Aggressive vs. Indolent Lymphoma: Practical Distinctions

• Aggressive lymphoma progresses quickly and is typically life‑limiting without treatment.
• Indolent lymphoma progresses slowly and may not require immediate intervention.

Identifying whether a lymphoma is aggressive or indolent is a key early step, as it informs diagnostic priorities, treatment recommendations, and expectations for disease course.

Aggresive Forms of Lymphoma in Dogs

Aggressive lymphomas are characterized by rapid progression and a higher risk of illness if not addressed promptly.

Multicentric Lymphoma

Multicentric lymphoma is the most common form of lymphoma in dogs. It typically presens iwth enlargement of multiple peripheral lymph nodes. Diffuse large B-cell lymphoma is the most common type of multicentric lymphoma. Oncologists often say that “B is better, and T is terrible” when it comes to lymphoma, meaning that the more common aggressive B-cell lymphomas generally have a better prognosis than the less common aggressive T-cell lymphomas.¹

Many dogs with multicentric B-cell lymphoma present without clinical signs other than enlarged lymph nodes at the time of diagnosis (“substage a”).² Obtaining a diagnosis by fine needle aspirate (FNA) or biopsy is relatively easy due to the presence of enlarged external lymph nodes.

The most effective chemotherapy treatment for dogs with multicentric lymphoma remains the CHOP protocol.¹ In one study, median response duration following treatment with CHOP for dogs with B-cell lymphoma was 252 days versus 146 days for dogs with T-cell lymphoma in another study.^3,4  

Mediastinal Lymphoma

Mediastinal involvement is reported in up to 36% of dogs with multicentric lymphoma and in more than half of dogs with T-cell multicentric lymphoma, but a distinct mediastinal lymphoma also exists. This form tends to be more aggressive than multicentric lymphoma and is characterized by a mass in the mediastinum and the absence of peripheral lymph node involvement. Mediastinal lymphoma is overwhelmingly T-cell in origin, with 28 of 29 cases with immunophenotyping performed confirmed as T-cell in one study. In the same study, 85.4% of dogs were “substage b” (meaning that they felt sick due to their cancer), and more than half were hypercalcemic.⁵

Clinical signs may initially be non-specific, including

• Lethargy
• Polyuria/polydipsia (prompting concern for hypercalcemia)
• Coughing or difficulty breathing

A diagnosis is typically made following identification of a mediastinal mass on X-rays or computed tomography and confirmed with an ultrasound-guided FNA or biopsy. There is a small risk associated with sampling inside the thorax, but many mediastinal masses are large, which limits the risk of aspirating the lungs. While chemotherapy can provide benefit, response rates and overall outcomes are generally poorer than those seen with multicentric B‑cell lymphoma, with a median response duration of 144 days when treated with CHOP.⁵

Gastrointestinal Lymphoma

Gastrointestinal lymphoma is a less common but more aggressive form of lymphoma characterized by involvement of the gastrointestinal tract and lack of peripheral lymph node involvement. This form most commonly affects the intestines and local lymph nodes, and a majority are T-cell in origin. 

Clinical signs are very common and typically include:

• Vomiting
• Diarrhea
• Anorexia
• Weight loss
• Combinations of the above

Intestinal masses or enlarged lymph nodes may be present on abdominal palpation. Clinical signs typically prompt an ultrasound, which often reveals masses or thickened intestinal walls with loss of layering and enlarged local lymph nodes. Ultrasound-guided FNA can often be performed from either site, and intra-abdominal lymph nodes may be large enough to biopsy safely. Full-thickness surgical biopsies can be performed, but this could delay the initiation of treatment. Gastrointestinal lymphoma tends to respond poorly to treatment compared to multicentric lymphoma in dogs. In one study, just half of the dogs with gastrointestinal lymphoma treated with CHOP or a variation of CHOP lived 60 days or longer.⁶

Indolent Forms of Lymphoma in Dogs

In contrast to aggressive forms of lymphoma that progress rapidly and eventually relapse or stop responding to treatment, there are well-recognized indolent forms that progress more slowly and can be managed with less intensive treatment options.

