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INTERMEDIATE MEDICAL LIFE INSURANCE UNDERWRITING ALU 201 TEXTBOOK Eighth Edition – 2022 THE ACADEMY OF LIFE UNDERWRITING Copyright 2022 The Academy of Life Underwriting GUIDING PRINCIPLES FOR THE UNDERWRITER Act promptly, while exercising sound, objective, and consistent judgment, in making underwri...

INTERMEDIATE MEDICAL LIFE INSURANCE UNDERWRITING ALU 201 TEXTBOOK Eighth Edition – 2022 THE ACADEMY OF LIFE UNDERWRITING Copyright 2022 The Academy of Life Underwriting GUIDING PRINCIPLES FOR THE UNDERWRITER Act promptly, while exercising sound, objective, and consistent judgment, in making underwriting decisions. Follow established risk classification principles that differentiate fairly on the basis of sound actuarial principles and/or reasonable anticipated mortality or morbidity experience. Treat all underwriting information with the utmost confidentiality, and use it only for the express purpose of evaluating and classifying risk. Comply with the letter and spirit of all insurance legislation and regulations, particularly as they apply to risk classification, privacy, and disclosure. Avoid any underwriting action which is in conflict with the obligation to act independently and without bias. Act responsibly as an employee with scrupulous attention to the mutual trust required in an employer/employee relationship. Provide information and support to sales personnel to help them fulfill their field underwriting responsibilities in selecting risks and submitting underwriting information. Strive to attain Fellowship in the Academy of Life Underwriting, maintain a high level of professional competency through continued education, and help promote the further education of all underwriters. Maintain the dignity and sound reputation of the Underwriting Profession. Increase the public’s understanding of underwriting by providing information about risk classification. These Guiding Principles are presented, not as specific standards for others to measure individual performance, but for the self-guidance of all those who are striving to understand and meet the responsibilities of an underwriter. i GENERAL NOTES FOR ALU TEXTS Copyright All rights reserved. Contents of this textbook are the copyrighted property of the Academy of Life Underwriting. No portion of this book may be reproduced in any form or by any means without the prior written permission of the copyright owner. Requests for permission should be addressed to the ALU Registrar at [email protected]. Gender Neutrality The pronouns “they, them, their” are to be interpreted as pertaining to both male and female genders wherever appropriate in context. Laws Laws and regulations discussed in the ALU text series are those of the United States of America, unless specifically noted as applying to other countries. Acknowledgements The Academy of Life Underwriting thanks all the authors who contributed to the ALU textbook series. We are grateful for their professionalism, dedication, and commitment to the future of quality underwriting. Their efforts are integral to the continuing success of the ALU education and examination program. Special Appreciation The Academy of Life Underwriting also wishes to express its gratitude to all the volunteers who have contributed to the revision of the ALU curriculum over the years. The members of the ALU Curriculum group, medical consultants, authors, and editors work diligently to develop, review, and update the curriculum each year. Without their knowledge, support, and enthusiasm, maintaining the integrity of the curriculum would not be possible. References and Bibliography References and bibliographies for each chapter can be found on the ALU Website, under the Curriculum section at www.alu-web.com. ii ALU EXAM 201 ASSIGNED READINGS FROM ESSENTIALS OF ANATOMY AND PHYSIOLOGY Required Text Scanlon, Valerie C. and Sanders, Tina, Essentials of Anatomy and Physiology, Eighth Edition, Philadelphia, PA, F. A. Davis Company, 2019. Essentials of Anatomy and Physiology, Eighth Edition can be purchased from an online bookseller such as Amazon.com or from the publisher. The ALU 201 student will be responsible for the material in the following chapters. The contents of each chapter, including the material in the boxes, tables, and figures, will be tested. Chapter 5 The Integumentary System Chapter 8 The Nervous System Chapter 9 The Senses Chapter 11 Blood Chapter 13 The Vascular System Chapter 15 The Respiratory System iii TABLE OF CONTENTS Intermediate Medical Insurance Underwriting - ALU 201 Eighth Edition – 2022 CHAPTER TITLE 1 THE GASTROINTESTINAL SYSTEM Shelley Rahn, MD; edited by Terri Apfelbaum, MD 2 LIVER AND BILE DUCT DISORDERS Cathy Percival, RN, BSN, MBA, FALU, FLMI; edited by Michael H. Wetzel, MD, DBIM, CLU 3 FOUR CANCERS: MALIGNANT MELANOMA OF THE SKIN, PROSTATE CANCER, BREAST CANCER, & COLORECTAL CANCER Clifton Titcomb, MD; Revision by Bradley Heltemes, MD 4 THE REPRODUCTIVE SYSTEM Vera Dolan, FALU, ELS, MSPH 5 DISORDERS OF THE NERVOUS SYSTEM Nicky Virgo, BSc 6 UNDERWRITING MENTAL ILLNESS AND PSYCHIATRIC DISORDERS Robert A. Coates, MD, FLMI 7 THE RESPIRATORY SYSTEM Joanne Mambretti, MD, FACP, FCCP, FLMI, edited by Rodney C. Richie, MD, FACP, FCCP, DBIM 8 DISORDERS OF THE KIDNEY AND URINARY TRACT Marty Meyer, FALU, CLU, ChFC, FLMI 9 AN OVERVIEW OF ENDOCRINOLOGY Alison Moy, MD 10 MUSCULSKELETAL SYSTEM DISORDERS Philip A. Baer, MDCM, FRCPC, FACR 11 ADULT VALVULAR DISEASE M. E. Cumming, BSc (Pharm), MSc, MD, DBIM, FAAIM, FALU, FLMI 12 HEMATOLOGICAL DISORDERS Marv Reber, FALU, CLU, FLMI 13 CORONARY ARTERY DISEASE Michael Clark, MD, FACC, FLMI 14 NON-CARDIAC BLOOD VESSEL DISORDERS M.E. Cumming, BSc (Pharm), MSc, MD, DBIM, FAAIM, FALU, FLMI 15 PHARMACOLOGY Patricia A. Aronson, PhD, ACT, LPTA, and Joy Dion Milardo, FALU, FLMI, CLU, ARA ALU 201 Students: See page iii for assigned readings in Essentials of Anatomy and Physiology. iv CHAPTER 1 THE GASTROINTESTINAL SYSTEM SHELLEY RAHN, M.D. Dr. Shelley Rahn is a Medical Director with Mass Mutual Life Insurance Company and is board certified in Internal Medicine, Gastroenterology, and Insurance Medicine. She received her B.A. from Cornell University and her M.D. from the State University of New York at Buffalo School of Medicine. Edited by TERRI APFELBAUM, M.D. Dr. Terri Apfelbaum is a Medical Director with New York Life Insurance Company. She is board certified in Internal Medicine, Gastroenterology, and Insurance Medicine. She received her B.A. from Barnard College and her M.D. from the Columbia College of Physicians and Surgeons. Revised 2022 Copyright 2022 The Academy of Life Underwriting Chapter 1: The Gastrointestinal System THE GASTROINTESTINAL SYSTEM Introduction The gastrointestinal system consists of the alimentary food tract, pancreas, and hepatobiliary system. This chapter will address the alimentary tract and the pancreas; the hepatobiliary system is covered in the next chapter. The alimentary tract is one continuous tube, beginning at the mouth and progressing through the esophagus, stomach, small intestine, large intestine, and ending with the anus. Digestion, the breakdown and absorption of nutrients, electrolytes, and water, occurs in a series of mechanical and chemical processes as food passes through the alimentary tract. The gastrointestinal system can be affected pathologically by ulceration, inflammation, infection, tumors (both benign and malignant), neurologic dysfunction, and mechanical obstruction. Digestion: Anatomy and Physiology The mouth is the site of initial digestion. Here, food is mechanically broken down by chewing and is lubricated by saliva produced by the salivary glands. There is some breakdown of starch in the mouth, but this is of minimal digestive importance. After food is chewed, it is passed to the esophagus through the neurologically mediated process of swallowing. Once food enters the esophagus, it is forced downward by gravity and the rhythmic contractions (i.e., peristalsis) of the muscles that make up the outer two layers of the esophagus. Food passes from the esophagus into the stomach through the lower esophageal sphincter, located just below the level of the diaphragm. This gastroesophageal junction (GE junction) is also known as the Z-line because of its zigzag appearance. Figure 1. Page 1 ALU 201: Intermediate Medical Life Insurance Writing The stomach is anatomically divided into several areas (Figure 1). The major function of the stomach is to continue the mechanical grinding of the food bolus and to enhance the chemical process of digestion. This is done through the secretion of hydrochloric acid (HCL) and pepsin. For the most part, the stomach does not absorb nutrients, though it is the main site of alcohol absorption. The stomach’s other role is the production of intrinsic factor, a protein that is necessary for the absorption of vitamin B12. The food is passed from the stomach through the pylorus, a muscular channel, into the first part of the small intestine, the duodenum. Digestive enzymes, produced in the pancreas, and bile, produced in the liver, empty into the duodenum through a common opening known as the ampulla or papilla of Vater. This fluid, along with locally produced pH neutralizing bicarbonate, mixes with the food, allowing for the major chemical breakdown of protein, carbohydrates, and fats into smaller, simpler, absorbable forms. As the nutrients pass through the rest of the small intestine (the jejunum and finally the ileum), they are absorbed through multiple projections of the mucosa called the villi. The terminal ileum is critical for the absorption of vitamin B12 and the reabsorption of bile salts. The small intestine on average is twenty-two feet long, and the villi produce many more feet of absorptive surface. The residual solution that is not absorbed by the small intestine passes through the ileocecal valve, located in the right lower quadrant of the abdomen, into the cecum, the first part of the large intestine (colon) (Figure 2). The appendix, a long, non-functional, narrow tube, also opens into this area of the large intestine. The colon extends up the right side of the abdomen (the ascending colon), takes a bend to the left at the liver (the hepatic flexure), and crosses the upper abdomen (the transverse colon). At the level of the spleen (the splenic flexure), the colon turns downward (the descending colon). It is configured into an S-shape towards the lower left quadrant and therefore is referred to as the sigmoid colon. The last 15 centimeters of the colon is the rectum. The structure that controls the fecal outflow is called the anus. Figure 2. Page 2 Chapter 1: The Gastrointestinal System The major function of the large intestine is to reabsorb water and electrolytes passing from the small intestine and to control the elimination of the digestive waste material. To accomplish this process, the transit time (forward motion) slows greatly in the colon. The large bowel is also host to many bacteria that aid in the production of vitamin K. Oral Diseases As mentioned earlier, the gastrointestinal tract can be subject to many pathologic processes. The mouth can be affected by cancer, infection, and inflammation. Oral cancer is usually squamous cell carcinoma, which tends to recur and has a high mortality rate. Many systemic diseases have associated oral lesions. For example, apthous ulcers (flat erosions of the mouth) can be associated with Crohn’s disease and systemic lupus erythematosus. A candida fungal infection of the mouth (thrush) can be a sign of an immune deficiency state such as acquired immunodeficiency syndrome (AIDS) or the result of inhaling steroid medication. Glossitis (an inflammation of the tongue) is seen with vitamin B12 deficiency. These mouth lesions and other oral lesions are of little importance, but the underlying disease can have a significant impact on morbidity and mortality. Esophageal Disease Esophageal disorders can occur because of primary esophageal motor abnormalities, central nervous system diseases, strictures, or masses. Dysphagia (i.e., difficulty swallowing) can be caused by any of these processes. The pain associated with dysphagia (i.e., odynophagia) is described as retrosternal and occurs while swallowing. Treatment requires first determining the underlying etiology. When a primary motor disorder (e.g., esophageal spasm) is diagnosed through