Skip to main content
NCBI home page
The Canadian Veterinary Journal logoLink to The Canadian Veterinary Journal
. 2008 Jul;49(7):694–702.

Immunoglobulin A multiple myeloma with cutaneous involvement in a dog

Monique N Mayer 1,✉, Moira E Kerr 1, Candace K Grier 1, Valerie S MacDonald 1
PMCID: PMC2430402  PMID: 18827847

Abstract

An 8-year-old rottweiler, diagnosed with multiple myeloma and multiple sites of cutaneous involvement, was treated with chemotherapy and radiation therapy. The diagnostic criteria for canine multiple myeloma, limitations of diagnostic testing for light chain proteinuria in dogs, and the role of radiation therapy in multiple myeloma patients is discussed.

An 8-year-old, 48 kg, intact male rottweiler was referred to the Veterinary Teaching Hospital at the Western College of Veterinary Medicine for staging and treatment of a previously diagnosed intraoral plasma cell tumor associated with the left maxilla. The dog had been presented to the referring veterinarian 11 d earlier with a left third eyelid prolapse and left-sided facial swelling of 1-day duration. The dog had been anorexic and lethargic for 2 d prior to referral, and multiple skin masses had been noted by the client 3 d prior to referral.

Case description

Physical examination revealed more than 50 soft cutaneous and subcutaneous nodules, ranging from 0.5 cm to 2.5 cm in diameter, located primarily on the ventral aspects of the thorax and abdomen and the medial aspect of the thighs (Figure 1). More superficially located nodules were moveable relative to underlying tissues, while deeper nodules were fixed. The skin was mobile over the deeper nodules.

Figure 1.

Figure 1

Open in a new tab

Multiple nodules composed of neoplastic plasma cells on the medial surface of the right thigh.

Under general anesthesia, a 4.0-cm × 4.7-cm, necrotic, intraoral mass, centered at the left upper 4th premolar, was identified (Figure 2).

Figure 2.

Figure 2

Open in a new tab

Soft tissue mass involving the left intraoral region with a depressed central area and necrosis, loss of tooth 208, and lateral displacement of tooth 209.

Results from a complete blood (cell) count (CBC), serum biochemical panel, and urinalysis were evaluated. In the CBC, there was a mild lymphopenia (0.980 × 109/L; laboratory reference interval, 1.2 to 5.0 × 109/L) and marked rouleaux. Abnormalities in the serum biochemical panel included hypercalcemia (serum total calcium 3.86 mmol/L; laboratory reference interval, 1.91 to 3.03 mmol/L), elevated urea and creatinine (urea 15.9 mmol/L; laboratory reference interval 3.5 to 11.4 mmol/L, creatinine 213 μmol/L; laboratory reference interval 41 to 121 μmol/L), hyperglobulinemia (globulins 75 g/L; laboratory reference interval 23 to 37 g/L), and hypoalbuminemia (albumin 25 g/L; laboratory reference interval 28 to 38 g/L). The urine specific gravity of a voided urine sample was 1.016.

Ancillary diagnostic tests included that for free calcium on a heparinized blood sample, serum and urine protein electrophoresis, urine sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), serum radial immunodiffusion assay, imaging studies (plain film radiography, ultrasonography, and computed tomography (CT)), fine-needle aspirates (FNAs) of a subcutaneous nodule on the medial aspect of the stifle and a splenic mass, cytological examination of a left humeral bone marrow aspirate and histopathological examination of a left ilial bone marrow core, and histopathological examination of 2 of the subcutaneous nodules.

Free calcium was elevated (1.81 mmol/L; laboratory reference interval, 1.27 to 1.51 mmol/L). In the serum protein electrophoretogram (Titan Gel Serum Protein System; Helena Laboratories, Beaumont, Texas, USA), a narrow-based peak was identified in the β-globulin region (48.0 g/L; laboratory reference interval, 13.0 to 17.0 g/L) (Figure 3a). A similarly located but smaller peak was found in the urine protein electrophoretogram (Figure 3b). A band within the 20–25 kDa range and high molecular weight bands (> 69 kDa) were identified on urine SDS-PAGE. The serum immunoglobulin (Ig) A concentration by radial immunodiffusion was elevated (229 g/L; published reference interval, 0.2 to 1.5 g/L) (1).

Figure 3.

Figure 3

Open in a new tab

Serum and urine protein electrophoretograms from an 8-year-old rottweiler with multiple myeloma. Note the monoclonal peak in the beta fraction in the serum electrophoretogram (left) and a small peak in a similar region in the urine electrophoretogram (right).

