Plasma cells are a differentiated form of B lymphocyte derived from the bone marrow and are capable of producing immunoglobulins. Neoplastic transformation results in monoclonal plasmacytic tumours which can present in a variety of forms, each with differing biological behaviours. In canines they most commonly include extramedullary plasmacytomas (EMP), solitary osseous plasmacytomas (SOP) and multiple myeloma (MM).
Plasma cell neoplasms can often be easily diagnosed via cytology due to their characteristic cytological appearance (Figure 1); plasma cells typically have a deep basophilic cytoplasm, an eccentric nucleus and a perinuclear clear zone which houses the Golgi apparatus. However, histopathology may be required to diagnose plasma cell tumours in some circumstances, utilising immunohistochemistry (IHC) if the plasma cell tumour cannot be differentiated from other round cell neoplasms. IHC for MUM-1 (multiple myeloma oncogene-1) is the most consistent specific marker for plasma cells, although being B-cells, they can also label positively for CD79a and CD20. Labelling for vimentin is variable. Although less commonly exploited, PCR for antigen receptor rearrangement (PARR) can also be used to confirm B-cell clonality if needed.
This article will focus on the clinical presentation, diagnosis and management of canine EMP and SOP, while canine MM will be discussed in the second article of this two-part series.
Extramedullary plasmacytoma
The term extramedullary plasmacytoma is used to describe plasmacytic tumours arising in soft tissues. In dogs, EMPs most commonly arise in the skin (86 percent) followed by the oral cavity (9 percent) and the gastrointestinal tract (4 percent); with regard to the cutaneous form, they are most commonly located on the limbs and head (Vail, 2019). Generally, the cutaneous and oral plasmacytomas are considered to have a benign biological behaviour, whereas the gastrointestinal plasmacytomas follow a more aggressive clinical course. The two exceptions to this rule are cutaneous plasmacytosis (multiple cutaneous plasmacytomas in absence of MM) which has a more aggressive behaviour, and colorectal plasmacytomas which are generally less aggressive than other gastrointestinal locations.
Generally, the cutaneous and oral plasmacytomas are considered to have a benign biological behaviour, whereas the gastrointestinal plasmacytomas follow a more aggressive clinical course
Cutaneous plasmacytomas
Cutaneous plasmacytomas typically present as solitary masses on the head, limbs or trunk, without associated clinical signs. They are often raised, smooth and poorly haired to alopecic, and can be ulcerated (Figure 2). As already discussed, diagnosis via fine needle aspirate cytology should be straightforward. Biopsy for histopathology and IHC can be considered if needed although it is important to note that cutaneous histiocytomas, a differential diagnosis clinically and sometimes cytologically/histologically, can also label positively for MUM-1 (Stilwell and Rissi, 2018).
Due to their generally benign behaviour, further investigations and staging are not routinely performed for solitary cutaneous plasmacytomas. However, in cases with multiple masses concerning for cutaneous plasmacytosis, or those with other features such as hyperglobulinaemia concerning for a more systemic myeloma-related disorder, further investigations are indicated and will be discussed later.
Conservative excision is sufficient and should prove curative as local recurrence rates are less than 5 percent and completeness of excision does not seem to influence risk of recurrence
Treatment of cutaneous plasmacytomas should consist of surgical excision where possible. Conservative excision is sufficient and should prove curative as local recurrence rates are less than 5 percent and completeness of excision does not seem to influence risk of recurrence (Baer et al., 1989; Ehrensing and Craig, 2018; Rakich et al., 1989; Vail, 2019). If surgical excision is not possible (for example due to tumour location) then radiation therapy (RT) can be considered as 86 percent of dogs demonstrate a complete response to treatment with a recurrence rate of 17 percent (Elliott et al., 2020). Electrochemotherapy (ECT) is an alternative to RT with 100 percent of tumours demonstrating a complete response according to one small case series, with response durations reported between 90 and 515 days (Santos Dos Anjos et al., 2020).
Cutaneous plasmacytosis
Canine cutaneous plasmacytosis is rare and defined as three or more simultaneous cutaneous plasma cell tumours in the absence of multiple myeloma. It carries a more aggressive biological behaviour compared to solitary cutaneous plasmacytoma. The main study in the veterinary literature describes 21 cases and showed that around 70 percent of dogs have over 10 lesions; however, the majority (80 percent) remain asymptomatic (Boostrom et al., 2017).
As around 20 percent of cases have lymph node metastasis and 10 percent have suspected bone marrow involvement, thorough staging to rule out metastasis or a more systemic myeloma-related disorder is important (Boostrom et al., 2017). This should ideally consist of haematology, biochemistry, urinalysis, bicavity imaging (ideally via computed tomography (CT) to assess for lytic bone lesions) and bone marrow aspiration with or without core biopsy.
As around 20 percent of cases have lymph node metastasis and 10 percent have suspected bone marrow involvement, thorough staging to rule out metastasis or a more systemic myeloma-related disorder is important
If there are only a few cutaneous masses, without evidence of metastasis or systemic involvement, then surgery can be considered as a treatment option with progression-free intervals (PFI) of between 43 and 567 days reported. If there are a large number of masses or metastasis, then medical management is indicated. Single-agent melphalan is first-line treatment with a 74 percent overall response rate (ORR) and median PFI of 143 days reported. Lomustine can also be considered with a 71 percent ORR and median PFI of 84 days. Prognosis is guarded to fair, with a median survival time (MST) of 542 days reported with treatment (Boostrom et al., 2017).
