A Rare Case of Adult Poorly Differentiated Chordoma of the Skull Base With Rapid Progression and Systemic Metastasis: A Review of the Literature

Chordoma is a rare tumor that arises from chordal tissue during fetal life. Recently, the concept of poorly differentiated chordoma, a subtype of chordoma characterized by loss of SMARCB1/INI1 with a poorer prognosis than conventional chordomas, was established. It predominantly occurs in children and is rare in adults. Here, we report a rare adult case of poorly differentiated chordoma of the skull base with a unique course that rapidly systemically metastasized and had the shortest survival time of any adult chordoma reported to date. The patient was a 32-year-old male with a chief complaint of diplopia. MRI showed a widespread neoplastic lesion with the clivus as the main locus. Endoscopic extended transsphenoidal tumor resection was performed. Pathological findings showed that the tumor was malignant, and immunohistochemistry revealed a Ki-67 labeling index of 80%, diffusely positive brachyury, and loss of INI1 expression. The final diagnosis was poorly differentiated chordoma. Postoperatively, the residual tumor in the right cavernous sinus showed rapid growth. The patient was promptly treated with gamma knife three fractions. The residual tumor regressed, but the tumor developed systemic metastasis in a short period, and the patient died seven months after diagnosis. This report of a rapidly progressing and fatal adult poorly differentiated chordoma shows the highest Ki-67 labeling index reported to date. Prompt multidisciplinary treatment should be considered when the Ki-67 labeling index is high.


Introduction
Chordomas are rare tumors that arise from fetal chordal tissue, i.e., notochordal tissue, and predominantly occur in adults [1,2].They occur in the spine, particularly in the sacrum and skull base, and are difficult to remove entirely due to their infiltrative nature [3].Median overall survival is reported to be less than 10 years [4].Furthermore, according to the World Health Organization Classification of Tumors, Soft Tissue and Bone Tumors (fifth edition), poorly differentiated chordoma is reported as a subtype of high-grade chordoma.Its features are similar to those of conventional chordoma in that brachyury and epithelial antigen expression are maintained.However, unlike conventional chordoma, SWI/SNF-related matrixassociated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1)/integrase interactor 1 (INI) expression is absent [5][6][7], the disease predominantly affects children, and the prognosis is poor with an average overall survival of approximately 50 months [8,9].
We experienced an adult case of poorly differentiated chordoma of the skull base with rapid local progression and systemic metastasis, resulting in uncontrolled disease and the shortest survival of any adult case reported to date.Here, a poorly differentiated chordoma with systemic metastasis is discussed with a review of the literature.

Pathological findings
Pathology revealed epithelial-like atypical cells with a pale eosinophilic to eosinophilic cytoplasm proliferated in sheets or foci.Nuclear atypia was strong, and the majority of the cells had a component without an intervening mucus matrix.The highest mitotic count was 2-3 cells/10 high-power field (field of view 0.55 mm) with necrosis.A small number of components with mild cellular atypia with mucus matrix inclusions were also observed (Figures 2A, 2B).Immunohistochemistry was performed on formalin-fixed paraffin-embedded specimens with validation of positive and negative controls according to our previously reported protocol [10,11].Immunostaining revealed that these atypical cells were diffusely positive for cytokeratin (AE1/AE3), and the Ki-67 labeling index was approximately 80%, suggesting malignancy (Figures 2C, 2D).Additionally, the tumor cells manifested diffuse positivity for brachyury (Figure 2E), a marker for chordoma, and loss of expression of INI1 (SMARCB1) (Figure 2F).According to the World Health Organization Classification of Tumors, Soft Tissue and Bone Tumors (fifth edition), the final diagnosis of poorly differentiated chordoma was made.

Survival analysis of poorly differentiated chordoma based on previous reports
We hypothesized that the prognosis of poorly differentiated chordoma with metastases, as in our case, would be poor and performed a prognostic analysis.

Results
As shown in Table 1, gender was known in 86 of the 88 cases, with 41 males and 45 females.Age was known in 79 cases and ranged from 0 to 52 years, and 54 cases (68.4%) were younger than 15 years of age.The outcome was known in 56 cases; 33 cases were alive, and 23 were deceased due to the primary disease.
Overall survival ranged from 0.3 to 276 months.Of the 23 patients who died of the original disease, only two (8.7%) were aged 15 years or older.The present case with distant metastases and a 22-year-old woman without metastases.The adult case with the shortest survival time was the present case.Information on metastasis was obtained from 53 patients, 29 (54.7%) had metastasis, and 24 (45.3%) did not.Overall survival was available for 34 of the 53 patients, 14 with metastases (three of whom died) and 20 without metastases (nine of whom died).Kaplan-Meier survival curve analysis showed no significant difference in survival by metastatic status (p = 0.19, log-rank test) (Figure 3).However, the present case had the shortest survival time among the deceased patients with metastases.The Ki-67 labeling index was reported in 18 patients, ranging from 2% to 80%, with the present case having the highest value reported.The Kaplan-Meier survival curve showed that the median overall survival was not reached for patients with metastases and the median overall survival for non-metastatic cases was 24 months.A log-rank test has no significant differences between them (p = 0.19).

