Turcot Syndrome

Etiology

The cause of Turcot syndrome is a mutation of several possible genes. The APC gene is a tumor suppressor gene that undergoes biallelic, or homozygous, deletion. Homozygous mutations of the MMR genes, or the mismatch repair genes, are the second cause of TS.[2]

Epidemiology

The incidence and prevalence of Turcot syndrome are difficult to ascertain considering the rarity of the condition and that it has had a shifting definition over the years. However, it is usually an inherited disease in an autosomal recessive or autosomal dominant fashion, and that it can also arise sporadically.

There have been 148,900 new cases of inherited colorectal cancers in 2008. Of all the colorectal cancers diagnosed, up to 10%, at most, are inherited.[3] A small number of those inherited cancers, which are most commonly HNPCC or FAP, would be TS.

In patients with FAP, the relative risk of developing medulloblastoma is 92%. As a result, one APC mutation is present, by default, in FAP. APC mutations are not found in sporadic medulloblastomas; therefore, medulloblastoma presenting in a patient with an APC mutation is most likely Turcot syndrome.[4] About 40% of patients with Turcot syndrome develop a medulloblastoma. About 30% of families identified with FAP resulted from new mutations or mosaic inheritance as opposed to autosomal recessive inheritance.[2] Patients are born with the disease but manifest with it in early adulthood or before. Approximately 75% to 80% of individuals with APC-associated polyposis conditions have an affected parent.[3]

Pathophysiology

Turcot syndrome can arise from mutations in the MMR genes (type I, associated with HNPCC) or the APC genes (type II, associated with FAP). Mutations of either gene can result in colorectal cancer and brain tumors; most commonly, glioblastomas and medulloblastomas. Glioblastomas are associated with MMR gene mutations, specifically, in the hMLH1 DNA mismatch repair gene. Medulloblastomas are associated with APC gene mutations.[4] The mutations that result in the development of Turcot syndrome have generally been shown to be biallelic mutations, compared to the single allele, or heterozygous mutation manifestations in HNPCC and FAP.[5]

A general summary of the pathological process is that tumor suppressor gene deletion leads normal colonic mucosa to transform into invasive carcinoma. Normal mucosa develops into polyps, then the polyps continue to develop into invasive cancer. There are several different types of polyps including non-neoplastic hamartomas, the hyperplastic proliferation of the mucosa, and adenomatous polyps. Colorectal cancers generally arise from adenomatous polyps. It is adenomatous polyps that develop in type I and type II of Turcot syndrome. Homozygous MMR or APC gene mutations further the progression of the disease. These mutations manifest as tumors existing beyond the colon, namely brain tumors in TS.[6]

In contrast to the single allelic loss of the APC gene which results in FAP, Turcot syndrome which results in colorectal cancer and brain tumors seems to require a biallelic loss of the APC gene and in the MMR genes. Cancer develops either by the loss of tumor suppressor genes, the activation of oncogenes, or both. The APC gene is a tumor suppressor gene. When it is missing, it contributes to a lack of regulation in cell division. Hence, in FAP, there is an uncontrolled development of adenomatous colonic polyps that eventually turn invasive. These polyps found in TS2 can turn invasive by 20, and by 40 years of age, most of these patients will have developed cancer if the colon is not removed.[7] TS patients that develop deadly brain tumors do not tend to live that long.[8]

The APC gene mutation starts via KRAS proto-oncogene point mutations. This leads to hypomethylation of DNA which leads to proto-oncogene activation. Then there is a loss of the APC alleles, which is a tumor suppressor gene. The APC gene is found on the long arm of chromosome 5. There has also been mention of the loss of the DCC gene on chromosomes 18q and 17p. The specific MMR genes which undergo mutation are the MLH1 and MSH2 genes, and occasionally hPMS2.[5] These genes are also involved in the pathogenesis of HNPCC, but there they are found as heterozygous mutations as opposed to homozygous mutations that lead to brain tumor development that would qualify the disease as TS.

