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CHAPTER FIVE
PATHOLOGY OF THE GIT
Starting Date: Sunday 27/10/2013
Lecturers:
1. Assist. Prof. Dr. Lubab Fadhil Talal
2. Dr. Bassam Musa Sadik
The lectures would be given in 3 weeks as follows:
1. Week 1: From start to Diseases of the Stomach
2. Week 2: Till Small & Large bowel (+ Case presentation)
3. Week 3: Till the end (+ Case presentation)
Certain less common or pathologically less important topics have been removed
THE ORAL CAVITY & OROPHARYNX
Many pathological processes can affect the constituents of the oral cavity. The more
important and frequent conditions will covered in this lecture. Diseases involving the
teeth and related structures will not be discussed.
PROLIFERATIVE LESIONS
The most common proliferative lesions of the oral cavity are
1. Irritation Fibroma and Ossifying fibroma
2. Ossifying fibroma
2. Pyogenic granuloma
3. Peripheral giant cell granuloma
Pyogenic granuloma (granuloma pyogenicum) is a highly vascular lesion that is usually
seen in the gingiva of children, young adults, and pregnant women (pregnancy tumor).
The lesion is typically ulcerated and bright red in color (due to rich vascularity) (Fig. 5-
3). Microscopically there is vascular proliferation similar to that of granulation tissue.
(Fig. 5-3) They lesion either regresses (particularly after pregnancy), or undergoes
fibrous maturation and may develop into ossifying fibroma.
INFLAMMATORY CONDITIONS
Inflammatory ulcerations
The most common inflammatory ulcerations of the oral cavity are
1. Traumatic
2. Aphthous
3. Herpetic
Traumatic ulcers, usually the result of trauma (e.g. fist fighting) or licking a jagged
tooth.
Aphthous ulcers are extremely common, single or multiple, painful, recurrent,
superficial, ulcerations of the oral mucosa. The ulcer is covered by a thin yellow exudate
and rimmed by a narrow zone of erythema. (Fig. 5-5)
Herpetic ulcers (see under herpes simplex infection)
Tip:
Please refer to the supplied
CDs for photos related to the
topic in hand
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INFECTIONS
1. Herpes simplex infections
Most of these are caused by herpes simplex virus (HSV) type 1 & sometimes 2. Primary
HSV infection typically occurs in children aged 2 to 4 years; is often asymptomatic, but
sometime presents as acute herpetic gingivostomatitis, characterized by vesicles and
ulcerations throughout the oral cavity. The great majority of affected adults harbor latent
HSV-1 (the virus migrates along the regional nerves and eventually becomes dormant in
the local ganglia e.g., the trigeminal). In some individuals, usually young adults, the virus
becomes reactivated to produce the common but usually mild cold sore. (Fig. 5-7)
Factors activating the virus include
1. Trauma
2. Allergies
3. Exposure to ultraviolet light (sunlight)
4. Upper respiratory tract infections
The viral infection is associated with intracellular and intercellular edema, yielding clefts
that may become transformed into vesicles. The vesicles range from a few millimeters to
large ones that eventually rupture to yield extremely painful, red-rimmed, shallow
ulcerations.
2. Other Viral Infections
These include
- Herpes zoster
- EBV (infectious mononucleosis)
- CMV
- Enterovirus
- Measles
3. Oral Candidiasis (thrush)
This is the most common fungal infection of the oral cavity. The thrush is a grayish
white, superficial, inflammatory psudomembrane composed of the fungus enmeshed in a
fibrino-suppurative exudates. (Fig. 5-8) This can be readily scraped off to reveal an
underlying red inflammatory base. The fungus is a normal oral flora but causes troubles
only
1. In the setting of immunosuppression (e.g. diabetes mellitus, organ or bone marrow
transplant recipients, neutropenia, cancer chemotherapy, or AIDS) or
2. When broad-spectrum antibiotics are taken; these eliminate or alter the normal
bacterial flora of the mouth.
3. In infants, where the condition is relatively common, presumably due to immaturity of
the immune system in them.
4. Deep Fungal Infections
Some fungal infections may extends deeply to involve the muscles & bones in relation to
oral cavity. These include, among others, histoplasmosis, blastomycosis, and
aspergillosis. The incidence of such infections has been increasing due to increasing
number of patients with AIDS, therapies for cancer, & organ transplantation
5. Diphtheria: characterized grossly by dirty white, fibrino-suppurative, tough,
inflammatory pseudomembrane over tonsils & posterior pharynx. (Fig. 5-9)
5. Pregnancy
6. Menstruation
7. Immunosuppression
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ORAL MANIFESTATIONS OF SYSTEMIC DISEASE
Many systemic diseases are associated with oral lesions & it is not uncommon for oral
lesions to be the first manifestation of some underlying systemic condition.
1. Scarlet fever: strawberry tongue: white coated tongue with hyperemic papillae
projecting (Fig. 5-10)
2. Measles: Koplik spots: small whitish ulcerations (spots) on a reddened base, about
Stensen
duct (Fig. 5-11)
3. Diphtheria: dirty white, fibrinosuppurative, tough pseudomembrane over the tonsils
and retropharynx
4. AIDS
a. opportunistic oral infections: herpesvirus, Candida, other fungi
b. Kaposi sarcoma (Fig. 5-12)
c. hairy leukoplakia
5. AML (especially monocytic leukemia): enlargement of the gingivae + periodontitis
(Fig. 5-13)
6. Melanotic pigmentation (Fig. 5-14)
a. Addison disease
b. hemochromatosis
c. fibrous dysplasia of bone
d. Peutz-Jegher syndrome
7. Pregnancy: pyogenic granuloma ("pregnancy tumor")
TUMORS AND PRECANCEROUS LESIONS
Many of the oral cavity tumors (e.g., papillomas, hemangiomas, lymphomas) are not
different from their homologous tumors elsewhere in the body. Here we will consider
only oral squamous cell carcinoma and its associated precancerous lesions.
Leukoplakia and Erythroplakia are considered premalignant lesions of squamous cell
carcinoma.
Leukoplakia (Fig. 5-16) is a white patch that cannot be scraped off and cannot be
attributed clinically or microscopically to any other disease i.e. if a white lesion in the
oral cavity can be given a specific diagnosis it is not a leukoplakia. As such, white
patches caused by entities such as candidiasis are not leukoplakias. All leukoplakias must
be considered precancerous (have the potential to progress to squamous cell carcinoma)
until proved otherwise through histologic evaluation.
Erythroplakias (Fig. 5-17) are red velvety patches that are much less common, yet much
more serious than leukoplakias. The incidence of dysplasia and thus the risk of
complicating squamous cell carcinoma is much more frequent in erythroplakia compared
to leukoplakias. Both leukoplakia and erythroplakia are usually found between ages of 40
and 70 years, and are much more common in males than females. The use of tobacco
(cigarettes, pipes, cigars, and chewing tobacco) is the most common incriminated factor.
Squamous cell carcinoma
The vast majority (95%) of cancers of the head and neck are squamous cell carcinomas;
these arise most commonly in the oral cavity. The 5-year survival rate of early-stage oral
cancer is approximately 80%, but this drops to about 20% for late-stage disease. These
figures highlight the importance of early diagnosis & treatment, optimally of the
precancerous lesions.
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The pathogenesis of squamous cell carcinoma is multifactorial.
1. Chronic smoking and alcohol consumption
2. Oncogenic variants of human papilloma virus (HPV). It is now known that at least
50% of oropharyngeal cancers, particularly those of the tonsils and the base of tongue,
harbor oncogenic variants of HPV.
3. Inheritance of genomic instability; a family history of head and neck cancer is a risk
factor.
4. Exposure to actinic radiation (sunlight) & pipe smoking are known predisposing
factors for cancer of the lower lip.
Gross features (Fig. 5-18 A)
Squamous cell carcinoma may arise anywhere in the oral cavity, but the favored
locations are
1. The tongue
2. Floor of mouth
3. Lower lip
In the early stages, cancers of the oral cavity appear as roughened areas of the mucosa.
As the lesion enlarges, it typically appears as either an ulcer or a protruding mass
(fungating).
Microscopic features (Fig. 5-18 B)
Early there is full-thickness dysplasia (carcinoma in situ) followed by invasion of the
underlying connective tissue stroma.
The grade varies from from well-differentiated keratinizing to poorly differentiated.
As a group, these tumors tend to infiltrate and extend locally before they eventually
metastasize to cervical lymph nodes and more remotely. The most common sites of
distant metastasis are mediastinal lymph nodes, lung, liver and bones
SALIVARY GLANDS
There are three major salivary glands—parotid, submandibular, and sublingual.
Additionally, there are numerous minor salivary glands distributed throughout the
mucosa of the oral cavity.
Xerostomia refers to dry mouth due to a lack of salivary secretion; the causes include
1. Sjögren syndrome: an autoimmune disorder, that is usually also accompanied by
involvement of the lacrimal glands that produces dry eyes (keratoconjunctivitis sicca).
2. Radiation therapy
Inflammation (Sialadenitis)
Sialadenitis refers to inflammation of a salivary gland; it may be
1. Traumatic
2. Infectious: viral, bacterial
3. Autoimmune
The most common form of viral sialadenitis is mumps, which usually affects the parotids.
The pancreas and testes may also be involved.
Bacterial sialadenitis is seen as a complication of
1. Stones obstructing ducts of a major salivary gland (Sialolithiasis), particularly the
submandibular. (Fig. 5-19)
2. Dehydration with decreased secretory function as is sometimes occurs in
a. patients on long-term phenothiazines that suppress salivary secretion.
b. elderly patients with a recent major thoracic or abdominal surgery.
4. Soft palate
5. Gingiva
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Unilateral involvement of a single gland is the rule and the inflammation may be
suppurative.
The inflammatory involvement causes painful enlargement and sometimes a purulent
ductal discharge.
Sjögren syndrome causes an immunolgically mediated sialadenitis i.e. inflammatory
damage of the salivary tissues.
NEOPLASMS OF SALIVARY GLANDS
Neoplasms of the salivary glands (benign and malignant) are generally uncommon,
constituting less than 2% of human tumors. We will restrict our discussion on the more
common examples.
The relative frequency distributions of these tumors in relation to various salivary glands
are as follows
Salivary gland
Relative frequency of tumors (%)
Parotid gland
80%
Submandibular gland
10%
Minor salivary and sublingual glands
10%
The incidence of malignant tumors within the glands is, however, different from the
above
Salivary gland affected
Relative frequency of malignant tumors (%)
Sublingual tumors
80%
Minor salivary glands
50%
Submandibular glands
40%
Parotid glands
25%
These tumors usually occur in adults, with a slight female predominance. Excluded from
this rule is Warthin tumor, which occurs much more frequently in males than in females.
The benign tumors occur most often around the age of 50 to 60 years; the malignant ones
tend to appear in older age groups. Neoplasms of the parotid produce distinctive
swellings in front of, or below the ear. Clinically, there are no reliable criteria to
differentiate benign from the malignant tumors; therefore, pathological evaluation is
necessary. (Fig. 5-21)
Pleomorphic Adenomas (Mixed Salivary Gland Tumors)
These benign tumors commonly occur within the parotid gland (constitute 60% of all
parotid tumors).
