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Malignant transformation of Neurofibromatosis
Alexander Zink Technische Universität München, Munich, Germany
Rotation at Beth Israel Deaconess Medical Center
Gillian Lieberman, MD Beth Israel Deaconess Medical Center,
Harvard Medical School
November 2010 www.werd-wieder-gesund.deTechnische Universität München
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Our patient: Presentation
Alexander ZinkGillian Lieberman, MD
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
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Our patient: History
Alexander ZinkGillian Lieberman, MD
History:
-
Recently adopted from an orphanage in eastern Europe, little is known about biologic mother and father
-
No past medical/surgical history
3
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Our patient: Physical examination
Alexander ZinkGillian Lieberman, MD
4
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
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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?
Our patient: Soft tissue tumor
Alexander ZinkGillian Lieberman, MD
5
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Our patient: Differential diagnosis
Alexander ZinkGillian Lieberman, MD
6
http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb5/bb5-classifsofttissue.pdf
Detailed investigation with imaging needed!
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Our patient: Overview imaging
Alexander ZinkGillian Lieberman, MD
7
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.
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Our patient: Unilateral increased soft tissue
Alexander ZinkGillian Lieberman, MD
8
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).
Imag
e co
urte
sy M
ai-L
an H
o, M
D
X-ray upper body, upright, PA-view
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Our patient: Expansive soft tissue tumor
Alexander ZinkGillian Lieberman, MD
Bot
h im
ages
cou
rtesy
Mai
-Lan
Ho,
MD
9X-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.
*
+
+
+
** ∆
∆
>>
+
+
+∆
∆>
>
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Our patient: Nerve sheath tumor
Alexander ZinkGillian Lieberman, MD
Image courtesy Mai-Lan Ho, MD
10Longitudinal ultrasound of right shoulder
Findings:Sonogram shows a well-defined and hypoechoic
mass (#) with posterior acoustic enhancement (+). Note direct continuitiy
with a
nerve (*).
* *#
#
#
+ + +
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Findings:
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.
Our patient:
Plexiform
neurofibroma
–
axial view
Alexander ZinkGillian Lieberman, MD
11
Axial MRI chest, T1 weighted, with contrast
Both images courtesy Mai-Lan
Ho, MD
Axial MRI chest, T1 weighted, without contrast
***
* * *
Left lungSpine
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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).
Lesion and area of infiltration are roughly marked by yellow lines.
Impression:Axial and coronal MRI show a plexiform
neurofibroma
Our patient: Plexiform
neurofibroma
–
coronal view
Alexander ZinkGillian Lieberman, MD
Imag
e co
urte
sy M
ai-L
an H
o, M
D
12Coronal MRI upper body, T1 weighted, with contrast
>*
>
>>
++x
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Our patient:
Diagnosis Neurofibromatosis type 1
Alexander ZinkGillian Lieberman, MD
Both images Boyd et al. Neurofibromatosis type 1. J Am Acad
Dermatol. 200913
Enough criteria for Neurofibromatosis type 1, because…
A
BCompanion patients with cafe-au-lait macules (A)
and axillary freckling (B)
Summary of our patient‘s findings:
> 20 cafe-au-lait macules
Axillary freckling
Plexiform neurofibroma
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Diagnostic criteria Neurofibromatosis Type 1 (NF1)
Alexander ZinkGillian Lieberman, MD
…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.
14
Our patient has the three findings typed in blue
and therefore was diagnosed Neurofibromatosis type 1.
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What is Neurofibromatosis Type 1 (NF1)?
Alexander ZinkGillian Lieberman, MD
Friedrich von Recklinghausen
First described in 1882 by Friedrich von Recklinghausen
Worldwide incidence 1 : 3500
Autosomal-dominant disorder
Responsible gene isolated in 1990
Loss-of-function of the tumor suppressor gene NF1
http://en.wikipedia.org/wiki/Friedrich_Daniel_von_Recklinghausen
15
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Pathomechanism
of Neurofibromatosis Type 1
Alexander ZinkGillian Lieberman, MD
16
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.
