Primary gastrointestinal lymphoma in dogs occurs in the absence of peripheral lymphadenopathy, and the disease is often confined within the abdominal cavity. The intestines are the most frequently affected extranodal site.1 Dogs with gastrointestinal lymphoma often have protracted signs of gastrointestinal disturbance, including inappetence, weight loss, vomiting, or diarrhea, alone or in combination.2 Generally, the clinical signs are not distinguishable from other benign or malignant conditions, and consequently, the disease is often insidious in nature.
In contrast to multicentric (nodal) lymphoma, which is well studied in dogs, there is limited information in the veterinary literature characterizing primary gastrointestinal lymphoma in the absence of peripheral disease. Previous studies2–4 have evaluated clinicopathologic features and associated prognostic factors for dogs with lymphoma involving the gastrointestinal tract; however, the inclusion of dogs with multicentric lymphoma affecting the gastrointestinal tract limits the usefulness of those results. Nevertheless, previous small-scale studies3–7 had 2 similar observations. First, most dogs with primary gastrointestinal lymphoma had disease of the T-cell phenotype. Second, dogs with gastrointestinal lymphoma had a poor survival time, with many deaths attributable to the disease occurring within a few weeks to months after diagnosis. Identification of prognostic indicators has been limited to 1 study4 in which dogs that had diarrhea as a component of the disease had a poorer prognosis, with a shorter overall survival time, than dogs that did not.
Another confounder associated with earlier studies was the failure to distinguish among different anatomic locations in the gastrointestinal tract with the assumption that characteristics of the disease would not vary by location. Studies8,9 of human patients have found that certain histologic subtypes of lymphomas have a predilection to arise from specific sites in the gastrointestinal tract. Mucosa-associated lymphoid tissue lymphoma is typically found in the stomach, whereas diffuse large B-cell lymphoma is identified in various sites throughout the gastrointestinal tract.8,9 Enteropathy-associated T-cell lymphoma is a rare form of gastrointestinal lymphoma in people and is more commonly located in the jejunum than in other regions.9 Distinguishing among these histologic subtypes has proven useful in determining prognosis and treatment in human patients. To the authors' knowledge, this type of information has yet to be investigated in veterinary medicine. However, a recent report10 indicated that dogs with rectal lymphoma had an overall mean survival time of 1,697 days, raising the possibility that disease subtype and prognosis could vary by anatomic location in dogs with gastrointestinal lymphoma.
Chemotherapy is presently considered the mainstay of the treatment for gastrointestinal lymphoma in dogs, with most treatments relying on multiagent CHOP-based chemotherapy protocols. Rassnick et al4 evaluated the use of a CHOP-based chemotherapy protocol, VELCAP-SC, in 18 dogs with either primary gastrointestinal lymphoma or multicentric lymphoma affecting the gastrointestinal tract. In that study,4 10 of 18 dogs had remission, and the MST for all dogs was 77 days. Dogs that did not have remission had an MST of 10 days, and the median duration of remission for 9 dogs with complete remission was 86 days, suggesting that efficacy of a CHOP-based protocol for treatment of this disease is limited.
Much information is still needed to understand gastrointestinal lymphoma, and specifically primary intestinal lymphoma, in dogs. The purpose of the multi-institutional study reported here was to expand our limited knowledge of primary intestinal lymphoma in dogs by evaluating the signalment, clinicopathologic features, and outcomes of dogs with confirmed primary intestinal lymphoma and assessing factors potentially associated with survival times in these patients.