Oral plasmacytomas
Oral plasmacytomas are most commonly located on the rostral mandible (46 percent), followed by the tongue (25 percent) and maxilla/hard palate (20 percent) (Wright et al., 2008). Similar to cutaneous plasmacytomas, oral plasmacytomas tend to demonstrate a benign clinical course so thorough staging and further investigations following diagnosis are not essential. Despite this, local recurrence rates can be high if adequate local tumour control is not achieved.
Treatment consists of surgical excision where possible, which can prove curative, and adjuvant RT should be considered in case of incomplete excision. Radiotherapy in the gross disease setting is also possible with a 64 percent complete response rate, 36 percent partial response rate and 27 percent local recurrence rate (Elliott et al., 2020). Electrochemotherapy has been reported in one case, which demonstrated a complete response and PFI of 515 days (Santos Dos Anjos et al., 2020). Although the MST reported for oral plasmacytoma is 474 days (with a range of 37 to 2,906 days) in one study, this is likely not representative as most dogs died of unrelated causes (Wright et al., 2008). The same study reported an MST of just 138 days for dogs with incomplete excision and no adjuvant therapy, highlighting the importance of adequate local control.
Gastrointestinal plasmacytomas
The limited literature surrounding gastrointestinal plasmacytomas in dogs precludes an accurate understanding of their behaviour. However, colorectal plasmacytomas are generally considered benign, whereas those arising from other sites (eg the oesophagus or small intestine) may be more unpredictable, necessitating more thorough work-up and staging.
In one small study of canine colorectal plasmacytoma, 56 percent of cases were solitary rectal tumours, 22 percent were solitary colonic tumours and 22 percent had both rectal and colonic tumours. Surgery is the treatment of choice, with an MST of 15 months (with a range of 5 to 33 months) reported for colorectal locations (Kupanoff et al., 2006). It should be noted, however, that this study reported MST rather than tumour-specific survival which may influence the results. It is expected that complete resection of colorectal plasmacytomas is curative in most cases. RT has been reported in one case of colorectal plasmacytoma with a complete response reported. The dog died 879 days later due to unrelated causes (Elliott et al., 2020).
Solitary osseous plasmacytoma
Solitary osseous plasmacytoma is rare, accounting for only 3 percent of all canine plasma cell neoplasia. It is defined by the presence of a solitary bone lesion with cytological/histological evidence of plasma cell neoplasia, in the absence of MM. Around 60 percent are located within the vertebral column, with other locations such as the maxilla, mandible, tibia and carpal bones reported (Reising et al., 2021; Rusbridge et al., 1999).
Clinical signs are mostly related to the presence of a lytic bone lesion and mass effect. Pain and, for vertebral SOPs, neurological signs such as ataxia and paresis are common. Diagnosis is based around the presence of a lytic bone lesion on radiographs or CT (Figure 3) in conjunction with cytological or histological confirmation of plasma cell neoplasia. Sampling of the bone lesion may require image-guidance, and it is important to note that in one study almost 70 percent of cases required immunohistochemistry to support the diagnosis (Reising et al., 2021). Further investigations, as outlined above, should be considered to exclude MM.
Treatment of canine SOP may depend on the accessibility of the bone lesion, presence/absence of pathological fracture and severity of clinical signs. The aim of treatment is to provide adequate local control which may require a combination of debulking surgery and adjuvant RT, especially for tumour locations that make complete excision challenging such as the vertebral body. Surgery alone may be possible in more accessible locations. RT has been used as a sole treatment and has been reported to provide clinical benefit in 100 percent of cases, although a radiographic improvement in the lesions may not be observed (Elliott et al., 2020). If surgery or RT are not possible then chemotherapy with melphalan could be considered but there is limited evidence about response rates or prognosis with medical management alone.
Due to the concern of future systemic progression of canine SOP, the question remains as to whether systemic chemotherapy (melphalan) should be started at the time of initial diagnosis
Around 60 percent of cases will progress despite treatment, with half developing new or additional bone lesions and half developing soft tissue lesions or demonstrating local progression, with an MST of 912 days reported (Reising et al., 2021). In humans around 50 percent of SOP cases progress to MM within 10 years, and many veterinary texts state that the majority of canine SOPs will also progress to MM. However, there is limited evidence to support this and of the 19 cases of canine SOP with adequate follow-up in the veterinary literature only three (16 percent) progressed to MM (Alcoverro et al., 2020; Elliott et al., 2020; Reising et al., 2021; Rusbridge et al., 1999). Due to the concern of future systemic progression of canine SOP, the question remains as to whether systemic chemotherapy (melphalan) should be started at the time of initial diagnosis. In humans there is no benefit to initiating chemotherapy prior to progression to systemic disease, and in dogs progression only occurs in a minority of cases and can take months or years to develop. Therefore, chemotherapy at diagnosis is not indicated to “prevent” or reduce the risk of future progression.
