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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 71-75

A young adult patient with Li-Fraumeni syndrome-associated glioblastoma: Case discussion and literature review

1 Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, China
2 Department of Radiation Oncology, Peking University Third Hospital, Peking University Health Science Center, Beijing, China
3 Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
4 Department of Neurosurgery/Neuro-Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China
5 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
6 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China

Date of Submission16-May-2020
Date of Acceptance02-Jun-2020
Date of Web Publication27-Jun-2020

Correspondence Address:
Prof. Qing Chang
Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing
Dr. Zhong-ping Chen
Department of Neurosurgery/Neuro.Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_17_20

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Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by germ line alterations in the tumor suppressor gene TP53, with an incidence of 1 in 5000–1 in 20,000. Li-Fraumeni syndrome is associated with numerous malignancies, including astrocytoma. Here, we report the case of a female patient diagnosed with glioblastoma in the right temporal lobe at the age of 22 years. She was treated with surgery followed by radiation and chemotherapy and achieved a complete response. Not surprisingly, the patient relapsed 7 years later and underwent a second surgery and radiation concurrent with temozolomide followed by chemotherapy with various agents. The patient currently remains tumor-free. Genetic testing revealed that the tumor contained a germ line mutation of TP53 (p.R282W). Pertinent family history included a mother who suffered from leukemia. Therefore, given the patient's medical and family history, we consider this is a case of Li-Fraumeni syndrome associated with glioblastoma. The ethics approval is not applied since the case was in consultation with experts arranged through meeting organizer.

Keywords: Glioblastoma, Li-Fraumeni syndrome, prognosis, temozolomide, TP53 mutation

How to cite this article:
Wu X, Tian S, Liang B, Yang Q, Ng H, Wu S, Chang Q, Chen Zp. A young adult patient with Li-Fraumeni syndrome-associated glioblastoma: Case discussion and literature review. Glioma 2020;3:71-5

How to cite this URL:
Wu X, Tian S, Liang B, Yang Q, Ng H, Wu S, Chang Q, Chen Zp. A young adult patient with Li-Fraumeni syndrome-associated glioblastoma: Case discussion and literature review. Glioma [serial online] 2020 [cited 2023 Oct 2];3:71-5. Available from: http://www.jglioma.com/text.asp?2020/3/2/71/288180

  Introduction Top

 Li-Fraumeni syndrome More Details (LFS) is an autosomal dominant cancer syndrome associated with a wide variety of cancers, most notably soft-tissue sarcoma, osteosarcoma, breast cancer, adrenal cortical carcinoma, brain tumors (including astrocytoma and medulloblastoma), and leukemia.[1] Germ line mutations in the tumor suppressor gene TP53 have been identified as the dominant molecular marker in most families with classic LFS.[2] It is reported that radiotherapy or chemotherapy of the first tumor in LFS patients may accelerate the development of subsequent tumors.[3],[4] The prognosis of LFS patients is generally worse than for patients with sporadic tumors.[5]

On March 2, 2020, the Chinese Society of Neuro-Oncology organized a multidisciplinary team discussion of a case of glioblastoma (GB) in a young adult patient in line with the diagnosis of LFS. The patient exhibited an excellent treatment response with a prognosis markedly better than expected for GB.

  Case Report Top

A 22-year-old female patient was admitted to the hospital in December 2011 with a right temporal lobe occupancy and underwent a total tumor resection. Postoperative magnetic resonance imaging (MRI) confirmed complete tumor resection [Figure 1]. The postoperative pathological diagnosis was WHO Grade IV GB multiforme. The results of immunohistochemical staining showed that isocitrate dehydrogenase 1 (IDH1) R132H mutation was negative, p53 mutation was positive, and the Ki-67 index was approximately 8%. The patient received radiotherapy (60 Gy) followed with temozolomide for ten cycles (150–200 mg/m2 for 5 days every 28 days) from February to December 2012. Subsequently, the patient received six cycles of cytokine-induced killer cell immunotherapy from January to May 2013. The patient was followed regularly until 2016 and remained tumor-free during that time.
Figure 1: Magnetic resonance imaging scans of the patient before and after treatment for initial glioblastoma tumor. (A) Scan prior to the first surgery shows a large enhanced mass in the right temporal lobe. (B) Postoperative scan confirmed total tumor resection. (C) Follow-up scan showed no tumor recurrence

