SLIDES

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Summary:
Gastric cancer can be divided into 2 major categories: early and advanced.  Early gastric cancer is characterized by limitation of the cancer cells to the mucosa or sub-mucosal layer, whereas in advanced cancer, the cancer cells infiltrate the proprial muscle layer or serosa.  Early gastric cancers are macroscopically classified into 5 types: I: protruded, IIa: superficially elevated, IIb: superficially flat, IIc: superficially depressed, and III: excavated. The histological characteristics of early gastric cancer are similar to those of advanced cancer.  IIa and IIc are the major types of early gastric cancer. IIa lesions are frequently located at the antrum and predominantly are differentiated (intestinal) carcinomas. IIc lesions are frequently located at the corpus and predominantly are undifferentiated (diffuse) carcinomas. Differentiated carcinoma is expansive, whereas undifferentiated carcinoma is infiltrative. Type I and IIa early cancers develop into Borrmann 1 and 2 type advanced cancers, while IIc and III early cancers develop into Borrmann 3 and 4 type advanced cancers via a IIc-like advanced cancer. Differentiated carcinoma is thought to arise from intestinal metaplasia, while undifferentiated carcinoma arises from the foveolar epithelium. Gastric cancer develops slowly from the early to the advanced phase over a long period of probably longer than 10 years. Therefore, there are frequent opportunities to detect gastric cancer in the early phase and the patient can expect a complete cure by the surgical operation or endoscopical mucosal resection.

Introduction: 
Although the age-adjusted death rate of gastric cancer per 100,000 head of population has been decreasing during the past 20 years in Japan, in contrast to the increasing tendencies of other organ malignancies such as lung, colon, liver, gallbladder, prostate and breast, the absolute number of gastric cancer deaths remains at a high level and was reported to be 50,700/120,000,000 in 1999 (1). The largest number of malignant tumor deaths was 52,200 from lung cancer. Therefore, gastric cancer is still an important malignancy and gastroenterologists, radiologists, surgeons, and pathologists are continuing to make a major effort to detect and treat early gastric cancer, which has a considerably better prognosis than advanced carcinoma.
  Gastric cancer forms a large protruded, ulcerated or infiltrative lesion in the stomach. When the cancer cell infiltrates the serosal surface, cancerous peritonitis occur. The cancer cells frequently metastasize to the lymph nodes, liver and other distant organs. This situation is referred to as advanced phase carcinoma, and any medication is ineffective with the patient likely to die within 1 or 2 years. On the other hand, the early phase carcinoma is a small and shallow lesion that has not yet infiltrated deeply in the gastric wall and distant metastasis is rare. To achieve a complete cure of the patient, early phase carcinoma must be detected to conduct successful surgical operation or endoscopic mucosal resection.      
  In this manuscript, typical cases of early gastric cancers are demonstrated, the clinico-pathological characteristics of early cancer are explained, and finally the general concepts relating to diagnosis and treatment of early gastric cancer in Japan are described.

General appearance of advanced gastric cancer
  Macroscopic pictures of advanced cancer (slide) show large protruded or ulcerated lesions in the stomach. The left upper photograph shows a protruded lesion, the left lower photograph shows a localized and ulcerated lesion, the right upper photograph shows an ulcerated and infiltrative lesion, and the right lower photograph shows a diffuse infiltrative lesion. The right lowest photograph shows the cut surface demonstrating diffuse thickening of the gastric wall with cancer infiltration from the mucosa to serosa.
  Macroscopic types of advanced gastric cancer can be understood from the schema depicted in 1925 by Dr. R. Borrmann, who was a Germany surgeon and pathologist (slide).  Borrmann's type 1 (Bor.1) is protruded, Bor.2 is localized and ulcerated, Bor.3 is ulcerated and infiltrative, and Bor.4 is diffuse infiltrative. Borrmann's classification also is very useful for understanding the successive growth pattern of gastric cancer. The Bor.1 or 2 types seem to develop to Bor.3 or 4.