Materials and Methods
Case selection
Electronic medical records searches were conducted to identify dogs with confirmed intestinal lymphoma treated at 7 institutions (Cummings School of Veterinary Medicine, Tufts University, North Grafton, Mass; New England Veterinary Oncology Group, Waltham, Mass; Red Bank Veterinary Hospital, Tinton Falls, NJ; Matthew J. Ryan Veterinary Hospital, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pa; Angell Animal Medical Center, Boston, Mass; Coral Springs Animal Hospital, Coral Springs, Fla; and Veterinary Specialty Hospital of San Diego, San Diego, Calif) from January 1997 to August 2012. Case selection was limited to dogs with histologically or cytologically confirmed lymphoma involving the small intestines, large intestines, or regional intestinal lymph nodes. Dogs were presumed to have primary intestinal lymphoma if there was no evidence of peripheral lymphadenopathy at the time of diagnosis. Dogs with concurrent neoplastic changes in extraintestinal organs in the abdominal cavity, lymphadenopathy or mediastinal masses in the thoracic cavity, or a combination of these were included in the study. Dogs with primary changes confined to the stomach were considered to have primary gastric lymphoma and were excluded from the study.
Medical records review
Data collected from the medical records included signalment (breed, sex and neuter status, and age), clinical signs at the time of diagnosis, body weight, physical examination results, diagnostic imaging findings, hematologic data, cytologic or histologic examination results, tumor location (categorized as intestinal tract alone, intestinal tract and local [abdominal] lymph nodes, or intestinal tract and extraintestinal organs, with or without abdominal lymph node involvement), results of staging tests (when available; including results of abdominal ultrasonography and thoracic radiography), methods used to confirm the diagnosis of lymphoma, and immunophenotyping results. Treatments (surgery, chemotherapy, radiation, or a combination of these), type and frequency of chemotherapeutic drug administration, dates of diagnosis and death, and adverse events (when reported) were also recorded.
Chemotherapy
Drugs used in primary or rescue treatment protocols included CCNU,a l-asparaginase,b cyclophosphamide,c doxorubicin hydrochloride,d vincristine sulfate,e mechlorethamine hydrochloride,f vinblastine sulfate,g procarbazine hydrochloride,h dacarbazine,i melphalan,j chlorambucil,k prednisone, cytosine arabinoside,l and actinomycin D.m The chemotherapy protocols varied, primarily because of the multi-institutional nature of the study; as a result, dogs were grouped on the basis of the intended first-line chemotherapy protocol (eg, CHOP or COP, CCNU, MOPP or MVPP, or l-asparaginase) for study purposes. The intended first-line chemotherapy protocol was defined as the attending clinician's chemotherapy protocol plan for each patient at the start of chemotherapy, regardless of rescue protocols added at the time of disease progression. Protocols were grouped as CHOP based or COP based, single agent (CCNU or l-asparaginase), or multiagent (MOPP or MVPP). Data regarding dose and dose adjustments were not included in the evaluations. The methods used to assess patient responses to chemotherapy agents were highly variable and subjective in nature, and therefore, survival time was used as the primary end point for these evaluations. Rescue chemotherapy protocols were implemented when deemed necessary by the attending clinician in consultation with the dog owner; these treatments consisted of a change from the first-line treatment to another chemotherapy protocol or agent.
