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Multi-Institutional Analysis of Solitary Extramedullary Plasmacytoma of the Head and Neck Treated With Curative Radiotherapy

International Journal of Radiation Oncology*Biology*Physics, 2, 82, pages 626 - 634

Purpose

The purpose of this study was to elucidate the efficacy and optimal method of radiotherapy in the management of solitary extramedullary plasmacytoma occurring in the head and neck regions (EMPHN).

Methods and Materials

Sixty-seven patients (43 male and 24 female) diagnosed with EMPHN between 1983 and 2008 at 23 Japanese institutions were reviewed. The median patient age was 64 years (range, 12–83). The median dose administered was 50 Gy (range, 30–64 Gy). Survival data were calculated by the Kaplan-Meier method.

Results

The median follow-up duration was 63 months. Major tumor sites were nasal or paranasal cavities in 36 (54%) patients, oropharynx or nasopharynx in 16 (23%) patients, orbita in 6 (9%) patients, and larynx in 3 (5%) patients. The 5- and 10-year local control rates were 95% and 87%, whereas the 5- and 10-year disease-free survival rates were 56% and 54%, respectively. There were 5 (7.5%), 12 (18%), and 8 (12%) patients who experienced local failure, distant metastasis, and progression to multiple myeloma, respectively. In total, 18 patients died, including 10 (15%) patients who died due to complications from EMPHN. The 5- and 10-year overall survival (OS) rates were 73% and 56%, respectively. Radiotherapy combined with surgery was identified as the lone significant prognostic factor for OS (p = 0.04), whereas age, gender, radiation dose, tumor size, and chemotherapy were not predictive. No patient experienced any severe acute morbidity.

Conclusions

Radiotherapy was quite effective and safe for patients with EMPHN. Radiotherapy combined with surgery produced a better outcome according to survival rates. These findings require confirmation by further studies with larger numbers of patients with EMPHN.

Extramedullary plasmacytoma, Radiotherapy, Head and neck, Multi-institutional analysis.

Introduction

Plasma cell malignancies include multiple myeloma (MM), solitary plasmacytoma of the bone (SPB), and extramedullary plasmacytoma (EMP). EMP is a rare tumor representing approximately 3% of all plasma cell tumors, yielding an MM:SPB:EMP incidence ratio of approximately 40:2:1 (1), (2), (3), and (4). The incidence of EMP has been measured at 0.04 cases per 100,000 individuals (5) . Although EMP can arise throughout the body, almost 90% of tumors arise in the head and neck, especially in the upper respiratory tract, including the nasal cavity, sinuses, oropharynx, salivary glands, and larynx (4), (6), (7), (8), (9), and (10). The next most frequent site of occurrence is the gastrointestinal tract. A variety of other sites, including testis, bladder, urethra, breast, ovary, lung, pleura, thyroid, orbit, brain, and skin, can be involved, albeit infrequently (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), and (21). Patients typically present in the fifth to seventh decade of life with localized submucosal masses or swellings and symptoms related to compression and obstruction of local structures.

Solitary extramedullary (soft-tissue) plasmacytoma is less common than SPB but carries a better prognosis, because the majority of patients can be cured by local radiotherapy (22) . The optimal management of EMP of the head and neck (EMPHN) is a matter of debate. Radiotherapy plays a central role in the treatment of EMP, even though the optimal radiationdose and the role of elective irradiation of regional lymphatics are still undetermined (23) . Surgery can also be considered as an alternative first-line therapy (6) . Surgery can achieve high rates of local control in certain situations. However, radical excision is often impossible because of the size of the tumor, the proximity of critical normal structures and the risk of poor cosmetic results. Potential morbidity associated with surgery and the radiosensitivity of EMP have made radiotherapy the mainstay of treatment at most centers (7) and (24). On the contrary, the role of chemotherapy in the treatment of primary tumors or recurrent disease or in preventing or delaying progression to MM remains controversial (3), (25), and (26). Adjuvant chemotherapy has not been shown to reduce relapse rates or to improve survival rates and, at present, has no place in the primary management of EMP (24), (27), and (28). Therefore, close communication among radiation oncologists, surgeons, and hematological oncologists is crucial for the optimum care for this disease.

