Signalment:  

15-year-old female spayed domestic short hair cat (Felis cats).This cat presented with a history of lethargy, anorexia, and vomiting of bile. Physical exam revealed a 1-pound weight loss within the past 4 months, grade 2-3 heart murmur, and doughy, slightly painful abdomen. Abdominal and thoracic radiographs showed no significant findings. An in-house CBC/serum chemistry/urinalysis panel showed mild azotemia, hypercalcemia, hyperproteinemia, hyperglobinemia and slight increase in ALT. The cat was hospitalized and started on fluid therapy and anti-emetics. Additional clinical samples were then collected and sent out to a commercial laboratory for CBC, routine serum chemistry, urinalysis, serum ionized Ca, serum protein electrophoresis, serum parathyroid hormone related protein (PTHrP) and serum parathyroid hormone (PTH) analyses (see included table). After the results of these tests were known, the owners elected to euthanize the cat upon hearing the presumptive diagnosis (multiple myeloma).

Gross Description:  

A partial necropsy was performed by the clinician with no gross abnormalities noted. Samples of femur bone marrow, spleen, kidney, liver and sections of small intestine were collected for histopathological examination.

Histopathologic Description:

Bone marrow: The bone marrow is 60% effaced and replaced by an unencapsulated, poorly circumscribed, infiltrative, highly cellular neoplasm. The neoplasm is composed of round cells arranged in sheets supported on a pre-existing fibrovascular stroma. Neoplastic cells have fairly distinct cell borders and moderate amounts of eosinophilic cytoplasm. Nuclei are round to oval, occasionally eccentrically placed, with coarsely stippled chromatin and up to three indistinct nucleoli. Mitoses average five per high power field. There is mild anisokaryosis and anisocytosis, and scattered multifocal single-cell necrosis. There are adequate numbers of megakaryocytes and adipocytes. 

Morphologic Diagnosis:  

Bone marrow (femur): Plasma cell myeloma, domestic short hair cat, feline.

Lab Results:  

Tests	Results	Reference Range	Units
Total Protein	10.7 (HIGH)	5.2-8.8	g/dL
Globulin	7.4 (HIGH)	2.3-5.3	g/dL
AST	152 (HIGH)	10-100	U/L
AST (ALT?)	155 (HIGH)	10-100	U/L
Urea Nitrogen	52 (HIGH)	14-36	mg/dL
Creatinine	2.6 (HIGH)	0.6-2.4	mg/dL
CPK	1109 (HIGH)	56-529	U/L
Calcium, ionized	2.20 (HIGH)	1.16-1.34	μmol/L
Calcium (verified)	18.3 (HIGH)	8.2-10.8	mg/dL
Protein Electrophoresis, serum
Total Protein	10.7 (HIGH)	5.2-8.8	g/dL
Gamma	4.83 (HIGH)	0.50-1.90	g/dL
PTHrP	0.0	Less than 1.0	pmol/L
PTH	4.0	4-25	pg/ml

• CBC: WNL
• Platelet count: 56 (LOW); due to platelet clumping.
• Urinalysis (cystocentesis): Light yellow, clear, SG 1.038, pH 6.0, proteinuria (3+), hematuria (3+) and >50 RBC. Glucose, ketone, bilirubin were negative. No casts, crystals or bacteria. WBC and squamous epithelial cells were WNL.
• Urine microalbumin (feline): 7.4 (HIGH) indicating microalbuminuria.

Condition:  

Myeloma

Contributor Comment:  

Plasma cell neoplasms originate from terminally differentiated B lymphocytes that have undergone malignant transformation. The two main recognized forms of plasma cell neoplasm in veterinary species are multiple myeloma and plasmacytoma. This case is a classical presentation of multiple myeloma, which refers to diffuse disease and, clinically, is the most important plasma cell neoplasm.

In animals, multiple myeloma is a rare, malignant tumor that arises in the bone marrow. It has a slowly progressive clinical course and sites of metastasis include the spleen, liver, lymph nodes and kidneys. Though rare, it has been reported in horses, cattle, cats and pigs, but it is seen more frequently in older dogs with a mean age of 8-9 years.(1,12) In cats, the median age is 12-14 years and there is possibly a male predisposition.(2,6-8) The cause in domestic animals is unknown, but in people, plasma cell neoplasms are associated with working in agriculture, exposure to petroleum products, and chronic exposure to an antigenic stimulus.(3,9-11) There is no evidence that feline immunodeficiency virus, feline leukemia virus, or feline infectious peritonitis virus infections are related to the development of multiple myeloma in cats.(7)

Neoplastic plasma cells usually secrete large amounts of immunoglobulin (Ig), and the hallmark laboratory finding is hyperglobulinemia. This homogeneous protein fraction is often called paraprotein or M-protein.(5)

Diagnosis of multiple myeloma is based on a minimum of two of the following abnormalities:(1,4-6,12-13)

1. Marked increase in numbers of plasma cells in the bone marrow (at least 30% of the nucleated cells are plasma cells which may be well differentiated to poorly differentiated cells with visible nucleoli, marked anisokaryosis and anisocytosis and multinucleation).
2. Monoclonal gammopathy because of clonal production of Ig or Ig fragments by the neoplastic cells. This is demonstrated by serum electrophoresis and can be characterized further using immunodiagnostic techniques. Most of the Igs migrate in the gamma-region, but some may migrate to the beta-region (particularly IgA and IgM), hence the usage of the term monoclonal gammopathy. Note that monoclonal gammapathy is not specific to multiple myeloma and has been reported in cases of B lymphocyte lymphoma and some nonneoplastic conditions such as canine ehrlichiosis or leishmaniasis. 
3. Radiographic evidence of osteolysis.
4. Light-chain proteinuria: Bence Jones proteins are free Ig light chains of low molecular weight that pass through the glomerular filter in the urine. These proteins do not react with urine dipstick protein indicators and are specifically detected by electroelectrophoresis and immunoprecipitation.

