ERYTHROLEUKEMIA IN A CAT. Erythro leu ke mie bij een kat

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1 Vlaams Dier ge nees kun dig Tijd schrift, 2007, 76, Case re port 44 ERYTHROLEUKEMIA IN A CAT Erythro leu ke mie bij een kat H. De Bos sche re, J. Poel voorde, G. De pourcq, K. Bruy land Me disch Labo Bruy land Afde ling Dier ge nees kun de, Mei weg 1, B-8500 Kort rijk Hen drik.de.bos sche re@bruy land.be ABSTRACT A 3-year-old neu te red male do mes tic cat was pre sen ted with anor exia and weight loss. Cli ni cal exa mi na ti on also re ve a led fe ver and pale mu co sae. The blood sme ar sho wed an ab nor mal pre sen ce of both erythro cy tic and leukocytic precursors in the circulation. The cat also tested positive for feline leukemia virus (FeLV). Due to the poor prog no sis, the cat was eu tha ni zed and pre sen ted for au top sy. Bone mar row sme ars also re ve a led the pre - sence of immature erythrocytic and leukocytic cells. This findings corresponded well with erythroleukemia, an uncommon form of leukemia. SAMENVATTING Een 3 jaar oude, ge cas treer de huis kat werd aang ebo den met anor exie en ver ma ge ring. Bij het kli nisch on der zoek werden koorts en bleke mucosae waargenomen. Het bloeduitstrijkje toonde een abnormale aanwezigheid van erythrocytaire en leukocytaire precursors in de algemene circulatie. De test voor het feliene leukemie virus (FeLV) was positief. Omwil le van de slech te prog no se werd de kat ge ëuthanaseerd en aang ebo den voor au top sie. Een been mer guit strijk je toonde ook immature erythrocytaire en leukocytaire cellen aan. Deze bevindingen wijzen sterk op erythroleukemie, een zeldzame vorm van leukemie. INTRODUCTION Erythro leu ke mia, as the name im plies, is a leu ke mia of both red and whi te cell li ne a ges. Both erythro cy tic and leukocytic precursors are present in the circulation (Harvey et al., 1978; Har vey, 1981; Re a gan et al., 1998; Smith et al., 2003). A key fe a tu re that dis ting uis hes acu te erythroleukemia from other types of acute leukemia is that the erythroid pre cur sors com pri se more than 50% of nu cle a ted bone mar row cells with a my e loid/erythroid ra tio of less than one. Pro mi nent me ga lo blas tic or aty pi - cal erythroid precursors are common. Myeloblasts and mo no blasts are < 30% of all nu cle a ted cells in the bone marrow (Grindem, 2000). Erythroleukemia and erythremic myelosis are considered different manifestations of the same illness. In erythre mic my e lo sis the re is a pre do - minance of immature erythroid cells in peripheral blood, which can pro gress to a mix tu re of ne oplas tic my e loid and erythroid cells in the pe rip he ral blood in acu te erythro leu ke mia (Jain, 1986; Har vey, 1981). In fact the dis tinc ti on is most ly ar bi tra ry and is ba sed on the fin ding of myeloblasts admixed with abnormal nucleated erythrocytes in peripheral blood (Jain, 1993). However, erythremic myelosis has historically been classified as a leukemia of the erythrocytic lineage. This disorder has recently been renamed as either myelodysplastic syndrome with erythroid predominance or erythroleukemia with ery - throid predominance (Reagan et al., 1998). Descriptive case reports of erythroleukemia are very li mi ted in the li te ra tu re. Herz and ot hers (1969a, 1969b) described a case with successive stages of myeloprolife - rative disorders, including erythroleukemia. Shimada and ot hers (1995) des cri bed erythro leu ke mia in two cats in the same hou se hold. Co maz zi and ot hers (2000) des - cribed a case of erythremic myelosis. However, various forms of hematologic appearances of myeloproliferative dis e a se in the cat have been des cri bed, each with a spe ci - fic terminology. Nowadays hematologists prefer simply to use the term erythro leu ke mia to en com pass the va ri ous forms of this dis e a se, as in hu mans (Har vey et al., 1978). The pre sent re port is a de scrip ti on of an erythro leu ke mia case via hematology, biochemistry, serology, cytology, autopsy and histopathology.

