Old challenges and new opportunities in treating feline lymphomaWhile feline lymphoma remains incurable, recent advances have made the disease manageable enough to ensure a good quality of life for many cats February 8, 2022 By Cindy Bacmeister, DVM, PhD, DACVP (anatomic pathology); Emily Manor, DVM, DACVIM (oncology); and Jennifer Ogeer, DVM, MSc, MBA, MALymphoma is the most common malignancy in cats and can cause a variety of clinical signs, depending on the site affected and extent of disease. In contrast to lymphoma in dogs, which is commonly the multicentric nodal form, lymphoma in cats can present in a variety of locations. Prior to vaccination and testing for feline leukemia virus (FeLV), the mediastinal form was considered the most common, primarily affecting younger cats. Since the widespread implementation of testing and vaccination against FeLV, gastrointestinal (GI) has been reported by several authors to be the most frequently recognized site of involvement in cats. In addition to classification based on anatomic location, other subdivisions include cell size (lymphoblastic/large cell versus lymphocytic/small cell) and lineage (T-cell versus B-cell). FeLV and feline immunodeficiency virus (FIV) are well-recognized risk factors for the development of feline lymphoma. Environmental factors, including tobacco smoke, as well as chronic gut inflammation are also proposed risk factors. Feline lymphoma is not considered a curable disease, although treatment with chemotherapy, radiation therapy, and occasionally surgery is often used to prolong survival times. In dogs, there are often many prognostic factors that may help predict response to therapy. In cats, unfortunately, reliable prognostic factors are less well established. Anatomic location is one of the most significant determinants of treatment options, as well as prognosis. Cats with renal or central nervous system (CNS) involvement and patients with widespread disease tend to do poorly with brief responses to treatment, while patients with nasal lymphoma or small cell gastrointestinal lymphoma can experience lengthy remission times. FeLV status is also an important predictor of outcome; patients who are positive tend to have shorter remission durations and overall survival times. Response to therapy itself is often used as a prognostic indicator. Duration of remission and median survival time tend to be longer for cats that reach complete remission compared to cats that reach only partial remission after initial induction of treatment. Immunophenotype (T-cell versus B-cell), a factor that is often a significant determinate of outcome in dogs, has not been shown to be an important prognostic indicator in feline lymphoma. GI lymphoma Gastrointestinal lymphoma can be further subdivided into lymphocytic (small cell) or lymphoblastic (large cell). The distinction is important, as there are typically significant differences in terms of clinical signs, treatment, and outcome between these two forms. Top: Ultrasound image in a feline patient with renal lymphoma showing irregular enlargement of the kidney and hypoechoic subcapsular thickening.Bottom: Lateral radiograph in a feline patient with renal lymphoma showing irregular marginated and enlarged kidneys.Images courtesy Emily Manor/VCA Advanced Veterinary Care Center Small cell (also clinically referred to as “low-grade”) lymphoma in cats is almost exclusively a gastrointestinal disease possibly, but not proven to be, associated with prolonged inflammatory bowel disease (enteritis associated T-cell lymphoma; EATL). It is considered an indolent disease, often leading to a prolonged period of symptoms prior to diagnosis. Like inflammatory bowel disease, clinical signs of low-grade GI lymphoma include weight loss, anorexia, and lethargy with or without vomiting and diarrhea. This disease commonly affects older cats of any breed and does not tend to be associated with FeLV. Definitive diagnosis is best facilitated by full thickness, surgical biopsies but often requires additional measures, including immunohistochemistry and/or demonstration of a clonal expansion (PCR for antigen receptor rearrangement [PARR]) to distinguish from inflammatory bowel disease. Less costly and less invasive approaches include presumptive diagnosis, which is based upon ultrasonographic evaluation and clinical signs, as well as endoscopically obtained biopsies. Endoscopy, while less invasive than surgery, runs the risk of missing a diagnosis if only more distal small intestinal segments are involved or if the infiltrate is confined to deeper aspects of the mucosa. Ultrasound-guided fine needle aspirates and cytology (+/- PARR) of enlarged lymph nodes or internal organs can also be considered, but are sometimes challenging to interpret given the similar cytologic findings seen with lymphoid hyperplasia. Treatment for low-grade intestinal lymphoma is similar to the treatment for severe inflammatory bowel disease and often consists of an oral steroid (prednisolone) and the oral alkylating agent, chlorambucil. With this approach, most feline patients experience partial or complete remission. Assessment of remission is often based on improvement in clinical signs and weight gain, though serial ultrasound to evaluate lymph node size and intestinal thickness can also be used. Concurrent management strategies can include dietary modifications (e.g. switching to a novel protein or hypoallergenic diet, added fiber), nutritional support via a feeding tube, and GI-supportive medications (including pre or probiotics and appetite stimulants). Radiation therapy is a newly researched treatment approach for both small and large cell GI lymphoma and may also provide benefit. The median survival time for cats with low-grade GI lymphoma treated with standard oral chemotherapy is two to 2.5 years. In contrast, large cell GI lymphoma is composed of large, poorly differentiated neoplastic lymphocytes. Due to the atypically large appearance of these cells and usual presence of severe lymphadenomegaly or discrete masses, ultrasound-guided needle aspirates and cytology are more likely to yield a definitive diagnosis than in cases of small cell lymphoma. This form of GI lymphoma typically results in more acute and severe clinical signs; anorexia, weight loss, vomiting, diarrhea, icterus, palpable abdominal mass(es), and presentation due to intestinal obstruction or perforation are common. Surgery is occasionally required in the emergency care setting to alleviate obstruction or treat a septic abdomen. Despite sometimes appearing focal at the time