- Email: [email protected]
Getting to the GIST of it …
Vol. 96, No. 3, 2001 ISSN 0002-9270/01/$20.00
WHAT’S NEW IN GI EDITOR
Jon S. Thompson, M.D., F.A.C.S. GASTROENTEROLOGY
Randall E. Brand Rene´e L. Young John K. DiBaise Hemant K. Roy Timothy M. McCashland RADIOLOGY
Splenic Index: Esophageal Varices, Cirrhosis, and Hepatic Functional Reserve Watanabe S, Hosomi N, Kitade Y, et al. Assessment of the presence and severity of esophagogastric varices by splenic index in patients with liver cirrhosis. J Comput Assist Tomogr 2000;24:788 –94.
Aurelio Matamoros, Jr.
PATHOLOGY
James L. Wisecarver
LIVER STUDY UNIT
Carol A. Casey PEDIATRIC GASTROENTEROLOGY
David R. Mack University of Nebraska Medical Center Omaha, Nebraska
Bleeding from esophageal varices with its high mortality rate is a known complication in patients with cirrhosis. The clinical course in these cirrhotic patients shows progressive splenomegaly. The purpose of this retrospective study by Watanabe et al. was to determine if splenic size in cirrhotic patients correlated with the severity of esophageal varices, gastric varices, and liver functions. Splenic size was determined by using computed tomography images showing the largest size of the spleen and calculating the splenic index (SI). SI ⫽ length ⫻ width ⫻ height of the spleen. Esophageal varices were evaluated with upper esophagogastroduodenoscopy. The study group consisted of 110 patients with various causes of cirrhosis, and the control group consisted of 112 patients. There was no significant difference in the SI in patients with and without gastric varices. In patients with uncompensated cirrhosis, the SI was greater than that in patients with well-compensated cirrhosis. Patients with esophageal varices showed a greater SI than those without esophageal varices. Patients showing red color signs on esophageal varices or risky varices had a greater SI than those patients not showing these signs. The study shows a good correlation between the presence of esophageal
varices, especially risky esophageal varices, in patients with cirrhosis and the SI. Esophageal varices were present in all patients with an SI ⬎ 963 cm3. In patients with cirrhosis, a high SI calculated on a noninvasive computed tomography scan may predict esophageal bleeding. A. Matamoros, Jr., M.D.
Getting to the GIST of It . . . Miettinen M, Sobin L, Sarlomo-Rikala M. Immunohistochemical spectrum of GIST’s at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol 2000;13: 1134 – 42. Wang L, Vargas H, French S. Cellular origin of gastrointestinal stromal tumors: A study of 27 cases. Arch Pathol Lab Med 2000;124:1471–5. Over the past few years, it has become clear that a gastrointestinal stromal tumor (GIST), a mesenchymal-derived tumor arising in the GI tract has a cellular phenotype similar to the interstitial cell of Cajal (ICC), the socalled GI pacemaker cell. These tumors express the c-kit proto-oncogene (CD117) encoding a tyrosine kinase receptor. Previously, these tumors were classified as smooth muscle tumors (leiomyosarcoma, leiomyoblastoma), although they rarely express a typical smooth muscle cell immunophenotype. A subset of CD117-positive GIST lesions have also been shown to co-express a stem cell marker (CD34). However, this relationship has not been fully explored. The two studies cited above add further insight into this relationship. In the first paper by Miettinen et al., the authors studied a series of
WHAT’S NEW IN GI
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
AJG – March, 2001
292, CD117-positive tumors for co-expression of several cell markers including CD34 and a smooth muscle marker (SMA). They found that GIST lesions arising in the esophagus and rectum were more likely to co-express the stem cell marker CD34 than those arising in the small bowel. The reverse relationship was found for SMA. True leiomyomas were uniformly negative for the CD117, CD34 ICC phenotype, and positive for SMA and desmin. The second paper by Wang et al. set out to test the hypothesis that a GIST is derived from a CD34-positive stem cell that differentiates into an ICC phenotype. In this study, they examined 27 GIST cases and found that all expressed CD117 with a subset co-expressing CD34. Interestingly, all eight tumors in the benign category failed to express CD34, whereas in the malignant group, 14 of 19 (74%) co-expressed CD34. Based upon this finding, the authors suggest that a GIST co-expressing both markers is composed of less well-differentiated ICC. In the discussion section, the authors speculate as to the possible cause of this co-expression in the malignant lesions caused by “gain-offunction” mutations of the c-kit gene. This study was carried out using a relatively small number of tumors, and many more cases will need to be studied to determine if this phenotypic relationship is a reliable predictor of biological behavior. These studies provide new information to further our understanding concerning this interesting group of neoplasms. If this phenotypic relationship between CD34 and CD117 proves accurate, it might ultimately provide a tool to gain important prognostic information. J. L. Wisecarver, M.D., Ph.D.
