Solitary Plasmacytoma 

Sara Grammatico, Emilia Scalzulli and Maria Teresa Petrucci

Hematology, Department of Cellular Biotechnologies and Hematology, “Sapienza” University, Rome, Italy

Published: August 23, 2017
Received: May 16, 2017
Accepted: July 21, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017052 DOI 10.4084/MJHID.2017.052
This article is available on PDF format at: 

Incidence, Signs and Symptoms and Diagnostic Criteria

Solitary plasmacytoma (SP) is an uncommon type of plasma cell (PC) dyscrasia that accounts for approximately 2-5% of all PC disorders.[1-3] It is characterized by a localized proliferation of neoplastic monoclonal PCs, with no radiologic evidence of additional skeletal lesions, absence of signs and symptoms of multiple myeloma (MM), present in the CRAB manifestation (hypercalcemia, renal insufficiency, anemia and/or bone lesions), and a bone marrow examination  morphologically normal or having a very low clonal PC infiltration (less than 10%).[4,5]
Due to the rarity of this disease, there are few studies about it and not a true consensus about the prognostic factors and treatment. Here, a literature review was performed to identify relevant articles about SP. PubMed, National Guideline Clearinghouse Cochrane Database of Systematic Reviews and ClinicalTrials.gov electronic databases were used for the search. Also oncology and hematology conference proceedings (European Hematology Association (EHA), American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH) and International Myeloma Working Group (IMW) were used. The search was restricted to documentation published in human subjects. Case reports were excluded.  In Table 1 A and 1 B the key points of the most relevant articles (limited to those published over the last 20 years) are summarized.

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Table 1A.  Keypoints of the most relevant articles from 1999 to 2009.

Figure 1B. Keypoints of the most relevant articles published in the last decade.

