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

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

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

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

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

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Our patient: Differential diagnosis

Alexander ZinkGillian Lieberman, MD

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http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb5/bb5-classifsofttissue.pdf

Detailed investigation with imaging needed!

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.

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

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X-ray upper body, upright, PA-view

Our patient: Expansive soft tissue tumor

Alexander ZinkGillian Lieberman, MD

Bot

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ages

cou

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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.

*

+

+

+

** ∆

∆

>>

+

+

+∆

∆>

>

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 (*).

* *#

#

#

+ + +

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

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

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12Coronal MRI upper body, T1 weighted, with contrast

>*

>

>>

++x

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

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.

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

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Pathomechanism

of Neurofibromatosis Type 1

Alexander ZinkGillian Lieberman, MD

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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

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

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

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)

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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)

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Companion patient 2:

Optic nerve glioma

Alexander ZinkGillian Lieberman, MD

PACS,Children‘s Hospital Boston

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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

Neurofibromatosis Types 1 and 2

Alexander ZinkGillian Lieberman, MD

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

Neurofibromatosis type 2.

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.

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

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

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

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)

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Our patient: Prognosis

Alexander ZinkGillian Lieberman, MD

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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.

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

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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

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