fdg-pet in two cases of neurofibromatosis type 1 and atypical malignancies

Case Report

fdg-pet in two cases of neurofibromatosis type 1 and atypical malignancies

P. de Blank , MD MSCE * , K. Cole , MD PhD , L. Kersun , MD MSCE , A. Green , MD , J.J. Wilkes , MD , J. Belasco , MD , R. Bagatell , MD , L.C. Bailey , MD , M.J. Fisher , MD

* Department of Pediatrics, Division of Pediatric Hematology and Oncology, Rainbow Babies and Children’s Hospital, Cleveland, OH, U.S.A.
Division of Oncology and Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia, Philadelphia, PA, U.S.A.
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, U.S.A.

doi: http://dx.doi.org/10.3747/co.21.1803


Patients with neurofibromatosis type 1 ( nf 1) are at increased risk for both benign and malignant tumours, and distinguishing the malignant potential of an individual tumour is a common clinical problem in these patients. Here, we review two cases of uncommon malignancies (Hodgkin lymphoma and mediastinal germ-cell tumour) in patients with nf 1. Although 18F-fluorodeoxyglucose positron-emission tomography ( fdg - pet ) has been used to differentiate benign neurofibromas from malignant peripheral nerve sheath tumours, fdg - pet characteristics for more rare tumours have been poorly described in children with nf 1. Here, we report the role of pet imaging in clinical decision-making in each case. In nf 1, fdg - pet might be useful in the clinical management of unusual tumour presentations and might help to provide information about the malignant potential of uncommon tumours.

KEYWORDS: Neurofibromatosis type 1 , pediatric oncology , Hodgkin lymphoma , germ-cell tumours , Klinefelter syndrome


Neurofibromatosis type 1 ( nf 1) is a common genetic syndrome associated with both benign and malignant tumours. Affected individuals have an increased risk of malignancy, most commonly malignant peripheral nerve sheath tumour ( mpnst ). Positron-emission tomography with 18F-fluorodeoxyglucose ( fdg - pet ) has been useful in differentiating mpnst from benign neurofibroma14, but few reports of fdg - pet in the evaluation of other nf 1-associated malignancies have been published. Here, we report fdg - pet characteristics of two unusual malignancies in nf 1 and discuss the utility of pet in the management of atypical tumour presentations.


2.1  Case 1

A 6-year-old boy was referred for evaluation of a non-tender 4-cm left axillary mass, which had recently increased in size. On examination, 6 café-au-lait macules more than 5 mm in diameter were noted, as well as axillary freckling, meeting the clinical diagnostic criteria for nf 1.

Chest radiography revealed no active disease in the thorax; a complete blood count was normal; and the erythrocyte sedimentation rate was not elevated. Magnetic resonance imaging using multiplanar short T1 inversion recovery sequences revealed a 3×1.6×5-cm mass within the left axilla abutting the chest wall (Figure 1). Imaging characteristics were consistent with benign neurofibroma, mpnst , or lymph node expansion from other malignancy. Because of the tumour’s rapid growth, imaging by combined fdg - pet and computed tomography ( ct ) was obtained to evaluate the lesion’s malignant potential. Images revealed a hypermetabolic focus with a maximum standardized uptake value ( suv max ) of 5.8 that corresponded with the soft-tissue mass.



FIGURE 1 Case 1. (A) Initial coronal and axial magnetic resonance short T1 inversion recovery images of left axillary Hodgkin lymphoma, (B) with corresponding coronal fluorodeoxyglucose ( fdg ) positron-emission tomography ( pet ) image and axial fdg-pet –computed tomography ( ct ) image. (C) Coronal fdg - pet and axial fdg - pet ct images 3 months after surgery show a new focus of fdg uptake in the left pectoralis major muscle.

Because of the increased fdg uptake and recent growth, excisional biopsy was performed. Pathology was consistent with nodular lymphocyte-predominant Hodgkin lymphoma ( hl ). Imaging of neck, chest, abdomen and pelvis by ct with intravenous contrast showed no other tumours, and the child received no further therapy at that time.

He returned 3 months after surgery for surveillance fdg - pet ct , which revealed no increased fdg uptake in the left axilla, but a new focus of abnormal activity in the left chest wall with an suv max of 5.4, corresponding to a 1.9×1.2-cm soft-tissue mass under the pectoralis major muscle that had not been present during the earlier study. Based on the imaging, a second surgical resection was performed, and histologic evaluation confirmed recurrence of nodular lymphocyte-predominant hl .

The patient received 3 cycles of chemotherapy with doxorubicin, vincristine, prednisone, and cyclophosphamide, achieving a complete response. He remained disease-free at 9 months after completion of therapy.

