ANTICANCER RESEARCH 27: 1819-1822 (2007)
Clinical Relevance of Positron Emission Tomography and Magnetic Resonance Imaging in the Progression of Internal Plexiform Neurofibroma in NF1 V.F. MAUTNER1, W. BRENNER2, C. FÜNSTERER3, C. HAGEL4, K. GAWAD5 and R.E. FRIEDRICH6 1Section 5General,
of Phacomatoses, Maxillofacial Surgery, 2Nuclear Medicine, 4Neuropathology, Thoracic and Visceral Surgery and 6Maxillofacial Surgery, Eppendorf University Hospital, University of Hamburg, 3MRI Institute, Hamburg-Othmarschen, Germany
Abstract. Neurofibromatosis type 1 (NF1) is a frequent and inherited disease with a predisposition for malignant peripheral nerve sheath tumor (MPNST) development. MPNST are soft tissue sarcomas that arise from peripheral nerves, being one of the most aggressive malignancies in humans with extremely poor prognosis. MPNST frequently arise from a previously undetected plexiform neurofibroma (PNF). The malignant transformation of an internal PNF to an MPNST is difficult to assess and requires advanced imaging techniques like magnetic resonance imaging or positron emission tomography. Despite the high quality of current diagnostics, the changing tumor biology inside a plexiform neurofibroma cannot currently be visualized accurately. We report 4 cases of NF1 patients with PNF who showed imaging findings suspicious for malignant degeneration, but proved to have MPNST in only one case. Three tumors might represent an intermediate type between PNF and MPNST. Ablative surgery and complete histological work-up of specimens is the only way to clarify tumor status, thereby enabling provision of adequate local treatment. Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disease (1, 2). About 30% of NF1 patients develop external plexiform neurofibroma (3). These tumors can cause severe functional and aesthetic deficits. The plexiform neurofibroma (PNF) is a benign tumor with different growth patterns (4-6). PNF can give rise to a distinct cancer entity, the malignant peripheral nerve sheath tumor (MPNST). Patients who carry PNF which are not surgically resectable
Correspondence to: Prof. Dr. R.E. Friedrich, MD, DMD, Maxillofacial Surgery, Eppendorf University Hospital, University of Hamburg, Martinist. 52, D-20246 Hamburg, Germany. Tel: +49 40428033259, e-mail:
[email protected] Key Words: Neurofibromatosis, positron emission tomography, standardized uptake values, SUV, magnetic resonance imaging, malignant peripheral nerve sheath tumor, plexiform neurofibroma.
0250-7005/2007 $2.00+.40
should undergo follow-up examinations with magnetic resonance imaging (MRI) to monitor if tumor growth leads to functional deficits or transforms to MPNST (6, 7). Patients with progressive PNF often present with pain, frequently invisible internal tumors and/or neurological deficits. In these patients it is essential to determine if plexiform tumors undergo malignant change. Whole body MRI was introduced in clinical care in NF1 patients to detect internal PNF that are not visible by clinical examination but at risk of presenting clinical complaints/complications (8). MRI of PNF showing inhomogeneous tumor lesions and patchy contrast enhancement, due to necrosis and haemorrhage, indicate malignancy (7). However, in a subset of symptomatic patients, MRI does not prove to be a reliable indicator of malignancy. Positron emission tomography (PET) with F-18fluorodeoxyglucose (FDG) was reported to be a sensitive tool to identify malignancy arising in PNF in NF1 (9). Recently, we were able to demonstrate that standardized uptake values (SUV) in PET are a sensitive marker for predicting outcome in NF1 patients with MPNST (10). However, Ferner et al. (9) noted that PET does not allow distinction between benign and malignant lesions with SUV ranging from 2.7 to 3.3. Similar results were observed in our patient group with MPNST showing FDG tumor SUV as low as 2.1 (10). During the follow-up of patients with internal PNF, some show radiological tumor progression, e.g. increase in size and altered internal texture of the tumor (7), associated with clinical complaints. We investigated several patients using both MRI and PET and found that the synopsis of both imaging modalities might identify an intermediate growth stage of PNF in NF1 that indicates the transformation of a benign to a malignant phenotype. We report on NF1 patients with PNF who showed tumor growth on MRI and had SUV on FDG-PET that were suspicious for malignancy. All patients underwent surgery and a complete histological work-up of the resection specimen.
1819
ANTICANCER RESEARCH 27: 1819-1822 (2007) Table I. Patient characteristics, MRI, PET and histological findings. Patient No.
Age (years)
Gender
Tumor localization
MRI
PET (SUV, mean values)
Histology
1
24
Female
Thorax
Increase of Tumor Volume
4.2
2 3 4
23 8 47
Male Male Female
Intestine (Colon) Thorax Iliosacral
Increase of Tumor Volume Increase of Tumor Volume Increase of Tumor Volume*
2.5 2.7 3.6
Nodular PNF; Atypical Cells MPNST PNF PNF
*Patient has a history of upper extremity amputation for treatment of MPNST (10 years ago) and had developed a second MPNST of the neck 4 weeks before current diagnosis of the tumor of the trunk.
