Clinical manifestations

Presentation and course

	• The usual presenting signs are secondary to a primary brain tumor (symptoms depending on tumors localization or mass effect) or colorectal symptoms (bleeding or constipation/obstruction from polyp or malignancy).
	• There is often a family history of colorectal cancer or brain tumors, or possibly other malignancies.
	• The prognosis is poor, mostly because of the malignant brain tumor and the increased risk for other malignancies.

Most patients with Turcot syndrome are younger than 30 years of age at the time of presentation (especially in the setting of CMMRD), but patients can also present in middle or older age (05; 14).

The usual presenting symptoms are those of a primary CNS tumor, often a brain tumor and rarely a spinal tumor. The primary brain tumor is usually a glioma (glioblastoma or astrocytoma of higher grade) or a medulloblastoma. Most cases of glial neoplasms were described prior to the inclusion of IDH mutational status in the formal classification of these tumors (26). Ependymomas have also been described in patients with Turcot syndrome (43; 30). The neurologic signs and symptoms depend on the location of the tumor and whether or not there is mass effect. There is usually a family history of familial adenomatous polyposis coli or colorectal carcinoma in the setting of Turcot syndrome.

Polyposis of the colon may be asymptomatic in the earlier stages. A large polyp can cause changes in bowel pattern and ultimately lead to obstruction of the colonic lumen requiring emergency surgery (39). Carcinomatous changes usually lead to rectal bleeding.

Skin manifestations of patients with Turcot syndrome (particularly in the setting of CMMRD) may include cafe-au-lait, neurofibroma, and axillary freckling (as also seen with neurofibromatosis type 1) and other pigmented spots, sebaceous cysts, and basal cell carcinomas (19; 18).

Prognosis and complications

The prognosis of Turcot syndrome depends on the underlying genetic alterations and the types of malignancies that develop. Rarely, the diagnosis of Turcot syndrome is made at autopsy (37).

The cause of death is usually the malignant brain tumor, but some patients die due to colorectal or other malignancies. Long survival is exceptional and most often occurs in cases with delayed development of the cerebral tumor. Long survival of patients with Turcot syndrome and malignant brain tumors has been described in various case reports (35; 06; 17; 27). One explanation of long survival in patients with glioblastoma is misclassification of tumors as diagnostic criteria have changed significantly over the last couple of decades. An example is IDH mutational status of gliomas, which is an important prognostic factor, and the presence now excludes a diagnosis of glioblastoma.

Clinical vignette

A 42-year-old man presented with progressive headache that was worse when supine and with associated nausea and vomiting, raising the concern for increased intracranial pressure with suspicion of a brain tumor. MRI was concerning for a high-grade glioma of the right frontal lobe. The patient also had a family history of colon cancer but had no gastrointestinal symptoms himself. The patient underwent resection of the brain mass, and pathology was consistent with glioblastoma. Genetic testing the of tumors revealed mutations of MMR genes MLH1 and PMS2, leading to the diagnosis of Turcot syndrome type 1. The patient was treated with chemotherapy and radiotherapy for his glioblastoma. He underwent colonoscopy. Two adenomatous polyps were discovered and could be excised completely. Histological examination showed low-grade dysplasia and no further treatment was considered necessary. Repeat colonoscopy at 6 months showed no evidence of recurrence. However, the glioblastoma recurred after 1 year and the patient died a few months later despite treatment. No evidence of cancer of colon was seen on autopsy.

Biological basis

• The suspected cause of Turcot syndrome is a mutation of several possible genes: APC (a tumor suppressor gene) and DNA mismatch-repair (MMR) genes MSH2, MSH3, MSH6, MLH1, and PMS2 or deletion in EPCAM.

Etiology and pathogenesis

Classification of Turcot syndrome. Several classification systems have been proposed. Paraf proposed two groups based on genetic findings (32). Type I consists of patients with glioma and hereditary nonpolyposis colorectal cancer. These patients show germline alterations in DNA mismatch repair genes. Type II consists of patients with a CNS tumor that occurs in familial adenomatous polyposis. These patients carry germline mutations in the adenomatous polyposis coli (APC) gene.

Turcot syndrome is now considered to be a genetic disorder, but it can also occur sporadically (de novo mutation). Turcot syndrome is associated with two different types of germline genetic defects.

