Eur J Pediatr (2005) 164: 306–310 DOI 10.1007/s00431-004-1602-y
O R I GI N A L P A P E R
Silvija Jerkic Æ Hendrik Rosewich Æ Jens-Gerd Scharf Christina Perske Æ Laszlo Fu¨zesi Ekkehard Wilichowski Æ Jutta Ga¨rtner
Colorectal cancer in two pre-teenage siblings with familial adenomatous polyposis Received: 19 August 2004 / Revised: 10 November 2004 / Accepted: 12 November 2004 / Published online: 22 February 2005 Ó Springer-Verlag 2005
Abstract Familial adenomatous polyposis (FAP) is an autosomal dominant disorder that characteristically presents with colon cancer in early adult life. We describe a Pakistani FAP family in which two sons had an unusually early manifestation of colorectal cancer. The index patient presented at 11 years of age with abdominal pain, rectal bleeding and iron deficiency anaemia. Colonoscopy showed that the colon was carpeted with a myriad of polyps. Oesophago-gastric and duodenal endoscopy revealed that polyps had also developed in the duodenum. Multiple biopsies indicated neoplastic lesions. The patient underwent a proctocolectomy and endoscopic duodenal mucosectomy. The diagnosis of an adenocarcinoma of the colon and further adenomatous polyps with low-grade and high-grade dysplasia was confirmed by histology. Family screening including a blood test for anaemia and bowel examination revealed that his 12-year-old brother was also affected. Conclusion: Children with familial adenomatous polyposis are at risk for colon cancer and emphasise the need for early tumour recognition. Gastrointestinal symptoms in children should be thoroughly evaluated and standard screening for colonic polyposis should be performed in all individuals with a positive family history and/or known
S. Jerkic Æ H. Rosewich Æ E. Wilichowski Æ J. Ga¨rtner (&) Department of Paediatrics and Paediatric Neurology, Georg August University, Faculty of Medicine, Robert-Koch-Strasse 40, 37075 Go¨ttingen, Germany E-mail:
[email protected] Tel.: +49-551-398035 Fax: +49-551-396252 J.-G. Scharf Department of Gastroenterology and Endocrinology, Georg August University, Faculty of Medicine, Go¨ttingen, Germany C. Perske Æ L. Fu¨zesi Department of Gastroenteropathology, Georg August University, Faculty of Medicine, Go¨ttingen, Germany
mutations in cancer-associated genes, particularly in children who are under 10 years of age. Keywords Abdominal pain Æ Adenomatous polyposis Æ Anaemia Æ Colon cancer Æ Rectal bleeding Abbreviations APC: adenomatous polyposis coli Æ FAP: familial adenomatous polyposis
Introduction Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder caused by mutations in the adenomatous polyposis coli (APC) gene [7, 8,10]. An autosomal recessive form of FAP, associated with mutations in the base excision repair gene MYH, has also been recognised [1]. Of individuals with FAP, 7% develop colorectal cancer by age 21 years, secondary to adenomatous polyps of the colon and rectum (http:// www.Geneclinics.org/profiles/fap/details.htlm). These polyps can also develop in the upper gastrointestinal tract. In children and very young adults, FAP can occur without symptoms or manifest with recurrent abdominal pain. In adults, initial clinical symptoms are usually those of malignancy such as weight loss, bowel obstruction and bloody diarrhoea. Extra-intestinal manifestations include hypertrophy of retinal pigmented epithelium, osteomata and cutaneous abnormalities such as epidermoid inclusion cysts, fibromas and increased skin pigmentation [6]. Associated malignancies outside the gastrointestinal tract are desmoid tumours, thyroid carcinoma, hepatoblastoma, medulloblastomas and astrocytomas. For individuals at risk, flexible sigmoidoscopy is currently recommended every 2 years after 12 years of age [8]. Here we report on two brothers with a familiar adenomatous polyposis syndrome who presented an unusually early manifestation of FAP and were diagnosed with a colonic adenocarcinoma at the ages of 11 and 12 years, respectively.