Gross features (Fig. 5-22 A)
Most tumors are rounded, encapsulated masses.
The cut surface is gray-white with myxoid and light blue translucent areas of
chondroid.
Microscopic features (Fig. 5-22 B)
The main constituents are a mixture of ductal epithelial and myoepithelial cells, and it
is believed that all the other elements, including mesenchymal, are derived from the
above cells (hence the name adenoma).
The epithelial/myoepithelial components of the neoplasm are arranged as glands,
strands, or sheets. These various epithelial/myoepithelial elements are dispersed within
a background of loose myxoid tissue that may contain islands of cartilage-like islands
and, rarely bone.
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Sometimes, squamous differentiation is present.
In some instances, the tumor capsule is focally deficient allowing the tumor to extend
as tongue-like protrusions into the surrounding normal tissue.
Enucleation of the tumor is, therefore, not advisable because residual foci (the
protrusions) may be left behind and act as a potential source of multifocal recurrences.
(Fig. 5-23)The incidence of malignant transformation increases with the duration of the
tumor.
Warthin Tumor is the second most common salivary gland neoplasm. It is benign,
arises usually in the parotid gland and occurs more commonly in males than in females.
About 10% are multifocal and 10% bilateral. Smokers have a higher risk than
nonsmokers for developing these tumors. Grossly, it is round to oval, encapsulated mass
& on section display gray tissue with narrow cystic or cleft-like spaces filled with
secretion. Microscopically, these spaces are lined by a double layer of neoplastic
epithelial cells resting on a dense lymphoid stroma, sometimes with germinal centers.
This lympho-epithelial lining frequently project into the spaces. The epithelial cells are
oncoytes as evidenced by their eosinophilic granular cytoplasm (stuffed with
mitochondria). (Fig. 5-24)
ESOPHAGUS
The main functions of the esophagus are to 1. Conduct food and fluids from the pharynx
to the stomach 2. Prevent reflux of gastric contents into the esophagus. These functions
require motor activity coordinated with swallowing, i.e. wave of peristalsis, associated
with relaxation of the LES in anticipation of the peristaltic wave. This is followed by
closure of the LES after the swallowing reflex. Maintenance of sphincter tone (positive
pressure relative to the rest of esophagus) is necessary to prevent reflux of gastric
contents.
CONGENITAL ANOMALIES
Several congenital anomalies affect the esophagus including the presence of ectopic
gastric mucosa & pancreatic tissues within the esophageal wall, congenital cysts &
congenital herniation of the esophageal wall into the thorax. The latter is due to
impaired formation of the diaphragm. Atresia and fistulas are uncommon but must be
recognized & corrected early because they cause immediate regurgitation, suffocation &
aspiration pneumontis when feeding is attempted. In atresia, a segment of the esophagus
is represented by only a noncanalized cord, with the upper pouch connected to the
bronchus or the trachea and a lower pouch leading to the stomach. (Fig. 5-28)
Webs, rings, and stenosis (Fig. 5-29)
Mucosal webs are shelf-like, eccentric protrusions of the mucosa into the esophageal
lumen. These are most common in the upper esophagus. The triad of upper esophageal
web, iron-deficiency anemia, and glossitis is referred to as Plummer-Vinson syndrome.
This condition is associated with an increased risk for postcricoid esophageal carcinoma.
Esophageal rings unlike webs are concentric plates of tissue protruding into the lumen of
the distal esophagus. Esophageal webs and rings are encountered most frequently in
women over age 40. Episodic dysphagia is the main symptom.
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Stenosis consists of fibrous thickening of the esophageal wall. Although it may be
congenital, it is more frequently the result of severe esophageal injury with inflammatory
scarring, as from gastroesophageal reflux disease (GERD), radiation, scleroderma and
caustic injury. Stenosis usually manifests as progressive dysphagia, at first to solid foods
but eventually to fluids as well.
LESIONS ASSOCIATED WITH MOTOR DYSFUNCTION (Fig. 5-30)
Coordinated motor activity is important for proper function of the esophagus. The major
entities that are caused by motor dysfunction of the esophagus are
1. Achalasia
2. Hiatal hernia
3. Diverticula
4. Mallory-Weiss tear
Achalasia
Achalasia means "failure to relax." It is characterized by three major abnormalities:
1. Aperistalsis (failure of peristalsis)
2. Increased resting tone of the LES
3. Icomplete relaxation of the LES in response to swallowing
In most instances, achalasia is an idiopathic disorder. In this condition there is
progressive dilation of the esophagus above the persistently contracted LES. The wall of
the esophagus may be of normal thickness, thicker than normal owing to hypertrophy of
the muscular wall, or markedly thinned by dilation (when dilatation overruns
hypertrophy). The mucosa just above the LES may show inflammation and ulceration.
Young adults are usually affected and present with progressive dysphagia. (Fig. 5-31)
Complications of achalasia are
1. Aspiration pneumonitis of undigested food
2. Monilial esophagitis
3. Esophageal squamous cell carcinoma (about 5% of patients)
4. Lower esophageal diverticula
Hiatal Hernia (Fig. 5-32)
Hiatal hernia is characterized by separation of the diaphragmatic crura leading to
widening of the space around the esophageal wall. Two types of hiatal hernia are
recognized:
1. The sliding type (95%)
2. The paraesophageal type
In the sliding hernia the stomach skates up through the patent hiatus above the diaphragm
creating a bell-shaped dilation. In paraesophageal hernias, a separate portion of the
stomach, usually along the greater curvature, enters the thorax through the widened
foramen. The cause of hiatal hernia is unknown. It is not clear whether it is a congenital
malformation or is acquired during life. Only about 10% of adults with a sliding hernia
suffer from heartburn or regurgitation of gastric juices into the mouth. These are due to
incompetence of the LES and are accentuated by positions favoring reflux (bending
forward, lying supine) and obesity.
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Complications of hiatal hernias include
1. Ulceration, bleeding and perforation (both types)
2. Reflux esophagitis (frequent with sliding hernias)
3. Strangulation of paraesophageal hernias
Diverticula (Fig. 5-33)
By definition a diverticulum is a "focal out pouching of the alimentary tract wall that
contains all or some of its constituents"; they are divided into
1. False diverticulum is an out pouching of the mucosa and submucosa through weak
points in the muscular wall.
2. True diverticulum consists of all the layers of the wall and is thought to be due to
motor dysfunction of the esophagus. They may develop in three regions of the esophagus
a. Zenker diverticulum, located immediately above the UES
b. Traction diverticulum near the midpoint of the esophagus
c. Epiphrenic diverticulum immediately above the LES.
Lacerations (Mallory-Weiss Syndrome)
These refer to longitudinal tears at the GEJ or gastric cardia and are the consequence of
severe retching or vomiting. They are encountered most commonly in alcoholics, since
they are susceptible to episodes of excessive vomiting, but have been reported in persons
with no history of vomiting or alcoholism. During episodes of prolonged vomiting, reflex
relaxation of LES fails to occur. The refluxing gastric contents suddenly overcome the
contracted musculature leading to forced, massive dilation of the lower esophagus with
tearing of the stretched wall.
Pathological features
The linear irregular lacerations, which are usually found astride the GEJ or in the gastric
cardia, are oriented along the axis of the esophageal lumen. The tears may involve only
the mucosa or may penetrate deeply to perforate the wall. (Fig. 5-34) Infection of the
mucosal defect may lead to inflammatory ulcer or to mediastinitis. Usually the bleeding
is not profuse and stops without surgical intervention. Healing is the usual outcome.
Rarely esophageal rupture occurs.
Esophageal Varices
Portal hypertension when sufficiently prolonged or severe induces the formation of
collateral bypass veins wherever the portal and caval venous systems communicate.
Esophageal varices refer to the prominent plexus of deep mucosal and submucosal
venous collaterals of the lower esophagus subsequent to the diversion of portal blood
through them through the coronary veins of the stomach. From the varices the blood is
diverted into the azygos veins, and eventually into the systemic veins. Varices develop in
90% of cirrhotic patients. Worldwide, after alcoholic cirrhosis, hepatic schistosomiasis is
the second most common cause of variceal bleeding.
Pathological features (Fig. 5-35)
The increased pressure in the esophageal plexus produces dilated tortuous vessels that are
liable to rupture.
Varices appear as tortuous dilated veins lying primarily within the submucosa of the
distal esophagus and proximal stomach.
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The net effect is irregular protrusion of the overlying mucosa into the lumen. The
mucosa is often eroded because of its exposed position.
Variceal rupture produces massive hemorrhage into the lumen. In this instance, the
overlying mucosa appears ulcerated and necrotic.
Rupture of esophageal varices usually produces massive hematemesis. Among patients
with advanced liver cirrhosis, such a rupture is responsible for 50% of the deaths. Some
patients die as a direct consequence of the hemorrhage (hypovolemic shock); others of
hepatic coma triggered by the hemorrhage.
Esophagitis
This term refers to inflammation of the esophageal mucosa. It may be caused by a variety
of physical, chemical, or biologic agents. Reflux Esophagitis (Gastroesophageal Reflux
Disease or GERD) is the most important cause of esophagitis and signifies esophagitis
associated with reflux of gastric contents into the lower esophagus. Many causative
factors are involved, the most important is decreased efficacy of esophageal antireflux
mechanisms, particularly LES tone. In most instances, no cause is identified. However,
the following may be contributatory
a. Central nervous system depressants including alcohol
b. Smoking
c. Pregnancy
d. Nasogastric tube
e. Sliding hiatal hernia
f. hypothyroidism
g. Systemic sclerosis
Any one of the above mechanism may be the primary cause in an individual case, but
more than one is likely to be involved in most instances. The action of gastric juices
is vital to the development of esophageal mucosal injury.
Gross (endoscopic) features (Fig. 5-36 A)
These depend on the causative agent and on the duration and severity of the
exposure.
Mild esophagitis may appear grossly as simple hyperemia. In contrast, the mucosa
in severe esophagitis shows confluent erosions or total ulceration into the
submucosa.
Microscopic features (Fig. 5-36 B)
Three histologic features are characteristic:
1. Inflammatory cells including eosinophils within the squamous mucosa.
2. Basal cells hyperplasia
3. Extension of lamina propria papillae into the upper third of the mucosa.
The disease mostly affects those over the age of 40 years. The clinical manifestations
consist of dysphagia, heartburn, regurgitation of a sour fluid into the mouth,
hematemesis, or melena. Rarely, there are episodes of severe chest pain that may be
mistaken for a "heart attack."
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The potential consequences of severe reflux esophagitis are
1. Bleeding
2. Ulceration
3. Stricture formation
4. Tendency to develop Barrett esophagus
Barrett Esophagus (BE)
10% of patients with long-standing GERD develop this complication. BE is the single
most important risk factor for esophageal adenocarcinoma. BE refers to columnar
metaplasia of the distal squamous mucosa; this occurs in response to prolonged injury
induced by refluxing gastric contents. Two criteria are required for the diagnosis of
Barrett esophagus:
1. Endoscopic evidence of columnar lining above the GEJ
2. Histologic confirmation of the above in biopsy specimens.
The pathogenesis of Barrett esophagus appears to be due to a change in the differentiation
program of stem cells of the esophageal mucosa. Since the most frequent metaplastic
change is the presence of columnar cells admixed with goblet cells, the term "intestinal
metaplasia" is used to describe the histological alteration.
