Chordoma
Encyclopedia
Chordoma is a rare slow-growing malignant neoplasm thought to arise from cellular remnants of the notochord
. The evidence for this is the location of the tumors (along the neuraxis
), the similar immunohistochemical staining patterns, and the demonstration that notochordal cells are preferentially left behind in the clivus
and sacrococcygeal regions when the remainder of the notochord
regresses during fetal life.
and in the sacrum
at the bottom of the spine.
gene was found to be responsible for causing chordoma.
A possible association with tuberous sclerosis complex (TSC1
or TSC2
) has been suggested.
, the annual incidence of chordoma is approximately 1 in one million (300 new patients each year).
There are currently no known genetic or environmental risk factors for chordoma
While most people with chordoma have no other family members with the disease, rare occurrences of multiple cases within families have been documented. This suggests that some people may be genetically predisposed to develop chordoma. Because genetic or hereditary risk factors for chordoma may exist, scientists at the National Cancer Institute are conducting a Familial Chordoma Study to search for genes involved in the development of this tumor.
free survival rate for sacral chordoma was 46%. Chondroid chordomas appear to have a more indolent clinical course.
In most cases, complete surgical resection
followed by radiation therapy
offers the best chance of long-term control. Incomplete resection of the primary tumor makes controlling the disease more difficult and increases the odds of recurrence.
Chordomas are relatively radioresistant, requiring high doses of radiation to be controlled. The proximity of chordomas to vital neurological structures such as the brain stem and nerves limits the dose of radiation that can safely be delivered. Therefore, highly focused radiation such as proton therapy
and carbon ion therapy are more effective than conventional x-ray radiation.
There are no drugs currently approved to treat chordoma, however a clinical trial conducted in Italy using the PDGFR inhibitor Imatinib
demonstrated a modest response in some chordoma patients. The same group in Italy found that the combination of imatinib and sirolimus
caused a response in several patients whose tumors progressed on imatinib alone.
was treated for a chordoma in 1998. While initially thought to be successfully removed, the tumor returned in 2005, and caused Heyward's death in May 2006.
Josh Sommer, a student researcher at Duke University
, created the Chordoma Foundation with his mother, Simone Sommer, after his diagnosis. The Chordoma Foundation has hosted three International Chordoma Research Workshops which together assembled over 100 leading scientists and physicians, many of whom were new to the field of chordoma research. The Foundation has also collected and distributed chordoma cell lines for research into the cancer's molecular cause and possible treatments.
Pro skateboarder Ray Underhill, a member of the Powell-Peralta Bones Brigade, battled chordoma for two years before succumbing to his disease in August 2008.
Cary Tennis
, the popular advice columnist for Salon.com
, announced in his column of November 19, 2009, that he has been diagnosed with a chordoma.
Notochord
The notochord is a flexible, rod-shaped body found in embryos of all chordates. It is composed of cells derived from the mesoderm and defines the primitive axis of the embryo. In some chordates, it persists throughout life as the main axial support of the body, while in most vertebrates it becomes...
. The evidence for this is the location of the tumors (along the neuraxis
Neuraxis
Neuraxis is a Canadian technical/melodic death metal band. It was formed in Montreal in 1994 by Steven Henry, Yan Thiel and Felipe Angel Quinzanos...
), the similar immunohistochemical staining patterns, and the demonstration that notochordal cells are preferentially left behind in the clivus
Clivus (anatomy)
The clivus is a part of the cranium, a shallow depression behind the dorsum sellæ that slopes obliquely backward. It forms a gradual sloping process at the anterior most portion of the basilar occipital bone at its junction with the sphenoid bone. On axial planes, it sits just posterior to the...
and sacrococcygeal regions when the remainder of the notochord
Notochord
The notochord is a flexible, rod-shaped body found in embryos of all chordates. It is composed of cells derived from the mesoderm and defines the primitive axis of the embryo. In some chordates, it persists throughout life as the main axial support of the body, while in most vertebrates it becomes...
regresses during fetal life.
