Primary Intracranial Leiomyosarcoma Secondary to Glioblastoma: Case Report and Literature Review

Background Leiomyosarcoma is a highly malignant soft-tissue sarcoma with a poor prognosis. In recent years, treatment for leiomyosarcoma has not shown much progress. Primary intracranial leiomyosarcoma (PILMS) is a much rarer type of neoplasm, which occurs more frequently in immunocompromised patients. PILMS cases reported in the literature are scarce and treatment strategy and prognosis are still under debate. In this study, a case of PILMS secondary to the total resection of giant cell glioblastoma is reported. Case Description A 38-year-old male was hospitalized with a three-month history of a temporal opisthotic bump. His medical history included a total resection of a tumor located in the right temporal lobe performed 4 years earlier. Pathological examination led to a diagnosis of giant cell glioblastoma, and the patient underwent postoperative chemotherapy with temozolomide for 6 weeks plus simultaneous radiotherapy with 63.66 Gary. Four years later, during regular follow-up, a preoperative MRI brain scan resulted in a well-defined signal pointing out two nodule-like features located at the right temporal lobe and subcutaneous soft tissue, respectively, and near the area where the previous giant cell glioblastoma was located. The mass was completely removed by a transtemporal approach and postoperative pathology revealed that the mass was a leiomyosarcoma. The patient underwent postoperative radiotherapy and no recurrence occurred until now. Conclusions To date, research on soft-tissue sarcoma, especially PILMS, has not made much progress, and a limited number of studies have provided few details on the management of PILMS. The treatment of choice for PILMS is aggressive multimodal treatment based on total tumor resection and radiotherapy. Moreover, systemic treatment with chemotherapy and targeted therapy, such as olaratumab, as well as further research still needs to be performed as many questions are left unanswered. To our knowledge, this is the first report on a case of PILMS secondary to glioblastoma, which might serve as a potential reference for clinicians and clinical studies.


INTRODUCTION
Intracranial leiomyosarcoma (LMS) is rare, and most often occurs as a result of metastasis of primary smooth muscle tissue tumors that can therefore develop in different organs due to the ubiquitous presence of the smooth muscle tissue in the body (1)(2)(3)(4). Primary intracranial leiomyosarcoma (PILMS) is extremely rare in the central nervous system (CNS) and previous studies suggested that less than 1% of brain biopsies (or 3 out of 25,000 brain tumors) are positive for LMS (5). They are speculated to derive from smooth muscle cells of the blood vessels or dura mater pluripotent mesenchymal cells (1,2,(6)(7)(8)(9), and display strong smooth muscle differentiation (10). In addition, PILMS usually occurs in immunocompromised patients or after exposure to radiation (8,11,12). Here we report a case of PILMS arising on the right temporal robe near to the location of a previous giant cell glioblastoma (GCG) totally excised 4-year earlier. The patient was not immunocompromised. To the best of our knowledge, this is the first report describing a case of PILMS secondary to a glioblastoma. Relevant literature has been reviewed, and diagnosis, and prognosis, especially regarding treatment strategy have been discussed.

