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Home , Comparative oncology, Cryoglobulinemia, Hypergammaglobulinemia, Monoclonal gammopathy, Plasmacytoma, Plasma cell leukemia

Case Report

Progression of a solitary, malignant cutaneous plasma-cell tumour to in a cat

A. Radhakrishnan1, R. E. Risbon1, R. T. Patel1, B. Ruiz2 and C. A. Clifford3 1 Mathew J. Ryan Veterinary Hospital of the University of Pennsylvania, Philadelphia, PA, USA 2 Antech Diagnostics, Farmingdale, NY, USA 3 Red Bank Veterinary Hospital, Red Bank, NJ, USA

Abstract An 11-year-old male domestic shorthair cat was examined because of a soft-tissue mass on the left tarsus previously diagnosed as a malignant extramedullary . Findings of further diagnostic tests carried out to evaluate the patient for multiple myeloma were negative. Five Keywords hyperproteinaemia, months later, the cat developed clinical evidence of multiple myeloma based on positive Bence , Jones proteinuria, monoclonal gammopathy and circulating atypical plasma cells. This case multiple myeloma, pancytopenia, represents an unusual presentation for this disease and documents progression of an plasmacytoma extramedullary plasmacytoma to multiple myeloma in the cat.

Introduction naemia, although it also can occur with IgG or IgA Plasma-cell are rare in companion ani- hypersecretion (Matus & Leifer, 1985; Dorfman & mals. They represent less than 1% of all tumours in Dimski, 1992). Clinical signs of hyperviscosity and are even less common in cats (Weber & include coagulopathy, neurologic signs (dementia Tebeau, 1998). Diseases represented in this category and ataxia), dilated retinal vessels, retinal haemor- of neoplasia include multiple myeloma (MM), rhage or detachment, and cardiomyopathy (IgM) macroglobulinaemia (Dorfman & Dimski, 1992; Forrester et al., 1992). and solitary plasmacytoma (Vail, 2001). These con- Coagulopathy can result from the M-component ditions can result in an excess secretion of Igs interfering with the normal function of platelets or (paraproteins or M-component) which produce a clotting factors. Renal dysfunction is often asso- monoclonal spike via serum protein electrophoresis. ciated with MM and may be the result of damage MM is a systemic proliferation of neoplastic by Bence Jones proteins, tumour infiltration,

Correspondence address: plasma cells from the . Consequences , amyloidosis or decreased perfu- Dr Anant Radhakrishnan of the systemic disease include bone pathology sion (MacEwen & Hurvitz, 1977). Other clinical Mathew J. Ryan Veterinary (lysis), hyperviscosity syndrome, dyscra- manifestations of MM include polyuria or poly- Hospital of the University sias, cytopenias and organ failure (MacEwen & dipsia secondary to hypercalcaemia or renal fail- of Pennsylvania 3900 Delancey Street Hurvitz, 1977). M-component elevation may ure, spinal pain and pathologic fractures. A Philadelphia, lead to hyperviscosity syndrome, characterized by diagnosis of MM requires at least two of four PA 19104-6010, USA increased serum viscosity, blood sludging and criteria: (1) greater than 20% plasma cells in the Tel: þ1 215 898 3207 Fax: þ1 215 573 6050 poor oxygen delivery to tissues. Hyperviscosity bone marrow, (2) monoclonal gammopathy, (3) e-mail: [email protected] occurs more commonly with IgM macroglobuli- osteolytic lesions and (4) Ig light chains (Bence

