Solitary Plasmacytoma

A plasmacytoma can arise in any part of the body. A solitary bone plasmacytoma (SBP) arises from the plasma cells located in the bone marrow, whereas an extramedullary plasmacytoma (EMP) is thought to arise from plasma cells located in mucosal surfaces.[3] Both represent a different group of neoplasms in terms of location, tumor progression, and overall survival rate.[4, 5] Some authors suggest that SBPs represent marginal cell lymphomas with extensive plasmacytic differentiation.[5] Both SBP and extramedullary plasmacytoma (EMP) do, however, share many of the biologic features of other plasma cell disorders.

Cytogenetic studies show recurrent losses in chromosome 13, chromosome arm 1p, and chromosome arm 14q, as well as gains in chromosome arms 19p, 9q, and 1q.[6] Interleukin-6 (IL-6) is still considered the principal growth factor in the progression of plasma cell disorders.[7]

The specific roles of surface markers, adhesion molecules, and angiogenesis in solitary plasmacytoma need to be studied further.

In a study by Kumar et al, high-grade angiogenesis in SBP was associated with increased progression to multiple myeloma and shorter progression-free survival. Some have postulated that SBP may be considered an intermediate step in the evolution from monoclonal gammopathy of undetermined significance to multiple myeloma.[7, 8]

No definite cause has been found for solitary bone plasmacytoma (SBP). Because of its presentation in the mucosa of the aerodigestive tract (>80%), the etiology of extramedullary plasmacytoma (EMP) may be related to chronic stimulation of inhaled irritants or viral infection.[9]

Solitary plasmacytoma (SP) has an annual incidence of less than 450 cases in the United States.[2]  Solitary bone plasmacytoma (SBP) affects fewer than 5% of patients with plasma cell disorders.[10, 7] Extramedullary plasmacytoma (EMP) represents approximately 3% of all plasma cell neoplasms.[11] In the United States during 2003‐2016, overall incidence rates in adults were 0.45 per 100,000 persons for SP and 0.09 per 100,000 persons for extramedullary plasmacytoma.[12]

Population studies have reported a male predominance in the SP with a male-to-female ratio of 1.6:1. In studies focusing primarily on SBP, the male-to-female ratio ranges from 1.5–2.4:1. Among EMP patients, a 3:1 male predominance has been reported in sites involving upper airway tract.[2]

SP primarily affects adults over 40 years old, and its incidence increases with age.[2]  The median age of patients with either SBP or EMP is 55 years. This median age is 10 years younger than in patients with multiple myeloma.[13, 3, 14, 15, 16]

A review by Sharpley et al of 66 patients with solitary plasmacytoma found that with a median follow-up of 53.6 months the 5-year overall survival was 90.7% (95% confidence index [CI] 79–96%). The median progression-free survival (PFS) from diagnosis was 61 months. The cumulative incidence of progression to multiple myeloma at 5 years was 49.9% (95% CI 35.6–62.6%) and was significantly higher with bone plasmacytoma (47.2%, 95% CI 31.9–61.1%), than extramedullary plasmacytoma (8.3%, 95%CI 0.4–32.3%, Gray test P = 0.0095).[17]

Solitary bone plasmacytoma (SBP)

Solitary bone plasmacytoma (SBP) progresses to multiple myeloma at a rate of 65-84% at 10 years and 65-100% at 15 years. The median onset of conversion to multiple myeloma is 2-5 years with a 10-year disease-free survival rate of 15-46%. The overall median survival time is 10 years.[14]

Kyle described the following 3 patterns of treatment failure[18] :

• Development of multiple myeloma (54%)
• Local recurrence (11%)
• Development of new bone lesions in the absence of multiple myeloma (2%)

Prognostic features for conversion of  SBP to multiple myeloma, although controversial, include the following[19, 20, 21] :

• Lesion size of at least 5 cm
• Patient age 40 years and older
• High M protein levels
• Persistence of M protein after treatment
• Spine lesions

In a study by Wilder et al, 10-year myeloma-free survival in patients whose M protein resolved within 1 year after radiation therapy was 91%, versus 29% in patients whose M-protein persisted beyond that time.[22]

Extramedullary plasmacytoma (EMP)

Patients with EMP have a 5-year survival rate of about 82% and 10-year disease-specific survival rate greater than 50%.[11]  The rate of progression to multiple myeloma is lower than in SBP, ranging from 11% to 30% at 10 years.[14]  Patients with EMP that progressed to multiple myeloma had a 5-year survival rate of 100%, compared with 33% for those with SBP.[23]  In a review of 721 cases by Alexiou and colleagues, after treatment, approximately 65% of patients were free of recurrence and did not progress to multiple myeloma, 22% experienced recurrence, and 15% of cases evolved to multiple myeloma.[15]

