Diagnosis of Gastric Cancer

Prof. Ahmed M BadheebProf. Ahmed M Badheeb

Epidemiology of gastric cancer GC remains one of the most common forms of GC remains one of the most common forms of

cancer worldwidecancer worldwide

~ 9.9% of new cancers~ 9.9% of new cancers

~ 870,000 new cases and 650,000 deaths/ yr~ 870,000 new cases and 650,000 deaths/ yr ~ 21,860 pts were diagnosed in 2006 in the US of ~ 21,860 pts were diagnosed in 2006 in the US of

whom 11,430 are expected to die.whom 11,430 are expected to die. Ferlay, Gobocan 2000: Lyon, IARCPress. Ferlay, Gobocan 2000: Lyon, IARCPress.

Atrophic gastritisAtrophic gastritis

Risk of developing GC during 4.4 yrs of follow-up Risk of developing GC during 4.4 yrs of follow-up period was increased 5.7-foldperiod was increased 5.7-fold

Correa, P. Cancer 1982; 50:2554Correa, P. Cancer 1982; 50:2554 Hypochlorhydria microbial colonization, some Hypochlorhydria microbial colonization, some

of which possess nitrate reductase, allowing of which possess nitrate reductase, allowing nitrosation that is genotoxic.nitrosation that is genotoxic.

Loss of endocrine cells, which normally secrete Loss of endocrine cells, which normally secrete EGF and TGF, thereby aiding the stomach in EGF and TGF, thereby aiding the stomach in regenerating damaged tissue. regenerating damaged tissue.

Risk factorsPrecursor lesions

Intestinal metaplasia/ dysplasia

H. pylori, bile reflux, induced experimentally by H. pylori, bile reflux, induced experimentally by irradiationirradiation

More frequent in countries with high incidence of GC More frequent in countries with high incidence of GC

Most pts with HG dysplasia already have or soon Most pts with HG dysplasia already have or soon develop GCdevelop GC

In gastrectomy specimens for GC, 20-40 % of pts had In gastrectomy specimens for GC, 20-40 % of pts had

dysplasia and GC developed at 21% for mild, and dysplasia and GC developed at 21% for mild, and 57% for severe dysplasia57% for severe dysplasia

Shimoyama, Virchows Arch 2000; 436:585. Shimoyama, Virchows Arch 2000; 436:585.

Environmental factorsDiet

Nitrates nitroso compounds.Nitrates nitroso compounds.

Diets low in vegetables, fruits, milk, and vit A and Diets low in vegetables, fruits, milk, and vit A and high in fried food, processed meat, and fish.high in fried food, processed meat, and fish.

Vitamin C reduce the formation of carcinogenic n-Vitamin C reduce the formation of carcinogenic n-nitroso compounds inside the stomach.nitroso compounds inside the stomach.

High salt intake damages stomach mucosa and High salt intake damages stomach mucosa and increases the susceptibility to carcinogenesis in increases the susceptibility to carcinogenesis in rodents.rodents.

Smoking Smoking The risk was increased by 1.5 to 1.60-foldThe risk was increased by 1.5 to 1.60-fold Alcohol Alcohol Not been demonstrated Not been demonstrated Socioeconomic statusSocioeconomic status 2-fold increase in populations with low socioeconomic status2-fold increase in populations with low socioeconomic status Gastric surgeryGastric surgery Relative risk in the range of 1.5 to 3.0,Relative risk in the range of 1.5 to 3.0, Helicobacter pyloriHelicobacter pylori 6-fold increase in the risk of GC6-fold increase in the risk of GC

Host-related factors Blood group A.Blood group A. 20% excess of GC than those of group O, B, or AB.20% excess of GC than those of group O, B, or AB.

Familial predisposition.Familial predisposition. GC has been described in association with certain GC has been described in association with certain

cancer syndromes (HNPCRC, FAP, Peutz Jeghers).cancer syndromes (HNPCRC, FAP, Peutz Jeghers).