Several classifications of the histological types of the gastric cancer have been historically proposed (slide). In the classification of the Japanese Research Society for Gastric Cancer, there are 5 main types and 4 subtypes (2).  The five main types are papillary (pap), tubular (tub), poorly differentiated (por), signet-ring cell (sig) and mucinous (muc) adenocarcinoma, and the 4 subtypes are well and moderately differentiated tubular (tub1 and tub2) and poorly solid and poorly non-solid adenocarcinomas (por1 and por2). When we explain the histological types of one gastric cancer case in a conference, pap or por1 or sig can be easily understood by all of the attending doctors. However, when we use this classification in a clinico-pathological study, the large number of histological types is very confusing and clear-cut results cannot be obtained. Therefore, Lauren's classification (3), which consists of intestinal and diffuse types, is more useful. In Japan, we prefer to use Nakamura's classification (4), which consists of differentiated and undifferentiated adenocarcinoma. Emeritus professor Dr. Kyoichi Nakamura was a pioneer in the pathological study of early gastric cancer. Differentiated adenocarcinoma includes pap, tub1 and around half of the tub2 cases, and undifferentiated carcinoma includes por, sig, muc and the remaining half of tub2 cases according to the Japanese classification.

Early gastric cancer
  With improvements in the quality of the gastroscope and techniques of the examination, many cases of smaller lesions were discovered in the stomach (slide: Macroscopic pictures of early gastric cancer). The left upper picture shows a slightly protruded lesion, the left lower picture shows an irregular mucosa, the right upper picture shows a wide erosive mucosa, and the right lower picture shows a shallow depressed lesion. In these cases, the cancer cells are histopathologically limited within the mucosal or sub-mucosal layer, which thus characterizes early phase gastric cancer. On the other hand, the cancer cells infiltrate the muscularis propria or serosa in advanced phase gastric cancer. 

Macroscopic typing of early gastric cancer (slide:Early gastric cancer, intramucosal carcinoma, m, sm) was proposed by the Japanese Research Association for Gastric Cancer more than 30 years ago (2). Many endoscopists, radiologists, surgeons and pathologists cooperated to conduct macroscopic typing of early gastric cancer after frequent discussion. This typing is actually a smaller scale version of Borrmann's classification.  Early phase gastric cancer cases are classified into 5 types: I: protruding, IIa: superficially elevated, IIb: superficially flat, IIc: superficially depressed, III: excavated. IIa and IIc are the two major types. Numerous cases show combined shapes, such as IIc+IIa, I+IIa, IIc+III, and IIa+IIb+IIc. Gastric adenoma cannot be differentiated from IIa macroscopically.
 Histological types of the early phase carcinoma are the same as those of advanced carcinoma, and the classification of pap, tub1, tub2, por1, por2, sig and muc can be used. Many American and European pathologists are not in agreement on early gastric cancer, because they have assumed that the histological pictures of early gastric cancer in Japan are different from those of advanced cancers. However, the histological characteristics of gastric cancer are the same at every stage of cancer development. 

Case demonstration of typical cases of early gastric cancer
  The first case is type I early gastric cancer (slide). The left upper photograph shows an endoscopic picture, the left lower picture shows the surgically resected stomach, the right upper photograph shows low-magnification and the right lower photograph shows high-magnification histological pictures. This is a case of a 75-year old male with a protruding lesion measuring 5x3.5 cm in size at the fundus, and the histological type is papillary adenocarcinoma (pap). The surface of the carcinoma is papillary or villous, but the carcinoma is infiltrating the sub-mucosal layer (sm). Apart from the main lesion, another smaller lesion (red arrow) can be observed at the portion near the gastric angle.
  This small lesion is a IIa type early cancer (slide), 6x6 mm in size, and the cancer cells are restricted to the lamina propria of the mucosa (m). With lower magnification pictures, we can observe atypical glands at the surface layers of the mucosa. With a higher magnification picture, the atypical glands show a sufficient degree of cellular and structural atypia to enable the diagnosis of a well-differentiated tubular adenocarcinoma (tub1).
  The next case is another IIa early gastric cancer (slide). The height of the type I lesion is more than twice that of the normal mucosa, but the height of IIa is less than twice the thickness. Therefore, this lesion cannot be distinguished easily between type I and IIa. The left upper photograph shows an endoscopic picture and the left lower photograph shows a partially resected stomach. Histologically, the lesion is pap limited to the mucosa (m), measuring 25x15mm.

An irregular mucosa is frequently observed by endoscopic examination, and we classified it as a IIa+IIc early gastric cancer (slide), because some parts are elevated and others depressed. The histological picture shows tub1, and the carcinoma has infiltrated the sub-mucosal layer. Recently, we sub-classified the sub-mucosal cancer into sm1 and sm2. Sm1 represents a shallow infiltration and sm2 is a deep infiltration in the sub-mucosal layer. This sub-classification is significant in deciding the indication of endoscopical mucosal resection.  

