[1]

MED II GI Module: Week 1 [C6-2012]

Peptic Ulcer Disease Disruption of mucosal integrity of the stomach

and/or duodenum >5 mm in size Often chronic Results when "aggressive" factors (gastric acid,

pepsin) overwhelm "defensive" factors involved in mucosal resistance (gastric mucus, bicarbonate, microcirculation, prostaglandins, mucosal "barrier")

Epidemiology Peptic ulcer disease (PUD)

o Incidence: 4 million individuals (new cases and recurrences) affected per year in the U.S.

o Duodenal ulcers (DU) Estimated to occur in 6-15% of

the Western population o Gastric ulcers (GU)

Less common than DU Tend to occur later in life than

DU, with peak incidence reported in the sixth decade

More than half occur in males Helicobacter pylori infection

o Prevalence ~30% in U.S. ~10% of Americans < 30 are

colonized with the bacteria. In developing parts of the world,

80% may be infected with H. pylori by age 20.

o Age: In U.S., individuals born before 1950 have a higher rate of infection than those born later.

o Race: African Americans and Hispanic Americans have double the rate seen in whites of comparable age.

Risk Factors Genetic predisposition. Psychological stress

o Evidence for causal effect is mainly anecdotal.

o Increased numbers of stressful life events do not distinguish patients with DU from those without DU.

Risk factors for H. pylori include: o Birth or residence in a developing

country o Domestic crowding o Unsanitary living conditions o Unclean food or water o Exposure to gastric contents of an

infected individual o Poor socioeconomic status o Less education

Risk factors for NSAID-induced PUD include: o Advanced age o History of ulcer o Concomitant use of glucocorticoids o High-dose NSAIDs o Multiple NSAIDs use o Concomitant use of anticoagulants o Serious or multisystem disease o Concomitant infection with H. pylori o Cigarette smoking o Alcohol consumption

Etiology H. pylori infection

o Increases average basal and nocturnal gastric acid secretion

o Virtually always associated with chronic active gastritis, but only 10-15% of infected individuals develop frank peptic ulceration

Basis for this difference unk NSAID-induced injury

o Topical and ingested NSAIDs interrupt prostaglandin synthesis and impair mucosal defense and repair, thus facilitating mucosal injury.

Causes other than H. pylori infection and NSAIDs

o Infection (cytomegalovirus, herpes simplex virus, Helicobacter heilmannii)

o Drugs/toxins Bisphosphonates Chemotherapy Clopidogrel Crack cocaine Glucocorticoids (when

combined with NSAIDs) Mycophenolate mofetil Potassium chloride

Associated Conditions All associated with gastric ulceration

o Systemic mastocytosis o Chronic pulmonary disease o Chronic renal failure o Cirrhosis o Nephrolithiasis o 1 antitrypsin deficiency o Hyperparathyroidism o Coronary artery disease o Polycythemia vera o Chronic pancreatitis

Zollinger-Ellison syndrome Stress-related mucosal injury Gastritis Mntrier's disease (rare): large, tortuous gastric

mucosal folds

DIAGNOSIS Symptoms & Signs

Asymptomatic in some cases, especially older adults

Burning epigastric pain 90 minutes to 3 hours after meals, relieved by food or antacids

o Pain that awakes patient from sleep (between midnight and 3 a.m.) is the most discriminating symptom.

o With GU, discomfort may actually be precipitated by food.

Nausea Dyspepsia Anorexia Food aversion Weight loss Epigastric tenderness

Differential Diagnosis Functional dyspepsia or essential dyspepsia: a

group of heterogeneous disorders typified by upper abdominal pain without the presence of an ulcer

Gastric carcinoma Gastritis

[2]

Crohn's disease (gastroduodenal) Pancreatitis Biliary colic Gastroesophageal reflux disease Vascular disease

Diagnostic Approach Large percentage of patients with symptoms

suggestive of an ulcer have non-ulcer dyspepsia o Empirical therapy is appropriate for

individuals who are otherwise healthy and < 45, before embarking on a diagnostic evaluation.

Documentation of ulcer requires either radiography (barium study) or endoscopy.

o Barium studies of proximal GI tract are commonly used as a first test.

o Radiographic studies that show a GU must be followed by endoscopy and biopsy.

o Endoscopy is the most sensitive and specific modality for examining upper GI tract.

Direct visualization of the mucosa

Photographic documentation of mucosal defect

Tissue biopsy to rule out malignancy (GU) or H. pylori

Identification of lesions too small to detect by radiography

Evaluation of atypical radiographic abnormalities

Determination of ulcer as a source of blood loss

Test for H. pylori o For some tests biopsy is required.

Rapid urease Histology Culture

o No biopsy required Serology Urea breath test Stool antigen

Occasionally, specialized testing such as serum gastrin and gastric acid analysis or sham feeding may be needed

o Complicated or refractory PUD (Zollinger-Ellison syndrome)

Screening for aspirin or NSAIDs (blood or urine) may be necessary for patients with refractory H. pylori-negative PUD

Laboratory Tests H. pylori tests:

o Sample obtained by endoscopy/biopsy Rapid urease test

Sensitivity: 80-90% Specificity: 95-100% Simple; false negative

with recent use of proton pump inhibitors (PPIs), antibiotics, or bismuth compounds

Histology Sensitivity: 80-90% Specificity: >95% Requires pathology

processing and staining; provides histologic information

Culture Time-consuming,

expensive, dependent on experience; allows determination of antibiotic susceptibility

o Noninvasive Serology

Sensitivity: >80% Specificity: >90% Inexpensive,

convenient, not useful for early follow-up

Urea breath test Sensitivity: >90% Specificity: >90% Simple, rapid; useful for

early follow-up; false negative with recent therapy; exposure to low-dose radiation with14C test

Fecal H. pylori antigen test Sensitivity: >90% Specificity: >90% Inexpensive,

convenient; not established for eradication

A urinary H. pylori antigen test and a refined monoclonal antibody stool antigen test appear promising.

Serum gastrin test indicated if Zollinger-Ellison syndrome is suspected.

Imaging Radiographic study with barium

o Sensitivity as high as 90% o Features suggesting malignancy

Ulcer within a mass Folds that do not radiate from

ulcer margin Large ulcer (>2.5-3 cm)

Diagnostic Procedures Endoscopy (sensitivity > 95%) Mucosal biopsy and cytology (excludes

malignancy in > 99%)

TREATMENT Treatment Approach

Goals o Alleviate symptoms o Restore mucosal integrity/heal ulcer o Prevent recurrence

Therapy mainstays o Eradicate H. pylori o Prevent NSAID-induced disease o Acid neutralization/inhibition

Specific Treatments Pharmacologic agents

Antacids: Most commonly used agents are mixtures of aluminum hydroxide and magnesium hydroxide.

o Mylanta, Maalox, Tums, Gaviscon: 100-140 mEq/L 1 and 3 hours after meals and hs

H2 receptor antagonists o Cimetidine-400 mg bid o Ranitidine-300 mg hs

[3]

o Famotidine-40 mg hs o Nizatidine-300 mg hs

PPIs o Omeprazole-20 mg/d

Available in a powder form that can be administered orally or via gastric tube

o Esomeprazole-20 mg/d o Lansoprazole-30 mg/d

Available in an orally disintegrating tablet that can be taken with or without water

o Rabeprazole-20 mg/d o Pantoprazole-40 mg/d

Available as a parenteral formulation for intravenous use

Acid inhibitory agents in development o Tenatoprozole: a PPI with a longer half

life than currently available medications o Potassium-competitive acid pump

antagonists (P-CABs), a new class Mucosal protective agents

o Sucralfate-1 g qid o Bismuth-containing compounds o Misoprostol

H. pylori eradication o Triple therapy (14 days)

Regimen 1 Bismuth subsalicylate (2

tabs qid) plus Metronidazole (250mg

qid) plus Tetracycline (500mg

qid) Alternative: use

prepacked Helidac Regimen 2

Ranitidine bismuth citrate (400mg bid)plus

Tetracycline (500mg bid) plus

Clarithromycin ormetronidazole (500 mg bid)

Regimen 3 Omeprazole

(lansoprazole), 20 mg bid (30 mg bid)plus

Clarithromycin (250 or 500 mg bid) plus

Metronidazole (500 mg bid) or amoxicillin (1 g bid)

Do not use both metronidazole and amoxicillin

Alternative: Use prepacked Prevpac.

o Quadruple therapy (14 days) Omeprazole (lansoprazole) 20

mg/d (30 mg/d) plus Bismuth subsalicylate (2 tablets

qid) plus Metronidazole (250 qid) plus Tetracycline (500 mg qid)

o Once therapy has been completed, acid-suppressing drugs (H2 receptor antagonist or PPIs) should be continued for a total of 4-6 weeks.

Surgical therapy Rarely required

When needed, reason for surgery is treatment of ulcer-related complications (GI bleeding, perforation, gastric outlet obstruction).

Surgical treatment is designed to decrease gastric acid secretion.

o Vagotomy and drainage (pyloroplasty, gastroduodenostomy, or gastrojejunostomy)

o Highly selective vagotomy (does not require a drainage procedure)

o Vagotomy with antrectomy Specific operations for GU

o Antrectomy (including the ulcer) with a Billroth I anastomosis

o Subtotal gastrectomy with a Roux-en-Y esophagogastrojejunostomy (Csendes' procedure)

o Antrectomy, intraoperative ulcer biopsy, and vagotomy (Kelling-Madlener procedure) is a less aggressive approach.

Lifestyle interventions Modify diet. Avoid cigarettes and alcohol. Decrease psychological stress.

ONGOING CARE Monitoring

Selection of patients for documentation of H. pylori eradication (organisms gone at least 4 weeks after completing antibiotics) is an area of some debate.

o Test of choice for documenting eradication is urea breath test (UBT)

o Stool antigen assay may also hold promise for this purpose, but data have not been as clear-cut

o Serologic testing is not useful for purpose of documenting eradication as antibody titers fall slowly and often do not become undetectable.