There are reports of at least 45 families worldwide There are reports of at least 45 families worldwide with with hereditary diffuse gastric cancerhereditary diffuse gastric cancer due to germline due to germline mutations of the e-cadherin gene CDH1.mutations of the e-cadherin gene CDH1.

Blair, Clin Gastroenterol Hepatol 2006; 4:262.Blair, Clin Gastroenterol Hepatol 2006; 4:262.

Model of gastric carcinogenesis

Adapted from Elder, JB. Carcinoma of the stomach. Gastroenterology, 5th ed, WB Saunders, Philadelphia, 1995, p. 862.

Clinical Features Most GCs are diagnosed in symptomatic pts Most GCs are diagnosed in symptomatic pts

presenting with advanced incurable disease. presenting with advanced incurable disease.

Surgically curable lesions are usually asymptomatic, Surgically curable lesions are usually asymptomatic, and rarely detected outside a screening program.and rarely detected outside a screening program.

Weight loss and persistent abdominal pain are the Weight loss and persistent abdominal pain are the most common symptoms at initial diagnosis.most common symptoms at initial diagnosis.

Ann Surg 1993; 218:583.Ann Surg 1993; 218:583.

Presenting symptoms in 18,363 pts

Adapted from Wanebo, HJ, Kennedy, BJ, Chmiel, J, et al, Ann Adapted from Wanebo, HJ, Kennedy, BJ, Chmiel, J, et al, Ann Surg 1993; 218:583. Surg 1993; 218:583.

SymptomSymptom PercentPercent Wt lossWt loss 6262

Abdominal painAbdominal pain 5252NauseaNausea 3434

DysphagiaDysphagia 2626MelenaMelena 2020

Early satietyEarly satiety 1818Ulcer type painUlcer type pain1717

~ 25% of pts have a history of GU.~ 25% of pts have a history of GU.

Pseudoachalasia syndrome may occur as the Pseudoachalasia syndrome may occur as the result of involvement of Auerbach's plexus.result of involvement of Auerbach's plexus.

Kahrilas, am J med 1987; 82:439Kahrilas, am J med 1987; 82:439.. Feculent emesis or passage of recently Feculent emesis or passage of recently

ingested material in the stool.ingested material in the stool.

Occult GI bleeding with or without ID anemiaOccult GI bleeding with or without ID anemia..

Signs of tumor extension

Palpable abdominal massPalpable abdominal mass Periumbilical nodule (sister Mary Joseph's node) or lt Periumbilical nodule (sister Mary Joseph's node) or lt

supraclavicular LN (Virchow's node).supraclavicular LN (Virchow's node). Morgenstern, am J Surg 1979; 138:703Morgenstern, am J Surg 1979; 138:703 Peritoneal spread Peritoneal spread Krukenberg's tumorKrukenberg's tumor Blumer's shelf (mass in the cul-de-sac on PR) Blumer's shelf (mass in the cul-de-sac on PR) Gilliland,. Br J Surg 1992; 79:1364.Gilliland,. Br J Surg 1992; 79:1364.

Ascites can be a manifestation of peritoneal Ascites can be a manifestation of peritoneal carcinomatosis,carcinomatosis,

Palpable liver mass can indicate metastases.Palpable liver mass can indicate metastases.

Jaundice or clinical evidence of liver failure is Jaundice or clinical evidence of liver failure is seen in the preterminal stages of metastatic seen in the preterminal stages of metastatic disease. disease.

Fuchs, N Engl J Med 1995; 333:32.Fuchs, N Engl J Med 1995; 333:32.

Paraneoplastic manifestations Rarely seen at initial presentation.Rarely seen at initial presentation. Dermatological findings:Dermatological findings: Sign of Leser-Trelat.Sign of Leser-Trelat. Sudden appearance of diffuse seborrheic keratoses.Sudden appearance of diffuse seborrheic keratoses. Acanthosis nigricans.Acanthosis nigricans. Velvety and darkly pigmented patches of skin folds.Velvety and darkly pigmented patches of skin folds. Neither finding is specific for gastric cancer.Neither finding is specific for gastric cancer. Dantzig, arch Dermatol 1973; 108:700.Dantzig, arch Dermatol 1973; 108:700.

Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia

Membranous nephropathyMembranous nephropathy

Hypercoagulable states (Trouseau's Hypercoagulable states (Trouseau's syndrome)syndrome)

Polyarteritis nodosaPolyarteritis nodosa Poveda, J Intern Med 1994; 236:679.Poveda, J Intern Med 1994; 236:679.

DIAGNOSIS Initial diagnosisInitial diagnosis Upper endoscopyUpper endoscopy Barium studiesBarium studies

StagingStaging CT scanCT scan EUSEUS Laparoscopy Laparoscopy

Upper GI endoscopy The mainstay for diagnosis of GC.The mainstay for diagnosis of GC.

The sensitivity and specificity is > 90%.The sensitivity and specificity is > 90%.

More sensitive and specific than alternatives.More sensitive and specific than alternatives.

The ability to perform Bx during endoscopy The ability to perform Bx during endoscopy adds to its clinical utility.adds to its clinical utility.

Graham, Gastroenterology 1982; 82:228.Graham, Gastroenterology 1982; 82:228.

Malignant and benign gastric ulcer Malignant GU of the cardia.

• absence of folds radiating to the base

•exophytic appearance.Benign GU in

the prepyloric region. •well- circumscribed

•folds radiating to the ulcer base.

Endoscopic appearances of gastric cancer

Adenocarcinoma in the antrum

(friable, ulcerated, and circumferential mass)

Adenocarcinoma of the cardia.

(large, lobulated,ulcerated mass)

Since up to 5 % of malignant ulcers may Since up to 5 % of malignant ulcers may appear benign grossly, it is imperative that all appear benign grossly, it is imperative that all such lesions be evaluated histologicallysuch lesions be evaluated histologically

These data provide a strong rationale for These data provide a strong rationale for

upper endoscopy as the initial diagnostic test upper endoscopy as the initial diagnostic test for pts in whom gastric cancer is suspected. for pts in whom gastric cancer is suspected.

Karita, Gastrointest Endosc 1994; 40:749.Karita, Gastrointest Endosc 1994; 40:749.

Endoscopic techniques A single Bx has a 70 % sensitivity for A single Bx has a 70 % sensitivity for

diagnosing GCdiagnosing GC

Performing 7 biopsies from the ulcer margin Performing 7 biopsies from the ulcer margin and base increases the sensitivity to > 98 %. and base increases the sensitivity to > 98 %.

Its important to take numerous Bx from Its important to take numerous Bx from smaller, benign-appearing GUsmaller, benign-appearing GU

Diffuse-type GC, so called "linitis plastica," can be Diffuse-type GC, so called "linitis plastica," can be especially difficult.especially difficult.

Stiff, "leather-flask" appearing stomach on barium Stiff, "leather-flask" appearing stomach on barium meal may be associated with a normal endoscopy.meal may be associated with a normal endoscopy.

These tumors tend to infiltrate the submucosa, so These tumors tend to infiltrate the submucosa, so superficial mucosal biopsies may be falsely negative.superficial mucosal biopsies may be falsely negative.

The combination of strip and bite Bx techniques.The combination of strip and bite Bx techniques.

Linitis plastica of the stomach

Fixed narrowing of the entire proximal stomach (arrows) due to submucosal invasion by a GC.

Brush cytologyBrush cytology

Increases the sensitivity of single biopsies, but the Increases the sensitivity of single biopsies, but the extent to which it enhances diagnostic yield when 7 extent to which it enhances diagnostic yield when 7 biopsies are obtained remains unknownbiopsies are obtained remains unknown

If bleeding with Bx is of concern, it is reasonable to If bleeding with Bx is of concern, it is reasonable to brush the ulcer base, since the risk of bleeding from brush the ulcer base, since the risk of bleeding from this technique is negligiblethis technique is negligible

Wang, Acta Cytol 1991; 35:195Wang, Acta Cytol 1991; 35:195

Follow up endoscopy for GU Follow-up endoscopy remains controversial.Follow-up endoscopy remains controversial.

