90981 ch FM 10/12/06 10:17 AM Page vi 90981 ch FM 10/12/06 10:16 AM Page i 90981 ch FM 10/12/06 10:16 AM Page ii 90981 ch FM 10/12/06 10:17 AM Page iii 90981 ch FM 10/12/06 10:17 AM Page iv Acquisitions Editor: David B Troy Development Editor: Dana L Knighten Marketing Manager: Marisa A O'Brien Production Editor: Jennifer P Ajello Designer: Terry Mallon Art Direction: Jennifer Clements, LWW; Craig Durant, Dragonfly Media Group Artists: Rob Fedirko, Rob Duckwall, and Paige Henson, Dragonfly Media Group Compositor: Maryland Composition, Inc Printer: R.R Donnelley & Sons–Willard Copyright © 2007 Lippincott Williams & Wilkins 351 West Camden Street Baltimore, MD 21201 530 Walnut Street Philadelphia, PA 19106 All rights reserved This book is protected by copyright No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner The publisher is not responsible (as a matter of product liability, negligence, or otherwise) for any injury resulting from any material contained herein This publication contains information relating to general principles of medical care that should not be construed as specific instructions for individual patients Manufacturers’ product information and package inserts should be reviewed for current information, including contraindications, dosages, and precautions Printed in the United States of America Librar y of Congress Cataloging-in-Publication Data McConnell, Thomas H The nature of disease : pathology for the health professions / Thomas H McConnell p ; cm Includes bibliographical references and index ISBN-13: 978-0-7817-5317-3 (alk paper) Pathology—Textbooks I Title [DNLM: Pathology QZ M4789n 2007] RB111.M21 2007 616.07—dc22 2006027273 The publishers have made every effort to trace the copyright holders for borrowed material If they have inadvertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320 International customers should call (301) 223-2300 V i s i t L i p p i n c o t t Wi l l i a m s & Wi l k i n s o n t h e I n t e rn e t : h t t p : / / w w w.LW W.com Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST 06 07 08 09 10 10 90981 ch FM 10/12/06 10:17 AM Page v This book is dedicated to: Hazel and T.H for gifts Marianne for unconditional love Anne, Allen, Lea, and Jim for keeping the faith Helen for pure devotion Jack, Margot, Andrew, Conner, JuJu, Kate, and Missa for hope Charles Ashworth for generosity Vernie Stembridge for showing me the way Adam, Clint, and Jason for renewal Mark and Peggy for good example William Marsh Rice, founder of Rice University and the citizens of Texas for a rigorous and free education 90981 ch FM 10/12/06 10:17 AM Page vi 90981 ch FM 10/12/06 10:17 AM Page vii Preface The Nature of Disease is a short textbook of pathology, but it took a long time to write Each sentence has been crafted for a particular audience: students studying for a degree in the health professions This text’s aim is twofold: • To present basic normal anatomy and physiology and contrast them with the essential pathology and pathophysiology of the most common and important human diseases • To make the material enjoyable and easy to read Classroom Vetted This textbook literally grew out of a classroom When I joined the academic community after a career in private practice, the classroom was an alien place to me I puzzled over the fact that the students I taught, who were of the very highest quality, still had trouble grasping the topics I began to pay more critical attention to the textbooks I had selected for them, and I quickly learned the student perspective of most pathology texts: they are difficult to read Most pathology books are compilations written by multiple authors, each with a certain writing style and with differing views about the relative importance of things The style is generally stilted and formal—the text doesn’t flow, and the reading is bare of enjoyment If I had a hard time with these texts, what about the students? And so I concluded to write an outline of pathology for them—a simple bullet list of important statements written in declarative sentences that I was sure were clear and easy to understand This proved a success, but the students wanted more The demand grew, and my simple outline soon became a self-published, spiralbound manual After three editions of this manual, I realized I had the makings of a textbook in my hands The result is The Nature of Disease Approach Having spent much of my professional life communicating with physicians buried in a blizzard of paper, I know that brevity, manner, and style are the essence of written communication The Nature of Disease adopts a deliberately casual, narrative style that served me well in medical practice It makes reading easier, holds the reader’s attention, and enhances understanding and recall of important points without sacrificing scientific relevance The Nature of Disease focuses on answering the most important questions that students and patients have about every disease: what?, why?, where?, and how? It does so by concentrating on the nuts and bolts of human pathology: the causes and the mechanisms of disease, its progress, and its outcome The science is flavored with a bit of humor to offer a break from the scientific drill Along the way, the text uses a number of devices to deepen understanding, retain interest, and enhance recall: • Much of the molecular and microscopic detail typically found in similar textbooks has been eliminated Each chapter focuses on the essentials necessary to build a broad, fundamental understanding, with supporting detail where relevant • Clinical examples from daily life are integrated throughout to explain basic concepts For example, fever blisters (cold sores, herpesvirus infection) illustrate the pathology of virus infections Placing disease in a realistic, familiar context enhances recall and develops insight • Key points and concepts are reiterated where appropriate Rather than assume that the reader recalls the details, the text errs (judiciously) on the side of restating the obvious Experience shows that students benefit from the redundancy • New terms are boldfaced and defined at their first use in the narrative This practice alerts the reader to the importance of the new term, which is defined in the same sentence or the one immediately following • Selected important points are italicized for emphasis For example, in Chapter 11, Diseases of Blood Cells and Blood Coagulation, the following italicized sentence emphasizes the threat of colon cancer: Iron deficiency anemia in a man or postmenopausal woman is to be considered bleeding from gastrointestinal cancer until proven otherwise vii 90981 ch FM 10/12/06 viii 10:17 AM Page viii Preface • The narrative is sprinkled with quotations—serious, whimsical, or humorous—to humanize the material and make the subject matter more memorable For example, Chapter 13, Diseases of the Heart, begins with a line from singer Tim McGraw’s tune, “Where the Green Grass Grows”: “ another supper from a sack, a ninety-nine cent heart attack ” This snippet of lyric speaks volumes about the American diet and heart disease, and students invariably enjoy and remember it • The History of Medicine boxes further