Short Communication Received: October 9, 2013 Accepted after revision: November 3, 2013 Published online: January 28, 2014
Oncology 2014;86:122–126 DOI: 10.1159/000357137
Clinical Signs of Neurofibromatosis Impact on the Outcome of Malignant Peripheral Nerve Sheath Tumors W. Lamm a, e, f S. Schur a, e, f W.J. Köstler a, e, f P. Funovics b R. Windhager b G. Amann c J. Panotopoulos b B. Pokrajac d T. Brodowicz a, e, f
a
Clinical Division of Oncology, Department of Medicine I, b Department of Orthopedics, c Department of Pathology, Department of Radiation Oncology and e Musculoskeletal Tumor Unit, Comprehensive Cancer Center, Medical University of Vienna and f Sarcoma Platform Austria, Vienna, Austria
d
Abstract Objective: Malignant peripheral nerve sheath tumors (MPNST) are a rare subtype of sarcoma, with a poor outcome. MPNST are regarded as being sporadic or associated with neurofibromatosis type 1 (NF1). Few comparative overallsurvival (OS) data in these 2 subsets of MPNST patients exist. The aim of this retrospective study was to assess OS in sporadic and NF1-associated MPNST patients. Methods: Fourteen consecutive patients with initial localized as well as initial metastatic MPNST were diagnosed and treated in our department. Patients with sporadic MPNST were assigned to group A and those with NF1-associated MPNST to group B. Results: Eight versus 6 patients were allocated to groups A and B. Primary tumors were located on the extremities in all but 1 patient. Two patients in group A and 4 patients in group B experienced a relapse. Four patients died in each of the 2 groups. Median follow-up was 66.2 and 57.2 months in group A and group B, respectively. Median OS in group A was 46.9 months versus 12.7 months in group B. Conclusions: In this small, single-center study, sporadic-MPNST patients had a longer median OS than those with NF1-associated MPNST.
Introduction
Malignant peripheral nerve sheath tumors (MPNST) are rare tumors that are considered to arise from the Schwann cells of peripheral nerves. MPNST are aggressive, locally invasive soft tissue sarcomas and compromise up to 10% of this type of tumor [1]. The most common sites of origin are the extremities. Patients with these tumors often present with pain and other neurological symptoms [2]. Prognosis is still poor. In 2 large studies, tumor size and location affected overall survival (OS) [3, 4]. In large series of patients with MPNST, 5-year survival rates range from 16–52% [4–6]. The major cornerstone of therapy for localized disease is surgery [7]. There are only a few reports on chemotherapy for unresectable or metastatic MPNST in the literature [8–10]. Half of MPNST occur sporadically in patients with no known germline mutations. The other half is predominantly associated with neurofibromatosis, an autosomal dominant disease which is characterized by Café au lait spots, Lisch nodules and neurofibromas [10]. MPNST can be classified as sporadic or neurofibromatosis type 1 (NF1)-associated. There is a paucity of data on the prognostic or predictive value of tumors and patient characteristics in NF1associated MPNST. In addition, comparative studies on
© 2014 S. Karger AG, Basel © 2014 S. Karger AG, Basel 0030–2414/14/0862–0122$39.50/0 E-Mail [email protected] www.karger.com/ocl
Thomas Brodowicz Medical University of Vienna Währinger Gürtel 18-20 AT–1090 Vienna (Austria) E-Mail thomas.brodowicz @ meduniwien.ac.at
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Key Words Malignant peripheral nerve sheath tumors · Neurofibromatosis I · Overall survival
Methods This single-center, retrospective analysis was performed on a cohort of 14 consecutive patients with MPNST who were treated at the Department of Oncology, Medical University of Vienna, between 2005 and 2011. Patients were identified via a retrospective chart review. Baseline characteristics are outlined in table 1. Patients with MPNST were routinely evaluated for the presence of characteristic features according to the diagnostic criteria of NF1 including multiple neurofibroma [11]. Clinical signs of NF1associated patients were diagnosed according to the recently published guidelines for the diagnosis (except the presence of optic pathway glioma, which was not routinely evaluated by imaging in our patients) and management of individual NF1 patients [13]. Patients without clinical signs of NF1 were classified as sporadic MPNST (group A) and those with the signs were classified as NF1associated MPNST (group B). Patient characteristics, tumor characteristics, treatment modalities, disease-free survival (DFS), progression-free survival (PFS) and OS were compared between the 2 groups. DFS was calculated from the time point of detection of localized disease until relapse or death (whichever occurred first). PFS was calculated from the start of any kind of therapy for metastatic disease until the date of progression or death. OS was calculated from the time of initial diagnosis until death from any cause or until the last follow-up. The data cut-off was April 2013. All 6 patients who are still alive had a follow-up visit in 2013. Survival curves were plotted using the Kaplan-Meier method using the statistical package IBM SPSS statistics 20.