Most of the literature supporting the need for Most of the literature supporting the need for follow-up of GU is based on older surgical follow-up of GU is based on older surgical and radiologic, rather than endoscopic data.and radiologic, rather than endoscopic data.

More recent studies have called into question More recent studies have called into question the common practice of repeating endoscopy.the common practice of repeating endoscopy.

The issue of whether it is cost-effective to The issue of whether it is cost-effective to routinely perform repeat endoscopy for all routinely perform repeat endoscopy for all gastric ulcers needs to be determined.gastric ulcers needs to be determined.

The American Society of GI Endoscopy The American Society of GI Endoscopy recommends follow-up endoscopy 8 to 12 recommends follow-up endoscopy 8 to 12 weeks after initial endoscopy and initiation of weeks after initial endoscopy and initiation of therapy to verify healing, with repeat biopsies therapy to verify healing, with repeat biopsies performed on remaining ulcers.performed on remaining ulcers.

Gastrointest Endosc 1988; 34:21SGastrointest Endosc 1988; 34:21S..

Serologic markers No serologic markers have been proven to be useful.No serologic markers have been proven to be useful.

Increases in serum pepsinogen II.Increases in serum pepsinogen II. Decreases in the pepsinogen I: pepsinogen II ratio.Decreases in the pepsinogen I: pepsinogen II ratio.

Has been used in screening programs to identify pts Has been used in screening programs to identify pts at increased risk for GC but are insufficiently at increased risk for GC but are insufficiently sensitive or specific for establishing a diagnosis.sensitive or specific for establishing a diagnosis.

Harie,. Cancer 1996; 77:991.Harie,. Cancer 1996; 77:991.

Barium studies Can identify both malignant GUs and infiltrating lesionsCan identify both malignant GUs and infiltrating lesions Some early gastric cancers also may be seenSome early gastric cancers also may be seen However, false negative barium studies can occur in However, false negative barium studies can occur in

as many as 50 % of casesas many as 50 % of cases This is a particular problem in early GC in which the This is a particular problem in early GC in which the

sensitivity of barium meals may be as low as 14 %sensitivity of barium meals may be as low as 14 % Dooley, CP Ann intern med 1984; 101:538Dooley, CP Ann intern med 1984; 101:538

Early gastric cancer

superficial ulcer in the gastric antrum (arrow) with thickened folds radiating towards the ulcer.

Malignant and benign gastric ulcer

Malignant GU of the distal LC. biconvex meniscus sign with

a nodular ulcer mound

Benign GU of the LC ulcer crater has smooth margins and projects beyond gastric wall

Staging Accurate tumor staging appropriate Accurate tumor staging appropriate

treatment.treatment.

TNM staging system of the AJCCTNM staging system of the AJCC

Methods:Methods: CT scan CT scan EUSEUS laparoscopylaparoscopy PET scanPET scan

American Joint Committee on Cancer (AJCC) TNM Staging Classification for GC

CT scan Recent data have shown the following results with CT Recent data have shown the following results with CT

scanning for staging of GC:scanning for staging of GC:

Accurate staging — 40 to 50 %Accurate staging — 40 to 50 % Understaging as the depth of invasion is Understaging as the depth of invasion is

underestimated — 10 to 35 % underestimated — 10 to 35 %

Overstaging as the depth of invasion is overestimated Overstaging as the depth of invasion is overestimated — 6 to 14 %— 6 to 14 %

Botet Radiology 1991; 181:419.Botet Radiology 1991; 181:419.

The accuracy of determining LN involvement The accuracy of determining LN involvement is no better, with overall accuracy rates is no better, with overall accuracy rates between 50-60%.between 50-60%.

