ANTICANCER RESEARCH 27: 1957-1960 (2007)
Malignant Peripheral Nerve Sheath Tumors (MPNST) in NF1-affected Children R.E. FRIEDRICH1, M. HARTMANN2 and V.-F. MAUTNER2 1Maxillofacial
Surgery and 2Section of Phacomatoses, Maxillofacial Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Abstract. Background: Malignant peripheral nerve sheath tumors (MPNST) constitute a heterogeneous group of malignant tumors that probably arise from cells of the peripheral nerve sheath. Association of MPNST with neurofibromatosis type 1 (NF1) is frequently reported. MPNST contribute significantly to the reduced life-span of NF1patients. At present there are only sparse data on MPNST in NF1-children. The aim of this study was to determine the outcome of children affected with NF1 who developed an MPNST. Materials and Methods: Over the period of 1985 to 2005, we followed 52 NF1 patients with MPNST at our outpatient department. All patients were diagnosed and reevaluated according to the updated NIH diagnostic criteria for NF1. Results: Out of this cohort, 8 patients with MPNST were aged 1 to 17 years at the time of MPNST diagnosis (mean age: 12 years; 5 girls and 3 boys). We noticed the following characteristics: MPNST arose from plexiform neurofibromas (PNF) with invasive or displacing growth pattern on MRI. Many patients reported pain and neurological deficits at the time of presentation. Diagnosis of MPNST in this age group took longer compared to adults. This cohort did not show longer survival periods than adults with MPNST. Adjunctive treatment with chemotherapy or radiation had no lasting effect. The overall survival time of this small cohort was 30.5 months. Those children who died showed a median survival time after diagnosis of 20 months. The longest survival of 112 months was achieved for a girl who presented with MPNST of the distal upper arm and underwent amputation. The NF1 mutation analysis in the MPNST pediatric age group revealed the same mutational spectrum as the adult group. Conclusion: Our data reveal MPNST in children with NF1. Children
Correspondence to: Prof. Dr. R.E. Friedrich, Maxillofacial Surgery, University Hospital Hamburg-Eppendorf, University of Hamburg, Germany. Tel: +49 40 428033259, Fax: +49 40 428038120, e-mail:
[email protected] Key Words: Neurofibromatosis, malignant peripheral nerve sheath tumor, children, cancer, MPNST, NF1.
0250-7005/2007 $2.00+.40
cannot verbalize physical alterations adequately; therefore the correct diagnosis might be hampered in these patients. Unresolved complaints of children with NF1 should be investigated thoroughly due to the risk for malignancy in NF1. The term "malignant peripheral nerve sheath tumor" (MPNST) currently describes a heterogeneous group of malignant tumors that possibly arise from cells of the nerve sheath (1). MPNST is mainly diagnosed in patients of 20 to 50 years of age (1). Association of MPNST with neurofibromatosis type 1 (NF1) is frequently reported (1) and MPNST contribute significantly to the reduced life-span of NF1-patients (2). At present, there are only sparse data on MPNST in NF1-children (3). The aim of this study was to summarize reports on MPNST in children with special reference to NF1-affected individuals and to determine the outcome of children affected with NF1, who developed an MPNST, in a large referral center for NF patients. Review. Some reports dealing with MPNST also refer to NF1-children (We refer to the original nomenclature of the articles. Malignant schwannoma and neurofibrosarcoma are synonyms of MPNST in this context). Hope and Mulvihill (4) summarized earlier studies and identified 7 NF1-children with neurofibrosarcoma over a time period of 30 years (1951-1980). However, their survey did not note the age of onset nor any data on therapy. Schneider et al. (5) investigated 45 NF1-children with malignant tumors who were investigated and treated from 1960 to 1983 in the Philadelphia Children’s hospital. Nineteen patients developed a neurofibrosarcoma (mean age: 11.9 years). The tumors occurred predominantly after puberty, with only 5 children aged less than 15 years. Six neurofibrosarcomas either arose from a plexiform neurofibroma (PNF) or a PNF was adjacent to the malignancy. Matsui et al. (6) analysed the data of 26,084 patients from 1969 to 1989 of the Japan Children’s Cancer Registry. Patients included were younger than 15 years of age. Among those children with cancer were 56 with NF1 (incidence: 0.21%). Regarding malignancies of the
