“Victor Babe?” UNIVERSITY OF MEDICINE AND PHARMACY TIMI?OARAFACULTY OF MEDICINE Department of Internal Medicine II Discipline of Gastroenterology VALESCA KIRCHHOFF LICENCE THESIS Scientific Coordinator Assist. Prof. BOGDAN MIU?ESCU T i m i ? o a r a 2 0 1 8 “Victor Babe?” UNIVERSITY OF MEDICINE AND PHARMACY TIMI?OARAFACULTY OF MEDICINE Department of Internal Medicine II Discipline of Gastroenterology VALESCA KIRCHHOFF LICENCE THESIS RESULTS OF GASTRIC CANCER EVALUATION IN A TERTIARY GASTROENTEROLOGICAL CARE CENTER Scientific Coordinator Assist. Prof.
BOGDAN MIU?ESCU T i m i ? o a r a 2 0 1 8 Table of Content TOC o “1-3” h z u LIST OF ABBREVIATIONS PAGEREF _Toc512445545 h 3PART I. INTRODUCTION PAGEREF _Toc512445546 h 4PART II REVIEW OF THE LITERATURE PAGEREF _Toc512445547 h 51. Definition PAGEREF _Toc512445548 h 52. Epidemiology PAGEREF _Toc512445549 h 53.
Aetiology PAGEREF _Toc512445550 h 53.1 Exogenous risk factors PAGEREF _Toc512445551 h 53.2 Endogenous risk factors PAGEREF _Toc512445552 h 54. Diagnosis PAGEREF _Toc512445553 h 74.1 Premalignant conditions PAGEREF _Toc512445554 h 74.2 Types of gastric cancer PAGEREF _Toc512445555 h 74.3 Clinical symptoms PAGEREF _Toc512445556 h 94.4 Paraclinical examinations PAGEREF _Toc512445557 h 104.5 Staging PAGEREF _Toc512445558 h 105. Treatment PAGEREF _Toc512445559 h 14PART II: PERSONAL CONTRIBUTIONS PAGEREF _Toc512445560 h 161. Introduction PAGEREF _Toc512445561 h 162. Material and Method PAGEREF _Toc512445562 h 163.
Results PAGEREF _Toc512445563 h 174. Discussion PAGEREF _Toc512445564 h 315. Conclusion PAGEREF _Toc512445565 h 33ACKNOWLEDGEMENTS PAGEREF _Toc512445566 h 34REFERENCES PAGEREF _Toc512445567 h 35Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al.Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. European Journal of Cancer (2013) 49, 1374-1403. PAGEREF _Toc512445568 h 35 LIST OF ABBREVIATIONS INDEX e “” h “A” c “2” CT Computer Tomography EGJ Oesophageal-gastric Junction ESMO European Society of Medical Oncology EUS Endoscopic Ultrasound GI Gastrointestinal HER2 Human Epidermal Growth Factor Receptor 2 HPHelicobacter Pylori IM Intestinal Metaplasia JGCA Japanese Gastric Cancer Association M Mucosa MPMuscularis PropriaOROdds Ratio pHPower of Hydrogen PPI Proton Pump Inhibitor SE Beyond Serosa SI Invading adjacent structures SM Submucosa SS SubserosaWHO World Health Organisation PART I.
INTRODUCTIONThe term cancer describes a group of diseases characterized by their uncontrolled division of abnormal cells as well as their ability to invade and spread to other tissues . The WHO (World Health Organisation) refers to cancer as the second leading cause of mortality worldwide with a number of 8.8 million deceased in 2015. 14.1 million cases of cancer were newly diagnosed in the year of 2012. In the WHO cancer statistics of 2017 gastric cancer is named among the 5 deadliest malignancies, being responsible for the fourth highest number of cancer related deaths worldwide . In 2012 8.2 million deaths as a consequence of cancer where accounted, 46% of these due to common cancers – malignancies of lung, liver, stomach and bowel .
Problematic of diagnosis in advanced stages; rarely early symptoms Comparison to development in Japan with screening program; Importance of topic due to high mortality; PART II REVIEW OF THE LITERATURE1. DefinitionGastric cancer describes a malignant tumour deriving from the epithelium of the stomach . 2. EpidemiologyThe incidence in Romania in the year 2012 was 15.1/100 000, with a significantly higher value in men 23.7/100 000 in comparison to 8.5/100 000 in women . Therefore it ranks as the seventh most common form of a malignant neoplasia in Romania.
In the countries of the European Union it accounts for 10.7 cases of gastric cancer per 100 000 inhabitants, with a male incidence of 15.2/100 000 and a female incidence of 7.1/100 000 . According to the WHO gastric cancer is accountable for the fourth highest number of cancer deaths worldwide in the year 2015, ranking after lung cancer, hepatic cancer and colorectal cancer NOTEREF _Ref512425007 h 1. 3. Aetiology3.1 Exogenous risk factorsAs in many forms of malignant neoplasia wide spread health risks our modern society is dealing with impact the probability to develop gastric cancer.
Among others these include alcohol and tobacco consumption. Adiposity owns a special validity regarding cancers of the oesophageal-gastric junction ,. Furthermore an alimentation rich in nitrate has been proven to be of significant impact . Following a diet low in fresh fruits and vegetables favours the appearance of a stomach malignancy. A study conducted on 521 457 men and women originating from 10 different European countries concludes in an increased meat consumption being an important risk factor especially in combination with a simultaneous HP infection .
3.2 Endogenous risk factorsOne of the essential risk factor for gastric cancer is a chronic Helicobacter Pylori (HP) infection. Even before Marshall and Warren discovered Helicobacter Pylori in the 1980s a connection between chronic gastritis and gastric cancer incidence was seen . The association between HP infection and chronic atrophic gastritis increases the risk of developing gastric cancer, particularly of the malignancy being located in the gastric antrum, body or fundus . Even though Prinz et al. presented the prevalence rates as declining in Western countries, HP infection remains the strongest risk factor for gastric cancer .
