A case series and literature review of thyroid cancer presenting with thyroid hot nodule

Abstract

Thyroid nodules are commonly found in clinical practice, with a prevalence of 5%–7% on physical examination and up to 20%–67% when detected by high-resolution ultrasound in adults. The annual incidence of thyroid cancer varies significantly in different countries, ranging from 2.0 to 3.8/100,000 in women and from 1.2 to 2.6/100,000 individuals in men, with papillary thyroid cancer being the most frequently diagnosed type. While most of these nodules are nonfunctioning and benign, some may be hyperfunctioning (“hot” nodules), potentially causing thyrotoxicosis. Differentiated thyroid cancers, such as papillary and follicular thyroid carcinoma, are typically considered “cold” on scintigraphy, rarely presenting with hyperthyroidism. This case series describes a unique presentation of papillary and follicular thyroid carcinoma in two patients with thyrotoxicosis secondary to a hyperfunctioning nodule (“hot” nodule). Both patients presented with signs of hyperthyroidism. Diagnostic imaging revealed a hyperfunctioning thyroid nodule and subsequent histopathology confirmed the presence of both papillary and follicular carcinoma. This case series highlights the rare coexistence of differentiated thyroid cancer and thyrotoxicosis due to a hot nodule. It emphasizes the importance of thorough evaluation of hyperfunctioning nodules to rule out malignancy. Early recognition and appropriate management are crucial in optimizing patient outcomes.

Keywords

thyroid nodules hot nodules papillary thyroid cancer US

Key clinical message

We highlight thyroid cancer presenting as a hot nodule—an unusual finding since hot nodules are often benign. This underscores the importance of considering malignancy in hyperfunctioning nodules and suggests a need for careful evaluation, including fine-needle aspiration (FNA) and molecular testing.

Introduction

The American Thyroid Association characterizes a thyroid nodule as a well-defined lesion located within the thyroid gland.¹ It is radiologically distinguishable from the adjacent thyroid parenchyma. These nodules may present as solitary, multiple, cystic, or solid formations. Thyroid nodules are a prevalent phenomenon and are identified in ~5%–7% of the adult demographic through physical examination alone. However, with the widespread use of high-resolution ultrasonography, the detection rate increases substantially to 20%–67% in the general adult population, depending on the study population and imaging technique used. This discrepancy highlights the importance of imaging modalities in detecting clinically occult nodules that may have significant clinical implications.²

Autonomously hyperfunctioning thyroid nodules constitute ~5%–10% of the total incidence of thyroid nodules. These entities, referred to as “hot nodules,” are characterized by an elevated uptake of radiotracers compared to the adjacent thyroid parenchyma as observed through scintigraphy.³

Hot nodules may manifest as isolated entities or as part of toxic multinodular goiters. Clinical management protocols for thyroid nodules advocate for assessing serum thyrotropin (TSH) levels, followed by scintigraphy for patients presenting with thyroid nodules and low TSH levels.⁴

Thyroid cancers are broadly divided into two main categories. The first group, non-medullary thyroid cancers (MTCs), arises from the thyroid’s epithelial cells and accounts for about 95% of all thyroid malignancies. The second group, MTC, originates from the calcitonin-secreting parafollicular (C) cells of the thyroid. Around one-fifth of MTC cases are inherited and can occur as part of multiple endocrine neoplasia syndromes.⁵

Thyroid cancer is a prevalent endocrine malignancy with a rising incidence globally. Concerns have been raised about the escalating incidence and associated mortality, particularly among women of reproductive age. The growing prevalence of abnormal thyroid nodules is believed to be driven by an accelerated increase in genetic cell activity.

