CLINICAL AND MORPHOLOGICAL RESEARCH
IN FAMILIAL ADENOMATOUS POLYPOSIS
G Stoyanova*, D Metodiev**, Ts Boshnakova**
* Department of Gastroenterology, Fifth City Hospital, Sofia
** City Clinic Oncological Centre, Sofia
St Kliment Ohridsky Sofia University, Sofia
Correspondence:
*
Department of Gastroenterology – Fifth City Hospital – Sofia, Bulgaria
1233 Sofia, bul Stoletov 67a, Bulgaria
Abstract:
The authors consider in contemporary aspect the relationship between hereditary and colorectal cancer. Clinical cases of familial adenomatous polyposis(FAP) are presented, which are diagnostically detected and treated by the team of Fifth City Hospital, Sofia, over a period of three years (2013-2015). Review of the literature on the familial adenomatous polyposis and also on a new form MYH associated polyposis (MAP) is made. A case of Gardner's syndrome as a phenotype variant of multiple polyposis coli is described.
The results and exposed literature review disclose a new insight into the diagnosis and complex therapeutic approach in patients with familial adenomatous polyposis, its geno- and phenotypic forms.
Key words: familial adenomatous polyposis, Gardner's syndrome, hereditary, colorectal cancer.
Introduction
A family history of colorectal cancer is found in 15% of all patients15. Among the well-described types of cancer, hereditary nonpolyposis colon cancer (HNPCC) is prominent, also known as Lynch Syndrome, found in 1 to 3% of all cases. In the second place are the forms of familial adenomatous polyposis (FAP), representing 1% of all colorectal neoplasia14, 15. The assumption is that all patients with FAP will develop carcinoma in the fifth or the sixth decade of life, unless they are diagnosed and treated in the early stage8.
FAP is an autosomal dominant genetic syndrome with extracolonic manifestations, first described in 1721 by Menzelio4, 8, 11. The FAP frequency varies to one in every 5,000 to 10,000 live births8, 14. The disease is characterised by a germline mutation of the tumour suppressor gene APC (adenomatous polyposis coli) localised on 5q21-q22 n. The APC gene is responsible for cell growth and for certain regulatory mechanisms of apoptosis4. The genetic APC mutations were studied in detail in 1991. Several isoforms of the multifunctional APC protein have been established, regulating the oncosuppression and chromosome stability phases. The impact on the genetic code of the APC gene leads to deactivation, incorrect chromosome segregation and aberrant mitosis9. In 2002 another polyposis gene was identified, known as the MUTYH (mutY homolog) gene with biallelic mutations present. They cause an autosomal-recessive inheritance pattern, known as MUTYH-associated polyposis (MAP) 9.
The development of adenomas in FAP precedes the clinical symptoms and thus the disease remains undiagnosed for a long time. The analysis of one of the oldest European FAP registries, the Danish one, shows that establishment of the disease occurs in mid-age , i.e. almost 19 years after the beginning of the disease process6, 8. The explanation lies in the screening programmes’ discrepancies, difficult access to health care, and neglect of the disease by doctors and patients alike.
A detailed study of familial polyposis must be preceded by good knowledge of its genotypic and phenotypic forms. According to the number of polyps and the age, two major phenotypic groups of FAP are described:
1. Classical form: characterised by hundreds to thousands adenomatous polyps in the colorectum and the appearance of colorectal cancer in the mean age of 25 to 40;
2. FAP with minimal affect with a reduced number of polyps (10–100), localised mainly in the right colon, in older age and with a lower risk of carcinoma (below 70%)8, 9, 10.
Gardner’s syndrome is also a phenotypic variant of FAP.
