Clinical characteristics, treatment, and outcome of dogs with presumed primary hepatic lymphoma: 18 cases (1992–2008)

Gillian Dank School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot 76100, Israel.

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Kenneth M. Rassnick Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Orna Kristal Chavat Daat Veterinary Specialty Center, Beit Berl, Kfar Saba 44905, Israel.

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Carlos O. Rodriguez Jr Department of Veterinary Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Craig A. Clifford Red Bank Veterinary Hospital, 197 Hance Ave, Tinton Falls, NJ 07724.

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Rebecca Ward Red Bank Veterinary Hospital, 197 Hance Ave, Tinton Falls, NJ 07724.

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Courtney L. Mallett Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Tracy Gieger Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Gilad Segev School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot 76100, Israel.

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Abstract

Objective—To determine outcome of dogs with presumed primary hepatic lymphoma treated with various multiagent, doxorubicin-based chemotherapeutic protocols and identify factors associated with prognosis.

Design—Retrospective case series.

Animals—18 dogs with presumed primary hepatic lymphoma.

Procedures—Medical records were reviewed for information on signalment, treatment, and outcome.

Results—8 dogs had a complete remission (CR), with a median remission duration of 120 days. Dogs with leukocytosis, neutrophilia, hypoalbuminemia, hyperbilirubinemia, or a combination of hypoalbuminemia and hyperbilirubinemia were less likely to achieve a CR. Overall median survival time (MST) was 63 days (range, 2 to 402 days). In a multivariate analysis, response to treatment and serum albumin concentration were associated with MST. Dogs that did not achieve a CR had a significantly shorter MST than did dogs that did achieve a CR (13 vs 283 days, respectively). Dogs with serum albumin concentration < 2.5 g/dL at the time treatment was initiated had a significantly shorter MST than did dogs with serum albumin concentration within reference limits (10 vs 128 days, respectively). There was also a positive correlation between serum albumin concentration and survival time (r = 0.74).

Conclusions and Clinical Relevance—Results suggested that dogs with primary hepatic lymphoma that underwent chemotherapy had a poor prognosis, with a low response rate. Dogs that responded to treatment had a better prognosis, and dogs with hypoalbuminemia had a poorer prognosis.

Abstract

Objective—To determine outcome of dogs with presumed primary hepatic lymphoma treated with various multiagent, doxorubicin-based chemotherapeutic protocols and identify factors associated with prognosis.

Design—Retrospective case series.

Animals—18 dogs with presumed primary hepatic lymphoma.

Procedures—Medical records were reviewed for information on signalment, treatment, and outcome.

Results—8 dogs had a complete remission (CR), with a median remission duration of 120 days. Dogs with leukocytosis, neutrophilia, hypoalbuminemia, hyperbilirubinemia, or a combination of hypoalbuminemia and hyperbilirubinemia were less likely to achieve a CR. Overall median survival time (MST) was 63 days (range, 2 to 402 days). In a multivariate analysis, response to treatment and serum albumin concentration were associated with MST. Dogs that did not achieve a CR had a significantly shorter MST than did dogs that did achieve a CR (13 vs 283 days, respectively). Dogs with serum albumin concentration < 2.5 g/dL at the time treatment was initiated had a significantly shorter MST than did dogs with serum albumin concentration within reference limits (10 vs 128 days, respectively). There was also a positive correlation between serum albumin concentration and survival time (r = 0.74).

Conclusions and Clinical Relevance—Results suggested that dogs with primary hepatic lymphoma that underwent chemotherapy had a poor prognosis, with a low response rate. Dogs that responded to treatment had a better prognosis, and dogs with hypoalbuminemia had a poorer prognosis.