36 ª 2004 Blackwell Publishing Ltd Feline multiple myeloma and plasmacytoma 37

Jones protein) in the urine (Drazner, 1982; Eastman, revealed four lobulated, soft-tissue masses that 1996; Weber & Tebeau, 1998; Bienzle et al., 2000). encompassed the tarsus circumferentially. Radio- In contrast to MM, are solitary graphs of the affected extremity revealed no evi- tumours containing neoplastic plasma cells. In dence of osteolysis. (CBC) dogs, two types of plasmacytomas have been and serum chemistry results were unremarkable. described: extramedullary and solitary osseous Segmental resection was carried out to remove forms that originate from and bone, two of the lateral masses. Histopathology revealed respectively. Extramedullary plasmacytomas are a poorly differentiated polymorphous blastic-type commonly cutaneous and typically benign, and malignant plasma-cell tumour that stained posi- surgical excision is often curative (Mandel & tively for amyloid. Serum protein electrophoresis, Esplin, 1994). Non-cutaneous extramedullary whole-body radiographs (thorax and abdomen) plasmacytomas tend to be more aggressive and and bone marrow aspiration were carried out to are commonly associated with gastrointestinal further investigate the extent of disease. Serum tract, and typically, there is to the protein electrophoresis revealed a mild elevation local lymph nodes (Brunnert et al., 1992; Trevor of alpha-2 concentration (1.65 g dLÀ1, et al., 1993; Jackson et al., 1994). Systemic pro- reference interval 0.2–1.5), consistent with an gression to MM is not typical with extramedullary inflammatory process. Radiographs revealed no plasmacytomas (Vail, 2001). Osseous plasmacyto- evidence of osteolytic lesions. Cytologic examin- mas occur in long bones, vertebral bodies, the ation of a bone marrow aspirate was interpreted as zygomatic arch and ribs. In dogs, solitary osseous erythroid hypoplasia, with only rare macrophages plasmacytomas can progress to MM (MacEwen and plasma cells reported. et al., 1984). The patient was transferred to a referral centre 4 There is a paucity of information in the veter- months later for further staging to rule out inary literature regarding plasmacytoma and MM abdominal organ involvement in anticipation of in the cat (Carothers et al., 1989; Forrester et al., . CBC and serum chemistry 1992; Larsen & Carpenter, 1994; Mandel & Esplin, results again were unremarkable. Abdominal 1994; Eastman, 1996; Sheafor et al., 1996; Weber & ultrasonography revealed an enlarged medial iliac Tebeau, 1998; Zikes et al., 1998; Bienzle et al., lymph node. Fine-needle aspiration of the lymph 2000; Hickford et al., 2000). In the cat, MM carries node was consistent with metastatic plasma-cell a poor prognosis, particularly when compared tumour (Fig. 1). Based on the diagnosis of metastasis with plasmacytomas, which may respond to sur- from the original solitary plasmacytoma, the patient gery alone (Mandel & Esplin, 1994). Cats with was referred to the service of the Veterin- MM do not typically develop osseous lesions nor ary Hospital of the University of Pennsylvania, do they commonly develop solitary osseous plas- approximately 6 months after the initial identifica- macytomas (Weber & Tebeau, 1998). Although case tion of the mass and 4 months after the initial reports exist documenting plasmacytoma with a workup for MM. monoclonal gammopathy (Carothers et al., 1989; At presentation, the owner reported no clinical Larsen & Carpenter, 1994; Mandel & Esplin, 1994), abnormalities, with the exception of the soft-tissue to the authors’ knowledge, progression of a solitary mass overlying the tarsus. Physical and ophthalmo- plasmacytoma to MM has not been reported in the scopic examinations were otherwise unremarkable. cat. This report describes a cat with a solitary extra- The cat’s body weight was 8.04 kg. Measurements of medullary plasmacytoma that progressed to MM. the mass were slightly greater than those taken 2 months earlier. A CBC indicated a normal leucocyte count (5.65 K mLÀ1, reference interval 4.0–18.7), Clinical report neutropenia (0.760 K mLÀ1, reference interval An 11-year-old intact male domestic shorthair cat 2.30–14.0), normocytic, normochromic anaemia was examined by the local veterinarian for a mass (hematocrit 27.5%, reference interval 31.7–48.0) around the left tarsus. Physical examination and (platelet count 55.1 K mLÀ1,

ª 2004 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 2, 1, 36–42 38 A. Radhakrishnan et al.

