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Basics ⬇

Basics

Definition

  • Clonal proliferation of B, T, or non-B-/non-T-type (null cell) lymphoblasts found primarily in enlarged peripheral lymph nodes.
  • Cells can spread systemically to invade bone marrow, peripheral blood, CNS, and visceral organs.

Pathophysiology

  • ∼85% of cases are multicentric (involving more than one lymph node).
  • ∼75% are B-cell in origin and ∼25% are T-cell in origin.
  • T-cell LSA is usually associated with hypercalcemia. Multicentric T-cell LSA includes aggressive (PTCL-NOS) and indolent (TZL, FL) subtypes.
  • Multicentric B-cell lymphoma is an aggressive disease.
  • Aggressive lymphomas respond to treatment quickly, but have a shorter overall survival.

Systems Affected

  • Lymphatic (∼85%)-generalized peripheral lymphadenopathy with or without splenic, hepatic, peripheral blood, and/or bone marrow involvement.
  • Gastrointestinal (∼5–7%)-focal or diffuse infiltration of intestines, and associated lymph nodes.
  • Mediastinal (∼5%)-proliferation of neoplastic lymphocytes in mediastinal lymph nodes, thymus, or both.
  • Skin-divided into cutaneous non-epitheliotropic B- and T-cell LSA and mycosis fungoides (epitheleiotropic T-cell LSA).
  • Hepatosplenic γδ T-cell LSA (rare)-liver/spleen sinusoidal infiltration of T-cells with eventual bone marrow infiltration.
  • Intravascular LSA (rare)-typically T- or null cell proliferation in lumen or wall of blood vessel.

Comparative Cytogenetics and Gene Expression Profiling

  • Some chromosome copy number aberrations are shared between human and canine lymphomas.
  • Gene expression profiling can be used to separate distinct subtypes of human and canine lymphoma.
  • Canine diffuse large B-cell lymphoma and marginal zone lymphoma may be a continuum of the same disease.

Incidence/Prevalence

  • 20–107 LSA cases per 100,000 dogs.
  • LSA comprises up to 24% of all canine neoplasms and 83% of all canine hematopoietic malignancies.

Signalment

Breed Predilections

  • Boxer, basset hound, golden retriever, Saint Bernard, Scottish terrier, Airedale terrier, and bulldog-reported high-risk breeds.
  • Dachshund and Pomeranian-reported low-risk breeds.
  • Breed determines relative risk for B-cell or T-cell disease: ∼85% of boxer LSAs are T-cell in origin, while golden retrievers develop both B- and T-cell LSA in a ∼50:50 ratio.

Median Age

Historically, 6–9 years

Signs

History

  • Multicentric-from no clinical signs to anorexia, lethargy, vomiting, diarrhea, weight loss, fever, polydipsia and polyuria secondary to hypercalcemia.
  • Gastrointestinal-vomiting, diarrhea, anorexia, weight loss, malabsorption.
  • Mediastinal-respiratory distress, pleural effusion, coughing, difficulty swallowing, caval syndrome.
  • Skin:
    • Cutaneous LSA-lesions usually generalized or multifocal: nodules, plaques, ulcers, focal alopecia and hypopigmentation.
    • Mycosis fungoides-initial scaling, alopecia, pruritus progressing to thickened, ulcerated, exudative lesions. Later stages include proliferative plaques and nodules with progressive ulceration. Oral mucosa many times involved.
  • Extranodal-vary with the anatomic site: ocular-photophobia and conjunctivitis; CNS-neurologic deficits, paresis, paralysis, seizures; hepatosplenic-lethargy, inappetance, weakness, icterus.

Physical Examination Findings

  • Multicentric-generalized, painless, enlarged peripheral lymph node(s) with or without hepatosplenomegaly.
  • Gastrointestinal-unremarkable to palpable thickened gut loops and/or abdominal mass, rectal mucosal irregularities, ascites.
  • Mediastinal-dyspnea; tachypnea; muffled heart sounds secondary to pleural effusion, pitting edema of head, neck, forelimbs.
  • Skin-raised plaques that may coalesce, patch lesions, and erythematous, exudative lesions.
  • Extranodal-ocular-anterior uveitis, retinal hemorrhages, and hyphema; CNS-dementia, seizures, and paralysis.

Causes

Suggested causes include heritable breed risks, chromosomal aberrations, increased telomerase activity, germline and somatic genetic mutations, epigenetic changes, retroviral infection, Epstein-Barr virus infection, and environmental factors.

