Introduction: Nerve-dependent growth and metastatic spread is established in several cancers including prostate, gastric and skin cancers.1 The relationship between nerves and thyroid cancer is unknown.
Methods: 4 micron sections of formalin-fixed paraffin-embedded blocks of primary papillary (n=75) or follicular (n=14) thyroid cancers or benign thyroid (n=27) were labelled for the pan-neuronal marker PGP9.5 using the Ventana Discovery immunohistochemistry platform, then counterstained with hematoxylin and scanned at 20x magnification using the Aperio AT2 scanner. Analysis was performed within QuPath.2 Nerve trunks were counted if they demonstrated (1) immunoreactivity; (2) typical morphology; (3) contained 3 or more axons and (4) were within 1mm of thyroid tissue. Correlation was made with clinical parameters. Results are presented as median [IQR], with significance assessed by Mann-Whitney with alpha of 0.05.
Results: Nerve trunks were frequently identified adjacent to and within thyroid tissue, typically near the anatomical edge. Tissue blocks containing cancer had a significantly higher total nerve-trunk density than tissue blocks containing benign thyroid only (11 [6-24] vs 7 [3-10] trunks/cm2, p=0.001). Significantly higher whole-slide nerve-trunk density was detected around papillary (14 [9-27] trunks/cm2) compared to follicular (4 [3-12] trunks/cm2) cancers (p=0.01); and around cancers with nodal metastases (17 [7-26] trunks/cm2 vs 10 [4-18] trunks/cm2 for cancers without nodal metastases, p=0.03). Because nerve-trunks grew in from the gland edge, we also divided lesional nerve density by the length of associated anatomical border. Assessed in this way, nerve-trunk density within 1mm of thyroid cancer was 7 [3-13] trunks/cm of anatomical edge, compared to 3 [1-6] trunks/cm of benign anatomical edge (p<0.0001).
Conclusion: Nerve density is increased around papillary thyroid cancers compared to benign thyroid tissue; and also around cancers with nodal metastases compared to cancers without nodal metastases. These data warrant further investigation to determine the role of innervation in thyroid cancer growth and progression.