There is also a second independent form of adenomatous polyposis with a different genotype. It is related to biallelic mutations of the MUTYH gene and is known as MUTYH adenomatous polyposis or MAP. It is described for the first time by Al-Tassan et al in 2002 in a family in Great Britain9. This form has an autosomal recessive inheritance pattern, it is characterised by a greater clinical variability and a smaller number of polypous formations (up to 100). The definitive importance of the MUTYH gene site must be underlined. It is localised on 1p34,3–1p32,1 and is part of the BER (base excision repair) system, which is responsible for protecting cells against the mutagenic effects of aerobic metabolism12. The biallelic mutation of the MUTYH gene in MAP leads to unstable protection, incorrect decoding, mutant replication and later on activates oncogenesis. There are many academic debates regarding MAP and the risk of colorectal carcinoma. It is accepted that serrated adenomas and colorectal neoplasia are found more often in MAP, which makes genetic over-screening of these patients mandatory5, 7, 9.
Finally, there is a third form of APC/MUTYH: negative cases12. Typical for this form are the lower percentage of extracolonic manifestations, later age of diagnosing (over 42) and greater frequency of extraintestinal tumours (stomach, liver and thyroid). Some authors believe that the frequency of the latter form reaches up to 20% of the classical FAP patients and for the time being it is considered a form of undefined APC/MUTYH mutations12.
Purpose
The aim of this paper is to present and discuss several cases of familial adenomatous polyposis, which have been monitored, diagnosed and operationally treated by a team of the Fifth City Hospital in Sofia in 2012-15.
Material and Methods
Five cases of FAP have been monitored, with a median age of 40 years. The males/females ratio is 2.5 to 1 and all patients have a family history of colorectal cancer and polyposis. In the study the following methods were used: endoscopy, computed tomography, biopsy and biochemical testing (CEA and CA 19-9). After a clinical analysis of the obtained data relevant operating techniques were applied.
Results and discussion
The main clinical symptoms are dyspeptic pain, defecation disorders with pathological additions, relapse, normochromic anaemia with mild iron and folic deficiency, as well as presentation of astheno-adynamic and consumptive syndromes. In two patients diffuse hyperplastic and tubular adenomas of the bowel, colorectal adenocarcinoma, as well as hyperplastic polyps of the duodenum and the jejunum were found. In one of the cases the colon was totally involved in the polyposis process, combined with rectal haemorrhage and persistent astheno-adynamic and anaemic syndromes. In two patients serrated adenomas with low-grade dysplasia and affection of the colon were described. In one of them was diagnosed and rectal adenocarcinoma. Adjunctive finding in a 36-year-old patient was an intraabdominal fibromatosis (desmoid tumour) was described and in another there were clinical data of a neoplastic process in the brain.
These pathological changes are presented in the following table:
Table 1: Clinical and pathological changes in familial multiple polyposis
Total number of patients / Mean age / Males/females ratio / Colorectal cancer / Serrated polyps / Extracolonic manifestations5 / 40 / 2.5/1.0 / 3 / 2 / 1 – intraabdominal fibromatosis (desmoid tumour)
1 – polyps in the duodenum and the jejunum
1 – brain tumour
Each of the cases is specific and it was studied in detail, accompanied by a genetic analysis and thoroughly followed-up. The clinical history of a 36-year-old male (Case History No 3722/2015) with familial adenomatous polyposis is individually presented. The patient was admitted for the first time in the Second Surgical Department of the hospital in December 2013 with abdominal pain and subileus indications. There was a family history: the mother has died at the age of 36 from colon cancer. The proctoscopy has indicated a voluminous rectal process with a functionally significant stenosis and a tumor infiltration of adjacent tissue. The man was operated on and a diffuse colon polyposis with a moderately differentiated adenocarcinoma (G2) of the rectum was found. The polypous formations were manifested by multiple tubular adenomas, some with low-grade, and others with high-grade epithelial dysplasia. During the postoperative monitoring, on the sixth month after the operation a complete endoscopic check-up (gastroscopy, enteroscopy and colonoscopy), CAT scan and tumour markers were done. Single polypoid formations in the duodenum and the jejunum were found, which were endoscopically removed and histologically confirmed as hyperplastic polyps, without indications of dysplasia. One year after the operation weight reduction, epigastric pain and pain in the right hypochondrium were observed in patient. Focal liver lesions were instrumentally (CAT scan) diagnosed, as well as an adjacent tumour infiltration in the right hypochondrium. The colonoscopy found extralumenal extrusion in the ileocecal area and polypous changes into the colon. A surgical therapy was performed with the following morphological findings: moderately differentiated adenocarcinoma of the cecum, grown through the full depth of the wall, with a macrometastasis in one lymph node (out of 12 examined) and defined as pT3 pN1 M1 G2 stage 4 (Figures 1 and 2).
