An 80-year-old man was referred to our clinic due to a 6-year history of PV. He previously received treatments with systemic corticosteroids and immunosuppressants, including azathioprine and mycophenolate mofetil, both pre-maturely interrupted after 6 and 4 months, respectively, due to inefficacy. A cycle of rituximab, followed by two maintenance administrations 6 and 12 months later, had revealed effective in establishing a prolonged remission off-therapy for about 2 years. He had an episode of thrombophlebitis of the lower limbs 2 years earlier, for which he was on treatment with rivaroxaban. At the time of the first dermatological visit, the physical examination showed erosions mainly affecting the trunk and scalp. The Pemphigus Disease Activity Index (PDAI) was 7. Because of the low disease activity, a treatment with topical steroids was attempted.
After 4 weeks, the patient returned because of a significant worsening of his cutaneous lesions, which were enlarging and increasing in number, located in the head and neck, trunk, and limbs, with no mucosal sites involved. Pemphigus exacerbation was associated with the onset of other symptoms, including a progressive dysphagia, weight loss, and melena. A periodic re-assessment of serum autoantibody concentration also indicated a significant increase in both anti-Dsg1 and anti-Dsg3 antibody titers. An endoscopic examination of the distal esophagus indeed revealed a stenosing esophageal mass; a PET/CT scan confirmed the presence of a lesion 3 cm in diameter, highlighting metabolic activity areas corresponding only to tumor location, without nodal or distant metastasis (Figure 1). Previously, the chest RX and abdominal ultrasound conducted as screening for immunosuppressive treatments 2 years before were unremarkable, as well as the routine blood tests performed at that time.
The Gastrointestinal Surgery Unit opted for endoscopic resection of the tumor. In order to rule out paraneoplastic pemphigus (PNP), blood samples were collected for indirect immunofluorescence (IIF) on rat bladder and normal human skin and immunoblot for anti-plakin and anti-desmocollin autoantibodies, which resulted negative (Figure 2; Supplementary Figures 1-3).
Before the surgical intervention, delayed due to the COVID-19 outbreak, PV was managed with two cycles of intravenous immunoglobulins (IVIg, 2 g/kg per cycle) 4 weeks apart. The prolonged treatment with systemic steroids before major surgical interventions is associated with a significant risk of surgical complications; thereby, systemic steroids were not administered. After two cycles of IVIg treatment, the PDAI score remained stable.
The patient underwent robot-assisted Ivor-Lewis esophagectomy with latero-lateral anastomosis and jejunostomy feeding tube (J-tube) placement. Tissue perfusion and esophagogastric anastomosis evaluation with the indocyanine green method were performed. After the surgery, the patient achieved early mobilization, with no signs of anastomotic leak at endoscopies and CT scan. The post-operative course was uneventful, except for an episode of atrial fibrillation, which was managed with two subsequent doses of verapamil according to the advice of the cardiologist. The patient was then discharged on post-operative day 11, with no dysphagia nor nausea reported. The histopathologic examination of the esophageal mass confirmed the diagnosis of gastric cardia adenocarcinoma.
Despite the successful surgical management of the tumor, PV continued to worsen, with blisters and erosions affecting the entire body, except for mucosal sites and feet (Figure 3).
Considering the recommendation to avoid high-dose systemic steroids also after surgery, due to the risk of anastomotic leakage, the patient was managed with 4 weekly infusions of rituximab at a dose of 500 mg (lymphoma protocol). A moderate-dose systemic steroid therapy (prednisone 0.6 mg/kg/day) was started only 2 weeks later in concomitance with the end of the national lockdown.
The skin of the patient started improving progressively, with complete resolution of the lesions. The anti-DSG1 and anti-DSG3 titers likewise decreased progressively (Figure 4).
At the 4-month dermatologic follow-up, only post-inflammatory hyperpigmentation or hypopigmentation was detectable, with no active lesions (Figure 3), while the last enzyme-linked immunosorbent assay (ELISA) performed resulted in lower anti-desmoglein autoantibody concentrations. No surgery-related criticalities or tumor recurrences were highlighted during this period.