3 Discussion
Liver cancer, one of the fatal cancers worldwide, is often treated with surgery, chemoembolization and chemotherapy1. Sorafenib and lenvatinib are first-line chemotherapy agents for the treatment of hepatocellular carcinoma. However, owing to their unsatisfactory results and numerous adverse side effects, many other chemotherapeutic drugs have been investigated to treat this disease2. Apatinib mesylate is a novel tyrosine kinase inhibitor (TKI) launched and approved in China in 2014. It can efficiently and competitively bind to vascular endothelial growth factor receptor-2 (VEGFR2), which inhibits angiogenesis in tumors and inhibits tumor growth and progression3.
As previously described, VEGFR TKIs have promising therapeutic efficacy for multiple tumors. However, a few skin toxicities have also been elucidated in the literature. In 2015, Massey et al. has revealed that HFS, rash and pruritis were significantly associated with VEGFR TKIs with the incidence of 0-37%, 13-41% and 14%, respetively4. Other cutaneous side effects include alopecia, pigmentation, depigmentation, xeroderma, ulcer and erythema multiforme have been reported as well4,5. The management of these lesions could refer to previous reviews6,7. In terms of apatinib, commonly reported side effects of apatinib to include hematologic toxicity, proteinuria, hypertension, fatigue, nausea, vomiting et al.8. Regarding cutaneous lesions, the hand-foot syndrome (HFS) is the most common skin reaction, which may result in a 50.5% incidence5. Moreover, some cases have reported skin pigmentation, rashes, and BP induced by apatinib9,10.
There was only one case reporting that a 62-year-old female patient developed drug-induced BP (DIBP) after taking apatinib (0.5 g/d) for two weeks for breast cancer. In the present case, the patient developed erythema and multiple bullae on the entire body after 10 days of apatinib treatment. The Naranjo score (a tool used to assess the possibility of drug-induced adverse reactions) was 7, which indicated a probable adverse drug reaction of apatinib mesylate. Combined with skin biopsy and DIF, apatinib-induced BP was diagnosed. The therapeutic effect of methylprednisolone was significant. Clinical differential diagnoses at the time of presentation included paraneoplastic pemphigus (PNP). PNP is a rare, autoimmune disease associated with neoplasm. Because the clinical features of PNP are polymorphous, it is sometimes difficult to distinguish it from other bullous diseases. Histopathological examination demonstrated suprabasal acantholysis and dyskeratosis, while DIF demonstrated intercellular IgG and/or C3 deposition in the epidermis, with positive IIF11. However, the clinical and pathohistological findings of this patient didn’t conform to PNP, thus, the diagnosis of BP induced by apatinib was finally made.
In fact, subepithelial autoimmune bullous dermatosis is a disease spectrum that includes inherited and acquired bullous skin disorders, such as BP, linear IgA bullous dermatosis, and lichen planus pemphigoid. They can be induced either spontaneously or by some drugs12. In our case, BP was indicated by the disruption of the basal membrane zone (BMZ) through autoantibodies. The underlying mechanism may be due to drug ingestion acting as an immunological trigger, which stimulates the hyperproduction of autoantibodies, and then the autoantibodies appear to target multiple antigens within BMZ13. Referring to treating autoimmune bullous dermatoses, the patient has been prescribed glucocorticoids as initial therapy and achieved satisfactory result14.