Thoracic, abdominal, and pelvic radiographs revealed a lytic expansile lesion involving the right 6th rib and a rounded swelling in the spleen. A 6.9-cm × 6.0-cm × 4.9-cm splenic mass was identified on abdominal ultrasonography. On CT examination, a 7.8-cm × 8.0-cm × 7.8-cm soft tissue density mass occupied the left nasal cavity and left frontal sinus, with destruction of the left maxillary, frontal, palatine, and zygomatic bones (Figure 4).

Figure 4.

Figure 4

Open in a new tab

Transverse computed tomographic (CT) image showing a soft tissue density mass occupying the left nasal cavity, with destruction of facial bones and dorsolateral displacement of the left eye. The dog has a soft tissue equivalent bolus material used in radiation therapy in the oral cavity (arrow).

Cytologic examination of FNAs of a subcutaneous nodule on the medial aspect of the stifle and the splenic mass yielded similar cytological findings. The direct smears were highly cellular and comprised a population of individual round to polygonal cells, 20–25 μm in diameter, with discrete cell borders and a moderate to high nuclear to cytoplasmic ratio. These cells had many features associated with plasma cells stained with hematoxylin and eosin (H&E) (smooth blue cytoplasm, paranuclear clearing, and, in rare cells, clumped chromatin). Multinucleated cells and mitotic figures were rare. The cytological diagnosis for the subcutaneous and splenic masses was a round (discrete) cell tumor; anaplastic plasma cell tumor was considered most likely.

Results from microscopic examination of the left humeral bone marrow aspirate and left ilial bone marrow core were unremarkable.

Histopathological examination of 2 excised subcutaneous nodules revealed multiple, poorly demarcated, nonexpansile, nonencapsulated, highly cellular, mid- to deep dermal nodules (Figure 5a). The nodules comprised sheets of pleomorphic round cells with some packeting of tumor cells by thin strands of fibrovascular connective tissue. Cellular features of malignancy included marked anisokaryosis and anisocytosis, abnormal nucleolar morphology (oblong and angular forms noted), and karyomegaly. Bi- and multinucleated cells were evident and there were multilobed nuclei. The mitotic rate was high (5 to 9 per 400× objective field). Chromosomal fragmentation and atypical arrangements were seen occasionally. The histopathological diagnosis, in keeping with the cytological diagnosis, was a round/discrete cell tumor; an anaplastic plasma cell tumor (cleaved type) was considered most likely (2). Histopathologic review of the oral tumor biopsy revealed a similar population of round cells (Figure 5b). Cytoplasmic expression of IgA by the neoplastic cells within the subcutaneous nodules was demonstrated by using a direct immunoperoxidase technique (Figure 5c). Neoplastic cells were weakly positive for cluster of differentiation (CD)79a, and negative for CD3, CD18, and CD138 antigens. Direct immunoperoxidase staining of the oral tumor biopsy submitted by the referring veterinarian did not reveal cellular expression of immunoglobulin.

Figures 5a and 5b.

Figures 5a and 5b

Open in a new tab

Photomicrographs of the histopathological features of 1 of the cutaneous masses (Figure 5a) and of the oral mass (Figure 5b): poorly differentiated, round to polyhedral cells arranged in a continuous sheet with indistinct cell borders, an eccentrically located nucleus with finely stippled chromatin, prominent nucleoli, and, often, a perinuclear halo. Note the presence of multinucleated giant cells (arrowheads) and mitoses (arrows). Hematoxylin and eosin. Magnification 500×. Bar = 100 μm.

Figure 5c.

Figure 5c

Open in a new tab

Photomicrograph of positive immunostaining of the subcutaneous nodule tumor cell cytoplasm with IgA antibody (arrowheads). Avidin biotin complex immunoperoxidase. Magnification 400×. Bar = 100 μm.

The dog was diagnosed as having multiple myeloma and initially administered prednisone (Apoprednisone; Apotex Incorporated, Toronto, Ontario), 0.5 mg/kg bodyweight (BW), PO, q24h for the duration of remission, and melphalan (Alkeran; Celgene, Summit, New Jersey, USA), 0.1 mg/kg BW, PO, q24h for 10 d, then 0.05 mg/kg BW, PO, q24h for the duration of remission. Radiation therapy of the intraoral mass, consisting of 6 weekly fractions of 600 cGy to a total dosage of 3600 cGy, prescribed to the isocenter was administered, using a cobalt radiotherapy machine (Theratron 780; Theratronics, Ottawa, Ontario). The initial dose of radiation was administered by using a parallel opposed beam arrangement. A CT-based 4 beam arrangement, created by using a 3-dimensional treatment planning computer (Pinnacle; Philips Medical Systems, New York City, New York, USA), was used for the remaining fractions. The clinical target volume (CTV) for the computerized plan was defined as the gross extent of the tumor visible on CT images, and the planning target volume (PTV) included the CTV plus an 0.8-cm margin. The dose prescription point was the isocenter, the minimum dose to the PTV was 95% of the prescribed dose, and the maximum dose to the PTV was 108% of the prescribed dose. Tissue heterogeneity correction was used.

