Indian J Gastroenterol (May–June 2015) 34(3):233–239 DOI 10.1007/s12664-015-0558-3
ORIGINAL ARTICLE
Colonic polyposis syndromes—An experience from a tertiary centre in South India Sreejesh Sreedharanunni 1 & Roopa Paulose 1 & Annie Jojo 1 & Puneet Dhar 2 & P. Gangadharan 3
Received: 3 January 2015 / Accepted: 1 April 2015 / Published online: 10 May 2015 # Indian Society of Gastroenterology 2015
Abstract Background Several polyposis syndromes of the gastrointestinal tract have been recognized which carry increased risk for cancer and have a genetic predisposition. There is a paucity of literature regarding the occurrence and the burden of colonic polyposis syndromes in the Indian subcontinent. This study attempts to highlight this hitherto unaddressed burden and the associated increased risk for inherited colonic cancer in this geographical location. Methods A retrospective study of various colonic polyposis syndromes encountered at a tertiary centre in South India over a period of 8 years (2005 to 2012) was performed. The diagnosis in each case was made histologically with clinicopathological correlation. Results Fifty cases were identified as belonging to a colonic polyposis syndrome, during the study period. There were 27 males and 23 females with a median age of 36.5 years (range 19 months to 78 years). The commonest syndrome was familial adenomatous polyposis (n=27; 54 %) followed by PeutzJeghers syndrome (n=11), attenuated familial adenomatous polyposis (n = 7), juvenile polyposis syndrome (n = 3), hyperplasic polyposis syndrome (n = 1) and CronkhiteCanada syndrome (n=1). Colonic malignancy was documented at first presentation in 22 patients (44 %).
* Roopa Paulose [email protected]
Conclusions Our study highlights the various colonic polyposis syndromes encountered in a tertiary care institution in Southern India. Keywords Attenuated familial adenomatous polyposis . Cronkhite-Canada syndrome . Familial adenomatous polyposis . Hyperplastic polyposis . Juvenile polyposis syndrome . Peutz-Jeghers syndrome
Introduction Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide after lung and gastric cancers. It is the fourth most common cause of cancer death in the world [1, 2]. Most of the CRCs are sporadic in origin, and hereditary colonic polyposis account for less than 1 % of all CRCs [3]. Accurate diagnosis of each type of colonic polyposis syndrome is essential as they are inherited in families, which necessitate genetic counselling. There is a paucity of data regarding the occurrence of various types of polyposis syndromes in the Indian subcontinent. The objective of the study was to address the burden of the inherited polyposis syndromes in this geographical location so that an effective bowel and family screening programme could be made available to the high-risk population.
1
Department of Pathology, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India
Methods
2
Department of Gastrointestinal Surgery, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India
3
Department of Cancer Registry, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India
This was a retrospective study of patients diagnosed with colonic polyposis over an 8-year period (2005 to 2012) at a tertiary centre in South India. The data, retrieved from the hospital information system included demographic details
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and family history, histological type of polyp, extracolonic/ extraintestinal manifestations and presence of malignancy. Only those patients with clinical and histological features of epithelial polyps, affecting the colon and rectum and satisfying the criteria for various colonic polyposis syndromes [4] were included in the study. The patients were diagnosed to have multiple polyps at a single point of time or over a period. Those patients with polyposis elsewhere in the gastrointestinal (GI) tract without involvement of colon or rectum were excluded from the analysis. The diagnosis in each case was made with clinical, endoscopic and pathological correlation. Molecular tests were not performed.
Results There were fifty cases of various types of colonic polyposis during the study period between 2005 and 2012. The pathological diagnosis was made on the colonoscopy biopsies/ proctocolectomy/small intestinal resection. The age of the patients’ ranged from 19 months to 78 years with a median age of 36.5 years. There were 27 males and 23 females with a male female ratio of 1.17:1. A positive family history of GI malignancy was documented only in 12 patients including two siblings. Twenty-two patients (44 %) had colonic malignancy at initial presentation itself. Twenty-four patients had extracolonic polyps and 11 patients had extraintestinal manifestation. None of the index cases had extraintestinal malignancy. The most common type of colonic polyposis was familial adenomatous polyposis (FAP) (n=27, 54 %), followed by Peutz-Jeghers polyposis (PJS) (n=11; 22 %), attenuated FAP (AFAP) (n=7), juvenile polyposis syndrome (JPS) (n= 3) and one case each of hyperplastic polyposis syndrome (HPS) and Cronkhite-Canada syndrome (CCS). The demographic details of each type are summarized in Table 1. During this study period, there were 1,909 surgically resected cases of colorectal cancers (CRC) at the centre.
