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Chindanai Hongsaprabhas, M.D.*, Sorranart Muangsomboon, M.D.***, Chandhanarat Chandhanayingyong,

M.D.**, Rapin Phimolsarnti, M.D.**, Saranatra Waikakul, M.D.**, Apichat Asavamongkolkul, M.D.**

*Department of Orthopaedics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ailand, **Department of Orthopaedic Surgery,

***Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

Outcomes and Prognostic Factors in Patients with

Malignant Peripheral Nerve Sheath Tumor

ABSTRACT

Objective: To investigate and report the clinical proles, treatment patterns, and oncologic outcomes in MPNST

patients, and to identify the prognostic factors that signicantly aect survival.

Materials and Methods: Patients diagnosed with and treated for histologically conrmed MPNST at our institute

during the January 1997 to June 2018 study period were included. Patient medical records and surgical specimens

were reviewed, and study-related data was extracted and analyzed.

Results: ere were 27 males and 32 females with a mean age of 44 years. Most patients presented with mass and

most patients were AJCC stage III. Twenty-nine percent of patients had MPNST that was associated with NF-1. At

a median follow-up time, 18 patients (30.51%) suered from local disease recurrence. Two-year and 5-year overall

survival was 72% and 46%, respectively. In univariate analysis, chemotherapy treatment and positive tumor margin

were adverse prognostic factors for disease-free survival. In multivariate analysis, chemotherapy treatment (hazard

ratio (HR): 3.415, 95% CI: 1.367-16.021; p=0.013) and positive tumor margin (HR: 4.680, 95% CI 1.828-10.314;

p=0.014) were found to be independent prognostic factors for disease-free.

Conclusion: Chemotherapy treatment and positive tumor margin were identied as independent adverse prognostic

factors for disease-free and overall survival, respectively. Accordingly, early detection and appropriate treatment

are essential for improved patient outcome.

Keywords: Malignant peripheral nerve sheath tumor; MPNST; prognostic factors; outcomes; survival (Siriraj Med

J 2021; 73: 763-771)

Corresponding author: Apichat Asavamongkolkul

E-mail: apichat.asa@mahidol.ac.th

Received 24 June 2021 Revised 28 September 2021 Accepted 5 October 2021

ORCID ID: https://orcid.org/0000-0002-7868-7426

http://dx.doi.org/10.33192/Smj.2021.99

INTRODUCTION

Malignant peripheral nerve sheath tumor (MPNST)

is a rare and aggressive malignant so-tissue tumor that

is characterized by high risk of local recurrence and

distant metastasis.

ere is a widely held misconception

that curative treatment for MPNST is complete tumor

removal, with adjuvant chemotherapy and radiotherapy

recommended only in large lesions or lesions with high-

grade histology.

Whether treatment for MPNST involves

extensive surgery alone or surgery combined with adjuvant

therapies, the prognosis for patients with this condition

remains poor.

Several studies have reported 5-year

overall survival rates that vary from 16% to 52%, and

5-year disease-free survival rates that range from 26%

to 49%.

4-13

Neurobromatosis type 1 (NF-1) or disease

recurrence when associated with MPNST were found

and reported to be adverse prognostic factors.

10,14

e aim of this study was to investigate and report

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the clinical proles, treatment patterns, and oncologic

outcomes in MPNST patients. e secondary objective

was to identify the prognostic factors that signicantly

aect survival.

MATERIALS AND METHODS

Seventy-one patients were diagnosed with and

treated for histologically conrmed MPNST during

the January 1997 to June 2018 study period. Of the 12

patients that were excluded, 3 were denied denitive

operative treatment and 9 were lost to follow-up prior

to 6 months aer commencement of treatment. e

remaining 59 patients were enrolled and included in

the nal analysis. Aer the protocol for this study was

approved by the Institutional Review Board, patient

medical records and surgical specimens were reviewed,

and study-related data was extracted and analyzed.

A wide excision of tumor was attempted in all MPNST

patients (Fig 1A-D). Radiation therapy with high-dose

regimen ranging from 45 to 65 Gy was considered in

patients with greater risk of recurrence based on operative

and pathologic ndings. ere were, however, no absolute

indications for radiation therapy at our center during

the study period. Adjuvant chemotherapy, consisting of

doxorubicin and ifosfamide, was considered in patients

with high-grade disease and distant metastasis. Each

patient was discussed at our weekly multidisciplinary

musculoskeletal tumor board meeting to determine the

most appropriate modality treatment.

