Monoclonal Gammopathies in the Dog: A Retrospective Study of 18 Cases (1986–1999) and Literature Review

Criteria for Selection of the 18 Case Reports

Between 1986 and 1999, 3,925 serum protein electrophoreses were performed by one author’s (Pagès) veterinary clinical practice. Clinical signs that resulted in a serum protein electrophoresis being performed are given in Table 1. Of the 3,925 serum protein electrophoreses performed, 16 monoclonal gammopathies were diagnosed. The other two cases of this study were identified among dogs referred to the Department of Small Animal Clinical Sciences of the National Veterinary School of Toulouse in 1997.

The cases selected for this study included only those patients for which the history, diagnostic and therapeutic protocols, and follow-up of the disease associated with the monoclonal gammopathy had been meticulously recorded.

Diagnosis of the monoclonal gammopathy was based on serum protein electrophoresis and, in most cases, was confirmed by either serum immunoelectrophoresis or serum immunofixation. Four cases (case nos. 6, 15–17) without specific electrophoretic confirmation (i.e., immunoelectrophoresis or immunofixation) were included in this study, because the serum protein electrophoretic pattern was highly suggestive of the presence of a paraprotein (i.e., a sharp and spike-like peak on the electrophoretic profile; a thin, dense, and homogeneous band on the electrophoretic strip; or both), and the owners elected not to pursue further testing.

Laboratory Methods

All cases had a minimum database done that included a complete blood count (CBC), a differential white blood cell count, a serum biochemical profile, and a urinalysis. Serum protein concentrations were measured for each patient using the biuret method.^6a Serum protein electrophoresis was performed on agarose gel^b in all 18 cases. A protein immunofixation kit^c was used in five cases (case nos. 10–13, 18), and immunoelectrophoresis was performed in nine cases (case nos. 1–5, 7–9, 14) using the Scheidegger’s micromethod on glass slides⁷ until 1993 and on Hydragel IEP^d from 1994 to 1999.

The proteinuria determination was based on Heller’s nitric acid test⁸ and was interpreted concurrently with urine specific gravity values. A urine protein/creatinine^e ratio was also performed in five cases (case nos. 2, 3, 7, 8, 11). A heat precipitation test was used in four cases (case nos. 1–4) to detect the presence of Bence Jones proteinuria; in three cases (case nos. 2, 3, 11), urine protein electrophoresis was performed with an agarose gel^f to determine the type of proteinuria.

After confirmation of the presence of a monoclonal immunoglobulin, various diagnostic tests were performed to determine the underlying disease responsible for secretion of a paraprotein. These tests included microscopic evaluation of bone-marrow aspirates in all the dogs (providing a definitive diagnosis in 12 of 18 cases); antibody titers to Ehrlichia canis and Leishmania (immunofluorescent antibody [IFA] assays for ehrlichiosis and leishmaniasis were performed in two and four cases, respectively; specific titers of 1:80 to Ehrlichia canis and 1:100 to Leishmania were used as cutoff points for positivity); fine-needle aspiration biopsy of palpable tumor masses (e.g., lymph nodes, spleen, and liver) in six cases; and survey skeletal radiographs when locomotor symptoms could be detected (in six cases).

Case Histories

Signalments and case histories of the 18 cases are given in Table 2. The duration of illness before the first examination was extremely variable and in accordance with the usually slow and insidious course of the underlying etiologies of monoclonal gammopathies. The most common complaints reported by the owners were anorexia, weight loss, weakness, and depression. Histories of bleeding problems (case nos. 3, 10, 13, 16, 17) and infections (i.e., babesiosis [case nos. 4, 14] and urinary tract infection [case no. 11]) were also frequent presenting features. In dogs with multiple myeloma, signs of skeletal involvement were identified in five of nine cases, whereas renal failure was a common finding leading to referral of these patients by other veterinarians.