The dog’s appetite and energy level had returned to normal at his 1-week recheck examination and remained normal for the next 73 d. Twenty-one days after the 1st radiation treatment, the patient’s intraoral mass had markedly decreased in size (Figure 6). Thirty-five days after starting chemotherapy and radiation therapy, a serum biochemical panel revealed a persistence of a mild azotemia and mild hyperglobulinemia, and increased serum activities of alkaline phosphatase (ALP), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), glutamate dehydrogenase (GLDH), and sorbitol dehydrogenase (SDH) (Table 1). There was a mild elevation in beta globulins in the serum and urine protein electrophoretograms. Serum IgA levels, by radial immunodiffusion, had decreased (64.0 g/L; published reference interval, 0.2 to 1.5 g/L). The number of cutaneous nodules had decreased to approximately 20. Acute radiation effects were assessed at each radiation treatment; they were limited to mild conjunctivitis and scleral injection in the left eye at days 29 and 35 after the 1st dose of radiation.

Figure 6.

Figure 6

Open in a new tab

Twenty-one days after the 1st fraction of radiation, the soft tissue mass has markedly decreased in size, with resulting mesial and palatal drifting of tooth 209.

Table 1.

Serial serum biochemical analysis, urinalysis, and serum protein electrophoresis (SPE) data

Analyte Day 0 Day 35 Day 80 Reference intervals
Sodium 145 153 148 145–158 mmol/L
Potassium 4.8 4.7 4.4 3.8–5.6 mmol/L
Sodium:potassium ratio 30 33 34 27–50 mmol/L
Chloride 107 108 103 103–118 mmol/L
Bicarbonate 24 22 18 15–25 mmol/L
Anion gap 19 28 31a 16–30 mmol/L
Calcium 3.86 2.87 4.23 1.91–3.03 mmol/L
Inorganic phosphorus 1.31 1.89 1.77 0.63–2.41 mmol/L
Magnesium 1.02 0.88 0.94 0.70–1.16 mmol/L
Urea 15.9 15.5 11.2 3.5–11.4 mmol/L
Creatinine 213 140 140 41–121 μmol/L
Glucose 5.5 5.8 5.8 3.1–6.3 mmol/L
Cholesterol 5.69 10.98 6.03 2.70–5.94 mmol/L
Total bilirubin 2 2 2 1.0–4.0 μmol/L
Alkaline phosphatase 28 566 401 9–90 U/L
Alanine aminotransferase 31 73 131 19–59 U/L
Gamma-glutamyl transpeptidase 6 9 11 0–8 U/L
Glutamate dehydrogenase 5 14 38 0–7 U/L
Sorbitol dehydrogenase 6 16 14 0.0–4.0 U/L
Creatinine kinase 205 176 187 51–418 U/L
Total protein 100 72 105 55–71 g/L
Albumin 25 29 17 28–38 g/L
Globulins 75 43 88 23–37 g/L
Albumin:globulin ratio 0.33 0.67 0.19 0.73–1.49
Urinalysis Voided Voided Voided
Urine specific gravity 1.016 1.014 1.025
pH 6.5 7.0 6.5
Protein g/L 11 31 41
Glucose normal normal normal
Ketones negative negative negative
Bilirubin trace negative negative
Blood negative negative negative
SPE
Total protein 100 72 105 55–71 g/L
Albumin 29.7 (29.7%) 30.2 (42.0%) 19.7 (18.8%) 24–40 g/L
Alpha-1 globulins 3.5 (3.5%) 3.1 (4.3%) 5.7 (5.4%) 2–4 g/L
Alpha-2 globulins 5.7 (5.7%) 13.4 (18.6%) 8.1 (7.8%) 4–9 g/L
Beta globulins 48.0 (48.0%) 21.8 (30.3%) 57.4 (14.1%) 13–17 g/L
Gamma globulins 13.1 (13.1%) 3.5 (4.8%) 14.1 (13.4%) 4–8 g/L
Albumin:globulin ratio 0.42 0.72 0.23 0.60–1.5 g/L
Open in a new tab
a

Bolded font indicates data outside of reference intervals

Eighty days after initiation of the chemotherapy and radiation therapy, the dog was presented to the referring veterinarian for right-sided epistaxis and 2 new cutaneous nodules. Abnormalities in the serum biochemical panel included hyper-calcemia, hyperglobulinemia, hypoalbuminemia, persistence of the azotemia, and elevations in the serum activities of ALP, ALT, GGT, GLDH, and SDH (Table 1). The serum and urine protein electrophoretograms revealed higher peaks in the beta fraction than at initial presentation.

