Introduction

Melanoma is the 5th most common cancer in the United Kingdom (UK) with 16,700 new cases diagnosed every year and it accounts for 1% of all cancer deaths [1]. Immunotherapy is an effective treatment due to the high immunogenicity of melanoma. Recent studies have shown a significantly higher success rate with a combination of immunotherapy and chemotherapy, radiotherapy, or targeted molecular therapy [2]. In the UK, immunotherapy is used to treat patients with advanced metastatic (stage IV) melanoma and unresectable stage III disease [3]. They are also commonly used agents in other cancers such as metastatic renal cell, non-small cell lung, hepatocellular and bladder. Immunotherapy agents are revolutionising melanoma and other cancer treatments and are becoming more widely used. However, they cause significant adverse events to multiple organ systems. Examples include endocrine disturbances, hepatitis, pneumonitis, colitis and dermatitis [4].

The thyroid gland is an organ that is commonly affected but diagnosis can often be delayed or missed due to a lack of clear signs and symptoms. It is an important condition to diagnose as it can lead to significant morbidity for patients. This case report of immunotherapy-induced thyroiditis in a 65-year-old male with malignant melanoma aims to highlight the role of clinical, laboratory and radiological factors in diagnosis. It will outline how a high index of clinical suspicion can facilitate a prompter diagnosis. The case will also aim to show how radiology, specifically careful analysis of serial imaging studies, can contribute to the diagnosis of this important condition.

Case report

Imaging findings

Please see Figures 1, 2, 3, 4, 5, and 6 for serial radiological studies of the patient’s thyroid gland. Computed tomography (CT) performed in September 2020 (Figure 1) and magnetic resonance imaging (MRI) performed in October 2021 (Figure 2) show normal thyroid volume. As detailed in the clinical history, the patient started immunotherapy in November 2021. An MRI study performed in January 2022 (Figure 3) shows a slight reduction of the thyroid volume (most apparent on the left side). MRI in May 2022 (Figure 4) shows further reduction in the thyroid volume which can be appreciated in both lobes. Up to this point the reduced thyroid volume had not been appreciated on imaging and the patient had not been formally diagnosed with thyroiditis. The patient presented with acute anterior neck pain in August 2022 so an ultrasound thyroid was performed (Figure 5) which showed significantly reduced thyroid volume. An MRI study also performed in August 2022 (Figure 6) shows similar findings. The findings on the August 2022 studies prompted a retrospective review of previous imaging and the gradual reduction in thyroid volume was then appreciated. The combination of this, the patient’s symptoms and their TFTs led to a diagnosis of immunotherapy-induced thyroiditis. This shows the importance of assessing the thyroid in serial imaging studies in these patients. Only with careful retrospective review could the atrophy be fully appreciated and contribute to the patient’s diagnosis.

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Figure 1. 

Axial CT image dated 2nd September 2020

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Figure 2. 

Axial T1 fat-saturated post-contrast image dated 28th October 2021

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Figure 3. 

Axial T1 fat-saturated post-contrast image dated 7th January 2022

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Figure 4. 

Axial T1 fat-saturated post-contrast image dated 15th May 2022

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Figure 5. 

Transverse ultrasound image of the thyroid dated 12th August 2022. Callipers on the right lobe measured approximately 12 mm × 11 mm. A: transverse diameter of the right lobe of thyroid = 11mm; B: longitudinal diameter of the right lobe of thyroid = 12mm

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Figure 6. 

Axial T1 fat-saturated post-contrast image dated 17th August 2022

Discussion

Immunotherapy agents focus on specific targets of the immune system’s counter-regulatory mechanisms. Although these agents are more targeted and therefore better tolerated compared to most chemotherapy agents, they are associated with a new group of specific immune-related adverse events (irAEs) of which one group is endocrine [2]. Endocrine toxicities include hyperthyroidism, hypothyroidism, thyroiditis, hypophysitis and adrenal insufficiency. They usually appear after 6 weeks of treatment and may take a long time to resolve, in some cases being irreversible. These toxicities are important to detect as they can lead to significant morbidity and severe electrolyte imbalances. However, they present a diagnostic challenge as they can often present insidiously with vague symptoms. A combination of clinical, biochemical and radiological factors is necessary for diagnosis [4].

Whilst scholars believe most patients on immunotherapy are at risk of thyroid irAEs, their exact incidence is not known and depends on the specific agent being used [5]. Thyroid irAEs seem to have some overlap with Hashimoto’s thyroiditis, Grave’s disease and other autoimmune thyroid diseases. The precise relationship between thyroid irAEs and these autoimmune diseases remains to be seen [5].

Clinical manifestations of thyroid irAEs are notably variable with some patients experiencing hypothyroidism and others transient thyroiditis. Patients are mostly detected during routine hormone monitoring and screening [6]. Indeed, the diagnosis of thyroid dysfunction is predominately based on TFTs, even in the absence of clinical symptoms. TFTs should be part of baseline laboratory testing in all patients undergoing treatment with immunotherapies and should be regularly monitored. However, interpretation should be undertaken with caution as numerous factors may affect the hypothalamic-pituitary-thyroid axis in cancer patients (such as steroids, non-thyroid illnesses and iodinated contrast injection) [7].

Information regarding imaging recommendations and findings in thyroid irAEs is sparse. Ultrasound provides an inexpensive, dynamic and extremely useful assessment of the thyroid to aid in diagnosis. During an active phase of thyroiditis, the gland can appear large and heterogeneous with increased vascularity. Any subsequent atrophy and reduced activity (with associated reduced vascularity) will be demonstrated [7]. It is known that active thyroiditis can be associated with increased 2-deoxy-2-[¹⁸F] fluoro-d-glucose (¹⁸FDG) positron emission tomography (PET)/CT activity when compared with baseline studies, especially when TFTs are abnormal [5]. Neck CT can also reveal abnormalities of thyroiditis such as diffuse enlargement of the gland with hypoattenuation and occasional areas of ring enhancement from gland necrosis. Once the active phase of the disease has resolved gland atrophy and subsequent hypothyroidism can develop with CT and PET/CT findings reflective of this [8].

Treatment of immunotherapy-induced thyroiditis depends on the severity and clinical/biochemical manifestations. Patients with hypothyroidism should be treated with continuous T4. Transient hyperthyroidism should be treated conservatively as it often subsides and transforms into hypothyroidism. However, patients with signs of severe thyrotoxicosis should be treated aggressively with a combination of supportive therapies (beta blockers and glucocorticoids) and anti-thyroid drugs to help relieve symptoms and avoid complications [6].

Fortunately, new agents are being developed to counter immunotherapy toxicities. For example, nanomaterial-based immunotherapies such as stimuli-responsive nanoparticles offer an exciting future. Emerging evidence shows positive outcomes in tumour response whilst adverse events are kept to a minimum when compared with immunotherapy alone [9, 10]. Once widespread utilisation of these treatment methods is adopted the burden of adverse events on patients should be reduced.

In conclusion, thyroid irAEs from immunotherapy treatments are an important cause of morbidity in cancer patients and present a diagnostic challenge to clinicians and radiologists. As the case report shows, a high index of clinical suspicion is important and could have aided earlier diagnosis, therefore in cancer patients suffering from thyroid dysfunction, the causative relationship with any immunotherapy treatments should always be considered. The case report also highlights how careful assessment of the thyroid in serial imaging studies can help detect any subtle evolving changes to aid early diagnosis and treatment.