Neck Nodal Metastases in Differentiated Thyroid Carcinoma

Thyroid cancer is the most common malignant tumor of the endocrine system.¹ In both American² and Japanese³ surveys, papillary thyroid carcinoma (PTC) has accounted for at least 80% of new cases of thyroid cancer. The majority of patients with thyroid cancer, whether derived from the follicular cell or the C-cell, present with a focal, often palpable, intrathyroidal primary lesion. At presentation, many differentiated thyroid cancer (DTC) patients have primary tumors, which have already spread to regional lymph nodes, mainly in the neck. The prevalence of neck nodal metastases (NNM) at presentation varies significantly among the various histologic types of DTC. In most reported series, PTC and the C-cell–derived medullary thyroid carcinoma (MTC) are the histologic groups most likely to have nodal involvement at diagnosis⁴ (see Chapter 14, Preoperative Radiographic Mapping of Nodal Disease for Papillary Thyroid Carcinoma).

Of 2348 consecutive DTC patients undergoing primary surgery at the Mayo Clinic from 1940 through 1991, 23% of 1916 PTC patients and 32% of 182 MTC patients had suspicious nodes by palpation. More than 50% of the PTC and MTC patients had neck nodes removed at surgery; 38% of the PTC patients and 40% of the MTC patients had nodes, which were found, on surgical pathology examination, to be involved with metastatic disease. By contrast, only 4% of patients with follicular thyroid cancer (FTC) and 6% of those with Hurthle cell cancer (HCC) had NNM at initial surgical diagnosis⁴ (see Chapters 18, Papillary Thyroid Cancer, 19, Papillary Thyroid Microcarcinoma, 20, Follicular Thyroid Cancer, 22, Hurthle Cell Tumors of the Thyroid, 23, Sporadic Medullary Thyroid Carcinoma, 24, Syndromic Medullary Thyroid Carcinoma: MEN 2A and MEN 2B, and 25, Sporadic Medullary Thyroid Microcarcinoma).

A significant number of DTC patients, despite potentially curative surgery, are also found to have NNM discovered at months to years after the date of the initial operation. The proportion of patients with these so-called recurrent NNM varies considerably among the principal histologic types of DTC. In 2172 DTC patients who were operated with curative intent (complete surgical resection and no distant metastases at presentation) at Mayo from 1940 to 1991, nodal “recurrence” (more than 180 days after primary surgery) in 124 cases of FTC was rare (a 2% rate at 20 years). However, 87 patients with HCC had an 18% rate by 20 years, which was just exceeded by the rate of 23% seen in the 160 patients with MTC.⁴ The 1801 PTC patients had a 20-year rate that was intermediate at 8%. In 2370 PTC patients treated with curative intent from 1940 to 2000 at Mayo, the cumulative occurrence rates for postoperative NNM at both 25 and 40 years was 10%.⁵

Initial Management of NNM in PTC and MTC

Although PTC and MTC are derived from different cells of origin (the follicular cell and C-cell, respectively), there are a considerable number of similarities between PTC and MTC.⁶ Both tumor types tend to be DNA diploid,⁷ and their tumor cells typically tend to remain differentiated enough to produce complex tumor markers, such as thyroglobulin and calcitonin, respectively. The ret prot-oncogene is involved in the pathogenesis of both types of tumors.⁶ Most cases of PTC and MTC are sporadic, but a minority of both can be familial. Moreover, the tumors in both types of cancer may be either unifocal or multicentric, and they can be either unilateral or bilateral. Perhaps most importantly, both tumor types, as described in the preceding section, tend to spread early to regional (neck) lymph nodes, and patients with either PTC or MTC can live sometimes for decades despite the presence of biopsy-proved NNM.⁸

Recently both the European Thyroid Association (ETA)⁹ and the American Thyroid Association (ATA)¹⁰ have published guidelines for the management of DTC. The ATA has also described separate guidelines for the management of MTC.¹¹ More recently, the National Comprehensive Cancer Network¹² in the United States has also produced its own guidelines for treating not only follicular cell–derived cancer (FCDC) but also MTC.

