Epidemiological data on 25 cases of mixed-etiology thyroid granulomas: a single-center retrospective cross-sectional study

Introduction

Granulomatous inflammation of the thyroid is an uncommon condition arising from infectious, autoimmune, idiopathic, and post-surgical causes (1,2). Regardless of etiology, the histopathology appears similar and is characterized by collections of epithelioid macrophages with or without multinucleated giant cells and necrosis (1,3). The current literature focuses largely on case reports and small series, and the clinical relevance of incidentally identified thyroid granulomas is not well defined (1,4-7).

The most common granulomatous disease of the thyroid is subacute granulomatous thyroiditis (also known as De Quervain’s thyroiditis), which is presumed to follow a viral infection (8,9). Other etiologies highlight the clinical breadth of thyroid granulomas. Tuberculosis of the thyroid is rare and often an overlooked diagnosis (10), while other infectious etiologies are reported only sporadically (11,12). Additionally, sarcoidosis can also involve the thyroid, though this is an uncommon manifestation and usually occurs in the setting of systemic disease (13). Autoimmune thyroid disease, including Hashimoto’s thyroiditis (chronic lymphocytic thyroiditis) and Graves’ disease, has also been reported in association with granulomatous lesions (7,14,15). Suture granulomas may also develop in the thyroid bed after surgery and may resemble local recurrence (2). Collectively, these diverse etiologies share the potential to mimic thyroid malignancy, setting the stage for significant diagnostic uncertainty.

Consequently, granulomatous thyroid disease remains a diagnostic and management challenge. Fine-needle aspiration (FNA) may raise suspicion but is seldom definitive (16,17), and distinguishing these lesions from sarcoidosis, metastatic disease, or primary thyroid cancer can be particularly difficult (18,19). Management is equally varied, ranging from observation in subacute thyroiditis, to antimicrobial therapy for infectious cases, to corticosteroids or surgery when malignancy cannot be excluded (1,16,20). Yet major gaps persist: the true incidence is unclear; long-term outcomes are poorly defined, and the clinical impact of incidental granulomas is largely unknown (10,18,21). This contemporary single-center retrospective cross-sectional study of 25 patients highlights the diverse etiologies and clinical presentations of thyroid granulomas, extending beyond classic subacute granulomatous thyroiditis and helping contextualize these findings in modern clinical practice. We present this article in accordance with the STROBE reporting checklist (available at https://aot.amegroups.com/article/view/10.21037/aot-2026-0016/rc).

Methods

The study team reviewed medical records and imaging studies of patients diagnosed with pathologic granulomatous thyroid disease (as either a primary or secondary finding) between January 1, 2008 to December 31, 2023.

Patients were included if they were adults aged 18 years or older at the time of thyroid surgery and had a pathology-confirmed diagnosis of granuloma within thyroid tissue. The study was designed to characterize thyroid granulomas in the adult surgical population. Pediatric cases were excluded from the scope of this study. Patients without granulomas identified in thyroid tissue or those with insufficient clinical or pathologic documentation were excluded. The study cohort comprised all patients meeting eligibility criteria identified over the 15-year study period.

Epic and CoPath records were queried for ‘thyroid’ in combination with ‘granuloma’, ‘granulomata’, or ‘granulomatous’. Of note, CoPath was used at Thomas Jefferson University Hospital until 2017, after which the electronic medical record was changed to Epic. Therefore, all queries prior to 2017 were within the CoPath system and all those after 2017 were within Epic. Patients were equally distributed among queries from 2008 to 2017 and 2017 to 2023. This keyword-based search strategy may not have captured all cases documented with non-standard terminology, and the transition between the two systems introduces potential for under-ascertainment. Clinical data were extracted from the electronic medical record and included demographic information such as age and sex, relevant past medical history, and clinical variables including indication for surgery, diagnoses, procedures, laboratory results, imaging findings, and operative, inpatient, and outpatient clinic data.

All granulomas were confirmed on final surgical pathology specimens. Although multinucleated giant cells were noted on FNA cytology in select cases, cytologic findings alone were not sufficient for inclusion. Histopathologic categories were assigned based on review of final diagnosis and narrative description in the surgical pathology report. For cases in which the pathologic diagnosis was nonspecific or a broad differential was provided without a committed etiology, available clinical history was used to guide categorization when applicable. Cases without a definitive etiology after report review and clinical correlation were classified as indeterminate. Categories were not mutually exclusive and patients with overlapping histopathologic features were recorded in all applicable categories. Categorization was reviewed by a pathology co-investigator.