Cytological examination of FNAs of 1 of the new cutaneous nodules yielded similar cytological findings to those of previous evaluations. Serum viscosity was 4.8 relative to water. Normal serum viscosity in dogs has been reported to be 1.6 relative to water (3).

The dog’s family declined further treatment and the patient was euthanized 83 d after initiation of therapy.

The dog was submitted for postmortem examination. On examination, multiple, raised, firm, white cutaneous, subcutaneous, and muscular nodules, ranging in size from 0.5 cm to 1.5 cm, were seen. Skin was mobile over the subcutaneous and muscular nodules. A hard intraoral mass, situated around the left 1st molar, extended into the left nasal cavity, and there was destruction of the nasal turbinates. Multifocal, well-demarcated, pale, firm nodules were present in the liver, pancreas, spleen, intestinal serosa, and heart (Figure 7). A 6.5-cm × 6.0-cm × 5.5-cm rubbery, well-demarcated mass was present in the spleen (Figure 8). Multiple ribs were focally swollen and fractured (Figure 9). There were multifocal, 3-mm to 6-mm, well-demarcated lesions in the costal bone marrow associated with fracture sites. Histopathological examination of bone marrow associated with a fracture of the right 6th rib revealed extensive tumor cell infiltration (Figures 10a,b). On histopathological examination of both kidneys, the Bowman’s capsules were mildly thickened by fibrous tissue, with multifocal mineralization of the Bowman’s capsules, the basal lamina of the tubules, and the tubular epithelial cells. Multifocal, moderate interstitial fibrosis was present in the renal cortices. The histopathologic diagnoses were multiple myeloma with pathological rib fractures and membranous glomerulonephritis with interstitial fibrosis.

Figure 7.

Figure 7

Open in a new tab

Multifocal, pale, firm nodules, ranging from 0.5 cm to 3 cm in diameter, present in the liver at necropsy.

Figure 8.

Figure 8

Open in a new tab

Solitary, rubbery, well-demarcated, 6.5-cm × 6-cm × 5.5-cm mass, present in the spleen at necropsy.

Figure 9.

Figure 9

Open in a new tab

The internal aspect of the right side of the thoracic cavity, showing multiple sites of rib involvement (black arrowheads) and the area of the right 6th rib that was visible as a lytic lesion on radiographs (white arrowhead).

Figure 10a.

Figure 10a

Open in a new tab

Photomicrographs of bone marrow involvement of the right 6th rib. Extensive infiltration of the medulla with bone lysis and extension into the surrounding connective tissue. Hematoxylin and eosin. Magnification 40×. Bar = 500 μm.

Figure 10b.

Figure 10b

Open in a new tab

Sheets of poorly differentiated, round to polyhedral cells arranged in a continuous sheet with indistinct cell borders; an eccentrically to centrally located nucleus with finely to coarsely stippled chromatin and a perinuclear halo. Note the presence of erythrophagocytosis (arrowheads). Hematoxylin and eosin. Magnification 500×. Bar = 20 μm.

Discussion

The dog in this case report was diagnosed with IgA multiple myeloma based on conventional diagnostic criteria (4). The dog had unusual cutaneous involvement and rapid progression of disease despite systemic therapy.

A plasma cell neoplasm is a clonal expansion of terminally differentiated B lymphocytes that have undergone malignant transformation. Plasma cell neoplasms are generally categorized into 4 groups: multiple myeloma (MM); plasma cell leukemia; extramedullary plasmacytoma (EMP); and solitary plasmacytoma of bone (SPB), which may also be called solitary osseous plasmacytoma (5). A plasmacytoma refers to a localized, frequently solitary, mass of neoplastic plasma cells in osseous or soft tissue, while MM and plasma cell leukemia refer to diffuse disease. An additional group, multiple solitary plasmacytoma, is recognized in humans. Biological behavior of the groups of plasma cell neoplasms varies from benign, in the case of the majority of single extramedullary plasmacytomas of the skin, to malignant. These groups may represent a continuum, as canine SPBs and EMPs can progress to MM (6).

A literature review revealed multiple sites of cutaneous involvement described in an 8-month-old boxer dog, diagnosed with MM, that presented with more than 180 soft nodules involving the neck, trunk, and limbs (7). Histological examination revealed large numbers of plasma cells in the skin nodules. There was no evidence of skeletal pain or bony swelling on physical examination, and no bony enlargement or loss of bone density on postmortem examination of skeletal tissues. This dog had neoplastic involvement of the bone marrow, as well as involvement of the liver, kidney, myocardium, spleen, and lungs. Serum and urine protein electrophoresis were not performed. Although the diagnosis of MM was likely correct, the minimum diagnostic criteria for canine MM were not met. To the authors’ knowledge, no other cases of multiple myeloma with multiple sites of cutaneous involvement have been described.

