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Pathology of epithelial tumours of the stomach
BASIC SCIENCE
Pathology of epithelial tumours of the stomach
occur in ‘developing’ countries. The highest incidences are in Eastern Asia, South America and Eastern Europe. It is extremely rare under the age of 30 years, but increases rapidly thereafter, with the highest rates in the oldest age groups in both males and females. The intestinal type is more common in males, while the diffuse type tends to affect younger age groups and is more common in females.
Gordon Reid Shaun V Walsh
Pathogenesis The changes in the stomach which precede the development of gastric adenocarcinoma often follow a stepwise progression. Chronic atrophic gastritis (often itself proceeded by Helicobacter pylori gastritis) with the development of intestinal metaplasia is often seen in the background mucosa of specimens resected for cancer. Metaplastic epithelium is unstable and can be prone to develop dysplasia or carcinoma in-situ, which are precursor lesions to adenocarcinoma. As well as H. pylori infection, diet (including high salt intake), smoking and bile reflux are factors important in the development of gastric adenocarcinoma. Approximately 10% of gastric adenocarcinomas have an inherited component, those patients with Lynch syndrome (HNPCC), FAP and PeutzeJeghers syndrome all have an increased risk. The hereditary gastric cancers have led to improved understanding of the genetic basis of sporadic gastric cancer. Mutations in CDH1 (associated with E-cadherin expression) are frequently seen in sporadic gastric cancers of the diffuse type (patients with BRAC2 mutations also linked to E-cadherin expression have an increased risk of these diffuse-type tumours). Sporadic intestinal type gastric carcinoma has been described in association with b-catenin mutations as well as microsatellite instability.
Abstract Most tumours of the stomach are epithelial in nature. Benign epithelial tumours come in the form of polyps: adenomas, hyperplastic and fundic gland polyps. Malignant epithelial tumours of the stomach are mostly adenocarcinomas. When poorly differentiated these may take the form of individual signet ring cells and have the distinctive clinical appearance of ‘linitis plastica’. Staging of gastric adenocarcinoma depends on extent of invasion into the gastric wall. Carcinoid tumours can also be seen in the stomach. By far the most common mesenchymal tumour of the stomach is the gastrointestinal stromal tumour or GIST. These are now easily recognized given the high proportion that mark immunohistochemically with KIT and DOG-1. These tumours can be managed surgically or with drugs which act specifically on the KIT protein. Lymphomas are also relatively common in the stomach, these are generally mucosa-associated lymphoid tissue (MALT) lymphomas and associated with Helicobactor pylori infection.
Keywords adenocarcinoma; GIST; Helicobacter pylori; MALToma
Benign epithelial tumours Unlike their counterpart in the large intestine, adenomas of the stomach are relatively uncommon entities. As in the colon however dysplasia is the characteristic feature and distinguishes them from the more common hyperplastic and fundic gland polyps of the stomach. Adenomas of the stomach are associated with a risk of progression to adenocarcinoma, which is not the case with the latter two mentioned polyps (although adenomatous change can be seen in large hyperplastic polyps). Adenomatous and hyperplastic polyps are often seen in conjunction with chronic gastritis and may be aetiologically associated. Polyps associated with polyposis syndromes commonly occur in the stomach. Both adenomas and fundic gland polyps are more common in patients with familial adenomatous polyposis (FAP). Distinctive polyps associated with PeutzeJeghers syndrome can also be seen in the stomach.
Pathology Gastric adenocarcinomas can be divided into four types based on their macroscopic appearance: polypoid, fungating, ulcerative (Figure 1) and diffuse. The diffuse type can give rise to the classical ‘linitis plastica’ appearance when extensive (Figure 2). Gastric adenocarcinomas are usually ‘gland forming’ microscopically, but when poorly differentiated can be solid or composed of discohesive single cells (signet ring cells). Gastric adenocarcinoma is classified either by the WHO or Lauren system. The simpler Lauren classification distinguishes between intestinal type carcinoma (polypoid, ulcerative or fungating) and diffuse (linitis plastica) types. Diffuse is automatically considered poorly differentiated and is associated with a worse prognosis whereas intestinal can be graded as either well, moderate of poorly differentiated. The WHO classification emphasizes microscopic features and describes four histological patterns; tubular, papillary, mucinous and signet ring. TNM staging in the stomach relates primarily to the depth of invasion through the stomach wall as well as the number of regional lymph nodes involved by the tumour. Pathological staging is the most powerful tool when it comes to predicting prognosis. The significance of tumour type (in isolation) is controversial. In the past the primary treatment of carcinomas involved an open surgical approach. However, with the advent of advanced endoscopic techniques, endoscopic mucosal resection of smaller lesions is now commonplace and following
Malignant epithelial tumours Epidemiology Although falling in incidence, gastric cancer is the second-most common cancer in the world; 60% of deaths from gastric cancer
Gordon Reid BMSc MB ChB is a Consultant Pathologist at Ninewells Hospital, Dundee, UK. Conflicts of interest: none declared. Shaun V Walsh MBBCh BAO FRCPath is a Consultant Pathologist at Ninewells Hospital, Dundee, UK. Conflicts of interest: none declared.