Discussion
Reaching a diagnosis of poorly differentiated chordoma is not always easy because the concept of this disease is not yet widely disseminated [1].The pathology of the present case revealed a highly atypical component with little myxoid stroma and a dense proliferation of epithelial-like atypical cells.Rhabdoidlike atypical cells with a deviated nucleus and eosinophilic cytoplasm were also partially observed.
Immunostaining showed that the patient was keratin-positive and S100 protein-negative, a feature similar to rhabdoid meningiomas and atypical teratoid/rhabdoid tumors (AT/RT).Furthermore, in this case, SMARCB1/INI1 was lost, and mutations or deletions of SMARCB1 have been reported in malignant rhabdoid tumors, which are also absent in AT/RT [6,13,17,20,21,31,32].An important distinction between these SMARCB1/INI1-expressing tumors and this case is the positive brachyury, a specific finding that indicates chordoid differentiation and is positive in all subtypes of chordomas.In the present case, the positive brachyury was sufficient to conclude that the patient had chordoma.Conventional chordoma does not show loss of SMARCB1/INI1 expression, and chordomas that show loss of SMARCB1/INI1 expression are considered poorly differentiated chordoma [2,6,16,19].Thus, the diagnosis of poorly differentiated chordoma was made in this case.
A total of 87 cases of poorly differentiated chordoma have been reported in the literature through 2022, and Table 1 includes a total of 88 cases, including our case.Poorly differentiated chordoma is most commonly diagnosed in early childhood, the average age of onset is about 10 years [8].Similarly, our literature review showed that about 70% of cases were under the age of 15, indicating that poorly differentiated chordoma is more common in children.Thus, the present case was diagnosed in the 30s, which is extremely rare.Metastasis of poorly differentiated chordoma has rarely been reported, accounting for about 20% of cases [20].Of the cases with known metastases, only about half (54.7%) had metastases, but the proportion with metastases is potentially higher because some cases have not been systemically examined and clinical data are lacking.In this case, stereotactic radiosurgery was performed as treatment, and the tumor within the irradiated field was reduced.However, systemic metastases developed, and the patient died approximately seven months after tissue diagnosis, the shortest overall survival reported to date.
We hypothesized that poorly differentiated chordoma with metastasis, as in this case, would have a poor prognosis and performed a prognostic analysis.However, we did not find a statistically significant difference in survival rate between patients with and without metastases.This may be because only three of the 14 patients with metastases were confirmed dead, and the others were censored cases, so the data were insufficient.The overall survival of the other two patients was 10 and 28 months, respectively, and the overall survival of this patient was the shortest at seven months.Regarding the proliferative potential of poorly differentiated chordoma, the Ki-67 labeling index is generally reported to be 10-15% [8,14], but in this case, the Ki-67 labeling index was extremely high at approximately 80%, the highest value reported.Therefore, the reason for the shortest survival in our case may be related to the highest Ki-67 labeling index reported to date, and prompt multidisciplinary treatment should be considered when the Ki-67 labeling index is very high.Carbon ion beam therapy has received much attention as radiation therapy for chordoma, but there are few reports of proton or heavy ion beams for poorly differentiated chordoma [33][34][35], and it is not known how effective these treatments are.Chemotherapy is not an effective treatment either [8,9,28].Immunotherapy, including an immune checkpoint inhibitor, was not administered due to low MSI, and a cancer gene panel test was attempted for TMB, but the patient was too advanced in stage to submit the test.Cancer gene panel testing should have been done at an earlier stage.As we previously reported [11], the development of immunotherapy and molecular-targeted agents and the collection of therapeutic data will be important in the future [9].

Conclusions
This report of a rapidly progressing and fatal adult poorly differentiated chordoma showed the highest Ki-67 labeling index reported to date.Prompt multimodality treatment, including immunotherapy, should be considered in cases with a high Ki-67 labeling index because of the possibility of early systemic metastasis.

FIGURE 1 :
FIGURE 1: Images during the course of the disease.MRI showing preoperative findings (A), third day after surgery (B), and two weeks after surgery (C).A 14-Gy dose was delivered to the tumor margin at the 40% isodose (yellow line) for a lesion from the cavernous sinus to the left middle cranial fossa (D left panel) and a 23-Gy dose was delivered to the tumor margin at the 40% isodose (yellow line) for a lesion from the right side of the clivus to the right middle cranial fossa (D right panel).Two months after irradiation by a gamma knife (E).Fludeoxyglucose-18 positron emission tomography three months after surgery (F) and 5.5 months after surgery (G).