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Diffuse Gastric Cancer

Signet Ring Cell Gastric Cancer

Diffuse gastric cancer (DGC) is one of three major histological types of gastric cancer, the other ones being intestinal-type and mixed gastric cancer. DGC diffusely invades the gastric wall and is unlikely to form a discrete mass. DGC-associated symptoms appear late in the cause of the disease and are non-specific, which is why this type of cancer is generally diagnosed in advanced stages. Unfortunately, the late diagnosis of DGC results in a poor outcome with mean survival times of less than two years. Although surgical tumor resection and adjuvant chemotherapy are often carried out with curative intent, relapses are common and cause the death of most patients.


Presentation

DGC patients tend to remain asymptomatic for prolonged periods of time. Epigastric pain, nausea, and early satiety are among the first symptoms triggered by this type of cancer, but they are frequently dismissed by the patient and the physician. Furthermore, they are most suggestive of common disorders like dyspepsia, gastric ulcer, and other forms of gastritis, so if therapeutic measures are taken, patients are usually prescribed antacids and proton pump inhibitors. DGC patients don't typically respond to such treatment. It is of utmost importance to pay attention to these symptoms and the patients' response to therapy, and a family history of gastric cancer should warrant clarifying imaging and genetic studies.

The presence of a palpable mass in the upper abdomen is another symptom of advanced-stage diffuse gastric cancer. Over the course of the disease, loss of appetite becomes more pronounced and patients are losing weight. Metastatic disease may accelerate the loss of weight, and may also cause additional symptoms. DGC most commonly metastasizes to regional lymph nodes, to the peritoneum and viscera. Peritoneal carcinomatosis is generally associated with ascites.

Italian
  • METHODS: We genotyped all known polymorphisms located within conserved sequences of CDH1 intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives[ncbi.nlm.nih.gov]
  • We searched for CDH1 germline defects in 32 HDGC Italian probands selected according to international consensus criteria and in 5 selected relatives.[ncbi.nlm.nih.gov]
  • Indeed, an Italian research group has shown that GSTP1 105 A/G and 105 G/G genotypes as well as the GSTT1-null genotype reduce the individual risk of developing DGC.[symptoma.com]
Lymphadenopathy
  • Common findings in images comprise a more or less diffuse thickening of the gastric wall, which may be explained by individual cells infiltrating the stomach wall without forming a discrete mass, lymphadenopathy, and ascites.[symptoma.com]
Dyspepsia
  • Furthermore, they are most suggestive of common disorders like dyspepsia, gastric ulcer, and other forms of gastritis, so if therapeutic measures are taken, patients are usually prescribed antacids and proton pump inhibitors.[symptoma.com]
Loss of Appetite
  • Over the course of the disease, loss of appetite becomes more pronounced and patients are losing weight. Metastatic disease may accelerate the loss of weight, and may also cause additional symptoms.[symptoma.com]
Nausea
  • Then, they may suffer pain in the stomach area, nausea, and early satiety. They tend to lose their appetite and weight.[symptoma.com]
Early Satiety
  • Then, they may suffer pain in the stomach area, nausea, and early satiety. They tend to lose their appetite and weight.[symptoma.com]
Suggestibility
  • Previous pre-clinical and subgroup analyses of clinical trials have suggested differing benefits from fluoropyrimidine-based chemotherapeutics for diffuse and intestinal gastric cancer.[ncbi.nlm.nih.gov]
  • Two recent studies have identified highly recurrent mutations of the gene encoding the small GTPase RhoA and suggest that RhoA activity may have a tumor suppressive role in this disease. Copyright 2014 Elsevier Inc. All rights reserved.[ncbi.nlm.nih.gov]
  • Haplotype analysis suggested the 163 37235A-allele contributes to disease risk independently of the other variants studied.[ncbi.nlm.nih.gov]
  • CONCLUSIONS: This study suggests that GSTP1 105A/G and GSTT1-null/positive genotypes might be associated with a reduced risk for sporadic diffuse gastric cancer. Clin Chem Lab Med 2007;45:822-8.[ncbi.nlm.nih.gov]
  • Present data are highly suggestive but do not unequivocally prove the cosegregation of germ-line CDH1 mutations with inherited invasive lobular breast cancer (ILBC).[ncbi.nlm.nih.gov]

