Isolated Lateral Neck Nodal Metastases in Patients With Papillary Thyroid Cancer: Does Cervical Compartment Matter?

The independent significance of lateral neck nodal metastases (levels II-V) in papillary thyroid cancer (PTC) remains controversial. Traditionally, thyroid cancers are thought to spread to the lymph nodes of the central compartments (levels VI-VII) first, with secondary progression to the lateral compartments. The most recent eighth edition of TNM staging system for thyroid cancer by the American Joint Committee on Cancer (AJCC) differentiates central compartment metastases from lateral neck disease with the denotations N1a and N1b, respectively (1). While these designations no longer affect overall stage grouping, they are included as “additional clinical factors that would be considered to aid in risk stratification for routine clinical care.” (2) Thus, according to the AJCC TNM system, N1b represents more advanced disease. In contrast, the American Thyroid Association (ATA) guidelines for the management of differentiated thyroid cancer do not distinguish between central and lateral compartment nodal metastases in their stratification system for risk of recurrence. Instead, the ATA risk stratification system relies on features such as the number and size of lymph node metastases, regardless of anatomic compartment (3). These differences in classification result, in part, from uncertainty in the literature as to whether lateral neck disease is an independent risk factor for either recurrence or survival.

Lateral neck “skip” metastases—spreading to lateral compartment nodes without involvement of central compartment nodes—therefore offer a unique opportunity to study the influence of anatomic compartment on recurrence and survival for patients with thyroid cancer. To assess recurrence-free survival in these patients, Weng et al (4) performed a retrospective review of a large cohort of patients treated for papillary thyroid microcarcinomas (PTMCs, tumors 1 cm in diameter or smaller) at their single institution in China from 2010 to 2020. They found that patients with isolated lateral neck disease had a prognosis similar to those with isolated central neck disease; both groups had better recurrence-free survival than patients with involvement of both compartments. Importantly, all patients in the cohort treated for PTMC underwent routine ipsilateral central lymphadenectomy, with lateral neck dissection performed selectively for patients with suspicious lymphadenopathy on preoperative ultrasound. In contrast, the ATA discourages prophylactic central neck dissections in patients with PTMC. Thus, it is not clear how these results may translate to US patients and practice patterns.

Weng and colleagues (4) also note that patients with superior pole tumors were more likely to develop skip metastases from PTMC than patients with tumors in other parts of the thyroid. Their data agree with many others who have found superior pole tumors of both papillary and medullary histology to be more likely to spread via skip metastases than tumors in other parts of the thyroid gland (5, 6). In fact, the lymphatic drainage of the superior poles of the thyroid gland courses along the superior thyroid artery and may bypass the central compartment entirely (5). In contrast, the isthmus, mid, and lower poles drain predominantly to the nodes of the central compartment. Therefore, skip metastases may simply be a manifestation of usual thyroid lymphatic drainage rather than different tumor biology or behavior.

Interestingly, skip metastases have been noted to more commonly occur in PTMC than in larger tumors (6). It is possible that tumors larger than 1 cm grow outside the region of isolated superior pole lymphatic drainage, and therefore spread both to the central and lateral nodes. However, among PTMCs, Weng et al (4) found that larger tumors (0.5-1.0 cm) were more likely to have skip metastases. Thus, cancers with skip metastases may represent a narrow window of superior pole PTC progression whereby tumors grow large enough to metastasize to draining nodes, but not so large as to grow into neighboring thyroid lymphatic basins that drain into other nodal compartments. This hypothesis is further supported by the finding that patients whose tumors developed skip metastases were much more likely to have positive nodes only in a single lateral neck compartment, compared to those patients who had both central and lateral neck disease.

These data support the ATA’s implied position that overall burden of lymphatic disease is a better prognostic marker than anatomic location of lymphatic disease. Prominent studies from other groups also support this approach. Schneider et al (7) used the Surveillance, Epidemiology, and End Results database to demonstrate that the ratio of positive lymph nodes to nodes removed for patients undergoing thyroidectomy with lymphadenectomy correlated linearly with overall survival. Ergo, patients with a higher percentage of positive nodes have poorer prognosis. Multiple subsequent studies have validated the “lymph node ratio” as an accurate predictor both of survival and recurrence in PTC (3). Furthermore, in addition to the number of nodes involved, the size of the metastatic deposits and the presence of extranodal extension are better predictors of locoregional recurrence than the cervical compartment involved (8). The majority of PTC patients with lateral neck disease also have central neck disease (3, 6); thus the presence of lateral neck metastases may simply be correlated with poor prognosis because it is a surrogate for disease burden in the majority of PTC patients.

The study by Weng and colleagues (4) has important implications for the care of PTC patients with skip metastases. Many patients with lateral neck disease are treated with total thyroidectomy and adjuvant radioactive iodine (RAI) based on the assumption that tumor spread to lateral compartments equates to more aggressive disease. Although skip metastases are rare in PTC—representing approximately 2% of patients (4, 6)—perhaps we should treat them identically to patients with isolated central neck disease, and perform total thyroidectomy and adjuvant RAI treatment only in those with high risk of recurrence because of higher burden of nodal metastasis. That is, those patients with small metastases to fewer than 5 lymph nodes perhaps may safely be spared total thyroidectomy and subsequent RAI. Ultimately, the study by Weng and colleagues (4) adds to the growing body of literature supporting the understanding that burden of lymphatic spread, rather than involved anatomic compartment, is the critical driver of disease recurrence in PTC.