Presentation
Chordomas can arise from bone in the skull base and anywhere along the spine. The two most common locations are cranially at the clivusClivus (anatomy)
The clivus is a part of the cranium, a shallow depression behind the dorsum sellæ that slopes obliquely backward. It forms a gradual sloping process at the anterior most portion of the basilar occipital bone at its junction with the sphenoid bone. On axial planes, it sits just posterior to the...
and in the sacrum
Sacrum
In vertebrate anatomy the sacrum is a large, triangular bone at the base of the spine and at the upper and back part of the pelvic cavity, where it is inserted like a wedge between the two hip bones. Its upper part connects with the last lumbar vertebra, and bottom part with the coccyx...
at the bottom of the spine.
Genetics
A small number of families have been reported in which multiple relatives have been affected by chordoma. In four of these families duplication of the brachyuryBrachyury
Brachyury is a protein that in humans is encoded by the T gene. Brachyury is a transcription factor within the T-box complex of genes. It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.-History:...
gene was found to be responsible for causing chordoma.
A possible association with tuberous sclerosis complex (TSC1
TSC1
Tuberous sclerosis protein 1, also known as TSC1 or hamartin, is a human protein and gene.- Function :This peripheral membrane protein was implicated as a tumor suppressor...
or TSC2
TSC2
Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
) has been suggested.
Epidemiology
In the United StatesUnited States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, the annual incidence of chordoma is approximately 1 in one million (300 new patients each year).
There are currently no known genetic or environmental risk factors for chordoma
While most people with chordoma have no other family members with the disease, rare occurrences of multiple cases within families have been documented. This suggests that some people may be genetically predisposed to develop chordoma. Because genetic or hereditary risk factors for chordoma may exist, scientists at the National Cancer Institute are conducting a Familial Chordoma Study to search for genes involved in the development of this tumor.
Classification
There are three histological variants of chordoma: classical (or "conventional"), chondroid and dedifferentiated.- The histological appearance of classical chordoma is of a lobulated tumorTumorA tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
composed of groups of cells separated by fibrous septa. The cells have small round nuclei and abundant vacuolated cytoplasmCytoplasmThe cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
, sometimes described as physaliferous (having bubbles or vacuoles). - Chondroid chordomas histologically show features of both chordoma and chondrosarcomaChondrosarcomaChondrosarcoma is a cancer composed of cells derived from transformed cells that produce cartilage. Chondrosarcoma is a member of a category of "soft tissue" malignancies known as sarcomas. About 30% of skeletal system cancers are chondrosarcomas...
.
Tumor Biology
- mTOR signaling is hyperactive in sporadic sacral chordomas: in one study 10 out of 10 sacral chordomas exhibited phosphorylation of Ribosomal protein s6Ribosomal protein s6Ribosomal protein S6 is a component of the 40S ribosomal subunit and is therefore thought to be involved in regulating translation. Once thought to regulate the translation of 5' terminal oligopyrimidine RNA, this has since been disproven...
and EIF4EBP1EIF4EBP1Eukaryotic translation initiation factor 4E-binding protein 1 is a protein that in humans is encoded by the EIF4EBP1 gene.-Interactions:EIF4EBP1 has been shown to interact with Mammalian target of rapamycin, EIF4E and KIAA1303.-Further reading:...
by immunohistochemistry
- Partial or complete PTEN (gene)PTEN (gene)Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
deficiency is observed in nearly all sacral chordomas
- In a study of 49 chordomas AktAKTAkt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
, TSC2TSC2Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
, and EIF4EBP1EIF4EBP1Eukaryotic translation initiation factor 4E-binding protein 1 is a protein that in humans is encoded by the EIF4EBP1 gene.-Interactions:EIF4EBP1 has been shown to interact with Mammalian target of rapamycin, EIF4E and KIAA1303.-Further reading:...
were phosphorylated in 92%, 96% and 98% of cases, respectively.
- In a tissue microarray containing 21 chordomas Platelet-derived growth factor receptorPlatelet-derived growth factor receptorPlatelet-derived growth factor receptors are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including...
-beta (PDGFR-b), epidermal growth factor receptorEpidermal growth factor receptorThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR), KIT (CD117CD117Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
) and HER2 were detected in 100%, 67%, 33% and 0% of cases, respectively.
- The CDKN2ACDKN2ACDKN2A can refer to:* P16 * p14arf...
(p16) and CDKN2BCDKN2BCyclin-dependent kinase 4 inhibitor B also known as multiple tumor suppressor 2 or p15INK4B is a protein that is encoded by the CDKN2B gene in humans.- Function :...