Statistical analysis

Descriptive statistics were used to analyze demographic

data. Cause-specic mortality, local recurrence, and distant

metastasis were the clinical endpoints in this study. Data

analysis were performed using statistical package Stata

version 14 (StatCorp, College Station, TX, USA) and

program R version 4.0.2 for windows. Shapiro-Wilk test

and histogram were used to evaluate normal distribution.

To summarize the data studied mean (sd) and median

(range) were reported for continuous variables when

appropriate, frequency and percentage for categorical

variables. Kaplan-Meier method and Cox proportional

hazard model was used to determine prognostic factors

for two events, disease free survival and overall survival.

Time to occurrence of event was calculated from the

date of surgery to the date when the event occurred, or

censored at the date of the last follow-up, death from

other cause. Variables of interesting were gender, tumor

Fig 1. A 19-year-old male with MPNST with right pelvic bone destruction who underwent internal hemipelvectomy without reconstruction:

A) Initial plain x-ray; B) Coronal view of T1-weighted MRI; C) Tumor mass aer en-bloc resection; D) Postoperative plain x-ray

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depth, NF-1, primary tumor, chemotherapy, radiotherapy,

tumor site, tumor size, surgery technique, margin and

severity. In this study, the variables with a univariate

signicance level of 0.25 or less were selected to perform

multivariable Cox regression. We also included other

variables from the literature which were reported clinically

relevant and eligible for using in the model. Backward

elimination technique was employed to select variables

into the model. Proportional hazard (PH) assumption was

evaluated using PH test based on Schoenfeld residuals and

in survival curves plot. Variance ination factor (VIF)

was determined whether there was multi-collinearity

among the variables. Candidate variables with VIF > 4

were excluded from data analysis. Goodness of t was

examined for lack of t using graphical approach; the

Cox-Snell residuals against the Nelson-Aalen cumulative

hazard function plot. Data analysis was 2-tailed test with

signicant level 0.05.

RESULTS

e mean age at presentation was 44 years, with an age

range of 13 to 86 years. Twenty-seven males and 32 females

were included. Demographic and clinical characteristics

of 59 study patients are shown in Table 1. Most patients

presented with only one symptom (66.1%) and mass was

the most frequent complaint (89.8%), followed by pain

(28.8%) and neuropathy (15.3%). Twenty-one patients

had been treated at other hospitals before being referred

aer presenting with local tumor recurrence. Most patients

in this study were American Joint Committee on Cancer

(AJCC) stage III (47.5%). Twenty-nine percent (17/59)

of patients had MPNST that was associated with NF-1.

Limb sparing surgeries could be performed in 48 patients

(81.3%), with amputation required in the remaining 11

patients. Negative tumor margin could be achieved in

34 patients (57.6%), with 14 patients (23.7%) emerging

from surgery with positive margins. irty-four patients

(57.6%) received adjuvant radiation therapy, 3 patients

(5.1%) received only adjuvant chemotherapy, and 11

patients (18.6%) received both adjuvant treatments.

At a median follow-up time of 48 months, 18 patients

(30.5%) suered from local recurrence of the disease.

Twenty-nine patients (58%) developed metastasis, and

9 of those had multiple sites metastasis. Pulmonary

metastasis was the most common site (44.1%), followed

by bone, brain, and other organ at percentages of 11.9%,

3.4%, and 6.8%, respectively. Complications occurred in

15 patients (25.4%), as follows: wound dehiscence (6.8%),

supercial wound infection (3.4%), phantom limb pain

(5.1%). Two-year and 5-year overall survival was 72%

and 46%, respectively. Median overall survival time was

58 months (Fig 2A). Median disease-free survival was 32

months based on analysis of 50 initially non-metastatic

patients. Two-year and 5-year disease-free survival was

52% and 40%, respectively (Fig 2B).

Subgroup survival analysis was performed for

NF-1 and type of disease presentation. Median overall

survival of patients with and without NF-1 was 38 months

(95% CI: 13.5-62.5) and 58 months (95% CI: 5.1-11.9),

respectively, with no signicant dierence found between

groups (p=0.648). Similarly, no signicant dierence was

observed between patients with recurrent and primary

tumor (p=0.978). Median overall survival of patients

with recurrent tumor was 46 months (95% CI: 21.7-

70.3), while patients with primary tumor had a median

survival time of 58 months (95% CI: 0.0-121.2).