The lymphopenia in this dog may have been caused by stress, or a decrease in normal cell replacement due to a lymphoid neoplasm, and the rouleaux were attributed to the hyperglobulinemia. The hyperglobulinemia was attributed to production by a neoplastic population of cells of B-cell origin. The hypoalbuminemia may have been due to renal loss, decreased hepatic synthesis to offset the hyperglobulinemia, or both. Proteinuria was likely due to renal protein loss. The increases in hepatic enzymes were indicative of cholestasis (ALP, GGT) and hepatocellular injury (ALT, GLDH, SDH), due, in part, to the prednisone therapy. The neoplastic infiltrates confirmed in the liver at necropsy also contributed to the hepatic enzyme elevations.

This patient had elevated serum total-calcium and heparinized blood free-calcium at his initial presentation, and elevated serum total-calcium at the time of his clinical disease progression. Hypercalcemia in MM patients may result from an increased production of osteoclast-activating factors, such as interleukin-6 and parathyroid hormone-related protein, produced by host cells within the bone marrow microenvironment and by myeloma cells, and from neoplastic destruction of bone (8). Decreased calcium excretion due to renal failure may have contributed to this dog’s hypercalcemia. Increased serum total calcium has also been reported to occur due to calcium binding with the abnormal immunoglobulin.

Renal dysfunction is common in canine multiple myeloma, occurring in 33% to 50% of dogs (9). The pathogenesis is multifactorial, and can include immunoglobulin-related nephrotoxicity, hypercalcemia, hyperviscosity, upper urinary tract infection, and neoplastic infiltration of the kidney (8). Immunoglobulin light chains can be directly toxic to the proximal tubular epithelium and damage done by urinary free light chains and other immunoglobulin fragments can lead to myeloma cast nephropathy (10). In addition to the tubular damage done by immunoglobulin light chains, this dog’s renal dysfunction most likely resulted from compromise from the hypercalcemia, and its circulatory compromise due to increased serum viscosity (8). Molecules of IgA immunoglobulin tend to form high molecular weight complexes that increase blood viscosity (11).

Despite an absence of plasma cell infiltration being observed on bone marrow aspiration and core biopsy, the dog in this report met the diagnostic criteria for canine multiple myeloma, as proposed by MacEwen and Hurvitz (12), at initial presentation. Five percent of humans with multiple myeloma have fewer than 10% plasma cells in the bone marrow, and the currently recommended human diagnostic criteria do not specify a minimum level of bone marrow plasma cells for this reason (13,14). The pattern of marrow infiltration by neoplastic plasma cells may be nodular, and a biopsy may sample only noninfiltrated bone marrow (14).

The absence of cellular expression of immunoglobulin A in the oral tumor biopsy may have resulted from a low level of immunoglobulin within the tumor tissue that was sampled. Our laboratory has observed variable intensity of staining of immunoglobulin across an individual plasma cell neoplasm. Direct immunoenzyme staining provides little amplification of the visible marker, so its use is limited in detection of low levels of antigen (15). As well, biopsy of the oral tumor biopsy was performed at the referring hospital, and the time the sample spent in formalin differed from that of the cutaneous mass samples. Formalin fixation almost always results in diminished antigenicity of tissues, and this may have affected the immunoperoxidase staining results (15). Immunostaining was performed at the same time on both biopsy samples, making it unlikely that variability in laboratory processing contributed to the difference in the staining results.

The epistaxis was most likely due to progression of the multiple myeloma. Coagulation-related complications have been reported in approximately 33% of dogs with multiple myeloma and macroglobulinemia, and in more than 33% of human patients with IgA myeloma (8,16). High levels of immunoglobulins are associated with inhibition of fibrin polymerization, qualitative platelet dysfunction, acquired coagulation factor deficiency, amyloid-associated factor X deficiency, hypercoagulable state, and heparin-like circulating anticoagulants in humans (17). Thrombocytopenia cannot be ruled out as a cause of the epistaxis, as a platelet count was not performed; however, platelet counts are not low enough to cause clinical bleeding in most dogs with multiple myeloma (3).

