Abstract

Recent developments in mucin  histochemistry and immunohistochemistry have made reliable determination of the gastric and intestinal phenotypes of gastric carcinoma cells possible. Phenotypic expression changes from gastric epithelial cell type to intestinal epithelial cell type with the growth of gastric tumours in experimental animals. We studied cell differentiation in gastric signet ring cell carcinomas with progression in 203 surgically obtained specimens. The results showed that the proportion of gastric phenotype carcinomas, in which over 90% of the tissue consists of gastric epithelial cell type cells, decreases with the depth of invasion. The proportion of mixed phenotype carcinomas (between 10% and 90% of the tissue made up of gastric and/or intestinal epithelial cell type cells) increases. The intestinal phenotype (over 90% intestinal epithelial cell type carcinoma cells) was found in four carcinomas (about 2%) involving the serosa. No clear relationship was evident between phenotypic expression of carcinoma cells and the degree of intestinal metaplasia of the surrounding mucosa.

Progression of gastric signet ring cell carcinomas is associated with a phenotypic shift from gastric to intestinal type expression.

Colon Signet Ring Cell Adenocarcinoma: Immunohistochemical Characterization and Comparison with Gastric and Typical Colon Adenocarcinomas

Goldstein, Neal S. M.D.; Long, Alison M.D.; Kuan, Shih-Fan M.D.; Hart, John M.D.

Abstract

Colon signet ring cell adenocarcinomas are uncommon, high-grade neoplasms. Given their rarity, the question of primary colon or metastatic gastric adenocarcinoma frequently arises when signet ring cell carcinoma is seen in a colonoscopic biopsy or in biopsies procured from other regions of the body. A second related question regarding colon and gastric signet ring cell carcinomas is their immunophenotypic similarities with the glandular form of adenocarcinoma in each site. We studied the immunohistochemical phenotype of 14 colonic signet ring cell adenocarcinomas and compared them with immunophenotype of 27 gastric signet ring cell adenocarcinomas. We also compared the immunophenotype of the 27 gastric signet ring cell with the immunophenotype of 19 gastric gland–forming adenocarcinomas, and the immunophenotype of the 14 colonic signet ring cell adenocarcinomas to the immunophenotype of 20 colonic gland–forming adenocarcinomas to identify staining differences in the neoplastic cells of the two architectures. Antibodies studied were cytokeratins 7, 17, 19, and 20, CA 19-9, CA-125, estrogen receptor, and gross cystic disease fluid protein 15. Sixty-four percent of colon signet ring cell adenocarcinomas had either no staining or focal staining with cytokeratin 7 compared with diffuse staining in 63% of gastric signet ring cell adenocarcinomas (P = 0.016). Seventy-two percent of colon signet ring cell adenocarcinomas had diffuse staining with cytokeratin 20 compared with no or focal staining in 50% of gastric signet ring cell adenocarcinomas (P = 0.019). Fifty-seven percent of the colon signet ring cell adenocarcinomas had a cytokeratin 7 (−)/cytokeratin 20 (+) staining pattern compared with 11% of gastric signet ring cell adenocarcinomas (P = 0.004). Forty-four percent of gastric signet ring cell adenocarcinomas had a cytokeratin 7 (+)/cytokeratin 20 (−) pattern, compared with none of the colon signet ring cell adenocarcinomas (P = 0.004). The staining distribution of the antibody battery was similar in colon signet ring cell and colon glandular adenocarcinoma and gastric signet ring cell and gastric glandular adenocarcinomas. When signet ring cell adenocarcinoma is encountered in a colon biopsy, a colon primary is supported if the neoplastic cells have a cytokeratin 7 (−)/cytokeratin 20 (+) staining pattern, and a gastric primary is supported if they have a cytokeratin 7 (+)/cytokeratin 20 (−) staining pattern. The signet ring morphology at each site had an identical immunophenotype as the cells forming their glandular counterpart.