esophageal manometry (i.e., pressure monitoring of the esophagus) and barium x-ray studies, the treatment often consists of the promotility medication metoclopramide (Reglan®), or antispasmodic agents such as nifedipine (Procardia®) and nitroglycerin. Strictures of the esophagus require dilatation that is usually performed by the passage of tubes or balloons through the mouth with the use of special fiberoptic instruments (i.e., upper endoscopes). Achalasia is the failure of the lower esophageal sphincter to relax. This results in significant dilation of the esophagus. It is treated with endoscopic balloon dilatation or surgery. Achalasia is associated with an increased risk of esophageal cancer, both squamous cell carcinoma and adenocarcinoma. Gastroesophageal Reflux Disease and Complications Gastroesophageal reflux disease (GERD), the reflux of gastric contents back into the esophagus, is a common disorder of the esophagus. GERD can occur idiopathically or in association with a hiatal hernia (see below). Reflux most often causes retrosternal burning pain, commonly referred to as heartburn (pyrosis), though it can cause a pressure-like sensation in the chest that can radiate into the neck, jaw, and arms. This pain syndrome can mimic cardiac angina and must, therefore, be distinguished from this life-threatening disease. Pathologically, reflux can induce inflammation that is usually mild but can occasionally be more severe, causing ulceration, bleeding, and the formation of strictures. In a minority of individuals, chronic inflammation can cause a transition of the normal squamous esophageal mucosa into Page 3 ALU 201: Intermediate Medical Life Insurance Writing glandular gastric mucosa. Further changes to the mucosa (i.e., metaplasia) causing it to resemble intestinal cells (i.e., intestinalization) is Barrett’s esophagus. Barrett’s can be detected visually using upper endoscopy. The instrument can be passed through the mouth to the duodenum allowing visualization, as well as biopsy, and the performance of therapeutic procedures (therapeutic esophagogastroduodenoscopy [EGD]). Endoscopically Barrett’s esophagus appears as pink areas of mucosa in an esophagus that ordinarily is a pearly white color. Confirmation, however, must be done microscopically on a biopsy specimen. Barrett’s esophagus is significant because it is a premalignant process. Over time, the newly transformed, intestinalized cells can become dysplastic (premalignant). The dysplasia is described as either low-grade or high-grade. Both grades have a high incidence of developing into an overt adenocarcinoma, with high-grade dysplasia being more ominous with a high mortality rate. Both grades require close follow up with frequent surveillance endoscopy and biopsies. Barrett’s can be treated with endoscopic therapies, such as radiofrequency ablation and photodynamic therapy, but, even after treatment, close surveillance to check for recurrence is required. Another complication of reflux is the aspiration of gastric contents into the respiratory tract causing bronchospasm and, in severe cases, pneumonia. GERD is usually diagnosed by history and confirmed by endoscopy, x-ray studies, and/or pH monitoring of the esophagus. GERD is treated with anti-reflux measures including: 1. 2. 3. 4. avoidance of citrus fruits, tomatoes, fats, coffee, alcohol, chocolate, and cigarettes restricting food intake for several hours prior to reclining raising the head of the bed weight loss. Acid-reducing medications and promotility drugs are frequently used to treat GERD. Surgery is undertaken when the GERD is severe and not responsive to the above measures. The most common surgery, in which the stomach is wrapped around the lower esophagus, is a Nissan fundoplication performed with a fiberoptic surgical instrument (laparoscope). Esophageal Squamous Cell Cancer Esophageal cancer, unrelated to reflux and Barrett’s esophagus, is usually squamous cell carcinoma (SCC). In the United States, there is a significant correlation between smoking and alcohol abuse and esophageal squamous cell carcinoma. In the past, SCC was the most common form of esophageal cancer, but now adenocarcinoma associated with Barrett’s esophagus is more common. All esophageal cancers have a high mortality rate. Esophageal Hernias As mentioned earlier, the stomach normally lies in the abdominal cavity with the gastroesophageal junction being just below the level of the diaphragm. When the stomach pushes up through the diaphragm into the chest, it is called an esophageal or hiatal hernia. There are two types of hiatal Page 4 Chapter 1: The Gastrointestinal System hernias – a sliding or axial hiatal hernia and a paraesophageal hernia (Figure 3). The former hernia results in the gastroesophageal junction being above the level of the diaphragm. Hiatal hernias are very common and usually do not result in symptoms; however, the abnormal position of the lower esophageal sphincter can allow the gastric contents to reflux into the esophagus more readily. A paraesophageal hernia occurs when part of the stomach folds back upon itself and gets trapped in the diaphragmatic ring. This hernia occurs with much less frequency than hiatal hernias. With this hernia, the gastroesophageal junction stays below the diaphragm. Strangulation of the stomach can occur with paraesophageal hernias, causing necrosis. This can be life threatening and often requires surgical repair. Esophageal hernias are detected by x-ray studies or endoscopy. Figure 3. Gastric and Duodenal Inflammation and Ulcer Disease The stomach and duodenum are both subject to inflammation and ulceration of the mucosa. Burning mid-epigastric pain, relieved by food or antacids, is the most common presentation. For years, the mechanism was felt to be strictly related to the acid content of the stomach and duodenum. Therefore, these ulcers are also referred to as peptic ulcers. The cause is now understood to be multifactorial and, in some instances, different for the stomach and the duodenum. There can be a genetic predisposition to ulcer disease. Stress has not been proven to induce or exacerbate ulcers. One of the most common causes of gastric and duodenal inflammation and ulceration is aspirin and the group of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). These include medications such as ibuprofen (Motrin®, Advil®) and naproxen (Naprosyn®, Aleve®). Alcohol is another common irritant to the gastric and duodenal mucosa causing inflammation, erosion, and Page 5 ALU 201: Intermediate Medical Life Insurance Writing ulceration. Cigarette smoking inhibits the healing of ulcers. Ulceration of the stomach can also be secondary to a gastric cancer. Approximately 1% of gastric ulcers are malignant. To rule out malignancy, it is standard practice to biopsy all significant gastric ulcers via endoscopy and to perform a follow-up endoscopy of large ulcers to verify that complete healing has occurred. The main complications of inflammation and ulceration of the stomach and duodenum are bleeding and, more rarely, perforation. Duodenal ulcers and pyloric channel ulcers can cause gastric outlet obstruction because of swelling. Gastritis, duodenitis, and ulcer disease are all treated with medications aimed at reducing the acid content of the stomach, no matter what the causative agent. These medications include liquid or tablet antacids (Maalox®, Mylanta®), H2 blockers (cimetidine/ Tagamet®, ranitidine/Zantac®, famotidine/Pepcid®), and proton pump inhibitors (omeprazole/ Prilosec®, esomeprazole/Nexium®, pantoprazole/Protonix®, lansoprazole/Prevacid®, rabeprazole/ Aciphex®). Diagnosis is made by endoscopic or x-ray evaluation. There is some suggestion that PPIs are associated with a small increased risk of coronary artery disease and renal insufficiency. These findings are still controversial, but the degree of increased risk is very small and not likely a significant insurance risk. Helicobacter Pylori In the early 1980s, it was determined that a small bacterium, Helicobacter pylori (H. pylori), was one of the causes of antral gastritis. It was later determined that H. pylori also plays a major role in duodenal and gastric ulcer disease that is not caused by aspirin or nonsteroidal anti-inflammatory agents. Ulcers and gastritis can be healed with traditional acid reducing agents but if H. pylori is present and not treated with antibiotics, there is a high likelihood of recurrence. Atrophy of the stomach lining (atrophic gastritis) and a small increased risk of gastric adenocarcinoma have also been linked to the bacteria. H. pylori also causes mucosa-associated lymphoid tissue (MALT) lymphoma, a type of gastric lymphoma. This tumor can regress with antibiotic treatment of the H. pylori. H. pylori can be detected directly by microscopic examination of a biopsy specimen. It can be detected indirectly through serum antibody testing, stool testing, or biopsy testing to detect urea produced by the bacteria (CLO-test or Pyloritek) or by a breath test to detect the urea. Pancreatic Disorders Pancreatitis The pancreas produces insulin and digestive enzymes. Inflammation of the pancreas, or pancreatitis, can be acute or chronic. It can be caused by alcohol, blockage by gallstones (gallstone pancreatitis), medications, infection, autoimmune disease, hypertriglyceridemia with triglyceride levels >1000, and idiopathically. Acute pancreatitis has a high mortality rate. The diagnosis is based on elevated serum amylase and lipase levels and imaging studies (e.g., ultrasound, CT scan, MRI, and/or magnetic resonance cholangiopancreatography [MRCP]). The inflamed pancreas can cause fluid and debris to collect adjacent to the pancreas, which over time can form into a cyst-like mass—a pseudocyst. Once resolved, the mortality risk of acute pancreatitis is Page 6 Chapter 1: The Gastrointestinal System determined by the underlying cause and the likelihood of recurrence. Chronic pancreatitis can cause inadequate insulin production (diabetes) and inadequate digestive enzyme production (pancreatic insufficiency) leading to malabsorption and weight loss. Diabetes often requires insulin injections. Pancreatic insufficiency requires oral digestive enzymes with meals (Creon®, Pancrease®). Pancreatic Tumors Solid Lesions The pancreas can be affected by tumors. These are categorized as benign, malignant, or hormone-producing (endocrine) tumors. The most common tumor of the pancreas is pancreatic adenocarcinoma, which has a very high mortality rate. The most common endocrine tumors are: 1. gastrinomas (Zollinger-Ellison syndrome) that cause refractory stomach and duodenal ulcers 2. insulinomas that cause precipitous low blood sugar (hypoglycemia) 3. vasoactive intestinal peptide producing tumors (VIPomas) that cause watery diarrhea 4. glucagonomas that cause hyperglycemia, diabetes, necrolytic migratory erythema and thromboembolic complications. These conditions cause disease by their mass effect, the effect of the excess hormone, and the spread to lymph nodes or the liver. They are often multiple and difficult to identify on imaging studies, thus making treatment difficult. Cystic Lesions Pancreatic cysts are fluid filled lesions that are often found incidentally at the time of imaging for other reasons. They present a diagnostic dilemma as to whether they are benign or malignant. Determination of the nature of the lesion and the risk it represents is made through various techniques including endoscopic retrograde cholangiopancreatography (ERCP), CT scan, MRI, MRCP and endoscopic ultrasound-guided biopsy or fine needle aspiration (FNA). Fluid withdrawn from cysts can be sent for cytology, measurement of CEA and amylase and DNA analysis. Worrisome features include size > 3 cm, any solid component, dilated pancreatic duct and rapid growth. Cysts with no worrisome features require surveillance and can be monitored with follow-up imaging studies at 1, 3 and 5 years. Those with worrisome features require FNA and, if suspicious for malignancy (e.g. elevated CEA, high risk DNA analysis, malignant cells on cytology), they require surgical resection. The management of these lesions is complicated and still evolving. These lesions are characterized as follows: Page 7 ALU 201: Intermediate Medical Life Insurance Writing No malignant potential Pseudocyst Lymphoepithelial cyst Retention cyst Congenital cyst Endometrial cyst Cystic lymphangioma Cavernous