Proton pump inhibitors (PPI) are part of HP infection treatment and often used long-term. According to a study conducted by Cheung et al. on 63 397 patients an association between the persistent use of PPIs and risk of gastric cancer development has been proven . A previously performed gastric operative intervention is counted as a risk factor for gastric cancer based on the its´ influence on the stomachs´ pH which may result in dysplastic and metaplastic changes .
The development of gastric cancer may also take place after a partial gastrectomy in the remnant body of the stomach or on the ground of a benign gastric ulcer ,. Especially the formerly common performed ulcer surgery resulted in an incidence rise. Furthermore some genetic disorders seem to be in cumulative relation to gastric cancer cases. These include: Familial adenomatous polyposis Peutz-Jeghers syndrome Li-Fraumeni syndrome Hereditary non-polypous colorectal cancer Neurofibromatosis type 1 (Morbus Recklinghausen) Cowden syndrome NOTEREF _Ref512424516 h 13 A family history with affection of a first degree relative by gastric cancer also raises the risk of developing this pathology. In 2010 a meta-analysis was published showing the increase of the odds-ratio of 1,98 (95% CI, 1,36-2,88) in case of a first-degree relative with gastric cancer in the family history ,. Patients with blood type A appear to have a higher risk to develop gastric cancer .
Other affections going along with gastric cancer are chronic atrophic autoimmune gastritis (type A), adenomatous gastric polyps and Ménétrier´s disease. Latter is a rare form of idiopathic hypertrophic gastropathy. 4. Diagnosis4.1 Premalignant conditionsMetaplasia is defined as the reversible transformation of a differentiated tissue to another differentiated tissue, especially in the context of regeneration as a result of chronic irritation by inflammatory, chemical or mechanical factors NOTEREF _Ref512435466 h 2. In case of intestinal metaplasia (IM) this signifies “the loss of gastric epithelium and replacement with an intestinal phenotype containing goblet cells, Paneth cells and absorptive cells” NOTEREF _Ref512425582 h 14.
Intestinal metaplasia is a known premalignant condition exposing the patient to risk up to 6-fold higher than average to develop gastric cancer NOTEREF _Ref512425582 h 14. This causality is based on the fact of IM being the groundwork for dysplasia and finally the progression to an adenocarcinoma as it has been described by Correa in 1988 NOTEREF _Ref512425582 h 14, , whereat the intermediate step of dysplasia is defined as pre-neoplastic cellular atypia of different severity in connection with a disturbed epithelial structure NOTEREF _Ref512435466 h 2. The progression of IM to gastric cancer has been investigated by at least 2 separate studies, one in Japan following up on 1246 patients with gastric IM for a average period of 7,8 years leading to a relative risk of progression of 6,4 (95% CI, 2,6-16,1) NOTEREF _Ref512425582 h 14, . In the Western world a large study has been performed by a Dutch team coming to a conclusion of a 10 year incidence of 1,8% after investigating 61 707 patients of whom 874 developed gastric cancer NOTEREF _Ref512425582 h 14, . 4.2 Types of gastric cancerHistologically gastric cancer is subclassified in 5 categories: Adenocarcinoma Gastrointestinal stromal tumorsCarcinoids AdenoacanthomasSquamous cell carcinomas Regardless of this categorization gastric cancer specimens may also be grouped by their gross appearance as being ulcerative, polypoid, scirrhous, superficially spreading, multicentric or Barret ectopic adenocarcinomas .
Out of the previously mentioned types the adenocarcinoma is the most prevalent form presenting 90 to 95% of malignancies developing in the stomach. According to their histological description they are further subcategorized into tubular, papillary, mucinous and signet-ring cell carcinomas NOTEREF _Ref512438490 h 1. Complementary gastric malignancies may be classified according to the 1965 established Laurén classification. Its’ division into an intestinal, diffuse and later added indeterminate type enables us to conclude clinically relevant information; nonetheless its’ prognostic value is still controversial . German S3 Guidelines e.
g. refers to the Laurén classification when recommending different resection margins for the intestinal and diffuse type NOTEREF _Ref512438510 h 8. The intestinal type is associated with chronic atrophic gastritis, limited invasiveness and a clearly defined margin, pathologically classified as epidemic and maintaining a glandular structure. A strong relation to environmental risk factors – as HP infection – has been shown as well as the absence of a family history of gastric cancer NOTEREF _Ref512438836 h 25. On the other hand the diffuse, infiltrative, endemic type defines itself by poorly differentiated scattered cell clusters with deceitful difficultly definable margins.
Studies show a higher incidence in younger patients and women with less influence of environmental factors and a greater significance of genetic factors and family history NOTEREF _Ref512438836 h 25, NOTEREF _Ref512438787 h 26. The review of Berlth et al takes these different epidemiologic and risk factor relationships as an indicator there might be different developmental pathways for gastric intestinal and diffuse adenocarcinomas NOTEREF _Ref512438787 h 26. Laurén classification WHO classification Intestinal type Papillary adenocarcinoma Tubular adenocarcinoma Mucinous adenocarcinoma Diffuse type Signet-ring cell carcinoma and other poorly cohesive carcinomas Indeterminate type Mixed carcinoma Adenosquamous carcinoma Squamous cell carcinoma Hepatoid carcinoma Carcinoma with lymphoid stroma ChoriocarcinomaCarcinosarcomaParietal cell carcinoma Malignant rhabdoid tumor Mucoepidermoid carcinoma Paneth cell carcinoma Undifferentiated carcinoma Mixed adeno-neuroendocrine carcinoma Endodermal sinus tumorEmbryonal carcinoma Pure yolk sac carcinoma Oncocytic adenocarcinoma Table SEQ Table * ARABIC 6 Laurén classification NOTEREF _Ref512438787 h 26 4.3 Clinical symptomsUnfortunately gastric cancer rarely leads to early symptoms and even if it does these are difficult to interpret accordingly do to their highly unspecialized character. Patients later diagnosed with gastric cancer are often hospitalized complaining about loss of appetite, progressive weight loss occurring over a longer period of time and fatigue, all of which are highly unspecific symptoms. Besides the previously mentioned symptoms abdominal pain especially epigastrically localized, dysphagia, dyspepsia, upper GI (gastrointestinal) bleeding and anaemia are indicators for the need of further evaluation.