For GU, repeat endoscopy to document healing at 8-12 weeks should be performed.

o With biopsy if ulcer is still present

Complications Bleeding ulcer (most common complication)

o Tarry stools or coffee ground emesis o Tachycardia and orthostasis from

vomiting or blood loss Perforation of stomach or duodenum (second

most common) o Sudden onset of severe, generalized

abdominal pain o Severely tender, board-like abdomen o Penetrating ulcer: a form of perforation

in which ulcer bed tunnels into an adjacent organ (pancreas most often)

Dyspepsia may become constant, is no longer relieved by food or antacids, or radiates to the back.

Gastric outlet obstruction o Pain worsening with meals o Nausea and vomiting of undigested food o Presence of a succussion splash

(indicating retained fluid in the stomach) Antibiotic resistance for H. pylori Surgical complications

o Recurrent ulcer o Afferent loop syndrome

[4]

o Dumping syndrome o Postvagotomy diarrhea o Bile reflux gastropathy o Maldigestion and malabsorption

Complications of persistent H. pylori infection o Gastric adenocarcinoma o Gastric mucosal-associated lymphoid

tissue (MALT) lymphoma

Prognosis The majority (>90%) of GU and DU heal with

conventional therapy.

Prevention NSAID-induced ulceration

o Discontinue NSAID if possible. o Misoprostol (200 g qid) o Use a PPI in conjunction with the

NSAID. o Ranitidine, famotidine, and nizatidine

can also be used once a day at bedtime. o Risk is less with COX-2 inhibitor class of

NSAIDs. Gastric protection therapy with a

PPI is required in individuals taking COX-2 inhibitors and aspirin prophylaxis.

Cancer of the Stomach Malignant tumor of the stomach 3 histologic types

o Adenocarcinomas (85% of patients) Diffuse (Discrete multicellular

structures are absent) Intestinal (Glandlike tubular

structures are present.) o Gastric lymphomas (< 15%)

Mucosa-associated lymphoid tissue (MALT)

Diffuse large-cell lymphoma o Gastric (nonlymphoid) sarcoma (1-3%)

or leiomyosarcoma Gastrointestinal stromal tumors

(GIST): a form of leiomyosarcoma that expresses c-kit

Epidemiology All stomach cancers

o Incidence/prevalence Worldwide incidence is highest

in Japan and China. U.S.: decreasing over

the past 75 years From 33 to 10 per

100,000 persons in men From 30 to 5 per

100,000 persons in women

Annual cases diagnosed (2008): 21,500

Deaths (2008): 10,880 o Mortality rates in the U.S.

Marked decrease in the past 75 years

Men: decreased from 28 to 5.8 per 100,000

Women: decreased from 27 to 2.8 per 100,000

o Age Peak is most common in the

sixth and seventh decades. Diffuse type occurs more often

in younger patients. o Sex

Male-to-female ratio, 2:1 o Race/ethnicity

More common in Latinos, African Americans, and Asian Americans

Gastric lymphomas o Incidence/prevalence

Increase in frequency in the past 25 years

o Age Most often detected during sixth

decade Gastric sarcomas

o Incidence/prevalence U.S.

150 cases diagnosed annually

0.07 cases per 100,000 persons

Age Peak incidence in sixth

and seventh decades Risk Factors

Adenocarcinoma o Smoking o Lower socioeconomic class o Birth in a high-incidence nation

Migrants maintain nation-of-origin susceptibility to gastric cancer.

However, risk for their offspring approximates that of the new homeland.

Theoretical explanation: unknown environmental exposure

Probably beginning early in life

Dietary carcinogens most likely factor

o Dietary factors Nitrates in dried, smoked, and

salted foods Long-term ingestion of

high concentrations Possible conversion to

carcinogenic nitrites by bacteria

Diet low in vegetables and fruits o Positive family history for gastric

carcinoma in first-degree relative o Atrophic gastritis o Helicobacter pylori infection o Barrett's esophagus o Billroth II gastrectomy o Gastrojejunostomy o Pernicious anemia o Hyperplastic gastric polyps o Mntrier's disease (hyperplastic,

hypersecretory gastropathy or giant hypertrophic gastritis)

o Gastric ulcers and adenomatous polyps Unconvincing data regarding

cause-and-effect relationship

[5]

Inadequate clinical distinction between benign gastric ulcers and small ulcerating carcinomas may account for the presumed association.

o Blood group A Higher incidence than group O May be related to differences in

mucous secretion, leading to altered mucosal protection from carcinogens

o Germline mutation in E-cadherin gene Inherited in autosomal dominant

pattern coding for cell adhesion protein

Linked to high incidence of occult gastric cancers in young asymptomatic carriers

Gastric lymphomas o Infection with H. pylori

Increases risk for gastric MALT lymphoma

Low-grade gastric MALT lymphoma can progress to high-grade diffuse large B-cell lymphoma.

Gastric sarcomas o No known risk factors

Etiology Adenocarcinoma

Etiology: not completely understood; likely complex interaction between genetics, infection, and diet

Role of nitrate-converting bacteria as a factor in causation

o Nitrates are thought to be converted to carcinogenic nitrites by bacteria.

o Exogenous sources of bacteria Bacterially contaminated food

(diminished by improved food preservation and refrigeration)

H. pylori infection may contribute by causing chronic gastritis, loss of gastric acidity, and bacterial growth in stomach; strains carrying the cytotoxin-associated antigen (cagA) gene are more carcinogenic.

o Endogenous factors favoring growth of nitrate-converting bacteria in the stomach

Decreased gastric acidity Previous gastric surgery

(antrectomy) (15- to 20-year latency period)

Atrophic gastritis and/or pernicious anemia

Prolonged exposure to histamine H2-receptor antagonists.

Role of host genetic factors o Family history of gastric cancer o Proinflammatory mutations in genes for

interleukin-1 and tumor necrosis factor

Gastric lymphomas Etiology: not completely understood H. pylori gastritis leads to chronic antigenic

stimulation. At least 2 pathways of lymphomagenesis

o No translocations: responsive to H. pylori eradication

o t(11;18) translocation: not responsive to H. pylori eradication

api2, an anti-apoptosis gene on chromosome 11, joins malt1 on chromosome 18.

Resulting fusion blocks apoptosis, but the role in etiology remains unclear.

Gastric sarcomas Etiology: unknown

DIAGNOSIS Symptoms & Signs

Adenocarcinoma Site of origin in U.S.

o Distal stomach: ~30% o Midportion of stomach: ~20% o Proximal third of stomach: ~37% o Entire stomach: 13%

Superficial disease o Usually asymptomatic

More extensive tumor o Insidious upper-abdominal discomfort

Varies in intensity from vague, postprandial fullness to severe, steady pain

o Anorexia, often with slight nausea o Weight loss o Early satiety o Nausea and vomiting

Particularly prominent with tumors of pylorus

o Dysphagia May be major symptom caused

by lesions of cardia o Acute or chronic GI bleeding

Heme-positive stool Melena Hematochezia

Physical findings o No early physical signs o As disease progresses:

Abdominal tenderness Pallor Cachexia Palpable abdominal mass

indicates longstanding growth and predicts regional extension.

Low-grade fever o Metastatic disease

Supraclavicular lymphadenopathy

Left supraclavicular lymph node (Virchow's node)

Lymphadenopathy to periumbilical region ("Sister Mary Joseph node")

Lymphadenopathy to peritoneal cul-de-sac (Blumer's shelf palpable on rectal or vaginal examination)

Malignant ascites Hepatomegaly Skin abnormalities (nodules,

dermatomyositis, acanthosis

[6]

nigricans, or multiple seborrheic keratoses)

Diffuse seborrheic keratosis is sometimes called Leser-Trelat sign.

o Unusual clinical features associated with adenocarcinomas

Migratory thrombophlebitis (Trousseau's syndrome)

Microangiopathic hemolytic anemia

Acanthosis nigricans Membranous nephropathy

Gastric lymphomas Epigastric pain Early satiety Generalized fatigue

GIST Epigastric pain Early satiety Nausea/vomiting Anorexia Weight loss Hematemesis Melena

Differential Diagnosis Hypertrophic gastritis Reflux esophagitis Peptic ulcer disease Benign gastric tumors

o Leiomyomas o Lipoma o Neurofibroma o Lymphangioma o Ganglioneuroma o Hamartoma (associated with Peutz-

Jeghers syndrome) o Juvenile polyposis (restricted to

stomach)

Diagnostic Approach History, with special attention to risk factors Physical examination Imaging studies

o Double-contrast radiographic examination: simplest diagnostic procedure in evaluation of epigastric complaints

Endoscopy o Gastroscopy (most sensitive and

specific test) o Recommended in all patients with

gastric ulcer diagnosed by radiography o Unlike imaging studies, permits

pathologic confirmation by biopsy and cytologic examination of mucosal brushings

o Superficial biopsies are less sensitive for lymphomas (frequently submucosal).

Staging

Laboratory Tests Adenocarcinoma

o Common Iron-deficiency anemia (two-

thirds of patients) Fecal occult blood (80%)

Liver function test abnormalities with metastatic disease

o Rare Pancytopenia Microangiopathic hemolytic

anemia (from marrow infiltration) Leukemoid reaction

Imaging Diagnosis

o Double-contrast radiographic examination

Simplest diagnostic procedure for evaluation of epigastric symptoms

Aids detection of small lesions by improving mucosal detail

The stomach should be distended at some time during every radiographic examination

Decreased distensibility may be the only indication of diffuse infiltrative carcinoma.

Gastric ulcers Can be detected fairly

early Distinguishing benign

from malignant lesions is difficult.

Anatomic location cannot predict presence or absence of cancer.