Results
Fourteen MPNST patients entered this retrospective analysis. Baseline characteristics are outlined in table 1. Table 2 shows a detailed outcome for each patient. Group A Four males and 4 females had a median age of 55 years (range 20–68). Median tumor volume of the primary tumor at initial diagnosis was 109 ml. Six patients had primary localized disease. Two presented with initial metastatic disease: 1 with lymph node and lung metastasis and the other with lung metastasis at initial diagnosis. Six of those with primary localized disease underwent initial resection of the tumor. Four underwent adjuvant radiotherapy and 1 reOutcome in NF1-Associated MPNST
Table 1. Baseline characteristics (n = 14)
Group A n = 8 Sex Female 4 Male 4 Mortality status Alive 4 Dead 4 Fibroma, yes/no 0/8 Histology – MPNST 8 Median volume of primary tumor 109 ml Location Superficial 5 Deep 3 Grade II 4 III 4 Median age at diagnosis, years (range) 55 (20–68) Location of primary disease Lower extremity 4 Upper extremity 4 Chest wall 0 Type of primary tumor Localized 6 Metastatic 2 Sites in patients with primary metastatic tumor Lung 2 Lymph nodes 1 Other 0 Therapy for localized disease at diagnosis Surgery 6 Re-resection 3 Radical 4 Marginal/debulking 2 Adjuvant radiotherapy 4 Adjuvant chemotherapy 1 Doxorubicin 0 Epirubicin/ifosfamide 1 Therapy for primary metastatic disease Surgery of the primary tumor 2 Radical 1 Marginal/debulking 1 Chemotherapy Doxorubicin 0 EVAIA 1 Pattern of relapse n = 2 Local 1 Distant 1 Therapy for relapsing patients Surgery 1 Amputation 1 Radiotherapy 0 Pulmonal metastasectomy 0 Median follow-up, months 66.2
Group B n = 6 3 3 2 4 6/0 6 205 ml 1 5 1 5 50 (25–80) 4 1 1 3 3 1 0 3 3 2 2 1 3 1 0 1 3 2 1 2 0 n = 4 1 3 1 0 1 1 57.2
EVAIA = Etoposide, vincristine, dactinomycin, ifosfamide and doxorubicin.
Oncology 2014;86:122–126 DOI: 10.1159/000357137
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both subsets of MPNST report inconsistent outcomes [4, 5, 11, 12]. The aim of this retrospective, single-center study was to compare sporadic and NF1-associated MPNST, focusing on baseline patient characteristics, tumor characteristics, treatment modalities and clinical outcomes.
