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Lymphoma in Dogs
- 2. BOBBY RAE Border Terrier 10 years old, ME Arrived from Vets Now without owner or carer Admitted over weekend for vomiting and lethargy Completely flaccid upon arrival
- 3. CLINICAL EXAM T 37.4oC P 108 R 66 Increased respiratory noise Extremely lethargic Generalised lymphadenopathy CRT <2s but slight yellow tinge Liver and spleen palpable Congested scleral vessels Opacity in L cornea
- 4. Submandibular LN 37mm x 22mm Prescapular LN 44mm x 25mm
- 5. Inguinal LN 41mm x 21mm Popliteal LN 28mm x 20mm
- 6. CLINICAL EXAM Ophthalmology consult Mass in anterior chamber of R eye Possible dry eye (left) Translimbal neovascularization L > R Cataract Severe anterior uveitis 17mmHg pressure in both eyes Too cloudy to examine retina
- 7. CLINICAL EXAM Ophthalmology consult Mass in anterior chamber of R eye Possible dry eye (left) Translimbal neovascularization L > R Cataract Severe anterior uveitis 17mmHg pressure in both eyes Too cloudy to examine retina Lymphoma infiltration of the eyes
- 8. PROVISIONAL DIAGNOSIS Stage Vb lymphoma Extranodal involvement (eyes) Showing clinical signs Ideally should do bone marrow aspirate to check for bone marrow involvement
- 9. LYMPHOMA Malignant proliferation of peripheral lymphoid tissues Predisposing factors 3 ways of classification Anatomical Histological (low/intermediate/high) Immunophenotype (B/T/null)
- 10. CLINICAL PRESENTATION Variable and depends on extent and location Generalised lymphadenopathy Paraneoplastic syndromes Hypercalcaemia Cancer cachexia Monoclonal gammopathy Globulin spike Alb
- 11. APPROACHING LYMPHOMA Bloods Haematology, biochemistry FNA of lymph nodes Thoracic radiographs Abdominal ultrasound Bone marrow aspirate
- 12. BACK TO BOBBY Bloods Haematology + biochemistry + coagulation FNA of submandibular and popliteal LNs Cytology PARR (PCR for Antigen Receptor Rearrangement) Thoracic radiographs Abdominal ultrasound
- 13. BOBBY’S BLOOD RESULTS Thrombocytopenia? Hypoglycaemic Decreased TP liver enzymes NH3 PT 22.9s 14 – 19 aPTT >200s 75 – 105
- 15. ULTRASOUND Lymphadenopathy Hepatomegaly Splenomegaly Cholecystitis Pancreatitis Prostatomegaly FNA of liver and spleen
- 19. CHEMOTHERAPY Combination protocols CHOP COP Doxorubicin single agent Re-induction or rescue therapy > 1m since stopping initial protocol: re-induction with that same protocol If re-induction fails, use rescue therapy Extranodal lymphoma Chemotherapy Local therapy
- 20. PROGNOSIS Immunophenotype B cell T cell Null cell WHO stages I, II, III, IV, V Sub-stage a Sub-stage b Any concurrent conditions
- 21. BOBBY’S INITIAL TREATMENT IVFT (normal saline + glucose) L-asparaginase Maropitant Vitamin K Dexamethasone (reduced dose) Ursodeoxycholic acid (Destolit)
- 22. AFTER THE INITIAL TREATMENT QAR but no longer comatose LN softer and smaller Improvements in biochemistry Appetite slowly returning Cautiously optimistic Continue with chemotherapy L-CHOP protocol Vincristine (reduced dose) Urinalysis
- 23. AFTER THE INITIAL TREATMENT QAR but no longer comatose LN softer and smaller Improvements in biochemistry Appetite slowly returning Cautiously optimistic
- 24. BOBBY’S PROGNOSIS Problems Stage Vb lymphoma Acute liver failure B cell lymphoma Overcame acute liver failure, fair prognosis 6 – 9 months
- 25. DAY OF DISCHARGE Terror terrier Normal sized lymph nodes Take home medications Ranitidine Destolit Prednisolone Promax Back Thursday (yesterday) for recheck and cyclophosphamide
- 26. TAKE HOME MESSAGES Step by step approach to lymphoma Clinical exam Stage – measure LN May involve other organs