In one study, local control following radiation therapy was achieved in 83% of patients with low-grade histology versus 17% of patients with intermediate- to high-grade tumors.[24]

Solitary bone plasmacytoma

The most common symptom of solitary bone plasmacytoma (SBP) is pain at the site of the skeletal lesion due to bone destruction by the infiltrating plasma cell tumor.[7, 18]

Compression fractures of the thoracic and lumbar vertebral bodies usually result in severe spasms and back pain. Patients with significant vertebral involvement may also have evidence of nerve root or spinal cord compression.[7] Spinal cord compression represents an emergency that requires immediate diagnosis and treatment to avoid permanent neurologic damage (eg, paraplegia, bowel and bladder dysfunction, chronic pain).

Pleuritic pain from pathologic rib and clavicular fractures are associated with marked local tenderness.

Extramedullary plasmacytoma

Extramedullary plasmacytoma (EMP) presents as a mass growing in the aerodigestive tract in 80-90% of patients, often with spread to lymph nodes, although other sites are affected as well. Common complaints include the following[13, 25, 26, 27] :

• Headache
• Nasal discharge
• Epistaxis
• Nasal obstruction
• Sore throat
• Hoarseness
• Dysphonia
• Dysphagia
• Dyspnea
• Epigastric pain
• Hemoptysis

Gastrointestinal EMPs can present as loss of appetite, bleeding, and abdominal discomfort or obstruction.[11]  

Symptoms from EMP in other tissues are associated with the site of the tumor, tumor size, and compression and/or involvement of the surrounding structures.

EMP involving the lung most commonly presents as a pulmonary nodule or hilar mass.

Solitary bone plasmacytoma

Solitary bone plasmacytoma (SBP) may involve any bone, but it has a predisposition for the red marrow–containing axial skeleton. Spinal disease is observed in 34-72% of cases. The thoracic vertebrae are most commonly involved, followed by the lumbar, sacral, and cervical vertebrae.[10]  The rib, sternum, clavicle, or scapula is involved in 20% of cases.[28]  Physical findings are related to the site of involvement, patients may present with a painful mass, pathologic fracture (in those with long bone involvement[10] ), or root or spinal cord compression syndrome.

Occasionally, patients with SBP may present with peripheral polyneuropathy,[29, 30]  or with features that are consistent with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes).[31]

Extramedullary plasmacytoma

Although extramedullary plasmacytoma (EMP) can occur in any site, 80-90% of tumors develop in the head and neck area, especially in the aerodigestive tract. Approximately 80% of cases involve the paranasal sinuses, pharynx, nasal cavity, or gums and oral mucosa.[10, 13, 3, 15, 16]  A mass (plasmacytoma) in these areas is the most common finding, with compression or invasion of the surrounding structures. Patients with tumors involving the base of the skull may present with cranial nerve palsies.

Case reports describe involvement of the following[10, 13, 3, 15, 16, 32] :

• Urinary bladder
• Central nervous system
• Orbit,
• Gastrointestinal tract
• Liver
• Spleen
• Pancreas
• Lung
• Breast,
• Skin
• Testis
• Parotid gland
• Mediastinum
• Thyroid gland (associated with goiter and Hashimoto thyroiditis)

In 30-40% of cases, local lymph nodes are involved at presentation or upon relapse.[14]

Solitary bone plasmacytoma (SBP)

Although levels are lower than in multiple myeloma, electrophoresis reveals a monoclonal protein in the serum or urine in 24-72% of patients.[34, 20, 35, 36, 37, 38, 21, 39]  Levels of uninvolved immunoglobulin are usually within the reference range. Peripheral blood cell count, kidney function, and calcium are within the reference range.

Extramedullary plasmacytoma (EMP)

Protein electrophoresis shows a monoclonal component in 14-25% of cases.[10, 13, 16] In a series of 46 patients by Galieni and colleagues, all patients had normal uninvolved immunoglobulin levels.[13]  Peripheral blood cell count, renal function, and calcium are within the reference range.

