Low-grade alimentary lymphoma

Transcription

1 Vet Times The website for the veterinary profession Low-grade alimentary lymphoma Author : Peter Roberts Categories : Companion animal, Vets Date : November 2, 2015 ABSTRACT Weight loss is a common presenting sign in elderly cats. Common conditions such as hyperthyroidism and renal disease are well-recognised causes, but in their absence diagnosis can be frustrating. Low-grade alimentary lymphoma (LGAL) should be considered a differential diagnosis even if weight loss is the only clinical sign. Diagnosis can be challenging and LGAL can easily be missed due to vague presenting signs and because it cannot be ruled out on the basis of blood tests or imaging. However, in many cases there will be suggestive clinical signs and also results of non-invasive diagnostics. Histopathology of full-thickness biopsies is required for definitive diagnosis and in some cases will be the only test to identify abnormalities. Treatment with oral chlorambucil and prednisolone is usually very well tolerated, with high remission rates and survival times of two to three years in many cases. Supplementation with vitamin B 12 is required in a large number of cases. A 13-year-old cat presents with weight loss despite an increased appetite, an unkempt coat and a progressively more grumpy temperament. The owner thought the cat was just getting old, but after an otherwise unremarkable clinical examination you discuss the typical signs of hyperthyroidism and gain permission to take routine bloods from the cat, including a thyroid level. Prepared for a straightforward set of results, your heart sinks as a very normal set of blood results is handed to you with a low-normal T4 and no indications of renal disease, diabetes or anything else to explain the weight loss. What now? 1 / 10

2 Cats presenting with weight loss should have gastrointestinal (GI) disease on the initial list of differential diagnoses, even without any specific GI signs. If diagnosis is pursued, GI lymphoma can be a rewarding disease to diagnose and treat. Classification Lymphoma in cats is usually classified based on location (for example, alimentary/gi, kidney, multicentric) and grade (low, intermediate, high) using the National Cancer Institute working formulation. GI/alimentary lymphoma is one of the more common forms of lymphoma in cats. Most cases are low-grade, with a predominance of small lymphocytic lymphoma (also referred to as low-grade or small cell lymphoma; Valli et al, 2000). Low-grade alimentary lymphoma (LGAL) has a particular presentation and a surprisingly fair prognosis with treatment in cats, so is worthy of discussion separate from other forms of lymphoma. Inflammatory bowel disease (IBD) can present in a similar way and is discussed here only as a major differential diagnosis, but essentially requires the same diagnostic approach; readers are referred elsewhere for treatment of IBD. Presentation LGAL is seen in older cats, with a median age of 13 years and no significant sex or breed predispositions (Kiselow et al, 2008; Stein et al, 2010). It is usually a chronic, slowly progressive condition and the most common presenting sign is weight loss importantly this may be the only presenting sign in some cases and it may be associated with a normal, decreased or increased appetite. Other common clinical signs include vomiting, diarrhoea and lethargy (Kiselow et al, 2008). Abdominal palpation is often unremarkable, but may reveal palpably thickened intestines. Discrete masses or abnormalities in other organs are more common with other forms of neoplasia/lymphoma, but enlarged mesenteric lymph nodes may be felt in LGAL. Risk factors Confirmed risk factors for this condition include feline leukaemia virus infection and exposure to tobacco smoke (Bertone et al, 2002; Louwerens et al, 2005). Although thus far unproven, it is thought by many chronic inflammation due to IBD may trigger or progress into intestinal lymphoma 2 / 10

3 in cats, based on similar disease in humans. A worsening of a previously stable IBD case would raise suspicion be suspicious of weight loss in a cat that has always had a lot of hairballs. Diagnosis Non-invasive testing A number of non-invasive diagnostic tests can support a diagnosis of IBD or lymphoma, but cannot provide a definitive diagnosis and normal results do not rule out either condition. Routine haematology, biochemistry and urinalysis are required to rule out other systemic diseases and will usually be unremarkable. There may be a neutrophilia, monocytosis or eosinophilia, and lymphopenia or lymphocytosis may occur. Biochemistry may have non-specific changes such as mildly raised liver enzymes. Hypocobalaminaemia is a frequent finding and is useful both to locate disease to the small intestine and also identify an area for therapeutic intervention (see later). Folate levels may be decreased, normal or increased and so are of limited specificity. Increased feline-specific pancreatic lipase may identify concurrent pancreatitis. Exocrine pancreatic insufficiency is not common in cats, but has similar presenting signs (weight loss, diarrhoea, vomiting and polyphagia most commonly in senior cats) and so it is advisable to rule this disease out by checking serum trypsin-like immunoreactivity (TLI) before undertaking more invasive diagnostics (Thompson et al, 2009). If diarrhoea is a clinical sign then a full faecal analysis (including Tritrichomonas if there are largebowel signs) should be submitted to look for primary infections, but also because cats with GI lymphoma may be predisposed to secondary infections. Imaging Imaging can provide a lot of supporting information; most commonly abdominal ultrasound is performed as it can be undertaken with only physical restraint in most cases. Typically, the small intestines will have thickened muscularis propria layers (Figures 1 and 2); however, the same change will also occur in IBD (Figure 3) and ultrasound cannot differentiate the two diseases (Daniaux et al, 2014). 3 / 10

