Long-Term Management with Chlorambucil and Prednisolone in a Case of Feline Alimentary Lymphoma

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pISSN 1598-298X / eISSN 2384-0749 J Vet Clin 34(3) : 193-196 (2017)

http://dx.doi.org/10.17555/jvc.2017.06.34.3.193

193

Long-Term Management with Chlorambucil and Prednisolone in a Case of Feline Alimentary Lymphoma

Myung-Jin Kim^†, Nam-Kyun Kim^†, Hyo-Mi Jang, Joong-Hyun Song, Tae-Sung Hwang, Hee-Chun Lee, Jung-Hyang Sur* and Dong-In Jung¹

Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, South Korea

*Department of Pathobiology, Small Animal Tumor Diagnostic Center, College of Veterinary Medicine, Konkuk University, Seoul 05029, South Korea

(Received: December 16, 2016 / Accepted: May 28, 2017)

Abstract : A 14-year-old, castrated male, domestic shorthair cat was referred for gastrointestinal (GI) signs, including nausea, regurgitation, anorexia, and weight loss. Abdominal ultrasonography revealed thickening of the wall of the gastric and proximal duodenum, moderately enlarged mesenteric lymph nodes, and coarse echotexture of the splenic parenchyma. The results of the feline leukemia virus test were positive. Based on gastrointestinal endoscopic characteristics and histopathological examinations, low-grade alimentary lymphoma was identified in multiple regions of the gastrointestinal tract. The patient was treated with oral prednisolone and chlorambucil chemotherapy, and the clinical signs resolved gradually. During serial follow-up, ultrasonographic findings demonstrated decreases in the duodenal wall thickness and size of the abdominal lymph nodes over a period of 550 days. Survival time was 886 days with prednisolone and chlorambucil chemotherapy. This report describes clinical features, imaging findings, endoscopic characteristics, histopathological features, and long-term management with chlorambucil chemotherapy in a case of feline low-grade alimentary lymphoma.

Key words : cat, low-grade alimentary lymphoma, chlorambucil, long-term management, endoscopy.

Introduction

Alimentary lymphoma is the most common anatomic form of lymphoma in cats (9,10,15). In a previous study of feline gastrointestinal tract tumors, it was found that 55% were lymphomas, 32% were adenocarcinomas, and 4% were mast cell tumors (11). Feline alimentary lymphoma is histologi- cally categorized by the National Cancer Institute Working Formulation (NCIWF) as low-grade, intermediate-grade, or high-grade in the diffuse form (16). Cats with low-grade alimentary lymphoma often present with weight loss, vomiting, anorexia, and diarrhea (5). The diagnosis of alimentary lymphoma is based on histological findings from gastrointestinal (GI) endoscopic biopsies or full-thickness biopsies obtained via exploratory laparotomy (4). Most low-grade alimentary lymphomas respond well to treatment with oral prednisolone and slow-alkylating agents (4,5,8,13). Currently, the prognosis of feline low-grade alimentary lymphoma treated with oral prednisolone and high-dose chlorambucil is good to excellent.

This report describes the clinical features, imaging findings, endoscopic characteristics, histopathological features, and long-term management with chlorambucil chemotherapy in a case of feline low-grade alimentary lymphoma.

Case

A 14-year-old, castrated male, domestic shorthair cat weigh- ing 5.2 kg was referred for GI signs including nausea, regurgitation, anorexia, and weight loss. Weight loss began two months prior to presentation and GI signs worsened gradually. GI protectant and antiemetic medications were administered at the local animal hospital, but there was no response.

Complete blood count (CBC) and total T4 test results were within the reference range, while abnormal serum chemistry results included the following: elevated alanine transaminase (alkaline phosphatase: 194 U/L, reference range: 20-110 U/

L), hyperglycemia (glucose: 209 mg/dL, reference range: 70- 150 mg/dL) and hypophosphatemia (phosphate: 3.3 mg/dL, reference range: 3.4-8.5 mg/dL). The results of the feline leukemia virus antigen test (SNAP FIV/FeLV Combo Test, IDEXX Laboratories, USA) were positive.