2 45 Vlaams Diergeneeskundig Tijdschrift, 2007, 76 CASE REPORT Case his to ry A 3-year-old neu te red male do mes tic cat (Felis vulgaris), which li ved in doors as well as out doors, was pre sen - ted with signs of anor exia and weight loss, which had star ted 2 weeks be fo re and were the re a son for the con sul - tation. The cat had been vaccinated annually against feline panleukopenia and rhinotracheitis (Felocell 3, Phizer). The re was no his to ry of pre vi ous illnes ses or tra vel his to - ry. Clinical examination also revealed fever and pale muco sae. Blood (clot ted, EDTA and flu o ri de tube) was col - ected for hematology and extended general, liver and kidney screening. Feline leukemia virus (FeLV), feline immunodeficiency virus (FIV) and feline infectious peritonitis (FIP) rapid tests were also requested. Meanwhile the cat was treated with antibiotics and corticosteroids. The re was a mild to mo de ra te res pon se to this tre at ment, i.e. weight gain and re turn of ap pe ti te. Be cau se the FeLV test was positive and the condition of the cat deteriorated one week after presentation, euthanasia was requested. He ma to lo gy, bi oche mis try and in fec ti ous se ro lo gy The results of hematology, biochemistry and infectious se ro lo gy can be found in Ta ble 1. The re was leu ko cy to - sis, mild non-regenerative anemia, mild hyperglycemia, hypergammaglobulinemia, slightly increased levels of creatinin, and markedly increased levels of AST, ALT and (total) bilirubin. The Bio Vet Test Speed Duo FeLV / FIV and the Speed FIP are rapid immunochromatographic tests for the detection of FeLV antigen, FIV antibody and FIP (feline coronavirus) antibody, respectively, in feline blood. The prin ci ple of the tests is as fol lows: as the sam ple (who le blood, se rum or plas ma) flows through the ab sor - bent pad, the labelled FeLV antibody-dye conjugate binds to any P27 FeLV an ti gen pre sent; the la be led syn - the tic FIV pep ti de (GP40) dye con ju ga te binds to any FIV antibodies present; and the labeled antigen dye conjugate (a unique recombinant protein specific to coronavirus) binds to the FIV/feline coronavirus antibodies. The antigen/antibody complexes move by capillary action along the path and are cap tu red wit hin the test re gi ons of each de vi ce, which are in di ca ted by a pink line in tho se areas. Cy to lo gy The blood sme ar (Mo di fied Wright stain, Sig ma Al - drich) sho wed an ab nor mal pre sen ce of both erythro cy tic and leukocytic precursors in the circulation, such as prorubricytes, rubricytes, metarubricytes and promyelocytes (Figure 1), characterized by a marked anisocytosis. The bone mar row (Mo di fied Wright stain) was very cellular and characterized by the presence of a population of large immature cells. The immature cells with intensely staining cytoplasm resembled erythroid precursors. The blasts with the pale stai ning cy to plasm ap pe a red to be pro - myelocytes (Figure 2). The maturation of the erythroid and myeloid forms was abnormal, meaning that appropriate num bers of cells in va ri ous sta ges of ma tu ra ti on were ab - sent. The per cen ta ge of erythroid pre cur sors was 57% of the nu cle a ted bone mar row cells, with a my e loid/ erythroid ra tio of Au top sy At au top sy, a pale (ane mic) as pect of the car cass, an en lar ged, pale and thic ke ned spleen, and an en lar ged, pale colored liver were noticed. No abnormalities were ob ser ved in ot her or gan sys tems. Sam ples of the li ver, spleen, and bone mar row were col lec ted for his