Patients with multiple myeloma often present with other pathologic findings including:(1,4-6,12-13)
1) hypercalcemia, due to neoplastic cell production of osteoclastic-activating factors (RANKL) resulting in resorption of bone,
2) hemorrhage that is caused by secondary platelet dysfunction due to the binding of the paraprotein to platelets (decreased aggregation),
3) hyperviscosity syndrome (IgM and IgA dimers cause an increased viscosity of blood resulting in tissue ischemia and hemorrhage),
4) cytopenias caused by high numbers of neoplastic cells displacing normal bone marrow elements, and
5) renal disease, which develops from nephrocalcinosis secondary to chronic hypercalcemia, hypoxic damage from hyperviscosity, renal toxicity of light chains and neoplastic cell infiltration into the kidney and/or renal amyloidosis. 

In this rare feline case of multiple myeloma, the diagnosis was made based on the hallmark laboratory finding of hyperglobulinemia and having two out of the four abnormalities for multiple myeloma: marked increase in numbers of plasma cells in the bone marrow and monoclonal gammopathy. In addition, there was metastasis to the spleen, kidney and liver. Hyperparathyroidism was ruled out based on PTHrP and PTH laboratory findings within normal limits. 

Acknowledgement: The author thanks Dr. Lynn Facemire for contributing the clinical case history and the tissue samples for histopathology.

JPC Diagnosis:  

Bone marrow: Plasma cell myeloma.

Conference Comment:  

In the histopathologic description, the contributor noted that 60% of the bone marrow nucleated cell population was replaced by neoplastic plasma cells, however, in conference it appeared that plasma cells accounted for a significantly smaller proportion of bone marrow, and neoplastic cells were largely confined to one or two foci within the section. Despite this disparity, conference participants agreed that plasma cells did constitute greater than 30% of the nucleated cell population, which, in combination with the laboratory finding of hypergammaglobulinemia, supports a definitive diagnosis of plasma cell myeloma. Evidence of osteolysis was not reported and there was no history of Bence-Jones proteinuria, the two other diagnostic criteria for diagnosing plasma cell myeloma. Other causes of monoclonal gammopathy in cats and dogs include lymphoma, leukemia, amyloidosis, ehrlichiosis, visceral leishmaniasis, feline infectious peritonitis and plasmacytic gastroenterocolitis.(5) The azotemia and proteinuria/microalbuminuria observed in this case are likely secondary to renal damage, which is a relatively common finding in plasma cell myeloma.(5) Hypercalcemia typically occurs due to neoplastic plasma cell production of osteoclastic-activating factors, which induce bone resorption and subsequent release of calcium.(5) The underlying cause of the elevations in ALT and AST (both of which are hepatocellular leakage enzymes) is not clear, but may be related to tumor metastasis and resultant hepatocellular injury.

References:

1. Fry MM, McGavin MD. Bone marrow, blood cells and the lymphatic system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Elsevier; 2012:729-730.

2. Hanna F. Multiple myelomas in cats. J Feline Med Surg. 2005;7(5):275-287.

3. Imahori S, Moore GE. Multiple myeloma and prolonged stimulation of reticuloendothelial system. NY State J Med. 1972;72(12):1625-1628.

4. Kumar V, Abbas AK, Fausto N, Aster JC. Diseases of white blood cells, lymph nodes, spleen and thymus. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA: Elsevier Saunders; 2009:609-610.

5. Latimer KS. Hematopoietic neoplasia. In: Latimer KS, ed. Duncan and Prasses Veterinary Laboratory Medicine Clinical Pathology. 5th ed. Ames, IA: Wiley-Blackwell; 2011:93-95,173-181.

6. Mellor PJ, Haugland S, Smith KC, et al. Histopathologic, immunohistochemical, and cytologic analysis of feline myeloma-related disorders: further evidence for primary extramedullary development in the cat. Vet Pathol. 2008;45(2):159-173.

7. Mellor PJ, Haugland S, Murphy S, et al. Myeloma-related disorders in cats commonly present as extramedullary neoplasms in contrast to myeloma in human patients: 24 cases with clinical follow-up. J Vet Intern Med. 2006;20(6):1376-1383.

8. Patel RT, Caceres A, French AF, et al. Multiple myeloma in 16 cats: a retrospective study. Vet Clin Pathol. 2005;34(4):341-352.

9. Penny R. Hughes S. Repeated stimulation of the reticuloendothelial system and the development of plasma-cell dyscrasia. Lancet. 1970;1(7637):77-78.

10. Rosenblatt J, Hall CA. Plasma-cell dyscrasia following prolonged stimulation of reticuloendothelial system. Lancet. 1970;1(7641):301-302.

11. Speer SA, Semenza JC, Kurosaki T, et al. Risk factors for acute myeloid leukemia and multiple myeloma: a combination of GIS and case control studies. J Environ Health. 2002;64(7):9-16.

12. Valli VE. Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. Vol. 3. 5th ed. Philadelphia, PA: Elsevier Ltd; 2007:107-324.

13. Valli VE, Jacobs RM, Parodi AL, Vernau W, Moore PF. Histological Classification of Hematopoietic Tumors of Domestic Animals. 2nd Series, Vol. VIII. Washington DC: Armed Forces Institute of Pathology; 2002.

Click the slide to view.

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3-1. Bone marrow

3-2. Bone marrow

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