Results Case 1. A 24-year-old female patient consulted the outpatient clinic for annual whole body MRI. She had developed a tumor on the right lateral thoracic wall predominantly intercostally with internal displacing growth characteristics. The tumor had increased in size during the previous year (3.1 cm x 2.9 cm x 2.4 cm). On PET, the SUV was 4.2. A thoracotomy was performed and the tumor was extirpated with adjacent bone. Intraoperatively, enlarged nerves were running perpendicular to the ribs across the pleura, forming small nodular tumors in continuity with enlarged nerves. Several excisional biopsies were taken from these altered nerves in the vicinity of the resected tumor. Healing was uneventful. All specimens proved to be plexiform neurofibroma without malignant degeneration (WHO grade I). Case 2. A 23-year-old male suffered from a heavy internal load of PNF. At the age of 22 years, on MRI the nodular and rope-like arranged tumors were predominantly localized around the thoracic and abdominal spine. The largest tumors were localized in the lumbo-sacral region. The spinal column showed no tumor invasion. The tumors were equally distributed on both sides of the trunk and showed a symmetric growth pattern. One year later, a remarkable increase in the size of a pelvic tumor (5 cm x 6 cm) adjacent to and displacing the rectum was noticed. This tumor showed an inhomogeneous internal structure and a strong uptake of contrast medium. No other tumors changed in size or appearance with contrast medium application. SUV of this region in PET was 2.5. Histology of the extirpated nodular tumor revealed an MPNST. Case 3. An 8-year-old boy had developed a large plexiform neurofibroma connatally, extending from the shoulder girdle and neck to the thorax and mediastinum. Inside this extensive PNF, a solid and displacing tumor of the right mediastinal side was demarcated on repeatedly taken MRI. This tumor showed progression and a suspicious uptake of contrast
1820
medium. On FDG-PET, the SUV of the tumor was 2.7. Following thoracotomy, the encapsulated tumor was completely excised (5 cm x 4.4 cm x 3.6 cm). Healing was uneventful. Histological investigation resulted in diagnosis of a large plexiform neurofibroma, WHO grade I. Case 4. A 47-year-old female had a history of right upper extremity amputation following diagnosis of an MPNST 10 years earlier. During the following years she was repeatedly examined with MRI. A plexiform neurofibroma of the right vagus nerve remained stable for many years until she was 46 years old, when she noticed a more rapid increase in size. The tumor was resected following lateral pharyngotomy. The tumor extended from the skull base to the clavicle and after extirpation the sliced tumor showed some inhomogeneities and a small area of necrosis. Diagnosis of MPNST not exceeding the pseudo-capsule was established following complete histological work-up (grade II, FNCLCC). A second-look pharyngotomy found no detectable tumor. A PET was performed that demonstrated high tracer uptake of the right sacral region (SUV 3.6), corresponding to a sharply demarcated tumor with high contrast enhancement on MRI (with no alteration of size and volume within the past year). The extirpated tumor proved to be a plexiform neurofibroma with no signs of malignancy (WHO grade I). The results are summarized in Table I.
Discussion These cases demonstrate a lack of diagnostic accuracy for differentiating PNF and MPNST in the course of NF1. This difference between the imaging and histological findings is of particular interest for such patients, who are considered at risk for malignancy due to their heavy tumor burden. All patients showed an excellent compliance that allowed an annual follow-up control with comparative investigation of tumor growth characteristics on MRI over several years. MRI is currently the best imaging technique that allows the identification of neurofibroma and other lesions associated with the disease and can be helpful to distinguish MPNST
Mautner et al: Clinical Relevance of PET and MRI in Progression of PNF
from PNF (7). Positron emission tomography (PET) was introduced in the diagnosis of NF1 and proved a valuable tool in identifying MPNST (9). Further investigation on PET and MPNST resulted in a prediction of survival deduced from differences of the SUV (10). One of our cases showed alterations of the tumor on MRI but had an SUV not characteristic of an MPNST (case 4). However, elevated SUV can also be registered in the course of inflammations of different pathogenesis (11, 12). Therefore, the precise prediction of tumor biology cannot be derived from MRI (13) nor PET (10). It is well known that PNF has to be considered as a precancerous lesion (14). Alterations of these tumors, either registered during physical examinations or from imaging, have to be taken seriously. The decision for surgical exploration and microscopic analysis of representative tumor is prudent in establishing correct diagnosis. However, PNF might show different grading inside one tumor, in particular in large tumors. Therefore, complete resection of a PNF suspected of being malignant is advisible. It is reasonable to assume that the reported images and morphological findings of plexiform neurofibromas in the 3 of the 4 NF1 patients possibly demonstrate an intermediate stage of PNF, located between the benign PNF and a true MPNST. The high SUV levels were suspicious of malignancy in all patients. An increase in SUV might be more helpful, indicating growth or progression. In the literature there are no data available on the time course of SUV obtained by serial PET. In one case, the history of MPNST forced us to exclude a metastasis. In a further case, the findings of pretherapeutic imaging were erroneously in favour of a plexiform neurofibroma. In one case, atypical tumor cells were noted. Atypical tumor cells in PNF are known and are obviously no risk factor for MPNST (14, 15). Histological investigations of all specimens were the gold standard to define the grade of tumors. Radiological measures might indicate the beginning of malignant transformation of a PNF in NF1. An intermediate stage between PNF and MPNST may be reflected in a high SUV, despite no signs of necrosis on MRI. There still remains a grey area where no imaging technique allows any distinction between a PNF and MPNST, as shown in case 4. In the patients presented in this report, surgical exploration is advocated and offers the chance to clarify the tumor’s grade. Serum markers to indicate malignant transformation of PNF to MPNST would be helpful tools to improve diagnosis and treatment in NF1 (16).