Gross features
Barrett esophagus is recognized as a red, velvety mucosa located between the smooth,
pale pink esophageal squamous mucosa and the light brown gastric mucosa.
It is displayed as tongues, patches or broad circumferential bands replacing the
squamocolumnar junction several centimeters. (Fig. 5-37 A)
Microscopic features
the esophageal squamous epithelium is replaced by metaplastic columnar epithelium,
including interspersed goblet cells, & may show a villous pattern (as that of the small
intestine hence the term intestinal metaplasia). (Fig. 5-37 B)
Critical to the pathologic evaluation of patients with Barrett mucosa is the search for
dysplasia within the metaplastic epithelium. This dysplastic change is the presumed
precursor of malignancy (adenocarcinoma). Dysplasia is recognized by the presence of
cytologic and architectural abnormalities in the columnar epithelium, consisting of
enlarged, crowded, and stratified hyperchromatic nuclei with loss of intervening stroma
between adjacent glandular structures. Depending on the severity of the changes,
dysplasia is classified as low-grade or high-grade.
Approximately 50% of patients with high-grade dysplasia may already have adjacent
adenocarcinoma.
Most patients with the first diagnosis of Barrett esophagus are between 40 and 60 years.
Barrett esophagus is clinically significant due to
1. The secondary complications of local peptic ulceration with bleeding and stricture.
2. The development of adenocarcinoma, which in patients with long segment disease
(over 3 cm of Barrett mucosa), occurs at a frequency that is 30- to 40 times greater than
that of the general population.
Other causes of esophagitis
In addition to GERD (which is, in fact, a chemical injury), esophageal inflammation may
have many origins. Examples include ingestion of mucosal irritants (such as alcohol,
corrosive acids or alkalis as in suicide attempts), cytotoxic anticancer therapy,
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bacteremia or viremia (in immunosuppressed patients), fungal infection (in debilitated or
immunosuppressed patients or during broad-spectrum antimicrobial therapy; candidiasis
by far the most common), and uremia.
TUMORS
Benign Tumors
Leiomyomas are the most common benign tumors of the esophagus. (Fig. 5-38)
Malignant Tumors
Carcinomas of the esophagus (5% of all cancers of the GIT) have, generally, a poor
prognosis because they are often discovered too late. Worldwide, squamous cell
carcinomas constitute 90% of esophageal cancers, followed by adenocarcinoma.
Other tumors are rare.
Squamous Cell Carcinoma (SCC)
Most SCCs occur in adults over the age of 50. The disease is more common in males
than females. The regions with high incidence include Iran & China. Blacks
throughout the world are at higher risk than are whites.
Etiology and Pathogenesis
Factors Associated with the Development of Squamous Cell Carcinoma of the
Esophagus are classified as
1. Dietary
Deficiency of vitamins (A, C, riboflavin, thiamine, and pyridoxine) & trace
elements (zinc)
Fungal contamination of foodstuffs
High content of nitrites/nitrosamines
Betel chewing (betel: the leaf of a climbing evergreen shrub, of the pepper family,
which is chewed in the East with a little lime.)
2. Lifestyle
Burning-hot food
Alcohol consumption
Tobacco abuse
3. Esophageal Disorders
Long-standing esophagitis
Achalasia
Plummer-Vinson syndrome
4. Genetic Predisposition
Long-standing celiac disease
Racial disposition
The marked geographical variations in the incidence of the disease strongly implicate
dietary and environmental factors, with a contribution from genetic predisposition.
The majority of cancers in Europe and the United States are attributable to alcohol
and tobacco. Some alcoholic drinks contain significant amounts of such carcinogens
as polycyclic hydrocarbons, nitrosamines, and other mutagenic compounds.
Nutritional deficiencies associated with alcoholism may contribute to the process of
carcinogenesis.
Human papillomavirus DNA is found frequently in esophageal squamous cell
carcinomas from high-incidence regions.
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Gross features (Fig. 5-39 A)
Like squamous cell carcinomas arising in other locations, those of the esophagus
begin as in situ lesions.
When they become overt, about 20% of these tumors are located in the upper
third, 50% in the middle third, and 30% in the lower third of the esophagus.
Early lesions appear as small, gray-white, plaque-like thickenings of the mucosa
but with progression, three gross patterns are encountered:
1. Fungating (polypoid) (60%) that protrudes into the lumen
2. Flat (diffusely infiltrative) (15%) that tends to spread within the wall of the
esophagus, causing thickening, rigidity, and narrowing of the lumen
3. Excavated (ulcerated) (25%) that digs deeply into surrounding structures and
may erode into the respiratory tree (with resultant fistula and pneumonia) or aorta
(with catastrophic bleeding) or may permeate the mediastinum and pericardium.
Local extension into adjacent mediastinal structures occurs early, possibly due to
the absence of serosa for most of the esophagus. Tumors located in the upper third
of the esophagus also metastasize to cervical lymph nodes; those in the middle
third to the mediastinal, paratracheal, and tracheobronchial lymph nodes; and
those in the lower third most often spread to the gastric and celiac groups of
nodes.
Microscopic features (Fig. 5-39 B)
Most squamous cell carcinomas are moderately to well-differentiated,
They are invasive tumors that have infiltrated through the wall or beyond.
The rich lymphatic network in the submucosa promotes extensive circumferential and
longitudinal spread.
Esophageal carcinomas are usually quite large by the time of diagnosis, produces
dysphagia and obstruction gradually. Cachexia is frequent. Hemorrhage and sepsis
may accompany ulceration of the tumor.
The five-year survival rate in patients with superficial esophageal carcinoma is about
75%, compared to 25% in patients who undergo "curative" surgery for more
advanced disease. Local recurrence and distant metastasis following surgery are
common. The presence of lymph node metastases at the time of resection
significantly reduces survival.
Adenocarcinoma
With increasing recognition of Barrett mucosa, most adenocarcinomas in the lower
third of the esophagus arise from the Barrett mucosa.
Etiology and Pathogenesis
These focus on Barrett esophagus. The lifetime risk for cancer development from
Barrett esophagus is approximately 10%. Tobacco exposure and obesity are risk
factors. Helicobacter pylori infection may be a contributing factor.
Gross features: (Fig. 5-40 A)
adenocarcinomas arising in the setting of Barrett esophagus are usually
located in the distal esophagus and may invade the adjacent gastric cardia.
As is the case with squamous cell carcinomas, adenocarcinomas initially
appear as flat raised patches that may develop into large nodular fungating
masses or may exhibit diffusely infiltrative or deeply ulcerative features.
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Microscopic features (Fig. 5-40 B)
Most tumors are mucin-producing glandular tumors exhibiting intestinal-type
features.
Multiple foci of dysplastic mucosa are frequently present adjacent to the
tumor.
Adenocarcinomas arising in Barrett esophagus chiefly occur in patients over the age
of 40 years and similar to Barrett esophagus, it is more common in men than in
women, and in whites more than blacks (in contrast to squamous cell carcinomas). As
in other forms of esophageal carcinoma, patients usually present because of difficulty
swallowing, progressive weight loss, bleeding, and chest pain. The prognosis is as
poor as that for other forms of esophageal cancer, with under 20% overall five-year
survival. Identification and resection of early cancers with invasion limited to the
mucosa or submucosa improves five-year survival to over 80%. Regression or
surgical removal of Barrett esophagus has not yet been shown to eliminate the risk for
adenocarcinoma.
Weeks 2:
STOMACH
In developed countries, peptic ulcers occur in up to 10% of the general population.
Chronic infection of the gastric mucosa by the bacterium H. pylori is the most common
infection worldwide. Gastric cancer is still a significant cause of death, despite its
decreasing incidence.
CONGENITAL ANOMALIES
These include various heterotopias (normal tissues in abnormal locations), which are
usually asymptomatic, e.g. pancreatic heterotopia. Congenital diaphgramatic hernia,
which is due to defective closure of the diaphragm; this leads to herniation of abdominal
contents into the thorax in utero. Congenital hypertrophic pyloric stenosis is encountered
in male infants four times more often than females. Persistent, projectile vomiting usually
appears in the second or third week of life. There is visible peristalsis and a firm, ovoid
palpable mass in the region of the pylorus resulting from hypertrophy and hyperplasia of
the muscularis propria of the pylorus. (Fig. 5-41)
Acquired pyloric stenosis in adults may complicate
1. Antral gastritis or peptic ulcers close to the pylorus.
2. Malignancy e.g. carcinomas of the pyloric region or adjacent panceas, or gastric
lymphomas
3. Hypertrophic pyloric stenosis (rare) due to prolonged pyloric spasm
GASTRITIS this is by definition, "inflammation of the gastric mucosa". It is a
microscopic diagnosis. The inflammation may be acute, with neutrophilic infiltration, or
chronic, with lymphocytes and/or plasma cells.
Acute gastritis is usually transient in nature. The inflammation may be accompanied by
hemorrhage into the mucosa (acute hemorrhagic gastritis) and, sometimes by sloughing
(erosions) of the superficial mucosa (acute erosive gastritis). (Fig. 5-42) The latter is a
severe form of the disease & an important cause of acute gastrointestinal bleeding.
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Although a large number of cases have no obvious cause (idiopathic), acute gastritis is
frequently associated with
1. Heavy use of nonsteroidal anti-inflammatory drugs (NSAIDs) particularly aspirin,
cancer chemotherapeutic drugs, or radiation
2. Excessive consumption of alcohol, heavy smoking, and ingestion of strong acids or
alkali as in suicidal attempts
3. Uremia
4. Severe stress (e.g., trauma, burns, surgery)
5. Mechanical trauma (e.g., nasogastric intubation)
6. Distal gastrectomy (reflux of duodenal contents).
Chronic Gastritis is defined as "chronic inflammation of the gastric mucosa that
eventuates in mucosal atrophy and intestinal metaplasia". The epithelial changes may
progress to dysplasia, which constitute a soil for the development of carcinoma.
Pathogenesis
The major etiologic associations of chronic gastritis are:
1. Chronic infection by H. pylori
2. autoimmune damage
3. Excessive alcohol consumption & heavy cigarette smoking
4. Post-antrectomy (due to reflux of bile-containing duodenal secretions)
5. Outlet obstruction, uremia, and other rare causes
Helicobacter pylori Infection and Chronic Gastritis
Infection by H. pylori is the most important etiologic cause of chronic gastritis. Effective
treatment with antibiotics has revolutionized the management of chronic gastritis and
peptic ulcer disease. Those with H. pylori-associated chronic gastritis are at increased risk
for the development of
1. Peptic ulcer disease
2. Gastric carcinoma 3. Gastric lymphoma
H. pylori are curvilinear, gram-negative rods. They have adapted to survive within gastric
mucus, which is lethal to most bacteria. The specialized features that allow these bacteria
to flourish include:
1. Motility (via flagella), allowing them to swim through the viscous mucus
2. Urease production, which releases ammonia and CO
2
from endogenous urea, thereby
buffering the harmful gastric acid in the immediate vicinity of the bacteria
3. Expression of adhesion molecules, which enhances binding of the bacteria to adjacent
foveolar cells
The bacteria appear to cause gastritis by stimulating production of pro-inflammatory
cytokines as well as by directly damaging epithelial cells by the liberation of toxins &
degrading enzymes e.g. vacuolating toxin (VacA), urease, proteases and phospholipases.
