To our knowledge, there are only 2 cases of fat necrosis associated with these agents that are reported in the literature that similarly manifested on the bilateral lower extremities, however, imaging results or histologic images and survival data were not presented in that two article [4, 5].
In our case, the subcutaneous nodules were thought to develop during the treatment with chemotherapy and immunotherapy. Subcutaneous fat necrosis as a paraneoplastic discovery has been described in association with pancreatic diseases but it is not typically seen in patients on PD-1 inhibitor treatment or with chemotherapy. We think the PD-1 inhibitor, or both, to the combination regimen of pembrolizumab and S1 may have contributed to the pathogenesis of subcutaneous fat necrosis in this patient. Chemical agents can improve many apoptotic pathways resulting in an increased risk of treatment necrosis. The realm of immunotherapy is relatively new and all related toxicities especially in combination with conventional chemotherapy are still being elucidated. Fat necrosis may be diagnosed clinically, confirmed with biopsy of the adipose tissue, and considered a common terminology criterion for adverse events (CTCAE) grade 1 skin toxicity. The concurrent use of PD-1 inhibitor therapy with conventional chemotherapy may present novel toxicities that are not yet reported in the literature. Interestingly, this patient had immune-linked skin toxicity when anti-tumor treatment was effective, and the patient did not have any special treatment. The nodules started to improve spontaneously one month after onset and disappeared within half a year. Even more surprising, this patient achieved long-term survival, so it is currently unclear whether subcutaneous fat necrosis during immunotherapy predicts a better prognosis.
Recognition of this novel and rare reaction is important, as it may be mixed with metastatic disease or other adverse events that occurred during PD-1 inhibitor treatment, affecting our treatment of the disease. Histopathology, including fascial biopsy, should be obtained to establish an accurate diagnosis and rule out metastatic disease. Although the relationship between anti–PD-1 therapy and subcutaneous fat necrosis is unclear, it may result from inflammatory panniculitis. The use of PD-1 therapy is increasingly prevalent; therefore, we suggest awareness of these clinical outcomes, and further studies are needed to confirm