Depressed IIc lesions are frequently seen (slide). Histologically, signet-ring cell carcinoma is observed in the mucosa. The higher magnification picture shows signet-ring cells. The sub-mucosal layer is fibrotic, but there is no infiltration by the cancer cells.
  A IIb+IIc early gastric cancer (slide) is sometimes found. A simple IIb lesion is very rare, and IIb frequently combines with IIc or IIa. The height of the lesion is the same as the surrounding normal mucosa. The carcinoma forms irregular tubular structures, but several mucus lakes are observed in the cancer tissue. Therefore, the histological type is tub2+muc. There is no sub-mucosal infiltration.
  A very small IIc lesion is frequently found (slide:IIc minute early gastric cancer).  Lesion smaller than 1 cm in diameter is called minute cancer. The lesion in the resected stomach is unclear. However, signet-ring cells can be observed histologically in a small part of the mucosa, measuring 6x5 mm.
 Another case of minute carcinoma, measuring 5 mm in diameter, can be seen (slide). In the biopsied mucosa, we found a small number of signet-ring cells. However, we did not find any macroscopic lesions in the resected stomach. We sectioned the whole stomach and made a large number of pathological slides. We finally detected a minute signet-ring cell carcinoma after a long microscopic examination. A small number of cancer cells can be observed in the middle layer of the mucosa by PAS staining. Do you agree that this is a signet-ring cell carcinoma? We believe this is a very early-phase lesion, namely an incipient phase carcinoma.
  Type III is rare lesion (slide). We believe secondary ulceration on the IIc or IIa forms a type III lesion. There is deep central ulceration, and the cancer cells remain in the mucosa of the ulcer edge.

IIc-like advanced carcinoma, superficial wide-spreading type and adenoma
  The endoscopic and macroscopic pictures of some cases look like IIc. However, histologically the carcinoma infiltrates the musclaris propria (mp). Therefore, this appears to be a IIc-like advanced cancer (slide).

A flat and erosive lesion, which is wider than 10 cm, is sometimes found.  Histologically, sig and tub2 can be observed in the mucosa of the most part of the lesion, but poorly differentiated cancer cells have infiltrated (por2) the submucosa and musclaris propria in a small area. Accordingly, this case actually is not an early lesion, but a IIb+IIc-like advanced cancer (slide).

Slightly elevated lesions like IIa are frequently found. However, the degree of cellular atypia of some of the cases is not high and the pathological diagnosis must be gastric adenoma (slide). If the pathological diagnosis is adenoma, surgical resection is never performed.

Clinico-pathological characteristics of the early gastric cancer
  Incidences of macroscopic types of the gastric cancer, resected in my hospital during the period from 1993 to 1998 are demonstrated in the table (slide). The total number of cases was 394. There were 183 early cancers and 211 advanced cancers. There were 9 Type I, 23 IIa, 6 IIb, 129 IIc, and 14 III. However, IIc of this table includes combined type lesions, such as IIc+IIa, IIa+IIc, and IIc+I, etc. There were 11 Bor. 1 advanced cancers, 62 Bor. 2, 80 Bor. 3, and 33 Bor. 4. There were 25 IIc-like advanced cancers. 