The medulloblastomas associated with TS2 come from neural stem cell precursors containing the homozygous APC mutation in the cerebellum.[9] Glioblastomas are generally found in TS1 associated with the homozygous MMR gene mutations.[10][6][10]

History and Physical

Although there are various genotypes that can cause Turcot syndrome, the phenotype is generally the same, by definition: colorectal cancer with a primary brain tumor.[1] Adenomatous polyps present at an early age, and they can be numerous or scarce. These patients can present with diarrhea/constipation and/or a positive FOBT. Most of the time, these patients will have a family history of early-onset colorectal cancer. Either before or after the polyps are found, neurological symptoms secondary to the development of a brain tumor can present.[7] This can include vision problems, auditory issues, sensorimotor deficits, among other issues, depending on the location of the tumor. Tumors can also arise from the spinal cord, manifesting with symptoms of spinal cord compression.

There is a phenotypic spectrum in TS.[4] This spectrum exists because various gene mutation combinations can be inherited, resulting in different phenotypes, often overlapping. The foundational presentation is colorectal cancer coupled with a primary CNS tumor.

In TS1, patients can also present with hematologic malignancies, café au lait spots, glioblastoma multiforme as a result of various MMR gene mutations. Patients with these mutations have fewer polyps in the colon, although on rare occasions, they can have significant polyposis as well. The converse is true for TS2. In TS2, patients can also present with epidermal cysts, tumors in other areas of the body, medulloblastoma because of a homozygous APC gene mutation. This mutation results in very significant polyposis of the colon, with polyps numbering in the thousands.

In TS2 analyses, it was found that patients who expressed the colonic polyposis phenotype tended to manifest the disease after age 17, and those that did not express the colonic phenotype manifested the disease (via brain tumor) by the age of 10.[4] It is of note, however, that these patients could have developed the polyposis later but that they simply did not survive until then. This demonstrates the concept of the phenotypic spectrum. There can be different manifestations of the disease at different times.

Patients present either with glioblastoma in TS1 and medulloblastoma in TS2. Patients can also present with pituitary adenomas, ependymomas, astrocytomas in rare cases.[4] Neurological signs and symptoms arise, depending on the location of the tumor.

Patients with TS1 are children of consanguinity in 20% of cases, with no family history of brain tumors or colon cancer. It is categorized by lesser and larger polyps. It is associated with gliomas and skin manifestations such as cafe au lait spots.[4] TS2 is less frequent and occurs typically in offspring of families with clustering of FAP. Medulloblastoma is the most common type of tumor here. The occurrence of colorectal cancer occurs later in TS2 than in TS1, and the skin lesions look more like epidermal cysts rather than cafe au lait spots, if present at all. Here, a brain tumor can occur without polyposis, and one theory is that the brain tumor just occurs much earlier than the polyposis and does not give it a chance to develop. The absence of polyposis and the absence of skin findings seem to suggest TS2 with a germ-line mutation as opposed to a somatic one.[4]

Evaluation

There is a lack of guidelines for the evaluation of patients with Turcot syndrome in screening or diagnosis. Of greatest importance is family history. Children of parents, either one parent or both, who were diagnosed with colorectal cancer at early age should certainly be monitored for pre-cancerous polyps.

The utility of genetic screening is debatable. Some argue that it should be performed on patients who are found to have pre-cancerous colorectal polyps to detect the presence of Turcot syndrome and thus anticipate the development of a primary brain tumor and render early treatment, and vice versa. Those in favor of genetic testing refer to the preventability of death in this disease if it is anticipated. A pitfall of this kind of genetic testing is cost-effectiveness since no real statistics show many people with inherited or sporadic genetic mutations resulting in colorectal cancer develop brain tumors and even less information vice versa. Turcot syndrome can also manifest with several genotypes, making genetic testing more complex. If a family member is identified with disease-causing mutations, then genetic testing either prenatally or during preimplantation could be beneficial.[11]

Other opinions state that the manifestation of either colorectal cancer or primary brain tumor at a young age should warrant screening for the other, depending on which comes first. Again, there is little data to guide the decision to screen. There is a recommendation for upper gastrointestinal (GI) surveillance every 3 years for peri-ampullary cancer in the duodenum in patients who have had a colectomy.[12]

Early serial colonoscopies should be a mainstay in patients with a family history of FAP, HNPCC, evidence of APC or MMR gene mutations. Screening until age 35 with proctosigmoidoscopy or testing DNA from peripheral mononuclear cells for mutation has generally been performed.[13] As far as brain tumors are concerned, screening is difficult. Imaging as frequently as once a year does not seem to be enough since medulloblastomas can arise and become fatal in as fast as six months.[14] Therefore, special attention should be made to neurologic signs and symptoms until guidelines can be established.

