INTRODUCTION
Chordoma is a tumor arising from embryonic notochordal remnants. It accounts for 17.5% of primary spine tumor, with a reported incidence of 0.5 to 0.8 per 1,000,000 population in the United States
8,15). Lesions arise from the sacrococcygeal region (50%), the base of the skull (35%) and vertebral column (15%)
4,8,15). Chordoma is classified as a malignant bone tumor, but slow growing feature is distinguished from other malignant bone tumors
22,23).
En bloc excision is the treatment of choice for chordoma. However, local recurrence is frequent because complete surgical removal of the tumor is difficult
12,13,24). Radiation therapy (RT) is often used as an adjuvant treatment modality and appears to reduce the incidence of local recurrence. However, the effect of RT on overall survival was not known exactly
3). Chemotherapy for a chordoma has been proven as an ineffective modality
5,17,18).
Dedifferentiated chordoma (DC) is a chordoma with sarcomatous components such as malignant fibrous histiocytoma most commonly, fibrosarcoma, osteosarcoma, or rhabdomyosarcoma rarely
21). DC is, for the most part, a transformation type, however de novo type is rarely reported
16,21). Transformation type has been reported as a result of malignant transformation of recurrent chordoma or post-irradiation changes
12,13,24). The clinical course of DC is distinguished from conventional chordoma by the rapidity of tumor growth and the potential for distant metastasis.
In this article, we report two cases of DC in recurrence.
DISCUSSION
The incidence of DC has been reported to be 6 to 9% of all the chordomas
16,21). DC was characterized as a sharp demarcation of a conventional chordoma with a high grade sarcomatous component
16). The histological appearance of sarcomatous component has been described as malignant fibrous histiocytoma, fibrosarcoma, osteosarcoma, or rarely rhabdomyosarcoma
21).
The differential diagnosis between DC and conventional chordoma is important because of the distinctions in clinical prognosis
16,23). Conventional chordoma is a slow growing tumor with a benign behavior and an indolent clinical course. In contrast, DC is characterized by the potential for distant metastasis and rapid progression. The metastasis commonly contains the dedifferentiated component. Dedifferentiated tumor arising de novo is rarely reported
16,21). Sarcomatous change following radiation has been observed more frequently, but a causal relationship is not proved yet
10,11,14).
It is difficult to distinguish conventional chordoma from DC based on imaging studies. Typical findings on a plain film of chordoma include osteolytic lesions of the bone with sclerotic bone reaction
7). Computed tomography (CT) scan or MR image studies are indicated to evaluated the extent of the tumor and to identify the tissues that the tumor has infiltarated
1,19,20). The characteristics of chordoma in CT scan are an expanding, destructive, osteolytic lesion with an associated soft tissue mass. MR image has a better resolution of the soft tissue component than CT scan. Chordoma shows hyperintensity in T2 and hypointensity in T1 weighted images on MR image.
Chou et al.
6) reviewed 16 cases of DC previously reported since 1970 in their article published in 2009. Seven out of 16 cases belonged to the de novo type while 9 cases to the transformation type. The median age of patients at the time of diagnosis of DC is 63 years old (range 24 to 73). The male to female ratio is nearly 2:1. The median transformation interval from conventional chordoma to DC in 9 cases was 6.6 years (range 2 to 26). Seven of nine patients experienced local RT before the transformation of chordoma into DC. Nine of the sixteen patients had distal metastatic lesions and lung metastasis presented in all the nine patients. Other metastatic sites include the pleura, inguinal and paraaortic lymph nodes, bone marrow, heart, and spine. The average survival time of all patients was 10.1 months (range 3 weeks to 4 years). De novo group had the average survival of 9.6 months (range 3 weeks to 2 years), transformation group had 10.4 months (range 1 month to 4 years).
In our study, 2 cases were both transformation types, with one male and one female patient. In case 1, the patient's age was 72 years old at the time of the diagnosis of DC, and there was a history of RT. The transformation interval was 6 years, and there was no distant metastasis. The survival was 12 months after the diagnosis of DC. In case 2, the patient was 41 years old at the time of the diagnosis. Interestingly, the patient did not receive any RT before the transformation of the chordoma. In addition, the transformation interval was only 4 months. The survival time was 31 months after the diagnosis of DC. Both of the 2 patients showed rapid disease progression, the second patient lives longer than the first in spite of short transformation time and multiple systemic metastases. Of course multiple factors influenced the survival time of the second patient, an aggressive treatment might be helpful to prolong the survival time.
The treatment of choice for DC seems to be a surgical resection. In Chou et al.
6), 6 of the 16 patients had undergone surgical resection alone for DC. A disease free status for more than 5 months was achieved in 3 of the patients. The other 3 patients had recurrent disease postoperatively. Two of the six patients expired at 3 and 8 months postoperatively as a result of the recurrent disease. Four of the sixteen patients had recurrent or metastatic disease, underwent surgical resection followed by local RT to the sacrum. The poor outcomes in these patients may have been due to the difficulty in resection of locally advanced disease, which in turn may have led physicians to boost local RT as adjuvant treatment postoperatively. RT is particularly limited as a primary treatment modality for DC.
In our study, after the diagnosis of DC, there was a difficulty in complete surgical removal of the tumor, so it wasn't achieved. We performed RT and Cyberknife® radiosurgery; however, the patients presented repeated recurrence and distant metastasis. In case 1, even if there were no distant metastasis, local tumor control was not accomplished in spite of several operations and 2 times of RT. In case 2, it seemed like there was a local control for certain duration by postoperative adjuvant RT, multiple recurrence occurred. Chemotherapy also had limited effect.
Felming et al.
9) reported the use a 6 drug regimen including etoposide, cisplatin, vincristine, dacarbazine, cyclophosphamide, and doxorubicin for 2 patients with DC who presented with multiple lung metastases. In one patient, complete response was achieved without recurrence for 24 months follow up period. Partial response to the 6 drug regimen was achieved in the other patient. However following salvage therapy with ifosphamide could achieve a complete response. The patient died with recurrent disease 28 months after DC was diagnosed.
Meis et al.
16) reported the use of a doxorubicin based regimen in 2 DC patients with lung metastasis. In one patient partial response was achieved after treatment with doxorubicin, dacarbazine and cyclophosphamide combination chemotherapy. The other patient presented with the regression of lung metastasis, however the sacral mass progressed after treatment with doxorubicin and cisplatin.
Chou et al.
6) reported the use of ifosfamide, epirubicin and cisplatin combination therapy. The sacral tumor progressed rapidly after chemotherapy and patient died of wound infection and uncontrolled sepsis one month later.
Casali et al.
2) reported that imatinib mesylate has been found to have antitumor activity in patients with chordoma. This activity might be mediated by inactivation of platelet derived growth factor receptor β. Six patients with chordoma were treated with imatinib mesylate at a dose of 800mg daily for one year. Clinical and radiological improvement was seen in all patients.
In our study, we performed chemotherapy with 4 drug regimen including vincristine, ifosfamide, doxorubicin, etoposide, and following a single regimen of etoposide for the treatment of the systemic metastasis in the second case. After the chemotherapy, lung metastasis remained stable, however the tumors at the sacrum and mobile spine showed rapid progression. The patient presented chemotherapy induced bone marrow suppression and died of uncontrolled sepsis complicated by pancytopenia.
It is not certain whether chemotherapy is beneficial or which chemotherapeutic agent is effective in the treatment of metastatic DC yet. The combination chemotherapy based with doxorubicin, cisplatin and cyclophosphamide appears to be effective for some patients. However, physicians have to be alert using chemotherapeutic agents to manage associated complications, especially myelosuppression.