their potpourri of echocardiography, angioplasty and ablation procedures, while the gastroenterologists have their diagnostic and therapeutic endoscopies. Certainly, in the United States, the endocrinologist in private practice is increasingly performing in his/her own office-based laboratory endocrine function tests, supervising within the same office bone mineral density measurements, and performing an increasing number of fine needle aspiration (FNA) biopsies of ever smaller examples of nodular thyroid disease (NTD). And in the past decade, there have been two areas of “hot thyroidology” that have significantly contributed to the groundswell of interest in patients with NTD and FCDC: these are the introduction of recombinant human TSH (rhTSH) and the increasing use by endocrinologists of high-resolution real-time thyroid sonography (HRTS).
   For years the clinical thyroidologist had been satisfied with a basic repertoire of endocrine testing that often consisted of fT4, fT3, TSH, Tg, anti-TPO, anti-Tg antibodies and TSH receptor antibodies. With the coming of increasingly sensitive TSH assays, the era of the TRH stimulation test was soon gone for ever. However, since the introduction in 1999 to the USA of rhTSH, this has heralded an explosion of interest in studies fueled by new financing, a huge increase in the number of meetings devoted to the topic of managing FCDC, and for the endocrinologist in practice the advent of a lucrative new tool, as well as a new thyroid function (and stimulation) test to interpret or misinterpret, perhaps not always for “the benefit of the individual thyroid patient”. And sadly, despite our recognition for decades that thyroglobulin (Tg) is a specialized complex protein made naturally by thyroid follicular cells, both benign and malignant, there now seems to be an almost acceptance that, in the post-thyroidectomy and ablation setting, a detectable serum Tg level (even the most tiny amount) should be viewed as a surrogate for the presence of FCDC. Moreover, a FCDC patient with a (presently) undetectable Tg on adequate thyroid hormone suppressive therapy (THST,) who has a detectable increment of Tg (no matter how small) after rhTSH stimulation, is now generally viewed with suspicion in the clinical thyroidology community!
    And what of HRTS…formerly the domain of the diagnostic radiologist, but often a very poor “Cinderella” to the much more affluent “ugly sisters” of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomographic (PET) scanning?  What of ultrasound-guided biopsy (USGB): a procedure that the Radiological Society of North America (RSNA) described in their recent annual meeting as a “procedure run amuck”?  Well, at least in the United States we are now observing a “turf war”, ( not being fiercely defended by the radiologic community), where increasingly it is non-radiologists who are wielding in their hands the ultrasound probes, which are unmasking the occult malignancies and swelling interest in the management of papillary thyroid microcancer (PTM). As Terry Davies has recently said, “the recommendation not to perform biopsy on any thyroid nodule less than 1 cm in size leaves me bewildered. Don’t all thyroid cancers start out as small nodules? Take a look at the microcarcinoma literature and I am not sure you will be as confident as you now feel” (1).
    In recent years, no annual scientific meeting in the United States of the AACE, AAES, ATA, TES or ACS has been considered complete without a rapidly over-subscribed CME-creditable satellite session devoted to “hands-on” experience of HRTS. Fellows in North American endocrine fellowship training programs now expect to leave their training equipped to do competent thyroid ultrasound (US) and to be proficient at USGB of patients with NTD. In 2005 an Academy of Clinical Thyroidologists (ACT) was formed at the AACE meeting in Washington, DC to allow a gathering together of the expertise of those specialist endocrinologists, whose mission it is to “take charge” of the patient with NTD and FCDC, to the point of supervising “in-house” the thyroid function tests, the radioiodine studies, the diagnostic US, the USGB and sometimes even to the interpretation of the cytology, in addition to the selection and supervision of subsequent management. And even Terry Davies, a lifelong academic, an acknowledged expert in thyroid autoimmunity and the present Editor-in-Chief of Thyroid, the official journal of the ATA,  last month proclaimed that “The only thing that has significantly changed my practice of thyroidology in recent years has been my thyroid ultrasound. I am in love with it…It gives me almost everything I want…Frankly, I do not know how anyone can see thyroid patients without their own ultrasound by their side” (1). Certainly, I would suggest, that this represents a very strong endorsement for clinical thyroidologists to take the ultrasound probe into their own hands!