- 27. REFERENCES Jane M. Dobson, B. Duncan X. Lascelles. (2011). Chapter 19: Tumours of the Haemopoietic System. In: Jane M. Dobson, B. Duncan X. Lascelles BSAVA Manual of Canine and Feline Oncology. 3rd ed. London: British Small Animal Veterinary Association. p285-291. Edward J. Hall, James W. Simpson, David A. Williams. (2005). Chapter 3: Imaging of the Gastrointestinal Tract, Liver and Pancreas. In: Edward J. Hall, James W. Simpson, David A. Williams BSAVA Manual of Canine and Feline Gastroenterology. 2nd ed. London: British Small Animal Veterinary Association. p29. Edward J. Hall, James W. Simpson, David A. Williams. (2005). Chapter 28: Therapeutics. In: Edward J. Hall, James W. Simpson, David A. Williams BSAVA Manual of Canine and Feline Gastroenterology. 2nd ed. London: British Small Animal Veterinary Association. p311. Companion Animal Studies (CAS) lecture – Oncology 3: Approach to lymphoma and leukaemia. J.S. Morris, BSc, BVSc, PhD, FRCVS Ian Ramsey (2014). BSAVA Small Animal Formulary . 8th ed. London: British Small Animal Veterinary Association I. Amores-Fuster, P. Cripps, P. Graham, A. M. Marrington, L. Blackwood. (2015). The diagnostic utility of lymph node cytology samples in dogs and cats. Journal of Small Animal Practice. 56 (2), p125-129. http://www.animalhealth.msu.edu/ClientEducation/MKTG.CARD.ANATOMICPATHOLOGY.010.PDF Information Cards by Lab Section - For Practitioners, Anatomic & Surgical Pathology, PCR for Antigen Receptor Rearrangements Nerschbach V, Eberle N, Joetzke AE, Hoeinghaus R, Hungerbuehler S, Mischke R, Nolte I, Betz D. (2014). Splenic and hepatic ultrasound and cytology in canine lymphoma: effects of findings on stage migration and assessment of prognosis. Veterinary and Comparative Oncology. 12 (4). https://www.marshfieldlabs.org/proxy/RefPointWinter13.1.pdf Marshfield Labs Claire Inderbinen Kaiser, Janean L. Fidel, Malgorzata Roos, and Barbara Kaser-Hotz (2007) Reevaluation of the University of Wisconsin 2-Year Protocol for Treating Canine Lymphosarcoma. Journal of the American Animal Hospital Association: March/April 2007, Vol. 43, No. 2, pp. 85-92. Stephen Withrow, David Vail. (2012). Chapter 32A: Canine Lymphoma and Lymphoid Leukemia. In: Stephen Withrow, David Vail Withrow and MacEwen's Small Animal Clinical Oncology. 5th ed. Gloucester: Elsevier Saunders. p608-627.
Editor's Notes
- BOBBY RAE Meet Bobby Rae. 10 year old ME Border Terrier who arrived from Vets Now without an owner or carer. He was initially admitted to Vets Now over the weekend for vomiting and lethargy by the owner’s niece.
- CLINICAL EXAM On clinical examination, his temperature was 37.4oC. He had a heart rate of 108 bpm and a respiratory rate of 66 breaths per minute, with increased respiratory noise. He was extremely lethargic and had a generalised lymphadenopathy. He had a CRT of <2 seconds but his mucous membranes had a slight yellow tinge. His liver and spleen were palpable. He also had congested scleral vessels and opacity in his left cornea.
- LYMPH NODES – SUBMANDIBULAR & PRESCAPULAR These are Bobby’s enlarged lymph nodes. As you can see, they are quite massive.
- LYMPH NODES – INGUINAL & POPLITEAL Based on this clinical presentation, we can make an educated guess that Bobby is most likely suffering from lymphoma.
- CLINICAL EXAM – OPHTHALMOLOGY CONSULT As I mentioned earlier, Bobby had some ocular signs as well. So we sought out George for an ophthalmology consult and these were his findings. We can summarise this up into a single sentence – Bobby’s lymphoma is infiltration his eyes.