Primary colon signet ring cell adenocarcinomas are uncommon compared with their gastric signet ring cell counterparts. The question invariably arises of whether signet ring cell adenocarcinoma represents a colonic primary or metastasis of a gastric adenocarcinoma when they are found in a colonoscopic biopsy or biopsy procured from another region of the body. Additional radiologic and endoscopic studies are often performed to answer this question. The use of immunohistochemistry to help identify the primary site of signet ring cells when seen on a colon biopsy has not been explored to our knowledge. If immunohistochemical profiles significantly differ between colonic and gastric signet ring cell adenocarcinomas, it may provide an opportunity for pathologists to aid in establishing the primary site of signet ring cell carcinoma cells without additional clinical studies.

Another question regarding colon and gastric signet ring cell carcinomas is whether their immunophenotype is similar to the more typical glandular form of adenocarcinoma in each organ site.

To address these two questions, we first studied the immunohistochemical phenotype of primary colonic signet ring cell adenocarcinomas and compared it with that of primary gastric signet ring cell adenocarcinomas. We then compared gastric signet ring cell with gastric glandular adenocarcinomas, and colonic signet ring cell to colonic glandular adenocarcinomas to identify staining differences, if any, between the two morphologies.

Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma

Shuichi Nakatsuru1,4,

Akio Yanagisawa2,

Shigetoshi Ichii1,

Eiichi Tahara3,

Yo Kato2,

Yusuke Nakamura1,* and

Akira Horii1

+ Author Affiliations

1Departments of Biochemistry, Cancer Institute 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170

2Departments of Pathology, Cancer Institute 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170

3First Department of Pathology, Hiroshima University School of Medicine 1-2-3, Kasumi, Minami-ku, Hiroshima 734

4Sanko Junyaku Co., Ltd. 1-10-6 Iwamoto-cho, Chiyoda-ku, Tokyo 101, Japan

*To whom correspondence should be addressed

Received September 18, 1992.

Revision received October 5, 1992.

Accepted October 5, 1992.

Abstract

We searched for somatic mutations of the adenomatous polyposis coli (APC) gene in DNA samples isolated from 57 sporadic gastric cancers, by means of a ribonuclease (RNase) protection analysis coupled with DNA amplification by the polymerase chain reaction (PCR). Examining 30% of the APC coding region, including a region where somatic mutations in colorectal tumors are known to be clustered, we detected somatic mutations in 12 tumors; seven in 17 very well differentiated adenocarcinomas, two in 19 well or moderately differentiated adenocarcinomas, and three in ten signet-ring cell carcinomas. So far, no somatic mutations have been identified in 11 poorly differentiated adenocarcinomas. Eight of the 17 somatic mutations found in 12 tumors caused truncation of the gene product due to a nonsense mutation and a 1-, 2- or 5-bp deletion; nine others were point mutations that altered amino acids. Our results suggest that inactivation of APC plays a role in development of some gastric cancers, particularly very well differentiated adenocarcinomas and signet-ring cell carcinomas.

CONCLUSIONS

Early gastric carcinoma with SRC is a distinct type of gastric carcinoma in terms of clinicopathologic features and prognosis. The favorable prognosis and lower rate of lymph node metastasis in early SRC suggest that the patients with early gastric carcinoma with SRC could be candidates for less invasive surgeries for an improved quality of life. Cancer 2002;94:78–83. © 2002 American Cancer Society.

According to World Health Organization (WHO) classification, gastric signet ring cell carcinoma (SRC) is a histologic type, primarily based on the microscopic characteristics of the tumor but not on the biologic behavior.1 SRC has been classified as “diffuse type” by Lauren,2 “infiltrative type” by Ming,3 and “undifferentiated type” by Sugano et al.4 To establish a scale of tumor aggressiveness related to prognosis, the WHO1 and the Union International Contra la Cancrum (UICC)5 adapted a grading system in which SRC has been classified as high grade.