Thoracic and abdominal radiographic examination demonstrated no remarkable findings. Abdominal ultrasonographic findings revealed thickening of the wall of the gastric and proximal duodenum, moderately enlarged mesenteric lymph nodes, and coarse echotexture of the splenic parenchyma (Fig 1). Ultrasound-guided percutaneous cytologic sampling was performed independently of the spleen and enlarged mesenteric lymph nodes, and the samples were stained with Diff- Quik. Microscopically, the samples were highly cellular, demonstrating a mixture of lymphocytes and a small number of lymphoblasts, with frequent mitotic figures; based on these

†These authors contribute equally to this work

1Corresponding author.

E-mail: jungdi@gnu.ac.kr

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Fig 1. Abdominal ultrasonography findings of the present case. (A) Mild generalized thickening of the muscular layer of the stomach and (B) the duodenum is observed; wall layering appears normal. (C) Enlarged mesenteric lymph nodes, presenting as oval-shaped, homogenous, hypoechoic nodules with irregular margins. (D) The spleen has a variable echogenicity throughout and developed a hyperechoic spleen with a coarse texture to the parenchyma.

Fig 2. Gastrointestinal endoscopic findings of the present case. Views of the stomach (A, B) and proximal duodenum (C, D; arrow) mucous layer demonstrating hyperemia and mucosal granularity. Views of the colon lesion (E, F; arrow) that is infiltrated with mucosal erosions.

Fig 3. Histopathological images of endoscopic biopsy specimens stained with H&E, diagnosed as lymphocytic lymphoma. The lamina propria and submucosa of the stomach (A), proximal duodenum (B) and colon (C) are diffusely infiltrated with neoplastic lymphocytes.

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Long-Term Management of Feline Alimentary Lymphoma 195

results, we suspected lymphoma.

Subsequently, we performed upper and lower GI endoscopy to examine for GI lesions. The gross findings revealed hyperemic lesions and some nodular changes in the stomach and duodenum, and multiple erosive lesions in the colon (Fig 2). Multiple endoscopic biopsy samples were obtained from the stomach, duodenum, and colon for histopathological examination.

Histopathological results indicated low-grade alimentary lymphoma in multiple regions of gastrointestinal tract. Neo- plastic lymphocytes had infiltrated throughout the GI mucosa and submucosa (Fig 3).

Based on imaging, GI endoscopic, and histopathological findings, we definitively diagnosed this patient with feline low-grade alimentary lymphoma. Chlorambucil (Leukeran, Samil Pharm., Korea; 20 mg/m²,PO, every two weeks) and prednisolone (Prednisolone, Korea Pharma, 2 mg/kg, PO, sid) were prescribed, and clinical signs improved immediately.

After administration of chlorambucil for 136 days, evidence of myelosuppression was noted on CBC profiles, including neutropenia (WBC: 3,900/µL, reference range: 6,000-17,000/

µL) and thrombocytopenia (PLT: 232 × 10³/µL, reference range:

300-800× 10³/µL). Recombinant human granulocyte-stimulating factor (Leucokain, CJ Corp., Korea; 5µg/kg, subcutane- ously [SC], q48h) was then administered until the leukopenia resolved, and the patient’s condition was well-controlled for 197 days. During serial follow-up, ultrasonographic findings demonstrated that the wall thickness of the duodenum and the size of the lymph nodes improved over a period of 437 days. However, 640 days after initial therapy commenced, the patient’s vomiting and anorexia relapsed, gradually grow- ing worse despite chemotherapy. On day 886, the patient was euthanized due to severe GI signs including weight loss, anorexia, and vomiting. The survival time was 886 days with prednisolone and chlorambucil chemotherapy.

Discussion

Feline GI lymphoma is classified into two major types, low-grade and high-grade. Recently, low-grade alimentary lymphoma has been found in cats, with low-grade alimentary lymphoma being synonymous with lymphocytic, well- differentiated and small-cell alimentary lymphoma (5,6,8).

One study reported that most of the low-grade alimentary lymphomas originated from T-cells, and were CD3-positive (CD3+) in 96% of the cats having the disease (13,15). Even though we did not proceed with immunohistochemistry, we suspected low-grade alimentary lymphoma of T-cell origin in the present case.

A variety of risk factors including age, viral infection, chronic exposure to cigarette smoke, and chronic inflammatory diseases, are associated with alimentary lymphoma (9).