hemangioma Serous cystic adenoma Malignant potential Malignant Intraductal papillary mucinous neoplasm (IPMN) Mucinous cystic neoplasm Intraductal tubular tumor Cystic ductal adenocarcinoma Cystic neuroendocrine tumor Solid pseudopapillary neoplasm Cystic pancreatoblastoma Cystic acinar cystadenocarcinoma Malabsorption and Diarrhea Abnormal or inadequate absorption of nutrients occurs because of insufficient breakdown of food, disruption of the intestinal lining, loss of absorptive surface area or the too rapid passage of food through the intestines. Insufficient breakdown of food can occur because of the inadequate production of pancreatic digestive enzymes (i.e., pancreatic insufficiency) or the blockage of the flow of pancreatic fluid into the duodenum. Blockage can be caused by tumor, stones, or a stricture of the pancreatic duct or ampulla of Vater. The blockage of the bile flow into the duodenum by tumors, stones, or strictures can interfere with the absorption of fats and fat-soluble vitamins. Other digestive enzymes produced in the intestine can also be inadequately produced, causing maldigestion and thus malabsorption. A common example of a mild form of insufficient intestinal enzyme production is lactase deficiency, causing the inability to digest the milk sugar, lactose (i.e., lactose intolerance). Disruption or destruction (i.e., blunting) of the villous surface of the small intestine, resulting in a decreased absorptive surface area, is another cause of malabsorption. This can occur due to infection, such as viral or bacterial gastroenteritis, or an immune or allergen-mediated destruction, such as celiac sprue (gluten-sensitive enteropathy). Clinically, malabsorption manifests with bloating, diarrhea, weight loss, abdominal pain, anemia, low serum albumin, osteoporosis, and other symptoms of vitamin deficiency. Celiac sprue is the most common cause of small bowel mucosal blunting. Diagnosis is initially assessed with serum antibody tests. Elevated IgA tissue transglutaminase (IgA tTG) with normal total serum IgA levels is the most reliable test though often other tests – anti-gliadin antibodies and endomysia tissue antibodies area also done. Definitive diagnosis is usually made with a biopsy of the duodenum performed during an upper endoscopy. All patients with celiac disease are HLADQ2 and/or HLA-D8 positive so a negative genetic marker rules out celiac sprue. Conversely, 30% of people without sprue can be HLA-D8 positive without having sprue. Celiac sprue is associated with a small risk of lymphoma and adenocarcinoma of the small intestine especially in those with poorly controlled disease. A lifelong gluten free diet is usually sufficient to treat celiac sprue, but, in rare cases, steroids can be needed. Page 8 Chapter 1: The Gastrointestinal System If food and water are not absorbed in the small intestine, the excess volume is presented to the large intestine. When this volume overwhelms the colon’s absorptive capacity, diarrhea (defined as greater than 200 grams of stool per day) occurs. Diarrhea can also occur as the result of infection of the large intestine, either by bacteria or viruses, which can inhibit absorption of water, cause increased secretion of water, or stimulate too rapid transit through the large intestine. Inflammatory Bowel Disease – Crohn’s Disease and Ulcerative Colitis In addition to ulceration and malabsorption, the small intestine can be affected by Crohn’s disease. Crohn’s disease, also known as granulomatous or regional enteritis, is an inflammatory process that can affect any part of the gastrointestinal tract, but most frequently affects the distal third of the small intestine (ileum) and the colon. The etiology is unclear but is felt to have an autoimmune basis. Crohn’s disease needs to be distinguished from the other inflammatory bowel disease (IBD), ulcerative colitis (UC). Ulcerative colitis affects only the large intestine. The evaluation of inflammatory bowel disease often includes endoscopic evaluations (usually colonoscopy but occasionally upper endoscopy), lab tests for anemia, infection, markers of inflammation (ESR – sed rate, CRP) and various imaging studies. Standard CT scanning is the most used imaging modality. A small bowel x-ray series is sometimes done to look for disease beyond the colon when Crohn’s disease is suspected. Beyond the initial diagnosis, small bowel evaluation is often done with either CT enterography or MRI enterography. Both studies can evaluate mucosal changes, strictures, fistulas, and abscesses. MRI has the advantage of not using radiation. In addition to location, there are other significant differences between these two disease entities (Table 1). Crohn’s disease can affect the bowel in a non-continuous pattern, creating what is known as skip lesions. With this, affected individuals can have areas of severe inflammation with intervening normal mucosa. Ulcerative colitis, conversely, always involves the rectum and is continuous to some proximal part of the large intestine. Crohn’s disease affects all layers of the bowel and can, therefore, be complicated by strictures, fistulas, and abscesses. The inflammation of ulcerative colitis is limited to the mucosa; therefore, the former complications do not occur unless there is a concomitant malignancy. Microscopically, Crohn’s can reveal granulomas (aggregates of giant cells). This does not occur in ulcerative colitis. In Crohn’s disease involving the colon (Crohn’s colitis) and in UC, there is an increased risk of colon cancer. It is well established that eight to ten years after the initial onset of the disease, there is a steady, significant, increased risk of developing cancer. This risk increases with the extent of the disease, i.e., how far up the colon the disease has spread and with the severity of the inflammation. Ulcerative colitis that is limited to the rectum (the distal 15 centimeters of the colon) is called ulcerative proctitis. Ulcerative proctitis and ulcerative proctosigmoiditis (up to 25 centimeters) have a small, increased cancer risk. Appropriate management of individuals with ulcerative or Crohn’s colitis for more than 10 years consists of full colonoscopy every one to two years, looking for overt cancer and performing multiple random biopsies looking for microscopic patches of dysplasia. Once dysplasia has been found, total colectomy (i.e., removal of the colon) is necessary to avoid future malignancy. Page 9 ALU 201: Intermediate Medical Life Insurance Writing The treatment goal for Crohn’s disease is to put the individual into remission. This is done with antibiotics, steroids (e.g., prednisone, budesonide/Entocort EC®), immunosuppressive agents (e.g., 6 mercaptopurine or 6MP, azathioprine/Imuran®), and/or sulfasalazine (Azulfidine®). Once remission is achieved, the medications can be tapered. Maintenance of the medications does not prevent relapse. Ulcerative colitis is treated with antibiotics, sulfasalazine or one of its derivatives (olsalazine/ Dipentum®, balsalazide/Colazal®, mesalamine/Pentasa®, Asacol®, Lialda® and Canasa® or Rowasa® enemas), and/or steroids. Sulfasalazine is often used to maintain remission and prevent relapse. Infliximab (Remicade®), Adalimumab (Humira®), Certolizumab pegol (Cimzia®), Golimumab (Simponi®), Natalizumab (Tysabri®), Vedolizumab (Entyvio®) and the recently approved Ozanimod® (Zeposia) are in a class of drugs known as biologic disease modifying agents (DMARDs). These drugs are used to avoid the prolonged need for steroids. They can be used in difficult to treat cases as well to maintain remission. They are associated with an increased risk of infections and a small risk of lymphoma and possibly other malignancies. Most of these medications are given intravenously or by injection every two to eight weeks; however, Ozanimod is an oral treatment. Surgery for Crohn’s disease is often palliative and required to treat a complication of the disease (e.g., a fistula). Surgery for ulcerative colitis with a total colectomy, including the rectal mucosa, is curative. The simplest operation consists of creating an ileostomy, a procedure that requires connecting the terminal ileum to an opening in the skin in the right lower quadrant of the abdomen, with an external bag to collect the fluid. A more complicated procedure, ileoanal anastomosis, involves attaching the ileum to the anus with the creation of an internal pouch. This allows for normal evacuation, though usually with five to six bowel movements a day. Inflammation of the pouch (pouchitis) is a complication of this surgery and can be refractory to treatment. From an underwriting perspective, Crohn’s disease mortality is associated with bleeding, malabsorption, complications of the medications used to treat the disease, and late cancer risk, as well as obstructive, infectious, and surgical complications. With ulcerative colitis, there is the risk of acute disease-causing bleeding, acute dilation (i.e., toxic megacolon), and perforation of the colon. When acute symptoms of ulcerative colitis are not severe, mortality is most significantly affected by the increased risk of cancer. Both Crohn’s disease and ulcerative colitis are associated with extraintestinal complications including ankylosing spondylitis, arthritis, iritis, pyoderma gangrenosum, and erythema nodosum. Liver tests can be affected by Crohn’s disease, causing elevated AST, ALT, and GGT. This is felt to be secondary to nonspecific inflammation around the microscopic bile ducts and is of little clinical significance. Abnormal liver enzymes in ulcerative colitis, predominantly alkaline phosphatase and GGT, can be the result of primary sclerosing cholangitis (PSC). In this poorly understood disease, the bile ducts throughout the liver become scarred and narrowed, causing obstruction of bile flow. This eventually leads to cirrhosis and death. It is also associated with an increased risk of bile duct cancer. PSC persists even after colectomy. Page 10 Chapter 1: The Gastrointestinal System Table 1. Differences between Ulcerative Colitis and Crohn’s Disease Rectal bleeding Abdominal Pain Rectal involvement Fistula formation Stricture, obstruction Perianal, perirectal abscesses Type of involvement Depth of involvement Small bowel involvement Risk of malignancy Ulcerative Colitis Common Uncommon Almost 100% No Only with malignancy Uncommon Continuous Mucosa & submucosa Not involved Greatly increased Crohn’s Disease Occasionally Common 50% Common Common Common Discontinuous (skip areas) Transmural Often involved Moderately increased Irritable Bowel Syndrome Inflammatory bowel disease (IBD) must be distinguished from the more common entity, irritable bowel syndrome (IBS). IBS is believed to be a disorder of the motor function of the gastrointestinal tract, creating areas of spasm and pain. This entity does not cause inflammation, bleeding, or obstruction. Several common lay terms used for this syndrome – spastic or mucous colitis – are, therefore, misnomers. Individuals present with symptoms of diarrhea, abdominal pain, bloating, and/or constipation. There is almost never any weight loss and symptoms usually do not occur during sleep. It is believed that psychological stress can influence this syndrome, unlike Crohn’s or ulcerative colitis, neither of which is affected by stress. Thus far, no diagnostic test has been devised to diagnose IBS. It is usually a diagnosis of exclusion based on the history and the absence of findings on endoscopic or x-ray tests. Treatment usually consists of fiber products, antispasmodics, antidiarrheal agents, and/or laxatives. There is no mortality risk from IBS but there can be significant morbidity issues. Tumors and Intestinal Polyps The large intestine is the part of the gastrointestinal tract that is most often affected by neoplasms. Neoplasms begin as outgrowths of the luminal surface of the colon and are called polyps. These can be broad-based (sessile) or on a stalk (pedunculated). They generally are slow growing. The histology of the polyp determines the malignancy potential. Pre-malignant polyps can be adenomas – tubular adenomas, villous adenomas, or tubulovillous adenomas. By definition, these polyps are low-grade dysplastic polyps. The larger or more villous the polyp is, the higher is the malignant potential. Serrated polyps or serrated adenomas are other premalignant polyps. Benign polyps with no malignant potential include