Depending on the localization of the “growth” and its´ extension it may impact other organs resulting in diffuse or localized pain, as well as an aversion to certain food or food in general due to a partial, total or mixed dysphagia in relation with a site of proliferation near the EGJ (esophagogastric junction). In case of a stomach lesion causing bleeding the patient presents himself with hematemesis, melena, anaemia or a combination of these symptoms depending on the localization and quantity of blood loss. These clinical symptoms have been proven to be relevant in the prognosis of gastric cancer survival. In a study by Stephens the link between the presence of “alarm symptoms” and the stage of the tumour has been shown. Stating that the patients with the most alarm symptoms at presentation where also the ones diagnosed with the most advanced stages of the disease. In the cited article the expression “alarm symptoms” describes the conglomerate of weight loss, dysphagia, signs and symptoms of upper GI bleeding, anaemia and persistent vomiting .
4.4 Paraclinical examinationsApart from the obligatory clinical examination of the patient technology gives us the chance to evaluate a suspected gastric cancer with the help of more or less invasive methods. Gold Standard in the evaluation of gastric and oesophageal cancer is the endoscopy of the upper GI tract. Gastroscopy enables us to evaluate the whole oesophagus and stomach visually, localize suspicious lesions as well as to take biopsies for histopathological investigations whereby only a very low case fatality rate must be accepted NOTEREF _Ref512438510 h 8. Another benefit is its´ high diagnostic accuracy of 95% NOTEREF _Ref512438836 h 25, as well as its´ ability to attend to eventual bleedings.
Complementary to esophagogastroduodenoscopy endoscopic ultrasound (EUS) can be used. The role of EUS lies in its´ ability to assess the depth of invasion of the neoplasia. Problematic is its´ limitation by the capability and experience of the operator and its´ overall accuracy of 46,2% for T classification and 66,7% for N classification in a large multi-institutional study regarding the use and accuracy of EUS in patients undergoing resections of gastric adenocarcinoma with a curative intention ,. Despite its´ limitations EUS is a useful tool regarding staging if its´ results are interpreted in combination with other paraclinical examinations. In case of severe restrictions of endoscopy due to the oesophagus or a part of the stomach being obstructed and circumvent the passage of the endoscope the possibility remains to obtain information by Barium swallow or double contrast upper GI series.
Due to their accuracy of 75% their value in optimal conditions of evaluations is limited NOTEREF _Ref512438836 h 25. CT and MRI studies of the chest, abdomen and pelvis are necessary for the assessment of local disease as well as potential metastasis and invaded lymph nodes NOTEREF _Ref512438490 h 1. Radiographies of the chest are also commonly performed in order to determine the presence of metastasis. 4.5 StagingStaging describes the specific extent of a malignant neoplasia by clinical examination or operative exploration, enabling physicians to informed decision making regarding treatment planning and providing prognostic data.
NOTEREF _Ref512435466 h 4, 4.5.1 TNM classification The aim of the TNM classification of malignant tumours is to describe the anatomical extension of a solid neoplasia in a universally accepted way. This is obtained by the use of 3 parameters – T describing the size of the original tumour and its´ eventual invasion of nearby situated structures, N describing the affection of regional lymph nodes and M the presence of distant metastasis . Primary Tumour (T) TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ: intraepithelial tumour without invasion of the lamina propriaT1 Tumour invades lamina propria, muscularis mucosae, or submucosa T1a Tumour invades lamina propria or muscularis mucosae T1b Tumour invades submucosa T2 Tumour invades muscularis propriaT3 Tumour penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures T4 Tumour invades serosa (visceral peritoneum) or adjacent structures T4a Tumour invades serosa (visceral peritoneum) T4b Tumour invades adjacent structures Regional lymph nodes (N) NX Regional lymph node(s) cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1-2 regional lymph nodes N2 Metastasis in 3-6 regional lymph nodes N3 Metastasis in seven or more regional lymph nodes N3a Metastasis in 7-15 regional lymph nodes N3b Metastasis in 16 or more regional lymph nodes Distant metastasis (M) M0 No distant metastasis M1 Distant metastasis Table SEQ Table * ARABIC 1 TNM classfication NOTEREF _Ref512438836 h 25 Stage T N M 0 Tis N0 M0 IIIA T4a N1 M0 IA T1 N0 M0 T3 N2 M0 IB T2 N0 M0 T2 N3 M0 T1 N1 M0 IIIB T4b N0 M0 IIA T3 N0 M0 T4b N1 M0 T2 N1 M0 T4a N2 M0 T1 N2 M0 T3 N3 M0 IIB T4a N0 M0 IIIC T4b N2 M0 T3 N1 M0 T4b N3 M0 T2 N2 M0 T4a N3 M0 T1 N3 M0 IV Any T Any N M1 Table SEQ Table * ARABIC 2 Anatomic stage/ prognostic groups of the TNM classification NOTEREF _Ref512438836 h 25 4.5.2 Japanese classification In comparison to the previously mentioned TNM classification, the Japanese Gastric Cancer Association has a slightly different approach to staging. Even though the clinical examination also acts as the foundation of staging it focusses on a much more detailed description of the tumour. In order to achieve this, imaging studies, endoscopic, laparoscopic and surgical findings, biopsies, cytology and biological investigations are consulted.