Group B Three males and 3 females had a median age of 50 years (range 25 – 80). Median tumor volume of the primary tumor was 205 ml. Five patients had a deep G3 primary tumor and 1 had a superficial G2 primary tumor. Three had primary localized disease. Three presented with initial metastatic disease in the lung and at other locations. Three underwent resection of the primary tumor, with re-resection being performed in 2 patients. Three received palliative radiotherapy and 1 received palliative chemotherapy. Two patients with initial metastatic disease underwent radical surgical resection of the primary tumor. Two received palliative chemotherapy with doxorubicin for initial metastatic disease. One had a local relapse and 3 had a distant relapse. Treatment modalities for relapsed/metastatic disease included surgery and radiotherapy. One patient with a relapse to the lungs underwent pulmonary metastasectomy and is still alive. Of 3 patients with distant relapse, 2 died a few days after diagnosis of the relapse and the third died 2 months afterwards withno therapy. PFS was 2.4 months (95% CI 1.3–3.5) (table 3). One patient with initial localized disease died after primary therapy due to tumor progress. This patient was disease-free for 17 months. Median follow-up was 57.2 months. Median OS was 12.7 months (95% CI 0–52.9).
Discussion
Reports on MPNST (sporadic vs. NF1-associated) in the literature are conflicting. Some show a decreased survival for NF1-associated MPNST patients while others show no difference in survival rates [11–13]. In our study, patients with sporadic MPNST had a numerically longer OS and were older than patients with NF1-associated MPNST. More NF1-associated than sporadic MPNST patients received adjuvant chemotherapy. 124
Oncology 2014;86:122–126 DOI: 10.1159/000357137
Table 2. Survival data for each patient
DFS PFS PFS2 OS Mortality months months months months status Group A Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Group B Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
n = 5
n = 3 4
n = 1
98 20 87
b
b
b
b
b
b
a
b
b
41 34
b
b
b
b
a
9 n = 3 5 2
5 n = 0
b
b
a
n=3 a a
17 13
b
b b
b
b
a
2
b
66
b
b
n = 8 5 108 31 92 1 41 37 47 n = 6 13 7 41 49 4 66
dead alive dead alive dead alive alive dead dead dead dead alive dead alive
a Not evaluable because of metastatic disease at initial diagnosis. b Not evaluable because of no relapse.
Table 3. Outcomes
Months, median (95% CI)
log HR rank (95% CI)
OS, DG until death Group A (n = 8) 46.9 (15.5–78.4) 0.62 0.564 (0.378–1.699) Group B (n = 6) 12.7 (0–52.9) PFS Group A (n = 3) 3.9 (0–8.1) 0.61 0.610 (0.101–3.833) Group B (n = 3) 2.4 (1.3–3.5) DG = Docetaxel plus gemcitabine treatment.
Anghileri et al. [14] reported on 205 patients with sporadic (n = 159) and NF1-associated (n = 46) MPNST. Potential prognostic factors and survival were evaluated. The authors concluded that patients with both these types of MPNST have similar prognostic factors with regard to gender and the site, depth, grade and margins of the tumor as well as radiation therapy. The only difference between the 2 groups was the greater volume of the tumor in the patients with NF1-associated MPNST, which agrees with our results. Lamm et al.
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ceived adjuvant chemotherapy. Two patients had initial metastatic disease and 1 of these underwent resection of the tumor. One patient had a local as well as a distant relapse (lymph nodes) and therefore underwent amputation of the upper extremity with dissection of the axillary lymph node, and was progression-free for 4 months (table 2). Four patients died (one death was not tumor-related). Median follow-up was 66.2 months. Median PFS after first-line chemotherapy for metastatic disease was 3.9 months (range 0–8.1). The one patient who received second-line chemotherapy for metastatic disease progressed after 5 months. Median OS was 46.9 months (range 15.5–78.4).