- PROVISIONAL DIAGNOSIS Just based on our clinical exam, we can make a provisional diagnosis of stage Vb lymphoma. It was decided Bobby was Stage V as he showed extranodal involvement (since his eyes were affected) and sub-stage b as he was showing clinical signs. Ideally a bone marrow aspirate should have been done to check for bone marrow involvement to definitely class him as a Stage V but he was already quite depressed and did not need to be stressed further.
- LYMPHOMA Lymphoma is the malignant proliferation of peripheral lymphoid tissues and there are several predisposing factors such as age, genetics, viruses (cats, FeLV) and the environment (passive smoking cats). There are 3 ways of classifying lymphoma, based on anatomy, histology and immunophenotype. For the anatomical classification, we have multicentric, alimentary, thymic/mediastinal, cutaneous and extranodal. Of these types, the multicentric form is most common in dogs (80-85%) while the alimentary form is most common in cats (40-50%). Histologically, lymphomas can also be classified according to different grades – low, medium and high. Low grade lymphomas are made up of small, mature lymphocytes with a low mitotic rate. This means they progress slowly but also makes them less responsive to chemotherapy drugs. On the other hand, intermediate and high grade lymphomas are generally made up of lymphoblasts with a high mitotic rate, allowing them to progress much faster and thus, are more responsive to chemotherapy drugs. Lymphomas can also be classified as being B cell, T cell or null cell (neither B nor T cell). Immunophenotype can be determined in several ways – PCR, flow cytometery and immunohistochemistry. Most cases of canine lymphoma have a B cell immunophenotype (about 70%).
- CLINICAL PRESENTATION The clinical presentation of lymphoma is variable and depends on its extent and location. However, the typical presentation is that of generalised lymphadenopathy, like in Bobby’s case. Several paraneoplastic syndromes are associated with canine lymphoma, with the most clinically significant paraneoplastic syndrome being hypercalcaemia. The neoplastic cells produce parathyroid hormone related peptide (PTH-rP), which mimics the effects of parathyroid hormone and resorbs calcium from its various stores in the body (bones, gut, kidney). This hypercalcaemia is most commonly seen with T cell lymphoma and patients with hypercalcaemia are more likely to relapse [2007]. Other associated paraneoplastic syndromes include cancer cachexia and monoclonal gammopathies. This is an example of a monoclonal gammopathy – it has a large globulin spike and the base of the albumin spike is similar to that of the globulin spike.
- APPROACHING LYMPHOMA There are several steps in approaching lymphoma. Routine bloods should be done (just to highlight any other problems the dog might have). A FNA of the lymph nodes can also be easily carried out and can definitely be done in first opinion practice – this will give you an idea of the cells involved and help with the diagnosis. [feb 2015 – 70% of FNA samples from enlarged lymph nodes are diagnostic] Thoracic radiographs and abdominal ultrasound will help with determining the presence of metastases in other organs. Aspirates of the liver and spleen can be done during the abdominal ultrasound to further determine if there has been any infiltration. A bone marrow aspirate can also be done to determine bone marrow involvement. However, if the client intends to have the dog treated regardless of the stage or prognosis or is financially strained, some of these tests (thoracic radiographs, abdominal ultrasound, bone marrow aspirate) may not be essential and you could proceed with treatment. treatment.
- BACK TO BOBBY This is what we did with Bobby. We included the coagulation test as we were planning on taking aspirates from his liver and spleen during his ultrasound. We took FNAs of his submandibular and popliteal LNs, which was very easy due to their size. We used the samples for cytology and for PCR (to determine the immunophenotype). We also took thoracic radiographs and did an abdominal ultrasound to check the extent of infiltration and to look for the presence of any metastases.
- BLOOD RESULTS Bobby’s blood results showed a thrombocytopenia (platelet count 34), which was worrying. However, the smear suggested his platelets were actually within the reference range and there were no signs of petechiation or haematomas after sampling. He was also dehydration, as seen by the slight decrease in total protein, and also hypoglycaemic. All parameter related to the liver were increased (ALT, AST, ALKP, GGT, bilirubin), suggesting he was in acute liver failure. We also checked Bobby’s ammonia levels, which were moderately elevated, yet more evidence that his liver was compromised. His coagulation results were also increased (slight increase in PT, moderate increase in aPTT)
- RIGHT LATERAL THORACIC RADIOGRAPH (yellow) There is a poorly defined circular mass dorsal to the tracheal bifurcation that is pushing the trachea ventrally. This is suggestive of tracheobronchial lymphadenopathy. (pink) The sternal lymph node also looks a bit enlarged. The liver also looked possibly enlarged but it was difficult to say for sure as it extended beyond the borders of the radiograph.