Immunophenotyping
Results of immunophenotyping and the methods used were recorded when available in the medical records. The methods for immunophenotyping included immunohistochemical, immunocytochemical, or PCR assays performed in various university and commercial diagnostic laboratories. Detailed methods for each procedure were not available for review. Negative immunochemical results for both B-cell and T-cell markers were considered to reflect either a false-negative result or a null cell phenotype.11
Statistical analysis
Median survival times were calculated by Kaplan-Meier analysis. Dogs were considered to have died of lymphoma unless death was determined by a veterinarian to be attributable to an unrelated cause. Survival time was defined as the time from diagnosis until death from any cause. Dogs were censored if they were alive at the end of the study or were lost to follow-up. Kaplan-Meier product limit estimates were used to compare survival times among dogs grouped by categorical variables of interest (ie, sex; tumor location; whether surgery was or was not performed in dogs that received chemotherapy; presence of biochemical and hematologic changes including hypoalbuminemia, anemia, or neutrophilia; and presence of diarrhea, vomiting, weight loss, anorexia, lethargy, or peritonitis). Cox proportional hazards regression analysis was used to assess associations between continuous variables (patient age and body weight) and survival time in univariate analyses. For all analyses, a value of P ≤ 0.05 was considered significant. Statistical analyses were performed with standard software.n
Results
Signalment and clinical signs
Eighty-four dogs with primary intestinal lymphoma were enrolled in the study. Most dogs were treated at Tufts Cummings School of Veterinary Medicine (n = 31), followed by the New England Veterinary Oncology Group (20), Red Bank Veterinary Hospital (13) and Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania (13), Angell Animal Medical Center (4), Coral Springs Animal Hospital (2), and Veterinary Specialty Hospital of San Diego (1). There were 31 breeds of dogs. Dogs included Golden Retrievers (16/84 [19%]), mixed breeds (11 [13%]), Boxers (7 [8%]), Labrador Retrievers (6 [7%]), Portuguese Water Dogs (3 [4%]), and Pugs (3 [4%]). Median age at the time of diagnosis was 8.9 years (range, 2.8 to 15.1 years). There were 44 males (37 castrated and 7 sexually intact) and 40 females (all spayed). Median weight of 80 dogs with data available was 24.1 kg (53 lb; range, 4.0 to 51.2 kg [8.8 to 112.6 lb]).
The most common clinical signs were vomiting (59/84 [70%]), anorexia (53 [63%]), diarrhea (41 [49%]), weight loss (36 [43%]), and lethargy (31 [37%]), with most dogs having > 1 of these signs at the time of hospital admission. Duration of clinical signs was variable, and onset was often insidious, with 36 of 59 (61%), 35 of 53 (66%), and 29 of 41 (71%) dogs having vomiting, anorexia, and diarrhea, respectively, for ≥ 2 to 3 months prior to diagnosis. Palpable abdominal masses were identified in 12 dogs. Four dogs had clinical signs consistent with sepsis as a result of intestinal perforation at the time of initial evaluation.
Clinicopathologic findings
Results of a CBC and serum biochemical analysis were available for 71 of 84 (85%) and 69 of 84 (82%) dogs, respectively. Relative to the reference ranges for the facilities where dogs were treated, 21 of 71 (30%) dogs had high neutrophil counts, and 3 of 21 (14%) dogs with neutrophilia had immature (band) neutrophils present. One dog with septic peritonitis had evidence of toxic neutrophil changes identified on a CBC. Twenty of 71 (28%) dogs had anemia, and 38 of 69 (55%) dogs had hypoalbuminemia.
Diagnostic imaging
Thoracic radiographs were obtained for 44 of 84 (52%) dogs. Eight of 44 (18%) dogs had radiographically detectable abnormalities, including sternal lymphadenopathy (5/44 [11%]), pleural effusion (2 [5%]), multiple pulmonary nodules (1 [2%]), a cranial mediastinal mass (1 [2%]), and pneumonia (1 [2%]). Causes of the changes (other than pneumonia) were not definitively determined for 6 dogs; 1 dog with sternal lymphadenopathy had a diagnosis of lymphoma confirmed by cytologic examination of a fine-needle aspirate.
Sixty-five of 84 (77%) dogs underwent abdominal ultrasonography. Abnormalities were noted in the intestinal tract (60/65 [92%]), lymph nodes (39 [60%]), liver (6 [9%]), spleen (4 [6%]), urogenital tract (1 [2%]), and adrenal glands (1 [2%]). Intestinal tract changes included a thickened intestinal wall with loss of layering to various degrees (n = 41), presence of ≥ 1 discrete mass (24), and ulceration (3). Five dogs had no intestinal abnormalities detected by ultrasonography; these dogs underwent collection of biopsy specimens by endoscopy (n = 3) or exploratory laparotomy (2). Diffuse intestinal tract thickening was identified during surgery in both dogs that underwent exploratory laparotomy. Ultrasonographically detected alterations of the liver were variably described in the 6 affected dogs. In 1 dog, the liver was confirmed to be affected by lymphoma; 3 dogs had nonneoplastic changes (vacuolar hepatopathy, hepatic fibrosis with lymphoplasmacytic inflammation, and sinusoidal telangiectasis) identified cytologically or histologically. The 2 remaining dogs did not undergo cytologic or histologic assessment for the liver abnormalities. Splenic abnormalities in 2 of 4 dogs were further examined; lymphoma in the spleen was cytologically confirmed in 1, and 1 had histologic evidence of extramedullary hematopoiesis. Abdominal or peritoneal effusions (or both) were observed in 12 of 65 (18%) dogs; however, fluid analysis was not routinely performed, and results of such analysis were not regularly noted in the medical records.
