Lymphoma

Lymphoma is a malignant neoplasm of lymphocytes, originating from lymphoid tissues including lymph nodes, spleen, bone marrow, and extranodal sites. It is one of the most common hematopoietic tumors in dogs and cats, characterized by clonal expansion of B- or T-lymphocytes. The disease can be classified anatomically (multicentric, alimentary, mediastinal, cutaneous, extranodal) and histologically (low, intermediate, high grade). In dogs, multicentric lymphoma is most common, while in cats, alimentary and mediastinal forms are frequent. The clinical course varies from indolent to highly aggressive, with systemic signs reflecting the extent of organ involvement.

The exact etiology of lymphoma is often unknown, but several factors are implicated. In cats, infection with feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) significantly increases risk, particularly for mediastinal and multicentric forms. In dogs, retroviruses are not implicated; however, genetic predisposition, environmental factors (e.g., exposure to herbicides, pesticides, electromagnetic fields), and immune dysregulation may contribute. Chromosomal abnormalities and mutations in tumor suppressor genes (e.g., p53) and oncogenes (e.g., MYC) have been identified. Chronic antigenic stimulation and immunosuppression are also considered risk factors.

Lymphoma accounts for approximately 7-24% of all canine neoplasms and up to 30% of feline tumors. In dogs, middle-aged to older animals (median age 6-9 years) are commonly affected, with certain breeds predisposed: Boxers, Golden Retrievers, Labrador Retrievers, Rottweilers, and Scottish Terriers. In cats, the disease often occurs in younger cats if FeLV-positive (median age 3 years) and older cats if FeLV-negative (median age 10-12 years). No consistent sex predilection is reported. Geographic variation exists, with higher incidence in industrialized areas.

Lymphoma arises from the clonal expansion of a single lymphocyte that has undergone malignant transformation. This transformation results from genetic mutations leading to uncontrolled proliferation, resistance to apoptosis, and impaired differentiation. The neoplastic cells accumulate in lymphoid organs and can infiltrate bone marrow, liver, spleen, and other tissues. The release of cytokines (e.g., IL-6, TNF-alpha) contributes to systemic signs such as fever, weight loss, and cachexia. Hypercalcemia, often seen in T-cell lymphoma, results from paraneoplastic secretion of parathyroid hormone-related protein (PTHrP). The disease disrupts normal immune function, leading to immunosuppression and secondary infections. In advanced stages, organ failure occurs due to infiltration and metabolic derangements.

Predisposing factors include genetic susceptibility (breed-specific), viral infections (FeLV, FIV in cats), exposure to environmental toxins (e.g., phenoxyacetic acid herbicides, ionizing radiation), chronic immunosuppression (e.g., long-term corticosteroid use), and possibly certain dietary factors. Age is a risk factor, with increased incidence in middle-aged to older animals. In cats, FeLV vaccination has reduced the incidence of FeLV-associated lymphoma, but non-viral cases remain.

Clinical signs vary with the anatomic form. Multicentric lymphoma: painless, generalized lymphadenopathy (peripheral, visceral), often with no systemic signs initially. As disease progresses, lethargy, anorexia, weight loss, fever, and pallor may appear. Alimentary lymphoma: vomiting, diarrhea, weight loss, melena, and palpable abdominal masses. Mediastinal lymphoma: dyspnea, cough, regurgitation (due to esophageal compression), and precaval syndrome (edema of head and neck). Cutaneous lymphoma: plaques, nodules, ulcers, and erythema. Extranodal forms (e.g., renal, nasal, ocular) present with organ-specific signs such as polyuria/polydipsia (renal), nasal discharge (nasal), and uveitis (ocular). Bone marrow involvement may cause anemia, thrombocytopenia, and leukopenia.

Differential diagnoses include: (1) Reactive lymphadenopathy (e.g., bacterial, fungal, or protozoal infections, immune-mediated disease) – distinguished by cytology showing mixed cell population and absence of clonality. (2) Metastatic neoplasia (e.g., mast cell tumor, carcinoma) – identified by cytology/histopathology with specific cell types. (3) Leukemia (e.g., lymphoblastic leukemia) – differentiated by bone marrow aspirate and peripheral blood evaluation. (4) Systemic histiocytosis – characterized by histiocytic infiltration on biopsy. (5) Inflammatory bowel disease (for alimentary form) – requires full-thickness biopsy for differentiation. (6) Thymoma (for mediastinal mass) – distinguished by histopathology and immunophenotyping. (7) Granulomatous diseases (e.g., fungal) – identified by cytology, culture, or PCR. (8) Multiple myeloma – characterized by monoclonal gammopathy and plasma cell infiltration. (9) Infectious lymphadenitis (e.g., bartonellosis) – serology and PCR. (10) Drug-induced lymphadenopathy – history of drug exposure.

