DOI: https://doi.org/10.21203/rs.3.rs-2079952/v1
Background：
Recent evidence suggests that immunotherapy is a standard treatment options in gastric cancer. However, immunotherapy may cause many known or unknown adverse events.
Case presentation:
We recently encountered a case of subcutaneous fat necrosis without pancreatic disease that arose during therapy with pembrolizumab in a patient with metastatic gastric cancer. And subcutaneous nodules started to spontaneously improve within a month of onset and disappeared within half a year with no special treatment. At the last follow-up, the patient did not receive immunotherapy with continuous stable disease. Her survival exceeded 24 months without other treatment.
Conclusion:
This case may be important for the discovery of rare adverse events in gastric cancer immunotherapy.
Immune checkpoint inhibitors (ICIs) blocking appeared to greatly improve the treatment outcome of various advanced cancer types. Nonetheless, there remain some challenges associated with systemic side effects. Immune-related adverse events may occur in any organ system, and there are numerous dermatologic toxicities associated with PD-1 inhibitors, including maculopapular exanthems, pruritus, lichenoid dermatitis, eczema, vitiligo-like leukoderma, bullous pemphigoid, granulomatous disorders, and severe cutaneous adverse reactions.
Subcutaneous fat necrosis, also referred to as pancreatic panniculitis, is a rare disorder associated with pancreatic diseases [1–3]. Clinically, it presents as subcutaneous nodules or masses that typically occur on the breasts, buttocks, or extremities. We recently encountered a case of subcutaneous fat necrosis without pancreatic disease that arose during therapy with pembrolizumab, a programmed cell death-1 (PD-1) inhibitor, in a patient with metastatic gastric cancer.
A 72-year-old female with a history of metastatic gastric adenocarcinoma who was treated with S1 and pembrolizumab for 2 months presented with multiple subcutaneous nodules on her legs with an average size of 0.5-1 cm. These nodules were mildly tender. She had no associated systemic symptoms and no pre-existing trauma, surgery, or irradiation to these sites. On physical examination, multiple normal, skin-colored, irregular, slightly sensitive subcutaneous nodules were dispersed over the two lower limbs. Pelvic computed tomography (CT) showed several fat masses involving her pelvis and the two lower limbs (Fig. 1). However, a pathologic review of biopsy results from the right thigh nodule demonstrated fat necrosis with no evidence of tumor (Fig. 2). We found no evidence of pancreatic disease on the CT scan. No special treatment. And nodules started to spontaneously improve within a month of onset and disappeared within half a year. At the last follow-up, the patient did not receive immunotherapy with continuous stable disease. She survived for over 24 months with no further treatment.
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
programmed cell death-1
computed tomography
immune checkpoint inhibitors
Acknowledgments
The authors thank all patients who participated in the present study.
Consent for publication
Not applicable.
Funding
This study was funded by the 2021 China Anti-Cancer Association-HengRui Anti-angiogenesis Targeted Tumor Research Fund (Grant No. 7).
Competing interests
The authors declare the submitted work was not carried out in the presence of any personal, professional, or financial relationships that could potentially be construed as a conflict of interest.
Ethics approval
Not applicable.
Patient anonymity and informed consent
Written informed consent was obtained from the patient for publication of this report and the accompanying images, and the patient’s anonymity was upheld.
Authors' contributions
RL was responsible for the final decision and submission. SZ and LS provide administrative, technical and material support. LS write the manuscript. All the authors participated in revising it critically and approved the final version to be submitted.
Availability of data and materials
All data supporting the conclusions of this study are included in this published article.