In univariate analysis in Table 2, chemotherapy

treatment (hazard ratio (HR): 3.176, 95% CI 1.464-6.891;

p=0.003) and positive tumor margin (hazard ratio (HR):

4.342, 95% CI 1.828-10.314; p=0.010) were shown to

be adverse prognostic factors for disease-free survival

(Fig 3A-B). Radiation therapy and type of surgery and

AJCC stages III and IV had a non-signicantly negative

impact on overall survival (Table 3). Of note, AJCC

staging could not be calculated as a prognostic factor

for disease-free survival, because some of our patients

had metastasis initially.

In multivariate analysis, only chemotherapy treatment

(hazard ratio (HR): 3.415, 95% CI: 1.367-16.021; p=0.013)

and positive tumor margin (hazard ratio (HR): 4.680, 95%

CI 1.828-10.314; p=0.014) were found to be independent

prognostic factors for disease-free and overall survival,

respectively.

DISCUSSION

MPNST is widely known to be a rare and aggressive

malignant so-tissue tumor. ey account for approximately

10% of all so tissue sarcomas.

1,3

e symptoms of MPNST

are non-specic. Painless mass is a common chief complaint

and most patients suer from nerve-related symptoms

that are caused by tumor compression.

13,15

Our ndings

revealed mass to be the most common presenting symptom,

while weakness and radicular pain were the least common

presenting symptoms. e most widely recognized risk

factor for MPNST development is NF-1, given that

10-30% of NF-1 patients will develop MPNST during

their lifetime.

In our series, 28.8% of MPNST developed

in NF-1 patients, which is comparable to the incidence

reported from other studies.

4,5,11

Asavamongkolkul,

et al. reported 2 cases of MPNST associated with NF-1,

both of whom died shortly aer diagnosis with distant

metastases.

Data from survival meta-analyses reported

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TABLE 1. Patient demographic and clinical characteristics.

Characteristic Overall Disease free

(n=59) (n=50)

Gender (Female) 32 (54.2) 28 (56.0)

Mean age (year) 44 45

Follow up (months) 48 (24 – 178)* 51.5 (24 – 178)*

Number of chief complaint

One 39 (66.1) 35 (70.0)

Two 18 (30.5) 14 (28.0)

Three 2 (3.4) 1 (2.0)

Chief complaint

Mass 53 (89.8) 46 (92.0)

Pain 17 (28.8) 13 (26.0)

Neuropathy 9 (15.3) 5 (10.0)

Others 2 (3.4) 2 (4.0)

Presentation (Primary case) 37 (62.7) 30 (61.2)

Visit (Referred case) 45 (76.3) 38 (76.0)

Tumor site

Neck and trunk 16 (27.1) 13 (26.0)

Extremity 42 (71.2) 36 (72.0)

Neck and Extremity 1 (1.7) 1 (2.0)

Size (More than 5 cm.) 40 (67.8) 33 (66.0)

Depth (Deep) 53 (89.8) 44 (88.0)

Grading

Low 7 (11.9) 7 (14.0)

Intermediate 12 (20.3) 10 (20.0)

High 40 (67.8) 33 (66.0)

AJCC staging

I 5 (8.5) 5 (11.9)

II 11 (18.6) 11 (26.2)

III 28 (47.5) 26 (61.9)

IV 7 (11.9) 0 (0.0)

Margin status

Negative 34 (57.6) 29 (58.0)

Closed 7 (11.9) 6 (12.0)

Positive 14 (23.7) 12 (24.0)

NF-1 (Yes) 17 (28.8) 13 (26.0)

Distant metastases** 29 (58.0) 29 (58.0)

Radiation therapy (Yes) 34 (57.6) 29 (58.0)

Chemotherapy (Yes) 14 (23.7) 12 (24.0)

Dealth 24 (40.7)

NF-1, neurobromatosis type 1; AJCC, American Joint Committee on Cancer.

*Median (range). ** nine cases have event before begin study.

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Fig 2. Survival rate of overall survival (A) and disease-free survival (B)

TABLE 2. Univariate and multivariate Cox proportional hazard regression for disease free survival (n=50).