The purpose of this study was to elucidate the efficacy and the optimal method of radiotherapy in the management of EMPHN.

Patients and Methods

Medical records of all patients treated for EMPHN at 23 institutions in Japan between 1983 and 2008 were retrospectively reviewed. Patients were identified from databases at each institution. This study was approved by the Kobe University Hospital and each relevant institutional Review Board. Patients were considered eligible for inclusion if they had a single lesion in the head or neck and a diagnosis of EMP based on a biopsy showing features characteristic of plasmacytoma, a negative skeletal survey, and a normal bone marrow biopsy. Patients with evidence of myeloma at the time of presentation were excluded. Then, a total of consecutive 67 patients from the 23 institutions were investigated. In general, patients were seen at follow-up evaluations every 3 months for the first 2 years, every 6 months for an additional 3 years, and then yearly or every other year thereafter. Follow-up imaging included fiberoptic endoscopy at each visit and computed tomography and/or magnetic resonance imaging every 6–12 months.

Statistical analysis

Statistical analysis was performed using Statview software (SAS Institute, Cary, NC) . Time to event was calculated from the starting date of radiotherapy to the event of interest, which was death (from any cause) for overall survival, first failure (death or disease) for disease-free survival (DFS), and local recurrence as confirmed by biopsy for recurrence rates. The Kaplan-Meier method was used to calculate the survival and recurrence curves. Follow-up duration was estimated for surviving patients. Differences in local recurrence rates between factors were calculated using the log–rank test.

Results

Patients and treatments

Details of tumor characteristics are shown in Table 1 . The median age at diagnosis was 64 years, with a range of 12–83 years. In this study, 43 patients were male, and 24 patients were female. The median tumor size was 3.5 cm (range, 1–10 cm). The most frequent tumor sites were nasal or paranasal cavities. Proportions of patients with positive M protein, Bence-Jones protein, and concomitant disease are listed in Table 1 . External beam radiation therapy was used in all cases. A 4- to 10-megavolt photon beam was primarily applied for 57 patients, whereas a telecobalt gamma ray was used for 8 patients. Electron beam irradiation was used for 2 patients. The radiation dose ranged from 30 to 60 Gy, with a median dose of 50 Gy. Treatment policies, radiation dose, and radiation fields are listed in the Table 2 . Although all patients were treated with 1.8–2 Gy per fraction, total doses were ranging from 30 to 64 Gy, and biological effective doses (BED) were ranging from 36 to 76.8 Gy calculated by using a ration of α/β = 10 ( Table 2 ). The treatment methods, choice of total dose, and choice of irradiation for regional lymph nodes were depending on each physician’s decision. Treatment choice was not differ significantly according to the age (<50 or ≥50) ( Table 2 ). Radiation dose did not differ significantly as a function of tumor size in a subgroup without surgery (p = 0.75) and in a subgroup with surgery (p = 0.33) ( Table 3 ).

Table 1 Patients and tumor characteristics

  Number Percentage (%)
Age 12–83 (64)  
Gender (M/F) 43/24  
ECOG performance status 46/18/1/2  
(0/1/2/unknown)    
Tumor size 1–10 cm (3.5)  
Sites    
 Nasal/paranasal 36 54
 Oropharynx 9 13
 Nasopharynx 7 10
 Orbita 6 9
 Larynx 3 5
 Salivary glands 2 3
 Lymph nodes 2 3
 Middle ear 1 1.5
 Thyroid 1 1.5
Positive for M protein 15/59 22
Positive for Bence-Jones proteins 2/56 4
Concomitant disease    
 Amyloidosis 2/67 3

median age, median tumor size.