Kamran et al. [15] investigated prognostic features in patients with MPNST. Sixty-two of 84 patients were diagnosed with MPNST, whereas 22 had a malignant triton tumor. Malignant triton tumors comprise a very rare subgroup of MPNST with rhabdomyoblastic differentiation; they are more aggressive and have a poorer prognosis than MPNST without this differentiation [16]. In this series, patients with a malignant triton tumor located in the torso had a worse prognosis than the other MPNST patients. NF1 status was not prognostic [15]. Porter et al. [12] investigated differences in the survival of MPNST patients with sporadic MPNST and NF1associated MPNST. In their study, 123 MPNST patients (33 with NF1-associated MPNST) were evaluated. Tumor site and stage were prognostic. After multivariate analysis, the investigators concluded that a tumor volume of >200 ml was a predictor of poorer outcome and that routine screening with MRI is necessary in patients with NF1-associated MPNST. Ducatman et al. [5] reported a decreased survival time for MPNST patients with NF1-associated MPNST. A total of 120 patients (52% NF1-associated MPNST, 11% postradiation sarcomas and 16% metaplastic foci) participated in their study. OS was decreased in patients with NF1-associated MPNST and tumors >5 cm. Total resection was the most important prognostic indicator for MPNST patients with sporadic MPNST and for those with NF1-associated MPNST. Kolberg et al. [17] performed a meta-analysis testing the outcome of NF1 status on MPNST, comparing the survival of patients with sporadic MPNST (n = 117) and those with NF1-associated MPNST (n = 62) by studying the results of various studies. While older studies reported a worse outcome in patients with NF1-associated
MPNST, in more recently published studies, outcomes have improved, with the investigators concluding that the survival rate in both groups is the same. In our study, the OS of group A was longer, but this was not statistically significant (p = 0.56). In a recent phase II study presented at the 2013 ASCO meeting in Chicago, Widemann et al. [18] reported a lower response rate in patients who were chemotherapy-naïve and had NF1-associated MPNST after they had received a combination therapy (2 cycles of ifosfamide and doxorubicin followed by 2 cycles of ifosfamide and etoposide) compared to sporadic MNST patients. In most of the patients, stabilization of the disease was achieved. In our study, 2 NF1-associated MPNST patients with initial metastatic disease received chemotherapy with doxorubicin. These 2 patients had progressive disease after 3 and 6 courses, respectively; this somehow reflects the currently available data of low chemosensitivity in this subentity [4, 5]. In our study, NF-1 status was assessed based upon clinical signs and symptoms. NF1 has not been assessed by means of mutational analyses; this might be a limitation of our study. In conclusion, patients with NF1-associated MPNST had a numerically shorter median OS compared to those with sporadic MPNST. This observation might be due to the greater number of deep tumor locations and grade 3 tumors as well as the younger age at first diagnosis in NF1-associated MPNST patients.
Disclosure Statement The authors have no relevant conflicts of interest to declare.
1 Prieto R, Pascual JM, Garcia-Cabezas MA, Lopez-Barea F, Barrios L, Gonzalez-Llanos F: Low-grade malignant triton tumor in the lumbar spine: a rare variant of malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation. Neuropathology 2012;32:180–189. 2 Hueman MT, Ahuja N: Soft tissue sarcomas. Preface. Surg Clin North Am 2008;88:xiii–xvii. 3 Stucky CC, Johnson KN, Gray RJ, Pockaj BA, Ocal IT, Rose PS, Wasif N: Malignant peripheral nerve sheath tumors (MPNST): the Mayo Clinic experience. Ann Surg Oncol 2012; 19: 878–885. 4 Wong WW, Hirose T, Scheithauer BW, Schild SE, Gunderson LL: Malignant periph-
Outcome in NF1-Associated MPNST
eral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys 1998; 42:351–360. 5 Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM, Ilstrup DM: Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 1986; 57: 2006– 2021. 6 Sordillo PP, Helson L, Hajdu SI, Magill GB, Kosloff C, Golbey RB, Beattie EJ: Malignant schwannoma – clinical characteristics, survival, and response to therapy. Cancer 1981; 47:2503–2509. 7 Dunn GP, Spiliopoulos K, Plotkin SR, Hornicek FJ, Harmon DC, Delaney TF, Williams Z: Role of resection of malignant peripheral
nerve sheath tumors in patients with neurofibromatosis type 1. J Neurosurg 2013; 118: 142–148. 8 Gupta G, Mammis A, Maniker A: Malignant peripheral nerve sheath tumors. Neurosurg Clin North Am 2008;19:533–543. 9 Widemann BC: Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Curr Oncol Rep 2009;11:322–328. 10 McCaughan JA, Holloway SM, Davidson R, Lam WW: Further evidence of the increased risk for malignant peripheral nerve sheath tumour from a Scottish cohort of patients with neurofibromatosis type 1. J Med Genet 2007; 44:463–466.
