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Canine Lymphoma

Andy H. Abbo, DVM, MS, DACVIM (Oncology), Veterinary Cancer Specialists of New England

Oncology

|
March 2016
|
Peer Reviewed

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PROFILE

Definition

  • Lymphoma is a diverse, heterogeneous disease that results from the uncontrolled clonal expansion of malignant lymphocytes. 
  • The B-cell phenotype is predominant; the remainder consists of T- or rarely NK-cell phenotypes.1

Lymphoma is generally considered a systemic disease.

Systems

  • Lymphoma is generally considered a systemic disease. 
  • Sites of origin include lymphoid-rich tissues (ie, lymph nodes, spleen, thymus, bone marrow). 
  • Extranodal sites affected may consist of epithelium, intestinal tract, and CNS. 
    • Because of the systemic nature of this disease, any tissue may be involved. 

Related Article: Rescue Therapy for Canine Lymphoma

Incidence

  • Lymphoma comprises 7% to 24% of all canine cancers; it is the most common hematopoietic cancer in dogs.2,3
  • Incidence is estimated at 13-24 per 100 000 dogs at risk.2,3
  • Incidence rate for dogs <1 year of age is 1.5 per 100 000; for dogs 10-11 years of age, incidence is 84 per 100 000.4

Geographic Distribution

  • Lymphoma is diagnosed worldwide in the canine population.

Causes

  • There is no known cause; the disease is likely multifactorial.5
  • Hypothesized but unproven causes include retroviral infection with Epstein-Barr virus–like viruses, environmental contamination with phenoxyacetic acid herbicides (2,4-dichlorophenoxyacetic acid [2,4-D]), magnetic field exposure, and immune dysfunction.5

Genetic Implications

  • Multiple genetic and molecular pathway aberrations have been noted, but none of these factors have translated into clinically relevant information. 
    • Chromosomal aberrations reported include gain of chromosome 13 and 31, as well as loss of chromosome 14.6
  • Germline and somatic mutations, altered oncogene/tumor-suppressor gene expression, and epigenetic changes have been reported.7,8
  • Immunophenotypic differences among different breeds suggest heritable risks.9

Signalment

  • Middle-aged dogs are most commonly affected, but young dogs can be affected.5
  • No sex predisposition has been reported consistently.5
  • Boxers, golden retrievers, basset hounds, Saint Bernard dogs, Scottish terriers, and mastiffs are overrepresented.5

Related Article: Cytotoxic Chemo­therapeutic Agents

Risk Factors

  • Dogs with impaired immune function are at increased risk for lymphoma.10
    • Dogs with immune-mediated diseases are at increased risk independent of age and sex.10
    • A case report of a dog that developed lymphoma following cyclosporine treatment has been reported.11
  • Infectious factors such as retroviral or Helicobacter infection may be involved though not definitive.5
  • Environmental factors include herbicides (eg, 2,4-D)12,13 and a weak association with magnetic fields.14

Pathogenesis

  • Uncontrolled, clonal, neoplastic transformation and expansion of lymphocytes not restricted to specific anatomic sites 
    • Disease progression in the lymph nodes, soft tissue, or extranodal sites leads to development of clinical signs. 
  • Other signs may be related to paraneoplastic syndromes; the most common of these are anemia,15 hypercalcemia,16 and immune-mediated thrombocytopenia.17 
    • Hypercalcemia, most commonly with T-cell variant of the disease18 

Classification is based on anatomic location, staging, histologic criteria, and immunophenotype.

Classification 

  • Classification is based on anatomic location, staging, histologic criteria, and immunophenotype.5,19 
  • The most common form of the disease is the multicentric form; this most commonly involves the peripheral nodes but may also include liver, spleen, and bone marrow. 
    • Other forms of the disease include GI (small or large bowel), mediastinal, cutaneous, and extranodal forms such as CNS, ocular, nasal, cardiac, lung, bladder, and bone. 
  • World Health Organization’s Clinical Staging System for Lymphoma5:
    • Stage I: 1 Lymph node involved or lymphoid tissue in a single organ (excluding bone marrow).
    • Stage II: Involvement of many lymph nodes in a regional area.
    • Stage III: Generalized lymphadenopathy.
    • Stage IV: Liver and spleen involved ± stage III.
    • Stage V: Bone marrow involvement or extranodal disease.
    • Substage5, 20-24
      • a: without systemic signs.
      • b: with systemic signs.