What’s New in GI
Slime production by biliary bacteria is more important than beta-glucuronidase production. J Gastrointest Surg 2000;4:547–53. Pigment gallstones are thought to be produced by deconjugation of bilirubin by -glucuronidase leading to precipitation of calcium bilirubinate. Three-fourths of pigment stones have microcolonies of bacteria present. Biliary bacteria produce -glucuronidase. Bacteria also produce slime, or glycocalyx, an anionic glycoprotein causing foreign body infections. Slime has been implicated in the formation of the precipitate that blocks biliary stents. Thus, anionic glycoproteins may also play a role in the formation of microscopic stones from calcium bilirubinate crystals. Stewart et al. sought to determine the role of slime production in the formation of pigment gallstones. Bacterial cultures were obtained from extracted gallstones in 61 patients with biliary stones, and stool cultures were obtained from 12 controls. Bacterial production of slime and -glucuronidase were quantitated. They confirmed that 73% of biliary bacteria produce slime compared to 8% of stool bacteria and at a 20-fold greater quantity. However, only 38% of biliary bacteria produced -glucuronidase. Furthermore, slime was almost uniformly present in common bile duct stones and stent-associated stones, but -glucuronidase was present in only 47% of these patients. Thus, slime production correlated better with stone formation than -glucuronidase activity. These findings suggest that slime formation plays a more essential role than -glucuronidase in the formation of biliary sludge and pigment stones. J. S. Thompson, M.D., F.A.C.S.
Slime and Pigment Gallstones
The Future of Colorectal Screening Is in the Stool
Stewart L, Ponce R, Oesterle AL, et al. Pigment gallstone pathogenesis:
Ahlquist DA, Skoletsky JE, Boynton KA, et al. Colorectal cancer screen-
645
ing by detection of altered human DNA in stool: Feasibility of a multitarget assay panel. Gastroenterology 2000;119:1219 –27. Current techniques for colorectal cancer screening are suboptimal because of invasiveness and patient/provider reluctance or disdain. Stool analyses with fecal occult blood tests have demonstrated a decrease in mortality and cancer incidence, although the low positive predictive value remains problematic. Ahlquist et al. applied our growing knowledge of the molecular genetic of colon cancer by studying the feasibility of using an altered DNA assay panel on stool specimens to detect colorectal cancer. Human DNA isolated from stool samples obtained at least 2 wk before colonoscopy were examined in a blinded manner for different assay targets in 22 patients with colorectal cancer, 11 with adenomas ⱖ1 cm, and 28 with normal endoscopies. Assay targets included K-ras, p53, APC, BAT-26, and “highly-amplifiable or long” DNA. Long DNA is believed to differentiate cells shed from tumors versus normal GI epithelial turnover. The latter occurs through apoptosis and therefore has DNA degraded into small fragments. The authors found a sensitivity of 91% (95% CI 71–99%) for cancer and 82% (95% CI 48 –98%) with a specificity of 93% (95% CI 76 –99%), when a full panel of assay targets was used. Excluding K-ras from their panel led to an increased specificity of 100% (95% CI 88 –100%) with no change in sensitivity and a minimal decrease in sensitivity for adenomas to 73% (95% CI 35–94%). The long DNA assay had the highest sensitivity of any of the assay panel and detected 61% of the neoplasms. This study demonstrates the potential use of molecular biology in the detection of colorectal cancer. As pointed out by the authors, larger clinical trials and simplification of the assay techniques are needed before
WHAT’S NEW IN GI EDITOR
Jon S. Thompson, M.D., F.A.C.S. GASTROENTEROLOGY
Randall E. Brand Rene´e L. Young John K. DiBaise Hemant K. Roy Timothy M. McCashland RADIOLOGY
Splenic Index: Esophageal Varices, Cirrhosis, and Hepatic Functional Reserve Watanabe S, Hosomi N, Kitade Y, et al. Assessment of the presence and severity of esophagogastric varices by splenic index in patients with liver cirrhosis. J Comput Assist Tomogr 2000;24:788 –94.
