Background

Immune checkpoint inhibitors (ICIs) are promising alternatives in cancer treatment in addition to surgery, chemotherapy, and radiotherapy. The basic mechanism of action of ICIs is releasing the brakes of the immune regulation, which is a crucial negative feedback mechanism for avoiding excessive immune reaction. Therefore, ICI therapy has resulted in outstanding success on the one hand and lethal immune-related adverse effects (irAEs) on the other, which are now becoming a major concern in further development of reliable cancer immunotherapy [1]. Hematologic adverse effects in particular are life-threatening but occur relatively infrequently; 7 cases of hemophagocytic lymphohistiocytosis (HLH) following ICI therapy have been reported so far (4 cases of melanoma and 1 case each of urinary bladder carcinoma, Merkel cell carcinoma, and non-small cell lung carcinoma) [2–6]. There has been only 1 reported case of thrombotic thrombocytopenic purpura (TTP) following ICI therapy with ipilimumab [7].

In this report, we present a case of pleomorphic lung carcinoma with significant anti-tumor response to nivolumab therapy. The patient also developed severe cytokine release syndrome (CRS), resulting in HLH and amputation of both lower extremities because of purpura fulminans (PF) probably induced by a TTP-like condition. This is the first report of such a case.

Case presentation

A 52-year-old woman visited a hospital with complaints of right axillary swelling. Computed tomography (CT) imaging identified a space-occupying lesion in the S2 region of the right lung. On histological analysis, the tumor showed high-grade cytological atypia with poor intercellular cohesion (Fig. 1a). Immunohistochemical analysis revealed that the tumor was positive for pan-cytokeratin, vimentin, and thyroid transcription factor 1, but negative for CD45 and CD30, indicating pleomorphic adenocarcinoma of the lung. Programmed cell death ligand 1 was positive in more than 95% of tumor cells (Anti-PD-L1, Clone 22C3; DAKO, Glostrup, Denmark; data not shown). The tumor was evaluated as cT4N2M0 in accordance with TNM classification of Malignant Tumors 8th edition (Union for International Cancer Control, Geneva, Switzerland). The patient underwent four courses of chemotherapy (nab-paclitaxel plus carboplatin). She had fever, polyarthralgia, and muscle soreness. In addition, leukocytosis and thrombocytosis were detected on laboratory testing (data not shown). Based on these clinical features, she was diagnosed as having paraneoplastic syndrome and not an adverse effect of chemotherapy because of paucity of association between symptoms and medication. The patient showed a partial response to chemotherapy based on the Response Evaluation Criteria in Solid Tumors guidelines at which time the tumor was 70 × 55 × 48 mm in size (Fig. 1b; left panel). Then, she was treated with four courses of 120 mg (3 mg/kg) of nivolumab every 2 weeks. Although the patient still had the same symptoms that was diagnosed as paraneoplastic syndrome before, there was no newly developed prodrome or mild noticeable irAEs until the last administration of nivolumab. In addition, laboratory tests performed in each hospital visit did not show any remarkable abnormality.

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Fig. 1

Clinical data and pathological images. a Tumor cells with a pleomorphic appearance but are less cohesive. Hematoxylin and eosin staining; original magnification × 200. b Computed tomography imaging shows a low-intensity lesion measuring approximately 7 cm in S2 of the right lung (left panel). By 4 months after the last nivolumab administration, no distinctive space-occupying lesion is found (right panel). Graphs representing the trends of c platelet count, d LDH and CPK from the time of admission (day 1) to day 16. e Images of the lower extremities at 2 days (left panel), 10 days (center panel), and 2 months (right panel) after the onset of purpura fulminans

However, 14 days after the last nivolumab administration, she was admitted to our hospital with complaints of asthenia. The patient felt sick only one day before the admission. She had a fever of 38.6 °C. There was livedo reticularis on the extremities with systemic purpura. Laboratory results on admission are shown in Table 1. The patient had no relevant past medical history or family history including autoimmune disease. In addition, autoantibodies, including antinuclear antibodies, proteinase 3, myeloperoxidase-antineutrophil cytoplasmic, and anticardiolipin antibodies, as well as multiple aminoacyl-tRNA synthetases or anti-CL-β2GP1 antibodies, were not detected. Culture and microscopy of the blood smear did not detect bacterial infection. Conversely, significantly increased serum levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, and G-CSF indicated a state of cytokine storm. Thrombocytopenia and increased serum soluble IL-2 receptor, ferritin, and triglyceride levels would imply possible HLH. Impaired liver function with increased lactate dehydrogenase and creatine phosphokinase together with exacerbated muscle soreness suggested rhabdomyolysis. The activity of A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) was decreased but not less than 10%, which is a criterion for TTP. There was no evidence of infection on blood culture.

Immediately after admission to the intensive care unit, pulse steroid therapy with methylprednisolone 1000 mg/day for 3 days and systemic prednisolone administration (50 mg/day) were instituted. Thrombomodulin and mycophenolate mofetil was administered thereafter. Any of them could not provide a dramatic amelioration of her general condition, although the laboratory test showed improvement after administration of thrombomodulin and mycophenolate. Trend of platelet count, blood concentration of lactate dehydrogenase and creatine phosphokinase, which were useful as indicator of the clinical state, are depicted in Fig. 1c and d. By 3 days after hospitalization, general hypokinesis of the left ventricular wall resulted in reduced ejection fraction (20%) and aggravation of respiratory distress. Although we did not perform myocardial biopsy, this was probably caused by CRS induced myocarditis, as evidenced by increased levels of the cardiac marker creatine kinase-muscle/brain in the circulation. Continuous hemodiafiltration was also initiated because of renal failure.

By 7 days after hospitalization, the lower extremities were turning black due to circulatory failure (Fig. 1e). Gangrene then spread with infection involving the entire lower extremities, suggesting PF. Amputation of the left and right lower limbs was performed at three and four months after admission, respectively. We could not find active microangiopathy or inflammation in the resected limbs presumably because of the modification by immune suppressants and complete necrosis.

CT evaluation of the pulmonary lesion at 4 months after the last administration of nivolumab demonstrated significant regression; the tumor had become a scar-like lesion (Fig. 1b; right panel) and there was no further progression thereafter. The patient was finally discharged from the hospital at 6 months after admission.