INTRODUCTION — Plasma cell neoplasms (plasma cell dyscrasias) are a group of entities characterized by the neoplastic proliferation of a single clone of plasma cells, typically producing a monoclonal immunoglobulin. Plasma cell neoplasms can present as a single lesion (solitary plasmacytoma) or as multiple lesions (multiple myeloma). Solitary plasmacytomas most frequently occur in bone (plasmacytoma of bone), but can also be found outside bone in soft tissues (extramedullary plasmacytoma) [1-4]. Why some patients develop multiple myeloma and others a single plasmacytoma is not understood, but it might be related to differences in cellular adhesion molecules or chemokine receptor expression profiles of the malignant plasma cells [5].
Solitary extramedullary plasmacytomas (SEP; solitary extraosseous plasmacytoma) are plasma cell tumors that arise outside of the bone marrow. They are solitary lesions, and are most often located in the head and neck region, mainly in the upper aerodigestive tract, but may also occur in the gastrointestinal tract, urinary bladder, central nervous system, thyroid, breast, testes, parotid gland, lymph nodes, and skin.
SEP refers to a solitary non-osseus plasma cell neoplasm in the absence of any other sign of multiple myeloma. The diagnosis and management of SEP will be discussed here. Note that extramedullary plasmacytomas can arise in patients with multiple myeloma at any time during the course of the disease, and should not be confused with SEP. The diagnosis and treatment of other plasma cell disorders (eg, solitary plasmacytoma of bone, multiple myeloma, primary AL amyloidosis, monoclonal gammopathy of undetermined significance) are discussed separately.
●(See "Diagnosis and management of solitary plasmacytoma of bone".)
●(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
●(See "Diagnosis of monoclonal gammopathy of undetermined significance".)
EPIDEMIOLOGY — SEPs account for approximately 3 percent of plasma cell malignancies [6,7]. The median age at diagnosis is 55 to 60 years, and approximately two-thirds of patients are male.
CLINICAL PRESENTATION — Most patients present with symptoms related to the location of the mass. Approximately 45 to 80 percent involve the upper respiratory tract (ie, oronasopharynx and paranasal sinuses), producing epistaxis, nasal discharge (rhinorrhea), or nasal obstruction [8-13]. Less common sites of involvement include connective/soft tissue [13], the gastrointestinal tract [14], liver [15], lymph nodes [16,17], testes [18], skin, and central nervous system [19]. Primary plasmacytoma of the lung often presents as a pulmonary nodule or hilar mass with or without hemoptysis [20]. Regional lymph nodes may be involved.
By definition, patients with SEP do not have anemia (ie, hemoglobin <10 g/dL or 2 g/dL below normal), hypercalcemia (ie, serum calcium >11.5 mg/dL [2.875 mmol/liter]), renal insufficiency (ie, serum creatinine >2 mg/dL [176.8 micromol/liter]), or bone lesions attributable to the underlying plasma cell disorder.
EVALUATION — The evaluation of a patient with a suspected SEP should include the following studies in addition to a complete history and physical examination:
●A biopsy of the suspected lesion.
●A complete blood count and differential with examination of the peripheral blood smear.
●A chemistry screen that includes measurements of serum calcium, creatinine, albumin, lactate dehydrogenase, beta-2 microglobulin, C-reactive protein, and serum free light chains. (See "Multiple myeloma: Staging and prognostic studies".)
●A serum protein electrophoresis (SPEP) with immunofixation and quantitation of immunoglobulins. (See "Laboratory methods for analyzing monoclonal proteins".)
●A routine urinalysis and a 24-hour urine collection for electrophoresis (UPEP) and immunofixation. Serum free monoclonal light chain (FLC) analysis is not an adequate replacement of a 24-hour urine collection in conjunction with SPEP and immunofixation in patients with a confirmed plasma cell proliferative disorder. (See "Laboratory methods for analyzing monoclonal proteins".)
●A unilateral bone marrow aspiration and biopsy.
●Cross sectional imaging with whole body combined fluorine-18-labeled fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan [21].
Spinal cord compression from an extramedullary plasmacytoma should be suspected in patients with severe back pain, weakness, or paresthesias of the lower extremities; bladder incontinence; or bowel dysfunction. Magnetic resonance imaging (MRI) or CT myelography of the entire spine must be performed immediately if this complication is suspected. On MRI, extramedullary plasmacytoma is usually hypointense or isointense on T1-weighted images and isointense or hyperintense on T2-weighted images [22]. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression".)
DIAGNOSIS — The diagnosis of an SEP requires the following (table 1) [11,14,23,24]:
●Biopsy-proven extramedullary tumor with evidence of clonal plasma cells (picture 1 and picture 2). (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Morphology and immunophenotype'.)
●18F-FDG PET/CT must show no lytic lesions.
●Bone marrow aspirate and biopsy must contain no clonal plasma cells.
●There is no anemia, hypercalcemia, or renal insufficiency that could be attributed to a clonal plasma cell proliferative disorder. (See 'Clinical presentation' above.)
