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10.1245/s10434-006-9053-5
Annals of Surgical Oncology 14:597-604 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Clinical Relevance of Pathological Grades of Malignant Peripheral Nerve Sheath Tumor: A Multi-Institution TMTS Study of 56 Cases in Northern Japan

Kyoji Okada, MD1,2, Tadashi Hasegawa, MD3, Takahiro Tajino, MD1,4, Tetsuo Hotta, MD1,5, Michiro Yanagisawa, MD1,6, Toshihisa Osanai, MD1,7, Jun Nishida, MD1,8, Kunihiko Seki, MD9 and Eiji Itoi, MD1,2

1 Tohoku Musculoskeletal Tumor Society, Yamagata, Japan
2 Department of Orthopedic Surgery, Akita University School of Medicine, Hondo 1-1-1, Akita 010-8543, Japan
3 Department of Surgical Pathology, Sapporo Medical University, Minami 1, Nishi 16, Sapporo 060-8543, Japan
4 Department of Orthopedic Surgery, Fukushima Medical University, Hikarigaoka 1, Fukushima 960-1295, Japan
5 Department of Orthopedic Surgery, Niigata University, Graduate School of Medicine and Dental Science, Asahichodori 1-757, Niigata 951-8510, Japan
6 Department of Orthopedic Surgery, National Hirosaki Hospital, Tominocho 1, Hirosaki 036-8545, Japan
7 Department of Orthopedic Surgery, Yamagata University School of Medicine, Iidanishi 2-2-2, Yamagata 990-9585, Japan
8 Department of Orthopedic Surgery, Iwate Medical School, Uchimaru 19-1, Morioka 020-8505, Japan
9 Pathology Division, National Cancer Center, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan

Correspondence: Address correspondence and reprint requests to: Kyoji Okada, MD; E-mail: cshokada{at}med.akita-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Malignant peripheral nerve sheath tumor (MPNST) is a relatively rare soft tissue tumor, and its clinical relevance of pathological grades remains obscure.

Methods: Fifty-six cases of MPNST identified from the files of seven oncology centers of the Tohoku Musculoskeletal Tumor Society (TMTS) and National Cancer Center were analyzed for histologic grades, demographics, treatments, and prognostic factors. The average follow-up period was 41 months.

Results: Twenty-two men and 34 women with a mean age of 45 years were involved. Forty-four (78.6%) of 56 tumors were in the lower extremity or trunk. Fifty tumors (89%) were classified as high grade, and the remaining six as low grade. Twenty-one (39.6%) of 53 patients who underwent tumor excision developed local recurrences. An axial site and inadequate surgical margin were defined as risk factors for local recurrence. The overall survival rates of the 56 patients were 55.1% at 3 years and 43.3% at 5 years. Univariate analysis of the 56 patients revealed large-sized tumors, metastasis at presentation, and histologically high grade were significantly associated with poor prognosis. Multivariate analysis revealed a large tumor and metastasis at presentation to be independent prognostic factors.

Conclusions: The current study involving 56 patients with MPNST showed the aggressive clinical behavior of the tumor. Large-sized tumors, metastasis at presentation, and high histological grade were related to poor prognosis on univariate analysis, but independency of histological grade was still obscure. In the treatment for a large and high-grade MPNST, an alternative strategy should be further considered.

Key Words: Malignant peripheral nerve sheath tumor • Sarcoma • Diagnosis • Histology


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Malignant peripheral nerve sheath tumor (MPNST) is a relatively rare malignant neoplasm, comprising approximately 5% of all malignant soft tissue sarcomas.1 Although MPNST has been generally regarded as a high-grade sarcoma with an aggressive clinical course and a high potential for metastasis,2–4 several authors have also reported its protracted nature in low-grade variants of MPNST.5–7 In this study, we evaluated the clinicopathologic features of 56 cases of MPNST treated at seven oncology centers in northern Japan, focusing on the prognostic impact of histological grades.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Seven oncology centers of the Tohoku Musculoskeletal Tumor Society (TMTS) and the National Cancer Center (Japan) participated in this retrospective collaborative study. Patients with MPNST who had been treated at each hospital between 1994 and 2002 were identified from files. The hematoxylin and eosin–stained slides of the primary tumors of these patients were sent to the National Cancer Center and reviewed by an expert pathologist (T. Hasegawa). All 56 cases were fulfilled the definitions of MPNST described previously,5,7 which is a tumor derived from a neurofibroma or arising de novo in a peripheral nerve, with the presence of a marble-like pattern, asymmetrically tapered spindle cells with irregular buckled nuclei, and palisading or whorled structures.