Table 2 Details of treatments

  Total numbers of patients (%) Age <50 Age ≥50 p value
Treatment policy        
 Without surgery 44 (66) 10 34 0.93
  Radiotherapy alone 39 (58) 8 31  
  Radiotherapy combined with chemotherapy 5 (8) 2 3  
 With surgery 23 (34) 5 18  
  Surgery followed by radiotherapy 19 (28) 4 15  
 Radiotherapy followed by surgery with or without chemotherapy 4 (6) 1 3  
 Radiation dose (BED: median, minimum, and maximum)        
 Median: 50 Gy, 1.8–2 Gy per fraction        
 ≤40 Gy (BED: 46.7, 36, and 48) 13 (20) 4 9 0.41
 40.1–45 Gy (BED: 51, 50.4, and 53) 4 (6) 1 3  
 45.1–50 Gy (BED: 60, 55.2, and 60) 39 (58) 6 33  
 50.1–64 Gy (BED: 72, 59.5, and 76.8) 11 (16) 4 7  
Radiation fields        
 Primary sites 51 (76) 11 40 0.2
 Primary sites and regional nodes 16 (24) 6 10  

Subgroups treated radiotherapy without surgery (n = 44) or with surgery (n = 23) were evaluated by a chi-square test.

Abbreviation: BED = biologically effective dose.

α/β = 10.

Table 3 Relationship of tumor size and radiation dose in patients treated with radiotherapy and without surgery

Radiation dose Total numbers of patients (%) Tumor size p value
≤5 cm >5 cm
Without surgery (n = 42)        
 ≤45 Gy 10 8 2 0.75
 >45.1 Gy 32 27 5  
With surgery (n = 16)        
 ≤45 Gy 5 4 1 0.33
 >45.1 Gy 11 6 5  

Two cases were excluded because their tumor sizes were not identified exactly.

Seven cases were excluded with the same reason.

Local control

The median follow-up duration was 63 months. Local recurrences developed in 7.5% of patients (5 of 67). The mean time from diagnosis to local recurrence was 65 months (median, 52 months). The overall 5- and 10-year local control (LC) rates were 95% and 87%, respectively ( Fig. 1 A). Only a single patient recurred locally, whereas 4 other patients had both local and distant diseases. Of 5 patients who developed local recurrences, 3 died of the disease. Regarding 2 other patients who experienced local recurrence, 1 was successfully treated and is alive without disease and the other developed multiple myeloma. Next, among 44 patients who treated radiotherapy and without surgery, influence of tumor size on local controllability was evaluated. Although 2 patients were excluded because their tumor size was not exactly determined, the tumor size was not a significant factor for the local control in the 42 patients (p = 0.46, Fig. 1 B).

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Fig. 1 (A) Local control rate for extramedullary plasmacytoma of the head and neck (EMPHN) (n = 67). (B) Comparison of local control rate according to the tumor size in patients treated with radiotherapy and without surgery (n = 42). Log–rank test was used for evaluation.

Disease progression and progression to MM

Disease progression was observed in 36% of patients (25 of 67). The 5- and 10-year DFS rates were 56% and 54%, respectively ( Fig. 2 ). Among patients with disease progression, 8 patients (12%) were diagnosed with progression to MM. The median duration of progression to MM was 18 months (range, 6–71 months). Among other 17 patients, 1 experienced local recurrence alone, 4 patients did both local and distant recurrence, and 12 did distant recurrence alone. Next, patterns of failure sites and the radiation fields were investigated ( Table 4 ). Only 1 patient who was treated to the primary tumor site without regional lymph nodes irradiation experienced regional lymph nodes recurrence, while none who were irradiated both primary and regional lymph nodes did. Salvage treatment was performed as follows: radiotherapy in 7 patients, chemotherapy in 9 patients, and surgery in 2 patients (including a patient treated with chemotherapy and surgery). The remaining 7 patients were followed only by careful observation.

gr2

Fig. 2 Disease-free survival rate for extramedullary plasmacytoma of the head and neck (EMPHN) (n = 67).