Lymphoma is a common disease in dogs, accounting for up to 24% of all neoplasms.1 The multicentric form of canine lymphoma is the most common, accounting for 80% of all cases. In this form, there is variable involvement of lymphoreticular organs, including the lymph nodes, liver, spleen, blood, and bone marrow. Canine lymphoma is commonly treated with chemotherapeutic protocols, including various CHOP protocols. Remission rates, median remission durations, and MSTs of 75% to 90%, 168 to 270 days, and 6 to 12 months, respectively, have been reported for dogs with multicentric lymphoma treated with various chemotherapeutic protocols.2–7

In contrast to the numerous studies evaluating the prognosis for dogs with multicentric lymphoma, there have been relatively few studies evaluating prognosis for dogs with primary lymphoma involving other anatomic locations. This lack of published information limits clinicians' ability to provide a reliable prognosis and may affect the willingness of dog owners to pursue treatment for their affected pets. The purpose of the study reported here was to determine outcome of dogs with presumed primary hepatic lymphoma treated with various multiagent, doxorubicin-based chemotherapeutic protocols and identify factors associated with prognosis.

Materials and Methods

Criteria for selection of cases—Medical records from the School of Veterinary Medicine, Hebrew University of Jerusalem, Israel; the College of Veterinary Medicine, Cornell University, Ithaca, NY; Chavat Daat Veterinary Specialty Center, Kfar Saba, Israel; the School of Veterinary Medicine, University of California-Davis; Red Bank Veterinary Hospital, Tinton Falls, NJ; the College of Veterinary Medicine, University of Georgia, Athens, Ga; and the School of Veterinary Medicine, Louisiana State University, Baton Rouge, La, were searched to identify dogs with presumed primary hepatic lymphoma examined between 1992 and 2008. Dogs were presumed to have primary hepatic lymphoma if they did not have peripheral lymphadenopathy and a cytologic or histologic diagnosis of lymphoma had been made on the basis of results of examination of a hepatic sample. Dogs with concurrent abdominal or thoracic lymphadenopathy and splenomegaly were eligible for inclusion in the study. Dogs were included only if initial treatment for the hepatic lymphoma had consisted of a multiagent, doxorubicin-based chemotherapeutic protocol that included CHOP. Dogs with lymphoma of the gastrointestinal tract were excluded. Dogs were also excluded if they were not treated or were treated only with corticosteroids or with a single-agent protocol.

Medical records review—Information obtained from the medical records of dogs included in the study consisted of signalment, clinical signs at the time of initial examination, diagnostic test results, anatomic sites affected, immunophenotype, response to treatment, and date of death. Dogs were clinically staged at the time of diagnosis by use of the World Health Organization criteria for canine lymphoma. In most cases, the initial staging workup included a physical examination, CBC (including examination of a blood smear by a clinical pathologist), serum biochemical profile, urinalysis, thoracic radiography, and abdominal ultrasonography; in some dogs, cytologic examination of a bone marrow aspirate was also performed. Dogs were further classified as either substage a (having no clinical signs) or substage b (having signs of gastrointestinal or respiratory tract disease, hypercalcemia [serum calcium concentration > 12 mg/dL], rectal temperature > 39.4°C [103°F], hyphema, or uveitis).

Response to treatment was determined mainly on the basis of results of clinical evaluations. Complete remission was defined as resolution of all clinical signs and disappearance of all clinical evidence of disease on the basis of a physical examination. When available, results of abdominal ultrasonography or thoracic radiography were used to evaluate changes in internal organs. Partial remission was defined as a ≥ 50% but < 100% reduction in size of all measurable masses when lymphadenopathy or a hepatic mass was reported or as partial resolution of alterations in hepatic echogenicity identified during abdominal ultrasonography. No response was defined as no change in clinical signs; a < 50% reduction in size of measurable masses, as described for a PR; an increase in the size of measurable masses; or the appearance of new lesions. Dogs that died before reevaluation 1 week after initiation of treatment were considered to have not responded. After completion of the initial doxorubicin-based chemotherapeutic protocol, dogs were generally rechecked on a monthly basis to evaluate remission status.

Duration of the first remission was defined as the time from when a dog first achieved a CR or PR until the time when a relapse (ie, recurrence of organomegaly or abdominal or thoracic lymphadenopathy) or progressive disease (≥ 25% increase in the size of measurable masses), respectively, was identified. Restaging was performed only after relapse. For analysis of remission duration, dogs were censored if relapse or progressive disease had not occurred before the end of the study, they were lost to follow-up, or they died before relapse or progressive disease occurred. Survival time was defined as the time from the first day of chemotherapy administration until death from any cause.

