Malignant transformation of Neurofibromatosis

Transcription

1 November Technische Universität München Malignant transformation of Neurofibromatosis Alexander Zink Technische Universität München, Munich, Germany Rotation at Beth Israel Deaconess Medical Center Beth Israel Deaconess Medical Center, Harvard Medical School

2 Our patient: Presentation 5 year old boy, recently adopted from eastern Europe Parents worried about his facial asymmetry and the swelling of his right shoulder and neck since birth Otherwise normal 5 year old No pain 2

3 Our patient: History History: - Recently adopted from an orphanage in eastern Europe, little is known about biologic mother and father - No past medical/surgical history 3

4 Our patient: Physical examination Physical examination: well-appearing child, alert and cooperative Increased soft tissue of doughy consistency on right side of face, neck and shoulder Multiple skin lesions: Brown freckles in his axillae Large macular hyperpigmentation (25 x 30 cm) on shoulder > 20 brown macules > 0.5 cm in diameter on whole body No other abnormalities found in the remainder of the physical examination and in a detailed neurologic examination 4

5 Our patient: Soft tissue tumor Our patient has unilateral increased soft tissue, id est in other words: a soft tissue tumor. What are the differential diagnoses for soft tissue tumors? 5

6 Our patient: Differential diagnosis Detailed investigation with imaging needed! 6

7 Our patient: Overview imaging Having these WHO differential diagnoses in mind, the workup of our patient included X-Ray, Ultrasound, and MRI, for further evaluation of his soft tissue tumor. 7

8 Our patient: Unilateral increased soft tissue Image courtesy Mai-Lan Ho, MD X-ray upper body, upright, PA-view Findings: Increased soft tissue of the patient s face, neck and shoulder on the right side (ellipse). Also compare difference of cheek size right and left (arrows). 8

9 Our patient: Expansive soft tissue tumor > > + * * * + + Both images courtesy Mai-Lan Ho, MD > > X-ray neck, upright, PA-view X-ray right shoulder, upright, PA-view Findings: Expansive soft tissue tumor (around blue line) with unilateral skin folding (>), pushing the trachea ( ) to the left lateral of spinous processes (+). In addition, extra density ( ) projecting at the apex of right lung * and a soft tissue skin nodule ( ) on shoulder. 9

10 Our patient: Nerve sheath tumor Findings: Sonogram shows a well-defined * * # # and hypoechoic mass (#) with posterior acoustic enhancement (+). Note direct continuitiy with a # nerve ( * ) Longitudinal ultrasound of right shoulder Image courtesy Mai-Lan Ho, MD 10

11 Our patient: Plexiform neurofibroma axial view * * * Both images courtesy Mai-Lan Ho, MD * * * Spine Left lung Axial MRI chest, T1 weighted, without contrast Findings: Axial MRI chest, T1 weighted, with contrast Extensive, infiltrative lesion of the skin ( ) and subcutaneous tissue of the anterior chest wall, that * extends into the apex of the right hemithorax and surrounds the brachial plexus. Lesion and infiltration are roughly marked by the yellow circle. 11

12 Our patient: Plexiform neurofibroma coronal view > + * + > > x Findings: Extensive, plaque-like lesion of the skin ( ) and subcutaneous tissue * that extends into neck ( ) and shoulder (+), surrounds the brachial plexus (not shown) and extends into the apex of the right hemithorax (x). > Image courtesy Mai-Lan Ho, MD Coronal MRI upper body, T1 weighted, with contrast Lesion and area of infiltration are roughly marked by yellow lines. Impression: Axial and coronal MRI show a plexiform neurofibroma 12

13 Our patient: Diagnosis Neurofibromatosis type 1 Summary of our patient s findings: > 20 cafe-au-lait macules Axillary freckling Plexiform neurofibroma A Enough criteria for Neurofibromatosis type 1, because Both images Boyd et al. Neurofibromatosis type 1. J Am Acad Dermatol B Companion patients with cafe-au-lait macules (A) 13 and axillary freckling (B)

14 Diagnostic criteria Neurofibromatosis Type 1 (NF1) according to the National Institutes of Health (NIH) the patient should have 2 or more of the following diagnostic criteria for the diagnosis Neurofibromatosis type 1: 6 or more café-au-lait spots 2 neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillae or groin Optic glioma 2 Lisch nodules Dysplasia of the sphenoid; dysplasia or thinning of long bone cortex First degree relative with NF1. Our patient has the three findings typed in blue and therefore was diagnosed Neurofibromatosis type 1. 14

15 What is Neurofibromatosis Type 1 (NF1)? First described in 1882 by Friedrich von Recklinghausen Worldwide incidence 1 : 3500 Autosomal-dominant disorder Responsible gene isolated in 1990 Friedrich von Recklinghausen Loss-of-function of the tumor suppressor gene NF1 15

16 Pathomechanism of Neurofibromatosis Type 1 Gaudet AD et al. The Journal of Neuroscience, 2007 The gene NF1 encodes the protein Neurofibromin (NF-1), which regulates the Ras-pathway involved in cell division of nerve sheats (a in figure above). Loss of function of NF-1 causes an unregulation of the pathway. This leads to pathological neurite elongations (b in figure above) and the development of neurofibromas. Neurofibromas are the main characteristic for Neurofibromatosis Type 1. 16

17 Characteristics of NF1: Nodular neurofibromas 3 clinically and histologically different types of Neurofibromas: 95 % of patients: discrete nodular neurofibromas (skin and peripheral nerves at any site, benign) 17

