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Stomach cancer is one of the most common malignant diseases. It is usually only discovered very late. Symptoms should therefore be clarified at an early stage.

Gastric carcinoma is a malignant epithelial tumor of the gastric mucosa. It is histologically divided into different types. According to the Laurén grading system, a distinction is made between an intestinal type with polypous, glandularly differentiated growth and clearly defined borders, a diffuse type with infiltrative growth, diffusely spread into the stomach wall and poorly defined borders, and a mixed type. The intestinal type is the most common, closely followed by the diffuse type. Histologically, the WHO also differentiates between papillary, tubular and mucinous adenocarcinoma - the most common type - with the subtypes of signet ring cell carcinoma, adenosquamous carcinoma, squamous carcinoma (also known as squamous cell carcinoma), small cell carcinoma and undifferentiated carcinoma.

Epidemiology

Gastric carcinomas occur with varying frequency throughout the world. The cancer accounts for around 3.5% of all malignant tumors in men - the eighth most common cancer location - and 2.5% in women - the tenth most common location. Around 34% of women survive the next five years, 32% the next 10, while the figures for men are 32% and 28% respectively. Overall, the number of newly diagnosed stomach cancers is declining.

Most patients are older than 50 when they are first diagnosed. However, around 10% of patients are diagnosed between the ages of 30 and 40. The disease peaks between the ages of 70 and 80. The most important risk factor is a Helicobacter pylori infection in the stomach. However, the Epstein-Barr virus is also thought to cause 5 to 10% of gastric carcinomas.

Gastric carcinoma is the sixth most common cause of all cancer deaths. Around 40% of all patients die within the first year of diagnosis.

Causes

One of the most common causes of stomach cancer is probably the bacterium Helicobacter pylori (HP). If a person is infected with it, it causes chronic active inflammation in the patient's stomach, known as HP gastritis. More than 90% of early gastric carcinomas exhibit such HP gastritis - HP is therefore considered a class I carcinogen for gastric carcinomas in the corpus and antrum. Adequate treatment is therefore essential in the prophylaxis of Helicobacter pylori infestation.

In addition to HP-associated gastric carcinomas, the Epstein-Barr virus is also considered a suspected risk factor. However, the figures are significantly lower. However, it is not yet possible to say exactly what role the virus plays in the development of stomach cancer.

In addition to HP gastritis, type A gastritis (autoimmune gastritis) is also responsible for an increased risk of stomach cancer, as is intestinal metaplasia. If an adenomatous gastric polyp is already present, this can also be responsible for gastric carcinoma, as in up to 20% of cases a gastric carcinoma develops on the basis of such a polyp. Other risk factors are also possible causes:

  • a partial gastric resection in the past
  • ménétrier's disease
  • a ventricular ulcer
  • a positive family history
  • a hereditary colon carcinoma
  • a non-polypous colon carcinoma (HNPCC for short)
  • familial adenomatous polyposis coli (FAP)
  • peutz-Jeghers syndrome
  • hereditary diffuse gastric carcinoma (HDGC) with mutations in the cadherin 1 (CDH) or catenin alpha 1 (CTNNA1) gene
  • li-Fraumeni syndrome

High nitrate content in the diet and alcohol or nicotine abuse are also considered avoidable risk factors that could be the cause of stomach cancer. Obesity and reflux disease are additional risk factors for tumors at the junction between the esophagus and stomach (gastroesophageal junction).

Pathogenesis

Like most cancers of the digestive tract, carcinomas develop in stages. The exact development depends on the cause. One explanation is that various noxious agents, a Helicobacter pylori infection or a predisposition lead to chronic or atrophic gastritis. In HP gastritis, for example, the pH value rises and the gastric mucosa is increasingly colonized by anaerobic bacteria. These in turn can promote the formation of carcinogenic N-nitroso compounds. Genetic characteristics of the Helicobacter bacterium itself are also being discussed as carcinogenic.

As a result of chronic or atrophic gastritis, telomeres shorten and telomerase activity increases. The normal epithelium changes and intestinal metaplasia develops. Further genetic changes, for example in the tumor suppressor genes, result in early carcinomas that develop into intestinal-type carcinomas.

In the diffuse type, on the other hand, telomere shortening and increased telomerase activity presumably occur directly. Genetic changes lead to an early carcinoma that develops into a diffuse-type carcinoma. The exact mechanism has not yet been sufficiently researched.

However, all these models only reflect current knowledge, as the exact molecular genetic development of gastric carcinoma depends not only on the type of carcinoma, but also on many other influences that have not yet been conclusively clarified.

Metastasis

One of the main problems of gastric carcinoma is metastasis (spread). This type of cancer spreads to other areas and organs at a very early stage, both lymphogenically and haematogenically. Around 70% of patients already have metastases at the time of diagnosis.