humanize the narrative by presenting historical anecdotes that put in its historical perspective For example, in Chapter 10, Disorders of Daily Life and Diet, the box titled “French Food, Fast Food, Fat Food” discusses the history of restaurants, the development of fast food in America, and the rise of obesity The “History of Medicine” box is my favorite feature Organization Although this textbook is unique in many ways, it is organized in a familiar fashion: it presents general aspects of pathology first, with the pathology of organ systems following Part 1, General Pathology, opens with a chapter titled The Nature of Disease, which discusses the actual nature of disease—that is, the intimate relationship between form and function in both health and sickness This chapter also emphasizes the difference between the disease itself and the signs and symptoms it produces The failure of health care professionals and their patients to appreciate this distinction accounts for a great deal of medical misdirection and misunderstanding The remainder of Part consists of a series of chapters that deal with pathologic forces that can affect any part of the body: the life and death of cells, inflammation and repair, disorders of fluid balance and blood flow, neoplasia, genetic and pediatric diseases, infectious disease, diseases of diet, workplace and environment, and diseases of the immune system Part establishes the foundation, and Part 2, Diseases of Organ Systems, expands understanding by discussing diseases of particular organs and organ systems Along the way the narrative is stitched together with liberal use of cross-references In early chapters they are used to steer the reader to more detailed discussion in later chapters In later chapters they are used to recall earlier discussion of basic concepts For example, in Chapter 21, Diseases of the Female Genital Tract and Breast, the discussion of dysplasia of the cervix calls on the reader to understand the concept of metaplasia, which was defined and discussed initially in Chapter The cross-reference is presented in the following sentence: “However, during puberty the ectocervix is transformed by metaplasia (Chapter 2) from flat squamous cells into tall, columnar glandular cells.” Art Program No textbook of human pathology can succeed without an excellent art program Both photographs and line drawings are necessary for a thorough understanding of the subject Line art simplifies the structures and concepts depicted by distilling them to their basic, most easily recognizable forms, while photographs show anatomic structures as they appear in real life The Nature of Disease is richly illustrated with both More than 600 full-color figures augment the discussions in this book In keeping with the core notion that anatomic form and function go hand in hand in health and disease, this text contains more pathologic gross photographs of patients and organs than comparable texts Each photograph has been chosen to illustrate a critical point and is intended to speak for itself The guiding principle in developing medical line art is that good art should be understandable at a glance, or with minimal study The high-quality line drawings in this book have been designed both to be esthetically pleasing and to guide the reader’s thought without needing to read a lengthy description Chapter Features: A Guided Tour Think of reading this textbook as a road trip through unfamiliar territory: there is a lot to see, and the driver (reader) needs a roadmap, a short list of the most important things to see, and reference material to study in detail Each chapter contains a set of consistent chapter opener features; narrative content with supporting features such as sidebar boxes, tables, and figures; and endof-chapter features to promote retention and comprehension CHAPTER OPENER FEATURES The chapter opener contains several features to help to orient and prepare the reader for the material that follows: • A brief overview of the chapter content provides a thumbnail sketch of what to expect • A chapter outline of major headings and subheadings serves as a large-scale atlas of the material ahead 90981 ch 15.qxd 374 10/9/06 10:11 AM Page 374 Part • Diseases of Organ Systems contamination One is amebic dysentery, caused by Entamoeba histolytica, a protozoan that burrows deeply into the colonic wall and, in about half of cases, spreads up the portal vein to the liver to produce amebic abscesses It is passed by oral-fecal contamination The other protozoal infection is giardiasis The agent is Giardia lamblia, a noninvasive protozoan that mainly affects the duodenum and small bowel and may produce an acute diarrhea or a chronic malabsorption syndrome MALABSORPTION SYNDROMES Malabsorption syndrome is characterized by poor intestinal absorption of nutrients (especially fats), electrolytes, minerals, and water Malabsorption with fatty stools (steatorrhea) is called sprue There are two types of malabsorption: luminal phase malabsorption and intestinal phase malabsorption Luminal phase malabsorption is caused by problems that occur in the lumen of the bowel, such as absence of pancreatic digestive enzymes Luminal phase malabsorption is most often caused by pancreatic disease and the absence of a fat-digesting enzyme (lipase) from the pancreas (Chapter 17), or by liver or biliary disease (Chapter 16) that causes a lack of bile salts that would otherwise alter dietary fat to make it soluble in water (emulsification) Intestinal phase malabsorption is caused by defects of the bowel itself, such as surgically shortened bowel Another cause is lack of mucosal digestive enzymes One such disease is lactose (milk sugar) intolerance because of absence of a mucosal enzyme necessary for lactose digestion Yet another is gluten-sensitive enteropathy (celiac sprue), an autoimmune disease caused by hypersensitivity to gluten, a protein in wheat, oats, barley and rye, which causes atrophy of mucosal villi and marked decrease of mucosal absorptive surface area It may present at any time from infancy to adulthood Removal of gluten from the diet results in dramatic improvement, but patients retain a slight increased risk for intestinal lymphoma and other malignancies These types of sprue are sometimes collectively called nontropical sprue Tropical sprue is a poorly understood disease that mimics gluten-sensitive enteropathy—villi are atrophic and absorption is impaired—however, it occurs almost exclusively in persons living in or visiting the Caribbean islands An infectious agent is suspected because antibiotic therapy is effective, but no causal agent has been identified Patients with malabsorption syndrome have bulky, frothy, greasy, yellowish, and especially malodorous stools They lose weight and suffer from abdominal distention and excessive gas, and, because of the loss of critical nutrients, they also suffer from a variety of diseases of other organ systems: • Hematopoietic disorders: anemia from failure to absorb iron, B12, or folic acid, and bleeding tendency caused by vitamin K deficiency owing to poor intestinal absorption of vitamin K • Musculoskeletal disorders: weak, brittle bones, and tetany (muscle spasms) from defective calcium and vitamin D absorption • Hormonal disorders: amenorrhea, impotence, and infertility from malnutrition • Skin disorders: purpura from vitamin K deficiency; osmotic edema associated with low levels of albumin as a result of protein deficiency; various other skin disorders resulting from other nutrient deficiencies • Nerve disorders: peripheral nerve disease (peripheral neuropathy) from vitamin A and B12 deficiency Laboratory tests are available to detect specific varieties of malabsorption An example is the D-xylose absorption test D-xylose is a nondigestible sugar that is absorbed and excreted unchanged into urine and whose absorption is not dependent on luminal-phase factors Therefore, in a patient with malabsorption syndrome, absorption of a normal amount indicates that the intestinal mucosa is functioning normally and the defect is in the luminal phase; decreased absorption indicates the defect is in mucosal absorption INFLAMMATORY BOWEL DISEASE Inflammatory bowel disease implies one of two rather common conditions—ulcerative colitis or Crohn disease They are similar in certain ways Both feature: • • • • Episodic bloody diarrhea Autoimmune etiology Tendency to familial clustering (genetic influence) Involvement of extraintestinal tissues However, ulcerative colitis and Crohn disease differ in critical ways, as is indicated in Table 15-1 and Figure 15-21 Crohn Disease Crohn disease is a systemic autoimmune disease featuring granulomatous inflammation, which affects the gastrointestinal tract anywhere from the esophagus to the anus The terminal ileum is most commonly affected Because of these characteristics it is sometimes called granulomatous enteritis, regional enteritis, or terminal 90981 ch 15.qxd 10/9/06 10:11 AM Page 375 Chapter 15 • Diseases of the Gastrointestinal Tract 375 Table 15-1 Comparison of Ulcerative Colitis and Crohn Disease Feature Ulcerative Colitis Crohn Disease Type of inflammation Nongranulomatous Granulomatous Depth of bowel wall involved Mucosa only Full thickness of bowel wall Continuity Continuous and contiguous Segmental involvement Site of bowel involvement Distal colon and rectum Anywhere in the gastrointestinal tract, but most often in the small bowel and colon ileitis Crohn disease often affects extraintestinal tissues Onset may occur at any age but most commonly in the teens or young adulthood Caucasians and females are more often affected than African Americans or males In Crohn disease the pathology is characterized by a sharply segmented inflammatory reaction—inflamma- tion is marked in one length of bowel and skips the next length before occurring again As is shown in Figure 1522, the full thickness of the bowel wall is involved, from mucosa through to the peritoneal surface, a feature that in gross examination produces bowel segments that are stiff like a rubber hose Microscopically, there is intense Crohn disease • Both large and small bowel involved Wall thickened • Areas of normal bowel skipped • Strictures • Linear ulcerations Inflammation through full thickness of colon wall Stricture Linear ulcerations Deep ulcers Ulcerative colitis • Small bowel not involved Wall remains thin • Continuous involvement –No skipped areas of normal bowel Pseudopolyp Superficial ulcer • Superficial inflammation • No strictures • Patchy, nonlinear ulceration Superficial inflammation Figure 15-21 Crohn disease and ulcerative colitis contrasted The two drawings illustrate critical differences in how the two diseases affect the gastrointestinal tract 90981 ch 15.qxd 376 10/9/06 10:11 AM Page 376 Part • Diseases of Organ Systems Small bowel mucosa Clusters of inflammatory cells Muscular wall of bowel Inflammation and fibrosis deep in bowel wall Granuloma with central necrosis Figure 15-22 The small bowel in Crohn disease The inflammatory reaction extends deep into the bowel wall, where a large granuloma is present chronic inflammation with formation of granulomas (Chapter 3) The inflammatory reaction has a burrowing quality that leads to bowel-wall fissures and abscesses The clinical onset of Crohn disease may be abrupt and acutely painful, to the point of mimicking an acute surgical abdominal emergency such as acute appendicitis, but in most cases onset is slow and features abdominal pain, diarrhea, and fever that abate only to return after ever shorter periods of relief Extraintestinal manifestations are fairly common and include arthritis and erythema nodosum (a skin disease featuring hard, red, tender nodules, often associated with arthritis, Chapter 24) and, much less often, sclerosing cholangitis, an inflammation and scarring of the hepatic bile ducts (Chapter 16) Some patients have mild disease with few relapses over many decades; others have rapidly progressive disease, with malabsorption syndrome, abdominal abscesses, and inflammatory tracts (fistulae) from bowel into the bladder or perianal skin, or into other loops of bowel Intestinal inflammation can cause fibrous scarring (stricture) and obstruction, which may require acute surgical intervention Patients with Crohn disease have a slightly increased risk for carcinoma of the colon Successful medical therapy usually relies on suppression of the immune system by steroids or other drugs If medical therapy fails, partial bowel resection may be necessary Ulcerative Colitis Ulcerative colitis is a systemic disease, and is very likely of autoimmune origin—some scientists theorize that dietary or bacterial antigens in the intestinal lumen react with mucosa to cause an autoimmune reaction Ulcerative colitis affects only the colon, not the small bowel The inflammatory reaction is most severe in the anus, rectum, and sigmoid colon; however, sometimes the entire colon is involved In direct contrast to Crohn disease, the inflammation is superficial—it affects the mucosa only and does not involve deeper layers Inflammation extends continuously; the “skip” areas seen in Crohn disease not occur in ulcerative colitis Ulcerative colitis also affects extraintestinal tissues, causing arthritis and bile duct inflammation similar to that of Crohn disease Ulcerative colitis shows no racial predilection and affects men and women equally It may arise at any age, but it tends to appear first in the second or third decade of life When examined grossly the colon usually shows most intense inflammation in the anus and rectosigmoid Typically the process spreads as broad, superficial ulcers that merge to leave stranded small polypoid (resembling a polyp) islands of inflamed mucosa (Fig 15-23) Microscopically the mucosa is ulcerated and chronically inflamed, but the inflammation does not extend deep into the bowel wall (Fig 15-24), an important diagnostic point that helps to distinguish ulcerative colitis from Crohn lesions in the colon No granulomas are present Polypoid islands of intact mucosa Broad superficial ulcers Figure 15-23 The colon in chronic ulcerative colitis Polypoid islands of intact mucosa are surrounded by mucosal ulcers 90981 ch 15.qxd 10/9/06 10:11 AM Page 377 Chapter 15 • Diseases of the Gastrointestinal Tract 377 Polypoid island of mucosa Ulcer Dense accumulations of