Physical Examinations

The clinical signs of the cases reported in this study could be classified in three groups: signs that were secondary to neoplastic infiltration of different organs by malignant B-cell lymphocytes; those due to excessive production of monoclonal immunoglobulins (i.e., hyperviscosity syndrome); and those related to the pathogenesis of the underlying disease (e.g., renal failure in leishmaniasis).

The most frequent presenting signs in both the lymphoproliferative and the nonmyelomatous gammopathies were nonspecific. Bleeding diathesis was also frequently demonstrated (seen in nine cases, of which six exhibited retinal hemorrhages either at the initial physical examination or during the course of their illness). Hyperviscosity syndrome was clinically observed in three of these dogs (tortuous retinal vessels were seen in case nos. 3 and 9, and retinal detachment was seen in case no. 10). In nine of the 18 dogs, palpable masses were a major clinical sign (hepatomegaly, splenomegaly, or both were seen in six cases; enlarged lymph nodes were seen in four cases; a preputial tumorous mass was seen in one dog; and a neoplastic infiltration of the skin was seen in one dog). Locomotor symptoms were more suggestive of a lymphoproliferative disorder; four of the dogs with multiple myeloma exhibited lameness, whereas in case no. 6, the plasma cell infiltration resulted in sudden paralysis of the hind limbs.

Clinical Pathology

Diagnosis of renal failure was based on plasma urea and creatinine concentrations interpreted concurrently with urine specific gravity values. This was demonstrated in four dogs (case nos. 1, 8, 11, 18). Clinically significant proteinuria was observed more frequently (in 12 dogs), showing the high prevalence of renal involvement in these diseases. Only two dogs in this study had Bence Jones proteinuria; diagnosis was based on urine protein electrophoresis (despite a negative heat precipitation test) in case no. 3 and a heat precipitation test in case no. 4. Among the four renal histopathological examinations performed, two dogs had glomerular abnormalities (hyperplasia of endothelial cells and thickening of the capillary walls in case no. 2, and glomerular amyloidosis in case no. 11); one dog (case no. 3) had plasma cell infiltration of the kidney; and one dog (case no. 4) had tubulointerstitial nephritis, probably due to Bence Jones proteinuria.

The main hematological and electrophoretic findings for the different dogs are provided in Tables 3 and 4. Anemia was obvious in seven dogs on initial hematological examination, and two became anemic during the course of their disease. Leukopenia was less common: only five dogs exhibited this hematological disorder in the terminal phase of the disease, whereas four dogs had leukocytosis (neutrophilia in case nos. 1, 7, 10; lymphocytosis in case no. 11) at the time of the first examination. Thrombocytopenia was only found in three dogs (case nos. 3, 9, 15), but in case no. 9, the platelet count was again within the reference range after treatment of disseminated intravascular coagulation. Except for case no. 9, the results of standard coagulation tests (partial thromboplastin and prothrombin times) were normal (in four out of five cases tested).

Plasmacytosis was the main feature in the bone-marrow aspirates taken from dogs with multiple myeloma and Waldenström’s macroglobulinemia. Although the neoplastic plasma cells were sometimes normal in appearance and well differentiated, they usually appeared in clusters and had immature and abnormal forms, with discretely vacuolated, light-blue cytoplasm or bright, diffusely eosinophilic cytoplasmic borders (flame cells). One dog (case no. 15) with ehrlichiosis also had mild plasmacytosis (5%), and in case no. 17 (with leishmaniasis), plasmacytosis (5%) was associated with lymphocytosis (17%). Lymphocytosis (i.e., infiltration of the bone marrow with 40% of small lymphocytes resembling those seen in blood smears) was also the major feature observed in the bone-marrow aspirate of case no. 11 (CLL).