18 Companion patient 1: Nodular neurofibromas Pictures of a patient with severe neurofibromas of the skin Posada et al. Von Recklinghausen s Disease and Breast Cancer, N Engl J Med,

19 Characteristics of NF1: Plexiform neurofibroma 3 clinically and histologically different types of Neurofibromas: 95 % of patients: discrete nodular neurofibromas (skin and peripheral nerves at any site, benign) 30 % of patients: plexiform neurofibromas (affect long portions of nerves, 2-16 % turn malignant) 19

20 Characteristics of NF1: Optic nerve glioma 3 clinically and histologically different types of Neurofibromas: 95 % of patients: discrete nodular neurofibromas (skin and peripheral nerves at any site, benign) 30 % of patients: plexiform neurofibromas (affect long portions of nerves, 2-16 % turn malignant) 15 % of patients: optic nerve gliomas (malignant, very slow growing, sometimes self-limiting) 20

21 Companion patient 2: Optic nerve glioma * + x x + + x PACS, Children s Hospital Boston MRI brain, T1 weighted, without contrast, two different axial slides Findings: Bilateral enlargement of the optic nerve, right ( ) bigger than left ( ), with infiltration of the optic chiasm ( ). As seen, optic gliomas are typically hypointens ( darker ) compared to orbital fat ( ), isointense to the cortex (+) and hypointens to the white matter (x) on T1 weighted * MRI images. 21

22 Neurofibromatosis Types 1 and 2 Talking about one type of Neurofibromatosis, the second type should also always be mentioned for completion. This is in our case: Neurofibromatosis type 2. 22

23 What is Neurofibromatosis Type 2 (NF2)? Autosomal dominant disorder Prevalence 1 : Loss-of-function of tumor suppressor gene NF2 Main manifestation: Bilateral schwannomas of vestibular branch of cranial nerve VIII. Findings: Bilateral contrast enhancing olive shaped tumors ( ) adjacent to the internal auditory meatus (yellow arrow ). Axial MRI head, T1 weighted, with contrast Image courtesy Mai-Lan Ho, MD 23

24 Treatment of Neurofibromatosis 1 and 2 Genetic disorders no causal therapy Watchful waiting and monitoring Surgery, if neurofibroma / schwannoma grows rapidly or changes in consistency, causes problems (neurologic, cosmetic etc.) or is painful. So what happened to our patient? 24

25 Our patient: Medical treatment Closely monitored with yearly MRI and detailed physical examination Plexiform neurofibroma remained stable with no symptoms for 4 years Then: - Pain in right shoulder - Neurofibroma with increased mass at the area of apex of the right lung seen on MRI compared to older images Further evaluation with PET-CT 25

26 Our patient: New mass with avid uptake Integrated PET-CT right shoulder PET-Scan whole body Both images PACS, Children s Hospital Boston Findings: Normal isotope uptake in tonsils, thymus, heart, renal collection systems and bladder (arrows, marked from above). Area of avid, pathological uptake in right shoulder (red circle). This area is seen as defined mass with high activity on the integrated PET-CT. Malignancy possible. 26

27 Our patient: Further treatment Biopsy of the mass seen on PET-CT to verify its dignity: Histopathology: Atypical neurofibroma or low grade malignant nerve sheath tumor. Surgical resection (incomplete due to size) NOW: Treatment with PEG-interferon alpha-2b (Phase II study, National Cancer Institute) 27

28 Our patient: Prognosis Complete surgical removal of our patient s malignant tumor is not possible due to its size and location. Also there are no known medical treatments for Neurofibromatosis so far. For this reason, the national study with PEG-Interferon alpha-2b is the only available therapy option for our patient at this point. And the study will show (completion in 2012), if this drug can be used for a successful treatment of malignant transformations of neurofibromatosis. 28

29 References Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR. Neurofibromatosis type 2. Lancet Jun 6;373(9679): Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol Jul; 61(1):1-14 Friedrich von Recklinghausen. In Wikipedia. Accessed 11/11/2010 Gaudet AD, Ramer LM. Mind the GAP: A Role for Neurofibromin in Restricting Axonal Plasticity. The Journal of Neuroscience, 2007, 27(21): Hartley N, Rajesh A, Verma R, Sinha R, Sandrasegaran K. Abdominal manifestations of neurofibromatosis. J Comput Assist Tomogr Jan-Feb;32(1):4-8 National Institutes of Health Clinical Center (CC). Pegintron to Treat Plexiform Neurofibromas in Children and Young Adults. Accessed 11/11/2010 National Institutes of Neurological Disorders and Stroke (NINDS). Neurofibromatosis Fact Sheet. Accessed 11/13/2010 Posada JG, Chakmakjian CG. Images in clinical medicine. Von Recklinghausen's disease and breast cancer. N Engl J Med Apr 28;352(17):17994 Reynolds RM, Browning GG, Nawroz I, Campbell IW. Von Recklinghausen's neurofibromatosis: neurofibromatosis type 1. Lancet May 3;361(9368): Rubin BJ, Gutmann DH. Neurofibromatosis type 1 a model for nervous system tumour formation? Nature Reviews Cancer 2005; 5, The International Agency for Research on Cancer. Pathology and Genetics of Tumours of Soft Tissue and Bone (IARC WHO Classification of Tumours). WHO Classification of Soft Tissue Tumours. Accessed 11/13/

30 Alexander Zink Acknowledgements Mai-Lan Ho, MD, Children s Hospital Boston Dr. Lieberman, MD, Beth Israel Deaconess Medical Center, Harvard Medical School Emily Hanson, Beth Israel Deaconess Medical Center Jim Brophy, Beth Israel Deaconess Medical Center 30