inflammatory cells Figure 15-24 The colon in chronic ulcerative colitis (microscopic study) Ulcers undermine the mucosa, leaving polypoid islands of intact mucosa Dotted line demonstrates polypoid form of remaining mucosa Muscular wall of bowel As is depicted in Figure 15-25, the clinical picture of ulcerative colitis is one of chronic, relapsing, debilitating disease Episodes of severe cramping, tenesmus (rectal spasm), and diarrhea may occur abruptly and then remit for weeks, months, or years Sometimes an explosive episode, bleeding and fluid loss, may produce a medical emergency Alternatively, a relentless extension of the disease may cause ileus (intestinal paralysis), distention, and necrosis of the entire colon (toxic megacolon) Patients also may have erythema nodosum, or pyoderma gangrenosum (a chronic ulcerative skin disease, Chapter 24) Long-term complications include malnutrition, severe diarrhea and electrolyte disturbances, massive hemorrhage, and toxic megacolon Patients are also at risk for sclerosing cholangitis, an inflammatory disease of bile ducts (Chapter 16) However, the most ominous long-term complication of ulcerative colitis is carcinoma of the colon A well-defined sequence of progressive mucosal dysplasia, carcinoma in situ, and invasive carcinoma occurs in some cases Occasionally the risk is great enough to warrant prophylactic complete excision of the colon (total colectomy) COLONIC DIVERTICULOSIS AND OTHER CONDITIONS A diverticulum is a blind pouch with a mouth opening onto the lumen of a space, in this instance the colon Ulcer No inflammation in or below muscular wall of bowel Congenital colonic diverticula are rare and represent a blind pouch of normal colon protruding to one side To the contrary, acquired diverticula are very common As is depicted in the enlargement in Figure 15-26, they have a very thin wall composed of mucosa and submucosa only; no muscle is present, a peculiarity owing to the way they arise: the mucosa and submucosa are extruded through the muscular wall at points where small arteries penetrate from the external surface They are found almost exclusively in the sigmoid colon The result is multiple small mucosal sacs opening onto the lumen of the colon— colonic diverticulosis An inflamed diverticulum is diverticulitis Figure 15-26 illustrates the anatomy of a diverticulosis and the complications of diverticulitis Colonic diverticulosis is uncommon in natives of non-Western countries who eat a traditional diet rich in grains, fruits and vegetables Western diets contain relatively small amounts of nondigestible bulk, which makes feces more compact and difficult to pass Straining at stool causes greatly increased pressure in the sigmoid colon and rectum, which forces diverticular pouches to form at weak points, as discussed above Colonic diverticula are uncommon before age 30 but by age 60 are present in about half of the population in developed nations Most diverticula are asymptomatic and are discovered incidentally at autopsy or during colorectal endoscopy or colon x-ray studies Colonic diverticula con- 90981 ch 15.qxd 378 10/9/06 10:11 AM Page 378 Part • Diseases of Organ Systems Systemic complications Uveitis Spinal arthritis (ankylosing spondylitis) Sclerosing cholangitis Malnutrition Erythema nodosum Local complications Perforation Arthritis Toxic megacolon Colonic carcinoma Pyoderma gangrenosum Hemorrhage Figure 15-25 Complications of ulcerative colitis tain feces and may trap seeds or other indigestible matter, which over time irritate the diverticulum and promote infection by colonic bacteria, as Figure 15-27 illustrates Diverticulitis is characterized by fever, and pain and tenderness in the left lower quadrant of the abdomen Perforation into the abdominal space can produce peritonitis Other complications include hemorrhage, abscess, fistulous connections to small bowel loops or bladder, colonic stenosis, and the formation of inflammatory masses that clinically mimic colonic carcinoma on x-ray studies Hemorrhoids are common and were discussed earlier Also common are anal fissures, tears in the anal mucosa Almost all arise from straining to pass large, hard stools They can be quite painful but usually heal quickly and without therapy However, they may bleed Blood from an anal fissure is bright red and appears on toilet tissue or the surface of stool 90981 ch 15.qxd 10/9/06 10:11 AM Page 379 Chapter 15 • Diseases of the Gastrointestinal Tract Pathologist’s incision Fistula Bowel lumen 379 Smooth muscle wall of colon Diverticulitis with abscess formation Small intestine Colon Enlarged, reactive lymph nodes Bleeding Bowel stenosis A Rupture Fibrosis of intestinal wall and pericolonic fat Fecal debris Serosa (peritoneum) Submucosa Mucosa Muscular wall of colon B Lumen of colon Figure 15-26 Colonic diverticulosis and diverticulitis A, Complications of diverticular inflammation (diverticulitis) B, Detail of the anatomy of an acquired diverticulum Peritonitis Peritonitis is an inflammation of the lining (peritoneum) of the abdominal cavity It is usually acute and may either be infectious or sterile and either local or generalized Infectious peritonitis usually arises as a result of bacteria escaping from the bowel, often as a consequence of perforation, as for example with a perforated gastric Abscess at site of perforated diverticulum Pericolic fat with fibrosis Figure 15-27 Acute and chronic diverticulitis In this cross-section of the colon, the opened bowel lumen appears at top center The incision extends from the lumen into an abscess that has obliterated the diverticulum ulcer or acute appendicitis with rupture Ascitic fluid in the abdomen invites peritonitis, especially chronic ascites in debilitated patients (as with alcoholic cirrhosis) It is, in effect, a sac of culture media that awaits bacterial seeding Other causes of peritonitis include ruptured liver abscess and acute infections of the fallopian tubes (salpingitis) Sterile peritonitis occurs with chemical irritation For example, in acute pancreatitis digestive enzymes may be spilled into the peritoneum, where they incite a severe inflammatory reaction In most cases of peritonitis, the inflammation is acute—a purulent inflammatory exudate spreads throughout the abdomen Healed peritonitis leaves bands of fibrous scar (adhesions) that may produce obstruction by snarling loops of bowel Neoplasms of the Large and Small Bowel Tumors of the small bowel are very uncommon and will not be discussed further; however, the colon is host to more neoplasms than any other organ in the body Fortunately, most colonic neoplasms are benign However, most benign colon neoplasms are premalignant, although it takes many years for them to become fully malignant and capable of metastasis Unfortunately, most premalignant intestinal lesions are not discovered in a 90981 ch 15.qxd 380 10/9/06 10:11 AM Page 380 Part • Diseases of Organ Systems timely fashion: in fact, colorectal carcinoma is the number two cancer killer behind lung cancer, but prostate and breast cancers garner more publicity Colorectal carcinoma kills about 50% more people each year (nearly 60,000) than automobile accidents (about 40,000) Virtually