Aurelio Matamoros, Jr.
PATHOLOGY
James L. Wisecarver
LIVER STUDY UNIT
Carol A. Casey PEDIATRIC GASTROENTEROLOGY
David R. Mack University of Nebraska Medical Center Omaha, Nebraska
Bleeding from esophageal varices with its high mortality rate is a known complication in patients with cirrhosis. The clinical course in these cirrhotic patients shows progressive splenomegaly. The purpose of this retrospective study by Watanabe et al. was to determine if splenic size in cirrhotic patients correlated with the severity of esophageal varices, gastric varices, and liver functions. Splenic size was determined by using computed tomography images showing the largest size of the spleen and calculating the splenic index (SI). SI ⫽ length ⫻ width ⫻ height of the spleen. Esophageal varices were evaluated with upper esophagogastroduodenoscopy. The study group consisted of 110 patients with various causes of cirrhosis, and the control group consisted of 112 patients. There was no significant difference in the SI in patients with and without gastric varices. In patients with uncompensated cirrhosis, the SI was greater than that in patients with well-compensated cirrhosis. Patients with esophageal varices showed a greater SI than those without esophageal varices. Patients showing red color signs on esophageal varices or risky varices had a greater SI than those patients not showing these signs. The study shows a good correlation between the presence of esophageal
varices, especially risky esophageal varices, in patients with cirrhosis and the SI. Esophageal varices were present in all patients with an SI ⬎ 963 cm3. In patients with cirrhosis, a high SI calculated on a noninvasive computed tomography scan may predict esophageal bleeding. A. Matamoros, Jr., M.D.
Getting to the GIST of It . . . Miettinen M, Sobin L, Sarlomo-Rikala M. Immunohistochemical spectrum of GIST’s at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol 2000;13: 1134 – 42. Wang L, Vargas H, French S. Cellular origin of gastrointestinal stromal tumors: A study of 27 cases. Arch Pathol Lab Med 2000;124:1471–5. Over the past few years, it has become clear that a gastrointestinal stromal tumor (GIST), a mesenchymal-derived tumor arising in the GI tract has a cellular phenotype similar to the interstitial cell of Cajal (ICC), the socalled GI pacemaker cell. These tumors express the c-kit proto-oncogene (CD117) encoding a tyrosine kinase receptor. Previously, these tumors were classified as smooth muscle tumors (leiomyosarcoma, leiomyoblastoma), although they rarely express a typical smooth muscle cell immunophenotype. A subset of CD117-positive GIST lesions have also been shown to co-express a stem cell marker (CD34). However, this relationship has not been fully explored. The two studies cited above add further insight into this relationship. In the first paper by Miettinen et al., the authors studied a series of
WHAT’S NEW IN GI
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
AJG – March, 2001
292, CD117-positive tumors for co-expression of several cell markers including CD34 and a smooth muscle marker (SMA). They found that GIST lesions arising in the esophagus and rectum were more likely to co-express the stem cell marker CD34 than those arising in the small bowel. The reverse relationship was found for SMA. True leiomyomas were uniformly negative for the CD117, CD34 ICC phenotype, and positive for SMA and desmin. The second paper by Wang et al. set out to test the hypothesis that a GIST is derived from a CD34-positive stem cell that differentiates into an ICC phenotype. In this study, they examined 27 GIST cases and found that all expressed CD117 with a subset co-expressing CD34. Interestingly, all eight tumors in the benign category failed to express CD34, whereas in the malignant group, 14 of 19 (74%) co-expressed CD34. Based upon this finding, the authors suggest that a GIST co-expressing both markers is composed of less well-differentiated ICC. In the discussion section, the authors speculate as to the possible cause of this co-expression in the malignant lesions caused by “gain-offunction” mutations of the c-kit gene. This study was carried out using a relatively small number of tumors, and many more cases will need to be studied to determine if this phenotypic relationship is a reliable predictor of biological behavior. These studies provide new information to further our understanding concerning this interesting group of neoplasms. If this phenotypic relationship between CD34 and CD117 proves accurate, it might ultimately provide a tool to gain important prognostic information. J. L. Wisecarver, M.D., Ph.D.
