Multifocal papillary thyroid carcinoma has a higher risk of recurrence than unifocal cancer

1. Multifocal papillary thyroid carcinoma (PTC) was associated with a higher risk of cancer recurrence than unifocal PTC.

2. Large (>1cm) and small (≤1 cm), adult and pediatric PTC, and high (≥3), but not low (2), foci count were associated with an increased risk of multifocal PTC recurrence.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. While in most patients it has an excellent prognosis, 30% of patients experience recurrence. Multifocality is the simultaneous presence of more than 1 tumor center (“focus”). This systemic review and meta-analysis assessed whether multifocality predicts a worse prognosis in PTC patients. Primary tumor size (≤1 cm vs >1 cm), number of tumor foci (2 vs ≥3), and patient age (<20 years old [pediatric] or >20 years old [adult]) were also investigated as factors that may increase the risk of recurrence of PTC. Multifocality and recurrence data from observational cohort studies on PTC patients recurrence were averaged across 26 eligible, high-quality, moderately heterogeneous studies. 28.1% of the 33,976 patients had multifocal PTC. 8.0% of the study population had their PTC recur. Multifocal PTC patients were at a higher risk of recurrence than unifocal PTC patients. All sizes of multifocal PTC (≤1 cm and >1cm) were associated with increased recurrence rates. High (≥3), but not low (<3), foci count was associated with a higher risk of multifocal PTC recurrence. Multifocal PTC recurrence was increased in both pediatric and adult populations. Over the 16.6 year follow-up, multifocal PTC cancer-specific mortality was 5.8%, which was similar to that for unifocal PTC. One limitation of this meta-analysis is the heterogeneity of methodologies in the studies included could have led to discrepancies when reporting multifocality/tumor foci number because of differences in definitions of a focus. A limitation of translating this study into practice is that while it demonstrated an association between multifocality and the risk of recurrence, there were no outcomes that focused on treatment.

Click to read the study in JAMA Otolaryngology–Head & Neck Surgery

Relevant Reading: An observational trial for papillary thyroid microcarcinoma in Japanese patients

In-Depth [systematic review and meta-analysis]: This systemic review and meta-analysis aggregated observational cohort studies on PTC foci number and recurrence published on PubMed, SCOPUS, Web of Science Core Collection, and Cochrane Database of Systematic Reviews. Study quality was assessed using the Newcastle-Ottawa Scale. Data on the country of publication, study period, number of patients, multifocality rates, and recurrence hazard ratio (HR) for recurrences was extracted. Publication bias was assessed by Begg and Egger regression funnel plot tests. Of the 2712 originally identified studies, 918 duplicates, 1682 irrelevant studies, and 86 reviewed but ineligible studies were removed. Moderate heterogeneity was detected between the 26 included eligible studies (I² = 67%; P < 0.001). 28.1% (range = 6.4%-60.1%) of the pooled 33,976 patients had multifocality. Patients were followed for an average of 6.6 years (range = 2.4-27.0 years) during which PTC recurrence occurred in 8.0% (range = 2.7%-46.4%) of patients. Patients with multifocal PTC had a higher risk of cancer recurrence than those with unifocal PTC (HR = 1.81; 95% CI = 1.52–2.14). 6 studies (n = 7550) measured tumor size, which showed that recurrence of multifocal PTC was increased for microcarcinoma (PTC ≤ 1 cm) (HR = 1.81, 95% CI = 1.18–2.77; I² = 46%, P = 0.11) but also for large tumors (> 1 cm) (HR = 1.90, 95% CI = 1.11–3.25; I² = 79%, P = 0.002). According to the 2 studies (n = 1758) that assessed number of foci, high foci count (≥3) was associated with a higher risk of recurrence (HR = 1.95, 95% CI = 1.33–2.85, P < 0.001; I² = 59%, P = 0.12), but not low foci count (HR = 1.45, 95% CI = 0.97–2.17, P = 0.07; I² = 40%, P = 0.20). Multifocality of PTC was associated with an increased risk of recurrence in both the pooled data from 4 studies on pediatric patients (n = 1139; HR = 3.19, 95% CI = 1.29–7.90, P = 0.01; I² = 62%, P = 0.03) and the 5 studies on adult patients (n = 1705; HR = 1.89, 95% CI = 1.06–3.38; P = 0.03; I² = 45%, P = 0.14). Over a mean follow-up of 16.6 years (range = 7.0–27.0 years), the cancer-specific mortality of the 4 studies (n = 3895) for multifocal PTC averaged 5.8% (range = 2.2 – 8.9%), which was similar to that for unifocal PTC (HR = 1.19, 95% CI = 0.85–1.68; P = 0.31). Begg (P = 0.39) and Egger (P = 0.14) statistical tests suggested there was unlikely publication bias in these studies.

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