Management of Hereditary Colorectal Cancer: A Multidisciplinary Approach

This book provides a comprehensive review of the clinical management of hereditary colorectal cancer. The text focuses on six distinct patient groups: patients with early age-of-onset colorectal cancer and adenomas, patients with hamartomatous colorectal polyps, patients afflicted with familial adenomatous polyposis (FAP), patients with attenuated familial adenomatous polyposis (AFAP), patients with MYH associated polyposis (MAP), and patients afflicted with lynch syndrome (LS). Each chapter illustrates how clinicians utilize current technologies in genetic testing, pathological review, and endoscopic, surgical, and chemotherapeutic/immunotherapeutic approaches to manage these patient groups. Topics such as the timing of genetic testing, endoscopic screening and surveillance, prophylactic surgical options and chemo-preventive interventions are also discussed in concise yet precise detail. 
Written by experts in their fields, Management of Hereditary Colorectal Cancer: A Multidisciplinary Approach is a valuable and timely resource for gastroenterologists, surgeons, genetic counselors, medical oncologists, psychologists, and any health caregivers involved with the management of patients and families afflicted with a hereditary form of colorectal cancer.

• Language: English
• Publisher: Springer
• Release date: Apr 2, 2020
• ISBN: 9783030262341

Book preview

© Springer Nature Switzerland AG 2020

J. G. Guillem, G. Friedman (eds.)Management of Hereditary Colorectal Cancerhttps://doi.org/10.1007/978-3-030-26234-1_1

1. Early-Age-of-Onset Colorectal Carcinoma: An Emerging Public Health Issue

Aung K. Win¹, ², ³, Garrett Friedman⁴, ⁵ and Jose G. Guillem⁶  

(1)

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Carlton, VIC, Australia

(2)

University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia

(3)

Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia

(4)

Department of Surgery, Mike O’Callaghan Federal Medical Center, Las Vegas, NV, USA

(5)

Department of Surgery, University of Las Vegas- Nevada School of Medicine, Las Vegas, NV, USA

(6)

Gastrointestinal Surgery, University of North Carolina, Chapel Hill, NC, USA

Jose G. Guillem

Email: [e-mail]

Keywords

ObesityType 2 diabetesColonoscopy ScreeningImmunohistochemical fecal occult blood test (iFOBT)Rectal bleedingAbdominal pain

The etiology of colorectal cancer (CRC) is complex and appears to involve a combination of underlying genetic susceptibility, somatic alterations, and environmental exposures which people experience since conception [1]. Young age at diagnosis is a hallmark of hereditary cancer syndromes as discussed in the chapters that follow. Currently known genetic predispositions to CRC include Lynch syndrome (caused by germline mutations in DNA mismatch repair genes), familial adenomatous polyposis (due to APC mutations), MUTYH-associated polyposis (due to mutations in both alleles of MUTYH gene), and germline mutations in other genes such as SMAD4, BRCA1, TP53, POLE, and POLD1. However, only 20–30% of CRC diagnosed under age 50 are attributable to these known hereditary syndromes [2–4]. The remaining majority of young adult CRC may be associated with other genetic predispositions which have yet to be identified [5], polygenic factors such as single-nucleotide polymorphisms (SNPs), and/or environmental and lifestyle factors of the person [6]. An analysis of 450 patients diagnosed with CRC under the age of 50 detected 75 gene mutations in 72 patients for a mutation rate of 16%. Of note, 33% of the patients that had a gene mutation did not meet current guidelines for genetic testing. The high frequency and wide spectrum of mutations noted in this study support the argument for more routine multigene testing [7]. In addition, these results are consistent with older studies demonstrating that the frequency of HNPCC (previous name for clinical diagnosis of Lynch syndrome ) in CRC patients 40–45 years of age ranges between 15% and 20%, which is greater than a fourfold increase in the rate of HNPCC noted in non-age-stratified CRC [8].