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adenoma, others being classified as tubular adenoma [5]. All cases had matting of polyps in the colon and rectum (overall >100 polyps). The size of polyps ranged from as small as 0.2 cms to large polyps of >5.5 cms. Microscopically, they showed a spectrum of changes ranging from flat adenoma to low-grade and high-grade dysplasia (Fig. 1). Sixteen (59 %) patients had synchronous colorectal adenocarcinoma at presentation with multicentric malignancy in three of them. One of these patients presented with gastric adenocarcinoma. In others (n=11), nine patients had adenomatous polyps with low-grade dysplasia and two patients with low and high-grade dysplasia. The presence of mixed hyperplastic adenomatous polyp and serrated adenoma [6] were also documented in one of the patients (Fig. 2). There was no relation between the age of presentation and presence of malignancy. The youngest patient presented with CRC at 22 years while the oldest at 59 years did not have malignancy at diagnosis. Extracolonic polyps in duodenum and/or stomach were detected in 12 (44 %) cases. Extraintestinal manifestations were documented in three cases, one with osteomas and lipomas and other two with desmoid tumor. Attenuated familial adenomatous polyposis The diagnosis of AFAP was made in patients with endoscopy or surgical resection specimen showing >10 but 100 adenomatous polyps in the colon and rectum [4]. This was the commonest colonic polyposis (n=27) with male:female ratio (M: F) of 1.25:1 and the median age at presentation was 43 years (range 22 to 59 years). A positive family history of FAP was documented only in one case and that of CRC was documented in 10 cases (37 %), two being sisters detected by family screening. These patients showed variable numbers of tubular, tubulovillous and villous adenomas classified based on the relative proportions of tubular and villous components. An adenoma with >80 % villous component is classified villous, while a minimum of 20 % villous component is seen in tubulovillous
Peutz-Jeghers syndrome is diagnosed in the presence of at least two of the diagnostic criteria: (1) two or more hamartomatous polyps in the small bowel, (2) hyperpigmentation of lips/buccal mucosa and (3) a family history of PJS [4]. Eleven patients had multiple Peutz-Jeghers type hamartomatous polyps (≥2 polyps) affecting the colon with size ranging from 0.2 to 6 cm (Fig. 2). The M:F was 1:1.2 and median age of presentation was 27 years (range 3 to 42 years). Seven patients (64 %) had multiple Peutz-Jeghers (PJ) polyps in the stomach and small intestine as well ranging in size from 0.5 to 4 cm. No other extraintestinal manifestations were documented apart from perioral mucocutaneous pigmentation, which was noted in seven patients. A positive family history
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Table 1
Summary of patients with colonic polyposis syndrome
Type
Number of cases (n=50)
Age median (range, years)
Sex ratio (male:female)
Positive family history of CRCs (number of cases)
Number (%) of cases with concomitant intestinal malignancy
Number (%) of cases with extracolonic polyps
FAP PJS AFAP JPS HP CCS
27 11 7 3 1 1
43 (22–59) 27 (3–42) 59 (26–78) 14 (1.7–32) 35 years 36 years
1.25:1 1:1.2 1:1.33 2:1 Male Male
10 2 Nil Nil Nil Nil
16 (59) 2 (18) 4 (57) Nil Nil Nil
12 (44) 7 (64) 1 (14.3) Nil Nil 1
CRCs colorectal cancers, FAP familial adenomatous polyposis, PJS Peutz-Jeghers syndrome, AFAP attenuated FAP, JPS juvenile polyposis syndrome, HP hyperplastic polyp, CCS Cronkhite-Canada syndrome
of CRC was documented in two cases. Two of these patients developed adenocarcinoma, one with dysplastic polyps and synchronous mucinous adenocarcinoma of small and large intestine and another patient developed signet ring cell carcinoma of stomach with cervical lymph node metastases. Juvenile polyposis syndrome Juvenile polyposis (≥3 polyps) [4] was detected in three patients with a median age of 14 years (range 1.7 to 32 years). All of these patients had multiple colonic polyps of varied sizes ranging from 0.1 to 2.5 cm (Fig. 2). None had intestinal or extraintestinal malignancies or documented family history. Cronkhite-Canada syndrome and hyperplastic polyposis syndrome There was one patient with hamartomatous polyps in stomach, duodenum and colon together with ridging of nails; extensive loss of hair and palmar hyperpigmentation, consistent with CCS [7] and another patient had multiple hyperplastic polyps. Neither was associated with CRC.