Hyperproteinemia (>7.5 g/dL; reference range, 5.5 to 7.5 g/dL) was observed in 14 cases, but all the 18 dogs were hyperglobulinemic. Hypoalbuminemia (<2.7 g/dL; reference range, 2.7 to 4 g/dL) was also a major finding, as 12 dogs exhibited this feature at the first examination. Monoclonal spikes were mainly located in the γ region (in nine cases), but the β region was also often involved (in eight cases). Immunoglobulin M-type monoclonal components were seen in the β region (multiple myeloma and CLL) [Figure 1] and in the β-γ region (Waldenström’s macroglobulinemia). Three of the four immunoglobulin A (IgA)-type paraproteins were located in the β region [Figure 2] and one was in the γ region. The IgG-type paraproteins were usually found in the γ region (five γ migrations versus two β migrations) [Figure 3].

The main immunoglobulin classes encountered in the patients with multiple myeloma were IgA and IgG in approximately equal prevalence (four IgA and three IgG); one of these IgG-type paraproteins (case no. 1) was a cryoglobulin. The IgM class was observed in multiple myeloma (case no. 9), in Waldenström’s macroglobulinemia (the paraprotein of case no. 10 was also a cryoglobulin), and in CLL (case no. 11). Lymphoplasmacytic lymphoma (low grade according to Kiel’s classification; stage IVa), extramedullary plasmacytoma, ehrlichiosis, and leishmaniasis were associated with IgG-type paraproteins.

Treatment and Follow-up

Treatment and follow-up of the cases are given in Table 2. Patients with multiple myeloma showed rapid death without specific treatment (per the owner’s request) in two cases (case nos. 5, 6); rapid death despite corticosteroids in one case (case no. 1); rapid death despite an adequate treatment in two cases (case nos. 3, 4); no clinical improvement despite rapid decrease of the monoclonal spike in two cases (case nos. 8, 9); transient improvement with corticosteroids in one case (case no. 7); and lasting biological and clinical improvement with melphalan and corticosteroids in one case (case no. 2).

The survival times of dogs with other lymphoproliferative tumors were good (between 10 months [CLL] and 88 months [extramedullary plasmacytoma]). The long-term follow-up of the three dogs with leishmaniasis was similar to that of polyclonal-secreting leishmaniasis, and specific therapy resulted in long clinical remissions. On the other hand, both dogs with ehrlichiosis died very rapidly, despite vigorous therapy.

Lymphoproliferative Disorders

Between 1986 and 1999, 3,925 serum protein electrophoreses were performed by the Croix du Sud veterinary clinical practice. Only 20 monoclonal gammopathies (including four cases for which there was insufficient data to include them in the study) were diagnosed, which demonstrates the rarity of this laboratory finding. In the 18 cases presented in this study, lymphoproliferative disorders represent 72% of the diseases associated with monoclonal gammopathies, the most frequent being multiple myeloma (50%). As previously reported, these lymphoproliferative disorders occurred in the older age group (average age, 10.5 years; range, 6 to 13 years) with no apparent sex predilection in patients with multiple myeloma (four males and five females).⁴⁹ All dogs were medium- and large-breed dogs, except case nos. 11 and 13 (two poodles). Some previous studies have reported a higher prevalence of concurrent tumors in patients with multiple myeloma.⁹ This is in keeping with the authors’ observations, as four of the nine dogs with multiple myeloma (case nos. 1–3, 7) had concurrent tumors.

The most striking feature of the historical and clinical data was the extreme variability. Chronic or acute skeletal pain was a common presenting sign, reported in 56% of the patients with multiple myeloma, which is close to the prevalence observed in other studies.⁴¹⁰¹¹ When all the dogs with lymphoproliferative disorders were considered, the major clinical finding was palpable masses (i.e., hepatomegaly, splenomegaly, or both [46%]; enlarged lymph nodes [15%]; skin infiltration [8%]; and a preputial mass [8%]). As in other reports, fine-needle aspiration biopsy of these masses provided a useful diagnostic tool.¹¹ In the Waldenström’s macroglobulinemia (case no. 10), for example, a needle aspiration biopsy of the spleen, liver, and a single lymph node showed large numbers of atypical plasma cells and B-lymphocytes. In addition, a skin biopsy performed in the ulcerated lesions of the face revealed dermal infiltration by similar plasmacytoid cells.