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

  • Multicentric-disseminated infections, metastatic disease, immune-mediated disorders, other hematopoietic tumors.
  • Gastrointestinal-other GI tumors, foreign body, enteritis, GI ulceration, systemic mycosis.
  • Mediastinal-other tumors (thymoma, chemodectoma, ectopic thyroid), infectious disease.
  • Skin-infectious dermatitis, pyoderma, immune-mediated dermatitis, histiocytic or mast cell disease.
  • Extranodal-depends on affected site.

Staging

CBC/Biochemistry/Urinalysis

  • Anemia of chronic disease, thrombocytopenia, lymphocytosis, lymphopenia, neutrophilia, monocytosis, circulating blasts, hypoproteinemia (gastrointestinal).
  • Hypercalcemia, increased liver enzymes with hepatic involvement, increased BUN or creatinine with renal involvement.
  • Urinalysis usually normal.

Imaging

  • Thoracic radiography-sternal or tracheobronchial lymphadenopathy, widened mediastinum, pulmonary densities, and pleural effusion.
  • Abdominal ultrasonography-abdominal lymphadenopathy, hepatosplenic involvement, thickened bowel loops, other visceral organ involvement, ascites.

Diagnostic Procedures

  • Fine-needle aspirate cytology of enlarged lymph nodes or other affected organs-for cytopathologic confirmation.
  • Lymph node biopsy or resection-for accurate histopathologic classification.
  • Bone marrow cytology-for accurate prognosis.
  • CSF analysis-if patient has neurologic signs.
  • ECG-identify arrhythmias before doxorubicin administration.

Other Laboratory Tests

  • Immunohistochemistry (LN biopsy/resection)-to determine immunophenotype.
  • Flow cytometry or PCR for antigen receptor rearrangements (PARR) (LN or affected organ fine-needle aspirates)-to determine immunophenotype.

Pathologic Findings

  • Multicentric-effacement of LN parenchyma with large, neoplastic CD3+ T cells (PTCL-NOS) or small, CD3+ cell proliferation between fading follicles (indolent TZL). Effacement of LN parenchyma with large, neoplastic CD79a+ B cells (high-grade DLBCL) or perifollicular proliferation of CD79a+ cells (MZL) or CD79a+ cell proliferation that maintains follicle architecture (FL).
  • Gastrointestinal-infiltration of neoplastic lymphocytes throughout mucosa and submucosa, with occasional transmural infiltration.
  • Skin-CD79a+ B-cells infiltrating mucosa and submucosa, but sparing the epidermis (non-epitheliotrophic)LSA or CD3+ T-cells invading the epidermis-Pautrier's microabcesses (mycosis fungoides). Hepatosplenic-sinusoidal infiltration of erythrophagocytic CD3+ T-cells.

Staging

  • I-one enlarged LNII-regionally enlarged LNs
  • III-generalized LN involvement
  • IV-visceral organ involvement
  • V-blood or bone marrow involvement
  • Substage a-not sick
  • Substage b-sick

Treatment ⬆ ⬇

Treatment

Current Standards Of Care

  • High-grade LSAs are exquisitely sensitive to both chemotherapy and radiation.
  • Systemic multi-agent chemotherapy-therapy of choice.
  • Radiation therapy-for refractory lymphadenopathy, large mediastinal masses, and solitary cutaneous areas.
  • Surgery-rarely used unless an acutely obstructive gastrointestinal mass is identified or to remove a refractory lymphadenopathy.
  • Autologous and allogeneic bone marrow transplantation can be considered.

Other Treatments

Fluid therapy-for advanced disease to treat clinically ill, azotemic, and/or dehydrated patients. Also to prevent tumor lysis syndrome and/or reduce calcium levels.

Client Education

  • Canine LSA is a treatable, but rarely curable disease.
  • Side effects of chemotherapy drugs include reversible gastrointestinal tract and bone marrow toxicities.
  • The vast majority of dogs receiving chemotherapy enjoy an excellent quality of life.

Medications ⬆ ⬇

Medications

Drug(s) Of Choice

  • Always consult a veterinary oncologist to discuss various treatment options, precautions, chemotherapy dosing schedules, and potential side effects.
  • Consider combination chemotherapy protocols to treat intermediate and high-grade diseases and single agent protocols to treat indolent diseases.
  • Most multi-agent protocols have superior remission and survival times when compared to single agent protocols.
  • Corticosteroids alone can induce significant multi-drug resistance.

Intermediate and High-Grade Lymphomas

  • L-CHOP-L-asparaginase 10,000 IU/m2, vincristine (Onvcovin) 0.7 mg/m2 IV, cyclophosphamide (Cytoxan) 250 mg/m2 IV or PO, doxorubicin (Adriamycin) 30 mg/m2 IV, prednisone 30, 20, 10 mg/m2 PO q24h tapering for 3 weeks. Consult a veterinary oncologist concerning the treatment schedule.
  • COP-vincristine 0.7 mg/m2 IV, cyclophosphamide (Cytoxan) 250 mg/m2 IV or PO, prednisone 30, 20, 10 mg/m2 PO q24h tapering for 3 weeks. Each drug given weekly.

