Gastric carcinosarcoma with FGFR2 amplification under long-term control with pazopanib: a case report and literature review | BMC Gastroenterology

Carcinosarcoma is found in organs such as the uterus, ovaries, bladder, lungs, and esophagus [2]. Gastric carcinosarcoma is an extremely rare disease, with approximately 70 cases reported in the Japanese and English scientific literature [1]. The pathogenesis of gastric carcinosarcoma remains unclear, and standard chemotherapy has not been established [2]. The prognosis is extremely poor, with an estimated mean survival time of 7–10 months [1]. We report a case of postoperative recurrence of gastric carcinosarcoma under long-term tumor control with pazopanib.

Gastric carcinosarcoma is rarely definitively diagnosed preoperatively and is usually detected based on by postoperative pathological examination findings. Gastric carcinosarcoma clinically resembles gastric adenocarcinoma and cannot be easily differentiated either endoscopically or radiologically [1]. Therefore, immunohistochemical analysis of surgical specimens is useful for obtaining a definitive diagnosis of gastric carcinosarcoma [3]. Cytokeratin AE1/AE3, carcinoembryonic antigen, epithelial membrane antigen, chromogranin A, CD56, and synaptophysin are specific markers to identify carcinomatous components, whereas desmin, vimentin, and α-smooth muscle/sarcomeric actin are specific markers to identify sarcomatous components [3]. In this case, cytokeratin AE1/AE3 was expressed in the adenocarcinoma component, and vimentin was expressed in the sarcoma component. Therefore, gastric carcinosarcoma was diagnosed.

No standardized chemotherapy has been established for gastric carcinosarcoma. Some studies have described the effects of chemotherapy, although few studies have shown satisfactory results [4,5,6,7]. We selected pazopanib, which has been approved for treating patients with metastatic soft tissue sarcoma. After chemotherapy for gastric cancer was ineffective, the patient was switched to treatment for the sarcoma. Doxorubicin was initially considered; however, because of the patient’s advanced age and decreased wall motion in the cardiac apex, which indicated a decreased myocardial reserve, we decided to use pazopanib, which is generally used after the second-line treatment and is considered to be better tolerated than chemotherapy. Pazopanib is a second-generation small-molecule tyrosine kinase inhibitor with high affinity against vascular endothelial growth factor receptor-1/2/3; and lower affinity against platelet-derived growth factor receptor-α/β, FGFR-1/2, and stem cell factor receptor [8]. The PALETTE trial showed a significantly prolonged progression-free survival (4.6 months for patients receiving pazopanib versus 1.6 months for patients receiving placebo) in patients with metastatic soft tissue sarcoma [8]. In this case, the sarcoma component constituted the majority of the tumor and had features of numerous nuclear mitoses that was indicative of high malignancy and strong proliferative potential. This suggests that chemotherapy targeting sarcoma components may be effective and that pazopanib is a suitable treatment.

With the advent of next-generation sequencers, genomic profiling tests for rare cancers have become popular in recent years. In our case, a genomic profiling test with the OncoGuide™ NCC Oncopanel System was performed using liver specimens after the patient became refractory to chemotherapy. Liver specimens selected as recurrent lesions may contain more accurate genetic information of the tumor at the time of pazopanib initiation than the primary lesions do. Abnormalities were identified in five cancer-related genes. Among these, a 23.66-fold amplification of FGFR2 was identified. Several preclinical models have indicated that abnormalities in FGFR may contribute to carcinogenesis [9,10,11]. FGFR amplification often leads to the overexpression of the protein, thereby causing increased accumulation of receptors and activation of downstream signaling pathways. Kim et al. reported that the treatment of gastric cancers with FGFR2 amplification with pazopanib resulted in a significant decrease in cell survival, while the same treatment showed no growth inhibitory effect on gastric cancers without FGFR2 amplification [12]. In addition, FGFR is structurally homologous with VEGFR, PDGFR, and other tyrosine kinase receptors, and each receptor has complementary and overlapping functions in promoting angiogenesis. Treatment with a multi-tyrosine kinase inhibitor could target each receptor, potentially leading to synergistic effects [10]. In conclusion, pazopanib, which is the only FGFR inhibitor for the treatment of sarcoma that is covered by insurance in Japan, may be effective against the carcinoma component of gastric carcinosarcoma with FGFR2 amplification.

Although other genetic abnormalities, such as AKT3 N127D, NOTCH1 A2036T, and POLD1 M161I, may also be involved in carcinogenesis, their significance is unclear. TP53:R209 is considered as a loss-of-function mutation. p53 can activate DNA repair genes or induce apoptosis in the presence of DNA damage. However, treatment for the loss of p53 tumor suppressor function is not common.

Although there is currently no established chemotherapy for gastric carcinosarcoma, pazopanib may be an effective treatment option for carcinosarcoma with highly malignant sarcoma components. Furthermore, consideration of therapeutic agents based on genetic profiling tests is essential for the effective treatment of gastric carcinosarcoma.

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