Solitary plasmacytoma (SP) shows nonspecific computed tomography (CT) and magnetic resonance imaging (MRI) findings.[40] Fluorodeoxyglucose positron emission tomogrpahy (FDG-PET) is the modality of choice for assessment of the skeletal abnormalities.[40] Whole-body PET/CT or MRI should be performed to exclude the presence of additional malignant lesions; the use of both may provide complementary information.[41] In a series of 43 cases, an abnormal involved serum free light chain (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.[42]

Solitary bone plasmacytoma 

On plain radiographs, solitary bone plasmacytoma (SBP) classically has a lytic appearance with clear margins and a narrow zone of transition to healthy surrounding bone.[7] Rare occurrences of a cyst, a trabeculated lesion resembling a giant cell tumor or an aneurysmal bone cyst, and sclerotic lesions have been described.[43] The sclerotic lesion is associated with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome.[44]

On MRI, the 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.[45]

Extramedullary plasmacytoma (EMP)

Radiographic assessment shows local bone destruction in most patients with nasal cavity or maxillary sinus involvement.[16]

Computed tomography (CT) scanning, MRI, and complete endoscopic examination of the aerodigestive and gastrointestinal tracts are required to determine the exact extent of the tumor and its potential for resectability.[15] These lesions may be associated with variable mass effect, infiltration and/or destruction of adjacent bone, muscle, fat, or vascular encasement.[46]

A European expert panel recommends that all patients with suspected solitary plasmacytoma undergo bone marrow aspiration and a bone marrow  biopsy to evaluate plasma cell morphology and the degree of total plasma cell infiltration. The degree of clonal plasma cell infiltration should be determined by flow cytometry or by kappa/lambda labeling on bone marrow aspirate or by immunohistochemistry on bone marrow biopsy.[41]

For solitary bone plasmacytoma (SBP), biopsy of the lesion reveals infiltration of the bone by monoclonal plasma cells.

In extramedullary plasmacytoma (EMP), the soft-tissue lesion commonly exhibits submucosal growth; depending on the tumor location, it may require deep biopsy, open biopsy, or complete excision.[15]  The final diagnosis of EMP is made through histological and immunohistochemical features, which demonstrate that the tumor is composed of neoplastic monoclonal plasma cells intensely positive for CD138 and show kappa light chain restriction.[11]  Histologically, EMPs are classified as low, intermediate, or high grade.[24]  Bone marrow biopsy shows less than 5% plasma cells without evidence of clonality.[13]

Wiltshaw classified soft-tissue plasmacytoma into 3 clinical stages, as follows[3] :

• Stage I – Limited to an extramedullary site
• Stage II – Involvement of regional lymph nodes
• Stage III – Multiple metastasis (although it is no longer a solitary plasmacytoma)

The therapeutic and prognostic value of this classification needs further evaluation.

Due to the rarity of solitary plasmacytoma (SP), there are no randomized studies to inform the best treatment approach, and the available data from small case series are controversial. Radiotherapy is the treatment of choice for SP, although its efficacy has been tested only in small retrospective series.[45]

Experts have yet to reach a consensus regarding the optimal treatment modality for extramedullary plasmacytoma (EMP). Current guidelines stipulate that head and neck EMP be treated with radiotherapy only, as surgical resection of these tumors can be highly invasive.[47]  

Chemotherapy, with regimens used in multiple myeloma, may be considered. Mignot et al reported that combining lenalidomide plus dexamethasone with radiation therapy improved myeloma-free survival and progression-free survival, compared with radiation therapy alone, in patients with SP.[48]

In a retrospective study by Thumallapally et al, 825 patients (49%) received radiotherapy and 197 (12%) underwent surgery, while 359 patients (21%) required both radiotherapy and surgery. The majority of SBP patients received radiation, while patients with EMP of upper airway tract and the central nervous system most commonly received radiotherapy plus surgery; those with lower airway tract involvement received radiotherapy only or neither radiotherapy nor surgery, and those with gastrointestinal tract localization were more frequently treated with surgery only.[2] ​

The survival rates of patients treated with radiotherapy were significantly higher than those of patients who did not receive radiotherapy (64.4% vs. 48.6%, P < 0.05). Moreover, patients who received neoadjuvant radiotherapy had a greater chance of 5-year relative survival than those who received adjuvant radiotherapy (86% vs. 73%, P < 0.05). A significant difference in survival was also observed in patients who underwent surgery, compared with patients who did not (69.7% vs 57.4%, P < 0.05).[2] ​

Solitary bone plasmacytoma

Local radiotherapy is the treatment of choice for solitary bone plasmacytome (SBP).[10, 7, 14, 20, 41] Treatment fields should be designed to encompass all disease observed on MRI and should include a margin of healthy tissue (at least 2 cm). For spinal lesions, the margins should include at least 1 uninvolved vertebra.

Local control is achieved in 88-100% of patients. Virtually all patients have major symptom relief,[14] and the local tumor recurrence rate is approximately 10%.

Most centers use approximately 40 Gy for spinal lesions and 45 Gy for other bone lesions. For lesions larger than 5 cm, 50 Gy should be considered.