Staging o CT and endoscopic

ultrasonography may aid in determining tumor resectability

Diagnostic Procedures Gastroscopic biopsy and brush cytology

o Recommended for all patients with gastric ulcer to exclude cancer

o Endoscopic biopsies should be made as deeply as possible, because lymphoid tumors may be submucosal

o Sensitivity of detection is enhanced to 98% by performing at least 7 biopsies from the ulcer margin and base

o Failure of gastroscopic biopsies to detect lymphoma should not be interpreted as conclusive

Superficial biopsies may miss deeper lymphoid infiltrate.

o Macroscopic pathology of gastric lymphoma may also mimic adenocarcinoma

Classification Adenocarcinoma

Primary tumor (T) o TX: Primary tumor cannot be assessed. o T0: No evidence of primary tumor o Tis: Carcinoma in situ: intraepithelial

tumor without invasion of the lamina propria

o T1: Tumor invades lamina propria or submucosa

o T2: Tumor invades the muscularis propria or the subserosa

T2a: Tumor invades muscularis propria

T2b: Tumor invades subserosa

[7]

o T3: Tumor penetrates the serosa (visceral peritoneum) without invading adjacent structures.

o T4: Tumor invades adjacent structures. Regional lymph nodes (N)

o NX: Regional lymph node(s) cannot be assessed.

o N0: No regional LN metastasis o N1: Metastasis in 1-6 regional LN o N2: Metastasis in 7-15 regional LN o N3: Metastasis in > 15 regional LN

Distant metastasis (M) o MX: Distant metastasis cannot be

assessed o M0: No distant metastasis o M1: Distant metastasis

Stage 0 (1% of cases) o Tis, N0, M0 o Node negative; limited to mucosa

Stage IA (7% of cases) o T1, N0, M0 o Node negative; invasion of lamina

propria or submucosa Stage IB (10% of cases)

o T2, N0, M0 o Node negative; invasion of muscularis

propria Stage II (17% of cases)

o T1, N2, M0 or T2, N1, M0 o Node positive; invasion beyond mucosa

but within wall o T3, N0, M0

Node negative; extension through wall

Stage IIIA (21% of cases) o T2, N2, M0 or T3, N1-2, M0

Node positive; invasion of muscularis propria or through wall

Stage IIIB (14% of cases) o T4, N0-1, M0 o Node negative; adherence to

surrounding tissue Stage IV (30% of cases)

o T4, N2, M0 o Node positive; adherence to

surrounding tissue o T1-4, N0-2, M1

Distant metastases

Gastric lymphomas Staged like other lymphomas

Gastric sarcomas No uniform staging system

TREATMENT Treatment Approach

Adenocarcinoma o Surgery o Radiation therapy (mainly palliative) o Chemotherapy o Combination treatments o Palliative therapy for pain, obstruction,

and bleeding Surgery Endoscopic dilatation Radiation therapy Chemotherapy

Gastric lymphomas o Antibiotic treatment o Chemotherapy

o Radiation therapy (rarely) o Surgery (rarely)

Gastric sarcomas o Surgery o Tyrosine kinase inhibitor o Chemotherapy

Specific Treatments

Adenocarcinoma Surgery

Subtotal gastrectomy o Treatment of choice for distal

carcinomas Total or near-total gastrectomy

o Treatment for more proximal tumors Extended lymph node dissection

o Increases risk for complications without enhancing survival

May still have a role even if disease believed to be incurable by surgery

o Resection of primary lesion in absence of ascites or extensive hepatic or peritoneal metastases

Reduction of tumor bulk Best form of palliation May enhance probability of

benefit from chemotherapy and/or radiation therapy

Radiation therapy Relatively resistant to radiation therapy Postoperative radiation therapy decreases local

recurrence rate but does not improve survival. Indications

o Palliation of pain in advanced disease

Chemotherapy Combinations of cytotoxic drugs

o Indications: advanced gastric carcinoma o Regimens: generally include 5-

fluorouracil (5-FU) and doxorubicin or epirubicin, together with mitomycin-C orcisplatin

o Partial responses in 30-50% of cases; significant benefit to those who respond to treatment

o A standard regimen is ECF: epirubicin, 50 mg/m2 every 3 weeks; cisplatin, 60 mg/m2every 3 weeks; infusional 5-FU, 200 mg/m2 daily.

o Despite encouraging response rate: Complete remission is

uncommon Partial responses are transient Overall influence of multidrug

therapy on survival has been debated

o Adjuvant chemotherapy alone after complete resection

In patients with T2 N1-2 gastric cancer, postoperative adjuvant chemotherapy with uracil-tegafur improved survival compared with gastrectomy alone

o A role is being explored in the neoadjuvant setting to make unresectable disease surgically resectable

Cochrane review found no benefit

[8]

Limited by small number of trials with few patients

Combined modality therapy Radiation plus chemotherapy in surgically

unresectable disease limited to epigastrium o Survival is prolonged slightly when 5-

FU is given with radiation therapy. o Other chemotherapeutic agents have

been shown to have benefit in Asian patients.

Postoperative chemotherapy plus radiation therapy in resectable disease

o Reduces recurrence rate and prolongs survival

o 3-year disease-free survival improved from 31% to 48%

o 3-year overall survival improved from 41% to 50%.

o Regimen 5-FU (425 mg/m2 ) and

leucovorin (20 mg/m2) daily for 5 days

1 month later, radiation therapy (45 Gy; 1.8-Gy/d fractions) given with 5-FU(400 mg/m2) and leucovorin (20 mg/m2) on days 1-4 and on the last 3 days of radiation therapy

Combination chemotherapy administered before and after surgery (perioperative treatment)

o Combined with radiation therapy reduces the recurrence rate and prolongs survival

Primary gastric lymphoma Antibiotic treatment

o Indications: to eradicate H. pylori infection in gastric MALT lymphomas

o Consider before surgery, radiation therapy, or chemotherapy.

o Lack of response linked to specific chromosomal abnormality [t(11;18)]

Chemotherapy o Indications: MALT unresponsive to H.

pylori eradication or diffuse large B-cell lymphoma

o Regimen: CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab is effective

Surgery: subtotal gastrectomy followed by combination chemotherapy

o Indications: diffuse large B-cell lymphoma

o Need for major surgical procedure not clear

Particularly if preoperative radiographic evidence of nodal involvement

Chemotherapy alone is effective.

Radiation therapy o Role not defined o Most recurrences develop at sites

distant from the epigastrium

Combination chemotherapy o Indications: widespread disease

discovered at time of laparotomy

Gastric (non-lymphoid) sarcoma Surgical resection

o Treatment of choice GISTs are unresponsive to conventional

chemotherapy but respond to imatinib mesylate. o Selective inhibitor of c-kit tyrosine kinase o Analyze all such tumors for mutation

in c-kit receptor. o ~50% with such tumors experience

objective response with imatinib therapy. o Dose: 400-800 mg PO daily o Many patients with GIST whose tumors

have become refractory to imatinib subsequently benefit from sunitinib (Sutent)

Another inhibitor of the c-kit tyrosine kinase

Combination chemotherapy o Reserve for metastatic disease

ONGOING CARE Monitoring

80% of patients who die of gastric adenocarcinoma develop a local recurrence; thus, monitoring of the area of the primary lesion is key

Differentiate benign from malignant gastric ulcers with multiple biopsies and follow-up examinations to demonstrate ulcer healing.

Monitor for complications and recurrence of disease through routine physical examination and endoscopy if indicated.

Patients with primary gastric lymphoma who are treated with antibiotics to eradicate H. pylori infection

o Responding patients should undergo periodic endoscopic surveillance.

o Unclear whether neoplastic clone eliminated or merely suppressed

o Lesions may take up to 12 months to regress.

Monitor with follow-up outpatient visits. o Recurrence of disease o Complications of disease o Complications of treatment

Complications Adenocarcinoma

o Recurrent disease o Bleeding/hemorrhage o Obstruction

Gastric outlet Small bowel

o Gastrocolic or other fistulae o Metastatic disease o Ascites o Migratory thrombophlebitis o Microangiopathic hemolytic anemia

Gastric lymphomas o Recurrent disease o Metastatic disease

Gastric sarcomas o Recurrent disease o Metastatic disease

Rarely invade adjacent viscera Characteristically do not

metastasize to lymph nodes May spread to liver and lungs

Prognosis Adenocarcinoma

o Overall 5-year survival rate: < 15%

[9]

o 5-year survival rate, by stage (data from American Cancer Society)

Stage 0: 90% Stage IA: 59% Stage IB: 44% Stage II: 29% Stage IIIA: 15% Stage IIIB: 9% Stage IV: 3%

o After complete surgical resection, depends on degree of tumor penetration into stomach wall

Rate of cure of early lesions limited to mucosa or submucosa is > 80%.

Adversely influenced by characteristics found in most U.S. patients

Regional lymph node involvement

Vascular invasion Abnormal DNA content

(i.e., aneuploidy) 5-year survival rate for 25-30%

of patients able to undergo complete resection

~20% for distal tumors < 10% for proximal

Recurrences continue to occur for 8 years after surgery.

o Diffuse type: poorer prognosis than intestinal type

Gastric lymphomas o Far more treatable than gastric

adenocarcinoma o MALT

Antibiotic therapy Led to regression in

about 75% of cases Complete remission in

50% of cases Remainder are responsive to

combination chemotherapy. o Diffuse high-grade lymphomas

5-year survival rate with treatment: 60-65%

GIST o Surgical resection curative in most

patients o Tumors expressing c-kit tyrosine kinase

(CD117) respond to imatinib mesylate in a substantial proportion of cases.

Prevention Eradication of H. pylori

o Effect on subsequent risk for gastric cancer in high-incidence areas is under investigation.

Reduced incidence of gastric cancer in U.S. o Better food preservation and availability

of refrigeration may have reduced ingestion of exogenous bacteria that convert nitrates into nitrites.

Screening endoscopy performed in Japan where incidence is much higher than in U.S.

