March 2016
Oncology
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

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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. 

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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 Show
References
  1. Ponce F, Marchal T, Magnol JP, et al. A morphological study of 608 cases of canine malignant lymphoma in France with a focus on comparative similarities between canine and human lymphoma morphology. Vet Pathol. 2010;47(3):414-433.

  2. Kaiser HE. Animal neoplasms: A systemic review. In: Kaiser HE, ed. Neoplasms: Comparative Pathology in Animals, Plants and Man. Baltimore, MD: Williams & Wilkins; 1981.

  3. Molten JE, Harvey JW. Tumors of lymphoid and hematopoietic tissue. In: Moulton JE, ed. Tumors in Domestic Animals. 3rd ed. Berkeley, CA: University of California Press; 1990.

  4. Dorn CR, Taylor DO, Schneider R. The epidemiology of canine leukemia and lymphoma. Bibl Haemtol. 1970;36:403-415.

  5. Withrow and McEwen’s Small Animal Clinical Oncology. 4th ed. In: Withrow SJ, Vail DM, eds. Philadelphia, PA: Saunders-Elsevier; 2007.

  6. Thomas R, Smith KC, Ostrander EA, Galibert F, Breen M. Chromosome aberrations in canine multicentric lymphomas detected with comparative genomic hybridisation and a panel of single locus probes. Br J Cancer. 2003;89(8):1530-1537.

  7. Veldhoen N, Stewart J, Brown R, Milner J. Mutations of the p53 gene in canine lymphoma and evidence for germ line p53 mutations in the dog. Oncogene. 1998;16(2):249-255.

  8. Nasir L, Argyle DJ. Mutational analysis of the tumor suppressor gene p53 in lymphosarcoma in two bull mastiffs. Vet Rec. 1999;145(1):23-24.

  9. Modiano JF, Breen M, Burnett RC, et al. Distinct B-cell and T-cell lymphoproliferative disease prevalence among dog breeds indicates heritable risk. Cancer Res. 2005;65(13):5654-5661.

  10. Weiden PL, Storb R, Kolb HJ, et al. Immune reactivity in dogs with spontaneous malignancy. J Natl Cancer Inst. 1974;53(4):1049-1056.

  11. Blackwood L, German AJ, Stell AJ, O’Neill T. Multicentric lymphoma in a dog after cyclosporine therapy. J Small Anim Pract. 2004;45(5):259-262.

  12. Hoar SK, Blair A, Holmes FF, et al. Agricultural herbicide use and risk of lymphoma and soft tissue sarcoma. JAVMA. 1986;256(9):1141-1147.

  13. Hayes HM, Tarone, RE, Cantor KP, Jessen CR, McCurnin DM, Richardson RC. Case-control study of canine malignant lymphoma: Positive association with dog owners’ use of 2, 4-dichlorphenoxyacetic acid herbicides. J Natl Cancer Inst. 1991;83(17):1226-1231. 

  14. Reif JS, Lower KS, Ogilvie GK. Residential exposure to magnetic fields and risk of canine lymphoma. Am J Epidemiol. 1995;141(4):352-359.

  15. Madewell BR, Feldman BF. Characterization of anemias associated with neoplasia in small animals. JAVMA. 1980;176(5):419-425.

  16. Weller RE. Paraneoplastic disorders in dogs with hematopoietic tumors. Vet Clin North Am Small Anim Pract. 1985;15(4):805-816. 

  17. Grindem CB, Breitschwerdt EB, Corbett WT, Page RL, Jans HE. Thrombocytopenia associated with neoplasia in dogs. JVIM. 1994;8(6):400-405.

  18. Weir EC, Norrdin RW, Matus RE, et al. Humoral hypercalcemia of malignancy in canine lymphosarcoma. Endocrinology. 1988;122(2):602-608.

  19. Valli VE, San Myint M, Barthel A, et al. Classification of canine malignant lymphomas according to the World Health Organization criteria. Vet Pathol. 2011;48(1):198-211.

  20. Barber LG, Weishaar KM. Criteria for designation of clinical substage in canine lymphoma: A survey of veterinary oncologists. Vet Comp Oncol. 2014; doi:10.1111/vco.12086. 

  21. Jagielski D, Lechowski R, Hoffmann-Jagielska M, Winiarczyk S. Retrospective study of the incidence and prognostic factors of multicentric lymphoma in dogs (1998-2000). J Vet Med A Physiol Pathol Clin Med. 2002;49(8):419-424.

  22. Keller ET, MacEwen EG, Rosenthal RC, Helfand SC, Fox LE. Evaluation of prognostic factors and sequential combination chemotherapy with doxorubicin for canine lymphoma. JVIM. 1993;7(5):289-295.

  23. Sorenmo K, Overley B, Krick E, Ferrara T, LaBlanc A, Shofer F. Outcome and toxicity associated with a dose-intensified, maintenance-free CHOP-based chemotherapy protocol in canine lymphoma: 130 cases. Vet Comp Oncol. 2010;8(3):196-208.