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In August 2018, the patient had been experiencing a 1-month intermittent headache and was referred to the hospital. MRI revealed tumor recurrence at the previous surgical defect site [Figure 2]. The patient underwent a second surgery, and total tumor resection was achieved. Postoperative pathology confirmed the tumor as recurrent GB (WHO IV). Immunohistochemical analysis was similar to that of the primary tumor, with weak positive staining for IDH1 R132H, mutant p53 (80% positive), and increased Ki-67 index (15%–20%).
Figure 2: Magnetic resonance imaging scans of the patient after tumor recurrence. (A) Scan prior to the second resection revealed a large space-occupying mass in the right temporal lobe near the previous surgical site. The margins were unclear, and heterogeneous enhancement was observed. (B) One month after the second surgery, mild enhancement was seen around the surgical defect site, representing a postoperative change. (C) Final follow-up scan revealed no tumor lesion

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The recurrent tumor specimen was sent for genetic sequencing [Table 1]. Germ line mutation TP53 p.R282W and somatic mutations of PIK3CA and NF1 were found. No methylation of the MGMT promoter was identified.
Table 1: Genetic analysis of the recurrent tumor

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Post surgery, the patient received radiotherapy (50 Gy) concurrent with temozolomide followed with another ten cycles of temozolomide chemotherapy from March 2019 to February 2020, with the last six cycles combined with cisplatin chemotherapy. Bevacizumab immunotherapy was given twice in May and June 2019. The patient was followed regularly by MRI and showed good response to treatment, and the final follow-up MRI revealed complete remission. As of March 2020, the patient remained tumor-free survival although with left limb weakness and a decrease in vision. This is an overall survival of more than 8 years since the initial diagnosis, with a relatively good quality of life. The ethics approval is not applied since the case was in consultation with experts arranged through meeting organizer.

  Discussion Top

GB has a dismal outcome despite the availability of multimodality therapy. The 5-year survival rate in general is <10%, and the median survival is <2 years.[6] GB is more common in the elderly, with a peak incidence from 45 to 70 years.[7] However, the patient in this case was quite young (22 years) when she was diagnosed with GB for the first time, with tumor recurrence 7 years later. Genetic testing revealed that the patient had a germ line mutation in the TP53 gene, and she had a family history of leukemia, indicating the likelihood of LFS. Although no methylation of the MGMT promoter was found, the patient exhibited an excellent treatment response.

In 1988, germline mutations in the TP53 tumor suppressor gene were identified in most families with classic LFS and remain the only known genetic defect associated with LFS.[7] Approximately 70% of the mutations are missense, causing the synthesis of an abnormal p53 protein, whereas around 20% are nonsense or splice site mutations, inhibiting protein synthesis.[8] Initially, the clinical diagnostic criteria for LFS were limited to sarcoma; however, after revision of the criteria in 2001, LFS was expanded to encompass a tumor spectrum, including soft-tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumors, adrenocortical carcinoma, leukemia, and bronchoalveolar lung cancer [Table 2].[9] The present case, taking into account the patient's clinical characteristics and family history, has been considered a case of LFS.
Table 2: Diagnostic criteria for Li-Fraumeni syndrome

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Genome-wide studies have suggested that the penetrance of LFS varies according to tumor location, age, and sex.[10] Patients may show distinct temporal phase patterns, with the childhood phase (0–15 years, representing 22% of all LFS patients) characterized by adrenal cortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma, and medulloblastoma; the early adulthood phase (16–50 years, 51% of patients) including breast cancer, osteosarcoma, soft-tissue sarcoma, leukemia, astrocytoma and GB, colorectal cancer, and lung cancer; and the late adulthood phase (51–80 years, 27% of patients) including pancreatic and prostate cancer.