- ULTRASOUND This is a summary of the ultrasound findings Mesenteric, ileocolic, splenic, hepatic, peri-aortic, medial iliac and hypogastric lymph nodes were noted to be enlarged. Liver was markedly enlarged with some moderately defined, hypoechoic nodular areas Spleen was moderately enlarged with a hypoechoic parenchyma These findings are supportive of neoplastic infiltrate into the abdominal organs and a FNA was done on the liver and spleen. Other findings on ultrasound include pancreatitis, thickened gall bladder wall (consistent with cholecystisis) and prostatomegaly (likely BPH).
- CYTOLOGY x4 Not to forget about cytology, we sent off the better slides to the lab but kept a few for ourselves to have a look. This is the x4 view of the LN FNA – highly cellular.
- CYTOLOGY – x10 This is the x10 view – many lymphoid cells are present. Lymphoid cells are identified by their large nuclei and small ring of cytoplasm.
- CYTOLOGY – x40 This is the x40 view – the lymphoid cells are of intermediate size. These cells are just slightly larger than the RBC and you would expect lymphoblasts to be at least twice the size of RBC. Some cells have mitotic figures and nucleoli can be seen in some cells as well (not very clear on this image). The pale pink blobs are bits of dying nuclei. We also got back the FNA results from the liver and spleen – both samples were highly cellular with a uniform population of medium – large lymphoid cells. All the results thus far have lead us to the diagnosis of lymphoma.
- CHEMOTHERAPY Once a diagnosis is established, untreated patients usually only have 4-6 weeks left. This makes it paramount to start treatment immediately. Combination protocols are the current treatment method of choice, most commonly the CHOP protocol. Remission rates of 80-90% are usually achieved, with a median remission of 8 months and a median survival time of 12 months. [2007 – study in 96 dogs found the mean first remission duration of 9 months] About 25% of dogs will be alive more than 2 years after commencing treatment and dogs who opted for the CHOP, which included doxorubicin, had a median survival of 1 year [Paper - 1993]. The classic CHOP protocol spans over 19 weeks, after which the dog is monitored monthly. There is also the COP protocol for owners who wish to take a less aggressive approach. As this is a less aggressive chemotherapy protocol, it is not unexpected that response rates and length of remission are both less than that of the CHOP protocol. Although initial chemotherapy might be successful, most patients will eventually relapse. If the relapse occurs more than a month after stopping the initial protocol, re-induce the patient with that same successful protocol. If the re-induction fails, rescue therapy should be attempted. Rescue therapy agents are used as single agents or as a combination and are usually not on the standard CHOP protocols. They are typically used specifically for cases with drug resistance. Such examples include lomustine, dacarbazine, vinblastine. Doxorubicin as a single chemotherapeutic agent is also an option for owners who are not keen on the aggressive CHOP protocol. It is the most effective single agent protocol and is cheaper and less time consuming than both the CHOP and COP protocols, having a response rate of 70%. If the multicentric lymphoma has an extranodal component, chemotherapy should be commenced. However, in cases where the extranodal site is solitary and not part of the multicentric presentation, local therapy such as surgery or radiation therapy can be performed. This offers the client another option if they are not keen about chemotherapy.
- PROGNOSIS Chemotherapy is generally successful at managing lymphoma, with response rates in 90% of dogs and dogs have a good quality of life during remission. However, majority of the dogs will succumb to their disease when they relapse as the lymphoma usually evolves to a more drug resistant form. There are two main factors in determining prognosis – immunophenotype and WHO sub-stage. Lymphoma has three immunophenotypes – B cell, T cell and null cell (of which the null cell is very rare). In cases of widespread lymphoma, a B cell lymphoma offers a better prognosis. On the other hand, in cases of contained lymphoma, a B cell lymphoma offers a worse prognosis. Dogs of low grade lymphoma (I, II) do better as a whole than those with high grade lymphoma (III, IV, V). Dogs of substage b show clinical signs of lymphoma and generally do worse than substage a patients. Also, any concurrent conditions the dog has will affect its prognosis.
