Hashimoto's Thyroiditis in Papillary Thyroid Cancer: A Dual Role of Higher Tumor Multiplicity but Lower Aggressiveness

Table of Contents

• Key Points
• Background: Why This Research Matters
• How the Research Was Conducted
• Overview of Included Studies
• Key Findings: Tumor Characteristics
• Key Findings: Metastasis and Recurrence
• Key Findings: Molecular Markers and Treatment
• What These Findings Mean for Patients
• Limitations of the Study
• Recommendations
• Frequently Asked Questions
• Source Information

Key Points

• A meta-analysis of 41 studies and 67,901 patients found Hashimoto's thyroiditis has a dual role in papillary thyroid carcinoma.
• Hashimoto's was linked to higher odds of multifocal tumors (13%) and bilateral tumors (20%) in patients with papillary thyroid carcinoma.
• Hashimoto's was linked to lower odds of capsular invasion, extrathyroidal extension, central lymph node metastasis, distant metastasis, and recurrence.
• Patients with Hashimoto's had a 45% lower odds of the BRAF V600E mutation, especially those over 45 years old.
• All included studies were observational, so findings show associations, not cause and effect, and individual outcomes may vary.

Background: Why This Research Matters

Thyroid cancer is the most common cancer of the endocrine system, which is the network of glands that produce hormones. The number of new cases has risen steadily around the world over the past several decades. In 2022, more than 821,000 new cases were diagnosed worldwide, making thyroid cancer the seventh most common cancer by incidence. The disease is about three times more common in women than in men. However, the number of deaths from thyroid cancer remains relatively low, with an estimated 44,000 deaths reported in the same year.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. It accounts for more than 70% of all thyroid malignancies. Despite the rising number of cases, PTC usually grows slowly, causes few deaths, and has excellent long-term survival for most patients.

Because the outlook for PTC is generally favorable, doctors now focus on long-term disease control and personalized treatment planning rather than short-term survival. One major question is how much thyroid tissue to remove during surgery. Surgeons may remove the entire thyroid gland (total thyroidectomy) or only one side (lobar thyroidectomy). This decision affects the risk of the cancer coming back, the risk of surgical complications, and whether additional treatment is needed.

Another important consideration is the use of thyroid-stimulating hormone (TSH) suppression after surgery. TSH is a hormone that tells the thyroid gland to work harder. Suppressing TSH with medication has been linked to a lower risk of cancer recurrence. However, long-term TSH suppression can harm the heart, weaken bones, and reduce overall quality of life. These challenges show that doctors need better tools to predict which patients face the highest risk. Better risk prediction would allow more personalized treatment.

Hashimoto's thyroiditis (HT) is the most common autoimmune thyroid disorder. In HT, the body's immune system mistakenly attacks the thyroid gland. This leads to widespread inflammation, the presence of thyroid-specific autoantibodies (immune proteins that target the thyroid), and progressive destruction of the gland. The number of people with HT has increased alongside the rise in thyroid cancer cases.

Many studies have reported that HT and PTC occur together in the same patients. However, the percentage of patients who have both conditions varies widely among different populations. The clinical significance of this overlap remains debated. Some researchers propose that the chronic inflammation caused by HT may actually promote the development of PTC through immune-mediated tissue damage and cancer-promoting signaling pathways. Others argue that HT may be linked to less aggressive tumor behavior and a better prognosis.

Because these findings conflict, the researchers performed this meta-analysis to determine whether HT has a measurable effect on the characteristics and long-term outcomes of PTC.

How the Research Was Conducted

This meta-analysis followed the PRISMA guidelines, which are internationally recognized standards for conducting and reporting systematic reviews. The researchers also considered recommendations from the MOOSE statement where applicable. The study protocol was registered in advance on PROSPERO, an international database of systematic review protocols, to ensure transparency and reduce the risk of bias. The registration number is CRD420251138031.

The main goal was to evaluate the tumor characteristics, treatment strategies, and outcomes of patients with PTC who also had HT, compared with patients who had PTC but no HT.

Because no randomized controlled trials exist on this topic, the researchers included only comparative cohort studies. These included prospective studies (which follow patients forward in time), retrospective studies (which look back at existing records), and matched cohort designs. A standard pairwise meta-analytic approach was used to compare the HT and non-HT groups across a range of clinical endpoints. A random-effects model was applied to account for differences between studies and to ensure the robustness of the combined estimates.

