Current Perspectives in Feline Lymphoma: Updates on Staging and Grading Approaches
Feline lymphoma continues to present unique challenges in veterinary oncology, with anatomical distribution, histological classification, and prognostic factors differing significantly from canine counterparts. Recent advances in understanding the biological behavior of feline lymphoma have prompted reconsideration of traditional staging methodologies. This review examines current evidence-based approaches to feline lymphoma staging and grading, with emphasis on anatomical site-specific considerations and the integration of novel diagnostic modalities.
Evolving Understanding of Feline Lymphoma
The historical World Health Organization (WHO) staging system for lymphoma was primarily developed for dogs and humans, often proving less applicable to feline patients. This classification system's applicability to feline patients has been tested through collaborative efforts of veterinary pathologists, including an initiative by the ACVP Oncology Committee that was later endorsed by the World Small Animal Veterinary Association (WASVA). Contemporary approaches increasingly recognize the distinctive features of feline lymphoma, particularly:
The high prevalence of alimentary forms (60-70% of cases)
The declining incidence of mediastinal lymphoma following widespread FeLV control
The increasing recognition of low-grade gastrointestinal lymphoma as a distinct entity
The emergence of renal lymphoma as a significant clinical entity
Recent epidemiological studies have documented important shifts in the presentation and characteristics of feline lymphoma. A 2018 comprehensive review found that low-grade alimentary lymphoma (LGAL) has increased significantly over the last decade and now represents 60-75% of gastrointestinal lymphoma cases in cats. This form is characterized by infiltration of neoplastic T-lymphocytes typically in the small intestine and shares many clinical, paraclinical, and ultrasonographic features with inflammatory bowel diseases, making diagnosis challenging.
Additionally, a 2023 study examining feline lymphoma in the Netherlands over a 10-year period found notable changes in patient demographics, with an increased median age (8.7 years) at diagnosis and shifts in anatomical distribution, with alimentary (24.5%) and nasopharyngeal (22.7%) being the most common subtypes. Interestingly, these changes could not be attributed solely to decreasing FeLV/FIV prevalence, suggesting other environmental or genetic factors may be involved in the changing epidemiology of feline lymphoma.
Feline 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 cats uses a modified 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 what appears to be "reverse stage migration" in feline lymphoma compared to historical data. A 2022 study on renal lymphoma found fewer stage IV and V cases and increased stage III cases compared to earlier data. The authors hypothesized that this shift may be due to the routine use of advanced diagnostics with greater sensitivity, providing a more accurate assessment of disease extent than techniques used in previous decades.
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 feline 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 feline lymphomas have historically been identified as intermediate (35%) to high-grade (50%), though this distribution has shifted with better recognition of low-grade forms.
More recently, the WHO classification has been applied to feline lymphomas to provide more specific categorization based on cell morphology and immunophenotype, including:
Diffuse large B-cell lymphoma
Peripheral T-cell lymphoma
T-cell-rich B-cell lymphoma
Lymphoblastic lymphoma
Small lymphocytic 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
Alimentary Lymphoma
The alimentary tract represents the most common site for feline lymphoma, with distinct high-grade and low-grade variants requiring different staging approaches:
Low-Grade Alimentary Lymphoma (LGAL)
Current Diagnostic Approach: Full-thickness biopsies remain the gold standard, but recent studies validate the utility of endoscopic biopsies when evaluated with appropriate immunohistochemistry (CD3, CD79a, CD20).
Staging Recommendations:
Complete blood count, serum biochemistry, and urinalysis
Thoracic radiographs
Abdominal ultrasonography with evaluation of mesenteric lymph nodes
FIV/FeLV testing
Fine needle aspiration of enlarged mesenteric lymph nodes when identified on imaging
Cytological assessment of aspirates for evidence of neoplastic infiltration
Notable Update: Bone marrow evaluation is generally unnecessary in cases with normal hematological parameters
For low-grade lymphoma, the gastrointestinal tract and internal lymph nodes are the most common locations. Clinical signs typically develop slowly over months to years and often overlap with inflammatory bowel disease (IBD). Additional testing on cytology or biopsy samples is frequently necessary to distinguish IBD from low-grade lymphoma, as this significantly impacts treatment plans and prognosis.
Kiselow et al. (2018) demonstrated that less than 5% of cats with LGAL and normal hematological parameters had bone marrow involvement, questioning the utility of routine marrow evaluation in these cases.