Location of the early gastric cancer is demonstrated by a histogram (slide). Many cases of IIa are located at the antrum, whereas more than half of the IIc cases are located at the corpus. Accordingly, we can say that IIa arise predominantly from the antrum, and IIc arise from the corpus.
  Histological classification according to the macroscopic types of the carcinoma is demonstrated (slide). Using Nakamura's classification, the differentiated adenocarcinoma consists of pap, tub1 and some cases of tub2, and undifferentiated carcinoma consists of por, sig, muc and some cases of tub2.  In other words, when tub2 is mixed with pap or tub1, this case should be classified as differentiated carcinoma. Moreover, when tub2 is mixed with por or sig, this case should be classified as undifferentiated. Most cases of type I, IIa, IIb and Bor.2 are differentiated carcinomas, but most cases of Bor.3, 4, and IIc-like advanced are undifferentiated carcinomas. On the other hand, differentiated and undifferentiated carcinoma account for half the cases of IIc, respectively.
 The next histogram shows the depth of cancer infiltration according to the macrosopic type (slide). Necessarily, the cancer cells are limited to the mucosa and sub-mucosal layer in the early cancers, but the ratio of sm cancer is higher in IIc than IIa. The degree of infiltration is increased from Bor.1 to 4. Most cases of I, IIa and Bor.2 are differentiated carcinomas, while most cases of IIc, Bor.3 and 4 are undifferentiated carcinomas. Therefore, undifferentiated carcinoma is more infiltrative than the differentiated carcinoma.
  Incidences of lymph node metastasis according to the types of the gastric cancer are demonstrated by a table (slide). We found 16 cases (11%) with lymph node metastasis in 151 cases of early gastric cancer. On the other hand, 132 (71%) cases out of 187 advanced cancers had lymph node metastasis. In 16 early cancers with lymph node metastasis, 3 cases were m-cancer and 13 cases were sm-cancer. Four cases were differentiated carcinoma and 12 cases were undifferentiated carcinoma. Therefore, the incidence of lymph node metastasis was higher in the sm-cancer and undifferentiated carcinoma cases. IIa lesions are predominantly located at the antrum and are histologically differentiated adenocarcinoma. Differentiated carcinoma frequently produces an elevated lesion and the border is well demarcated. Lymph node metastasis is rare. IIc lesions are predominantly located at the corpus and are histologically undifferentiated adenocarcinoma. Undifferentiated adenocarcinoma is infiltrative and produces IIc and III lesions. Some IIc lesion cases consisting of undifferentiated adenocarcinoma show lymph node metastasis. Therefore, endoscopic mucosal resection can be safely performed in IIa cases, but not in IIc cases.

Five-year survival rate
  The 5-year survival rate according to the clinical stage of UICC and depth of the cancer infiltration in the gastric wall is shown (slide)(5). The survival rate is the highest in Stage I and the lowest in Stage IV. Concerning the depth of cancer infiltration, the survival rate is the highest in m-cancer, followed by sm-, mp-, ss- and se-cancer. Even in the cases of m-cancer, 0.5% of the patients died of recurrent cancer within 5 years, because, 2-3% cases of the m-cancer have lymph node metastasis.

Early cancer develops to advanced cancer (slide)
  On the basis of clinico-pathological findings, we believe that type I and IIa early gastric cancer will develop into Borrmann 1 and 2 advanced cancer, and IIc and III will develop into Borrmann 3 or 4 via IIc-like advanced cancer. We predict type I and IIa early cancer rarely develop into Bor.3 and 4 advanced cancer.

Differences between differentiated and undifferentiated adenocarcinomas of the stomach are shown in a table (slide), describing the predominant features. Clinicopathological knowledge about the different behaviors of the carcinoma is useful for the endoscopic detection and treatment of the gastric cancer.

Histogenesis of the gastric cancer
Next, I will talk about the histogenesis of the gastric cancer. When we observe the pathological slides of minute gastric cancers, we notice the surrounding mucosa of the differentiated carcinoma is frequently intestinal metaplasia (slide). On the other hand, that of undifferentiated carcinoma is frequently atrophic foveolar epithelium.
  The next table (slide) was the work of Dr. Nakamura (7). He examined 96 minute cancers, which was unbelievably difficult work even in Japan. He demonstrated that the surrounding mucosa of the differentiated carcinoma consisted mostly of intestinal metaplasia.  In contrast, that of undifferentiated carcinoma consisted predominantly of foveolar epithelium. He concluded that the differentiated carcinoma must originate from the intestinal metaplasia, and undifferentiated carcinoma from the foveolar epithelium.
  Concerning the site of cancer cell distribution in the minute cancers, undifferentiated cancer cells are located at the intermediate zone of the mucosa (slide). On the other hand, differentiated cancerous glands occupy the full thickness of the mucosa. Emeritus Professor Dr. Nakamura predicted that undifferentiated carcinoma originates from the mitotic cell zone that is located in the middle portion of the foveolar epithelium. On the other hand, differentiated carcinoma originates from the bottom of the intestinal metaplasia, where the mitotic zone is located (slide: Incipient phase of the gastric cancer).