CLINICAL SIGNS

  • Patients typically are presented with a history of rapidly progressive, nonpainful, generalized lymphadenopathy ± hepatosplenomegaly.
    • Most are presented without signs of systemic illness (substage a).
  • Clinical signs may be nonspecific (eg, mild lethargy, weight loss) or may represent the organ system that is infiltrated.
    • Dogs that are clinically ill (substage b) have profound inappetence, lethargy, weight loss, vomiting, and/or diarrhea.5,20-24
    • Polyuria and polydipsia may be present in dogs with hypercalcemia of malignancy, secondary to other underlying disease or UTI.
  • Other clinical signs related to the anatomic location of the disease include:
    • Uveitis
    • Cranial abdominal enlargement
    • Dyspnea
    • Mediastinal involvement or pleural fluid
    • Regional lymph edema
    • Dermal or subcutaneous masses
    • Vomiting or diarrhea
    • Bruising
    • Pallor
    • Stridor and stertor if retropharyngeal nodes are involved

Related Article: Fine-Needle Aspiration

DIAGNOSIS

  • Complete physical examination, including rectal examination, should be performed. 
  • Complete staging before initiation of therapy is always recommended; however, in select cases, staging may not be performed in entirety because of owner financial constraints.
  • Minimum database includes CBC, serum chemistry panel, urinalysis ± urine culture if clinically indicated.
    • CBC may indicate infection that requires treatment prior to chemotherapy or cytopenia consistent with myelophthisic or paraneoplastic syndromes. 
    • Serum chemistry panel often reveals changes consistent with infiltrative disease such as:
      • Elevated ALP, ALT
      • Hyperbilirubinemia
      • Hypercalcemia
      • Azotemia
    • Urinalysis may indicate infectious cystitis that should be treated prior to initiation of chemotherapy. 
  • Three-view thoracic radiographs are recommended.
    • Mediastinal lymph node enlargement or tracheobronchial lymph node enlargement may be noted.
    • Occult pneumonia may be present.
    • Rarely, infiltrative disease (diffuse interstitial pattern) will be seen.
  • Abdominal ultrasonography is recommended if GI signs are present or if no peripheral lymphadenopathy is appreciated.
  • Echocardiography prior to doxorubicin may be recommended if patient is an at-risk breed for cardiomyopathy or if murmur or arrhythmias are noted.5,24,25 
  • Lymphoma findings may be present on examination of a bone marrow aspirate.
    • Involvement conveys a worse overall prognosis.
    • Determine if marrow reserves are sufficient for chemotherapy. 
  • Fine-needle aspiration of affected node(s) or organs should be performed.
    • Results are often adequate to obtain diagnosis, as most cases are large-cell variant; monomorphic population of small or intermediate cells may require histopathology or molecular diagnostics to further characterize.
    • The author recommends avoiding areas of high reactivity if possible (eg, mandibular nodes).
    • Cells are generally >2 times the diameter of a red blood cell or larger than neutrophils and appear as a monomorphic population.
  • Histopathology is considered the gold standard and allows for evaluation of tissue architecture.
    • It also allows for classification into low-, intermediate-, and high-grade variants, which may affect treatment and prognosis.19
    • Immunohistochemistry is provided through commercial laboratories.26
  • Molecular diagnostics may be recommended when cytology and histopathology are suggestive but confirmation or immunophenotyping is indicated.
    • PARR (PCR for Antigen Receptor Rearrangement) can determine if the majority of cells in the sample are derived from the same original clone vs multiple clones.26
      • PARR assay is 94% specific for lymphoid neoplasia; sensitivity is 75%.
      • It can be performed on blood, lymph node, bone marrow, cavity fluid, and CSF.5,26
    • Flow cytometry involves staining live cells with labeled antibodies that bind proteins expressed on the cell surface. 
      • Flow cytometry is an interpretive test and can provide additional useful information regarding prognosis and treatment.27,28
      • T-cells express CD3 (CD4 and CD8)
      • B-cells express CD21 (CD20, CD79a)
      • This can be performed on blood, lymph node, bone marrow, cavity fluid, and CSF.

Related Article: Unresponsive Alopecia in an Older Dog

Differential Diagnoses 

  • Reactive lymphoid hyperplasia
  • Systemic infection
    • Bacterial (eg, Rickettsial disease)
    • Fungal
    • Parasitic
    • Viral
  • Immune-mediated disease

Prognostic Factors

  • The prognostic factors with the most significance regarding overall survival time are phenotyping and clinical substaging.
    • Median survival times for dogs without treatment is 4-6 weeks29,30; with gold standard therapy, survival times are 1 year with 25% chance for 2-year survival.5
  • The most significant negative prognostic factors are substage b, T-cell phenotype, mediastinal location, and hypercalcemia.
    • Other negative factors include the presence of anemia, gastrointestinal location, and stage V disease (bone marrow involvement).
  • Small cell/low grade/indolent lymphomas are associated with longer survival times because of slow progression of disease but are considered less chemoresponsive.
  • Clinical staging is controversial; in general, I=II>III=IV>V.
  • Dogs with a longer initial remission generally have a better long-term outcome and often respond favorably to re-induction therapy when relapse is noted. 

