FINAL DIAGNOSIS: CHORDOMA
Chordomas are malignant tumors arising from embryonic notochord remnants in the craniospinal axis, usually the sacrococcygeal (50%) and the spheno-occipital region (35 %) although a significant minority (15%) occur in the true vertebrae (Heffelfinger et al. 1973). The notochord arises from ectoderm at the rostral end of the primitive streak in association with the closure of the neuropores at about the fourth week of gestation. It serves to organize induction of chondrification and segmentation of the mesenchymal elements of the vertebral column until its involution at approximately eight weeks. In adults, remnants of the notochord form the nucleus pulposus of the intervertebral disks. Occasionally, notochordal remnants persist in the cranial base, sacrococcygeal area and, less commonly, in vertebral bodies. The first two sites represent areas where the notochord undergoes complicated folding thereby incurring greater risk of incomplete involution. These are the sites where chordoma can arise, the frequency of which parallels the frequencies at which notochordal remnants occur. Interestingly, chordomas do not develop in the nucleus pulposus (Horn et al. 2001).
Histologically, notochordal tissue resembles immature cartilage somewhat. It is characterized by ovoid cells lying in an eosinophilic, myxomatous matrix. Early in embryonic development, notochordal cells have a homogeneously eosinophilic, well delineated cytoplasm. Later, cells acquire large, clear, intracytoplasmic vacuoles producing characteristic "physaliphorous cells". Immunohistochemically, notochordal cells show features of both cartilage and epithelial cells in being both positive for S100 as well as cytokeratin and epithelial membrane antigen. This co-expression of S100 and epithelial markers is also found in chordoma.
Chordoma comprises approximately 3 to 4% of primary malignant bone tumors (although some authors feel this should be 1%), and is the 4th most common primary malignancy in bone after osteosarcoma, chondrosarcoma and Ewing's sarcoma. Incidence increases slowly and peaks in the 5th to 7th decades. A small peak occurs in children during the 1st and 2nd decades of life, usually in the 2nd cervical vertebra. The average age at the time of diagnosis for sacrococcygeal chordoma is 48 years and for cranial lesions is 38 years. A few cases of congenital chordoma have been reported. There may be a slight male predominance in occurrence in sacrococcygeal chordoma. Cranial lesions tend to exhibit an equal sex ratio.
Chordomas grow slowly over years and metastasize late (in 20% to 40% of patients) to lungs, liver, bone, and soft tissue. Although relatively indolent in its nature, this tumor has an infiltrative growth pattern and is locally destructive. Seventy to 80% of patients die in 5 to 10 years (Mirra 1989). Cranial base and cervical spine tumors are usually smaller at diagnosis, but almost impossible to completely excise secondary to their inaccessibility and proximity to vital structures. Sacral lesions are often quite large at presentation and tend to be diagnosed later in life (mean age 48 years versus 38 years) than intracranial lesions, and are less problematic to resect than tumors in the cranial base and cervical spine (Holton et al. 2000).
The definitive treatment for chordoma is wide, intracompartmental excision. Complete resection, however, is difficult to achieve due to tumor size, infiltrative nature, central location and proximity to vital structures. Residual tumor is often unavoidable and invariably leads to recurrence. Tumor spillage during surgery is another cause of recurrence. Post-operative radiation is recommended to increase the time interval to recurrence even though chordoma is relatively radioresistant (Mirra 1989).
Clinically, pain is the most common presenting symptom regardless of site. Pain is often present for a long time and insidious in development because of the relatively indolent nature of the tumor. The average interval between the onset of symptoms and establishment of the correct diagnosis is 12 months with a range of one month to 5 years (Smith et al. 1987). Pain related to sacral nerve compression and constipation secondary to rectal obstruction are the most common presenting symptoms of sacrococcygeal chordomas. Hemorrhoids, dysuria, fecal and urinary incontinence, and lower extremity weakness are also common. The most common presenting sign is a large, often palpable, and tender sacral mass. Intracranial lesions commonly cause diplopia secondary to CN VI palsy, headache, and facial pain (Soo 2001). Dysphagia, abnormalities of the visual fields, and disturbances of endocrine function may also occur. Vertebral lesions produce symptoms related to spinal cord and nerve root compression.
On plain film, the hallmark presentation of chordoma in the spine is the lytic, asymmetric destruction of a single vertebra with an adjacent soft tissue mass, usually growing anteriorly to the dural sac. Calcifications are often visible within the mass probably secondary to tumor necrosis. Destruction of multiple adjacent vertebrae, however, is not uncommon. In the sacrum there is usually massive destruction of several segments with a large soft tissue mass anterior to the sacrum. On CT, sacrospinal chordomas are predominately osteolytic with well-circumscribed margins and usually show irregular, dense enhancement with contrast. On MRI they are inhomogeneous due to calcifications, fibrous bands and hemorrhage/necrosis (Soo 2001). Epidural extension within the spinal canal is usually present.