Among the differences lies the subclassfication according to macroscopic tumour morphology in superficial (T1) and advanced (T2-T4) types, as well as the categorization of lymph nodes in 33 stations. The group of the first 12 lymph nodes and 14v are denominated are regional gastric lymph nodes, the involvement of any of the other LN is counted as metastases NOTEREF _Ref512440331 h 30. Macroscopic types of advanced gastric cancer Type 0 (superficial) Typical of T1 tumours. Type I (mass) Polypoid tumours, sharply demarcated from the surrounding mucosa. Type II (ulcerative) Ulcerated tumours with raised margins surrounded by a thickened gastric wall with clear margins.
Type III (infiltrative ulcerative) Ulcerated tumours with raised margins, surrounded by a thickened gastric wall without clear margins. Type IV (diffuse infiltrative) Tumours without marked ulceration or raised margins, the gastric wall is thickened and indurated and the margin is unclear. Type V (unclassifiable) Tumours that cannot be classified into any of the above types Table SEQ Table * ARABIC 3 Macroscopic types of advanced gastric cancer according to Japanese classification NOTEREF _Ref512440331 h 30 1528360567855Type 0-II SuperficialType 0 Superficial, flat Type 0-I Protruding Type 0-IIa Sup elevatedrudingType 0-IIb Sup. flat Type 0-IIc Sup. depressedType 0-III Excavated00Type 0-II SuperficialType 0 Superficial, flat Type 0-I Protruding Type 0-IIa Sup elevatedrudingType 0-IIb Sup. flat Type 0-IIc Sup.
depressedType 0-III Excavated Figure SEQ Figure * ARABIC 1Subclassification of type 0 NOTEREF _Ref512440331 h 30 Depth of tumour invasion (T) TX Depth of tumour unknown T0 No evidence of primary tumour T1 Tumour confined to the mucosa (M) or submucosa (SM) T1a Tumour confined to the mucosa T1b Tumour confined to the submucosa T2 Tumour invades the muscularis propria (MP) T3 Tumour invades the subserosa (SS) T4 Tumour invasion is contiguous to or exposed beyond the serosa(SE) or tumor invades adjacent structures (SI) T4a Tumour invasion is contiguous to the serosa or penetrates the serosa and is exposed to the peritoneal cavity (SE) T4b Tumour invades adjacent structures Lymph node metastasis (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1–2 regional lymph nodes N2 Metastasis in 3–6 regional lymph nodes N3 Metastasis in 7 or more regional lymph nodes N3a Metastasis in 7–15 regional lymph nodes Distant metastasis (M) MX Distant metastasis status unknown M0 No distant metastasis M1 Distant metastasis Table SEQ Table * ARABIC 4 Japanese classification NOTEREF _Ref512440331 h 30 N0 N1 N2 N3 T1a (M), T1b (SM) IA IB IIA IIB T2 (MP) IB IIA IIB IIIA T3 (SS) IIA IIB IIIA IIIB T4a (SE) IIB IIIA IIIB IIIC T4b (SI) IIIB IIIB IIIC IIIC M1 (any T, any N) IV Table SEQ Table * ARABIC 5 Stage grouping according to Japanese classification NOTEREF _Ref512440331 h 30 5. TreatmentDepending on the preoperative stage, general state of the patient, paraclinical and clinical results a multidisciplinary team decides about the most appropriate treatment strategy. In the optimal case this team is composed of gastroenterologists, surgeons, oncologists and pathologists discussing the specific case and coming to a joint conclusion. Gold standard in a case with curative intention is a surgical approach consisting of a total or subtotal gastrectomy and a systemic lymphadenectomy NOTEREF _Ref512424516 h 17.
The relationship between the extent of lymph node dissection and improved survival rates has been evaluated by several studies with different results in Asian and Western countries. The European Society of Medical Oncology recommends medically fit patients to undergo D2 resection in high-volume surgical centres. LN group D1 is defined as perigastric LN, the D2 group as perigastric LN as well as the ones along the left gastric, common hepatic and splenic arteries as well as the coeliac axis . In case of an early gastric cancer (T1a) the European Society of Gastrointestinal Endoscopy guideline recommends endoscopic submucosal dissection as the treatment of choice. Therefor the following criteria have to be met: Clearly confined to mucosa Well defined ? 2cm Non-ulcerated NOTEREF _Ref512442441 h 32 As a matter of principal chemosensibility of gastric malignancies perioperative (pre- and postoperative) chemotherapy is recommended by the ESMO guideline, as well as postoperative chemoradiotherapy and adjuvant chemotherapy. On the other hand due to studies still being ongoing, recommendations regarding intraoperative radiotherapy and intraperitoneal chemotherapy are not indicated NOTEREF _Ref512424516 h 17.
Polychemotherapies show a remission rate between 30 and 50% with median remission duration of 6 to 9 months. In case of palliative treatment of a patient in good general state, systemic chemotherapy aims for enhanced survival and preservation of quality of life. Furthermore it is important to test the tumour tissue in advanced cases of gastric cancer for HER2 receptors. A positive result stipulates the treatment with Trastuzumab in combination with a polychemotherapy NOTEREF _Ref512442441 h 32. PART II: PERSONAL CONTRIBUTIONS1.
