Treatment of Persistent or Recurrent Papillary Carcinoma of the Thyroid—The Good, the Bad, and the Unknown

This is the authors' abstract. We don't add key points for this paper.

The diagnosis and treatment of recurrent or persistent papillary carcinoma of the thyroid can pose significant clinical dilemmas. The tumor generally has a relatively indolent biology; however, recurrent or persistent disease is not uncommon, although tumor-specific mortality is infrequent (1). The exquisite detection sensitivity of the combination of TSH-stimulated serum thyroglobulin (Tg) in conjunction with the ease, sensitivity, and availability of ultrasonography [including ultrasound-guided fine-needle aspiration (FNA)] yields a patient cohort with persistent or recurrent disease. The compulsive physician employs these techniques and frequently detects small-volume cervical disease, and the physician in concert with the patient reacts by employing ablative or resectional therapy. Treatment options include 131I, surgical resection, and ethanol or radiofrequency ablation (2–5). All are capable of destroying target lesions, and 131I has the advantage of ablating extracervical disease. Each technique has unique, but acceptable, morbidities. Surgery is generally the preferred technique for resectable loco-regional cervical disease (6). Careful observation alone may also be an option in select patients. In this edition of the Journal, Al-Saif et al. (7) report a cohort of 70 patients with recurrent or persistent papillary thyroid carcinoma (PTC) of the thyroid who had undergone a previous thyroidectomy (with or without nodal dissection) and 131I therapy. Recurrent or persistent disease was detected by imaging studies or the presence of detectable TSH-stimulated serum Tg in patients who did not have anti-Tg antibodies. Each patient underwent one, two, or three remedial cervical reexplorations, and 19 (27%) achieved a biochemical complete remission as defined by an undetectable TSH-stimulated serum Tg level. The first re-resection achieved a remission rate of 17% (12 of 70), and the second re-resection achieved a remission rate of 18% (five of 28). No patient achieved remission (zero of seven) with a third re-resection. Two additional patients achieved complete biochemical remission during long-term follow-up without further intervention, presumably due to the latent effects of previous 131I treatment. The duration of complete biological responses ranged from 4–116 months. It is noteworthy that in 10 (9%) of the lymphadenectomies, the intervention was nontherapeutic because the surgeon was unable to identify or resect residual PTC. This emphasizes the difficulty of locating small-volume disease in the remedial neck even in the setting of a positive preoperative ultrasound-guided FNA. It is also worth noting that there were no cases of new long-term hypoparathyroidism or recurrent nerve injury. A thoracic duct injury in one patient required reoperative intervention. It is clear that for a subset of patients, surgical treatment, in expert hands, can resect all residual cervical disease with minimal morbidity. The rigorous definition of curative resection employed in this study is commendable and confirms the adequacy of resection. It most be emphasized, however, that remedial exploration for central cervical recurrent disease will expose the recurrent laryngeal nerves and parathyroid glands to inadvertent injury. The current standard and treatment of choice for patients with significant loco-regional cervical disease is referral to an expert surgeon for resectional therapy. Fundamental and unresolved issues relate to both efficacy and beneficence. It is rational and emotionally gratifying for the physician, the patient, and their families to know that all identifiable cancer has been resected and remission has been achieved. It is less clear, however, when or whether surgical or other ablative procedures are of biological relevance. Many patients live and die from unrelated causes in the setting of de novo or residual PTC that in itself has no effect upon their quality of life or longevity. A recent observational trial in Japan by Ito et al. (8) compared the outcomes of 340 patients with small (less than 1 cm) biopsy-proven PTC who did not undergo initial resection with 1055 patients who underwent immediate surgery. This nonrandomized patient-preference trial was offered to individuals in the absence of unfavorable prognostic features. In the observational group, the proportions of patients whose primary tumor demonstrated enlargement by 3 mm or more were 6.4 and 15.9% at 5 and 10 yr of follow-up, respectively. Novel nodal metastases in the observational group were noted in 1.4% of patients at 5 yr and 3.4% at 10 yr. However, only 39 of the 340 patients achieved 10 yr of follow-up at the time of publication. Eventually, 109 of the 340 observational patients (32%) underwent surgery due to tumor enlargement (n = 32), tumor location (n = 17), patient choice (n = 12), the suspicion of multicentricity (n = 7), novel nodal metastases (n = 5), or a variety of other reasons. There were no apparent deleterious effects due to nonintervention or delayed surgical resection. The authors concluded that observation is an acceptable option, and delayed surgical intervention can be employed based on signs of disease progression. This study confirms the indolent nature of PTC in many patients and the apparent safety of nonintervention. A fundamental goal of oncological treatment is achievement of a durable cure. Yet, overzealous treatment can, at times, be more moribund than natural disease progression. Clinicians must balance therapeutic options based on incomplete data. It is clear, however, that persistent cervical disease after initial thyroidectomy for PTC is a result of inadequate initial surgical treatment. The most common site of persistence is in the cervical lymph nodes, most commonly in the central neck. Accordingly, preoperative assessment of the central and lateral cervical nodal groups by ultrasound examination is recommended for all patients with biopsy-proven PTC (6). Preoperative ultrasound will identify suspicious nodes in 20–30% of patients and is likely to alter the surgical procedure (9, 10). Clinically involved nodes should be excised (therapeutic resection) at the initial operation by compartment-based nodal dissections that can include the central and lateral cervical nodal basins. The central nodes (level VI) are readily accessible during thyroidectomy, and a variety of guidelines including those promulgated by the American Thyroid Association, indicate that prophylactic central (ipsilateral or bilateral) compartment-based cervical node dissection may be performed during initial total thyroidectomy especially for advanced primary tumors (6, 11). Detailed illustrations defining the anatomic limits of these zones were recently published (12). Nonetheless, evidence for the benefit of prophylactic nodal resection in patients with PTC is limited and based on surrogate markers of the completeness of resection, including postoperative Tg levels (13). More aggressive surgery is likely to result in more frequent morbidity, including iatrogenic hypoparathyroidism (14). A rational basis for employment of prophylactic nodal resections will likely be derived by detection of preoperative FNA-derived molecular markers that correlate with aggressive disease such as the presence of a BRAF mutation (15). Our endocrine surgery team has been progressively employing prophylactic central neck dissections for the majority of patients with biopsy-proven PTC during initial thyroidectomy. We have incorporated routine BRAF mutation screening with our cytological analyses and when positive advocate a bilateral central neck dissection. We do not advocate prophylactic lateral neck dissections in PTC patients in the absence of clinically suspicious lateral nodal disease. Therapeutic compartment-based nodal dissections are routinely employed in patients with clinically involved nodes in the central or lateral nodal basins. Clinicians and their patients with PTC are subject to interventional treatment bias and the exquisite sensitivities of disease detection techniques. Restraint and judgment are required to balance treatment options. Well-designed prospective trials are required to resolve these controversies. Disclosure Summary: The author has nothing to disclose. Fine-needle aspiration papillary thyroid carcinoma thyroglobulin