Statistical analysis—Results of clinicopathologic testing were classified as normal or abnormal by comparison with established reference ranges for the participating institution where the test was performed. For all continuous variables, the Shapiro-Wilk test was used to determine whether data were normally distributed. Continuous variables were summarized as median, mean, and range, and values were compared between groups (eg, CR vs PR) with the Mann-Whitney test. The χ2 and Fisher exact tests were used to test for associations between categorical variables and response to treatment (CR vs PR or no response). The Spearman rank correlation test was used to test for associations between survival time and continuous variables. The Kaplan-Meier product limit method was used to estimate MSTs for dogs grouped on the basis of various potential risk factors. For each categorical risk factor (eg, hyperbilirubinemia or hypoalbuminemia), the log-rank test was used to compare estimated MSTs between categories. Variables significantly (ie, P ≤ 0.05) associated with MST in univariate analyses were examined by means of multivariate analysis (logistic regression and forward stepping procedure, P ≤ 0.05). For all analyses, a value of P ≤ 0.05 was considered significant. All calculations were performed with standard statistical software.a

Results

Signalment and clinical signs—Forty dogs with hepatic lymphoma were initially identified during the retrospective search of the medical records of the participating institutions. Seven dogs were excluded because they did not receive specific treatment for hepatic lymphoma, 13 were excluded because they had multicentric involvement, and 2 were excluded because they were not treated with a doxorubicin-based chemotherapeutic protocol. The remaining 18 dogs met the criteria for inclusion and were enrolled in the study.

Median age of the 18 dogs included in the study was 7.5 years (mean, 7.6 years; range, 3 to 12.5 years). Six dogs were castrated males, 4 were sexually intact males, and 8 were spayed females. Median body weight at the time of the initial examination was 29.7 kg (65.3 lb), with a mean body weight of 26.8 kg (60.0 lb; range, 9.6 to 36.5 kg [21.1 to 80.3 lb]). There were 6 mixed-breed dogs and 4 Golden Retrievers; the remaining 8 dogs represented 8 different breeds.

The most common clinical signs at the time of initial examination were lethargy (14/18 [78%]), anorexia (13/18 [72%]), vomiting (12/18 [67%]), diarrhea (8/18 [44%]), and polydipsia and polyuria (5/18 [28%]). Most dogs had > 1 clinical sign. The most common findings on initial physical examination included hepatomegaly (10/18 [56%]), ascites (7/18 [39%]), and cranial abdominal organomegaly (5/18 [28%]). Only 3 (17%) dogs had evidence of jaundice. By definition, none of the dogs had peripheral lymphadenopathy.

Disease staging—The diagnosis of lymphoma was made on the basis of results of cytologic examination of a hepatic sample in 11 dogs and on the basis of results of histologic examination of a hepatic sample in 7. All slides had been reviewed by board-certified clinical pathologists or pathologists at the participating institutions, and the reports were available for review. Six dogs were classified as stage IV, 1 was classified as stage V, and 11 were classified as at least stage IV, but could not be further classified because cytologic examination of bone marrow aspirates had not been performed. All dogs were subclassified as substage b.

Clinicopathologic findings—The most common clinicopathologic abnormalities at the time of initial examination were anemia (6/16 [38%]), thrombocytopenia (9/16 [56%]), leukocytosis (10/17 [59%]), neutrophilia (10/17 [59%]), hypoalbuminemia (9/18 [50%]), and hyperbilirubinemia (12/18 [67%]; Table 1). Thirteen of 16 (81%) dogs had high serum alanine aminotransferase activity, 11 of 12 (92%) had high serum aspartate aminotransferase activity, 13 of 17 (76%) had high serum alkaline phosphatase activity, 4 of 16 (25%) had low serum cholesterol concentration, 2 of 6 (33%) had high serum γ-glutamyltransferase activity, and 1 of 16 (6%) had low BUN concentration. Hypoglycemia was not documented in any of the dogs. Eight dogs had both hypoalbuminemia and hyperbilirubinemia.