Statistical analysis

Descriptive statistics were used to summarize the data. Continuous variables were reported as medians with ranges. Categorical variables were reported as frequencies and percentages. No formal inferential statistical testing was performed given the small cohort size and purely descriptive study design. Reported associations were interpreted descriptively and were not used to infer statistical significance. Data analysis was performed using Microsoft Excel and GraphPad Prism. Variables with missing data were noted and reported with appropriate denominators rather than imputed. Given the retrospective single-center design, potential selection bias from referral patterns and ascertainment differences between the CoPath and Epic systems were recognized as inherent limitations. Malignancy rates were compared descriptively between patients with and without a history of sarcoidosis.

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and approved by the institutional review board of Thomas Jefferson University (IRB; IRISID-2023-2944). Publication of this study and accompanying images was waived from patient consent according to the institutional review board.

Results

Patient demographics and clinical characteristics

Of 30 patients identified, 5 patients were excluded for inadequate historical information and for granulomas identified external to the thyroid gland (skin at the site of prior surgery and soft tissue adjacent to a thyroglossal duct cyst), leaving 25 meeting inclusion criteria. Demographic and clinical characteristics are summarized in Table 1.

The median age at surgery was 57.2 years (range, 24.3–85.8 years), and 18 (72%) were female. Five patients (20%) had a documented history of sarcoidosis and one patient (4%) had a history of tuberculosis exposure. Six patients (24%) had undergone prior thyroid surgery. Two patients were taking levothyroxine preoperatively: one for hypothyroidism following a prior thyroid lobectomy, and one for clinically documented hypothyroidism without histologic evidence of chronic lymphocytic thyroiditis. Thyroid function tests and serum calcium levels were not consistently documented across the study period and are not reported. Ten of 25 patients were symptomatic at presentation. Symptom status was unknown for 2 patients. Medical history and presenting symptoms are summarized in Table 2.

Surgical indications and preoperative evaluation

Surgical indications and procedure types are summarized in Table 1. FNA was performed in 23 of 25 patients (92%); cytology results are summarized in Table 1. Three patients presented with mass-forming granulomatous lesions and underwent molecular testing: one Afirma Gene Expression Classifier result was suspicious for malignancy, one in-house next-generation sequencing (NGS) panel was negative, and one targeted NRAS/BRAF mutation analysis was negative.

Histopathologic findings

All granulomas were non-necrotizing, with 22 (88%) identified incidentally and 3 (12%) presenting as mass-forming lesions. Granulomas reflected diverse but predominantly noninfectious histopathologic patterns. The most common categories assigned from the surgical pathology reports were autoimmune/thyroiditis-associated and post-procedural/foreign body, identified in 9 and 10 patients, respectively. Five patients were classified as indeterminate, including cases in which the pathology report raised a broad differential but no definitive etiology was confirmed in available clinical or follow-up documentation. Neoplasm-associated and cholesterol granulomas were identified in 2 patients each. Three patients had overlapping histopathologic categories, reflecting combinations of thyroiditis-associated and post-procedural/foreign body patterns. Case-level histopathologic findings are summarized in Table 3. Three patients demonstrated chronic lymphocytic thyroiditis on final surgical pathology. None had documented a preoperative diagnosis of Hashimoto’s thyroiditis. Eleven cases underwent ancillary infectious testing including Kinyoun or auramine-rhodamine stains for acid-fast bacilli (AFB) and/or Grocott methenamine silver (GMS) or periodic acid-Schiff (PAS) stains for fungal organisms; all were negative. One case additionally underwent cytomegalovirus immunohistochemistry; however, the focus of interest was lost on deeper sections and could not be evaluated. No infectious etiology was identified in any tested case.

On preoperative ultrasound, the three mass-forming lesions appeared as irregular hypoechoic or complex solid masses. Two were designated Thyroid Imaging Reporting and Data System (TIRADS) 4 and one had no TIRADS designation. All three yielded Bethesda III cytology. One patient was found to have two nodules, one was the mass-forming granulomatous lesion, while the other was a follicular adenoma. Cytology for both nodules was interpreted as atypia of undetermined significance (Bethesda III). Representative ultrasound imaging from the mass-forming lesion is shown in Figure 1. Representative histologic findings are shown in Figure 2.

Figure 1 Thyroid ultrasound images of bilateral thyroid nodules (3.2 cm left, 3.0 cm right) (red circles) sampled by FNA and confirmed as mass-forming granulomas. FNA, fine needle aspiration.