Figure 1. (A) Cytologic smear made from an ultrasound-guided fine-needle aspirate of an iliac lymph node from a cat. There are large round-to-ovoid neoplastic cells admixed with moderate numbers of small lymphocytes and abundant blood [Wright– Giemsa stain, bar ¼ 40 mm]. (B) Two neoplastic round cells with a slight paranuclear Golgi clearing. One is binucleated, whereas the second cell shows a cleaved nucleus [Wright–Giemsa stain, bar ¼ 5 mm]

reference interval 175–500). Cytologic review of the spike was detected within fraction blood smear revealed 53% (2.99 K mLÀ1)ofthe (3.73 g dLÀ1, reference interval 0.5–1.90) on serum leucocytes to be atypical plasma cells (Fig. 2). protein electrophoresis. Ig quantification by radial Abnormalities on serum chemistry included hyper- immunodiffusion identified an IgA gammopathy proteinaemia (11.7 g dLÀ1, reference interval 6.0–8.6), (IgA concentration >2000 mg dLÀ1, reference inter- hyperglobulinaemia (8.4 g dLÀ1, reference interval val 102–582). Radiographs of the thorax and abdo- 2.2–6.2), hypernatraemia (162 mmol LÀ1, reference men revealed no evidence of osteolytic lesions. The interval 146–157) and elevated aspartate aminotrans- bone marrow aspirate was haemodiluted precluding ferase activity (59 U LÀ1, reference interval 1–37). definitive analysis, but 73% of the nucleated cells Bence Jones proteins were detected in the urine with (500 cell differential count) were atypical plasma classical heat precipitation methods. A monoclonal cells. Based upon the monoclonal gammopathy, Bence Jones proteinuria and atypical plasma cells in blood, a diagnosis of MM was made. There was no evidence of hyperviscosity syndrome, ocular dis- ease, renal disease or bleeding diathesis at the time of diagnosis of MM. Therapy was initiated using (Alkeran, Glaxo Smith Kline, Research Triangle Park, NC, USA) (0.25 mg kgÀ1 peroral every 24 h, given for 5 consecutive days every 3 weeks), (1 mg kgÀ1 every 24 h) and enrofloxacin (Baytril, Bayer Corporation, Shawnee Mission, KS, USA) (5 mg kgÀ1 every 12 h). The cat demonstrated clin- ical improvement for 2 months following the onset Figure 2. Peripheral blood smear: A single is shown. These cells constituted 53% (3000 cells mLÀ1) of the of therapy. There was a decrease in total serum À1 leucocyte differential [Wright–Giemsa stain, bar ¼ 5 mm] protein (9.0 g dL , reference interval 5.2–8.8) and