Discussion Colonic polyposis syndromes can be broadly categorized based on the type of polyps (Fig. 3). Adenomatous polyps are seen in FAP, AFAP, MYH associated polyposis (MAP). Hamartomatous polyps are seen in PJS, JPS and Cowden syndrome (CS). Hyperplastic polyps are seen in HPS. Although only up to 5 % of CRCs are associated with distinct monogenic disorders including hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome), FAP, MAP, JPS and PJS [4], it is important to recognize these conditions as these patients require more intensive surveillance in view of their natural history for neoplasia. All are autosomal dominant except MAP, which is
autosomal recessive, and hence, implications for surveillance of relatives are different. People with an increased risk of CRC due to high penetrance genetic disorders are identified in one or more of the following ways: Family history consistent with an autosomal dominant cancer syndrome; pathognomic features of a characteristic polyposis syndrome in an individual or in a close relative; the presence of a germ line pathogenic mutation in a colorectal cancer susceptible gene; molecular features of a familial syndrome in a colorectal cancer arising in a first degree relative [8]. FAP is the second most common cause of inherited CRC, which accounts for 1 % of all CRCs and confers a 100 % risk for CRC. The causative germ line mutations occurs in APC gene tumor suppressor gene located on chromosome 5q21, which plays a central role in wnt signalling pathway. In up to 30 % cases, there may not be any family history because of de novo mutations or because of germ line mosaicism [4]. FAP is an excellent example for adenoma carcinoma sequence. Our cases also showed a wide spectrum of dysplasia ranging from flat adenoma to low-grade, high-grade dysplasia and carcinomas. In addition to colorectal adenomas, they are associated with duodenal and ampullary adenomas as well as fundic gland polyps of stomach in up to 90 % of cases. Duodenal carcinomas can develop in up to 4 % of cases [4]. Gardner syndrome is a phenotypic variant of FAP, which is associated with fibromas, desmoids tumors, osteomas, lipomas, epidermoid cysts and nasopharyngeal angiofibromas. Desmoid tumors develop in 10 % to 25 % of patients with FAP [9]. Other extracolonic manifestations include congenital hypertrophy of retinal pigment epithelium (CHRPE), hepatoblastomas, medulloblastoma, thyroid and pancreatic carcinoma [10]. Our data indicates a higher median age at presentation of 43 years. A proper surveillance programme will help to detect affected relatives at a younger age. We had a 59 year old presenting with FAP and without an invasive malignancy exemplifying phenotypic heterogeneity. Conversely, a 22 year old with FAP had CRC at presentation. In our study, family history of CRC (based on history) was
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Indian J Gastroenterol (May–June 2015) 34(3):233–239
Fig. 1 a Gross photograph from a case of familial adenomatous polyposis (FAP) showing numerous polyps matting a segment of colon. b–e Photomicrographs from FAP showing polyps of various degrees of dysplasia (haematoxylin and eosin). b Flat adenoma (red arrow) (2×); c tubular adenoma with low-grade dysplasia (4×); d tubulovillous adenoma with low-grade dysplasia (4×); e adenoma showing areas of high-grade dysplasia (4×); and f invasive adenocarcinoma (2×)
documented only in 37 % of patients. A positive family history of FAP could be documented only in a single patient. Whether this lower rate is due to higher incidence of sporadic mutations in our population or due to bias in the collection of data is not clear. Mutation analysis was not done in any of our cases. The exact prevalence cannot be determined in the absence of a proper genetic counselling and family screening strategy. There is absence of reliable data regarding the type of mutations also in our population, which warrants further study. AFAP is a less severe form of FAP, associated with fewer than 100 but more than 10 polyps and with inactivating mutations in specific regions of the APC gene (extreme 5' portion of the gene and the 3' portion of exon 15). These polyps with/ without invasive malignancy occur at a later age compared to FAP. Similar to FAP, they are also associated with extracolonic manifestations like duodenal and gastric adenomas, fundic gland polyps as well as extraintestinal cancers like breast carcinomas and hepatoblastomas [10]. A group of patients presenting with AFAP can be negative for APC mutation and show biallelic mutation in the base excision repair (BER) gene called MUTYH, the condition being called MAP or MUTYH attenuated polyposis. It was first described by Al-Tassan et al.,
and the gene is located on chromosome 1 and follows autosomal recessive inheritance. Therefore, lack of autosomal dominant pattern of inheritance of the polyposis phenotype in the family should raise the possibility of MAP. The risk of CRC is 1.68 to 3 times in monoallelic carriers [10–12] and 28 to 93fold in biallelic carriers of MYH mutation [11–14]. Polyps in MAP are usually of adenomatous type but hyperplastic polyps or sessile serrated adenomas can also occur [10, 15]. Duodenal polyps are seen in around 17 % and the risk of duodenal cancer is 4 % [16]. MYH mutation screening should be considered in a case of attenuated or classical polyposis when there is an autosomal recessive pattern of inheritance or absence of pathogenic APC mutation [17]. There were seven patients in our study with AFAP phenotype. They had a higher median age of presentation compared to FAP (59 vs. 43 years), which is in concordance with the literature. Both groups had similar proportion of patients presenting with CRC at diagnosis (57 % vs. 59 %). Obviously, there is an overlap between FAP and AFAP phenotypes. Eighteen out of twenty-seven (66.7 %) patients with FAP and 57 % of patients with AFAP had either invasive carcinoma or high-grade dysplasia at diagnosis. This figure is alarming as timely diagnosis and surveillance can help prevent the development of CRC in these
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Fig. 2 a Gross photograph of juvenile polyp. Photomicrographs (haematoxylin and eosin) of b juvenile polyp (4×); c PeutzJeghers polyp (4×); d mixed hyperplastic adenomatous polyp (2×)
patients. The polyps in FAP and AFAP are usually of adenomatous type; however, serrated polyps can also be seen especially in attenuated type [18]. Mixed adenomatous hyperplastic polyps and serrated polyps were documented in one case each of FAP ad AFAP. Flat adenomas were infrequently reported in our patients as polypectomies, and tissue sampling were directed towards the larger polyps/polypoidal carcinoma for staging and prognostication. The recent World Health Organization (WHO) classification defined new histological criteria for all currently recognized subtypes of serrated polyps: hyperplastic polyp, sessile serrated adenoma (SSA/ P) and traditional serrated adenoma (TSA) [5]. Prospective studies will help to assess the exact frequency of flat adenoma and serrated polyps in the cases of FAP and AFAP.