Impact of Sonography on PTC recognition
 
   But has this renewed interest in thyroid sonography, both in private and academic practice, made a difference to the detection of patients with FCDC? Between 1975 and 2001, the incidence of thyroid cancer in the United States rose by 52% (2) and, in a retrospective cohort evaluation of patients with thyroid cancer using the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program, Davies and Welch (3) also demonstrated that the incidence of thyroid cancer has increased from 3.6 per 100,000 in 1973 to 8.7 per 100, 000 in 2002: a 2.4 fold increase. Virtually, the entire increase was attributable to an increase in the incidence of PTC, which increased from 2.7 to 7.7 per 100,000: a 2.9 fold increase. However, mortality from thyroid cancer was stable between 1973 and 2002 (approximately 0.5 deaths per 100,000). These authors concluded that “these trends, combined with the known existence of a substantial reservoir of subclinical cancer and stable overall mortality, suggest that increasing incidence reflects increased detection of subclinical disease, not an increase in the true occurrence of thyroid cancer” (3).
    These authors are in no doubt that “increased diagnostic scrutiny” explains the apparent increased PTC incidence, and that the case for “overdiagnosis”, a term more often applied to prostate cancer,  is strengthened because “almost all the increased incidence is attributable to the detection of small cancers best discovered by use of the new technologies: ultrasound and fine needle-aspiration”. Noting that HRTS is “increasingly performed in the physician’s office”, Davies and Welch went on to caution that “if ultrasound continues to grow as an office-based adjunct to physical examination, there could be a dramatic increase in the number of nodules, and ultimately, cancers, identified”, and they advised that “further studies will be needed to determine if a more cautious diagnostic approach, perhaps simply providing follow-up for symptomatic thyroid nodules, is worthwhile”. They concluded that “in addition, papillary cancers smaller than 1 cm could be classified as a normal finding”, a conclusion remarkably similar to those derived from the meticulous pathologic anatomical studies of Fransilla and colleagues in Helsinki, which had been published in Cancer during 1985 (4). And reminiscent too of the observations on “benign metastases from thyroid malignancies” published twenty one years ago by TB Schwartz in the Lancet (5).
 
Pursuit of consensus in the presence of potential conflict of interest and in the absence of presently published prospective controlled therapeutic trials for FCDC

  And into this present era of FCDC patients being hotly pursued by both endocrinologists and medical oncologists, and during a time when it could appear that the notion of a management program, consisting of surgery followed by thyroxine supplementation and increasing use of radio-iodine remnant ablation (RRA), has not much changed in almost four decades, and no prospective multicenter controlled trials have ever been performed, would come in the year of 2006  the apparent “voices of authority” from the Thyroid Associations of both the United States (6) and Europe (7).
    As stated by the ATA Guidelines Taskforce in their February 2006 Thyroid contribution, other groups (the AACE, AAES, BTA, RCP,  NCCN and SSO) had previously developed guidelines “ which have provided somewhat conflicting recommendations because of the lack of high-quality evidence from randomized controlled trials” (6).The ATA  taskforce used a strategy similar to that used by NIH for its Consensus Development Conferences and “developed a series of questions pertaining to thyroid nodule and thyroid cancer diagnosis and treatment”. They admitted that “given the paucity of randomized controlled trials in the treatment of thyroid cancer, the panel relied on all the available published evidence.” The taskforce described in their methods section their meetings in January through June 2005, and their painstaking attempts to review and categorize “all English-language papers published between 1995 and December 2004”, while also being supplied with “relevant review articles, book chapters, and pre-1995 articles”. However, they were forced to admit that “when evidence was judged to be insufficient, the taskforce members also relied on their experience and judgment to answer the questions that had been posed” (6). After categorizing the published data using modified criteria adopted from the U.S. Preventive Services Task Force (USPSTF), the task force then “made specific recommendations using the schema proposed by the USPTSF”. Under this scheme, a rating of A was based on “good evidence that the service or intervention can improve health outcomes”, a B rating was based on “fair evidence”, while C was a recommendation “based on expert opinion”.
     Perhaps symptomatic of the time in which we live, the third page of the resulting 33 page document documented that seven (70%) of the ten authors, selected by the ATA,  had “financial interests, arrangements, or affiliations “ with either the manufacturers of rhTSH or levothyroxine. When the ATA group considered and gave a rating B for a recommendation ( R37 out of a total of 85) of a role for rhTSH stimulation, as an alternative to thyroxine withdrawal, in preparing patients for RRA, (a role that to date is not yet approved by the FDA in the USA), it was noted in the text that “because of varying degrees of involvement with the manufacturer of rhTSH, five (of 10) authors recused themselves from the discussion of this recommendation” (6).