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17 Kolberg M, Holand M, Agesen TH, Brekke HR, Liestol K, Hall KS, Mertens F, Picci P, Smeland S, Lothe RA: Survival meta-analyses for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro Oncol 2013; 15: 135– 147. 18 Widemann BC, Reinke DK, Helman LJ, Ludwig JA, Schuetze S, Staddon AP, Milhem MM, Rushing DA, Moertel CL, Goldman S, et al: SARC006: phase II trial of chemotherapy in sporadic and neurofibromatosis type 1 (NF1)associated high-grade malignant peripheral nerve sheath tumors (MPNSTs). ASCO Annual Meeting, Chicago, 2013. J Clin Oncol 2013;31:abstr 10522.
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11 Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A: Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 2002;39:311–314. 12 Porter DE, Prasad V, Foster L, Dall GF, Birch R, Grimer RJ: Survival in malignant peripheral nerve sheath tumours: a comparison between sporadic and neurofibromatosis type 1-associated tumours. Sarcoma 2009; 2009: 756395. 13 Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, et al: Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007;44:81–88.
Oncology 2014;86:122–126 DOI: 10.1159/000357137
Clinical Signs of Neurofibromatosis Impact on the Outcome of Malignant Peripheral Nerve Sheath Tumors W. Lamm a, e, f S. Schur a, e, f W.J. Köstler a, e, f P. Funovics b R. Windhager b G. Amann c J. Panotopoulos b B. Pokrajac d T. Brodowicz a, e, f
a
Clinical Division of Oncology, Department of Medicine I, b Department of Orthopedics, c Department of Pathology, Department of Radiation Oncology and e Musculoskeletal Tumor Unit, Comprehensive Cancer Center, Medical University of Vienna and f Sarcoma Platform Austria, Vienna, Austria
d
Abstract Objective: Malignant peripheral nerve sheath tumors (MPNST) are a rare subtype of sarcoma, with a poor outcome. MPNST are regarded as being sporadic or associated with neurofibromatosis type 1 (NF1). Few comparative overallsurvival (OS) data in these 2 subsets of MPNST patients exist. The aim of this retrospective study was to assess OS in sporadic and NF1-associated MPNST patients. Methods: Fourteen consecutive patients with initial localized as well as initial metastatic MPNST were diagnosed and treated in our department. Patients with sporadic MPNST were assigned to group A and those with NF1-associated MPNST to group B. Results: Eight versus 6 patients were allocated to groups A and B. Primary tumors were located on the extremities in all but 1 patient. Two patients in group A and 4 patients in group B experienced a relapse. Four patients died in each of the 2 groups. Median follow-up was 66.2 and 57.2 months in group A and group B, respectively. Median OS in group A was 46.9 months versus 12.7 months in group B. Conclusions: In this small, single-center study, sporadic-MPNST patients had a longer median OS than those with NF1-associated MPNST.