While the majority of thyroid nodules are benign, a small proportion can be cancerous, necessitating careful evaluation and management.⁶ Hot nodules are not a common feature of thyroid cancer. The incidence of malignancy in hot nodules is significantly lower compared to cold nodules, However, it is essential to note that thyroid cancer can still manifest as a hot nodule, although this is rare.⁷ Therefore, a thorough evaluation of all thyroid nodules, including hot nodules, is essential for accurate diagnosis and management.⁸

Recent studies revealed malignancy rates in hot nodules that exceeded anticipated levels, with a cumulative malignancy rate of 8.5%. The documented malignancy rates for hot nodules exhibit considerable variability, from 0.34% to 44% among individuals undergoing thyroid surgical interventions. In contrast, the malignancy rate associated with non-toxic nodules is reported to range between 8% and 16%.⁹

Case presentation

Case 1

Case history and examination

A 33-year-old Filipino lady known case of hypertension, and type 2 diabetes for 2 years was referred to the endocrine clinic due to neck swelling and abnormal thyroid function test (TFT). The patient started to notice neck swelling 2 months prior to presentation and on and off palpitation in the same period. The physical exam showed normal vital signs. Physical examination showed that the patient looks anxious, with a right thyroid nodule, firm in consistency, regular borders, mobile, 2.5 cm in the largest diameter, no eye signs, tremor, or lower limb edema.

Methods

Differential diagnosis

The primary differential diagnosis was a toxic thyroid nodule. The patient’s history, TFT result, and thyroid uptake scan further supported this diagnosis. Other potential diagnoses included follicular neoplasm (given indeterminate findings on FNA) and thyroid carcinoma (due to a solid nodule with follicular features and a size of >2 cm). However, these were less likely, given her history and clinical presentation.

Investigations

Her laboratory test showed TSH: <0.01 mIU/l, FT4: 17 pmol/l, FT3: 5.17 pmol/l. Ultrasound (US) of the neck showed a right thyroid nodule of 27 × 24 × 32 mm solid hypoechoic nodule occupying the entire lobe, No calcifications, and No evidence of regional infiltrations (Figure 1); she also, underwent US-guided FNA of the right thyroid nodule, which showed Follicular lesion of undetermined significance, we planned to repeat FNA, and to do thyroid uptake scan.

Figure 1.

US neck showed right thyroid nodule of 27 × 24 × 32 mm solid hypoechoic nodule occupying the entire lobe, no calcifications, no evidence of regional infiltrations.

A thyroid uptake scan showed a 3 cm hot nodule in the right lobe showing intense uptake (a large toxic nodule). Thyroid uptake in the nodule was 3.8% (normal: 0.5%–2%, occasionally up to 4%; Figure 2).

Figure 2.

Thyroid uptake scan showed 5 cm sized hot nodule in the right lobe showing intense uptake (large toxic nodule), thyroid uptake in the nodule = 3.8% (normal: 0.5%–2%, occasionally up to 4%). The red arrow marks a hyperfunctioning (hot) thyroid nodule with increased radionuclide uptake.

Our patients underwent routine breast cancer screening according to age-appropriate clinical guidelines,¹⁰ including mammography and breast US when indicated. All screening results were unremarkable, with no evidence of breast pathology.

Treatment

The case was discussed in the thyroid multidisciplinary team and planned for right hemithyroidectomy, and she underwent right hemithyroidectomy.

Conclusion and results

Histopathology result showed follicular carcinoma, encapsulated angio invasive, after which she underwent completion thyroidectomy, histopathology report showed follicular nodular disease, no malignancy identified.

She was started on levothyroxine 125 µg and fractionated low-dose radioactive iodine (RAI) ablation.

Outcome and follow-up

Posttotal thyroidectomy, follow-up nuclear medicine (NM) iodine 131 whole body showed four foci of increased uptake at the neck. With no distant metastasis, the patient was planned for a second dose of RAI ablation after 6 months with repeat TFT.

Case 2

Case history and examination

A 44-year-old Qatari lady, referred to the endocrine clinic due to abnormal TFT on routine testing before starting glucagon-like peptide-1 agonist; she had a positive family history of thyrotoxicosis in her brother and sister. The physical exam revealed normal vital signs. Physical examination showed that the patient looks anxious, with a right thyroid nodule, firm in consistency, regular borders, mobile, 2.5 cm in the largest diameter, no eye signs, tremor, or lower limb edema.

Methods

Differential diagnosis

The primary differential diagnosis was a multinodular goiter with an autonomous thyroid nodule. The patient’s history, TFT result, and thyroid uptake scan further supported this diagnosis. Other potential diagnoses included thyrotoxicosis (considering suppressed TSH, family history, and nodule presence) and thyroid carcinoma (due to hypoechoic nodule, with multiple punctuate foci and size of >2 cm. However, these differential diagnoses are less likely based on her presentation.

