Razmara Aryana M, Wittenburg Luke A, Al-Nadaf Sami, Toedebusch Ryan G, Meyers Frederick J, Toedebusch Christine M
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
UCD Comprehensive Cancer Center, Sacramento, CA, United States.
Front Oncol. 2022 May 27;12:868004. doi: 10.3389/fonc.2022.868004. eCollection 2022.
Central nervous system (CNS) involvement is the leading cause of death in malignant melanoma. Rodent models, while vital to mechanistic investigation, have had limited success identifying effective therapies for melanoma brain metastases. The companion dog with melanoma is a promising complementary model for developmental therapeutic investigation, as these tumors occur in an immunologically outbred host that has shared environmental exposures with humans. However, relatively little is known regarding the prevalence and clinicopathological features of canine melanoma metastasis to the CNS. To further validate the dog as an appropriate model for human metastatic melanoma, the aims of this study were to determine the rate of CNS metastasis and associated clinicopathologic features in canine malignant melanoma.
Medical records of dogs diagnosed with malignant melanoma from 1985-2019 at the University of California Davis Veterinary Medical Teaching Hospital were assessed retrospectively. Clinicopathologic features were compared between dogs with CNS metastasis (CNS+) and dogs without CNS metastasis (CNS-). Site of CNS involvement and associated neurological signs were analyzed Wilcoxon-Mann-Whitney rank sum and Fisher's exact tests. Survival data were analyzed Kaplan-Meier estimates.
CNS metastasis was identified in 38% of dogs in this study (20/53). The oral cavity was the most common site of primary melanoma in both groups [CNS+: n=12 (60%) vs. CNS-: n=22 (67%); p>0.99]. The total burden of metastatic disease was higher in the CNS+ group (CNS+: 4, 95% CI 3-5 vs. CNS-: 3, 95% CI 1-3; p<0.001). The cerebrum was the most common site of CNS metastasis (n=15, 75%) and seizures were the most observed neurological sign (n=9, 64%). There was no difference in overall survival between CNS+ and CNS- groups. However, the median survival time following onset of neurological signs was 9.5 days (95% CI 1-43), with 5 dogs euthanized within 24 hours of the onset of neurological signs.
Canine and human MM patients share similar rates of CNS metastasis and clinical presentation. This study will guide clinical management of canines with malignant melanoma and inform future studies using dogs with spontaneously occurring melanoma as a preclinical model for human melanoma brain metastases.
中枢神经系统（CNS）受累是恶性黑色素瘤死亡的主要原因。啮齿动物模型虽然对机制研究至关重要，但在确定黑色素瘤脑转移的有效治疗方法方面成效有限。患有黑色素瘤的伴侣犬是发育性治疗研究的一种有前景的补充模型，因为这些肿瘤发生在与人类有共同环境暴露的免疫远交宿主中。然而，关于犬黑色素瘤转移至中枢神经系统的患病率和临床病理特征，人们了解得相对较少。为了进一步验证犬作为人类转移性黑色素瘤的合适模型，本研究的目的是确定犬恶性黑色素瘤中枢神经系统转移的发生率及相关临床病理特征。
回顾性评估1985年至2019年在加利福尼亚大学戴维斯分校兽医医学教学医院诊断为恶性黑色素瘤的犬的病历。比较有中枢神经系统转移（CNS+）的犬和无中枢神经系统转移（CNS-）的犬的临床病理特征。采用Wilcoxon-Mann-Whitney秩和检验和Fisher精确检验分析中枢神经系统受累部位及相关神经症状。采用Kaplan-Meier估计法分析生存数据。
本研究中38%（20/53）的犬出现中枢神经系统转移。两组中口腔都是原发性黑色素瘤最常见的部位[CNS+组：n = 12（60%），CNS-组：n = 22（67%）；p > 0.99]。CNS+组转移疾病的总负担更高（CNS+组：4，95%可信区间3 - 5；CNS-组：3，95%可信区间1 - 3；p < 0.001）。大脑是中枢神经系统转移最常见的部位（n = 15，75%），癫痫是最常见的神经症状（n = 9，64%）。CNS+组和CNS-组的总生存期无差异。然而，出现神经症状后的中位生存时间为9.5天（95%可信区间1 - 43），5只犬在出现神经症状后24小时内实施安乐死。
犬和人类恶性黑色素瘤患者中枢神经系统转移率和临床表现相似。本研究将指导犬恶性黑色素瘤的临床管理，并为未来将自发发生黑色素瘤的犬作为人类黑色素瘤脑转移的临床前模型的研究提供信息。
