Current Perspectives in Canine Lymphoma: Updates on Staging and Grading Approaches
Canine lymphoma remains one of the most common hematologic malignancies in veterinary oncology, with distinct anatomical distribution, histological classification, and prognostic factors that differ from feline counterparts. Recent advances in understanding the biological behavior of canine lymphoma have refined traditional staging methodologies. This review examines current evidence-based approaches to canine lymphoma staging and grading, with emphasis on anatomical site-specific considerations and the integration of novel diagnostic modalities.
Evolving Understanding of Canine Lymphoma
The World Health Organization (WHO) staging system for lymphoma was primarily developed for dogs and humans, making it highly applicable to canine patients. This classification system has been extensively validated through collaborative efforts of veterinary pathologists and remains the gold standard for canine lymphoma staging. Contemporary approaches recognize the distinctive features of canine lymphoma, particularly:
The high prevalence of multicentric forms (80-85% of cases)
The relatively lower incidence of alimentary lymphoma compared to cats (5-7% of cases)
The significance of mediastinal lymphoma in younger dogs
The emergence of cutaneous T-cell lymphoma as an increasingly recognized entity
Recent epidemiological studies have documented important shifts in the presentation and characteristics of canine lymphoma. A 2023 comprehensive review found that multicentric large B-cell lymphoma remains the most common form, representing 70-80% of all canine lymphoma cases. This form is characterized by peripheral lymphadenopathy and typically affects middle-aged to older dogs, with certain breeds showing increased predisposition.
Additionally, studies examining canine lymphoma demographics over the past decade have found notable changes in patient presentation, with breed predispositions becoming more apparent in Golden Retrievers, Boxers, and German Shepherds. The median age at diagnosis has remained stable at 6-9 years, though aggressive forms are increasingly recognized in younger dogs.
Canine Lymphoma staging and Grading Schemas
Staging Systems
Unlike many other tumor types that use the TNM (Tumor-Node-Metastasis) system with stages 0-IV, lymphoma in dogs uses the WHO system with stages I-V. This staging system reflects the unique biological behavior of lymphoma as a systemic disease rather than a localized tumor:
Stage I: A single tumor (extranodal) or a single anatomic area (nodal). This includes primary intrathoracic tumors.
Stage II: A single tumor (extranodal) with regional lymph node involvement. Two or more nodal areas on the same side as the diaphragm. Two single (extranodal) tumors with or without regional lymph node involvement on the same side of the diaphragm. Resectable primary GI tumor, usually in the ileocecal area, with or without involvement or associated mesenteric nodes only.
Stage III: Two single tumors (extranodal) on opposite sides of the diaphragm. Two or more nodal areas above and below the diaphragm. All extensive primary unresectable intraabdominal disease. All paraspinal or epidural tumors, regardless of other tumor site or sites.
Stage IV: Stages I-III with liver and/or spleen involvement
Stage V: Stage I-IV with blood and bone marrow involvement
Additionally, each stage is subclassified as:
Substage a: Without systemic signs
Substage b: With systemic signs (weight loss, fever, etc.)
It's important to differentiate tumor stage (extent of disease spread) from tumor grade (degree of cellular differentiation and aggressiveness). One of the most common mistakes in veterinary cancer medicine is starting a patient with lymphoma on corticosteroids after diagnosis but before staging, as this can make determining the initial stage impossible and lead to an inaccurate prognosis.
Recent studies have documented improved staging accuracy in canine lymphoma with the routine use of advanced diagnostics. A 2022 study on canine multicentric lymphoma found more precise stage determination compared to historical data, with better differentiation between stage III and IV disease due to enhanced imaging capabilities.
Grading Systems
Tumor grading is a method to quantify the putative clinical aggressiveness of a neoplasm based on specific histological features. In lymphomas, grading is typically assessed in sections of lymph nodes and primarily based on mitotic activity, though other features may be considered.
The most common grading system for canine lymphoma divides cases into:
Low-grade lymphoma: Characterized by small, well-differentiated lymphocytes with low mitotic rates
Intermediate-grade lymphoma: Showing moderate cellular pleomorphism and mitotic activity
High-grade lymphoma: Featuring marked cellular pleomorphism, high mitotic rates, and often extensive necrosis
Based on the National Cancer Institute's Working Formulation (NCI-WF) classification scheme, the majority of canine lymphomas are identified as intermediate (40%) to high-grade (45%), with low-grade forms representing approximately 15% of cases.
More recently, the WHO classification has been extensively applied to canine lymphomas to provide more specific categorization based on cell morphology and immunophenotype, including:
Diffuse large B-cell lymphoma (most common)
Peripheral T-cell lymphoma
T-cell-rich B-cell lymphoma
Lymphoblastic lymphoma
Marginal zone lymphoma
Follicular lymphoma
And others
The application of these classification schemes allows for better prognostication and treatment planning than simple grading alone.
