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Dogs
Atypical, non-secretory presentation of multiple myeloma in a dog
  1. James William Elliott
  1. Oncology Department, Willows Referral Service, Solihull, UK
  1. Correspondence to Dr James William Elliott, jameselliott44{at}hotmail.com

Abstract

A 9-year-old, female-neutered West Highland White Terrier presented with a left forelimb lameness and maxillary oral mass. Radiography revealed a large, extensive aggressive bone lesion in the distal radius. CT scan revealed a large invasive oral mass and widespread skeletal osteolysis. Cytology and histology samples confirmed multiple myeloma. Haematology and biochemistry revealed no typical changes, including an absence of hyperglobulinaemia. There was no monoclonal gammopathy detected on protein electrophoresis.

  • Oncology
  • Chemotherapy
  • Dogs

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Background

  • Multiple myeloma (MM) is a relatively rare, diffuse plasma cell neoplasia in dogs.

  • Almost all reported cases have serum hyperglobulinaemia due to immunoglobulin production (which is usually monoclonal) by neoplastic cells.

  • Non-secretory MM, where serum globulin is within the reference interval, is very rarely reported in dogs, and in some of these cases a monoclonal gammopathy can still be detected with protein electrophoresis.

Case presentation

A 9-year-old, female-neutered West Highland White Terrier presented with a 1-week history of mild left forelimb lameness. Resentment to palpation was localised around the carpus. There was complete resolution of the lameness with meloxicam (Metacam Oral Suspension for Dogs), but the lameness recurred on cessation of the drug. Resolution of the lameness occurred again when meloxicam was recommenced, but after 2 weeks, the lameness recurred when the drug was stopped. The dog was fully vaccinated, wormed and there was no travel history. There was no reported trauma.

Physical examination revealed a 2 cm smooth, well-demarcated mucosal mass caudal and medial to the right upper canine tooth that appeared to be soft, spongy and friable with some subtle surface haemorrhage (Fig 1). There was a moderate left forelimb lameness and discomfort on palpation of the left carpal region. There was also severe discomfort on lifting the tail dorsally during physical examination (to examine the perineum), but no palpable abnormalities could be found to explain this in the surrounding area. No other abnormalities were detected.

FIG 1:

Oral mass diagnosed on cytology and histology as plasmacytoma

Investigations

Under sedation, lateral and craniocaudal radiographic views were taken of the left distal limb, centred on the carpus. This revealed an aggressive bone lesion affecting the distal radius characterised by a mixture of lysis (including cortical lysis) with sclerosis and some surrounding marked periosteal reaction. There was no involvement of the carpal joint. Right and left lateral thoracic radiographs were performed to assess for pulmonary metastatic disease and were unremarkable.

Differential diagnosis

The radiographic lesion was highly consistent with a primary bone tumour (eg, osteosarcoma, chrondrosarcoma, fibrosarcoma, haemangiosarcoma, histiocytic sarcoma) though other causes of aggressive bone lesions include bacterial or fungal infection and much less likely benign bone neoplasia. Also, other less common neoplastic causes (solitary osseous plasmacytoma (SOP)) or metastatic disease are possible differentials. Differential diagnosis for the oral mass included amelanotic melanoma, squamous cell carcinoma, fibrosarcoma or other less common neoplastic diseases. Less likely differentials included haematoma, granuloma inflammatory disease or benign tumours (eg, acanthomatous ameloblastoma or fibromatous epulis).

Further investigation

CT scan was performed of the head, left forelimb, thorax and abdomen for better characterisation of the extent of the left radius lesion and oral mass to investigate the severe tail-base pain and as a staging tool given the likely neoplastic disease(s).

This revealed a soft tissue mass in the rostral maxilla causing extensive underlying bony lysis. The mass was expansile and invaded the alveolar bone and nasal cavity, resulting in marked disruption of the local hard palate (Fig 2). There was also a similar but much smaller mass in the region of the left carnassial that was not visible clinically. A third lesion was present just deep to the hard palate overlying the choanae. An extensive lytic/osteoproductive lesion was present in the left distal radius corresponding to the previously noted lesion on plain radiography (Fig 3). Multiple, 1–9 mm lytic lesions of variable radiographic attenuation were present throughout the skull, ribs, left femur and various vertebrae. An expansile soft tissue lesion centred on the bone was present within the sixth coccygeal vertebrae causing marked cortical lysis (Fig 4).