Investigations

Her laboratory test showed TSH: <0.01 mIU/l, FT4: 19.4 pmol/l, FT3: 7.4 pmol/l, US neck well-defined mixed solid and cystic, heterogenous but predominantly mildly hypoechoic nodule with multiple punctate echogenic foci, measuring 44 mm in mid and lower left thyroid lobe (Figure 3), as well as well-defined solid mildly hypoechoic nodule in upper right lobe measuring 14 mm (Figure 4).

Figure 3.

US thyroid showing left thyroid nodule, heterogenous but predominantly mildly hypoechoic nodule with multiple punctate echogenic foci, 44 mm in size.

Figure 4.

US thyroid showing right thyroid nodule, defined solid mildly hypoechoic measuring 14 mm.

A thyroid uptake scan showed a goitrous gland with well-circumscribed photogenic regions in the left lobe. These findings should be correlated with US, which showed mild asymmetrical increased uptake in the left lobe, possibly due to a hyperfunctioning nodule (Figure 5). The patient underwent Left thyroid FNA, and histopathology showed papillary thyroid carcinoma, Bethesda category 6.

Figure 5.

Thyroid uptake scan goitrous gland with asymmetrical increased uptake in the left lobe may be due to a hyperfunctioning nodule. The red arrow marks a hyperfunctioning (hot) thyroid nodule with increased radionuclide uptake.

Treatment

The case was discussed in the thyroid multidisciplinary team and planned for total thyroidectomy with left neck dissection (due to possibly suspicious left cervical lymph node), and she underwent total thyroidectomy with left neck dissection.

Conclusion and results

Histopathology report confirmed papillary thyroid carcinoma, classical type. The patient was started on 125 µg of levothyroxine tablet daily and one fractionated dose of RAI ablation.

Outcome and follow-up

Posttotal thyroidectomy, follow-up NM iodine 131 whole body showed a small remnant of thyroid tissue in the thyroid bed with no local or distant metastasis.

Discussion

The increasing incidence of thyroid cancer, particularly among younger women, is a significant public health concern. While infrequent, the presence of neoplasms within hyperfunctioning thyroid nodules is documented. The prevalence rate fluctuates among various studies, with observed rates ranging from 1% to 12% of instances involving hyperfunctioning nodules that have undergone surgical excision.¹¹ The most frequently identified forms of differentiated thyroid malignancies within these nodules are papillary and follicular carcinomas, although they are typically less prevalent in hyperfunctioning nodules than “cold” ones.¹²

The historical perception that hyperfunctioning thyroid nodules rarely harbor malignancy stems from scintigraphic studies conducted between the 1960s and 1980s, which reported malignancy rates of <1% in hot nodules. However, these early studies had significant limitations, including small sample sizes, lack of standardized US evaluation, and selection bias.¹³ With the advent of high-resolution ultrasonography and more sensitive molecular diagnostic techniques, our understanding of malignancy risk in hot nodules has evolved considerably. Contemporary studies using modern imaging and cytological techniques have revealed higher malignancy rates than previously appreciated, ranging from 3% to 12% in some series.¹⁴

Detecting carcinoma within the hyperfunctioning nodule presents considerable technical challenges and necessitates robust interdisciplinary cooperation. The localization of thyroid carcinoma within a discrete nodule is complicated in cases of multinodular thyroid glands. Nevertheless, precise cytological–histological correlation of carcinomas is essential for comprehending the genuine malignant potential associated with hypermetabolic nodules.¹⁵

A significant obstacle in evaluating thyroid malignancy, especially in the context of multinodular goiters, pertains to the precise localization of the malignancy.¹⁶ It is not atypical for a malignant nodule to exist concurrently alongside a benign nodule within the same thyroid lobe. This complication similarly extends to hyperfunctioning nodules.¹⁷

Although the etiological factors remain elusive, research conducted by Niepomniszcze et al. posits that the concurrent presence of the TSH receptor mutation and the RAS (G12C) mutation may collaboratively contribute to both the mechanisms underlying carcinogenesis and the hyperactive nature of the malignant nodule. Specifically, the TSH receptor mutation instigates the intracellular cAMP signaling pathway, producing hormone secretion by neoplastic cells and ensuing hyperthyroidism.¹²

