Indolent Lymphoma in Dogs
You diagnose indolent lymphoma in a dog. What is indolent lymphoma? What is the prognosis and what are the treatment options?
What is indolent lymphoma?
Indolent lymphoma (also called small-cell or low-grade lymphoma) is an uncommon form of lymphoma in dogs, representing around 5-29%1 of all canine lymphoma. The subtypes described include follicular lymphoma, marginal zone lymphoma, mantle zone and T-zone lymphoma, which are all derived from B-cells (except for T-zone lymphoma, which is T-cell in origin).2,3
In general, indolent lymphoma is characterised by small lymphocytes, a low mitotic index and slow clinical course of progression. Most dogs with indolent lymphoma present with generalised lymphadenopathy. Some dogs present with solitary lymph node involvement or only splenic involvement.
Few dogs present with clinical signs, and if clinical signs are present (including lymphadenopathy), it can wax and wane and is usually mild.
T-zone lymphoma (TZL)
T-zone lymphoma is the most common subtype in canine indolent lymphoma representing around 60% of dogs with indolent lymphoma.1 TZL is characterised by unique loss of CD45 expression, T-zone distinct histologic pattern and small clear cell cytomorphology.4-6 This subtype is associated with the longest median survival times in dogs with indolent lymphoma.1
Middle-aged to older dogs are primarily affected (median age 8 to 10 years).5 Common breeds affected include Golden retriever (40-50%)6,7 and Shih Tzu.5 There is no apparent gender predilection.
Dogs typically present with generalised peripheral lymphadenopathy (that may wax and wane) and/or lymphocytosis with no clinical signs of illness (clinical substage a, 80%).5 If clinical signs are present, it is usually non-specific and mild. TZL is classified as stage V in 93% of cases due to peripheral blood and/or bone marrow involvement.6 Dogs can also present with splenomegaly and/or hepatomegaly. 70% of dogs present with concurrent medical problems such as adult-onset of demodicosis (10- 50% of dogs), infection or other neoplastic diseases.8 These are speculated to occur due to immune dysfunction from the indolent lymphoma.
The most common abnormal clinicopathologic finding is lymphocytosis (50-65%), and it is typically mild (median 5-6K cells/μL, range 1K to 31K cells/μL). Peripheral cytopaenias are uncommon (<10%) and if present is generally mild.5
The prognosis for canine TZL has not been extensively studied. However, unfavourable prognostic factors include high lymphocyte counts and perhaps dogs that present unwell (i.e. clinical substage b). In one study of canine indolent lymphoma, dogs with lymphocyte counts >9K cells/μL have median survival times of 15.4 months compared to not reached if lymphocyte counts <9K cells/μL.1
Generally, indolent lymphoma is a slowly progressive cancer associated with prolonged survival times (with and without treatment). Some dogs will not require therapy for a year or more after diagnosis. However, unlike some canine high-grade or large-cell lymphoma, it is ultimately incurable. Despite this, many dogs with indolent lymphoma will live near-normal lifespans and ultimately die of non-lymphoma-related disorders.
Although canine TZL is incurable, the prognosis is generally good (with or without treatment), with reported median survival times of 2 to 2.75 years.5,8 However, 10% of dogs will develop a second malignancy, eventually leading to death.
In asymptomatic dogs, therapy is not recommended until there is conceivable disease-related clinical signs (such as extreme fatigue), clinically significant cytopaenias, progressive lymphocytosis or lymphocytosis >9K cells/μL, or massive or progressive lymphadenopathy or hepatosplenomegaly.
In asymptomatic dogs with stable lymphadenopathy and/or lymphocytosis and no cytopaenias, ‘active surveillance’ is recommended. This will entail regular monitoring of complete blood counts (including blood film review), and physical examination is recommended, initially monthly for three months, and if stable, then every two to three months thereafter. This can be challenging for many owners. However, it is best not to start treatment as long as the dog feels well.
When therapy is deemed necessary, the treatment of choice for canine TZL is chlorambucil and prednisolone.
