According to the preferred site of EMP in the UAD, the most frequent clinical symptoms are obstruction of the respiratory tract due to tumor growth, epistaxis, rhinorrhea, pain, and swelling of the soft tissue of the neck.30 If there is suspicion of EMP, then a series of examinations is required to establish the diagnosis.
Evaluation of a primary (true) EMP
Diagnostic procedures should be carried out in two steps: An extensive imaging with computed tomography and magnetic resonance imaging31 and a complete endoscopic examination (including a tracheobronchoscopy and endoscopy of the main nasal cavities and the nasopharynx) of the ear, nose, and throat under general anesthesia are required to determine the exact extent of the tumor. Similar endoscopic examinations (i.e., gastroscopy, etc.) are required for EMP in other anatomic regions. Due to the submucosal growth of extramedullary plasmacytomas, deep biopsies, open biopsies, or, depending on the location, complete excision of the tumor are required to histologically confirm the diagnosis. The differential diagnostic evaluation often is very difficult because of the similarity of the histologic appearance of EMP to that of other tumors (i.e., lymphoma, undifferentiated carcinoma, esthesioneuroblasts, etc.) or because the benign inflammatory plasma cell granuloma is large and requires immunohistochemical demonstration of monoclonal kappa or lambda light chains or heavy chains found in plasma cell tumors (IgA, IgD, IgG, IgM).14, 32 Congo red stains are positive in amyloid deposits, which are the result of deposition of light chains in soft tissue.33
The diagnosis of extramedullary plasmacytoma is based on the morphologic and immunophenotypical finding of a localized collection of monoclonal plasma cells in the absence of plasma cell proliferation elsewhere, especially in the bone marrow, and without the presence of malignant lymphoma. EMP must be particularly distinguished from low grade B-cell non-Hodgkin lymphoma, which also may show plasmacytic differentiation, for example, as is seen in lymphoplasmacytic lymphoma. Similar features also can be seen in follicular lymphoma, monocytoid B-cell lymphoma, and extranodal marginal zone lymphoma (low grade lymphoma of the mucosa-associated lymphoid tissue [MALT] type), which often occur in the same locations as EMP.34, 35 Other than morphologic criteria, including centrocyte-like cells, reactive follicles, or the presence of lymphoepithelial lesions, immunostaining for perinuclear or cytoplasmatic Ig expression (IgM rather than IgA or IgG), kappa or lambda light-chain restriction, or the lack of B-lymphocyte antigens (such as CD20) are helpful in differentiating MALT lymphoma from EMP.33–35 In our cases, there was no evidence of nonplasmacytic neoplastic component, and the cells showed the typical features of plasma cells. We observed centrocyte-like cells that were interpreted as infiltrating reactive lymphocytes and not as a neoplastic part of the tumor. Neither lymphoepithelial lesions nor reactive follicles were present. The Ig heavy-chain expression of our 7 cases were IgA or IgG, and all presented cases showed negative staining for the CD20 antigen.
Although there is some evidence in the literature that supports the categorization of EMP as extranodal marginal zone lymphoma (low grade lymphoma of MALT type),37, 38 our results support the classification of our cases as EMP rather than extranodal marginal zone lymphoma (low grade MALT lymphomas). Table 1 shows that immunohistochemical studies revealed the type of immunoglobulins being synthesized by the neoplastic cells in six patients of our clinical group. Mostly IgG immunoglobulins were detected. These findings are in accordance with the results of our literature search, in which 40.4% of EMP cases in the UAD and 54.3% of EMP cases in the remaining body parts produced IgG immunoglobulins. According to the study by Mock et al.,39 the development of myeloma in patients with EMP was observed to occur much more commonly in those producing non-IgG immunoglobulin classes and might support the concept that some EMP cases may be an early manifestation of MM. The criteria used for the histologic grading of extramedullary plasmacytomas were established by Bartl et al. (1987)4 for MM: Grade 1, low grade; Grade 2, intermediate grade; and Grade 3, high grade. In 1976, Wiltshaw40 classified EMP according to three stages: Stage I, EMP limited to an extramedullary site; Stage II, regional lymph nodes affected; and Stage III, multiple metastases. In the literature research, we found that, in 55 cases (7.6%) of EMP in the UAD and in 4 cases (2.6%) in non-UAD areas, regional lymph nodes were involved. If a plasmacytoma is confirmed histologically, then secondary diagnostic procedures must be carried out to exclude systemic involvement.