After exposure to H. pylori, gastritis occurs in two patterns:
1. Antral-predominant gastritis with high acid production and elevated risk for duodenal
ulcer
2. Pan gastritis with low acid secretion and higher risk for adenocarcinoma
IL-1β is a potent pro-inflammatory cytokine and a powerful gastric acid inhibitor.
Patients who have higher IL-1β production in response to the infection tend to develop
pangastritis, while patients who have lower IL-1β production exhibit antral-predominant
gastritis.
15
A number of diagnostic tests have been developed for the detection of H. pylori.
(Fig. 5-43)
1. Noninvasive tests including
a. Serologic test for antibodies
b. Stool culture for bacterial detection
c. Urea breath test: based on the generation of ammonia by bacterial urease.
2. Invasive tests (through gastroscopy): detection of H. pylori in gastric biopsy tissue
samples including
a. visualization of the bacteria in histologic sections with special stains (Fig.
b. bacterial culture of the biopsy
c. bacterial DNA detection by the polymerase chain reaction
Autoimmune gastritis
About 10% of chronic gastritis are autoimmune in nature. It results from the presence of
autoantibodies to components of parietal cells, including the acid-producing enzyme
H+/K+-ATPase, gastrin receptor, and intrinsic factor. Gland destruction and mucosal
atrophy lead to loss of acid production (hypo- or achlorhydria). (Fig. 5-44) In the most
severe cases, production of intrinsic factor is also impaired, leading to pernicious anemia.
Affected patients have a significant risk for developing gastric carcinoma and endocrine
tumors (carcinoid tumor).
Pathological features of chronic gastritis
Autoimmune gastritis is characterized by diffuse mucosal damage of the body-fundic
mucosa, with sparing of antral rgion (Corpus-predominant gastritis).
Environmental gastritis i.e. due to environmental etiologies (including H. pylori
infection) tends to affect antral mucosa (antral gastritis) or both antral and body-fundic
mucosa (pangastritis).
Gross (endoscopic) features
The mucosa of the affected regions is usually hyperemic and has coarser rugae than
normal.
With long-standing disease, the mucosa may become thinned and flattened because of
atrophy.
Microscopic features (Fig. 5-45)
Irrespective of cause or location, the microscopic changes are similar:
The mucosa is infiltrated by lymphocytes & plasma cells.
Frequently the lymphocytes are disposed into aggregates i.e. follicles, some with
germinal centers.
Neutrophils may or may not be present.
Several additional histologic features are characteristic; these include
Intestinal metaplasia: the mucosa may become partially replaced by metaplastic
columnar cells and goblet cells of intestinal morphology; these may display flat or
villous arrangement. If the columnar cells are absorptive (with ciliated border) the
metaplasia is termed complete, otherwise it is incomplete.
Atrophy as evidecnced by marked loss of the mucosal glands. Parietal cells, in
particular, may be absent in the autoimmune form.
16
Dysplasia: with long-standing chronic gastritis, the epithelium develops dysplastic
changes. Dysplastic alterations may become so severe as to constitute in situ
carcinoma. The development of dysplasia is thought to be a precursor lesion of gastric
cancer. It occurs in both autoimmune and H. pylori- associated chronic gastritis.
In those individuals infected by H. pylori, the organism lies in the superficial mucus
layer on the surface and within the gastric pits. They do not invade the mucosa. These
bacteria are most easily demonstrated with silver or Giemsa (special) stains.
PEPTIC ULCER DISEASE
An ulcer is defined as "a breach in the mucosa of the alimentary tract that extends into the
submucosa or deeper." Although they may occur anywhere in the alimentary tract, they
are most common in the duodenum and stomach. Ulcers have to be distinguished from
erosions. The latter is limited to the mucosa and does not extend into the submucosa.
Peptic Ulcers are chronic, most often solitary lesions and usually small. They occur in
any portion of the GIT exposed to the aggressive action of acid-peptic juices. They are
located, in descending order of frequency in:
1. Duodenum (first portion)
2. Stomach, (usually antral, along the lesser curve)
3. Gastro-esophageal junction (complicating GERD or Barrett esophagus)
4. Margins of a gastro-jejunostomy
5. Multiple in the duodenum, stomach, and/or jejunum (in Zollinger-Ellison syndrome)
6. Within or adjacent to a Meckel diverticulum (containing ectopic gastric mucosa)
The male-to-female ratio for duodenal ulcers is 3:1, and for gastric ulcers 2:1. Women are
most often affected at or after menopause.
Pathogenesis of peptic ulcers
Peptic ulcers are produced by an imbalance between gastro-duodenal mucosal
defenses and the damaging forces, particularly of gastric acid and pepsin.
Hyperacidity is not necessary; only a minority of patients with duodenal ulcers has
hyperacidity, and it is even less common in those with gastric ulcers.
H. pylori infection is a major factor in the pathogenesis of peptic ulcer. It is present in
virtually all patients with duodenal ulcers and in about 70% of those with gastric
ulcers; that is why peptic ulcer disease is now considered infectious in nature.
Antibiotic treatment of the infection promotes healing of ulcers and prevents their
recurrence. The possible mechanisms by which this tiny organism impairs mucosal
defenses include:
1. H. pylori induce intense inflammatory and immune responses. As a result there is
increased production of pro-inflammatory cytokines, most notably, IL-8, by the
mucosal epithelial cells. This recruits and activates neutrophils with their damaging
properties.
2. Several bacterial products cause epithelial cell injury; this is mostly caused by a
vacuolating toxin called VacA. H. pylori also secrete urease, proteases and
phospholipases, which also cause direct epithelial damage.
3. H. pylori enhance gastric acid secretion and impair duodenal bicarbonate production,
thus reducing luminal pH in the duodenum with its damaging effects on the duodenal
mucosa.
17
4. Thrombotic occlusion of surface capillaries is provoked by a bacterial platelet-
activating factor. Thus, an additional ischemic element may contribute to the mucosal
damage.
Most persons (80-90%) infected with H. pylori do not develop peptic ulcers. Perhaps
there are unknown interactions between H. pylori and the mucosa that occur only in
some individuals.
Other factors may act alone or in concert with H. pylori to encourage peptic
ulceration:
1. Gastric hyperacidity: this when present, may be strongly ulcerogenic. The classic
example is Zollinger-Ellison syndrome, in which there are multiple peptic ulcerations
in the stomach, duodenum, and even jejunum. This is due to excess gastrin secretion
by a gastrinoma and, hence, excess gastric acid production.
2. Chronic use of NSAIDs: this suppresses mucosal prostaglandin synthesis; aspirin also
is a direct irritant.
3. Cigarette smoking: this impairs mucosal blood flow and healing of the ulcer.
4. Corticosteroids: these in high doses and with repeated use encourage ulcer formation.
5. Rapid gastric emptying: this is present inn some patients with duodenal ulcers; this
phenomeneon exposes the duodenal mucosa to an excessive acid load & hence
ulcerations
6. Patients with the following diseases are more prone to develop duodenal ulcer exposes
a. alcoholic cirrhosis
b. chronic obstructive pulmonary disease
c. chronic renal failure
d. hyperparathyroidism.
Chronic renal failure and hyperparathyroidism are associated with hypercalcemia. The
latter stimulates gastrin production and therefore acid secretion.
7. Personality and psychological stress seems to be important contributing factors.
Gross features (Fig. 5-46)
The vast majority of peptic ulcers are located in the first portion of the duodenum or
in the stomach, in a ratio of about 4:1. Gastric and duodenal ulcers may coexist in up
to 20% of the cases. Gastric ulcers are predominantly located along the lesser
curvature.
Although over 50% of peptic ulcers have a diameter less than 2 cm but about 10%
are greater than 4 cm. Ulcerated carcinomas (which tend to be large) may be less than
4 cm in diameter and may be located anywhere in the stomach. Thus, size and
location do not differentiate a benign from a malignant ulcer.
The classic peptic ulcer is a round to oval with sharply demarcated crater. The
margins are usually level with the surrounding mucosa or only slightly elevated.
Heaping-up of these margins is rare in the benign ulcer but is characteristic of the
malignant ones.
Peptic ulcers penetrate the wall to a variable extent. When the entire wall is
penetrated, the base of the ulcer may be formed by adherent pancreas, omental fat, or
liver.
The base of a peptic ulcer is smooth and clean, owing to peptic digestion of any
exudate that may form. Sometimes, thrombosed or patent blood vessels (the source of
life threatening hemorrhage) are evident at the base of the ulcer.
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Ulcer-related scarring may involve the entire thickness of the gastric wall; puckering
of the surrounding mucosa creates mucosal folds that radiate from the crater in
spoke-like fashion. This is different from malignant ulcers where there is flattening
of the mucosal folds (because of malignant infiltration) in the immediately
surrounding of the ulcerative.
Microscopic features (Fig. 5-46 B)
In active ulcers four zones are recognized
1. The base and walls have a superficial thin layer of necrotic fibrinoid necrosis.
2. Beneath this layer is a zone of predominantly neutrophilic inflammatory
infiltrate.
3. Deeper still, there is granulation tissue infiltrated with inflammatory cells. This
rests on
4. Fibrous or collagenous scar.
H. pylori-associated chronic gastritis is seen in up to 100% of patients with duodenal
ulcers and in 70% with gastric ulcers. With present-day therapies aimed at inhibition
of acid secretion (H
2
receptor antagonists and parietal cell H
+
/K
+
-ATPase pump
inhibitors), and eradication of H. pylori infection (with antibiotics), most ulcers heal
within a few weeks.
The complications of peptic ulcer disease are
1. Bleeding is the most frequent complication (20%). It may be life-threatening; fatal in
25% of the affected patients. It may be the first warning of an ulcer.
2. Perforation is much less frequent (5% of patients) but much more serious being fatal
in 60% of patients.
3. Obstruction (from edema or scarring) occurs in 2%, most often due to pyloric channel
ulcers but may occur with duodenal ulcers. Total obstruction with intractable vomiting is
rare.
4. Malignant transformation does not occur with duodenal ulcers and is extremely rare
with gastric ulcers. When it occurs, it is always possible that a seemingly benign gastric
ulcer was, from the outset an ulcerative gastric carcinoma.
Acute Gastric Ulceration
Focal, acutely developing gastric mucosal defects are a well-known complication of
1. Therapy with NSAIDs
2. Severe stress (stress ulcers) as in shock states, extensive burns & severe trauma; they
usually occur in proximal duodenum (Curling ulcers)
3. Sepsis
4. Rraised intracranial pressure or intracranial surgery; these are seen as gastric,
duodenal, and esophageal ulcers & are designated as Cushing ulcers, which carry a high
incidence of perforation.