High-Grade Alimentary Lymphoma
Current Diagnostic Approach: Cytology is often sufficient for diagnosis; histopathology with immunophenotyping is recommended for definitive classification
Staging Recommendations:
Standard database (CBC, biochemistry, urinalysis)
Three-view thoracic radiographs
Comprehensive abdominal ultrasonography
FIV/FeLV testing
Fine needle aspiration of abdominal masses and regional lymph nodes
Cytological assessment of peripheral lymph nodes, even when not obviously enlarged
Flow cytometry on aspirate samples when available
Notable Update: Bone marrow aspiration remains recommended due to higher metastatic potential
The value of cytological assessment in high-grade alimentary lymphoma cannot be overstated. Aspirates from neoplastic tissue typically yield highly cellular samples with a monomorphic population of large, immature lymphoid cells exhibiting features of malignancy. When combined with clinical findings and imaging, FNA cytology may provide sufficient diagnostic confidence to initiate treatment without requiring more invasive procedures.
Factors reported to affect prognosis in high-grade lymphoma include FeLV status, response to therapy, anatomic location, stage, grade, clinical substage, and body weight.
Mediastinal Lymphoma
While less common in the post-FeLV era, mediastinal lymphoma requires specific considerations:
Current Diagnostic Approach: Ultrasound-guided fine needle aspiration typically yields diagnostic samples
Staging Recommendations:
Standard database
FIV/FeLV testing (particularly important given higher FeLV association)
Abdominal ultrasonography
Notable Update: Flow cytometry of effusion fluid, when present, provides valuable immunophenotyping data and has largely replaced the need for excisional biopsy
Valli et al. (2020) reported that flow cytometric analysis of mediastinal effusions provided definitive immunophenotyping in 87% of cases, significantly reducing the need for more invasive diagnostic procedures.
Renal Lymphoma
Renal involvement occurs in approximately 5-10% of feline lymphoma cases, often as part of multicentric disease:
Current Diagnostic Approach: Ultrasound-guided FNA typically yields diagnostic samples
Staging Recommendations:
Standard database with particular attention to renal parameters
Thoracic radiographs
Comprehensive abdominal ultrasonography
Notable Update: SDMA and symmetric dimethylarginine have emerged as early biomarkers of renal dysfunction and may provide prognostic information
Cats with renal lymphoma can have concurrent central nervous system involvement and show behavioral changes, seizures, or difficulty walking. This unique presentation requires consideration of additional diagnostic procedures such as cerebrospinal fluid analysis and advanced imaging of the nervous system.
Cutaneous Lymphoma
Feline cutaneous lymphoma presents distinctive epitheliotropic and non-epitheliotropic forms:
Current Diagnostic Approach: Incisional or punch biopsies with immunohistochemistry are essential
Staging Recommendations:
Standard database
Thoracic radiographs
Abdominal ultrasonography
Notable Update: Clonality testing via PARR (PCR for Antigen Receptor Rearrangement) helps differentiate lymphoma from inflammatory dermatoses in equivocal cases
For equivocal cases, PARR analysis now provides an objective assessment of clonality, which is particularly valuable in differentiating inflammatory conditions from neoplastic processes.
Modern Diagnostic Modalities and Their Impact on Staging
Cytological Assessment
Fine Needle Aspiration (FNA): Despite being a cornerstone diagnostic tool in veterinary oncology, lymph node aspiration has been inconsistently included in standardized staging protocols for feline lymphoma. This omission is notable given that cytological assessment provides rapid, minimally invasive diagnostic information that can guide further staging procedures.
The role of FNA in lymphoma staging includes:
Initial diagnosis in cases with peripheral lymphadenopathy
Assessment of lymph node involvement in cases with primary disease at other sites
Sample collection for ancillary tests such as flow cytometry
Evaluation of treatment response during follow-up
Recent studies have highlighted both strengths and limitations of cytological assessment in feline lymphoma. A 2021 study demonstrated significant interobserver variability in cytological evaluation of feline nodal lymphomas, finding that cytological criteria commonly used for canine lymphomas are not readily adaptable to feline cases. This suggests the need for feline-specific cytological classification schemes. Additionally, research published in Frontiers in Veterinary Science found that probability modifiers (terms like "suspicious for" or "consistent with") are used more frequently in cytological diagnoses of neoplasia compared to non-neoplastic lesions, reflecting the diagnostic challenges in definitively identifying lymphoma via cytology alone.
Despite these challenges, when combined with complementary techniques such as flow cytometry and clonality testing, cytological assessment remains an essential component of comprehensive lymphoma staging.
Advanced Imaging
Computed Tomography: Increasingly available in referral settings, CT provides superior sensitivity for detection of subtle thoracic involvement and improved assessment of intra-abdominal lymphadenopathy.
Staging tests determine the extent of local disease and look for evidence of metastasis. The TNM system devised by the World Health Organization is the standard system for most tumors in veterinary medicine, though lymphoma has its own specific staging system.
Taylor et al. (2019) demonstrated that CT identified additional lesions not detected by conventional radiography in 27% of feline lymphoma cases, potentially altering staging in these patients.