4 Figure 1. Thickening of the ileum, it is important to examine as this may be the only portion affected. Figure 2. Thickening of the ileum, histopathology confirmed small cell lymphoma. 4 / 10

5 Figure 3. Small intestinal thickening, histopathology confirmed chronic lymphoplasmacytic enteritis with mild eosinophilic infiltrate. Enlarged hypoechoic mesenteric lymph nodes suggest metastatic disease, but again this is not a specific finding and could represent reactive change in IBD or another neoplasm. Unfortunately, ultrasound-guided fine-needle aspiration of mesenteric lymph nodes does not provide accurate results for differentiation (Lingard et al, 2009). Importantly, in some cases of GI neoplasia the ultrasound appearance will be normal so it is not possible to exclude disease using ultrasound (Marolf et al, 2015). Histopathology Figure 4. Changes in the ileum and associated lymph nodes visualised at surgery. 5 / 10

6 Figure 5. Use of a 4mm biopsy punch to obtain full-thickness biopsies. Definitive diagnosis can only be achieved by histological evaluation of samples obtained during endoscopy or exploratory coeliotomy. The least invasive method is via endoscopy, which has the advantage of a short recovery period and minimal risk of complications. Both gastroduodenoscopy and ileocolonoscopy should ideally be performed so the mucosa of stomach, duodenum and ileum can be visualised and small biopsy specimens taken. Unfortunately, comparisons of endoscopic and full-thickness biopsy methods have shown cases of lymphoma may be misdiagnosed as IBD compared to full-thickness samples obtained surgically (Evans et al, 2006). A coeliotomy approach allows direct visualisation of the entire GI tract and associated lymph nodes (Figure 4), then biopsies of these and any other abnormal structures. Several areas should be biopsied to include duodenum, ileum and jejunum (even if grossly normal in appearance) and associated lymphoid tissue if possible (Figure 5). Although this is the more invasive way of obtaining histology samples, in cats the rate of complications is actually low even in cases of lymphoma (Smith et al, 2011). Choice of sampling method is best decided on a case by case basis; in many cases proceeding straight to full-thickness biopsies is appropriate, but a certain amount of clinical bravery may be required to recommend full thickness biopsies in a cat only presenting with weight loss and where there are no specific indications of GI disease on bloods or imaging, so in others endoscopy may be performed first. 6 / 10

7 In both cases, ensure the owner is fully aware of the limitations and potential complications of the method recommended. In cases with no specific indications of neoplasia a therapeutic trial with a hypoallergenic diet would be appropriate as a precursor to biopsies, but avoid trials of glucocorticoids (see later). Differentiating LGAL from IBD histologically can be difficult and the application of immunophenotyping and clonality testing can be an aid to diagnosis in inconclusive cases. Advice of the histopathologist is advised to determine if these tests would be of benefit. Differentiation of low/high grade or small/large cell form is important as the higher grades have very different treatment requirements and a much poorer prognosis. Treatment Chemotherapy Table 1. Chlorambucil protocols. As a diffuse, metastatic disease LGAL is best treated with systemic chemotherapy. Fortunately, a combination of oral prednisolone and chlorambucil is well tolerated, has good response rates and survival times are favourable usually two to three years. Several protocols have been published (Table 1) with largely similar response rates and median survival times. A potentially appealing protocol involving a higher dose of chlorambucil every two weeks has been suggested to have comparable results to the other protocols. 7 / 10

8 Table 2. Chlorambucil side effects. Although compliance may be improved and there appears to be a higher chance of complete remission, the higher doses will increase the risk of side effects, particularly seizures. Side effects are otherwise uncommon, but possible (Table 2). As with other forms of lymphoma the response rate is expected to be poorer if glucocorticoids have been administered previously, so trial treatments with steroids alone should be avoided until neoplasia has been ruled in or out. Doses of glucocorticoids used vary even within each study from 1mg/kg to 3mg/kg daily or 5mg/cat to 10mg/cat daily, usually weaned to 1mg/kg to 2mg/kg every other day once in remission. Given the similar outcomes, any of the published protocols could be used and consultation with a veterinary oncologist is advised to guide treatment planning in case of recent developments. As an example, the author has used 2mg chlorambucil Monday, Wednesday, Friday as a practical and low-risk schedule, with prednisolone 2mg/kg daily, weaning down to every other day or the nonchlorambucil days once clinical signs are controlled. Monitoring of haematology is recommended every three to four weeks initially and then every three months once in remission. As weight loss is the predominant clinical sign, monitoring improvement in this is often the best guide to success of treatment. No information is available on the requirement for long-term administration of chemotherapy. As treatment is well tolerated patients are frequently kept on the same protocol long-term. There is a cost associated with this and continued monitoring needed, as well as the ongoing potential side effects so some cases can be weaned off the medication if they are showing no clinical signs of the disease. Close monitoring for relapse is required and if clinical signs reoccur, diagnostics including histopathology would ideally be repeated before restarting treatment. Adjunctive treatments If hypocobalaminaemia is identified then correction is essential with injectable vitamin B 12, otherwise response to treatment will probably be disappointing. Initial recommended dose is 0.125mg/cat to 0.25mg/cat SC every seven days for four to six weeks. The requirement for long-term supplementation will vary and so ongoing supplementation should be based on repeat blood cobalamin levels. Some cases will require long-term supplementation despite remission of the underlying disease so if frequent injections are required long-term, owners can be taught to administer these at home. 8 / 10