Cases were histologically classified as high grade (grades 3 or 2) or low grade (grade 1) tumors according to the World Health Organization grading system on the basis of nuclear atypia, cellularity, nuclear enlargement, hyperchromasia, mitotic rate, and necrosis. The mitotic rate was expressed as the average mitotic count present in 10 high-power fields, which were examined in each case. Representative blocks of formalin-fixed, paraffin-embedded tissues of the biopsy samples were cut to a 4-µm thickness and were examined by the labeled streptavidin-biotin method with appropriate use of negative controls throughout, after pretreatment with heat-induced epitope unmasking in a 10 mM citrate buffer, pH 6.0, in an autoclave at 121°C for 10 minutes. The primary antibodies for S-100 (x500; Dako, Tokyo, Japan) were applied in all 56 cases. In six cases of low-grade MPNST, immunoreactivity for epithelial membrane antigen (x100; Dako) was examined. Only homogeneous staining was assessed as 2+ positive; heterogeneous or focal staining was assessed as 1+.

Patient demographics, treatments, and outcomes were extracted from their clinical records. The demographic analysis included sex, age, duration of symptoms, tumor size and location, association with neurofibromatosis type 1 (NF1), and existence of metastasis at presentation. The margins of surgical excision were classified as intralesional (positive margin), marginal (within the reactive zone), or wide (beyond the reactive zone through normal tissue) according to the definition of Enneking and Maale.8 The average follow-up period for the 56 patients was 41 months (range, 2–156 months). All surviving patients were followed up over 2 years.

Survival rates were estimated by the Kaplan-Meier methods. The prognostic significance of the following variables on overall survival was determined by the log rank test: age (≥47 or <47 years), sex (male or female), duration of symptom (≥5 or <5 cm), tumor size (≥7 or <7 cm), tumor depth (subcutaneous or deep tissues), NF1, tumor site (trunk or extremities), histologic grade (low or high grades), S-100 expression (positive or negative), lung metastasis at presentation, chemotherapy, radiotherapy, and surgical margin of initial surgery (adequate or inadequate). Adequate surgery represented wide excision or amputation, and inadequate surgery included intralesional and marginal excision. Similarly, risk factors for local recurrence were estimated in 53 patients who underwent surgery. The relative risk of each variable for prognosis was estimated by Cox’s proportional-hazard model. Multivariate analysis was conducted with variable selection by a stepwise forward procedure. A probability of less than .05 was considered significant. All protocols were accepted by the institutional review boards of our institutions. Informed consent was obtained from all patients.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
There were 22 men and 34 women. The mean age at diagnosis was 45 years (range, 14–83 years), and the most common decade of life was the fourth decade. Twenty-two (47%) of 56 tumors were located in the lower extremities, 22 tumors were in the trunk, 7 were in the upper extremities, and 5 were in the head and neck (Fig. 1Go). With regard to lesion depth, 10 tumors were located in the subcutaneous tissues and 46 were in deeper tissues (Fig. 2Go). The tumor diameter of the largest tumor ranged from 2 to 23 cm (average, 8.7 cm). The most common symptom was pain; 29 patients (51.8%) noted pain or a painful mass, 22 patients noted a mass without pain, and the remaining 5 patients noted numbness both with and without muscle weakness of the extremities. Patients with MPNST associated with NF1 tended to experience pain; 15 (60%) of 25 patients with NF1 had pain, and 14 (45.2%) of 31 patients without NF1 had pain. The duration of symptoms, which was evaluated in 49 patients, varied from 1 to 62 months (average, 14 months). Three (5.4%) of 56 patients had lung metastatic lesions at presentation.


Figure 1
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  		FIG. 1. Demographics of 56 patients with malignant peripheral nerve sheath tumor (MPNST).