hyperplastic, inflammatory, or isolated juvenile polyps. Juvenile polyposis syndrome, on the other hand, is associated with a high risk of colorectal cancer (see Table 2 below). Most polyps tend to be multiple in number and frequently new polyps arise over Page 11 ALU 201: Intermediate Medical Life Insurance Writing time. Several inherited syndromes have been identified in which numerous polyps occur. These polyposis syndromes are outlined in Table 2. Table 2. Polyposis Syndromes. Syndrome Polyp type/ Predominant location Familial Adenomatous Adenoma/Colon Polyposis (FAP) and Attenuated FAP Gardner’s Syndrome – Adenoma/Colon FAP plus other lesions Other intestinal lesions Possible Gardner’s or Turcot Syndrome Extraintestinal lesions Ampulla of Vater tumors Small intestinal tumors Turcot Syndrome – Adenoma/Colon FAP plus brain tumors MYH Polyposis Adenoma, serrated/ Colon See above Osteomas Congenital hypertrophy of the retinal pigment epithelium (CHRPE) Mesenteric desmoid tumors Brain tumors Hereditary NonPolyposis Colon Cancer (HNPCC or Lynch Syndrome) Peutz-Jeghers Syndrome Adenoma/Colon Stomach, small intestine, and biliary cancer Hamartoma/Small intestine Polyps: Stomach, colon Polyps: Renal pelvis, Cancer: Stomach, colon bronchus, gall bladder, nasal passages, bladder, and ureter. Cancer: Pancreas, breast, and ovary, cervix Dark spots on lips, inside cheeks, fingers Juvenile Polyposis Hamartoma/Colon Entire GI tract polyps -benign with malignant transformation risk Duodenal cancer Possible Gardner’s or Turcot Syndrome Ovary, bladder, skin, papillary thyroid cancer. Sebaceous gland tumors thyroid nodules. ? increased risk for breast and endometrial cancer. Endometrial, ovarian, prostate, ureter, and kidney cancer Pancreas Treatment of non-inherited benign polyps consists of polypectomy. This is usually performed by colonoscopy, during which a fiberoptic flexible tube is passed through the anus to the cecum. Follow-up with periodic colonoscopy is essential for all pre-malignant and malignant polyps to monitor for new lesions and recurrence of prior cancers. Colon polyps and cancer occur more Page 12 Chapter 1: The Gastrointestinal System frequently after the age of 50. Screening with fiberoptic colonoscopy beginning at age 50 in average risk individuals and at age 40 (or ten years before the age at diagnosis of the youngest affected relative, whichever is earlier) in those with a family history of colon polyps or cancer has become routine. The American Cancer Society recently changed their guidelines to recommend that colorectal cancer screenings begin at age 45, instead of 50, because colorectal cancer cases are on the rise among young and middle-aged people. Repeat colonoscopy in three to five years in those individuals with premalignant polyps or a family history is recommended. In all others, the current recommendation is a repeat colonoscopy in eight to ten years. Virtual colonoscopy (CT colonography) is a noninvasive, radiographic technique for colon polyp/ cancer screening. It is not as reliable as standard colonoscopy and still requires a colonoscopy to biopsy or to remove any lesions found. Other, less sensitive methods of screening for colon polyps include stool testing for blood (guaiac, occult blood, or Hemoccult® cards, FIT testing), barium enema, flexible sigmoidoscopy, and/or stool testing for cancer DNA (Cologuard). Colon cancer spans the spectrum from carcinoma in situ, which is confined to the superficial layer of the bowel, to invasive cancer. Colon cancer spreads locally to adjacent lymph nodes and organs. Most frequently, it metastasizes to the liver, lung, and brain. Prognosis is determined by the extent of the disease. Diverticular Disease of the Colon Diverticula are outpouchings of the colon. They occur most commonly on the left side of the colon but can be located throughout the large intestine. Diverticulosis, the existence of these pockets, is a very common finding but is usually asymptomatic and found incidentally. When diverticulosis does present with symptoms, it does so in one of two ways: lower intestinal hemorrhage or diverticulitis. Lower intestinal hemorrhage can spontaneously occur from a bleeding diverticulum. The diverticulum is almost never inflamed when hemorrhage occurs. The bleeding usually stops spontaneously but can require surgery or an angiographic embolization procedure. Diverticula can also become inflamed and infected, causing the condition diverticulitis. This presents with abdominal pain and often fever. There may be an intra-abdominal abscess. Occasionally, an infected diverticulum can perforate, causing a life-threatening abdominal cavity infection (peritonitis). Treatment for diverticulitis without perforation usually consists of bowel rest (i.e., nothing ingested by mouth) and antibiotics. Surgery can be required for recurrent episodes of diverticulitis and for perforations. Gastrointestinal Bleeding Gastrointestinal bleeding spans the spectrum from small amounts of bleeding to massive hemorrhage. Signs and symptoms often depend on the acute or chronic nature of the bleeding, as well as the volume of blood lost. Small volume and infrequent bleeding episodes often go undetected. Individuals are often asymptomatic. An evaluation for small volume gastrointestinal bleeding can be prompted by the discovery of iron deficiency anemia on routine complete blood Page 13 ALU 201: Intermediate Medical Life Insurance Writing count (CBC) or microscopic quantities of blood detected using Hemoccult® cards. The clinician will pursue a work-up using patient history, physical exam, and eventually endoscopic and/or x-ray testing. The causes of slow gastrointestinal bleeding include esophagitis, gastritis, duodenitis, inflammatory bowel disease, vascular anomalies, gastric and duodenal ulcers, and malignant and benign tumors throughout the gastrointestinal tract. Hemorrhoids (i.e., dilatation of the rectal veins) rarely cause iron deficiency anemia though they can cause positive Hemoccult® cards. Attributing significant gastrointestinal blood loss to hemorrhoids should only be done after an extensive workup has revealed no other source and the hemorrhoids bleed frequently and profusely. Large volume acute gastrointestinal blood loss can be caused by any of the entities that can cause slow blood loss. Clinically, acute gastrointestinal bleeding is divided into upper and lower gastrointestinal sites. Upper gastrointestinal bleeding (above the jejunum) usually presents with vomiting of blood (i.e., hematemesis) and/or melena (i.e., black, tarry stools). The most common sources of large volume upper gastrointestinal bleeding are: 1. 2. 3. 4. esophageal varices (distended veins secondary to portal hypertension) ulcers severe gastritis Mallory-Weiss tear (tear of the lower esophagus usually after vomiting). Lower gastrointestinal bleeding usually presents with bright red blood per rectum. Large volume lower gastrointestinal bleeding (hematochezia - bloody stools) is most caused by: 1. 2. 3. 4. diverticulosis arteriovenous malformations (AVMs) polyps cancers. Mortality is associated with the underlying cause, the acute complications associated with rapid blood volume loss (syncope, shock, and myocardial infarction), and the risks of the therapy needed to control and treat bleeding (surgery and transfusions). For underwriting purposes, the cause of the bleeding is the key to determining the mortality risk. In older age groups, colon cancer is the major impairment of concern in view of its high incidence and high mortality risk. In younger age groups, inflammatory causes and their concomitant mortality risk are the concern. Intestinal Obstruction Intestinal obstruction can be caused by: 1. blockages within the small or large intestine by tumors, polyps or foreign bodies 2. bowel twisting on itself (volvulus) 3. adhesions from prior surgery or prior intrabdominal infection causing tethering of the bowel and obstruction Page 14 Chapter 1: The Gastrointestinal System 4. telescoping of the bowel on itself (intussusception) 5. herniation of the bowel through the abdominal wall, inguinal ligament, or diaphragm. The last four conditions also cut off the blood supply to the intestine and can result in ischemia or infarction with gangrene and risk of perforation. Volvulus, obstruction due to adhesions, herniation and even intussusception can resolve on their own with “bowel rest” – gastric suction and not taking anything by mouth. If this is not successful, then surgery is required. Intestinal Ischemia Any disruption of blood flow to the intestines can cause ischemia. In addition to obstruction cited above, blood flow can be diminished by clotting of the intestinal arteries. This can occur due to gradual narrowing due to atherosclerosis, a clot due to a hypercoagulable condition, or an acute embolism. A sudden drop in blood pressure can also result in ischemia of the bowel. Decreased blood flow causes damage to the mucosa and bleeding. Prolonged ischemia can result in necrosis and gangrene with perforation. Ischemic colitis of the left colon can often mimic colitis due to infection or inflammatory bowel disease. Often, the cause of ischemia is unknown. It can resolve on its own with bowel rest but can require surgery. Bariatric Surgery Obesity has become an epidemic in the United States. Surgery to induce weight loss has become more common with newer, easier surgical techniques. The most common operations performed in the U.S. are gastric bypass (also known as a Roux-en-Y bypass), sleeve gastrectomy, and an adjustable gastric band (i.e., lap banding). These procedures are most performed laparoscopically rather than through an open incision. Gastric bypass involves dividing the stomach so that a smaller reservoir is created and connecting it to a part of the small intestine so that it empties further down the intestine. This causes intended partial malabsorption. A sleeve gastrectomy involves removing the pouch-like portion of the stomach, creating a narrow “sleeve–like” shaped stomach. The lap band is a silicone ring that is placed around the outside of the upper stomach. It is connected to an injectable port that is placed under the skin. This allows for the injection of saline into the band to adjust the tightness. Obsolete or rarely performed procedures are vertical banded gastroplasty and biliopancreatic diversion with or without a duodenal switch. These have fallen out of favor due to the associated structural and metabolic complications of these procedures. The goal of bariatric surgery is to facilitate weight loss to improve overall health with decreased morbidity and mortality. Weight reduction varies between 45-80% of excess weight corresponding to an approximately 60-120-pound loss. This occurs over the first 12-18 months with gastric bypass and sleeve gastrectomy and 24 months with the lap band. Once individuals attain their desired body weight, over time they can be expected on average to regain about ten percent of the weight lost. There is a small amount of 30-day post-operative mortality (66%. The treatment of NAFLD is primarily focused on the modification of risk factors to prevent progression of the disease. These measures include weight loss, dietary modifications that reduce carbohydrate and fat intake, and tighter of control of hyperlipidemia and diabetes/insulin resistance. Risk factors for disease progression are: 1. 2. 3. 4. 5. 6. 7. 8. histologic evidence of hepatic inflammation older age DM heavy alcohol use elevated serum transaminases presence of ballooning degeneration plus Mallory hyaline or fibrosis on liver biopsy BMI >28 higher visceral adiposity index, which is determined by assessing the waist circumference, BMI, TG and HDL. There is some controversy regarding the mortality risk of NAFLD. Some studies show an increase in cardiovascular mortality while others show no increased risk of all-cause mortality. People with NASH are at increased risk of liver-related deaths compared to those without NASH. Alcoholic Liver Disease Alcohol use is widespread in the U.S. with approximately 75% of the population consuming alcohol at least occasionally. Approximately 10% of this group abuse alcohol or are alcohol dependent. Chronic and excessive alcohol ingestion is one of the major causes of liver disease in the western world. The spectrum of alcoholic liver disease ranges from alcohol-associated fatty liver (steatosis) to alcohol-associated steatohepatitis and eventually to alcohol-associated cirrhosis, which may lead to hepatocellular carcinoma. Fatty liver is present in over 90% of binge and chronic drinkers. It is estimated that a third of people with steatosis will progress to steatohepatitis if they continue to drink. Cirrhosis is more likely to develop in someone with steatohepatitis than steatosis. Although alcohol is considered a direct hepatotoxin, only 10% to 20% of alcoholics will develop alcoholic hepatitis. While quantity and duration of alcohol intake are the most important risk factors involved in the development of alcoholic liver disease, the roles of beverage type and pattern of drinking are less clear. Progression of hepatic injury beyond the fatty liver stage seems to require additional risk factors that remain incompletely defined. Page 34 Chapter 2: Liver and Bile Duct Disorders Risk factors for alcoholic liver disease include: 1. 