Fig. 3 Types of colorectal cancer syndromes (based on references 3 and 4)
Hamartomatous polyposis syndromes include familial JPS, PJS, phosphatase and tensin homolog gene (PTEN) associated syndromes like Cowden syndrome (CS), Bannavan-RileyRuvalcaba syndrome (BRRS), CCS and hereditary mixed polyposis syndromes (HMPS) [19]. PJS is an autosomal dominant hamartomatous polyposis due to germ line mutations in serine threonine-protein kinase (STK11/LKB1) gene on chromosome19 p13.3 [19]. The mean age of presentation was 25 years with a M:F ratio of 1:1.2; which is similar to one of the largest series in the literature in which the average age at diagnosis was 23 years in men and 26 years in women with a male-female ratio of 1:1.13 [20]. Polyposis usually affects jejunum and ileum but can also affect colon, stomach, duodenum and rectum [20]. The number of polyps ranges from one to hundreds and can present with intestinal obstruction, bleeding or intussusception [20, 21]. These patients also tend to have extraintestinal polyps like nasal polyps, ureteral polyps, tonsil as well as pancreas, hamartomatous/adenomatous polyps of gallbladder [22]. It may be associated with skeletal anomalies like clubbed foot and scoliosis and ovarian cystic neoplasms. Patients with PJS can develop intestinal and extraintestinal malignancies, and the risk of malignancy by 50 years is about 31 %, commonly affecting GIT. The most common extraintestinal malignancy is carcinoma breast, and therefore, breast screening is recommended in these patients. Other rare malignancies include carcinoma of pancreas, lung, breast, uterus, ovary and testis especially Sertoli cell tumors [23, 24]. JPS, an autosomal dominant condition, is defined by the presence of at least three colorectal juvenile polyps or juvenile
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polyps throughout the GI tract or any number of juvenile polyps if there is positive family history of JPS [3]. Up to 60 % of JPS patients have mutations in SMAD4 or BMPR1 which includes point mutations and deletions [25]; the genes implicated in rest of the cases are not clear. The mean age of presentation was 16 years, while it ranged from 4–57 years with a median of 27 years [26] in another study. The number of polyps can range from five to hundreds. It can affect the stomach (80 %), duodenum (30 % to 40 %) and rest of small intestine in addition to or even in the absence of colonic polyps. Seven percent of these polyps can show dysplasia [26]. They may present in infancy or in late childhood, adolescence or in adults as a generalized form or polyposis coli [27]. The cumulative risk of developing CRC is 34 % [27, 28]. They could be associated with extraintestinal manifestations like cardiac abnormalities like mitral valve prolapse, vascular abnormalities like telangiectasia or birth defects like macrocephaly, hydrocephalus or cleft lip [26]. Unlike other polyposis, CCS is a sporadic condition characterized by the presence of hamartomatous polyps resembling JPS or inflammatory polyp and associated with alopecia, onychodystrophy, hyperpigmentation and protein losing enteropathy [29]. It probably has an autoimmune mechanism of origin evidenced by the presence of IgG4 positive mononuclear cells in the polyps [30]. Polyps are seen in both upper and lower GIT and are associated with carcinomas of stomach, colon and rectum in up to 25 % cases [31]. HPS is diagnosed based on any one of the following criteria: (1) ≥5 hyperplastic or serrated colorectal polyps proximal to sigmoid colon; (2) ≥2 hyperplastic polyp or serrated colorectal polyps at least 10 mm in size; (3) ≥20 hyperplastic or serrated colorectal polyp anywhere in the colon or rectum; (4) any hyperplastic or serrated colorectal polyp in a first degree relative with hyperplastic polyposis [32]. The study by Kalady et al. has divided hyperplastic polyps into right-sided, left-sided and mixed phenotypes and has found notable differences among them. The median age of diagnosis ranges from 44 to 62 years [32–36]. The incidence of CRC ranges from 25 % to 70 % [32–34, 36–39]. A family history of CRC is seen in 10 % to 50 % [32, 33, 36–38], and associated pancreatic carcinoma has also been documented [40]. Large polyps, usually in small numbers, are seen on the right side of colon while small polyps often in large numbers are more common on the left side of colon. The presentation as a right-sided phenotype is more common compared to that of left. Sessile serrated polyps are more common on the right side. Smaller left-sided polyps may be associated with KRAS mutations while large right-sided ones with BRAF mutations. They may be associated with extracolonic cancers like carcinoma prostate, breast, etc. in both patients and their families [32]. Hyperplastic polyp and sessile serrated adenomas can be seen associated with MAP also; hence, MYH mutations may be responsible for at least a subset of HPS especially when adenomas occur simultaneously with hyperplastic polyp [15, 41].
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In conclusion, this study provides a snapshot of colonic polyposis syndromes seen in a tertiary care institution in southern India. Conflict of interest SS, RP, AJ, PD, and PG confirm that they have no conflict of interest to declare. Ethical statements The study was performed in a manner to conform with the Helsinki Declaration of 1975, as revised in 2000 and 2008 concerning Human and Animal Rights, and the authors followed the policy concerning informed consent as shown on http://www.springer. com.