 

Figure 2
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  		FIG. 2. Magnetic resonance images of a 17-year-old woman with a lesion of the thigh (left upper, T1, 540/9; left lower, T2, 4440/99.2; right, gadolinium enhanced).

 
Histologically, all 56 tumors had marble-like patterns and whorled structures. Tumor cells were symmetrically tapered spindle cells with irregular buckled nuclei, and nuclear pseudoinclusions were frequently observed. Fifty (89.3%) of 56 tumors showed marked nuclear atypia, marked increased cellularity with nuclear enlargement, and hyperchromasia. Their mitotic rates were more than 10 per 10 high-power fields. These 50 tumors were classified as high-grade MPNST (Fig. 3AGo). In the 50 high-grade tumors, 3 showed epithelioid features resembling glands, and 1 showed marked and diffuse differentiation to cartilage and bone. Six (10.7%) of 56 tumors showed low to moderate cellularity with mild to moderate nuclear atypia. Their mitotic rates were <5 per 10 high-power fields, and necrosis was rare. Interlacing bundles of collagen and a moderate amount of extracellular fibromyxoid material were occasionally noted. Infrequently, epithelioid or hemangiopericytoma-like patterns were observed. There was no high-grade component in the six tumors. These six tumors were diagnosed as low-grade MPNST (Fig. 3BGo). S-100 was strongly positive in 19 cases, partially positive in 21 cases, and negative in 16 cases (Fig. 4Go). Positive rate of S-100 was 76%. In the six tumors diagnosed as low-grade MPNST, S-100 was strongly positive in five cases and positive in one case. There was no immunoreactivity for epithelial membrane antigen in the six tumors. Clinicopathologic details of the six cases with low-grade MPNST are listed in Table 1Go.


Figure 3
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  		FIG. 3. (A) Fifty (89.3%) of 56 tumors showed marked nuclear atypia and marked increased cellularity with nuclear enlargement and hyperchromasia. These 50 tumors were classified as high-grade malignant peripheral nerve sheath tumor (MPNST). (B) Six tumors showed low to moderate cellularity with mild to moderate nuclear atypia. Interlacing bundles of collagen and a moderate amount of extracellular fibromyxoid material were occasionally noted. These six tumors were diagnosed as low-grade MPNST.

 

Figure 4
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  		FIG. 4. Immunohistochemical feature for S-100. S-100 was strongly positive in 19 cases, partially positive in 21 cases, and negative in 16 cases.

 

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  		TABLE 1. Clinical data of six patients with low-grade malignant peripheral nerve sheath tumor
 
Surgical treatment was performed in 53 of 56 patients, and no surgery was performed in the remaining 3 patients. Initial surgical treatments constituted 23 wide excisions and 30 inadequate excisions (22 marginal excisions; 8 intralesional excisions). Nine patients received preoperative chemotherapy; 25 underwent postoperative chemotherapy. In chemotherapy, reagents used to treat other soft tissue sarcomas such as doxorubicin, ifosfamide, cisplatinum, and dacarbazine were used in various combinations. In the nine tumors treated with preoperative chemotherapy, the effect was clinically and histologically evaluated as "no change" in all nine cases. Preoperative radiotherapy was performed in four patients and postoperative radiotherapy in 13 patients. In the four patients treated with preoperative radiotherapy, the effect was clinically evaluated as "no change" in one and "partial response" in three patients. A total dose of 30 to 75 Gy was used for radiotherapy.

Twenty-one (39.6%) of 53 patients who underwent surgical treatment developed local recurrence. Durations between initial surgery and local recurrence ranged from 3 to 36 months (average, 14 months). Additional treatments for these 21 patients constituted wide excisions with or without chemotherapy in 6 patients, chemotherapy in 2 patients, and a combination of chemotherapy and radiotherapy in 5 patients. The remaining eight patients received no treatment because of their poor general condition and severe systemic extension of the tumor.

Three patients had metastatic tumors in the lung at presentation. Treatments for these three patients varied: a combination of systemic chemotherapy and radiotherapy for the primary tumor in one patient, marginal excision for the primary tumor with systemic chemotherapy in one, and no treatment in one. All three patients died of disease 4 months, 11 months, and 33 months after presentation, respectively.