With this approach, the goal of therapy is to control the disease (i.e. partial remission or stable disease). Although a complete remission is ideal and may occur in dogs with TZL, it is unusual in dogs with indolent lymphoma. Despite not attaining complete remission, dogs can still live a long time. The median survival times for canine indolent lymphomas treated with chlorambucil and prednisolone exceed 44 months, compared to 22 months in dogs receiving a CHOP based chemotherapy protocol.1 Although this is numerically different, treatment type was not found to be significantly different statistically. Also, when dogs go into complete remission from therapy, other associated infections (such as demodicosis) typically resolves.
Splenic marginal zone lymphoma
Splenic marginal zone lymphoma is a form of indolent B-cell lymphoma representing between 4 and 36% of canine indolent lymphoma. It is characterised by abnormal proliferation of small mature lymphocytes in the marginal zone of lymphoid follicles, in the spleen (stage IV) and generally, has a relatively slow clinical course of disease.9
Middle-aged to older dogs are primarily affected (mean age 8 to 10 years). There is no apparent gender or breed predilection.9
The most common clinical signs at presentation is a haemoabdomen and distended abdomen, secondary to a bleeding splenic mass (clinical substage b). Some dogs present with non-specific clinical signs such as lethargy, anorexia, vomiting and weight loss. However, 48% present asymptomatic and incidentally found when clinicians notice a splenic mass or splenomegaly on physical examination or routine abdominal ultrasonogram. It is common for dogs to present with concurrent medical problems such as non-malignant diseases (48%) and other neoplastic diseases (35%).9 These are speculated to occur due to immune dysfunction from the indolent lymphoma.
Anaemia and thrombocytopaenia are the most common abnormal clinicopathologic findings. Lymphocytosis is rare and if present, is generally mild. Abdominal ultrasonogram typically reveals a splenic mass (66%), although multiple splenic nodules and splenomegaly are observed in 24% and 7% of dogs, respectively. Occasionally there is the involvement of splenic hilar lymph nodes.9
The prognosis for canine splenic marginal zone lymphoma has also not been extensively studied. However, unfavourable prognostic factors include high lymphocyte counts and dogs that present unwell (i.e. clinical substage b). In one study of canine indolent lymphoma, dogs with lymphocyte counts >9K cells/μL have median survival times of 15.4 months compared to not reached if lymphocyte counts <9K cells/μL.1 In one study of canine splenic marginal zone lymphoma, dogs that present with no clinical signs of illness had median survival times of three years after splenectomy, compared to 10 months in dogs that presented with clinical signs of illness due to cancer.9
Generally, splenic marginal zone lymphoma is a slowly progressive cancer associated with prolonged survival times after splenectomy ± chemotherapy. Some dogs will not require therapy for a year or more after splenectomy alone. However, unlike some canine high-grade or large-cell lymphoma, it is ultimately incurable. Despite this, many dogs with indolent lymphoma will live near-normal lifespans and ultimately die of non-lymphoma-related disorders.
Although canine splenic marginal zone lymphoma is incurable, the prognosis is generally good after splenectomy (with or without chemotherapy) with reported median survival times of 1 to 3 years.10
The benefits of adjuvant chemotherapy in dogs after splenectomy is not clearly defined. In one study of 34 dogs with splenic marginal zone lymphoma that underwent splenectomy, 18% of dogs received various forms of adjuvant chemotherapy. Due to the small numbers and heterogeneity in chemotherapy treatment administered, it is unclear whether adjuvant chemotherapy is required in all dogs after splenectomy. In this study, for asymptomatic dogs, the median survival time after splenectomy (± chemotherapy) was three years, compared to 10 months in dogs that presented with clinical signs of illness due to cancer.9
For asymptomatic dogs, splenectomy alone has the potential to provide long survival times. Therefore, one option is 'active surveillance', which entails regular monitoring with complete blood counts (including blood film review), physical examination and abdominal ultrasonogram, initially monthly for three months, then every two-three months thereafter. Treatment can be considered when there is evidence of progressive disease. However, some dogs can succumb to their disease within a few months after surgery. Chemotherapy is most effective in the adjuvant setting. Therefore, if owners are willing to try everything possible to give their dog the best chance of the most prolonged disease-free interval and survival time possible and provided the dog has a good quality of life, splenectomy followed by adjuvant chemotherapy will improve those chances.
For dogs that have clinical signs related to their splenic marginal zone lymphoma, I recommend adjuvant oral chlorambucil and prednisolone.