Bleeding tendencies were observed in more than half (60%) of the patients with multiple myeloma or Waldenström’s macroglobulinemia, which is more frequent than in other studies (approximately 30% in those of MacEwen and Hurvitz⁴ and of Matus and Leifer¹⁰). Retinal hemorrhages were the most common forms of bleeding (seen in 83% of the dogs with lymphoproliferative disorders and bleeding diathesis), which shows the importance of a systematic fundus examination. Signs of hyperviscosity syndrome were observed in 23% of the dogs. This compares with 25% in previous studies where hyperviscosity had been quantitatively assessed.⁴¹⁰¹¹ The three paraproteins involved were of IgA- (case no. 3) and IgM-type (case nos. 9, 10), and the fact that the paraprotein of case no. 10 had cryoglobulin properties might have contributed to the onset of this syndrome.⁹

Renal involvement was a common finding in these lymphoproliferative disorders (23% with renal failure; 62% with proteinuria). Matus et al.¹¹ reported renal failure and proteinuria in 33% and 35% of the dogs with multiple myeloma, respectively. In case no. 4, the tubulointerstitial nephritis revealed on histopathological examination was a result of Bence Jones proteinuria (i.e., light chains of paraprotein in the urine), which resulted in dilated tubules with a flattened epithelium and tubular casts. In case no. 3, urine protein electrophoresis demonstrated the presence of Bence Jones proteinuria, and histopathology of the kidney showed infiltration of this organ by numerous plasma cells. In summary, the renal lesions reported in this study are similar to those classically described in other series of similar cases: hyperplasia of endothelial cells and thickening of the capillary walls in the glomeruli (case no. 2); plasma cell infiltration of the kidney (case no. 3); and direct tubular damage and atrophy secondary to Bence Jones proteinuria (case no. 4).¹¹¹² Bence Jones proteinuria was less frequent in this study (seen in 15% of the cases) than in previous reports where 30% to 40% of the dogs with multiple myeloma had Bence Jones proteinuria.¹⁰¹¹ This is probably due to the fact that urine protein electrophoresis was only performed in three cases; therefore, additional cases may have been missed.

Concurrent glomerular amyloidosis, although commonly associated with monoclonal light chain deposition in human patients with lymphoproliferative disorders, has been infrequently reported in dogs.¹³ The urine electrophoresis and the high protein/creatinine ratio of case no. 11 (with CLL) were suggestive of a severe glomerulopathy. Histopathological examination confirmed this kidney damage, showing severe glomerular amyloid deposition. Similar examination of the spleen revealed plasma cell infiltration; these neoplastic cells were completely surrounded by the same amyloid deposition as in the kidney. These concurrent features suggest that the β-pleated sheets could be of plasma cell origin and that the amyloid deposition consisted of intact or partial monoclonal immunoglobulin light chains. To the authors’ knowledge, this dog represents the first case of CLL associated with amyloid-L systemic amyloidosis. In case no. 13, the neoplastic cells were also surrounded by amyloid deposits. This has been described in other reports of cutaneous plasmacytomas,¹⁴ but case no. 13 is the first primary mucocutaneous plasmacytoma associated with an IgG-type paraprotein in the blood. The corresponding monoclonal spike disappeared completely after surgical removal of the tumor and radiotherapy. Long-term follow-up of the physical condition, the serum protein electrophoretic pattern, and the cellular content of the bone marrow showed absolutely no abnormality until the dog died secondary to cardiac failure 88 months after the monoclonal gammopathy had been diagnosed.