2.2  Case 2

A young man (15 years of age) followed for known sporadic nf 1 (diagnosed clinically at a young age) and with a large abdominal–pelvic–lumbar spine plexiform neurofibroma diagnosed by magnetic resonance imaging, presented with a 1-week history of fevers, intractable cough, and shortness of breath. Chest ct and multiplanar short T1 inversion recovery magnetic resonance imaging (Figure 2) revealed a 17.8×11.8×14-cm heterogeneous mass in the anterior mediastinum, with internal foci of calcifications and fat, separate from his known plexiform neurofibroma. The mass caused rightward deviation of the heart and compression of the left main pulmonary artery and left mainstem bronchus. Lymph nodes in the paratracheal and prevascular regions measured up to 1.3×3.0 cm. Differential diagnosis included mpnst , germ-cell tumour, lymphoma, thymoma, or metastatic disease. Laboratory evaluation was significant for mild anemia (hemoglobin 12.9 g/dL), but no elevation in lactic dehydrogenase or uric acid was found. Alpha-1–fetoprotein was elevated [59.7 ng/mL (normal range: 0.6–3.9 ng/mL)], and the beta subunit of human chorionic gonadotropin was undetectable (<1.0 mIU/mL).



FIGURE 2 Case 2. (A) Axial and coronal magnetic resonance short T1 inversion recovery images of the left thorax tumour with mass effect on the mediastinum. (B) Corresponding coronal fluorode-oxyglucose ( fdg ) positron-emission tomography ( pet ) and axial fdg - pet –computed tomography images of the same mass.

Percutaneous needle biopsy of the mediastinal mass before fdg - pet was nondiagnostic. Subsequent fdg - pet ct identified a hypermetabolic focus with a suv max of 5.6 within the chest mass, but no other areas of significantly increased fdg uptake. Because of the size of the focus, the elevated germ-cell markers, and increased metabolic activity inconsistent with typical neurofibroma, a malignant component of the tumour was suspected. A decision to attempt a complete resection was therefore made.

The mass was successfully resected; pathology revealed immature teratoma with intermixed yolk sac tumour with moderate-to-strong staining for alpha-1–fetoprotein. Analysis of the tumour tissue by single nucleotide polymorphism array demonstrated whole-chromosome gains of X and 7. Subsequent cytogenetic analysis of whole blood revealed a karyotype of XXY, consistent with Klinefelter syndrome. Testing for nf 1 mutation was not performed because clinical criteria for nf 1 had already been met.

Chemotherapy with bleomycin, etoposide, and cisplatin was started. Serum alpha-1–fetoprotein subsequently normalized, and the patient remained disease-free at 16 months from completion of therapy.


The autosomal-dominant disorder nf 1 is caused by a mutation of the NF1 gene at chromosome 17q11.2. It affects approximately 1 in 3000 individuals5. The NF1 gene is a tumour suppressor encoding the protein neurofibromin, a gtp ase inactivator for the Ras pathway6. Lack of neurofibromin results in stimulation of mitogen-activated protein kinases and phosphoinositide 3 kinases, leading to cellular proliferation and increased cell survival7.

Individuals with nf 1 have an increased risk of malignancy that predominantly affects children and youths. The overall incidence of cancer in nf 1 patients is 2.7 times that in the general population; in nf 1 patients less than 20 years of age, it is 27.8 times the incidence in the age-matched general population8. The most common tumours in nf 1 are mpnst and gliomas; however, other malignancies have been associated with nf 1, including rhabdomyosarcoma9, pheochromocytoma10, breast cancer8, and leukemia11. A review of previously published cohorts and population-based studies of individuals with nf 1 described an incidence of malignancy between 4% and 52%, but identified only a single case of germcell tumour (malignant teratoma of the retroperitoneum in a Japanese registry12) and no cases of hl among 535 nf 1-associated malignancies reviewed13. Although individuals with nf 1 are at increased risk for non-Hodgkin lymphoma11, only one prior report describes hl in a patient who had segmental nf 114. In addition to the germ-cell tumour already mentioned, a single case report of a peripheral germ-cell tumour in an individual with nf 1 was previously described15. Germ-cell tumours are rarely associated with nf 1, but are more common in adolescents with Klinefelter syndrome, as occurred with our second patient16.