Data Sources and Search Strategy

The researchers searched four major electronic databases: PubMed, EMBASE, the Cochrane Library, and Web of Science. They used a combination of Medical Subject Headings (MeSH) and free-text keywords to ensure comprehensive coverage. Search terms included "Thyroid Neoplasms," "Thyroid Carcinoma," "Cancer of the Thyroid," "Thyroid Cancers," "Thyroid Adenoma," "Papillary Thyroid Cancer," "Papillary Thyroid Cancers," "Papillary Thyroid Carcinomas," "Hashimoto Disease," "Hashimoto's Disease," "Chronic Lymphocytic Thyroiditis," "Hashimoto Thyroiditides," "Hashimoto's Syndrome," "Hashimoto's Syndromes," and "Hashimoto Struma."

The search covered all publications from the inception of each database through August 25, 2025. Both controlled vocabulary terms and free-text keywords were combined to maximize sensitivity and capture all relevant studies.

Selection Criteria

To be included, studies had to meet the following requirements:

1. Adult patients (18 years or older) with PTC confirmed by tissue examination.
2. Comparative cohort studies, including prospective, retrospective, or matched cohort analyses, that assessed patients with coexisting HT versus those without.
3. Patients undergoing initial thyroid surgery, with or without additional therapy.
4. Studies reporting at least one of the outcomes of interest.

The primary outcomes were divided into two groups. The first group included clinicopathological features. These were multifocality (more than one tumor in the thyroid) and bilaterality (tumors in both lobes of the thyroid). They also included capsular invasion (cancer spreading into the fibrous capsule around the thyroid) and vascular invasion (cancer entering blood vessels). They also included extrathyroidal extension (cancer spreading beyond the thyroid gland). The second group included metastasis and recurrence-related characteristics. These were central lymph node metastasis (CLNM, cancer spread to lymph nodes near the thyroid). These were also lateral lymph node metastasis (LLNM, cancer spread to lymph nodes on the sides of the neck). They also included distant metastasis (cancer spread to organs far from the thyroid) and disease recurrence.

Secondary outcomes included BRAF V600E mutation status (a specific genetic change in the tumor), treatment strategies (total thyroidectomy and radioactive iodine therapy), and both all-cause and disease-specific mortality.

Studies were excluded for the following reasons:

• No clear comparison between HT and non-HT groups.
• Incomplete or non-extractable outcome data.
• Involvement of children, patients with other autoimmune thyroid diseases such as Graves' disease, patients with prior thyroid cancer treatment, or patients with other concurrent cancers.
• No surgical intervention.
• Duplicate publications, case series, conference abstracts, or review articles.

Study selection began with title and abstract screening. All included articles were then independently reviewed in duplicate to ensure accuracy and eligibility. Disagreements were resolved by a third reviewer through discussion and consensus.

Data Extraction and Quality Assessment

Three reviewers independently extracted data following the PRISMA guidelines. The extracted variables included study characteristics (first author, year of publication, country, study design, and sample size). They also included patient demographics (age and sex). They also included tumor features (tumor stage, bilaterality, multifocality, capsular invasion, and extrathyroidal extension). They also included treatment strategies (extent of thyroidectomy and use of radioactive iodine). They also included all eligible outcome indicators with their corresponding 95% confidence intervals (CIs) or raw event counts.

The methodological quality of each included cohort study was assessed using the Newcastle-Ottawa Scale (NOS). This scale evaluates studies across three areas: selection (maximum 4 stars), comparability (maximum 2 stars), and outcomes (maximum 3 stars), for a total possible score of 9 stars. Studies were categorized as high quality if they received 6 or more stars, moderate quality if they scored 3 to 5 stars, and low quality if they scored fewer than 3 stars. Studies rated as low quality were excluded from the final analysis. Discrepancies in data extraction or quality assessment were resolved through consensus-based group discussion.