top atho - logy. His top atho lo gy Histopathology (Hematoxylin-eosin) of the liver revealed moderate to severe centrolobular to midzonal vacuolar degeneration, marked centrolobular fibrosis and diffusely spread foci of extramedullary hematopoiesis (Fi gu re 3). The spleen sho wed a loss of nor mal ar chi tec - ture and a massive proliferation of blood cells, especially erythroid cells (extramedullary hematopoiesis). According to the hematological (erythrocytic and leukocytic precursors in circulation, nonregenerative anemia) and bone marrow (abnormal maturation of erythroid and myeloid cells) cytological findings, together with the other data (such as case his to ry, FeLV po si ti ve), the most li ke ly diagnosis was erythroleukemia. DISCUSSION As in humans, the hematologic appearance of cats with erythro leu ke mia may change with time (Har vey, 1981). Da mes hek (1965) and Har vey (1981) stres sed the exis - tence of three successive stages of myeloproliferative disorders in cats, initially involving the erythrocytic series and later the granulocytic precursors, as follows: (1) a period of erythremic myelosis characterized by striking erythroid hy per pla sia of the bone mar row; (2) a sta ge of mixed erythroid and myeloid proliferation, namely erythroleukemia, and (3) the eventual termination of some cases in myeloblastic leukemia. Each phase is generally

3 Vlaams Dier ge nees kun dig Tijd schrift, 2007, Table 1. Results of hematology, biochemistry and serology. He ma to lo gy Re fe ren ce va lu es Erythro cy tes 5.14 x /l Leu ko cy tes 37.6 x 10 9 /l %ban ded neu tro %seg men ted neu tro %lymp ho %aty pi cal lymp ho 62 %mono %eos %baso %nu cle a ted red cells 28 He mog lo bin 3.9 mmol/l He ma to crit ml/l MCV 40 fl MCH 7 fmol MCHC 19 mmol/l %RETIC 0.52 % <1 #RETIC 27.0 x 10 9 /l Pla te lets 159 x 10 3 /µl Bi oche mis try Glu co se (fas ting) 6.9 mmol/l To tal pro teins 84.0 g/l PR. elec tro for. alb 51.0 % Al fa1 3.1 % Al fa % Beta 10.8 % Gam ma 21.4 % Albu min 37.8 g/l Ureum 7.3 mmol/l Cre a ti nin µmol/l ALT (GOT) 365 U/l < 60 + ALT (GPT) 132 U/l Bi li ru bin to tal 8.89 µmol/l Bi li ru bin di rect < 0.51 µmol/l gam magt < 2 U/l 0 8 Alc. Phosph. 7 U/l Bile acids 9 µmol/l < 20 Amy la se 884 U/l Li pa se 24 U/l < 250 Cho les te rol 2.9 mmol/l So di um 155 mmol/l Po tas si um 4.1 mmol/l Chlo ri de 110 mmol/l Cal ci um 2.7 mmol/l Phosp ho rous 1.6 mmol/l Infec ti ous se ro lo gy FeLV Po si ti ve Bio Veto Test Speed Duo FeLV-FIV (Fran ce) FIV Ne ga ti ve FIP Ne ga ti ve

4 47 Vlaams Diergeneeskundig Tijdschrift, 2007, 76 Fi gu re 1. Mi crop ho to graph of blood sme ar with an ab nor - mal presence of both erythrocytic and leukocytic precursors in the circulation, such as large immature cells, probably early granulocytic precursors (1), metarubricytes (2) and nu cle a ted red blood cells (3) (Mo di fied Wright stain objective 100x). Figure 2. Microphotograph of bone marrow. Notice a large population of large immature cells. The immature cells with intensely blue staining cytoplasm (+) resemble erythroid pre cur sors. The blasts with the pale blue stai ning cy to - plasm (*) appear to be promyelocytes (Modified Wright stain). Figure 3. Microphotograph of liver showing a focus of extramedullary hematopoiesis with megakaryocytes (arrows) (HE staining objective 40x). ob ser ved for a few weeks or a few months. My e lo blasts are ge ne ral ly pre sent in low num bers, even in sta ges of the disease when abnormal erythroid cells predominate. If the pa tient does not die or is not eu tha ni zed, im ma tu re