IntroductionGastric cancer is one of the malignancies not commonly presenting early symptoms. This among other factors leads to patients being diagnosed in advanced stages, diminishing their chances of a curative treatment. The study performed with the aim of analysing data of gastric cancer patients admitted to the gastroenterological department of “Pius Brînzeu” county hospital Timi?oara, Romania, a tertiary care centre, provides structured insight in all those cases. According to Pschyrembel medical dictionary being a tertiary referral centre is defined as offering highly specialized medical care and complex diagnostic capabilities for patients referred from primary or secondary care .
Taking into consideration the general problem of late establishment of gastric cancer diagnosis the obtained information might be used to train the eye of medical professionals in primary and secondary care centres with the aim of facilitating an earlier referral. 2. Material and MethodIn the framework of this license thesis all patients with a biopsy result positive for gastric cancer admitted to the gastroenterological department of “Pius Brînzeu” county hospital Timi?oara, Romania, in the time between January 2016 and October 2017 were studied. The medical charts of the patients were reviewed and demographic variables as well as specific risk factors, patient medical history, results of clinical, paraclinical examinations and subsequent treatment recommendations were extracted and collected in a database.
The study includes 43 patients diagnosed with gastric cancer by biopsy in the time between January 2016 and October 2017 in the gastroenterological department of “Pius Brînzeu” county hospital, Timi?oara. On the basis of the following inclusion criteria the selection of the patients was performed: Biopsy result positive for gastric cancer First admission with given diagnosis in the time interval of January 2016 and October 2017 The statistical analysis including all tables and diagrams was conducted using Microsoft Excel and Microsoft Word. 3. ResultsIf not stated otherwise the following results given in percentages are referred to the studied population as a whole (100% = 43 patients).
The studied group of 43 patients diagnosed with gastric cancer is composed by 24 males (55,81%) and 19 females (44,19%). Figure SEQ Figure * ARABIC 2 Gender distribution The age of the patients at admission to the hospital ranges between 47 and 80 years with a median of 64 years. The distribution of age has the highest incidence of gastric cancer cases in the age group 61-65 with 25,58% (11), followed by the age group 66-70 with 18,60% (8) and 76-80 years with 16,28% (7). The age groups 56-60 and 71-75 account for 11,63% (5) of the gastric cancer cases each. 9,30% (4) of the cases can be allocated to the age group 45-50 and 6,98% (3) to the range between 51-55 years. Figure SEQ Figure * ARABIC 3 Age distribution The 43 studied patients were hospitalized for a period between 1 and 24 days after their admission with a median of 3 days.
The more than half of the patients (53,49% (23)) were hospitalized for 3 days or less. 30,23% (13) left the hospital after 4-7days and 16,28% (6) of patients were discharged after more than a week. Figure SEQ Figure * ARABIC 4 Distribution of days of hospitalization As mentioned in the general part several risk factors are related to the likelihood of developing gastric cancer. The risk factor with the most widespread distribution in the evaluated population is male gender with 55,81% (24), followed by the presence of a gastric ulcer with 30,23% (13).
Risk factors in relationship with (an unhealthy) lifestyle can be found in the form of alcohol consumption in 25,58% (11), smoking in 23,25% (10) and a BMI>25 in 20,93% (9). Local risk factors apart from gastric ulcers are intestinal metaplasia and atrophic gastritis with 18,6% (8) each and reflux esophagitis with 6,98% (3). Apart from that 9,3% (4) have blood type A, 2,32% (1) present pernicious anaemia and 2,32% (1) showcase a positive family history. Figure SEQ Figure * ARABIC 5 Distribution of risk factorsOf the 43 patients presenting gastric cancer 19 could be analysed regarding their Body Mass Index.
The BMI was calculated using the formula BMI=weight (in kg)height (in meter)2. In the following section the percentages refer to 19 patients=100%. With normal weight being defined by the WHO as having an BMI between 18,5 and 24,9 kg/m2 47,37% (9) can be categorized in this group. 21,05% (4) presented as pre-obese with a BMI between 25 and 29,9 kg/m2. Grade I obesity (BMI 30,0-34,9 kg/m2) accounts for 15,79% (3) and grade II obesity (BMI 35,0-39,9 kg/m2) for 10,53% (2). The smallest percentage presents the group of underweight (BMI <18,5 kg/m2) with 5,26% (1).
In conclusion this means by WHO definition 47,37% (9) of the patients presenting gastric cancer are considered obese (BMI >25 kg/m2). Figure SEQ Figure * ARABIC 6 BMI distribution A variety of symptoms were described by the patients at admission and led to their hospitalization. The symptom with the widest distribution at admission among the studied cases was secondary anaemia in 58,14% (25), followed by abdominal pain with a prevalence of 51,16% (22). Of the 22 patients describing abdominal pain (22=100%), 12 (54,55%) specified it as localized in the epigastric region, 5 (22,73%) as having a diffuse character and 1 (4,55%) as flank pain.
Figure SEQ Figure * ARABIC 7 Distribution of abdominal pain localization 39,53% (17) complained about unintentional weight loss in the months previous to admission. 32,56% (14) were hospitalized with the objective of re-evaluating a suspicious ambulant ultrasound or endoscopy result. Fatigue and dysphagia were symptoms present in 23,25% (10) each. The latter being described in 10 cases of which 50% (5) were a dysphagia for solids, 30% (3) mixed dysphagia and 20% (2) were not further specified.
Figure SEQ Figure * ARABIC 8 Distribution of dysphagia 20,98% (9) stated nausea and emesis as a symptom, also documented in 20,98% (9) of cases was asthenia. 16,28% (7) were diagnosed with upper GI bleeding. Another 16,28% (7) complained about loss of appetite. 6,98% (3) stated pyrosis and 2,32% (1) each cachexia, difficulties of gastric evacuation and absent intestinal transit.