Molecular Diagnostics
Clonality Testing: PARR analysis now provides an objective assessment of clonality, particularly valuable in differentiating inflammatory bowel disease from LGAL in equivocal cases.
Immunophenotyping: Beyond basic B-cell versus T-cell distinction, expanded immunophenotyping panels help predict biological behavior.
A collaborative study involving 20 pathologists examining 300 canine lymphoma cases has helped establish standards for applying the WHO classification system to veterinary patients, with work ongoing to refine these approaches for feline patients.
Moore et al. (2022) demonstrated that specific T-cell phenotypes (CD4+/CD8-) in cutaneous lymphoma correlated with significantly shorter survival times compared to other immunophenotypes, highlighting the prognostic value of comprehensive immunophenotyping.
Recommended Contemporary Staging Protocol
Based on current evidence, a comprehensive approach to feline lymphoma staging should include:
Complete clinical database:
Thorough physical examination with palpation of all accessible lymph nodes
Complete blood count with careful cytomorphological evaluation
Comprehensive biochemistry panel including renal parameters
Urinalysis
FIV/FeLV testing
Cytological assessment:
Fine needle aspiration (FNA) of peripheral lymph nodes, when enlarged
Ultrasound-guided FNA of internal lymph nodes or masses
Cytological evaluation with Wright-Giemsa or similar stains
Consideration of flow cytometry on aspirates for immediate immunophenotyping
Imaging studies:
Three-view thoracic radiographs (or CT, where available)
Complete abdominal ultrasonography with evaluation of all lymph nodes and parenchymal organs
Site-specific advanced imaging as indicated
Immunophenotyping:
Preferably performed on diagnostic samples via immunohistochemistry or flow cytometry
Can be performed on lymph node aspirates, tissue biopsies, or effusions
Bone marrow evaluation:
Recommended for high-grade lymphomas and cases with hematological abnormalities
May be omitted for low-grade alimentary lymphoma with normal hematological parameters
Clonality testing:
Valuable in histologically equivocal cases, particularly in differentiating inflammatory from neoplastic conditions
Complete blood count, chemistry panel, FeLV/FIV testing, and urinalysis are recommended for all feline lymphoma patients. Abdominal ultrasound and thoracic radiographs provide essential evaluation of potential disease sites and establish a baseline for monitoring treatment response.
Prognostic Implications of Modern Staging and Grading
Recent studies have identified several prognostic factors that may be identified during comprehensive staging:
Immunophenotype: T-cell phenotype generally carries worse prognosis than B-cell phenotype in most anatomical locations
Multiple Anatomic Sites: Involvement of multiple anatomic sites typically confers poorer prognosis
Hypercalcemia: Associated with more aggressive disease and poorer outcomes
FeLV Positivity: Generally associated with poorer response to therapy
Histological Grade: High-grade lymphomas typically have shorter survival times than low-grade forms
The median prognosis for low-grade lymphoma is 2-3 years with treatment using prednisolone and chlorambucil, which are generally well-tolerated by feline patients. In contrast, high-grade lymphomas typically have median survival times of less than 1 year even with aggressive multi-agent chemotherapy protocols.
Interestingly, clinical stage as traditionally defined has shown inconsistent prognostic value in feline patients. Louwerens et al. (2019) demonstrated that anatomical location and histological grade had greater prognostic significance than stage in a multivariate analysis of 145 feline lymphoma cases.
There is great variability in the grades, forms, stages, and subtypes of lymphoma in cats. This variability and the relatively low numbers of cats seen in clinical practice has often led to combining different anatomic forms and grades of lymphoma in both retrospective and prospective studies, potentially obscuring important prognostic differences.
Conclusion
Modern approaches to feline lymphoma staging and grading emphasize anatomical site-specific considerations, judicious use of advanced diagnostics, and recognition of the unique biological features of feline disease. While core elements of traditional staging remain valuable, contemporary protocols increasingly incorporate immunophenotyping, selective application of bone marrow evaluation, and consideration of molecular features.
The inclusion of cytological assessment through fine needle aspiration has emerged as a critical component of comprehensive lymphoma staging that has sometimes been overlooked in formal protocols. FNA offers a rapid, minimally invasive approach to diagnosis and staging that complements other diagnostic modalities. The integration of cytology with advanced techniques such as flow cytometry and PCR-based clonality testing has further enhanced its utility in the clinical management of feline lymphoma.
This tailored, multimodal approach to staging and grading allows for more accurate prognostication and treatment planning in feline lymphoma patients, ultimately improving clinical outcomes through more precise therapeutic targeting.
In the future, veterinary pathology will likely incorporate molecular data with histologic and cytologic assessment to yield more detailed and accurate information regarding tumor biology, though this will require collaborative, multicenter studies that standardize tumor collection and assessment protocols.
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