In the follow-up study of the 53 patients who had no metastasis at presentation, 32 (57%) developed distant metastases including lung, bone, brain, and skin. Of these 32, all patients exhibited lung metastasis. Only 3 of 32 patients underwent thoracotomy with or without chemotherapy, and these 3 were alive without any evidence of disease at the latest follow-up. However, the remaining 29 patients had no thoracotomy for metastatic lesions, and all died of disease.

The univariate analysis of data for the 53 patients who underwent surgery found that axial sites and inadequate surgical margins were associated with high rates of local recurrence (Fig. 5Go). None of the other variables, including age, sex, duration of symptom, size, depth, NF1, histological grade, S-100 expression, metastasis at presentation, radiation, and chemotherapy, revealed important associations with local recurrence.


Figure 5
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  		FIG. 5. In the 53 patients who underwent surgery, an axial site and inadequate surgical margin were associated with a high rate of local recurrence. (A) Axial, tumors in axial sites (n = 27; median follow-up, 20 months), extremity, tumors in extremities (n = 29; median follow-up, 27 months). (B) Inadequate surgery (n = 23; median follow-up, 18 months) and adequate surgery (n = 30; median follow-up, 32 months).

 
Overall survival rates of the 56 patients were 55.1% at 3 years (95% confidence interval, 41.6–68.6), and 43.3% at 5 years (28.5–58.1). Univariate analysis of the 56 patients found that large size (≥7 cm), metastasis at presentation, and histological high grade were associated with a poor prognosis (Fig. 6Go, Table 2Go). There was no statistically significant association between the variables of age, sex, duration of symptom, depth, site, NF1, S-100 expression, surgical margin, radiation, chemotherapy, and survival. Multivariate analysis showed that only large size and metastasis at presentation were independent prognostic factors (Table 3Go).


Figure 6
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  		FIG. 6. Overall survival rates (A) of 56 patients were 55.1% at 3 years (95% confidence interval, 41.6–68.6) and 43.3% at 5 years (28.5–58.1). Univariate analysis of the 56 patients found that large size (≥7 cm), lung metastasis at presentation, and histologically high grade were significantly associated with poor prognosis. (B) Tumor size: ≥7 cm, large-size tumor (n = 32; median follow-up, 17 months), <7 cm, small-size tumor (n = 24; median follow-up, 34 months). (C) Metastasis: M1, lung metastasis at presentation (n = 3; median follow-up, 11 months), M0, no metastasis at presentation (n = 53; median follow-up, 32 months). (D) Grade: high grade (n = 50; median follow-up, 28 months); low grade (n = 6; median follow-up, 44 months).

 

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  		TABLE 2. Patient and tumor characteristics and univariate analysis for overall survival
 

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  		TABLE 3. Multivariate analysis for overall survival in 56 patients with malignant peripheral nerve sheath tumor
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this multi-institution study, we reviewed the clinical and pathologic records of 56 cases of MPNST to investigate the prognostic impact of clinicopathological features. Univariate analysis indicated that large tumor, lung metastasis at presentation, and a high-grade tumor were risk factors, and of these three factors, large tumor and lung metastasis at presentation were independent prognostic factors. The existence of lung metastasis at presentation in our three cases were confirmed by computed tomographic examination.

A systemic survey by modern imaging studies is essential for the staging of patients with sarcomas. In the literature, it has been described that older age, large tumor size, local recurrence, axial tumor site, inadequate surgery, NF1, and previous radiotherapy were related with poor prognosis.2,9–11 In regard to other histological features, only one report revealed a correlation between a high mitotic rate and poor prognosis.2 Although histological grading was found to be an important factor affecting survival and the distant control of many types of sarcomas, that of MPNST has not been well discussed. In 2003, Yamaguchi et al.7 reported four cases of MPNST that were histologically regarded as low grade (grade 1 of World Health Organization classification). All four showed better clinical outcomes. In 1998, a Mayo Clinic study analyzed the relationship between histological grading and prognosis in 134 patients with MPNST.12 In their study, they used four grading systems, and 14 (10%) of 134 were grade 1. The relationship between their grading system and prognosis was found to be statistically significant by univariate analysis, but was not significant by multivariate analysis. Similarly, in the current study, histological grade was statistically significantly related with prognosis by univariate analysis, but was not significant by multivariate analysis. Relatively few of the patients with low-grade tumors in the current study can be related with the negative results of the multivariate analysis.

