# Survival in Malignant Peripheral Nerve Sheath Tumours: A Comparison between Sporadic and Neurofibromatosis Type 1-Associated Tumours

Authors: D. E. Porter; V. Prasad; L. Foster; G. F. Dall; R. Birch; R. J. Grimer
Journal: Sarcoma
 (2009)

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## Abstract

We studied 123 patients with malignant peripheral nerve sheath tumours (MPNSTs) between 1979 and 2002. However, 90 occurred sporadically whereas 33 were associated with neurofibromatosis type 1 (NF1). Survival was calculated using Kaplan-Meier survival curves and we used Cox's proportional hazards model to identify independent prognostic factors. A 5-year survival for 110 nonmetastatic patients was 54%; (33% NF1 and 63% sporadicP=.015). Tumour stage and site were significant prognostic indicators after univariate analysis. After multivariate analysis, however, only NF1 (P=.007) and tumour volume more than 200 m (P=.015) remained independent predictors of poor outcome.
We recommend that NF1 be taken into account during MPNST staging.
As the survival rate in the NF group was dependant on tumour volume, routine screening of these patients with FDG PET and/or MRI may be warranted, thereby staging and controlling them at the earliest possible opportunity.


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## Body

## 1. Introduction

Malignant
peripheral  nerve sheath tumours (MPNSTs) are aggressive, locally invasive soft
tissue sarcomas, typically presenting as a rapidly growing and painful
lump.  These tumours account for up to 10% of all soft tissue sarcomas [1] and are associated with poor prognosis unless wide excision of the tumour is
undertaken before local invasion or distant metastasis can occur. The incidence
of sporadic MPNSTs is low, with a lifetime risk of 0.001% [2, 3] but
in association with the familial condition neurofibromatosis type 1 (NF1),
where these tumours often arise from malignant transformation of a plexiform
neurofibroma, the incidence is much higher.
Evans et al. [4] estimate the lifetime risk of developing
MPNSTs in the population of patients with NF1 to be as high as 13%. A number of studies have compared survival in
sporadic and NF1-associated tumours [1, 4–9] but no
consensus has been reached on whether NF1 is an independent poor prognostic
factor or not.Our
study aimed to determine factors important to outcome in a large population of
patients with MPNSTs from two United Kingdom centres for soft tissue tumour
surgery.


## 2. Patients and Methods

The
medical records from 135 patients diagnosed with MPNSTs treated between 1979
and 2002 at two UK centers were reviewed. In 12 patients, there was
insufficient follow-up data and they were excluded; leaving 123 patients that had follow-up data from 6 months to 21 years and they were included in the analysis.Patients
with NF1 were identified by the presence of certain characteristic features
based on the diagnostic criteria for NF1 [10] including features
such as café au lait spots, Lisch nodules, multiple neurofibromata, and a
positive family history. A statement in the patient’s medical records of an NF1
diagnosis was accepted as sufficient evidence for that individual to be placed
in the NF1 group.Histopathologists
sitting on the national musculoskeletal tumour panel confirmed the diagnoses of
MPNSTs and used the Trojani system to histologicaly grade the tumours. The date
of diagnosis taken to be the date of first biopsy or excision from which a
histological diagnosis of MPNSTs was made.Operation
notes and histology reports were utilised
to determine the extent of surgery and the margins achieved. For the purposes of this analysis, amputation
or wide excision was deemed to give adequate clearance; marginal excision and
debulking were
deemed to give inadequate clearance margins. Chemotherapy and radiotherapy intents were documented
and tumour size and volume were
calculated using surgical or magnetic resonance imaging records.Survival
data was calculated using Kaplan-Meier curves and multivariate analysis was
performed using Cox’s proportional hazards model using the statistical package
SPSS 13.0. The effect of each variable
was compared to the effect of the group as a whole.