T-Zone Lymphoma

T-zone lymphoma is the most common indolent lymphoma in dogs, and it's an important exception to the “B is better, and T is terrible” saying. T-zone lymphoma is frequently seen in golden retrievers and may present as a few or many enlarged lymph nodes, abnormal cells in the blood, or, rarely, in other tissues such as the tongue.^7,8,9

A biopsy with immunohistochemistry and/or cytology with flow cytometry is typically needed to confirm the diagnosis. T-zone lymphomas typically express many T-cell antigens (CD3+, CD4+, CD25+) but don’t express CD45 (which is normally expressed by many types of white blood cells). T-zone lymphomas often do not require treatment, however if lymph nodes are large enough to cause illness, can be managed with the oral chemotherapy drug chlorambucil and prednisone, and in some cases may not rapidly progress even without treatment. T-zone lymphoma is associated with significantly longer survival times than aggressive T-cell lymphomas that express CD45 (median survival time of 637 days vs. 159 days, respectively).^7,10 

Splenic Marginal Zone Lymphoma (MZL)

MZL is an indolent form of B-cell lymphoma typically characterized by a solitary splenic mass or a diffusely enlarged spleen. Clinical signs vary: Half of the dogs reported no clinical signs, and the other dogs showed combinations of non-specific signs such as:

• Lethargy
• Decreased appetite
• Weight loss
• Spontaneous hemoabdomen

Obtaining a diagnosis usually requires histopathology after splenectomy. Chemotherapy after splenectomy may not be indicated, and many dogs are successfully treated with splenectomy alone. In one study, half of all dogs with MZL treated with splenectomy, with or without other treatments, lived more than a year, and half of all dogs that initially had no clinical signs suggesting a splenic mass lived more than 1,000 days.¹¹

Clinical Revance for General Practice

Lymphoma is sometimes referred to as just one disease, but it is actually a complex group of cancers that can have different presentations requiring different treatments, and associated with different outcomes. Distinguishing between aggressive and indolent lymphoma is important so that veterinarians can tailor the care and treatment recommendations for our patients and provide clear guidance to our clients. Starting with the right diagnostic tests and setting realistic expectations about treatment options and outcomes helps clients navigate a complex diagnosis.

 

References:

1. Vail DM, Pinkerton M, Young KM. "Hematopoietic Neoplasia." Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition. Edited by Vail DM, Thamm DH, Liptak JM. Elsevier, 2019, pp 688-772.

2. Licenziato L, Minoli L, & Aresu L. Predicting outcome in dogs with diffuse large B-cell lymphoma with a novel immune landscape signature. Veterinary Pathology 2023 60(3):308-315. doi: 10.1177/03009858231162209

3. Childress MO, Ramos-Vara JA, Ruple A. Retrospective analysis of factors affecting clinical outcome following CHOP-based chemotherapy in dogs with primary nodal diffuse large B-cell lymphoma. Vet Comp Oncol 2018; 16(1):E159-E168. doi: 10.1111/vco.12364

4. Rebhun RB et al. CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma. Vet Comp Oncol 2011; 9(1):38-44 doi: 10.1111/j.1476-5829.2010.00230.x

5. Moore EL et al. Patient characteristics, prognostic factors, and outcome of dogs with high-grade primary mediastinal lymphoma. Vet Comp Oncol 2018; 16:E45-51. doi: 10.1111/vco.12331

6. Sogame N, Risbon R, & Burgess KE. Intestinal lymphoma in dogs: 84 cases (1997-2012). JAVMA 2018 252(4):440-447.

7. Seeling DM, et al. Canine T-zone lymphoma: unique immunophenotypic features, outcome, and population characteristics. J Vet Intern Med 2014; 28(3);878-886. doi: 10.1111/jvim.12343

8. Stein L, Bacmesiter C, Kiupel, M. Immunophenotypic characterization of canine nodal T-zone lymphoma. Vet Pathol 2020; 58(2):288-292. doi: 10.1177/0300985820974078

9. Harris LJ et al. Clinicopathologic features of lingual canine T-zone lymphoma. Vet Comp Oncol 2018 Mar;16(1):131-139. doi: 10.1111/vco.12322.

10. Avery PR et al. Flow cytometric characterization and clinical outcome of CD4+ T-cell lymphoma in dogs: 67 cases. J Vet Intern Med 2014; 28(2):538-546. doi: 10.1111/jvim.12304

11. O’Brien D et al. Clinical characteristics and outcomes in dogs with splenic marginal zone lymphoma. J Vet Intern Med. 2013 Jul-Aug;27(4):949-54. doi: 10.1111/jvim.12116

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