pISSN 1598-298X / eISSN 2384-0749J 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, includingnausea, regurgitation, anorexia, and weight loss. Abdominal ultrasonography revealed thickening of the wall of thegastric and proximal duodenum, moderately enlarged mesenteric lymph nodes, and coarse echotexture of the splenicparenchyma. The results of the feline leukemia virus test were positive. Based on gastrointestinal endoscopiccharacteristics and histopathological examinations, low-grade alimentary lymphoma was identified in multiple regionsof the gastrointestinal tract. The patient was treated with oral prednisolone and chlorambucil chemotherapy, and theclinical signs resolved gradually. During serial follow-up, ultrasonographic findings demonstrated decreases in theduodenal wall thickness and size of the abdominal lymph nodes over a period of 550 days. Survival time was 886days with prednisolone and chlorambucil chemotherapy. This report describes clinical features, imaging findings,endoscopic characteristics, histopathological features, and long-term management with chlorambucil chemotherapy ina 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 ali-

mentary lymphoma often present with weight loss, vomiting,

anorexia, and diarrhea (5). The diagnosis of alimentary lym-

phoma 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 find-

ings, endoscopic characteristics, histopathological features,

and long-term management with chlorambucil chemother-

apy 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, regur-

gitation, anorexia, and weight loss. Weight loss began two

months prior to presentation and GI signs worsened gradu-

ally. GI protectant and antiemetic medications were adminis-

tered 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 leu-

kemia virus antigen test (SNAP FIV/FeLV Combo Test,

IDEXX Laboratories, USA) were positive.

Thoracic and abdominal radiographic examination demon-

strated 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 mesen-

teric lymph nodes, and the samples were stained with Diff-

Quik. Microscopically, the samples were highly cellular, de-

monstrating a mixture of lymphocytes and a small number of

lymphoblasts, with frequent mitotic figures; based on these

†These authors contribute equally to this work1Corresponding author.E-mail : jungdi@gnu.ac.kr

194 Myung-Jin Kim et al.

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.

Long-Term Management of Feline Alimentary Lymphoma 195

results, we suspected lymphoma.

Subsequently, we performed upper and lower GI endos-

copy 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-stimulat-

ing factor (Leucokain, CJ Corp., Korea; 5 µg/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 alimen-

tary 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 inflamma-

tory diseases, are associated with alimentary lymphoma (9).

According to previous findings, the feline leukemia virus

(FeLV) is an oncogenic retrovirus that directly induces lym-

phoma, 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 alimen-

tary lymphoma may not be strongly correlated. The inci-

dence of FeLV in antigen-negative cats has increased (9). In

addition, a cat infected with FeLV or feline immunodefi-

ciency 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 clin-

ical 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 clin-

ical 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 histopathologi-

cal examination of biopsy sections stained with hematoxylin

and eosin (HE) could be used to diagnose low-grade alimen-

tary 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 ultrasono-

graphic 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 histopathologi-

cal 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-differen-

tiated 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

196 Myung-Jin Kim et al.

combination with prednisolone, that resulted in clinical

remission in 197 days, and survival for 886 days.

Reported side effects of chlorambucil are myelosuppres-

sion, 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 eutha-

nized due to severe gastrointestinal signs including weight

loss, anorexia, and vomiting.

This case report describes imaging findings, endoscopic

characteristics, histopathological findings, and long-term man-

agement 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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