Plain film appearance of intracranial lesions is usually of a purely lytic lesion centered in the area of the floor of the sella, the posterior clinoid processes, the clivus and portions of sphenoid, and/or petrous temporal bone. As with sacrospinal lesions, cranial base chordomas are mainly osteolytic lesions on CT with a inhomogeneous appearance on MRI (Soo 2001). Large lesions may extend into the nasopharynx or cavernous sinus thereby extending to the middle fossa. Instances of invasion of the dura, and subarachnoid space have been reported. Although extensive compression of the base of the brain by these soft bulky tumors is common, invasion into the brain parenchyma is not.
The differential diagnosis of chordoma on imaging includes metastatic carcinoma, myeloma, giant cell tumor, neurogenic tumors, aneurysmal bone cyst, chondrosarcoma, and tuberculosis of the spine (Mirra 1989).
Grossly, chordomas are soft, encapsulated, gray, mucogelatinous tumors composed of numerous lobules separated by thin fibrous bands. Cystic, hemorrhagic, and necrotic foci are common. Rarely, small calcifications are grossly evident. Tumor size can vary from 2 to 20 cm with the larger lesions most commonly located in the sacrococcygeal region (Burger et al. 2002).
Histologically, chordomas are classified into three types; conventional or classic chordoma, chondrochordoma, and dedifferentiated chordoma. Classic chordoma has a lobular pattern with syncytial arrangements of neoplastic cells separated by fibrous septae and set in a bluish myxoid matrix. The tumor cells vary appreciably in cytology. Many have abundant, homogeneous and well-defined cytoplasm thought to represent early notochordal morphology. The majority of chordomas also contain neoplastic cells with varying amounts of mucin and/or glycogen. The hallmark cell of chordoma is the large phsaliphorous cell with a central nucleus and numerous clear cytoplasmic vacuoles. Signet ring type morphology is also common (Burger et al. 2002, Barnes et al. 1997). Presumably, the vacuole-laden cells develop from the eosinophilic cells in a recapitulation of notochordal embryology. Appreciable pleomorphism and mitoses are uncommon. The differential diagnosis of the histologic appearance of this tumor includes liposarcoma, metastatic carcinoma (particularly signet ring cell and renal carcinomas), chondrosarcoma (particularly the myxoid variant), and, intracranially, mixed tumor of the salivary gland (Mirra 1989)
In 1973, Heffelfinger and colleagues described a variant of chordoma termed chondrochordoma which, in their series, comprised approximately 14% of all chordomas. Chondrochordomas are biphasic, exhibiting both areas with classic morphology and others resembling hyaline cartilage. According to Heffelfinger et al., these areas represented chondroid differentiation and denoted a prognosis similar to that of low grade chondrosarcoma (considered better than conventional chordoma). This assertion sparked a controversy that continues to this day and a number of studies have attempted to identify tumors with true biphasic differentiation both histomorphologically and immunohistochemically.
Brooks et al. 1987 found 100% (7/7) of lesions classified morphologically as chondrochordoma had immunological features of chondrosarcoma and concluded that tumors should be classified as either chordoma or low grade chondrosarcoma. Conversly, Mitchell et al. 1993 and Ishida and Dorfman 1994 found that chordomas in which there are even small areas of chondroid differentiation express epithelial markers throughout the tumor, which raises the possibility that the chondrochordomas of the previous study were misclassified chondrosarcomas, probably of the myxoid variety. It is now established that true chordomas and cartilaginous tumors all express S100. Both fetal notochord and chordoma are positive for cytokeratin and epithelial membrane antigen. Fetal cartilage, chondroma and chondrosarcoma are negative for cytokeratin and EMA and are positive for vimentin. Therefore the expression of cytokeratin diffusely in a morphologically heterogeneous tumor is central to the diagnosis of chondroid chordoma (Radner et al. 2001).
In their immunohistologic analysis of 41 cases, Mitchell and Scheithauer 1993 found no difference in prognosis between classic chordoma, chondroid chordoma, and low grade chondrosarcoma when tumor site and patient age were taken into account. Probably more useful prognostic indicators are those related to tumor recurrence. Ishida and Dorfman (1994 ) found that increasing patient age, mitotic activity, Ki67 labeling index in excess of 6% were associated with faster growing tumors and therefore shorter disease free intervals.
Dedifferentiated chordoma is also a biphasic tumor exhibiting areas of conventional chordoma morphology and areas of high grade spindle cell or pleomorphic sarcoma. They comprise approximately 1% to 8% of all chordomas and may occur spontaneously or after radiation to a conventional chordoma. Prognosis is exceedingly poor with most patients dying of tumor related complications within one year (Barnes et al. 1997).
Contributed by Kathryn McFadden, MD