ª 2004 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 2, 1, 36–42 Feline multiple myeloma and plasmacytoma 39 globulin concentrations (5.3 g dLÀ1, reference inter- given, and prednisone was increased to 1 mg kgÀ1 val 2.3–5.3) and an increase in the blood neutrophil every 12 h. Melphalan was discontinued. count (1600 K mLÀ1, reference interval 2.30–14.0). Improvement was noted in the patient for 3 Two and a half months after the onset of weeks, with an increase in appetite and physical , the cat was examined because of activity. However, by the end of 3 weeks, the cat severe anaemia. Abnormalities in physical exam- demonstrated anorexia, lethargy and vomiting. ination included tachycardia (heart rate 200 Abnormalities in physical examination included minÀ1), pale mucous membranes, grade II/VI sys- tachycardia (heart rate 260 minÀ1), pale pink tolic heart murmur and the mass on the left tarsus. mucous membranes, grade II/VI systolic heart The cat’s body weight was 6.7 kg. CBC results murmur and the mass on the left tarsus. The included (3.06 K mLÀ1, reference cat’s body weight was 6.0 kg. Haematology results interval 4.00–18.7), macrocytic, normochromic, revealed a normal leucocyte count (8.17 K mLÀ1, non-regenerative anaemia (mean corpuscular reference interval 4.00–18.7), normal neutrophil volume 54.7 fL, reference interval 36.7–53.7; count (4.54 K mLÀ1, reference interval 2.3–14.0), mean corpuscular hemoglobin concentration but normocytic, normochromic anaemia (hema- 32.4 g dLÀ1, reference interval 30.1–35.6; hemato- tocrit 11.0%, reference interval 31.7–48.0), and crit 13.2%, reference interval 31.7–48.0) and thrombocytopenia (57.8 K mLÀ1, reference interval thrombocytopenia (42.6 K mLÀ1, reference interval 175–500). Sixteen per cent (1307 cells mLÀ1) of all 175–500). The reticulocyte count was WBC were neoplastic plasma cells. Serum chem- 4 103 reticulocytes mLÀ1, with an absolute ery- istry revealed an elevated creatinine concentration throcyte count of 2.13 106 cells mLÀ1. Serum (2.5 mg dLÀ1, reference interval 1.0–2.0), hyper- chemistry abnormalities included hypernatraemia phosphataemia (6.8 mg dLÀ1, reference interval (163 mmol LÀ1, reference interval 146–157), 3.0–6.6), hypercalcaemia (13.0 mg dLÀ1, reference hypercalcaemia (12.1 mg dLÀ1, reference interval interval 9.1–11.2), hypernatraemia (161 mmol LÀ1, 9.1–11.2) with mildly elevated ionized calcium reference interval 146–157) and hyperkalaemia (1.35 mmol LÀ1, reference interval 1.13–1.33), (5.3 mmol LÀ1, reference interval 3.5–4.8). Concern hypermagnesaemia (3.4 mg dLÀ1, reference inter- over potential renal insufficiency prompted À1 val 1.9–2.6) and hyperproteinaemia (11.7 g dL , change in chemotherapy to L-asparaginase reference interval 6.0–8.6). The cat was given 1 unit (Elspar, Merck, Whitehouse Station, NJ, USA) of packed red blood cells and was re-evaluated (400 IU kgÀ1 subcutaneous) and lomustine by the oncology service 1 week later. The owner (CeeNU, Bristol-Myers Squibb, Princeton, NJ, reported that the patient continued to have a very USA) (60 mg mÀ2 PO). One unit of packed red poor appetite and was extremely lethargic. The blood cells was transfused, and the cat was cat had a mild tachycardia (heart rate 160 minÀ1), discharged. Owing to continued deterioration in pale mucous membranes, grade II/VI systolic heart the patient’s condition, the cat was euthanized 1 murmur and the mass on the left tarsus. CBC week later. A necropsy was not performed. abnormalities included normocytic, normochromic anaemia (hematocrit 13.9%, reference interval À1 31.7–48.0) and thrombocytopenia (73.8 K mL , Discussion reference interval 175–500). Blood leucocyte count was 7.44 K mLÀ1 (reference interval 4.0–18.7), and Most of the veterinary literature regarding there were 5550 neutrophils mLÀ1 (reference interval plasma-cell neoplasia in cats is limited to case 2300–14000). The absolute blood lymphocyte count reports (Carothers et al., 1989; Forrester et al., was 1702 cells mLÀ1 (reference interval 800–6100), 1992; Larsen & Carpenter, 1994; Mandel & Esplin, and the majority of the lymphocytes were identified 1994; Eastman, 1996; Sheafor et al., 1996; Weber as plasmacytoid small lymphocytes or plasmacytoid & Tebeau, 1998; Zikes et al., 1998; Bienzle et al., lymphoblasts. (Bedford Laboratories, 2000; Hickford et al., 2000). One case report Bedford, OH, USA) (1 mg kgÀ1 intravenous) was described a cat with hepatic plasmacytoma and