2. 3. 4. 5. 6. 7. quantity of alcohol consumed female gender hepatitis C (HCV) genetic variability in alcohol-metabolizing enzymes malnutrition co-exposure to drugs or toxins immunologic dysfunction. Continued alcohol ingestion results in fat accumulation throughout the entire hepatic lobule. Despite extensive fatty change and distortion of the hepatocytes with macrovesicular fat, the cessation of drinking results in normalization of the hepatic architecture and fat content within the liver. Cirrhosis The World Health Organization defines cirrhosis as “…a diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules that lack normal lobular organization.” It results in irreversible chronic injury of the hepatic parenchyma and includes extensive fibrosis in association with the formation of regenerative nodules. The following criteria are used to determine a diagnosis of cirrhosis: 1. pronounced, insufficiently repaired necroses of the parenchyma (with or without inflammatory processes) 2. diffuse connective tissue proliferation 3. varying degrees of nodular parenchymal regeneration 4. loss and transformation of the lobular structure within the liver as a whole 5. impaired intrahepatic and intra-acinar vascular supply. Cirrhosis is classified based on etiology of the disease because (1) morphologic classification is more difficult to determine due to the overlap of findings among different etiologies, and (2) treatment and prognosis are based on etiology. The major causes of cirrhosis in the U.S. include alcohol, chronic infection (hepatitis B, C), autoimmune hepatitis, and NASH. The structural changes in the liver cause impairment of hepatic function, resulting in jaundice, portal hypertension, esophageal varices, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, and coagulopathy. Jaundice Serum bilirubin levels reflect the liver’s ability to take up, process, and secrete bilirubin into the bile. Excessive levels of bilirubin stain the fatty tissues of the skin yellow, resulting in jaundice. Jaundice, or icterus, is a yellowish discoloration of skin, conjunctiva, and mucous membranes that occurs as a result of hyperbilirubinemia. Page 35 ALU 201: Intermediate Medical Life Insurance Writing There are three classes of causes for jaundice: 1. pre-hepatic or hemolytic jaundice – a result of increased breakdown of red blood cells 2. hepatic jaundice 3. extrahepatic jaundice (obstructive jaundice). Portal Hypertension The liver has a dual blood supply: arterial blood (25%) from the general circulation and venous blood (75%) supplied by the portal circulation in the liver. The portal vein receives venous blood from the intestine, spleen, pancreas, and gallbladder. In a normal liver, this system allows blood to flow through the hepatic lobules to be filtered so that nutrients can be metabolized, and toxins excreted. Once this is completed, blood flows through the hepatic vein into the inferior vena cava, which transports the venous blood back to the right side of the heart. Normal pressure in the portal vein is low. Portal hypertension is defined as abnormally high pressure in the portal circulation. Clinically significant portal hypertension is present in >60% of those with cirrhosis because of increased resistance to blood flow through the liver. This increased resistance leads to the development of collateral veins that divert blood flow to the general circulation, bypassing the liver. Major sites of collateral flow involve the veins around the cardioesophageal junction (between the lower esophagus and upper part of the stomach), the rectum, retroperitoneal space, and the falciform ligament of the liver. At these sites, the vessels develop varicosities, becoming engorged and dilated, while the vessel walls become thin and fragile. Also, because the collateral blood vessels bypass the liver, detoxification of the blood does not occur. As toxins build up in the systemic circulation, hepatic encephalopathy develops, resulting in significant neurologic changes. Increased pressure in the portal blood vessels can cause protein-containing (ascitic) fluid from the surface of the liver and intestine to leak into the abdominal cavity (ascites). The major clinical manifestations include hemorrhage from gastroesophageal varices, splenomegaly with hypersplenism, ascites, and acute and chronic hepatic encephalopathy. Portal hypertension occurs in the presence of cirrhosis after considerable irreversible injury to the liver has significantly impaired its functional capacity. It is consistent with end-stage liver disease. Esophageal Varices Approximately 50% of those with alcoholic cirrhosis will develop esophageal varices within two years of diagnosis, and 70% to 80% will do so within ten years. In individuals with cirrhosis secondary to hepatitis C, the risk is lower, in that 30% develop esophageal varices within six years of the initial diagnosis of cirrhosis. Individuals with cirrhosis who develop large esophageal varices because of portal hypertension have a 25% to 35% risk of variceal hemorrhage and a 30% to 50% mortality rate associated with each bleeding episode. Page 36 Chapter 2: Liver and Bile Duct Disorders Esophageal varices are dilated blood vessels within the wall of the esophagus that develop because of portal hypertension. This dilation can be profound. The original diameter of the blood vessels is measured in millimeters while the esophageal varices can be 0.5 to 1.0 cm or larger in diameter. As the blood vessels dilate, the walls of the vessels become increasingly stretched and thin, making them extremely fragile and at risk of rupture. Variceal bleeding usually occurs spontaneously without obvious precipitating factors. The individual typically presents with painless but massive hemorrhage, which accounts for the high mortality rate associated with a variceal bleed. Each episode of hemorrhage is life threatening and requires immediate medical attention. Ascites Ascites is defined as the pathological accumulation of fluid within the peritoneal cavity. In the United States, 85% of cases of ascites occur in the setting of cirrhosis. The presence of ascites in an individual with cirrhosis represents advanced progression of disease — 50% of those with ascites will die within two years. Other causes of ascites include other liver diseases, malignancy, heart failure, infection, and pancreatitis. Ascitic fluid infections develop primarily in individuals with pre-existing ascites in the setting of cirrhosis and less commonly in those with subacute liver disease. Those with ascites and cirrhosis carry a 10% annual risk of developing an ascitic fluid infection without an apparent primary source of infection. The most common is spontaneous bacterial peritonitis. Hepatorenal Syndrome Hepatorenal syndrome (HRS) refers to the development of acute renal failure in individuals with advanced chronic liver disease and fulminant hepatitis, who have portal hypertension and ascites. Estimates indicate that at least 40% of individuals with cirrhosis and ascites will develop HRS within five years of the development of their disease. It is characterized by: 1. marked decrease in glomerular filtration rate (GFR) and renal plasma flow in the absence of other identifiable causes of renal failure 2. marked abnormalities in systemic hemodynamics 3. activation of endogenous vasoactive systems. Although the exact cause is unknown, the pathology involved in the development of HRS is thought to be an alteration in blood flow and blood vessel tone in the splanchnic circulation, which is the circulation that supplies the intestines, and in renal circulation. It is an extreme manifestation of circulatory dysfunction and is usually indicative of an end-stage of perfusion to the kidneys due to deteriorating liver function. Page 37 ALU 201: Intermediate Medical Life Insurance Writing Hepatic Encephalopathy Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs in the setting of significant liver disease. The specific cause of HE is unknown. It is characterized by disturbances in consciousness and behavior, personality changes, fluctuating neurologic signs, asterixis or “flapping tremor,” and distinctive electroencephalographic changes. Encephalopathy can be acute and reversible or chronic and progressive. In severe cases, irreversible coma and death can occur. Coagulopathy Individuals with cirrhosis demonstrate a variety of abnormalities in both cellular and humoral clotting function. Thrombocytopenia can result from hypersplenism. In the alcoholic individual, there can be direct bone marrow suppression due to the alcohol. Diminished protein synthesis can lead to reduced production of fibrinogen, prothrombin, and factors V, VII, IX, and X. In cirrhosis, factor VII is the first of the factors to be depleted. Bleeding generally occurs when the prothrombin time becomes elevated and the platelet count drops to 5 cm or who are experiencing symptoms should undergo surgical resection. Men have an increased risk of malignant transformation and should undergo surgical resection, regardless of the size of the adenoma. Hemangioma Hemangioma is the most common benign tumor of the liver. Due to vascular malformation, thin-walled spaces, which are filled with blood and lined with endothelium, develop. Most often, they are found incidentally and have no major clinical implications. The estimated prevalence ranges from 0.4% to 20%. Page 46 Chapter 2: Liver and Bile Duct Disorders In most cases, hemangiomas are small and asymptomatic. When symptoms are present, right upper quadrant abdominal pain is common. Less commonly are nausea, anorexia, and early satiety. Infrequently, they can grow to a large size and can press or displace adjacent structures. In an asymptomatic individual, no treatment is recommended, and the person is observed for the development of symptoms. The follow up imaging surveillance is determined by size. A lesion < 5 cm does not require any follow up imaging. A lesion > 5 cm should be imaged in 6 to 12 months and if it found to be stable, no further imaging is recommended. Bleeding from a ruptured hemangioma is rare and is not related to the lesion size. Although hemangiomas can increase in size over time, they have no potential to become malignant. They usually do not require treatment; there is no additional mortality risk associated with hemangiomas. Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is the second most common benign solid tumor of the liver found predominantly in women. Diagnosis is often made based on specific tumor characteristics found on CT. The lesions are often stable or regress and do not require any treatment or surveillance. The risk of bleeding is minimal and there is no risk of malignant transformation. If diagnosis cannot be made, liver biopsy or surgical resection can be indicated to rule out hepatocellular carcinoma. Hepatic Cysts Most liver cysts are found incidentally on imaging studies and tend to have a benign course. However, a minority can cause symptoms and rarely can be associated with serious morbidity and mortality. Larger cysts are more likely to cause complications, such as spontaneous hemorrhage, rupture into the peritoneal cavity, compression of biliary ducts, and rupture into the biliary tree. Specific types of cysts can have unique complications such as malignant transformation. The most common hepatic cysts are simple cysts. They are cystic formations that contain clear fluid and do not communicate with the intrahepatic biliary tree. The presence of a liver cyst does not cause elevation of liver enzymes. Their size ranges from a few millimeters to massive lesions of 30 cm or more. Simple cysts are usually solitary, but occasionally multiple cysts can be found. Only a small minority cause symptoms and complications are rare. Most simple cysts do not require treatment. Hepatocellular Carcinoma Primary hepatocellular carcinoma (HCC) is the most common non-metastatic malignancy of the liver, and the second most lethal tumor after pancreatic cancer. HCC is less common in most parts of the developed western world; its incidence is increasing. It is the most common cause of death in individuals with cirrhosis. Risk factors for development of HCC include cirrhosis, chronic hepatitis B and/or C, NASH, alcohol and tobacco usage, obesity, and DM. Although the prognosis of primary HCC is determined Page 47 ALU 201: Intermediate Medical Life Insurance Writing by the tumor grade and stage, the average survival is only five months from time of diagnosis. Metastatic tumors of the liver are common, ranking second only to cirrhosis as a cause of fatal liver disease. In the U.S., the incidence of metastatic carcinoma is at least 20 times greater than that of primary carcinoma. At autopsy, hepatic metastasis occurs in 30% to 50% of individuals dying from malignant disease. The most frequent sites of origin for hepatic metastases are lung, breast, gastrointestinal, and genitourinary tracts. Portal Vein Thrombosis Portal vein thrombosis is a form of venous thrombosis that affects the portal veins in the liver; it is the most common cause of non-cirrhotic portal hypertension. The most common causes of portal vein thrombosis include cirrhosis, malignancy, pancreatitis, hypercoagulable disorders, and sepsis. When blood flow through the portal vein is impeded, it causes hepatic inflow obstruction and increased pressure in the vascular bed. This leads to portal hypertension and its associated complications, including variceal bleeding, hepatic encephalopathy, and ascites. In cases where there is no associated cirrhosis, the primary complication that appears as a result of portal hypertension is variceal bleeding. The overall prognosis for portal vein thrombosis can be quite favorable in those individuals who do not have cirrhosis or a malignancy as an etiologic factor. In adults with portal vein thrombosis, the 10-year survival has been reported to be 38% to 60%, with most of the deaths occurring secondary to the underlying disease (e.g., cirrhosis, malignancy). In the absence of cirrhosis, the two-year bleeding risk from esophageal varices is reported to be 0.25% and of those that bleed the mortality rate is approximately 5%. Those with cirrhosis and varices have a 20% to 30% two-year bleeding risk with a mortality rate of 30% to 70%. This difference is primarily a consequence of the normal hepatic function in the non-cirrhotic individual. Wilson’s Disease Wilson’s disease is a rare, autosomal recessive inherited disorder of copper metabolism. It primarily affects the liver, brain, kidneys, eyes, and joints. Copper is an essential co-factor for many enzymes, and the maintenance of normal copper homeostasis depends on the balance between gastrointestinal absorption and biliary excretion. Copper is known to be hepatoxic at excess levels. As a result of these toxic changes, three major patterns of liver damage can occur: cirrhosis, chronic hepatitis, or fulminant hepatic failure. When the storage capacity of the liver for copper is exceeded or when hepatocellular damage results in the release of cellular copper into the circulation, levels of non-ceruloplasmin-bound copper in the circulation become elevated. Once this occurs, copper is deposited in extra-hepatic organs, primarily the brain. The primary complications associated with progressive disease include hepatitis leading to cirrhosis and destruction of basal ganglia in the brain. Page 48 Chapter 2: Liver and Bile Duct Disorders The areas of the brain affected by Wilson’s disease are those that coordinate movement. The three main neurologic problems are dystonia, incoordination, and tremor. Psychiatric features can also be present including behavioral, affective, schizophrenic-like, and cognitive abnormalities. The prognosis depends on the severity of disease at diagnosis and its appropriate management. If discovered early, recovery during the first two years of treatment is substantial. However, approximately 40% to 50% of individuals present with liver disease, and 35% to 50% present with neurologic or psychiatric symptoms. Early recognition is critically important since untreated Wilson’s disease is always fatal. Diagnosis is made using a scoring system that assesses specific biochemical tests, such as ceruloplasmin, urine copper and hepatic copper, clinical manifestations, and genetic mutation testing. Treatment of Wilson’s disease is done in two phases. The first removes or detoxifies the accumulated tissue copper and the second prevents re-accumulation. Chelating agents enhance excretion of copper and inhibit absorption of copper by the body. Oral zinc salts may be used to prevent copper absorption. A low copper diet needs to be followed and copper-rich foods avoided. Other measures include management of complications from the disease. Treatment of Wilson’s disease is life-long and crucial to improving life expectancy associated with the disease. Glycogen Storage Disease Glycogen storage disease (GSD) is a group of disorders that develop because of any one of several inborn errors of metabolism. These occur because of enzyme defects that affect the process of glycogen synthesis or its breakdown within the liver, muscles, and other cell types. The most common glycogen storage disease is type 1 disorder, glucose-6-phosphatase deficiency. The onset of symptoms usually occurs early in childhood but can manifest in infancy. Since individuals with type 1 GSD can store glucose as glycogen but not able to release it normally, over time, the stores of glycogen in the liver build up, causing hepatomegaly as well as enlargement of the kidneys. Levels of hormones, lactic acid, triglycerides, lipids, uric acid, and other metabolic by-products increase in the blood as the body attempts to raise blood sugar. Fats get stored in the liver along with the glycogen, causing further enlargement of the liver. The acute and rapid episodes of hypoglycemia can lead to seizures, cyanosis, and apnea. The continued presence of low blood sugar can eventually lead to delayed growth and development. Significant long-term complications of type 1 GSD include hepatic adenomas, hepatocellular carcinoma, progressive renal insufficiency, severe hypoglycemia, coma, brain damage, and severe anemia. These individuals can also develop chronic pancreatitis and inflammatory bowel disease. Treatment of type 1 GSD is aimed at maintaining normal blood glucose levels, maximizing growth and development, and preventing complications of the disease. Individuals who are promptly identified and properly treated should have reasonable life expectancy. Page 49 ALU 201: Intermediate Medical Life Insurance Writing Disorders of the Biliary Tract Gilbert’s Syndrome Gilbert’s syndrome is the most common hereditary cause of unconjugated hyperbilirubinemia and is found in approximately 5% of the population. This condition is characterized by intermittent jaundice in the absence of hemolysis or underlying liver disease. The hyperbilirubinemia is mild with considerable variation in bilirubin levels at any given time. Aminotransferases and alkaline phosphatase concentrations are normal. Hyperbilirubinemia can be precipitated by dehydration, fasting or stressors, such as vigorous exercise or illness. Individuals can report symptoms such as vague abdominal discomfort and general fatigue for which no cause is found. These episodes resolve spontaneously, and no treatment is required. Gilbert’s syndrome is a benign condition with no associated mortality risk. Cholangitis The term cholangitis refers to localized or diffuse inflammatory changes affecting the intrahepatic and extrahepatic bile ducts. Cholangitis can be acute or chronic. It can originate as a primary disease in the bile ducts or develop as a secondary consequence of another underlying disease. Acute Cholangitis Acute cholangitis is a syndrome that is characterized by fever, jaundice, and abdominal pain. While viral, parasitic, and mycotic organisms can cause acute cholangitis, bacterial infection is the most common cause. Acute cholangitis is a result of stasis and infection of the biliary tract. The most frequent causes of biliary obstruction are biliary stones, biliary stricture, and malignant obstruction, due to a tumor in the gallbladder, bile duct, ampulla, duodenum, or pancreas. Acute cholangitis can also be a complication from endoscopic retrograde cholangiopancreatography (ERCP). The incidence of complications is based on the severity of the disease as well as the underlying cause of the bacterial cholangitis. Treatment includes antibiotics, supportive care and biliary drainage or decompression. The complications that occur with this disease include liver failure, sepsis with septic shock, disseminated intravascular coagulopathy (DIC), infected portal thrombosis, acute renal failure, hepatic abscesses, metastatic abscesses, and catheter-related complications related to treatment. Mortality has improved with advances in treatment to a fatality rate of 11% but remains high in those with severe acute cholangitis at 20 – 30%. Prognosis depends on several factors, including early recognition and treatment, response to therapy, and elimination of underlying obstruction. Page 50 Chapter 2: Liver and Bile Duct Disorders Primary Sclerosing Cholangitis Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology whose incidence is higher in males with a median age at diagnosis of 41 years. It is frequently found in association with inflammatory bowel disease. Although the mechanisms responsible for the development of PSC are unknown, alterations in the immune system are thought to cause the disease. An autoimmune response, causing damage to the biliary tree, is the most likely etiology. PSC is characterized by fibrosing inflammation of both the intrahepatic and extrahepatic biliary tree. It is a progressive disease that results in irreversible damage to the bile ducts and ultimately leads to cholestasis, cirrhosis, and liver failure. Long-term follow up of those with PSC has revealed a high frequency of colon and bile duct cancers, both of which are probably related to the chronic inflammation of those structures. Medical therapies are not effective in preventing progression of the disease, and liver transplantation is the only effective therapeutic option for individuals with end-stage liver disease from PSC. A statistical model is used to predict survival and determine the timing of a liver transplant. The components of the model include age, serum bilirubin, serum albumin, serum AST and a history of variceal bleeding. Primary Biliary Cholangitis Primary biliary cholangitis (PBC), previously called primary biliary cirrhosis, is a rare form of liver disease caused by destruction of the bile ducts. It is characterized by cholestasis and progressive liver disease. Primary biliary cholangitis is a chronic and progressive cholestatic liver disease that predominantly affects middle-aged females. The etiology is unknown, although it is presumed to be autoimmune in nature. There also appears to be a genetic component, as familial occurrences have been observed. The major pathology of the disease is the continuous destruction of small and medium bile ducts, resulting in chronic cholestasis. After the loss of intrahepatic bile ducts, a disruption of the normal bile flow occurs with retention and deposition of toxic substances, which are normally excreted in bile. The retention of toxic substances, such as bile acids and copper, can cause a further secondary destruction of the bile ducts and hepatocytes, resulting in liver damage and eventual cirrhosis. The prognosis of PBC has improved with ursodeoxycholic acid (UDCA) treatment, leading to a normal life expectancy if treated in the early stage. Factors that are associated with a worse prognosis include the presence of symptoms at time of diagnosis, elevated