Case 5 -
Autoimmune Pancreatitis Type 1 IgG4-Related Cholecystitis
Marco Novelli, University College London, London, United Kingdom
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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.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
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
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
Constitutinal mismatch repair deficiency syndrome (also known as "Mismatch repair
cancer Syndrome" and "Childhood cancer syndrome".
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
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
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.
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
Paraf F, Jothy S, Van Meir EG. Brain tumor-polyposis syndrome: two genetic diseases? J Clin Oncol.