Pseudo-Progression of Melanoma Treated with Nivolumab/Ipilimumab: A Case Report

Background

Melanoma is an aggressive type of skin cancer that can be difficult to manage. Its treatment has been transformed by immunotherapy. Melanoma cells frequently have mutations that make them vulnerable to be attacked by the immune system and this is how immunotherapy can fight this cancer. Immunotherapy with checkpoint inhibitors targets the mechanisms that malignant cells use to evade detection by the immune system [1]. It blocks proteins produced by the tumor, which allows the immune system to identify and attack cancerous cells. Pembrolizumab and nivolumab, both of which target a protein called PD-1, are two of the most common checkpoint inhibitors used to treat melanoma. By preventing PD-1 from functioning, these drugs enable T cells to attack melanoma cells more effectively [2]. Immunotherapy has significantly enhanced melanoma patients’ clinical outcomes and survival, especially for those with metastatic disease [3]. Although immunotherapy can produce long-term remissions, not all patients respond to it. Some patients can experience a phenomenon called pseudo-progression, in which the inflammation inside the tumor can give the appearance of increasing the size of the tumor. We present a case of pseudo-progression of melanoma treated with immunotherapy.

Case Report

The patient was a 74-year-old woman with a medical history of hypertension and dyslipidemia who initially presented with a lump on the right side of her chest. The patient had a bilateral diagnostic mammogram, which noted enlargement of axillary lymph nodes bilaterally. Ultrasound noted an abnormal appearing right axillary lymph node measuring 15 mm and a left axillary lymph node measuring 10 mm. An ultrasound-guided right axillary lymph node biopsy discovered a metastatic malignant tumor with melanocytic differentiation. Genetic findings included NF1, CIC P331, TERT promoter, and amplification of FGF10, MITF, and RICTOR. KIT, NRAS, and BRAF V600 were negative for mutations. The PD-L1 tumor proportion score was 1%.

An initial positron emission tomography-computed tomography (PET-CT) scan noted metastatic involvement, with a soft tissue mass in the right (standardized uptake value [SUV] 13.8 measuring 2.4×2.4 cm) and left (SUV 13.5 measuring 2.1×1.8 cm) chest wall, a large right lower lobe lung mass measuring 5.3×4 cm (SUV of 17.6), and a lobular mass in the right abdomen 2.5×2.2 cm (SUV 14.2) (Figure 1A–1C).

Stage IV melanoma was diagnosed, and the patient started therapy with nivolumab/ipilimumab every 21 days for 4 cycles for palliative intent, which she tolerated without adverse effects. Unfortunately, the patient was hospitalized for Clostridioides difficile colitis after 3 treatment cycles. A CT scan of the chest, abdomen, and pelvis with contrast was obtained at that time, and the findings were suggestive of disease progression, with enlargement of the subcutaneous masses anterior to the right shoulder (2.5×1.8 cm), left chest wall (2.4 cm), and the intra-abdominal mass posterior to the lower portion of the right kidney (2.6 cm). The right lung mass was stable (Figure 2).

After the standard treatment of antibiotics, she was discharged. Although the CT imaging was worrisome for disease progression, clinically, she was doing well. A decrease in the size of her subcutaneous masses involving the right and left chest wall was noted on her physical examination during her outpatient follow-up 2 weeks after her discharge. Therefore, we decided to obtain new PET-CT imaging for further evaluation. The new PET-CT showed a complete metabolic response at all disease sites (Figure 1D–1F). The initial progression was most likely a pseudo-progression from the use of immunotherapy, as it was seen only at the previously known areas of disease involvement, with no new sites of metastasis and complete response on subsequent imaging without additional therapies. Given the great response to immunotherapy, the patient continued her immunotherapy with nivolumab as a single agent and has been doing well.

Discussion

Pseudo-progression is a phenomenon in which tumors appear to grow or worsen on imaging scans after a patient has undergone immunotherapy treatment. While this can initially be concerning, it could represent a response to the treatment. Pseudo-progression in melanoma is estimated to occur in less than 10% of the patients treated with PD-1 inhibitors [4,5]. This pseudo-progression occurs because immunotherapy stimulates the immune system to attack and destroy malignant cells. This can cause inflammation, making tumors appear larger on scans due to swelling. However, this inflammation should eventually subside, and the tumors will decrease in size. It is imperative to closely monitor the patient while on treatment to distinguish between pseudo-progression and lack of response to treatment with real disease progression, as treatment decisions can differ. Differentiating between pseudo-progression and tumor progression can be challenging. To facilitate this differentiation, the iRECIST criteria were proposed to guide when to perform imaging evaluations and how to interpret new lesions [6,7]. Although this method is helpful, it has its limitations, and this differentiation requires a careful evaluation of imaging, timing, and other clinical factors. Regular imaging tests may not help to differentiate between both. Depending on the situation, a PET scan or repeat biopsies can be necessary to confirm whether the apparent growth is due to inflammation or actual disease progression [8]. While pseudo-progression can be a concerning phenomenon, the clinical evaluation of the patient should be considered when deciding to continue with immunotherapy or to change to an alternative therapy.

Conclusions

This case highlights the importance of careful evaluation of immunotherapy response in patients with melanoma. The initial progression noted in this patient was most likely a pseudo-progression, which resolved with further immunotherapy. Clinicians should consider PET-CT imaging in cases of suspected pseudo-progression to avoid unnecessary changes in therapy. The patient’s response to immunotherapy demonstrates the effectiveness of immunotherapy in treating advanced melanoma.