Statistical Analysis

Effect estimates were calculated as odds ratios (ORs) with corresponding 95% confidence intervals. These estimates quantified the association between HT and each clinical endpoint in patients with PTC, compared with those without HT. An odds ratio is a statistical measure that compares the odds of an outcome occurring in one group versus another. An OR of 1.0 means no difference between groups. An OR greater than 1.0 means the outcome is more likely in the HT group. An OR less than 1.0 means the outcome is less likely in the HT group.

All statistical analyses were performed using STATA version 16.0. Pooled effect sizes were computed using a random-effects model based on the DerSimonian-Laird method to account for between-study variability. Statistical heterogeneity was assessed using the I-squared (I²) statistic, with an I² value greater than 50% indicating substantial heterogeneity. Heterogeneity refers to how much the results of different studies differ from each other.

Publication bias was evaluated by visual inspection of funnel plots and quantitatively assessed using Egger's regression test, with statistical significance defined as alpha = 0.05.

Only 24 of the 41 included studies were published after 2017. Most reported a mean patient age under 50 years, with only one exception. Because of this, the researchers conducted a predefined subgroup analysis using 45 years as the cutoff. This cutoff follows the AJCC 7th edition staging criteria. A two-sided P-value less than 0.05 was considered statistically significant throughout.

Overview of Included Studies

The systematic database search initially retrieved 7,779 records. After removing duplicates and screening titles and abstracts for relevance, 311 studies were selected for full-text evaluation. Upon review, 270 studies were excluded for the following reasons: incompatible research population (84 studies), unavailable or incomplete outcome data (89 studies), incompatible study design (50 studies), and unrelated research directions (47 studies).

Ultimately, 41 studies met the predefined inclusion criteria and were included in the meta-analysis. These studies comprised a pooled sample of 67,901 patients. Among them, 17,516 patients were in the HT group, and 50,385 patients were in the non-HT group.

The included studies came from many countries, including the United States, Korea, China, Brazil, Turkey, Saudi Arabia, Singapore, Jordan, and others. Most were retrospective cohort studies, with a few prospective cohort studies. Follow-up periods ranged from a few months to over 100 months in some studies. The NOS quality scores of the included studies ranged from 6 to 9, indicating that all were high-quality studies.

Key Findings: Tumor Characteristics

The meta-analysis revealed that HT has a dual role in PTC. It is associated with both an increased risk of certain tumor features and a decreased risk of others.

Multifocality and Bilaterality

Eight studies investigated bilaterality in patients with PTC. A fixed-effects model was used because heterogeneity was moderate (I² = 44%, P = 0.08). The combined analysis revealed a significantly higher incidence of bilateral disease in patients with coexisting HT. The odds ratio was 1.20 (95% CI: 1.12–1.29, P < 0.0001). This means that patients with HT had a 20% higher odds of having tumors in both lobes of the thyroid compared with patients without HT. Sensitivity analyses confirmed the robustness of this association.

For multifocality, 36 studies contributed relevant data. Because of substantial heterogeneity across studies (I² = 75%, P < 0.001), a random-effects model was applied. The meta-analysis demonstrated a significantly increased risk of multifocal disease in the HT group compared with the non-HT group. The odds ratio was 1.13 (95% CI: 1.03–1.24, P = 0.01). This means that patients with HT had a 13% higher odds of having more than one tumor in the thyroid.

To examine whether age affected this relationship, subgroup analyses were conducted using 45 years as the cutoff. The positive association between HT and multifocality persisted in both age groups. For patients aged 45 years or younger, the odds ratio was 1.16 (95% CI: 1.00–1.36). For patients older than 45 years, the odds ratio was 1.17 (95% CI: 1.05–1.30).

Together, these findings indicate that the presence of HT is significantly associated with an increased likelihood of both multifocal and bilateral disease in PTC patients. This association may reflect a biological tendency toward multicentric tumor development in the setting of autoimmune thyroiditis.

Aggressive Pathological Features

Several findings indicate that HT may be associated with reduced tumor invasiveness in PTC.

Ten studies reported on vascular invasion. There was substantial heterogeneity (I² = 78%, P < 0.01). A random-effects model showed no statistically significant association between HT and vascular invasion. The odds ratio was 1.02 (95% CI: 0.82–1.26). Subgroup analyses stratified by age also showed no significant differences. For patients aged 45 years or younger, the odds ratio was 1.58 (95% CI: 0.81–3.08). For patients older than 45 years, the odds ratio was 0.90 (95% CI: 0.71–1.13).

