Clinical manifestations

Presentation and course

	• The usual presenting sign is a primary brain tumor, which is often malignant.
	• There is a history of familial adenomatous polyposis coli, or the diagnosis is established after the brain tumor.
	• The prognosis is poor mostly because of the malignant brain tumor.

Most Turcot syndrome patients are younger than 30 years of age at the time of presentation. Rarely, the syndrome may present in old age. For example, a woman presented for the first time at 67 years of age with clinical manifestations of a glioblastoma; she was found to have multiple colonic polyps with adenocarcinomatous changes (04). In another patient diagnosed with glioblastoma at 60 years of age, there was a history of hereditary nonpolyposis colon carcinoma (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 glioblastoma, an astrocytoma of higher grade, or a medulloblastoma. Ependymomas have also been described in patients with Turcot syndrome (55; 39). Most cases with tumors of astrocytic lineage (astrocytomas, glioblastoma) were described prior to the inclusion of IDH mutational status in the formal classification of these tumors. The neurologic signs and symptoms depend on the location of the tumor. There is usually a family history of familial adenomatous polyposis coli or colorectal carcinoma.

Some of these patients have a history of familial adenomatous polyposis coli. In some cases, the diagnosis of familial adenomatous polyposis coli was established after that of the CNS neoplasm, or the adenocarcinoma of the colon developed years after the primary brain tumor. Medulloblastoma usually presents at a younger age than colonic polyps. It is very rare for a patient with Turcot syndrome to develop more than 1 type of CNS neoplasm (38).

Polyposis of the colon may be asymptomatic in the earlier stages. A large polyp can cause obstruction of the colonic lumen requiring emergency surgery (50). Carcinomatous changes usually lead to rectal bleeding.

Skin manifestations of patients with Turcot syndrome may include cafe-au-lait (as also seen with neurofibromatosis type 1) and other pigmented spots, sebaceous cysts, and basal cell carcinomas (20). Multiple cutaneous lesions are present in more than 30% of patients with Turcot syndrome.

Ophthalmological findings in Turcot syndrome include diplopia due to cranial nerve palsies resulting from a brainstem glioma and oval pigmented ocular fundus lesions (40).

Prognosis and complications

The prognosis of Turcot syndrome is generally poor. More than two-thirds of the patients die within 5 years of the manifestation of the disease’s first symptoms, but survival may be exceptionally long in some cases. Rarely, the diagnosis of Turcot syndrome is made at autopsy (47).

The cause of death is usually the malignant brain tumor, but some patients die due to colorectal malignancy. Long survival is exceptional and most often occurs in cases with delayed development of the cerebral tumor. Survival to 22 years after development of astrocytoma was reported in 1 case (05). The underlying germline genetic alteration may favorably influence the prognosis of glioblastoma (17). One case of glioblastoma and Turcot syndrome survived for 14 years at the time of reporting and was under treatment for adenocarcinoma of colon (45). One explanation of long survival in patients with glioblastoma is misinterpretation of original histological slides, as some of these patients have turned out to have oligodendrogliomas (52). An additional explanation may rest on the IDH mutational status of the gliomas, which is an important prognostic factor that was first described in gliomas in 2009 but has not been included in most of reports on Turcot syndrome. A final potential explanation may be a particular sensitivity to DNA damaging therapies such as radiation and alkylating chemotherapies in the setting of a germline DNA repair deficiency. A 28-year-old female patient in Russia with history of familial adenomatous polyposis and carrying an APC gene mutation presented with cerebellar signs and was diagnosed as cerebellar ependymoma, which was treated by surgery as well as radiotherapy (30). She was followed up, and benign adenomatous polyposis was monitored. Two years later, there was no further growth of the brain tumor, but she underwent surgery for malignant change familial adenomatous polyposis.