Anatomical Site-Specific Staging Considerations
Multicentric Lymphoma
The multicentric form represents the most common presentation of canine lymphoma, typically manifesting as generalized peripheral lymphadenopathy:
Current Diagnostic Approach: Fine needle aspiration typically provides sufficient diagnostic material; histopathology with immunophenotyping is recommended for definitive classification and prognostic assessment.
Staging Recommendations:
Complete blood count, serum biochemistry, and urinalysis
Thoracic radiographs (three views)
Abdominal ultrasonography with evaluation of internal lymph nodes and organ involvement
Fine needle aspiration of peripheral lymph nodes
Cytological assessment of bone marrow when hematologic abnormalities are present
Flow cytometry when available for rapid immunophenotyping
Notable Update: Bone marrow evaluation remains standard practice due to the systemic nature of multicentric disease, with approximately 15-20% of dogs having detectable bone marrow involvement at diagnosis.
For multicentric lymphoma, the peripheral lymph nodes, spleen, and liver are the most common locations. Clinical signs typically develop rapidly over weeks and include lethargy, inappetence, and obvious lymph node enlargement. The distinction between B-cell and T-cell phenotypes is crucial, as T-cell lymphomas generally carry a poorer prognosis.
Alimentary Lymphoma
While less common than in cats, alimentary lymphoma in dogs presents unique diagnostic and staging challenges:
Current Diagnostic Approach: Endoscopic or surgical biopsies are often necessary for diagnosis; cytology alone may be insufficient due to the focal nature of many lesions.
Staging Recommendations:
Standard database (CBC, biochemistry, urinalysis)
Thoracic radiographs
Comprehensive abdominal ultrasonography
Upper and/or lower GI endoscopy with multiple biopsies
Fine needle aspiration of regional lymph nodes
Assessment of peripheral lymph nodes
Notable Update: Advanced imaging (CT or MRI) is increasingly used to assess the extent of bowel wall involvement and detect subtle lymphadenopathy.
The distinction between inflammatory bowel disease and lymphoma can be challenging in dogs, though typically less so than in cats. Immunohistochemistry and clonality testing may be necessary in equivocal cases.
Mediastinal Lymphoma
Mediastinal lymphoma in dogs often affects younger animals and may be associated with hypercalcemia:
Current Diagnostic Approach: Ultrasound-guided fine needle aspiration typically yields diagnostic samples; thoracocentesis may be necessary if pleural effusion is present.
Staging Recommendations:
Standard database with particular attention to calcium levels
Thoracic radiographs or CT
Abdominal ultrasonography
Echocardiography to assess cardiac involvement
Flow cytometry of effusion fluid when present
Notable Update: T-cell phenotype is more common in mediastinal lymphoma and often associated with more aggressive behavior and hypercalcemia.
Cutaneous Lymphoma
Canine cutaneous lymphoma presents as either epitheliotropic (mycosis fungoides) or non-epitheliotropic forms:
Current Diagnostic Approach: Multiple skin biopsies with immunohistochemistry are essential; progression from epitheliotropic to systemic disease requires careful monitoring.
Staging Recommendations:
Standard database
Thoracic radiographs
Abdominal ultrasonography
Peripheral lymph node assessment
Flow cytometry of blood for circulating neoplastic cells
Notable Update: Clonality testing via PARR (PCR for Antigen Receptor Rearrangement) helps confirm the neoplastic nature of lymphoid infiltrates and monitor for systemic progression.
Central Nervous System Lymphoma
Primary CNS lymphoma is rare in dogs but requires specific diagnostic approaches:
Current Diagnostic Approach: Advanced imaging (MRI) is essential; cerebrospinal fluid analysis and flow cytometry may provide diagnostic information.
Staging Recommendations:
Complete neurological examination
MRI of the brain and/or spinal cord
Cerebrospinal fluid analysis with cytology and flow cytometry
Ophthalmologic examination
Standard staging for systemic disease
Modern Diagnostic Modalities and Their Impact on Staging
Cytological Assessment
Fine Needle Aspiration (FNA) remains a cornerstone diagnostic tool in canine lymphoma staging. The role of FNA in lymphoma staging includes:
Initial diagnosis in cases with peripheral lymphadenopathy
Assessment of internal organ involvement
Sample collection for ancillary tests such as flow cytometry
Monitoring treatment response during follow-up
Recent studies have highlighted the high diagnostic accuracy of cytological assessment in canine lymphoma. A 2021 study demonstrated good correlation between cytological and histological diagnoses in multicentric lymphoma, with cytology providing rapid, cost-effective diagnosis in the majority of cases.
The advantages of cytological assessment include rapid turnaround time, minimal invasiveness, and the ability to perform multiple sampling sites during initial staging. When combined with flow cytometry, cytology provides both morphological and immunophenotypic information essential for treatment planning.