Table 4 Patterns of recurrence according to the radiation fields

Radiation fields Total numbers of patients Controlled (%) Sites of recurrence
Local (%) Regional lymph nodes (%) Progression to MM or distant metastases (%)
Primary tumor 51 29 4 1 21
Primary tumor and regional lymph nodes 16 13 1 0 2
Total 67 42 (62) 5 (7.5) 1 (1.5) 23 (34)

4 patients experienced both local recurrence and progression to MM.

Abbreviation: MM = multiple myeloma.

Survival

The overall 5- and 10-year survival rates were 73% and 56%, respectively ( Fig. 3 ). The cause-specific 5- and 10-year survival rates were 82% and 76%, respectively. At last follow-up, 18 patients had died. Among those patients, 10 (15%) had died of the disease, whereas 8 patients (12%) died of other diseases.

gr3

Fig. 3 Overall survival rate for extramedullary plasmacytoma of the head and neck (EMPHN) (n = 67).

Prognostic factors for overall survival

Several factors were evaluated to determine whether they influenced overall survival. Radiotherapy combined with surgery was identified as the lone significant prognostic factor for overall survival (OS) (p = 0.04), whereas tumor size, age, gender, radiation dose, and chemotherapy were not predictive ( Fig. 4 , Table 5 ). To exclude the possibility of selection bias, an influence of age was evaluated. As shown in the Table 2 , the cohorts of patients who were treated radiotherapy combined without surgery, and of patients with surgery, proportions of younger subgroup (≤50 years) and that of older subgroup did not differ significantly (p = 0.93). Of course, although larger numbers of cases and prospective studies will be needed, our results ( Fig. 4 ) might not be influenced by a selection bias especially in regard with age.

gr4

Fig. 4 Overall survival rates according to patients who received radiotherapy either with surgery (n = 23) or without surgery (n = 44).

Table 5 Prognostic factors for overall survival

Prognostic factors p value
Tumor size  
 ≤5 cm (n = 45) vs. >5 cm (n = 13) 0.59
Age  
 ≤50 (n = 15) vs. >51 (n = 52) 0.3
Gender  
 Male (n = 43) vs. female (n = 24) 0.95
Radiation dose  
 ≤40 Gy (n = 13) vs. >40.1 Gy (n = 54) 0.82
 ≤45 Gy (n = 17) vs. >45.1 Gy (n = 50) 0.73
 ≤50 Gy (n = 56) vs. >50.1 Gy (n = 11) 0.72
Surgery  
 With surgery (n = 23) vs. without surgery (n = 44) 0.04
Chemotherapy  
 With chemotherapy (n = 9) vs. without chemotherapy (n = 58) 0.75

Morbidities associated with radiotherapy

Acute morbidity was examined according to CTCAE version 3.0. Data regarding radiation dermatitis and radiation mucositis were obtained from 44 (66%) patients. Of these, 8 patients had Grade 2 radiation dermatitis, and 27 patients had Grade 1 radiation dermatitis ( Table 6 ). A single patient experienced Grade 3 radiation mucositis, 13 patients experienced Grade 2, and 20 patients experienced Grade 1. No patient experienced morbidity after radiotherapy.

Table 6 Adverse effects after the radiotherapy according to CTCAE ver. 3.0

  Grade
0 1 2 3 4 5
Dermatitis 9 27 8 0 0 0
Mucositis 10 20 13 1 0 0

A case successfully treated with radiotherapy combined with surgery

A 70-year-old male suffered from a vast tumor located in the nasal cavity and extending to the paranasal cavity. At first, a radical surgery was planned, but the planned procedure seemed to be extremely invasive because the tumor had invaded into the base of the skull. Therefore, radiotherapy was employed as an initial treatment for this disease, and a total of 60 Gy (in 30 fractions over 6 weeks) was delivered using three-dimensional conformal radiotherapy ( Fig. 5 ). At 3 months after the completion of radiotherapy, a residual tumor was observed at the concha nasalis media, and a less invasive tumorectomy was performed. The case was not expected to be cured by a single modality (either surgery or radiotherapy), but radiotherapy combined with surgery was successfully applied to the extensive EMPHN tumor (>5 cm in diameter) ( Fig. 6 ).