Gaudet AD et al.The Journal of Neuroscience, 2007
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Characteristics of NF1: Nodular neurofibromas
Alexander ZinkGillian Lieberman, MD
3 clinically and histologically
different types of Neurofibromas:
95 % of patients:
discrete nodular neurofibromas(skin and peripheral nerves at any
site, benign)
17
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Companion patient 1:
Nodular neurofibromas
Alexander ZinkGillian Lieberman, MD
18Posada et al. Von Recklinghausen‘s Disease and Breast Cancer, N Engl J Med, 2005.
Pictures of a patient with severe neurofibromas of the skin
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Characteristics of NF1: Plexiform
neurofibroma
Alexander ZinkGillian Lieberman, MD
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
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Characteristics of NF1: Optic nerve glioma
Alexander ZinkGillian Lieberman, MD
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
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Companion patient 2:
Optic nerve glioma
Alexander ZinkGillian Lieberman, MD
PACS,Children‘s Hospital Boston
21
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.*
*
+ x+
+ x x
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Neurofibromatosis Types 1 and 2
Alexander ZinkGillian Lieberman, MD
22
Talking about one type of Neurofibromatosis, the second type should also always be mentioned for completion. This is in our case:
Neurofibromatosis type 2.
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What is Neurofibromatosis Type 2 (NF2)?
Alexander ZinkGillian Lieberman, MD
Image courtesy Mai-Lan Ho, MD 23Axial MRI head, T1 weighted, with contrast
▲ ▲
▲ ▲
Findings: Bilateral contrast enhancing olive shaped tumors (▲) adjacent to the internal auditory meatus
(yellow arrow ).
Autosomal
dominant disorder
Prevalence 1 : 210 000
Loss-of-function of tumor suppressor gene NF2
Main manifestation: Bilateral schwannomas
of vestibular branch of cranial nerve VIII.
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Treatment of Neurofibromatosis 1 and 2
Alexander ZinkGillian Lieberman, MD
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
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Our patient: Medical treatment
Alexander ZinkGillian Lieberman, MD
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
25 Further evaluation with PET-CT
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Our patient: New mass with avid uptake
Alexander ZinkGillian Lieberman, MD
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.
26PET-Scan whole body
Integrated PET-CT right shoulder
Both images PACS, Children‘s Hospital Boston
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Our patient: Further treatment
Alexander ZinkGillian Lieberman, MD
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
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Our patient: Prognosis
Alexander ZinkGillian Lieberman, MD
28
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.
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References
Alexander ZinkGillian Lieberman, MD
•
Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR. Neurofibromatosis type 2. Lancet. 2009 Jun 6;373(9679):1974-86
•
Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad
Dermatol. 2009 Jul; 61(1):1-14•
Friedrich von Recklinghausen. In Wikipedia. http://en.wikipedia.org/wiki/Friedrich_Daniel_von_Recklinghausen.
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):5533–5534
•
Hartley N, Rajesh A, Verma R, Sinha R, Sandrasegaran K. Abdominal manifestations of neurofibromatosis. J Comput
Assist Tomogr. 2008 Jan-Feb;32(1):4-8•
National Institutes of Health Clinical Center (CC). Pegintron to Treat Plexiform Neurofibromas in Children and Young Adults. http://clinicaltrials.gov/ct2/show/NCT00678951. Accessed 11/11/2010
•
National Institutes of Neurological Disorders and Stroke (NINDS). Neurofibromatosis Fact Sheet. http://www.ninds.nih.gov/disorders/neurofibromatosis/detail_neurofibromatosis.htm.
Accessed 11/13/2010•
Posada JG, Chakmakjian CG. Images in clinical medicine. Von Recklinghausen's disease and breast cancer. N Engl J Med. 2005 Apr 28;352(17):17994
•
Reynolds RM, Browning GG, Nawroz
I, Campbell IW. Von Recklinghausen's neurofibromatosis: neurofibromatosis type 1. Lancet. 2003 May 3;361(9368):1552-4.
•
Rubin BJ, Gutmann
DH. Neurofibromatosis type 1 — a model for nervous system tumour formation? Nature Reviews Cancer 2005; 5, 557-564.
•
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. http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb5/bb5-classifsofttissue.pdf. Accessed 11/13/2010
29
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www.werd-wieder-gesund.de
Acknowledgements
Alexander ZinkGillian Lieberman, MD
•
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