Initial invited British and European editorial responses to the American Guidelines
 
    Jayne Franklyn (8), in an invited accompanying editorial to the ATA Guidelines publication, noted that in the ATA manuscript “what is striking is the relative paucity of new (and old) evidence enabling the Taskforce to give grade ‘A’ recommendations (i.e. strong recommendations based on consistent results from well designed and conducted studies)”. Indeed, of the 65 recommendations for the treatment of FCDC, only 6 (9%) were awarded an ‘A’ rating. Professor Franklyn further commented that “the lack of prospective evidence means that there is inevitably heavy reliance on carefully documented and detailed, but often retrospective evidence , and reliance on consensus opinion and experience” (8).  Commenting on the ATA recommendation (at level ‘B’) that HRTS “should be performed in all patients with one or more suspected nodules” (6), she noted that “while intuitively it would seem important to detect (and treat) early-stage disease, proof of this principle is still awaited in the context of this generally slow-growing and relatively ‘benign’ malignancy” (8). She contrasted the taskforce’s recommendation with the UK guidelines, which “presently recommend against initiation of thyroid imaging (including ultrasound) by the primary care practitioner before referral to the specialist (in order to avoid delay) and recommend against routine use of ultrasonography in the specialist setting [in favor of immediate use of fine needle aspiration cytology]” (8).
   In his invited commentary on the ATA Guidelines, Furio Pacini (9), himself the lead author of the subsequently published ETA Guidelines, opined that “in the last ten years or so, the clinical presentation of differentiated thyroid cancer has been changing from advanced cases requiring intense treatment and surveillance to sub-clinical cancers detected by fortuitous neck ultrasound requiring less aggressive treatment and follow-up”. He also noted that “these considerations dictate the need for applying the more appropriate, less invasive, and less expensive procedures able to guarantee the best management and the best quality of life for a disease that in view of its intrinsic low mortality has to face with life-long follow-up” (9). In describing the 2006 ATA Guidelines, he concluded that the result of their considerations was a “text clear, concise, easy to read and, most of all, easy to be applied in daily practice” (9).
  In the following overview of the ATA Guidelines, commentary will be restricted to those recommendations that are directly relevant to the initial management and follow-up of PTC patients, who now represent on both sides of the Atlantic the vast majority (80-95%) of FCDC patients. And, as Pacini (9)has commented, it will be of relevance to determine in future years whether such guideline documents, published in 2006, will prove to have served the dual objectives of “improvement in healthcare outcomes….and promotion of cost-effective strategies” .