Figure SEQ Figure * ARABIC 9Distribution of symptoms and reason of admission 39,53% (17) of the evaluated population presented the cancer at the oesophageal-gastric junction, in 20,93% (9) in the antrum of the stomach, in 18,6% (8) the affected part of the stomach was not further specified or overlapped several areas. In 9,3% (4) the cancer was situated at each gastric curvature and in 2,32% (1) at the gastric angle. Figure SEQ Figure * ARABIC 10 Distribution of gastric cancer localization The biopsy results giving the positive gastric cancer diagnosis also provided further information about the histological type. With 69,77% (30) adenocarcinomas account for the majority of gastric cancers in the evaluated population. As stated in the general part the adenocarcinomas are being composed of different subtypes.
Out of the 30 adenocarcinomas (30=100%), 30% (9) are tubular adenocarcinomas, 20% (6) are signet ring cell carcinomas, 10% (3) tubulo-papillary adenocarcinomas, 3,33% (1) mucus secreting adenocarcinomas, 36,67% (11) were poorly differentiated and 37,53% (9) were not further specified. Figure SEQ Figure * ARABIC 11Distribution of adenocarcinoma subtypes Mixed carcinomas constitute the second largest histological group with 11,63% (5), followed by epidermoid carcinomas with 4,65% (2) and 2,32% (1) neuroendocrine carcinomas. In 11,63% (5) of the population the type of gastric carcinoma was not further specified in the histological report. Figure SEQ Figure * ARABIC 12Distribution of types of gastric cancer In all of the cases some kind of further investigations were performed in order to achieve a more comprehensive view of each case.
In 32 of the cases an ultrasound was performed (100%=32), leading to the following results: 43,75% (14) of the population presented with metastases. In 34,37% (11) the US revealed a thickening of the gastric wall. 28,12% (9) demonstrated ascites, 15,62% (5) demonstrated adenopathies and in 6,25% (2) the visualization of a formation within the stomach was possible. Figure SEQ Figure * ARABIC 13 Distribution of ultrasound results In 41 cases a gastroscopy was performed showcasing a proliferation within the stomach in 80,95% (34). A gastric ulceration was visualised in 61,90% (26), in 26,19% (11) bleeding was observed during the procedure, 23,81% (10) presented a stenosis of the stomach, 9,52% (4) showcased an infiltration of gastric wall.
Figure SEQ Figure * ARABIC 14 Distribution of gastroscopy results In 20 cases out of the total 43 a computer tomography was performed showcasing adenopathies in 85% (17). A thickened gastric wall was found in 70% (14). In 40% (8) metastasis were found in the CT scan and 15% (3) presented an either internal or external stenosis of the stomach. Figure SEQ Figure * ARABIC 15 Distribution of CT results The adenopathies found in the previously described investigations can be categorized into regionally affected lymph nodes, including perigastric and perilesional lymph nodes, in 30,23% (13) of the evaluated population. Retropertioneal lymph nodes were enlarged in 23,26% (10) being defined as retropancreatic, pricoeliac, periaortic lymph nodes as well as those in proximity to the internal iliac artery.
13,95% (6) of the cases, presented with thoracic adenopathies being found in the locations of the aortopulmonary window, Loja Barety, the lung hilum and peritracheal. Another 13,95% (6) adenopathies´ can be categorized as intraperitoneal lymph nodes, including perihepatic, interaortocaval lymph nodes and lymph nodes in the splenic hilum. 2,32% of the population presented supraclavicular adenopathy. Figure SEQ Figure * ARABIC 16 Distribution of adenopathiesOut of the total 43 cases of the population, 20 (46,51%) were diagnosed with metastases. 32,56% (14) of the population presented liver metastases, making those the most widespread type of metastases.
Metastases of the peritoneum and carcinomatous ascites each account for 6,98% (3) and pulmonary metastases for 4,65% (2). Figure SEQ Figure * ARABIC 17Distribution of metastases By discharge 41,86% (18) received the recommendation to consult an oncologist for their subsequent treatment, 18,60% (8) were referred to a surgeon in order to evaluate a probable indication for surgery. In 13,95% (6) the patient was advised to present himself to regular follow-ups at the gastroenterological department. In 25,58% of the cases the subsequent treatment recommendation was not further specified.
Figure SEQ Figure * ARABIC 18 Distribution of subsequent treatment recommendation In the following part some of the parameters will be evaluated in relation to one another, starting with the distribution of histological types in relation to gender. The 30 cases of adenocarcinoma are composed of 16 male and 14 female patients. The mixed form of carcinomas consists of 2 male and 3 female patients, adding up to a total of 5 cases. With just 2 cases in epidermoid carcinomas the male-female ratio is 1:1.
The evaluated population included 1 case of neuroendocrine carcinoma of male gender and 5 cases not further specified histologically with a male-female ratio of 4:1. Figure SEQ Figure * ARABIC 19 Distribution of histological type in relation to gender Evaluating the age and gender distribution in adenocarcinomas we can observe the highest incidence in the age group 61-65 years with a total number of 7 cases and a male-female ratio of 4:3. The age group 66-70 years shows the second highest deflections with a male to female ratio of 2:1 and 6 cases. The age group 71-75 years with a male to female ratio of 3:2 ranges on third place together with the cases in age group 56-60 years with a male to female ratio of 2:3. As second to last identifies the youngest age group with a male to female ratio of 1:1. The age group with the lowest incidence is 51-55 years with 1 male case.
