Page 711 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 33 Hematopoietic Tumors 689

• BOX 33.1 Key Clinical Summary Points: Canine Immunologic Factors
Lymphoma Impaired immune function has also been implicated in dogs with
lymphoma. Immune system alterations, such as immune-medi-
VetBooks.ir • Lymphoma is a catch-all term for approximately two dozen lymphocyte ated thrombocytopenia, independent of age and sex, have been
associated with a higher risk of subsequently developing lym-
cancer subtypes (Table 33.1).
• Most are intermediate or high grade, but indolent forms exist. phoma compared with the normal population. 54,55 Additional
• Dogs with lymphoma most commonly have peripheral lymphadenopathy, evidence comes from observations in human and feline transplan-
although varied anatomic locations can be affected (Box 33.2). tation patients. 56–58 In a case-control study of cats undergoing
• For nodal disease, needle aspirate cytology is a good first screening renal transplant, 24% of cases developed cancer (36% of those
step; ancillary diagnostics are required to subtype for prognosis or to were lymphoma) while on cyclosporine immunosuppressive ther-
confirm diagnosis in equivocal cases (Figs. 33.3, 33.8).
• Many treatment protocols exist, but most involve CHOP-based apy compared with 5.1% of control cats, none of which developed
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combination chemotherapy (Table 33.4). lymphoma (OR, 6.1; p = 0.001). A case of lymphoma develop-
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• Initially gratifying to treat, as response rates are high and often durable ing in a dog after treatment with cyclosporine also exists. One
(>6 months); however, cures are rare (<10%) and it is ultimately a report suggests an association between the immunodysregulation
uniformly fatal disease. observed in dogs with atopic dermatitis and the risk of developing
• Dogs with indolent subtypes may live years, often without therapeutic epitheliotropic T-cell lymphoma; whether lymphoma is associated
intervention. with the primary disease or the immunomodulatory treatments
• A veterinary oncology specialist should be consulted on individual cases, commonly applied is unknown.
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as the clinical, diagnostic, and therapeutic landscape changes rapidly.
Classification and Pathology
evidence of Helicobacter sp. infection in laboratory beagle dogs Classification of malignant lymphoma in dogs is based on ana-
resulting in gastric lymphoid follicle formation that is considered tomic location, histologic criteria, and immunophenotypic char-
a precursor of mucosa-associated lymphoid tissue (MALT) lym- acteristics. The most common anatomic forms of lymphoma, in
phoma in humans. 40 order of decreasing prevalence, are multicentric, gastrointestinal
Alterations in the gut microbiome have been implicated as (GI), mediastinal, and cutaneous forms. Primary extranodal
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playing a role in susceptibility to certain tumors. Fecal microbiota forms, which can occur in any location outside the lymphatic sys-
of dogs with lymphoma have been shown to be significantly dif- tem, include the eyes, skin, central nervous system (CNS), bone
ferent than control dogs, although a cause–effect relationship is marrow, bladder, heart, and nasal cavity. The pathologic charac-
41
unclear. teristics of the various anatomic classifications will be discussed in
this section and clinical characteristics will be described in subse-
Environmental Factors quent sections.
In humans, evidence has accumulated implicating phenoxyacetic More than 80% of dogs with lymphoma are presented with
acid herbicides, in particular 2,4-dichlorophenoxyacetic acid (2, the multicentric form, which is usually characterized by the pres-
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4-D), in the development of NHL. Some epidemiologic evidence ence of peripheral lymphadenopathy (Fig. 33.1). The alimen-
also implicates lawn herbicide use and occurrence of lymphoma tary form of lymphoma is much less common, accounting for 5%
incidence in dogs. 42–45 In one case-control study, the risk of canine to 7% of all canine lymphomas. Primary GI lymphoma in dogs
lymphoma was reported to rise two-fold (odds ratio [OR] = 1.3) may occur focally, but more often affects multiple segments with
with four or more yearly owner applications of 2,4-D. The results of thickening of the wall, narrowing of the lumen, and frequently
this study have come under criticism, and three additional follow-up mucosal ulceration. 61,62 Histologically, there is infiltration of neo-
investigations have not validated this increased risk. 46–48 In another plastic lymphocytes throughout the mucosa and submucosa with
study, dogs exposed to lawn treatment within 7 days of application occasional transmural infiltration. Liver and local LNs are often
were greater than 50 times more likely to have 2,4-D urinary levels secondarily involved. Lymphocytic-plasmacytic inflammatory
of 50 μg/L or higher. In an environmental case-control study per- bowel disease (LP-IBD) can be seen adjacent to or distant from
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formed in Europe, two variables, residency in industrial areas and the primary tumor. Pathologically, some of these neoplasms may
use of chemicals (defined as paints or solvents) by owners, mod- resemble plasma cell tumors and aberrant production of immu-
estly increased the risk of developing lymphoma; however, no link noglobulins may occur. Histologically, distinguishing between GI
was found with pesticide use. A more recent epidemiologic study lymphoma and LP-IBD can be difficult. Some have suggested that
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investigating multiple environmental factors showed increased risk LP-IBD may be a prelymphomatous change in the GI tract. A
of canine lymphoma with use of lawn care products, in particular syndrome of immunoproliferative intestinal disease characterized
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professionally applied pesticides. This study did not find an asso- by LP-IBD has been described in Basenjis, which subsequently
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ciation with flea and tick control products. develop GI lymphoma. In addition, plasma cell–rich areas with
A weak association between lymphoma in dogs and exposure heterogeneous lymphomatous infiltration may resemble lesions
to strong magnetic fields was observed in a preliminary epidemio- of LP-IBD. Only a few reports specifically identify the immuno-
logic study. In this hospital-based case-control study, the risk phenotype of the lymphocyte subpopulations in GI lymphoma
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of developing lymphoma with high or very high exposure was in dogs. Historically, it was presumed that they most likely origi-
increased (OR = 1.8). More thorough studies are necessary to eval- nate from B cells; however, recent evidence suggests that most GI
uate this association further. Proximity to environmental waste lymphomas in dogs arise from T cells and often exhibit epith-
was implicated in two European studies; however, it was felt to be eliotropism. 62,64,65 The boxer and Shar-pei breeds may be over-
a risk indicator rather than a risk factor and would require further represented in cases of alimentary lymphoma. 65,66
case-control investigations. 51,52 Exposure to tobacco smoke was The mediastinal form of the disease occurs in approximately
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also implicated in one study. 5% of cases. This form is characterized by enlargement of the