Gastrointestinal Bleeding Bleeding from the GI tract may present in 5

ways. o Hematemesis: vomitus of red blood or

"coffee grounds" material

o Melena: black, tarry, foul-smelling stool o Hematochezia: passage of bright red or

maroon blood from the rectum o Occult GI bleeding: blood in the stool in

the absence of overt bleeding o Symptoms of blood loss or anemia (e.g.,

light-headedness or shortness of breath) Upper GI bleeding

o Source in the upper GI tract (above the ligament of Treitz)

Lower GI bleeding o Source in the small intestine or colon

(below the ligament of Treitz) Obscure GI bleeding

o Recurrent acute or chronic bleeding for which no known source is identified

Epidemiology Incidence

o Hospital admissions for upper GI bleeding in the U.S. and Europe: approximately 100 per 100,000 persons annually

o Hospitalization rate for lower GI bleeding is about one-fifth that for upper GI bleeding.

Mechanism Disruption of the GI mucosa secondary to

inflammation, infection, trauma, or cancer Vascular abnormalities, such as vascular

ectasias or varices due to portal hypertension See Differential Diagnosis for discussion of

specific sources of GI bleeding.

DIAGNOSIS Symptoms & Signs

Differentiation of upper GI bleeding from lower GI bleeding

o Hematemesis Vomiting of blood or altered

blood ("coffee grounds" appearance) indicates an upper GI source of bleeding (above the ligament of Treitz)

o Melena Altered (black) blood passed by

rectum (>100 mL blood for 1 melenic stool)

Indicates that blood has been present in the GI tract for at least 14 hours

Usually indicates bleeding proximal to ligament of Treitz, but may be as distal as ascending colon

The more proximal the bleeding site, the more likely melena will occur.

o Hematochezia Bright red or maroon rectal

bleeding Usually represents a lower GI

source of bleeding, although an upper GI lesion may bleed so briskly that blood does not remain in the bowel long enough for melena to develop

When hematochezia is the presenting symptom of upper GI bleeding, it is associated with

[10]

hemodynamic instability and decreasing Hgb concentration

Bleeding lesions of the small bowel may present as melena or hematochezia

Hematochezia that presents with abdominal pain may represent ischemic colitis, particularly in elderly persons or those with cardiovascular risk factors

Hematochezia associated with diverticulosis and colonic tumors are typically painless

o Other clues Hyperactive bowel sounds and

an elevated blood urea nitrogen level(due to volume depletion and blood proteins absorbed in the small intestine) suggest upper GI bleeding

Nasogastric tube lavage usually, but not always, yields blood or "coffee grounds" material

Nonbloody nasogastric aspirate may be seen in up to 18% of patients with upper GI bleeding

Usually from a duodenal source

Bile-stained appearance does not exclude a bleeding postpyloric lesion because reports of bile in the aspirate are incorrect in about 50% of cases

Mallory-Weiss tears usually occur in patients who have a history of vomiting, retching, or coughing preceding hematemesis, especially in an alcoholic patient

Erosive gastropathy (subepithelial hemorrhages or erosions) is commonly related to NSAID use, alcohol intake, and stress

Diverticular (colonic) bleeding is abrupt in onset, usually painless, sometimes massive, and often from the right colon; minor and occult bleeding is not characteristic.

Physical examination o Clinically significant bleeding leads to

postural changes in heart rate or blood pressure, tachypnea, tachycardia, and recumbent hypotension.

o Hemodynamic changes Orthostatic decrease in blood

pressure > 10 mmHg usually indicates > 20% reduction in blood volume.

Systolic blood pressure < 100 mmHg usually indicates > 30% reduction in blood volume.

Differential Diagnosis Upper GI bleeding

o Ulcers (31-59%) o Varices (7-20%), depending on group o Mallory-Weiss tears (4-8%)

o Gastroduodenal erosions (2-7%) o Erosive esophagitis (1-13%); major

bleeding is rare o Cancer (2-7%) o Vascular ectasias (0-6%) o No source identified (8-14%)

Possible causes: erosive duodenitis, aortoenteric fistulae, Dieulafoy's lesion, prolapse gastropathy, hemobilia, hemosuccus pancreaticus

o Non-GI sources of bleeding Generally involves swallowing

blood from other sources Epistaxis Hemoptysis

o Pseudomelena Ingestion of iron, bismuth,

licorice, beets, blueberries, charcoal, or red-tinted foods (e.g., red gelatin)

Lower GI bleeding o Diverticulosis (33-50%) o Vascular ectasias (8-20% overall; more

common in persons > 65 years of age) o Tumors (19%)

Adenocarcinoma, leiomyoma, lymphoma, benign polyps, carcinoid, metastases, lipoma

o Colitis (18%) Inflammatory bowel disease

(Crohn's disease, ulcerative colitis)

Infection Ischemic Radiation-induced

o Hemorrhoids or anal fissures (5%) o Meckel's diverticulum

Most common cause of significant lower GI bleeding in children

With age, decreases in frequency as a cause of bleeding

o Less common causes Vasculitis, small-bowel varices,

duplication cysts, intussusceptions, polypectomy, rectal ulcers, rectal varices, lymphoid nodular hyperplasia, aortocolic fistulae

Chronic, obscure GI bleeding (recurrent iron-deficiency anemia or guaiac-positive stool of unknown source)

o Small-intestinal erosions and ulcers related to NSAID use

o In adults < 40-50 years of age, small-bowel tumors often account for obscure GI bleeding.

o In patients >50-60 years of age, vascular ectasias are usually responsible.

Diagnostic Approach History and physical examination

o Focused history to identify risk factors (e.g., NSAID or alcohol use) and to evaluate likely source of bleeding

o Physical examination Evaluate hemodynamic stability

by measurement of heart rate and blood pressure

[11]

Search for signs of an underlying disorder (e.g., liver disease)

Rectal examination is usually indicated; consider anoscopy if appropriate

Laboratory evaluation o Degree of anemia

Diagnostic procedures o Upper endoscopy in patients with

suspected upper GI bleeding o Colonoscopy in patients with suspected

lower GI bleeding Other imaging studies, when indicated

Laboratory Tests Complete blood count

o Hemoglobin concentration and hematocrit

May be normal initially in acute GI bleeding

Decrease as extravascular fluid enters the vascular space to restore volume

Patients with slow, chronic GI bleeding may have very low Hgb and Hct values despite normal blood pressure and heart rate

o Mild leukocytosis & thrombocytosis are typical

o Mean corpuscular volume and red-cell distribution width may be helpful in suggesting chronicity

Expect microcytic anemia with elevated red-cell distribution width in iron-deficiency anemia related to chronic GI blood loss

Serum chemistry o Elevated blood urea nitrogen level is

common in upper GI bleeding. Occult blood testing

o Fecal occult blood test should be performed on stool that has passed naturally rather than that obtained from rectal examination to decrease the likelihood of false-positive results related to local trauma.

o Testing of nasogastric aspirates that are not grossly bloody is not useful.

Stool studies o Fecal leukocytes may be present in

conditions characterized by inflammation or infection.

o If infection is suspected, send stool cultures for evaluation of likely causes of infectious colitis.

Imaging

99mTechnetium-labeled red-cell scintigraphy o Can detect bleeding rate of 0.1-0.5

mL/min o Used primarily as a screening test

When bleeding is intermittent and of unclear origin

To identify the general area of lower GI bleeding

To confirm that bleeding is rapid enough for arteriography to be of value

o Allows repeated imaging for up to 24 hours after initial injection of the patient's radionuclide-labeled cells

o Perform in: Patients with continued obscure

GI bleeding who require transfusions or repeated hospitalizations

In diagnosis of Meckel's diverticulum, especially in the evaluation of young patients

o Radionuclide scans should be interpreted with caution because results are highly variable, especially from later images.

Angiography o Requires bleeding rate > 0.5 mL/min o Can detect the site of bleeding in active

lower GI bleeding (extravasation of contrast into the gut) and permits treatment with intra-arterial infusion of vasopressin or embolization

o Even after bleeding has stopped, angiography may identify lesions with abnormal vasculature, such as vascular ectasias or tumors

Radiographic examination of small bowel (e.g., enteroclysis)

o If enteroscopy and video-capsule endoscopy are negative or unavailable

o May be considered in patients with iron-deficiency anemia

Upper GI barium radiography o Accuracy ~80% in identifying an upper

GI lesion o Does not confirm source of bleeding o Acceptable alternative to endoscopy in

resolved or chronic low-grade bleeding Selective mesenteric arteriography

o When brisk bleeding precludes identification of source at endoscopy

CT and MR enterography are newer imaging techniques currently being investigated.

Diagnostic Procedures Upper endoscopy

o Test of choice in patients with upper GI bleeding

o Should be performed urgently to identify source of bleeding and allow intervention in patients with hemodynamic instability

Hypotension Tachycardia Postural changes in heart rate

or blood pressure o Patients with hematochezia and

hemodynamic instability should have upper endoscopy before evaluation of the lower GI tract

o Interventions can be performed to decrease bleeding, e.g., injection or cauterization of ulcers and ligation or sclerotherapy of bleeding varices

o In patients with occult GI bleeding who have normal colonoscopy, upper endoscopy is usually recommended if iron-deficiency anemia or upper GI symptoms are present.

Colonoscopy o Oral lavage solution followed

by colonoscopy is the procedure of

[12]

choice in patients admitted with lower GI bleeding unless:

Bleeding is too massive Sigmoidoscopy has disclosed

an obvious actively bleeding lesion

o Evaluation of a positive test for fecal occult blood generally should begin with colonoscopy, particularly in patients > 40 years of age.

Sigmoidoscopy o Patients with presumed lower GI

bleeding may undergo early sigmoidoscopy for the detection of obvious, low-lying lesions.