The demographic characteristics of the current 56 cases, such as predominance of female sex (M:F = 22:34) and tumor location (78.6% in the lower extremities or trunk and 82% in deep tissues), were consistent with those documented in previous large studies,9,10,12–14 although the mean patient age (45 years old) in the current study was slightly older than in previous studies.10–12,14 It is well known that the mean age at presentation was younger for patients with NF1 than for patients without NF1.2,11 In the current study, the relatively small percentage of patients with NF1 (44.6%) might be associated with the difference.

In general, a painless mass or swelling was the most common symptom in patients with other types of soft tissue sarcomas, but patients with MPNST associated with NF1 tended to experience pain.15 Leroy et al.14 had mentioned that pain was a common symptom in his study of 17 patients with MPNST in 2001. In the current study, more than 50% of the patients experienced pain, and patients with NF1 tended to experience pain. In contrast to other types of soft tissue sarcomas, the mass effect of MPNST tends to cause numbness in regions of the affected nerve. In the current study, five patients noted numbness and/or muscle weakness of the extremities. In three of the five patients, the tumors occurred around the spine. In the other two patients, tumors arose from the sciatic nerve, and the chief complaint was numbness of the lower leg. These two were treated for a while under the misdiagnosis of lumbar disc herniation, and physical examination several months after the first visit revealed a mass at the posterior thigh. It should be stressed that palpation of the thigh or buttock is an essential procedure in the diagnosis of patients with numbness of the lower extremities.

Twenty-one (39.6%) of 53 patients who underwent surgery developed local recurrence in the current series. Previous studies reported recurrence rates ranging from 38% to 68%.2,9,11–13 In our statistical analysis, tumors in the axial site and treatment with an inadequate surgical margin were risk factors in local recurrence. Wanebo et al.10 also pointed out the relationship between an inadequate surgical margin and poor prognosis, although other series, including the current one, did not show this correlation. In regard to radiotherapy, its effect on local control is still controversial. In the current study, four patients were treated with preoperative radiotherapy. The effect was clinically evaluated as "no change" in one and "partial response" in three. However, in 17 patients who received radiotherapy preoperatively or postoperatively, 11 (64.7%) developed local recurrence. In the literature, several authors recommended radiotherapy for preventing local recurrence,10,12,16 but others reported that radiotherapy was ineffective.2,17 The effect of radiotherapy, including modern external beam therapy,18 for the local control of MPNST should be further investigated. Similarly, preoperative chemotherapy including doxorubicin, ifosfamide, cisplatinum, and dacarbazine was not effective clinically and histologically in any case. Therefore, it should be stressed that a wide surgical margin is the only reliable procedure in the local control of MPNST. An axial tumor site was another risk factor of local recurrence. The difficulty of the excision of an axial site tumor has already been mentioned for many soft tissue sarcomas.15 In the case of an axial-site MPNST, an alternative preoperative therapy to obtain a safe surgical margin should be further developed.

Although this current multi-institution retrospective study was designed to include patients with MPNST treated at oncology centers in northern Japan between 1994 and 2001, various treatment protocols, especially adjuvant therapies, were used. In addition, although the surgical margin was determined according to the guidelines of the Japanese Orthopedic Association, there remains difficulty in obtaining strict margin consistency among the hospitals who contributed to the study. These aspects are limitations of this study.

In conclusion, the current study involving 56 cases of MPNST showed the aggressive clinical behavior of the tumor. Large tumor size, lung metastasis at presentation, and high histological grade were related with poor prognosis, although an independency of histological grade of MPNST was still obscure. A wide excision was the most reliable procedure in the local control of MPNST. In the treatment of large and high-grade MPNST, an alternative strategy should be considered.

Received for publication December 13, 2005. Accepted for publication March 18, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  18. Kamada T, Tsuji H, Tsuji H, et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin Oncol 2002; 20:4466–71.[Abstract/Free Full Text]




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