Figure 1. Moderately differentiated adenocarcinoma intestinal type
Figure 2. metastasis of intestinal type (with the presence of the so-called "Dirty necrosis") in lymph node adenocarcinoma
A mesenchymal tumour was removed: fibromatosis of the intestinal mesentery (Figures 3 and 4).
Figure 3. Intra-abdominal fibromatosis(HE)
Figure 4. Intra-abdominal fibromatosis (van Gieson)
We believe that in this clinical case the criteria of one of the main forms of familial adenomatous polyposis were manifested – Gardner’s syndrome10, 12.
A histological examination of all adenomatous formations in FAP patients is virtually impossible. That is why algorithms must be created, based on size, localisation and endoscopic features of the polypoid formations.
Gastrointestinal polyps are the most frequent extracolonic manifestation of FAP: in the fundus of the stomach and in the duodenum. Single cases of stomach carcinoma are reported2, 9, 12, although it is the duodenum rather than the stomach, following the colorectum as the second most frequent polyp localisation in FAP9. Duodenal polyps have a predilection for the second and the third section of the duodenum, more specifically the periampullary area. In the presented case hyperplastic polyps on the duodenal mucosa were found. At the same time duodenal cancer is the second most frequent cause of death in FAP patients3, 9. Apart from gastrointestinal manifestations, congenital hypertrophy of the retinal pigment epithelium is the most common one, followed by epidermoid cysts, fibromas and osteomas, dental abnormalities and desmoid tumors9, 12. The latter, albeit benign, affect mostly the mesentery and are subject to surgical interventions of varying complexity, depending on different APC gene mutations. Mesenteric fibromatosis is considered a significant cause of death of FAP patients9, 12, 13. Extraintestinal malignant manifestations include thyroid carcinoma (the third most frequent malignancy in FAP), mucin-producing pancreatic adenocarcinoma, hepatocellular carcinoma and brain tumors9, 14. The combination of bowel and extracolonic manifestations is known as the phenotypic variant of FAP, Gardner’s syndrome, while the combination of colorectal polyposis and brain tumours corresponds to Turcot’s syndrome.
In conclusion it should be noted that the purpose of familial adenomatous polyposis therapy and control is to prevent colorectal carcinoma1, 9, with endoscopic polypectomy and surgical interventions included. The age of initial screening must be determined by the risk of malignant transformation of colorectal adenomas. In FAP patients under 20 this risk is minimal. Once discovered, the adenomas must be controlled every year. The frequency of the control, the chemoprevention and the volume of surgical intervention in other mutant forms must be determined by genetic screening9, 14. It is considered that if a patient bears biallelic MUTYH mutations, a presymptomatic testing of the relatives should be performed, and particularly of those of the same generation, who have a 25% risk of bearing biallelic mutations9, 10.
The prognosis of FAP patients depends on genetic identification and determination of genotypic and phenotypic algorithms. Presymptomatic diagnosing determining genetic mutations turns genetic information into part of the clinical and diagnosing and therapeutic process in different FAP/MAP forms. Extracolonic manifestations are a defining prognostic factor in FAP patients, more specifically duodenal carcinoma and intraabdominal fibromatosis. With regard to extracolonic manifestations and the increased risk of relapse, FAP patients must undergo annual endoscopic (including histological verification), instrumental and laboratory control. Prospective research is needed of the use of genetic information in surgical practice in familial adenomatous polyposis.
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