Workup

Diagnostic imaging, namely upper gastrointestinal endoscopy and computed tomography, are important tools to depict DGC. Endoscopy is the technique of choice to visualize the inner surface of the stomach and to obtain tissue samples for subsequent histological examination. DGC may be below a grossly depressed or ulcerated surface, but superficial lesions are not an exclusion criterion for gastric cancer [1]. Thus, it may be helpful to perform endoscopic sonography or a computed tomography scan before defining the site of biopsy. Common findings in images comprise a more or less diffuse thickening of the gastric wall, which may be explained by individual cells infiltrating the stomach wall without forming a discrete mass, lymphadenopathy, and ascites [2]. In comparison with sonography, computed tomography and other tomographic techniques bear the advantage of possibly demonstrating the presence of metastases. Positron emission tomography/computed tomography is particularly helpful for tumor staging because increased fluorodeoxyglucose uptake is likely to reveal metastases even at uncommon sites [3]. Of note, diagnostic imaging may not yield any pathological findings during early stages of the disease.

In any case, biopsies have to be carried out and histological studies are required to confirm the diagnosis. In general, DGC is characterized by poorly cohesive, diffusely infiltrating cells that may form irregular microtrabeculae or abortive glands, but there are additional features to be analyzed in order to distinguish low- and high-grade neoplasms [1] [4]:

  • Tumor cells that are embedded in abundant fibrous tissue can be seen in low-grade DGC, and this phenomenon is referred to as tumor-embedding desmoplasia. It's this same fibroblast-rich tissue that impedes the invasion of blood and lymphatic vessels, an observation associated with a more favorable prognosis if there are no or few foci of signet-ring or anaplastic cells.
  • Signet-ring DGC is composed of mucin-rich cells that may or may not show the classic signet-ring pattern. Non-signet-ring cells may resemble histiocytes, lymphocytes, or plasma cells.
  • Distinguishing features of anaplastic DGC are pleomorphic, highly atypical nuclei and prominent nucleoli in cytokeratin-positive cells, high cellularity with scarce stroma, and high mitotic index.
  • Finally, there may be DGC combining features of the desmoplastic, signet-ring, and anaplastic subtypes.

Treatment

Surgery is the mainstay of treatment. Depending on imaging and histological findings, patients may be recommended for subtotal or total gastrectomy plus lymphadenectomy. Regardless of the extent of surgery, it may be difficult to determine an appropriate surgical margin because DGC spread diffusely. They are especially likely to expand within the gastrointestinal tract via the submucosal and subserosal lymphatics. Therefore, tissue samples should be obtained from the surgical margin and assessed for the presence of occult tumor cells. In this context, immunohistochemical staining is a highly valuable diagnostic tool [1]. But despite all efforts, it remains difficult to guarantee complete tumor resection. In fact, cure rates have been reported to not exceed 40% [5]. This is a major cause of concern, and it is highlighted by high rates of recurrence and poor survival. Up to 75% of DGC patients relapse within 18 months after surgery, but recurrence has also been observed >5 years after the initial diagnosis [6]. This should be considered when scheduling follow-up examinations.

In order to prolong survival, DGC patients usually undergo chemotherapy after surgery. Fluoropyrimidine-based regimens are most commonly applied to combat gastric cancer, with possible combinations of fluoropyrimidines with doxorubicin and methotrexate, or with cisplatin and epirubicin [6] [7]. Neoadjuvant chemotherapy has also been proposed to improve the outcome [7]. Unfortunately though, DGC has shown remarkable resistance to 5-fluorouracil and capecitabine [6]. Still, there are almost no alternatives. Molecular targeted therapies have not yet been approved for DGC treatment, but may become available as progress is made in the characterization of DGC subtypes. Indeed, knowledge on specific properties of DGC subtypes may also allow for the design of more suitable chemotherapeutic regimens: These subtypes may be associated with an increased or diminished sensitivity to determined compounds [6]. Active compounds currently on trial for their efficacy in the treatment of gastric cancer are PARP inhibitor olaparib, monoclonal antibody pembrolizumab, VEGF receptor 2 inhibitor apatinib, and multikinase inhibitor regorafenib [8].

