Paraneoplastic acral vascular syndrome in a patient with metastatic melanoma under immune checkpoint blockade

Abstract

Background: Paraneoplastic acral vascular syndrome (PAVS) is a rare phenomenon which is observed in patients with adenocarcinomas and other malignancies. Various potential pathogenic mechanisms such as tumour invasion of sympathetic nerves, hyperviscosity, hypercoagulability, vasoactive tumour-secreted substances, and immunological mechanisms have been suggested.

Case presentation: We report a 60-year-old Caucasian male attended our hospital with a bulky lymph node mass in the right axilla. Extirpation of a lymph node conglomerate revealed 5 melanoma lymph node metastases. Computed tomography showed a liver metastasis (diameter: 3.8 cm), several retroperitoneal metastases, bilateral metastases in the lung hilus, and prepectoral subcutaneous metastases (Stage IV; pTx, N3, M1c). Lactate dehydrogenase and S100B were slightly elevated. Combination therapy of nivolumab (1 mg/kg BW) and ipilimumab (3 mg/kg BW) was started. Three weeks after the first combination therapy he developed progressive erythema, paraesthesia and pain on the fingertips of both hands. Both cold and warmth was not well tolerated by the patient. Complete work-up excluded associated conditions or factors such as haematological disorders, rheumatologic disorders, hypertension, diabetes or smoking. Treatment was initiated with prostacyclin 20 μg twice daily and oral prednisolone 50 mg in tapering dosage. However, prostacyclin was stopped after the first applications because the pain increased during infusion. The second course of nivolumab and ipilimumab was administered. About 2 weeks later, the patient presented with increased pain and small subungual necrosis. We treated the patient with oral analgetics and intravenous prednisolone 500 mg in tapering dosage. On digital substraction angiography occlusion of all arteries of the fingers was demonstrated. Further rheologic and anti-melanoma treatments were refused by the patient. About 2 months after the second course of nivolumab and ipilimumab combination therapy several fingers showed severe gangrene which finally led to amputations of end phalanges of several fingers. Histopathology did not reveal evidence for vasculitis or other primary vascular pathologies. During the following 2 months the patient experienced dramatic progress of his metastatic disease and finally died at multi-organ failure.

Conclusion: Presence of rapidly progressive digital ischemia in an elderly patient with cancer should always raise clinical suspicion of a paraneoplastic phenomenon when other possible causes have been excluded. In patients treated with immune checkpoint inhibitors such as CTLA-4 and PD-L1 blockers PVAS-like events have not been reported so far. However, it is debatable whether immune checkpoint blockade may play a pathogenetic role in the development of PAVS in patients with malignancies.

Keywords: Digital ischemia; Gangrene; Immune-checkpoint blockade, ipilimumab, nivolumab; Melanoma.

Fig. 1

Twenty-five days after the first application of ipilimumab/nivolumab combination therapy the patient reported paraesthesia and pain in the fingertips; a slight erythema is visible on the fingertip of digitus 4 of the left hand (a). Five days after the second course ipilimumab/nivolumab combination therapy, a violaceous erythema was observed on digitus 3 and 4 of the left hand (b). Paraesthesia and pain also deteriorated

Fig. 2

On digital substraction angiography an almost complete occlusion of digiti 2–5 was observed on the left hand (a). Nitroglycerin applications during angiography did not result in vasodilatation (b)

Fig. 3

Twenty days after the second application of ipilimumab/nivolumab combination therapy the violaceous erythema was increased (a). The patient suffered from paraesthesia and strong pain. Six weeks later a severe gangrene was observed on digitus 3 of the left hand (b)

Fig. 4

Histopathology of the skin assessed near the necrotic border of digitus 3 of the left hand (Fig. 3) predominantly revealed altered tissue with fibrosis and strong mainly perivascular inflammatory infiltrates including lymphocytes, plasma cells, and neutrophils (a, b). The inflammatory infiltrate was dominated by CD4+ cells (c) when compared to CD8+ lymphocytes (d)