Fluorodeoxyglucose-avid pituitary lesion in metastatic melanoma during immune checkpoint therapy: A case report

INTRODUCTION

Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is an established immune checkpoint inhibitor for metastatic melanoma. While it improves survival, it is associated with immune-related adverse events, including inflammation of the pituitary gland (hypophysitis). Distinguishing hypophysitis from pituitary metastasis is critical, as management strategies differ significantly. We describe a case of ipilimumab-induced hypophysitis initially suspected to be pituitary metastasis based on findings from 18F-fluorodeoxyglucose–positron emission tomography-computed tomography (FDG-PET/CT) and brain magnetic resonance imaging (MRI), which later resolved after discontinuation of ipilimumab.

CASE REPORT

A 58-year-old man with metastatic melanoma presented for FDG-PET/CT evaluation after four cycles of ipilimumab and nivolumab. His primary melanoma originated in the right ankle, with known metastases to the right popliteal fossa, groin lymph nodes, iliac chain, and lung.

At the time of evaluation, the patient reported symptoms consistent with pituitary dysfunction, including fatigue, myalgia, lethargy, fever, chills, and decreased appetite. Laboratory evaluation revealed hormonal disturbances: Thyroid-stimulating hormone 0.04 μIU/mL (normal range: 0.30–4.20), free T4 0.40 ng/dL (normal range: 0.90–1.70), cortisol level 2.4 μg/dL (normal range: 3.7–19), undetectable luteinizing hormone, and undetectable total testosterone.

An FDG-PET/CT performed on June 10, 2016, revealed a new hypermetabolic lesion in the pituitary gland with a maximum standardized uptake value (SUV) of 15.4 [Figure 1]. A brain MRI on July 10, 2016, confirmed a newly enlarged pituitary gland with heterogeneous enhancement and mild suprasellar extension [Figure 2]. These findings were initially interpreted as pituitary metastasis.

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Figure 1:

A 58-year-old man with metastatic melanoma presenting with fatigue, myalgia, and hormonal disturbances. (a) Whole-body fludeoxyglucose-positron emission tomography-computed tomography (FDG-PET/CT) maximum intensity projection (MIP) image shows hypermetabolic skin lesions in the right ankle (red arrow) consistent with known primary melanoma, along with FDG-avid right popliteal and inguinal lymph nodes, multifocal pulmonary metastases, mediastinal involvement, and a left supraclavicular lymph node (blue arrows). (b) Magnified sagittal CT, (c) PET, and (d) fused PET/CT images of the pituitary fossa reveal a hypermetabolic pituitary lesion (red arrows) with a maximum maximum standardized uptake value of 15.4. (e) Head-and-neck MIP image demonstrates intense FDG uptake in the pituitary fossa (grey arrow).

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Figure 2:

A 58-year-old man with metastatic melanoma presenting with pituitary dysfunction following immunotherapy. (a-b) Pre-treatment post-contrast T1-weighted (a) sagittal and (b) coronal brain magnetic resonance imaging (MRI) images show normal pituitary gland size and homogeneous enhancement (red arrow), post-treatment (c) sagittal and (d) coronal post-contrast T1-weighted brain MRI following four cycles of ipilimumab and nivolumab demonstrate pituitary gland enlargement with heterogeneous enhancement and mild suprasellar extension, raising suspicion for metastasis (red arrows), (e-f) Follow-up post-contrast T1-weighted (e) sagittal and (f) coronal MRI images obtained 4 months after discontinuation of ipilimumab show resolution of pituitary enlargement and restoration of normal gland appearance and enhancement pattern, consistent with immune-related hypophysitis (red arrows).

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Given disease progression, ipilimumab was discontinued, and the patient continued nivolumab monotherapy. A repeat FDG-PET/CT 2 months after discontinuing ipilimumab demonstrated resolution of pituitary FDG uptake [Figure 3], and a follow-up brain MRI [Figure 2] confirmed complete resolution of the enhancing pituitary lesion, supporting a diagnosis of ipilimumab-induced hypophysitis rather than metastasis.

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Figure 3:

58-year-old man with metastatic melanoma and ipilimumab-induced hypophysitis. (a-c) Follow-up magnified (a) sagittal computed tomography (CT), (b) positron emission tomography (PET), and (c) fused PET/CT images of the pituitary fossa 2 months after discontinuation of ipilimumab show resolution of previously noted fluorodeoxyglucose (FDG) uptake (red arrows), indicating metabolic remission. (d) Maximum intensity projection image of the head demonstrates the absence of abnormal FDG avidity in the pituitary region (red arrow), supporting the diagnosis of immune-related hypophysitis rather than metastatic disease.