In our cases, nf 1 might have influenced the timing and appearance of the malignancies. Case 1 describes a common tumour ( hl ) presenting unusually early (in a 6-year-old), illustrating the increased incidence of malignancy in young children with nf 1, given that 90% of childhood hl occurs in children more than 9 years of age17. Case 2 describes a child with nf 1 and a new mediastinal mass. Although mediastinal germ-cell tumours are associated with Klinefelter syndrome, nf 1 might have additionally influenced its appearance. A single patient having both nf 1 and Klinefelter syndrome is unusual. However, both genetic syndromes are common in the general population (1:1000 for Klinefelter syndrome) and could overlap. Hatipoglu et al. reported another case of a patient with nf 1 and Klinefelter syndrome not associated with malignancy18. These cases are reminders of the diversity of the tumours that present in patients with nf 1.

Many tumours in patients with nf 1 are benign, but distinguishing those tumours from malignancy is a common clinical problem. Most studies of fdg - pet in nf 1 have investigated its ability to differentiate benign neurofibromas from mpnst s14. In the largest study of 116 lesions in 105 patients with nf 1 and symptoms concerning for mpnst , the mean suv max was significantly lower for plexiform neurofibromas than for mpnst s (1.5 vs. 5.7)4. Overall sensitivity of fdg - pet to identify mpnst in subjects with nf 1 ranges from 75% to 100%, with specificity between 72% and 100%19. However, a comparison of studies is difficult because of inconsistencies in the cut-off values used to identify malignant tumours, and variability in the type and timing of suv measurements.

The range of suv max seen in benign lesions and mpnst s often overlap, and individual lesions can be misidentified3,4,20,21. Although studies of the use of fdg - pet in children with nf 1 demonstrated results similar to those seen in adults22, further prospective studies are warranted in the pediatric population. Imaging by fdg - pet has the potential to distinguish benign from malignant lesions in nf 1; however, methods must be standardized, and larger prospective trials that include less common malignancies must be conducted before fdg - pet is routinely recommended for the evaluation of symptomatic lesions.

Here, we describe the pet imaging characteristics of two such malignancies uncommonly seen in nf 1. Only two earlier studies described fdg - pet results in patients with nf 1 and non- mpnst malignancies. Ferner et al. 4 described 2 other malignant tumours (of thyroid and esophagus) discovered incidentally. Bredella and colleagues3 reported 3 additional tumours (2 gastrointestinal stromal tumours and 1 poorly differentiated carcinoma of the colon). Although no quantitative measurements were described, and methods of testing varied, all non- mpnst tumours were considered traceravid on fdg - pet except for the carcinoma of the colon.

Imaging by fdg - pet is not without risk or cost, and screening for new tumours with fdg - pet in children with nf 1 is not routinely recommended23. Unnecessary radiation exposure should be avoided, especially in individuals with nf 1, because of the risk of secondary malignancy24 and other potential complications25 seen with higher doses of radiation therapy. However, fdg - pet might be useful for the assessment of malignant potential (as in our case 1) and for clinical and surgical planning of unusual presentations (our cases 1 and 2).


Imaging by fdg - pet has been used to distinguish benign plexiform neurofibromas from mpnst 26. It is also promising for predicting the likelihood of growth in plexiform neurofibroma27. However, pet should be reserved for situations in which it might contribute to clinical decision-making. Here, we report two unusual malignancies ( hl and germ-cell tumour) in patients with nf 1 in whom pet imaging helped with identification and guided surgical management and clinical care.


PdB was supported by the Case Comprehensive Cancer Center (K12 CA076917). JJW was supported by a National Institutes of Health T32 training grant during the production of this manuscript.


The authors have no financial conflicts of interest to declare.


1. Ferner RE, Lucas JD, O’Doherty MJ, et al. Evaluation of 18fluorodeoxyglucose positron emission tomography (18fdg pet) in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1. J Neurol Neurosurg Psychiatry 2000;68:353–7.
cross-ref  pubmed  pmc  

2. Cardona S, Schwarzbach M, Hinz U, et al. Evaluation of F18-deoxyglucose positron emission tomography (fdg-pet) to assess the nature of neurogenic tumours. Eur J Surg Oncol 2003;29:536–41.
cross-ref  pubmed  

3. Bredella MA, Torriani M, Hornicek F, et al. Value of pet in the assessment of patients with neurofibromatosis type 1. AJR Am J Roentgenol 2007;189:928–35.
cross-ref  pubmed  

4. Ferner RE, Golding JF, Smith M, et al. 18F 2-fluoro-2-deoxyd-glucose positron emission tomography (fdg pet) as a diagnostic tool for neurofibromatosis 1 (nf1) associated malignant peripheral nerve sheath tumours (mpnsts): a long-term clinical study. Ann Oncol 2008;19:390–4.

5. Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 2005;141:71–4.
cross-ref  pubmed  

6. Li Y, Bollag G, Clark R, et al. Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell 1992;69:275–81.
cross-ref  pubmed  

7. Weeber EJ, Sweatt JD. Molecular neurobiology of human cognition. Neuron 2002;33:845–8.
cross-ref  pubmed  

8. Walker L, Thompson D, Easton D, et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br J Cancer 2006;95:233–8.
cross-ref  pubmed  pmc  

9. Sung L, Anderson JR, Arndt C, Raney RB, Meyer WH, Pappo AS. Neurofibromatosis in children with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study iv. J Pediatr 2004;144:666–8.
cross-ref  pubmed  

10. Walther MM, Herring J, Enquist E, Keiser HR, Linehan WM. Von Recklinghausen’s disease and pheochromocytomas. J Urol 1999;162:1582–6.
cross-ref  pubmed  

11. Stiller CA, Chessells JM, Fitchett M. Neurofibromatosis and childhood leukaemia/lymphoma: a population-based ukccsg study. Br J Cancer 1994;70:969–72.
cross-ref  pubmed  pmc  

12. Matsui I, Tanimura M, Kobayashi N, Sawada T, Nagahara N, Akatsuka J. Neurofibromatosis type 1 and childhood cancer. Cancer 1993;72:2746–54.
cross-ref  pubmed  

13. Patil S, Chamberlain RS. Neoplasms associated with germline and somatic nf1 gene mutations. Oncologist 2012;17:101–16.
cross-ref  pmc  

14. Dang JD, Cohen PR. Segmental neurofibromatosis of the distal arm in a man who developed Hodgkin lymphoma. Int J Dermatol 2009;48:1105–9.
cross-ref  pubmed  

15. Groot–Loonen JJ, Voute PA, de Kraker J. Testicular tumor concomitant with von Recklinghausen’s disease. Med Pediatr Oncol 1988;16:116–17.

16. Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer 1995;71:416–20.
cross-ref  pubmed  pmc  

17. Ries LAG, Smith MA, Gurney JG, et al., eds. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975–1995. Bethesda, MD: National Cancer Institute, seer Program; 1999.

18. Hatipoglu N, Kurtoglu S, Kendirci M, Keskin M, Per H. Neurofibromatosis type 1 with overlap Turner syndrome and Klinefelter syndrome. J Trop Pediatr 2010;56:69–72.

19. Treglia G, Taralli S, Bertagna F, et al. Usefulness of whole-body fluorine-18–fluorodeoxyglucose positron emission tomography in patients with neurofibromatosis type 1: a systematic review. Radiol Res Pract 2012;2012:431029.

20. Warbey VS, Ferner RE, Dunn JT, Calonje E, O’Doherty MJ. 18F fdg pet/ct in the diagnosis of malignant peripheral nerve sheath tumours in neurofibromatosis type-1. Eur J Nucl Med Mol Imaging 2009;36:751–7.
cross-ref  pubmed  

21. Ahlawat S, Blakeley J, Montgomery E, Subramaniam RM, Belzberg A, Fayad LM. Schwannoma in neurofibromatosis type 1: a pitfall for detecting malignancy by metabolic imaging. Skeletal Radiol 2013;42:1317–22.
cross-ref  pubmed  

22. Moharir M, London K, Howman–Giles R, North K. Utility of positron emission tomography for tumour surveillance in children with neurofibromatosis type 1. Eur J Nucl Med Mol Imaging 2010;37:1309–17.
cross-ref  pubmed  

23. Hersh JH on behalf of the American Academy of Pediatrics Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics 2008;121:633–42.
cross-ref  pubmed  

24. Sharif S, Ferner R, Birch JM, et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol 2006;24:2570–5.
cross-ref  pubmed  

25. Pierce SM, Barnes PD, Loeffler JS, McGinn C, Tarbell NJ. Definitive radiation therapy in the management of symptomatic patients with optic glioma. Survival and long-term effects. Cancer 1990;65:45–52.
cross-ref  pubmed  

26. Fisher MJ. The use of pet in the evaluation of tumors in children with neurofibromatosis type 1. PET Clinics 2008;3:531–49.

27. Fisher MJ, Basu S, Dombi E, et al. The role of 18F-fluorodeoxy-glucose positron emission tomography in predicting plexiform neurofibroma progression. J Neurooncol 2008;87:165–71.

Correspondence to: Peter de Blank, Division of Pediatric Hematology/Oncology, Rainbow Babies and Children’s Hospital, 11100 Euclid Avenue, Cleveland, Ohio 44106 U.S.A. E-mail: Peter.deBlank@UHhospitals.org

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Current Oncology , VOLUME 21 , NUMBER 2 , APRIL 2014

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ISSN: 1198-0052 (Print) ISSN: 1718-7729 (Online)