The diagnostic workup begins with a thorough history and physical examination, including palpation of all lymph nodes and abdominal organs. Initial tests include complete blood count (CBC), serum biochemistry profile, urinalysis, and thoracic radiographs (three views) to assess for mediastinal mass or pulmonary involvement. Abdominal ultrasound is recommended to evaluate liver, spleen, and abdominal lymph nodes. The cornerstone of diagnosis is cytology via fine-needle aspiration (FNA) of enlarged lymph nodes or masses; if cytology is inconclusive, excisional biopsy for histopathology and immunophenotyping (flow cytometry, PARR) is performed. Bone marrow aspiration is indicated if cytopenias or circulating abnormal cells are present. Staging (WHO substage a/b) includes assessment of bone marrow, liver, spleen, and other organs. Advanced imaging (CT, MRI) may be used for precise staging, especially for mediastinal or nasal lymphoma. Immunophenotyping (B vs. T cell) is crucial for prognosis and treatment planning.

Hematology: Anemia (non-regenerative), thrombocytopenia, leukopenia or leukocytosis, and circulating lymphoblasts may be seen. Serum biochemistry: Hypercalcemia (especially in T-cell lymphoma), elevated liver enzymes (ALT, ALP) with hepatic infiltration, azotemia with renal involvement, and hypoalbuminemia. Urinalysis: May show proteinuria, hematuria, or casts. Blood gas analysis: May reveal metabolic acidosis in advanced disease. Specific biomarkers: Elevated lactate dehydrogenase (LDH), thymidine kinase, and C-reactive protein (CRP) may be present. In cats, FeLV and FIV testing (ELISA, IFA, PCR) is essential. PARR (PCR for antigen receptor rearrangement) detects clonality. Flow cytometry can identify cell surface markers (CD3, CD79a, CD4, CD8).

Radiography: Thoracic radiographs may reveal cranial mediastinal mass, tracheobronchial lymphadenopathy, or pulmonary infiltrates. Abdominal radiographs may show hepatosplenomegaly or abdominal masses. Ultrasonography: Enlarged, hypoechoic lymph nodes; hepatic and splenic changes (diffuse or nodular); intestinal wall thickening in alimentary lymphoma. Doppler ultrasound can assess vascular invasion. CT: Provides detailed assessment of lymph node size, organ involvement, and staging; particularly useful for nasal and mediastinal lymphoma. MRI: Superior for central nervous system involvement. Endoscopy: Allows visualization and biopsy of gastrointestinal lesions. Echocardiography: May be indicated if cardiac involvement is suspected.

Cytology: FNA of lymph nodes typically shows a monomorphic population of large, immature lymphocytes with prominent nucleoli, high nuclear-to-cytoplasmic ratio, and basophilic cytoplasm. Mitotic figures are common. Histopathology: Lymph node architecture is effaced by neoplastic lymphocytes. Grading (low, intermediate, high) is based on cell size and mitotic count. Immunohistochemistry (CD3 for T-cell, CD79a for B-cell) and flow cytometry confirm lineage. PARR demonstrates clonal rearrangement of immunoglobulin or T-cell receptor genes. Special stains (e.g., Ki-67) assess proliferation index.

Treatment is primarily systemic chemotherapy. The standard protocol for canine multicentric lymphoma is CHOP-based (cyclophosphamide, doxorubicin, vincristine, prednisone) administered over 19-25 weeks. For cats, similar protocols are used but with dose adjustments. Rescue protocols (e.g., L-asparaginase, lomustine, MOPP) are used for relapse. Supportive care includes antiemetics (e.g., maropitant), antidiarrheals, and nutritional support. For hypercalcemia, aggressive fluid therapy and furosemide are indicated. Radiation therapy is effective for localized forms (e.g., nasal lymphoma). Surgery may be considered for solitary extranodal masses. In cats, treatment of concurrent FeLV/FIV infection is supportive. Novel therapies include tyrosine kinase inhibitors (e.g., toceranib) and monoclonal antibodies (e.g., rituximab, though not approved for veterinary use).