## 3. Results

Of the 123 patients in this study with MPNSTs, 33
patients (27%) had NF1. NF1 patients
were significantly younger at diagnosis than those with sporadic tumours with a
median age of 26 years compared with 53 years for sporadic MPNSTs,(X2=23.65,P<.001). There were also
significant differences in the distribution of the site of tumours between the
two groups with relative overrepresentation of peripheral limb tumours in the sporadic
group and axial tumours in the NF1 group (X2=24.3,P<.001) (see Figure 1). There were no significant
differences in the tumour volumes found in the NF1 and sporadic groups (P=.36).Figure 1
Tumour frequency by site.Overall 5-year survival for all
123 patients was 51% and was significantly worse for patients with NF1 than
those with sporadic MPNSTs (32% versus 60%;P=.01). 13 patients (11%)
had IUCC-TNM stage IV disease (metastases at diagnosis). Stage IV
disease was more common in NF1 patients (15%) than those with sporadic tumours
(9%) but NF1 was still associated with a significantly worse 5-year survival if
patients with stage IV disease were removed from the analysis (33% versus 63%; P=.015)
(see Figure 2).Figure 2
Kaplan-Meier survival in patients without metastases at diagnosis.The effect of other factors on
survival in the group of patients without metastases at diagnosis was
investigated using Kaplan-Meier analysis and is documented in Table1.Table 1
Univariate analysis to determine factors significant for survival in
patients without metastases at diagnosis.
FactorNF1SporadicAll patients5 year survival (%)P5 year survival (%)P5 year survival (%)PStage1100100100246.2.37576.1.07971.1.033SiteLower limb55.669.466.7Upper limb10083.390.9Brachial
plexus42.975.068.4Sciatic plexus50.0.139100.03588.9.036Volume<200 ml57.185.782.9>200 ml50.0.11966.7.01563.6.002GradeLow44.474.270.0High50.0.86279.2.71373.4.606DepthSubcutaneous50.090.083.3Deep50.0.37276.1.75572.2.571Two factors remained significant
on multivariate Cox regression analysis. Tumours with volume<200 ml had a
significantly better prognosis (HR 0.355, 95% CI 0.15–0.82, P=.015)
than larger tumours, and NF1 tumours were associated with significantly poorer
prognosis compared with those occurring sporadically (HR 1.811, 95% CI 1.175–2.791, P=.007).Local treatment included surgery in 94% and radiotherapy in
61%. Chemotherapy was given in 26%. 2/33
(94%) of the NF1 group and 5/90 (94%) of the non-NF1 group received
surgery. 20/33 (65%) of the NF1 group
and 55/90 (61%) of non-NF1 group received radiotherapy. The type of treatment
had no significant effect on survival. Adequate excision margins were achieved
in a similar proportion of NF1 and sporadic tumours (31% versus 28%). Local
recurrence occurred in 24 patients. Where surgery was attempted, adequate
surgical margins were achieved in 28% of patients, 6% of whom developed local
recurrence. In the remaining 72% of patients in whom adequate surgical margins
were not achieved, the local recurrence rate was 30%. This difference in local
recurrence was statistically significant using the chi-square test(P<.001).Although patients with local recurrence displayed a trend towards
worse survival, this did not reach statistical significance. A trend was
observed towards worse local recurrence-free survival in NF1 (5-year survival
70% versus 81% in sporadic tumours) but this did not reach statistical
significance.


