In Press, Corrected Proof, Available online 28 October 2024

Background: The tall cell variant of papillary thyroid cancer generally has a worse prognosis compared
with the classical variant. Thyroid GuidePx is a genomic classifier capable of classifying papillary thyroid
cancer into 3 molecular subtypes using fine-needle aspirate. Type 1 and 2 have low recurrence rates,
particularly in early tumors (1e4 cm and N0). Type 3 is characterized by aggressive biology and high
recurrence rates regardless of size and lymph node status. The study examines the interaction of tall cell
variant histology with Thyroid GuidePx risk stratification.

Methods: Gene expression data from 736 patients (The CancerGenome Atlas, Canada, and South Korea), were
submitted to the Thyroid GuidePx classifier. Results across the 3 molecular subtypes were further dichotomized into “early” papillary thyroid cancer (tumor size 1e4 cm and N0) (n¼ 369; 51%) or “advanced” papillary
thyroid cancer (n ¼ 359; 49%). Structural recurrence was the primary outcome measure in our analysis.
Transcriptomic and genomic analysis was conducted to explore what biological differences could account for
clinical differences between tall cell variant and non- tall cell variants.

Results: Thyroid GuidePx identified 369 early papillary thyroid cancers: 129 (35%) type 1, 168 (45.5%) type 2,
and 72 (19.5%) type 3. The recurrence rates for early type 1, type 2, and type 3 papillary thyroid cancers were
3.9%,1.9%, and 19.4%, respectively. Therewere no type 1 tall cell variants. In type 2 papillary thyroid cancers, the
incidence of tall cell variant was greater in advanced than early papillary thyroid cancers (10.2% vs 4.2%, P ¼
.04). Notably, none of the 7 early type 2 tall cell variants recurred. In type 3 papillary thyroid cancers, the
prevalence of tall cell variants was similar in early and advanced tumors (10% vs 9%,NS).When compared with
non-tall cell variants, early type 3 tall cell variants trended toward greater recurrence (28.6% vs 18.5%, not
significant) whereas advanced type 3 tall cell variants had a significantly greater recurrence rate (50% vs 28.6%,
P ¼.01). Biologically, type 3 tall cell variants had had a pronounced enrichment in cell proliferation, epithelialmesenchymal transition, invasion, and inflammation.

Conclusion: Thyroid GuidePx reliably identifies a low-risk subgroup (early type 1 and early type 2
papillary thyroid cancers) for which conservative procedures would be appropriate. Tall cell variants in
this subgroup are uncommon (1.2%), and none of the tall cell variants in this subgroup recurred. Type 3
papillary thyroid cancers have greater recurrence rates in both early and advanced papillary thyroid
cancers. Tall cell variant appears to further increase recurrence in this subgroup.