SURGERY 29:11
547
Ó 2011 Published by Elsevier Ltd.
BASIC SCIENCE
Figure 1 (a) En face view of an intestinal-type gastric carcinoma (fresh state) showing raised rolled edges (black arrow) and a central bleeding point (red arrow). (b) Same tumour as a sliced and viewed in transverse section (after fixation). The tumour invades through the muscularis propria (black arrow) and invades omental adipose tissue (red arrow). Flanking normal stomach wall is uninvolved.
histopathological assessment informed decisions about further surgery may be made.
endocrine cells. Carcinoids are all low-grade malignancies, but their prognosis is extremely variable and many behave in a benign fashion. Indicators of aggressive behaviour include invasion of the muscularis propria, a size of more than 1 cm, angioinvasion, a functioning tumour, a high mitotic rate, and sporadic occurrence.
Adenocarcinoma of the oesophagogastric junction Adenocarcinomas that straddle the oesophagogastric junction are more closely related to tumours of the oesophagus than to those of the distal stomach. This is reflected in their consistent association with gastro-oesophageal reflux rather than with diet or infection by Helicobacter pylori. However the final common pathway in all of these adenocarcinomas of the upper gastrointestinal tract is via the progression from intestinal metaplasia to dysplasia and finally carcinoma. Because of their macroscopic and histological similarity to Barrett’s-associated carcinomas of the oesophagus, distinction between true cardiac gastric carcinomas and oesophageal adenocarcinomas may be difficult.
Mesenchymal tumours of the stomach Gastrointestinal stromal tumours (GIST): GIST is the most common mesenchymal tumour of the stomach. In the past these tumours have been regarded as variants of other mesenchymal tumours of the stomach such as smooth muscle and nerve sheath tumours. Modern immunohistochemistry (IHC) helps greatly in the distinction of GIST (as approximately 90% demonstrate KIT protein expression and 95% express DOG-1). GISTs are now thought to originate from the interstitial cells of Cajal (also KIT positive) which are the pacemaker cells of peristalsis. Approximately 85% of GISTs are driven by mutations in the ckit protooncogene and another 5% by mutations in the platelet-derived growth factor receptor a gene. Rarely GISTs are associated with mutations in BRAF or are wild type. Macroscopically GISTs lie within the stomach wall, and they are often large, solitary tumours with a fleshy homogeneous cut surface (Figure 3). Often, because of tumour size, there can be
Endocrine tumours of the stomach Gastric carcinoid tumours (endocrine tumours) are increasingly being detected at upper gastrointestinal endoscopy. They may arise in hypergastrinaemic states such as in autoimmune chronic atrophic gastritis (in which case they are often multiple), the ZollingereEllison syndrome in association with multiple endocrine neoplasia type-1, or they may be sporadic. The tumours usually consist of nests and trabeculae of monomorphic
Figure 2 (a) En face view of a diffuse-type gastric carcinoma (fresh state) showing diffuse thickening of gastric rugae (arrow) surrounding a flattened roughened area. (b) Same tumour as a sliced and viewed as two transverse sections (after fixation) showing diffuse thickening of all layers of the gastric wall (black arrow). Numerous lymph nodes are positive for carcinoma in the omentum (red arrow).
SURGERY 29:11
548
Ó 2011 Published by Elsevier Ltd.