Lymphogenic metastasis occurs in three compartments. First, the cancer spreads to the lymph nodes located directly on the large and small curvature of the stomach. Subsequently, the second compartment with all lymph nodes on and around the celiac trunk up to the hepatic artery and the splenic hilus is affected. The paraaortic and mesenteric lymph nodes form the third compartment.

Gastric cancer spreads hematogenously via the liver, then to the lungs, bones and brain. The oesophagus, duodenum, colon and pancreas can also be infiltrated as neighboring structures. The same applies to the peritoneum with peritoneal carcinomatosis. A special feature of gastric carcinoma is the Krukenberg tumor. This is a drip metastasis in the ovaries or the Douglas space.

Symptoms

Gastric carcinoma usually causes only discrete and vague symptoms. Many patients, if they notice them at all, attribute them to their diet, stress or similar.

More frequently, general symptoms such as weight loss, chronic iron deficiency anemia (anemia caused by iron deficiency) or an aversion or aversion to meat are described.

Nausea and vomiting, a feeling of pressure in the upper abdomen, a drop in performance, weight loss, an early feeling of fullness or subfebrile temperatures (elevated temperatures) can also occur. The upper abdominal symptoms also manifest as a feeling of fullness and pain on fasting. Acute gastric bleeding can also occur. It is sometimes only noticed by tarry stools if it is not so severe that the patient begins to vomit blood.

In the case of advanced carcinomas, the tumor can be felt in the upper abdomen. The cancer has then often already spread and the metastases become symptomatically noticeable, for example through an enlarged liver (hepatomegaly), ascites or left supraclavicular Virchow's lymph nodes. Gastric outlet stenosis and tumor cachexia are also known to accompany the disease. As well as acanthosis nigricans maligna.

Diagnostics

In addition to the classic medical history and physical examination, clinical chemistry (laboratory tests), instrumental diagnostics and histology are particularly important for the diagnosis of gastric carcinoma.

Early diagnosis is crucial here, as advanced gastric carcinomas are associated with a poor prognosis. Therefore, if gastric complaints or "irritable stomach syndrome" is suspected, treatment with proton pump inhibitors, for example - often referred to colloquially as "stomach protection" or "acid blockers" - should not be attempted for longer than three weeks. After this, endoscopic biopsies must be performed to clarify what is behind the persisting symptoms. Patients with a high risk of gastric cancer, such as those with ulcer or reflux disease, should undergo an annual gastroscopy to detect any changes in the tissue at an early stage.

A laboratory test is often recommended. However, it only plays a subordinate role in primary diagnostics and is sometimes used primarily to rule out other diseases. A blood count, kidney and liver function parameters and TSH are taken for this purpose. Tumor markers are only helpful as a follow-up and in the context of clinical studies. These tumor markers include CA72-4, CA19-9 and CEA.

Instrumental diagnostics

An oesophagogastroduodenoscopy, or OGD for short, is performed at an early stage if symptoms and alarm signals are unclear.

The alarm signals include

  • persistent swallowing disorders (dysphagia)
  • recurrent vomiting
  • Loss of appetite (inappetence)
  • unclear weight loss: the rule of thumb here is: at least 10% of body weight in the last six months and without active or passive intervention by the patient.
  • gastrointestinal bleeding
  • unclear iron deficiency anemia

The first step in the OGD is a macroscopic search for conspicuous areas using high-resolution video endoscopy. The transitions are of particular interest, but the entire area from the oral cavity to the transition from the stomach to the duodenum should be examined. If conspicuous areas are present, they are all biopsied several times. At least eight biopsies should be taken from all areas if gastric carcinoma or other malignant changes are suspected. If the suspicious areas, the lesions, are particularly large, at least ten biopsies are taken. This is supplemented by four further biopsies, two of which are taken from the antrum and two from the corpus of the stomach. Without exception, the samples are all histologically processed and examined in order to find or exclude tumorous tissue. However, biopsies from normal mucosa are not taken as standard in accordance with guidelines.

If the findings are unremarkable, the OGD can be repeated at an early stage and biopsied again. Abnormal lymph nodes can also be examined using fine needle aspiration cytology. Alternatively, an endosonography or endoscopic ultrasound examination (EUS) with targeted biopsy of suspected lesions can be ordered. In this context, endosonography also helps to find out how deep the carcinoma has penetrated into the stomach wall and whether neighboring lymph nodes are affected. It is helpful for staging, but also requires histology in order to differentiate between benign and malignant growths.

Staging and classification

How advanced the disease is depends on how far it has spread. As the therapy also depends on this, a diagnosis of the spread, also known as staging, is carried out after the initial diagnosis.