Light-chain proteinuria, also termed Bence Jones proteinuria, has been reported in dogs with multiple myeloma, based on a thermal precipitation test or on urine electrophoresis (3,12,18–20). However, the light-chain proteinuria was not unequivocally confirmed in these dogs. The thermal precipitation test may not be sufficiently sensitive or specific for the detection of light-chain proteinuria in dogs, and the results are unreliable (21). A monoclonal gammopathy on urine electrophoresis may result from loss of intact immunoglobulin associated with concurrent glomerular disease, and light-chain proteinuria cannot be diagnosed conclusively, using urine electrophoresis (21). Immunoelectrophoresis or immunofixation electrophoresis, using heavy- and light-chain-specific antibodies, can be used to identify free light chains in urine. However, to the authors’ knowledge, there is no commercially available monoclonal antibody specific to canine free light chains. Therefore, free light chains cannot be distinguished from light chains associated with intact immunoglobulin. Identification of light chains by using anti-light-chain antibody, together with the absence of evidence of heavy chains on electrophoresis, would be required to diagnose light-chain proteinuria definitively. Light-chain proteinuria could not be confirmed in this dog. The presence of a peak in the beta region on the urine protein electrophoretogram may have been due to intact immunoglobulin, whose presence in the urine could not be ruled out, due to the presence of high molecular weight proteins on the urine SDS-PAGE. The presence of low molecular weight proteins on the SDS-PAGE in this dog may have been due to the increased filtration of monoclonal free light chains or intact immunoglobulins produced in excess by malignant cells, the production of canine prostate specific esterase, the failure of reabsorption of free light chains produced by normal B lymphocytes, or the presence of other low molecular weight proteins due to proximal tubular damage (22,23). Due to the lack of specificity for urine free light chains with standard veterinary diagnostic tests, this criterion for diagnosis of multiple myeloma is of questionable value in canine patients.

Myeloma cells are very sensitive to irradiation, and radiation therapy is a rapid, highly effective palliative treatment for multiple myeloma (24,25). Drug treatment alone is not always sufficient to relieve local pain and discomfort, and over 70% of humans with multiple myeloma are treated with radiation therapy during the course of their disease (26,27). A total dose of 3000 cGy given in 10 to 15 treatments is commonly used for pain relief in humans (28). The radiation protocol used in this dog was altered from the teaching hospital’s standard protocol for multiple myeloma of 10 daily fractions of 300 cGy to a total dose of 3000 cGy, due to the patient being presented immediately prior to a University holiday period. Radiation therapy was used in this dog to relieve the discomfort associated with a large soft tissue plasma cell mass. Other indications for radiation therapy of multiple myeloma include painful bone lesions, spinal cord compression, and pathological fracture (26). Half-body irradiation is effective in achieving pain relief in human patients with drug-resistant multiple myeloma, but its use has not been reported in canine patients (29).

There are 3 published reports of radiation therapy being used in combination with chemotherapy for palliation of multiple myeloma in 5 dogs (16,30,31). A 10-year-old, male cocker spaniel, diagnosed with nonsecretory multiple myeloma, received 3600 cGy to his left femur and tibia after surgical immobilization of a pathological fracture of the femur (30). A lytic lesion of the right femur was also treated with 3600 cGy. Healing of the left femoral fracture was evident on radiographs 1 y after treatment. Eighteen months postirradiation, the dog was in remission. A 13-year-old, female greyhound diagnosed with light-chain myeloma had a lytic left scapular lesion on radiographs and intense technetium-99-m uptake in the left distal tibia (31). The dog was treated with cobalt radiotherapy, using 6 fractions of 300 cGy to a total dose of 1800 cGy, to the tibial and scapular lesions. The dog’s activity level improved for 1 mo, but a probable fracture of the left shoulder was diagnosed at day 52 after treatment. A nonweight bearing lameness of the right hind leg developed 2 mo after treatment, and the dog was euthanized. Three dogs diagnosed with multiple myeloma-related spinal cord compression responded to orthovoltage or cobalt radiation therapy (16).

The conventional diagnostic criteria used for canine MM include the presence of at least 2 of 4 abnormalities: increased numbers of plasma cells in the bone marrow, monoclonal serum gammopathy, radiographic osteolysis, and immunoglobulin light-chain proteinuria (4). These diagnostic criteria were first proposed for use in canine patients by MacEwen and Hurvitz in 1977 (12); they are similar to the diagnostic criteria for human patients described at that time. While the published criteria for diagnosis of multiple myeloma in the dog vary, the recognition of a systemic form of plasma cell neoplasia and indication for systemic therapy, as opposed to the localized therapy used for solitary plasmacytomas, is the critical issue. Current human diagnostic criteria for the systemic form include monoclonal protein in serum, urine, or both; bone marrow plasma cells or plasmacytoma; and related organ or tissue impairment (ROTI) (13). Related organ or tissue impairment includes elevated serum calcium, renal insufficiency, anemia, and bone lesions, and it is considered the most critical criterion for symptomatic multiple myeloma requiring treatment. Definitions of the current human diagnostic criteria are based on readily available laboratory tests, and the use of these criteria for dogs should be considered. Uniform use of diagnostic criteria for canine multiple myeloma will facilitate comparison of treatment outcomes and characterization of the relationships between EMP, SPB, and MM.

Cutaneous involvement of MM is rare in humans (32). Skin lesions most commonly involve the trunk and abdomen and display 2 histopathological skin lesion patterns; diffuse interstitial and nodular patterns (32). Cutaneous involvement in humans is associated with advanced disease, high tumor burden, and short survival. Based on this dog’s short survival, cutaneous involvement with MM may be a negative prognostic indicator in canine patients, as it is in humans.