Mutation of the mismatch repair genes. These include MLH1, MSH2, MSH6, or PMS2, located on 3p22.2, 2p21, 2p16.3, and 7p 22.1, respectively (51), or in MSH3 or deletion in EPCAM (18). MLH1 and PMS2 are usually found in hereditary nonpolyposis colorectal cancer associated with glioblastoma.

CMMRD is caused by biallelic pathogenic variants in one of the DNA mismatch-repair genes (MMR), whereas monoallelic variants in these genes cause the autosomal-dominant Lynch syndrome. This means that both parents of a child with CMMRD often have Lynch syndrome, which might be unknown (especially in the setting of PMS2), given the low penetrance.

Common malignancies in CMMRD include colorectal cancer, brain tumors (particularly glioblastoma), as well as hematological and lymphoid and gynecologic malignancies. Furthermore, the clinical phenotype of CMMRD may fulfill criteria for neurofibromatosis 1 (NF1) with café-au-lait spots, neurofibromas, axillary freckling, etc.

Patients with CMMRD and Lynch syndrome with glioblastoma often acquire mutations in POLD1 or POLE that lead to an ultra-mutator phenotype with a molecular signature characterized by single-nucleotide changes present in exponentially high numbers (> 100/mb) (40). CMMRD and Lynch syndrome-related tumors often display a high mutational burden and microsatellite instability (MSI) that can now be assessed reliably using next-generation sequencing data (18), although non-GI tumors may not display MSI (02).

Mutations of the adenomatous polyposis coli (APC) gene. APC is a tumor-suppressor gene and is located on the chromosome 5q21 (25; 33). Familial adenomatous polyposis is an autosomal dominantly inherited cancer predisposition syndrome due to a pathogenic variant of the APC gene. Individuals often develop numerable (often > 1000) gastrointestinal polyps that at some point become malignant. They also have an increased risk of brain tumors, particularly medulloblastomas. In patients with a germline alteration of APC, inactivation of the second copy of the gene seems to be crucial for brain tumor development (04).

Variations in pathogenesis. Multiple tumors may be seen in patients with Turcot syndrome, and the risk for specific malignancies depend on the underlying genetic predisposition. It is possible that immunosuppression or DNA damage associated with the treatment of one malignancy in some cases may have helped precipitate the development of other tumors.

In patients with germline APC mutations, inactivation of the second copy of the gene appears to be a factor in the development of brain tumor (17). Mutations of another tumor suppressor gene, TP53, which is common in various cancers, have also been reported in some patients with Turcot syndrome but did not involve the germline of these patients. This suggests that TP53 alteration may play a role in the progression, but not the initiation, of the disease (21; 03).

A suggested explanation of the rarity of Turcot syndrome is that a carrier of a constitutive alteration in a caretaker gene will need at least one or two more hits (one for an oncogene and two for a tumor suppressor gene) independently in each tissue to initiate the oncogenic process (46). The penetrance of the APC gene mutation in the colon epithelium is different from that in the brain because the colonic phenotype is present in about 100% of patients with familial adenomatous polyposis coli by the age of 40, but few develop medulloblastoma.

DNA instability causes the early development of multiple cancers in Turcot syndrome type 1. Germline mutations of DNA mismatch repair genes associated with instability at the microsatellite region have been associated with the progression of Turcot-associated colorectal tumors. In a study of three patients with Turcot syndrome, each with colorectal adenocarcinoma and malignant glioma, all colorectal tumors showed a frameshift in the coding sequence of transforming growth factor beta type II receptor gene, but no such change was seen in any of the brain tumors (07).

Epidemiology

	• Turcot syndrome is rare, but the exact incidence is difficult to determine and depends on classification.
	• The detected incidence of HNPCC and familial adenomatous polyposis is likely to increase with increased molecular and genetic testing, but data regarding how many of these patients will develop Turcot syndrome, type 1 and 2, are lacking.

The incidence and prevalence of Turcot syndrome are difficult to determine because of the rarity of the condition and the possibility that diagnosis may have been missed because the definition has varied over the years. Most reported cases in the literature are from North America, Europe, and Japan, and some cases have been reported from Latin America and China. It is possible that a greater number of diagnoses of cancer predisposition syndromes associated with CNS tumors may be made with increased utilization of next-generation sequencing of primary brain tumors and associated germline mutation detection.