of diagnosis, this type of lymphoma often progresses to involve other parts of the GI tract or abdominal organs, and chemotherapy is recommended following surgery or as a single treatment modality. CHOP-based chemotherapy, including vincristine, cyclophosphamide, and doxorubicin, is most commonly used, though other protocols using CCNU/lomustine and mustargen have also been investigated. Response to therapy is variable and challenging to predict. While the median survival times are reported to be four to six months, treatment outcomes are highly variable, with some cats going into complete remission and others with survival times far short of the median. (Table 1 summarizes the differences between small cell and large cell GI lymphoma.) Forms of extraintestinal lymphoma Lateral radiograph in a feline patient with lymphoma of the mediastinum showing increasing soft tissue opacity in the cranial thorax and dorsal deviation of the trachea. Common forms of extraintestinal lymphoma include nasal, mediastinal, nodal, and renal, as well as laryngeal, CNS, and cutaneous. Clinical presentation, diagnosis, and treatment of extraintestinal lymphomas depends on the site of involvement and extent of disease, though there are many commonalities. Most lymphomas that occur outside of the intestinal tract are considered large cell, typically causing acute symptoms and rapid progression without treatment. In addition to tumor diagnosis, staging is often recommended and typically includes a complete blood count, serum chemistry profile, urinalysis, FeLV/FIV testing, thoracic and abdominal imaging (radiographs and ultrasound), and sometimes advanced imaging (CT or MRI) or bone marrow aspiration. Using a well-established reference laboratory that offers diagnostic testing, imaging and pathology consulting services allows for cohesive review of all the patient information. Cats with nasal lymphoma generally present with symptoms of nasal discharge, facial deformity, and/or sneezing. Advanced imaging, often with CT scan, is necessary to assess the extent of disease and plan treatment, and whole-body staging is necessary to confirm the disease is confined to the nose. A definitive diagnosis is typically made with histopathologic evaluation of biopsy samples and most nasal lymphomas are large B cell. Radiation therapy is the standard treatment (when other parts of the body are not affected) and results in complete remission in 75 to 95 percent of patients. Survival times are typically 1.5 to three years. Chemotherapy can be considered if disease extends beyond the nose or upon relapse. Treatment Renal lymphoma commonly causes symptoms of weight loss, polyuria/polydipsia, and inappetence due to renal insufficiency, and renomegaly is often apparent on physical examination. Ultrasound typically reveals the pathognomonic change of bilaterally enlarged kidneys with a thickened and hypoechoic subcapsular space. Fine needle aspirates are often diagnostic. Cross-sectional CT image in a patient with nasal lymphoma showing increased soft tissue in the right nasal passage. Treatment standardly involves CHOP-based chemotherapy, though adjustments may be needed due to impaired renal function. Median survival times are reported to be three to six months with treatment. Approximately 50 percent of patients are also positive for FeLV, which carries the potential for other complicating issues. Renal lymphoma has a 40 to 50 percent chance of spreading to the CNS (brain and spinal cord) and patients should be monitored closely for neurologic symptoms, including gait abnormalities, cranial nerve abnormalities, or seizures. Most mediastinal lymphoma patients are young adults (less than five years old), and the majority (80 percent) are feline leukemia virus positive. Siamese cats seem to be predisposed to this form of lymphoma. Clinical symptoms and exam findings are usually attributed to the space occupying intrathoracic lymph nodes or secondary pleural effusion and can include dyspnea as well as noncompressible cranial thorax. This form of lymphoma is often treated with chemotherapy +/- radiation therapy. Survival times tend to be longer (median of nine months to a year) for those patients without FeLV compared to patients who are positive (median of three to six months). Central nervous system lymphoma can involve the brain, spinal cord, or both. Advanced imaging is required and usually reveals multiple lesions or lesions outside of the nervous system. In many cases, diagnosis is presumptive or is made postmortem due the challenging location for sampling. Treatment can include radiation when confined or chemotherapy with drugs including CCNU/lomustine which can penetrate the blood brain barrier. This form of lymphoma, unfortunately, carries a poor prognosis with low response rates and median survival times of one to three months are reported. Historically, feline lymphoma had a grave prognosis with poor outcome. While it remains incurable, vaccine rates, advanced knowledge of the different types of lymphoma, and new diagnostic modalities to detect disease and monitor treatment have made the disease manageable enough to ensure a good quality of life for many cats. Cindy Bacmeister, DVM, PhD, DACVP (anatomic pathology), graduated with a DVM from Cornell University in 1990 and completed her residency at Kansas State University. She received her PhD from Kansas State University in 1998 and became board certified in Diplomate ACVP (anatomic pathology). In 1999-2000, Dr. Bacmeister completed her post-doctoral fellowship at the Armed Forces Institute of Pathology in Washington, D.C. She worked in private practice for three years and has a special interest in avian and exotics, as well as surgical pathology. Emily Manor, DVM, DACVIM (oncology), is originally from Cincinnati, Ohio. She completed her undergraduate degree at Clemson University and her DVM at The Ohio State University. Dr. Manor was fortunate to then start a rotating internship at the University of Tennessee (UT) and, following completion, stayed at UT for a three-year residency in medical oncology. She has published research on canine histiocytic sarcoma and is a member of the VCA Pet Cancer Care Alliance. Her professional interests include the early detection of cancer and individualizing oncology care to meet the unique needs of each pet and family. Jennifer Ogeer, DVM, MSc, MBA, MA, is the vice president medical affairs for Antech Diagnostics. She is a graduate of Canada’s Ontario Veterinary College at the University of Guelph. 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