ª 2004 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 2, 1, 36–42 40 A. Radhakrishnan et al. biclonal gammopathy; however, no evidence for a diagnosis of MM. The authors also suspect of bone marrow involvement was detected at that the bone marrow was infiltrated with plasma necropsy examination (Larsen & Carpenter, 1994). cells because the blood leucocytes were more than Another case report documented extramedullary 50% atypical plasma cells and the patient was plasmacytoma with monoclonal gammopathy and pancytopenic. Although cats frequently have soft- Ig-associated amyloidosis, although the cat had tissue involvement at the time of diagnosis of normal bone marrow cytology at the time of MM, to the authors’ knowledge, the documented necropsy examination. Also, the monoclonal gam- progression of a local tumour to systemic disease mopathy resolved after prednisone, melphalan and in a cat has not been previously shown. The evo- nandrolone decanoate chemotherapy (Carothers lution of an extramedullary plasmacytoma into et al., 1989). Another report described a cat with MM in this case is unusual. In dogs, it is known retroperitoneal extramedullary plasmacytoma and a that a solitary osseous plasmacytoma may develop monoclonal gammopathy that resolved after surgi- into systemic myelomatosis; however, cutaneous cal excision of the mass (Mandel & Esplin, 1994). plasmacytomas are not considered to be highly Bone marrow evaluation did not reveal any neo- metastatic (Vail, 2001). One case report exists of plastic cells. On subsequent necropsy examination, a with a cutaneous extramedullary plasmacy- serum protein electrophoresis and bone marrow toma that progressed to MM (Lester & Mesfin, evaluation did not definitively diagnose MM. A 1980), and the case reported here appears to be fourth case report involved a cat with a cutaneous unique for cats. The high histopathologic grade of plasmacytoma and osteolytic lesions, but mono- the tumour described here may account for the clonal gammopathy was not identified (Eastman, progression as this type of plasmacytoma may be 1996). There was evidence of metastasis of more aggressive, but one previous study was plasma-cell tumours at necropsy examination, but unable to correlate tumour cell morphology to a a diagnosis of MM was not established. prognostically relevant grading scheme (Platz et al., The case presented here illustrates some com- 1999). Furthermore, the patient described here had mon points for patients suffering from MM. This an IgA gammopathy that is another unusual fea- patient was ultimately diagnosed with MM by ture; IgG is the Ig found in most cats with virtue of a monoclonal gammopathy and Bence MM (Jacobs, 1994; Bienzle et al., 2000). Jones proteinuria, two common findings in MM Hypercalcaemia is common in humans and dogs (Matus & Leifer, 1985; Bienzle et al., 2000). Also, with MM but has been rarely reported in cats when the patient ultimately became symptomatic (Sheafor et al., 1996). Proposed mechanisms of for MM, the signs were non-specific (lethargy, hypercalcaemia in MM include increased produc- anorexia and weight loss). These signs have been tion of osteoclast-activating factors by neoplastic cited in previous case reports as the most common cells (MacEwen & Hurvitz, 1977; Drazner, 1982; presenting complaints in patients diagnosed with Sheafor et al., 1996; Bienzle et al., 2000) and direct MM (Drazner, 1982; Forrester et al., 1992; Sheafor osteolysis (Sheafor et al., 1996). Binding of calcium et al., 1996; Hickford et al., 2000). by myeloma proteins has been proposed as another Previous case reports differ from the one cause of hypercalcaemia; however, serum-ionized described here in that none had documented evi- calcium should be normal in this circumstance dence of a localized extramedullary plasmacytoma (MacEwen & Hurvitz, 1977; Matus & Leifer, 1985; progressing to MM. The cat in this case could not Dorfman & Dimski, 1992; Sheafor et al., 1996). be diagnosed with MM at initial examination with The increased secretion of osteoclast-activating serum electrophoresis, radiographs and bone mar- factors may be responsible for osteolytic lesions row cytology. Progression of disease in this cat was that are observed in MM (MacEwen & Hurvitz, established several months later based on the pres- 1977; Drazner, 1982). Renal disease has also been ence of Bence Jones proteinuria and monoclonal implicated as a cause of hypercalcaemia; however, gammopathy, which satisfies the requirement of at serum-ionized calcium should be normal to least two of the four previously discussed criteria decreased in this circumstance (Sheafor et al.,

ª 2004 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 2, 1, 36–42 Feline multiple myeloma and plasmacytoma 41