The goal of screening in TS, whether genetic or clinical, would be to prevent complications of the disease. Detecting genetic mutations in a patient identified with a primary brain tumor can allow for adequate screening for and thus prevention of colorectal cancer. Detecting genetic mutations in a patient with early diagnosed colorectal cancer can help us screen for primary brain tumors, allowing for early detection and treatment. Detecting these mutations in a patient with family history and without any disease manifestations can allow for the prevention of any manifestations of the disease at all, which would be optimal.[11]

Since TS is very closely related to FAP and HNPCC, screening guidelines for these two diseases apply as well. The most important thing to do is recognize that there is inherited CRC in the family and that depending on the specific mutations, any of the syndromes can arise. Therefore, genetic screening can be a useful tool in the future to help prepare for the different manifestations of these various mutations, namely malignant brain tumors in the case of Turcot syndrome.[11]

Diagnosing Turcot syndrome is helpful because making correlations between brain tumors and colorectal cancer can help guide preventative action for either condition.[7] It also provides anticipatory guidance–to know and expect brain vs. colon cancer in patients that exhibit either clinical presentation; early diagnosis leads to early treatment. 

One of the most comprehensive guidelines for using a clinical presentation to diagnose patients with either TS1 or TS2 was suggested by Paraf et al. in 1997. They suggested the categorization of patients based on the presence or absence of 4 factors: (1) the phenotype of the polyps, (2) type of brain neoplasm, (3) presence of skin lesions, and (4) consanguinity.[4]

Treatment / Management

Treatment of patients with Turcot syndrome is fairly rudimentary. In the event of tumor development, surgical resection is the mainstay of treatment. In patients presenting with adenomatous, precancerous colorectal polyps, especially if genetic confirmation exists, total colectomy is the conclusive way of preventing the development of colorectal cancer. In patients that develop brain tumors, surgical resection also applies. Surgery, chemotherapy, and occasionally radiation therapy have all been used to treat patients with TS.

Otherwise, there is no way developed to reverse inherited genetic mutations. Therefore, treatment targeting Turcot syndrome is largely preventative or defensive.[13] There has been a suggestion that the development of Turcot syndrome in patients with either HNPCC or FAP may be a result of environmental factors inciting mutations in additional loci.[4] Future research may shed light on what these additional mutations may be or the environmental factors that may cause them.(A1)

Differential Diagnosis

Since Turcot syndrome can present first with either polyposis of the colon or primary brain tumor, the differential list depends upon what presents first. Polyposis of the colon can be familial adenomatous polyposis (FAP). Fewer precancerous polyps present at an early age can be hereditary nonpolyposis colorectal cancer (HNPCC). Mutations of the APC gene can sometimes present with cafe au lait spots, which may resemble the neurofibromatosis syndromes.[14] Colorectal cancer besides a brain tumor may not be the whole picture; patients may continue to develop tumors, especially hematologic malignancies, which could categorize them as having constitutional mismatch repair deficiency syndrome (CMMRDS).[5]

Prognosis

Much of the information about the prognosis of TS has been gained from analyses of reported cases. The overall survival for children with medulloblastoma alone with treatment is 52% at 10 years.[15] In patients with APC mutations or TS2, 7 of 8 patients who died in a familial analysis done by Hamilton et al. died because of a brain tumor.[2]

Since there are several deadly comorbidities in TS, the prognosis depends on the disease presentation. One case report describes a patient with glioblastoma multiforme early in life that was resected and radiated who subsequently developed adenocarcinoma of the colon. The patient survived into his 60s.[16]

Patients who develop any malignancy that metastasizes have a poor prognosis. Inherited MMR or APC mutations cause CRC 70% to 100% of the time if no treatment or prevention is applied.

Prognosis may be worse in those patients that present with both CNS tumor, specifically, glioma, and CRC. The development of glioblastoma multiforme seems to render TS patients the worst prognosis, with an average survival being 27 months.[17]

Also of note, FAP patients who undergo a prophylactic colectomy most frequently end up dying because of duodenal cancer, usually located in the peri-ampullary region of the duodenum.[18]