Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report

Abstract

Background: Immune checkpoint inhibitors (ICIs) are the treatment of choice for several cancers and can be associated with remarkable clinical benefit, but can also cause serious immune-related adverse events (irAEs). Management of rare and severe irAEs is challenged by an incomplete knowledge of their natural history and pathogenetic mechanisms. We report a case of fatal acute-onset gastro-intestinal (GI) hypomotility from myenteric plexus neuropathy following a single dose of ipilimumab plus nivolumab given for treatment of Merkel cell carcinoma (MCC).

Case presentation: A 66-year-old man with recurrent metastatic MCC involving several organs (liver, bones and disseminated retroperitoneal lymphadenopathy) developed profound pharyngeal dysphagia and ileus that started 7 days after receiving a single administration of combination immune checkpoint blockade consisting of nivolumab (3 mg/kg) and low-dose ipilimumab (1 mg/kg). A swallowing study showed oropharyngeal dysfunction and aspiration. Imaging studies were consistent with diffuse intestinal paresis. An extensive work-up did not reveal obvious causes of these symptoms, and enteric plexopathy was suspected. Empiric immune suppressive therapy was initiated urgently. Despite an escalating immunosuppressive regimen that included high dose steroids, tacrolimus and therapeutic plasma exchange, no improvement in GI motility was seen and the patient suffered repeated episodes of aspiration. Seven weeks after the onset of GI hypomotility, the patient succumbed to sepsis from intestinal perforations. At autopsy, histologic specimens obtained from the entire GI tract (pharynx to rectum) showed near complete loss of ganglion cells within the myenteric and submucosal plexuses. An associated inflammatory infiltrate was not seen, suggesting a 'burned out' phase of illness. C4d complement deposition was found at the ganglionic sites, suggesting antibody-mediated pathogenesis. Remarkably, at sites of previously suspected Merkel cell metastases, no residual viable Merkel cell carcinoma was identified.

Conclusions: GI-tract paresis due to myenteric neuritis is a rarely reported toxicity of ICIs. Because the window of reversibility is likely to be very brief, quick and decisive interventions are warranted. Subtle functional and anatomic perturbations of the myenteric nervous system from the use of ICIs may be more prevalent than realized and should be suspected and addressed in both clinical and investigational settings.

Trial registration: ClinicalTrials.gov NCT02488759.

Keywords: Enteric neuropathy; Ileus; Immune checkpoint inhibitor; Immune-related adverse events; Ipilimumab; Merkel cell; Myenteric plexopathy; Neuritis; Nivolumab; Pseudo-obstruction.

Fig. 1

CT images obtained following the administration of IV contrast prior to (panels a, c, and e) and 51 day following treatment (panels b, d, f) with ipilimumab and nivolumab. The pretreatment scans show a 4.2 × 4.0 cm lesion within the right lobe of the liver lateral to the inferior vena cava (a, the lesion is identified by arrowheads), as well as peripancreatic retroperitoneal adenopathy (c, identified by arrowheads). Following treatment, the lesion within the liver has decreased to 2.0 × 1.6 cm (b, identified by arrowheads) and the retroperitoneal adenopathy has resolved (d). Dilated loops of large bowel as well as peritoneal air is present (panels d and f, identified by arrowheads) as well as a percutaneous gastrostomy tube (panel d, double arrowhead)

Fig. 2

Representative histology from a control section of comparably autolyzed colon (not from this patient) demonstrating a representative myenteric ganglion (a) containing ganglion cells (arrowheads) and scattered surrounding glia. This is in contrast to the patient’s ganglia (b) which show morphologic absence of ganglion cell bodies and no conspicuous inflammatory infiltrate. While myenteric ganglions cells in control tissue (not from this patient) are highlighted by anti-Hu (c, arrowheads), no immunoreactive ganglion cells are present in this patient (d). Rare submucosal ganglion cells were seen (Fig. 2b and d, insets). Similarly, immunohistochemistry using PGP9.5 on the control myenteric plexus (e) highlights neuronal bodies (arrowheads), adjacent neural processes (np) and intramuscular nerves (in), in contrast to the patient whose myenteric plexus (f) demonstrates sparse residual processes in the plexus and no intramuscular nerves. Immunohistochemistry for SOX10 in both the control plexus (g) and the patient’s tissue (h) show residual glial cells (arrowheads). Scale bars: 50 μm

Fig. 3

C4d immunoreactivity around ganglia and nerves. a Intense C4d immunolabelling is observed around an aneuronal ganglion (g) and in the location of small intramuscular nerves (arrows) in the colon of the patient. b In contrast, no significant C4d expression is observed in ganglia (g) in the colon from a cadaveric control patient with no history of ipilimumab or novilumab exposure or dysmotility. v, blood vessel. Scale bars = 100 μm