Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis
Scott R Plotkin, Miriam A Bredella, Wenli Cai, Ara Kassarjian, Gordon J Harris, Sonia Esparza, Vanessa L Merker, Lance L Munn, Alona Muzikansky, Manor Askenazi, Rosa Nguyen, Ralph Wenzel, Victor F Mautner, Scott R Plotkin, Miriam A Bredella, Wenli Cai, Ara Kassarjian, Gordon J Harris, Sonia Esparza, Vanessa L Merker, Lance L Munn, Alona Muzikansky, Manor Askenazi, Rosa Nguyen, Ralph Wenzel, Victor F Mautner
Abstract
Purpose: Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease.
Methods: We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors.
Results: WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10).
Conclusion: WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations.
Conflict of interest statement
Competing Interests: Dr. Kassarjian is employed by Corades, S.L. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
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References
- Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990;62:193–201.
- Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;75:826.
- Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature. 1993;363:515–521.
- Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, et al. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet. 2007;80:805–810.
- MacCollin M, Chiocca EA, Evans DG, Friedman JM, Horvitz R, et al. Diagnostic criteria for schwannomatosis. Neurology. 2005;64:1838–1845.
- NIH Consensus Conference. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol. 1988;45:575–578.
- Duong TA, Sbidian E, Valeyrie-Allanore L, Vialette C, Ferkal S, et al. Orphanet J Rare Dis 6: 18. 1750-1172-6-18 [pii];10.1186/1750-1172-6-18 [doi]; 2011. Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980-2006 in France.
- Evans DG, O'Hara C, Wilding A, Ingham SL, Howard E, et al. Eur J Hum Genet. ejhg2011113 [pii];10.1038/ejhg.2011.113 [doi]; 2011. Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989.
- Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet. 2001;68:1110–1118.
- Otsuka G, Saito K, Nagatani T, Yoshida J. Age at symptom onset and long-term survival in patients with neurofibromatosis Type 2. J Neurosurg. 2003;99:480–483.
- Mulvihill JJ, Parry DM, Sherman JL, Pikus A, Kaiser-Kupfer MI, et al. NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Ann Intern Med. 1990;113:39–52.
- Baser ME, Friedman JM, Wallace AJ, Ramsden RT, Joe H, et al. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology. 2002;59:1759–1765.
- Cai W, Kassarjian A, Bredella MA, Harris GJ, Yoshida H, et al. Tumor burden in patients with neurofibromatosis types 1 and 2 and schwannomatosis: determination on whole-body MR images. Radiology. 2009;250:665–673.
- Sbidian E, Wolkenstein P, Valeyrie-Allanore L, Rodriguez D, Hadj-Rabia S, et al. NF-1Score: a prediction score for internal neurofibromas in neurofibromatosis-1. J Invest Dermatol. 2010;130:2173–2178.
- Mautner VF, Lindenau M, Baser ME, Kluwe L, Gottschalk J. Skin abnormalities in neurofibromatosis 2. Arch Dermatol. 1997;133:1539–1543.
- Baser ME, Kuramoto L, Joe H, Friedman JM, Wallace AJ, et al. Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study. Am J Hum Genet. 2004;75:231–239.
- Huson SM, Harper PS, Compston DA. Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain 111 (Pt. 1988;6):1355–1381.
- Deltas G. The small-sample bias of the Gini coefficient: results and implications for empirical research. Rev Econ Statist. 2003;85:226–234.
- Clauser CE, McConville JT, Young JW. Weight, volume, and center of mass of segments of the human body. 1969;AMRL-TR-69-70:1–101.
- R Development Core Team. R: a language and environment for statistical computing, version Vienna: R Foundation for Statistical Computing. 2008.
- Mautner VF, Asuagbor FA, Dombi E, Funsterer C, Kluwe L, et al. Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol. 2008;10:593–598.
- Waggoner DJ, Towbin J, Gottesman G, Gutmann DH. Clinic-based study of plexiform neurofibromas in neurofibromatosis 1. Am J Med Genet. 2000;92:132–135.
- Friedman JM, Birch PH. Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients. Am J Med Genet. 1997;70:138–143.
- North K. Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic. J Child Neurol. 1993;8:395–402.
- Tonsgard JH, Kwak SM, Short MP, Dachman AH. CT imaging in adults with neurofibromatosis-1: frequent asymptomatic plexiform lesions. Neurology. 1998;50:1755–1760.
- Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology. 2001;56:1433–1443.
- Aghi M, Kluwe L, Webster MT, Jacoby LB, Barker FG, et al. Unilateral vestibular schwannoma with other neurofibromatosis Type 2-related tumors: clinical and molecular study of a unique phenotype. J Neurosurg. 2006;104:201–207.
- Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, et al. Nf1-dependent tumors require a microenvironment containing Nf1+/− and c-kit-dependent bone marrow. Cell. 2008;135:437–448.
- Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, et al. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet. 1994;7:353–361.
- Giovannini M, Robanus-Maandag E, van d, V, Niwa-Kawakita M, Abramowski V, et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 2000;14:1617–1630.
- Vogel KS, Klesse LJ, Velasco-Miguel S, Meyers K, Rushing EJ, et al. Mouse tumor model for neurofibromatosis type 1. Science. 1999;286:2176–2179.
- Cichowski K, Santiago S, Jardim M, Johnson BW, Jacks T. Genes Dev 17: 449–454. 10.1101/gad.1054703 [doi]; 2003. Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor suppressor.
- Curto M, McClatchey AI. Br J Cancer 98: 256–262. 6604002 [pii];10.1038/sj.bjc.6604002 [doi]; 2008. Nf2/Merlin: a coordinator of receptor signalling and intercellular contact.
- Li W, You L, Cooper J, Schiavon G, Pepe-Caprio A, et al. Cell 140: 477–490. S0092-8674(10)00064-4 [pii];10.1016/j.cell.2010.01.029 [doi]; 2010. Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus.
- Biegel JA, Kalpana G, Knudsen ES, Packer RJ, Roberts CW, et al. The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors. Cancer Res. 2002;62:323–328.
- Wu BL, Austin MA, Schneider GH, Boles RG, Korf BR. Am J Med Genet 59: 528–535. 10.1002/ajmg.1320590427 [doi]; 1995. Deletion of the entire NF1 gene detected by the FISH: four deletion patients associated with severe manifestations.
- Upadhyaya M, Huson SM, Davies M, Thomas N, Chuzhanova N, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007;80:140–151.
- Tucker T, Wolkenstein P, Revuz J, Zeller J, Friedman JM. Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology. 2005;65:205–211.
- Dugoff L, Sujansky E. Neurofibromatosis type 1 and pregnancy. Am J Med Genet. 1996;66:7–10.
- Lammert M, Mautner VF, Kluwe L. Do hormonal contraceptives stimulate growth of neurofibromas? A survey on 59 NF1 patients. BMC Cancer. 2005;5:16.
- McLaughlin ME, Jacks T. Progesterone receptor expression in neurofibromas. Cancer Res. 2003;63:752–755.
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