ATA recommendations for initial surgical management of PTC

   The ATA manuscript consists of 20 printed pages of text, 301 references, 2 tables and 4 figures. The taskforce made 85 recommendations, 65 of which related to FCDC management. Given the immensity of this text described by Pacini as “concise” (9), one has to marvel at the remarkable skill of our forefathers in so briefly summarizing the so-called Ten Commandments! As stated above, in considering the ATA guidelines, this overview will be restricted to the initial therapy and the broad principles of the postoperative surveillance of patients with papillary carcinoma. Indeed, with relevance to the ATA guidelines, the following discussion, for reasons of required length restriction, will be limited to only 13 (20%) of the 65 recommendations made for differentiated thyroid cancer.
  Further to the point raised by Dr Franklyn (8 ), in relation to HRTS and NTD patients, it is perhaps of relevance that the first recommendation of the ATA in the initial management of FCDC is to recommend (R21) with a B rating that preoperative  neck HRTS be performed in “all patients undergoing thyroidectomy for malignant cytologic findings on biopsy”!  Although at Mayo we strive unsuccessfully to achieve this in all operated PTC cases (10), such a procedure is certainly not being performed regularly in most North American institutions during 2006-7. The  A-rated recommendation (R26) of a “near-total or total thyroidectomy for most patients with thyroid cancer” seems hardly surprising, although recommending lobectomy alone as “sufficient treatment” for “small low-risk isolated intrathyroidal” node-negative PTC seems rather extraordinary in the face of prior published reports ( 11, 12, 13) and the aggressive nature of the ATA taskforce’s  subsequent recommendations.
   It seems likely that the AAES representative on the taskforce (13) was responsible for the B-rated recommendation (R27) that “routine central compartment (level VI) neck dissection should be considered” for PTC patients. This is thought currently at Mayo to represent optimal surgical care (15), but in most academic centers of surgical excellence in the USA this is not the presently expected standard of care. Indeed, one wonders whether many North American academic thyroidectomists would be willing or able to add a central neck dissection to their routine initial surgical treatment of PTC! Less controversial was the recommendation (R28) of lateral neck compartment dissection (16) for biopsy-proven nodal metastases, “especially when they are likely to fail radioactive iodine treatment based on lymph node, size, number, or other factors” (6).The final recommendation relevant to initial surgery (R30) advised  a second surgical procedure, namely, a completion thyroidectomy, after an initial lobectomy  for all PTC patients “except those with small (<1cm) intrathyroidal node-negative low-risk tumors”.
   With regard to postoperative staging, the ATA recommended (R31) with a B-rating the use of AJCC/UICC staging, while also recognizing the utility of “postoperative clinicopathologic staging systems to improve prognostication and to plan follow-up”. The taskforce acknowledged that schemes such as AGES, AMES, and MACIS (17) permit accurate identification of the majority of patients who are at low-risk of death from PTC, “allowing the follow-up and management of these patients to be less intensive than the higher risk minority, who may benefit from a more aggressive management strategy”.

Remnant ablation for patients with papillary thyroid carcinoma

    With regards to postoperative radioiodine remnant ablation (RRA), the ATA taskforce stated that  the reported advantage of reducing tumor recurrence (TR) and cause-specific mortality (CSM) in PTC  “appears to be restricted to patients with larger tumors (>1.5 cm) or with residual disease after surgery, while lower risk patients do not show evidence for benefit”. However, rather than advocating a selective use of RRA for only  higher-risk patients, the ATA recommended with a B-rating (R32) that RRA be performed in “patients with stage III and IV disease (AJCC 6th edition), all patients with stage II disease younger than age 45 years (Any T Any N M1) and most patients with stage II disease 45 years or older (T2N0M0), and selected patients with stage I disease, especially those with multifocal disease, nodal metastases, extrathyroidal or vascular invasion, and/or more aggressive histologies” (6).
    Franklyn (8) has pointed out that the UK guidelines presently argue for “almost routine” RRA for FCDC, and she considers the ATA approach, when compared to the UK, to be “more conservative, especially in selected patients with stage I disease”. Since studies from Mayo (18, 19) and the NTCTCSG (20) have convincingly demonstrated a lack of efficacy in terms of reducing either TR or CSM in low-risk PTC patients, and a European consensus report recommended in 2005 that RRA “should be selective, given that uncertainty persists concerning its benefits” (21), it seems disappointing that the ATA taskforce did not advocate a more selective use of RRA, confining its use to patients in the high-risk category..  Under the proposed ATA guidelines, the only PTC patients avoiding RRA would be those stage I patients with disease confined to the neck (M0), who were either aged <45 years with unifocal (any tumor size) intra-thyroidal node-negative (T1 or T2N0) PTC and favorable histology, or were aged 45 or more with a PTC of 2cm or less (T1), that would be unifocal, intra-thyroidal and node-negative. Thus, of patients with PTC having an initial near-total or total thyroidectomy with curative intent, one would estimate that approximately 70% would be submitted to RRA, although all current staging and scoring systems would identify the high-risk minority, who could potentially  benefit from RRA, to be only about 15 to 20% of  PTC cases!
   Such a draconian recommendation seems all the more extraordinary, since three members of the ATA taskforce presented both in 2001 and again at the 2nd annual ATA Spring Meeting in 2005 the results of a registry study (with data gathered during 1986-2001 from 11 North American institutions, including Johns Hopkins, NIH, MGH, MD Anderson and University of Colorado) that was “unable to show any impact, positive or negative, of specific therapies in stage I patients” (20). Indeed, these same authors published in Thyroid, ten months after the Guidelines were distributed, the remarkable conclusion that “postoperative RAI therapy does not provide significant benefit in stage I patients, and could even be harmful” (20)!
   Perhaps somewhat less controversial were the B-rated recommendations (R35) that the “minimum activity necessary to achieve successful remnant ablation (30-100 mCi) should be chosen” in low-risk patients, that (R38) patients should have a low iodine diet for 1-2 weeks prior to RRA, and (R39) that after RRA a posttherapy scan should be performed at 5-8 days after the therapeutic dose is administered. And, as was discussed above, the ATA (R37) did recommend with a B-rating that RRA could be performed  “following thyroxine withdrawal or rhTSH stimulation”, despite the fact that in the United States, as against Europe, rhTSH was not at that time approved for such an indication.