TREATMENT

Chemotherapy 

  • Because of the systemic nature of disease, chemotherapy is considered the mainstay of therapy for large-cell lymphoma.
    • There are many protocols available, and the individual protocol should be tailored to patient and owner. 
      • However, current standard of care consists of CHOP-based protocols.
  • The following protocols are recommended as a starting point when discussing therapeutic options with owners:
    • CHOP-based therapy 5,22,29-31
      • 80%-90% of patients experience remission within the first 4 weeks of therapy
      • Median survival time of 12 months with 25% survival at 2 years5
      • 70% response and 6-8 month survival for stage V or T-cell disease
    • Single-agent doxorubicin therapy 32,33
      • 50%-75% response rate
      • Median survival of 6-9 months
    • Single-agent CCNU therapy34
      • ≈40%-50% response rate
      • Median survival of ≈4 months
      • Frontline therapy for canine cutaneous lymphoma35
    • Prednisone monotherapy30
      • ≈50% response rate
      • 1-3 month survival time
  • The author strongly recommends reviewing the necessary personal protective equipment, administration techniques, and chemotherapy side effects/adverse events before consideration of any chemotherapeutic agent.
  • Consultation with a board-certified medical oncologist is recommended.
    • There is not a one-size-fits-all protocol, and new protocols, treatment options, and clinical trials may be available.

There is not a one-size-fits all protocol, and new protocols, treatment options, and clinical trials may be available.

New Options

  • Monoclonal antibody therapy for large T-cell lymphoma36
    • This is being used on a clinical trial basis under a conditional USDA license in combination with chemotherapy.
    • AT005, first T-cell biological therapeutic
      • Caninized monoclonal antibody37
      • Targeted immunotherapy that specifically recognizes CD-52 expressed on T-Cell
    • No known contraindications for use in T-cell lymphoma.
    • Standard hypersensitivity reactions (eg, vomiting, nausea, cutaneous erythema  swelling, pruritus) are uncommon.
    • Efficacy data is pending trial results.
  • Monoclonal antibody therapy for large B-cell lymphoma.38-40
  • Canine Lymphoma Vaccine, DNA (merial.com; conditional licensure by USDA)
    • Targeted immunotherapy that specifically recognizes CD20.
    • Therapeutic immunization to be used on achieving remission with chemotherapy. 
    • Survival time of vaccinates after completion of 25-week CHOP protocol is >734 days, median not reached, which represents a significant improvement over previously reported historical survival times of 1 year.31

Related Article: Feline Lymphoma

Radiation Therapy

  • The role of radiation therapy in the management of lymphoma remains under investigation, and no protocols are well-established in clinical practice.41-42
  • Discussion with a board-certified radiation oncologist is strongly recommended prior to referral for this modality. 
  • Radiation therapy may be used in select cases: 
    • Localized (nasal, CNS) or stage I disease (1 node involved)
    • Palliation of local disease (solitary location or refractory node)
    • Whole-body radiation with bone-marrow transplant
    • Staged half-body irradiation after chemotherapy

Costs

  • Staging test costs are dependent on decision-making between owner and clinician, depending on the degree of work up: $$-$$$$
    • Diagnosis, cytology $$
    • Diagnosis, histopathology $$$
    • Diagnosis, IHC-Flow cytometry $$$
  • Treatment
    • Multi-agent protocol $$$$$
    • Monoclonal therapy $$$$$
    • Single-agent doxorubicin $$$$
    • Radiation therapy $$$-$$$$
    • Single-agent CCNU $$$
    • Prednisone therapy $
Cost Key

$$$$$ = >$4500

$$$$ = $2001-4500

$$$ = $501-2000

$$ = $251-500

$ = <$250

2,4=D = 2,4-dichlorophenoxyacetic acid, ALP = alkaline phosphatase, ALT = alanine aminotransferase, CNS = central nervous system, CSF = cerebrospinal fluid, PARR = PCR for Antigen Receptor Rearrangement, PCR = polymerase chain reaction

References and Author Information

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