Prognosis depends on immunophenotype, stage, substage, and response to therapy. Dogs with B-cell lymphoma and substage a have a median survival of 12-18 months with CHOP; T-cell lymphoma has a poorer prognosis (median 6-9 months). Cats with FeLV-negative lymphoma have a median survival of 6-12 months with chemotherapy. Negative prognostic factors include advanced stage (V), substage b (systemic signs), hypercalcemia, and high proliferation index. Complete remission is achieved in 60-90% of dogs, but most relapse. Long-term survival (>2 years) is possible in a minority.

During chemotherapy, patients are monitored weekly for CBC and clinical assessment. After completion of induction, re-staging (physical exam, imaging, lab work) is recommended every 1-3 months for the first year, then every 3-6 months. Serial measurements of lymph node size and body weight are essential. If relapse occurs, rescue protocols are initiated. Long-term monitoring includes assessment for chemotherapy-related toxicities (e.g., cardiotoxicity from doxorubicin, cystitis from cyclophosphamide).

Pearls: (1) Always perform FNA before biopsy; cytology is often diagnostic. (2) Immunophenotype is crucial for prognosis; request flow cytometry or IHC. (3) In cats, test for FeLV/FIV. (4) Hypercalcemia is a medical emergency; treat aggressively. (5) Use a central venous catheter for chemotherapy to prevent extravasation. Pitfalls: (1) Do not administer corticosteroids before definitive diagnosis, as it may interfere with histopathology. (2) Avoid using doxorubicin in patients with pre-existing cardiac disease. (3) Do not skip staging; it affects treatment decisions. (4) Be cautious with cyclophosphamide-induced sterile hemorrhagic cystitis; ensure adequate hydration. (5) Do not assume a solitary mass is benign; always biopsy.

CHOP Protocol (canine): Vincristine 0.7 mg/m² IV on weeks 1, 3, 6, 8, 13, 15, 18, 20; Cyclophosphamide 250 mg/m² IV or PO on weeks 2, 7, 12, 17; Doxorubicin 30 mg/m² IV on weeks 4, 9, 14, 19; Prednisone 2 mg/kg PO q24h for 1 week, then 1.5 mg/kg q24h for 1 week, then 1 mg/kg q24h for 2 weeks, then 0.5 mg/kg q48h until week 25. For cats: Vincristine 0.5 mg/m² IV, Cyclophosphamide 200 mg/m² PO, Doxorubicin 20 mg/m² IV, Prednisone 2 mg/kg PO q24h tapering. Rescue protocols: L-asparaginase 10,000 IU/m² IM or SC once weekly; Lomustine (CCNU) 60-90 mg/m² PO every 3 weeks; MOPP (mechlorethamine, vincristine, procarbazine, prednisone). Supportive drugs: Maropitant 1 mg/kg SC q24h for nausea; Ondansetron 0.5-1 mg/kg IV q12h; Metoclopramide 1-2 mg/kg/day CRI. For hypercalcemia: 0.9% NaCl IV at 60-100 ml/kg/day, Furosemide 1-2 mg/kg IV q8h, and prednisone 1-2 mg/kg PO q24h. Dose adjustments for renal/hepatic impairment: reduce cyclophosphamide and doxorubicin doses by 25% if azotemia or hepatopathy. Contraindications: doxorubicin in dilated cardiomyopathy; vincristine in severe hepatic disease. Drug interactions: avoid NSAIDs with corticosteroids due to GI ulceration risk.

Key studies include the Veterinary Cooperative Oncology Group (VCOG) consensus on staging and response criteria. A landmark trial by Garrett et al. (2002) compared CHOP vs. COP in dogs, showing improved remission and survival with CHOP. Another study by Vail et al. (1998) demonstrated that maintenance chemotherapy after CHOP does not prolong survival. In cats, a study by Teske et al. (2002) showed that FeLV-negative cats with lymphoma have better response to chemotherapy. The use of L-asparaginase in induction has been evaluated in multiple studies, showing improved remission rates. Recent research on toceranib (Palladia) has shown activity in relapsed lymphoma. ACVIM consensus guidelines on lymphoma diagnosis and treatment were published in 2016, emphasizing the importance of immunophenotyping and minimal residual disease monitoring.