In a first step, a sonography of the abdomen is performed. This is to rule out liver metastases and other distant metastases. If lymph node metastases are suspected, the neck is also sonographically imaged. This is particularly important if the carcinoma is located at the junction between the oesophagus and stomach. If the findings are unclear, contrast medium can also be used during sonography. If the carcinoma or the suspected carcinoma structure is located at the junction between the oesophagus and stomach - a so-called AEG - a sonography of the neck is also performed. In the case of such carcinomas, positron emission tomography, or PET for short, can also be performed in order to better plan the subsequent therapy for resectable tumors.

Endosonography, which has already been mentioned in the diagnostics section, is used in staging at the latest when it is necessary to assess how deep the tumor has grown into the tissue and whether local lymph nodes could be affected. However, endosonography cannot rule out lymph node metastases with certainty. For this reason, a CT scan of the abdomen and pelvis should also be performed - ideally with intravenous contrast medium and a stomach filled orally with contrast medium or water - as well as a CT scan of the thorax. Only if a CT scan cannot be performed can a magnetic resonance imaging (MRI) scan be requested. However, this is an exception. Locally advanced gastric carcinomas that are probably at stage cT3 or cT4 (the "c" here stands for "clinical", i.e. a clinically suspected but not yet pathologically confirmed stage). In this case, the exact stage can influence the therapy.

The tumor is graded histologically according to Laurén or according to WHO grading. In the case of advanced cancer, a laparoscopy with cytology is also performed for this purpose.

The degree of differentiation is described as G1=high, G2=medium, G3=low and G4=lack of differentiation. Gastric carcinoma is classified according to the TNM classification with the categories T, N and M for the extent of the tumor, affected lymph nodes and distant metastases.

In addition, histological or molecular classification is used according to various classifications. The Laurén classification distinguishes between three different types:

  • intestinal type
  • diffuse type
  • indeterminable type

The WHO classification subdivides into the types based on histology:

  • tubular
  • papillary
  • mucinous
  • low cohesive (including signet cell carcinoma)

A third classification is made according to the molecular characteristics of gastric carcinoma. It currently has no effect on treatment decisions. It is The Cancer Genome Atlas (TCGA) classification and classifies on the basis of genome, transcriptome, epigenome and proteome:

  • chromosomally unstable (CIN)
  • Epstein-Barr virus-associated (EBV)
  • Microsatellite unstable (MSI)
  • genomically stable (GS)

Staging is based on the UICC (Union of International Cancer Control) criteria with stages 0 (carcinoma in situ), Ia, Ib, II, IIIA, IIIB and IV.

The R classification is also taken into account for gastric carcinoma, as it is decisive for the prognosis and further treatment. It indicates how much residual tumor remains in the incision area after surgery. R0 means that the tumor could be completely removed (no residual tumor). R1 stands for a microscopic residual tumor and R2 for a macroscopic residual tumor.

Differential diagnoses

  • Gastric ulcer
  • Reflux esophagitis
  • Ménétrier's disease
  • Irritable stomach syndrome
  • Liver, pancreatic or biliary tract diseases
  • other gastric tumors such as MALT lymphomas, sarcomas and co
  • gastrointestinal stromal tumor (GIST)
  • polypous gastric mucosal changes

Therapy

All gastric carcinomas are treated according to their stage and subtype. In all cases, the tumor should be removed as completely as possible in order to achieve an adequate prognosis.

Endoscopic resection

If a tumor is intraepithelial - a so-called dysplasia - it can often be removed endoscopically. The same applies to early gastric carcinomas. Both should be a maximum of 2 cm in diameter, not ulcerated, only a mucosal carcinoma and of the intestinal type or well to moderately histologically differentiated. The technique of choice today is endoscopic submucosal dissection, or ESD for short. Resection pursues a curative approach. However, if at least one extended criterion is present, resection is necessary. The extended criteria are

  • differentiated mucosal carcinoma grade G1 or G2 without ulceration and larger than 2 cm
  • Differentiated mucosal carcinoma with ulceration and a maximum size of 3 cm
  • Well-differentiated carcinoma with submucosal invasion of less than 500 micrometers and a size of less than 3 cm
  • Undifferentiated mucosal carcinoma smaller than 2 cm in diameter and at least 1 cm tumor-free margin

If an R0 resection is successful - i.e. the resection margin is tumor-free - the patient should be closely monitored endoscopically. If only an R1 resection can be achieved in the ESD, a resection should be performed.

Surgical therapy

If there is no early gastric carcinoma because the disease is already more advanced, more invasive interventions are performed. In most stages, the tumor or the entire stomach (gastrectomy) and the regional lymph nodes are completely removed. The first step in treatment is therefore surgery.