Advanced Imaging
Computed Tomography: Increasingly available in referral settings, CT provides superior sensitivity for detection of internal lymphadenopathy, organ involvement, and treatment monitoring.
Magnetic Resonance Imaging: Particularly valuable for CNS lymphoma and detailed assessment of complex anatomical regions.
Studies have demonstrated that CT identifies additional lesions not detected by conventional radiography in approximately 30-40% of canine lymphoma cases, potentially altering staging and treatment planning.
Molecular Diagnostics
Flow Cytometry: Provides rapid immunophenotyping and can detect minimal residual disease during treatment monitoring.
Clonality Testing: PARR analysis provides objective assessment of clonality, particularly valuable in distinguishing reactive hyperplasia from early lymphoma.
Immunophenotyping: Beyond basic B-cell versus T-cell distinction, expanded panels help predict biological behavior and treatment response.
Recent collaborative studies have helped establish standards for applying WHO classification systems to canine patients, with specific emphasis on reproducible immunophenotyping protocols.
Recommended Contemporary Staging Protocol
Based on current evidence, a comprehensive approach to canine lymphoma staging should include:
Complete clinical database:
Thorough physical examination with measurement of all accessible lymph nodes
Complete blood count with careful morphological evaluation
Comprehensive biochemistry panel including liver enzymes, kidney parameters, and calcium
Urinalysis
Lactate dehydrogenase (LDH) levels
Cytological assessment:
Fine needle aspiration of multiple peripheral lymph nodes
Ultrasound-guided FNA of internal masses or lymph nodes
Cytological evaluation with Romanowsky-type stains
Flow cytometry on aspirates for immediate immunophenotyping when available
Imaging studies:
Three-view thoracic radiographs (or CT when available)
Complete abdominal ultrasonography with assessment of all lymph nodes and organs
Advanced imaging (CT/MRI) for specific indications
Immunophenotyping:
Preferably performed on diagnostic samples via flow cytometry or immunohistochemistry
Essential for prognostic assessment and treatment planning
Bone marrow evaluation:
Recommended for all cases with hematological abnormalities
Consider in all multicentric cases for complete staging
Cytology and flow cytometry preferred over core biopsy
Additional testing:
Histopathology when cytology is inconclusive or for WHO classification
Clonality testing in equivocal cases
Site-specific procedures as indicated by clinical presentation
Prognostic Implications of Modern Staging and Grading
Recent studies have identified several prognostic factors that may be identified during comprehensive staging:
Immunophenotype: B-cell phenotype generally carries better prognosis than T-cell phenotype in most anatomical locations, with median survival times of 12-18 months versus 6-9 months respectively.
Clinical Stage: Higher stages (IV-V) are associated with shorter survival times, though this varies by anatomical form.
Substage: Dogs with systemic signs (substage b) generally have poorer prognoses than those without clinical signs (substage a).
WHO Classification: Specific subtypes have distinct prognostic implications, with diffuse large B-cell lymphoma having intermediate prognosis and T-cell lymphomas generally having poorer outcomes.
Treatment Response: Early response to therapy remains one of the strongest prognostic indicators.
The median survival for dogs with multicentric lymphoma treated with combination chemotherapy protocols ranges from 10-14 months, with approximately 80-90% achieving complete remission. Dogs with T-cell lymphoma typically have shorter remission duration and overall survival times.
Recent studies have also identified novel prognostic biomarkers, including serum thymidine kinase activity, which correlates with tumor burden and treatment response in dogs with lymphoma.
Conclusion
Modern approaches to canine lymphoma staging and grading emphasize comprehensive diagnostic protocols that incorporate traditional staging with advanced immunophenotyping and molecular diagnostics. The high prevalence of multicentric disease in dogs necessitates thorough systemic evaluation, while site-specific considerations guide targeted diagnostic approaches for other anatomical forms.
The integration of cytological assessment, advanced imaging, and flow cytometry has significantly improved diagnostic accuracy and prognostic assessment in canine lymphoma. Unlike feline lymphoma, where staging has shown inconsistent prognostic value, clinical stage remains an important prognostic factor in dogs, particularly when combined with immunophenotype and WHO classification.
Current staging protocols emphasize the importance of complete immunophenotyping, as the distinction between B-cell and T-cell lymphomas has profound implications for treatment selection and prognosis. The routine use of flow cytometry has revolutionized rapid diagnosis and monitoring, allowing for more timely therapeutic intervention.
Future directions in canine lymphoma staging will likely incorporate additional molecular markers, including gene expression profiling and next-generation sequencing techniques, to further refine prognostic assessment and guide personalized therapeutic approaches. The establishment of standardized protocols across veterinary institutions will be essential for advancing our understanding of this complex disease and improving outcomes for canine patients.