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SP can be subdivided into two entities: solitary bone plasmacytoma (SBP) and solitary extramedullary plasmacytoma (SEP), depending on whether the lesion originates in bones or soft tissues.[6] The incidence of SBP is approximately 40% higher than SEP.[3]
The median age at diagnosis of SP is 55-60 years, significantly lower than in MM patients; the male to female ratio varies from 1,2:1 to 2:1.[3,6-10]
Some authors report a higher incidence rate of SP in the black race, around 30% more than white race;[3,9,10] African American to Caucasian incidence rates ratio to develop SP was found to be approximately 1.25/1.30. [9,10] Incidence in Asian population is lower than previous ones; however, its cohort of patients studied is small (about 5.4%).[3] In fact, it is important to consider that the majority of studies refer to a predominantly Caucasian population.
SBP most frequently occurs in the axial skeleton, such as a vertebra, while SEP is observed in the head and neck, and these two entities have a clinical course and prognosis that are quite different from each other.[2,3,5-7,11-17]
All these data reported are prevalently based on historical studies; there are few series reported in the most recent years. However, last year, de Waal et al. reported the experience between 1988 and 2011 in the northern area of the Netherlands about 76 SP patients, confirming the historical data. Median age was 61 years (range 26–87), and 60% were male; 66% had an SBP, localized in the axial skeletal in 78% of these patients. In the SEP patients, the plasmacytoma was most frequently located in the oropharynx or nasopharynx (65%).[18]
In the largest and most recent cohort analyzed, Thumallapally et al. published a retrospective study of 1691 SP diagnosed in the United States of America (USA) from 1998 to 2007, analyzing and reporting data from the Surveillance, Epidemiology and End Results (SEER) database, a population-based registry in the USA. The median age at diagnosis was 60.38 ± 14.22 years. The male to female ratio was 1.7:1. The cohort was predominantly Caucasian (80%) followed by African American (14%) and other races (5.4%). More favorable outcomes were recorded for Caucasians and patients of other races relative to the African American cohort, but these differences were not statistically significant (59.1% vs. 57.6%, p = .083). Bone was the most common site of involvement (57.78%). Additionally, 831 (49%) and 146 (8%) patients had axial and appendicular skeletal involvement, respectively, while PC proliferation in soft tissues was noted in 540 patients (32%). In patients with SEP, the most commonly encountered site was the upper airway tract (12%).[10]
Signs and symptoms that patients usually refer are a pain due to: bone destruction, spinal cord and/or nerve root compression or compression and enlargement of the soft tissue involved.
Diagnosis of SP needs:
•   history and physical examination,
•   complete blood count, white blood cell differential, platelet count,
•   serum chemistry for creatinine, albumin, corrected calcium,
•   serum LDH and Beta-2 microglobulin,
•   serum quantitative immunoglobulins and serum protein electrophoresis,
•   24-h urine for total protein,  Bence Jones protein, and urine protein electrophoresis,
•   serum Free Light Chain (FLC) assay,
•   bone marrow aspiration and biopsy,
•  skeletal survey [at least radiography, and/or computed tomography (CT), magnetic resonance imaging (MRI) or 18 Fluorodeoxyglucose positron emission tomography (FDG-PET)].
In particular, diagnosis of SBP requires a solitary bone lesion confirmed by the skeletal survey, the clonal PC infiltration lower than 10% proven by biopsy, and lack of myeloma-related organ dysfunction.
Diagnosis of SEP requires a tissue biopsy indicating monoclonal PC histology, bone marrow clonal PC infiltration less than 10% of all nucleated cells, the absence of osteolytic bone lesions or other tissue involvement without CRAB.
Recent advances have improved the precision of diagnosis. Flow cytometry studies and molecular detection of heavy- and light-chain gene rearrangements may reveal clonal PCs in the bone marrow. MRI or FDG-PET that are more sensitive tests than conventional skeletal survey could better define patients with systemic disease at diagnosis.[19] In addition, quantitation of kappa and lambda chains not bound to intact immunoglobulin molecules in the serum (FLCs), can define more precisely the diagnosis of MM. This test allows the determination of clonality based on the involved/uninvolved serum FLCs ratio, which needs to be ≥100 according to the most recent diagnostic criteria of MM.[20]
Solitary extramedullary and bone plasmacytoma show non-specific CT and MRI imaging findings. Usually, the MRI appearance of SBP is consistent with that of a focal area of bone marrow replacement; the signal intensity is similar to muscle on T1-weighted images and hyperintense about muscle on T2-weighted images. MRI is the modality of choice for soft tissue evaluation; also, MRI of the axial skeleton has been shown to be superior to whole body X-rays and is recommended in patients with SBP of the spine and suspected cord or nerve root compression.[21] FDG-PET is the modality of choice for assessment of the skeletal abnormalities.[22-25] Recently an abnormal involved serum FLC value and the presence of at least two hypermetabolic lesions on FDG PET at diagnosis of SP were reported as the two predictors of early evolution.[26]
Some patients with SP have a small monoclonal protein (also called M protein) detectable in the serum and/or in the urine; more frequently SBP than SEP. The percentage in SBP varies from 24% to 72% of patients in different reports; levels of uninvolved immunoglobulins are usually normal.[6,16] In SEP M protein is detected less frequently (about 20% of cases).[7,13,27] Moreover, Dingli et al. reported in 116 SBP that the FLC ratio was normal in 53% patients and abnormal in 47%. Patients with an abnormal FLC had a higher incidence of monoclonal protein in the urine (p < 0.001) and a larger serum M- protein (p = 0.04).[16]
Finally, Hill e Paiva reported the importance of multiparameter flow cytometry (MFC) for detecting clonal PCs in the bone marrow;[28,29] the presence of “minimal occult” bone marrow disease indicates a high risk of progression for SBP patients and could suggest a tailored of patients’ follow-up. Conversely, flow diagnostic criteria may also allow the accurate identification of “true” SP, characterized by flow-negative bone marrow and absence of M protein, which would represent a signature for the possibility of cure.
Therefore, nowadays, a correct diagnosis of SP must include the modern techniques as MFC and FLC detection in addition to FDG-PET or MRI for the study of bone lesions. Here we present a possible diagnostic algorithm for SP divided into three different steps of examinations (Figure 1).

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Figure 1. Diagnostic algorithm for SP divided in 3 different steps.