Clinical vignette

A 42-year-old man presented with headache and raised intracranial pressure with suspicion of a brain tumor. MRI was suspicious for a glioblastoma of the right frontal lobe. The patient also had a family history of colon cancer but no gastrointestinal symptoms. After resection of glioblastoma followed by chemotherapy and radiotherapy, 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. Genetic testing of tumors revealed mutations of MMR genes MLH1 and PMS2, leading to the diagnosis of Turcot syndrome type 1. 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 recurrence 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 mismatch repair genes.
	• Several variants have been described.

Etiology and pathogenesis

Turcot syndrome is now considered to be a genetic disorder. It is inherited in an autosomal recessive or autosomal dominant manner, but it can also occur sporadically. Turcot syndrome is associated with 2 different types of germline genetic defects:

	(1) Mutation of the mismatch repair genes (MMR): MLH1, MSH2, MSH6, or PMS2, located on 3p22.2, 2p21, 2p16.3, and 7p 22.1, respectively (60). hMLH1 and hPMS2 are usually found in hereditary nonpolyposis colorectal cancer associated with glioblastoma.
	(2) Mutations of the adenomatous polyposis coli (APC) gene are located on the chromosome 5q21. The discovery that adenomatous polyposis coli gene may have tumor suppressor activity indicates that predisposing germline mutation may be causally linked to neuroepithelial and colonic tumors (31). Medulloblastomas are more commonly linked to adenomatous polyposis coli mutations.

Classification of Turcot syndrome. Several classification systems have been proposed. Lewis proposed 3 groups (35):

	• Cases in which siblings are affected and there is a family history of brain tumors
	• Cases in which 2 or more generations in a family presented with polyposis of the colon
	• Isolated nonfamilial cases

A classification of glioma-polyposis syndrome based on a review of 127 cases is as follows (20):

A classification of Turcot syndrome into 2 types on a genetic basis has been proposed (44).

	(1) Cases of Turcot syndrome that had characteristic colonic and brain manifestations
	(2) Cases of familial adenomatous polyposis coli associated with glioma
	(3) Suspicious cases of glioma polyposis
	(4) Cases other than glioma-polyposis syndrome

Type I consists of patients with glioma and hereditary nonpolyposis colorectal cancer and their siblings with glioma and colorectal adenomas. The tumors of these patients show germline alterations in DNA mismatch repair genes. Affected patients were younger than 20 years of age. The first case of type I Turcot syndrome was reported from Colombia in a 20-year-old male with a clinical presentation of both glioblastoma and multiple adenomatous colonic polyps who had an Asp12 mutation in the Kras gene and altered expression of HMSH2 and HMSH6 genes in 2 of the colonic polyps (08). This patient was still alive after 7 months of treatment at the time of reporting.

Type II consists of patients with a CNS tumor that occurs in a familial adenomatous polyposis kindred (familial adenomatous polyposis coli cases). These patients carry germline mutations in the adenomatous polyposis coli gene (APC).

A homozygous mutation in MSH6 in a family with Turcot syndrome is consistent with an autosomal recessive mode of inheritance (18). Two families with Turcot syndrome have been reported to have 2 germline mutations in each, 1 in the MLH1 gene and 1 in MSH2 (32).

Variations in pathogenesis. Multiple tumors may be seen in patients with Turcot syndrome, and a case has been reported with medulloblastoma, low-grade fibromyxoid sarcoma (following cranial radiation), pilomatrixomas, colonic adenomas, and abdominal desmoid tumor (following colectomy) (10). It is possible that immunosuppression or DNA damage associated with the treatment of 1 malignancy in some cases may have helped precipitate the development of other tumors. Although inherited APC mutations may be associated with ependymoma development in certain Turcot syndrome type II cases, mutation analysis of adenomatous polyposis coli and beta-catenin genes in sporadic ependymomas indicates that somatic mutations affecting these genes do not play a major role in the pathogenesis of sporadic ependymomas (43).

