- 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.
- 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.
- 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
- Lymphoma is diagnosed worldwide in the canine population.
- 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
- 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
- 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
- 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
- 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 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.
- 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:
- Cranial abdominal enlargement
- Mediastinal involvement or pleural fluid
- Regional lymph edema
- Dermal or subcutaneous masses
- Vomiting or diarrhea
- Stridor and stertor if retropharyngeal nodes are involved
- 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
- 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.
- Reactive lymphoid hyperplasia
- Systemic infection
- Bacterial (eg, Rickettsial disease)
- Immune-mediated disease
- 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.
- 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.
- 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
- 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
- Staging test costs are dependent on decision-making between owner and clinician, depending on the degree of work up: $$-$$$$
- Diagnosis, cytology $$
- Diagnosis, histopathology $$$
- Diagnosis, IHC-Flow cytometry $$$
- Multi-agent protocol $$$$$
- Monoclonal therapy $$$$$
- Single-agent doxorubicin $$$$
- Radiation therapy $$$-$$$$
- Single-agent CCNU $$$
- Prednisone therapy $
$$$$$ = >$4500
$$$$ = $2001-4500
$$$ = $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
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