1996). Ionized calcium was measured in this abnormal Ig production in the setting of normal patient at presentation to the emergency service gamma serum protein levels (Kyle, 1975). (1.35 mmol LÀ1, reference interval 1.13–1.33). The Another limitation was the delay of clinical sta- mildly elevated ionized calcium concentration ging. Four months passed after the plasmacytoma suggests that the increased total calcium may have was diagnosed prior to the patient being examined been due to a paraneoplastic syndrome. by an oncologist, and another month passed Because MM is a rare disorder in cats, the efficacy before abdominal ultrasound examination was of treatment has been difficult to evaluate. Recom- performed. It is impossible to know the status of mended treatment is melphalan at 2 mg mÀ2 orally the iliac lymph node at the time of initial presen- once a day for 10 days, then every other day or, tation. Haemogram and serum chemistry results alternatively, 7 mg mÀ2 orally once a day for 5 days were available for that time period and were nor- (Weber & Tebeau, 1998). Melphalan is used in mal, suggesting progression of the disease over a combination with prednisone, 20 mg mÀ2 orally 6-month period. It is the authors’ clinical impres- once a day for 10 days, then every other day or, sion that this cat did not have MM at the time of alternatively, 5 mg once a day continuously. Clinical the initial staging because it survived for 6 months response is judged on the basis of reduction of without treatment. Bence Jones proteinuria and the serum monoclonal Plasma-cell leukaemia is a disease with clinical globulin spike and alleviation of haemogram features similar to MM (Bernasconi et al., 1989). It abnormalities (anaemia, thrombocytopenia and is also a malignant proliferation of plasma cells leukopenia). A decrease in Bence Jones proteinuria where greater than 20% of the differential leuco- is often the first sign of improvement, although cyte count or an absolute count of greater than reduction of M-proteins may take 1–2 months 2 109 cells LÀ1 in blood are plasma cells (Bernasconi (MacEwen & Hurvitz, 1977; Drazner, 1982). In et al., 1989). The cat described here satisfied dogs, the response rate is 92% for partial or com- this criterion. However, plasma-cell leukaemia plete remission and the median survival time is 540 typically involves the visceral organs, progresses days (Weber & Tebeau, 1998). In human patients, rapidly and has a much poorer prognosis when approximately 50% respond with a median survival compared with MM (Couto et al., 1984; Bernasconi time of over 2 years (Weber & Tebeau, 1998). In the et al., 1989). There has only been one case of plasma- cat described here, based on decreasing total protein cell leukaemia reported in the veterinary literature and globulin concentrations and an increase in the and that was in a dog (Couto et al., 1984). The neutrophil count, initial treatment with melphalan cat described here did not have organomegaly and prednisone appeared efficacious. Treatment on radiograph or ultrasound examinations, and it response, however, was transient as the blood dys- survived for 4 months after the was crasias returned and signs reappeared within 2.5 noted, which is atypical of plasma-cell leukaemia. months. In the authors’ opinion, the veterinary literature There are some limitations with the information suggests cats with plasmacytomas may develop presented in this case report. First, urine was not myelomatosis, yet no true documentation of the submitted at the time of first examination for phenomenon exists. This report describes a cat analysis. It is possible to have that developed MM from a localized extramedul- light-chain proteinuria despite normal serum pro- lary tumour. It is possible that this progression is tein electrophoresis (Hoenig & O’Brien, 1988; King not uncommon. We suspect that cases of feline et al., 2002). There is also the possibility that malig- plasma-cell neoplasia may not be diagnosed at an nant plasma cells existed in the bone marrow and early stage because of non-specific clinical signs, that the first sample of bone marrow was obtained variability in the course of clinical disease and from an area that was not infiltrated by plasma inconsistencies in results of diagnostic tests used cells. Indolent myeloma may be an explanation to diagnose MM. A greater understanding of this for this phenomenon, but clinical diagnosis of this syndrome is necessary in order to determine the phenomenon is difficult. It is also possible to have most appropriate therapy and long-term prognosis.

ª 2004 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 2, 1, 36–42 42 A. Radhakrishnan et al.

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