CASE REPORT History and Examination
A 38-year-old male with a 3-month history of a temporal opisthotic bump was admitted to the hospital. The patient had no history of immunosuppressive medical treatment, intravenous drug use, previous organ transplantation or sexual promiscuity. Moreover, he did not experience any signs of headaches, dizziness, nausea, vomiting nor did he have any other sensory or motor deficits. Routine laboratory analysis showed standard parameters within normal limits, and the serologic test was negative for Human Immunodeficiency Virus (HIV), Hepatitis-B Virus (HBV), Hepatitis-C Virus (HCV), and Epstein Barr virus (EBV). According to his medical history, the patient underwent craniotomy 4 years earlier, because of the presence of an abnormal and heterogeneous magnetic resonance imaging (MRI) enhancement signal located in the right temporal and parietal lobe, together with evident edema (Figures 1A-C). The MRI performed 3 months after follow-up ( Figures 1D-F) revealed that the tumor was successfully removed. Postoperative pathological examination of the tumor led to a diagnosis of GCG, with a Ki-67 index of 50%. Histological examination showed that many giant tumor cells were densely arranged, with blood vessel hyperplasia and focal necrosis.
The tumor cells had obvious atypia and eosinophilic cytoplasm, and the nuclei were eccentric with mitosis that was easy to observe ( Figure 2A). Moreover, pathological findings were evaluated. Pyrosequencing presented that no O6-methylguanine-DNA methyltransferase promoter methylation was shown ( Figure 3). Fluorescence in situ hybridization suggested no loss of heterozygosity in 1p/19q chromosome ( Figures 2B, C). Levels of IDH1, TERT, and BRAF were determined by multiple polymerase chain reaction amplification combined with high-throughput sequencing, which did not indicate a mutation of IDH1-R132/ R172, TERT-C228T/C250T or BRAF-V600E. The patient accepted to be subjected to postoperative chemotherapy with temozolomide for 6 weeks, and concomitant local 63.66 Gray radiotherapy. Follow-up was not stopped after the first surgery. During a visit after 4 years when the patient presented the bump, the MRI brain scan resulted in a well-defined signal pointing out two nodule-like features of 3.1x2.5 cm and 4.0x1.8x3.7 cm located kin the right temporal lobe and subcutaneous soft tissue, respectively (Figures 4A-F), with a slightly hypointense signal on T1-weighted imaging (T1WI, Figure 4A), isointense and slightly hyperintense signal on T2-weighted imaging (T2WI, Figure 4B), and isointense signal on fluid attenuated inversion recovery ( Figure 4C). The lesion showed significant edge enhancement and heterogeneous reinforcement inside the tumor ( Figures 4D-F). A preoperative diagnosis of a recurrent glioblastoma was made.

Surgery
The patient underwent transtemporal craniotomy under preoperative and intraoperative neuronavigation, together with electrophysiological monitoring. The tumor was pinkish in color, solid, bloody, and was closely adherent to the brain parenchyma and subcutaneous tissue. The entire tumor was removed.

Postoperative Course
The postoperative course was uneventful and no postoperative complications occurred. In addition, positron emission tomography (PET) was performed to identify potential extracranial primary sites, and serum tumor markers were measured; both were negative. One month after surgery, the patient underwent postoperative 54 Gray radiotherapy. Immediate post-operative cranial CT ( Figure 4G) and follow-up MRI were performed 3 months after surgery ( Figures 4H, I), and demonstrated complete removal of the tumor and no signs of recurrence. During the last telephone follow-up in December 2020, the patient stated that he did not report any abnormal condition and that he was leading a normal daily life. Based on these results, Abbreviations: CT, computed tomography; LMS, leiomyosarcoma; PILMS, primary intracranial leiomyosarcoma; STS, soft-tissue sarcomas; GCG, giant cell glioblastoma; IDH, isocitrate dehydrogenase; MGMT, O6-methylguanine-DNA methyltransferase; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; HIV, human immunodeficiency virus; HBV, hepatitis-B virus; HCV, hepatitis-C virus; EBV, Epstein-Barr virus; MRI, magnetic resonance imaging; PET, positron emission tomography; CNS, central nervous system; T1WI, T1weighted imaging; T2WI, T2-weighted imaging; BBBP, blood brain barrier permeability; PFS, progression-free survival; OS, overall survival; GTR, gross tumor resection; PDGFR, platelet-derived growth factor receptor. his conditions seem stable and therefore, the patients will undergo routine follow-up with MRI.
Co-infection with EBV in immunosuppressed patients with HIV is considered a leading factor in the development of LMS (9,22,26,27), and EBV-transformed and infected smooth muscle cells may contribute to the pathogenesis of LMS in patients with AIDS (2,3,17). However, immunocompetent patients in whom LMS occurred, were invariably negative for EBV (2,17,24,28). Radiotherapy (2) and chemotherapy (27,29) are also considered as potential factors inducing PILMS. Radiation oncogenesis was first defined by Cahan et al. (30), in 1948. Since then, it was clear that radiation doses above 50 Gray cause cell death, while lower doses (e.g.< 30 Gray) are associated with genomic instability and cell repair mechanisms of the caused damages (2). Suzuki et al. (31), also described a radiation-induced sarcoma usually within or at the edge of the tumor. Since the radiation is not uniformly distributed within the tissue, a sufficient dose does not reach the edge to ensure the killing of all tumor cells (31). Furthermore, Fujimoto et al. (9), described a case of LMS arising after the resection of a neurofibroma at the left cerebellopontine angle and concluded that the mechanical and/or heat stimulation during a previous surgery was associated with the development of LMS. The patient in this case report is the first ever described with PILMS secondary to a glioblastoma, and the pathogenesis was hypothesized as associated with the history of malignant tumor and radiation exposure together with the mechanical and heat stimulation during the first surgery. Nevertheless, these hypotheses did not explain all cases of PILMS in immunocompetent patients and further studies are needed to clarify the clinical features involved.