without exception, carcinomas of the colon arise from colonic adenomas (benign neoplasms), most of which have been present for about 10–15 years before becoming fully malignant • The colon is host to more neoplasms than any other organ in the body • With extremely rare exception, all carcinomas of the colon arise from colonic adenomas, most of which have been present for about 10–15 years before becoming invasive malignancies • Iron deficiency anemia (which is usually caused by intestinal bleeding) in man or postmenopausal woman should be considered to be caused by intestinal carcinoma until proven otherwise NONNEOPLASTIC POLYPS It is important to distinguish between the neoplastic and nonneoplastic polyps because neoplastic polyps are premalignant; nonneoplastic polyps are not Recall that “polyp” is a term that describes a shape— a mass rising above a mucosal surface A sessile polyp is one with a broad, short base; a pedunculated polyp has a relatively long, narrow stalk The overwhelming majority of intestinal polyps, especially in the colon, are benign hyperplastic polyps—small, nipple-like foci of mucosa a few millimeters in diameter They occur most commonly in the lower colon and rectum of adults and elderly persons Juvenile polyps, also called retention polyps, are nonneoplastic, polyp-shaped glandular malformations a few centimeters in diameter that are most often found as single lesions in children NEOPLASTIC POLYPS (ADENOMAS) A colonic adenoma is a benign neoplasm of colonic mucosal epithelial cells; almost all colon cancers arise from preexisting adenomas About 50% of people over age 50 have at least one colonic adenoma; men and women are affected equally; and there is a distinct familial predisposition to develop adenomas As Figure 15-28 illustrates, there are two types of adenomas, each with distinctive gross shape and microscopic appearance and with different tendencies to become malignant The most common kind of adenoma is the tubular adenoma, commonly called adenomatous polyp The names derive from the fact that microscopically the tumor glands are simple tubules, and they usually appear grossly as polyps (Fig 15-29) The second, less common type, is villous adenoma, which is a broad-based (sessile) polyp having a villous or fern-like microscopic pattern of epithelial growth Villous adenomas have a much higher malignant potential than tubular adenomas The type of polyp and the degree of microscopic nuclear abnormality (cell atypia) are important in assessing malignant potential, but size is the most important predictor of malignant tendency For example, malignant change is rare in small tubular adenomas, whereas 40% of villous adenomas larger than cm in diameter have become malignant Most adenomas are asymptomatic when small As they enlarge they tend to bleed, often subclinically, so Colonic adenomas Pedunculated tubular adenoma Sessile villous adenoma Mucosa Submucosa Muscular wall of colon Figure 15-28 Colonic adenomas Tubular adenomas are usually pedunculated Villous adenomas are usually sessile 90981 ch 15.qxd 10/9/06 10:11 AM Page 381 Chapter 15 • Diseases of the Gastrointestinal Tract 381 Dysplastic colonic epithelium Head of polyp Stalk (pedicle) of polyp Figure 15-29 Pedunculated tubular adenomas of the colon These tubular adenomas (adenomatous polyps) have unusually long pedicles that iron deficiency anemia may become the first sign of something amiss For this reason, careful practitioners rely on this rule: iron deficiency anemia in an adult man or postmenopausal woman is intestinal carcinoma until proven otherwise Familial polyposis syndrome is an uncommon genetic disorder in which the colon contains thousands of small polyps with a great tendency to become malignant Hereditary nonpolyposis colorectal carcinoma syndrome (HNPCC) is a rare genetic disorder that deserves mention because it is the sole exception to the rule that all colon cancers arise from preexisting polyps Normal colonic epithelium Figure 15-30 Dysplastic (premalignant) change in colonic adenoma Dysplastic cells have large, dark nuclei and have lost their ability to make mucin Colonic carcinoma (Fig 15-31) is widespread in industrialized nations and is much less common in Asian and African nations These differences are unexplained Heretofore, the high colon cancer rate in industrialized nations was attributed to low dietary fiber content, a theory that has been disproved by more recent studies There has been a significant change in the pathology and clinical behavior of colorectal carcinomas Fifty years ago most occurred in the lower-left colon and rectum (the rectosigmoid), but now more occur in the CARCINOMA OF THE COLON Almost all colon carcinomas are adenocarcinomas: gland-forming malignant neoplasms of colon epithelial cells According to the American Cancer Society, in 2003 163,000 Americans died of lung cancer; 57,000 of colon cancer; 40,000 of breast cancer; and 30,000 of prostate cancer The tragedy of colon cancer is that, because virtually all colon cancers arise from adenomas, and because it takes about ten years for an adenoma to become fully malignant, people with colonic adenomas have a curable and diagnosable lesion for about ten years before cancer develops Cancer does not leap into being in an instant Long before development of invasive malignancy, the epithelium in the colonic adenoma becomes progressively dysplastic (Fig 15-30) and passes through a stage of carcinoma in situ before becoming invasive (see Case Study 15.1 at the end of this chapter) History of Medicine FAMOUS PEOPLE WHO DIED OF COLON CANCER • Audrey Hepburn, celebrated film actress; best remembered for her role as Holly Golightly in Breakfast at Tiffany’s • Vince Lombardi, legendary coach of the Green Bay Packers, after whom the Super Bowl trophy is named • Jackie Gleason, actor and comedian best remembered for his TV portrayal of New York bus driver Ralph Kramden in The Honeymooners, arguably the best TV situation comedy ever produced • Charles Schultz, creator of the most famous of all American cartoon strips: Peanuts 90981 ch 15.qxd 382 10/9/06 10:11 AM Page 382 Part • Diseases of Organ Systems Clinical Stage and Survival in Table 15-2 Colonic Carcinoma (Astler-Coller) Stage Degree of Tumor Invasion and Spread 5-Year Survival A Limited to mucosa ∼100% B1 Invading muscular wall, negative nodes ∼67% B2 Full penetration of muscular wall, negative nodes ∼54% C1 Invading muscular wall, positive nodes ∼43% C2 Full penetration of muscular wall, positive nodes ∼22% D Distant metastasis Very low % Figure 15-31 Carcinoma of the colon The tumor has raised, rolled edges and a deeply excavated center right colon: few are reachable by a fingertip and only about half can be seen by office examination with a sigmoidoscope (which reaches about 60 cm—two feet— into the lower colon) In the right colon they tend to be bulky masses that have plenty of room to grow, produce less obvious bleeding, and not cause a dramatic change in bowel habits On the other hand, cancers in the lower-left colon tend to be encircling, constricting, “napkin-ring” lesions that produce more noticeable bleeding or pain and changed bowel habits