Generally, acute ulcers are multiple lesions predominantly gastric but sometimes also
duodenal. They range in depth from mere shedding of the superficial epithelium
(erosions) to deeper lesions that involve the entire mucosal thickness and deeper
(ulceration). Acute ulcers are not precursors of chronic peptic ulcers.
Gross features (Fig. 5-47)
Acute ulcers are usually small (less than 1 cm) and circular.
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The ulcer base is frequently stained a dark brown by the acid digestion of blood.
They differ from chronic peptic ulcers by the following
1. They are found anywhere in the stomach, and are often multiple
2. The margins and base of the ulcers are not indurated
3. The related mucosal folds (rugae) are normal (cf. chronic peptic ulcer, which show
convergence on the ulcer)
Microscopically
There is focal loss of the mucosa & at least part of the submucosa
Unlike chronic peptic ulcers, there is no chronic gastritis or scarring.
Healing with complete re-epithelialization occurs after the causative factor is
removed.
Bleeding from superficial gastric erosions or ulcers sufficient to require transfusion
develops in up to 5% of these patients. If the underlying cause is corrected recovery is
complete.
TUMORS OF THE STOMACH
These can be classified as benign and malignant lesions.
BENIGN TUMORS
Gastric polyps
In the alimentary tract, the term polyp is applied to any nodule or mass that projects
above the level of the surrounding mucosa. They are uncommon and classified as non-
neoplastic or neoplastic.
Hyperplastic polyps (the most frequent; 90%) are small, sessile and multiple in about
25% of cases. There is hyperplasia of the surface epithelium and cystically dilated
glandular tissue. (Fig. 5-48)
Adenomatous polyp (adenoma) (10% of polypoid lesions) (Fig. 5-49): They contain
proliferative dysplastic epithelium and hence have malignant potential. They are usually
single, and may grow up to 4 cm in size before detection. Up to 40% of gastric adenomas
contain a focus of carcinoma; there may also be an adjacent carcinoma that is why
histologic examination of all gastric polyps is obligatory.
Other specific types of gastric polyps are relatively uncommon and include fundic gland
polyps, hamartomatous Peutz-Jeghers polyps, juvenile polyps, and inflammatory fibroid
polyp
CANCERS OF THE STOMACH
Carcinoma is the most important and the most common (90%) of malignant tumors of the
stomach. Next in order of frequency are lymphomas (5%); the rest of the tumors are even
rarer e.g. carcinoids, and gastrointestinal stromal tumors (GISTs), leiomyosarcoma, and
schwannoma.
Gastric Carcinoma is a quite common tumor in the world. There are, however, marked
geographical variations in its incidence; it is particularly high in countries such as Japan.
It is more common in lower socioeconomic groups. There has been a steady decline in
both the incidence and the mortality of gastric cancer. There are mainly two subtypes of
20
carcinoma: intestinal and diffuse. These sub-types appear to have different pathogenetic
mechanisms of evolution.
Pathogenesis
The major factors thought to affect the genesis of gastric cancer apply more to the
intestinal type, as the risk factors for diffuse gastric cancer are not well defined.
1. Helicobacter pylori Infection: this generally increases the risk five- fold. The bacterial
infection causes chronic gastritis, followed by atrophy, intestinal metaplasia, dysplasia,
and carcinoma. Long-standing mucosal inflammation is associated with damage of
epithelial cells, which leads to compensatory epithelial cell proliferation, and hence
increased risk of genomic mutation. Since most individuals infected with H. pylori do not
develop cancer, other factors must be involved in carcinogenesis.
2. Adenomatous polyps: 40% of adenomas harbor carcinmatous foci; also adjacent
carcinoma is found in relation to adenomatous polyps in 30% of the cases.
3. Environmental factors: when families migrate from high-risk to low-risk areas (or the
reverse), successive generations acquire the level of risk that prevails in the new
environments. The diet is suspected to be a primary factor. Consumption of preserved
and salted foods; water contamination with nitrates; and lack of fresh fruit and vegetables
are common in high-risk areas. The intake of green, leafy vegetables and citrus fruits,
which contain antioxidants such as vitamin C, vitamin E and beta-carotene, seems to play
a protective role.
4. Autoimmune gastritis, like H. pylori infection, increases the risk of gastric cancer.
Gross features
The most common location of gastric carcinomas is the pyloric antrum (50%). A
favored location is the lesser curvature. Although less common, an ulcerative lesion
on the greater curvature is more likely to be malignant.
Depth of invasion is the most important determinant of prognosis. Early gastric
carcinoma is defined as "a lesion confined to the mucosa and submucosa." Advanced
gastric carcinoma is a neoplasm extending into the muscular wall.
The three macroscopic growth patterns of gastric carcinoma, which may be evident at
both the early and advanced stages, are: 1. Fungating (exophytic) 2. Flat or depressed
3. (Fig. 5-50) Ulcerative (excavated). Fungating tumors are readily identified by
radiography and endoscopy in contrast to flat (depressed) malignancy. Ulcerative
cancers may closely mimic chronic peptic ulcers. In advanced cases, there are
heaped-up, beaded margins and necrotic bases. The neoplastic tissue extends into the
surrounding mucosa and wall; this leads to flattening of the mucosa surrounding the
ulcer. (Fig. 5-51)
Uncommonly, a broad region of the gastric wall or the entire stomach is extensively
infiltrated by malignancy, creating a rigid, thickened "leather bottle," termed linitis
plastica. (Fig. 5-52)
Microscopic features
There are two main microscopic type of gastric carcinoma; intestinal and diffuse.
The intestinal variant is composed of neoplastic glands with mucin in their lumina.
The diffuse variant is composed of mucus-containing cells, which do not form glands,
but infiltrate the mucosa and wall as scattered individual and small clusters of cells.
In this variant, mucin formation expands the malignant cells and pushes the nucleus
to the periphery, creating"signet ring" morphology. (Fig. 5-53)
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Sometimes, there is excessive mucin production that generates large mucin lakes
(mucinous carcinoma).
Infiltrative tumors often evoke a strong desmoplastic reaction (fibrosis), in which the
scattered cells are embedded; the fibrosis creates local rigidity of the wall.
Whatever the microscopic type, all gastric carcinomas eventually penetrate the wall to
involve the serosa and spread to regional and more distant lymph nodes.
For obscure reasons, gastric carcinomas frequently metastasize to the supraclavicular
(Virchow) node as the first clinical manifestation of an occult neoplasm. (Fig. 5-54) The
tumor can also metastasize to the periumbilical region to form a subcutaneous nodule.
This nodule is called a Sister Mary Joseph nodule, after the nun who noted this lesion as
a marker of metastatic carcinoma. (Fig. 5-55) Local extension of gastric carcinoma into
the duodenum, pancreas, and retroperitoneum is also characteristic. At the time of death,
widespread peritoneal seeding and metastases to the liver and lungs are common. A
notable site of visceral metastasis is to one or both ovaries. Although uncommon,
metastatic adenocarcinoma to the ovaries (from stomach, breast, pancreas, and even
gallbladder) is distinctive & designated Krukenberg tumor. (Fig. 5-56)
Gastric carcinoma is an insidious disease that is generally asymptomatic until late in its
course.
The symptoms include weight loss, abdominal pain, anorexia, vomiting, dysphagia,
anemia, and hemorrhage. In Japan, where mass endoscopy screening programs are
employed (because of the high incidence of the disease), early gastric cancer constitutes
about one third of all newly diagnosed gastric cancers. In Europe and the United States,
this figure is only 10% to 15%.
Prognosis
This depends primarily on
1. The depth of invasion and
2. The extent of nodal and distant metastasis
The histologic type (intestinal or diffuse) has minimal independent prognostic
significance. The five-year survival rate of surgically treated early gastric cancer is 90%;
this drops to below 15% for advanced gastric cancer.
Gastric Lymphomas represent 5% of all gastric malignancies. However, the stomach is
the most common site for extra-nodal lymphoma (20%). Nearly all primary gastric
lymphomas are B-cell type and of mucosa-associated lymphoid tissue (MALT
lymphomas). The majority of gastric lymphomas (>80%) are associated with chronic
gastritis and H. pylori infection. The role of H. pylori infection as an important etiologic
factor for gastric lymphoma is supported by the elimination of about 50% of early gastric
lymphomas with antibiotic treatment for H. pylori. Generally, the prognosis of gastric
lymphoma is better than carcinoma.
Gastrointestinal Stromal Tumors (GISTs) these are thought to originate from the
interstitial cells of Cajal (normally control gastrointestinal peristalsis). 95% of GISTs
stain with antibodies against c-KIT (CD117). The tumor can protrude into the lumen or
extrude on the serosal side of the gastric wall. Microscopically, the tumor can exhibit
22
spindle cells, plump "epithelioid" cells, or a mixture of both. Most of the tumors are quite
cellular but mitotic activity is variable.
Gastric Neuroendocrine Cell (Carcinoid) Tumors
Most gastric carcinoid tumors originate from the enterochromaffin-like cells (ECL) cells
in the oxyntic mucosa. The tumor can arise in the setting of chronic atrophic gastritis.
The underlying pathogenesis is probably related to the hypergastrinemia, resulting in
ECL-cell hyperplasia, a presumed pre-neoplastic condition. Gastric carcinoid tumors
exhibit similar histologic features to other carcinoid tumors. The clinical course is quite
variable.
Weeks 3:
SMALL & LARGE INTESTINE
Several pathological conditions, such as infections, inflammatory diseases, motility
disorders, and tumors, affect both the small and large intestines simultaneously. These
two organs will therefore be considered together.
CONGENITAL ANOMALIES
Anomalies of the intestine are rarely encountered; these include duplication of the small
intestine or colon; malrotation of the entire bowel; omphalocele (birth of an infant with
herniation of abdominal contents into a ventral membranous sac related to umbilicus);
heterotopia of pancreatic tissue or gastric mucosa; atresia and stenosis; imperforate
anus (due to failure of the cloacal diaphragm to rupture).
Meckel diverticulum (Fig. 5-57) results from failure of involution of the vitelline duct,
which embryologically connects the lumen of developing gut to the yolk sac. The small
pouch lies on the antimesenteric side of the bowel, usually 30 cm proximal to the ileo-
cecal valve. It consists of mucosa, submucosa, and muscularis propria. The mucosal
lining may be that of normal small intestine, but heterotopic gastric mucosa or pancreatic
tissue are frequently found. Meckel diverticula are present in 2% of the normal
population, but most remain asymptomatic. When peptic ulceration occurs in the small
intestinal mucosa adjacent to the heterotopic gastric mucosa, intestinal bleeding or
symptoms simulating those of an acute appendicitis may result. Other complications
include intussusception, incarceration, or perforation.