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ORIGINAL ARTICLE
Colonic polyposis syndromes—An experience from a tertiary centre in South India Sreejesh Sreedharanunni 1 & Roopa Paulose 1 & Annie Jojo 1 & Puneet Dhar 2 & P. Gangadharan 3
Received: 3 January 2015 / Accepted: 1 April 2015 / Published online: 10 May 2015 # Indian Society of Gastroenterology 2015
Abstract Background Several polyposis syndromes of the gastrointestinal tract have been recognized which carry increased risk for cancer and have a genetic predisposition. There is a paucity of literature regarding the occurrence and the burden of colonic polyposis syndromes in the Indian subcontinent. This study attempts to highlight this hitherto unaddressed burden and the associated increased risk for inherited colonic cancer in this geographical location. Methods A retrospective study of various colonic polyposis syndromes encountered at a tertiary centre in South India over a period of 8 years (2005 to 2012) was performed. The diagnosis in each case was made histologically with clinicopathological correlation. Results Fifty cases were identified as belonging to a colonic polyposis syndrome, during the study period. There were 27 males and 23 females with a median age of 36.5 years (range 19 months to 78 years). The commonest syndrome was familial adenomatous polyposis (n=27; 54 %) followed by PeutzJeghers syndrome (n=11), attenuated familial adenomatous polyposis (n = 7), juvenile polyposis syndrome (n = 3), hyperplasic polyposis syndrome (n = 1) and CronkhiteCanada syndrome (n=1). Colonic malignancy was documented at first presentation in 22 patients (44 %).
* Roopa Paulose [email protected]
Conclusions Our study highlights the various colonic polyposis syndromes encountered in a tertiary care institution in Southern India. Keywords Attenuated familial adenomatous polyposis . Cronkhite-Canada syndrome . Familial adenomatous polyposis . Hyperplastic polyposis . Juvenile polyposis syndrome . Peutz-Jeghers syndrome
Introduction Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide after lung and gastric cancers. It is the fourth most common cause of cancer death in the world [1, 2]. Most of the CRCs are sporadic in origin, and hereditary colonic polyposis account for less than 1 % of all CRCs [3]. Accurate diagnosis of each type of colonic polyposis syndrome is essential as they are inherited in families, which necessitate genetic counselling. There is a paucity of data regarding the occurrence of various types of polyposis syndromes in the Indian subcontinent. The objective of the study was to address the burden of the inherited polyposis syndromes in this geographical location so that an effective bowel and family screening programme could be made available to the high-risk population.
1
Department of Pathology, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India
Methods
2
Department of Gastrointestinal Surgery, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India
3
Department of Cancer Registry, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India
This was a retrospective study of patients diagnosed with colonic polyposis over an 8-year period (2005 to 2012) at a tertiary centre in South India. The data, retrieved from the hospital information system included demographic details
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and family history, histological type of polyp, extracolonic/ extraintestinal manifestations and presence of malignancy. Only those patients with clinical and histological features of epithelial polyps, affecting the colon and rectum and satisfying the criteria for various colonic polyposis syndromes [4] were included in the study. The patients were diagnosed to have multiple polyps at a single point of time or over a period. Those patients with polyposis elsewhere in the gastrointestinal (GI) tract without involvement of colon or rectum were excluded from the analysis. The diagnosis in each case was made with clinical, endoscopic and pathological correlation. Molecular tests were not performed.
Results There were fifty cases of various types of colonic polyposis during the study period between 2005 and 2012. The pathological diagnosis was made on the colonoscopy biopsies/ proctocolectomy/small intestinal resection. The age of the patients’ ranged from 19 months to 78 years with a median age of 36.5 years. There were 27 males and 23 females with a male female ratio of 1.17:1. A positive family history of GI malignancy was documented only in 12 patients including two siblings. Twenty-two patients (44 %) had colonic malignancy at initial presentation itself. Twenty-four patients had extracolonic polyps and 11 patients had extraintestinal manifestation. None of the index cases had extraintestinal malignancy. The most common type of colonic polyposis was familial adenomatous polyposis (FAP) (n=27, 54 %), followed by Peutz-Jeghers polyposis (PJS) (n=11; 22 %), attenuated FAP (AFAP) (n=7), juvenile polyposis syndrome (JPS) (n= 3) and one case each of hyperplastic polyposis syndrome (HPS) and Cronkhite-Canada syndrome (CCS). The demographic details of each type are summarized in Table 1. During this study period, there were 1,909 surgically resected cases of colorectal cancers (CRC) at the centre.