Although there have been studies of the clinicopathologic characteristics including prognosis of SRC, the results were not consistent. To our knowledge, no study has focused on early stage SRC (early SRC).6–9 Furthermore, few treatment strategies specific to histology for gastric carcinoma have been developed, especially for SRC, while the various types of newly developed treatment modalities have been introduced.

The purpose of this study was to clarify the biologic behavior of the early SRC by comparing the clinicopathologic features, including prognosis, with other histologic types of early gastric carcinoma. In addition, we also analyzed and compared the patterns of lymph node metastasis in patients with early SRC with other histologic types to find out the applicability of less invasive surgery for early SRC.

Stomach

Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone

A Charlton1,

V Blair2,

D Shaw3,

S Parry4,

P Guilford5,

I G Martin2

+ Author Affiliations

1Department of Pathology, Middlemore Hospital, Auckland, New Zealand

2Department of Surgery, Middlemore Hospital, Auckland, New Zealand

3Department of Gastroenterology, Tauranga Hospital, Tauranga, New Zealand

4Department of Gastroenterology, Middlemore Hospital, Auckland, New Zealand

5Cancer Genetics Laboratory, University of Otago, Dunedin, Aotearoa, New Zealand

Correspondence to:
I G Martin
University Department of Surgery, Middlemore Hospital, Private Bag 93 311, Otahuhu, Auckland 6, New Zealand; i.martin@auckland.ac.nz

Accepted 15 September 2003

Abstract

Background and aims: Germline mutations in the CDH-1/E-cadherin gene are, to date, the only known cause of hereditary diffuse gastric cancer (HDGC). While two recent series of prophylactic gastrectomy described microscopic foci of signet ring cell carcinoma in sample sections from 10 macroscopically normal stomachs, whole stomach phenotype has not been mapped. We aimed to describe the size and distribution of foci in relation to mucosal zones and anatomical location.

Methods: Six patients (from three HDGC kindred) were referred for total gastrectomy via three different referral pathways. Following fixation, five stomachs were completely blocked and one extensively sampled. Histopathology was mapped to a mucosal photograph of each stomach, enabling precise localisation of carcinoma foci, benign pathology, and mucosal zones.

Results: There were 4–318 microscopic foci of intramucosal signet ring cell adenocarcinoma in the six macroscopically normal stomachs (foci size 0.1–10 mm in diameter). The distal third of the stomach contained 48% of total foci (range 29–75%). The body-antral transitional zone occupied 7.7% of mucosal area (range 3.6–11.8) but had 37% of foci (range 10%–75%). The largest foci were found in the transitional zone and foci density was five times greater in the transitional zone than in body or antral type mucosa.

Conclusions: In germline CDH-1 mutation carriers, multiple microscopic foci of intramucosal signet ring cell carcinoma show a predilection for the distal stomach and the body-antral transitional zone. Targeting the transitional zone would maximise the likelihood of finding foci in macroscopically normal gastrectomies, and particular attention should be paid to this area during endoscopy.

Establishment and Characterization of Human Signet Ring Cell Gastric Carcinoma Cell Lines with Amplification of the c-myc Oncogene1

Kazuyoshi Yanagihara2,

Toshio Seyama,

Masaru Tsumuraya,

Nanao Kamada, and

Kenjiro Yokoro

+ Author Affiliations

Departments of Pathology [K. Y., T. S., K. Y.] and Hematology [N. K.], Research Institute for Nuclear Medicine and Biology, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734, and Clinical Research Laboratory, Tochigi Cancer Center, 4-9-13 Yohnan, Utsunomiya, Tochigi 320 [M. T.], Japan