Single Agent

  • Any drug of L-CHOP can be used as a single agent, but expect shorter overall survival than multiagent.
  • Doxorubicin (Adriamycin) 30 mg/m2 IV every 3 weeks (1 mg/kg for dog <15 kg) 5–6 treatments.
  • CCNU (lomustine) 70 mg/m2 PO every 3 weeks, prednisone 2 mg/kg PO daily.

Low-Grade Lymphomas

  • Chlorambucil (Leukeran) 6 mg/m2 PO daily for 7–14 days, prednisone 2 mg/kg PO daily. Consider reducing chlorambucil dose to 3 mg/m2 for maintenance.
  • CCNU (lomustine) as above.

Precautions

  • Doxorubicin-use dexrazoxane (Zinecard) in conjunction with doxorubicin or substitute epirubicin for dogs with cardiac issues.
  • Always use a freshly placed catheter when administering intravenous doxorubicin.
  • L-asparaginase and doxorubicin-pretreat with diphenhydramine (1–2 mg/kg SC) 15 minutes before administration.

Possible Interactions

Most chemotherapy drugs have overlapping gastrointestinal and bone marrow toxicities. Consider anti-diarrheal (metronidazole, loperamide) and antiemetics (metoclopramide, maropitant, ondansetron) to abrogate these effects.

Alternative (Rescue) Protocols

  • Many published rescue protocols have been reported; therefore always consult with a medical oncologist.
  • MOPP-methchlorethamine (Mustargen), vincristine, procarbazine, and prednisone.
  • DMAC-dexamethasone, melphalan, actinomycin-D, and cytosine arabinoside.
  • CCNU ± L-asparaginase, prednisone, or DTIC (dacarabazine).
  • Mitoxantrone alone or Adriamycin/DTIC.

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

  • Weekly physical examination to assess response and CBC to gauge bone marrow toxicities.
  • If neutropenia (neutrophils <1,500 cells/mm3) is noted, reduce dosage (20–25%) of drug when given again.

Most Common Complications

  • Reversible neutropenia 4–7 days after chemotherapy.
  • Temporary vomiting, diarrhea, and anorexia 2–5 days after chemotherapy.
  • Alopecia in certain dog breeds (poodle, Shih Tzu, etc.).
  • Febrile neutropenia (treated with broad-spectrum antibiotics).

Expected Course and Prognosis

  • >80% of dogs will go into clinical remission during the first month of induction chemotherapy.
  • Stage, substage, and immunophenotype are important prognostic indicators.
  • Expect median survivals of ∼12–14 months and ∼6–9 months in dogs with high-grade multicentric B- and T-cell LSA, respectively, when treated with a multi-agent protocol. Dogs with indolent disease can live years. Gastrointestinal, mediastinal (T-cell ± hypercalcemia), and mycosis fungoides are associated with poorer response to treatment and an overall shorter survival time.

Miscellaneous ⬆

Miscellaneous

Pregnancy/Fertility/Breeding

Treatment of pregnant dogs is usually contraindicated.

Synonyms

  • Lymphosarcoma
  • Malignant lymphoma

Abbreviations

  • CNS = central nervous system
  • DLBCL = diffuse, large B-cell lymphoma
  • FL = follicular LSA
  • LN = lymph node
  • LSA = lymphoma
  • MZL = marginal zone lymphoma
  • PTCL-NOS = peripheral T-cell lymphoma–not otherwise specified
  • TZL = T-zone lymphoma

Suggested Reading

Bienzle D, Vernau W. The diagnostic assessment of canine lymphoma: implications for treatment. Clin Lab Med 2011, 31(1):21–39.

Flood-Knapik KE, Durham AC, Gregor TP, et al. Clinical, histopathological, and immunohistochemical characterization of canine indolent lymphoma. Vet Comp Oncol 2013, 11(4):272–286.

Garrett LD, Thamm DH, Chun R, et al. Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet Intern Med 2002, 16(6):704–709.

Rassnick KM, McEntee MC, Erb HN, et al. Comparison of 3 protocols for treatment after induction of remission in dogs with lymphoma. J Vet Intern Med 2007, 21(6):1364–1373.

Author Steven E. Suter

Consulting Editor Timothy M. Fan

Acknowledgment The author and editors acknowledge the prior contribution of Wallace B. Morrison.

Client Education Handout Available Online