gr5

Fig. 5 A 70-year-old male patient suffered from a vast extramedullary plasmacytoma (EMP) located in the nasal and the paranasal cavities treated by three-dimensional conformal radiotherapy (3D-CRT). (A) A port of the 3D-CRT avoiding right optic nerve, right eye, and optic chiasm. (B) Directions and images of the five ports illustrated by using Xio software. (C) The isodose curves for the patient. (D) The dose‒volume histogram (DVH) of the 3D-CRT plan.

gr6

Fig. 6 Magnetic resonance imaging (MRI) of the 70-year-old male patient treated with the radiotherapy followed with the surgery. (A) Pretreatment images of the extramedullary plasmacytoma of the head and neck (EMP) located in the nasal cavity extended to the paranasal cavity. (B) A coronal image of MRI showing an invasion of the base of the skull. (C, D) Axial and coronal images of the residual tumor at the concha nasalis media shrunk after the radiotherapy. (E, F) Images of nasal and paranasal cavities after the surgical removal.

Discussion

Our study represents one of the largest in terms of scale (that is, a large number of patients with solitary EMP of the head or neck regions treated at multiple institutions with sufficient follow-up duration) ( Table 7 ).

Table 7 Comparison and reviews of literatures for plasmacytoma of the head and neck

Series (ref.) Year Institution Numbers of patients Follow-up (m) Dose (median) OS (%) LCR (%) DFS (%)
5-y 10-y 5-y 10-y 5-y 10-y
Liebross (4) 1999 Single 22 44 40–60 (50) 73 50 95 95 56 NA
Chao (37) 2005 Single 16 66 40–50.4 (45) 85 54 100 100 75 75
Tournier-Rangeard (32) 2006 Single 17 80 40–65 (52.6) 82 63 88 73 64 54
Bachar (41) 2008 Single 68 96 10–50 (35) 76 56 91 88 NA NA
Creach (34) 2009 Single 18 82 34–56 (50.4) 80 54 NA NA 74 53
Present study 2010 Multiple 67 63 30–60 (50) 73 56 95 87 56 54

Abbreviations: DFS = disease-free survival; LCR = local control rate; OS = overall survival.