Anemia was the most common hematological abnormality of the dogs presented here (38% of the cases at first examination and 54% of the cases in the terminal phase of the disease). At initial examination, leukopenia was reported in 23% of the cases, but the prevalence of leukocytosis was higher (31%). Persistent and severe thrombocytopenia was only observed in case no. 3 and was associated with massive infiltration of the bone marrow with plasma cells. These findings agree with a previous report where anemia, leukopenia, and thrombocytopenia were observed in 68%, 25%, and 17% of the cases, respectively.¹¹ In case no. 10, atypical lymphocytes resembling those of the lymph node and bone-marrow aspirates were seen in blood smears. This has been described elsewhere¹⁵ but is less frequent in Waldenström’s macroglobulinemia than in CLL. In multiple myeloma, neoplastic plasma cells are sometimes observed in the blood, but finding a high number of these cells is relatively unusual.

Standard coagulation tests (i.e., partial thromboplastin and prothrombin times) were normal in 80% of the cases tested. Case no. 9 showed disseminated intravascular coagulation. After regulation of this syndrome, the assessment of platelet aggregation revealed decreased platelet adhesiveness and aggregation. Other authors have also described cases without impaired bleeding tests except buccal mucosal bleeding time.¹¹ Indeed, despite various other mechanisms that may prolong bleeding times (e.g., hyperviscosity syndrome and interference with clotting factors), acquired thrombopathia due to paraprotein coating of the platelets might be the major cause of bleeding in these patients.

In the dogs of this study, total protein concentrations were often very high; however, in some dogs with a monoclonal spike on serum electrophoresis, total protein concentrations were normal (case nos. 12 [7.1 g/dL] and 13 [7.2 g/dL]) or only slightly increased (case nos. 2 [8 g/dL], 3 [8.3 g/dL], 5 [8.3 g/dL], and 11 [8.2 g/dL]). Therefore, it is crucial to perform protein electrophoresis (or at least to assess albumin or globulin concentrations) on suspicious cases, even if the serum protein concentrations are not increased. In case no. 11, for example, low albuminemia (1.15 g/dL) resulted in a nearly normal protein concentration, despite a major hyperglobulinemia (7.05 g/dL) [Figure 1]. The low protein concentrations in case nos. 12 and 13 (i.e., lymphoma and mucocutaneous plasmacytoma) were due to the small amount of monoclonal immunoglobulins produced by the neoplastic cells.

Serum protein electrophoresis revealed a frequent monoclonal spike in the β region when the paraprotein was of IgA type (75% of these immunoglobulins were found in the β region). Immunoglobulin G paraproteins were also frequently found in association with lymphoproliferative diseases and, as these paraproteins were usually located in the γ region (60% of these immunoglobulins were found in the γ region), this location was also often affected (38% of the cases with lymphoproliferative diseases). In fact, both sites are equally frequent, and migration in the α₂ region is exceptional.⁹¹²¹⁶ Case no. 4 is slightly disturbing, because the electrophoretic pattern revealed two spikes in the β region [Figure 2], whereas the immunoelectrophoresis demonstrated IgA-type monoclonal gammopathy. A few similar cases have been described in the veterinary literature in association with multiple myeloma.¹⁶ The authors believe that this might be due to differential migration of various types of polymers of the same monoclonal immunoglobulin. Sometimes such an electrophoretic pattern can also be associated with a true biclonal gammopathy. Peterson and Meininger, for instance, described a multiple myeloma associated with an IgA and IgG biclonal gammopathy.¹⁷

The immunoglobulin classes involved were of IgG-, IgA-, and IgM-type, with approximately the same prevalence (42%, 33%, and 25%, respectively) and, in contrast to that observed in human medicine (a higher prevalence of IgG-type multiple myelomas), it appears that IgG- and IgA-type multiple myelomas (38% and 50% of the cases in this study, respectively) are actually of equal prevalence in dogs.¹¹ Immunoglobulin M secretion was observed in three cases: Waldenström’s macroglobulinemia (case no. 10), CLL (case no. 11), and multiple myeloma (case no. 9).