Increasing Incidence of CRC in Young Adults Is a Global Health Issue

In the USA, whereas overall CRC incidence and mortality have been steadily declining over the last 30 years, both incidence and mortality of CRC have been increasing in young adults under age 50 years. The increase occurs in both men and women of all race/ethnicities combined, for white men and women and for black men, especially for distal colon and rectal cancers, during the last three decades [9, 10]. In Canada, CRC incidence has been increasing in young adults of all age groups of 15–29, 30–39, and 40–49 years between 1997 and 2010 [11]. In an analysis using the 1990–2010 population incidence data from the Australian Institute of Health and Welfare (AIHW), it was noted that CRC incidence has been increasing steadily in young adults under age 40 years over the last two decades, whereas the overall incidence of CRC has remained stable and mortality has declined in recent decades. Incidences have increased by 85–100% in the age group 20–29 years, and by 35% in those aged 30–39 between 1990 and 2010 [12]. An analysis of 25 population-based state registries in the USA also noted the incidence of CRC has risen significantly in young adults (age 25–49), with steeper increases that rise in successively younger generations [13]. This increasing trend also occurs in some European as well as Asian countries such as Japan, Korea, and Singapore [14, 15]. Interestingly, in some studies, it appears that these increases in early-onset CRC have been driven primarily by left-sided and rectal cancers. The incidence of rectal cancer in younger patients has increased from 3.0 per 100,000 in 1992 to 4.7 per 100,000 in 2015 [16], outpacing the increased incidence of more proximal colon cancers during this time period.

Reasons for Increasing Incidence of CRC in Young Adults Are Not Known

Population-based screening for CRC is assumed to be the main factor influencing the stabilizing or decreasing trend of CRC cancer incidence and mortality overall or in people aged ≥50 years [9]. The fact that such routine screening is largely confined to those older people, therefore, might partially explain age-related disparities in colorectal cancer incidence and mortality trends [14]. But this does not explain the reasons for the increasing incidence of CRC cancer in young adults.

Currently Known Risk Factors for CRC May Not Be Relevant for Young Adults

Epidemiological studies have identified several factors associated with the risk of CRC diagnosed at all ages or older age. Obesity [17], type 2 diabetes [18], cigarette smoking [19], low physical activities [20], and consumption of red meat and processed meat [21] are associated with an increased risk of CRC, while use of estrogen and progesterone [22], folate, calcium [23], and aspirin [24] are inversely associated with the disease risk. However, the majority of these studies are based on cohorts of people of all ages or older than age 50. Therefore, these known risk factors may not be relevant for CRC in young adults. Consequently, almost all existing CRC risk prediction tools are not applicable to young people [25, 26].

The recent analysis of 25 US cancer registries examining cancer trends for 30 common cancers, including 12 obesity-related cancers in young adults demonstrated an increase in 6 of 12 obesity-related cancers in the younger cohort. CRC was one the six cancers that demonstrated an increase in incidence [13]. Although this study raises questions of why some and not all obesity-related cancers increased in young adults, it nevertheless emphasizes the need for careful epidemiological and etiological studies of exposures (such as obesity and other risk factors) that may explain the trend noted in early-age-of-onset CRC.

Current Data on Risk Factors for CRC in Young Adults Are Limited

Given that 90% of CRCs are diagnosed in individuals over age 50 years, any associations with risk factors––and differences in associations––for those younger than 50 years are difficult to detect (8% of cases are diagnosed between ages 40 and 49 years and 2% before age 40). One main reason is the lack of relevant data because almost all cohorts or studies around the world recruited or studied only CRC diagnosed in later ages. Only three relatively small case-control studies investigated just a few lifestyle factors for CRC diagnosed at a young age and they all have been underpowered [27–29].

A case-control study from Italy (329 cases diagnosed at age 19–45 and 1361 controls) has reported that family history, meat consumption, and alcohol consumption are associated with an increased risk of CRC diagnosed at a young age and there is no evidence of associations with increased body mass, physical activity, and diabetes [27]. A case-control study from Los Angeles County (147 cases diagnosed at age 25–44 and 147 controls) has reported that organic dust was associated with an increased risk of rectal cancer and there is no evidence of associations with alcohol consumption and cigarette smoking [29]. A New Zealand study reported no evidence of school milk consumption associated with CRC in a subset of study participants of age 30–49 years [28].

Population-Based CRC Screening Programs Do Not Cover Young Adults

The incidence of CRC generally increases with age; particularly the incidence rises sharply and progressively from age 50 [10, 12]. Therefore, at the population level CRC screening is generally recommended for everyone aged 50 and above [30]. In Australia, the National Bowel Cancer Screening Program provides free screening to everyone aged between 50 and 74 years using the immunohistochemical fecal occult blood test (iFOBT) biennially. However, in Australia the sentiment is that screening for everyone under age 50 is currently not justified due to low yield, and procedure-related complications that have the potential to exceed any benefit from screening [31]. Recently, however, the American Cancer Association has updated their colonoscopy screening guidelines, moving the initial screening age for average risk individuals from 50 to 45 [32], in acknowledgement of the increased incidence of early-onset CRC noted in the USA.