alkaline phosphatase and bilirubin levels, advanced histological stage, presence of antinuclear antibodies, cigarette smoking and certain genetic mutations. Page 51 ALU 201: Intermediate Medical Life Insurance Writing Hepatic Sarcoidosis The liver is involved in most people with sarcoidosis but is only symptomatic in 5 to 15% of those diagnosed. If symptoms are present, they are commonly abdominal pain and pruritis. Hepatomegaly may be present. Most people will have elevation of the alkaline phosphatase and GGT. Rare complications include cirrhosis, cholestatic liver disease resembling sclerosing cholangitis and hepatic vein thrombosis. Alpha 1-Antitrypsin Deficiency Alpha 1-antitrypsin deficiency is a genetic disorder caused by a variety of mutations to the alpha 1-antitrypsin (A1AT) gene, leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT proteins in the liver. There are several forms and degrees of deficiency based on the type of gene mutation. The A1AT protein is produced in the liver; one of its functions is to protect the lungs from enzymes that can damage connective tissue and destroy alveoli. Deficiencies in normal A1AT production result in failure of this protective mechanism, with the development of significant pulmonary disease, primarily emphysema. This occurs in 75% to 80% of individuals with this deficiency. Damage to the liver is thought to be caused by accumulation of the mutant A1AT molecule in hepatocytes with subsequent hepatotoxicity, leading to cirrhosis and liver failure. People who develop end-stage liver disease are candidates for a liver transplant. The donor’s liver will correct the A1AT deficiency by producing and secreting the normal protein, slowing the progression of the lung disease in some recipients. Gaucher’s Disease Gaucher’s disease is one of the most common lipid storage diseases. It occurs as a result of mutations to the gene that regulates lipid storage and is characterized by the deposition of a glycolipid that is accumulated in the body. The severity of the disorder is extremely variable and depends upon the type of gene mutation. Gaucher’s disease exists in three clinical forms, delineated by the absence or presence of neurologic involvement and its progression: 1. Type 1 - is distinguished by the lack of central nervous system involvement and is the most common form, and onset can occur at any age. It is more common among individuals of Ashkenazi Jewish descent. Clinical features include hepatosplenomegaly, thrombocytopenia, and pathologic bone fractures. The disease is associated with an increased risk of malignancy. 2. Type 2 – Infantile or acute neuronopathic commonly results in death within the first two year of life. These individuals develop hepatosplenomegaly and progressive neurologic deterioration. 3. Type 3 – Juvenile or subacute neuronopathic is a less severe form of the disease that affects children. It progresses more slowly with survival into late adolescence and early adulthood. Page 52 Chapter 2: Liver and Bile Duct Disorders The abnormal accumulation of the glycolipid in the bone marrow, liver, spleen, lungs, and other organs contributes to pancytopenia, massive hepatosplenomegaly, and occasionally diffuse infiltrative pulmonary disease. The factors that contribute to neurologic involvement in types 2 and 3 disease may be related to the accumulation of cytotoxic glycolipids in the brain. Many individuals with type 1 Gaucher’s disease have few manifestations and a normal life expectancy without any intervention. The prognosis for symptomatic individuals with types 1 and 3 disease who receive treatment is also favorable. Reye’s Syndrome Reye’s syndrome is a rare disorder characterized by acute noninflammatory encephalopathy and hepatic failure. It occurs almost exclusively in children, although very rare cases in adults have been reported. Although the etiology of this syndrome is unknown, it typically occurs after a viral illness, particularly an upper respiratory infection, influenza, varicella or gastroenteritis, and it is associated with the use of aspirin during the illness. Early recognition and treatment are essential to prevent death and to minimize the risk of neurologic impairment. The incidence has fallen dramatically since 1980 following the identification of aspirin use as a risk factor and the advisories against its use in febrile children. Death usually occurs because of cerebral edema or increased intracranial pressure, but death can also be due to myocardial dysfunction, cardiovascular collapse, respiratory failure, renal failure, GI bleeding, status epilepticus, or sepsis. Individuals who survive can have complete recovery, although neurologic impairment is common in children. Page 53 ALU 201: Intermediate Medical Life Insurance Writing Review Questions – ALU 201, Chapter 2 1. Functions of the liver include all the following EXCEPT: 1. 2. 3. 4. storing iron destroying damaged white blood cell removing toxin synthesizing cholesterol 2. An accumulation of excess fluid within the abdominal cavity is: 1. 2. 3. 4. icterus jaundice ascites cholestasis 3. All of the following statements regarding the hepatitis B virus surface antigen (HBsAg) are correct EXCEPT: 1. 2. 3. 4. It is the earliest marker of acute infection. It measures the viral load. It appears before onset of symptoms. It clears by the convalescence stage of acute infection. 4. Name and differentiate between the liver function tests (LFTs) that are used as the basis for screening the liver for underlying pathology. 5. Define Wilson’s disease and describe its treatment options and prognosis. Page 54 Chapter 2: Liver and Bile Duct Disorders 6. Medical treatment for hepatitis C includes which of the following? A. interferon alpha B. methotrexate C. ribavirin Answer Options: 1. 2. 3. 4. A and B only are correct. A and C only are correct. B and C only are correct. A, B, and C are correct. 7. Non-alcoholic fatty liver disease (NALFD) can be caused by all the following EXCEPT: 1. 2. 3. 4. obesity hypertension metabolic syndrome insulin resistance 8. What are the primary factors that affect prognosis in hereditary hemochromatosis? 9. Discuss the correlation between liver enzyme levels and liver histology in nonalcoholic fatty liver disease (NAFLD). 10. What are the major causes of cirrhosis? Page 55 ALU 201: Intermediate Medical Life Insurance Writing Answers and Sources of Review Questions Review Question 1 Answer 2: destroying damaged white blood cells – pages 25-26. Review Question 2 Answer 3: ascites – page 37. Review Question 3 Answer 2: It measures the viral load – page 40. Review Question 4 Refer to pages 26-30. Review Question 5 Refer to pages 48-49. Review Question 6 Answer 2: A and C only are correct – pages 42-43. Review Question 7 Answer 2: hypertension – pages 32-34. Review Question 8 Refer to pages 44-46. Review Question 9 Refer to pages 32-34. Review Question 10 Refer to page 35. Page 56 CHAPTER 3 FOUR CANCERS Malignant Melanoma of the Skin Prostate Cancer Breast Cancer Colorectal Cancer CLIFTON TITCOMB, MD Cliff Titcomb, MD retired as Chief Medical Director at Hannover Re after 30 years in the insurance industry. He was active in AAIM, having served as President, was the Medical Consultant to “On the Risk,” contributed articles to the Journal of Insurance Medicine and “On the Risk,” and was a regular presenter at industry meetings such as AHOU, AAIM, and regional meetings. He is now a consultant medical director with International Medical Risk Consultants, Inc. Chapter revision and edits BRADLEY HELTEMES, MD Brad Heltemes, MD is VP and Medical Director of R&D/Innovation at Munich Re where he is involved in mortality research, medical underwriting consultation, client support and underwriter education, and the assessment of medical and technological trends. He is active in the American Academy of Insurance Medicine (AAIM), being a Past President and Scientific Program chair, and the current Finance Committee Chair. He is a member of the Morbidity and Mortality Committee and an instructor for the Basic Mortality Methodology Course. He has written and spoken on mortality and underwriting topics on numerous occasions throughout the industry, including at the past five AAIM Triennial Meetings. Revised 2019 Copyright 2022 The Academy of Life Underwriting FOUR CANCERS Introduction This chapter presents information on cancers of the breast, prostate, colon and rectum, and malignant melanoma of the skin. These cancers were chosen because of their importance in underwriting. What makes malignancies of importance in the risk selection process is the frequency with which they are seen, their associated mortality risk, and the time course of the illness. The latter is of relevance because conditions that have a more protracted course have a longer period when an individual is alive and able to apply for insurance, while remaining at increased risk for early mortality. Proposed insureds with tumors that are rapidly fatal, such as lung cancer, infrequently survive long enough to apply for insurance. The challenge for underwriters is to appropriately assess that extra risk in the cases they do see. The best way to accomplish this is with a thorough knowledge of the cancer in question. Tumors of the breast and prostate are the most diagnosed cancers in females and males, respectively, and the second leading causes of cancer death in each of the sexes after lung cancer. In addition, the clinical course is often prolonged with these malignancies, making it very common for underwriters to encounter proposed insureds with a history of the disease who still fall within the insurable range. Colon and rectal tumors have the third highest incidence and death rates from cancer in both males and females and are, thus, both frequently encountered and of practical importance in the risk selection process. Malignant melanoma, while far less common than the other tumors cited, has had the fastest growing incidence rate of any other cancer world-wide. It is increasingly seen in the underwriting environment and a serious mortality risk, if deeply invasive. In addition, its clinical course is often quite prolonged. The chapter is presented in four separate sections: Section A - Malignant Melanoma of the Skin Section B - Prostate Cancer Section C - Breast Cancer Section D - Colorectal Cancer. ALU 201: Intermediate Medical Life Insurance Writing Page 60 Chapter 3: Four Cancers Section A Malignant Melanoma of the Skin Malignant melanoma has increasingly become a problem for underwriting professionals. The overall number of clinical cases of melanoma has been increasing at the annual age adjusted rate of 2-4% per year in the United States, and this increase has carried over into the insurance environment. Insurers have had to deal with a rising number of cases in their underwriting files. While most lesions are limited and have no significant extra mortality risk, a sizable subset carries a substantial probability of premature death. Thus, a thorough understanding of the tumor, its clinical parameters, risk factors, and likely outcomes is important in order to segment the risk appropriately. Melanoma is a tumor resulting from the malignant transformation of the cells that produce the pigment melanin. These cells can be found in a variety of tissues, but this discussion will center on those found in the skin. The median age at diagnosis for malignant melanoma was 59 to 63 years in blacks and Caucasians and 52 to 56 years in other ethnic groups. It represents about 4-5% of all skin malignancies. In the United States, it is the fifth most common cancer in both males and females and it is estimated that approximately 96,480 individuals will be diagnosed with the disease and 7,230 will die from it in 2019. Incidence rates worldwide have been increasing rapidly in recent years as well. The highest rates are found in Australia and New Zealand. However, the pace at which the incidence rates have increased has diminished to some degree in the last 10 years compared to prior time periods. For non-Hispanic whites in the U.S., the lifetime risk for developing melanoma is 1 in 28 for males and 1 in 44 for females. Of note, the greatest increases in incidence rates have been in older males and in young females. Despite the increase in incidence of the disease, in the U.S. the mortality rates have followed a more irregular course and have been relatively