Congenital Aganglionic Megacolon (Hirschsprung Disease) (Fig. 5-58)
This congenital disorder is characterized by the absence of ganglia of the submucosal and
myenteric neural plexuses, within a portion of the intestinal tract. The outcome is
contraction and functional obstruction of the aganglionic segment with secondary
proximal dilation. The rectum is always affected and most cases involve the rectum and
sigmoid colon only (short-segment disease). In some cases longer segments, and rarely
the entire colon may be aganglionic (long-segment disease). Proximal to the aganglionic
segment, the ganglionic colon undergoes progressive dilation and hypertrophy,
sometimes massively (megacolon). When distention overruns hypertrophy, the colonic
wall becomes markedly thinned and may rupture. Diagnosis of Hirschsprung is made
histologically by failure to detect ganglion cells in intestinal biopsy samples of the
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contracted (agnaglionic) segment. The disease usually manifests itself in the immediate
neonatal period by failure to pass meconium, followed by obstructive constipation.
Abdominal distention may secondarily develop. The major threats to life are
superimposed enterocolitis with fluid and electrolyte disturbances and perforation with
peritonitis.
ENTEROCOLITIS
These are divided into three etiological categories
I. Infectious (caused by microbiologic agents)
II. Malabsorption-associated
III. Idiopathic inflammatory bowel diseases
INFECTIOUS ENTEROCOLITIS
This is the cause of more than 12,000 deaths per day among children in developing
countries, and constituting 50% of all deaths before the age of 5 years worldwide. Acute,
self-limited infectious diarrhea is most frequently caused by enteric viruses (such as
rotavirus and adenoviruses). Bacterial infections, such as that caused by enterotoxigenic
Escherichia coli, are also common. In up to 50% of cases, the specific agent cannot be
isolated.
Viral enterocolitis
The lesions caused by enteric viruses in the intestinal tract are similar. The small
intestinal mucosa shows partial villous atrophy (shortening of the villi) with infiltration of
the lamina propria by lymphocytes. However, in infants, rotavirus and adenoviruses can
produce total villous atrophy (flat mucosa), thus resembling celiac disease (see later).
BACTERIAL ENTEROCOLITIS
Salmonellosis and Typhoid Fever
Campylobacter Enterocolitis
Cholera
Antibiotic-Associated Colitis (Pseudomembranous Colitis) (Fig. 5-59)
Tuberculous enteritis
Intestinal tuberculosis contracted by the drinking of contaminated milk was common as a
primary focus of the disease. In developed countries today, intestinal tuberculosis is more
often a complication of advanced pulmonary tuberculosis i.e. secondary to the
swallowing of coughed-up infective sputum.
General pathological features of bacterial enteric diseases
These are quite variable.
Dramatic, even lethal, diarrhea may occur without a significant pathologic lesion, as
in cholera.
Characteristic histology may enable diagnosis with reasonable certainty, as with C.
difficile-induced pseudomembranous colitis, and caseating granulomas of TB.
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PARASITIC ENTEROCOLITIS
Parasitic diseases collectively affect over one-half of the world's population on a chronic
or recurrent basis. The intestine can harbor as many as 20 species of parasites, including
roundworms Ascaris and Strongyloides, hookworms, pinworms, flatworms, tapeworms,
flukes, and protozoa.
Ascaris lumbricoides
Strongyloides
Hookworm (Necator duodenale and Ancylostoma duodenale) infection
Enterobius vermicularis (pinworms)
Amebiasis is caused by the protozoan Entamoeba histolytica. The parasite infects
approximately 500 million persons in developing countries resulting in approximately 40
million cases of dysentery and liver abscesses. The presence in stool of trophozoites
containing ingested red blood cells is diagnostic. The patient may present with abdominal
pain & bloody diarrhea.
Pathologic features (Fig. 5-61)
Amebiasis most frequently involves the cecum and ascending colon. In severe
cases, however, the entire colon is involved (pancolitis).
Amebae invade through the crypt epithelium and burrow into the mucosa and
submucosa, eliciting a neutrophilic reaction.
They are stopped by the muscularis propria thus forced to spread out laterally to
create a flask-shaped ulcer with a narrow neck and broad base.
The mucosa between ulcers is often normal.
Giardiasis
Other less common causes:
Necrotizing enterocolitis (NEC)
Collagenous and lymphocytic colitis
Solitary rectal ulcer syndrome
THE MALABSORPTION SYNDROMES
Malabsorption is characterized by defective absorption of fats, fat-soluble and other
vitamins, proteins, carbohydrates, electrolytes and minerals, and water. The most
common clinical presentation is chronic diarrhea, and the hallmark of malabsorption is
steatorrhea (excessive fecal fat content). Although many causes of malabsorption can be
established clinically, small intestinal mucosal biopsy may be required to satisfactorily
identify or exclude celiac disease.
Major Malabsorption Syndromes
Clinically, the malabsorption syndromes resemble each other more than they differ. The
consequences of malabsorption affect many organ systems. The passage of abnormally
bulky, frothy, greasy, yellow, or gray stools (steatorrhea) is a prominent feature of
malabsorption; this is accompanied by weight loss, abdominal distention, and muscle
wasting.
25
The malabsorptive disorders most commonly encountered are
1. Celiac disease
2. Pancreatic insufficiency
3. Crohn disease
Pancreatic insufficiency
Primarily from chronic pancreatitis or cystic fibrosis, is a major cause of defective
intraluminal digestion that leads to diarrhea and steatorrhea.
Celiac Disease
Celiac disease (gluten-sensitive enteropathy, GSE) is a chronic disease, in which there is
a characteristic mucosal lesion of the small intestine and impaired nutrient absorption,
which improves on withdrawal of wheat gluten from the diet.
Pathogenesis
The fundamental disorder in celiac disease is sensitivity to gluten component
called gliadin, which is a protein present in wheat and closely related grains (e.g.
oat).
There is a T-cell mediated chronic inflammatory reaction, which develops as a
consequence of a loss of tolerance to gluten.
Interplay between genetic predisposing factors, the host immune response, and
environmental factors, is central to disease pathogenesis.
The small intestinal mucosa, when exposed to gluten, accumulates intraepithelial
CD8+ T cells and large numbers of lamina propria CD4+ T cells, which are
sensitized to gliadin.
Gliadin is deamidated by the enzyme transglutaminase; the resultant peptides are
recognized by CD4+ T cells. This leads to secretion of interferon γ, which
damages enterocytes.
Pathological features (5-63)
By endoscopy, the duodenal mucosa appears flat (normally shows mucosal folds).
Biopsies demonstrate enteritis with partial or total loss of villi (partial villous
atrophy or completely flat mucosa respectively)
The surface epithelium shows degeneration, loss of the microvillus brush border,
and an increased number of intraepithelial lymphocytes.
The crypts exhibit increased mitotic activity and are hyperplastic, so that, despite
villous atrophy, the overall mucosal thickness remains the same.
The lamina propria has an overall increase in plasma cells and lymphocytes.
Although the above changes are characteristic of celiac disease, they can be
mimicked by other diseases, most notably tropical sprue.
Mucosal histology usually reverts to normal or near-normal following gluten
exclusion from the diet.
Dermatitis herpetiformis (DH) is a characteristic itchy skin-blistering disease can occur in
some patients with celiac disease.
Detection of serum anti-gliadin or "anti-endomysial" antibodies strongly favors the
diagnosis of celiac disease.
Definitive diagnosis of celiac disease rests on
1. clinical documentation of malabsorption
2. demonstration of the intestinal lesions by small bowel biopsy and
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3. Definite improvement in both symptoms and mucosal histology on gluten
withdrawal from the diet.
4. If there is doubt about the diagnosis, gluten challenge (reintroduction of
gluten to the diet) followed by rebiopsy has been advocated.
5. Serologic tests, mentioned above, are used for screening or treatment
follow-up.
Most patients with celiac disease who adhere to a gluten-free diet remain well
indefinitely and ultimately die of unrelated causes. However, there is a long-term risk of
malignant disease, which includes small intestinal non-Hodgkin lymphoma (moderate
risk), small intestinal adenocarcinoma, and esophageal squamous cell carcinoma (50- to
100-fold higher risk than the general population).
Tropical Sprue (Postinfectious Sprue)
This condition is a celiac-like disease that occurs almost exclusively in people living in or
visiting the tropics. Malabsorption usually becomes apparent within days or a few weeks.
The condition improves on treatment with broad-spectrum antibiotics. This supports an
infectious etiology. Intestinal lymphoma does not appear to be associated with this
disorder (cf. celiac disease).
Other causes include:
Disaccharidase (Lactase) Deficiency
Abetalipoproteinemia
IDIOPATHIC INFLAMMATORY BOWEL DISEASE (IBD)
The two disorders known as inflammatory bowel disease (IBD) are Crohn's disease (CD)
and ulcerative colitis (UC). These diseases have distinctly different clinical and
pathological features. Both CD and UC are chronic, relapsing inflammatory disorders of
obscure origin. CD is an autoimmune disease that may affect any portion of the
gastrointestinal tract from mouth to anus, but most often involves the distal small
intestine and colon. UC is a chronic inflammatory disease limited to the rectum and
colon. Both exhibit extra-intestinal inflammatory manifestations.
Etiology and Pathogenesis
In the normal GIT, the mucosal immune system is always ready to respond against
ingested pathogens but is unresponsive to normal intestinal microflora. In IBD, this state
of homeostasis is disrupted, leading to two key pathogenic abnormalities
1. Strong immune responses against normal microflora
2. Defects in epithelial barrier that cause microflora to reach the lymphoid tissue of
the intestine
The exact cause (s) leading to the above is still not established, hence the designation
idiopathic. It is postulated that IBD result from exaggerated local immune responses to
microflora in the gut, in genetically susceptible individuals.
Thus, the pathogenesis of IBD involves
1. Failure of immune regulation
2. Genetic susceptibility
3. Environmental triggers specifically microbial flora.
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CD appears to be the result of a chronic delayed-type hypersensitivity reaction induced
by IFN-γ- producing T
H
1 cells. This is supported by the presence of granulomas in this
disease.
Experiments on animals suggest that UC is caused by excessive activation of T
H
2 cells.
Diagnosis of IBD
Since the exact etiology of IBD is not known, the diagnosis of IBD and the distinction
between CD and UC depend on clinical history, radiographic examination, laboratory
findings (serum ANCA is positive in 75% of UC Vs only 10% of CD.), and pathologic
examination of tissues involved. Pathologic appearances, both macroscopic and
microscopic, play a central role in establishing a definitive diagnosis.
CROHN DISEASE (CD)
This disease may involve any level of the alimentary tract. CD occurs at any age, but the
peak age of incidence is between 10 and 30 years. Smoking has been found to be a strong
risk factor.
Pathological features
When fully developed, Crohn disease is characterized pathologically by
1. Sharply segmental and typically transmural involvement of the bowel by an
inflammatory process with mucosal damage
2. The presence of
- Small noncaseating granulomas
- Deep fissures that may eventuate in the formation of fistulae
In CD, there is involvement of the small intestine alone in about 40% of cases, of small
intestine and colon in 30%, and of the colon alone in about 30%. Other portions of the
GIT may also be uncommonly involved.
Gross features (Fig. 5-64 A)
Segments of the small bowel involved by the disease show granular and dull gray
serosa (normally transparent and glistening).
