Prevalence and Clinicopathologic Features of Canine Metastatic Melanoma Involving the Central Nervous System: A Retrospective Analysis and Comparative Review

Abstract

Background: 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 de novo 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.

Methods: 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 via Wilcoxon-Mann-Whitney rank sum and Fisher's exact tests. Survival data were analyzed via Kaplan-Meier estimates.

Results: 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.

Conclusions: 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.

Keywords: brain; canine; central nervous system; large-animal model; malignant melanoma; seizure.

Figure 1

Distribution, age, and primary tumor characteristics of dogs with malignant melanoma. (A) Distribution of dogs with central nervous system (CNS) metastasis of malignant melanoma at the time of necropsy. (B) Median age at diagnosis was similar between groups. Primary tumor (C) distribution and (D) diameter were similar between CNS+ and CNS- dogs (primary tumor site was not determined for 2 CNS+ dogs). Comparisons based on Wilcoxon-Mann-Whitney rank sum test.

Figure 2

Clinicopathologic features of canine malignant melanoma. CBC and chemistry panel data were available for comparison between CNS+ (n=7) and CNS- (n=16) dogs. (A) The median neutrophil count was higher in CNS+ dogs (p= 0.015). (B) Neutrophil to lymphocyte ratios were not different between groups (p= 0.579). (C) The median platelet count for CNS+ dogs was higher than CNS- dogs (p= 0.018). No differences were observed in (D) serum calcium (p=0.299) or (E) albumin (p=0.077) between groups. Dashed lines represent hospital normal reference ranges. Comparisons based on Wilcoxon-Mann-Whitney rank sum test. *p<0.05.

Figure 3

Total burden of CNS and extra-CNS metastases in dogs with malignant melanoma. (A) The metastatic burden scoring system comprised the number of 1) metastases and 2) organs affected. (B) The median metastatic burden score was higher in CNS+ (n=19) dogs (p=0.0014). One CNS+ dog did not have an extra-neural post-mortem examination and therefore could not be assigned a score. Comparison based on Wilcoxon-Mann-Whitney rank sum test. **p<0.01.

Figure 4

Neurological signs and CNS disease burden. (A) Of the 20 CNS+ dogs, 14 developed neurological signs prior to humane euthanasia or death. (B) Elapsed time between the initial diagnosis of melanoma and the onset of neurologic signs (n=11). (C) Of those that developed neurological signs, the most common initial sign noted was seizures, followed by paresis, postural reaction deficits, mentation change, and cranial nerve neuropathy. (D) Although location of CNS metastases varied among CNS+ dogs, the cerebrum was the most common site of metastases. Location of metastases were similar between dogs with and without neurological signs (cerebrum p=0.642; brainstem p=0.521, spinal cord p=0.999). (E) The number of CNS metastases between dogs with and without neurological signs was not different (1, p=0.161; 2-4, p=0.613; 5-7, p=0.521; 8-10 and > 10, p= 0.999). Comparisons were made by two-tailed Fisher’s Exact tests.

Figure 5

Treatment modalities utilized in dogs with melanoma. (A) Percentage of dogs treated with each modality, either alone or in combination, was similar between dogs that developed CNS metastasis and those that did not. (B) The median number of treatment modalities was not significantly different between groups (p=0.263). Comparison based on Wilcoxon-Mann-Whitney rank sum test. Chemo, cytotoxic chemotherapy; Palliative RT, palliative radiation therapy; Immune, immunotherapy (i.e., melanoma vaccine).

Figure 6

Kaplan-Meier estimates for (A) interval between initial diagnosis of malignant melanoma to euthanasia in CNS+ and CNS- dogs, demonstrating no significant difference in median survival (p=0.580). Dogs with unknown dates of diagnosis and dogs who exhibited signs prior to diagnosis were excluded. (B) The interval between onset of neurological signs to humane euthanasia was 9.5 days (n=14). Comparisons in survival made by Mantel-Cox Log-rank analysis.