The therapeutic results in case nos. 1 through 10 were disappointing. Lasting tumor response and clinical improvement were only observed in two dogs (case nos. 2, 10), but case no. 2 demonstrated that early diagnosis and adequate treatment may produce a good therapeutic outcome in terms of quality and duration of life (21 months without clinical relapse). These overall poor results can be explained by the late stage of the disease in some dogs and by the owners’ reluctance to pursue further investigations or treatment. For the other lymphoproliferative diseases (case nos. 11–13), the survival times were better and varied from 10 months (for CLL) to 88 months (for mucocutaneous plasmacytoma), with case no. 12 still being alive 40 months after diagnosis with lymphoma.

As reported in previous studies, it is likely that life expectancy can be significantly extended if the diagnosis of the underlying cause of the monoclonal gammopathy is established early in the course of the illness. Thus, specific therapy and a good supportive management of associated complications can significantly improve the duration of remission; median survival times ranged from 12 months to 24 months in two of the major studies of patients with multiple myeloma or Waldenström’s macroglobulinemia.⁴¹⁰ Approximately 75% of the patients respond to therapy, and good response usually becomes clinically evident within 3 to 6 weeks. Nevertheless, the most convenient and reliable method of monitoring the response to treatment is serum or urine protein electrophoresis, or both (identification of paraprotein concentration decrease ≤50% within 6 to 12 weeks).⁴¹⁰

Nonmyelomatous Monoclonal Gammopathies

In accordance with previous reports,⁴ most of the cases in this study were associated with lymphoproliferative tumors, but the percentage of nonmyelomatous monoclonal gammopathies (28% in this study) was significant. Ehrlichiosis and leishmaniasis should be considered differential diagnoses in dogs with monoclonal gammopathies, because associated historical, clinical, laboratory, and immunological findings may be similar to those of lymphoproliferative disorders.

Anorexia, weight loss, fever, weakness, and depression were the major presenting features of patients with ehrlichiosis, whereas epistaxis, ocular lesions, and enlargement of lymph nodes were observed in the dogs with leishmaniasis. Thus, with the exception of lameness due to bone involvement in multiple myeloma, the historical findings and clinical data were very similar as in lymphoproliferative disorders.

In regard to the ehrlichiosis cases, the clinical features of the cases reported in this study were similar to those of patients with ehrlichiosis associated with polyclonal gammopathies. In previous reports, hyperviscosity syndrome seemed to be a more distinctive and frequent feature in patients with monoclonal gammopathies.¹⁸¹⁹ Large quantities of IgG, an abnormal molecular configuration, and the presence of IgG aggregates have been suggested as conditions that can result in this syndrome.¹⁹ Anemia, thrombocytopenia, and less frequently leukopenia are common hematological findings. One dog (case no. 14) had pancytopenia, which is a common complication associated with either the acute or the chronic phase of ehrlichiosis.²⁰ In the late stage of the disease, blood cytopenias are often associated with marrow hypoplasia.²¹ Nevertheless, some authors believe that, with the exception of severe chronic ehrlichiosis (especially in German shepherd dogs), true marrow pancytopenia is less common than previously assumed.²¹²² Thus, normal or hypercellular marrows were reported in 63% to 100% of some studies.²⁰ Bone-marrow hypoplasia was observed in case no. 14, whereas plasmacytosis (5%) with adequate numbers of erythrocytic and granulocytic precursors was reported in case no. 15. Plasmacytosis of marrow aspirates has been described as a common, although inconsistent, finding in bone-marrow aspirations.^19–21 Sometimes large numbers of reactive plasma cells can mimic plasma cell infiltration of multiple myeloma.¹⁸²⁰ Consequently, if the plasma cell infiltration is not pathognomonic of a lymphoproliferative disease, it is of the greatest relevance to the differential diagnosis to perform an IFA test for Ehrlichia canis (E. canis), because it is sometimes difficult to identify E. canis morulae in blood or bone-marrow smears.