CT is better for evaluating more widely CT is better for evaluating more widely metastatic disease, especially liver mets; metastatic disease, especially liver mets; however, the risk of false positive and false however, the risk of false positive and false negative results still exists.negative results still exists.

Sussman, Radiology 1988; 167:33Sussman, Radiology 1988; 167:33

Endoscopic ultrasonography Newer and more accurate means of preoperative Newer and more accurate means of preoperative

staging of GC.staging of GC.

Has low risk, although it is more invasive than CTHas low risk, although it is more invasive than CT

Risk of serious complications of 0.3 %, most of which Risk of serious complications of 0.3 %, most of which occurred in the setting of obstructing esophageal occurred in the setting of obstructing esophageal tumors.tumors.

Pollack, BJ, EUS. Semin Oncol 1996; 23:336.Pollack, BJ, EUS. Semin Oncol 1996; 23:336.

Pooled data for over 2000 pts who underwent EUS Pooled data for over 2000 pts who underwent EUS found an accuracy of 77% for staging the depth of found an accuracy of 77% for staging the depth of invasion and 69% for nodal stageinvasion and 69% for nodal stage

Most inaccuracies are due to understaging nodal Most inaccuracies are due to understaging nodal involvement and the depth of invasioninvolvement and the depth of invasion

Distinguishing T2 from T3 lesions is especially Distinguishing T2 from T3 lesions is especially difficult.difficult.

Although EUS has been shown to accurately Although EUS has been shown to accurately assess the presence of distant mets in one assess the presence of distant mets in one report, its field of vision is only 5 to 7 cm and report, its field of vision is only 5 to 7 cm and its utility for this purpose is still in question. its utility for this purpose is still in question.

EUS guided FNA of suspicious nodes and EUS guided FNA of suspicious nodes and regional areas is being evaluated, and may regional areas is being evaluated, and may further add to its accuracy further add to its accuracy

Chang, JJ,. Gastrointest Endosc 1994; 40:694Chang, JJ,. Gastrointest Endosc 1994; 40:694..

Laparoscopy Laparoscopy, while more invasive than CT or EUS, Laparoscopy, while more invasive than CT or EUS,

has the advantage of directly visualizing the liver has the advantage of directly visualizing the liver surface, the peritoneum, and local LNs. surface, the peritoneum, and local LNs.

It is a sensitive modality for diagnosing liver mets It is a sensitive modality for diagnosing liver mets and, in one review, it diagnosed peritoneal mets in and, in one review, it diagnosed peritoneal mets in 23% of pts in whom no such involvement was seen 23% of pts in whom no such involvement was seen by CT.by CT.

Conlon, KC, Semin Oncol 1996; 23:347.Conlon, KC, Semin Oncol 1996; 23:347.

Summary The ultimate choice of staging modalities is largely The ultimate choice of staging modalities is largely

dependent upon pt selection and local expertise.dependent upon pt selection and local expertise.

CT should be performed to look for M disease, it CT should be performed to look for M disease, it should not be relied upon for assessing T or N.should not be relied upon for assessing T or N.

Paracentesis should be performed when ascites is Paracentesis should be performed when ascites is detected.detected.

Liver lesions on CT should be biopsiedLiver lesions on CT should be biopsied

Laparoscopy should be considered in selected ptsLaparoscopy should be considered in selected pts

EUS is better than CT at assessing tumor depth and EUS is better than CT at assessing tumor depth and perhaps LN, particularly if FNA is performedperhaps LN, particularly if FNA is performed

Its use has been shown to alter therapy in ~ 1/3 of Its use has been shown to alter therapy in ~ 1/3 of ptspts

At present, the use of EUS depends largely upon At present, the use of EUS depends largely upon local availability and expertiselocal availability and expertise

Any pt with good PS ultimately requires laparotomy Any pt with good PS ultimately requires laparotomy

for curative or palliative surgery unless unresectability for curative or palliative surgery unless unresectability is clearly demonstrated.is clearly demonstrated.