Local recurrence of papillary thyroid cancer

Abstract

Management of advanced papillary thyroid cancer (PTC >10 mm) is changing its focus. Mortality was the main outcome measure for patients treated before the 90s. In the past two decades, however, most patients diagnosed with PTC belong to the very low risk of death group. On the other hand, local recurrence of PTC remains a clinical problem, with rates up to 25% depending on the presence of nodal metastasis, tumor diameter, and the skill of the surgeon to completely remove the primary tumor and the associated lymph node metastasis at first-time thyroidectomy. After optimized surgery (total thyroidectomy plus central neck dissection), radioiodine ablation has very little influence on lymph node recurrence that now presents mostly as lateral neck node metastasis that was overlooked or incompletely resected at the time of initial surgery.

Keywords:

• central neck dissection
• optimized surgery
• papillary
• recurrence
• thyroid cancer

Recurrence but not death from papillary thyroid cancer

Death due to papillary thyroid cancer (PTC) has become a rare event with figures <3% at 10-year follow-up [1]. Most patients with PTC have low-risk disease, irrespective of classifications used to predict mortality. This is mostly due to increased diagnostic awareness – of smaller tumors – better surgery and more accurate follow-up strategies.

Incidental microcarcinomas (PTC <10 mm) found in pathological specimens of thyroid glands removed for benign disease, as well as microcarcinomas identified incidentally on neck imaging for unrelated causes, can be treated conservatively (hemithyroidectomy) and will not be addressed here. These patients do not have an increased risk of death compared with the normal population, and only exceptionally develop locoregional lymph node recurrences [1]. On the opposite end, patients over 45 years old with large extrathyroidal tumors, aggressive histology, particularly if not completely resected, have a mortality of up to 50% at 20 years [2].

Fortunately, most PTCs currently treated belong to the very low risk of death group (metastasis, age, local invasion, completenes of resection, size [MACIS] <6) [2]. In these patients, the most relevant issue is not to predict the risk of death but the risk of recurrence. Local recurrence is still observed in 10–25% of patients treated for non-microcarcinoma PTC despite the widespread use of radioiodine. Data from observational long-term cohort studies at Mayo Clinic and Memorial SKCC suggest that the risk of recurrence is not influenced by postoperative radioiodine ablation both in N0 and N1 patients [3,4]. For the purpose of this review, recurrence is defined as structural evidence of disease and/or reoperation with positive pathology. As many patients are now followed without radioiodine ablation and/or whole body scans, raised thyroglobulin serum concentrations in the absence of detectable structural (clinical or radiological) disease will not be considered as synonymous of recurrence. We suggest that PTC recurrence almost always occurs in patients with locoregional metastatic lymph nodes at the time of initial surgery and is often an undesired consequence of an incomplete initial surgical procedure.

Cervical lymph nodes as site of recurrence

As most patients with PTC >10 mm are currently treated with total or near total thyroidectomy, according to most recent international recommendations, postoperative recurrences no longer occur on thyroid remnants, as happened before the 1980s [5], but instead they involve the locoregional lymph nodes. The most relevant factor for nodal recurrence is the prevalence of lymph node metastasis at the time of initial surgery (as high as 60%), the number of metastatic nodes and tumor size [6]. Nodal recurrence may happen in three different settings: in the central neck; the lateral neck, which was judged clinically negative at the time of initial surgery; or any previously dissected or non-dissected compartment due to incomplete nodal clearance.

Central neck recurrence

Central neck recurrences are the most common nodal recurrences if central neck dissection was not performed at first-time surgery. Noguchi et al. [7] were the first to map nodal involvement in PTC and proved that the central neck was the most commonly involved lymph node compartment. Thus, it is by no means surprising that the most common recurrence site after total thyroidectomy without central neck dissection are the paratracheal lymph nodes [8,9]. Frasoldati et al. [10] followed over 400 patients with differentiated thyroid cancer treated with isolated total thyroidectomy, radioiodine ablation and suppressive T4. They diagnosed 48 recurrences, two-thirds of which developed in the central neck. This has led to a more widespread intraoperative assessment of central node metastasis and dissection. Compartment VI clearance at the time of thyroidectomy was initially proposed by Scandinavian surgeons [11,12] and has been implemented in many referral institutions. There is agreement that therapeutic central neck dissection must always be carried out in cases of macroscopic or biopsy-proven lymph node involvement. Structural disease at the time of initial surgery should be completely removed as there is growing consensus that radioiodine ablation cannot eliminate structural residual disease. Potential drawbacks of therapeutic central lymph node dissection, which usually involves both sides of the neck, such as hypoparathyroidism or recurrent nerve palsy (often unavoidable to obtain a R0 resection) are to be assumed, as incomplete tumor and metastatic node removal will lead to local recurrence and may compromise patient’s life expectancy.