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adenoma, others being classified as tubular adenoma [5]. All cases had matting of polyps in the colon and rectum (overall >100 polyps). The size of polyps ranged from as small as 0.2 cms to large polyps of >5.5 cms. Microscopically, they showed a spectrum of changes ranging from flat adenoma to low-grade and high-grade dysplasia (Fig. 1). Sixteen (59 %) patients had synchronous colorectal adenocarcinoma at presentation with multicentric malignancy in three of them. One of these patients presented with gastric adenocarcinoma. In others (n=11), nine patients had adenomatous polyps with low-grade dysplasia and two patients with low and high-grade dysplasia. The presence of mixed hyperplastic adenomatous polyp and serrated adenoma [6] were also documented in one of the patients (Fig. 2). There was no relation between the age of presentation and presence of malignancy. The youngest patient presented with CRC at 22 years while the oldest at 59 years did not have malignancy at diagnosis. Extracolonic polyps in duodenum and/or stomach were detected in 12 (44 %) cases. Extraintestinal manifestations were documented in three cases, one with osteomas and lipomas and other two with desmoid tumor. Attenuated familial adenomatous polyposis The diagnosis of AFAP was made in patients with endoscopy or surgical resection specimen showing >10 but 100 adenomatous polyps in the colon and rectum [4]. This was the commonest colonic polyposis (n=27) with male:female ratio (M: F) of 1.25:1 and the median age at presentation was 43 years (range 22 to 59 years). A positive family history of FAP was documented only in one case and that of CRC was documented in 10 cases (37 %), two being sisters detected by family screening. These patients showed variable numbers of tubular, tubulovillous and villous adenomas classified based on the relative proportions of tubular and villous components. An adenoma with >80 % villous component is classified villous, while a minimum of 20 % villous component is seen in tubulovillous
Peutz-Jeghers syndrome is diagnosed in the presence of at least two of the diagnostic criteria: (1) two or more hamartomatous polyps in the small bowel, (2) hyperpigmentation of lips/buccal mucosa and (3) a family history of PJS [4]. Eleven patients had multiple Peutz-Jeghers type hamartomatous polyps (≥2 polyps) affecting the colon with size ranging from 0.2 to 6 cm (Fig. 2). The M:F was 1:1.2 and median age of presentation was 27 years (range 3 to 42 years). Seven patients (64 %) had multiple Peutz-Jeghers (PJ) polyps in the stomach and small intestine as well ranging in size from 0.5 to 4 cm. No other extraintestinal manifestations were documented apart from perioral mucocutaneous pigmentation, which was noted in seven patients. A positive family history
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Table 1
Summary of patients with colonic polyposis syndrome
Type
Number of cases (n=50)
Age median (range, years)
Sex ratio (male:female)
Positive family history of CRCs (number of cases)
Number (%) of cases with concomitant intestinal malignancy
Number (%) of cases with extracolonic polyps
FAP PJS AFAP JPS HP CCS
27 11 7 3 1 1
43 (22–59) 27 (3–42) 59 (26–78) 14 (1.7–32) 35 years 36 years
1.25:1 1:1.2 1:1.33 2:1 Male Male
10 2 Nil Nil Nil Nil
16 (59) 2 (18) 4 (57) Nil Nil Nil
12 (44) 7 (64) 1 (14.3) Nil Nil 1
CRCs colorectal cancers, FAP familial adenomatous polyposis, PJS Peutz-Jeghers syndrome, AFAP attenuated FAP, JPS juvenile polyposis syndrome, HP hyperplastic polyp, CCS Cronkhite-Canada syndrome
of CRC was documented in two cases. Two of these patients developed adenocarcinoma, one with dysplastic polyps and synchronous mucinous adenocarcinoma of small and large intestine and another patient developed signet ring cell carcinoma of stomach with cervical lymph node metastases. Juvenile polyposis syndrome Juvenile polyposis (≥3 polyps) [4] was detected in three patients with a median age of 14 years (range 1.7 to 32 years). All of these patients had multiple colonic polyps of varied sizes ranging from 0.1 to 2.5 cm (Fig. 2). None had intestinal or extraintestinal malignancies or documented family history. Cronkhite-Canada syndrome and hyperplastic polyposis syndrome There was one patient with hamartomatous polyps in stomach, duodenum and colon together with ridging of nails; extensive loss of hair and palmar hyperpigmentation, consistent with CCS [7] and another patient had multiple hyperplastic polyps. Neither was associated with CRC.