flat over the past 20 years. To a large extent because the disease is being diagnosed at earlier stages in the U.S., 84% of melanomas are localized at time of diagnosis, with only 9% having extension to regional nodes or in-transit and 4% with distant metastases, and thus the overall prognosis is quite good. Risk Factors Race and Gender The risk for developing melanoma is highest in Caucasians. The relative risk (comparing the risk in one group to another) for the development of a cutaneous melanoma is 20:1 for whites compared to non-whites. Overall, males are more likely to develop the disease than females, and their lesion distribution pattern is different. The tumor is more likely to develop on the head and neck in males. In females, lesions on the extremities and torso are more common. However, in those under the age of 49, the disease is more common in females. Age Melanoma is primarily a disease of adults and is uncommon before puberty, even in those with a genetic predisposition. Fewer than 1% of lesions are diagnosed in children, although the incidence Page 61 ALU 201: Intermediate Medical Life Insurance Writing rate in this group has been increasing. Older individuals have the highest incidence rate and poorer survival, with a more aggressive disease that is more likely to be located on the head and neck. Sun Exposure Perhaps the most commonly recognized risk factor for melanoma is sun exposure. Intermittent, intense, recreational exposure appears to impart a higher risk than the overall time spent in the sun. For example, sunburns, both in childhood and as an adult, increase the probability of a later melanoma development (RR 2.1). Skin tone also matters. The highest risk is in fair-skinned individuals who have freckles. Compared to dark-haired individuals, the relative risk for development of melanoma is 1.8 in blondes and 2.4 in those with red hair. The use of tanning beds has led to an increase in melanoma with a relative risk of 1.25. Younger age at exposure carries a higher relative risk of 1.69. This increased risk can explain the recently noted higher number of melanoma cases in younger females. Ultraviolet (UV) radiation appears to be the principle culprit in producing tumors. Both UVA (wavelength 320-400 nm) and UVB (290-320 nm) rays are carcinogenic. Most sunscreens effectively block UVB rays; however, adequate cancer protection requires the use of special ingredients that also block the full spectrum of UVA radiation. These are not available in all products, and one cannot rely on a product’s sun protection factor (SPF) rating alone as an indication of UVA protection. Organ Transplantation and Prior History of Cancer The risk of developing malignant melanoma is increased three to four times in individuals with a history of organ transplantation. In addition, the prognosis is poorer in those individuals. The risk of developing melanoma is also greater in those individuals with a history of a prior melanoma or other forms of skin cancer and in those with a history of other non-cutaneous, adult or childhood, malignancies. Benign Nevi The presence of benign nevi also increases the risk for developing melanoma. For common nevi, the probability of developing melanoma increases with the number and size of the lesions. For five or more nevi greater than 5 mm in size, or 50 or more nevi greater than 2 mm in size, the relative risk (RR) is approximately three-times that of those not meeting these criteria. Congenital nevi (those present at birth) also increase the risk, again related to the size of the primary lesion. For congenital nevi greater than 20 cm in size, the lifetime risk of malignant transformation is 5-8%. The histology of the lesion is also important. Atypical (Dysplastic) Nevi Atypical nevi represent another well-recognized risk factor. These lesions are found in 2-7% of the Caucasian population, but in 25-40% of individuals with a melanoma. Development of Page 62 Chapter 3: Four Cancers melanoma within a dysplastic nevus is unusual and, thus, it is not necessary to remove all atypical lesions. The real significance of atypical nevi is as a marker for a higher risk of developing melanoma. The risk increases with the number of atypical nevi and is up to 10 times higher in individuals with five or more lesions. Atypical nevi are nevi characterized by a larger size (>5 mm) and two or more of the following characteristics: 1. variable pigmentation 2. irregular outline 3. indistinct borders. For those with atypical nevi, the risk of melanoma is increased further if family members also have these lesions or have had a melanoma and is increased substantially if there is family history of both. When multiple family members are affected there becomes an increasingly higher likelihood of familial atypical multiple mole and melanoma (FAMMM) syndrome, a genetic condition caused by a mutation in the CDKN2A gene that imparts a high risk of developing melanoma – approximately 30% chance by age 50 and close to an 80% lifetime risk – along with an increased risk of pancreatic and brain cancers. Despite these associations, it should be remembered that the presence of risk factors is not a requirement for the development of a tumor. The majority of melanomas arise anew (i.e., not from a pre-existing nevus or mole). Only 20-30% of cases are the result of the transformation of a preexisting skin lesion. Histologic Subtypes Definitive diagnosis of melanoma requires a skin biopsy and microscopic examination. However, clinically suspicious lesions can be identified using the so-called ABCDE criteria. In these criteria: 1. 2. 3. 4. 5. A = asymmetry of the lesion B = border irregularity C = color variation D = diameter greater than or equal to 6 mm E = evolving with changes over time (growth, color variation, itching, bleeding). Thus, the classic melanoma will be a large, pigmented lesion that has an asymmetrical shape, an irregular, poorly-demarcated border, a varying color pattern or one that may be changing over time. However, many tumors do not follow the typical pattern. Most clinicians have learned to be cautious and frequently will biopsy lesions that meet only a few of these criteria. It has been shown that the use of dermoscopy improves diagnostic accuracy for melanoma over naked-eye examination and use of this technology suggests a better level of surveillance for those at risk. Occasionally, melanoma lesions can lack pigment. These are designated amelanotic melanoma. These lesions are very difficult to detect and require a high degree of clinical concern and acumen to diagnose. Page 63 ALU 201: Intermediate Medical Life Insurance Writing There are four major histologic subtypes of melanoma: 1. 2. 3. 4. superficial spreading melanoma nodular melanoma lentigo maligna acral lentiginous melanoma. Superficial Spreading Melanoma Superficial spreading melanoma is the most common subtype (60-70%) and can occur in both sun- and non-sun-exposed areas of the body. It is characterized by irregular margins and pigment variation. In these lesions, growth is initially in a radial manner along the skin surface, but it eventually enters a vertical phase in which spread is into the deeper dermal layers. As will be discussed later, risk of metastasis and, consequently, mortality risk increase as the thickness of the tumor increases. Nodular Melanoma Nodular melanoma is the next most common subtype (15-30%) and is characterized by a dark blue-black or bluish-red uniformly colored lesion. It has a more rapid onset than superficial spreading melanoma, and it goes more rapidly into the dangerous vertical growth phase. Nodular melanomas are more commonly found in males and on the trunk of the body. Lentigo Maligna Lentigo maligna occurs in about 5% of cases and is generally found in older individuals. It occurs most commonly on sun-exposed skin, especially on the face, and frequently arises from a pre-existing benign pigmented lesion known as a Hutchinson freckle. These lesions are generally thin and tend to be indolent, or more slowly progressive, in character. They usually carry a better prognosis than either superficial spreading or nodular melanomas. Acral Lentiginous Melanoma Acral lentiginous melanomas are the least common subtype. They frequently occur on the palm, sole, or under the nail and are more common in individuals with black or dark complexions. They are often difficult to diagnose because of their location and generally carry a poorer prognosis than the other subtypes. Prognostic Factors for Mortality The most important prognostic factors for mortality in melanoma are the depth of invasion, the presence or absence of ulceration, the mitotic rate, and if there are metastases to lymph nodes or other sites. With an increasing depth of invasion, called the Breslow level, (generally expressed in millimeters), the risk of metastasis and mortality steadily rises. The thicker the lesion, the higher the risk, and there is no critical level below which the risk is zero. It should be kept in mind that the Page 64 Chapter 3: Four Cancers individual’s immune system can attack the tumor, leading to some regression of the original lesion. In this case, the measured depth on pathological examination can be less than the true prognostic depth. The presence of ulceration is also an important prognostic factor. The term ulceration does not mean that the lesion has a classic ulcer crater. Instead, it means that pathologically (i.e., under the microscope) there are no skin surface cells or epidermis overlying the tumor. Thus, the malignant cells extend through the skin surface layer. Prognostically, invasion through the epidermis is a marker for metastatic potential. Though no longer part of the staging criteria, the presence of mitoses, or dividing cells on microscopic examination, remains an important independent prognostic factor. Individuals with one or more detectable mitoses per square millimeter have a significantly reduced survival, and that risk increases with increasing numbers of mitoses. The presence of metastases to lymph nodes and elsewhere is a particularly adverse prognostic feature, though cures can occasionally be obtained, primarily when only a small number of lymph nodes are involved and they have only microscopic amounts of tumor. The presence of palpable lymph nodes, a thick or ulcerated primary tumor, and, especially, metastases to non-regional nodes and other sites, are particularly adverse features. A number of other prognostic factors of importance have been identified. These include: 1. Age of onset – The incidence rate of melanoma is higher in older individuals as is the number of cases with advanced disease, but increasing age is an independent risk factor as well. However, the relative risk for mortality is greater in those under age 50, due to the lower expected death rate in younger individuals. 2. Anatomic site – Lesions on the trunk, head, and neck have a higher relative mortality risk. 3. Vascular invasion with malignant cells produces an increase in the risk for death, similar to that seen with ulceration 4. Clark level – An indicator of the level of skin (e.g., epidermis, papillary dermis, reticular dermis, and subcutaneous fat) to which the tumor has invaded: a. Clark level I – epidermis only b. Clark level II – upper portion of the papillary dermis c. Clark level III – fills the papillary dermis d. Clark level IV – reticular dermis e. Clark level V –subcutaneous fat. The Clark system is familiar to most underwriters and has been used in the past as a major prognostic indicator. However, recent data has confirmed that the Clark level of invasion is of little or no prognostic importance when the presence of ulceration and the mitosis count are taken into account. In addition, some other prognostic factors which have been identified include: Page 65 ALU 201: Intermediate Medical Life Insurance Writing 1. Microsatellites (i.e., nests of tumor cells separated from the main body of the lesion), being a marker for the ability of the tumor cells to implant and survive, are associated with a greater depth of invasion and predictive of an increased risk of relapse and reduced survival. 2. Tumor infiltrating lymphocytes represent an inflammatory immune response to the lesion and a greater response is associated with thinner tumors and a better outcome. 3. With increasing age, males tend to present with more advanced lesions than females