Diagnosis, anatomic location, and immunophenotype of intestinal lymphoma
Diagnosis of intestinal lymphoma was made histologically in 55 dogs and cytologically in 29 dogs. Histologic samples were obtained by exploratory laparotomy with resection and anastomosis of a mass (n = 31), full-thickness intestinal biopsy (13), endoscopic biopsy (10), and ultrasound-guided percutaneous core needle biopsy (1). The disease was localized to the intestinal tract (34/84 [40%]), intestinal tract and local lymph nodes (40 [48%]), or intestinal tract and extraintestinal organs (10 [12%]). Thirty-three dogs had intra-abdominal lymph nodes evaluated cytologically or histologically; of these, 31 (94%) tested positive for lymphoma. Abnormal-appearing lymph nodes from only 2 dogs were identified as reactive lymph nodes on histologic evaluation. Seven dogs with enlarged or abnormal-appearing abdominal lymph nodes that were not evaluated further were considered, for study purposes, to have lymphoma involving the lymph nodes. Extraintestinal organs were considered lymphoma-positive only when histologic or cytologic confirmation was available; affected organs included the liver (n = 4 dogs), mesentery (3), spleen (1), stomach (1), and a sternal lymph node (1).
Immunophenotyping was performed for 22 dogs by means of immunohistochemical (n = 15), PCR (6), or immunocytochemical (1) assay. Samples from 20 of 22 (91%) dogs tested positive for T-cell markers, and 1 dog was confirmed to have B-cell lymphoma. Immunohistochemical staining results were negative for T- and B-cell markers for 1 dog.
Treatment
Forty-nine of 84 (58%) dogs were treated by chemotherapy only, 24 (29%) had both surgical resection and chemotherapy, and 4 (5%) had surgical resection of the affected area as sole treatment. Of the remaining 7 (8%) dogs, 1 had surgical resection, chemotherapy, and half-body radiation therapy; 5 received palliative treatment (surgery and corticosteroid administration [n = 2] or corticosteroid treatment alone [3]); and 1 had no treatment after diagnosis. Three of 84 dogs had received various corticosteroid treatments of unknown duration before a definitive diagnosis of lymphoma was made.
Of 31 dogs that had intestinal resection and anastomosis, 3 (10%) developed postoperative complications. Two dogs were euthanized because of septic peritonitis (one 4 days after surgery and the other 5 days after surgery). One dog was euthanized 7 days after surgery because of fulminant pancreatitis; this dog had a perforated duodenal mass and septic peritonitis at the time of diagnosis.
Chemotherapy protocols used as first-line treatment varied; 48 dogs received CHOP or COP, 14 dogs received CCNU as a single agent, 4 dogs were given l-asparaginase as a single agent, and 3 dogs received MOPP or MVPP. Four dogs received a hybrid of CHOP and CCNU protocols in which vincristine, cyclophosphamide, and doxorubicin were followed with 1 treatment of CCNU, and this multiagent cycle was repeated until disease progression was noted. One dog received a CHOP-based protocol with half-body radiation therapy. Of the 48 dogs receiving CHOP- or COP-based intended chemotherapy, 1 dog continued to receive maintenance chemotherapy including vincristine, l-asparaginase, and chlorambucil.
