Page 710 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

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Hematopoietic Tumors

SECTION A: CANINE LYMPHOMA AND Genetic and Molecular Factors
LYMPHOCYTIC LEUKEMIAS Advances in molecular cytogenetics (see Chapter 1, Section A),
including array-comparative genomic hybridization and chromosome
painting, have been and are currently being applied to investigations
DAVID M. VAIL, MARIE PINKERTON, AND of chromosomal aberrations in dogs with lymphoma. 12–18 Publica-
KAREN M. YOUNG tion of the canine genome and commercial availability of canine gene
microarrays (GeneChip Canine Genome 2.0 Array, Affymetrix, Inc.)
Lymphoma have led to advances in our understanding of deregulations of gene
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expression occurring in lymphoma. Gains of canine chromosomes
Lymphoma (malignant lymphoma or lymphosarcoma) comprises 13 and 31 and loss of chromosome 14 have been documented as the
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a diverse group of neoplasms that have in common their origin most common aberrations in a group of 25 cases analyzed. Chro-
from lymphocytes. The neoplasms usually arise in lymphoid tis- mosomal aberrations have also been associated with prognosis in dogs
sues such as lymph nodes (LNs), spleen, and bone marrow; how- with lymphoma. A study of 61 dogs with lymphoma demonstrated a
ever, they may arise in almost any tissue in the body. Although prognostic advantage in dogs with trisomy of chromosome 13 (25%
the annual incidence of lymphoma is difficult to predict in the of the dogs studied), as evidenced by increase in duration of first remis-
absence of a national canine tumor registry, it is clear that it rep- sion and overall survival time (ST). Germline and somatic genetic
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resents one of the most common neoplasms seen in the dog. The mutations and altered oncogene/tumor suppressor gene expression,
annual incidence has been estimated to range between 13 and epigenetic changes (e.g., DNA hypomethylation), signal transduc-
114 per 100,000 dogs at risk. The rates at specific ages are esti- tion, and death-pathway alterations (e.g., Bcl-2 family) are common
mated to be 1.5 per 100,000 for dogs less than 1 year of age in human lymphomas and have been reported in the dog as well (see
and 84 per 100,000 for dogs 10 to 11 years old. 1–4 Lymphoma Chapter 1, Section A, and Chapter 15, Section B). 21–25 These include
comprises approximately 7% to 24% of all canine neoplasias and N-ras, p53, Rb, p16 cyclin-dependent kinase, telomerase, and NF-κB
5,6
83% of all canine hematopoietic malignancies. In a review of among others. 22,26–31 Somatic mutations, as determined by exome
the Veterinary Medical Database Program (VMDP) at Purdue sequencing, have shown much overlap in canine breeds with respect
University from 1987 to 1997, the frequency of dogs presented to B-cell lymphoma, specifically mutations in TRAF3-MAP3K14,
with lymphoma to 20 veterinary institutions increased from FBXW7, and POT1, but little overlap in somatic mutations among
0.75% to 2.0% of total case load, and it appears the frequency breeds with T-cell lymphoma. In addition, differences in the preva-
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is continuing to increase. A similar trend is present in physician- lence of immunophenotypic subtypes of lymphoma among different
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based oncology; non-Hodgkin’s lymphoma (NHL) represents 5% breeds indicate heritable risks. Telomerase activity (see Chapter 2)
of all new cancer cases, the fifth leading cause of cancer death, has also been documented in canine lymphoma tissues. 33–35 As
and the second fastest growing cancer in terms of mortality in somatic mutations are often implicated, it is not surprising that
humans. Middle-aged to older (median age of 6–9 years) dogs alterations or deficiencies in DNA repair mechanisms would also
7
are primarily affected, although dogs with T-cell lymphoma tend be implicated, as has been demonstrated in golden retrievers with
8
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to be younger. A decreased risk for lymphoma is reported for lymphoma.
intact females. Breeds reported to have a higher incidence include
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boxers, bullmastiffs, basset hounds, St. Bernards, Scottish terriers, Infectious Factors
Airedales, pitbulls, Briards, Irish setters, Rottweilers, and bulldogs; The hypothesis that a retrovirus may be involved in the pathogen-
breeds at lower risk include dachshunds and Pomeranians. 8,10,11 esis of canine lymphoma has not been confirmed. Epstein–Barr
See Box 33.1. virus, a gammaherpesvirus linked to some forms of lymphoma in
humans, has also been investigated in canine lymphoma; however,
Etiology there was no association between serologic or molecular detection
of gammaherpesvirus and development of lymphoma. 37,38
The etiology of canine lymphoma is likely multifactorial and In humans, a direct association between Helicobacter sp. infec-
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largely unknown; however, investigations are currently shedding tions and development of gastric lymphoma has been made.
significant light on the subject. Although this has not been definitively shown in dogs, there is

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