Variables Univariate analysis Multivariate analysis

HR p value HR p value

(95 % CI) (95 % CI)

Gender: (Female) 1.159 0.697 - -

(0.551-2.435)

Tumor depth: (Deep) 1.263 0.702 0.552 0.416

(0.381-4.190) (0.132-2.310)

NF-1: (No) 1.134 0.785 - -

(0.459-2.799)

Presentation: (Recurrence) 1.510 0.286 - -

(0.708-3.222)

Chemotherapy: (Yes) 3.176 0.003 3.415 0.013

(1.464-6.891) (1.293-9.022)

Radiotherapy: (Yes) 1.548 0.259 0.509 0.235

(0.725-3.305) (0.167-1.551)

Site: (extremity) 1.065 0.887 2.465 0.092

(0.449-2.525) (0.862-7.049)

Size: (> 5 cm.) 1.229 0.608 1.136 0.787

(0.559-2.702) (0.450-2.873)

Surgery: (limb salvage) 2.649 0.114 3.481 0.092

(0.791-8.866) (0.817-14.836)

Margin*:

Close 4.342 0.010 4.680 0.014

(1.828-10.314) (1.367-16.021)

Negative 0.571 0.458 0.570 0.481

(0.130-2.505) (0.120-2.718)

Grade: (High) 1.902 0.124 1.094 0.858

(0.838-4.318) (0.408-2.930)

AJCC Staging: (III + IV) 1.468 0.355 - -

(0.651-3.308)

* Positive qualied reference group.

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Fig 3. Disease free survival rate related to chemotherapy treatment (A) and tumor margin (B)

TABLE 3. Univariate and multivariate Cox proportional hazard regression for overall survival (n=59).

Variables Univariate analysis Multivariate analysis

HR p value HR p value

(95 % CI) (95 % CI)

Gender: (Female) 1.406 0.420 - -

(0.614-3.217)

Tumor depth: (Deep) 1.139 0.861 - -

(0.265-4.890)

NF-1: (Yes) 1.228 0.648 - -

(0.508-2.968)

Presentation: (Primary) 1.021 0.978 - -

(0.442-2.317)

Chemotherapy: (Yes) 1.644 0.255 - -

(0.699-3.867)

Radiotherapy: (Yes) 1.918 0.148 2.095 0.119

(0.793-4.638) (0.826-5.312)

Site: (extremity) 1.152 0.780 1.528 0.425

(0.427-3.112) (0.540-4.324)

Size: (> 5 cm.) 1.386 0.469 1.660 0.305

(0.573-3.355) (0.631-4.370)

Surgery: (limb salvage) 1.678 0.406 - -

(0.495-5.687)

Margin*:

Close 1.952 0.164 1.669 0.314

(0.762-5.001) (0.616-4.519)

Negative 0.573 0.462 0.474

(0.130-2.526) (0.103-2.182) 0.338

Grade: (High) 2.430 0.079 1.799 0.267

(0.903-6.544) (0.638-5.069)

AJCC Staging: (III + IV) 2.251 0.107 - -

(0.838-6.048)

* Positive qualied reference group.

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a lower odds ratio for survival in MPNST patients associated

with NF-1; however, the prognosis for these patients has

improved in studies published in recent years.

Magnetic resonance imaging (MRI) is a valuable

investigation prior to histo-pathologic study. e main

objective is to dierentiate MPNST from benign peripheral

nerve sheath tumor using criteria that includes peripheral

enhancement, mass dimension, perilesional edema,

and intratumoral cystic lesion. e presence of two or

more of these features is suggestive of malignancy with a

specicity of 90%.

In contrast, target sign is also helpful

in dierentiating benign neurobroma from MPNST.

Fluorodeoxyglucose positron emission tomography (FDG-

PET) has been reported as being able to dierentiate

MPNST and forecast patient prognosis.

2,4

Most patients in our series were in the advance stage

– predominantly AJCC stage III (47.5%) e aggressive

nature of the tumors in our study was reected, as follows:

67.8% of tumors were high grade, 89.8% were deeply located,

and 67.8% were larger than 5 cm in diameter, which was

comparable to data reported from other studies.

8,10,11,13

e number of patients who received isolated adjuvant

radiation therapy, isolated adjuvant chemotherapy, and

combined adjuvant treatments was 43%, 4%, and 20%,

respectively, which was comparable to data from other

studies.

8-11,13

Adjuvant radiation therapy is recommended

for tumors with high grade, large size, tumor recurrence,

and closed margin. Alternatively, adjuvant chemotherapy

is considered in tumors with high grade, large size, and

metastasis. Although MPNST has relatively low sensitivity

to radiation, adjuvant irradiation to doses more than 60

Gy is still associated with improved local control, but not

with overall disease survival.

2,6

Carbon ion irradiation

is becoming more popular due to its higher biological

eectiveness compared to photons or protons, but a

study in MPNST treatments revealed that it provided

short-term benets, especially in patients with gross

residual or unresectable tumor.

Local recurrence is common in MPNST. Incidence

of recurrence ranges from 32% to 65%.