Familial adenomatous polyposis coli constitutes about 1% of all cases of colorectal cancer, and by the age of 40, almost all people with familial adenomatous polyposis will have developed cancer if the colon is not removed (16). The occurrence of brain tumors in patients with familial adenomatous polyposis coli is more than an association by chance. The relative risk of medulloblastoma in patients with familial adenomatous polyposis has been found to be 92 times higher than in the general population (17). The Cleveland Clinic Familial Polyposis Registry found 13 patients with gliomas in 168 kindred. This is a higher incidence than the expected rate of 8.2/100,000 in the general population (23). There is a 3-fold increased risk of brain tumors when there are APC mutations between codons 697 and 1224 and a 13-fold increased risk of medulloblastoma compared with patients with familial adenomatous polyposis with other APC mutations (09).

HNPCC may account for approximately 2% to 6% of colorectal cancers, with a higher risk when colorectal cancer is diagnosed in patients younger than 50 years old (16; 29). The relative risk of brain tumor in patients with hereditary nonpolyposis colorectal cancer and their first-degree relatives was six times greater than in the general population (47). In a study based on the national Danish Hereditary Nonpolyposis Colorectal Cancer Register, brain tumors occurred in 14% of the families at a median age of 41.5 years in patients with Lynch syndrome and in childhood in patients with CMMRD. There were significantly higher risks for individuals with MSH2 gene mutations and constitutional mismatch repair defects (42). The tumors associated with HNPCC were glioblastomas (56%), astrocytomas (22%), and oligodendrogliomas (9%). It has been estimated that approximately 1 in 279 people carry a mutation in DNA mismatch repair genes (52).

Prevention

	• Currently, there are no known measures for the prevention of brain tumors in patients with Turcot syndrome, but there are different screening recommendations depending on the underlying cancer disposition syndrome.
	• Cancer vaccines in patients with familial adenomatous polyposis and HNPCC syndrome are under investigation.

In patients with known Lynch syndrome, NCCN guidelines recommend annual physical and neurologic examinations starting around the age of 25 to 30 years old, but supporting data are limited (34). A surveillance protocol for patients with CMMRD has been published and recommend regular blood tests, imaging (including brain), and endoscopy from 6 years of age; however, prospective data to fully evaluate these protocols will be critical (41).

Identification of family history of familial adenomatous polyposis or APC gene mutations may allow the clinician to perform clinical surveillance for a potential brain tumor. There seems to be no advantage in performing surveillance MRIs, but there should be a low threshold if there is clinical concern, and patients and family members should be educated regarding signs and symptoms of brain tumors (48; 50). It is recommended that individuals at risk for familial adenomatous polyposis have annual colonoscopies starting around 10 to 12 years of age. If a patient is diagnosed with medulloblastoma, WNT subgroup, and absence of a somatic CTNNB1 exon 3 mutation, there should be a high suspicion for familial adenomatous polyposis, especially in the setting of positive family history or if gastrointestinal polyps are present (04; 18).

If there is clinical suspicion for a cancer predisposition syndrome, genetic counseling should be offered.

Cancer vaccines composed of commonly occurring frameshift peptides have been investigated in clinical trials and have proven to be safe and immunogenic in Lynch syndrome carriers (38). The feasibility and utility for more precise targeting is currently being explored in ongoing clinical trials. APC gene mutation-derived peptides have also been shown to be immunogenic (28). The effect that potential vaccines may have on preventing brain tumors remains unknown.

Effective and safe cancer prevention and screening guidelines are needed to improve both quality of life and survival.

Differential diagnosis

Confusing conditions

MYH-associated polyposis syndrome is an autosomal recessive, polyposis syndrome caused by biallelic mutations in the MYH gene, but the exact risk of developing brain tumors remains unknown (12).

Muir-Torre syndrome is a rare, hereditary condition thought to be a variant of Lynch syndrome and is also caused by germline inactivation of MMR genes. It is clinically characterized by sebaceous skin tumors or keratoacanthoma as well as at least one visceral malignancy (22; 13; 49).

An important differential diagnosis is metastatic brain tumor secondary to colorectal carcinoma.