FIG 2:

CT image of the large, aggressive bone lesion in the left distal radius, cytology confirmed plasma cell tumour

FIG 3:

CT image of the marked cortical lysis of coccygeal vertebrae 6; cytology confirmed plasma cell tumour

FIG 4:

CT image of the oral mass diagnosed as plasmacytoma on cytology and histology showing invasion into the nasal cavity with extensive permeative lysis of the nasal and maxillary bones

Haematology, biochemistry and urinalysis were unremarkable. Serum and urine protein electrophoresis were performed as MM was suspected based on the presence of polyostotic nature of the bony lesions. This revealed no monoclonal (or oligoclonal) gammopathy.

Fine-needle aspiration of the oral mass, distal radius lesion, one rib lesion and the coccygeal vertebral lesion were examined by a boarded clinical pathologist, and all revealed the same findings. There was a large population of round cells with a large eccentric nucleus, often with a perinuclear clear zone with moderately abundant deeply basophilic cytoplasm. The nuclei contained open, coarse chromatin with 2–3 nucleoli. There were occasional bi- or multinucleated forms. They were consistent with atypical plasma cells with a morphology consistent with immature myeloma/plasmablastic myeloma.

Subsequent histology (punch biopsy) of the oral mass confirmed the diagnosis of plasma cell tumour. No immunohistochemistry was performed as the diagnosis was categorical on plain H&E section. PCR for antigen-receptor rearrangements (PARR) performed on the cytological smears revealed a monoclonal B-cell population confirming neoplasia.

While awaiting cytology and histology results, the dog was continued on meloxicam orally and also given paracetamol 13 mg/kg orally three times a day (Paracetamol, M&A Pharmachem, UK) and tramadol 5.3 mg/kg orally twice a day–three times a day (Tramadol Bristol Laboratories Ltd, UK) for analgesia.

The final diagnosis was non-secretory, MM.

Outcome and follow-up

The dog was started on chemotherapy with melphalan (Melphalan, Aspen, Ireland) at 2 mg (4.1 mg/m2) orally on alternate days and prednisolone (Prednidale, Dechra, UK) at 20 mg orally daily.

After 3 weeks, there was dramatic clinical improvement with complete resolution of the lameness and a 75 per cent reduction in size of the oral mass. The dog freely moved the tail with no pain on manipulation. The owners reported that there was also a general improvement in demeanour. Haematology revealed no abnormalities.

After eight weeks of therapy, there was resolution of the oral mass and no haematological or biochemical abnormalities. Chemotherapy is being continued with melphalan at 2 mg orally every third day with prednisolone 10 mg orally on alternate days. No analgesia is being given.

Discussion

MM is a relatively rare diffuse plasma cell neoplasia that is well documented in dogs (Matus and others 1986). These dogs can present in a multitude of ways, often due to bone pain because of tumour-induced bony lysis (which can be multifocal) or because of complications secondary to hyperglobulinaemia such as blindness or neurological problems (Osborne and others 1968; Finnie and Wilks 1982; Matus and others 1986).

The normal role of plasma cells is to produce immunoglobulin (Ig), and the vast majority of neoplastic plasma cells retain the ability to do this. This results in serum hyperglobulinaemia in almost all canine MM cases (Matus and others 1986). Usually, because the tumour cells are derived from one malignant clone, serum protein electrophoresis (SPE) reveals a monoclonal gammopathy; though bi- or oligoclonal myeloma-like disorders have been described in dogs (Ramaiah and others 2002). While it has only been very rarely described in dogs (Marks and others 1995; Souchon and others 2013), non-secretory MM is well documented in humans due to neoplastic plasma cells that do not secrete immunoglobulin (Khan and others 2008; Maruyama and others 2013). As in this case, SPE should be performed in cases even when the serum globulin is within the normal reference range as monoclonal gammopathy can still be detected (Seelig and others 2010). In this case, the electrophoretic trace was normal, implying no detectable Ig production from the neoplastic cells.

Polyostotic bone lesions due to lysis by the diffuse neoplastic cells in the bone marrow occur in a large number of dogs, as in this case (Matus and others 1986). This is likely to have been causing the tail pain (coccygeal vertebral lesion) and left forelimb lameness (distal radius lesion) given these were two of the most severe radiographic lesions. Unfortunately the extent of osteolysis in this case may be a negative prognostic factor.