Schroder and Marthaler analyzed 63 publications on hyperfunctioning nodules and their association with follicular or papillary thyroid carcinoma. Only ten studies confirmed carcinoma within these nodules, while others were unclear if malignancy was in the hyperfunctioning nodule or a nearby non-toxic one.^12,18 This study and Pazaitou-Panaylotou et al.’s work showed higher mortality in cases where carcinoma was found within the hyperfunctioning nodule.^19,20

The perception that a hyper functional nodule infrequently contains malignancy originates from scintigraphic investigations carried out between the 1960s and 1980s on diverse patient cohorts presenting with thyroid nodules; however, advancements in ultrasonographic methodologies have occurred since these initial studies.³

Currently, the malignancy risk associated with a hyperfunctioning nodule may be undervalued due to the prevailing belief in the infrequent association between thyroid carcinoma and hyperfunctional nodules revealed through scintigraphy. This belief contributes to the reluctance to recommend FNA or thyroidectomy for such nodules.²¹ Furthermore, most referenced studies are case reports, necessitating cautious interpretation of their findings.¹¹

It is becoming clearer that a “hot” nodule is not automatically benign, and certain risk factors should still prompt a closer look. Factors like large nodule size (over 3 cm), suspicious features on an US (like irregular borders or microcalcifications), or a family history of thyroid cancer are important red flags.^3,22 In our own cases, the nodules were quite large and had concerning appearances on the US, which was key to the diagnosis. This really shows that we can’t rely on functional status alone and must consider the whole clinical picture when deciding which nodules need further investigation.

Earlier studies have suggested a possible link between breast cancer and thyroid cancer, although a comprehensive meta-analysis specifically examining their bidirectional association had been lacking. A recent systematic review of 18 studies demonstrated a notable increase in the risk of developing thyroid cancer after breast cancer, as well as a modest rise in breast cancer risk following thyroid cancer. These findings support the concept that each malignancy may predispose to the other as a second primary tumor.²³

In our cases, however, screening mammography and breast US were consistently unremarkable, and none of the patients had a family history of breast cancer.

The findings from this case series and literature review highlight the need for a comprehensive evaluation of all thyroid nodules, including hot nodules, to rule out the possibility of malignancy. While the incidence of malignancy in hot nodules is relatively low, a thorough assessment is still essential, as thyroid cancer can occasionally present as a hot nodule.

These advancements in our understanding of thyroid cancer biology are increasingly necessitating the development of new diagnostic tools, prognostic and predictive biomarkers, and novel therapeutic approaches.

Conclusion

This case series describes the rare presentation of papillary and follicular thyroid carcinomas as hyperfunctioning (“hot”) nodules causing thyrotoxicosis. Although hot nodules are usually benign, this highlights the need for vigilance, as malignancy can still occur. FNA and histopathology are essential for accurate diagnosis, with surgical intervention often needed to prevent complications. Early detection and management improve outcomes, underscoring the importance of careful assessment in thyroid disease.

Learning points

Rare malignancy in hot nodules: Hyperfunctioning thyroid nodules are typically benign, but malignancy should be suspected if atypical features are present.

Comprehensive evaluation: Accurate diagnosis requires FNA biopsy, molecular testing, and integration of clinical, radiological, and cytological findings.

Impact on outcomes: Early identification of malignancy in hot nodules improves patient outcomes, emphasizing individualized diagnostic approaches.

Footnotes

Acknowledgements

The authors would like to acknowledge the internal medicine residency program for scientific support.

ORCID iDs

Elabbass A. Abdalmahmuod

Maab F. Elhaj

Ethical considerations

These cases were approved by the Hamad Medical Corporation’s Medical Research Center.

Consent for publication

The patients provided informed consent for the publication of these case series, including all clinical details and any accompanying images, to contribute to medical education and literature.

Author contributions

Maab F. Elhaj, Elabbass A. Abdalmahmuod, Mohamed Khair Hamad, Shahd I. Ibrahim, Mahmoud Zirie contributed to the writing, editing, and final approval of these cases report.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by Qatar National library.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

Data and materials are available on reasonable request.