Table 1—

Results of clinicopathologic testing in 18 dogs with presumed primary hepatic lymphoma.

VariableNo. of dogs testedMedianRangeMean ± SDNo. (%) with value < LRLNo. (%) with value > URL
WBC (X 103 cells/μL)1715.26.2–104.024.3 ± 25.80 (0)10 (59)
RBC (X 106 RBCs/μL)165.523.0–8.35.30 ± 1.596 (38)0 (0)
PCV(%)1538.124–5337.7 ± 10.346 (38)0 (0)
Platelets (X 103 platelets/μL)1612025–452165.6 ± 129.210 (59)0 (0)
Neutrophils (X 103 cells/μL)1712.184.1–63.715.5 ± 13.40 (0)10 (59)
Albumin (g/dL)182.551.7–3.82.55 ± 0.5311 (61)0 (0)
Bilirubin (mg/dL)180.620.1–6.91.2 ± 1.60 (0)12 (67)
ALP (U/L)1747770–13,580428 ± 3,2150 (0)13 (77)
ALT (U/L)1635437–1,354741 ± 3700 (0)13 (81)
AST (U/L)1296.522–314125 ± 860 (0)11 (92)
GGT (U/L)69.47.8–63.022.2 ± 22.60 (0)2 (33)
Calcium (mg/dL)189.38.2–11.09.31 ± 0.740 (0)0 (0)
Cholesterol (mg/dL)1613737–412162 ± 874 (25)1 (6)
Creatinine (mg/dL)160.90.6–1.790.97 ± 0.310 (0)2 (13)
BUN (mg/dL)16157–8522.1 ± 22.51 (6)1 (6)
Glucose (mg/dL)159074–13293.5 ± 15.20 (0)1 (7)

ALP = Alkaline phosphatase. ALT = Alanine aminotransferase. AST = Aspartate aminotransferase. GT = γ-Glutamyltransferase. LRL = Lower reference limit. URL= Upper reference limit.

Immunohistochemical staining of tumor cells was performed in 3 dogs; 1 had T-cell lymphoma, and the other 2 had B-cell lymphomas. In 7 dogs, bone marrow aspirates had been submitted for cytologic evaluation. One dog had evidence of 10% infiltration of lymphoblasts in the bone marrow aspirate.

Diagnostic imaging—Reports of abdominal ultrasonography performed at the time of initial examination were available for 16 dogs. A hepatic mass was documented in 4 (25%) dogs, and diffuse hepatomegaly was documented in 13 (81%). One dog had evidence of both a hepatic mass and diffuse hepatomegaly. Splenomegaly was seen in 7 (44%) dogs, and mesenteric lymphadenopathy was seen in 6 (38%).

Reports of thoracic radiography performed at the time of initial examination were available for 11 dogs. Two (18%) dogs had evidence of lymphadenopathy, 2 (18%) had an infiltrative pattern consistent with lymphoma, 1 (9%) had a mediastinal mass, and 1 (9%) had a lung mass subsequently identified as a bronchogenic carcinoma.

Chemotherapy protocols—All dogs were treated with doxorubicin-based chemotherapy protocols, including the L-CHOP protocol with actinomycin8 (a CHOP protocol including l-asparginase and actinomycin; n = 6), CHOP-L5 (a CHOP protocol including l-asparginase; 6), VELCAP-S7 (a short CHOP protocol including l-asparginase and prednisone; 2), CVT X9 (a CHOP protocol including l-asparginase and methotrexate; 2), VCAA10 (a CHOP protocol including l-asparginase and cytosar; 1), and University of Wisconsin-Madison11 (1) protocols.

Outcome and risk factors—Eight of the 18 (44%) dogs had a CR, 4 (22%) had a PR, and 6 (33%) had progressive disease (ie, they did not respond to chemotherapy). Factors found to be significantly associated with development of a CR (vs PR or progressive disease) included leukocytosis (OR, 0.10; 95% CI, 0.01 to 0.96; P = 0.05), neutrophilia (OR, 0.083; 95% CI, 0.009 to 0.77; P = 0.05), serum bilirubin concentration > 1.0 mg/dL (OR, 0.33; 95% CI 0.15 to 0.74; P = 0.013), and the combination of serum albumin concentration < 2.5 g/dL and serum bilirubin concentration > 1.0 mg/dL (P = 0.036).