In patients with germline mutations of the adenomatous polyposis coli, 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 (25). In 1 case, an adenomatous polyposis coli germline mutation and a somatic TP53 mutation were identified in the colorectal carcinoma that developed a few years after the excision of an astrocytoma (01). The TP53 mutations observed in 2 different sites and stages of the disease indicate a multistep progression of the malignant events. Following the loss of mismatch repair function, TP53 disruption and chromosomal instability are not necessary for development of colorectal carcinoma but appear to be required for genesis of glioblastoma (34). In another case of type I Turcot syndrome, molecular genetic analysis detected microsatellite instability and TP53 mutation only in the grade III astrocytoma tissue removed from the right frontal lobe, suggesting alteration of the DNA mismatch repair system (42).

A suggested explanation of the low penetrance and rarity of Turcot syndrome is that a carrier of a constitutive alteration in a caretaker gene will need at least 1 or 2 more hits (1 for an oncogene and 2 for a tumor suppressor gene) independently in each tissue to initiate the oncogenic process (57). The penetrance of the adenomatous polyposis coli gene mutation in the colon epithelium is different from that in the brain because the colonic phenotype is present in about 100% of familial adenomatous polyposis coli patients by the age of 40, but few develop medulloblastoma.

DNA instability in normal tissues causes the early development of multiple cancers in Turcot syndrome. 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 1 study of 3 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 (06). Mutations in insulin-like growth factor type II receptor were found in only 1 glioma. These findings suggest that mutation may target different pathogenic pathways in the oncogenic process in the 2 organs.

Clinicopathological and genetic features of 3 patients with Turcot syndrome type 1, all of whom had glioblastoma, have been reviewed (37). The study concluded that the giant cell variant of glioblastoma is overrepresented in Turcot syndrome, although gliosarcomas may also be encountered, and these patients usually have long survival despite histological anaplasia (37).

Epidemiology

	• Turcot syndrome is a rare, but the exact incidence is difficult to determine.
	• The occurrence of brain tumors in patients with familial adenomatous polyposis coli is more than an association by chance.

The incidence and prevalence of Turcot syndrome are difficult to determine because of the rarity of the condition; only 183 cases have been reported in the literature up to November 2020. It is possible that some cases have not been reported, and diagnosis may have been missed in others because the definition has varied over the years. The occurrence of brain tumors in patients with familial adenomatous polyposis coli is more than an association by chance. Familial adenomatous polyposis coli constitutes about 1% of all cases of colorectal cancer. 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 (29). True incidence of Turcot syndrome may be masked by early death of patients with medulloblastoma, which also prevents these young patients from passing on the genetic abnormality to a subsequent generation. Some published cases of brain tumor associated with colorectal carcinoma and PMS2 mutation are not indexed as Turcot syndrome.

The relative risk of brain tumor in patients with hereditary nonpolyposis colorectal cancer and their first-degree relatives was 6 times greater than in the general population (58). In a study based on the national Danish Hereditary Nonpolyposis Colorectal Cancer Register, brain tumors occurred in 14% of the families with significantly higher risks for individuals with MSH2 gene mutations and constitutional mismatch repair defects (53).

Most reported cases in the literature are from North America, Europe, and Japan. Further cases have been reported from Latin America and China. It is possible that a greater number of diagnoses may be made of cancer predisposition syndromes associated with CNS tumors with increased utilization of next generation sequencing of primary brain tumors and associated germline tissue.

Prevention

• Currently, there are no known measures for the prevention of Turcot syndrome.

At present, no known method exists that will prevent the development of a brain tumor in patients with familial adenomatous polyposis coli. Prophylactic colectomy is usually carried out in patients with familial adenomatous polyposis coli to prevent the development of colon cancer. Presymptomatic diagnosis of hereditary nonpolyposis colorectal cancer is not yet possible as some additional responsible genes remain to be discovered. Prophylactic colectomy may not seem appropriate in a patient who has already been diagnosed with a malignant brain tumor.

Because the germline gene defects responsible for Turcot syndrome are known, germline gene therapy remains a theoretical possibility to prevent this syndrome in the offspring of families affected by this disease. It is also questionable that development of tumors in these patients can be prevented with a high degree of certainty by correction of genetic defects alone, as additional unknown factors may be involved in oncogenesis.