Figure 2 Histologic findings in one case of mass-forming granulomatous thyroiditis. (A) Fibrosis and multinucleated giant cells admixed with atrophic thyroid follicles (10×, H&E stain). (B) Granulomas with asteroid bodies (arrows) within multinucleated giant cells (dotted red circles) (40×, H&E stain). (C) Multinucleated giant cell reaction surrounding polarizable foreign material (black circle) (40×, H&E stain). H&E, hematoxylin and eosin.

Malignancy and patient outcomes

Coexisting malignancy was identified in 9 of 25 patients (36%), including papillary thyroid carcinoma (n=7), medullary thyroid carcinoma (n=1), and metastatic squamous cell carcinoma (n=1). Four of the 9 patients with malignancy had a history of sarcoidosis. Among the full sarcoidosis subgroup, 4 of 5 patients (80%) had coexisting malignancy, a finding that should be interpreted cautiously given the small subgroup size.

Median follow-up from the date of surgery was 12.4 months (range, 0-202 months) across the full cohort. Two patients had no documented follow-up beyond the index surgical admission. No patient developed recurrence of granulomatous disease. New or growing thyroid nodules were identified on follow-up imaging in 3 patients. All underwent repeat FNA with benign results or remained stable on surveillance. Among the 9 patients with coexisting malignancy, follow-up was longer, reflecting ongoing oncologic care. Median oncologic follow-up was 97 months (range, 7-202 months). All 9 had documented follow-up and none demonstrated evidence of disease recurrence at last contact. Three patients died during the follow-up period. None had coexisting malignancy and none of the deaths were attributed to thyroid disease or granulomatous pathology based on available documentation.

Discussion

This retrospective cross-sectional study of 25 patients provides insight into the breadth of clinical and pathologic presentation of granulomatous processes of the thyroid. Nearly all granulomas discovered were incidentally identified and coexisted with other pathologies. However, in two cases, no coexisting pathology was identified, and in a third case a follicular adenoma was identified in a separate nodule, suggesting that the granulomatous inflammation had formed the masses seen on imaging or palpated on clinical exam. Characteristics of the granulomas aided in formulating the suspected etiology and triaging ancillary testing: iatrogenic granulomas showed foreign body-type giant cells and polarizable material; autoimmune-associated granulomas demonstrated microgranulomas centered on ruptured follicles with interstitial fibrosis; and sarcoid-pattern granulomas were compact and well-formed with minimal to absent necrosis.

Histopathologic patterns were diverse and not mutually exclusive, spanning autoimmune or thyroiditis-associated, post-procedural, neoplasm-associated, cholesterol, and indeterminate etiologies, as detailed in Table 3. In the eleven cases evaluated with special stains for AFB and fungi, no mycobacterial or fungal etiology was identified, consistent with the predominantly noninfectious nature of this cohort. Clinical presentation did not appear to distinguish histopathologic category in this cohort. The majority of patients were asymptomatic regardless of histopathologic category, suggesting that clinical features alone may be unlikely to reliably distinguish granuloma etiology prior to surgical pathology.

Published studies of thyroid granulomas have largely focused on individual disease entities rather than the spectrum of findings encountered in routine surgical practice. Subacute granulomatous thyroiditis remains the most extensively characterized condition, including a population-based cohort of 160 patients reported by Fatourechi et al. (8). between 1960 and 1997 and a more recent cytology-focused single-center series of 69 cases diagnosed by FNA (17). Outside of classic subacute thyroiditis, thyroid granulomas have been described less frequently and typically in much smaller cohorts. The largest single-institution series describing sarcoidosis-associated thyroid malignancy included 16 patients (18), while the largest series of suture granulomas reported 14 lesions in 10 patients (2). Although reviews of thyroid tuberculosis have identified several dozen cases across the literature (10), individual case series remain limited in size (22,23). In contrast, our contemporary single-center cohort of 25 patients captures a broader etiologic spectrum of thyroid granulomas reflective of modern diagnostic and surgical practice. To our knowledge, this is among the largest contemporary single-center retrospective cross-sectional study of thyroid granulomas of mixed etiology reported to date.