Of the 8 dogs that achieved a CR, 6 relapsed and 2 were euthanized for other reasons while in remission (probable tick-borne disease in 1 dog and bronchogenic carcinoma in the other). Of the 4 dogs that achieved a PR, 1 relapsed and 3 died while still in PR. Overall median remission duration for the 12 dogs that achieved a CR or PR was 98 days (range, 4 to 287 days). Median remission duration for dogs that achieved a CR was 120 days (range, 2 to 402 days); median remission duration for dogs that achieved a PR was 21 days (range, 4 to 32 days). Median remission duration was not significantly different between dogs that achieved a CR and dogs that achieved a PR.

Two of the 6 dogs that achieved a CR and subsequently relapsed were euthanized at the time of relapse because the owners declined further treatment, and 4 were treated. Two of these 4 dogs were treated with CHOP protocols and died 6 months later; 1 attained a PR, and the other attained a CR. The remaining 2 dogs were treated with l-asparaginase, lomustine, and prednisone and achieved CR, but then died 1 and 3 months later.

The MST for all dogs in the study was 63 days (mean, 124 days; range, 2 to 402 days, 95% CI, 154 to 176 days). All dogs had died by the time of data collection; 16 had died as a result of lymphoma, and 2 had died of other causes. Factors found to be associated with a shorter survival time in univariate analyses included lack of a CR, thrombocytopenia, serum albumin concentration < 2.5 g/dL, and hyperbilirubinemia. Dogs that did not achieve a CR (n = 10) had a significantly (P < 0.001) shorter MST than did dogs that did achieve a CR (8; 13 vs 283 days, respectively). Dogs with thrombocytopenia (n = 9) had a significantly (P = 0.026) shorter MST than did dogs with platelet counts within reference limits (n = 7; 49 vs 287 days, respectively). Dogs with serum albumin concentration < 2.5 g/dL (n = 9) had a significantly (P = 0.004) shorter MST than did dogs with serum albumin concentration within reference limits (9; 10 vs 128 days, respectively). Dogs with serum bilirubin concentration > 1.0 mg/dL (n = 12) had a significantly (P = 0.007) shorter MST than did dogs with serum bilirubin concentration within reference limits (6; 8 vs 126 days, respectively). Dogs with both serum albumin concentration < 2.5 g/dL and serum bilirubin concentration > 1.0 mg/dL (n = 6) had a significantly shorter MST than did the other dogs (12; 6 vs 126 days, respectively). There was a significant positive correlation between serum albumin concentration and survival time (r = 0.74; P < 0.001) and a significant negative correlation between serum bilirubin concentration and survival time (r = −0.57; P = 0.013). In the multivariate analysis, lack of a CR and serum albumin concentration < 2.5 g/dL were significantly (P = 0.043 and 0.009, respectively) associated with shorter MSTs. Dogs that did not achieve a CR had a significantly shorter MST than did dogs that did achieve a CR (13 days [range, 2 to 93 days] vs 283 days [range, 49 to 402 days]; P < 0.001; Figure 1). Dogs that did not achieve a CR were 22.4 times as likely to have a shorter survival time, compared with dogs that did achieve a CR (95% CI, 2.7 to 183.2; P = 0.004). Dogs with serum albumin concentration < 2.5 g/dL at the time treatment was initiated had a significantly shorter MST than did dogs with serum albumin concentration within reference limits (10 days [range, 2 to 339 days] vs 128 days [range, 41 to 402 days]; P < 0.001; Figure 2). Dogs with hypoalbuminemia were 6.2 times as likely to have a shorter survival time, compared with dogs with serum albumin concentration within reference limits (95% CI, 1.3 to 10.60; P = 0.012).