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Case report An 11-year-old boy of Pakistani origin went to see his general paediatrician because of abdominal pain and bright red blood on the surface of normal stool. Family history was inconspicuous and the symptoms were considered as the consequence of an anal fissure without further investigations. During the following weeks, the boy complained of recurrent peri-umbilical pain and abdominal cramps especially after meals and while exercising. Additional symptoms, such as vomiting, diarrhoea, and constipation as well as further rectal bleeding did not occur. Because of ongoing abdominal pain, a blood test was taken that showed an anaemia with a haemoglobin concentration of 7.9 g/dl and white blood cell count of 15.600/ll. The boy was referred to our hospital for further investigations. On admission, the patient was in good physical shape. His weight was 38.3 kg (50th percentile) and his height 154.0 cm (75th percentile). Several spots of hyperpigmentation and hypopigmentation as well as cafe´au-lait spots were scattered throughout his skin, but did not appear on the lips and buccal mucosa (Fig. 1). His face was pale. Cardiac auscultation revealed a 2/6 systolic murmur. Bowel sounds were obvious; the abdomen was distended and tender on pressure. A mass was not palpable; liver and spleen were not enlarged. Laboratory investigations revealed the following: a decreased haemoglobin concentration (8 g/dl), a haematocrit of 23.8% and a mean corpuscular volume of 51 fl. White and red blood cell counts as well as leukocyte differential were normal. Iron studies showed a decreased serum ferritin concentration of 3 lg/l, a low serum iron concentration of 3.8 lmol/l and a normal transferrin saturation of 302 mg/dl. Other laboratory
Fig. 1 Skin abnormalities associated with FAP. The 11-year-old patient has increased skin pigmentation as well as hypopigmentation and cafe´-au-lait spots
blood tests including electrolytes, urea nitrogen, uric acid, creatinine, ALT, AST, c-glutamyltranspeptidase, bilirubin, LDH, glucose, albumin, total protein, coagulation factors, prothrombin time, partial thromboplastin time, amylase and lipase were normal. Occult blood testing in stool was positive; stool cultures and examinations for worm ova and parasites did not reveal any abnormalities. The tumour markers CEA and CA 19-9 were negative. The abdominal ultrasound scan was normal. Gastric and duodenal endoscopy including biopsies was performed and showed a broad polyp in the pars descendens of the duodenum (Fig. 2). Fibre-optic colonoscopy including biopsies revealed a single polyp in the rectum, multiple polyps in the sigma and colon descendens and in particular, one polyp in the distal sigma at 34 cm ad ano that was highly suggestive of a cancerous lesion. Histology of this sigma polyp confirmed the diagnosis of colon cancer and showed a moderately differentiated adenocarcinoma classified as WHO grade II. High resolution computed tomography of the abdomen followed to assess the size and invasiveness of the adenocarcinoma and the status of the regional lymph nodes and showed mural thickening and two enlarged lymph nodes adjacent to the tumour. The polyp at the Vater papilla as well as further polyps in the duodenum, rectum and anus were revealed as neoplastic low-grade tubulovillous adenomas. One polyp in the caecum was a neoplastic low-grade tubulous adenoma. Gastric biopsies revealed a non-malignant chronic non-active gastritis. As clinical and endoscopic results were consistent with APC, we initiated further investigations to exclude extracolonic manifestations. Fundoscopic examination of the eyes was normal and did not show congenital hypertrophy of the retinal pigment epithelium. Magnetic resonance imaging of the brain, chest and sinus X-ray films as well as bone scans did not reveal FAP associated malignancies or metastases. An endoscopic