Often the mesenteric fat wraps around the bowel (creeping fat)
The involved bowel wall is thick and rubbery (because of edema, inflammation, and
fibrosis). As a result, the lumen is narrowed.
A classic feature of CD is the sharp demarcation of diseased bowel segments from
adjacent uninvolved, essentially normal bowel (skip lesions).
Early disease shows small mucosal ulcers that coalesce to form long, serpentine linear
ulcers (
i.e. long and twisted or sinuous).
As the intervening mucosa (between the ulcers) tends to be accentuated by
inflammation and edema, it acquires a cobblestone appearance. (
Cobble-stone, is a
rounded stone, esp. of the size used for paving
).
Narrow fissures develop between the mucosal folds, often penetrating deeply through
the bowel wall. Further extension of these fissures leads to fistulae or sinus tracts
formation, between the diseased intestinal segment and adherent structures (bowel
loops, vagina, urinary bladder, skin of the abdomen) or the sinuses may end blindly
within the abdominal cavity.
Free perforation or localized abscesses may develop.
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Microscopic features (Fig. 5- 64 B)
The characteristic histologic features of CD are:
1. Acute mucosal inflammation: there is neutrophilic infiltration of the surface & crypt
epithelium that eventually collects within the lumen of the crypts forming crypt
abscesses.
2. Chronic mucosal damage:
This is the hallmark of chronicity of CD (and UC). It manifests as architectural distortion
(in the small intestine as villus blunting; in the colon, the crypts exhibit irregularity, and
branching). Crypt destruction leads to progressive mucosal atrophy.
3. Ulcerations are the usual outcome of severe active disease; these may be superficial, or
may penetrate deeply (as fissures) into underlying tissue layers.
4. Transmural chronic inflammation affecting all layers: chronic inflammatory cells
(lymphocytes and plasma cells) fill the affected mucosa and, to a lesser extent, all
underlying intestinal layers. Lymphoid aggregates are usually scattered throughout the
bowel wall.
5. Noncaseating granulomas: in about 50% of the cases, noncaseating small granulomas
may be present in all tissue layers. Because they are not always present; the absence of
granulomas does not rule out the diagnosis of CD.
5. Other mural changes: in diseased segments, the muscularis mucosae usually exhibits
duplication & thickening. There is also fibrosis of the submucosa, muscularis propria,
and serosa that eventually leads to stricture formation.
6. Dysplastic changes of the mucosal epithelial cells are particularly important in persons
with long-standing chronic disease are. These may be focal or widespread, tend to
increase with time, and are thought to be related to increased risk of carcinoma,
particularly of the colon.
Clinical Features
The disease usually begins with intermittent attacks of diarrhea, fever, and abdominal
pain, spaced by asymptomatic periods lasting for weeks to many months. In those with
colonic involvement, occult or overt fecal blood loss may lead to anemia. During this
lengthy, chronic disease, complications may arise from
1. Fibrosing strictures, particularly of the terminal ileum (intestinal obstruction)
2. Fistulas formed to other loops of bowel, urinary bladder, vagina, or perianal skin,
or into a peritoneum. In the latter focal abscesses may occur.
3. Extensive involvement of the small bowel, including the terminal ileum, may cause
a. marked loss of albumin (protein-losing enteropathy)
b. generalized malabsorption
c. specific malabsorption of vitamin B
12
(pernicious anemia), or malabsorption of
bile salts, leading to steatorrhea.
Extraintestinal manifestations of this disease include
1. Arthritis & finger clubbing
2. Red nodules of the skin (Erythema nodosum)
3. Primary sclerosing cholangitis, (but the association is not as strong as in UC).
4. Renal disorders secondary to trapping of the ureters in the inflammatory process
sometimes develop and leading to hydronephrosis and pyelonephritis.
5. Systemic amyloidosis (rare late consequence).
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6. An increased incidence of cancer of the GIT in patients with long-standing progressive
CD; however, the risk of cancer in CD is considerably less than in patients with chronic
UC.
ULCERATIVE COLITIS
In contradistinction to CD, ulcerative colitis is a chronic ulcero-inflammatory disease
limited to the colon and affecting only the mucosa and submucosa; it extends in a
continuous fashion proximally from the rectum. Well-formed granulomas are absent.
However, like CD, UC is a systemic disorder associated in some patients with arthritis,
uveitis, hepatic involvement (primary sclerosing cholangitis), and skin lesions. The onset
of disease peaks between ages 20 and 25 years. Nonsmoking is associated with UC; ex-
smokers are at higher risk for developing UC than never-smokers.
Pathological features
Ulcerative colitis involves the rectum and extends proximally in a retrograde fashion to
involve the entire colon ("pancolitis") in the more severe cases. It is a disease of
continuity, and "skip" lesions are not found (cf. CD).
Gross features (Fig. 5-65 A)
A key feature of UC is that the mucosal damage is continuous from the rectum and
extending proximally.
The mucosa may exhibit reddening and granularity with easy bleeding.
With fully developed severe, active inflammation, there may be extensive ulcerations of
the mucosa.
Isolated islands of regenerating mucosa bulge upward to create polypoid projections
(pseudopolyps).
With chronicity or healing of active disease, progressive mucosal atrophy occurs.
Thickening of the bowel wall does not occur in UC; the serosal surface is usually
completely normal (cf. CD).
Only in the most severe cases of ulcerative disease (UC, CD, and other severe
inflammatory diseases) does toxic damage to the muscularis propria and neural plexus
lead to complete shutdown of neuromuscular function. In this instance the colon
progressively swells and becomes gangrenous, a life-threatening condition called toxic
megacolon.
Microscopic features (Fig. 5-65 B)
The basic mucosal alterations in UC are similar to those of colonic CD, with
inflammation, chronic mucosal damage, and ulceration.
There is diffuse, predominantly chronic inflammatory infiltrate in the lamina propria.
Neutrophilic infiltration of the epithelial layer may produce crypt abscesses. The latter
are not specific for UC and may be observed in CD or any active inflammatory colitis.
Unlike CD, there are no granulomas.
Destruction of the mucosa leads to broad-based ulcerations that are superficial i.e.
extending at most into the submucosa.
Isolated islands of regenerating mucosa bulge upward to create pseudopolyps.
Features of chronic but healed (inactive) disease include submucosal fibrosis; mucosal
architectural distortion and atrophy.
30
Particularly significant is the spectrum of epithelial dysplasias, which are divided into
low-grade and high-grade depending on the severity. Invasive carcinoma is the ultimate
lesion arising from dysplasia.
To summarize UC differs pathologically from CD in the following
a. Well-formed granulomas are absent.
b. There are no skip lesions.
c. The mucosal ulcers rarely extend below the submucosa, and
d. There is surprisingly little fibrosis.
e. Mural thickening does not occur, and the serosal surface is usually completely
normal.
f. There appears to be a higher risk of carcinoma development.
Course & prognosis
Ulcerative colitis typically presents as a recurrent attacks of bloody mucoid diarrhea that
may persist for days, weeks, or months and then subside, only to recur after an
asymptomatic interval of months to years.
The outcome of UC depends on two factors:
1. The severity of active disease
2. The duration of the disease
The majority of the cases can be controlled medically; however, about 30% of patients
require colectomy due to uncontrollable active disease. On rare occasion, the disease runs
a fulminant course; unless medically or surgically controlled, this toxic form of the
disease can lead to death soon after onset.
The most serious long-term complication of UC is colonic carcinoma. There is a
tendency for dysplasia to arise in multiple sites. The associated carcinomas are often
infiltrative without obvious exophytic masses. Historically, the risk of cancer is highest in
patients with pancolitis of 10 or more years' duration. It is believed that with 10 years of
disease limited to the left colon the risk is minimal, and at 20 years the risk is on the order
of 2%. With pancolitis, the risk of carcinoma is 10% at 20 years and up to 25% by 30
years. Overall, the annual incidence of colon cancer in persons with ulcerative colitis of
more than 10 years' duration is 1%.
VASCULAR DISORDERS
Ischemic Bowel Disease
Ischemic lesions may be restricted to the small or large intestine, or may affect both,
depending on the particular vessel(s) affected. Acute occlusion of one of the three major
supply arteries of the intestines—celiac, superior mesenteric, and inferior mesenteric
arteries—may lead to infarction of several meters of intestine. However, gradual
occlusion of one vessel may be without effect, due to the rich anastomotic
interconnections. Lesions within the end arteries, which penetrate the gut wall, produce
small, focal ischemic lesions.
The predisposing conditions for ischemia are:
1. Arterial thrombosis complicating usually severe atherosclerosis.
2. Arterial embolism complicating cardiac vegetations and aortic atheroembolism.
3. Venous thrombosis complicating hypercoagulable states, oral contraceptives,
intraperitoneal sepsis, etc.
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4. Nonocclusive ischemia complicating cardiac failure, shock, dehydration, and
vasoconstrictive drugs (e.g., digitalis, vasopressin, propranolol)
5. Miscellaneous such as radiation injury, volvulus, and internal or external herniae.
Hemorrhoids (Fig. 5-67) are essentially varices of the anal and perianal venous
plexuses. They are extremely common affecting 5% of the general population. They
develop secondary to persistently elevated venous pressure within the hemorrhoidal
plexus. The most frequent predisposing influences are constipation with straining at stool
and the venous stasis of pregnancy. Except for pregnant women, they are rarely
encountered in persons under the age of 30. Much more rarely, but much more
importantly, hemorrhoids may reflect collateral anastomotic channels that develop
because of portal hypertension (as in liver cirrhosis). The varicosities may develop in the
inferior hemorrhoidal plexus and thus are located below the anorectal line (external
hemorrhoids) or from dilation of the superior hemorrhoidal plexus (internal
hemorrhoids). Commonly, both plexuses are affected (combined hemorrhoids).
Microscopically these lesions consist of thin-walled, dilated, submucosal vessels.
Superficial ulceration, fissure formation, and infarction of the hemorrhoids secondary to
their strangulation may develop.
DIVERTICULAR DISEASE
A diverticulum is a blind pouch related to the alimentary tract. It is lined by mucosa that
communicates with the lumen of the gut. Congenital diverticula is typified by Meckel
diverticulum. Virtually all other diverticula are acquired and either lack or have an
attenuated muscularis propria. The most common site of multiple diverticula is the left
side of the colon, with the majority in the sigmoid colon; this is termed diverticular
disease of the colon. It manifests mostly after the age of 30 years. They are much less
frequent in underdeveloped tropical countries than in developed countries.
TUMORS OF THE SMALL AND LARGE INTESTINE
The large intestine is responsible for more primary neoplasms than any other organ in the
body. The vast majority are adenocarcinomas. The small intestine, despite its great length
(3/4 of the GIT), is an uncommon site for benign or malignant neoplasms.
Tumors of the small intestine
The most common benign tumors in the small intestine are adenomas (Fig. 5-73) and
mesenchymal tumors. Of malignant tumors adenocarcinomas and carcinoids have roughly
equal incidence, followed in order by lymphomas and sarcomas.
Tumors of the Colon and Rectum
Non-neoplastic and benign neoplastic lesions of the colo-rectum are collectively known as
polyps, which are common in the older adult population. Epithelial polyps that arise as the
result of proliferation and dysplasia are termed adenomatous polyps (adenomas). They are
precursors of carcinoma.