Introduction
Malignant peripheral nerve sheath tumors (MPNST) are rare tumors that are considered to arise from the Schwann cells of peripheral nerves. MPNST are aggressive, locally invasive soft tissue sarcomas and compromise up to 10% of this type of tumor [1]. The most common sites of origin are the extremities. Patients with these tumors often present with pain and other neurological symptoms [2]. Prognosis is still poor. In 2 large studies, tumor size and location affected overall survival (OS) [3, 4]. In large series of patients with MPNST, 5-year survival rates range from 16–52% [4–6]. The major cornerstone of therapy for localized disease is surgery [7]. There are only a few reports on chemotherapy for unresectable or metastatic MPNST in the literature [8–10]. Half of MPNST occur sporadically in patients with no known germline mutations. The other half is predominantly associated with neurofibromatosis, an autosomal dominant disease which is characterized by Café au lait spots, Lisch nodules and neurofibromas [10]. MPNST can be classified as sporadic or neurofibromatosis type 1 (NF1)-associated. There is a paucity of data on the prognostic or predictive value of tumors and patient characteristics in NF1associated MPNST. In addition, comparative studies on
© 2014 S. Karger AG, Basel © 2014 S. Karger AG, Basel 0030–2414/14/0862–0122$39.50/0 E-Mail [email protected] www.karger.com/ocl
Thomas Brodowicz Medical University of Vienna Währinger Gürtel 18-20 AT–1090 Vienna (Austria) E-Mail thomas.brodowicz @ meduniwien.ac.at
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Key Words Malignant peripheral nerve sheath tumors · Neurofibromatosis I · Overall survival
Methods This single-center, retrospective analysis was performed on a cohort of 14 consecutive patients with MPNST who were treated at the Department of Oncology, Medical University of Vienna, between 2005 and 2011. Patients were identified via a retrospective chart review. Baseline characteristics are outlined in table 1. Patients with MPNST were routinely evaluated for the presence of characteristic features according to the diagnostic criteria of NF1 including multiple neurofibroma [11]. Clinical signs of NF1associated patients were diagnosed according to the recently published guidelines for the diagnosis (except the presence of optic pathway glioma, which was not routinely evaluated by imaging in our patients) and management of individual NF1 patients [13]. Patients without clinical signs of NF1 were classified as sporadic MPNST (group A) and those with the signs were classified as NF1associated MPNST (group B). Patient characteristics, tumor characteristics, treatment modalities, disease-free survival (DFS), progression-free survival (PFS) and OS were compared between the 2 groups. DFS was calculated from the time point of detection of localized disease until relapse or death (whichever occurred first). PFS was calculated from the start of any kind of therapy for metastatic disease until the date of progression or death. OS was calculated from the time of initial diagnosis until death from any cause or until the last follow-up. The data cut-off was April 2013. All 6 patients who are still alive had a follow-up visit in 2013. Survival curves were plotted using the Kaplan-Meier method using the statistical package IBM SPSS statistics 20.
Results
Fourteen MPNST patients entered this retrospective analysis. Baseline characteristics are outlined in table 1. Table 2 shows a detailed outcome for each patient. Group A Four males and 4 females had a median age of 55 years (range 20–68). Median tumor volume of the primary tumor at initial diagnosis was 109 ml. Six patients had primary localized disease. Two presented with initial metastatic disease: 1 with lymph node and lung metastasis and the other with lung metastasis at initial diagnosis. Six of those with primary localized disease underwent initial resection of the tumor. Four underwent adjuvant radiotherapy and 1 reOutcome in NF1-Associated MPNST
Table 1. Baseline characteristics (n = 14)
Group A n = 8 Sex Female 4 Male 4 Mortality status Alive 4 Dead 4 Fibroma, yes/no 0/8 Histology – MPNST 8 Median volume of primary tumor 109 ml Location Superficial 5 Deep 3 Grade II 4 III 4 Median age at diagnosis, years (range) 55 (20–68) Location of primary disease Lower extremity 4 Upper extremity 4 Chest wall 0 Type of primary tumor Localized 6 Metastatic 2 Sites in patients with primary metastatic tumor Lung 2 Lymph nodes 1 Other 0 Therapy for localized disease at diagnosis Surgery 6 Re-resection 3 Radical 4 Marginal/debulking 2 Adjuvant radiotherapy 4 Adjuvant chemotherapy 1 Doxorubicin 0 Epirubicin/ifosfamide 1 Therapy for primary metastatic disease Surgery of the primary tumor 2 Radical 1 Marginal/debulking 1 Chemotherapy Doxorubicin 0 EVAIA 1 Pattern of relapse n = 2 Local 1 Distant 1 Therapy for relapsing patients Surgery 1 Amputation 1 Radiotherapy 0 Pulmonal metastasectomy 0 Median follow-up, months 66.2
Group B n = 6 3 3 2 4 6/0 6 205 ml 1 5 1 5 50 (25–80) 4 1 1 3 3 1 0 3 3 2 2 1 3 1 0 1 3 2 1 2 0 n = 4 1 3 1 0 1 1 57.2
EVAIA = Etoposide, vincristine, dactinomycin, ifosfamide and doxorubicin.
