Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmacytoma

Most patients with plasma cell neoplasia have generalized disease at diagnosis, i.e. multiple myeloma (MM). However, a minority (<5%) of patients with plasma cell malignancies present with either a single bone lesion, or less commonly, a soft tissue mass, of monoclonal plasma cells: solitary bone plasmacytoma (SBP) or extramedullary plasmacytoma (SEP). SBP has a high risk of progression to MM and on magnetic resonance imaging (MRI) examination at least 25% of patients with an apparent solitary lesion have evidence of disease elsewhere (Moulopoulos et al, 1993). In contrast, SEP is nearly always truly localized and has a high cure rate with local treatment. The diagnosis and management of patients with solitary plasmacytoma requires the same range of clinical and laboratory expertise as for patients with MM (UK Myeloma Forum, 2001). The primary treatment for most patients will be radiotherapy, but surgery may also be required, where close liaison among the haematologist, radiotherapist and surgeon is crucial for planning optimum care. A literature search was performed by a professional librarian using MEDLINE and EMBASE from 1996 to March 2002. A search was made for randomized-controlled trials involving plasmacytoma, papers where plasmacytoma was the major focus of the paper and reviews where plasmacytoma was the major focus. The literature was then reviewed by the subgroup of the Guidelines Working Group of the UK Myeloma Forum. Levels of evidence and grades of recommendation are shown in Table I. SBP and SEP are rare diseases and most of the evidence relates to retrospective data from patient series collected over long periods of time. Very few formal clinical trials have been performed. The majority of the recommendations given are therefore based on consensus of expert opinion. Epidemiology and clinical features. Solitary bone plasmacytoma has a male:female ratio of 2:1, with a median age of 55 years and primarily affects the axial skeleton especially the vertebrae (see Table II) (Dimopoulos et al, 2000). Malignant bone tumours of the spine are extremely rare (<0·05% of primary neoplasms). Solitary plasmacytoma is the commonest separate entity within this group, accounting for approximately 30% of the total (McLain & Weinstein, 1989). These tumours occur in the spine twice as often as other bony sites (Chang et al, 1994). The commonest symptom is pain but it can also present with cord or root compression. Involvement of the base of the skull can present with cranial nerve palsies (Vaicys et al, 1999; Vijaya-Sekaran et al, 1999). Localized amyloidosis can be a feature of both SBP and SEP (Pambuccian et al, 1997; Nagasaka et al, 2001). As well as the appropriate blood and urine tests (see below), specific imaging of the spine is required and best achieved by MRI ± computed tomography (CT). Bone scans are unreliable. Biopsy is usually possible percutaneously, guided either by fluoroscopy or CT. The presence of a monoclonal paraprotein (M protein) has been reported in 24–72% of patients in different series (Dimopoulos et al, 2000). The frequency probably depends on the level of sensitivity of the tests used. In a recently reported series of 60 patients from the MD Anderson Hospital presenting between 1995 and 2000 (Wilder et al, 2002), a serum or urinary paraprotein was detectable in 43 patients (62%) by routine electrophoresis or immunofixation/immuno-electrophoresis. However, the levels of paraprotein were generally low. Of the 37 patients who had a serum paraprotein, only 11 had levels over 10 g/l and the highest level was 22 g/l. In the six patients who only had Bence Jones protein in the urine, total daily excretion of urinary-free light chain was below 100 mg/d in all patients. Natural history and prognosis. The majority of patients with apparent SBP develop myeloma, with a median time to progression of 2–4 years (Table II). The median overall survival in different series varies from 7·5 to 12 years (Dimopoulos et al, 2000). Most reported series extend over a long time period and the majority of included patients have not had MRI scans. These patients will therefore include a proportion of patients with asymptomatic myeloma. The progression-free and overall survival in patients with SBP may improve as MRI examination becomes an established part of the staging criteria for the diagnosis and patients with early MM are excluded. Quoted adverse prognostic features for progression to MM include low levels of uninvolved immunoglobulins, axial disease, older age, lesion size >5 cm and persistence of the M protein after treatment (Bataille & Sany, 1981; Holland et al, 1992; Tsang et al, 2001). However, these adverse prognostic features have not been consistent between series (Chak et al, 1987; Frassica et al, 1989; Bolek et al, 1996; Liebross et al, 1998). A recent multivariate analysis of prognostic factors in a series of 60 patients from the MD Anderson Hospital (most of whom were not staged by MRI) concluded that persistence of M protein for more than 1 year after radiotherapy was the only independent adverse prognostic factor (Wilder et al, 2002). The paraprotein disappeared in 13 patients and persisted in 32, while 15 patients had non-secretory disease. At a median follow-up of 7·8 years, only one of 13 patients with resolution of the paraprotein progressed to MM while over 90% of patients with persistent paraprotein had progressed. Most patients with persistent M protein progressed to MM within 2 years of treatment. Age, tumour size and level of paraprotein at diagnosis had no independent prognostic value. In this series, patients with non-secretory disease appeared to do less well than those with a paraprotein that disappeared after radiotherapy. As already indicated, it is likely that many of the patients with apparent SBP who progress actually have disseminated disease at presentation. MRI examination of the spine can detect occult disease in approximately 26% of patients with apparent SBP (Moulopoulos et al, 1993; Wilder et al, 2002). Conversely, a negative MRI of the spine is a good prognostic feature. Liebross et al (1998) showed that in a series of 15 patients with a spinal plasmacytoma who did not have a positive MRI examination, progression to MM occurred in seven of eight patients where MRI had not been performed as opposed to one of seven with a negative MRI of spine (patients with other lesions on MRI were considered to have MM). Positron emission tomography (PET scanning) has recently been evaluated in the staging of patients with myeloma and plasmacytoma (Orchard et al, 2002; Schirrmeister et al, 2002). PET scanning, like MRI, appears to be useful in detecting occult disease in patients with apparent solitary SBP. Those patients with SBP who do subsequently develop MM have a relatively good prognosis. Liebross et al (1998) reported that their patients with SBP who progressed to MM were characterized by low tumour mass, 77% response rate to chemotherapy and a median survival from progression of over 5 years. Patients progressing to MM should be treated according to the British Committee for Standards in Haematology (BCSH) guideline on the management of MM (UK Myeloma Forum, 2001). In addition, patients presenting as SBP but found upon MRI scan to have more extensive disease should be considered as having MM and treated accordingly (see below). Diagnostic criteria. Recommended diagnostic criteria are summarized in Table III. Based on the data discussed above, the following criteria are recommended: single area of bone destruction due to clonal plasma cells; histologically normal marrow aspirate and trephine (<5% plasma cells); normal results on skeletal survey, including radiology of longbones; no anaemia, hypercalcaemia or renal impairment due to plasma cell dyscrasia; absent or low serum or urinary level of monoclonal immunoglobulin (level of >20 g/l suspicious of MM, see above); no additional lesions on MRI scan of the spine (see below for criteria of involvement). Pathology review. Solitary bone plasmacytoma is generally diagnosed by biopsy or fine needle aspiration. Percutaneously guided biopsy of the spine is usually possible either by fluoroscopy or CT. As these tumours are rare, pathology review by a histopathologist with a special interest in either bone tumours or lymphoproliferative disorders is strongly recommended. Further investigations. The following investigations should be performed in all patients: full blood count; biochemical screen including electrolytes and corrected calcium; serum immunoglobulin levels; serum and urine protein electrophoresis and immunofixation; full skeletal survey, including standard X-rays of the skeleton including lateral and anteroposterior cervical, thoracic and lumbar spine, skull, chest, pelvis, humeri and femora (UK Myeloma Forum, 2001); MRI of thoracic and lumbar spine; bone marrow aspirate and trephine. Additional investigations may be useful in selected patients, including MRI of pelvis, proximal femora and humeri; immunophenotyping and molecular assessment of bone marrow plasma cells; PET scanning. The role of β2 microglobulin in the diagnosis and management of SBP has not been established. There are, at present, no data on the use of the serum-free