Case 5 -

Autoimmune Pancreatitis Type 1 IgG4-Related Cholecystitis Marco Novelli, University College London, London, United Kingdom

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Clinical History: A 12 year old boy of Arabic origin presented with a microcytic anaemia. Clinical examination revealed cutaneous stigmata of neurofibromatosis and neurological symptoms. CT scanning showed a brain tumour (subsequently found to be a glioblastoma multiforme on biopsy). Colonoscopy showed multiple colorectal tumours. Subtotal colectomy was performed. Case 5 - Figure 1 Subtotal colectomy specimen showing multiple mucosal lesions. Case 5 - Figure 2 Polyps in right colon. Case 5 - Figure 3 Two large tumours in descending colon with cross section of one tumour and corresponding photomicrograph showing moderately differentiated adenocarcinoma. Case 5 - Figure 4 Single rectosigmoid tumour Case 5 - Figure 5 Photomicrographs from rectosigmoid tumour showing moderately and poorly differentiated adenocarcinoma with evidence of mucinous differentiation. Case 5 - Figure 6 Mismatch repair immunostaining from rectosigmoid tumour showing normal staining patterns for MLH1, MSH2 and MSH6 but no staining of tumour or stromal cells for PMS2. Case 5 - Figure 7 PMS2 Case 5 - Figure 8 MSH2 Case 5 - Figure 9 MSH6 Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Subtotal colectomy: Descending colon and rectosigmoid moderately and poorly differentiated adenocarcinomas x 2. pT3 and pT4 N2 Mx, Dukes' C2. 4/107 nodes contained metastatic adenocarcinoma. Multiple tubular adenomas with low + focal high grade dysplasia. Mismatch repair staining on the rectosigmoid tumour shows normal staining for MLH1, MSH2 and MSH6 but no staining (in tumour and background normal stromal cells) for PMS2 Differential Diagnoses: This child obviously has a cancer syndrome of some sort (Glioblastoma multiforme, 2 colorectal cancers and multiple adenomatous polyps). The following syndromes should/could be considered: Turcot syndrome Familial adenomatous Polyposis MAP (MYH-associated polyposis) Constitutional mismatch repair deficiency syndrome Final Diagnosis: Constitutinal mismatch repair deficiency syndrome (also known as "Mismatch repair cancer Syndrome" and "Childhood cancer syndrome". Case Discussion: The presentation of multiple separate malignant tumours in a child should immediately raise the possibility of a genetic cancer syndrome. In this case the combination of malignant brain and intestinal tumours has traditionally been labelled Turcot syndrome. More recent research would suggest that Turcot syndrome encompasses both familial adenomatous polyposis with brain tumours (Paraf 1997, Attard TM 2007) and constitutional mismatch repair deficiency syndrome (CMMR-D). In both these syndromes patients may develop colorectal polyposis in childhood and brain tumours although in this context the development of a malignant colorectal tumour in childhood would strongly favour CMMR-D. The presence of cutaneous stigmata of neurofibromatosis (in particular café-au-lait spots) is a very typical feature of CMMR-D. Constitutional mismatch repair deficiency syndrome is due to germline biallelic mutations in a single mismatch repair protein (MLH1, PMS2, MSH2 or MSH6). Family history is particularly important when assessing such patients. FAP will typically show an autosomal dominant pattern of inheritance (although MYH-associated polyposis may mimic FAP and is inherited as an autosomal recessive). CMMR-D is inherited in an autosomal recessive fashion. Autosomal recessive inheritance is generally more difficult to pick up clinically as in most cases there is unlikely to be a history of disease in older generations and with modern small families the chances of having an affected sibling (1 in 4) are reduced. However, ethnicity provides a useful clue to the diagnosis of CMMR-D as the mutations causing this syndrome are prevalent at low incidence in the general population and so cases of CMMR-D most frequently occur in populations where there are high rates of consanguineous marriage (e.g. patients of Arabic and Pakistani ancestory). Congenital mismatch repair syndrome patients typically present in childhood with a combination of: Café-au-lait spots Brain tumours (Medulloblastoma, gliomas/glioblastomas, SPNET) Haematological tumours (AML, T-cell lymphomas) Colorectal tumour (adenomas and carcinomas) The diagnosis of CMMR-D relies on a high index of clinical suspicion followed by immunostaining for mismatch repair (MMR) proteins (and/or microsatellite instability studies) and germline mismatch repair gene mutation analysis. It should be noted that neither immunostaining for mismatch repair proteins or microsatellite instability studies are abnormal in every case, with some syndromic patients harbouring biallelic germline mutations but showing normal MMR immunostaining and normal microsatellite instability studies. In affected individuals MMR immunostaining typically shows complete loss of staining in both tumour cells and normal epithelial/stromal cells for one or a pair of mismatch repair proteins (MLH1/PMS2, PMS2, MSH2/MSH6 or MSH6). Without a high index of suspicion this can easily be interpreted as a technical failure of staining. The clue to interpreting this immunostaining lies in the fact that at least some of the other mismatch repair proteins will stain normally. Conclusion(s): 1. Consider constitutinal mismatch repair deficiency syndrome in children/young adults presenting with colorectal polyposis. 2. Complete loss of staining for a mismatch repair protein (within both tumour cells and normal epithelial/stromal cells) is usually due to technical problems with immunostaining. However, in children/young adults if repeated staining for one or a pair of proteins is negative, and the other mismatch repair proteins stain normally, consider the possibility of constitutinal mismatch repair deficiency syndrome. References: General reference articles/sites #276300 MISMATCH REPAIR CANCER SYNDROME http://omim.org/entry/276300 Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Wimmer K, Etzler J. Hum Genet. 2008 Sep;124(2):105-22. Epub 2008 Aug 18. Review. Constitutional mismatch repair-deficiency syndrome. Wimmer K, Kratz CP. Haematologica. 2010 May;95(5):699-701. Durno CA, Holter S, Sherman PM, Gallinger S. The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations. Am J Gastroenterol. 2010 Nov;105(11):2449-56. Epub 2010 Jun 8. Specific references Attard TM, Giglio P, Koppula S, Snyder C, Lynch HT. Brain tumors in individuals with familial adenomatous polyposis: a cancer registry experience and pooled case report analysis. Cancer. 2007 Feb 15;109(4):761-6. Paraf F, Jothy S, Van Meir EG. Brain tumor-polyposis syndrome: two genetic diseases? J Clin Oncol. 1997 Jul;15(7):2744-58.