my e loid cells tend to in cre a se in num bers un til the re is a clear mix tu re of ne oplas tic my e loid and erythroid cells. Fi nal ly, some ca ses may pro gress to the ap pe a ran ce of a pure granulocytic leukemia (Harvey, 1981). However, it is not known how consistently individual cases of erythroleukemia in animals follow the course outlined abo ve (Har vey, 1981). It is be lie ved that the pre sent case showed a mixed erythroid and myeloid proliferation and can therefore be diagnosed as erythroleukemia. The cat was euthanized before the disorder could develop into another stage. This type of leu ke mia al most al ways oc curs in FeLV po si ti ve cats (Gas kell and Ben nett). The pre sent case and all reports of erythroleukemia in the literature tested FeLV positive. This is a condition that primarily affects cats in fec ted with FeLV sub group C, a mu ta ti on of the in - fec ti ve form of the vi rus, i.e. type A (Gas kell and Ben nett, 1996). FeLV-C is the le ast com mon sub ty pe en coun te red (Gas kell and Ben nett, 1996) and is more pa tho ge nic than FeLV-A (Ram sey and Ten nant, 2001). Feline leukemia virus (FeLV) can cause neoplasia of lymp hoid or my e loid tis sue, alt hough the most com mon hemopoietic malignancy in the cat is lymphosarcoma, which ac counts for 90% of the he mo poi e tic tu mors and around one-third of all fe li ne ne opla sia. Most ca ses of lymphosarcoma in the cat are associated with FeLV (Gaskell and Bennett, 1996). However, feline lymphoma has historically been associated with FeLV infection. Nowadays there is a significant decrease in the importance of FeLV-as so ci a ted ty pes of lymp ho ma in cats due to mass testing and vaccination programs (Louwerens et al., 2005). The symptoms most commonly noticed are progressive ane mia, in ter mit tent py rexia and weight loss (Jain, 1993). The ab nor mal va lu es of the red blood cell count may be due to a de fi cient for ma ti on of new ma tu re red blood cells and an increased production of immature red blood cells and erythroid pre cur sors. The ab nor mal whi te blood cell count and for mu la is a con se quen ce of the ne oplas tic chang es in the bone mar row, which pro du ce and re le a se im ma tu re blood cells into the cir cu la ti on. The slight hy - per gly ce mia may have been due to ex ci ta ti on pri or to the blood sampling. The hyperglobulinemia can be explained by the ne oplas tic change of the whi te blood cells. The high AST, ALT and bi li ru bin (to tal) le vels are due to li ver cell necrosis (centrolobular and midzonal degeneration and the infiltrative neoplastic leucemic intra-hepatic meta sta ses). The pre sen ce of ne oplas tic chang es in the bone

5 Vlaams Dier ge nees kun dig Tijd schrift, 2007, marrow results in release of neoplastic immature erythroid and my e loid cells into the cir cu la ti on and blood smear. On histopathology, the centrolobular and midzonal are as of the li ver lo bu li are the most sen si ti ve to noxes, resulting in degeneration and fibrosis (in chronic ca ses). In both the li ver and the spleen, the re were me ta - static foci of neoplastic extramedullary hematopoiesis. The pri ma ry le si on is in bone mar row, with pos si ble se - con da ry le si ons in li ver, spleen and lymph no des (Gas - kell and Ben nett, 1996), as was also de mon stra ted in the pre sent case in the li ver and spleen. The diagnosis of erythroleukemia is usually made by biopsy findings in bone marrow and hematology. The hematological and bone marrow cytological findings of the pre sent case