ATA recommendations for followup of patients with DTC

   Possibly the most interesting question posed in the ATA Guidelines manuscript was “what is the appropriate method of following patients after surgery with or without remnant ablation”?  Under this heading comes a listing of criteria for absence of persistent tumor relevant to patients undergoing total or near-total thyroidectomy and RRA, which reads as: “Disease free status comprises all of the following: no clinical evidence of tumor, no imaging evidence of tumor (no uptake outside the thyroid bed on the initial posttreatment whole body scan, on a recent diagnostic scan or neck ultrasound), and undetectable serum thyroglobulin levels during TSH suppression and stimulation in the absence of interfering antibodies (Figs. 2 and 3).” Figures 2 and 3 in the Guidelines document depicted algorithms for initial (1-3 months after surgery) and longer term (6-12 postoperative months) follow-up of DTC patients.
    These complex algorithms, along with fig 4 on empiric radioiodine therapy, occupy three full pages (approximately 20%) of the portion of the ATA guidelines paper devoted to thyroid cancer, and apparently were “modified and reprinted with permission” from the July 2005 issue of the Journal of Nuclear Medicine.  Curiously, neither the author nor the title of this paper was identified on the accompanying twenty line Fig. 3 legend, which does give full details of the authors and titles of four other papers!
   My curiosity thereby piqued, I searched through the 301 references of the guidelines manuscript to try to identify the full details of this paper, where I found it to be unlisted.  Subsequent web searching led to the discovery that these three algorithms were derived from an “Invited Perspective” contribution, written by one of the taskforce members in April 2005 to accompany a Chinese meta-analysis, and entitled “Empirically treating high serum thyroglobulin levels” (22). This review described surveillance paradigms that the author noted to have changed substantially in the past five years, “sparked mainly by the introduction of rhTSH into clinical practice” (22).  The author stated in his review that “the most common scenario for referral to my clinic is an rhTSH-stimulated Tg level of >2mcg/L with negative findings for tumor”, and he went on to define what he described as “my approach to treating patients with high serum Tg levels and negative imaging studies” (22).
    Considering that this ten person taskforce prided itself on mastering the 1995-2004 literature, and grading the strength of the panelists’ recommendations according to “all the available published evidence”, it would seem somewhat extraordinary that the only management algorithms in this ATA document (6) would prove to be “modified and reprinted” from a non peer-reviewed “invited perspective” (22)!
 