Rescue chemotherapy was given to 23 dogs; the treatments included CCNU, CHOP, MOPP, cytosine arabinoside, melphalan, dacarbazine, and actinomycin D. Fifteen dogs received 1 rescue protocol, 4 dogs received 2 rescue protocols, 3 dogs received 3 rescue protocols, and 1 dog received 5 rescue protocols. The most common reason for initiation of rescue protocols was documentation of progressive disease (16/23 [70%]). However, 1 dog was switched from CCNU to a CHOP-based protocol because of a grade 4 increase in alanine transaminase activity.12 This dog was determined to be in complete remission prior to discontinuation of CCNU by the attending clinician.
Outcomes
Seventy dogs had died or were euthanized by the end of the study; 66 were presumed to have died of a tumor-related cause. Three dogs died of postoperative complications, and 1 died of progressive kidney disease. Fourteen dogs were lost to follow-up. The overall MST (all dogs) was 62 days (range, 1 to 537 days; 95% confidence interval, 41 to 84 days; Figure 1). Clinical factors found to be associated with a shorter survival time in univariate analyses included anorexia, presence of peritonitis at the time of diagnosis, and anatomic location of the tumor. Anorexic dogs (n = 53) had an MST of 50 days (range, 1 to 438 days), whereas dogs without anorexia (31) had an MST of 81 days (range, 4 to 537 days). These values differed significantly (P = 0.047; Figure 2). Dogs with (n = 4) and without (80) septic peritonitis at the time of initial evaluation had MSTs of 33 days (range, 7 to 38 days) and 65 days (range, 1 to 537 days), respectively (P = 0.011; Figure 3). Finally, the MST for 34 dogs with lymphoma confined to the intestinal tract was 121 days (range, 1 to 537 days), whereas that for 40 dogs with abdominal lymph node involvement was 57 days (range, 1 to 438 days) and that for 10 dogs with extraintestinal organ involvement was 35 days (range, 4 to 81 days). The MSTs differed significantly (P = 0.045) among these groups (Figure 4).
Kaplan-Meier curve depicting overall survival time in 84 dogs with primary intestinal lymphoma. Vertical lines denote dogs that were censored. The MST was 62 days (95% confidence interval, 41 to 84 days).
Citation: Journal of the American Veterinary Medical Association 252, 4; 10.2460/javma.252.4.440
Kaplan-Meier survival curves for dogs with (n = 53; dotted line) or without (31; solid line) anorexia at the time of diagnosis of intestinal lymphoma. The MSTs for anorexic and nonanorexic dogs were 50 and 81 days, respectively (P = 0.047). See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 252, 4; 10.2460/javma.252.4.440
Kaplan-Meier survival curves for dogs with (n = 4; dotted line) or without (80; solid line) septic peritonitis at the time of diagnosis of intestinal lymphoma. The MSTs for dogs with and without septic peritonitis were 33 and 65 days, respectively (P = 0.011). See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 252, 4; 10.2460/javma.252.4.440
Kaplan-Meier survival curves for dogs with lymphoma confined to the intestinal tract (n = 34; solid line), intestinal tract with abdominal lymph node involvement (40; dashed and dotted line), and intestinal tract with extraintestinal organ involvement (10; dotted line). The MSTs for dogs with only the intestinal tract (121 days), intestinal tract and lymph nodes (57 days), and intestinal tract and extraintestinal organs (35 days) affected differed significantly (P = 0.045). See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 252, 4; 10.2460/javma.252.4.440
Evaluation of the most commonly used protocols revealed that the MST for 14 dogs that received CCNU as first-line treatment was 144 days (range, 28 to 372 days). The MST for 48 dogs that received a CHOP- or COP-based protocol as first-line treatment was 60 days (range, 4 to 537 days). These results did not differ significantly (P = 0.178; Figure 5). There was no difference in the MSTs for dogs that did and did not have surgery (129 and 125 days, respectively).