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Prognostic Factors

For SP, it is hard to identify prognostic factors. Several authors reported various parameters that influence the outcome of these patients, such as age, lesion size, localization (bone or soft tissue) and the presence of M protein at the onset and that could disappear after therapy.[5,13,17,22,30-39] However, these adverse prognostic features have not been consistent between series.[13,31,36,40,41]
In our previous study, in univariate analysis, the only adverse prognostic factor for overall survival (OS) was the bone localization rather than the extramedullary localization. In fact, we could demonstrate a statistically significant difference between the two groups regarding 5- and 10-year OS probability, with SEP showing a longer survival probability. Regarding progression-free survival (PFS), the two adverse prognostic factors in univariate analysis were bone disease and the larger size of the lesion (>5 cm). In multivariate analysis, the only significant independent prognostic factor was the bone localization compared to the extramedullary localization, both regarding OS and PFS. It must underlie that we identified some important differences between SBP and SEP patients, particularly a prevalence of serum M protein and larger tumor size in SBP. We did not observe significant differences in terms of OS and PFS between patients with age greater or lower than 60 years.[27]
SBP versus (vs.) SEP. Other authors reported poor prognosis of SBP in comparison with SEP. Ozsahin et al. reported in SBP a median time to MM development of 21 months (range 2–135), with a 5-year probability of 45%. The 5-year OS, disease-free survival (DFS) and local control (LC) rate (considered as the resolution of the tumor mass and associated symptoms in the treatment area, with no subsequent evidence of local tumor progression) was 74%, 50%, and 86%, respectively. SBP had a significantly higher risk of progression to myeloma at a rate of 65–84% in 10 years and 65–100% in 15 years. In spite of a curative treatment, the median time to progression to MM was 2 to 3 year.[38] However, some authors reported that the median OS in patients with SBP was 10 years, and 10% to 20% of patients died of unrelated causes.[6]
Also, a recent review by Suh et al. confirmed that SBP progressed more frequently to MM compared with SEP (p = 0.02). In fact, the Myeloma-free survival (MFS) rate of SEP was 71.2% both at 10-year and 5-, whereas the rates of SBP were at 10-year 36.4% and 0%, at 5, respectively. The median time of MFS in SBP was 36 months, while SEP was not attained because of its low progression rate to MM. The median time of progression to MM following diagnosis was 45 (range, 8–142) and 25 (range, 4–108) months in SEP and SBP, respectively. The 5- and 10-year PFS rates for all patients were 43% and 25%, respectively. Patients with SBP demonstrated worse PFS rates compared with SEP patients; however, this difference was not statistically significant (p = 0.16).[42] Also, the Greek experienced recently reported a 5 and 10-year OS of 92% and 89% in SEP and 86% and 69% in SBP, respectively (p = 0.2). The 5- and 10-year MFS probability was 90% and 70% for patients with SEP vs. 59% and 50% for patients with SBP, respectively (p = 0.054). Overall, the 5- and 10-year OS probability, plasmacytoma relapse-free survival (PRFS), PFS and MFS was 84% and 78%, 72% and 58%, 58%, and 43%, and 70% and 59%, respectively. In addition, in this study, impairment of humoral immunity (immunoparesis), defined as a suppression of at least one uninvolved immunoglobulin (i.e., for IgG<700 mg/dL, for IgA <70 mg/dL and IgM<40 mg/dL), was the only negative predictor of progression to MM.[43]
On the contrary, less than 30% of patients with SEP develop systemic progression; some groups reported that the median time to progression to systemic disease is approximately 2 years.[2,33,44] Liebross et al. reported an LC rate in 95% of patients with SEP. MM developed in 32%: the 5-year rate of freedom from progression to MM was 56%, and the median survival was 9.5 years.[13] Galieni et al. achieved complete remissions in 85% patients, 11% of partial remissions and 4% of non-response to therapy. Local recurrence or recurrence at other sites occurred in 7.5% and 10% of patients, respectively. Moreover, 15% of patients developed MM. The 15-year survival rate was 78%, and the diffusion-free survival was 83%.[7]
Recently de Wall et al. confirmed all these data in his cohort of 76 SP patients. Among SBP patients, 70% progressed to MM with a median time to progression of 19 months (range 5–131). In SEP patients, 3 (12%) progressed to MM after 6, 33 and 71 months. The 5-year PFS was significantly different between SBP and SEP (38% vs. 93%, p = 0.0001). However, the OS between SBP and SEP was not significantly different (p = 0.294) with an OS of 70% vs. 81% at 5 years and 64% vs. 77% at 10 years, mainly because 4 SEP patients died within 5 years of diagnosis due to disorders unrelated to MM. No association with progression to MM was observed except for the location of the plasmacytoma.[18]
Moreover, this year, the German group examined the survival of patients with rare PC and plasmacytoid malignancies (SP, MM, and lymphoplasmacytic lymphoma) in Germany compared to that in the USA in a period from 1998 to 2012. In Germany, patients with SP had a 5-year relative survival (RS) of 56.5%, with a lower survival for intraosseous (47.7%) versus extraosseous (62.0%). Five-year RS estimated for USA patients with SP was higher at 62.3%, with survival for patients with intraosseous SP at 60.4% and extraosseous SP at 67.8%. Survival trends between 2003 to 2007 and 2008 to 2012 were compared. Five-year age-adjusted RS for patients with LPL/SP increased in Germany, from 69.2% between 2003 and 2007 to 74.2% in the period 2008 to 2012. In the USA, overall 5-year age-adjusted RS for these conditions went from 73.3% to 76.8%. Similar increases were seen for both men and women. However, 5-year RS increased more for patients with LPL with smaller increases observed for SP. A better identification of SP might be related to the survival improvement.[45]
Table 2 A and B summarize the results of the most relevant series of SBP and SEP cases, highlighting the better results for SEP regarding LC rate, progression to MM and OS.