Difficult with brisk bleeding Usually not possible to identify

the area of bleeding Useful primarily in patients < 40

years of age with minor bleeding Push enteroscopy

o May identify probable bleeding sites in 20-40% of patients with obscure GI bleeding

Video-capsule endoscopy o Allows endoscopic examination of the

entire small intestine and increases diagnostic yield in obscure GI bleeding

Bleeding sites were identified in approximately 30-65% of cases in the initial published reports.

Lack of control of the capsule prevents its manipulation and full visualization of the intestine.

Tissue cannot be sampled, and therapy cannot be applied.

Double-balloon enteroscopy o New endoscopic technique o Allows the endoscopist to potentially

examine and provide therapy to much or all of the small intestine.

Intraoperative endoscopy o Indicated when all tests are unrevealing

in patients with severe recurrent or persistent bleeding requiring repeated transfusions

TREATMENT Treatment Approach

Hemodynamic resuscitation and stabilization Procedural intervention

o Endoscopic hemostatic therapy o Colonoscopic removal of bleeding polyp

or mass o Surgical resection if necessary

Targeted medical therapy

Specific Treatments Hemodynamic resuscitation and stabilization

Venous access o Large-bore needle (14-18 gauge) o Central venous line for major bleeding

and patients with cardiac disease Monitor vital signs, urine output, and hemoglobin

and hematocrit (decrease may lag) Gastric lavage is of unproven benefit but clears

the stomach before endoscopy o Iced saline may lyse clots and reactivate

bleeding; room-temperature tap water may be preferable.

Intubation may be required to protect the airway

Support blood pressure with isotonic fluids (normal saline) and blood products as necessary.

Type and cross-match blood (6 units for major bleeding)

o Packed red blood cells o Whole blood if massive bleeding o Transfuse as necessary on the basis of

clinical signs, with a target Hct > 25-30% Reverse coagulopathy (if present) with fresh-

frozen plasma and vitamin K. o Consider in cirrhotic patients or those

taking anticoagulants. Intravenous calcium (up to 10-20 mL

10% calcium gluconate IV over 10-15 min) if serum calcium level decreases due to transfusion of citrated blood

Surgical standby when bleeding is massive Indications for emergency surgery

o Uncontrolled or prolonged bleeding, severe rebleeding, aortoenteric fistula

o For intractable variceal bleeding, consider transjugular intrahepatic portosystemic shunt (TIPS)

o One-third of patients with active bleeding or a nonbleeding visible vessel have further bleeding that requires urgent surgery if they are treated conservatively.

Upper GI bleeding

Peptic ulcers o Endoscopic therapy with bipolar

electrocoagulation, heater probe, or injection therapy (e.g., absolute alcohol, 1:10,000 epinephrine) if indicated

o High-dose, constant IV infusion of proton-pump inhibitor (PPI), to increase intragastric pH to >6 and enhance clot stability

Decreases further bleeding, need for surgery, and repeat endoscopy

No effect on mortality except possibly in patients with high-risk ulcers (active bleeding, non-bleeding visible vessel) [1]

Many clinical trials have used intravenous omeprazole

In the U.S., pantoprazole and lansoprazole are the PPIs that are available in an intravenous formulation

IV pantoprazole: initial dose, 80-mg bolus, followed by 8 mg/h

IV lansoprazole: initial dose, 60-mg bolus, followed by 6 mg/h

o Eradication of Helicobacter pylori in patients with bleeding ulcers decreases rates of rebleeding to < 5%

o If a bleeding ulcer develops in a patient taking NSAIDs, the NSAID therapy should be discontinued if possible

If NSAID therapy must be continued, treatment with a PPI should be continued, and the risk-benefit profile of switching to a cyclooxygenase 2 (COX-2)-

[13]

specific inhibitor (coxib) should be carefully reviewed

Among nonselective NSAIDs, risk of bleeding seems to be lowest for ibuprofen

Either PPI co-therapy with a nonselective NSAID or use of a coxib alone is associated with an annual rebleeding rate of ~10% in high-risk patients (i.e., a recent bleeding ulcer)

Combination of a coxib and PPI provides a further significant decrease in ulcers and recurrent bleeding and should be employed in very high-risk patients

Use of misoprostol (100 g tid or qid, increasing to 200 g tid or qid, if necessary) can prevent NSAID GI toxicity

o Patients with bleeding ulcers unrelated to H. pylori or NSAIDs should continue to receive full-dose antisecretory therapy indefinitely

o Patients with clean-based ulcers may be discharged on the first hospital day after stabilization if there is no other reason for hospitalization

o Patients without clean-based ulcers should usually remain in the hospital for 3 days as most episodes of recurrent bleeding occur within this time frame

Mallory-Weiss tears o Bleeding usually occurs on the gastric

side of the gastroesophageal junction. o Stops spontaneously in 80-90% of

patients o Endoscopic therapy is indicated for

active bleeding o Angiographic therapy with intra-arterial

infusion of vasopressin or embolization and operative therapy with oversewing of the tear are rarely required

Esophageal varices o Endoscopic therapy for acute bleeding

and repeated sessions of endoscopic therapy to eradicate esophageal varices significantly reduces rebleeding and mortality

o Ligation is the endoscopic therapy of choice for esophageal varices compared with sclerotherapy

Less rebleeding Lower mortality rate Fewer local complication Fewer treatment sessions to

achieve variceal eradication o Short-term treatment with octreotide (50-

g bolus and 50-g/h IV infusion for 2-5 days) may help control acute bleeding.

Has replaced vasopressin as the medical therapy of choice for acute variceal bleeding

Somatostatin and terlipressin, available outside the U.S., are also effective

o Antibiotic therapy (e.g., quinolones) is also recommended for patients with cirrhosis presenting with upper GI

bleeding, as antibiotics decrease bacterial infections and mortality in this population

o Long-term treatment with nonselective beta blockers decreases recurrent bleeding from esophageal varices.

Commonly given along with long-term endoscopic therapy

o In patients who have persistent or recurrent bleeding despite endoscopic and medical therapy, more invasive therapy is warranted

TIPS decreases rebleeding more effectively than endoscopic therapy, although hepatic encephalopathy is more common and mortality rates are similar

Most patients with TIPS have shunt stenosis within 1-2 years and require reinstrumentation, although the use of coated stents appears to markedly decrease shunt dysfunction, at least in the first year

TIPS is most appropriate for patients with more severe liver disease and those in whom transplant is anticipated

Patients with milder, well-compensated cirrhosis require fewer re-interventions with decompressive surgery (e.g., distal splenorenal shunt), although the higher initial risks of surgery must also be considered

o Portal hypertension is also responsible for bleeding from gastric varices, varices in the small and large intestine, and portal hypertensive gastropathy and enterocolopathy

Hemorrhagic and erosive gastropathy ("gastritis")

o Removal of the offending agent if possible (e.g., NSAIDs, alcohol).

o Multiple trials document the efficacy of intravenous H2-receptor antagonist therapy, which is more effective than sucralfate but not superior to a PPI immediate-release suspension given via nasogastric tube

Small-intestinal bleeding Vascular ectasias

o Treated with endoscopic therapy if possible

o Surgical therapy can be used for vascular ectasias isolated to a segment of the small intestine when endoscopic therapy is unsuccessful

o Estrogen/progesterone compounds have been used for vascular ectasias, but a double-blind trial found no benefit in prevention of recurrent bleeding

o Isolated lesions, such as tumors, diverticula, or duplications, are generally treated with surgical resection

[14]

Colonic bleeding Bleeding colonic diverticula stop bleeding

spontaneously in approximately 80% of patients o Intra-arterial vasopressin or

embolization by superselective technique should stop bleeding in a majority of patients

o If bleeding persists or recurs, segmental surgical resection is indicated

Endoscopic polypectomy, if possible, is used to treat bleeding colonic polyps

Colonic tumors typically require surgical resection

Bleeding from right colonic vascular ectasias in elderly persons tends to be chronic and only occasionally is hemodynamically significant

Surgical therapy is generally required for major, persistent, or recurrent bleeding from the wide variety of colonic sources of GI bleeding that cannot be treated medically or endoscopically

ONGOING CARE Monitoring

Patients with acute GI bleeding typically require hospitalization.

Patients with subacute or chronic GI bleeding may undergo outpatient evaluation if they do not have significant comorbid conditions.

Patients who present with active GI bleeding require close monitoring.

Intensive care unit may be indicated for patients with hemodynamic instability, those requiring blood transfusions, and those with continued active bleeding.

After endoscopy o Patients with lower-risk endoscopic

findings (clean-based ulcer) may be discharged on medical therapy.

o Patients with higher-risk endoscopic findings (active bleeding or visible vessel) require continued inpatient monitoring for several days.

After colonoscopy, the level of monitoring may be determined by whether definitive intervention has eliminated source of bleeding.

Complications Hypovolemic shock and subsequent end-organ

damage Complications related to blood transfusions,

such as acquired infections or transfusion reaction

Complications related to procedural interventions, such as perforation and infection

Prognosis Upper GI bleeding

o Mortality rate of ~5%-10% < 1% in patients < 60 years of

age in the absence of major concurrent illness

o Patients rarely die of exsanguination; rather, they die of decompensation from other underlying illnesses.

o Adverse prognostic signs 3 independent clinical predictors

of death in patients hospitalized with upper GI bleeding

Increasing age Comorbid conditions Hemodynamic

compromise

(tachycardia or hypotension)

Other poor prognostic signs: coagulopathy, immunosuppression presentation with shock, rebleeding, onset of bleeding in hospital, variceal bleeding, endoscopic stigmata of recent bleeding

o Peptic ulcer Patients with clean-based ulcers

have a rate of recurrent bleeding of approximately 5% and a mortality rate of approximately 2%

Patients with actively bleeding ulcers at endoscopy have a rebleeding rate of approximately 50% and a mortality rate of approximately 10%

o Mallory-Weiss tears Bleeding recurs in 0-7% of

patients o Esophageal varices

Patients with variceal hemorrhage have poorer outcomes than patients with other sources of upper GI bleeding

o Stress-related gastric mucosal injury Mortality rate is high because of

serious underlying illness Lower GI bleeding

o Bleeding colonic diverticula Approximately 20-25% of

patients have episodes of rebleeding

Prevention Prevention of recurrent bleeding is focused on

treatment of the underlying cause. Examples

o Recurrent bleeding ulcer Address 3 main factors in ulcer

pathogenesis. Treat Helicobacter

pylori infection Discontinue NSAID

therapy Provide acid

suppression with a PPI o Esophageal varices

Nonselective beta blocker to decrease portal hypertension

TIPS for severe disease o GI cancer

Treatment of underlying condition and surgery if appropriate

o

o Angiodysplasia Rebleeding risk may be as high

as 30% after local therapy (endoscopic coagulation).