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ANTICANCER RESEARCH 27: 1957-1960 (2007) peripheral nervous system, the rate of malignant schwannoma was high (11 of 36 patients, 31.4%). One malignant schwannoma was diagnosed congenitally. Also noted were 2 Triton tumors. No follow-up data were presented. Leroy and co-workers (7) found 17 NF1-patients with MPNST in their cohort of 395 patients. All tumors developed from pre-existing plexiform or nodular neurofibroma, excepting one patient. Only 2 patients were younger than 18 years of age (both: 17 years). Boulanger and Labrisseau (8) studied 987 pediatric patients over the period January 1991 to July 2002. They identified 279 NF1-children in their cohort. Out of this group, 1.8% (5 patients) developed MPNST. Age at diagnosis of MPNST was 3 to 14.5 years (mean 10.3 years). None of the MPNST arose from a PNF. All 5 patients underwent surgery and 4 of them had additional measures taken. Follow-up control was incomplete in 3 of 5 patients. Kim and co-workers recent report (9) deals with the surgical management of peripheral nerve sheath tumors of 397 patients, treated at a single institution. The number of MPNST associated with NF1 was 12. No data on the age of the patients affected with MPNST were published. Carli et al. (3) analysed 167 pediatric patients with MPNST who were registered between 1975 and 1998. In this group, 17% of the children were NF1-affected individuals (n=29, male=10, female=19). Twenty-five patients were 10 years of age or more, leaving only 4 in the 1 to 9 years age-group. No MPNST occurred in children aged younger than 1 year. MPNST was localized in the extremities, trunk, retroperitoneal/visceral, and head and neck (n=11, 8, 5 and 5, respectively). Twentyfour patients investigated on admission had a primary tumor with a diameter of 5 cm or more (82.8%). The rate of response to chemotherapy was significantly lower in NF1 patients, compared to MPNST patients without NF1 (17.6% vs. 55.3%, p=0.007). Treatment response in general was poor in NF1 patients: treatment failure was judged in 22 of 29 patients, regarding both overall/ progression-free survival (five-year overall survival=32%; progression-free survival=19%). Therapy. Surgery is the first-line therapy for MPNST (10). The aim of surgery is to achieve complete primary tumor resection. Chemotherapy for MPNST follows certain protocols, e.g. CWS-96. Radiation was reported as a palliative measure. Radiation can be applied in conventional fractionation or as a hyperfractionated accelerated setting (3).
Materials and Methods NF1-patients with MPNST who had been investigated in the NF1 outpatient clinic between January 1985 and September 2005 were retrospectively evaluated. A total of 52 NF1-patients with MPNST were identified. All NF1-patients were diagnosed according to the revised diagnostic criteria for NF1 as proposed by the US National
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Institute of Health (10, 11). Eight of these patients were younger than 18 years at the time of MPNST diagnosis (15.3%; 3 boys and 5 girls: 1 to 17 years). Diagnostics were allocated as described elsewhere (11, 12). Clinical features and outcome were compared between the pediatric and adult group.
Results We identified 8 children with MPNST (male: 3, female: 5). The age at the time of MPNST diagnosis was 1 to 17 years (median age of onset: 12 years). The children with MPNST mainly presented with pain, swelling and neurological deficits. Diagnosis of MPNST in this age group took longer than for adults (mean=3.9 months). All MPNST arose from plexiform neurofibromas with invasive or displacing growth characteristics on magnetic resonance images (MRI). This cohort did not show longer survival periods than adults with MPNST, even considering adjunctive treatment with chemotherapy or radiation. The overall survival was 30.5 months, but those children who died showed a median survival time after diagnosis of 20 months. Patients with MPNST in extremities had a tendency for a better prognosis. The NF1 mutation analysis in the pediatric group revealed the same mutation spectrum as the adult group (data not shown). The results are summarized in Table I.
Discussion This study shows that the survival time in NF1-children with MPNST is the same as for NF1-adults who experience this aggravation of the disease. The review on MPNST in children with NF1 reveals no current studies on the treatment of children with MPNST. Reports on follow-up controls deal with children and MPNST in general and identify the genetic background of NF1 as an indicator of poor prognosis (3). If MPNST occurs in children with NF1, this tumor is often the first malignant tumor. In rare cases, however, MPNST can develop as a second malignancy after successful therapy for a first malignant tumor (13). In the presented series, no child had had any prior malignant tumor. Invasive or displacing PNF as visualized on MRI gave rise to the MPNST in the children of this study. These findings support the proposed MRI-based typing of PNF in NF1 (11). Obviously patients with tumors of this growth type are more at risk of developing MPNST. However, plexiform neurofibroma might be very small in size and not detectable on MRI. Therefore, MRI does not spare regular physical investigation. Complete surgical removal is obviously the mainstay of treatment and a strong predictor of survival (10). Whereas every effort is made to perform adequate initial surgery with tumor-free histological margins in every single patient, there are several factors that undermine the curatively intended ablative surgery. First, MPNST is a very aggressive tumor
Friedrich et al: MPNST in NF1-affected Children
Table I. Clinical data on NF1-children with MPNST. No Gender