Prognosis

More than 60 DGC patients have been included in a retrospective study on gastric cancer, and 90% of these patients were diagnosed with DGC in stages 3 or 4. Furthermore, about 70% of them presented lymph node metastases at the time of diagnosis [6]. Considering that the tumor stage is of major importance for the patients' prognosis, it is easily comprehensible why they usually have a poor prognosis. Nevertheless, subtype-specific differences should be considered. DGC rich in anaplastic cells are related to the worst outcome. By contrast, desmoplastic DGC, a subtype of gastric cancer characterized by tumor-embedding desmoplasia as described above, is associated with lower rates of lymph node and distant metastases as well as significantly longer survival [4]. Regardless of tumor stage and histological subtype, the mean survival time of DGC patients is less than two years [6].

Etiology

Contrary to the intestinal type of gastric cancer, which has been associated with Helicobacter pylori infection, dietary habits and life style, DGC is usually related to chromosomal and gene aberrations [1]:

  • On the one hand, there is hereditary DGC, which is the result of germline mutations that often affect tumor suppressor gene CDH1.
  • On the other hand, there is sporadic DGC. Its development may be favored by predisposing, inherited sequence anomalies and by mutations acquired in the course of life.

As per definition, hereditary DGC may be diagnosed if there are at least two cases of DGC in relatives of first or second degree, with at least one of them being diagnosed before the age of 50; or if there are at least three cases of DGC in relatives of first or second degree, independent of their age at diagnosis [1]. But this doesn't exclude a certain predisposition for DGC in patients diagnosed with sporadic disease. Indeed, an Italian research group has shown that GSTP1 105 A/G and 105 G/G genotypes as well as the GSTT1-null genotype reduce the individual risk of developing DGC [9]. Both GSTP1 and GSTT1 encode for proteins implicated in xenobiotic metabolism and DNA damage repair, and it seems likely that polymorphisms in these and other genes may also augment the risk for DGC.

Epidemiology

Gastric cancer is the fourth most common cancer; it is also the second most common cause of death from cancer [1]. Although an overall decline of gastric cancer incidence is frequently described, it is mainly due to a decreasing incidence of intestinal-type gastric cancer. Incidence and prevalence of DGC have been reported to be stable or even to increase [10] [11]. The incidence of DGC approximates 2 per 100,000 inhabitants, and while men and women are affected almost equally, patients of African ancestry are more likely to develop this type of cancer than Caucasian individuals [11]. Sporadic DGC is typically diagnosed in the elder adult: At the time of diagnosis, most patients are >60 years old [6]. By contrast, the hereditary form of the disease usually manifests before the age of 40 [5].

Sex distribution
Age distribution

Pathophysiology

DGC develops in a multistep and multifactorial process that favors the accumulation of genetic anomalies [12]. These anomalies may include, but are not limited to, the excess activation of proto-oncogenes encoding for growth factors and their receptors, proangiogenic mediators and matrix metalloproteinases, as well as the inactivation of tumor suppression genes encoding for cell-cycle regulators and genes implicated in DNA repair or cell adhesion [1]. While DNA sequence alterations may account for such anomalies, epigenetic aberrations should also be considered. DNA methylation, histone modification and chromatin remodeling may all contribute to DGC cancerogenesis [12].

Prevention

Because increasing genetic instability due to the accumulation of genetic anomalies is assumed to be the cause of DGC development, genetic studies might be employed to assess an individual patient's risk for this disease. Preliminary studies have been carried out to this end and yielded promising results [9] [12]. However, we are still far from a gene-based risk assessment as a prophylactic measure against sporadic DGC. By contrast, genetic studies and genetic counseling should be offered to families affected by hereditary DGC.

Summary

Gastric cancer is one of the most common cancers worldwide [12]. In the middle of the 20th century, a classification scheme has been proposed for gastric cancer. Intestinal-type gastric cancer, diffuse-type gastric cancer, and intermediate-type gastric cancer have then been defined according to clinical and histological features [13]. These categories continue to provide a rough orientation regarding the nature of gastric cancer, but in the meantime, the classification scheme has been supplemented by subtypes. For instance, there are papillary, tubular, and mucinous adenocarcinoma as subtypes of intestinal-type gastric cancer, and signet-ring cell carcinoma as well as other poorly cohesive carcinoma as subtypes of DGC [1].