Radiological Characteristic
Due to the rarity of PILMS, radiological details describing it are lacking in the literature. In general, PILMS presents a hyperdense signal on CT and homogenous enhancement on enhanced scanning images (3,16). In addition, calcifications can be observed (16,35). MRI is considered the primary neurological approach to assess PILMS, which is also important for surgical planning (14). PILMS can develop as either extra-axial or intraaxial tumor, and the imaging features are different in these two locations (4). The extra-axial PILMS is usually characterized by uniform hypointense or isointense T1WI and T2WI (4,36). After gadolinium enhancement, well-defined homogeneous (22,23,28) or inhomogeneous (17, 37) enhancement with (6) or without (4) dural tail signal is detected, resembling meningioma (18,22,23,28,38). Moreover, the tumors were always significantly enhanced (18,36). No significant differences in survival were observed in patients with dura involvement (39). Intra-axial PILMS often appears as an irregular mass presenting a heterogeneous intense and heterogeneous enhanced pattern (2,24,26,40). Ultra-sound examination could also be performed for patients with skull involvement (36).

Treatment
Due to the rarity of PILMS, standard management guidelines have not yet been established (39). However, currently, a multimodal approach, including surgery, radiotherapy, and chemotherapy is the main treatment (12,21,42). In addition, surgical resection is the leading treatment to perform gross tumor resection (GTR) and the achievement of negative surgical margins due to extension of the resection is one of the most frequently reported predictors of recurrence and survival (2,15,16,28,33). Zhang et al. (39) demonstrated that the extent of excision might result in differences because of the difference in score systems that are presented in the literature, which needs further unification.

Radiotherapy
In PILMS, postoperative radiotherapy is used to control local recurrence (2,43). In many previous studies, GTR combined with postoperative radiotherapy is indeed the main treatment strategy for PILMS (1,3,26,27,44,45). However, the specific benefit of radiotherapy in terms of the survival of PILMS patients is not clear (39). To date, there is no consensus that patients with PILMS should undergo radiotherapy regardless of the extent of resection. In several studies, radiotherapy was not recommended for patients with GTR (15). However, considering the aggressive character, immediate adjuvant radiotherapy after GTR was approved in some cases (3,28,37). In this case, the patient underwent radiotherapy immediately after GTR, and had a relatively good survival without recurrence. In addition, radiation therapy represents an adjuvant option in patients with relapse or progression (39). In case of recurrent LMS, Gallagher et al. (28), suggested to perform a re-irradiation according to their experience in the treatment of recurrent glioblastoma. Recently, gamma knife radiosurgery (43,46) and stereotactic robotic cyber knife radiosurgery (47) have been performed to treat PILMS, revealing their feasibility and effectiveness in treating this type of tumor, although the number of patients was small, thus, they can be considered potential treatment strategies. The specific treatment advantage needs to be verified in future multicenter prospective studies.

Chemotherapy
In previous studies, it was demonstrated that PILMS is inclined to progress to extra-cranial metastasis, such as the spinal cord, lung, pleural, spleen, and hip (6,26,48). Although the role of chemotherapy in preventing extracranial metastasis is currently unknown, we speculate that it is difficult for radiation alone to confine the aggressive behavior of LMS. Chemotherapy is not a routine treatment of PILMS (9,17), and the choice of effective chemotherapeutic agents remains unclear (28). Because of its good blood brain barrier permeability (BBBP) and acceptable level of toxicity, temozolomide was the first chemotherapy drug used in the treatment of PILMS (49). Temozolomide has moderate activity in residual or metastatic STS, with a response rate of 8% (41,49,50), which makes it a promising drug in the treatment of PILMS. In some studies, it was revealed that temozolomide was effective at a dose that was equivalent to that of dacarbazine (9,51,52). However, the validity of monotherapy of chemotherapeutic drugs has been questioned (3), and the combination with other therapeutic approaches seems somewhat effective (1)(2)(3)6). In a recent study, Francisco et al. (53), reported a case of PILMS where maintenance treatment involved temozolomide and nimotuzumab. Nimotuzumab is an epidermal growth factor receptor monoclonal antibody. STS, like LMS, can express epidermal growth factor receptor-34, and its blocking promoted tumor inactivation and decreased chemoresistance (54). However, in this study, no improvement in survival was observed. For the current treatment of sarcomas, anthracyclines (doxorubicin and epirubicin) remain the first-line standard treatment regimens of advanced STSs (55), with a median overall survival (OS) of 12-18 months (56,57). When combined with other drugs, such as ifosfamide, a significant improvement in the response rate and progression free survival (PFS), but not in OS, was observed (58,59). The treatment experience with anthracyclines in PILMS is limited and controversial, and no improvement in survival was observed (60, 61), due to its poor BBBP and limited treatment experience of this disease (12,42).