Differential diagnosis

Patients with Lynch syndrome also have an increased risk for colorectal cancer associated with cancer of other organs such as brain. Carriers of MLH1 and MSH2 gene mutations have a 1% to 4% risk of brain tumors compared to the less than 1% in the general population (27). Apart from mismatch repair mutations, genetic testing may reveal MYH-associated polyposis syndrome as an autosomal recessive, polyposis syndrome caused by biallelic mutations in the MYH gene (11).

A patient who presented with sebaceous carcinoma, colon cancer, and a malignant astrocytoma was found to have Turcot syndrome with overlapping Muir-Torre syndrome, which is characterized by sebaceous neoplasms, keratoacanthomas, and internal malignancies due to a defect in DNA mismatch repair (26). Basis for this overlap is that patients have mutations in both the MLH1 and MSH2 genes in Muir-Torre syndrome, whereas patients with Turcot syndrome type I carry mutations in the MLH1, MSH2 and the PMS2 genes. Another patient with a history of being treated for colonic adenocarcinoma and skin lesions leading to a diagnosis of Muir-Torre syndrome later developed a glioblastoma requiring surgical resection and pathology showed mutations in MSH2 and MSH6 mismatch repair genes (13). One patient with Muir-Torre syndrome and colorectal cancer who showed loss of expression of proteins MSH2 and MSH6 had a son who died of glioblastoma; because of the paternal phenotype of Muir-Torre syndrome, it is likely that the son suffered from Turcot syndrome (59). This case raises the issue if patients with Muir-Torre syndrome and their family members should be routinely screened for brain tumors.

In familial adenomatous polyposis (autosomal dominant), there is a predisposition to the development of medulloblastoma, which would justify the diagnosis of Turcot syndrome.

Confusing conditions

The following are important among the conditions to be considered in the differential diagnosis of patients with multiple tumors, including those involving the gastrointestinal system and the brain. The important differentiating point would be the genetic basis.

An important differential diagnosis would be metastatic brain tumor in cases with colorectal carcinoma.

Another condition to be considered is the association of polyposis coli with multiple neoplasms, including gliomas, in the presence of an immune deficiency such as immunoglobulin A deficiency. A case of Turcot syndrome with gastrointestinal stromal tumor, the most common mesenchymal neoplasm gastrointestinal tract, has been reported (03). A patient with Turcot syndrome and a novel APC gene mutation presented with multiple tumors, including a low-grade fibromyxoid sarcoma, indicating the importance of a broad differential diagnosis (10).

Li-Fraumeni syndrome is a rare autosomal dominant disease that presents with multiple neoplasms including brain tumors and colon tumors (49). This cancer predisposition syndrome is associated with germ line TP53 gene mutations in most families.

Turcot syndrome overlaps with, but should be differentiated from, the tumor spectrum of a childhood cancer syndrome due to biallelic PMS2 mutations, which encompasses atypical brain cancers, hematologic malignancies, and colonic polyposis (51). Early recognition of this familial cancer syndrome should prompt investigation for familial hereditary nonpolyposis colorectal cancer mutations.

Gardner syndrome usually presents with benign osteomas of the skull and facial bones, subcutaneous lesions such as epidermoid cysts, desmoid tumors, and dental abnormalities in patients with familial adenomatous polyposis coli. Gardner syndrome should be differentiated from Turcot syndrome, familial adenomatous polyposis, and other attenuated forms of familial polyposis. Apart from characteristic polyps in the colon and osteomas, Gardner syndrome also exhibits abnormalities in the retinal epithelium that differentiate it from others (23). There is 1 case report of Gardner syndrome, with a history of familial adenomatous polyposis, presenting as an isolated, giant cerebellopontine angle craniopharyngioma (36). There is no known genetic link between familial adenomatous polyposis and craniopharyngioma. The authors considered the possibility that this case was Turcot syndrome but, according to the criteria outlined in this article, it would not qualify for this diagnosis. Extracolonic carcinomas can also be a part of Gardner syndrome. This syndrome is genetically similar to Turcot syndrome because it is also due to a mutation of the adenomatous polyposis coli gene. Both Turcot and Gardner syndromes can occur simultaneously in a patient (28)

