Dante Meza Ruiz DVM, M.Ed., DVSc, Dipl. ACVP/ASVCP

Case presentation

A 12-year-old spayed female Beagle was presented to a veterinary clinic with a history of a golf ball-sized mass on the neck. A fine-needle aspiration (FNA) was performed, and the sample was submitted to NationWide Laboratories for evaluation.

Cytological findings

The sample was highly cellular and mildly hemorrhagic. It was predominantly composed of a monomorphic population of intermediate to large lymphocytes. These cells displayed scant to moderate amounts of pale blue cytoplasm, often containing multiple magenta granules. The nuclei were round to angular, occasionally cleaved, with finely stippled chromatin and one to two nucleoli observed in some cells. Occasional mitotic figures were present. Scattered throughout the sample were a few small lymphocytes and rare plasma cells.

Figure 1: Photomicrograph of direct smears from a fine-needle aspirate of a golf ball-sized mass on the neck of a dog, stained with Leishman stain. The smear shows several intermediate to large lymphocytes with scant to moderate amounts of pale blue cytoplasm, frequently containing multiple magenta granules. Scattered among them are low numbers of small lymphocytes, x60 objective.

Figure 2: Several intermediate to large lymphocytes with pale blue cytoplasm, containing multiple magenta granules. The nuclei are round to angular, with finely stippled chromatin, and one to two nucleoli are visible in some cells. Leishman stain, x100 objective.

Figure 3: Occasional mitotic figures present. Leishman stain, x100 objective.

Interpretation

A diagnosis of lymphoma was established, and based on the cytological characteristics of the cells, it was classified as a large granular lymphocyte lymphoma (LGLL).

Discussion

Canine lymphoma is a heterogenous disease with variable clinical presentations, morphologic features, and biological behaviour. Subtyping lymphoma according to the World Health Organization (WHO) classification can assist in guiding treatment decisions and predicting prognosis1.

Large granular lymphocytes (LGLs) are a type of intermediate to large lymphocyte distinguished by their prominent azurophilic cytoplasmic granules. They originate from either cytotoxic T cells (T-LGL) or natural killer (NK) cells (NK-LGL). In dogs, granular lymphocyte neoplasia most frequently manifests as chronic lymphocytic leukaemia (CLL)2.

Canine large granular lymphocyte lymphoma (LGLL) is rarely reported, with extra-nodal presentations and a T-cell immunophenotype being most common. Among these, hepatosplenic involvement is the most frequently observed form, frequently originating from CD11d+ TCRγδ-restricted LGLs within the splenic red pulp3.  γδ T lymphocytes are primarily found in the spleen, though small numbers have also been identified in lymph nodes and certain epithelial-rich tissues. While their exact function remains unclear, they are thought to play a role in the first line of defence within the epidermal and mucosal epithelial barriers4.

Other reported primary sites for canine LGLL include peripheral lymph nodes, skeletal muscle, mediastinum, skin, urinary bladder, small intestine, and kidney. Due to the variability in clinical presentations and treatment protocols described in the current literature, an optimal treatment approach for canine LGLL has yet to be established 3. Nevertheless, canine LGLL appears to follow an aggressive clinical course, with most dogs presenting at diagnosis with substage b disease (exhibiting clinical signs of illness). While hypercalcemia is a common contributor to clinical signs in dogs with T-cell lymphoma, a recent study on LGLL found that only a small proportion of affected dogs were hypercalcaemic. This suggests that hypercalcemia is unlikely to be a major factor in the high frequency of clinical signs observed in these cases 3.

Haematological abnormalities are commonly observed in cases of LGLL, with anaemia, neutrophilia/neutropenia, monocytosis, and thrombocytopenia frequently reported. Although the underlying mechanisms are not fully understood, potential contributing factors include bone marrow involvement, haemophagocytic syndrome, immune dysregulation, and elevated inflammatory biomarkers, all of which have been previously associated with a poorer prognosis5.

Unfortunately, no additional clinical history or further diagnostic testing was provided to the laboratory, and information regarding the outcome of the case is unavailable. However, based on previously reported cases, this form of lymphoma is considered aggressive and is typically associated with a short median progression-free interval and overall survival time. Currently, the optimal management approach for canine LGLL has not been determined.

References

1.       Valli VE, San Myint M, Barthel A, Bienzle D, Caswell J, Colbatzky F, Durham A, Ehrhart EJ, Johnson Y, Jones C, Kiupel M, Labelle P, Lester S, Miller M, Moore P, Moroff S, Roccabianca P, Ramos-Vara J, Ross A, Scase T, Tvedten H, Vernau W. Classification of canine malignant lymphomas according to the World Health Organization criteria. Vet Pathol. 2011 Jan;48(1):198-211. doi: 10.1177/0300985810379428. Epub 2010 Sep 22. PMID: 20861499.

2.       McDonough SP, Moore PF. Clinical, hematologic, and immunophenotypic characterization of canine large granular lymphocytosis. Vet Pathol. 2000 Nov;37(6):637-46. doi: 10.1354/vp.37-6-637. PMID: 11105953.

3.       Yale AD, Crawford AL, Gramer I, Guillén A, Desmas I, Holmes EJ. Large granular lymphocyte lymphoma in 65 dogs (2005-2023). Vet Comp Oncol. 2024 Mar;22(1):115-124. doi: 10.1111/vco.12959. Epub 2023 Dec 29. PMID: 38156420.

4.       Ortiz AL, Carvalho S, Leo C, Riondato F, Archer J, Cian F. Gamma delta T-cell large granular lymphocyte lymphoma in a dog. Vet Clin Pathol. 2015 Sep;44(3):442-7. doi: 10.1111/vcp.12265. Epub 2015 May 12. PMID: 25965815.

5.       Varvil MS, Messick JB, Dos Santos AP. Hemophagocytic syndrome associated with large granular lymphoma in an adult dog. Vet Clin Pathol. 2022 Mar;51(1):115-118. doi: 10.1111/vcp.13053. Epub 2022 Feb 9. PMID: 35141916.