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DISCUSSION

Ipilimumab-induced hypophysitis is a well-documented immune-related adverse event, occurring in approximately 10–15% of patients receiving CTLA-4 inhibitors.^[1,2] It typically presents with headache, fatigue, and endocrine dysfunction, though imaging findings may resemble pituitary metastases. The high FDG avidity observed in our patient’s lesion initially raised concern for metastasis; however, the resolution of the lesion following ipilimumab discontinuation supports a diagnosis of immune-related hypophysitis.

Differentiating ipilimumab-induced hypophysitis from melanoma metastasis to the pituitary can be challenging, but there are key imaging and clinical features that help distinguish them [Table 1]. Table 1 highlights key clinical and imaging features that differentiate immune-related hypophysitis from metastatic involvement of the pituitary gland, aiding in accurate diagnosis and appropriate management.

Key Clues in this patient’s case:

• The patient had recently been on ipilimumab

• The imaging findings of high SUV uptake (15.4) and heterogeneous enhancement on MRI were more typical of pituitary metastasis, increasing diagnostic uncertainty

• The resolution of the lesion after discontinuation of ipilimumab ultimately confirmed immune-related hypophysitis, demonstrating how imaging features alone may not always be definitive.

This case is particularly interesting because typical hypophysitis cases usually present with homogeneous enhancement on MRI, whereas our patient had heterogeneous enhancement, which is more characteristic of pituitary metastasis. In addition, the high FDG uptake further contributed to the diagnostic dilemma, reinforcing the importance of clinical and follow-up imaging correlation in such cases.^[3,4]

Management of ipilimumab-induced hypophysitis involves discontinuing the offending agent and providing hormone replacement therapy as needed. Unlike other immune-related adverse events, hypophysitis may not always necessitate high-dose corticosteroids unless symptoms are severe.^[5]

DIFFERENTIAL DIAGNOSIS

In patients with metastatic melanoma presenting with a new pituitary lesion and signs of endocrine dysfunction, several diagnostic possibilities must be considered. The key differential diagnoses in this clinical context include:

• Pituitary Metastasis: Melanoma is among the malignancies with a high propensity for pituitary metastasis. Imaging findings such as heterogeneous enhancement and high FDG uptake – both observed in our case – can raise strong suspicion. Metastases frequently involve the posterior lobe and may present with diabetes insipidus.

• Ipilimumab-induced Hypophysitis: A well-recognized immune-related adverse event associated with CTLA-4 inhibition. Hypophysitis typically manifests with anterior pituitary hormonal deficiencies and homogeneous enhancement on MRI, but atypical features – such as heterogeneous enhancement and intense FDG uptake – can lead to diagnostic confusion [Table 2]. Table 2 outlines distinguishing clinical, imaging, and management features between immune-related hypophysitis caused by checkpoint inhibitor therapy and pituitary macroadenomas (PITNets), aiding in accurate diagnosis and appropriate therapeutic decisions in patients presenting with pituitary lesions.

• Primary Pituitary Tumor (e.g., Non-functioning Adenoma): These lesions may cause mass effects and hormonal disturbances. However, they tend to show lower FDG avidity and are not associated with immunotherapy.

• Lymphocytic Hypophysitis: An autoimmune inflammatory disorder that may mimic drug-induced hypophysitis but is unrelated to immunotherapy. It is more common in women, particularly in the peripartum period, but can occur sporadically in other groups.

• Granulomatous Infiltration (e.g., Sarcoidosis, Tuberculosis): These systemic diseases can involve the pituitary and present similarly on imaging. Diagnosis often relies on clinical correlation, laboratory studies, and evidence of multisystem involvement.

CONCLUSION

This case underscores the importance of recognizing ipilimumab-induced hypophysitis as a potential pituitary lesion in patients with metastatic melanoma. Clinicians should maintain a high index of suspicion for immune-related hypophysitis in patients receiving checkpoint inhibitors to avoid unnecessary interventions and ensure appropriate management.

TEACHING POINTS

1. Immune-related hypophysitis can mimic pituitary metastasis on imaging, particularly with intense FDG uptake and heterogeneous MRI enhancement – features traditionally associated with malignancy. Clinical context and follow-up imaging are essential for accurate diagnosis

2. Resolution of pituitary abnormalities following discontinuation of ipilimumab strongly supports the diagnosis of immune-related hypophysitis and highlights the importance of considering immunotherapy-induced endocrine toxicity in differential diagnoses

3. Diabetes insipidus is uncommon in immune-related hypophysitis but more typical in pituitary metastases, providing a useful clinical clue when distinguishing between these two entities in patients with metastatic melanoma.