What’s New in GI
Slime production by biliary bacteria is more important than beta-glucuronidase production. J Gastrointest Surg 2000;4:547–53. Pigment gallstones are thought to be produced by deconjugation of bilirubin by -glucuronidase leading to precipitation of calcium bilirubinate. Three-fourths of pigment stones have microcolonies of bacteria present. Biliary bacteria produce -glucuronidase. Bacteria also produce slime, or glycocalyx, an anionic glycoprotein causing foreign body infections. Slime has been implicated in the formation of the precipitate that blocks biliary stents. Thus, anionic glycoproteins may also play a role in the formation of microscopic stones from calcium bilirubinate crystals. Stewart et al. sought to determine the role of slime production in the formation of pigment gallstones. Bacterial cultures were obtained from extracted gallstones in 61 patients with biliary stones, and stool cultures were obtained from 12 controls. Bacterial production of slime and -glucuronidase were quantitated. They confirmed that 73% of biliary bacteria produce slime compared to 8% of stool bacteria and at a 20-fold greater quantity. However, only 38% of biliary bacteria produced -glucuronidase. Furthermore, slime was almost uniformly present in common bile duct stones and stent-associated stones, but -glucuronidase was present in only 47% of these patients. Thus, slime production correlated better with stone formation than -glucuronidase activity. These findings suggest that slime formation plays a more essential role than -glucuronidase in the formation of biliary sludge and pigment stones. J. S. Thompson, M.D., F.A.C.S.
Slime and Pigment Gallstones
The Future of Colorectal Screening Is in the Stool
Stewart L, Ponce R, Oesterle AL, et al. Pigment gallstone pathogenesis:
Ahlquist DA, Skoletsky JE, Boynton KA, et al. Colorectal cancer screen-
645
ing by detection of altered human DNA in stool: Feasibility of a multitarget assay panel. Gastroenterology 2000;119:1219 –27. Current techniques for colorectal cancer screening are suboptimal because of invasiveness and patient/provider reluctance or disdain. Stool analyses with fecal occult blood tests have demonstrated a decrease in mortality and cancer incidence, although the low positive predictive value remains problematic. Ahlquist et al. applied our growing knowledge of the molecular genetic of colon cancer by studying the feasibility of using an altered DNA assay panel on stool specimens to detect colorectal cancer. Human DNA isolated from stool samples obtained at least 2 wk before colonoscopy were examined in a blinded manner for different assay targets in 22 patients with colorectal cancer, 11 with adenomas ⱖ1 cm, and 28 with normal endoscopies. Assay targets included K-ras, p53, APC, BAT-26, and “highly-amplifiable or long” DNA. Long DNA is believed to differentiate cells shed from tumors versus normal GI epithelial turnover. The latter occurs through apoptosis and therefore has DNA degraded into small fragments. The authors found a sensitivity of 91% (95% CI 71–99%) for cancer and 82% (95% CI 48 –98%) with a specificity of 93% (95% CI 76 –99%), when a full panel of assay targets was used. Excluding K-ras from their panel led to an increased specificity of 100% (95% CI 88 –100%) with no change in sensitivity and a minimal decrease in sensitivity for adenomas to 73% (95% CI 35–94%). The long DNA assay had the highest sensitivity of any of the assay panel and detected 61% of the neoplasms. This study demonstrates the potential use of molecular biology in the detection of colorectal cancer. As pointed out by the authors, larger clinical trials and simplification of the assay techniques are needed before