Regardless of these patterns, the tumors are microscopically similar Evidence of the preexisting adenoma is usually obliterated by cancer at the time cancer is found Most cases are diagnosed because patients become symptomatic with weight loss, overt intestinal bleeding, anemia, metastasis, or pain By the time patients become symptomatic, most lesions have metastasized Colorectal carcinomas grow by direct extension through the bowel wall and spread beyond the colon by invasion of lymphatics and blood vessels The most common sites of metastasis are lymph nodes, liver (via the portal circulation), lungs, and bones About a third of cases are beyond cure at the time of initial diagnosis The most important prognostic factor in colorectal carcinoma is the clinical stage of the neoplasm at the time of diagnosis Various schemes have been proposed; the most widely accepted is Astler-Coller staging, illustrated in Figure 15-32 and detailed in Table 15-2 The Astler-Coller staging system relies on assessment of the depth of bowel wall invasion by the tumor, the presence or absence of lymph node metastases, and clinical assessment of distant metastasis to liver or other organs Colorectal carcinomas secrete a tumor marker, carcinoembryonic antigen (CEA), into the bloodstream As with other tumor markers, CEA has not proved to be a useful screening test because it rarely is elevated when the carcinoma is in a curable stage and because CEA is also produced by other tumors, such as carcinomas of the lung, bladder, prostate, breast, ovary, and urinary bladder, and by other conditions including smoking, cirrhosis, pancreatitis, and ulcerative colitis Nevertheless, CEA is useful as a monitoring tool to check for tumor regression or recurrence after therapy Screening tests for any disease should be inexpensive and sensitive (few false negatives), and they should detect a serious but potentially curable disease The stool occult blood test fits these criteria: it costs a few dollars and screens for a deadly but completely curable disease A single stool test is not very sensitive, but when used annually over a ten-year period, the test can detect about half of colon cancers and reduce colon cancer deaths by about 30% However, this leaves many curable tumors undiagnosed Therefore, there is growing belief that all people over age 50 should have a complete colon exam by colonoscopy or radiographic “virtual colonoscopy” every five years, or every ten years in people with a negative study and no family history of colon polyps or cancers These exams can detect the great majority of cancers and polyps and reduce the colon cancer death rate by about 60% 90981 ch 15.qxd 10/9/06 10:11 AM Page 383 Chapter 15 • Diseases of the Gastrointestinal Tract 383 Mucosa Submucosa 100% Muscular wall of colon Serosa A Lymph node 67% B1 54% B2 43% C1 22% C2 Figure 15-32 Astler-Coller staging system for colonic carcinoma Approximate five-year survival figures for each stage (A, B1, and so on) are included Table 15-2 describes the degree of tumor invasion and spread that characterize each of the six stages Very low % D 90981 ch 15.qxd 384 10/10/06 10:18 AM Page 384 Part • Diseases of Organ Systems Diseases of the Appendix The appendix is a functionless little organ, but one that looms large in medical practice because the differential diagnosis of acute appendicitis is especially difficult, requiring consideration of a very broad range of acute medical and surgical conditions About 10% of people experience an episode of acute appendicitis at some time in their life Acute appendicitis occurs most commonly in teenagers and young adults and is more common in males than females As Figure 15-33 illustrates, it is usually the result of a fecalith, a small ball of dried fecal matter that obstructs the lumen and blocks drainage of mucus As pressure increases behind the obstruction, blood flow into the appendix is hindered and edema, ischemia, necrosis, and bacterial overgrowth follow However, often no anatomic cause can be identified The typical case begins with abdominal discomfort, anorexia, nausea, and vomiting followed by fever and right-lower quadrant pain and tenderness However, many cases not present the classic picture Some cases may be remarkably silent, especially in the elderly or debilitated The differential diagnosis includes other causes of abdominal pain, such as acute mesenteric lymphadenitis, fallopian tube infection, ectopic pregnancy, and the low abdominal pain normally associated with ovulation Because signs and symptoms vary Intact mucosa Fecalith Empty lumen; mucosa inflamed and necrotic Tip of appendix Figure 15-33 Acute appendicitis A fecalith is wedged into the mouth of the appendix (left) widely, and because delay of surgical intervention risks the very serious hazard of rupture and peritonitis, it is accepted that 10–20% of abdominal surgery for presumptive appendicitis will find either some other disease process—or nothing ■ CASE STUDY 15-1 “I’M IN GREAT SHAPE” TOPICS Carcinoma of the colon THE CASE Setting: You work in the office of a solo family practitioner Your duties include insurance physicals, seeing some new referrals before they see the physician, helping with minor surgery, changing wound dressings, removing sutures, authorizing prescription refills, and taking patient telephone calls Clinical history: Sheila W is a 53-year-old single white woman, self-employed as a commodities trader, whom you see for the first time to a history and physical exam required for a large insurance policy she is seeking Your routine review of systems reveals no serious medical problems There is no family history of diabetes or cancer Her parents are still living and in good health “I’m in great shape,” she says when you ask about exercise She reports that she jogs for exercise, takes yoga classes, has not smoked since she was in college, and takes adventure hiking vacations in rugged terrain She sees her gynecologist regularly for an annual physical exam, mammogram, and Pap smear, all of which have been unremarkable Physical examination and other data: She is lean and fit—5’5”, 114 lb, BP 110/65, heart rate 52, respirations 14, temperature 98.2Њ F Physical exam is unremarkable Clinical course: Per insurance company requirements, you collect blood and urine specimens and give her a stool sampling kit for her to use at home to collect specimens for stool occult blood testing While giving her instructions for collecting the stool specimens and mailing them back to you, it becomes clear that she has never done a home test for stool blood You inquire further, asking if her gynecologist 90981 ch 15.qxd 10/9/06 10:11 AM Page 385 Chapter 15 • Diseases of the Gastrointestinal Tract [Case 15-1, continued] did a digital rectal exam on her regular office visit Again, the answer is No You offer to a simple digital rectal exam, but she says she is pressed for time and promises to mention it her gynecologist on her next visit A week later, you receive her stool test cards in the mail, and test the stool smears for occult blood All are positive In a telephone call to the patient, you explain to her that the insurance company will not issue the