Usual source is another lesion rather than the same lesion.

[15]

Dysphagia Sensation of "sticking" or obstruction of the

passage of food through the mouth, pharynx, or esophagus

Other symptoms related to swallowing o Aphagia: complete esophageal

obstruction Usually due to bolus impaction Medical emergency

o Difficulty in initiating a swallow o Odynophagia: painful swallowing o Globus pharyngeus: sensation of a lump

lodged in throat o Misdirection of food

Results in nasal regurgitation, laryngeal and pulmonary aspiration of food during swallowing

o Phagophobia: fear of swallowing o Refusal to swallow o Esophageal sensitivity: feeling food as it

goes down the esophagus o Feeling of fullness in epigastrium

Epidemiology Prevalence

o 7-10% of adults > 50 years of age have dysphagia

o Aspiration was observed in more than one-third of stroke patients undergoing radiologic evaluation

Age o More common with advancing age

Mechanism General

Dysphagia based on anatomic site o Oral o Pharyngeal o Esophageal

Normal transport of ingested bolus through swallowing passage depends on:

o Size of ingested bolus o Luminal diameter of swallowing passage o Force of peristaltic contraction o Deglutitive inhibition, including normal

relaxation of upper and lower esophageal sphincters during swallowing

Mechanical dysphagia: dysphagia caused by a large bolus or a narrow lumen

Motor dysphagia: dysphagia due to weakness of peristaltic contractions or to impaired deglutitive inhibition causing nonperistaltic contractions and impaired sphincter relaxation

Oral and pharyngeal dysphagia Oral-phase dysphagia: associated with poor

bolus formation and control o Food may either drool out of the mouth

or overstay in the mouth, or the patient may experience difficulty in initiating the swallowing reflex

o Premature spillage of food into the pharynx and aspiration into the unguarded larynx and/or nasal cavity

Pharyngeal-phase dysphagia: associated with stasis of food in the pharynx due to poor pharyngeal propulsion and obstruction at the upper esophageal sphincter (UES)

o Nasal regurgitation and laryngeal aspiration during or after a swallow

Oropharyngeal mechanical dysphagia o Mechanical causes, including a variety

of developmental abnormalities, head and neck tumors, radiation therapy, and inflammatory processes (See Differential Diagnosis.)

Oropharyngeal motor dysphagia o Results from impairment of the voluntary

effort required in bolus preparation or neuromuscular disorders affecting bolus preparation, initiation of the swallowing reflex, timely passage of food through the pharynx, and prevention of entry of food into the nasal and the laryngeal opening

o Motor dysphagia of pharynx results from neuromuscular disorders, causing muscle paralysis, simultaneous nonperistaltic contraction, or loss of opening of the UES

o Loss of opening of the upper sphincter is caused by paralysis of geniohyoid and other suprahyoid muscles or loss of deglutitive inhibition of cricopharyngeus muscle

o Because each side of the pharynx is innervated by ipsilateral nerves, a unilateral lesion of motor neurons leads to unilateral pharyngeal paralysis.

o For oropharyngeal causes of motor dysphagia,

Esophageal dysphagia Esophageal mechanical dysphagia

o In an adult, the esophageal lumen can distend up to 4 cm in diameter

Dysphagia to normal solid food can occur when the esophagus cannot dilate beyond 2.5 cm in diameter

Dysphagia is always present when the esophagus cannot distend beyond 1.3 cm

o Circumferential lesions produce dysphagia more consistently than do lesions that involve only a portion of circumferences of the esophageal wall, as uninvolved segments retain their distensibility

o For esophageal causes of mechanical dysphagia, see Differential Diagnosis.

Esophageal motor dysphagia o May result from abnormalities in

peristalsis and deglutitive inhibition due to diseases of the esophageal striated or smooth muscle

o Diseases of striated muscle Diseases of the striated muscle

often also involve the cervical part of the esophagus, in addition to affecting the oropharyngeal muscles

Clinical manifestations of the cervical esophageal involvement are usually overshadowed by those of the oropharyngeal dysphagia

o Diseases of smooth-muscle segment Involve the thoracic part of the

esophagus and the lower esophageal sphincter (LES)

[16]

Dysphagia occurs when the peristaltic contractions are weak or absent or when the contractions are nonperistaltic

Loss of peristalsis may be associated with failure of LES relaxation

Weakness of contractile power occurs due to muscle weakness, as in scleroderma or impaired cholinergic effect

Nonperistaltic contractions and failure of LES relaxation occur due to impaired inhibitory innervation

Diffuse esophageal spasm: Inhibitory innervation only to the esophageal body is impaired

Achalasia: Inhibitory innervation to both the esophageal body and LES is impaired

Dysphagia due to esophageal muscle weakness is often associated with symptoms of gastroesophageal reflux disease (GERD)

Dysphagia due to loss of the inhibitory innervation is typically not associated with GERD but may be associated with chest pain

DIAGNOSIS Symptoms & Signs Characteristics of dysphagia

Type of food causing dysphagia o Difficulty only with solids implies

mechanical dysphagia with a lumen that is not severely narrowed.

o In advanced obstruction, dysphagia occurs with liquids as well as solids

o Motor dysphagia due to achalasia and diffuse esophageal spasm affects ingestion of solids and liquids from onset

o Patients with scleroderma have dysphagia to solids that is unrelated to posture and to liquids while recumbent but not upright

o When peptic stricture develops in scleroderma, dysphagia becomes more persistent

Duration and course o Transient dysphagia may be due to an

inflammatory process o Progressive dysphagia lasting a few

weeks to a few months suggests carcinoma of the esophagus

o Episodic dysphagia to solids lasting several years indicates benign disease characteristic of the lower esophageal ring

Site of dysphagia o Patients can often pinpoint where the

obstruction lies. o Lesion is at or below perceived location

of dysphagia Associations with esophageal stricture

o Prolonged nasogastric intubation o Ingestion of caustic agents o Ingestion of pills without water o Previous radiation therapy

o Associated mucocutaneous diseases In patients with AIDS or other immunodeficiency

states, the following should be suspected: o Esophagitis from opportunistic

infections, such as Candida, herpes simplex virus, or cytomegalovirus

o Tumors, such as Kaposi's sarcoma and lymphoma

Related signs and symptoms Nasal regurgitation and tracheobronchial

aspiration with swallowing o Hallmarks of pharyngeal paralysis or

tracheoesophageal fistula Severe weight loss out of proportion to degree of

dysphagia o Highly suggestive of carcinoma

Hoarseness o Preceding dysphagia: primary lesion

usually in larynx o After dysphagia: suggests involvement

of recurrent laryngeal nerve by extension of esophageal carcinoma

o Sometimes due to laryngitis secondary to gastroesophageal reflux

o Association of laryngeal symptoms and dysphagia occurs in various neuromuscular disorders

Hiccups o May rarely occur with lesion in distal

portion of esophagus Unilateral wheezing

o May indicate mediastinal mass involving esophagus and large bronchus

Chest pain o Occurs in diffuse esophageal spasm

and related motor disorders o May occur in esophageal obstruction

due to large bolus Prolonged history of heartburn and reflux

preceding dysphagia o Suggests peptic stricture

Odynophagia o Following should be suspected.

Candidal or herpes esophagitis Pill-induced esophagitis

Signs of bulbar or pseudobulbar palsy suggest a neurologic cause.

o Dysarthria o Dysphonia o Ptosis o Tongue atrophy o Hyperactive jaw jerk

Thyromegaly o May cause extrinsic compression

Spinal abnormality o May cause extrinsic compression

Changes in skin and extremities may suggest: o Scleroderma or other collagen vascular

disease o Mucocutaneous diseases, such as

pemphigoid or epidermolysis bullosa, which may involve the esophagus

Differential Diagnosis

Oropharyngeal mechanical dysphagia

Luminal Large bolus Foreign body

[17]

Wall defects Congenital

o Cleft lip, cleft palate o laryngeal clefts

Postsurgical

Intrinsic narrowing Inflammatory

o Viral (herpes simplex, varicella-zoster,cytomegalovirus)

o Bacterial (peritonsillar abscess) o Fungal (Candida) o Mucocutaneous bullous diseases o Caustic, chemical, thermal injury

Web o Plummer-Vinson syndrome

Strictures o Congenital micrognathia o Caustic ingestion o Post-radiation

Tumors o Benign

Leiomyoma Lipoma Angioma Inflammatory fibroid polyp Epithelial papilloma

o Malignant Primary carcinoma Squamous-cell carcinoma Adenocarcinoma Carcinosarcoma Pseudosarcoma Lymphoma Melanoma Kaposi's sarcoma Metastatic carcinoma

Extrinsic compression Retropharyngeal abscess, mass Zenker's diverticulum Thyroid disorders Vertebral osteophytes

Oropharyngeal motor dysphagia

Disease of cerebral cortex and brainstem With altered consciousness or dementia

o Dementias including Alzheimer's disease

o Altered consciousness, metabolic encephalopathy, encephalitis, meningitis, cerebrovascular accident, brain injury