duodenal polypectomy was performed followed by proctocolectomy (Fig. 3). He was classified as T3b N2 M0 R0 and was given chemotherapy with 5-fluorouracil, folic acid and a platinum derivative. He is now treated with a COX-2 inhibitor to prevent formation of new polyps. Genetic analyses did not reveal mutations in the APC gene. Although the family history of this patient was noninformative for FAP, we went on to screen the family. The parents and the three brothers were in good physical condition and there was no history of abdominal pain, gastrointestinal bleeding or malabsorption. In his 1-year-old brother, 6-year-old brother, his father and mother, anaemia and iron deficiency could be excluded. Occult blood testing in stool was negative. Colonoscopy in the 6-year-old brother, father and mother revealed neither intestinal lesions nor polyps. In contrast, physical examination of the oldest brother, a 12-year-old boy, disclosed skin abnormalities comparable to those of the index patient. Laboratory investigations revealed an anaemia with a decrease of
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Fig. 2 Colonoscopy in the 11-year-old boy revealed a polyp at the Vater papilla (a) that was removed by endoscopic duodenal mucosectomy (b)
haemoglobin concentration of 8.0 g/dl, a haematocrit of 27,3% and a mean corpuscular volume of 53 fl. Iron studies showed a decreased serum ferritin concentration of 4 lg/l, a normal serum iron concentration and an increased transferrin saturation of 443 mg/dl. Occult blood testing in stool was positive. Other laboratory blood tests were normal including negative tumour markers for CA 19-9 and CEA. Upper gastric and duodenal endoscopy including biopsies was performed and identified two polyps in the duodenum. Fibre-optic colonoscopy including biopsies revealed multiple polyps from the colon ascendens to the
rectum. Several of these polyps were up to 5 cm in length and highly suggestive of a cancerous lesion. Histology confirmed the diagnosis of colon cancer and showed a poorly differentiated adenocarcinoma located 25 cm ad ano classified as WHO grade III, a moderately differentiated adenocarcinoma in the colon ascendens classified as WHO grade II and two carcinomas in situ in the colon descendens and sigma. One duodenal polyp and one in the colon descendens were revealed as neoplastic high-grade tubulous adenomas; a further polyp in the colon ascendens was a neoplastic high-grade tubulovillous adenoma. Several colorectal polyps and one in the duodenom were neoplastic low-grade tubulous adenomas. Gastric biopsies revealed a non-malignant chronic non-active gastritis without malignancy. High resolution computed tomography of the abdomen showed lesions compatible with polyps scattered from the rectum to the colon ascendens, mural thickening at the left colon flexur and a stenosis at the transition of the colon descendens to the sigma. There was no pathological enlargement of regional lymph nodes. Further diagnostic procedures did not reveal any extra-intestinal manifestations. The patient was treated by an endoscopic duodenal mucosectomy followed by proctocolectomy. He was classified as T3b N0 M0 R0 and will thus not receive chemotherapy. Now he is treated with a COX-2 inhibitor to prevent formation of new polyps.
Discussion
Fig. 3 Colon segments of the 11-year-old patient removed by proctocolectomy. They display multiple adenomatous polyps and a partially ulcerated adenocarcinoma (T3N2) of up to 5.8 cm in length ( arrow)
Colorectal cancer is one of the most frequent cancers in men and women with a lifetime risk in the general population of 5%–6% [8,15]. Sporadic forms account for more than 90% of all patients with colorectal cancer whereas only approximately 10% are inherited. Colorectal cancer is very rare in the paediatric age group; nevertheless, it does occur and is then almost always associated with a familial cancer syndrome.