Acknowledgment

The authors thank Dr. Eric Zini for his comments on the current limitations of urine-free light-chain diagnosis in dogs. CVJ

Footnotes

Authors’ contributions

Dr. Mayer was involved with the case management, writing the manuscript, and providing the clinical photographs. Dr. Grier was involved with the primary case management, data collection, and revising the manuscript. Dr. Kerr was involved with histopathologic studies, providing the microscopic photographs, and writing and revising the manuscript. Dr. MacDonald was involved in interpreting the data and revising the manuscript.

References

  • 1.Tizard IR. Veterinary Immunology: An Introduction. 6. Philadelphia: WB Saunders; 2000. pp. 139–148. [Google Scholar]
  • 2.Platz SJ, Breuer W, Pfleghaar S, Minkus G, Hermanns W. Prognostic value of histopathological grading in canine extramedullary plasmacytomas. Vet Pathol. 1999;36:23–27. doi: 10.1354/vp.36-1-23. [DOI] [PubMed] [Google Scholar]
  • 3.Thrall MA. Lymphoproliferative disorders. Lymphocytic leukemia and plasma cell myeloma. Vet Clin North Am Small Anim Pract. 1981;11:321–347. doi: 10.1016/s0195-5616(81)50033-7. [DOI] [PubMed] [Google Scholar]
  • 4.Fry MM, McGavin MD. Bone marrow, blood cells, and lymphatic system. In: McGavin MD, Zachary JF, editors. Pathologic Basis of Veterinary Disease. 4. St. Louis: Mosby Elsevier; 2007. pp. 743–832. [Google Scholar]
  • 5.Nolan KD, Mone MC, Nelson EW. Plasma cell neoplasms. Review of disease progression and report of a new variant. Surg Oncol. 2005;14:85–90. doi: 10.1016/j.suronc.2005.05.001. [DOI] [PubMed] [Google Scholar]
  • 6.Vail DM. Hematopoietic tumors section D plasma cell neoplasms. In: Withrow SJ, Vail DM, editors. Small Animal Clinical Oncology. 4. St. Louis: Saunders Elsevier; 2007. pp. 769–784. [Google Scholar]
  • 7.Walton GS, Gopinath C. Multiple myeloma in a dog with some unusual features. J Small Anim Pract. 1972;13:703–708. doi: 10.1111/j.1748-5827.1972.tb06825.x. [DOI] [PubMed] [Google Scholar]
  • 8.Munshi NC, Anderson KC. Plasma cell neoplasms. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer Principles and Practice of Oncology. 7. Philadelphia: Lippincott Williams & Wilkins; 2005. pp. 2155–2188. [Google Scholar]
  • 9.Jacobs RM, Messick JB, Valli VE. Tumors of the hemolymphatic system. In: Meuten DJ, editor. Tumors in Domestic Animals. 4. Iowa: Iowa State Univers Pr; 2002. pp. 119–198. [Google Scholar]
  • 10.Clark AD, Shetty A, Soutar R. Renal failure and multiple myeloma: Pathogenesis and treatment of renal failure and management of underlying myeloma. Blood Rev. 1999;13:79–90. doi: 10.1016/s0268-960x(99)90014-0. [DOI] [PubMed] [Google Scholar]
  • 11.Preston FE. Antibody-mediated tissue damage. Hyperviscosity and other complications of paraproteinaemia. J Clin Pathol Suppl (R Coll Pathol) 1979;13:85–89. doi: 10.1136/jcp.s3-13.1.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.MacEwen EG, Hurvitz AI. Diagnosis and management of monoclonal gammopathies. Vet Clin North Am. 1977;7:119–132. doi: 10.1016/s0091-0279(77)50010-x. [DOI] [PubMed] [Google Scholar]
  • 13.Kyle KA, Child JA, Anderson K, et al. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group. Br J Haematol. 2003;121:749–757. [PubMed] [Google Scholar]
  • 14.Bartl R, Frisch B, Diem H, Mundel M, Fateh-Moghadam A. Bone marrow histology and serum beta 2 microglobulin in multiple myeloma — a new prognostic strategy. Eur J Haematol Suppl. 1989;51:88–98. doi: 10.1111/j.1600-0609.1989.tb01499.x. [DOI] [PubMed] [Google Scholar]
  • 15.Haines DM, Chelack BJ. Technical considerations for developing enzyme immunohistochemical staining procedures on formalin-fixed paraffin-embedded tissues for diagnostic pathology. J Vet Diagn Invest. 1991;3:101–112. doi: 10.1177/104063879100300128. [DOI] [PubMed] [Google Scholar]