Four studies assessed capsular invasion. The initial combined analysis showed no significant difference between groups. The odds ratio was 0.92 (95% CI: 0.50–1.70), with considerable heterogeneity (I² = 89%, P < 0.001). However, when the researchers performed a sensitivity analysis excluding the study by Feng Zhu and colleagues from 2015, heterogeneity dropped substantially (I² = 15%, P = 0.31). Under a fixed-effects model, HT was then significantly associated with a lower incidence of capsular invasion. The odds ratio was 0.73 (95% CI: 0.60–0.89). This means that patients with HT had a 27% lower odds of capsular invasion.

Thirteen studies evaluated extrathyroidal extension (ETE). Despite notable heterogeneity (I² = 75%, P < 0.01), the combined estimate indicated a significantly lower risk of ETE in the HT group. The odds ratio was 0.85 (95% CI: 0.76–0.94). This means that patients with HT had a 15% lower odds of the cancer spreading beyond the thyroid gland. Subgroup analyses stratified by age confirmed this protective association in both age groups. For patients aged 45 years or younger, the odds ratio was 0.83 (95% CI: 0.72–0.95). For patients older than 45 years, the odds ratio was 0.84 (95% CI: 0.71–1.00).

Taking these results together, HT is significantly associated with reduced risks of capsular invasion and extrathyroidal extension in PTC. However, no meaningful association was observed for vascular invasion.

Key Findings: Metastasis and Recurrence

The meta-analysis also examined how HT affects the spread of cancer to lymph nodes and other organs, as well as the risk of the cancer returning.

Lymph Node Metastasis

A total of 18 studies reported on overall lymph node metastasis (LNM) in patients with PTC. Because of substantial heterogeneity across studies (I² = 71%, P < 0.01), a random-effects model was used. The combined analysis revealed no statistically significant difference in overall LNM rates between patients with and without HT. The odds ratio was 0.91 (95% CI: 0.77–1.06).

To better understand the regional impact of HT on lymph node involvement, the researchers performed subgroup analyses for central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM).

Twenty studies indicated a significantly lower risk of CLNM in HT-positive patients. The odds ratio was 0.75 (95% CI: 0.66–0.86, I² = 77%, P < 0.001). This means that patients with HT had a 25% lower odds of cancer spreading to the central lymph nodes near the thyroid.

In contrast, analysis of nine studies evaluating LLNM showed no significant difference between the HT and non-HT groups. The odds ratio was 0.89 (95% CI: 0.74–1.07, I² = 42%, P = 0.22).

These findings suggest that HT is associated with a decreased likelihood of central, but not lateral, lymph node metastasis in PTC.

Distant Metastasis

Pooled data from eight studies demonstrated a significantly reduced risk of distant metastasis among HT patients. The odds ratio was 0.33 (95% CI: 0.22–0.49), with negligible heterogeneity (I² = 3%). This means that patients with HT had a 67% lower odds of cancer spreading to organs far from the thyroid. This was one of the strongest protective associations found in the entire meta-analysis.

Recurrence

Eighteen studies evaluated recurrence, showing a trend toward lower recurrence rates in the HT group. The odds ratio was 0.74 (95% CI: 0.55–1.00), accompanied by moderate heterogeneity. This means that patients with HT had a 26% lower odds of the cancer coming back, though the result was at the boundary of statistical significance.

Key Findings: Molecular Markers and Treatment

The meta-analysis also examined molecular markers and treatment outcomes.

BRAF V600E Mutation

A total of 11 studies evaluated the BRAF V600E mutation. This is a specific genetic change in the BRAF gene that is found in many papillary thyroid cancers and is associated with more aggressive tumor behavior. The meta-analysis found that HT was significantly associated with a reduced frequency of the BRAF V600E mutation. The odds ratio was 0.55 (95% CI not reported in the abstract). This means that patients with HT had a 45% lower odds of having this mutation. The association was especially strong in patients over 45 years old.

Treatment Outcomes

The meta-analysis found no significant differences between the HT and non-HT groups for vascular invasion, lateral lymph node involvement, mortality, or radioactive iodine use. This means that patients with HT were just as likely to receive radioactive iodine therapy as patients without HT. There was no difference in death rates between the two groups.