References

Eszlinger

Hegedüs

Paschke

Thyroid nodule. Endocrinology 2023; 12: 165–201.

Larios

Toro-Tobon

Jacome

, et al. Factors and outcomes of inappropriate thyroid ultrasonography. JAMA Otolaryngol Head Neck Surg 2025; 151(9): 843–852.

Mirfakhraee

Mathews

Peng

, et al. A solitary hyperfunctioning thyroid nodule harboring thyroid carcinoma: review of the literature. Thyroid Res 2013; 6(1): 7.

Gharib

Papini

Paschke

, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. Endocr Pract 2010; 16(3): 468–475.

Bongers

Kluijfhout

Devon

, et al. Long-term risk of thyroid cancer after initially negative thyroid biopsy results. JAMA Otolaryngol Head Neck Surg 2019; 145(6): 579–580.

Osorio

Ballestas

Barrios

, et al. Clinical characteristics associated with the finding of thyroid cancer originating from hot nodules in patients with hyperthyroidism: a case report and systematic review of the literature. Rev Colomb Cir 2021; 36(4): 682–695.

Dirikoc

Polat

Kandemir

, et al. Comparison of ultrasonography features and malignancy rate of toxic and nontoxic autonomous nodules: a preliminary study. Ann Nucl Med 2015; 29(10): 883–889.

Kadia

Dimala

Bechem

, et al. Concurrent hyperthyroidism and papillary thyroid cancer: a fortuitous and ambiguous case report from a resource-poor setting. BMC Res Notes 2016; 9(1): 369.

Shinkai

Ohba

Kakudo

, et al. Hyperfunctioning papillary thyroid carcinoma with a BRAF mutation: the first case report and a literature review. Eur Thyroid J 2021; 10(3): 262–267.

10.

Oeffinger

Fontham

ETH

Etzioni

, et al. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA 2015; 314(15): 1599–1614.

11.

Liu

Wang

, et al. Hyperfunctioning thyroid carcinoma: a systematic review. Mol Clin Oncol 2019; 11(6): 535–550.

12.

Lai

Caschili

Baldussu

, et al. Papillary thyroid carcinoma presented as a hypercaptant nodule: a case report. Endocr Metab Sci 2024; 15: 100179.

13.

Wong

Farrell

Grossmann

Thyroid nodules: diagnosis and management. Med J Aust 2018; 209(2): 92–98.

14.

Cerci

Eroglu

, et al. Thyroid cancer in toxic and non-toxic multinodular goiter. J Postgrad Med 2007; 53(3): 157–160.

15.

Cooper

Doherty

Haugen

, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009; 19(11): 1167–1214.

16.

Pringle

Yin

Lee

, et al. Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer. Endocr Relat Cancer 2012; 19(3): 435–446.

17.

Niepomniszcze

Suárez

Pitoia

, et al. Follicular carcinoma presenting as autonomous functioning thyroid nodule and containing an activating mutation of the TSH receptor (T620I) and a mutation of the Ki-RAS (G12C) genes. Thyroid 2006; 16(5): 497–503.

18.

Nair

Jacob

Babu

, et al. Toxic thyroid carcinoma: a new case. Indian J Endocrinol Metab 2012; 16(4): 668.

19.

Gharib

Papini

Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol Metab Clin North Am 2007; 36(3): 707–735.

20.

Ashcraft

Van Herle

AJ.

Management of thyroid nodules. I: history and physical examination, blood tests, X-ray tests, and ultrasonography. Head Neck Surg 1981; 3(3): 216–227.

21.

Lau

Ghaznavi

Frolkis

, et al. Malignancy risk of hyperfunctioning thyroid nodules compared with non-toxic nodules: systematic review and a meta-analysis. Thyroid Res 2021; 14(1): 3.

22.

Durante

Grani

Lamartina

, et al. The diagnosis and management of thyroid nodules: a review. JAMA 2018; 319(9): 919–924.

23.

Joseph

Edirimanne

Eslick

GD.

The association between breast cancer and thyroid cancer: a meta-analysis. Breast Cancer Res Treat 2015; 152(1): 173–181.