policy until the source of the bleeding is identified After getting the report, the Ms W returns to her gynecologist, who performs a rectal exam Stool on the exam glove finger tests positive for blood In consultation with the general practitioner for whom you work, Ms W is referred to a radiology group for barium enema examination, which reveals a mass in the right side of the colon She is referred again, this time to a general surgeon, who resects the right half of the colon The surgeon reports that the peritoneal cavity was smooth and free of metastasis, and no liver metastases were seen The pathologist’s consultation on the surgical specimen reported a grade III adenocarcinoma invading through the full thickness of the wall of the colon Eleven mesenteric lymph nodes are identified and studied Two contain microscopic tumor metastases The tumor is classified Astler-Coller stage C2 Ms W is referred to an oncologist for further treatment Liver function tests are normal, and imaging of the liver reveals no masses However, liver metastases are detected 18 months later, and Ms W dies in hepatic coma, years after initial diagnosis 385 DISCUSSION This sad story is repeated in one variation or other thousands of times annually in the United States This woman had everything going for her: career success, apparent good health, and regular private medical care, but it all came to nothing because no one did the simplest of things: check her stool regularly for blood or suggest she have a complete colon exam when she turned 50 The statistics are clear: this woman surely had had a benign colonic adenoma for 10 or 15 years as it slowly evolved into an invasive colon cancer It is not clear how long the cancer may have been present in a more curable form before invading and metastasizing, but it was probably several years Altogether, she had had a curable lesion for perhaps 10 or 15 years, but no one found it because they had not bothered to look for it Current guidelines call for all adults over 50 (some suggest 40) to have an initial full colon exam by direct colonoscopy or radiographic study and follow-up exams every or 10 years for life Stool exams for occult blood should be performed annually POINTS TO REMEMBER • With rare exception, all carcinomas of the colon arise from preexisting benign colonic adenomas • It takes many years for a colonic adenoma to evolve into invasive cancer • Regular stool occult blood tests and full colon exams can prevent many colon cancer deaths CASE STUDY 15-1 THE ROAD NOT TAKEN—AN ALTERNATIVE SCENARIO For all sad words of tongue or pen, The saddest are these: “It might have been.” JOHN GREENLEAF WHITTIER (1807–1892), AMERICAN QUAKER POET AND REFORMER, MAUD MULLER THE CASE With a bit of imagination, we can speculate how this case might have had a happier ending Setting: You work in the office of a very busy obstetriciangynecologist; in addition to your many other duties, it is your job to visit with patients about at-home self-collection of stool samples for occult blood testing Clinical history: Sheila W is a 47-year-old self-employed woman who is in the office for the first time for a routine annual gynecologic examination and Pap smear You explain the stool sampling procedure in all of its unpleasant detail—using special paper from the kit to catch three separate stools in the toilet bowl, scraping stool onto the tip of a wooden spatula, and smearing each sample onto a stiff cardboard mailer She grimaces and says, “Ugh Is this really necessary? I’ve never had to this before.” You reply, “Well, I recommend it You know, cancer of the colon is the number-three cancer killer of women, close behind lung cancer and breast cancer.” Then you launch into a well-rehearsed mini-lecture, one you’ve given hundreds of times, explaining how colon cancers arise very slowly from preexisting polyps, and how polyps and early cancers tend to bleed while they are still 100% curable “Okay,” she says with a grin, holding up her hands in mock surrender, “You can stop I give up.” About 10 days, later her specimens arrive in the mail; all three test positive for blood The physician calls her and recommends a colon and rectal surgeon, who does a colonoscopy and finds several 90981 ch 15.qxd 386 10/9/06 10:11 AM Page 386 Part • Diseases of Organ Systems [Case 15-1, continued] adenomatous polyps in the colon The largest one is in the right colon and is several centimeters in diameter All are removed intact The pathology report reads as follows: • Four polyps from various colonic sites: Benign tubular adenoma • Large polypoid mass from right colon: Tubular adenoma with focal severe epithelial dysplasia (carcinoma in situ); no invasive carcinoma identified Margins of resection are free of atypical epithelial changes DISCUSSION Patients rely on caregivers to know the right thing to do— and to it In this scenario the patient was surely spared an early death from colon cancer because she was urged to participate in a messy and unpleasant stool-collection routine Objectives Recap Define melena, hematochezia, and hematemesis, and explain the different implications of slow gastrointestinal bleeding and rapid gastrointestinal bleeding: Melena is the passage of stool with high content of altered blood, which makes stool black Hematochezia is the passage of overtly bloody stool Hematemesis is the vomiting of blood Rapid gastrointestinal bleeding is usually manifest by hematochezia or hematemesis or signs and symptoms of acute blood loss Slow gastrointestinal bleeding is often from an intestinal malignancy and tends to be clinically silent and without obvious evidence of blood in the stool Persistent slow gastrointestinal bleeding is sometimes discovered because of the anemia it can produce Explain the importance of stool occult blood tests: Annual occult blood testing of stool detects many premalignant lesions of the colon before they become malignant and also detects many colon carcinomas early enough for surgical cure Distinguish between intestinal mechanical obstruction and ileus: Normal intestinal function requires constant peristalsis, which may be interrupted by mechanical obstruction or by peristaltic paralysis (ileus) Name the cause of most tooth loss and explain its pathogenesis: Periodontitis causes most tooth loss and arises as a result of poor oral hygiene, which allows accumulation at the gum margin of a film of bacteria known as plaque Bacterial invasion downward into the soft tissues around the tooth root is the cause of periodontitis Define achalasia, and offer a short discussion of it: Achalasia is a spastic condition of the lower esophageal sphincter, which produces a functional partial obstruction in the lower esophagus, causing dysphagia and esophageal pain The cause is unknown 10 Define Barrett esophagus, and discuss its pathogenesis and implications: Barrett esophagus is a change (metaplasia) of the epithelium of the lowest part of the esophagus from normal squamous epithelium to gastric glandular epithelium Barrett metaplasia is caused by gastric acid refluxing upward from the stomach (reflux esophagitis) It is painful and can cause bleeding and narrowing because of fibrous scar (stricture) Patients with Barrett metaplasia have an increased risk of esophageal adenocarcinoma Name some risk factors for esophageal carcinoma: Smoking, alcohol abuse, Barrett metaplasia Name some conditions associated with Helicobacter pylori infection: Chronic atrophic gastritis, chronic peptic ulceration, and gastric carcinoma (usually in association with chronic atrophic gastritis) Explain the difference in the pathogenesis of acute gastric erosions and chronic peptic ulceration: Acute gastric erosions are superficial ulcers of the gastric mucosa that are usually associated with severe trauma, sepsis, major surgical procedures, grave illnesses, alcohol abuse, extensive burns, CNS trauma or surgery, and chronic exposure to nonsteroidal antiinflammatory drugs (NSAIDs) and corticosteroids Chronic peptic ulceration, a much deeper ulceration of the stomach wall, may burrow into or through the muscular wall Peptic ulcers are associated with a combination of atrophic gastritis, exposure to gastric juices, and H pylori infection Explain the cause of Hirschsprung megacolon: Hirschsprung megacolon results from a localized, genetic absence of the autonomic ganglionic neural plexus in the colon wall, which controls peristalsis Deprived of neural control, no peristalsis occurs in the affected segment, fecal movement is impaired, and the upstream colon distends with feces 90981 ch 15.qxd 10/9/06 10:11 AM Page 387 Chapter 15 • Diseases of the Gastrointestinal Tract 11 12 13 14 15 16 Name the most common cause worldwide of acute enterocolitis: Rotavirus Name some bacteria responsible for epidemic bacterial enterocolitis: Salmonella sp causes salmonellosis; Shigella sp causes shigellosis; Vibrio cholerae causes cholera Explain the pathogenesis of pseudomembranous colitis: Pseudomembranous colitis occurs with colonic overgrowth of Clostridium difficile, which secretes an enterotoxin that causes necrosis of colonic mucosa The most common cause is broadspectrum antibiotic therapy that kills normal colonic flora, allowing C difficile overgrowth Among patients with malabsorption syndrome, distinguish between luminal and intestinal malabsorption: Intestinal malabsorption consists of those cases in which a mucosal defect or disease is present that interferes with absorption, or in patients with shortened bowel Luminal malabsorption is caused by the absence of digestive enzymes or bile salts necessary for hydrolysis or emulsification of ingested foodstuffs (as in patients with pancreatic disease who not have enough pancreatic enzymes for normal digestion) Characterize and contrast the important differences between ulcerative colitis and Crohn disease: 1) type of inflammation: granulomatous inflammation in Crohn disease; nongranulomatous inflammation in ulcerative colitis; 2) depth of inflammation: deep transmural in Crohn disease; superficial mucosal in ulcerative colitis; 3) site of involvement: anywhere in the gastrointestinal tract, but most often in the colon and terminal ileum in Crohn disease; colon only in ulcerative colitis; 4) continuity of inflammatory involvement: discontinuous (skip areas) involvement in Crohn disease; continuous involvement in ulcerative colitis Name several extraintestinal manifestations of Crohn disease and ulcerative colitis: Both may be associated with inflammation in the eye (uveitis), 17 18 19 20 387 joint disease (various types of arthritis), skin disease, and inflammation of hepatic bile ducts (sclerosing cholangitis) Explain the pathogenesis of colonic diverticulosis: Diverticula have a very thin wall composed of mucosa and submucosa only; no muscle is present, a peculiarity stemming from the way they arise: the mucosa and submucosa are extruded through the muscular wall at points where small arteries penetrate from the external surface Colonic diverticulosis is uncommon in natives of non-Western countries who eat a traditional diet rich in grains, fruits, and vegetables Western diets contain relatively small amounts of nondigestible bulk, which makes feces more compact and difficult to pass Straining at stool causes greatly increased pressure in the sigmoid colon and rectum, which forces diverticular pouches to form at weak points Explain the importance of nonneoplastic polyps of the colon: Nonneoplastic polyps have no premalignant potential It is important to distinguish them from colonic adenomas, which are frequently polypoid and are premalignant Explain the difference between a tubular adenoma and a villous adenoma of the colon: Both are benign, premalignant neoplasms The most common is the tubular adenoma, which has a microscopic pattern of simple tubular glands and is commonly called adenomatous polyp The second, less common, variety of colonic adenoma is a broad-based, sessile polyp with a fern-like microscopic pattern of epithelial growth that is called villous adenoma Villous adenomas have a much higher malignant potential than tubular adenomas Explain the relationship between colonic adenomas and colonic carcinoma: Almost without exception all carcinomas of the colon arise from preexisting benign colonic adenomas that gradually become dysplastic and then malignant over ten to fifteen years 90981 ch 15.qxd 388 10/9/06 10:11 AM Page 388 Part • Diseases of Organ Systems Typical Test Questions Concerning aphthous oral ulcers, which is true? A Associated with periodontitis B Cause unknown C Caused by herpesvirus D Caused by Candida E Associated with poor oral hygiene Which of the following is a condition involving the stomach? A Peptic ulcer B Malabsorption syndrome C Clostridium difficile ulceration D Adenomatous polyp Which of the following is associated with increased risk of esophageal carcinoma? A Helicobacter pylori infection B Esophageal varices C Herpesvirus infection D Barrett metaplasia E Hiatal hernia Which of the following is a cause of luminal phase malabsorption syndrome? A Chronic pancreatitis B Gluten-sensitive enteropathy (celiac sprue) C Whipple disease D Tropical sprue E Short bowel Which of the following is characteristic of colonic carcinoma? A Usually occurs in the rectosigmoid B Sessile shape C Silent bleeding D Early bowel obstruction True or false? Carcinoma of the colon kills more people annually than breast cancer does True or false? Helicobacter pylori infection is the cause of most malabsorption syndromes True or false? Barrett esophagus carries an increased risk of carcinoma True or false? A single stool exam for occult blood can detect most premalignant lesions of the colon 10 True or false? Most peptic ulcers occur in the stomach ... aspects of pathology first, with the pathology of organ systems following Part 1, General Pathology, opens with a chapter titled The Nature of Disease, which discusses the actual nature of disease—that... Study 1-2 at the end of the chapter offers another example to think about THE EFFECT OF DISEASE PREVALENCE ON TEST USEFULNESS The prevalence of a disease is the number of persons who have the disease... Chapter 21, Diseases of the Female Genital Tract and Breast, the box explains the use of the Pap smear in the detection of lesions of the cervix, especially dysplasia and cancer • Therapies as a natural