- BOBBY’S INITIAL TREATMENT Bobby was put on normal saline, supplemented with glucose to help with his hypoglycaemia. This combination was chosen over Hartmann’s as the HCO3- in Hartmann’s is metabolised in the liver and Bobby. Furthermore, lymphoma can cause hypercalcaemia, in which Hartmann’s is contraindicated. Bobby was also given L-asparaginase immediately. L-asparaginase is not metabolised in the liver, thus reducing the workload of the liver. Bobby was also given maropitant as the L-asparaginase was likely to cause him to vomit and dehydrate himself further. Bobby was also put on vitamin K to help with his clotting (vitamin K activates clotting factors). Also, he was scheduled to have a FNA of his liver and spleen during his ultrasound and his PT was slightly increased, hence vitamin K was indicated. There was overnight improvement of his lymph nodes, which were palpably smaller and softer. He was then given a reduced dexamethasone to continue his chemotherapy and help increase the tumour cell kill – high levels of steroids are very poisonous to lymphocytes. The dexamethasone would also improve his appetite and make the body more sensitive to chemotherapy. He was also put on Destolit (ursodeoxycholic acid) to help his liver with the lymphoma infiltration and improve bile flow. The improvement of bile flow would also increase vitamin K absorption.
- AFTER INITIAL TREATMEN On Wednesday, after a day and a half of treatment, Bobby started to show a fair amount of improvement. His lymph nodes were, as a whole, softer and smaller. Improvements were also seen in his biochemistry – parameters were almost within the normal range, he was maintaining his glucose levels and keen to eat later in the day. Hence, he was taken off his glucose supplementation and left on normal saline at twice maintenance. At this point, we were cautiously optimistic about his survival – still QAR but heading in the right direction. On Thursday, we continued with Bobby’s chemotherapy. He was on the L-CHOP protocol and was given vincristine at a slightly reduced dose as his liver enzymes, though decreasing, were still slightly elevated. Also, he was borderline neutropenic on the day. A urine sample was also collected as a baseline before he was started on his cyclophosphamide. As Bobby was doing well thus far, there was no indication to not continue with his chemotherapy
- BOBBY’S PROGNOSIS Bobby’s initial prognosis was guarded as he had both stage Vb lymphoma and seemed to be in acute liver failure, hence he had an uphill battle ahead of him. However, his PCR results came back – B cell lymphoma. This was a positive prognostic indicator as in cases of widespread lymphoma, like Bobby’s, a B cell lymphoma offers a better prognosis. Bobby eventually overcame his acute liver failure and his prognosis was fair (6-9 months). The likely explanation for Bobby’s situation would be that the lymphoma infiltration of his liver sent him into acute liver failure, which resulted in rapid deterioration over the weekend before he arrived at the Small Animal Hospital. In addition the his lymphoma, Bobby also appeared to be in acute liver failure, which made his prognosis worse as acute liver failure requires intensive treatment and if often fatal. The liver usually copes well with damage and only shows signs of stress when more than 75% is damaged. Bobby eventually overcame his acute liver failure and his prognosis was fair (6-9 months). If he was a stage IV, he would likely have more than a year. The likely explanation for Bobby’s situation would be that the lymphoma infiltration of his liver sent him into acute liver failure, which resulted in rapid deterioration over the weekend before he arrived at the Small Animal Hospital.
- DAY OF DISCHARGE Bobby was pretty much back to his normal self by Thursday, with normal lymph nodes, and was discharged on Friday. He was discharged with Zantac, Destolit, prednisolone and Promax (probiotic). Bobby was due to return in a week for a recheck and, if doing well, to start his cyclophosphamide.
- TAKE HOME MESSAGES The main take home messages from this is that take a step by step approach to lymphoma is first opinion practice. Always start off with your general, but thorough, clinical exam. It would be a good idea to take measurements of the enlarged lymph nodes for records. It’s not essential to do all the diagnostic tests (radiographs, ultrasound, bone marrow aspirate) for staging but routine bloods and a FNA of the enlarged lymph nodes would be helpful. Routine bloods will provide a bigger picture and highlight any other concurrent issues the dog might have and it is possible to make a diagnosis with a FNA sample of lymph nodes. It is very important not to forget that lymphoma can involve other organs as well – I was not expecting to have to consult my liver notes in this case.