Discussion Colonic polyposis syndromes can be broadly categorized based on the type of polyps (Fig. 3). Adenomatous polyps are seen in FAP, AFAP, MYH associated polyposis (MAP). Hamartomatous polyps are seen in PJS, JPS and Cowden syndrome (CS). Hyperplastic polyps are seen in HPS. Although only up to 5 % of CRCs are associated with distinct monogenic disorders including hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome), FAP, MAP, JPS and PJS [4], it is important to recognize these conditions as these patients require more intensive surveillance in view of their natural history for neoplasia. All are autosomal dominant except MAP, which is
autosomal recessive, and hence, implications for surveillance of relatives are different. People with an increased risk of CRC due to high penetrance genetic disorders are identified in one or more of the following ways: Family history consistent with an autosomal dominant cancer syndrome; pathognomic features of a characteristic polyposis syndrome in an individual or in a close relative; the presence of a germ line pathogenic mutation in a colorectal cancer susceptible gene; molecular features of a familial syndrome in a colorectal cancer arising in a first degree relative [8]. FAP is the second most common cause of inherited CRC, which accounts for 1 % of all CRCs and confers a 100 % risk for CRC. The causative germ line mutations occurs in APC gene tumor suppressor gene located on chromosome 5q21, which plays a central role in wnt signalling pathway. In up to 30 % cases, there may not be any family history because of de novo mutations or because of germ line mosaicism [4]. FAP is an excellent example for adenoma carcinoma sequence. Our cases also showed a wide spectrum of dysplasia ranging from flat adenoma to low-grade, high-grade dysplasia and carcinomas. In addition to colorectal adenomas, they are associated with duodenal and ampullary adenomas as well as fundic gland polyps of stomach in up to 90 % of cases. Duodenal carcinomas can develop in up to 4 % of cases [4]. Gardner syndrome is a phenotypic variant of FAP, which is associated with fibromas, desmoids tumors, osteomas, lipomas, epidermoid cysts and nasopharyngeal angiofibromas. Desmoid tumors develop in 10 % to 25 % of patients with FAP [9]. Other extracolonic manifestations include congenital hypertrophy of retinal pigment epithelium (CHRPE), hepatoblastomas, medulloblastoma, thyroid and pancreatic carcinoma [10]. Our data indicates a higher median age at presentation of 43 years. A proper surveillance programme will help to detect affected relatives at a younger age. We had a 59 year old presenting with FAP and without an invasive malignancy exemplifying phenotypic heterogeneity. Conversely, a 22 year old with FAP had CRC at presentation. In our study, family history of CRC (based on history) was
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Fig. 1 a Gross photograph from a case of familial adenomatous polyposis (FAP) showing numerous polyps matting a segment of colon. b–e Photomicrographs from FAP showing polyps of various degrees of dysplasia (haematoxylin and eosin). b Flat adenoma (red arrow) (2×); c tubular adenoma with low-grade dysplasia (4×); d tubulovillous adenoma with low-grade dysplasia (4×); e adenoma showing areas of high-grade dysplasia (4×); and f invasive adenocarcinoma (2×)
documented only in 37 % of patients. A positive family history of FAP could be documented only in a single patient. Whether this lower rate is due to higher incidence of sporadic mutations in our population or due to bias in the collection of data is not clear. Mutation analysis was not done in any of our cases. The exact prevalence cannot be determined in the absence of a proper genetic counselling and family screening strategy. There is absence of reliable data regarding the type of mutations also in our population, which warrants further study. AFAP is a less severe form of FAP, associated with fewer than 100 but more than 10 polyps and with inactivating mutations in specific regions of the APC gene (extreme 5' portion of the gene and the 3' portion of exon 15). These polyps with/ without invasive malignancy occur at a later age compared to FAP. Similar to FAP, they are also associated with extracolonic manifestations like duodenal and gastric adenomas, fundic gland polyps as well as extraintestinal cancers like breast carcinomas and hepatoblastomas [10]. A group of patients presenting with AFAP can be negative for APC mutation and show biallelic mutation in the base excision repair (BER) gene called MUTYH, the condition being called MAP or MUTYH attenuated polyposis. It was first described by Al-Tassan et al.,
and the gene is located on chromosome 1 and follows autosomal recessive inheritance. Therefore, lack of autosomal dominant pattern of inheritance of the polyposis phenotype in the family should raise the possibility of MAP. The risk of CRC is 1.68 to 3 times in monoallelic carriers [10–12] and 28 to 93fold in biallelic carriers of MYH mutation [11–14]. Polyps in MAP are usually of adenomatous type but hyperplastic polyps or sessile serrated adenomas can also occur [10, 15]. Duodenal polyps are seen in around 17 % and the risk of duodenal cancer is 4 % [16]. MYH mutation screening should be considered in a case of attenuated or classical polyposis when there is an autosomal recessive pattern of inheritance or absence of pathogenic APC mutation [17]. There were seven patients in our study with AFAP phenotype. They had a higher median age of presentation compared to FAP (59 vs. 43 years), which is in concordance with the literature. Both groups had similar proportion of patients presenting with CRC at diagnosis (57 % vs. 59 %). Obviously, there is an overlap between FAP and AFAP phenotypes. Eighteen out of twenty-seven (66.7 %) patients with FAP and 57 % of patients with AFAP had either invasive carcinoma or high-grade dysplasia at diagnosis. This figure is alarming as timely diagnosis and surveillance can help prevent the development of CRC in these
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Fig. 2 a Gross photograph of juvenile polyp. Photomicrographs (haematoxylin and eosin) of b juvenile polyp (4×); c PeutzJeghers polyp (4×); d mixed hyperplastic adenomatous polyp (2×)
patients. The polyps in FAP and AFAP are usually of adenomatous type; however, serrated polyps can also be seen especially in attenuated type [18]. Mixed adenomatous hyperplastic polyps and serrated polyps were documented in one case each of FAP ad AFAP. Flat adenomas were infrequently reported in our patients as polypectomies, and tissue sampling were directed towards the larger polyps/polypoidal carcinoma for staging and prognostication. The recent World Health Organization (WHO) classification defined new histological criteria for all currently recognized subtypes of serrated polyps: hyperplastic polyp, sessile serrated adenoma (SSA/ P) and traditional serrated adenoma (TSA) [5]. Prospective studies will help to assess the exact frequency of flat adenoma and serrated polyps in the cases of FAP and AFAP.
