Turcot Syndrome: A Synchronous Clinical Presentation of Glioblastoma Multiforme and Adenocarcinoma of the Colon

Turcot syndrome (TS) is a rare hereditary disorder clinically characterized by the occurrence of primary tumors of the colon and the central nervous system (CNS). Here we present the case of an 11-year-old boy with a synchronous clinical presentation of both glioblastoma multiforme (GBM) and colonic adenocarcinoma. A molecular genetic study revealed microsatellite instability in the DNA mismatch repair (MMR) gene. This patient ultimately survived for 13 months after clinical presentation. Based on this case study, the synchronous presentation of glioblastoma multiforme and adenocarcinoma of the colon might suggest a shorter survival rate for patients with Turcot syndrome. A literature review complements this paper.


Introduction
Turcot syndrome (TS) was originally described by Turcot in 1959 [1][2][3]. It is characterized by the development of primary tumors of the central nervous system (CNS), such as glioblastoma multiforme (GBM) and medulloblastoma, along with numerous adenomatous colorectal polyps and colonic adenocarcinoma. TS usually develops in the patient's teens and can be genetically distinguished as either familial adenomatous polyposis (FAP) or hereditary nonpolyposis colon carcinoma (HNPCC) [4]. The syndrome was divided into two types by Paraf and colleagues in 1997 [5]. TS type I is characterized by the presence of glial tumors, relatively few colonic polyps, and cancer. TS type II is characterized by thousands of colonic polyps and increased risk of medulloblastoma.
Since the time when this syndrome was first identified, there have only been isolated case reports or case series with a limited number of patients being discussed in the literature. The synchronous clinical presentation of CNS tumors and colonic adenocarcinoma in this syndrome is extremely rare. In this paper, we present a case of TS with simultaneous clinical presentation of GBM and colonic adenocarcinoma.

Case Report
An 11-year-old boy presented with headache for the past 5 days, vomiting, and history of a single tonic clonic seizure. He had no history of weakness, loss of consciousness, or memory disturbance. He was also suffering from vague abdominal pain and loose motion over a period of one month prior to presentation. He had positive family history of colonic cancer. His sister had multiple café-au-lait spots and multiple colonic polyps.
During clinical examination, he was fully awake and oriented with a Glasgow coma scale (GCS) score of 15. His pupils were bilaterally equal and reacting; no motor or sensory deficit was noticed. His gait and posture were normal. On his skin there were multiple café-au-lait spots and areas of hypopigmentation ( Figure 1). Brain CT showed that he had a 4 × 4 cm left frontal cystic tumor with perifocal edema, effacement of left lateral ventricle, and subfalcine herniation. The brain appeared tight. The tumor had an intense ringenhancing rim. He underwent left-frontal craniotomy and gross total resection of the tumor. Histopathology showed GBM with giant-cell features (WHO grade IV) ( Figure 1). Immunohistochemistry of the tumor showed positive p53 and Ki-67 >90%. He continued to have abdominal pain and diarrhea and developed melena and intermittent frank bleeding from the rectum. His blood cell count, platelets, and renal and coagulation profiles were within the normal range. Upper GI endoscopy was normal; however, colonoscopy showed multiple colonic polyps of various sizes with ulceration and active bleeding ( Figure 2). Punch biopsy of the polyps revealed grade 2 adenocarcinoma ( Figure 2). A molecular genetic workup of the patient showed mutation in the DNA mismatch repair (MMR) gene with microsatellite instability. He was diagnosed with Turcot syndrome with cerebral GBM and adenocarcinoma of the colon. For adenocarcinoma of the colon, he underwent laparoscopic total colectomy and ileocolic anastomosis. A month later, he had recurrent bleeding from the rectum and developed new rectal polyps. To address this issue, he underwent proctectomy and terminal ileostomy. The patient received adjuvant radiotherapy for the brain cancer and chemoradiotherapy for the colonic cancer.
Nine months later, he presented with headache and was found to have mild right hemiparesis with an overall Karnofsky performance score of over 90. CT and MRI of the brain showed a left temporal ring-enhancing lesion about 4 × 5 cm in size with uncal herniation (Figure 3). He also had another lesion at the site of the previous surgery. He underwent redo left temporal craniotomy and gross total resection of the tumor. The biopsy report revealed pathological features similar to those of GBM. He was started on temozolomide as palliative therapy. Three months later, he had multiple recurrences and dissemination of the cerebral tumors on the left temporal, multifocal frontal, and parietal areas. At the same time, he had a massive progression of colonic carcinoma (Figure 3). He died 13 months after the initial diagnosis.

Discussion
Turcot syndrome is also known as brain-tumor polyposis and is characterized by the occurrence of primary tumors of Case Reports in Oncological Medicine the CNS and multiple colorectal adenomas and/or colonic adenocarcinoma [5,11]. From a genetic standpoint, TS can be divided into two subtypes: the first is manifested by the MMR gene and PMS2 with a high risk of developing GBM, and the second type is manifested by the adenomatous polyposis coli gene germline mutation with a high risk of developing medulloblastoma [5,16]. However, this classification cannot be applied to all cases reported in the literature. There are reports of cases with the occurrence of both GBM and medulloblastoma, as in the report from McLaughlin and colleagues [12]. Nevertheless, their patient was treated for medulloblastoma and received whole-brain radiation therapy 10 years prior to the diagnosis of GBM. Therefore, radiation-induced GBM cannot be excluded. Moreover, the occurrence of tumors other than GBM and medulloblastoma has been reported [17]. Based on TS classification, our patient fit the clinical and molecular genetic features of TS type I. The pathological differentiation between sporadic GBM and TS-associated GBM has not been adequately addressed in the literature. Recently, Lusis and colleagues reported on three cases involving patients with TS-associated GBM [11]. The histopathological and molecular genetic features in all three cases consisted of giant-cell GBM, and the patients in two of the cases had sarcomatous changes. The Ki-67 indices were found to range between 18% and 45%, and all three GBMs demonstrated positive nuclear p53. The first two patients survived 44 and 55 months, respectively, and the last patient survived 29 months and was still alive when the report was published. For our patient, the Ki-67 was >90% and the tumor showed p53 positivity in addition to MMR gene mutation. The tumor did exhibit giant-cell features. The patient survived only 13 months after initial clinical presentation. The average survival rate of patients with TS and GBM was found to be 27 months; however, when the investigators excluded the two patients with the longest-term survival, the average survival rate dropped to 16 months [18,19]. In contrast, the survival rate of sporadic GBM has been found to be around 15 months [20]. GBM and anaplastic astrocytoma are the most commonly reported CNS tumor associated with TS. In a review of 33 reported cases, 21 reports were for GBM and anaplastic astrocytoma [21].
Most of the reported TS cases in the literature are characterized by different time intervals between the clinical presentation of CNS tumors and the colonic adenocarcinoma [18,22]. The presence of symptomatic CNS GBM and colorectal cancers at the same time carries more management difficulties and, more important, might shorten the survival rate. Our patient presented with CNS and gastrointestinal

Conclusion
Simultaneous also negatively affect the survival rate in contrast to other types of TS-associated CNS tumors.