As it is particularly important that the resection margins are tumor-free, a safety margin of 5 cm to 8 cm is maintained between the tumor and the incision margin - depending on the tumor type according to Laurén. This is usually achieved by subtotal distal gastric resection or gastrectomy with subsequent reconstruction. With a few exceptions, a Roux-Y reconstruction with a jejunum interposition is chosen as the reconstruction method. If the tumor cannot be completely removed and an R1 resection is confirmed histologically, a resection can be attempted first. If this is not possible, the operation is followed by radiochemotherapy. In these cases, the case should be discussed in the tumor board or another interdisciplinary tumor conference.

Together with the surgical resection, both compartment I and compartment II of the regional lymph nodes are removed. This so-called D2 lymphadenectomy is particularly necessary for curative therapy, as this is where metastases are most frequently found. If the spleen and pancreas remain completely in the patient's body, the guidelines recommend removing at least 25 regional lymph nodes. The minimum number of regional lymph nodes to be removed is 16 in order to fully classify the cancer histopathologically and to find possible lymph node metastases.

Palliative stages of the disease are an exception to this therapy. If patients in these stages are asymptomatic and have no gastric bleeding, the primary tumor is not surgically removed. In these cases, as well as in cases of functional inoperability or irresectability, definitive radiochemotherapy can or will be carried out.

Multimodal therapy

At the latest from stage T3 or cT3 (clinically diagnosed stage T3 - here histological confirmation is still pending), perioperative chemotherapy is carried out for locally advanced gastric carcinoma. Patients receive chemotherapy before the operation, which is continued after the operation. In this way, the staging of the carcinoma (downstaging) and the recurrence rate can be reduced. Combinations based on platinum and 5-FU are used. As a rule, the FLOT regimen is used.

Perioperative chemotherapy can also be used for non-distantly metastasized adenocarcinoma of the oesophagogastric junction. It is particularly suitable for stage cT4 or a resectable cT4 tumor. Alternatively, neoadjuvant radiochemotherapy is carried out. If preoperative or neoadjuvant therapy is used, restaging is then carried out. This is usually done using CT or OGD.

Preoperative, perioperative and neoadjuvant therapies are also usually supplemented by a surgical intervention in which the tumor is removed as completely as possible. Whether further chemotherapy should be given after the operation is decided on an interdisciplinary basis. This depends, among other things, on the stage of the disease, the general condition and the success of the operation. Further treatment operations may be carried out as part of clinical trials. These include antibody studies, for example. They are carried out at specialized centers.

Aftercare

One part of aftercare is nutrition. The nutritional status of all patients should be assessed before the start of therapy and also afterwards with every intervention, inpatient admission or treatment, as nutrition is particularly impaired after a gastrectomy, partial resection or other major procedures or therapies. This is why all patients are offered nutritional therapy. This applies in particular to patients who would otherwise probably not be able to cope with a planned therapy.

In the case of a gastrectomy, it is not only general food intake that is affected. Vitamin B12 can no longer be absorbed at all. It must therefore be substituted parenterally by injection for the rest of the patient's life after gastrectomy. If fatty stools also occur, pancreatic enzymes must also be administered. Unlike vitamin B12, however, they can be given orally.

In addition to nutritional control and therapy, the focus is on structured follow-up appointments. Follow-up appointments with clinical checks, endoscopic checks and imaging should take place at least after 6, 12, 18 and 24 months. After two years, there is a switch to annual check-ups, which continue until the fifth year.

Prognosis

As with most cancers, the prognosis depends on the stage. averaged across all stages, the 5-year survival rate is 30 to 32% for men and 33 to 34% for women. However, the earlier gastric cancer is detected, the better the prognosis. This also reinforces the fact that symptoms must be clarified at the latest when they have been present for three weeks.

If patients have undergone curative surgery, the 5-year survival rate by stage in the earlier stages is around

  • pTis (carcinoma in situ): approx. 100%
  • pT1 (early carcinoma): 90%
  • pT1N1M0 or pT2N0M0: 70%

If the cancer is already advanced, the success of treatment depends to a large extent on how well and, above all, how completely the tumor could be removed in the first operation. If the tumor and all affected lymph nodes can be completely removed (R0 resection), the 5-year survival rate in the later stages is around 45%. However, if the entire tumor cannot be removed and only an R1 or R2 resection is successful, almost all patients die within the next five years.

Prophylaxis

A healthy diet can partially prevent stomach cancer from developing. An important prophylaxis is the eradication of Helicobacter pylori in HP gastritis and regular check-up gastrostomies in patients at risk. More than 90% of early gastric carcinomas are discovered in patients with HP gastritis. Stopping or giving up smoking could also have a positive effect on the development of gastric cancer.