BASIC SCIENCE
Other mesenchymal tumours True smooth muscle tumours of the stomach (leiomyomas, leiomyosarcomas) are exceptionally rare. Other tumours include glomus tumours, schwannomas, lipomas and granular cell tumours. Gastric lymphoma The stomach is the most common site for primary lymphomas of the gastrointestinal tract. Most gastric lymphomas are low-grade B-cell non-Hodgkin lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas). Most MALT lymphomas of the stomach are associated with infection by Helicobacter pylori. Microscopically, these tumours consist of a diffuse population of small lymphoid cells that infiltrate and destroy the gastric glandular mucosa with formation of characteristic lymphoepithelial lesions. The immunophenotype of these tumours is that of a B-cell marginal zone lymphoma. The distinction between florid gastritis and low-grade MALT lymphoma can be very difficult, and analysis by polymerase chain reaction is being used increasingly in routine diagnosis to confirm the clonal nature of the lymphoid infiltrate. Most low-grade MALTs are indolent and regress after eradication of Helicobacter pylori infection, although they may recur after treatment is stopped. Transformation of low-grade to high-grade MALT lymphoma is characterized by groups and diffuse sheets of large, transformed blast cells. Most authors use the term ‘high-grade MALT lymphoma’ if areas of low-grade lymphoma are identifiable. Once this latter component is lost, the tumour becomes indistinguishable from a high-grade diffuse large B-cell lymphoma of unspecified type. High-grade lymphomas do not usually respond to eradication of Helicobacter pylori and, similarly to such lesions at other sites, behave aggressively requiring systemic conventional chemotherapy.
Figure 3 Malignant gastrointestinal stromal tumour of the stomach viewed in transverse section (fresh state). The tumour shows a fleshy cut face with a central ulcer (black arrow) and areas of intratumoral haemorrhage (red arrow).
areas of necrosis and haemorrhage as well as ulceration of the overlying mucosa. Microscopically the tumour can be composed of spindle cells or tumour cells can have a more ‘epithelioid’ appearance. The most important factors in the assessment of a GIST are the site, macroscopic size and the mitotic rate of tumour cells. A high value for either size or mitotic rate relates to an adverse prognosis and origin in the small intestine is generally worse than origin in the stomach. Surgery is the primary treatment option in the management of primary GISTs and may also be important in the management of secondary disease. However specific tyrosine kinase inhibitor drugs which act directly on the KIT protein receptor are the mainstay of therapy for advanced or metastatic disease. The dose and choice of drug depends increasingly on the specific driving mutation in the tumour.
SURGERY 29:11
Secondary tumours of the stomach Metastatic disease involving the stomach is unusual. Most gastric metastases are from breast carcinoma, followed by malignant melanoma and lung carcinoma. A
549
Ó 2011 Published by Elsevier Ltd.
Pathology of epithelial tumours of the stomach
occur in ‘developing’ countries. The highest incidences are in Eastern Asia, South America and Eastern Europe. It is extremely rare under the age of 30 years, but increases rapidly thereafter, with the highest rates in the oldest age groups in both males and females. The intestinal type is more common in males, while the diffuse type tends to affect younger age groups and is more common in females.
Gordon Reid Shaun V Walsh
Pathogenesis The changes in the stomach which precede the development of gastric adenocarcinoma often follow a stepwise progression. Chronic atrophic gastritis (often itself proceeded by Helicobacter pylori gastritis) with the development of intestinal metaplasia is often seen in the background mucosa of specimens resected for cancer. Metaplastic epithelium is unstable and can be prone to develop dysplasia or carcinoma in-situ, which are precursor lesions to adenocarcinoma. As well as H. pylori infection, diet (including high salt intake), smoking and bile reflux are factors important in the development of gastric adenocarcinoma. Approximately 10% of gastric adenocarcinomas have an inherited component, those patients with Lynch syndrome (HNPCC), FAP and PeutzeJeghers syndrome all have an increased risk. The hereditary gastric cancers have led to improved understanding of the genetic basis of sporadic gastric cancer. Mutations in CDH1 (associated with E-cadherin expression) are frequently seen in sporadic gastric cancers of the diffuse type (patients with BRAC2 mutations also linked to E-cadherin expression have an increased risk of these diffuse-type tumours). Sporadic intestinal type gastric carcinoma has been described in association with b-catenin mutations as well as microsatellite instability.
Abstract Most tumours of the stomach are epithelial in nature. Benign epithelial tumours come in the form of polyps: adenomas, hyperplastic and fundic gland polyps. Malignant epithelial tumours of the stomach are mostly adenocarcinomas. When poorly differentiated these may take the form of individual signet ring cells and have the distinctive clinical appearance of ‘linitis plastica’. Staging of gastric adenocarcinoma depends on extent of invasion into the gastric wall. Carcinoid tumours can also be seen in the stomach. By far the most common mesenchymal tumour of the stomach is the gastrointestinal stromal tumour or GIST. These are now easily recognized given the high proportion that mark immunohistochemically with KIT and DOG-1. These tumours can be managed surgically or with drugs which act specifically on the KIT protein. Lymphomas are also relatively common in the stomach, these are generally mucosa-associated lymphoid tissue (MALT) lymphomas and associated with Helicobactor pylori infection.
