Breach of the thyroid capsule and lymph node capsule in node-positive papillary and medullary thyroid cancer: Different biology
Introduction
Growth of thyroid cancer through a tissue barrier can reflect the invasive properties of the thyroid primary (breach of the thyroid capsule) or the metastatic tumor deposit (breach of a lymph node capsule). Different clinical weights have been attached to such invasive growth depending on whether it originates from within the thyroid parenchyma (extrathyroidal extension) or the lymphatic mesenchyma (extranodal growth). Although the former type of invasion is well-established and continues to form an integral element of tumor staging systems,1, 2 the latter has attracted little attention until recently. As a result, no consensus has emerged on the clinical implications of extranodal growth to date.
In 1989 appeared a first small series of 25 patients with papillary thyroid cancer (PTC) and extranodal growth describing comparable rates of regional recurrence, distant metastasis, cancer-specific death or recurrence-free survival relative to 63 controls without extranodal growth.3 On a more powerful univariate analysis 23 years later, however, the 75 patients presenting with node-positive PTC and extranodal growth had worse rates of 10-year recurrence-free survival (75 vs. 92%; P = 0.009) and 10-year disease-specific survival (97 vs. 100%; P = 0.004) than the 161 patients with node-positive PTC in the absence of extranodal growth.4 On multivariate analysis, none of these factors remained significant. Similar findings have appeared for medullary thyroid cancer (MTC). In one series, the 12 patients with MTC and extranodal growth had worse 10-year (75 vs. 99%; P < 0.0001) and 20-year (56 vs. 97%; P < 0.0001) rates of disease-specific survival than the 106 patients with MTC without extranodal growth.5 In another MTC study of 12 patients with and 20 patients without extranodal growth, extranodal growth was a significant predictor of overall survival (hazard ratio 3.1; 95% CI 1.1–8.5; P = 0.03) on univariate but not on multivariate analysis.6
Recently, Clain et al.7 reported a significant correlation between extrathyroidal extension and extranodal growth in 193 patients with differentiated thyroid cancer: 41 (72%) of their 72 patients with extrathyroidal extension had extranodal growth, as opposed to only 12 (10%) of their 121 patients without extrathyroidal extension (P < 0.001). This striking finding prompted the authors to conclude that the biology of the primary thyroid tumor was conferred to the lymph node in that the presence of extrathyroidal extension resulted in a significantly higher incidence of extranodal growth. If confirmed, this observation may have important clinical ramifications for PTC, supporting the upstaging of patients with minimal extrathyroidal extension,7 and conceivably also for malignancies other than follicular cell-derived thyroid cancer.
The present validation study of 702 patients with node-positive PTC and 548 consecutive patients with node-positive MTC was set up to clarify, separately for each tumor entity, the dependence or independence of extranodal growth from extrathyroidal extension by quantifying the individual contributions of various clinical-pathological risk factors to extranodal growth on multivariate analysis.
Section snippets
Study population
Between November 1994 and May 2014, 702 of 1367 patients with PTC and 548 of 898 patients with MTC (144 patients with hereditary and 404 patients with sporadic disease) underwent initial neck surgery or reoperation at this institution for node-positive PTC or node-positive MTC. Patients with sporadic and hereditary MTC, faring the same after adjustment for extent of disease,8 were evaluated as one group. Because extranodal growth (breach of a lymph node capsule) by implication required the
Characteristics of all patients with node-positive PTC or node-positive MTC
As illustrated in Table 1, patients with node-positive PTC differed significantly (P < 0.001) from patients with node-positive MTC in age at diagnosis (means of 39.7 vs. 46.5 years); male gender (38 vs. 50%); extrathyroidal extension (54 vs. 35%); numbers of involved (means of 11.4 vs. 15.2) and removed (means of 45.6 vs. 63.6) nodes; and distant metastasis (13 vs. 26%). These clinical-histopathological disparities reflect fundamental differences in tumor biology between PTC and MTC. In light
Discussion
This comprehensive clinical-histopathological analysis, the largest series on this topic, encompassed 702 patients with node-positive PTC and 548 patients with node-positive MTC. Intriguingly, our present study disclosed, separately for each tumor entity, a correlation between the number of lymph node metastases and extranodal growth that was independent of the presence of extrathyroidal extension. Contrary to previous findings from smaller series,7 extrathyroidal extension was unassociated
Conflicts of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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