According to previous findings, the feline leukemia virus (FeLV) is an oncogenic retrovirus that directly induces lymphoma, as contrasted with antigen-negative status (12). How- ever, the prevalence of FeLV infection in cats with lymphoma was only 20.8%; therefore, FeLV antigenemia and alimentary lymphoma may not be strongly correlated. The incidence of FeLV in antigen-negative cats has increased (9). In

addition, a cat infected with FeLV or feline immunodeficiency virus (FIV) is more likely to present with secondary immune dysfunction during the period of chemotherapy (14).

Despite the apparent weak correlation between alimentary lymphoma and FeLV, we obtained a positive result from the FeLV antigen test in this case. If necessary, FeLV test results can be verified using polymerase chain reaction or immunof- luorescent assay methods of virus detection.

In low-grade alimentary lymphoma, the most common clinical signs are weight loss, vomiting, diarrhea, and anorexia;

less commonly, lethargy and polydipsia are exhibited. Most signs of the gastrointestinal tract disease are chronic (1,3,8).

Alimentary lymphoma should be considered in senior cats exhibiting chronic GI signs. The present patient’s major clinical signs were weight loss, vomiting, and anorexia for two months, and showed no improvement with GI protectant and antiemetic medications.

Clinical signs, imaging characteristics, and histopathological examination of biopsy sections stained with hematoxylin and eosin (HE) could be used to diagnose low-grade alimentary lymphoma (4). Imaging tests may be useful tools to detect GI disease; abdominal ultrasonography revealed that the wall, layering and motility and other organ’s lesions. In this case, it allowed evaluation of the wall thickness of the GI tract, and metastatic lesions of the spleen and mesenteric lymph nodes. Therefore, we suspected a GI tumor based on the presence of chronic GI signs and abdominal ultrasonographic findings.

Endoscopy is a useful tool for establishing a diagnosis, prognosis, and therapeutic approach in dogs and cats. Endo- scopic biopsy is a non-invasive procedure that easily obtains specimens from the gastrointestinal tract for histopathological examination. This procedure is faster than a full-thickness biopsy via laparotomy or laparoscopy, and allows visualiza- tion of mucosal lesions of the esophagus, stomach, portions of the small intestine, and large intestine (17). In addition, healing of the biopsy site is steady and fast. In the present case, endoscopy revealed the presence of abnormal lesions in the stomach, duodenum, and colon, and enabled assessment of the distribution and severity of the multifocal lesions.

Through histopathological evaluation, partial-thickness biopsy specimens obtained by endoscopy facilitated the diagnosis of low-grade alimentary lymphoma.

Low-grade alimentary lymphoma demonstrates a positive response to treatment with a combination of chlorambucil and prednisolone (13). Chlorambucil is a slow-alkylating agent that is effective at treating the slowly dividing, well-differentiated lymphocytes. Several studies report that combinations of prednisolone and chlorambucil chemotherapy result in complete resolution of clinical signs in 59% to 79% of cats, and median survival durations of approximately 786 days (4,5,8). Chlorambucil is administered at 20 mg/m² biweekly or 2 mg/cat orally every other day. In human medicine, there are reports of chlorambucil being used in the treatment of chronic lymphocytic leukemia and lymphocytic lymphoma.

The administration of chlorambucil on a biweekly basis, rather than every other day, maintains a prolonged duration of clinical remission (7). In this case, the patient initially received chlorambucil at a dosage of 20 mg/ m² biweekly, in

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combination with prednisolone, that resulted in clinical remission in 197 days, and survival for 886 days.

Reported side effects of chlorambucil are myelosuppression, GI signs, and myoclonus (13). During chlorambucil therapy, the present patient exhibited hematological toxici- ties, including neutropenia and thrombocytopenia, at 136 days, and presented with intermittent vomiting at 200 days. Anti- emetic and GI protectant medications, along with granulocyte- stimulating factors, were administered as supportive treatment.

We monitored the hematologic parameters and performed abdominal ultrasonography every four weeks. The improved condition was maintained until 640 days, but clinical symp- toms returned thereafter. On day 866, the patient was euthanized due to severe gastrointestinal signs including weight loss, anorexia, and vomiting.

This case report describes imaging findings, endoscopic characteristics, histopathological findings, and long-term management with chlorambucil chemotherapy in feline low-grade alimentary lymphoma. Endoscopic biopsy is a useful method for diagnosis of low-grade alimentary lymphoma in multiple regions. This clinical course could be useful for long-term management of patients with feline low-grade alimentary lymphoma.

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