light chain assay in SBP. MRI examination. There are no reported guidelines to define involvement on an MRI scan in the context of apparent SBP. However, the MRI appearances in MM have been well described (Baur et al, 2002). The presence of one or more foci of abnormal signal intensity [low on T1 weighted imaging and high on T2 weighted or STIR (Short TI Inversion Recovery) images], which enhance after the administration of paramagnetic contrast in the absence of known recent compression fractures, other primary malignancy or typical characteristics of benign or malignant primary bone tumours, is considered evidence of distant involvement in patients with apparent SBP (M. Dimopoulos, personal communication). Radiotherapy. This subject has recently been reviewed (Hu & Yahalom, 2000). Radical radiotherapy is the treatment of choice for SBP. In common with other rare tumours, the evidence base for treatment is largely composed of retrospective studies of small numbers of patients. Progression to MM is common, despite high local control rates of 83–96% achieved with moderate doses of radiotherapy (Mayr et al, 1990; Holland et al, 1992; Bolek et al, 1996; Liebross et al, 1998; Tsang et al, 2001). Data on dose–response relationships are weak in most series, due to relatively low patient numbers and narrow range of doses used. Mendenhall et al (1980) recommended a minimum dose of 40 Gy following a dose response analysis based on a review of the literature including 81 patients. They reported a 6% local failure rate in patients with SBP treated with doses of 40 Gy or above, in contrast to 31% for doses below 40 Gy. Some centres prefer to use higher doses of 45–50 Gy (Mayr et al, 1990; Liebross et al, 1998), but is evidence for a dose response 40 Gy and local have been reported after doses of Gy (Mayr et al, 1990; Liebross et al, 1998). Tsang et al reported the Hospital of patients with SBP treated between and and concluded that was no dose–response Gy. They reported that tumour was the most factor local control with local control for SBP of 5 cm or less and only for SBP >5 data that SBP of >5 cm requires a higher dose treatment for local This is by other (Mayr et al, 1990; Holland et al, Based on the evidence above, a dose of 40 Gy in is recommended for SBP of 5 cm or SBP >5 a higher dose of to Gy in should be for tumours >5 cm is chemotherapy by radiotherapy. This is but is evidence to The choice of clinical for radiotherapy is also Some that the bone should be treated (Mayr et al, The for this is largely based on in retrospective series treated MRI bone marrow and soft tissue of SBP for radiotherapy recent series local control rates following of the tumour on MRI scan with a than the bone et al, 1997; Liebross et al, 1998; Tsang et al, 2001). The clinical should include tumour that is on MRI with a of at least 2 small as this will include the bone with one uninvolved and the clinical will not include the as this of normal of response following radiotherapy depends upon in levels of monoclonal resolution or progression of and evidence of disease on Patients monoclonal protein with treatment a with a high of cure (see while many of those with persistent paraprotein after 1 year will develop In contrast, on imaging are to and do not with et al, 1998). In of patients the monoclonal protein with radiotherapy. The monoclonal protein usually but the can be years. persistence and level are not an for treatment but these patients should be for of disease Some patients to an monoclonal of Patients not to radiotherapy do not have They may have persistent as a of bone while paraprotein may disease at other In these a biopsy is to the is recommended that SBP is treated with radiotherapy, the tumour shown on MRI with a of at least 2 cm and to a dose of 40 Gy in based on level SBP >5 a higher dose of to Gy in should be considered based on level Patients with SBP to detect progression to MM, for with of of and should be in with laboratory investigations serum and urine paraprotein based on level Patients not to radiotherapy (see should be treated with A is to guidelines for the treatment of MM (UK Myeloma Forum, 2001). In patients, this include high dose and cell based on level Patients presenting as SBP but found on MRI to have disease at other sites should be considered as having MM and treated accordingly based on level the treatment of choice of the primary pathology and surgery is in the absence of or However, early diagnosis and for a is in most with spinal to the of spinal over the treatment is a and for patients who develop pain by within the or a of A of have been recently this et al, 1997; et al, 1998; et