—  SPECIALTY CONFERENCE  —

PEDIATRIC PATHOLOGY

Case 1 - Turcot Syndrome (medulloblastoma with familial adenomatous polyposis)

Stephen J. Qualman, M.D.
Children's Hospital
Columbus, Ohio

Clinical History
A nine-year-old girl who presented with a mass in the posterior cranial fossa underwent suboccipital decompression and C1 laminectomy with tumor resection. Rectal bleeding developed after surgical resection of the tumor and chemotherapy, five-and-a-half months after initial brain tumor biopsy. Two colon biopsies were collected during proctoscopy, which revealed a friable, granular and exudative mucosa.

Resection of the posterior fossa tumor yielded a total of 1 X 1 X 0.5 cm of tissue which was diagnosed as medulloblastoma ("primitive neuroectodermal tumor"). One of the two biopsies taken from the proctoscopy was found to be normal; the other was markedly abnormal. Much of the glandular epithelium was denuded and the glands were cystically dilated. Neutrophils were present in the glands and interstitium. The remaining epithelium showed cytologic atypia thought consistent with attempted regeneration. The clinical impression at this point was one of possible pseudomembranous colitis. Stools were sent for bacterial and viral culture. The patient was maintained on Flagyl therapy.

Nine years later, the patient presented again with rectal bleeding (hemoglobin decreased to 8 g/DL) with history of intervening stroke and recurrent bleeding thought secondary to hemorrhoids. Upper endoscopy and colonoscopy now revealed multiple nodules in the stomach, duodenum and colon. Polypectomies from the upper endoscopy and colonoscopy revealed adenomatous polyps in the duodenum and ascending colon (part C) with the latter displaying focal high grade dysplasia. The gastric biopsies (part A) showed polyps with a hamartomatous mixture of gastric fundic gland cells and mucinous columnar gland cells with cystic change.

Slides  (Click to enlarge)


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Medulloblastoma, cerebellum Cystic glandular change with atypia and inflammation, colon Fundic gland polyp Tubular adenoma with focal high-grade dysplasia

Differential Diagnosis
This case illustrates two differential diagnostic considerations which offer valuable learning experiences to both the general and pediatric pathologist. The first is the differential diagnosis of cystic glandular dilation with acute inflammation in an immunocompromised brain tumor patient. One obvious consideration, infectious colitis, was ruled out. However, another more obscure relationship, that of a coincidental brain tumor and intestinal polyposis, was not considered at the time of initial gastrointestinal biopsy (biopsies were not multifocal or widespread as to site), nor in the ensuing nine years when the patient's rectal bleeding was ascribed to hemorrhoids without re-biopsy. Initial biopsy of the upper gastrointestinal tract might also have helped clarify this diagnosis. The patient actually has a combination of Familial Adenomatous Polyposis (FAP) with medulloblastoma; a variant of so-called Turcot Syndrome.

Turcot's Syndrome is defined by development of colorectal carcinomas and adenomas and primary central nervous system tumors. In one series, two-thirds of the brain tumors seen were medulloblastomas1  but other studies2  report the occurrence as closer to one-third. Medulloblastomas tend to arise in younger patients and are usually associated with familial adenomatous polyposis (FAP). Adenomas usually develop in the second decade of life. It is typical for hundreds or thousands of polyps to develop. Nearly all cases will eventually progress into colon cancer, most by the age of 40. Adenomas also develop in the upper GI tract with nearly all patients developing duodenal adenomas sometime in their life. Fundic gland polyps are also characteristic of FAP.

Eighty percent (80%) of FAP cases have a germ-line mutation, usually a truncation, in the adenomatous polyposis coli (APC) gene3  located on chromosome 5q21-22. The inheritance pattern is autosomal dominant but 30% of cases appear tomr  There is genetic evidence that Turcot Syndrome is not allelic to FAP.5 

Nearly all of the residual Turcot syndrome cases are comprised of hereditary non-polyposis colon cancer (HNPCC) and glioblastomas or astrocytomas. HNPCC is also autosomal dominant arising from mutations in one of five DNA mismatch repair genes. The majority of HNPCC cases (50-70%) have mutations in hMSH2 and hMLH1, but mutations also occur in hPMS1, hPMS2 and hMSH6.1  Mutations in hPMS2 or hMLH1 have been noted in glioblastomas of two Turcot cases6  and hMSH2 mutations in all three Turcot cases7  studied by another group. Ninety-five percent (95%) of HNPCC cases have microsatellite instability caused by errors in mismatch repair as opposed to 15% amongst unselected colon cancers. Microsatellite instability is also exhibited by gliomas in Turcot's syndrome.6  Women with HNPCC, as determined by mutations in mismatch repair genes, also have a higher chance of developing endometrial cancer.

At least 95 cases of Turcot's Syndrome have been reported in the literature2  with associated brain tumors including: 31 cases with glioblastoma, 31 cases with astrocytoma and 27 cases with medulloblastoma. Dividing this syndrome in two components according to the presence of FAP versus HNPCC and the type of brain tumors leaves one with the intriguing observation8  that the original cases described by Turcot9  were siblings, both with polyps, one with glioblastoma and the other a medulloblastoma. New candidate genes to consider in Turcot syndrome include the DMBT1 gene10  or the PTC gene.11 

Diagnosis
Turcot Syndrome (medulloblastoma with familial adenomatous polyposis)

References

  1. Hampel H, and Peltomaki P. Hereditary Colorectal Cancer: Risk Assessment and Management. Clin Genet 2000;58:89-97.
  2. Hamada H, Kurimoto M, Endo S, Ogiichi T, Akai T, Takaku A. Turcot's syndrome presenting with medulloblastoma and familiar adenomatous polyposis: a case report and review of the literature. Acta Neurochir (Wein) 1998;140:631-632.
  3. Powell SM, Petersen GM, Krush AJ, et al. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 1993;329:1982-1987.
  4. Petersen GM. Genetic testing and counseling in familial adenomatous polyposis. Oncology (Huntingt) 1996;10:89-94.
  5. Tops CMJ, Vasen HFA, van Berge Henegouwen G, Simoons PP, van de Klift HM, van Leeuwen ISJ, Breukel C, Fodde R, den Hartog Jager FCA, Nagengast FM, Griffioen G, Khan PM. Genetic evidence that Turcot syndrome is not allelic to familial adenomatous polyposis. Am J Med Gen 1992;43:888-893.
  6. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, Burger PC, Wood PA, Taqi F, Booker SV, Petersen GM, Offerhaus GJA, Tersmette AC, Giardiello FM, Vogelstein B, Kinzler, KW. The Molecular Basis of Turcot's Syndrome. N Engl J Med 1995;332:839-847.
  7. Chan TL, Yuen ST, Chung LP, Ho JWC, Kwan K, Fan YW, Chan ASY, Leung SY. Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome. Genes, Chromosomes & Cancer 1999;25:75-81.
  8. Van Meir EG. Letter in Int J Cancer 1998;75:162-164.
  9. Turcot J, Després, J-P, Pierre FS. Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum, 1959;2:465-468.
  10. Mollenhauer J, Wiemann S, Scheurlen W, Korn B, Hayashi Y, Wilgenbus KK, von Deimling A, Poustka A, DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3-26.1 is deleted in malignant brain tumors. Nature Genet 1997;17:32-39.
  11. Hahn H, et al. Mutations in the human homolog of Drosophila patched in the nevoid basal-cell-carcinoma syndrome. Cell 1997;85:841-851.