What These Findings Mean for Patients

This meta-analysis provides important insights for patients with papillary thyroid carcinoma and their doctors.

The dual role of Hashimoto's thyroiditis means that patients with both conditions may face a mixed picture. On one hand, HT is associated with a higher chance of having multiple tumor sites within the thyroid (multifocality and bilaterality). This finding may influence surgical planning. For example, doctors may consider whether to remove the entire thyroid gland rather than just one lobe in patients with HT. This is because of the higher risk of tumors in both lobes.

On the other hand, HT is associated with several protective effects. Patients with HT had lower risks of:

• Capsular invasion (27% lower odds)
• Extrathyroidal extension (15% lower odds)
• Central lymph node metastasis (25% lower odds)
• Distant metastasis (67% lower odds)
• Recurrence (26% lower odds)
• BRAF V600E mutation (45% lower odds)

These protective associations suggest that the chronic inflammation caused by HT may create a tumor environment that is less favorable for aggressive cancer growth and spread. The lower frequency of the BRAF V600E mutation in HT patients may partly explain the less aggressive tumor biology. This mutation is known to drive more aggressive cancer behavior.

The finding that HT is associated with lower central lymph node metastasis but not lateral lymph node metastasis is also important. It suggests that the protective effect of HT may be specific to certain regions of lymph node spread.

The researchers concluded that incorporating HT status into preoperative evaluation may enhance individualized risk stratification. This means that doctors could use information about whether a patient has HT to better predict that patient's risk level and guide surgical and adjuvant treatment decisions.

Limitations of the Study

This meta-analysis has several limitations that patients and doctors should consider.

First, all included studies were observational cohort studies. No randomized controlled trials were available. This means that the findings show associations, not cause-and-effect relationships. The researchers cannot prove that HT directly causes the observed differences in tumor behavior.

Second, there was substantial heterogeneity across many of the analyses. For multifocality, the I² value was 75%. For vascular invasion, the I² value was 78%. For extrathyroidal extension, the I² value was 75%. For central lymph node metastasis, the I² value was 77%. This high heterogeneity means that the studies differed considerably in their results, which may be due to differences in patient populations, study designs, or other factors.

Third, the definition and diagnosis of Hashimoto's thyroiditis may have varied across studies. Some studies may have used different criteria for diagnosing HT, which could affect the results.

Fourth, the follow-up periods varied widely across studies, from a few months to over 100 months. This variation could affect the detection of recurrence and other long-term outcomes.

Fifth, most included studies reported a mean patient age under 50 years, with only one exception. This means the findings may not fully apply to older patient populations.

Sixth, the meta-analysis found no significant differences for vascular invasion, lateral lymph node involvement, mortality, or radioactive iodine use. However, the absence of a statistically significant difference does not necessarily mean there is no difference. It may mean that the studies were not large enough to detect a small difference.

Recommendations

Based on the findings of this meta-analysis, the following recommendations may be helpful for patients with papillary thyroid carcinoma:

1. Ask your doctor whether you have Hashimoto's thyroiditis. If you do, this information may be important for planning your treatment.
2. Discuss the extent of thyroid surgery with your surgical team. Because HT is associated with a higher risk of multifocal and bilateral tumors, your doctor may recommend removing the entire thyroid gland rather than just one lobe.
3. Understand that having HT may be associated with a less aggressive form of PTC. The study found lower risks of capsular invasion, extrathyroidal extension, central lymph node metastasis, distant metastasis, and recurrence in patients with HT.
4. Ask about BRAF V600E mutation testing. This genetic marker is associated with more aggressive cancer, and patients with HT are less likely to have this mutation.
5. Follow your doctor's recommendations for postoperative monitoring. Even though HT is associated with lower recurrence risk, regular follow-up remains important.
6. Discuss the risks and benefits of TSH suppression therapy with your doctor. This treatment can reduce recurrence risk but may also affect heart and bone health over the long term.
7. Participate in shared decision-making with your healthcare team. The findings of this study support personalized treatment planning based on each patient's individual risk factors, including HT status.

Patients should remember that this meta-analysis provides population-level findings. Individual outcomes may vary. Always discuss your specific situation with your healthcare provider.