Solitary EMP is believed to be radiosensitive. However, because of the rarity of the disease, there have been few reports concerning the effective radiation dose. Several investigators have reported that local control rates of 80–100% are consistently found after moderate doses of radiotherapy (2), (3), (4), (25), (29), (30), (31), (32), (33), (34), (35), (36), and (37). Tsang et al. (29) achieved local control in 13 of 14 (93%) of patients with a dose of 35 Gy. The only failure was in a patient with a large primary tumor (>5 cm). Similarly, Jyothirmayi et al. (30) achieved local control in 6 of 7 patients with doses of 35–45 Gy (median dose, 40 Gy in 20 fractions). The only failure was in a patient with an extensive nasopharyngeal tumor. Holland et al. (25) also reported poorer local control in tumors >5 cm and similarly observed no evidence of a radiation dose–response effect over a dose range of 16–62 Gy (median dose, 46 Gy). Several series have reported 100% local control rates. Bolek et al. (31) reported 100% local control in 10 patients with doses ranging from 9 to 50 Gy (median dose, 45 Gy) and concluded by recommending a dose of 40 Gy in 20 fractions. Shih et al. (3) reported on 10 patients with SEP, seven of whom were treated with radiotherapy, using doses of 47–65 Gy. Tounier-Rangeard et al. (32) reported that a minimum dose of 45 Gy is recommended to the clinical target volume (CTV) of an EMPHN tumor. Mendenhall et al. (33) reported a study of 81 patients composed of a literature review and their own patients. These authors found a local control rate of 94% when the dose to the CTV was greater than 40 Gy and a rate of 69% when the dose to the CTV was less than 40 Gy. Creanch et al. (34) reported excellent local control in their series of 16 consecutive patients receiving a median dose of 50.4 Gy. The optimal radiation dose recommended by the UK Myeloma Forum in their 2004 guidelines is in the range of 40–50 Gy (35) . In the guideline, tumors with SEP <5 cm have an excellent chance of local control with radiation doses of approximately 40 Gy in 20 fractions. There is a higher risk of local failure in tumors >5 cm, which require a higher dose (approximately 50 Gy in 25 fractions). From these previous investigations, it seems that the optimal radiation dose is in the range of 40–50 Gy, although tumor size might be a critical factor affecting local control. In our series from multiple institutions, with a similar median dose of 50 Gy administered (range, 30–60 Gy), the local control rate was similar and consistent with these previous reports ( Table 7 ). From the results of our series, significance of regional lymph node irradiation seemed to be still undetermined. However, it was at least speculated that progression to multiple myeloma or distant metastases was observed more frequently and seemed to be much more important than regional lymph nodes ( Table 4 ). The subject whether, in any subgroup of plasmacytoma of the head and neck, single modality of radiotherapy could achieve comparable or favorable treatment outcome should be discussed and further investigated. For example, overall survival rate of a subgroup consisted of 20 cases treated with radiotherapy, without surgery, and whose tumor sizes were less than 3 cm were almost similar to those of all 67 cases with or without surgery (5-year OS: 76% vs. 73%; and 10-year OS: 51% vs. 56%, respectively) (data not shown). Therefore, a single modality of radiotherapy might be applied if a tumor size was less than 3 cm. Although local controllability by either a single modality of radiotherapy or a combination of radiotherapy and surgery seemed to be satisfying, it might be discussed whether the local controllability could be truly led to prolong OS of the disease or not. In this study, population who received chemotherapy was small, and it was difficult to evaluate the efficacy of the chemotherapy. Further investigation, for example, into the significance of radiotherapy combined with chemotherapy might be evaluated. On the contrary, with using recent technological advances such as intensity-modulated radiotherapy (IMRT), image-guided radiotherapy, IGRT, or particle therapy, morbidities might be reduced compared with the morbidities of this study treated by conformal X-ray beams. Employment of such modalities might be recommended in the recent future.

Progression to multiple myeloma is also important for the outcome of solitary EMP. Unlike SPB, which progresses to disseminated disease in approximately 60% of cases, solitary EMP has a better prognosis, with 8–44% of patients developing multiple myeloma (1), (2), (4), (6), (9), (25), (27), (28), (32), (38), (39), (40), and (41). In our series, although 12% of patients developed MM (with an average time to myeloma development of 17 months), 18% of patients experienced distant metastases but were not diagnosed with progression to MM. In the literature, progression to multiple myeloma usually occurs within 2 years of the initial diagnosis, but has occurred up to 15 years later, indicating the need for long-term follow-up of patients (4), (6), (28), (39), (41), and (42). As shown in the Table 4 , there were only 1 patient who was treated to primary tumor site that experienced a regional lymph node recurrence. Therefore, it was still difficult to answer the question whether regional lymph nodes should be included in the radiation field form our series. However, significance of regional lymph node irradiation seemed to be undermined, because our series included various primary sites, various tumor size, and inhomogeneous total dose. Therefore, further larger scale investigation might be needed. Although the results of our series show a rather small percentage of patients developing MM, longer and careful follow-up observation might be needed.

