Chronic Myelomonocytic Leukemia with Central Nervous System Involvement in a Dog
ABSTRACT
An 8 yr old, male, mixed-breed dog was presented with a 2 mo history of progressive weakness, worsened in the last 2 days before examination. Neurological examination revealed ambulatory tetraparesis, ataxia, and proprioceptive deficits in all four limbs. Menace response was reduced in the right eye and discomfort was detected on neck manipulation.
Hematologic abnormalities included marked monocytosis. Magnetic resonance imaging of the brain and cervical spinal cord revealed multifocal lesions with heterogeneous contrast enhancement. Cerebrospinal fluid analysis showed atypical monocytoid cells with similar cells to those observed in peripheral blood and in bone marrow preparations. The dog was diagnosed with chronic myelomonocytic leukemia. Prednisolone and toceranib were administered with improvement of the neurological signs. After 6 wk, the dog presented for worsening of neurological signs and with the onset of epileptic seizures. The results of flow cytometry were compatible with the possible transformation to acute myeloid leukemia. Although rare, myeloid leukemia may be included in differential diagnosis of patients with central nervous system signs, especially in dogs with relevant hematological abnormalities. In this case, cerebrospinal fluid examination played a key role identifying atypical cells.
Introduction
Chronic myelomonocytic leukemia (CMML) is a clonal myeloid neoplasm classified as a myelodysplastic/myeloproliferative neoplasm and is characterized by sustained persistent peripheral blood (PB) monocytosis (≥0.5 × 109/L; monocytes ≥10% of white blood cell count [WBC]) and bone marrow (BM) dysplasia.1,2 Two subtypes are recognized based on WBC: myelodysplastic CMML with WBC <13 × 109/L and myeloproliferative CMML with WBC ≥13 × 109/L.1 In addition, based on PB and BM blast and promonocytes percentage, CMML can be subclassified into two categories: CMML-1 (<5% in PB and <10% in BM) and CMML-2 (5–19% in PB and 10–19% in BM).1
In human medicine, the prognosis for patients with CMML is generally poor, with a 15–30% risk of transformation to acute myeloid leukemia (AML).3,4 In dogs, myeloid neoplasms are rare and occur 10 times less frequently than lymphoproliferative disorders.5
Dogs with CMML tend to be 5–8 yr of age, but cases have occurred in 2 yr old animals.6 Characteristics of the blood abnormalities are a monocytosis with mild normochromic normocytic anemia, low normal lymphocytes, and, often, neutropenia.6 Acute myeloid leukemia results from the accumulation of immature myeloid blast cells in the bone marrow and peripheral blood.5
In veterinary literature, only two dogs and one cat with CMML have been described,7–9 and in only one study, there was a suspected involvement of the central nervous system (CNS).8
To the authors’ knowledge, none have been reported with neurological signs and potential CNS infiltration by neoplastic cells.
The purpose of this report is to describe a case of CMML in a dog with CNS involvement detected by MRI and cerebrospinal fluid (CSF) examination, with later apparent transformation to AML.
Case Report
An 8 yr old, intact male, mixed-breed dog was presented to the Veterinary Neurological Center “La Fenice” with a 2 mo history of slowly progressive weakness, which worsened in the last 2 days before examination with the appearance of incoordination of all limbs. A blood count, performed the month before the onset of the neurological signs, showed a moderate leukocytosis (23.1 × 109/L; reference interval [RI]: 5.05–16.76 × 109/L) with marked monocytosis (8.51 × 109/L; RI: 0.16–1.12 × 109/L). Serological tests for Ehrlichia canis and Leishmania infantum were negative and chest radiographs were normal.
At the time of presentation at the Veterinary Neurological Center “La Fenice,” the general physical examination was normal. Neurological examination revealed normal mental status, behavior, and posture. Ambulatory tetraparesis, ataxia, and proprioceptive deficits in all four limbs were observed. Menace response was reduced in the right eye and spinal reflexes were normal in all limbs. Discomfort was detected on neck manipulation. These findings were suggestive of a left forebrain localization and possibly a multifocal lesion with involvement of the cervical spinal cord. Differential diagnosis included inflammatory or neoplastic diseases.
Complete blood count (CBC) revealed moderate nonregenerative normocytic normochromic anemia (erythrocytes: 3.89 × 1012/L; RI: 5.65–8.87 × 1012/L; hemoglobin: 9.1 g/dL; RI: 13.1–20.5 g/dL), severe thrombocytopenia (15 × 109/L; RI: 148–484 × 109/L) with increased mean platelet volume (21.6 fL; RI: 8.7–13.2 fL) and moderate to marked leukocytosis (27.17 × 109/L; RI: 5.05–16.76 × 109/L) characterized by severe monocytosis (15.15 × 109/L; RI: 0.16–1.12 × 109/L), moderate lymphocytosis (7.55 × 109/L; RI: 1.05–5.10 × 109/L), and suspected band neutrophils (4.32 × 109/L; RI: 2.95–11.64 × 109/L). The prereferral biochemistry profile, performed 1 day before the arrival, was within normal limits.