were si mi lar to tho se des cri bed by Per man et al. (1979). At this time, the re is no cure for erythro leu ke mia and the long-term prog no sis is gra ve (Wellman and Ra din, 1999). In conclusion, the most common tumor associated with FeLV infection is lymphoma/lymphosarcoma (Ramsey and Tennant, 2001). Occasionally, FeLV infection is associated with leukemia, such as erythroleukemia as in the present case. ACKNOWLEDGEMENTS We wish to thank the staff of Me disch Labo Bruy land for their as sis tan ce and Dr. Ingel been J. (Ge lu we) for his cooperation. REFERENCES Comazzi S., Paltrinieri S., Caniatti M., De Dominici S. (2000). Erythre mic my e lo sis (AML6er) in a cat. Journal of Feline Medical Surgery 2, Da mes hek W. (1965). Si der blas tic anae mia: Is this a ma lig - nancy? British Journal of Haematology 11, 52. Gas kell R. M., Ben nett M. (1996). Fe li ne leu kae mia vi rus in - fection. In: Feline and Canine Infectious Diseases. Black - well Scien ce, Lon don, pp Grin dem B. G. (2000). Acu te My e loid Leu ke mia. In: Feld man B. F., Zinkl J. G., Jain N. C. (eds.). Schalm s Veterinary Hematology. 5 th ed., Lea & Fe bi ger, Phi la delp hia, pp Har vey J. W., Shields R. P., Gas kin J. M. (1978). Fe li ne My e - loproliferative Disease. Changing manifestations in the peripheral blood. Veterinary Pathology 15, Harvey J. W. (1981). Myeloproliferative disorders in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 11, Herz A. et al. (1969a). C-type virus particles demonstrated in bone marrow cells of a cat with myeloproliferative disease. California Veterinary Journal 23, 16. Herz A. et al. (1969b). Demonstration of C-type particles, Toxoplasma gon dii and He mo bar to nel la fe lis in a cat with a my e - loproliferative disorder. California Veterinary Journal 23, 18. Jain N. C. (1986). The leu kae mia com plex. In: Schalm s Ve te - rinary Hematology. 4 th ed., Lea & Fe bi ger, Phi la delp hia, pp Jain N. C. (1993). Eryt ho leu ke mia. In: Essentials of Veterinary Hematology. Lea & Fe gi ber, Phi la delp hia, pp Jain N. C. (1993). Classification of myeloproliferative disorders in cats using cri te ria pro po sed by the ani mal leu kae mia stu dy group: A re tro spec ti ve stu dy of 181 ca ses ( ). Comparative Clinical Pathology 3, Lou we rens M., Lon don C. A., Pe der sen N. C., Ly ons L. A. (2005). Feline lymphoma in the post-feline leukaemia virus era. Journal of Veterinary Internal Medicine 19, Per man V., Alsa ker R. D., Riis R. C. (1979). Cytology of the dog and cat. American Animal Hospital Association, Indi - a na, pp Re a gan W. J., San ders T. G., DeNi co la D. B. (1998). Lymp - hoproliferative and myeloproliferative disorders. In: Veterinary Hematology, Atlas of Common Domestic Species, Iowa Sta te Uni ver si ty Press, Iowa, pp Ram sey I., Ten nant B. (2001). Fe li ne Leu kae mia vi rus. In: Manual of Canine and Feline Infectious Disease. Bri tish Small Animal Veterinary Association, Gloucester, pp Shimada T., Matsumoto Y., Okuda M., Momoi Y., Bonkobara M., Wa ta ri T., Goit su ka R., Ono K., Goto N., Tsu ji mo to H. (1995). Erythroleukemia in two cats naturally infected with feline leukaemia virus in the same household. Journal of Veterinary Medical Science 57, Smith J. L., La ti mer K. S., Bain P. J., Kri mer P. M. (2003). Me - tarubricytosis in the absence of significant polychromasia. Last ac ces sed on 21st June Wellman M. L., Ra din M. J. (1999). Bone mar row eva lu a ti on in dogs and cats. In: Ralston Purina Company Clinical Handbook Series. Wil ming ton, The Gloyd Group Inc., pp