The role for surgery in the treatment of EMPHN is undetermined. Alexiou et al. (7) compared the outcomes of EMP patients treated with surgery alone, radiotherapy alone, or combined surgery and radiotherapy in a detailed and large-scale review. Most of the patients were treated with surgery alone (56%) or a combined-modality treatment (20%), and only 11% were treated with radiotherapy alone. Overall and recurrence-free survival rates were best in those treated with combined therapy (p = 0.0027). The authors concluded that patients with plasmacytoma localized to the upper aerodigestive tract benefit from a combined approach. On the contrary, there are some criticisms of the analysis, because the review included patients from a long period (almost a century, 1905‒1997), and appropriate radiotherapy might not have been available in any meaningful form for at least half of this period. In the guidelines regarding this disease published by Soutar et al. (35) , it is recommended that radical surgery should be avoided in EMPHN. In the same report, complete surgical removal was suggested to be considered for solitary EMP at other sites if feasible. Bachar et al. (41) demonstrated that patients with involved surgical margins should receive adjuvant radiotherapy. However, no recommendation for adjuvant radiotherapy should be made for patients with negative margins who have undergone complete surgical excision. The authors reported that they found a similar local recurrence rate for patients treated with either radiation or surgery alone (12.5%). They also indicated that complete surgical excision is often not possible, especially in the upper aerodigestive tract, because adjacent vital organ structures may preclude radical intervention. For such patients, either radiotherapy followed by surgery, if needed, or surgical excision followed by radiotherapy is recommended. In our series, a group of 19 patients who received surgery followed by postoperative radiotherapy and 4 patients who received radiotherapy and surgery showed significantly better overall survival. This result indicates that combining radiotherapy with surgery might be less invasive and may represent an optimal strategy for treating EMPHN.

Some authors believe that EMP and multiple myeloma are different phases of the same disease process (43) , whereas others believe that they are different diseases (44) . If solitary EMP is an initial stage of MM, chemotherapy might play a more important role in management of the disease. However, in the literature and in our series, progression to MM occurred in a rather small proportion of patients. There is no published evidence on the role of adjuvant chemotherapy in the treatment of SEP, although it may have a role in selected high-risk patients. Susnerwala et al. (9) reported a higher failure rate in “high-grade” tumors using the MM grading criteria of Bartl et al. (36) . Tsang et al. (29) and Holland et al. (25) suggested that patients with tumors >5 cm are at higher risk of failure. The UK Myeloma Forum (35) has suggested that chemotherapy is considered for EMP in the following cases: patients with tumors larger than 5 cm, patients with high-grade tumors, patients with refractory and/or relapsed disease, and patients with MM.

In conclusion, radiotherapy was effective and safe for patients with EMPHN. Radiotherapy combined with surgery produced a better outcome in terms of survival. These findings should be confirmed using further investigations with larger numbers of patients with EMPHN.

Acknowledgment

Grants-in-aid 18209040 and 21249066 (S.Y., R.S.) for Scientific Research, Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

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Footnotes

Division of Radiation Oncology, Kobe University Graduate School of Medicine

¶¶ Division of Otolaryngology–Head and Neck Surgery, Kobe University Graduate School of Medicine

Department of Radiology, Hokkaido University School of Medicine

Division of Radiation Oncology, Graduate School of Medical and Dental Sciences, Niigata University

§ Department of Radiation Oncology, Shimane University Faculty of Medicine

Radiation Oncology Division, National Cancer Center Hospital East

Department of Radiology, Graduate School of Medicine, Chiba University

# Department of Radiology, Hyogo College of Medicine

∗∗ Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University

†† Radiation Oncology Division, National Cancer Center Hospital

‡‡ Department of Radiology, Nagoya City University Graduate School of Medical Sciences

§§ Department of Radiology, Sapporo Medical University

‖‖ Department of Radiology, Osaka City University Graduate School of Medicine

## Department of Radiation Oncology, Tohoku University School of Medicine

Reprint requests to: Ryohei Sasaki, M.D., Ph.D., Division of Radiation Oncology, Kobe University Graduate School of Medicine, 7-5-2 Kusunokicho, Chuouku, Kobe City, Hyogo, 650-0017, Japan. Tel: +81-78-3826104; Fax: +81-78-3826129

Conflict of interest: none.