Serum Tg measurements and appropriate imaging in followup of PTC
 
  With regards to the role of Tg in follow-up, the taskforce (R43) advised with an A-rating that serum Tg should be measured every 6-12 months in patients who had undergone near-total thyroidectomy and RRA. The recommendations were less clear (awarded only a C-rating) for patients who had less than total thyroidectomy, or had a total thyroidectomy but no RRA. The panel suggested that “periodic serum Tg measurements should be considered”, but they intimated that “the cutoff levels to detect tumor during TSH suppression or stimulation are not known, but unstimulated or stimulated levels greater than 2 ng/mL that increase over time may represent recurrent disease” (6).
    The final recommendation (R45) relevant to Tg measurement in low-risk ablated patients with “negative cervical ultrasound and TSH-suppressed thyroglobulin 6 months after treatment” seems a little puzzling, as it states: “serum thyroglobulin should be measured after thyroxine withdrawal or rhTSH stimulation approximately 12 months after the ablation to verify the absence of disease. The timing or necessity of subsequent stimulated testing is uncertain for those found to be free of disease”.  This is certainly not a practice that I will be performing in upcoming years, as I find the notion of measuring Tg after thyroxine withdrawal quite outmoded and barbaric. Moreover, for years our group have accepted that, akin to the prediction of TRH-induced TSH increments using high sensitivity thyrotropin assays, little relevant information is gained from rhTSH- stimulated Tg testing if the patient has no Tg antibodies, and one has familiarity with a highly sensitive Tg assay, with a functional sensitivity around 0.1 ng/mL (23). The definition of an “undetectable’ Tg is forever changing, but a Tg <0.1 ng/mL in a low-risk PTC patient on adequate thyroid hormone suppressive therapy certainly  provides reassurance to most of the endocrinologists and surgeons at our institution (24).
  The penultimate A-rated recommendation related to the role of diagnostic whole body radioiodine scanning in low-risk patients. Here the ATA recommend (R46) that “after the first RxWBS performed after radioiodine remnant ablation, low-risk patients with negative TSH-stimulated thyroglobulin and cervical ultrasound do not require routine DxWBS during follow-up.” The ATA taskforce do admit that “cervical metastases occasionally may be detected by neck ultrasonography even when TSH-stimulated serum thyroglobulin levels remain undetectable” (25). Not surprisingly, therefore, they recommended (R48) that “after surgery, cervical ultrasound to evaluate the thyroid bed and central and lateral cervical nodal compartments should be performed at 6 and 12 months and then annually for at least 3-5 years, depending on the patient’s risk for recurrent disease and thyroglobulin status” (6).

Thyroid hormone suppression and management of regional and distant metastases

    For the degree of thyroid hormone suppression, the ATA had three recommendations (R49-51). For persistent disease, a TSH below 0.1 mU/L  indefinitely was advised (B-rating). For high-risk patients presently free of disease, a TSH between 0.1 and 0.5 mU/L for  5-10 years was recommended (C-rating). And for low-risk patients presently free of disease, the taskforce recommended with a C-rating that the serum TSH “may be kept within the low normal range (0.3 to 2 mU/L)”. For the next 34 recommendations, mainly relating to the management of patients with locoregional recurrence and distant metastases, and the role of radiotherapy and chemotherapy, there was only one last A-rated recommendation. This related to the treatment of lung metastases, particularly those with pulmonary lesions smaller than 1 cm diameter. Such “micrometastases should be treated with radioiodine therapy, repeated every 6-12 months as long as disease continues to respond, as the highest rates of complete remission are reported in these subgroups”.
  The taskforce concluded their report with a statement regarding directions for future research. In discussing small cervical lymph node metastases, they conceded that cervical nodal metastases did comprise the majority of all tumor recurrences. Their final statement was that “future research must be directed to develop techniques to identify small cervical metastases, which in a substantial number of cases progress to overt, clinically significant metastases” (6).

Practical implications for PTC patients and providers

Table 1. Actual and Proposed Rates of RRA after Successful Near-Total
or Total Thyroidectomy for Localized Papillary Thyroid Cancer

If we consider PTC patients who have undergone an optimal primary surgery (near-total or total thyroidectomy) and at the procedure’s end there is no gross residual disease, then, at the  Mayo Clinic, Rochester, during three decades (1970-99), only 45% of such patients received RRA within 6 postoperative months (18,19). In 2000, the minority ablated during that year was only 36%. If one applies the exclusion guidelines proposed by the recent Guidelines of either the ATA (6) or the British Thyroid Association (8), [who would ablate all PTC patients with a primary tumor > 1cm diameter], to our 1970-2000 cohort of optimally treated PTC patients, one would see the rates for RRA as outlined in Table 1. Compared to Mayo’s past prescribing habits, almost 100% more patients would be ablated currently, if the new Guidelines were closely followed.  Since neither the Mayo (18, 19 ) nor the NTCTCSG (20 ) data can demonstrate improvement in either tumor recurrence or cause-specific mortality rates with RRA , especially in low-risk patients, such an escalation of aggressive postoperative adjunctive therapy can hardly be justified. Indeed, one must seriously doubt whether the proposed increased use of RRA and the increasing evaluation of rhTSH-stimulated thyroglobulin levels will either be cost-effective, or lead in future years to improved outcome results for patients with PTC, the commonest endocrine cancer.