al, 2001). of requires of and this is most performed by In of is also surgery usually best to the a to the which can occur in i.e. et al, 2000). to the high of survival in these patients (McLain & Weinstein, of the of the spine may be and have been used. As are no data to the of from the of the to be more The relatively of et al, 2002), which has been with in MM, has not been reported in solitary is in of of in solitary plasmacytoma with is likely to be of given in most the of destruction the The choice of surgery and to be to the specific of on as and of and of the and the and of the in of and pain have been reported in small series in the using this et al, 1998; et al, 1998). is often recommended that surgery is required or in the it should be radiotherapy is is more in patients who have radiotherapy. However, it is to that surgery may radiotherapy, by the of which may of disease from liaison between haematologist, radiotherapist and surgeon is therefore crucial in planning optimum treatment for patients. the treatment of choice for SBP and surgery is in the absence of or based on level surgery is required radiotherapy should also be given and the of surgery to radiotherapy should be for patient based on level In of spinal plasmacytoma, for an from an surgeon or in spinal surgery is based on level of the may be based on level The role of chemotherapy is at present not & & Yahalom, 2000). The of chemotherapy to radiotherapy in the treatment of SBP be in local control and or progression to Some that chemotherapy may progression to MM (Mayr et al, 1990; Holland et al, However, no et al, Tsang et al, 2001). one randomized-controlled has been This from and given for years after radiotherapy et al, a median follow-up of years, 15 of patients in the radiotherapy progressed to myeloma with only of patients in the treatment between the of patients showed a survival for this was a randomized-controlled the of patients was The results therefore to be by studies that chemotherapy is in of of and There are data to chemotherapy in SBP. may be appropriate to chemotherapy in patients at higher risk of treatment those with disease based on level The literature search no with the role of in the management of There are, as no reported data on the role of in progression of asymptomatic myeloma or SBP. is an Group to the of in these et al, at the present time an recommendation be is interest in the role of in plasma cell has been in the treatment of soft tissue plasmacytoma in the context of MM et al, and is in the of asymptomatic myeloma but are no data on in SBP. Patients that present as SBP but are found upon MRI scan to have more extensive disease marrow should be considered as having However, the plasmacytoma is the only of clinical and is no other involvement it be appropriate to the plasmacytoma according to the guidelines and to chemotherapy are of as the UK Myeloma Committee for Standards in Haematology guidelines for myeloma (UK Myeloma Forum, 2001). Solitary extramedullary are less common than SBP but a as the majority can be by local radiotherapy (Dimopoulos et al, 1999). SEP can the 90% in the and especially in the including the and et al, 1990; et al, 1993; et al, 1997; Liebross et al, 1999; et al, 2000). The most is the A of other sites can be including and et al, 1990; et al, 1990; et al, 1992; et al, 1992; et al, et al, 1996; et al, 1996; & 1996; et al, 1999; et al, et al, 2001). A monoclonal paraprotein is in the serum urine in than 25% of patients (Table II). rates of have been after radiotherapy et al, 1999). The risk of distant appears to be i.e. less than with SBP (Mayr et al, disease may present as MM, SBP or soft tissue involvement of or distant this to be within years of At least of patients for years et al, 1990; et al, 2000). Diagnostic criteria. or MRI is required to the of the lesion but the role of MRI of other in the staging of SEP has not been As is a low risk of progression to MM in these patients and the role of MRI in the staging of SEP has not been do not MRI of the spine to be for the diagnosis of Recommended diagnostic criteria are shown in Table III. Pathology review. most patients the diagnosis can be established by fine needle or biopsy et al, As these tumours are rare, and can be with pathology review by a histopathologist with a special interest in lymphoproliferative disorders is strongly recommended. As above, or MRI is required to the of the lesion but do not MRI of other (see to be investigations should be as for SBP (see Radiotherapy. Solitary extramedullary plasmacytoma are control rates of are reported with moderate doses of radiotherapy (Mayr et al, 1990; Bolek