  24. Van Vleet JF, Ferrans VJ, Weirich WE. Cardiac disease induced by chronic adriamycin administration in dogs and an evaluation of vitamin E and selenium as cardioprotectants. Am J Pathol. 1980;99(1):13-42.

  25. Mauldin GE, Fox PR, Patnaik AK, Bond BR, Mooney SC, Matus RE. Doxorubicin-induced cardiotoxicosis. Clinical features in 32 dogs. JVIM. 1992;6(2):82-88.

  26. Thalheim L, Williams LE, Borst LB, Fogle JE, Suter SE. Lymphoma immunophenotype of dogs determined by immunohistochemistry, flow cytometry, and polymerase chain reaction for antigen receptor rearrangements. JVIM. 2013;27(6):1509-1516.

  27. Poggi A, Miniscalco B, Morello E, et al. Prognostic significance of Ki67 evaluated by flow cytometry in dogs with high-grade B-cell lymphoma. Vet Comp Oncol. 2016;doi:10.1111/vco.12184.

  28. Avery PR, Burton J, Bromberek JL, et al. Flow cytometric characterization and clinical outcome of CD4+ T-cell lymphoma in dogs: 67 cases. JVIM. 2014;28(2):538-546.

  29. MacEwen EG, Brown NO, Patnaik AK, Passe S. Cyclic combination chemotherapy of canine lymphosarcoma. JAVMA. 1981;178(11):1178-1181.

  30. Rosenthal RC, MacEwen EG. Treatment of lymphoma in dogs. JAVMA. 1990;196(5):774-781.

  31. Garrett LD, Thamm DH, Chun R, Dudley R, Vail DM. Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma. JVIM. 2002;16(6):704-709.

  32. Carter RF, Harris CK, Withrow SJ, Valli VEO, Susaneck SJ. Chemotherapy of canine lymphoma with histopathological correlation: doxorubicin alone compared to COP as first treatment regimen. JAAHA. 1987;23:587-596.

  33. Postorino NC, Susaneck SJ, Withrow SJ, Harris C. Single agent therapy with Adriamycin for canine lymphosarcoma. JAAHA. 1988;25(2):221-225.

  34. Sauerbrey ML, Mullins MN, Bannink EO, Van Dorp TE, Kaneene JB, Obradovich JE. Lomustine and prednisone as a first-line treatment for dogs with multicentric lymphoma: 17 cases (2004 -2005). JAVMA. 2007;230(12):1866-1869.

  35. Risbon RE, de Lorimier LP, Skorupski K, et al. Response of canine cutaneous epitheliotropic lymphoma to lomustine (CCNU): A retrospective study of 46 cases (1999-2004). JVIM. 2006;20(6):1389-1397.

  36. Palomba ML, Roberts WK, Dao T, et al. CD 8+ T-cell-dependent immunity following xenogeneic DNA immunization against CD20 in a tumor challenge model of B-cell lymphoma. Clin Canc Res. 2005;11(1):370-379.

  37. Rodriguez C, Guerro T, Hansen G. Bioavailability and safety of caninized anti-CD52 monoclonal antibody in dogs with T-cell lymphoma. In: Proceedings of the 34th Annual Veterinary Cancer Society Conference. 2014; St. Louis, MO.

  38. Bergman PJ, Liebman NF, Wolchok JD, et al. Phase 1 clinical trial of murine CD20 DNA vaccination in dogs with B-cell lymphoma. In: Proceedings of the 28th Annual Conference of the Veterinary Cancer Society. 2008; Seattle, WA;55.

  39. Pawlak A, Rapak A, Drynda A, et al. Immunophenotypic characterization of canine malignant lymphoma: A retrospective study of cases diagnosed in Poland Lower Silesia, over the period 2011-2013. Vet Comp Oncol. 2014;doi:10.1111/vco.12112.

  40. Thrall DE, Dewhirst MW. Use of radiation and/or hyperthermia for treatment of mast cell tumors and lymphosarcoma in dogs. Vet Clin North Am Small Anim Pract. 1985;15(4):835-843.

  41. Meleo KA. The role of radiotherapy in the treatment of lymphoma and thymoma. Vet Clin North Am Small Anim Pract. 1997;27(1):115-129.

  42. Williams LE, Johnson JL, Hauck ML, Ruslander DM, Price GS, Thrall DE. Chemotherapy followed by half-body radiation therapy for canine lymphoma. JVIM. 18(5):703-709.

Author

Andy H. Abbo

DVM, MS, DACVIM (Oncology) Veterinary Cancer Specialists of New England

Andy H. Abbo, DVM, MS, DACVIM (Oncology), is the owner of Veterinary Cancer Specialists of New England and is a mobile ultrasonographer and consultant with New England Veterinary Specialists. He earned his DVM from Kansas State University and master’s degree in clinical studies from Purdue University, where he also completed an internship and residency in comparative medical oncology.

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