## 4. Discussion

Due to the relative rarity of MPNSTs, there have been
few large studies into survival and those reporting 5-year survival lack
consistency, with survival rates in the range of 39–85% [6, 11]. Our overall survival of 51% is within
this range. There is a similar lack of consensus on the issue of whether or not NF1
is an independent indicator of poor prognosis. A number of studies report no
significant difference between the 2 groups [1, 6, 11, 12]. Others, including this study report a poorer outcome
in patients with NF1 [13–18]. It has been suggested that patients with NF1
are more likely to present late with MPNSTs because they may not be as
concerned by the appearance of new swellings as the rest of the population. In
our study, a greater percentage of NF1 patients had metastatic disease at
presentation (15% versus 9%) but even with the exclusion of these cases from
the analysis, our study of the remaining 110 patients demonstrated 5-year
survival rates in NF1 patients only half as good as in patients with sporadic
tumours. NF1 was also an independent predictor of poor prognosis on
multivariate analysis. Possible explanations for the poorer prognosis seen in
NF1 patients include differences in the genetic profile of tumours arising in
these 2 groups [19–21] which might affect aggressive potential.
Other cancers such as breast and ovarian cancers have also shown worse
prognosis in familial cases compared to those occurring sporadically [20, 22].Reports that patients with NF1 have an estimated
lifetime risk of developing MPNSTs in excess of 10% [4], in
conjunction with our findings of significantly poorer survival in NF1,
underline the risk posed by these tumours, and the danger of complacency about
new episodes of pain or swellings in these individuals.This report clearly demonstrates that patients with
NF1 are diagnosed with malignancy at a significantly younger age than in those
with sporadic tumours and is consistent with other studies [3, 5, 9]. This reflects the nature of NF1 as a familial
neoplastic trait that predisposes to both benign and malignant tumours. The NF1
gene was identified in 1987 [23] and functions as a tumour
suppressor gene. Other familial neoplastic traits also exhibit age-dependent
malignant change at a younger age than in the general population [20, 21].On univariate
analysis, the tumour volume, stage, and site were also found to be significant
predictors of survival. Tumour volume
was the only other factor that, together with NF1, remained significant on
multivariate analysis. Histological grade
was not found to correlate with survival; however, the result may have been skewed
due to small numbers (15/129) of low-grade tumours. Recent published data from Hagel et al. [21] support
our findings that the NF1 group is younger, has more axially located tumours, and has a worse prognosis.
Interestingly, they presented evidence that the histopathology of NF1-associated
tumours differs
from the sporadic type. This may explain
why we did not see a correlation between histological grade and survival. They
postulated that and if a new grading system included NF1 as an independent
prognosticator, then perhaps grade and survival would correlate.There was no observable difference between tumour
volumes in the sporadic and NF1 groups(P=.36). Independent of biology, a small volume tumour
offers a better prognosis because of the higher chance of achieving wide
resection margins.We found that tumours affecting the peripheral
portion of the upper limb were associated with the best survival on univariate
analysis. Interestingly, tumours sited in the lumbosacral plexus also seemed to
have a
favourable prognosis. Since this group
represents only 11% of the total, however, this finding should be interpreted
with caution. Peripheral lower limb tumours accounted for the greatest
proportion of tumours from the NF1 group (32%) and formed the majority (58%) of
large volume tumours. These poor prognostic
cofactors in our group of lower limb tumours cause the univariate site-specific
survival differences to disappear on multivariate analysis. Other studies have
reported that peripheral rather than centrally located tumours have better
survival rates [11, 15]. This is likely to result from these tumours
being more amenable to resection with wide margins or may be because they are
detected earlier.Recently,
specialist centers have been using positron emission tomography to detect
18F-fluorodeoxyglucose (FDG PET) uptake in these tumours. Fisher et al. [24] showed that FDG
PET is a useful tool in monitoring clinically stable NF1 patients with
plexiform neurofibromas as it could predict which were more likely to
subsequently grow rapidly. Also Brenner et al. [25] found that in
NF1patients with MPNSTs, higher uptakes during FDG PET were associated with
significantly worse survival whilst histopathological tumour grading did not
predict outcome.Definitive treatment for MPNSTs involves surgical
removal of the tumour. Adjuvant or
neoadjuvant therapy is increasingly considered but has not been shown to
consistently improve survival [11, 26]. Only five patients in this
study did not receive some form of surgical treatment.It is well documented that these tumours can extend
considerable distances along nerves and if suspected, a frozen section should
be carried out at the proximal and distal limits of nerve resection to ensure
clear margins. Adequate surgical margins
were achieved in 31 out of 118 patients (26%) and only 6% of these patients
developed local recurrence of their tumour, in contrast to 30% of patients in
which clearance margins were deemed inadequate. When local recurrence did
occur, this was associated with a worse outcome but the trend did not reach
statistical significance. Other studies report that the failure to achieve
local control of the tumour bears a major association with treatment failure
and poor outcome [26, 27].Any patient with an MPNST in association with NF1
should be carefully staged prior to treatment and should be managed by a
multidisciplinary team familiar with both soft tissue sarcomas and NF1. In
those patients who were treated with curative intent and had a marginal
resection, recurrence rates remained low 3/32. Therefore, we recommend that
postoperative surveillance should remain in accordance with current NICE sarcoma
guidelines [28] and NF1 conference statement [10].We conclude that as NF1 is an independent indicator
of poor prognosis in MPNSTs, we recommend that this must be taken into account during the
tumour staging. It may be necessary to have separate staging systems for
sporadic and NF1-associated tumours to reflect this. As the survival rate in the
NF group was dependant on tumour volume, routine screening of these patients
with FDG PET and or MRI may be warranted, thereby staging and controlling them
at the earliest possible opportunity.



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*Source: 756395-2009-04-07.xml*