Chordoma 101 - Chordoma Foundation

Chordoma 101
Chandranath Sen, MD
NYU Medical Center
New York, New York
What is chordoma
• Malignant tumor arising from the bone of
the skull base and spine
• It is a cancer and has a tendency to be
locally invasive and a tendency to spread
(metastasize)
• Its origin is traced to remnants of primitive
embryonal cells called the “notochord”
Incidence
• Approx 2380 cases of bone malignancies
diagnosed annually
• 5% of these are located in the spine
• 8% of the spinal tumors are Chordomas
NCI database 1973 to 2003
Incidence
Facts:
•Affects people of all ages, most diagnosed in 50’s for
sacral and 40’s for other types.
•Most frequent in skull base and lower spine
•More frequent in men than women (2:1) for sacral
chordoma; 1:1 for clival and spinal.
•Incidence: 1 new case per million people per year
•~300 new cases per year in US
Where does it grow?
• Skull base (clivus)
~35%
• Sacrum/coccyx
~50%
• Other spinal
~15%
Phylum chordata: subphylum vertebrata
• 550 million years ago Chordates emerged from
the common ancestor
• Presence of the notochord is the most
prominent feature of the Phylum Chordata
• Notochord is ectodermal and guides
development of mesenchymal spine
• We are vertebrates: the notochord is replaced by
vertebrae
classification
The Notochord and neural tissue formation
17th day
The notochord
Fate of the notochord
• Essential for neural tube formation and embryonal
organization
• Not normally found in the vertebral bodies after 10
weeks of gestation
• The last vestiges of the notochord disappear by age 10
years
• Notochordal cells in the nucleus pulposus also disappear
• This regression may get arrested leading to persistence
of notochordal remnants
• Remnants are known as ecchordosis physaliphora
T-box gene: Brachyury
• T box family of transcription factors involved in
tissue organization in the embryo
• Expressed in undifferentiated notochord
• Essential for development
• Absence is lethal
Notochord and brachyury
• Brachyury is over expressed in chordomas and many
epithelial cancers
• Brachyury causes epithelial cells to grow uncontrollably
and become more invasive and mobile
• These strongly suggest that brachyury may transform
the notochordal remnants to become tumors
• Overexpressed in chordomas but not in other bone and
cartilage tumors
• Duplication of brachyury gene has been observed in
familial chordomas
• Inhibition of brachyury in chordoma cell cultures leads to
decreased proliferation
The clivus
The Spine
Clivus chordoma
Cervical spine chordoma
Sacral chordoma
Ecchordosis physalifora
Absence of bone
destruction
Benign notochordal cell tumor (BNCT)
H&E
cytokeratin
Benign notochordal cell tumor
• Asymptomatic lesions within the axial skeleton that are
larger than a normal notochordal remnant
• They are confined within the bone
• Imaging signal characteristics are like a chordoma
• Histolgically, physaliphorous cells; but lacks myxoid
matrix, trabecular destruction, nuclear anomalies,
mitosis, necrosis
• Some reports indicate these as precursors of chordomas
• Treatment of this entity is debated
Current treatment
• Radical removal either piecemeal or en
bloc depending on location
• Followed by stabilization of the spine
• Radiation therapy (high dose)
– Proton beam
– Carbon ion
– Intensity modulated radiation therapy
– Stereotactic radiosurgery (gamma knife,
cyberknife)
Implications
• High rate of recurrence and numerous high
risk surgeries
• Significant morbidity - patients often live for
years with disease and disability
• No effective chemotherapy
• 20-30% cure rate
NCI database 1973
2003
Survival: Prior surgery v/s Initial surgery
Sen C, Shrivastava R, Triana A, Berglind
N, Godbold J: Clival Chordomas
Sekhar Metaanalysis
Sacral Chordomas
Sacral chordomas
Survival
•
•
•
•
Median: 6.29 years
5 years
67.6%
10 years
39.9%
20 years
13.1%
Other prognostic factors
Prognostic factors
• Proliferation index
• Expression of cell cycle markers
Histological Classification
• Classical
• Chondroid
• Dedifferentiated
Chordoma v. Chondrosarcoma
• Misdiagnosis on routine histology
• Epithelial v. Mesenchymal origin
• Immunohistochemistry
– Cytokeratin
– Brachyury
• Survival
– Much better for chondrosarcoma (gr 1)
what happens to the cells
Acquired capabilities of cancer (Hanahan
&Weinberg)
Hanahan and Weinberg. Cell (100):57-70, Jan 2000
The cell cycle
Cell architecture
Normal
• Tight adhesion to each
other
• Adhesion to basement
membrane
• Cell-cell signaling
Cancer
• Disruption of adhesion
• Motility of cells
• Disruption of signaling
Research tools
• Study of the tumor specimen
• Cell lines
• Animal models
Drug therapy
Cell cycle control
Drug therapy
JNS Spine 2011
Mission
Our mission is to rapidly develop
effective treatments, and ultimately a
cure for chordoma, while improving the
diagnosis, treatment and quality of life
for chordoma patients.