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both subsets of MPNST report inconsistent outcomes [4, 5, 11, 12]. The aim of this retrospective, single-center study was to compare sporadic and NF1-associated MPNST, focusing on baseline patient characteristics, tumor characteristics, treatment modalities and clinical outcomes.
Group B Three males and 3 females had a median age of 50 years (range 25 – 80). Median tumor volume of the primary tumor was 205 ml. Five patients had a deep G3 primary tumor and 1 had a superficial G2 primary tumor. Three had primary localized disease. Three presented with initial metastatic disease in the lung and at other locations. Three underwent resection of the primary tumor, with re-resection being performed in 2 patients. Three received palliative radiotherapy and 1 received palliative chemotherapy. Two patients with initial metastatic disease underwent radical surgical resection of the primary tumor. Two received palliative chemotherapy with doxorubicin for initial metastatic disease. One had a local relapse and 3 had a distant relapse. Treatment modalities for relapsed/metastatic disease included surgery and radiotherapy. One patient with a relapse to the lungs underwent pulmonary metastasectomy and is still alive. Of 3 patients with distant relapse, 2 died a few days after diagnosis of the relapse and the third died 2 months afterwards withno therapy. PFS was 2.4 months (95% CI 1.3–3.5) (table 3). One patient with initial localized disease died after primary therapy due to tumor progress. This patient was disease-free for 17 months. Median follow-up was 57.2 months. Median OS was 12.7 months (95% CI 0–52.9).
Discussion
Reports on MPNST (sporadic vs. NF1-associated) in the literature are conflicting. Some show a decreased survival for NF1-associated MPNST patients while others show no difference in survival rates [11–13]. In our study, patients with sporadic MPNST had a numerically longer OS and were older than patients with NF1-associated MPNST. More NF1-associated than sporadic MPNST patients received adjuvant chemotherapy. 124
Oncology 2014;86:122–126 DOI: 10.1159/000357137
Table 2. Survival data for each patient
DFS PFS PFS2 OS Mortality months months months months status Group A Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Group B Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
n = 5
n = 3 4
n = 1
98 20 87
b
b
b
b
b
b
a
b
b
41 34
b
b
b
b
a
9 n = 3 5 2
5 n = 0
b
b
a
n=3 a a
17 13
b
b b
b
b
a
2
b
66
b
b
n = 8 5 108 31 92 1 41 37 47 n = 6 13 7 41 49 4 66
dead alive dead alive dead alive alive dead dead dead dead alive dead alive
a Not evaluable because of metastatic disease at initial diagnosis. b Not evaluable because of no relapse.
Table 3. Outcomes
Months, median (95% CI)
log HR rank (95% CI)
OS, DG until death Group A (n = 8) 46.9 (15.5–78.4) 0.62 0.564 (0.378–1.699) Group B (n = 6) 12.7 (0–52.9) PFS Group A (n = 3) 3.9 (0–8.1) 0.61 0.610 (0.101–3.833) Group B (n = 3) 2.4 (1.3–3.5) DG = Docetaxel plus gemcitabine treatment.