Kaplan-Meier curves of survival time for dogs that received CCNU (n = 14; dotted line) or dogs that received a CHOP-based or COP-based protocol (48; solid line) as first-line therapy for treatment of intestinal lymphoma. The MSTs for dogs in these 2 categories were 144 and 60 days, respectively (P = 0.178). See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 252, 4; 10.2460/javma.252.4.440
Discussion
In the present study, dogs with primary intestinal lymphoma in the absence of peripheral lymphadenopathy were evaluated. The clinical course of intestinal lymphoma has been previously thought to be rapid and to carry a poor prognosis even with multiagent chemotherapy protocols. The results of this study confirmed the aggressive nature of this disease, with an overall MST of only 62 days. This result was comparable to the previously published MST of 77 days for dogs treated with VELCAP-SC.4
Lymphoma is a heterogeneous disease for which clinical course and response to treatment vary by features such as morphological subtype, immunophenotype, and primary location.8,13,14 In dogs, primary extranodal forms of the disease, including cutaneous and hepatic forms, have been associated with a poorer prognosis, compared with that in dogs with a primary nodal or multicentric form of lymphoma.15–17 Results obtained in the present study suggest that primary intestinal lymphoma has a prognosis similar to that for other extranodal forms of lymphoma. Alternatively, it is possible the poor survival time for dogs with gastrointestinal3–7 or intestinal lymphoma is reflective of an advanced disease state at the time of diagnosis owing to nonspecific clinical signs.
Vomiting, anorexia, and diarrhea were the 3 most common clinical signs observed in our study population, similar to findings in other studies.2–4 Most (51/84 [61%] to 60/84 [71%]) dogs in the present study had these clinical signs for 2 to 3 months before the diagnosis of intestinal lymphoma was made. Rassnick et al4 observed that 13 dogs that had diarrhea as an initial clinical sign had a shorter MST than dogs that did not (70 vs 700 days). A similar result was not observed in the present study. There was a significant difference in the MST between dogs with and without anorexia on initial evaluation (50 vs 81 days, respectively). Anorexia has previously been associated with a shorter overall remission duration in dogs with multicentric lymphoma.18 However, an owner-assessed factor such as anorexia is difficult to evaluate for association with survival time because it is reliant on owner perceptions, which can be highly variable, and because such perceptions would impact the decision to euthanize a pet.
Four dogs in our study had septic peritonitis at the time of initial evaluation, and these dogs had a significantly shorter MST than did dogs without septic peritonitis (33 vs 65 days). The shorter survival time seen in this group of dogs despite surviving the early postoperative period might have reflected a more advanced disease state in these dogs.
In the present study, dogs with lymphoma confined to the intestinal tract had a longer MST of 121 days, compared with 57 days for dogs with regional lymph node involvement and 35 days for dogs with extraintestinal organ involvement. Gouldin et al19 identified significant associations for clinical stage with disease-free interval and MST in cats with high-grade gastrointestinal lymphoma, although this finding has not been consistently supported in all investigations of cats with alimentary lymphoma.19–21 The study by Gouldin et al19 found that the risk of progressive disease and the risk of death increased by factors of 2.4 and 2, respectively, as the clinical stage increased. One of the limitations in evaluating the clinical stages of dogs in our patient population was a lack of standardized staging methodology. Stage migration has been reported in dogs with lymphoma, but additional tests are often not pursued because of the financial burden on the owners, especially when the clinical relevance of stage is unclear.22 In the present study, the degree of potential stage migration was unknown, as a limited number of abdominal organs were evaluated during the initial staging.