Li-Fraumeni syndrome is a rare autosomal dominant disease associated with pathogenic variants in the tumor suppressor gene, tumor-protein p53 (TP53), which often presents with multiple neoplasms, including brain tumors and colon tumors, although colorectal cancer is relatively rare (11; 36).

Gardner syndrome is thought to be a variant of familial adenomatous polyposis with alterations in the APC gene. It is a rare autosomal dominant disorder characterized by the triad of multiple osteomas, mesenchymal tumors of the skin, and soft tissue as well as colonic polyposis (10). Patients usually present with benign osteomas of the skull and facial bones, subcutaneous lesions such as epidermoid cysts, desmoid tumors, and dental abnormalities. They typically have a family history of adenomatous polyposis coli.

Diagnostic workup

	• Cancer screening should be conducted according to the recommendations for the underlying cancer predisposition syndrome. This includes colonoscopy screening in those with a family history of familial adenomatous polyposis.
	• Routine diagnostic work-up is recommended for the suspected brain tumor and includes appropriate imaging, pathology review, and molecular studies. If there is a known cancer predisposition in the family, the specific underlying gene should be tested.
	• Genetic counseling should always be offered prior to genetic germline testing.

The diagnostic workup of a patient with a suspected CNS tumor is like that of primary brain and spinal cord tumors.

A germline mutation in the APC gene confirms a diagnosis of familial adenomatous polyposis. Genetic testing for familial adenomatous polyposis and MUTYH-associated polyposis is typically performed in individuals with 10 or more adenomas, but broader multigene panels are also available (48).

In patients with MSI-high (MSI-H) tumors or immunohistochemistry with loss of expression of an MMR protein, it is recommended to proceed with additional germline testing preceded by genetic counseling. It is, however, important to keep in mind that even though colon tumors might show MSI-H, this is not always the case for the brain tumors, even within the same patient (20; 44). This additional germline testing is typically completed by a multigene panel evaluating various high-risk genes simultaneously (53).

The American College of Medical Genetics and Genomics provides guidelines for clinical laboratories in validating testing for inherited colorectal cancers.

Management

	• The management of patients with Turcot syndrome takes into consideration both the CNS and colorectal lesions as well as the risk for additional malignancies.
	• Patients who present with a brain or spinal cord tumor are treated according to the guidelines based on pathology and molecular results.
	• Referral for genetic counseling is often a component of the management for these patients and their families, as well as appropriate cancer screening.

Management of brain tumors. Early detection of brain tumors in patients with familial adenomatous polyposis coli might improve outcome. Surveillance MRI imaging is not routinely recommended, but annual physical exams are, and there should be a low threshold to obtain imaging if there is clinical concern for a brain tumor. Decision for surgery, if required, is made on neurosurgical consultation. Referral to a clinical cancer genetics program should also be considered. For more information, see the articles on medulloblastoma and malignant glioma.

It remains controversial whether some patients have particular sensitivity to DNA-damaging therapies, such as radiation and alkylating chemotherapies in the setting of a germline DNA repair deficiency, and whether these treatment modalities should be avoided (24). The use of immune checkpoint inhibitors has now been approved by the FDA for solid tumors with MSI or MMR deficiency; in some studies, use in patients with biallelic MMR deficiency glioblastoma multiforme have shown encouraging results (01). It is thought that tumors harbor a high mutation load, resulting in the expression of neoantigens that act as a target for immunotherapy.

Management of colorectal lesions. Additional considerations include the detection and management of colorectal lesions. This involves treatment of affected individuals, counseling of patients and their families, screening of at-risk individuals, and surveillance of affected patients for extracolonic cancers. Treatment of adenomatous polyposis is primarily colectomy during the second or third decade.

Outlook for future. Finding better preventive agents, potentially including vaccines, improving screening for colonic and extracolonic cancers, and applying new radiological and endoscopic technology to the diagnosis and management of extracolonic features will be the major challenges for the management of Turcot syndrome in the future.

Outcomes

Outcome depends on underlying malignancy, its pathology, and genetic mutations.

Special considerations

Pregnancy

If there is a diagnosis of Turcot syndrome, genetic counseling is recommended prior to planned pregnancy as prenatal testing options, including preimplantation genetic diagnosis, can be offered.