Hope for Diagnosing and Treating Histiocytic Malignancies in Dogs

01/06/2020
Author: Sharon M. Albright, DVM, CCRT

Histiocytic malignancies (HM), also known as histiocytic sarcoma or malignant histiocytosis, represent an aggressive form of cancer seen most frequently in Bernese Mountain Dogs (BMD) and Flat-Coated Retrievers (FCR). HM is also found in Golden Retrievers, Labrador Retrievers, Rottweilers, and other breeds, including mixed breeds. While rare in the general dog population, HM is devastating for these more commonly affected breeds, accounting for up to 60% of splenic tumors in Flat-Coated Retrievers and up to 64% of all malignancies in the BMD.

 

Histiocytic Malignancies

Histiocytes are cells of the immune system that differentiate into macrophages, which engulf antigens, or dendritic cells, which present antigens to T cells.

Flat-Coated Retrievers typically present with localized disease, limited to an extremity or within a single organ such as the spleen.

Bernese Mountain Dogs typically present with the disseminated form of the disease, exhibiting multiple tumors involving the spleen, lung, liver, and abdominal lymph nodes.

Scientists believe these may be early and late forms of the same disease.

The prognosis for affected dogs is poor, with a median survival time of less than six months, even with multi-modal treatment. The AKC Canine Health Foundation (CHF) and its donors are dedicated to improving outcomes for dogs affected by HM. Thanks to recent advances in genetic technology, CHF-funded researchers are making exciting discoveries that may improve diagnostic and treatment options for this aggressive cancer.

Clinical signs of HM are non-specific and include fever, weight loss, inappetence, lethargy, and possibly a visible mass. These symptoms are also seen with other common cancers such as lymphoma and hemangiosarcoma. Since the treatment strategies and prognoses for these cancers are very different, it is critical to get an accurate diagnosis as soon as possible in order to maximize a dog’s chances for a positive outcome.

With funding from CHF Grant 01557: Narrowing the Search for the Genetic Basis of Histiocytic Malignancies, investigators at North Carolina State University examined the genetic characteristics of HM in dogs. Their results were recently published in Chromosome Research2 and confirm that HM is a complex disease with changes throughout the genome such as:

  • Extensive copy number alterations on two canine chromosomes. Copy number alterations are a type of structural variation in the genome caused by duplications or deletions and result in an abnormal number of one or more genes. The genetic alterations found in canine HM are deletions of tumor suppressor genes, resulting in more tumors.
  • Increased expression of matrix metallopeptidase 9 (MMP-9) gene and protein levels. MMP-9 is involved in tumor progression and metastasis in human cancer and may contribute to the aggressive nature of HM in dogs.
  • Wide variation in the number of chromosomes present in cells from the same and different tumors. Such variety may explain why treatment response is so poor – any one treatment may not eliminate 100% of the cancerous cells.

One promising finding from this research is that the copy number alterations noted above were unique to HM and could differentiate HM from lymphoma and hemangiosarcoma with great accuracy.  Investigators will continue to examine these unique genetic properties to create a rapid and accurate diagnostic test for HM. Funding from CHF grant 02446: Development of Genetic Biomarkers to Improve Diagnosis and Treatment of Canine Histiocytic Sarcoma will contribute to this work as investigators at the University of Rennes in France develop a blood test to accurately diagnose HM and see if earlier diagnosis and targeted treatment selection do, in fact, improve the prognosis for affected dogs.

 

One Health Implications

Canine histiocytic malignancies are most commonly compared to human sarcomas that arise from the histiocytic or dendritic cell lines. Similar to canine HM, these cancers are rare in people, making up less than one percent of all tumors originating in the blood or lymphoid tissue, and carry a poor prognosis. Because of their rarity in people, they are not well-studied and offer little insight into the diagnostic and treatment challenges of canine HM. However, advances in genetic technology may help close this gap. Recent genomic data suggest that canine HM may originate from macrophage cell lines and not dendritic cell lines. As research continues and scientists better understand the molecular characteristics of canine HM, they can more accurately compare it to comparable human cancers and collaborate with human oncology researchers to improve outcomes for both affected dogs and people.



Understanding how and why this cancer is so aggressive will hopefully result in more accurate diagnostic tests and more effective and targeted treatments. This research, as part of CHF’s extensive canine cancer research portfolio, will impact the health of all dogs affected by cancer.

Support canine cancer research at akcchf.org/cancer.

 

References:

  1. Kennedy, K., Thomas, R., & Breen, M. (2016). Canine Histiocytic Malignancies—Challenges and Opportunities. Veterinary Sciences3(1), 2. https://doi.org/10.3390/vetsci3010002
  2. Kennedy, K., Thomas, R., Durrant, J., Jiang, T., Motsinger-Reif, A., & Breen, M. (2019). Genome-wide DNA copy number analysis and targeted transcriptional analysis of canine histiocytic malignancies identifies diagnostic signatures and highlights disruption of spindle assembly complex. Chromosome Research. https://doi.org/10.1007/s10577-019-09606-0

 

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