Abstract

Two unique human signet ring cell gastric carcinoma cell lines (designated HSC-39 and HSC-40A) were established in vitro from the ascites of a 54-year-old male patient. Both cell lines were biologically quite similar, grew in vitro in suspension with a population doubling time of 28–30 h, and had cytological features of mucinous epithelial tumor cells. They formed colonies in soft agar, with a cloning efficiency of 0.8–1.0%. Ultrastructurally, numerous granules were observed in the cytoplasm, suggesting secretory activity. The frequent presence of desmosome and the tight junction at the cell boundary certifies the epithelial origin of the lines. Immunocytochemistry and radioimmunoassay showed production of tumor marker antigens (carcinoembryonic antigen, CA 19-9, and sialyl-Lex-i) and gastrin in both lines. These lines were transplantable in athymic BALB/c nude mice. The histopathology of each line growing in athymic BALB/c nude mice was similar to that of the original tumor. The karyotype of the cells was highly aberrant with structural and numerical changes. The presence of numerous double minute chromosomes and loss of the 13 chromosome and Y-chromosome characterize these lines. In addition, the amplified c-myc oncogene (16–32-fold) was found in both cell lines and original ascitic tumor cells. Overexpression of the c-myc mRNA was noted. These cell lines may be a useful tool, providing both in vivo and in vitro systems for further studies of the biology and therapy of human signet ring cell (or Borrmann's type IV carcinoma) gastric carcinoma.

Gastric and Intestinal Phenotypic Expressions of Human Signet Ring Cell Carcinomas Revealed by Their Biochemistry, Mucin Histochemistry, and Ultrastructure1

Masae Tatematsu2,

Chie Furihata,

Tsutomu Katsuyama,

Kazumasa Miki,

Hidekuni Honda,

Yoichi Konishi, and

Nobuyuki Ito

+ Author Affiliations

First Department of Pathology, Nagoya City University Medical School, Mizuho-ku, Nagoya 467, Japan [M. T., N. I.]; Department of Molecular Oncology, University of Tokyo, Minato-ku, Tokyo 108, Japan [C. F.]; First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113, Japan [K. M.]; Department of Pathology, Faculty of Medicine, Shinshu University, Matsumoto 390, Japan [T. K.]; Department of Oncological Pathology, Cancer Center, Nara Medical College, Kashihara 634, Japan [Y. K.]; and Department of Surgery, Johoku Hospital, Nagoya 462, Japan [H. H.]

Abstract

Gastric and intestinal phenotypic expression in 37 surgically obtained primary signet ring cell carcinomas, five of their metastases to lymph nodes, and three signet ring cell carcinomas transplanted into nude mice were determined by biochemical, mucin, histochemical, and ultrastructural studies. Crude extracts of cancer tissues were used for measurements of pepsinogen isozymes, sucrase, aminopeptidase (microsomal), and alkaline phosphatase. Histochemical staining of mucin by paradoxical concanavalin A, the galactose oxidase-Schiff sequence and sialidase-galactose oxidase-Schiff, and the periodate-borohydride technique/potassium hydroxide/periodic acid-Schiff procedure was performed. The procedures allowed clear definition of pyloric gland, surface mucous, small and large intestinal goblet, and intestinal absorptive cell types. Of 40 specimens examined, 19 consisted entirely of gastric-type cells, and three entirely of intestinal-type cells. The others consisted of mixtures of gastric and intestinal-type cells. The observed high incidence of intestinal-type cells in signet ring cell carcinomas suggested that intestinal-type cells develop independently from intestinal metaplasia within signet ring cell carcinomas (diffuse-type gastric cancers), which probably originate from nonmetaplastic gastric mucosa.

Immunohistochemical Characterization of Signet-Ring Cell Carcinomas of the Stomach, Breast, and Colon