All three of these guidelines are in uniform agreement¹³ that compartment-oriented neck dissection should be done at the time of initial thyroidectomy for PTC patients with known NNM (therapeutic neck dissection). However, all three guidelines note that routine central neck dissection of clinically uninvolved lymph nodes (prophylactic neck dissection) is controversial. None of the three organizations recommend prophylactic lateral neck dissection (levels II to V). With regard to central neck (level VI) dissection, the ETA has noted that the information obtained by the procedure may permit more accurate staging and therefore could guide subsequent treatment and follow-up. The NCCN noted that prophylactic central compartment neck dissection (CCND) should be “considered,” but this was a level 2B recommendation (lower quality evidence, nonuniform agreement). The ATA guidelines noted that total thyroidectomy without prophylactic node dissection “may be appropriate” for small (T1 or T2), noninvasive, clinically node-negative PTC. However, prophylactic CCND “may be performed” in patients with PTC, especially those with advanced tumors (T3 or T4).

All three guidelines recommended selective use of radioiodine remnant ablation (RRA) on the basis of the standard clinicopathologic features that define the risk of tumor recurrence and cause-specific mortality. There is uniform agreement that patients with very low risk PTC (less than 1 cm confined to the thyroid) do not require RRA. Likewise, there is uniform agreement that high-risk FCDC patients (gross extrathyroid invasion, primary tumor greater than 4 cm, known distant metastases) should receive RRA as part of routine care.¹³ Both the ATA and ETA note that there continues to be controversy regarding the benefit of RRA in patients with tumors between 1 and 4 cm, with or without NNM. All three guidelines call for the selective use of RRA in these intermediate-risk patients on the basis of conflicting, retrospective data.^14,15

Clearly, there is no role for RRA in the initial management of MTC patients.^11,12 In the setting of an MTC patient with suspected limited central compartment nodal involvement but with a normal ultrasound (US) of the lateral neck compartments, the ATA (recommendation 62) advises a total thyroidectomy (TT) and level VI compartment dissection. In MTC patients with suspected NNM in both central and lateral compartments (with US-visible lateral compartment NNM) and in the setting of no distant metastases (DM), or limited DM, the ATA (recommendation 63) advises a TT, CCND, and lateral neck (levels IIA, III, IV, and V) dissection.¹¹

Trends in the Management of Recurrent/Persistent NNM in PTC and MTC

When patients with PTC were, in past years, discovered on a radioactive iodine (RAI) whole-body scan (WBS) to have, despite apparently successful radioiodine remnant ablation (RRA), a persistent focus of RAI uptake in the region of the thyroid bed or in a location suspicious for lateral compartment nodal involvement, this would generally prompt the administration to the patient of a significantly high therapeutic dose of ¹³¹I, usually as an inpatient. Subsequent doses of ¹³¹I would be administered in future months or years until the RAI-avid focus would be eliminated. Such behavior was commonplace in the United States during the period following the reports in the 1970s by Beierwaltes¹⁶ at the University of Michigan and Mazzaferri¹⁷ at the Ohio State University.

The increasing recognition that RRA may not reduce or eliminate the postoperative discovery of NNM,^14,15 particularly in young patients with pTNM stage I PTC, has led not only to a more selective use of RRA in PTC management, but also to an increasing dependence by clinicians on serum thyroglobulin (Tg) levels, either basal, on thyroxine suppressive therapy (TST), or stimulated, whether after thyroxine withdrawal or recombinant human thyroid-stimulating hormone (rhTSH) injections^9,10 During the same period, the postoperative neck in PTC, formerly studied by either computed tomography (CT) or magnetic resonance imaging (MRI), is now being increasingly evaluated by radiologists and, more recently, endocrinologists, using the powerful tool of high-resolution real-time sonography (US),¹⁸ a theme to which we will return later in this chapter.