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Table 2. Results of the largest series of solitary bone plasmacytoma- SBP (table 2 A) and solitary extramedullary plasmacytoma - SEP (table 2 B). SEP shows better LC, MMP and OS than SBP.

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Age, sex, and race. Numerous studies reported a substantial impact of age on the outcome; age> than 55 or 60 years is considered poor prognostic factor.[3,9,17,38,41,46] Recently, Thumallapally et al., in the retrospective analysis on 1691 SP, noted the highest survival rates for the younger age group (<40 years), while patients aged 60 years or older had the most unfavorable outcomes (87.45% vs. 45%, p < 0.05). Moreover, males had a higher chance of survival than females (63.7% vs. 52.9%, p < 0.05), and Caucasians and other races had more favorable outcomes respect to the African American cohort, but these differences were not statistically significant (59.1% vs. 57.6%, p = 0.083).[10] Recently, El-Fattah et al. also reported black race as a poor prognostic factor.46 However, in the past, Dores did not find differences in survival between males and females or whites and blacks,[3] while Jawad reported poorer prognosis for races different from Caucasian or African American, even if other races represented only the 4.2% of the cohort analyzed in the study.[9]
Tumor size and localization. Different authors agree on the importance of tumor size as a prognostic factor[33,38,41] and the impact of extramedullary involvement vs. bone involvement.[36,38]
For example, Tsang et al. showed that patients with lesions < 5 cm had an LC rate of 100%, whereas patients with larger tumors had a rate of nearly 40%;[37] similar results were obtained by Knobel et al..[41] Other reports suggested a more favorable prognosis for SBP of the appendicular than an axial skeleton in some,[30] but not all studies confirmed this.[41] In a recent large retrospective USA study, there was no substantial difference in 5-year relative survival between SBP occurring in the axial or appendicular skeleton.[3]

M protein and FLC. Wilder et al. reported that, in multivariate analysis, the persistence of M protein more than one year after radiotherapy was the only independent adverse prognostic factor for MFS (p = 0.005) and cause-specific survival (p = 0.04). Most patients with M protein that persisted for more than one year after radiotherapy were diagnosed with MM within 2.2 years of treatment.[30,47]
Dingli et al. created a risk stratification model based on 2 variables of FLC ratio and M protein level. Patients with a normal FLC ratio at baseline and M protein level less than 5 g/L at 1 to 2 years following diagnosis were considered low risk, patients with either risk factors were considered intermediate risk and high risk with both risk factors. The corresponding progression rates at 5 years were significantly different in the low, intermediate, and high groups: 13%, 26%, and 62%, respectively (p < 0.001).[16]