Peiguo G. Chu, MD, PhD and

Lawrence M. Weiss, MD

+ Author Affiliations

From the Division of Pathology, City of Hope National Medical Center, Duarte, CA

Abstract

We studied the immunophenotype of signet-ring cell carcinoma (SRCC) of the stomach (30 cases), breast (21 cases), and colon (9 cases) with the following expression patterns: (1) breast: consistent, MUC1 (21 [100%]), cytokeratin (CK) 7 (20 [95%]), estrogen receptor (ER; 17 [81%]); infrequent, E-cadherin (6 [29%]), MUC2, MUC5AC, CK20 (1 [5%] each); negative, CDX2 and hepatocyte paraffin 1 (Hep Par 1; 0 [0%] each); (2) gastric: frequent, CDX2 (27 [90%]) and Hep Par 1 (25 [83%]); variable, E-cadherin and CK20 (17 [57%] each), MUC2 and MUC5AC (15 [50%] each), MUC1 (5 [17%]); negative, ER (0 [0%]); and (3) colon: frequent, MUC2 (9 [100%]), CDX2 and MUC5AC (8 [89%] each); infrequent or negative, MUC1 (3 [33%]), Hep Par 1 (2 [22%]), ER (0 [0%]).

Immunohistochemical staining distinguished breast from gastric SRCC (ER, MUC1, Hep Par 1, CDX2) and colon SRCC (ER, CDX2, MUC2, and MUC5AC). Gastric and colon SRCCs showed a similar staining pattern for antibodies tested except for Hep Par 1 and CDX2 (gastric, 83% Hep Par 1 positivity and heterogeneous, weak, patchy CDX2 nuclear staining; colon, 22% Hep Par 1 positivity and homogeneous, strong, diffuse CDX2 nuclear staining). About half of the cases of gastric SRCC expressed MUC2 and MUC5AC, whereas virtually all cases of colon SRCC expressed them.

Article Citation:

Donald Earl Henson, Christopher Dittus, Mamoun Younes, Hong Nguyen and Jorge Albores-Saavedra (2004) Differential Trends in the Intestinal and Diffuse Types of Gastric Carcinoma in the United States, 1973–2000: Increase in the Signet Ring Cell Type. Archives of Pathology & Laboratory Medicine: July 2004, Vol. 128, No. 7, pp. 765-770.

ORIGINAL ARTICLES

Differential Trends in the Intestinal and Diffuse Types of Gastric Carcinoma in the United States, 1973–2000: Increase in the Signet Ring Cell Type

Donald Earl Henson, MD, Christopher Dittus, MPH, Mamoun Younes, MD, Hong Nguyen, CTR, MPH, and Jorge Albores-Saavedra, MD

From the Department of Pathology and the Office of Cancer Prevention and Control, The George Washington University Cancer Institute, Washington, DC (Dr Henson); The George Washington University School of Public Health and Health Services, Washington, DC (Mr Dittus); the Department of Pathology, Baylor College of Medicine, The Methodist Hospital, Houston, Tex (Dr Younes); Cancer Program, The George Washington University Hospital, Washington, DC (Ms Nguyen); and the Department of Pathology, Louisiana State University, Shreveport (Dr Albores-Saavedra)

Context.—During the last 50 years, the incidence and mortality of gastric cancer has declined in many countries. This decline has primarily included the intestinal type (Lauren classification). However, there is an impression among pathologists that the diffuse type, especially the signet ring cell subtype, has become more prevalent.

Objectives.—Using data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, we analyzed the trends of the 2 primary types (intestinal and diffuse) of gastric carcinomas from 1973 through 2000.

Design.—Trends in age-adjusted rates were determined for gastric carcinomas through the SEER statistical program (SEER*Stat), which is available on the Internet to the public.

Results.—During the period studied, the intestinal type continued to decline in males, females, African Americans, and whites. The intestinal type was more common in males than in females and more common in African Americans than in whites. In contrast, a consistent increase in the rate of the diffuse type of gastric carcinoma was seen during this period. The rate increased from 0.3 cases per 100 000 persons in 1973 to 1.8 cases per 100 000 persons in 2000. This increase was seen in males, females, African Americans, and whites. The predominant increase occurred in the signet ring type.

Conclusions.—The results indicate a progressive decrease in the incidence of the intestinal type of gastric cancer and an increase in the diffuse type of gastric carcinoma, especially the signet ring cell type. The clinical implications of the increase are considered.