In dogs, primary intestinal lymphoma is commonly of the T-cell phenotype.3–7 Immunophenotyping was performed in 22 of 84 (26%) dogs in the present study, and 20 of 22 (91%) were confirmed to have T-cell lymphoma. This finding was in contrast to what is known about gastrointestinal tract lymphoma in human patients, where the B-cell lineage is more common.9
Despite the known heterogeneity of lymphoma characteristics in dogs, depending on tumor anatomic location, stage, morphological appearance, and phenotype, most chemotherapy protocols rely on CHOP or are CHOP based. This approach currently requires alterations in treatments according to an individual animal's response or lack of response to a given drug. This approach may be inappropriate if subtypes of lymphomas carry an inherent resistance to particular chemotherapy agents. Evidence to support this hypothesis is growing in the veterinary literature, including the poor response of hepatic lymphoma to treatment with CHOP.17 Findings by Beaver et al23 also suggested that dogs with T-cell lymphoma have a decreased rate of response to chemotherapy protocols that include doxorubicin.
A few studies have evaluated the role of alkylating agents in the management of T-cell lymphoma, and favorable responses have been documented. One such drug, CCNU, has commonly been used as first-line therapy for epitheliotropic lymphoma in dogs, with reported overall response rates of 78% and 83% in 2 studies.15,16 Brodsky et al24 evaluated the efficacy of MOPP treatment in dogs with multicentric T-cell lymphoma. Those authors found a median progression-free interval and overall MST of 189 and 270 days, respectively, with 25% of dogs still alive 939 days after initiation of treatment.24 These numbers appear numerically better, compared with some historical progression-free intervals and MSTs associated with CHOP therapy for T-cell lymphoma.25,26 Interestingly, a higher expression level of MDR-1 RNA (which encodes for the p-glycoprotein transporter) has been identified in dogs with gastrointestinal lymphoma, compared with that in dogs with multicentric lymphoma.27 This may explain why the standard CHOP treatment (which contains multiple p-glycoprotein substrates) is not effective in the management of gastrointestinal lymphoma in dogs, and alkylating agents may be a better alternative to the use of CHOP for such patients.
In the present study, multiagent CHOP- or COP-based protocols and single-agent CCNU chemotherapy were the 2 most commonly used first-line treatments. Although the MST of dogs that received CCNU as a first-line treatment was numerically greater than that for dogs that received CHOP (or COP) treatment (144 vs 60 days, respectively), the difference was nonsignificant. One possible explanation for a lack of survival benefit with CCNU in the present study may have been that the low number of dogs in this group (14) caused a type II error. Alternatively, CCNU may not be the most effective agent for treatment of intestinal lymphoma in dogs. This could be attributable to reduced absorption of the orally administered drug through the diseased gastrointestinal tract. In this scenario, the use of injectable alkylating agents could potentially have better results in the initial stage of treatment until better gastrointestinal health is restored, but research in this area is needed.
Chemotherapy is generally considered the treatment of choice for nodal or extranodal forms of lymphoma because of the high incidence of systemic disease. Whether surgery is beneficial for treatment of primary small-bowel lymphoma in human patients is controversial; multiple studies28,29 failed to show a survival advantage for this approach over the use of chemotherapy alone. In our study, 31 dogs underwent resection of the affected intestinal area. Notably, there was no difference in the MST for dogs that did and did not have surgery (129 and 125 days, respectively). The postoperative complication rate in the present study for dogs that underwent intestinal surgery was 3 of 31 (10%). This was comparable to previously reported complication rates of 19 of 121 (15.7%) to 20 of 90 (22%) for dogs that underwent intestinal surgeries for reasons other than foreign bodies (eg, for treatment of neoplasia, intussusception, or traumatic injury).30,31 Many dogs in the present study had surgical intervention because of a functional obstruction or the presence of intestinal perforation without prior disease staging. Ideally, a thorough perioperative evaluation including abdominal ultrasonography and cytologic assessment of accessible lesions should be completed prior to surgery owing to the perioperative complications and the poor prognosis associated with primary intestinal lymphoma. Gouldin et al19 reported an MST of 417 days and median disease-free interval of 357 days for cats that underwent surgery and adjuvant chemotherapy for discrete intermediate or high-grade gastrointestinal lymphoma. The MST reported by that group was comparable to, or better than, a previously published MST of 75 to 270 days when cats were treated with chemotherapy alone.32–34 However, this apparent difference requires further evaluation, considering the inherent limitations associated with a small retrospective study and with comparisons among studies that can vary in design and include different populations.