Controversy on prophylactic central neck dissection

The rationale for prophylactic central neck dissection in clinically N0 patients lies in the fact that micrometastasis from PTC are found in 30–60% of cases and in the hypothesis that clearing them may reduce the rate of local recurrence. Some authors, however, believe that its potential benefit is overridden by its complications, namely postoperative hypocalcaemia and permanent hypoparathyroidism [13]. Other groups have even stated that central neck recurrences can be dealt with no special risk for the patient [14,15]. This is at variance with other reports stressing the fact that reoperations on compartment VI are associated with a higher risk of inferior laryngeal nerve injury and hypoparathyroidism, even in expert hands [16–18]. A recent meta-analysis supports the implementation of prophylactic neck dissection in terms of decreasing local recurrences [19]. The authors reviewed six comparative studies that included 1740 patients. The overall recurrence rate was 7.9% in the isolated thyroidectomy group and 4.7% in the thyroidectomy plus prophylactic central dissection group. The relative risk of recurrence was almost halved by central neck dissection. In our initial [20] and current experience with implementing routine central neck dissection, no patient has developed recurrence in compartment VI in a consecutive series of 160 patients with advanced PTC (mean tumor size 26 mm). Concerning permanent hypoparathyroidism, this was found in our series (unpublished observations) to be almost exclusively observed in patients undergoing therapeutic central neck dissection.

The main adverse effect of prophylactic neck dissection is postoperative parathyroid failure resulting from a combination of patient’s parathyroid gland position/anatomy and technical expertise. Preserving the parathyroid glands in situ, avoiding both autotransplantation and accidental parathyroidectomy, is essential to prevent hypocalcaemia and permanent hypoparathyroidism [21]. This can be more easily achieved if prophylactic dissection is limited to the ipsilateral and pretracheal areas. In any case, optimized surgery for PTC should be performed by expert surgeons to avoid complications and preventable reoperations [22].

The only clinical trial published so far on the subject, is a non pre-registered, single institution, prospective randomized trial [23] including 181 patients assigned either to total thyroidectomy alone or to total thyroidectomy plus prophylactic central neck dissection. After 5 years of follow-up, no difference was observed in the recurrence rate. A higher proportion of patients with total thyroidectomy alone were treated with more ¹³¹I courses, whereas a very high, previously unheard prevalence of permanent hypoparathyroidism was observed both after total thyroidectomy plus central neck dissection (19%) and after total thyroidectomy alone (8%).

Recurrence in the lateral neck

De novo appearance of lateral node metastasis is, in our and others’ experience [20,24], the most common recurrence site after total thyroidectomy plus central neck dissection. Lateral recurrences are diagnosed in two different settings: the lateral neck was not dissected initially (clinically and imaging N0); node metastasis reappears in a previously dissected or undissected lateral compartment in known N1b patients. If a modified neck dissection was not performed initially, the most relevant factor for lateral recurrence is the number of metastatic nodes present initially in compartment VI and the lymph node ratio N+/N0 >0.6 [20,25,26]. Skip metastasis are uncommon (<10%) and usually related to PTC located at the upper pole of thyroid lobes [27].

Recurrence may also develop (10–20%) in previously dissected lateral neck compartments in N1b patients. Variables predicting lateral recurrences in this setting are: male gender, aggressive histology, number on metastatic nodes and T4-off thyroglobulin levels >4 ng/ml [28]. Previous incomplete surgery (‘berry picking’) may also be a cause of recurrence. There is consensus that the minimum required would be clearance of compartments IIa, III and IV. Dissection of compartments IIb and V should be performed selectively [29] to avoid overtreatment and prevent complications and shoulder discomfort.

Conclusion

Optimized surgery has become the main step to prevent PTC recurrence. Precise assessment of nodal status at the time of first-time surgery is crucial to tailor the extension of surgery. Prophylactic central neck dissection probably reduces paratracheal recurrences and if performed on only one side by expert surgeons should not be associated with an excessive risk of permanent hypoparathyroidism. Therapeutic central neck dissection usually involves both sides of the neck and, as expected, is associated with a higher rate of complications. The role of radioiodine ablation after optimized surgery is, at best, uncertain [30,31].

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.