With normal cognitive functions o Brain injury o Cerebral palsy o Rabies, tetanus, neurosyphilis o Cerebrovascular disease o Parkinson's disease and other

extrapyramidal lesions o Multiple sclerosis (bulbar and

pseudobulbar palsy) o Amyotrophic lateral sclerosis(motor

neuron disease) o Poliomyelitis and post-poliomyelitis

syndrome

Disease of cranial nerves (V, VII, IX, X, XII) Basilar meningitis (chronic inflammatory,

neoplastic) Nerve injury

Neuropathy (Guillain-Barr syndrome, familial dysautonomia, sarcoid, diabetic and other causes)

Neuromuscular Myasthenia gravis Eaton-Lambert syndrome Botulinum toxin Aminoglycoside and other drugs

Muscle disorders Myositis (polymyositis, dermatomyositis,

sarcoidosis) Metabolic myopathy (mitochondrial myopathy,

thyroid myopathy) Primary myopathies (myotonic dystrophy,

oculopharyngeal myopathy)

Esophageal mechanical dysphagia

Luminal Large bolus Foreign body

Wall defects Congenital Tracheoesophageal fistula

Intrinsic narrowing Inflammatory esophagitis

o Viral (herpes simplex, varicella zoster, cytomegalovirus)

o Bacterial o Fungal (Candida) o Mucocutaneous bullous diseases o Caustic, chemical, thermal injury o Eosinophilic esophagitis

Webs and rings o Esophageal (congenital, inflammatory) o Lower esophageal mucosal ring

(Schatzki's ring) o Eosinophilic esophagitis o Host-versus-graft disease,

mucocutaneous disorders Benign strictures

o Peptic o Caustic o Pill-induced o Inflammatory (Crohn's disease,

Candida mucocutaneous lesions) o Ischemic o Postoperative o Post-radiation therapy o Congenital

Tumors o Benign

Leiomyoma Lipoma Angioma Inflammatory fibroid polyp Epithelial papilloma

o Malignant Primary carcinoma Squamous-cell carcinoma Adenocarcinoma Carcinosarcoma Pseudosarcoma Lymphoma Melanoma Kaposi's sarcoma Metastatic carcinoma

[18]

Extrinsic compression Vascular compression (dysphagia lusoria,

aberrant right subclavian artery, right-sided aorta, left atrial enlargement, aortic aneurysm)

Posterior mediastinal mass Postvagotomy hematoma and fibrosis

Esophageal motor dysphagia

Disorders of the cervical esophagus See oropharyngeal motor disorders (above).

Disorders of the thoracic esophagus Diseases of smooth muscle or excitatory nerves

o Weak muscle contraction or LES tone Idiopathic Scleroderma and related

collagen vascular diseases Hollow visceral myopathy Myotonic dystrophy Metabolic neuromyopathy

(amyloid, alcohol, diabetes) Drugs: anticholinergics, smooth

muscle relaxants o Enhanced muscle contraction

Hypertensive peristalsis (nutcracker esophagus)

Hypertensive LES, hypercontracting LES

Disorders of inhibitory innervation o Diffuse esophageal spasm o Achalasia

Primary Secondary (Chagas' disease,

carcinoma, lymphoma, neuropathic intestinal pseudo-obstruction syndrome)

o Contractile (muscular) lower esophageal ring

Diagnostic Approach Dysphagia is usually a symptom of organic

disease rather than a functional complaint. History and physical examination

o Can provide presumptive diagnosis in > 80% of patients

o Difficulty initiating a swallow associated with coughing, nasal regurgitation, or choking suggests oropharyngeal problems.

o Sensation of food getting stuck in the esophagus suggests esophageal problems

Usually, symptoms appear with some delay after swallowing.

Problems with solids and/or liquids suggest a motor disorder.

Problems with solid but not liquids suggest a mechanical disorder.

Imaging is often indicated to confirm diagnosis. o Choice of study depends on what type

of dysphagia is suspected. o See Diagnostic Procedures for details.

Laboratory Tests Measure thyroid-stimulating hormone if

thyromegaly is detected.

Imaging Videofluoroscopy

o Rapid-sequence videofluoroscopy is necessary to permit detection and analysis of abnormalities of oral and pharyngeal function.

o Fluoroscopic images are captured as patient swallows a bolus of barium.

May reveal difficulties in the oral phase of swallowing

Pharynx is examined to detect stasis of barium in the valleculae and pyriform sinuses and regurgitation of barium into the nose and tracheobronchial tree

Pharyngeal contraction waves and opening of UES with a swallow are carefully monitored

o Identifies impairment of the muscular apparatus of the oropharynx and presence of a cricopharyngeal bar or pharyngoesophageal diverticulum

Barium swallow o To confirm diagnosis for causes of both

mechanical and motor dysphagia o Achalasia produces a "bird's beak"

appearance at the gastroesophageal junction

Diagnostic Procedures General

o Esophageal motility studies To confirm diagnosis for causes

of motor dysphagia caused by abnormalities of peristalsis

o Esophagogastroscopy To aid in diagnosis of causes of

both mechanical and motor dysphagia

To exclude associated structural abnormality

Based on suspected etiology o Oral or pharyngeal dysphagia suspected

Videofluoroscopic swallowing study by both a radiologist and a swallow therapist is procedure of choice.

Videoendoscopy: currently performed only in specialized centers

o Esophageal mechanical dysphagia suspected

Diagnostic procedures of choice Barium swallow Esophagogastroscopy

with or without mucosal biopsies

Some cases CT examination and

endoscopic ultrasound may be useful.

Esophageal motor dysphagia suspected; useful diagnostic tests include:

Barium swallow Esophageal manometry Esophageal pH Impedance testing Esophagogastroscopyis

also often performed in

[19]

patients with motor dysphagia to exclude an associated structural abnormality.

TREATMENT Treatment Approach

Goals of dysphagia therapy are to: o Improve ability to eat and swallow o Optimize nutritional status o Reduce risk of aspiration o Treat underlying medical condition, if

possible

Specific Treatments Treatment, by major cause of dysphagia

GERD o Small meals, no eating at bedtime,

remaining upright after eating o Pharmacologic therapy o Smoking cessation

Stroke, multiple sclerosis o Dietary modification o Swallow therapy

Parkinson's disease, myasthenia gravis, polymyositis

o Pharmacologic therapy for the underlying disease

o Dietary modification, swallow therapy if primary pharmacologic therapy is not successful

Peptic stricture of the lower esophageal sphincter

o Esophageal dilatation Achalasia

o Esophageal dilatation o Surgical myotomy o Injection of lower esophageal sphincter

with botulinum toxin Diffuse esophageal spasm

o Pharmacologic therapy Esophageal cancer

o Esophagectomy Globus pharyngeus

o Reassurance is main treatment o Some patients have associated reflux

esophagitis and may respond to the treatment of esophagitis.

Swallow therapy Usually provided by a speech-language

pathologist who is trained in testing and treating swallowing disorders

Therapies o Compensatory techniques, such as

postural maneuvers o Indirect therapy: exercises to strengthen

swallowing muscles o Direct therapy: exercises to perform

while swallowing

Pharmacologic therapy For GERD (See Gastroesophageal Reflux

Disease for details.) o Histamine-2 receptor blocking agents o Proton-pump inhibitors

Diffuse esophageal spasm o Calcium-channel blockers o Nitrates

Esophageal dilatation Used commonly in achalasia, sometimes for

mechanical obstruction May only be effective for a short period of time

Surgery Cricopharyngeal myotomy

o Used occasionally in patients with oral or pharyngeal dysphagia

o May be helpful in severely symptomatic cases of persistent cricopharyngeal bar caused by fibrosis with functional evidence of obstruction by the cricopharyngeal muscle

Contraindicated in presence of GERD because it may lead to pharyngeal and pulmonary aspiration

o Cricopharyngeus muscle is disrupted to reduce resistance of the pharyngeal outflow tract.

o Injection of cricopharyngeus with botulinum toxin may be an alternative to myotomy

Esophagectomy o For certain patients with esophageal

carcinoma Esophageal stents

o Stents are placed directly in the esophagus by using a gastroscope and fluoroscopy

o When released, the stents expand and compress the obstruction against the esophageal wall, thereby making the lumen larger

Myotomy o Effective in patients with severe diffuse

esophageal spasm o Effective in some patients with achalasia

ONGOING CARE Monitoring

Ongoing monitoring is generally not required and depends on underlying cause

Complications Weight loss Malnutrition Dehydration Pulmonary complications

o Aspiration pneumonia o Chronic aspiration

Prognosis Depends on underlying cause Prognosis is generally good, as most causes of

dysphagia are benign and can be corrected. When dysphagia is due to cancer, prognosis is

very poor.

Prevention Depends on underlying cause, but in most cases

cannot be prevented Early detection and treatment of GERD may

prevent peptic strictures. Esophageal cancer may be prevented by

smoking cessation and early detection and management of Barrett's esophagus, a complication of GERD.

[20]

Diseases of the Esophagus Conditions that impair:

o Esophageal transport of food from mouth to stomach

o Ability to prevent retrograde flow of GI contents

Chest pain, heartburn, and dysphagia are the major ways in which these conditions present.

May be due to: o Motor disorders o Gastroesophageal reflux disease

(GERD) o Inflammatory disorders o Mechanical problems

Epidemiology Prevalence

o GERD Up to 15% of persons have

heartburn and/or regurgitation at least once a week

7% have symptoms daily o Barrett's esophagus (complication of

reflux) Long-segment (>2-3 cm) of

involvement is present in 1.5% of patients with GERD

Short-segment (< 2-3 cm) of involvement occurs in up to 15% of patients with GERD

o Webs and rings Asymptomatic hypopharyngeal

webs occur in < 10% of normal persons.