9 Feeding a balanced, easily digestible diet (such as a prescription GI diet or a senior diet) will assist weight gain in patients with this condition; alternatively and especially if there is concurrent or previous IBD, a hypoallergenic diet would be advisable. Consideration should be given to omega-3 fatty-acid supplementation as this has been shown to improve outcome in dogs with lymphoma (though this has not been tested in cats). Relapse or treatment failure If symptoms return or fail to improve during treatment, check/correct vitamin B 12 levels first and, if there is diarrhoea, repeat faecal analysis. In cases no longer in remission, rescue with cyclophosphamide has been suggested (Fondacaro et al, 1999; Stein et al, 2010) or a standard cyclophosphamide, vincristine and prednisolone protocol. A veterinary oncologist can advise on latest recommendations. A study has explored the potential for using abdominal irradiation as an alternative modality for rescue (Parchley et al, 2011). Summary Weight loss in older cats is a very common presentation in first opinion practice. If GI disease is considered in the initial list of differential diagnoses the investigation can proceed more logically and will detect cases of LGAL that would otherwise be missed. Treatment with chlorambucil and prednisolone plus correction of hypocobalaminaemia is straightforward and can yield very rewarding results. Unanswered questions remain regarding the best treatment schedule the long survival times and relatively small sizes of studies make it very difficult to truly compare doses, frequency and longterm treatment. Additionally, treatment of hypocobalaminaemia and dietary management may have a large bearing on treatment response and long-term survival, so ideally would be standardised when comparing dose schedules. Please note some drugs discussed in this article are not licensed in animals and are used under the cascade. Acknowledgement The author thanks Louise Worth and Andrew Holloway for providing images. 9 / 10

10 Powered by TCPDF ( References Bertone ER, Snyder LA and Moore AS (2002). Environmental tobacco smoke and risk of malignant lymphoma in pet cats, Am J Epidemiology 156(3): Daniaux LA, Laurenson MP et al (2014). Ultrasonographic thickening of the muscularis propria in feline small intestinal small cell T-cell lymphoma and inflammatory bowel disease, J Feline Med Surg 16(2): Evans SE, Bonczynski JJ et al (2006). Comparison of endoscopic and full-thickness biopsy specimens for diagnosis of inflammatory bowel disease and alimentary tract lymphoma in cats, J Am Vet Med Assoc 229(9): 1,447-1,450. Fondacaro JV, Richter KP et al (1999). Feline gastrointestinal lymphoma: 67 cases ( ), Eur J Comp Gastroenterol 4(2): Kiselow MA, Rassnick KM et al (2008). Outcome of cats with low-grade lymphocytic lymphoma: 41 cases ( ), J Am Vet Med Assoc 232(3): Lingard AE, Briscoe K et al (2009). Low-grade alimentary lymphoma: clinicopathological findings and response to treatment in 17 cases, J Feline Med Surg 11(8): Louwerens M, London CA, Pedersen NC and Lyons LA (2005). Feline lymphoma in the post-feline leukemia virus era, J Vet Intern Med 19(3): Marolf AJ, Bachand AM, Sharber J and Twedt DC (2015). Comparison of endoscopy and sonography findings in dogs and cats with histologically confirmed gastric neoplasia, J Small Anim Prac 56(5): Parchley DL, LaRue SM et al (2011). Abdominal irradiation as a rescue therapy for feline gastrointestinal lymphoma: a retrospective study of 11 cats ( ), J Feline Med Surg 13(2): Smith AL, Wilson AP et al (2011). Perioperative complications after full-thickness gastrointestinal surgery in cats with alimentary lymphoma, Vet Surg 40(7): Stein TJ, Pellin M et al (2010). Treatment of feline gastro-intestinal small-cell lymphoma with chlorambucil and glucocorticoids, J Am Anim Hosp Assoc 46(6): Thompson KA, Parnell KN et al (2009). Feline exocrine pancreatic insufficiency: 16 cases ( ), J Fel Med Surg 11(12): Valli VE, Jacobs RM et al (2000). The histologic classification of 602 cases of feline lymphoproliferative disease using the National Cancer Institute working formulation, J Vet Diagn Invest 12(4): / 10