Frequently Asked Questions

What is Hashimoto's thyroiditis and how common is it?

Hashimoto's thyroiditis is the most common autoimmune thyroid disorder. In it, the immune system mistakenly attacks the thyroid gland, causing inflammation, thyroid-specific autoantibodies, and progressive destruction of the gland. The number of people with Hashimoto's has increased alongside the rise in thyroid cancer cases, and many studies report that Hashimoto's and papillary thyroid carcinoma occur together in the same patients.

Does having Hashimoto's make my papillary thyroid cancer more dangerous?

The evidence is mixed. In a meta-analysis of 41 studies and 67,901 patients, Hashimoto's was linked to higher odds of multifocal tumors (13% higher) and bilateral tumors (20% higher). But it was also linked to lower odds of capsular invasion, extrathyroidal extension, central lymph node metastasis, distant metastasis, and recurrence. So it appears to have a dual role, not a single direction.

What does an odds ratio of 0.33 for distant metastasis mean?

An odds ratio compares the odds of an outcome in one group versus another. An odds ratio of 1.0 means no difference. In this meta-analysis, the odds ratio for distant metastasis in patients with Hashimoto's was 0.33, meaning they had 67% lower odds of cancer spreading to organs far from the thyroid. This was one of the strongest protective associations found.

Will having Hashimoto's change how much of my thyroid is removed during surgery?

It may. Because Hashimoto's was linked to a higher risk of multifocal and bilateral tumors, doctors may consider removing the entire thyroid gland rather than just one lobe. The meta-analysis authors suggest incorporating Hashimoto's status into preoperative evaluation to help guide surgical planning. Discuss the extent of surgery with your surgical team, since this decision also affects recurrence risk and complications.

Does Hashimoto's affect whether I need radioactive iodine or my risk of dying from thyroid cancer?

In this meta-analysis, there were no significant differences between patients with and without Hashimoto's for radioactive iodine use or mortality. That means patients with Hashimoto's were just as likely to receive radioactive iodine therapy, and death rates did not differ between the two groups. However, the absence of a significant difference does not prove there is no difference; studies may have been too small to detect one.

What is the BRAF V600E mutation and why does it matter if I have Hashimoto's?

BRAF V600E is a specific genetic change found in many papillary thyroid cancers and is associated with more aggressive tumor behavior. In this meta-analysis of 11 studies, Hashimoto's was linked to a 45% lower odds of having this mutation, with the association especially strong in patients over 45 years old. This may partly explain the less aggressive tumor biology seen in some patients with Hashimoto's.

What are the limitations of this research on Hashimoto's and thyroid cancer?

All included studies were observational, so findings show associations, not cause and effect. There was substantial heterogeneity across many analyses, meaning studies differed considerably. Definitions of Hashimoto's varied, follow-up periods ranged from a few months to over 100 months, and most studies had a mean patient age under 50. These factors mean the findings may not fully apply to every patient.

I have papillary thyroid cancer with Hashimoto's thyroiditis — should I get a second opinion before deciding between total thyroidectomy and lobectomy?

Hashimoto's thyroiditis is linked to a 20% higher odds of tumors in both lobes and a 13% higher odds of multifocal disease, which may influence whether the whole gland or one lobe is removed. It is also linked to lower risks of capsular invasion, extrathyroidal extension, central lymph node metastasis, distant metastasis, and recurrence. Because surgical extent and TSH suppression carry trade-offs, an independent review of your pathology and imaging can help confirm whether the recommended operation fits your individual risk profile. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: The dual oncogenic and protective roles of hashimoto's thyroiditis in papillary thyroid carcinoma: a cohort-based meta-analysis.

Authors: Xuejiao Ma, Huiyuan Shang, Yanying Zhang, and Zhongyuan Xia

Author affiliations: Beijing University of Chinese Medicine, Beijing, China; Department of Surgery of Traditional Chinese Medicine, China-Japan Friendship Hospital, Beijing, China

Journal: World Journal of Surgical Oncology (2026) 24:70

DOI: https://doi.org/10.1186/s12957-025-04184-4

PROSPERO registration: CRD420251138031

Publication type: Research article, Open Access

Note: This patient-friendly article is based on peer-reviewed research. The original article was published under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.