Keywords adenocarcinoma; GIST; Helicobacter pylori; MALToma
Benign epithelial tumours Unlike their counterpart in the large intestine, adenomas of the stomach are relatively uncommon entities. As in the colon however dysplasia is the characteristic feature and distinguishes them from the more common hyperplastic and fundic gland polyps of the stomach. Adenomas of the stomach are associated with a risk of progression to adenocarcinoma, which is not the case with the latter two mentioned polyps (although adenomatous change can be seen in large hyperplastic polyps). Adenomatous and hyperplastic polyps are often seen in conjunction with chronic gastritis and may be aetiologically associated. Polyps associated with polyposis syndromes commonly occur in the stomach. Both adenomas and fundic gland polyps are more common in patients with familial adenomatous polyposis (FAP). Distinctive polyps associated with PeutzeJeghers syndrome can also be seen in the stomach.
Pathology Gastric adenocarcinomas can be divided into four types based on their macroscopic appearance: polypoid, fungating, ulcerative (Figure 1) and diffuse. The diffuse type can give rise to the classical ‘linitis plastica’ appearance when extensive (Figure 2). Gastric adenocarcinomas are usually ‘gland forming’ microscopically, but when poorly differentiated can be solid or composed of discohesive single cells (signet ring cells). Gastric adenocarcinoma is classified either by the WHO or Lauren system. The simpler Lauren classification distinguishes between intestinal type carcinoma (polypoid, ulcerative or fungating) and diffuse (linitis plastica) types. Diffuse is automatically considered poorly differentiated and is associated with a worse prognosis whereas intestinal can be graded as either well, moderate of poorly differentiated. The WHO classification emphasizes microscopic features and describes four histological patterns; tubular, papillary, mucinous and signet ring. TNM staging in the stomach relates primarily to the depth of invasion through the stomach wall as well as the number of regional lymph nodes involved by the tumour. Pathological staging is the most powerful tool when it comes to predicting prognosis. The significance of tumour type (in isolation) is controversial. In the past the primary treatment of carcinomas involved an open surgical approach. However, with the advent of advanced endoscopic techniques, endoscopic mucosal resection of smaller lesions is now commonplace and following
Malignant epithelial tumours Epidemiology Although falling in incidence, gastric cancer is the second-most common cancer in the world; 60% of deaths from gastric cancer
Gordon Reid BMSc MB ChB is a Consultant Pathologist at Ninewells Hospital, Dundee, UK. Conflicts of interest: none declared. Shaun V Walsh MBBCh BAO FRCPath is a Consultant Pathologist at Ninewells Hospital, Dundee, UK. Conflicts of interest: none declared.
SURGERY 29:11
547
Ó 2011 Published by Elsevier Ltd.
BASIC SCIENCE
Figure 1 (a) En face view of an intestinal-type gastric carcinoma (fresh state) showing raised rolled edges (black arrow) and a central bleeding point (red arrow). (b) Same tumour as a sliced and viewed in transverse section (after fixation). The tumour invades through the muscularis propria (black arrow) and invades omental adipose tissue (red arrow). Flanking normal stomach wall is uninvolved.
histopathological assessment informed decisions about further surgery may be made.
endocrine cells. Carcinoids are all low-grade malignancies, but their prognosis is extremely variable and many behave in a benign fashion. Indicators of aggressive behaviour include invasion of the muscularis propria, a size of more than 1 cm, angioinvasion, a functioning tumour, a high mitotic rate, and sporadic occurrence.
Adenocarcinoma of the oesophagogastric junction Adenocarcinomas that straddle the oesophagogastric junction are more closely related to tumours of the oesophagus than to those of the distal stomach. This is reflected in their consistent association with gastro-oesophageal reflux rather than with diet or infection by Helicobacter pylori. However the final common pathway in all of these adenocarcinomas of the upper gastrointestinal tract is via the progression from intestinal metaplasia to dysplasia and finally carcinoma. Because of their macroscopic and histological similarity to Barrett’s-associated carcinomas of the oesophagus, distinction between true cardiac gastric carcinomas and oesophageal adenocarcinomas may be difficult.