No dose-response relationship between radiation dose and disappearance of monoclonal protein was noted in a series of patients with SBP, as reported by Liebross et al.[20]  Monoclonal protein is markedly reduced after radiotherapy in the majority of patients, but protein disappearance is observed in only 20-50% of patients.[15] Persistence of a serum monoclonal protein after initial radiation therapy predicts a higher risk of progression to multiple myeloma, so monitoring of serum electrophoresis and immunofixation after the completion of therapy is mandatory in such patients.[41]

Surgery is contraindicated in the absence of structural instability or neurologic compromise.[47]

Chemotherapy may be considered for patients not responding to radiation therapy. Regimens useful in multiple myeloma can be considered.[47] Mignot et al reported improved results with the addition of lenalidomide-dexamethasone to intensity-modulated radiation therapy (IMRT).[48, 49] No role exists for adjuvant chemotherapy in SBP.

Extramedullary plasmacytoma

Based on the documented radiation sensitivity of plasma cell tumors, the accepted treatment of extramedullary plasmacytoma (EMP) is radiotherapy.

When a lesion can be completely resected, surgery provides the same results as radiotherapy.

Combined therapy (surgery and radiotherapy) is an accepted treatment depending on the resectability of the lesion.[10, 13, 14, 15, 16] In fact, combination treatment may provide the best results.[15]

The optimal radiation dose for local control is 40-50 Gy (depending on tumor size) delivered over 4-6 weeks.[14, 15, 16]

Because of the high rate of lymph node involvement, local nodes should be included in the radiation field.[14]

Adjuvant radiotherapy should be recommended to patients with positive surgical margins.

Chemotherapy may be considered for patients with refractory or relapsed disease. Regimens used for multiple myeloma can be considered.[47]

Adjuvant chemotherapy may be considered for patients with tumors larger than 5 cm, as well as those with high-grade histology.

Surgery is considered a specific treatment for plasmacytomas for distinct localizations (eg, spine with neurological damage, upper airway that cannot be treated with radiotherapy, or vertebral fractures that require stabilization).[45, 2]  

Radical surgery of EMP of the neck and head with curative intent is often a mutilating procedure; because these tumors are highly radiosensitive, radical surgery should be avoided. However, for other sites, surgical removal, if feasible, should be considered. It is unclear whether additional treatment with radiotherapy is necessary for resected EMP with clear surgical margins.[45]

Orthopedic evaluation is recommended for patients with solitary bone plasmacytoma (SBP) because lesions may cause spinal cord compression syndrome or pathologic fractures. Therapeutic procedures, such as kyphoplasty, can be implemented in order to restore vertebral structure.

An ear, nose, and throat evaluation is recommended for patients with extramedullary plasmacytoma (EMP) of the head and neck to precisely localize the lesion, obtain an adequate biopsy (including lymph nodes), and plan possible resection.

Periodic evaluation for progression and development of multiple myeloma is recommended every 6 weeks for the first 6 months for solitary bone plasmacytoma (SBP) and extramedullary plasmacytoma (EMP), with extension of clinic appointments thereafter. Besides a complete history and physical examination, the following tests are recommended:

• Complete blood cell (CBC) count

• Complete metabolic panel with lactic dehydrogenase (LDH), calcium, phosphorus, C-reactive protein (CRP), and beta2 microglobulin

• Erythrocyte sedimentation rate (ESR)

• Serum protein electrophoresis with immunofixation

• Serum immunoglobulin quantification

• Urinary protein electrophoresis with immunofixation (24-h urine sample)

• Skeletal bone survey

Orthopedic follow-up is recommended for solitary bone plasmacytoma (SBP) and/or ear-nose-throat follow-up is recommended extramedullary plasmacytoma (EMP), based on the tumor location.

The National Comprehensive Cancer Network (NCCN) has released guidelines for the management of multiple myeloma that includes the following specific recommendations for treatment and surveillance of solitary plasmacytoma[33] :

• Radiation therapy (40-50 Gy in 1.8–2.0 Gy/fraction) to involved field
• Consider surgery if there is structural instability or neurologic compression

The NCCN recommends follow-up surveillance every 3-6 months that includes[33] :

• Complete blood cell count with differential
• Serum chemistry: creatinine, albumin, corrected calcium
• Serum quantitative immunoglobulins, serum protein electrophoresis, with serum immunofixation electophoresis as needed
• 24-hour urine for total protein, urine protein electrophoresis with urine immunofixation electophoresis as needed
• Serum free light chain assay

The following tests should be completed as clinically indicated:

• Serum lactate dehydrogenase (LDH) and beta-2 microglobulin levels
• Bone marrow aspirate and biopsy
• Skeletal survey
• Whole-body MRI or low-dose CT or PET/CT scan 

In addition, the NCCN recommends yearly imaging of all plasmacytomas, preferably with the same technique used at diagnosis, for at least 5 years.