Asymptomatic rings may be present in ~10% of normal persons.

o Hiatal hernia In persons in the sixth decade of

life, the prevalence is ~60%. Age and sex

o Achalasia Affects patients of all ages and

both sexes o Hiatal hernia

More common in older patients The incidence increases with

age o Globus pharyngeus (feeling of a lump in

the throat) May be a sign of actual

esophageal disease in up to 25% of patients

The majority of cases are probably due to psychopathology and are seen predominantly in persons with emotional disorders, more often in women than men

o Barrett's esophagus Incidence is increasing across

all populations. More common in men,

particularly white men The prevalence increases with

age. o Eosinophilic esophagitis

More common in children and in males

Risk Factors Infectious esophagitis

o Immunocompromise Esophageal webs

o Iron-deficiency anemia Mallory-Weiss tear

o Severe nausea and vomiting Barrett's esophagus and esophageal cancer

o Persistent GERD leading to injury to the esophagus

o In patients with Barrett's, risk of esophageal cancer is increased ~30 times over that of unaffected patients.

Pill esophagitis o Sudden, usually midesophageal, pain

due to medication Drugs with highest risk include

bisphosphonates (e.g., alendronate), NSAIDs, and potassium

Etiology

Motor disorders Disorders of striated muscle

Oropharyngeal paralysis o Paralysis of oral muscles o When the suprahyoid muscles are

paralyzed, upper esophageal sphincter does not open with swallowing, leading to paralytic achalasia of the upper esophageal sphincter and severe dysphagia.

o Occurs in a variety of neuromuscular disorders

Cricopharyngeal bar o Failure of the cricopharyngeus to relax

on swallowing o If persistent, may be caused by fibrosis

in the cricopharyngeus Globus pharyngeus

o Sensation of a constant lump in the throat without difficulty in swallowing

o Both reflux and psychogenic factors are causative.

Disorders of smooth muscle Achalasia

o The lower esophageal sphincter (LES) does not relax normally with swallowing, and the esophageal body undergoes nonperistaltic contractions

Result is hypertonicity and failure of peristalsis

o Underlying abnormality is a loss of myenteric intramural neurons

Inhibitory neurons containing vasoactive intestinal peptide and nitric oxide synthase are predominantly involved.

Cholinergic neurons are also affected in advanced disease

o Primary idiopathic achalasia accounts for most cases in the U.S.

o Secondary achalasia may be caused by: Gastric carcinoma that infiltrates

the esophagus Lymphoma Chagas' disease Certain viral infections Eosinophilic gastroenteritis Neurodegenerative disorders

[21]

Diffuse esophageal spasm (nonperistaltic contractions)

o Caused by dysfunction of inhibitory nerves

o Histopathologic studies show patchy neural degeneration localized to nerve processes.

Unlike the prominent degeneration of nerve cell bodies seen in achalasia

o Diffuse esophageal spasm may progress to achalasia.

o Hypertensive peristaltic contractions and hypertensive or hypercontracting LES may represent cholinergic or myogenic hyperactivity.

Hypertensive motor disorders o Amplitude of esophageal contractions is

increased in: Nutcracker esophagus:

Esophageal contractions are normally peristaltic but hypertensive.

Hypercontracting LES: The normal sphincter relaxation is followed by hypertensive contractions.

o Hypertensive LES: Basal LES pressure is elevated, but sphincter relaxation and contraction are normal.

Scleroderma esophagus o Esophageal lesions in systemic

sclerosis consist of atrophy of smooth muscle.

o Manifested by weakness in the lower two-thirds of the esophageal body and incompetence of the LES

o The esophageal wall is thin and atrophic, and may exhibit areas of patchy fibrosis.

o See also Systemic Sclerosis (Scleroderma).

DIAGNOSIS

Symptoms & Signs General symptoms of esophageal disease

Different types of pain can exist together in the same patient.

~50% of patients with unexplained chest pain will have GERD and respond to therapy.

Frequently, patients cannot describe the pain accurately enough to allow simple classification.

Dysphagia (difficulty swallowing) Heartburn

o Burning retrosternal discomfort that may move up and down the chest like a wave

o When severe, may radiate to the sides of the chest, neck, and angles of the jaw

o May be associated with regurgitation of gastric contents and/or a feeling of warm fluid climbing up the throat

o Aggravated by bending forward, straining, or lying recumbent

o Worse after meals o Relieved by upright posture; swallowing

saliva or water; more reliably, by antacids and other antireflux measures

o The most characteristic symptom of reflux esophagitis

Odynophagia (painful swallowing)

o The most characteristic symptoms of nonreflux esophagitis, particularly monilial and herpes esophagitis

o May also occur with: Peptic ulcer of the esophagus

(Barrett's ulcer) Carcinoma with periesophageal

involvement Caustic damage of the

esophagus Esophageal perforation

Atypical chest pain (other than heartburn and odynophagia)

o Also termed noncardiac chest pain o Occurs in reflux esophagitis and

esophageal motility disorders (e.g., diffuse esophageal spasm)

o Spasm may occur spontaneously or during a meal

o Chest pain due to periesophageal involvement with carcinoma or peptic ulcer may be constant and agonizing

Regurgitation o Effortless appearance of gastric or

esophageal contents in the mouth o In distal esophageal obstruction or

stasis (achalasia or a large diverticulum), regurgitated material consists of tasteless mucoid fluid or undigested food.

o In severe gastroesophageal reflux, regurgitation is sour or bitter-tasting.

Symptoms and signs of specific disorders Achalasia

Dysphagia, chest pain, and regurgitation o Appears early o Occurs with both liquids and solids o Is worsened by emotional stress and

hurried eating Various maneuvers designed to increase

intraesophageal pressure, including the Valsalva maneuver, may aid passage of food into the stomach.

Regurgitation and pulmonary aspiration occur because of esophageal retention of large volumes of saliva and ingested food.

Patients may have difficulty belching. Achalasia associated with carcinoma is

characterized by severe weight loss.

Diffuse spasm and related motor disorders Hypertensive peristaltic contraction,

hypertensive LES, and hypercontracting LES o Chest pain or dysphagia, or both o Chest pain is particularly marked in

patients with esophageal contractions of large amplitude and long duration.

o Chest pain usually occurs at rest but may be brought on by swallowing or by emotional stress.

Retrosternal and may radiate to the back, sides of the chest, both arms, or sides of the jaw

May last from a few seconds to several minutes

o Pain may be acute and severe, mimicking pain of myocardial ischemia.

o Dysphagia for solids and liquids may occur with or without chest pain and is correlated with

[22]

Esophageal Cancer Malignant tumor of the esophagus Relatively uncommon but extremely lethal 2 histologic types

o Adenocarcinoma (>60%) o Squamous cell

Epidemiology Incidence/prevalence

o Worldwide incidence varies strikingly. Highest incidence: China, Iran,

Afghanistan, Siberia, Mongolia High-incidence "pockets"

present in disparate locations: Finland, Iceland, Curaao, southeastern Africa, and northwestern France

o U.S. Annual cases diagnosed (2007):

15,560 Deaths (2007): 7550 Incidence: 3.2 per 100,000

persons Trends by cancer type over the

past 25 years Squamous cell:

decreased somewhat in both black and white persons

Adenocarcinoma: increased dramatically, particularly in white men (male-to-female ratio, 6:1)

Race o In North America and western Europe:

more common in black persons than in white persons

Sex o In North America and western Europe:

more common in men than in women Age

o Most often in person > age 50 years

Risk Factors Squamous-cell carcinoma

o Excess alcohol consumption Relative risk increases with the

amount of alcohol consumed. Whiskey is linked to a higher

incidence than is wine or beer. o Cigarette smoking

Relative risk increases with amount of tobacco smoked.

o Excess alcohol and cigarette smoking act synergistically.

o Other ingested carcinogens Nitrates (converted to nitrites) Smoked opiates Fungal toxins in pickled

vegetables o Mucosal damage from physical agents

Long-term exposure to extremely hot tea

Lye ingestion Radiation-induced strictures Chronic achalasia

o Host susceptibility Plummer-Vinson or Paterson-

Kelly syndrome Esophageal web in

association with

glossitis and iron deficiency

Congenital hyperkeratosis and pitting of palms and soles (tylosis palmaris et plantaris)

History of head and neck cancers

o Dietary deficiencies (possible risk factor) Molybdenum Zinc Vitamin A Selenium

o Celiac sprue (possible risk factor) o Lower socioeconomic status

Adenocarcinoma o Chronic gastric reflux o Gastric metaplasia of epithelium

(Barrett's esophagus) o Conditions that increase esophageal

exposure to gastric acid Acid hypersecretory states (e.g.,

Zollinger-Ellison syndrome) Surgical interventions that alter

gastroesophageal sphincter (e.g., balloon dilation, myotomy)

Etiology Squamous-cell carcinoma

o Etiology: unknown o Theoretical

Repeated exposure of the esophageal mucosa to toxic and noxious stimuli (e.g., alcohol, cigarette smoke) result in the following sequence of events.

Dysplasia Carcinoma in situ Carcinoma

Adenocarcinomas o Etiology: not completely understood o Arise within dysplastic columnar

epithelium in distal esophagus o Aneuploidy and p53 mutations are found

in dysplastic epithelium even before frank neoplasia

o Behave clinically like gastric adenocarcinomas

DIAGNOSIS Symptoms & Signs

Location in the esophagus o ~10% occur in the upper third of the

esophagus (cervical esophagus). o 35% in middle third o 55% in lower third

Squamous-cell cancers tend to occur in the middle- and upper third of the esophagus

Adenocarcinoma tends to occur in the lower third of the esophagus

Initial symptoms in most patients o Weight loss of short duration o Progressive dysphagia

Initially occurs with solid foods Gradually progresses to include

semisolids and liquids Symptom does not occur until >

60% of esophageal circumference is infiltrated with cancer.

Dysphagia may be associated with: o Pain on swallowing (odynophagia) o Pain radiating to chest and/or back

[23]

o Regurgitation