2,8-11,13

ere were

18 patients (30.5%) who developed local recurrence in this

study. However, we were not able to correlate recurrence

with initial presentation from survival analysis.

Twenty-nine patients (50.8%) developed metastasis,

and 9 of those had multiple sites metastasis. Pulmonary

metastasis was the most common site (44.1%), followed

by bone, brain, and other locations at percentages of

11.9%, 3.4%, and 6.8%, respectively, and these rates are

comparable to rates published in other reports.

6,8-11,13

Five-year overall survival and disease-free survival in

this study was 46% and 40%, respectively. Our survival

rates are comparable to rates from other studies that

described 5-year overall survival rates that varied from

16% to 52%, and 5-year disease-free survival rates that

ranged from 26% to 49%.

4-13

A variety of signicant favorable prognostic factors

have been reported from several studies. (Table 4) In

the present study, chemotherapy treatment and positive

tumor margin was shown to be an adverse prognostic

factor for disease-free survival. Cashen, et al. identied

Musculoskeletal Tumor Society (MSTS) Rating Scale

as an adverse prognostic outcome.

MPNST with

rhabdomyoblastic dierentiation or malignant triton

tumor (MTT) was reported to be associated with poor

prognosis and more aggressive tumor behavior.

Brekke,

et al. reported that p53-positive MPNST patients are a

high-risk group and they are candidates for adjuvant

treatment.

Chemotherapy for so-tissue sarcoma is limited in

benet and in variety. Chemotherapy options that include

vincristine, doxorubicin, ifosfamide, and etoposide have

a positive eect among metastatic MPNST patients,

but not in non-metastatic patients.

A positive trend

for adjuvant radiation, but not for chemotherapy, was

observed for disease-free survival and overall survival.

13,23,24

Interestingly, we found chemotherapy treatment to be

an adverse prognostic factor for disease-free survival.

Targeted therapy is becoming a compelling treatment

option for patients with MPNST (e.g., erlotinib, sorafenib);

however, some targeted therapy studies are still ongoing

and some have shown no clinical response.

Moreover,

there are studies that have demonstrated the feasibility

of anti-survivin and oncolytic measles virus as a novel

treatment for MPNST patients that should be studied

in future clinical trials, especially in the NF-1-related

group.

25-27

is study has some mentionable limitations. First

and consistent with the retrospective nature of this

study, some patient data may have been incomplete.

Second, the size of the study population was relatively

small. As a result, our study may have lacked sucient

power to identify all signicant associations. ird, the

patients enrolled in this study were from a single center,

the largest tertiary referral hospital. Most patients were

referred to our institute with complicated and intransigent

conditions.

CONCLUSION

Patients with MPNST in this series had survival

rates that are comparable to those reported in other

studies. Chemotherapy treatment and positive tumor

margin were identied as independent adverse prognostic

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factors for disease-free and overall survival, respectively.

Accordingly, early detection and appropriate treatment

are essential for improved patient outcome.

ACKNOWLEDGEMENTS

e authors gratefully acknowledge Miss Krabkaew

Soparat, M.Sc and Miss Nichakorn Khomawut for assistance

with data analysis and research coordination.

Conict of interest declaration: e authors hereby

declare no personal or professional conicts of interest

regarding any aspect of this study.

TABLE 4. Signicant favorable prognostic factors.

Publications Year Numberofcases Signicantfavorableprognosticfactors

Anghileri

2005 205 - smaller tumor size

- lack of local recurrence

- extremity located

Stucky

2012 175 - tumor size < 5 cm

- lack of local recurrence

- low histologic grade

- extremity located

Zou

2009 140 - tumor size < 10 cm

- low intensity p53 staining

Wong

1998 134 - smaller tumor size

- low histologic grade

- perineural histologic subtype

Lafemina

2012 105 - tumor size <5 cm

- low histologic grade

- lack of local recurrence

- extremity located

Cashen

2004 80 - anatomical location

- MSTS staging

- lower part of lower extremity

Brekke

2009 64 - tumor size < 8 cm

- complete surgical resection

- lower intensity p53 staining

Okada

2007 56 - tumor size < 7 cm

- lack of metastasis

Baehring

2003 54 - tumor size < 5 cm, complete surgical

resection, young age, radiation therapy,

lack of chemotherapy

This study 2021 51 - lack of chemotherapy, negative tumor margin

MSTS, Musculoskeletal Tumor Society; AJCC, American Joint Committee on Cancer

Funding disclosure: is was an unfunded study.

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