It is unusual, in the author's experience, for dogs to present with such large bony lesions in canine MM and typically multifocal small lesions are more common. This is an interesting feature of this case as clinicians may fail to consider the possibility of myeloma when such a large, apparently solitary, bony lesion is present, particularly in the absence of any other clinical clues such as hyperglobulinaemia. Indeed, many such cases with solitary aggressive bone lesions with normal chest radiographs are presumed osteosarcomas and amputation is performed, which would have been inappropriate in this case given the disseminated disease and alternative systemic chemotherapy options. This perhaps implies that at least a fine-needle aspirate should be obtained from radiographically aggressive bony lesions prior to making treatment decisions to exclude non-sarcomatous lesions for which other staging, testing or therapeutic options may be considered (Britt and others 2007). Dogs can develop SOPs without the typical MM manifestations; however, reportedly most go on to develop MM later in the course of the disease (Lester and Mesfin 1980; Rusbridge and others 1999) though these are rare. It may be that the reason for such a large mass in the left distal radius is that it was the primary site for the disease with subsequent dissemination to ‘true’ MM. Given the short-term nature of the lameness and the widespread, established nature of the lesions elsewhere in the body, it seems probable that the radial lesion is simply part of a simple case of MM, though it is impossible to be sure. It is noteworthy that while SOP is a possible differential based on the radiographic features alone, one might not expect a mixed lytic/sclerotic lesion, but one that is predominantly osteolytic. This is another atypical feature of this case.

Plasmacytomas are reported to occur in the oral cavity; however, it is rare for them to occur as part of MM. Indeed, typically they are solitary and have an excellent prognosis with surgery and/or radiation (Wright and others 2008; Smithson and others 2012; Culp and others 2013). Similar to the case for the radius lesion being the primary site, this is plausible also for the oral mass, but it is just as possible that it is one of the multifocal lesions of MM in a slightly atypical site and of atypical appearance. It is possible that the dog had two concurrent plasma cell malignancies: a solitary extramedullary plasmacytoma in the oral cavity and MM, as has been previously reported (Chen and others 2012).

The clonality test (PARR) was performed due to the atypical presentation of the case, including lack of the usual monoclonal hyperglobulinaemia±Bence–Jones proteinuria or any haematological/biochemical changes (eg, neutropenia, hypercalcaemia, azotaemia). The positive PARR result is highly specific for neoplasia in B-cell lymphoproliferative disorders and helps confirm the MM diagnosis (Avery 2012), though by itself still leaves lymphoma as a possible differential diagnosis. It is PARR in combination of clinical features of the case and cell morphology that confirmed the diagnosis of MM (ie, a plasma cell tumour).

Typically, a diagnosis of MM can be made by fulfilling at least two of the following criteria (Matus and others 1986):

  1. radiographic evidence of osteolysis

  2. >20% plasma cells in the marrow

  3. monoclonal gammopathy on SPE

  4. Bence–Jones proteinuria

Given the widespread osteolysis on CT, histological diagnosis of plasma cell tumour on biopsy of the oral mass, multifocal demonstration of >20% plasma cells (with atypical appearance) at several bony sites and demonstration of a clonal B-cell population, the diagnosis of MM is considered very robust despite a lack of some of the more classical MM features.

Dogs typically respond well, as in this case, to melphalan and prednisolone chemotherapy (Matus and others 1986). This is a very minimally invasive option for these patients, and only approximately 8% of dogs do not show either a complete or partial response (Matus and others 1986). Median survival times are generally lengthy; with 540 days being reported. Several negative prognostic factors have been reported in dogs with MM, including particularly extensive bony lysis, hypercalcaemia and Bence–Jones proteinuria (Matus and others 1986).

Because it is so rarely reported in dogs, there is no indication as to what impact non-secretory MM may have on prognosis. However, in humans, it does not seem to have a negative impact, and in some reports survivals may be more protracted (Fonseca 2013). Frustratingly monitoring response to therapy may be more difficult as typically this is performed by assessing serum globulins. It may however still be worth monitoring globulins in the future as it is plausible that the neoplastic cells may become secretory; though this does not appear to occur in humans with non-secretory myeloma (Lonial and Kaufman 2013). The oral mass and lameness may however allow some objectivity with regards to monitoring chemotherapy responsiveness and remission status.

The response to treatment so far in this case is pleasing, though unfortunately most cases will relapse in the future with recurrence of the same or similar signs (Matus and others 1986).

References

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Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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