The PB smears showed the presence of high numbers (∼80% of the total leukocytes) of mononuclear cells characterized by medium/small dimensions of the order of 10–15 microns and rounded shapes with scant basophilic cytoplasm with irregular nuclei, which were frequently indented or with a horseshoe shape. Thrombocytopenia was also confirmed.
An MRI examination of the brain and cervical spinal cord was performed with a 0.3 Tesla scanner, with the dog under general anesthesia. T2-weighted (T2W) images were acquired in the sagittal and transverse planes. Fluid-attenuated inversion recovery images were obtained in the dorsal plane. T1-weighted images were acquired in the sagittal, dorsal, and transverse planes before and after IV gadoteric acida 0.1 mmol/kg injection.
The MRI scan revealed the presence of multifocal intra-axial lesions with involvement of the cranial portion of the left caudate nucleus and the dorsal portions of the parietal lobes bilaterally. The lesions appeared hyperintense in T2-weighted and fluid-attenuated inversion recovery sequences and isointense on T1-weighted sequences (Figure 1A–C) with a moderate heterogeneous contrast enhancement. Diffuse meningeal enhancement, more evident in the frontal and parietal lobes bilaterally, was also noted (Figure 1D). The cervical spinal cord MRI revealed a C2–C3 intramedullary fusiform lesion, similar to the brain lesions observed (Figure 1E).
Citation: Journal of the American Animal Hospital Association 61, 1; 10.5326/JAAHA-MS-7442
Cerebrospinal fluid was collected from the cerebellomedullary cistern. Analysis revealed a marked mononuclear pleocytosis (64 cells/µL) and increased protein concentration (50 mg/dL) (normal range <5 cells/µL and protein concentration <30 mg/dL) in the absence of blood contamination.10 A cytological evaluation revealed the presence of atypical monocytoid cells, with characteristics similar to the cells seen on PB preparations (Figure 2A, B).
Citation: Journal of the American Animal Hospital Association 61, 1; 10.5326/JAAHA-MS-7442
Bone marrow aspirates were also obtained. They revealed hypercellularity with maturational arrest and severe depletion of the erythroid and megakaryocytic lineage. The cellularity was composed almost exclusively of medium/small-sized mononuclear cells of the same nature as those found in PB, mixed with rare precursors of myeloid appearance and rare plasma cells.
The morphologic characteristics found in the PB and BM together with the marked monocytosis and the chronicity of the signs were consistent with presumptive diagnosis of CMML.
Prednisoloneb 1 mg/kg twice daily and toceranib phosphatec 2.7 mg/kg twice per week were administered with marked improvement of the neurological signs, with no alteration detected on neurological examination after 1 wk.
After 6 wk, the dog presented with a worsening of neurological signs and with the onset of epileptic seizures. A repeat CBC revealed moderate nonregenerative macrocytic hypochromic anemia (3.12 × 1012/L; RI: 5.65–8.87 × 1012/L), an improvement of the thrombocytopenia (139 × 109/L; RI: 148–484 × 109/L) with increased mean platelet volume (20 fL; RI: 8.7–13.2 fL), moderate leukocytosis (23.55 × 109/L; RI: 5.05–16.76 × 109/L) with an improvement of the monocytosis (15.15 × 109/L; RI: 0.16–1.12 × 109/L), a worsening of the lymphocytosis (7.55 × 109/L; RI: 1.05–5.10 × 109/L), and mild neutropenia (2.94 × 109/L; RI: 2.95–11.64 × 109/L) with suspected band neutrophils.
The PB smears now revealed medium-sized blast cells (max the size of two red blood cells in diameter), with fine chromatin and clearly visible nucleoli. Leukocytes appeared mildly increased in concentration, with manual differential formula showing segmented neutrophil granulocytes 15%; lymphocytes 5%; monocytes 3%; and eosinophilic granulocytes and basophil granulocytes 0%. Platelet estimation was mildly decreased and with macroplatelets.
Immunophenotyping on the PB was performed by flow cytometric analysis. The antibody panel included CD45, CD18, CD3, CD5, CD4, CD8, CD21, CD14, CD34, CD11b, and MCH II. Eighty-eight percent of the cells expressed the panleukocyte antigen CD45, and 87% of them were positive for panleukocyte antigen predominantly in myeloid cells CD18. Seventy-seven percent of the cells were positive for blast antigen. Nine percent of the cells expressed myeloid antigen CD11b, and 5% of cells showed expression of APC/lymphocytes antigen MHC II. Approximately 6.5% of the cells also showed expression of the lymphoid differentiation antigens, such as CD3, CD4, CD5, CD8, and CD2. Only a few monocytes (0.5%), that expressed monocytic differentiation antigen CD14, were observed.
The results of flow cytometry immunophenotyping were compatible with the possible transformation to AML.
Owing to the worsening of neurological signs and poor prognosis, the owner elected humane euthanasia. No necropsy examination was performed. The authors declare that informed consent was obtained from the pet owner and the dog described in this study was clinically managed according to contemporary standards of care.