Age at Survival Present diagnosis (Months) status of MPNST (Years) (Mean:12) (Mean:30.5)
1
m
17
5
2
f
13
112
3
m
1
24
4
f
15
23
5
f
10
10
Deceased, evidence of the disease
6
f
13
14
7
f
14
8
m
13
Location and size of tumor
Growth Surgery Chemo- Radiation First type therapy symptoms of tumor of tumor
Neuro- Duration from logicial diagnosis of deficits MPNST (Months)
Alive, Right thoraco-dorsal Invasive evidence of and paravertebral the disease region, lower thoracic column 8.5 cm x 10 cm
Yes
Yes
No
Back pain, cannot sit longer than 15 minutes
No
5
Invasive
Yes
No
No
Swelling
Yes
2
Right proximal upper leg; 4.5 cm x 3 cm x 2 cm
Displacing
Yes
Yes
Yes
Swelling and pain of leg
No
2
Alive, Right upper leg no evidence of (8 cm above the disease knee joint) 3 cm x 2 cm
Displacing
Yes
Yes
Yes
Pain and No swelling of right foot and right lower leg
5
Right side of skull base and neck, invasion of the sternocleidomastoid muscle; 3.3 cm x 2.9 cm x 1.8 cm
Invasive
Yes
No
No
Swelling of right side of the neck
Yes
4
Deceased, evidence of the disease
Left paravertebral, intraspinal, in the height of D7-10; 2.4 cm x 2.5 cm
Invasive
Yes
Yes
Yes
Back pain
Yes
2
22
Deceased, evidence of the disease
Right side of the neck, invasion of the sternocleidomastoid muscle; 7.3 cm x 4.6 cm
Invasive
Yes
Yes
Yes
Swelling of left neck, hoarseness, chronic dry cough
Yes
6
42
Deceased, evidence of the disease
Left side of skull base, size unknown
Invasive
Yes
Alive, Left distal lower no evidence arm, 9 cm x of the disease 5 cm x 4.5 cm Alive, evidence of the disease
with a high number of local recurrences, indicating the speed of a jump-like local spread despite histological tumorfree margins. The aggressive nature of the entity is obvious when considering the extension of the primary of MPNST
Unknown Unknown Swelling, Unknown pain
5
patients at the time they are admitted to the hospital and the short history of local tumor symptoms. A further adverse point that reduces the feasibility of surgery for MPNST treatment is the localisation of the tumor, e.g.
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ANTICANCER RESEARCH 27: 1957-1960 (2007) tumors of the head and neck will rarely be resectable with adequate wide resection margins, in particular in children, without mutilation. Local control is probably achieved more easily in patients where a wide resection margin can be defined. However, the knowledge on the speed of MPNST growth is mirrored in the recommendation of an International Consensus Meeting on MPNST in NF1, claiming a distance of the resection border to the tumor equal or more than 10 cm (10). Therefore, it is not surprising that the longest survival period so far was achieved in a child with MPNST developed in a distal part of an extremity and treated with amputation.
Conclusion Our data reveal that MPNSTs occur also as a rare feature in children with NF1. As children are not able to report pain, tumor growth or neurological deficit as adults are capable of doing, each complaint about pain or tumor of NF1-children should be investigated thoroughly. Unclear persistent pain in children with NF1 requires exclusion of an MPNST by MRI/PET.
Acknowledgements The authors wish to express their appreciation to Dr. Lan Kluwe for providing the genetic analyses. This study was supported by the Deutsche Krebshilfe (project Ma 70-3072).
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4 Hope DG and Mulvihill JJ: Malignancy in neurofibromatosis. In: Neurofibromatosis. Riccardi VM and Mulvihill JJ (eds.). Adv Neurol 29: 33-56, 1981. 5 Schneider M, Obringer AC, Zackai E and Meadows AT: Childhood neurofibromatosis: risk factors for malignant disease. Cancer Genet Cytogenet 21: 347-54, 1986. 6 Matsui I, Tanimura M, Kobayashi N, Sawada T, Nagahara N and Akatsuka J: Neurofibromatosis type 1 and childhood cancer. Cancer 72: 2746-2754, 1993. 7 Leroy K, Dumas V, Martin-Garcia N, Falzone MC, Voisin MC, Wechsler J, Revuz J, Créange A, Levy E, Lantieri L, Zeller J and Wolkenstein P: Malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1. Arch Dermatol 137: 908-913, 2001. 8 Boulanger JM and Labrisseau A: Neurofibromatosis type 1 in a pediatric population: Ste. Justine’s experience. Can J Neurol Sci 32: 225-231, 2005. 9 Kim DH, Murovic JA, Tiel RL, Moes G and Kline DG: A series of 397 peripheral neural sheath tumors: 30-years’ experience at Louisiana State University Health Sciences Center. J Neurosurg 102: 246-255, 2005. 10 Ferner RE and Gutmann DH: International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res 62: 1573-1577, 2002. 11 Mautner VF, Hartmann M, Kluwe L, Friedrich RE and Fünsterer C: MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1. Neuroradiology 48: 160-165, 2006. 12 Mautner VF, Friedrich RE, von Deimling A, Hagel C, Korf B, Knofel MT, Wenzel R and Fünsterer C: Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma. Neuroradiology 45: 618-625, 2003. 13 Coffin CM, Cassity J, Viskochil D, Randall RL and Albritton K: Non-neurogenic sarcomas in four children and young adults with neurofibromatosis type 1. Am J Med Gen 127A: 40-43, 2004.
Received December 13, 2006 Revised March 7, 2007 Accepted March 9, 2007