Mesenchymal tumours of the stomach Gastrointestinal stromal tumours (GIST): GIST is the most common mesenchymal tumour of the stomach. In the past these tumours have been regarded as variants of other mesenchymal tumours of the stomach such as smooth muscle and nerve sheath tumours. Modern immunohistochemistry (IHC) helps greatly in the distinction of GIST (as approximately 90% demonstrate KIT protein expression and 95% express DOG-1). GISTs are now thought to originate from the interstitial cells of Cajal (also KIT positive) which are the pacemaker cells of peristalsis. Approximately 85% of GISTs are driven by mutations in the ckit protooncogene and another 5% by mutations in the platelet-derived growth factor receptor a gene. Rarely GISTs are associated with mutations in BRAF or are wild type. Macroscopically GISTs lie within the stomach wall, and they are often large, solitary tumours with a fleshy homogeneous cut surface (Figure 3). Often, because of tumour size, there can be
Endocrine tumours of the stomach Gastric carcinoid tumours (endocrine tumours) are increasingly being detected at upper gastrointestinal endoscopy. They may arise in hypergastrinaemic states such as in autoimmune chronic atrophic gastritis (in which case they are often multiple), the ZollingereEllison syndrome in association with multiple endocrine neoplasia type-1, or they may be sporadic. The tumours usually consist of nests and trabeculae of monomorphic
Figure 2 (a) En face view of a diffuse-type gastric carcinoma (fresh state) showing diffuse thickening of gastric rugae (arrow) surrounding a flattened roughened area. (b) Same tumour as a sliced and viewed as two transverse sections (after fixation) showing diffuse thickening of all layers of the gastric wall (black arrow). Numerous lymph nodes are positive for carcinoma in the omentum (red arrow).
SURGERY 29:11
548
Ó 2011 Published by Elsevier Ltd.
BASIC SCIENCE
Other mesenchymal tumours True smooth muscle tumours of the stomach (leiomyomas, leiomyosarcomas) are exceptionally rare. Other tumours include glomus tumours, schwannomas, lipomas and granular cell tumours. Gastric lymphoma The stomach is the most common site for primary lymphomas of the gastrointestinal tract. Most gastric lymphomas are low-grade B-cell non-Hodgkin lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas). Most MALT lymphomas of the stomach are associated with infection by Helicobacter pylori. Microscopically, these tumours consist of a diffuse population of small lymphoid cells that infiltrate and destroy the gastric glandular mucosa with formation of characteristic lymphoepithelial lesions. The immunophenotype of these tumours is that of a B-cell marginal zone lymphoma. The distinction between florid gastritis and low-grade MALT lymphoma can be very difficult, and analysis by polymerase chain reaction is being used increasingly in routine diagnosis to confirm the clonal nature of the lymphoid infiltrate. Most low-grade MALTs are indolent and regress after eradication of Helicobacter pylori infection, although they may recur after treatment is stopped. Transformation of low-grade to high-grade MALT lymphoma is characterized by groups and diffuse sheets of large, transformed blast cells. Most authors use the term ‘high-grade MALT lymphoma’ if areas of low-grade lymphoma are identifiable. Once this latter component is lost, the tumour becomes indistinguishable from a high-grade diffuse large B-cell lymphoma of unspecified type. High-grade lymphomas do not usually respond to eradication of Helicobacter pylori and, similarly to such lesions at other sites, behave aggressively requiring systemic conventional chemotherapy.
Figure 3 Malignant gastrointestinal stromal tumour of the stomach viewed in transverse section (fresh state). The tumour shows a fleshy cut face with a central ulcer (black arrow) and areas of intratumoral haemorrhage (red arrow).
areas of necrosis and haemorrhage as well as ulceration of the overlying mucosa. Microscopically the tumour can be composed of spindle cells or tumour cells can have a more ‘epithelioid’ appearance. The most important factors in the assessment of a GIST are the site, macroscopic size and the mitotic rate of tumour cells. A high value for either size or mitotic rate relates to an adverse prognosis and origin in the small intestine is generally worse than origin in the stomach. Surgery is the primary treatment option in the management of primary GISTs and may also be important in the management of secondary disease. However specific tyrosine kinase inhibitor drugs which act directly on the KIT protein receptor are the mainstay of therapy for advanced or metastatic disease. The dose and choice of drug depends increasingly on the specific driving mutation in the tumour.
SURGERY 29:11
Secondary tumours of the stomach Metastatic disease involving the stomach is unusual. Most gastric metastases are from breast carcinoma, followed by malignant melanoma and lung carcinoma. A
549
Ó 2011 Published by Elsevier Ltd.