et al, 1996; et al, 1997; Liebross et al, 1998). dose and should be to early and and local There is no established dose–response of small patient series and low local failure Tsang et al achieved local control in 13 of of patients with Gy. The only failure was in a patient with a primary tumour >5 et al achieved local control in six of seven patients with Gy dose 40 Gy in The only failure was in a patient with an extensive dose–response was Holland et al also reported local control in tumours >5 cm and no evidence of a dose–response over a dose range of Gy dose series local control Bolek et al reported local control in 10 patients with doses from to Gy dose and concluded by a dose of 40 Gy in et al reported on 10 patients with seven of whom were treated by radiotherapy, using doses of Gy. control was achieved in all the patients, the that local control have been achieved with The dose therefore appears to be in the range of Gy. SEP cm have an of local control with doses in the of 40 Gy in is a higher risk of local failure in tumours >5 which a higher dose in the of Gy in The radiotherapy is SEP in the or of to in of et al, 1997; & Yahalom, 2000). The of in the to and especially which may not local control rates are reported the are included et al, However, good results are also reported from series in which the are only included Tsang et al the primary in patients primary was in the tissue of the were There were no in patients. et al the primary only in seven patients and reported no et al treated the primary only in patients and only included the in patients with clinical no In contrast, et al reported in of 11 patients treated to the primary only and recommended In of the of and the high local control rates reported the of evidence a of the primary with a and including the only or as at high as in primary sites involving Solitary extramedullary plasmacytoma should be treated by radiotherapy the primary tumour with a of at least 2 cm based on level The should be included The should be included in SEP of based on level SEP to 5 cm a radiotherapy dose of 40 Gy in is recommended. SEP of >5 a higher dose of to Gy in is recommended based on level The majority of SEP occur in the and is generally not required for Radical surgery with is a generally that is not as the tumours are generally and the majority of patients are with radiotherapy. patients with SEP in other should be A review of the literature by et al the of patients treated with surgery radiotherapy or surgery and radiotherapy. They found of involving the and in other Most of the patients were treated with surgery or treatment and only were treated with radiotherapy The risk of was the same for the treatment is not the patients that a did of the most of the patients with SEP in the were treated with radiotherapy or radiotherapy and surgery surgery was in and survival were in those treated with They concluded that patients with plasmacytoma from a However, this review is to as it a to and radiotherapy was not in for at least of this are likely to have been between the patients treated by the different There is therefore no good evidence that surgery additional over radiotherapy in patients with SEP of the and is in the majority of patients. However, patients have been treated by primary radiotherapy only be required in patients with In contrast to radiotherapy can be following surgery as are not in this is the treatment of choice for and SEP based on level Radical surgery should be in and SEP based on level SEP at other sites should be considered based on level Patients with should radiotherapy based on level recommendation for radiotherapy can be made for patients who have with negative There is no evidence on the role of chemotherapy in the treatment of may have a role in selected patients. et al a higher failure rate in tumours using the MM criteria of et al Tsang et al and Holland et al that tumours >5 cm are at higher risk of chemotherapy should be considered in patients with tumours >5 cm and those with high tumours based on level is for patients with disease. as for MM is based on level treatment There is no and no data the use of in has been to extramedullary plasmacytoma in the context of MM with results et al, et al, et al, but is no data on use in of appropriate patient and an part of the of patients with SBP and are the same as those for patients with myeloma (UK Myeloma Forum, 2001). The Myeloma a for patients with solitary The and in these guidelines is to be and at the time of to However, the the British for Haematology and the do not or for or that may have been are to for with the literature with the of an from the Myeloma