According to the Progress Review Group on “adolescent and young adult” (AYA) oncology, our patient belonged to the AYA group, which generally includes patients aged 15–39 years.[11] The relative lack of progress in treating cancer in AYAs is, in part, due to a lack of appreciation of differences in the biology of malignant diseases in this age group relative to younger and older individuals. Malignant tumors in AYA have been described in detail by Bleyer et al.[12] A proportion of the malignant tumors in AYA are attributable to germ line mutations of certain genes, such as tumor suppressor genes (TP53, MMR, APC, MUTYH, and BRCA1/2) and oncogenes (KRAS).[12] This case may reveal a pathogenesis of GB in the AYA population despite reports indicating that TP53-driven, high-grade gliomas are rare, only 3.75% of all tumors, in the AYA population.[13]

Recently, another case of LFS-related GB in the AYA population with a good prognosis has been reported.[14] The 29-year-old female patient also exhibited a germ line TP53 p.R282W mutation and prolonged survival, similar to our case. The patient was first diagnosed with two metachronous breast tumors and later with synchronous GB, lung adenocarcinoma, and breast cancer metastases. She was treated with intensively, including brain surgery and radiotherapy plus temozolomide, lung surgery, and a bilateral mastectomy. Thirteen years after the initial diagnosis of breast cancer and 6 years after the diagnosis of GB, the patient remained alive with an excellent performance status. The authors of the report believe that the coordinated care of a multidisciplinary team and the patient's extraordinary sensitivity to treatment played major roles in her remarkable outcome.

There have also been reports of LFS-related GB in the AYA population with poor prognosis, Yamada et al.[15] reported a male patient with a germ line c. 584T > C (p. Ile195Thr) mutation of the TP53 gene, who was diagnosed with GB at 20 years of age and died of colon cancer at 21 years. Penetrance in germ line TP53 mutation carriers has been reported to be close to 100% over their lifetime. Penetrance varies according to the mutation type, with the highest penetrance for p.R248W (58%, at the age of 30 years) and the lowest for p.R213Q (21%, at the age of 30 years). In the present case, the patient had a mutation of TP53 p.R282W (arginine to tryptophan), which carries a relatively high penetrance of 56% at 30 years of age and 75% at 50 years of age, explaining her early GB onset. Surprisingly, the R248W mutant is significantly associated with shortened survival time in LFS.[16]

It is well known that nonmethylation of the MGMT promoter is considered an indicator of temozolomide resistance. It was reported that MGMT expression can be negatively regulated by wild-type p53 in cancer cells.[17] Overexpression of wild-type p53 has been shown to increase the sensitivity of cancer cells to temozolomide in bothin vitro andin vivo studies.[17] Thus, mutated TP53 may cause the accumulation of MGMT protein and reduce sensitivity to temozolomide.

Conversely, another study has raised the possibility that response to temozolomide treatment may be influenced by non-MGMT mechanisms. Data from glioma cell lines have indicated an association between the absence of functional p53 and increased temozolomide sensitivity, an effect that is independent of MGMT methylation status.[18] This might explain why patients with mutated TP53 are sensitive to temozolomide treatment. As for the present case, a patient with a TP53 mutation has no MGMT promoter methylation but a good response to temozolomide and 8-year survival time.

Other mutations present in the GB tumor of our case included somatic mutations of NF1 (47.06%) and PI3KCA (14.10%), which are commonly observed in gliomas. Research has shown that activation of the PI3K/Akt/mTOR pathway leads to the development of drug resistance, thereby dampening the therapeutic effect of temozolomide.[19] About 8.7% of GB and 9.6% of anaplastic astrocytoma tumors exhibit somatic NF1 mutations.[20] Moreover, somatic NF1 mutations are a genetic signature of “mesenchymal GB,” a molecular subtype of GB[21] that has a poorer outcome compared to the proneural subtype.[22],[23]

  Conclusion Top

This case of LFS-associated GB underscores the importance of integrating molecular genetic techniques into tumor diagnostics. Genetic testing revealed that the tumor contained a germ line mutation in TP53 (p.R282W). Pertinent family history included a mother who suffered from leukemia. Therefore, given the patient's medical and family history, we consider this to be a case of LFS associated with GB. In particular, surveillance protocols developed for individuals with LFS have demonstrated improved long-term survival for these patients.

Financial support and sponsorship


Institution review board statement

The ethics approval is not applied since the case was in consultation with experts arranged through meeting organizer.

Declaration of participant consent

The authors certify that they have obtained the appropriate patient consent form. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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