Natural history of the gastric cancer
  The natural history of the gastric cancer was clearly explained by Emeritus Professor Dr. Setsuya Fujita (8)(slide). The horizontal axis indicates the years from carcinogenesis, and the vertical axis indicates the diameter of the carcinoma. The cancer cell appears at the middle or deeper layer of the gastric mucosa. The cancer cells increase in number rapidly and reach the mucosal surface when the size of the carcinoma is about 2 mm in diameter. After the carcinoma is exposed at the mucosal surface, the gastric juice and food stimuli degenerate the carcinoma and the growth speed is very low. Professor Fujita estimated that the total length of intra-mucosal carcinoma might be from 14 to 21 years. The intra-mucosal cancer infiltrates the sub-mucosal layer at the average size of 3 cm in diameter. After the cancer infiltrates the deeper layer, the cancer cells are free from the gastric juice and food stimuli. The carcinoma, therefore, rapidly grows again with infiltration and metastasis, and the patient will die at the average size of 10 cm in diameter. The duration after sub-mucosal invasion to the patient's death is from 1.5 to 8 years. His estimation of the total length of the natural history of the gastric cancer appears to be too long. However, we have no definitive evidence about the intra-mucosal growth speed of the gastric cancer.
  The most important point of his theory is that gastric cancer develops slowly in the mucosa, thereby providing frequent chances for detection of m-cancer.  Detection of m-cancer smaller than 2 cm in diameter provides the best opportunity for achieving a complete cure of gastric cancer, because m-cancer starts to infiltrate the sub-mucosal layer at the average size of 3 cm in diameter.

General concept of early gastric cancer in Japan
  Japanese medical doctors believe that gastric cancer is limited to the mucosa or sub-mucosal layer in the early phase, that usually appears no symptoms. The early gastric cancer develops slowly to the advanced phase over a long period of probably more than 10 years. The prognosis of early cancer after medical treatment is considerably better than advanced cancer. Therefore, the early gastric cancer must be detected for a complete cure by the surgical operation or endoscopical mucosal resection. Health check of non-symptomatic individuals is effective to detect the early gastric cancer.  

Vienna Classification (slide) 
  The Vienna classification of gastrointestinal epithelial neoplasia was created to achieve a diagnostic consensus between the Western and Japanese pathologists (8). The most important feature of this classification is that Category 4 includes both high-grade dysplasia and intraepithelial carcinoma. This means that high-grade dysplasia is the same as intraepithelial carcinoma. Japanese pathologists have believed that high-grade dysplasia is an early cancer, while Western pathologists believe it to be a precancerous lesion. The diagnosis of a precancerous lesion or early gastric cancer makes a significant difference in the method selected to treat the lesion. Dysplasia will be followed up, but early cancer must be resected as soon as possible. On the basis of strict analysis of many cases, however, we have obtained apparent evidences that early phase carcinoma will develop to advanced cancer over a rather long period. The clinical doctors must start treatment of a stomach lesion when they receive a pathological report indicating a diagnosis of high-grade dysplasia or intramucosal carcinoma. If the treatment is started swiftly, the patient can achieve a complete cure.  However, if the treatment is delayed, the probability of patient death will become higher.

Acknowledgement: 
I sincerely appreciated the invitation to the Messina seminar on early gastric cancer. I was delighted to have the opportunity to visit the beautiful island of Sicilia. I was also very pleased to be able to discuss early gastric cancer with Italian doctors. I hope that my lecture will contribute to your understanding of early gastric cancer.

References
1) Ministry of Health and Labor of Japan. Vital statistics of Japan, 1999.
2) Japanese Research Society of Gastric Cancer. Japanese Classification of Gastric Cancer. Kanehara Co. Ltd., Tokyo, 1995
3) Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31-49, 1965
4) Nakamura K. Carcinoma of the stomach in the incipient phase: Its histogenesis and histological appearance. GANN 59:377-387, 1967   
5) Japanese Research Society for Gastric Cancer. Gastric cancer in Japan (in Japanese). Kanehara Co. Ltd. Tokyo 1996
6) Nakamura K. Structure of gastric cancer (in Japanese). Igaku-shoin Co. Tokyo 1990 
7) Fujita S. Biology of early gastric cancer. Pathol Res Pract 163:297-309, 1978   
8) Schlemper RJ, Kato Y, Itabashi M, et al. Vienna classification of gastrointestinal epithelial neoplasia. Gut 47:251-5, 2000