Case Study September 2010 Diagnoses
Diagnosis: glioblastoma multiforme.
Genetic testing revealed that the patient carried the familial Lynch syndrome-associated germline mismatch repair gene mutation. In addition, immunohistochemistry of the brain tumour showed a lack of staining of the corresponding mismatch repair protein.
Diagnosis: glioblastoma multiforme in Lynch syndrome (variant Turcot’s syndrome).
Turcot’s syndrome is historically characterized by the concurrence of primary brain tumours and colorectal adenomas and/or cancers.1 As reviewed by Hamilton et al. (1995), Turcot's syndrome can be due to familial adenomatous polyposis (FAP), with germline mutations in the adenomatous polyposis coli (APC) gene, and Lynch syndrome (previously designated as hereditary nonpolyposis colorectal carcinoma (HNPCC)), with germline mutations in DNA mismatch repair genes.2;3 In addition, the combination of brain tumours and colorectal neoplasms can be due to bi-allelic mutations in mismatch repair genes, a syndrome called constitutional mismatch repair deficiency. In fact, the family described by Turcot et al. had bi-allelic PMS2 mutations.4
Glioblastoma cases in Turcot’s syndrome are usually associated with Lynch variant, whereas FAP is associated with medulloblastoma.3 Our patient had Lynch syndrome with a brain tumour as the extracolonic manifestation. The main cancer associated with Lynch syndrome is colorectal cancer. In addition, approximately 50% of female Lynch syndrome patients will manifest endometrial cancer. Furthermore, patients with Lynch syndrome have a higher risk for other extracolonic cancers, such as cancer of ovaries, stomach, small bowel, pancreas, hepatobiliary tract and upper genitourinary tract cancer and as in the case presented brain tumours.5
The relative risk of glioma for patients with Lynch syndrome is 4,3-6, and usually have tumours at a younger age.6 It has been suggested that the underlying germ-line genetic alteration favourably influences the prognosis of patients compared to GBM patients without this mutation3, although the alkylating agent temozolomide might be less effective as the effect of temozolomide is dependent on an intact mismatch repair system.
Our patient underwent resection, postoperative chemo-irradiation with temozolomide, and PCV chemotherapy after tumour recurrence. He died approximately 15 months after histological diagnosis, which is not significantly longer than the median survival for GBM patients in the chemo-irradiation era.
1. TURCOT J, DESPRES JP, ST PF (1959), Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases, Dis.Colon Rectum 2: 465-468
2. Grips E, Wentzensen N, Sutter C, Sedlaczek O, Gebert J, Weigel R, Schwartz A, von Knebel-Doeberitz M, Hennerici M (2002), [Glioblastoma multiforme as a manifestation of Turcot syndrome], Nervenarzt 73: 177-182
3. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, . (1995), The molecular basis of Turcot's syndrome, N.Engl.J.Med. 332: 839-847
4. De Vos, M, Hayward BE, Picton S, Sheridan E, Bonthron DT (2004), Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome, Am.J.Hum.Genet. 74: 954-964
5. Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR (2009), Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications, Clin.Genet. 76: 1-18
6. Vasen HF, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG, Griffioen G, Nagengast FM, Meijers-Heijboer EH, Bertario L, Varesco L, Bisgaard ML, Mohr J, Fodde R, Khan PM (1996), Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis, Gastroenterology 110: 1020-1027
This case study was provided by:Dhr Dr J.C. Reijneveld, neuroloog