Conclusion These case reports demonstrate a possible intermediate stage of PNF to MPNST in NF1 patients. The patients showed altered tumor characteristics, in particular an increase in tumor volume on MRI over distinct periods of time and
increased SUV in PET. The combined application of MRI and PET gives no precise information on the tumor’s grade in these few cases. There is currently no non-invasive investigation available that allows a precise distinction of a benign or malignant course in NF1, emphasizing the importance of thorough clinical investigation and the need for follow-up controls. Surgical exploration is required to gain information about tumor biology, also allowing local treatment in many cases.
Acknowledgements The investigations were supported by Deutsche Krebshilfe (project Ma 70-3072).
References 1 Von Recklinghausen FD: Ueber die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen. A. Hirschwald, Berlin, 1882. 2 Riccardi VM: Neurofibromatosis. Phenotype, Natural History, and Histogenesis. 2nd edition, The Johns Hopkins University Press, Baltimore and London, 1992. 3 Huson SM, Harper PS and Compston DA: Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain 111: 1355-1381, 1988. 4 Friedrich RE, Korf B, Fünsterer C and Mautner VF: Growth type of plexiform neurofibromas in NF1 determined on magnetic resonance images. Anticancer Res 23: 949-952, 2003. 5 Friedrich RE, Hagel C, Brehme Z, Kluwe L and Mautner VF: Ki-67 proliferation-index (MIB-1) of neurofibromas in neurofibromatosis type 1 patients. Anticancer Res 23: 953-955, 2003. 6 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. 7 Mautner VF, Friedrich RE, von Deimling A, Hagel C, Korf B, Knöfel 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. 8 Kehrer-Sawatzki H, Kluwe L, Fünsterer C and Mautner VF: Extensively high load of internal tumors determined by whole body MRI scanning in a patient with neurofibromatosis type 1 and a non-LCR-mediated 2-Mb deletion in 17q11.2. Hum Genet 116: 466-475, 2005. 9 Ferner RE, Lucas JD, O'Doherty MJ, Hughes RA, Smith MA, Cronin BF and Bingham J: Evaluation of (18)fluorodeoxyglucose positron emission tomography [(18)FDG PET] in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1. J Neurol Neurosurg Psychiatry 68: 353-357, 2000. 10 Brenner W, Friedrich RE, Gawad KA, Hagel C, von Deimling A, de Wit M, Buchert R, Clausen M and Mautner VF: Prognostic relevance of FDG PET in patients with neurofibromatosis type 1 and malignant peripheral nerve sheath tumours. Eur J Nucl Med Mol Imaging 33: 428-432, 2006.
1821
ANTICANCER RESEARCH 27: 1819-1822 (2007) 11 Roivainen A, Parkkola R, Yli-Kerttula T, Lehikoinen P, Viljanen T, Mottonen T, Nuutila P and Minn H: Use of positron emission tomography with methyl-11C-choline and 218F-fluoro-2-deoxy-D-glucose in comparison with magnetic resonance imaging for the assessment of inflammatory proliferation of synovium. Arthritis Rheum 48: 3077-3084, 2003. 12 Zhuang HM, Cortes-Blanco A, Pourdehnad M, Adam LE, Yamamoto AJ, Martinez-Lazaro R, Lee JH, Loman JC, Rossman MD and Alavi A: Do high glucose levels have differential effect on FDG uptake in inflammatory and malignant disorders? Nucl Med Commun 22: 1123-1128, 2001. 13 Korf B: Malignancy in neurofibromatosis type 1. The Oncologist 5: 477-485, 2000. 14 Scheithauer BW, Halling KC, Nascimento AG, Hill EM, Sim FH and Katzmann JA: Neurofibroma and malignant peripheral nerve sheath tumor: a proliferation index and ploidy study. Path Res Pract 19: 177, 1995.
1822
15 Scheithauer BW, Woodruff JM and Erlandson RA: Atlas of Tumor Pathology. Tumors of the Peripheral Nervous System. Armed Forces Institute of Pathology, Washington, pp. 202-210, 1999. 16 Mashour GA, Driever PH, Hartmann M, Drissel SN, Zhang T, Scharf B, Felderhoff-Muser U, Sakuma S, Friedrich RE, Martuza RL, Mautner VF and Kurtz A: Circulating growth factor levels are associated with tumorigenesis in neurofibromatosis type 1. Clin Cancer Res 10: 5677-5683, 2004.
Received December 13, 2006 Revised March 7, 2007 Accepted March 9, 2007