(p15) loci on chromosome 9p21 are frequently deleted in chordomas Another study found CDKN2A immunoreactivity in just 4% of cases.
- 62% of chordomas express the High Molecular Weight Melanoma Associated Antigen, also known as Chondroitin sulfate proteoglycan 4 (CSPG4CSPG4Chondroitin sulfate proteoglycan 4 or melanoma-associated chondroitin sulfate proteoglycan is a chondroitin sulfate proteoglycan that in humans is encoded by the CSPG4 gene....
) which has been the target of immune therapy.
- Recently, scientists have discovered that an inherited Gene duplication is responsible for the familial form of this disorder.
Prognosis and treatment
In one study, the 10-year tumorTumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
free survival rate for sacral chordoma was 46%. Chondroid chordomas appear to have a more indolent clinical course.
In most cases, complete surgical resection
Segmental resection
Segmental resection is a surgical procedure to remove part of an organ or gland. It may also be used to remove a tumor and normal tissue around it. In lung cancer surgery, segmental resection refers to removing a section of a lobe of the lung.- External links :* entry in the public domain NCI...
followed by radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
offers the best chance of long-term control. Incomplete resection of the primary tumor makes controlling the disease more difficult and increases the odds of recurrence.
Chordomas are relatively radioresistant, requiring high doses of radiation to be controlled. The proximity of chordomas to vital neurological structures such as the brain stem and nerves limits the dose of radiation that can safely be delivered. Therefore, highly focused radiation such as proton therapy
Proton therapy
Proton therapy is a type of particle therapy which uses a beam of protons to irradiate diseased tissue, most often in the treatment of cancer. The chief advantage of proton therapy is the ability to more precisely localize the radiation dosage when compared with other types of external beam...
and carbon ion therapy are more effective than conventional x-ray radiation.
There are no drugs currently approved to treat chordoma, however a clinical trial conducted in Italy using the PDGFR inhibitor Imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
demonstrated a modest response in some chordoma patients. The same group in Italy found that the combination of imatinib and sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
caused a response in several patients whose tumors progressed on imatinib alone.
Notable cases
Former NFL player Craig HeywardCraig Heyward
Craig William "Ironhead" Heyward was an American football running back who played for the New Orleans Saints, Chicago Bears, Atlanta Falcons, St...
was treated for a chordoma in 1998. While initially thought to be successfully removed, the tumor returned in 2005, and caused Heyward's death in May 2006.
Josh Sommer, a student researcher at Duke University
Duke University
Duke University is a private research university located in Durham, North Carolina, United States. Founded by Methodists and Quakers in the present day town of Trinity in 1838, the school moved to Durham in 1892. In 1924, tobacco industrialist James B...
, created the Chordoma Foundation with his mother, Simone Sommer, after his diagnosis. The Chordoma Foundation has hosted three International Chordoma Research Workshops which together assembled over 100 leading scientists and physicians, many of whom were new to the field of chordoma research. The Foundation has also collected and distributed chordoma cell lines for research into the cancer's molecular cause and possible treatments.
Pro skateboarder Ray Underhill, a member of the Powell-Peralta Bones Brigade, battled chordoma for two years before succumbing to his disease in August 2008.
Cary Tennis
Cary Tennis
Cary D. Tennis , an American author and columnist. He is best known for his work as an advice columnist in his column "Since You Asked," which appears on the website Salon.com.-Personal:Tennis is a native of Tidewater, Virginia....
, the popular advice columnist for Salon.com
Salon.com
Salon.com, part of Salon Media Group , often just called Salon, is an online liberal magazine, with content updated each weekday. Salon was founded by David Talbot and launched on November 20, 1995. It was the internet's first online-only commercial publication. The magazine focuses on U.S...
, announced in his column of November 19, 2009, that he has been diagnosed with a chordoma.
External links
- Harfe, Brian A Mouse Model of Sarcoma ESUN (August 15, 2008)
- Chordoma Foundation - organization coordinating the development of new treatments for chordoma and supporting and informing patients
- Research Wiki on Chordoma (Chordoma Foundation)
- Images of Chordoma - mostly radiological (CT and MRI scans), one autopsy image
- Research information on chordoma (WikiGenes)