Other indolent B-cell lymphomas
Canine nodal marginal zone lymphoma, although it is designated an indolent B-cell lymphoma, it is generally more aggressive with median progression-free intervals of five months and overall survival times of 8.5 months.11 This is substantially less than splenic marginal zone lymphoma, which is associated with long-term survival after splenectomy (with and without chemotherapy).
Mantle zone lymphoma and follicular lymphoma are rare in dogs but appear to have a good prognosis with treatment.
Some indolent lymphomas are bad
Some dogs with indolent lymphoma will develop a second malignancy, eventually leading to death. Moreover, there will be a subset of dogs that do not behave in the typical indolent manner and despite aggressive treatment, die within a short period.6,12 Moreover, indolent lymphomas can occasionally transform into high-grade or large-cell lymphoma (known as ‘Richter’s syndrome) or develop a more aggressive form of lymphoma.13,14 When these occur, further treatment can be pursued (particularly in dogs that do not respond to initial therapy). However, in dogs that develop ‘Richter’s syndrome’, the disease is rapidly progressive, and the prognosis is usually guarded, even after treatment with aggressive chemotherapy. It is important for owners to be aware of all of this.
Vets, I hope this information helps you understand a bit more about the prognosis and treatment options for dogs with indolent lymphoma. If you have a question about indolent lymphoma in dogs or have a case that you would like evaluated, please do not hesitate to get in touch by clicking here.
References
1. Flood-Knapik KE, Durham AC, Gregor TP, et al. Clinical, histopathological and immunohistochemical characterization of canine indolent lymphoma. Vet Comp Oncol 2013;11:272-286.
2. Valli VE, Kass PH, San Myint M, et al. Canine lymphomas: association of classification type, disease stage, tumor subtype, mitotic rate, and treatment with survival. Vet Pathol 2013;50:738-748.
3. Valli VE, Vernau W, de Lorimier LP, et al. Canine indolent nodular lymphoma. Vet Pathol 2006;43:241-256.
4. Martini V, Cozzi M, Arico A, et al. Loss of CD45 cell surface expression in canine T-zone lymphoma results from reduced gene expression. Vet Immunol Immunopathol 2017;187:14-19.
5. Seelig DM, Avery P, Webb T, et al. Canine T-zone lymphoma: unique immunophenotypic features, outcome, and population characteristics. J Vet Intern Med 2014;28:878-886.
6. Martini V, Marconato L, Poggi A, et al. Canine small clear cell/T-zone lymphoma: clinical presentation and outcome in a retrospective case series. Vet Comp Oncol 2016;14 Suppl 1:117-126.
7. Hughes KL, Labadie JD, Yoshimoto JA, et al. Increased frequency of CD45 negative T cells (T zone cells) in older Golden retriever dogs. Vet Comp Oncol 2018;16:E109-e116.
8. Mizutani N, Goto-Koshino Y, Takahashi M, et al. Clinical and histopathological evaluation of 16 dogs with T-zone lymphoma. J Vet Med Sci 2016;78:1237-1244.
9. O'Brien D, Moore PF, Vernau W, et al. Clinical characteristics and outcome in dogs with splenic marginal zone lymphoma. J Vet Intern Med 2013;27:949-954.
10. Stefanello D, Valenti P, Zini E, et al. Splenic marginal zone lymphoma in 5 dogs (2001-2008). J Vet Intern Med 2011;25:90-93.
11. Cozzi M, Marconato L, Martini V, et al. Canine nodal marginal zone lymphoma: Descriptive insight into the biological behaviour. Vet Comp Oncol 2018;16:246-252.
12. Aresu L, Martini V, Rossi F, et al. Canine indolent and aggressive lymphoma: clinical spectrum with histologic correlation. Vet Comp Oncol 2015;13:348-362.
13. Suwa A, Shimoda T. Concurrent with T-zone lymphoma and high-grade gastrointestinal cytotoxic T-cell lymphoma in a dog. J Vet Med Sci 2017;79:736-739.
14. Parachini-Winter C, Curran KM, Russell DS, et al. A case of canine high-grade T-cell lymphoma immunophenotypically consistent with T-zone lymphoma. Vet Clin Pathol 2018;47:643-648.