Case of small bowel perforation secondary to nivolumab and ipilimumab related tumour regression

Abstract

A 56-year-old man undergoing immunotherapy treatment for metastatic melanoma presented with sudden onset testicular pain radiating into his abdomen. On examination, the abdomen was generally tender with associated guarding. Imaging revealed a perforation of the small bowel at the site of a metastatic lesion. Histology revealed that this process was non-inflammatory in nature. A diagnosis of small bowel perforation secondary to immunotherapy driven rapid tumour regression was made. The patient was treated with a small bowel resection plus anastomosis and made a full recovery. This case highlights the rare potential side effect of immunotherapy in causing non-inflammatory bowel perforations secondary to rapid tumour regression.

Background

Melanoma is the most serious form of skin cancer and is the fifth most common cancer in the UK, with roughly 10% of patients presenting with metastatic disease.¹

Ipilimumab and nivolumab are immunotherapy-based treatments used in the management of metastatic melanoma. By blockade of immune checkpoints, these medications have achieved significant tumour regression in patients with metastatic disease.^{2 3}

Ipilimumab works by inhibiting CTLA-4, a protein that downregulates the immune system, which in turn sensitises the cytotoxic T lymphocytes against cancer cells.² Nivolumab works by blocking programmed cell death protein 1 (PD-1), a protein found on activated T cells, from binding to programmed cell death 1 ligand 1 (PD-L1), a protein often secreted by cancers. When PD-1 bind to PD-L1, T cells are inhibited; nivolumab stops this process.³

Effectiveness of these medications has led them to become a mainstay in the management of advanced melanoma.^{4 5} These medications are not without risk, with both being known to cause colitis, hepatitis, pneumonitis and other major inflammatory responses in the body.^{6 7}

Case presentation

The patient was a 56-year-old man who presented to hospital in April 2019 with sudden onset, severe testicular pain radiating into his abdomen. He had associated vomiting but no diarrhoea with no previous history or trauma. There were no recent changes in his diet reported and he had been well prior to onset of the pain.

The patient had a background of metastatic melanoma with unknown primary with lesions within the small bowel with associated mesenteric lymphadenopathy. He had responded well to immunotherapy of ipilimumab and nivolumab and was currently asymptomatic from his melanoma.

Medical history included Barrett’s oesophagus, hiatus hernia and sigmoid polypectomy of tubulovillous adenoma.

The patient has completed four cycles of dual therapy of nivolumab and ipilimumab from July to September 2018. This was stepped down to due to immunotherapy related hepatitis requiring 4 weeks of steroid therapy. He was then treated with nivolumab from October 2018 to April 2019 without side effect and favourable tumour response. Other regular medications included folic acid 5 mg once daily, omeprazole 20 mg once daily and cyanocobalamin 50 mg once daily.

The patient had no known drug allergies. Social history showed that he was a non-smoker and had minimal alcohol consumption of 1–2 units monthly, with no recreational drug use reported. He worked as an heavy goods vehicle (HGV) driver and lived with his partner.

On examination, his abdomen was generally very tender with associated guarding. Cardiorespiratory examination was unremarkable.

Observations showed that the patient was in septicaemic shock with grossly deranged inflammatory markers.

CT scan of the abdomen and pelvis showed a perforation of the jejunum with pneumoperitoneum (figure 1), with the perforation site at the same site as his metastatic lesions. There was also associated free fluid in the pelvis.

Figure 1.

CT scan of the abdomen showing pneumoperitoneum secondary to jejunal perforation. April 2019.

A laparotomy was performed later that day with a jejunal resection and small bowel anastomosis.

Outcome and follow-up

The patient was admitted to the intensive care unit (ICU) postoperatively but had good recovery and was stepped down to the ward and discharged 10 days after his operation. On discharge, he was mobilising independently, eating and drinking without issue and bowels were open daily.

Histology report showed that the jejunal wall had infiltration of a pleomorphic and pigmented solid tumour, composed of large sized atypical cells with cytolomorphological features consistent with a metastatic malignant melanoma. Tumour nests were infiltrating the wall from mucosal surface to the serosa leading to a secondary perforation of the bowel, associated with necrosis and fibrin deposits. Prior to immunotherapy the tumour was 90×50 mm on CT scan taken May 2018 (figure 2) while the tumour at the time of resection measured 28×22 mm (figure 3). This report showed no evidence of immunotherapy related colitis. Given the tumour had shrunk in size the most likely cause for perforation suggested by the histopathology team was rapid decrease in tumour size caused by immunotherapy.

Figure 2.

CT scan of the abdomen showing jejunal tumour measuring 90×50 mm. May 2018.

Figure 3.

CT scan of the abdomen showing jejunal tumour measuring 28×22 mm. March 2019.

There were no acute or delayed postoperative complications.

Discussion

Bowel perforations have a multitude of causes including trauma, infection and inflammatory bowel disease.⁸ However, this case highlights how immunotherapy tumour response can cause perforations within the bowel. We believe that patient’s response to nivolumab and ipilimumab was so drastic that the tumour shrinkage caused by the medications, led to perforation within the small bowel. Similar cases have been described in Gardner’s syndrome, where drastic regression of tumour secondary to chemotherapy have resulted in bowel perforations in multiple patients.⁹

There have been other cases of bowel perforation secondary to nivolumab and ipilimumab use, however both perforations were caused by immunotherapy driven colitis and not tumour regression. These cases were far less acute with the patients experiencing diarrhoea and abdominal pain days prior to the perforation.^{10 11}

In conclusion, this case report highlights a relatively unknown potential complication with immunotherapy. Given this case, I hope the possibility of bowel perforation is considered in all patients presenting with acute onset bowel pain who have a background of immunotherapy treatment.

Learning points.

• Intestinal perforation can occur due to rapid tumour regression.

• Immunotherapy use is expanding rapidly making awareness of the adverse events progressively more paramount.

• Cancer treatments have the potential for greater harm than the diseases they are used to treat.