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Non-Neoplastic Polyps include
1. hyperplastic polyp
2. hamartomatous polyp
3. inflammatory polyp
4. lymphoid polyp
Hyperplastic Polyps
These are the most common polyps of the colon and rectum. They are small (usually <5 mm
in diameter) and appear as smooth protrusions of the mucosa. They are often multiple and
consists of well-formed glands and crypts lined by non-neoplastic epithelial cells.
Hamartomatous Polyps
1. Juvenile polyps (Fig. 5-74) are essentially hamartomatous proliferations, mainly of the
lamina propria, enclosing widely spaced, dilated cystic glands. They occur most frequently in
children younger than 5 years old but also are found in adults of any age; in the latter group
they may be called retention polyps. The lesions are usually large in children (1-3 cm in
diameter) but smaller in adults; they are rounded, smooth, or slightly lobulated and
sometimes have a stalk as long as 2 cm. In general, they occur singly and in the rectum, and
have no malignant potential. Juvenile polyps may be the source of rectal bleeding and in
some cases become twisted on their stalks to undergo painful infarction.
2. Peutz-Jeghers polyps (Fig. 5-75) are also hamartomatous polyps that involve the mucosal
epithelium, lamina propria, and muscularis mucosae. They may occur sporadically or in the
setting Peutz-Jeghers syndrome (PJS). PJS is a rare autosomal dominant syndrome
characterized by
a. multiple hamartomatous polyps scattered throughout the entire GIT
b. melanotic mucosal and cutaneous pigmentation especially around the lips & in the oral
mucosa.
Patients with this syndrome are at risk for intussusception, which is a common cause of
mortality.
The polyps are present most frequently in the small intestine.
Adenomas (Adenomatous polyps)
Adenomas are intraepithelial neoplasms that range from small, often pedunculated lesions to
large neoplasms that are usually sessile. The prevalence of colonic adenomas increases
progressively with age. Males and females are affected equally. Adenomatous polyps are
divided into three subtypes on the basis of the epithelial architecture (Fig. 5-76):
1. Tubular adenomas: compose of tubular glands
2. Villous adenomas: composed of villous projections
3. Tubulovillous adenoma: composed of a mixture of the above two.
All adenomas by definition arise as the result of dysplastic epithelial proliferation. The
dysplasia ranges from low-grade to high-grade. There is strong evidence that adenomas are
precursors for invasive colorectal adenocarcinomas. The risk of cancer is high (approaching
40%) in villous adenomas more than 4 cm in diameter. Adenomas may be single or multiple,
may be asymptomatic, and many are discovered during evaluation of anemia (due to occult
bleeding) through endoscopy. Villous adenomas are often are discovered because of overt
rectal bleeding. The most distal villous adenomas may secrete sufficient amounts of mucoid
33
material rich in protein and potassium to produce hypoproteinemia or hypokalemia. The only
adequate treatment for adenomas is complete resection.
FAMILIAL POLYPOSIS SYNDROMES
These are uncommon autosomal dominant disorders. Their importance lies in
their tendency for malignant transformation.
1. Peutz-Jeghers syndrome
2. Juvenile polyposis syndrome
3. Familial adenomatous polyposis (FAP)
Another hereditary condition in this context but is not associated with polyp formations is the
hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome).
Familial Adenomatous Polyposis (FAP) Syndrome (Fig. 5-77)
This is caused by mutations of the adenomatous polyposis coli (APC) gene on chromosome
5.
In the classic FAP syndrome, affected patients typically develop 500 to 2500 colonic
adenomas that carpet the mucosal surface; the presence of a minimum of 100 polyps is
necessary for a diagnosis. The lifetime risk of cancer development is 100%. Some patients
already have cancer of the colon or rectum at the time of diagnosis. Cancer-prevention
measures include early detection of the condition and prophylactic colectomy.
COLORECTAL CARCINOMA
A widely accepted proposal of carcinogensis is the adenoma-carcinoma sequence (Fig. 5-
78), i.e. most carcinomas arise from preexisting adenomas. This has been supported by the
following observations:
1. Populations that have a high prevalence of adenomas have a high prevalence of colorectal
cancer.
2. The distribution of adenomas parallel that of colorectal cancer.
3. The peak incidence of adenomas precedes that of carcinoma by some years.
4. When invasive carcinoma is identified at an early stage, a related adenoma is often present
5. The risk of cancer is directly related to the number of adenomas, that is why carcinoma
complicates all those with FAP syndrome.
6. Removal of all adenomas that are suspicious reduces significantly the incidence of
cancerinoma. 98% of all cancers in the large intestine are adenocarcinomas. They usually
arise in polyps and produce symptoms relatively early and at a stage generally curable by
surgical resection. Yet, it is responsible for 10% of all cancer-related deaths. The peak
incidence for colorectal carcinoma is between ages 60 and 79.When colorectal carcinoma is
found in a young person, pre-existing ulcerative colitis or one of the polyposis syndromes
must be suspected. Environmental factors, particularly dietary practices, are implicated in
the striking geographic variations in incidence. Japanese families that have migrated from
their low-risk areas to the United States (high-risk areas) have acquired, over the course of 20
years, the rate prevailing in the new environment; mainly because the immigrants adopted the
common dietary practices of the U.S. population. The dietary factors receiving the most
attention as predisposing to a higher incidence of cancer are
1. Excess dietary caloric intake relative to requirements
2. Low content of unabsorbable vegetable fibers & high content of refined carbohydrates
34
3. Intake of red meat
Several epidemiological studies suggest that the use of aspirin and other nonsteroidal anti-
inflammatory drugs exerts a protective effect against colon cancer.
Gross features (Fig. 5-79 A)
The rectosigmoid colon is the most frequent location (60%), followed by cecum/ascending
colon (20%).
Tumors in the proximal colon tend to grow as polypoid, exophytic masses; obstruction is
uncommon. In the distal colon, they tend to be annular, encircling lesions that produce
napkin-ring constrictions. The lumen is markedly narrowed leading to obstruction with
secondary proximal distention.
Both forms (polypoid and annular) directly penetrate the bowel wall over the course of
time (probably years) and may appear as subserosal and serosal white, firm masses.
Microscopic features (Fig. 5-79 B)
The features of right- and left-sided colonic adenocarcinomas are similar.
Differentiation (grade) may range from well-differentiated tumors to undifferentiated,
frankly anaplastic masses.
Invasive tumor provokes a strong desmoplastic (fibrotic) stromal response (responsible for
the characteristic firm, hard consistency of most carcinomas).
Carcinomas arising in the anal canal are mostly of squamous cell type.
Clinical features
Colorectal cancers remain asymptomatic for years; symptoms develop insidiously and
frequently have been present for months, sometimes years, before diagnosis. Patients with
cecal and right colonic cancers are most often presented with iron-deficiency anemia (due to
insidious blood loss). Left-sided lesions come to attention by producing occult bleeding,
changes in bowel habit or intestinal obstruction. Iron-deficiency anemia in an older male
means gastrointestinal cancer until proved otherwise. In females the situation is less clear,
since menstrual losses, multiple pregnancies, or abnormal uterine bleeding may underlie such
an anemia.
Spread & metastasis
All colorectal tumors spread by direct extension into adjacent structures and by metastasis
through the lymphatics and blood vessels. The favored sites of metastatic spread are the
regional lymph nodes, liver, lungs, and bones. In general, the disease has spread beyond the
range of curative surgery in 25% of patients. The single most important prognostic factor of
colorectal carcinoma is the extent of the tumor at the time of diagnosis (stage). Currently, the
staging system most widely used is the tumor-nodes-metastasis (TNM). (Fig. 5-80) The
principal aim is to discover these neoplasms when curative resection is possible. Indeed, each
death from colonic cancer must be viewed as a preventable tragedy.
CARCINOID TUMORS
The term carcinoid means carcinoma-like lesion because it shows a much more indolent
clinical course than genuine carcinoma. Carcinoid tumor is derived from resident endocrine
cells, with the gastrointestinal tract and lung as the predominant sites of occurrence. They
comprise less than 2% of colorectal malignancies but 50% of small intestinal malignant
tumors. These tumors may be confined to the mucosa and submucosa or may be deeply
invasive with metastatic spread to regional lymph nodes and the liver. Appendiceal and rectal
carcinoids almost never metastasize.
35
Gross features (Fig. 5-81)
The appendix is the most common site of gut carcinoid tumors. In the appendix, they appear
as rounded swellings of the tip. A characteristic feature is a solid, yellow-tan appearance on
transection.
Microscopic features
The neoplastic cells may form islands, trabeculae, glands, or sheets. The tumor cells show
very little if any variation in cell and nuclear size, having a scant, pink granular cytoplasm
and a round to oval nucleus. Mitoses are infrequent or absent.
Gastrointestinal carcinoids only rarely produce local symptoms; many (especially rectal and
appendiceal) are asymptomatic and are found incidentally. However, the secretory products
of some carcinoids may produce a variety of syndromes such as Zollinger-Ellison syndrome
(excess production of gastrin), Cushing syndrome (excess production of corticotrophin).
Hyperinsulinism may also occur leading to hypoglycemia. Some neoplasms are associated
with the distinctive carcinoid syndrome, which occurs especially with carcinoids associated
with widespread metastases. Most manifestations are thought to arise from excess
elaboration of serotonin (5-hydroxytryptamine, 5-HT). Elevated levels of 5-HT and its
metabolite, 5-hydroxyindoleacetic acid (5-HIAA), are present in the blood and urine of most
patients with the classic syndrome. The syndrome is characterized by
- Cyanosis of the face and anterior part of the chest
- Intermittent hypertension & palpitation
- Frequent watery stools
The tumor, sometimes, induces fibrosis of the right-sided cardiac valves that results in so-
called carcinoid heart disease.
GASTROINTESTINAL LYMPHOMAS
Any segment of the gastrointestinal tract may be secondarily involved by systemic
dissemination of nodal-based non-Hodgkin lymphomas. However, up to 40% of lymphomas
arise in sites other than lymph nodes (extra-nodal lymphomas), and the gut is the most
common location.
Primary gastrointestinal lymphomas usually arise without an obvious predisposing factor but
they also occur more frequently in certain patient groups
1. Chronic gastritis caused by H. pylori
2. Chronic celiac disease
3. Natives of the Mediterranean region (Mediterranean lymphoma)
4. Congenital immunodeficiency states, infection with HIV or following organ
transplantation with immunosuppression
Most gut lymphomas are of B-cell type (over 95%) and are either low- or high-grade
tumors. Early discovery is the key to survival. The depth of local invasion, size of tumor
and its histologic grade as well as extension into adjacent viscera are important
determinants of prognosis.
TUMORS OF THE ANAL CANAL
Pure squamous cell carcinomas of the anal canal are closely associated with chronic HPV
infection. The latter often causes precursor lesions such as condyloma acuminatum,
squamous epithelium dysplasia, and carcinoma in situ. Pure adenocarcinoma of the anal
canal is often the extension of rectal adenocarcinoma.