Some patients may have a small monoclonal protein, usually IgA, in the serum or urine, which often disappears following treatment. The bone marrow of patients with SEP should have no clonal plasma cells.
Some patients with a solitary extramedullary lesion may demonstrate up to 10 percent clonal plasma cells, and are considered as having SEP with minimal marrow involvement [25]. These patients are treated in a similar fashion to SEP, but may have a higher risk of progression to symptomatic myeloma. If patients suspected to have SEP demonstrate 10 percent or more clonal plasma cells in the bone marrow, they should be considered to have multiple myeloma rather than SEP. These patients are also often treated in a similar fashion to SEP, but may require additional systemic therapy. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnosis'.)
DIFFERENTIAL DIAGNOSIS — It is important to distinguish SEPs from other plasma cell dyscrasias for the purposes of prognosis and treatment. The main condition to consider in the differential diagnosis is multiple myeloma, but other hematologic and non-hematologic neoplasms must also be considered. Solitary plasmacytoma can be distinguished from most neoplasms based on the morphologic appearance of plasma cells and on the clonal nature of the plasma cells, which can be established by immunostaining for kappa and lambda light chains or by flow cytometry. Typically, plasma cells in solitary plasmacytoma will be positive for CD138, CD38, and show light chain restriction (ie, stain positive for either kappa or lambda but not both). Distinction between solitary plasmacytoma and multiple myeloma or other closely related plasma cell tumors (eg Waldenström macroglobulinemia) requires additional studies as noted below.
Multiple myeloma — SEP is composed of plasma cells that are histologically and immunophenotypically identical to those seen in multiple myeloma; however, the treatment of these two entities differs significantly, necessitating a careful review of the diagnosis. A distinction between these two conditions is made based on the exclusion of additional lesions in patients with SEP. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
As mentioned above, the diagnosis of SEP requires the exclusion of features of multiple myeloma as evidenced by the following:
●Normal bone marrow with no evidence of clonal plasma cells. Patients with an apparent SEP who have clonal involvement of the marrow <10 percent are considered to have SEP with minimal marrow involvement. Patients with an apparent SEP but 10 percent or more clonal plasma cells meet the criteria for multiple myeloma [25].
●18F-FDG PET/CT is negative for evidence of multiple myeloma.
●Absence of lytic lesions, anemia, hypercalcemia, and renal insufficiency, unless these are due to a cause other than a plasma cell dyscrasia.
Waldenström macroglobulinemia — Waldenström macroglobulinemia (WM) is a distinct clinicopathologic entity demonstrating lymphoplasmacytic lymphoma (LPL) in the bone marrow with an IgM monoclonal gammopathy in the blood. Patients may present with symptoms related to the infiltration of the hematopoietic tissues or the effects of monoclonal IgM in the blood. In comparison, patients with SEP will have no clonal lymphoplasmacytic cells on bone marrow biopsy and only rarely have an unrelated IgM monoclonal gammopathy. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)
TREATMENT — The treatment of choice for SEP is radiation therapy (RT) given with curative intent at a dose of 40 to 50 Gy over a four-week period [13,26-28]. If a complete surgical resection was performed as part of the diagnosis, the role of adjuvant RT is less clear. Small lesions may be cured with surgery alone and no adjuvant RT is indicated unless there is suspicion of residual local disease. Adjuvant chemotherapy does not appear to improve relapse rate or increase disease-free survival [6]. Bisphosphonates are not recommended for patients with SEP, except in the setting of underlying osteopenia. (See "Multiple myeloma: The use of osteoclast inhibitors", section on 'Indications'.)
For patients with incompletely resected SEP, we recommend the use of local RT rather than further surgery, chemotherapy, or observation. For patients with completely resected SEP after diagnostic biopsy, we suggest observation rather than adjuvant RT or chemotherapy. This approach is based on retrospective analyses [13,26,29,30]. As examples:
●A retrospective single institution analysis of 18 consecutive patients who received RT (median dose 50 Gy) for SEP of the head and neck reported no recurrences in the radiation field [26]. There was a marginal recurrence that was treated successfully with another course of RT. At a median follow-up of 6.8 years, six patients experienced disease progression to multiple myeloma (2 patients) or developed plasmacytoma at another site (4 patients).
●A second retrospective single institution analysis of 25 consecutive patients who received RT (median dose 45 Gy) for SEP reported local recurrence in five patients (one marginal and four in-field) [29]. At a median follow-up of 64 months, the five-year probability of progression to myeloma was 30 percent and the five-year overall survival rate was 85 percent.
●In a retrospective analysis of 5056 patients with solitary plasmacytoma, including 1528 patients with SEP, treatment with both radiation and surgery resulted in superior overall survival than use of either modality alone [13]. Since treatment differed significantly by site of involvement, it is not known whether these survival differences are due to treatment given, site involved, or a combination of the two.
The ideal dose of radiation in this setting is unknown. Retrospective analyses have suggested that radiation doses of 40 Gy or greater are associated with improved local control (eg, local failure rates of 9 versus 23 percent) [7,13,26].