Where, formerly, a successful outcome in PTC was predicted if the “scintigraphic slate was wiped clean,”¹⁹ we now find ourselves in an era where it is possible in PTC patients to identify by US tiny (and possibly clinically “unimportant”) NNM with diameters as small as 3 mm. Moreover, many endocrinologists now seem uncomfortable if a PTC patient does not have on TST a postoperative “undetectable” Tg level, which ideally does not significantly stimulate with Thyrogen (rhTSH). In the apparently vexing circumstance of the “Tg-positive WBS-negative” patient, some practitioners turn to the “blind” administration of large ¹³¹I doses,²⁰ whereas others make increasing use of the novel technology of¹⁸ F-fluoro-deoxyglucose (FDG) whole-body positron emission tomography (PET) scanning²¹ to help identify the source of the detectable Tg.

In a PTC patient who has in the past had successful RRA and now has a negative WBS with ¹²³I or ¹³¹I, the choice for the clinician is either to follow a small NNM²² with serial imaging or, if the node is larger (e.g., > 1 cm diameter), or especially if multiple nodes appear to be involved, to seek help from an experienced surgeon, who ideally would not perform a “berry picking” procedure¹⁰ but rather would dissect the appropriate neck compartment and successfully remove the involved NNM.²³ Hopefully, in the present era, few endocrinologists would consider radiation therapy in this setting, and, in the absence of concomitant distant metastases (DM), medical oncologists would probably not consider targeted therapy with kinase inhibitors.²⁴

In the setting of sporadic MTC, the presence of hypercalcitoninemia, or increasing serum carcinoembryonic antigen (CEA) levels, has generally led to the ordering of an US of the neck and CT scanning of the thorax and abdomen. More recently, whole-body FDG PET-CT, metaiodobenzylguanidine (MIBG), and bone MRI have also had their proponents. In MTC, the discovery of postoperative NNM has traditionally led to nodal dissection surgery, and rarely have such patients been submitted to directed radiation therapy. However, there are sometimes circumstances where, in MTC, there can be discovered biopsy-proved small NNM by US, which, in the setting of a multiply operated neck or in the presence of potentially more threatening DM, neck surgeons would prefer not to reoperate. It is in this relatively unusual setting that ablation by percutaneous ultrasound-guided ethanol injection (PUEI) may play a role, and it is in just such a circumstance that the author of this chapter turned to PUEI in the 1990s to achieve local control and to permit the elimination of MTC in a multiply operated neck.

First Use at Mayo of PUEI in the Management of NNM in DTC

The Mayo Clinic was among the first to describe in 1979 the sonographic appearance of the thyroid, as visualized during so-called B-mode scanning to localize parathyroid tumors.²⁵ By 1984, the advent of US had led to a more widespread awareness that nodular thyroid disease affected more than 50% of the population, and only about 2% to 3% of such nodules were proving to be PTC.²⁶ By 1987, the typical sonographic appearances of intrathyroidal and regionally metastatic PTC and MTC were being increasingly recognized,²⁷ and in 1988 the ultrasound-guided biopsy (USGB) of NNM due to PTC in the postoperative setting was described by Mayo authors.²⁸ During the late 1980s and early 1990s, PUEI was being regularly used at Mayo to control small hepatocellular carcinomas and, in 1988, PUEI was successfully employed to ablate a parathyroid adenoma, which had resulted in persistent primary hyperparathyroidism in an elderly and debilitated patient considered unsuitable for neck reexploration.²⁹ By 1990, PUEI was being employed in many European centers to treat autonomously functioning thyroid adenomas,³⁰ and it had also been used in the treatment of an inoperable primary DTC tumor.³¹ However, by 1991, there were no reports in the literature of patients with DTC being treated by PUEI³² for persistent/recurrent NNM (see also Chapter 16, Laser and Radiofrequency Treatment of Thyroid Nodules and Parathyroid Adenoma). It was in that year that a 46-year-old Canadian psychiatrist with stage IV MTC came to the Mayo Clinic for advice.