For the second diagnostic step they should consist of the following examinations: laboratory examinations, including blood sedimentation rate, a complete blood count and blood smear, electrolytes (including Ca2+) and enzyme determination, serum and urine protein electrophoresis, quantitative Ig determination in serum, immunoelectrophoresis and/or immunofixation in serum and in urine, and beta-2-microglobulin determination in serum. For true EMP, chemical laboratory findings are normal, except for the quantitative Ig determination. At the time of diagnosis of EMP, a monoclonal gammopathy is present in approximately 25% of cases of EMP and disappears after successful treatment of the tumor.41 A systemic X-ray examination of the skeleton (cranium, cervical spine, thoracic spine, pelvis, etc.) is definitely required for further diagnosis. An involved skeleton (osteolytic lesions) excludes true EMP and is consistent with MM or SPB. A bone marrow biopsy and aspiration is of utmost importance to determine the percentage of plasma cells. Although some authors accept that less than 10% of plasma cells in a bone marrow smear is compatible with EMP,42 others require that this should be less than 5%.43 We agree with the latter percentage, because, at the onset of MM, many patients have less than 10% of plasma cells in the bone marrow smear.2
There currently are no general guidelines for the treatment of patients with EMP. However, based on the well-known radiation sensitivity of the plasma cell tumor, radiotherapy is accepted as the treatment of choice for EMP.41 The total radiation dose administered ranges between 40 Gy and 60 Gy and is given over a period of 4–6 weeks.41 Surgery or combined therapy (surgery and XRT) has been applied as often as XRT alone in the treatment of EMP in the UAD (Fig. 4, top). Single patients who underwent chemotherapy with or without combined treatment (i.e., XRT, surgery) are also described.41 Detailed evaluation of the literature revealed that, comparing the three types of therapy described above (Fig. 4) for the treatment of patients with EMP in the UAD, 61.1% of patients (n = 436) were recurrence free or without systemic involvement, 22.0% (n = 157) had a local recurrence, and 16.1% (n = 115) had disease that converted to MM (Fig. 7, top). Six patients (0.8%) with EMP developed solitary plasmacytoma of the bone (SPB). The observation period for all patients with EMP in the UAD ranged from 5 months to >350 months. In our patient group, we achieved local control without evidence of systemic involvement for 50 months (range, 11–102 months).
After treatment of EMP in non-UAD regions, 64.7% of all patients (n = 100) had no recurrence or systemic involvement, 21.2% (n = 33) had recurrence, and 14.1% (n = 22) converted to MM (Fig. 7, bottom). These data may emphasize that patients with EMP in locations other than the UAD have outcomes similar to patients with EMP in the UAD. The observation period for these cases ranged from 5 months to over 140 months. Contrary to these findings, Dimopoulos et al.44 reported that patients suffering from SPB developed a systemic involvement (i.e., MM) in two-thirds of cases: Other authors describe conversion to MM in 53% (Holland et al.45), in 48% (Knowling et al.43), and in 50 % (Corwin and Lindberg42), respectively. Patients with MM rarely have a survival time of longer than 10 years (<10%), depending on the classification of the cell type.2, 41
Of all plasma cell tumors, EMP has the best prognosis. According to Holland et al.,45 36% of patients with EMP had conversion to MM compared with 8% of the patients described by Knowling et al.43 and 17% of the patients described by Corwin and Lindberg.42 In our search, we found that EMP converted to MM in 16.1% of the patients with EMP in the UAD and in 14.1% of the patients with EMP in non-UAD areas. There is some evidence that patients with EMP who receive XRT alone tend to have a higher risk of progression to MM compared with those treated with surgical intervention or with combined therapy (surgery and XRT; Table 4). These data are consistent with our clinical group, despite the fact that we had only seven patients. All of our patients underwent surgery, and five received additional XRT (i.e., combined therapy). None developed a recurrence or a systemic involvement in the observation period (median follow-up, 50 months).
Table 4. Extramedullary Plasmacytoma of the Upper Aerodigestive Tract: Conversion to Multiple Myeloma Dependent on Treatment According to the Literature Search
|Surgery and radiation||13.5|
We have attempted for the first time to survey all EMP cases found in the UAD and in other locations published in the medical literature. Referring to our own clinical experience with patients suffering from EMP, we recommend the following therapeutic concept. If EMP is present in the soft tissue and is locally and well operable, then surgical excision usually is sufficient.46 Of all of the patients with EMP outside the UAD, 55.6% were treated with surgery alone. However, complete removal of an EMP often is not possible, especially in the UAD, because adjacent vital organ structures may preclude a radical intervention. For such patients, we recommend surgery followed by XRT. This combined therapy seems to provide the best results for treating patients with EMP in the UAD (Fig. 5). However, because the present investigation is predominantly a retrospective study, these results should be confirmed in a multicenter randomized trial.
Patients who are diagnosed with primary EMP remain under life-long medical observation, because, even if therapy is successful, relapses or a generalized plasmacytoma still may appear years later. The use of positron emission tomography may be helpful for the detection of locally recurrent disease.