There are limited data regarding the preferred radiation volume for SEP. A retrospective study of patients with SEP of the head and neck suggested an increased risk of recurrence when RT was administered to the gross tumor plus a 2 cm margin when compared with those who received RT to the entire nasal cavity or paranasal sinuses [26]. However, with improved imaging, recurrence rates without nodal radiation are very low (approximately 5 percent), and elective lymph node coverage is not recommended for SEP [28].
As mentioned above, the role of RT after a complete surgical resection is less clear with some series suggesting improved median survival rates when adjuvant RT is used [8] and others suggesting no difference in outcomes [9]. Given the lack of proven benefit and potential for RT-associated complications, including radiation-induced second malignancies, we reserve adjuvant RT for patients with suspected local residual disease.
PROGNOSIS — Less than 7 percent of patients with SEP will develop a local recurrence after tumoricidal radiation [27,31]. Approximately 10 to 15 percent of patients will ultimately develop multiple myeloma [32,33]. The progression rate is higher (20 percent) in patients with SEP with minimal marrow involvement.
Reported five-year overall survival rates for patients with SEP have ranged from 40 to 85 percent [9,34-37]. It is unknown if tumor location affects outcome. Initial reports suggest that involvement of the head and neck may portend a better prognosis, while connective/soft tissue lesions may portend a worse prognosis. However, it is unclear whether differences in management can account for these different outcomes. In a retrospective analysis that included 1528 patients with SEP, the median overall survival was 11 years the population overall, 6.8 years for the 295 patients with connective/soft tissue involvement, and not reached for the 681 patients with head and neck involvement [13]. In another series of 18 patients with SEP of the head and neck treated at the Mayo Clinic, the median overall survival was 12.5 years with five- and 10-year survival rates of 88 and 55 percent, respectively [26]. Six patients developed multiple myeloma or plasmacytoma at a distant site. In addition, an analysis of the Surveillance, Epidemiology, and End Results (SEER) database that included 1185 patients with extramedullary plasmacytoma reported superior median survival among patients with involvement of the head and neck when compared with patients with other sites of extramedullary plasmacytoma (13 versus 4 years) [12]. Patients with involvement of the head and neck were less likely to be treated with surgery alone and more likely to have combined modality treatment with surgery and radiation therapy.
FOLLOW-UP — Following the completion of therapy, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depend on the comfort of both the patient and physician. If the SEP was measurable by an imaging modality prior to therapy, the same modality (eg, 18F-FDG PET/CT) should be repeated three to four months after completing therapy, and periodically thereafter.
In general, we see patients every three months for the first two years, then every six months for an additional three years, then yearly or every other year after five years. At these visits we perform a history and physical examination, urine and serum protein electrophoresis with immunofixation, complete blood count, serum creatinine, and serum calcium. For patients with head and neck involvement, we also perform a fiberoptic endoscopy at each visit. All patients undergo 18F-FDG PET/CT or MRI (whichever imaging modality was used for the initial evaluation) every 6 to 12 months for the first five years after therapy. Other follow-up imaging depends on the original tumor site.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma" and "Society guideline links: Solitary plasmacytoma".)
SUMMARY AND RECOMMENDATIONS
●Clinical presentation – Solitary extramedullary plasmacytomas (SEP) are plasma cell tumors that arise outside of the bone marrow. Most patients present with symptoms related to the location of the mass, which are most frequently located in the head and neck region. (See 'Epidemiology' above and 'Clinical presentation' above.)
●Diagnostic evaluation – The evaluation of a patient with a suspected SEP should include a biopsy of the suspected lesion, a unilateral bone marrow aspirate and biopsy, and laboratory studies. Imaging should include a fluorine-18-labeled fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan. (See 'Evaluation' above.)
The diagnosis of an SEP requires the following (table 1) (see 'Diagnosis' above):
•Biopsy-proven extramedullary tumor with evidence of clonal plasma cells.
•18F-FDG PET/CT must show no lytic lesions.
•Bone marrow aspirate and biopsy must contain no clonal plasma cells.
•There is no anemia, hypercalcemia, or renal insufficiency that could be attributed to a clonal plasma cell proliferative disorder.
The presence of clonal plasma cells (less than 10 percent) in the bone marrow is considered solitary plasmacytoma with minimal marrow involvement. Presence of 10 percent or more clonal bone marrow plasma cells in a patient with SEP will automatically meet required criteria for multiple myeloma.
●Management – The treatment of SEP depends primarily on whether the diagnostic biopsy was a complete or incomplete resection of the tumor:
•For patients with an incompletely resected SEP after diagnostic biopsy, we recommend the use of local radiation therapy rather than further surgery, chemotherapy, or observation (Grade 1C). (See 'Treatment' above.)
•For patients with completely resected SEP after diagnostic biopsy, we suggest observation rather than adjuvant radiation therapy or chemotherapy (Grade 2C). (See 'Treatment' above.)
●Limited role for bisphosphonates – Bisphosphonates are not recommended for patients with SEP, except in the setting of underlying osteopenia. (See "Multiple myeloma: The use of osteoclast inhibitors", section on 'Indications'.)