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The hereditary colorectal cancer syndromes are characterised by an increased frequency of adenocarcinoma of the colon with an early age of onset. Most of them follow an autosomal dominant mode of inheritance. There are two major forms, FAP, also classified as adenomatous polyposis and hamartomatous polyposis syndrome that makes up approximately 1% of all annual colorectal cancers and the hereditary non-polyposis colorectal cancer syndromes, also called the Lynch or family cancer syndrome that account for 5%–10% [8,11]. Gardner syndrome, a colonic polyposis with extra-intestinal tumours, especially osteomas, and a rather characteristic retinal lesion, is a phenotypic variant of FAP [5,9]. Children with a family history of colorectal cancer and/or FAP are at high risk to develop multiple colorectal adenomas at an early age with malignant malformation in most patients. In classical FAP, colorectal adenomatous polyps begin to appear at an average age of 16 years (http://www.Geneclinics.org/profiles/ fap/details.htlm). By the age of 35, 95% of individuals have polyps. Without colectomy, colon cancer is inevitable. Of all patients with FAP, 7% develop colon cancer by 21 years of age. However, like our cases, there are also young children who present with a primary adenocarcinoma of the colon. Besides the early onset cases described here, Eccles and coworkers [3] reported a family where the index case was diagnosed with FAP at 7 years of age and with colon cancer at 9 years of age. Children with colorectal cancer usually have a far more advanced stage of disease at the time of recognition when compared to the general population. One reason for the delay of diagnosis is almost certainly the fact that physicians do not consider the possibility of malignancy in children with intestinal symptoms. Mutations in the APC gene are an initiating event for both familial and sporadic colorectal tumourigenesis [10]. APC mutations in the first or last third part of the gene are associated with an attenuated polyposis with a late onset, whereas most APC mutations cluster in the central region of the gene and correlate with a severe phenotype of numerous polyps at a young age and/or with additional extracolonic manifestations [4, 12,13]. Mutations in the APC gene seem to play a major role in early development of colorectal neoplasm and more than 60% of colorectal carcinomas and adenomas analysed contained a mutated APC gene [10]. Regarding that so far these two boys are the only affected cases in their family and that the parents do not seem to have the disease, an autosomal dominant form of FAP in this family is unlikely. Molecular analyses of the APC gene did not reveal a mutation. Moreover, the family history is consistent with an autosomal recessive inheritance of FAP. One of these forms is the recently described MYHassociated polyposis [1,14]. It is a FAP characterised by multiple colorectal adenomas and a recessive pattern of inheritance. Patients with attenuated and classical polyposis, but also those with young onset colorectal cancer without polyps do have mutations in the MYH gene, a base excision repair gene. The current screening
guidelines for FAP and also for other hereditary colorectal cancer syndromes are not consistent [8,15]. Regarding FAP, screening for colonic polyposis is usually recommended for all individuals who have one or more first-degree relatives with colorectal cancer and/or an identified mutation in the APC gene. Flexible sigmoidoscopy is the preferred screening procedure and should begin between the ages of 10 to 12 years. Surveillance for gastric, duodenal, and peri-ampullary polyps should be added when the diagnosis of colonic polyposis is made. Since COX-2 inhibitor seems to reduce the number of colorectal polyps, it might be considered as an adjunct to endoscopic surveillance [2]. These two cases emphasise the fact that children with an inherited colorectal cancer syndrome are indeed at risk to develop colorectal cancer in pre-teenage years. Although iron deficiency anaemia due to malnutrition, chronic infections and benign gastrointestinal lesions are more frequent differential diagnoses in children with abdominal pain and anaemia than FAP, physicians should be aware of these familial syndromes and thoroughly evaluate these symptoms in children, even if their family history is non-informative. After confirming the diagnosis of FAP in an index patient, it is important to obtain a complete family history and provide effective clinical and genetic screening as well as genetic counselling to identify all family members at risk. All paediatric FAP patients identified should undergo a yearly upper gastrointestinal screening and surveillance endoscopy, irrespective of age and referrable symptoms. Depending on the extent of polyposis, prophylactic colectomy should be discussed to prevent colorectal cancer. Acknowledgements We thank Waltraut Friedl, Institute of Human Genetics, University of Bonn for APC gene analyses. We thank Karl-Michael Doering, General Paediatrician, Go¨ttingen for his continuous support in taking care of the affected family.
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