  • 16.Matus RE, Leifer CE. Immunoglobulin-producing tumors. Vet Clin North Am Small Anim Pract. 1985;15:741–753. doi: 10.1016/s0195-5616(85)50033-9. [DOI] [PubMed] [Google Scholar]
  • 17.Eby C, Blinder M. Hemostatic complications associated with paraproteinemias. Curr Hematol Rep. 2003;2:388–394. [PubMed] [Google Scholar]
  • 18.Osborne CA, Perman V, Sautter JH, Stevens JB, Hanlon GF. Multiple myeloma in the dog. J Am Vet Med Assoc. 1968;153:1300–1319. [PubMed] [Google Scholar]
  • 19.Matus RE, Leifer CE, MacEwen EG, Hurvitz AI. Prognostic factors for multiple myeloma in the dog. J Am Vet Med Assoc. 1986;188:1288–1292. [PubMed] [Google Scholar]
  • 20.Giraudel JM, Pages JP, Guelfi JF. Monoclonal gammopathies in the dog: A retrospective study of 18 cases (1986–1999) and literature review. J Am Anim Hosp Assoc. 2002;38:135–147. doi: 10.5326/0380135. [DOI] [PubMed] [Google Scholar]
  • 21.Boone LI. Bence-Jones proteins. In: Feldman BF, Zinkl JG, Jain NC, editors. Schalm’s Veterinary Hematology. 5. Baltimore: Lippincott Williams & Wilkins; 2000. pp. 925–928. [Google Scholar]
  • 22.Schellenberg S, Gentilini F, Glaus TM, Reusch CE. The effect of hydrocortisone on urinary protein excretion in dogs [abstract]. Research Abstract Program of the 24th Annu ACVIM Forum, Louisville, Kentucky, May 31 – June 3, 2006. J Vet Intern Med. 2006;20:741. [Google Scholar]
  • 23.MacNamara EM, Aguzzi F, Petrini C, et al. Restricted electrophoretic heterogeneity of immunoglobulin light chains in urine: A cause for confusion with Bence Jones protein. Clin Chem. 1991;37:1570–1574. [PubMed] [Google Scholar]
  • 24.Leigh BR, Kurtts TA, Mack CF, Matzner MB, Shimm DS. Radiation therapy for the palliation of multiple myeloma. Int J Radiat Oncol Biol Phys. 1993;25:801–804. doi: 10.1016/0360-3016(93)90308-i. [DOI] [PubMed] [Google Scholar]
  • 25.Rowell NP, Tobias JS. The role of radiotherapy in the management of multiple myeloma. Blood Rev. 1991;5:84–89. doi: 10.1016/0268-960x(91)90039-f. [DOI] [PubMed] [Google Scholar]
  • 26.Bosch A, Frias Z. Radiotherapy in the treatment of multiple myeloma. Int J Radiat Oncol Biol Phys. 1988;15:1363–1369. doi: 10.1016/0360-3016(88)90232-5. [DOI] [PubMed] [Google Scholar]
  • 27.Adamietz IA, Schober C, Schulte RW, Peest D, Renner K. Palliative radiotherapy in plasma cell myeloma. Radiother Oncol. 1991;20:111–116. doi: 10.1016/0167-8140(91)90144-6. [DOI] [PubMed] [Google Scholar]
  • 28.Terpos E, Dimopoulos MA. Myeloma bone disease: Pathophysiology and management. Ann Oncol. 2005;16:1223–1231. doi: 10.1093/annonc/mdi235. [DOI] [PubMed] [Google Scholar]
  • 29.Singer CR, Tobias JS, Giles F, Rudd GN, Blackman GM, Richards JD. Hemibody irradiation. An effective second-line therapy in drug-resistance multiple myeloma. Cancer. 1989;63:2446–2451. doi: 10.1002/1097-0142(19890615)63:12<2446::aid-cncr2820631214>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  • 30.MacEwen EG, Patnaik AK, Hurvitz AI, et al. Nonsecretory multiple myeloma in two dogs. J Am Vet Med Assoc. 1984;184:1283–1286. [PubMed] [Google Scholar]
  • 31.Cowgill ES, Neel JA, Ruslander D. Light-chain myeloma in a dog. J Vet Intern Med. 2004;18:119–121. doi: 10.1892/0891-6640(2004)18<119:lmiad>2.0.co;2. [DOI] [PubMed] [Google Scholar]
  • 32.Requena L, Kutzner H, Palmedo G, et al. Cutaneous involvement in multiple myeloma: A clinicopathologic, immunohistochemical, and cytogenetic study of 8 cases. Arch Dermatol. 2003;139:475–486. doi: 10.1001/archderm.139.4.475. [DOI] [PubMed] [Google Scholar]

Articles from The Canadian Veterinary Journal are provided here courtesy of Canadian Veterinary Medical Association

RESOURCES