Current CRC Screening Guidelines Are Limited in Use for Young Adults

Most current CRC clinical practice guidelines do not recommend young adults under age 50 for screening unless they have moderate or strong family history of CRC or known hereditary colorectal cancer syndromes or predisposing conditions (e.g., inflammatory bowel disease) [33]. However, only 10–15% of the population have a family history of colorectal cancer in their first-degree relatives.

Most CRC in Young Adults Present in Late Stages

Most CRC diagnosed under the age of 50 years are due to symptoms and usually present in late stages [12, 14] and have bad pathological features [34]. Unfortunately, there are delays in diagnosis and treatment of CRC in young adults. Missed symptoms and initial misdiagnosis occur in 15–50% of CRC cases diagnosed under age 50. This delay may be due to both patient (such as lack of awareness of potential serious symptoms, embarrassment about or denial of symptoms) and doctors (low suspicion of cancer in young adults may delay the thorough symptom evaluation needed to effectively establish or rule out CRC) [14]. Most CRCs in young adults present symptoms such as rectal bleeding (51%), change in bowel habits (18%), abdominal pain (32%), weight loss (13%), and nausea/vomiting (7%), and a majority (approx. 60%) are in their late stages (Stage III or IV) [35].

Burden of Young Adult CRC Is Huge

Although less than 10% of all CRCs are diagnosed before age 50 [36], the cancer burden in terms of years of life lost, quality of life, and morbidity is greater for men and women diagnosed at a young age given their comparatively longer time living with the disease and potential years of life to lose due to mortality.

Risk-Based Screening Is a Way to Reduce the CRC Burden in Young Adults

Although it is not feasible to screen everyone under age 50, identification of those at high risk of developing CRC can facilitate targeted screening in a cost-effective, efficient manner. To enable such targeted screening, all potential risk factors for the disease (personalized risk assessment) have to be taken into consideration. Currently, very little is known about risk factors for CRC in young adults, which are essential for risk assessment of disease.

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© Springer Nature Switzerland AG 2020

J. G. Guillem, G. Friedman (eds.)Management of Hereditary Colorectal Cancerhttps://doi.org/10.1007/978-3-030-26234-1_2

2. Management of Hamartomatous Polyps

Peter C. Ambe¹, ² and Gabriela Möslein², ³  

(1)

Department of Visceral, Minimally Invasive and Oncologic Surgery, Marien Hospital Düsseldorf, Düsseldorf, Germany

(2)

University Witten/Herdecke, Witten, Germany

(3)

Center for Hereditary Gastrointestinal Tumors, Helios University Hospital Wuppertal, Wuppertal, Germany

Gabriela Möslein

Email: [e-mail]

Keywords

Hamartomatous polyposisPeutz-Jeghers syndromeJuvenile polyposisPTEN hamartoma tumor syndromeHereditary polyposis syndromesFamilial polyposis syndromesGenetic testingProphylactic colorectal surgery

Introduction

Hamartomatous polyps (HPs) in the gastrointestinal (GI) tract are the most common type of polyps in children and are overall extremely rare compared to other histologies, especially adenomas. Index patients usually present with symptoms of rectal bleeding, anemia, abdominal pain, obstipation, and/or small bowel obstruction (specifically in Peutz-Jeghers syndrome ). Based on their histopathological features, HPs are classified as juvenile polyps or Peutz-Jeghers polyps . Frequently, especially if occurring in childhood, a solitary polyp may be removed successfully endoscopically, and if only one or a few juvenile polyps are identified, clinical follow-up is not usually recommended, since based on the underlying histology, the malignant potential is anticipated to be low. However, this first polyp may be indicative of an underlying HPS and as such presents a tremendous preventative potential for the affected individual, based on a substantially increased risk of cancer, recurrences of polyps, and extraintestinal complications, causing severe morbidity and mortality. Some of the affected may have an indicative family history; however sporadic mutations have been estimated to be the underlying genetic cause in up to 30% of syndromic patients.

In an era of more broadly available genetic testing (gene panel testing,