Figure SEQ Figure * ARABIC 20 Distribution of age and gender in adenocarcinomasLooking at the distribution of the histological type in relation to age we can observe that again the age group 61-65 years accounts for the highest incidence with 7 adenocarcinomas, 1 mixed carcinoma, 1 neuroendocrine carcinoma and 2 histologically unaccounted cases, resulting in a total of 11 cases. The age group 66-70 years follows with an incidence of 8 cases (6 adenocarcinomas, 1 mixed carcinoma and 1 epidermoid carcinoma). 7 cases (4 adenocarcinomas, 1 mixed carcinoma, 1 epidermoid carcinoma and 1 histologically unaccounted case) configure the age group of 76-80 years. The age groups 71-75 and 56-60 years each comprise 5 adenocarcinomas. The age group of 45-50 is constituted of 4 patients, 2 diagnosed with adenocarcinomas and 2 with mixed carcinomas.
The lowest incidence of gastric cancer cases can be observed in the age group of 51-55 years with 1 adenocarcinoma and 2 histologically unaccounted cases. Figure SEQ Figure * ARABIC 21 Distribution of histological type in relation to age Evaluating the relation between histological type of gastric cancer and metastasis we observe a ratio of 1,1:1 in adenocarcinomas in favour of those without metastases. The mixed carcinomas constitute of 1 case without metastases and 4 with metastases. Histologically unaccounted cancers are composed by 4 cases without and 1 case with metastases. A 1:1 ratio is found in epidermoid carcinomas and neuroendocrine carcinomas constitute just out of 1 case without metastases.
Figure SEQ Figure * ARABIC 22 Distribution of histological type in relation to metastases Setting subsequent treatment in relation to gender the following results are obtained. An oncological consult or a subsequent oncological treatment being the most frequent recommended treatment has a 5:4 male to female ratio, followed by the surgical consult with a 5 to 3 ratio in favor for the male gender. A gastroenterological follow-up lies on third place of the treatment recommendations with a male-female ratio of 2:1. In 11 cases the patients were discharged without a specified subsequent treatment suggestion (5 male and 6 female). Figure SEQ Figure * ARABIC 23 Distribution of subsequent treatment in relation to gender Assessing the suggestions of subsequent treatment in relation to the histological type of cancer we can observe in adenocarcinomas 46,67% (14) of the patients were recommended an oncological consult or subsequent oncological treatment. 20% (6) were referred to a surgeon for a consult, 3,33% (1) were advised a gastroenterological follow-up and in 30% (7) no recommendation was made.
Out of the 5 cases of mixed gastric cancers 40% (2) were referred to an oncologist, 40% (2) were advised a gastroenterological follow-up and 20% (1) were suggested a surgical consult. 50% (1) of the patients diagnosed with epidermoid carcinoma received the recommendation to see an oncologist for their subsequent treatment. The other half did not receive a specified suggestion, just like the case with a neuroendocrine carcinoma diagnosis (1). Out of the histologically unclassified cases 60% (3) were recommended a gastroenterological follow-up, 20% (1) a surgical consult and 20% (1) an oncological consult or subsequent oncological treatment.
Figure SEQ Figure * ARABIC 24 Distribution of subsequent treatment in relation to histological type Displaying the relation between subsequent treatment and the presence or absence of metastases we may observe the recommendation of oncological care being the most prominent in cases with metastases (65%, 13), followed by the surgical consult and the cases without subsequent treatment suggestion, each accounting for 15% (3). 5% (1) of gastric cancer cases with metastasis were recommended a gastroenterological follow-up. In 34,78% (8) of the cases without metastasis no treatment recommendation was expressed, 21,74% (5) were advised an oncological consult or subsequent treatment and the same amount were suggested a surgical consult. The final 17,39% (4) without metastases were told to present for a gastroenterological follow-up. Figure SEQ Figure * ARABIC 25 Distribution of subsequent treatment in relation to metastases 4. DiscussionEven though the incidence of gastric carcinomas is decreasing in Western countries it remains among the five deadliest malignancies according to the WHO.
Being responsible for more than 107 000 deaths in 2012, gastric cancer is the fourth most common cause of cancer deaths in Europe. Out of the 7.4 million males diagnosed with cancer in 2012 worldwide, gastric cancer accounts for 9% and out of the 6.7 million females diagnosed with cancer in 2012 worldwide, 5% were gastric cancer cases . The study carried out in the gastroenterological department of the “Pius Brînzeu” county hospital Timi?oara, aimed at analysing the distribution of demographics, symptomatology, as well as results of paraclinical examinations among admitted gastric cancer patients. The review of patient records documenting the time interval January 2016 – October 2017 concluded in a population of forty-three patients complying with the inclusion criteria of this study. The data utilized for the study were extracted from the handwritten admission sheet, laboratory and biopsy results, as well as the discharge letters. The evaluated parameters comprise anamnestic readings, age, gender, days of hospitalization, BMI.
They also include the presence of risk factors defined as tobacco and alcohol consumption, pernicious anaemia, atrophic gastritis, gastric ulcer, family history positive for gastric cancer, blood type A, reflux esophagitis and intestinal metaplasia. The utilized data picturing the symptomatology at admission were comprised by secondary anaemia, abdominal pain, weight loss, dysphagia, fatigue, asthenia, nausea and emesis, upper GI bleeding, loss of appetite, pyrosis, difficulties of gastric evacuation, absent intestinal transit and cachexia. The paraclinical analysed data comprise biopsy results, documentation of ultrasound examinations, gastroscopy and computer tomography. The results of the study showed the population being formed by twenty-four males (55,81%) and nineteen females (44,19%). In comparison to an analysis performed by the Cancer Research UK based on the 2015 data by the Office for National Statistics of the United Kingdom resulting in the statement of 65% out of the 6 740 newly diagnosed gastric cancer cases in the UK being male and 35% female . This gender gap also reflects in the numbers of the European Network of Cancer Registries with 60% of the 139 600 newly diagnosed gastric cancer cases being male and 40% female .