Mass-forming disease was uncommon but clinically important. Three patients had mass-forming granulomatous nodules that raised concern for carcinoma. On preoperative ultrasound, these lesions demonstrated hypoechoic and complex solid features that have been described in both granulomatous and malignant disease (2,24,25). In all three patients, FNA cytology was read as atypical (Bethesda III). In one case, the imaging findings, clinical symptoms, and suspicious molecular findings collectively prompted diagnostic excision. This diagnostic ambiguity mirrors recent reports where granulomatous etiology resulted in indeterminate cytology and subsequent surgical intervention (6,16,17). Final histology was benign in all three cases, showing compact, non-necrotizing aggregates of epithelioid histiocytes and multinucleated giant cells without cytologic or architectural atypia. These cases underscore the potential for mass-forming granulomas to mimic malignancy across multiple diagnostic modalities, highlighting the importance of recognizing this pattern to avoid misclassification.

A preliminary finding in this cohort was the elevated rate of malignancy among patients with a history of sarcoidosis, though the small subgroup size precludes formal statistical comparison. This observation may reflect referral bias, as patients with known sarcoidosis and thyroid nodules may be more likely to undergo surgical resection given diagnostic uncertainty, enriching the surgical cohort for malignancy. Alternatively, the association may reflect shared immune dysregulation between sarcoidosis and thyroid neoplasia, a relationship complicated by the diagnostic challenge of distinguishing sarcoidosis from concurrent thyroid malignancy (18). The present data do not allow us to distinguish between these explanations. Among the 9 patients with coexisting malignancy, none demonstrated disease recurrence at last contact over a median oncologic follow-up of 97 months, though this may reflect the favorable biology of papillary thyroid carcinoma, which comprised the majority of malignancies in this cohort, rather than any effect of the granulomatous process itself. Clinicians should remain aware that sarcoidosis does not exclude concurrent thyroid malignancy, and thyroid nodules in this population may warrant careful cytologic and molecular evaluation (18,19). Prospective studies with larger sarcoidosis cohorts are needed to clarify the nature and magnitude of this association.

Strengths and limitations

This study captures a broad etiologic spectrum of thyroid granulomas and adds to the current literature largely focused on single disease entities. All cases were confirmed on final surgical pathology rather than cytology alone, and patient-level histopathologic patterns are reported transparently with overlapping features. The 15-year study period and contemporary cohort [2008–2023] reflect modern diagnostic practice, including the use of molecular testing and standardized ultrasound classification.

Several limitations should be acknowledged. The retrospective single-center design introduces potential selection bias, as this cohort consists exclusively of surgically treated patients, excluding those managed conservatively or medically. The inclusion of only surgically treated patients may have enriched the cohort for clinically complex or malignancy-associated cases. The keyword-based EMR search strategy may not have captured cases documented with non-standard terminology, and the transition from CoPath to Epic in 2017 introduces the possibility of differential ascertainment across the study period. The small sample size (n=25) precludes formal statistical analysis and all reported associations are descriptive and hypothesis-generating. Follow-up duration varied considerably across the cohort and two patients had no documented follow-up beyond the surgical admission, limiting the representativeness of long-term outcome data. Histopathologic categorization was based on review of final surgical pathology reports. Several cases had nonspecific descriptions without a definitive etiologic diagnosis, requiring clinical correlation to guide category assignment. Formal assessment of interobserver variability was not performed, though categorization was reviewed by a pathology co-investigator. Finally, missing clinical data, including thyroid function tests, serum calcium levels, and symptom status in two patients, limit the completeness of clinical characterization.

Conclusions

In summary, thyroid granulomas are uncommon and most often incidental, demonstrating predominantly noninfectious histopathologic patterns in this surgically treated cohort. Mass-forming lesions were rare but clinically significant, capable of producing indeterminate cytology and prompting surgical excision despite benign histology. The elevated rate of concurrent malignancy observed among patients with sarcoidosis is a preliminary finding warranting further investigation in larger prospective cohorts. Recognizing that thyroid granulomas can arise in mixed etiologic contexts with overlapping histopathologic patterns may help prevent misclassification as malignancy and overinterpretation of incidental granulomas.

Acknowledgments

A portion of this work was presented at the American Thyroid Association Annual Meeting, September 2025, Scottsdale, Arizona.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://aot.amegroups.com/article/view/10.21037/aot-2026-0016/rc

Data Sharing Statement: Available at https://aot.amegroups.com/article/view/10.21037/aot-2026-0016/dss

Peer Review File: Available at https://aot.amegroups.com/article/view/10.21037/aot-2026-0016/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aot.amegroups.com/article/view/10.21037/aot-2026-0016/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and approved by the institutional review board of Thomas Jefferson University (IRB; IRISID-2023-2944). Publication of this study and accompanying images was waived from patient consent according to the institutional review board.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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