Diagnostic workup

	• Routine diagnostic workup for suspected brain tumor.
	• Colonoscopy in those with family history of adenomatous polyposis.
	• Polymerase chain reaction sequencing and genotyping of tissue removed at surgery in cases of Turcot syndrome.
	• Cytogenetic testing is done if standard molecular tests are negative.
	• Whole exome sequencing for microsatellite instability status.

The diagnostic workup of a patient with a suspected CNS tumor is like that of primary brain and spinal cord tumors. Those with a family history of adenomatous polyposis coli should undergo screening and surveillance colonoscopy. Patients with Turcot syndrome should undergo genetic testing, and tissue removed at surgery should be genotyped. Polymerase chain reaction sequencing is a reliable method for screening the adenomatous polyposis coli gene for germline mutations. This method has been used to test members of families with familial adenomatous polyposis.

Gene mutations are absent in 20% to 30% of patients with familial polyposis, as shown in the case of a 30-year-old woman with a positive family history of Turcot syndrome (46). She was negative for APC and MUTYH, but fluorescent in situ hybridization analysis demonstrated that 5q22 breakpoint disrupted the APC gene. This case shows that where standard molecular tests are negative, cytogenetic testing is helpful in determining that the subject is a carrier of Turcot syndrome.

Although a clinical diagnosis of familial adenomatous polyposis can be made by colonoscopy, genetic testing is necessary because of the overlapping phenotypes of Mut Y homolog–associated polyposis with Lynch syndrome, Gardner syndrome, and Turcot syndrome (19). The American College of Medical Genetics and Genomics provides guidelines for clinical laboratories in validating testing for inherited colorectal cancers.

Microsatellite instability due to mismatch repair gene mutations in tumor DNA can be type A or type B; the former is characterized by smaller, more subtle allelic shifts compared to the latter. Knowledge of the association between Turcot syndrome–related glial tumors and subtle type A microsatellite instability is important for full assessment of these patients and appropriate counseling. Whole exome sequencing provides insights into genomic alterations in Turcot syndrome. For example, germline analysis of a case of Turcot syndrome presenting with glioblastoma and endometrial carcinoma revealed a novel heterozygous deleterious MSH6 mutation and a somatic MSH6 mutation, but low microsatellite instability was found in glioblastoma (24).

Management

	• The management of patients with Turcot syndrome takes into consideration both the CNS and colorectal lesions.
	• Patients who present with a brain or spinal cord tumor are treated for these in the usual manner.
	• Referral for genetic counseling is often a component of the management for these patients and their families.

The management of patients with Turcot syndrome takes into consideration both the CNS lesions and colorectal lesions. Patients who present with a brain or spinal cord tumor are treated for these in the usual manner. Referral for genetic counseling is often a component of the management for these patients and their families.

Management of brain tumors. Early detection of brain tumors in patients with familial adenomatous polyposis coli might improve outcome. Therefore, surveillance for brain tumors is considered worthwhile in these patients. 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.

Management of colorectal lesions. Additional considerations are 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. It is known that a familial adenomatous polyposis coli patient whose adenomatous polyposis coli gene mutation located at codon 1309 developed cancer 10 years earlier in comparison to the rest of the cases. Consequently, risky rectal mucosa should be removed in this group of patients.

Outlook for future. Finding better preventive agents, improving screening for 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. A boy with Turcot-like syndrome and a constitutional homozygous mutation of the mismatch repair gene PMS2 went into remission from his glioblastoma for 7 years after multimodal treatment followed by retinoic acid chemoprevention (12). Long-term daily use of acetylsalicylic acid has been recommended for reduction of cancer risk in patients with constitutional mismatch repair deficiency (33).