Figure 1—
Figure 1—

Kaplan-Meier curves of survival time for 18 dogs with presumed primary hepatic lymphoma treated with a multiagent, doxorubicin-based chemotherapy protocol and grouped on the basis of whether dogs achieved a CR (n = 8; solid line) or had a PR or progressive disease (10; dotted line).

Citation: Journal of the American Veterinary Medical Association 239, 7; 10.2460/javma.239.7.966

Figure 2—
Figure 2—

Kaplan-Meier curves of survival time for 18 dogs with presumed primary hepatic lymphoma treated with a multiagent, doxorubicin-based chemotherapy protocol and grouped on the basis of whether dogs had a serum albumin concentration < 2.5 g/dL (n = 9; dotted line) or a serum albumin concentration within reference limits (9; solid line).

Citation: Journal of the American Veterinary Medical Association 239, 7; 10.2460/javma.239.7.966

Discussion

Results of the present study suggested that dogs with primary hepatic lymphoma that underwent chemotherapy with a multiagent, doxorubicin-based protocol had a poor prognosis, with a low response rate, short remission duration, and short MST.

The low response rate for dogs in the present study (12/18, with only 8/18 with a CR) was comparable to the reported response rate for dogs with gastrointestinal tract lymphoma (56%).7,12,13 One likely explanation for the low response rate relates to the fact that dogs with non-multicentric lymphoma are typically brought for medical care only when clinical signs are apparent, whereas dogs with multicentric lymphoma may be examined because of lymphadenopathy, often before other systemic clinical signs are apparent. The former population is clinically ill at the time of initial examination and therefore may be less likely to respond to treatment. Similarly, dogs with multicentric lymphoma that are classified as substage b are reported to have a CR rate of 46%, compared with a rate of approximately 80% for dogs classified as substage a.13 In the present study, all dogs were classified as substage b, similar to the case for dogs with gastrointestinal tract lymphoma.7,12,13

Median remission duration for dogs in the present study that achieved a CR was only 120 days, compared with reported durations of 307 to 330 days for dogs with multicentric lymphoma that achieve a CR.2,5 Therefore, it appeared that the prognosis for dogs with hepatic lymphoma was worse, even for those that responded to treatment.

The overall MST for dogs in the present study was only 63 days, whereas dogs with multicentric lymphoma have been reported to have MSTs of 308 to 397 days when treated with similar doxorubicin-based protocols.2–5 Findings of the present study were in agreement with results of other studies, demonstrating that multicentric lymphoma carries a better prognosis, compared with the prognosis for lymphoma in other anatomic locations, including gastrointestinal and cutaneous lymphoma.12,14–17

Several factors were found to be negative prognostic indicators in univariate analyses in the present study. Factors found to be significantly associated with development of a CR included leukocytosis and neutrophilia. To our knowledge, leukocytosis and neutrophilia have not been shown to be negative prognostic indicators in previous studies of canine lymphoma. Liptak et al18 reported leukocytosis in 26.8% of dogs with hepatocellular tumors. Leukocytosis in our study might have been related to stress, hepatic inflammation, and necrosis secondary to the lymphoma, which can be associated with more severe infiltration and thus a poorer prognosis.

Factors associated with shorter MST in univariate analyses in the present study included lack of a CR, thrombocytopenia, hyperbilirubinemia, and hypoalbuminemia, but in the multivariate analysis, only lack of a CR and serum albumin concentration < 2.5 g/dL remained significantly associated with MST. It is possible that because of the relatively low number of cases, the multivariate analysis was underpowered and thus prone to type II error.