Discussion
In this report, we describe a dog with a diagnosis of myelomonocytic leukemia with involvement of the CNS. The chronicity of the signs together with the initial hematological findings led us to classify it as CMML.
In human medicine, CMML is rarely associated with extramedullary manifestations and is seen in organs such as the spleen, liver, and lymph nodes. Central nervous system involvement is exceedingly uncommon.11–15 Patients with CMML may be asymptomatic or present with a wide variety of symptoms.11 In the veterinary literature, to the authors’ knowledge, no cases of CMML with confirmed CNS involvement have been reported. In one study a dog with a diagnosis of CMML was presented for stiffness, right forelimb lameness, and neck pain, but possible involvement of the CNS was not investigated.8
On the basis of hematological and cytological features, the dog in this study was diagnosed as having myeloproliferative CMML based on World Health Organization classification (2022).1 Unfortunately, because of the impossibility of rapid delivery of the blood sample to the laboratory, the flow cytometry immunophenotyping was not performed at the time of initial diagnosis. In human medicine, flow cytometry immunophenotyping is the preferred method for immunophenotypic identification, enumeration, and characterization of immature and mature leukemic cells.16 However, in AML, the clinical signs have an acute onset and rapid course with immature myeloid blast cells that usually accumulate in BM and PB. Production of normal peripheral blood cells is usually diminished or absent, and anemia, neutropenia, and thrombocytopenia are common.5
The association between morphology and immunophenotype may also improve the accuracy of the diagnosis. However, one study demonstrated the usefulness of a standard blood count in suggesting the type of hemoproliferative disorder.17
According to the literature, the diagnosis of CNS leukemic infiltration has to be confirmed by cytological examination of the CSF.15 When CNS involvement has been documented, mature monocytes, rather than blasts, have been seen in the CSF.11,12
In human medicine, intrathecal chemotherapy with cytarabine, methotrexate, and methylprednisolone was reported as effective for the meningeal involvement of CMML caused by infiltrations of mature monocytic cells.12,15 In veterinary medicine, an appropriate treatment protocol for CMML has not yet been established. There is too little information about the response to uniform chemotherapeutic protocols because of the rarity of the disease and because of the high rate of euthanasia owing to the poor prognosis.
A genetic mutation termed the “Raleigh” chromosome has been identified in a dog with a diagnosis of CMML.8 This genetic mutation results in the production of a BCR-ABL fusion protein with aberrant tyrosine kinase activity.18 In humans, the corresponding mutation is present in 95% of adult patients with chronic myeloid leukemia (CML).18 In contrast, the BCR-ABL fusion is rarely seen in human CMML, and when it presents, the disease pattern seems to be intermediate between CML and CMML.19 The use of imatinib leads to decreased proliferation of the neoplastic cells in human patients with CML who express this aberrant BCR-ABL fusion protein with the tyrosine kinase inhibitor.18
Furthermore, toceranib phosphate is a tyrosine kinase inhibitor with both direct antitumor and antiangiogenic activity; thus, it can also be useful in the treatment of CMML in dogs.20 The dog in this study was treated with toceranib and prednisolone, with a normal neurological examination after 1 wk. However, a CBC was not performed to evaluate possible concurrent hematological improvement.
After 6 wk, the dog presented with a worsening of neurological status with the onset of epileptic seizures. At that time, a flow cytometry immunophenotyping was performed, and it was compatible with the possible transformation to AML.
In human medicine, numerous prognostic models have been developed for CMML.4 Risk stratification is important to predict disease evolution and mortality in patients with CMML.21
The MD Anderson prognostic system is CMML specific and identified a hemoglobin level <12 g/dL, presence of PB immature myeloid cells, absolute lymphocyte count >2.5 × 109/L, and ≥10% BM blasts as independent predictors for inferior overall survival.22
Furthermore, patients with CMML-1 have better expected prognosis than those with CMML-2, probably owing to their lower risk of developing AML.15
These prognostic system from human medicine could be useful to assess the prognosis and mortality in veterinary patients with CMML, but further studies are needed to assess its suitability.
Conclusion
Although rare, CMML may involve the CNS, and in addition to the usefulness of the relevant hematological abnormalities and the MRI, CSF examination may play a key role to identify potential atypical cells.
(A) MRI of brain, dorsal plane, fluid-attenuated inversion recovery sequence. Hyperintensity on the left caudate nucleus (arrow). (B–D) MRI images of transverse sections through the parietal lobes. Lesions in the dorsal portion of the parietal lobes, which appear hyperintense in fast spin-echo T2-weighted sequences (B) and isointense in spin-echo T1-weighted sequences (C). On spin-echo T1-weighted postcontrast administration, meningeal enhancement was noted, as were heterogeneous intra-axial lesions (D). (E) MRI of cervical spinal cord, sagittal plane, fast spin-echo T2 sequence. Hyperintensity intramedullary on C2–C3 segment.
(A) Peripheral blood smear; a round-shaped cell with scant basophilic cytoplasm and indented nucleus (arrow). (B) Cerebrospinal fluid cytospin: atypical monocytoid cells with atypical nuclear shape. Diff Quick Stain, ×100.
Contributor Notes
