The pathophysiology underlying this lethal disease is demonstrated to be complex. Starting from the histological characterization performed by Virchow in 1857 [30] up to the discovery of brachyury’s involvement, numerous progresses have been performed in the pathogenesis of this tumor. Examination of human embryos and fetus showed that notochordal cell nests topographically correspond and distribute to the sites of occurrence of chordoma and histological appearance of tumor cells led to hypothesize the notochordal origin [31, 32]. Molecular research has so far yielded significant findings on the mechanisms underlying the initiation and further progression of chordoma cells. The most compelling evidence of the notochordal hypothesis derived from researches focused on a transcription factor named “brachyury.” It is an important transcription factor in notochord development, but duplicated regions contained only the brachyury gene have been discovered in familial chordoma [33–36]. The remarkable overexpression revealed this transcription factor to be a crucial aspect of chordoma, although it is still unclear what role brachyury has in the pathogenesis [37]. Some other notochordal factors (Shh, Wnt, galectin-3, NCAM) seem to be relevant in notochord formation and in chordoma, as well as the other overexpression of cell cycle regulatory pathways and an activated receptor tyrosine kinase pathway [11]. The molecular biology process behind the initiation and progression of a chordoma needs to be revealed for a better understanding of the disease and to develop more effective therapies [38].

Chordomas are classified on the basis of their location along the spine in sacrococcygeal, clival, cervical, thoracic, and lumbar (listed by the most frequent site) [1–3]. Recent studies reported an almost equal distribution in the clivus (32%), mobile spine (32.8%), and sacrum 29.2% [39]. Other epidemiological studies report that the sacrococcygeal area is the most common affect (40–50%) compared to clivus (35–40%) and vertebral bodies (20–40%) [40, 41]. Sacrococcygeal chordomas have very low incidence in patients below 40 years old and are more frequent in males (male to female ratio 2:1) [42–45].

Chordomas of the sacrum often present with non-specific symptoms which can delay diagnosis, such as localized deep pain or radiculopathies related to the spinal level at which they occur [46–49]. In advanced disease the tumors can present at the time of diagnosis as a slow-growing palpable mass associated with rectal or urinary dysfunction [46, 47, 50]. The average duration of symptoms is about 14 months (range, 4–24 months) [45]. Diagnosis is further complicated by the fact that lytic sacral lesions might be overlooked on plain radiographs of the pelvis, and CT or MRI studies are often not performed without a clinical suspicion of sacral tumor [45, 49]. Differential diagnosis for lumbosacral chordomas includes pilonidal sinus disease, deep abscesses, rectal sarcomas, and several retrorectal tumors (teratomas, extraperitoneal adenomucinosis, cystic lymphangiomas, neurogenic tumors, and cysts, developmental tailgut cysts, sacral myelomeningocele, rectal duplication) [51–53]. Most sacrococcygeal chordomas can protrude anteriorly into the pelvis, and rectal examination may be useful for clinical detection of sacral mass even if the tumor is limited by presacral fascia [54].

Chordomas are midline lesions and often appear radiographically as destructive lytic bone lesions. Unlike other primary tumor (osteosarcomas and chondrosarcomas) of the spine, chordomas locally invade the intervertebral disk space as they spread to adjacent vertebral bodies [49]. Computed tomography (CT) and magnetic resonance imaging (MRI) are the gold standard for diagnosis. The tumors are often associated with soft tissue mass (Fig. 15.4). Calcification and bony expansion are present in 30–70% of the cases and appear isointense or hypointense on T1-weighted MRI images and hyperintense on T2-weighted MRI images and enhance with gadolinium [55]. On bone scan, chordomas show reduced or normal uptake of radioisotope when juxtaposed to other bone tumors [56]. Careful preoperative assessment of imaging within the multidisciplinary team is essential in planning surgical approach and discussing strategy of treatment.

Chordomas were first described histologically by Virchow in 1857, when he identified the typical “physaliferous” tumor cell chordomas [30]. Physaliferous cells appear as large white cells with round nuclei and abundant vacuolated cytoplasm separated by fibrous septa into lobules [41, 42] and are typical of classic chordomas. Chordomas are classified as classical (or conventional), chondroid, or dedifferentiated [41]. Classic chordomas are pathologically identified by their typical cells and immunoreactivity for S-100, epithelial membrane antigen (MUC1), and cytokeratins [57, 58]. Brachyury staining is used to discriminate chordomas from other chondroid lesions [59]. Chondroid chordoma is a histological variant that account for 5–15% of all chordomas [41]. It shows histological features resembling chondrosarcoma, with hyaline cartilage associated with expression of chordoma markers [60, 61]. Dedifferentiated chordomas account for less than 10% of all chordomas and are characterized by sarcomatous areas with spindle cells such as fibrosarcoma, osteosarcoma, or rhabdomyosarcoma [62–66]. It is characterized by a fulminant clinical course resulting in metastases and/or death within 1 year of diagnosis in most of the cases [64–68].

The most accredited treatment consists of surgical resection with wide margins, as no chemotherapy has been demonstrated to be effective against chordoma and conventional radiotherapy is only partially effective [5, 11, 69–74]. Complex pelvic anatomy coupled with the need of wide margins means that surgery is challenging to preserve essential neural function and avoid injury to visceral and vascular structures during resection. Frequently, margins are positive (marginal or contaminated) [11, 70, 71, 75, 76], and adjuvant treatment strategies must be considered.

Several prognostic factors associated with poor survival have been reported: age [78, 130, 131], tumor size [46, 71, 72, 131–133], preoperative C-reactive protein >1.0 mg/dL [134], tumor site regarding the proximal extent of the tumor, local invasion into other tissues [131, 135], inadequate surgical margins [46, 69, 70–72, 75, 133, 136–138], content of extracellular matrix and high Ki-67 index [138], histological category such as dedifferentiated chordomas [41, 139], and local recurrence [46, 138, 140]. Patient survival seems to be less affected by distant metastasis than by local progression of the disease, underlining the role of local control to improve oncological outcomes.

Local recurrence (LR) after surgical treatment is common (43–85%) despite resection with adequate margins [71, 72]. Some authors suggested that infiltration of the musculature adjacent to the sacrum and/or involvement of the sacroiliac joints increases the tendency to local recurrence, even after apparently successful en bloc resection [135, 141, 142]. This hypothesis could also justify also the observation of similar recurrence rate between major resections of proximal part of the sacrum and small resections distal to S3 level [70, 71]. Therefore, in cases of infiltration of the sacroiliac joint, we should consider the tumor at an advanced stage with increased risk of satellite lesions which may promote disease recurrence. The factors associated with higher risk of local recurrence are: old age [82, 140], higher sacral localization [140], inadequate surgical margins [46, 69, 70, 78], and previous intralesional surgery [69–71, 78]. Adjuvant radiotherapy may improve oncological outcomes in patients with inadequate surgical margins or dedifferentiated disease, but optimal radiotherapeutic regimens with long-term survival have not been developed. In fact, despite combining en bloc resection with particle radiation therapy, frequent local recurrence remains a reality, and the 5- and 10-year overall survival rates are circa 65% and 35%, respectively [39, 143, 144].