Thrombocytopenia has been evaluated as a prognostic indicator in several studies3,7,13 with conflicting results. In recent studies7,13 evaluating multidrug protocols for canine lymphoma, thrombocytopenia was found to be negatively associated with duration of the first remission. Conversely, in another study3 evaluating a 6-month chemotherapy protocol for canine lymphoma with no maintenance treatment, thrombocytopenia was associated with a longer survival time. There are several potential causes for thrombocytopenia in dogs with lymphoma, including splenic sequestration, immune-mediated thrombocytopenia, disseminated intravascular coagulation, vasculitis, bone marrow suppression, and high concentrations of inhibitory cytokines produced by or in response to the neoplasm.13,19,20 Bone marrow suppression was considered less likely as the underlying mechanism of the thrombocytopenia in the present study because other cytopenias (eg, leukopenia) were not commonly detected. Because measurement of prothrombin time, activated thromboplastin time, and D-dimer and antithrombin concentrations were not part of the routine diagnostic workup, the presence of disseminated intravascular coagulation as a potential cause of thrombocytopenia cannot be assessed. Nevertheless, if disseminated intravascular coagulation is present, it likely would be associated with a worse outcome. Splenomegaly was detected in 7 of the 16 (44%) dogs in which abdominal ultrasonography was performed and may have contributed to the thrombocytopenia. Owing to the retrospective nature of the present study, it was difficult to assess which of the aforementioned mechanisms was the main cause of thrombocytopenia.

Results of the present study indicated that dogs with hepatic involvement with hypoalbuminemia, hyperbilirubinemia, or both had a significantly shorter MST, compared with dogs with 1 or both values within reference limits. Both albumin and bilirubin concentration are used to evaluate liver function; however, liver failure might not have been the sole mechanism for hypoalbuminemia in the present study. Other possible mechanisms are protein loss (through the gastrointestinal tract or kidney) and inflammation. Because a urinalysis was not performed in most dogs, protein-losing nephropathy cannot be excluded as a contributing factor for the hypoalbuminemia. Nevertheless, decreased albumin production by the liver secondary to lymphoma was the most plausible explanation for the hypoalbuminemia in these dogs. Likewise, hyperbilirubinemia may have been an indicator of liver failure and thus a marker of more severe disease. Prehepatic or posthepatic causes of hyperbilirubinemia were considered less likely as a cause of the hyperbilirubinemia identified in the present study. We hypothesize that the poorer prognosis for dogs with hypoalbuminemia or hyperbilirubinemia was related to the severity of liver involvement and liver failure.

Seven dogs in the present study had evidence of both hepatic and splenic involvement. Hepatosplenic T-cell lymphoma has been characterized in the literature as a disease with an aggressive clinical course.19,20 The 2 dogs in these previous studies19,20 had splenic, hepatic, and bone marrow involvement at the time of initial examination, with an absence of peripheral lymphadenopathy. The clinical signs reported were similar to those seen in the present study, including lethargy, anorexia, and weight loss, with clinicopathologic testing revealing pancytopenia, high hepatic enzyme activities, hyperbilirubinemia, and hypoalbuminemia. Dogs in the present study differed in several ways. First, there was gross involvement of additional organs in several dogs, including 5 dogs with mesenteric or thoracic lymphadenomegaly and 1 dog with an infiltrative pattern on thoracic radiographs. The 1 dog without other organ involvement had no evidence of lymphoma in a bone marrow aspirate, and immunophenotyping revealed B-cell lymphoma. In addition, pancytopenia was not documented in any of the dogs in the present study. To evaluate whether dogs in the present study could have been classified as having T-cell hepatosplenic lymphoma, additional testing would have been required.

There were several important limitations to the present study. First, the small number of dogs limited the statistical power of our analyses, increasing the risk of a type II error. Second, the retrospective nature of the study meant that underlying mechanisms responsible for factors associated with MST could not be determined. Future studies including more comprehensive diagnostic testing are likely to identify additional risk factors and to shed light on the underlying mechanisms of those factors. Third, because this was an uncontrolled study, the effect of the treatment could not be evaluated. Finally, the study included multiple treatment protocols and multiple investigators.

In conclusion, results of the present study suggested that dogs with primary hepatic lymphoma treated with a multiagent, doxorubicin-based protocol had a poor prognosis. In addition, dogs with neutrophilia, thrombocytopenia, hypoalbuminemia, or hyperbilirubinemia had a worse prognosis, whereas dogs that responded to treatment had a better prognosis.

ABBREVIATION

CHOP

Cyclophosphamide, doxorubicin, vincristine, and prednisone

CI

Confidence interval

CR

Complete remission

MST

Median survival time

OR

Odds ratio

PR

Partial remission

a.