In this study, the serum protein abnormalities associated with ehrlichiosis were hyperproteinemia, hyperglobulinemia, hypoalbuminemia, and a monoclonal spike in the β (case no. 15) or γ region (case no. 14) [Figure 3]. These monoclonal spikes seemed to be superimposed on a polyclonal gammopathy and thus differed slightly from the usual electrophoretic pattern of lymphoproliferative disorders [Figure 1]. Some previous authors¹⁸¹⁹ have reported this former type of pattern or monoclonal spikes with a broader base, but narrow and distinct spikes in patients with ehrlichiosis are also frequent.¹⁸ As in previous reports,¹⁸¹⁹ the immunoelectrophoresis performed in case no. 14 demonstrated an IgG-type monoclonal gammopathy. Diagnosis of a monoclonal immunoglobulin requires the demonstration of a single class and subclass of heavy chain and a single type of light chain.²³ Perhaps some of the cases of this study would not have met all these requirements if the authors could have performed these analyses. Nevertheless, a diagnosis of a monoclonal gammopathy relies predominantly on the demonstration of a narrow homogeneous spike (i.e., serum protein electrophoresis) corresponding to a single type of immunoglobulin (i.e., serum immunoelectrophoresis or immunofixation), and it was interesting to demonstrate in this study that nonmyelomatous diseases can be associated with these electrophoretic findings.

The therapeutic results concerning the two dogs with ehrlichiosis were disappointing. Case no. 14 was probably in a severe chronic phase with severe leukopenia, which has been suggested to be of prognostic value in some studies where it was correlated with a higher mortality rate.²² Case no. 15 likely died due to secondary discospondylitis, as ehrlichiosis seemed to be less severe (i.e., there were no abnormal hematological findings and adequate erythrocytic and granulocytic precursors in the bone marrow). Good therapeutic results with clinical remission and decreased globulin concentration within 3 to 9 months have been described in some recent studies, even in cases with severe blood cytopenias and hypoplasia of the bone marrow.^1820–22 As in case nos. 14 (with a history of babesiosis) and 15 (concurrent discospondylitis), the occurrence of combined infections (e.g., babesiosis, hepatozoonosis, hemobartonellosis) has been reported in some of these studies and requires meticulous examination of peripheral blood smears.^20–22

Leishmaniasis is rarely included as a differential diagnosis in dogs with monoclonal gammopathy. To the authors’ knowledge, very few reports²⁴ of leishmaniasis associated with paraproteinemia have been published, because the majority of leishmaniasis-infected dogs have hyperproteinemia with polyclonal gammopathy. Genetic predisposition associated with persistent, chronic, antigenic stimulation leading to immunological dysregulation has been suggested to explain the selection of a single clone of B-lymphocytes.²⁵

Historical and clinical findings (i.e., skin involvement, epistaxis, ocular lesions, and enlarged lymph nodes) of the three dogs with leishmaniasis in this study were similar to those observed in leishmaniasis with polyclonal gammopathy. Case no. 17 demonstrated the difficulty in establishing a definitive diagnosis of leishmaniasis when no organisms can be seen in the bone marrow or in the lymph nodes and when the antibody assay is negative. The diagnosis was achieved only after repeated serological tests, and the results of bone-marrow and lymph-node examinations concluded that plasmacytosis of the bone marrow was due to leishmaniasis and not to a lymphoproliferative disorder. Serum protein electrophoresis of these three dogs revealed monoclonal spikes with a broad-base pattern located in the γ region [Figure 4]. Immunofixation demonstrated the presence of a monoclonal IgG lambda light chain-type in case no. 18, which was in keeping with the previously described report showing IgG-type paraproteinemia.²⁴ These results are consistent with the fact that nonmyelomatous monoclonal gammopathies are believed to arise at the later stages of lymphocyte maturation (i.e., mature plasma cells that only secrete IgA or IgG).²⁵ Therefore, it is likely that only IgG and perhaps IgA (but not IgM) paraproteins could be compatible with the diagnosis of leishmaniasis, ehrlichiosis, or other nonmyelomatous causes of monoclonal gammopathies.

The therapeutic results were good for the cases with leishmaniasis. Case no. 16 survived for 5.5 years, and case nos. 17 and 18 are still alive, with rapid normalization of the electrophoretic pattern in case no. 17.