Patient Information

Gastric cancer is one of the most common cancers worldwide. There are distinct types of gastric cancer, with one of them being diffuse gastric cancer (DGC). In this context, "diffuse" refers to the characteristic growth behavior of this type of tumor. It diffusely infiltrates the stomach wall, which causes gastric wall thickening and loss of flexibility. DGC are unlikely to grow as discrete, solid masses.

DGC patients don't usually experience any symptoms until advanced stages of the disease. Then, they may suffer pain in the stomach area, nausea, and early satiety. They tend to lose their appetite and weight. Neither of these symptoms is specific for gastric cancer and it is not possible to diagnose the disease without employing certain diagnostic tools. On the one hand, it is necessary to visualize the inner surface of the stomach, its wall, regional lymph nodes and surrounding tissues. This is generally done by endoscopy, endoscopic ultrasound, and computed tomography. Images obtained by these techniques allow for a tentative diagnosis and facilitate tumor staging, i.e., they provide valuable hints on the possible presence of metastases. On the other hand, tissue samples have to be obtained for subsequent histological examination. Biopsies are typically performed during the endoscopic examination and after tissue samples have been assessed under the microscope, the diagnosis of DGC may be confirmed.

Surgical removal of the tumor and regional lymph nodes plus chemotherapy is the most common approach to therapy. Due to the diffuse growth behavior of DGC, it is difficult to remove it entirely. Therefore, most patients are recommended for chemotherapy after the respective surgical intervention. The patients' prognosis largely depends on the stage of DGC at the time of diagnosis: If the tumor is detected early, they have a favorable prognosis. If it is diagnosed in advanced stages, the prognosis is poor.

References

Article

  1. Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol. 2012; 3(3):251-261.
  2. Hommel C, Knoedler M, Bojarski C, et al. Diffuse gastric cancer with peritoneal carcinomatosis can mimic Crohn's disease. Case Rep Gastroenterol. 2012; 6(3):695-703.
  3. Morita K, Sakamoto T, Ota S, et al. Ultrasound findings of diffuse metastasis of gastric signet-ring-cell carcinoma to the thyroid gland. J Med Ultrason (2001). 2017; 44(1):133-139.
  4. Chiaravalli AM, Klersy C, Tava F, et al. Lower- and higher-grade subtypes of diffuse gastric cancer. Hum Pathol. 2009; 40(11):1591-1599.
  5. Kaurah P, Huntsman DG. Hereditary Diffuse Gastric Cancer. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  6. Pattison S, Mitchell C, Lade S, Leong T, Busuttil RA, Boussioutas A. Early relapses after adjuvant chemotherapy suggests primary chemoresistance in diffuse gastric cancer. PLoS One. 2017; 12(9):e0183891.
  7. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006; 355(1):11-20.
  8. Recio-Boiles A, Babiker HM. Cancer, Gastric. StatPearls. Treasure Island (FL): StatPearls Publishing LLC; 2017.
  9. Ruzzo A, Canestrari E, Maltese P, et al. Polymorphisms in genes involved in DNA repair and metabolism of xenobiotics in individual susceptibility to sporadic diffuse gastric cancer. Clin Chem Lab Med. 2007; 45(7):822-828.
  10. Faria GR, Pinto-de-Sousa J, Preto JR, Sousa HS, Barbosa JA, Costa-Maia J. Three decades of clinical-pathological trends in gastric cancer: prospective data from a Portuguese hospital. Int J Surg. 2013; 11(6):472-476.
  11. Henson DE, Dittus C, Younes M, Nguyen H, Albores-Saavedra J. Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973-2000: increase in the signet ring cell type. Arch Pathol Lab Med. 2004; 128(7):765-770.
  12. Yasui W, Sentani K, Motoshita J, Nakayama H. Molecular pathobiology of gastric cancer. Scand J Surg. 2006; 95(4):225-231.
  13. 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. 1965; 64:31-49.

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Last updated: 2019-07-11 20:52