Targeted Therapy
Here, we describe the application and research progress of targeted drugs in PILMS. To date, monoclonal antibodies to LMS, especially to PILMS, are scarce (28). However, along with increasing the understanding of the pathophysiology and underlying molecular mechanisms of action of LMS, there is an increase in research studies. For example, somatostatin receptor subtypes have been detected in moderate and malignant sarcomas. In 2016, Crespo-Jara A et al. (62), reported a case of metastatic and multiple drug-resistant sarcoma, which was successfully treated with radiolabeled somatostatin analogs. However, this agent has not been approved in China. Moreover, platelet-derived growth factor receptor (PDGFR), especially the alpha (a) isoform, has been confirmed to be associated with the metastasis and proliferation of LMS cells. Therefore, drugs that block the action of PDGFR could be a promising antitumor regimen (63,64). Lartruvo ® (olaratumab) is a PDGFR-a antagonist, a first-in-class recombinant human immunoglobulin-G subclass-1 monoclonal antibody that blocks binding and activation of the PDGF receptor (55 , described a treatment including the combination of vincristine, ifosfamide, doxorubicin, and etoposide with radiotherapy on a pediatric PILMS patient, which did not result in recurrence in 18 months. The use of the vascular endothelial growth factor inhibitor bevacizumab is also a promising approach, and has been increasingly used to treat LMS (32,52). Three Phase II clinical trials demonstrated that bevacizumab is an effective treatment for some STS (69,70). Gallagher et al. (28), also reported recurrence of PILMS treated with re-operation and bevacizumab (7.5mg/kg, 4 doses at 3-week intervals), and the follow-up was lost two-months after the re-operation. Notably, active antiretroviral therapy is imperative for PILMS patients with retroviral infections, such as HIV (28).

Prognosis
The prognosis of PILMS is overall poor (3,4,15,32,33), and the long-term prognosis is not clear (53). A limited number of studies reported a survival range from 6 to 44 months (4,37,45), and the average follow-up was 12 months, although Niwa et al. (19), reported a patient who died 8 years after the initial surgery, which represented the longest survival ever published. The poor prognosis and high local recurrence rate were considered as associated with the difficulty in obtaining negative surgical resection margins and an inadequate radiotherapeutic dose (6,14,28 (73), also suggested that the perineural invasion is an important predictor of survival and recurrence (10). The local recurrence rate is approximately 25.9% after radiotherapy on the initial lesion (15). Taken together, GTR has a significant and unexpected favorable outcome on survival (17,24,39).

CONCLUSION
Since PILMS is an extremely rare type of neoplasm, studies reporting on PILMS cases are rare. More future clinical trials, treatment experience, and long-term follow-up are required to fully understand this disease. Olaratumab might be a potential targeted drug for the treatment of PILMS, but has never been applied to PILMS patients. Thus, further studies are needed for its validity and BBBP. Here, we reported on PILMS secondary to GCG for the first time, and represented an additional reference among the few available, which might serve as a potential guide for clinicians and clinical studies.

ETHICS STATEMENT
The studies involving human participant was reviewed and approved by Ethics Committee of the First Hospital of Jilin University. The patient/participant provided his written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

AUTHOR CONTRIBUTIONS
LZ and YJ made study design, data collection, data analysis and interpretation, and composed the manuscript and literature review. YL and YW were the surgeons that performed the surgery, and did data collection, data analysis, and interpretation. YS and YB made English and grammar corrections, critical revisions, and approved final version. YL had the acquisition, analysis or interpretation of data for the work, revising it critically for important intellectual content, final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.