Occult Bone Marrow Disease (OMD)

Therapy

Discussion

SBP and SEP are rare forms of localized PC dyscrasia; these two entities have a clinical course and prognosis that are quite different from each other. The updated guidelines recommend to exclude the possibility of a systemic disease: therefore, all patients with plasmacytoma should undergo a complete staging that includes: at least whole body X-rays of the skeleton, bone marrow biopsy and blood tests to rule out full-organ damage. However, given the recent innovations regarding a diagnosis for MM, a spine MRI or FDG-PET, serum FLC ratio, immunoglobulin levels and MFC should be introduced even for the diagnosis of plasmacytoma (Figure 1). In fact, a better definition of a possible systemic disease, often underestimated, should reduce the percentage of patients with SP that evolve in MM. Percentage of evolution in MM is higher in SBP (more than 60%) respect to SEP (less than 30%), with a lower PFS and OS of SBP than SEP. In general progression to MM develop in 2-3 years.
Due to the rarity of the disease, there are no randomized studies about the best treatment approach, and data reported in the literature are controversial. Radiotherapy is the treatment of choice for SP, but no clear relationship has been documented between response and radiotherapy dose. For SBP it is recommended treatment with radical radiotherapy, with a margin of at least 2 cm and a dose of 40 Gy in 20 fractions. For SBP >5 cm, a higher dose of up to 50 Gy in 25 fractions should be considered.[5]
Surgery is contraindicated in the absence of structural instability or neurological compromise. However, due to the development of modern spinal fixation systems over the last decade, surgical treatment is now a feasible and successful option for patients who develop pain caused by structural compromise within the vertebra, vertebral instability, neurological compromise or both. Loss of structural integrity requires some forms of stabilization procedure; in cases of neurological compromise, decompression is also required. The choice of surgery and approach needs to be tailored to the specific situation of each patient, the general fitness, and clinical conditions; also the site and the extent of the tumor must be evaluated. Moreover, if surgery is required, it should be carried out before starting radiotherapy because surgery is more difficult in patients who have received radiotherapy and initial surgery may sometimes compromise radiotherapy, e.g. by the placing of metal supports.[5]
Patients with a bulky disease or not responding to radiotherapy could benefit from chemotherapy; however, studies are limited, and its role is controversial. The better prognosis of patients with SEP compared to SBP allows speculating that these are indeed two different diseases also from a biologic point of view. It is possible to suggest that SEP patients probably can be treated with surgery or radiotherapy alone, while SBP patients, who more frequently have an extensive disease, should be treated with chemotherapy after surgery and/or local radiotherapy, to prevent disease progression. Moreover, the potential use of the systemic treatment in addition to local radiotherapy could be suggested in the high-risk group of SBP with OMD. About chemotherapy, it is important to consider the possibility of using novel agents, taking into account the well-documented role that angiogenesis plays in several hematologic disorders, particularly in PC dyscrasias. However, there are some small series of cases treated with bortezomib-based regimens and fewer cases treated with IMiDs.[43,57,58] Here we report a hypothesis for a therapeutic algorithm (Figure 2).

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Figure 2. Therapeutic algorithm for SP (SBP and SEP).

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Radiotherapy remains the treatment of choice for both SBP and SEP; surgery should be indicated only in particular and feasible cases. Chemotherapy should be considered in cases of bulky disease at the onset or in high-risk patients. 
According to the data reported in the literature, we can consider high-risk patients cases with abnormal FLC ratio and M protein level of at least 5 g/L,[16] the presence of OMD,[28,29] or presence of at least two hypermetabolic lesions on FDG-PET.[26] The patients with disease resistant to radiotherapy could benefit from chemotherapy too. New drugs could lead to optimal results, as for MM; also, autologous stem cell transplantation should be considered in young and fit high-risk or resistant SBP patients. However, larger prospective clinical studies need to be performed to refine our understanding of SP (taking into account that SBP and SEP could be considered as two different entities) and to optimize management of affected patients, in particular, the role of novel agents for the treatment of this disease.

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