Fig. 3 Types of colorectal cancer syndromes (based on references 3 and 4)
Hamartomatous polyposis syndromes include familial JPS, PJS, phosphatase and tensin homolog gene (PTEN) associated syndromes like Cowden syndrome (CS), Bannavan-RileyRuvalcaba syndrome (BRRS), CCS and hereditary mixed polyposis syndromes (HMPS) [19]. PJS is an autosomal dominant hamartomatous polyposis due to germ line mutations in serine threonine-protein kinase (STK11/LKB1) gene on chromosome19 p13.3 [19]. The mean age of presentation was 25 years with a M:F ratio of 1:1.2; which is similar to one of the largest series in the literature in which the average age at diagnosis was 23 years in men and 26 years in women with a male-female ratio of 1:1.13 [20]. Polyposis usually affects jejunum and ileum but can also affect colon, stomach, duodenum and rectum [20]. The number of polyps ranges from one to hundreds and can present with intestinal obstruction, bleeding or intussusception [20, 21]. These patients also tend to have extraintestinal polyps like nasal polyps, ureteral polyps, tonsil as well as pancreas, hamartomatous/adenomatous polyps of gallbladder [22]. It may be associated with skeletal anomalies like clubbed foot and scoliosis and ovarian cystic neoplasms. Patients with PJS can develop intestinal and extraintestinal malignancies, and the risk of malignancy by 50 years is about 31 %, commonly affecting GIT. The most common extraintestinal malignancy is carcinoma breast, and therefore, breast screening is recommended in these patients. Other rare malignancies include carcinoma of pancreas, lung, breast, uterus, ovary and testis especially Sertoli cell tumors [23, 24]. JPS, an autosomal dominant condition, is defined by the presence of at least three colorectal juvenile polyps or juvenile
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polyps throughout the GI tract or any number of juvenile polyps if there is positive family history of JPS [3]. Up to 60 % of JPS patients have mutations in SMAD4 or BMPR1 which includes point mutations and deletions [25]; the genes implicated in rest of the cases are not clear. The mean age of presentation was 16 years, while it ranged from 4–57 years with a median of 27 years [26] in another study. The number of polyps can range from five to hundreds. It can affect the stomach (80 %), duodenum (30 % to 40 %) and rest of small intestine in addition to or even in the absence of colonic polyps. Seven percent of these polyps can show dysplasia [26]. They may present in infancy or in late childhood, adolescence or in adults as a generalized form or polyposis coli [27]. The cumulative risk of developing CRC is 34 % [27, 28]. They could be associated with extraintestinal manifestations like cardiac abnormalities like mitral valve prolapse, vascular abnormalities like telangiectasia or birth defects like macrocephaly, hydrocephalus or cleft lip [26]. Unlike other polyposis, CCS is a sporadic condition characterized by the presence of hamartomatous polyps resembling JPS or inflammatory polyp and associated with alopecia, onychodystrophy, hyperpigmentation and protein losing enteropathy [29]. It probably has an autoimmune mechanism of origin evidenced by the presence of IgG4 positive mononuclear cells in the polyps [30]. Polyps are seen in both upper and lower GIT and are associated with carcinomas of stomach, colon and rectum in up to 25 % cases [31]. HPS is diagnosed based on any one of the following criteria: (1) ≥5 hyperplastic or serrated colorectal polyps proximal to sigmoid colon; (2) ≥2 hyperplastic polyp or serrated colorectal polyps at least 10 mm in size; (3) ≥20 hyperplastic or serrated colorectal polyp anywhere in the colon or rectum; (4) any hyperplastic or serrated colorectal polyp in a first degree relative with hyperplastic polyposis [32]. The study by Kalady et al. has divided hyperplastic polyps into right-sided, left-sided and mixed phenotypes and has found notable differences among them. The median age of diagnosis ranges from 44 to 62 years [32–36]. The incidence of CRC ranges from 25 % to 70 % [32–34, 36–39]. A family history of CRC is seen in 10 % to 50 % [32, 33, 36–38], and associated pancreatic carcinoma has also been documented [40]. Large polyps, usually in small numbers, are seen on the right side of colon while small polyps often in large numbers are more common on the left side of colon. The presentation as a right-sided phenotype is more common compared to that of left. Sessile serrated polyps are more common on the right side. Smaller left-sided polyps may be associated with KRAS mutations while large right-sided ones with BRAF mutations. They may be associated with extracolonic cancers like carcinoma prostate, breast, etc. in both patients and their families [32]. Hyperplastic polyp and sessile serrated adenomas can be seen associated with MAP also; hence, MYH mutations may be responsible for at least a subset of HPS especially when adenomas occur simultaneously with hyperplastic polyp [15, 41].
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In conclusion, this study provides a snapshot of colonic polyposis syndromes seen in a tertiary care institution in southern India. Conflict of interest SS, RP, AJ, PD, and PG confirm that they have no conflict of interest to declare. Ethical statements The study was performed in a manner to conform with the Helsinki Declaration of 1975, as revised in 2000 and 2008 concerning Human and Animal Rights, and the authors followed the policy concerning informed consent as shown on http://www.springer. com.
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