Anghileri et al. [14] reported on 205 patients with sporadic (n = 159) and NF1-associated (n = 46) MPNST. Potential prognostic factors and survival were evaluated. The authors concluded that patients with both these types of MPNST have similar prognostic factors with regard to gender and the site, depth, grade and margins of the tumor as well as radiation therapy. The only difference between the 2 groups was the greater volume of the tumor in the patients with NF1-associated MPNST, which agrees with our results. Lamm et al.
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ceived adjuvant chemotherapy. Two patients had initial metastatic disease and 1 of these underwent resection of the tumor. One patient had a local as well as a distant relapse (lymph nodes) and therefore underwent amputation of the upper extremity with dissection of the axillary lymph node, and was progression-free for 4 months (table 2). Four patients died (one death was not tumor-related). Median follow-up was 66.2 months. Median PFS after first-line chemotherapy for metastatic disease was 3.9 months (range 0–8.1). The one patient who received second-line chemotherapy for metastatic disease progressed after 5 months. Median OS was 46.9 months (range 15.5–78.4).
Kamran et al. [15] investigated prognostic features in patients with MPNST. Sixty-two of 84 patients were diagnosed with MPNST, whereas 22 had a malignant triton tumor. Malignant triton tumors comprise a very rare subgroup of MPNST with rhabdomyoblastic differentiation; they are more aggressive and have a poorer prognosis than MPNST without this differentiation [16]. In this series, patients with a malignant triton tumor located in the torso had a worse prognosis than the other MPNST patients. NF1 status was not prognostic [15]. Porter et al. [12] investigated differences in the survival of MPNST patients with sporadic MPNST and NF1associated MPNST. In their study, 123 MPNST patients (33 with NF1-associated MPNST) were evaluated. Tumor site and stage were prognostic. After multivariate analysis, the investigators concluded that a tumor volume of >200 ml was a predictor of poorer outcome and that routine screening with MRI is necessary in patients with NF1-associated MPNST. Ducatman et al. [5] reported a decreased survival time for MPNST patients with NF1-associated MPNST. A total of 120 patients (52% NF1-associated MPNST, 11% postradiation sarcomas and 16% metaplastic foci) participated in their study. OS was decreased in patients with NF1-associated MPNST and tumors >5 cm. Total resection was the most important prognostic indicator for MPNST patients with sporadic MPNST and for those with NF1-associated MPNST. Kolberg et al. [17] performed a meta-analysis testing the outcome of NF1 status on MPNST, comparing the survival of patients with sporadic MPNST (n = 117) and those with NF1-associated MPNST (n = 62) by studying the results of various studies. While older studies reported a worse outcome in patients with NF1-associated
MPNST, in more recently published studies, outcomes have improved, with the investigators concluding that the survival rate in both groups is the same. In our study, the OS of group A was longer, but this was not statistically significant (p = 0.56). In a recent phase II study presented at the 2013 ASCO meeting in Chicago, Widemann et al. [18] reported a lower response rate in patients who were chemotherapy-naïve and had NF1-associated MPNST after they had received a combination therapy (2 cycles of ifosfamide and doxorubicin followed by 2 cycles of ifosfamide and etoposide) compared to sporadic MNST patients. In most of the patients, stabilization of the disease was achieved. In our study, 2 NF1-associated MPNST patients with initial metastatic disease received chemotherapy with doxorubicin. These 2 patients had progressive disease after 3 and 6 courses, respectively; this somehow reflects the currently available data of low chemosensitivity in this subentity [4, 5]. In our study, NF-1 status was assessed based upon clinical signs and symptoms. NF1 has not been assessed by means of mutational analyses; this might be a limitation of our study. In conclusion, patients with NF1-associated MPNST had a numerically shorter median OS compared to those with sporadic MPNST. This observation might be due to the greater number of deep tumor locations and grade 3 tumors as well as the younger age at first diagnosis in NF1-associated MPNST patients.
Disclosure Statement The authors have no relevant conflicts of interest to declare.
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