The present study had many limitations. The number of dogs newly diagnosed as having primary intestinal lymphoma each year is small, and thus, a prospective study in a single institution would be impractical. The multi-institutional retrospective study reported here allowed inclusion of the largest number of such cases (to our knowledge) in a single study, but this introduced substantial variability in terms of medical recordkeeping accuracy, initial staging, chemotherapeutic protocols, and interpretations of patient responses to chemotherapy agents. Selection bias was also possible in that all cases were collected from specialty or referral centers. Histologic evaluation was another limitation in the present study; assessment or review of all samples by 1 pathologist was not possible because multiple facilities were involved, and some samples had been collected 15 years prior to the start of the study. In some cases, the morphological information recorded in the original report was limited, and immunophenotyping to confirm the diagnosis of lymphoma was not always done. This raised the possibility of including not only dogs with other round-cell neoplasms but also dogs with inflammatory bowel disease and small-cell lymphoma in the study. As with cats, distinguishing inflammatory bowel disease from intestinal lymphoma in dogs can be challenging, especially with endoscopic biopsy samples, and the addition of immunohistochemical evaluation and PCR clonality assays might improve diagnostic accuracy. The study findings and limitations underscored a theme in the veterinary literature that infrequently occurring cancers are difficult to define within the confines of small retrospective studies. On the basis of information from the present and previous studies, the authors recommend that practitioners conduct a thorough staging and careful selection of surgical candidates for patients with suspected intestinal lymphoma while taking risks and benefits into consideration. Larger studies evaluating the location, stage, and clinicomorphologic features and better assessment of responses to treatment are necessary to understand the biological behavior and define ideal treatment approaches.
Acknowledgments
No outside funding or support was received in connection with this study. The authors declare that there were no conflicts of interest.
Presented in abstract form at the 28th Annual Conference of the Veterinary Cancer Society, Seattle, October 2008.
The authors thank Drs. Esther Chon, Brenda Phillips, Rebecca Seaman, and Pascale Salah for contributing cases.
ABBREVIATIONS
| CCNU | 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea |
| CHOP | Cyclophosphamide, doxorubicin, vincristine, and prednisone with or without l-asparaginase |
| COP | Cyclophosphamide, vincristine, and prednisone |
| MOPP | Mechlorethamine, vincristine, procarbazine, and prednisone |
| MST | Median survival time |
| MVPP | Mechlorethamine, vinblastine, procarbazine, and prednisone |
| VELCAP-SC | Vincristine, l-asparaginase, cyclophosphamide, doxorubicin, and prednisone followed by 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, mechlorethamine, and procarbazine |
Footnotes
CeeNU (lomustine) capsules, Bristol-Myers Squibb Co, Princeton, NJ.
Elspar, Merck & Co, Whitehouse Station, NJ.
Cyclophosphamide injection, BDI Pharma, Columbia, SC.
Adriamycin for injection, Bedford Laboratories, Bedford, Ohio.
Vincristine powder for injection, Advacare Pharma, Wilmington, Del.
Mustargen, Lundbeck Inc, Deerfield, Ill.
Vinblastine powder for injection, Advacare Pharma, Wilmington, Del.
Matulane, 50-mg tablet, Sigma-Tau Pharmaceuticals Inc, Gaithersburg, Md.
Dacarbazine, American Pharmaceutical Partners Inc, Schaumburg, Ill.
Melphalan tablets, ApoPharma Inc, Toronto, ON, Canada.
Leukeran tablets, GlaxoSmithKline, Research Triangle Park, NC.
Cytosar-U, Pharmacia & Upjohn, Simi Valley, Calif.
Cosmegen, Ovation Pharmaceuticals, Deerfield, Ill.
SPSS, version 20, IBM Corp, Armonk, NY.
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