SPSS, version 15.0 for Windows, SPSS Inc, Chicago, Ill.

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  • 14.

    Risbon RE, de Lorimier LP, Skorupski K, et al. Response of canine cutaneous epitheliotropic lymphoma to lomustine (CCNU): a retrospective study of 46 cases (1999–2004). J Vet Intern Med 2006; 20:13891397.

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    Couto CG, Cullen J, Pedroia V, et al. Central nervous system lymphosarcoma in the dog. J Am Vet Med Assoc 1984; 184:809813.

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    Couto CG, Rutgers HC, Sherding RG, et al. Gastrointestinal lymphoma in 20 dogs. A retrospective study. J Vet Intern Med 1989; 3:7378.

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    Frank JD, Reimer SB, Kass PH, et al. Clinical outcomes of 30 cases (1997–2004) of canine gastrointestinal lymphoma. J Am Anim Hosp Assoc 2007; 43:313321.

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    Liptak JM, Dernell WS, Monnet E, et al. Massive hepatocellular carcinoma in dogs: 48 cases (1992–2002). J Am Vet Med Assoc 2004; 225:12251230.

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    Cienava EA, Barnhart KF, Brown R, et al. Morphologic, immunohistochemical, and molecular characterization of hepatosplenic T-cell lymphoma in a dog. Vet Clin Pathol 2004; 33:105110.

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    Fry MM, Vernau W, Pesavento PA, et al. Hepatosplenic lymphoma in a dog. Vet Pathol 2003; 40:556562.

  • Figure 1—

    Kaplan-Meier curves of survival time for 18 dogs with presumed primary hepatic lymphoma treated with a multiagent, doxorubicin-based chemotherapy protocol and grouped on the basis of whether dogs achieved a CR (n = 8; solid line) or had a PR or progressive disease (10; dotted line).

  • Figure 2—

    Kaplan-Meier curves of survival time for 18 dogs with presumed primary hepatic lymphoma treated with a multiagent, doxorubicin-based chemotherapy protocol and grouped on the basis of whether dogs had a serum albumin concentration < 2.5 g/dL (n = 9; dotted line) or a serum albumin concentration within reference limits (9; solid line).

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    Rassnick KM, Moore AS, Collister KE, et al. Efficacy of combination chemotherapy for treatment of gastrointestinal lymphoma in dogs. J Vet Intern Med 2009; 23:317322.

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  • 13.

    Zemann BI, Moore AS, Rand WM, et al. A combination chemotherapy protocol (VELCAP-L) for dogs with lymphoma. J Vet Intern Med 1998; 12:465470.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Risbon RE, de Lorimier LP, Skorupski K, et al. Response of canine cutaneous epitheliotropic lymphoma to lomustine (CCNU): a retrospective study of 46 cases (1999–2004). J Vet Intern Med 2006; 20:13891397.

    • Search Google Scholar
    • Export Citation
  • 15.

    Couto CG, Cullen J, Pedroia V, et al. Central nervous system lymphosarcoma in the dog. J Am Vet Med Assoc 1984; 184:809813.

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    Couto CG, Rutgers HC, Sherding RG, et al. Gastrointestinal lymphoma in 20 dogs. A retrospective study. J Vet Intern Med 1989; 3:7378.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Frank JD, Reimer SB, Kass PH, et al. Clinical outcomes of 30 cases (1997–2004) of canine gastrointestinal lymphoma. J Am Anim Hosp Assoc 2007; 43:313321.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Liptak JM, Dernell WS, Monnet E, et al. Massive hepatocellular carcinoma in dogs: 48 cases (1992–2002). J Am Vet Med Assoc 2004; 225:12251230.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Cienava EA, Barnhart KF, Brown R, et al. Morphologic, immunohistochemical, and molecular characterization of hepatosplenic T-cell lymphoma in a dog. Vet Clin Pathol 2004; 33:105110.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Fry MM, Vernau W, Pesavento PA, et al. Hepatosplenic lymphoma in a dog. Vet Pathol 2003; 40:556562.

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