The most common age for gastric cancer diagnosis in the evaluated population is between 61 and 65 years with 25,58%, followed by the age group 66-70 years with 18,60%. In the UK the highest incidence rates were found in the age groups 85-89 years, with an average of 51% of the new diagnosis being in the population 75 years or older NOTEREF _Ref512443772 h 34. Both results correspond with the strong relation of gastric cancer incidence and age. Their difference needs to be evaluated bearing in mind the different life expectancies depending on the evaluated country.
In Romania the life expectancy in the year 2015 was 75 years in comparison with the life expectancy in the UK of 83 years. A wide variety of risk factors can be associated with gastric cancer and are found in the evaluated population REF _Ref512517220 h * MERGEFORMAT Figure 5. Conform with the fact of gastric cancer developing mainly in patients with an age above 55 years, 83,72% of the studied population diagnosed with gastric cancer were older than 55 years NOTEREF _Ref512438510 h 8. 55,81% of the patients diagnosed with gastric cancer are male, correspondent with the male gender being a risk factor. Gastric ulcers were found in 30,23% of the population.
Alcohol consumption and smoking also being established risk factors for gastric cancer account for 25,58% and 23,25%. Nine-teen out of the 43 patients could be analysed regarding their BMI, resulting in 47,37% of the gastric cancer patients whose BMI it was possible to calculate having a BMI >25. A meta-analysis of prospective cohort studies of 3 097 794 patients resulted in the statement of the gastric cancer risk being significantly higher in patients with a BMI >25 . The risk is especially higher for carcinomas of the oesophageal-gastric junction, as was the conclusion of another meta-analysis . Evaluating the seven-teen cases of cancer of the oesophageal-gastric junction accounted for in the population, 23,53% presented with a BMI >25, 35,29% with a BMI <25 and in 41,18% of the cases no values were provided to calculate the BMI.
In order to agree with this statement it would be necessary to analyse the whole population in regard to each patients BMI. With Helicobacter pylori confirmed by the WHO as a class I carcinogen since 2009 a meta-analysis on 19 studies with 2491 patients and a control group of 3959 patients, resulted in an OR of 1,92 for the development of gastric cancer in patients infected with HP NOTEREF _Ref512438510 h 8. Unfortunately the records of the patients admitted with gastric cancer did not allow us to make a statement on this subject since in the majority of cases no examination to diagnose a HP infection was performed. According to an Italian meta-analysis evaluating the role of symptoms in gastric cancer alarm symptoms as weight loss, dysphagia, signs and symptoms of upper GI bleeding, anaemia and persistent vomiting have a higher likelihood to be associated with malignancies of the upper gastro-intestinal system NOTEREF _Ref512505385 h 27. In the conducted study 88,37% of the 43 patients featured one or more of the previously defined alarm symptoms.
58,14% presented anaemia, 39,53% weight loss, 23,26% dysphagia and 16,28% upper GI bleeding REF _Ref512506452 h * MERGEFORMAT Figure 9. A study by Kapoor on a population of 1785 patients, resulted in the statement of dysphagia and weight loss being the only symptoms representing significant predictive factors for cancer (Odds Ratio (OR) 3,1 and 2,6 respectively) . Out of the 43 gastric cancer patients admitted to the Timisoara county hospital 48,84% presented one or both of these symptoms at admission. Unfortunately based on the data extracted from the patient records it was not possible to evaluate the correlation between the presence of alarm symptoms with an advanced TNM stage, as stated by another Italian study .
The symptom described the most frequent at admission in this study is abdominal pain present in 51,16%. Out of the twenty-two patients with abdominal pain, 54,54% described it as epigastrically localized, 22,73% as diffuse, 4,54% as flank pain and in 18,18% of cases it was not further specified REF _Ref512509332 h * MERGEFORMAT Figure 7. The most prevalent localization of gastric cancer in the conducted study is the oesophageal-gastric junction with 39,53% followed by the antrum with 20,93% and overlapping parts of the stomach /unspecific stomach location with 18,60%. A similar distribution can be observed in the results of the Cancer Research UK, with the majority affecting overlapping or unspecified parts of the stomach, followed by a great percentage of cardia carcinomas NOTEREF _Ref512443772 h 34. These results correspond to the changes mentioned in textbooks stating the rise in incidence of tumours of the oesophageal-gastric junction NOTEREF _Ref512438490 h 1.
With 69,77% adenocarcinoma is the histological type most prevalent in the evaluated population conform with the general research consent of it being the main histological type. Its´ distribution across the age groups correlates with the age distribution for the appearance of gastric cancer in general in the evaluated population REF _Ref512502555 h * MERGEFORMAT Figure 21, REF _Ref512502529 h * MERGEFORMAT Figure 3. Metastases were found in 46,51% of the population and the same percentage presented adenopathies. With 53,33% of adenocarcinomas presenting no metastases and 46,67% presenting metastases the distribution is almost balanced.
The histological type of gastric cancer with the highest percentage of metastasised tumours is the mixed form with 80% REF _Ref512519124 h * MERGEFORMAT Figure 22. Out of the patients diagnosed with metastases 65% were recommended oncological consult /subsequent oncological treatment, in comparison to only 21,74% of the cases without metastases receiving the same suggestion. In reference to the whole population, oncological consult /subsequent oncological treatment accounts with 41,86% for the most prevalent recommendation, followed by a surgical consult in 18,6% and a gastroenterological follow-up in 13,95% REF _Ref512520889 h * MERGEFORMAT Figure 18. The gender seems to have no separate influence on the subsequent treatment recommendation derived from the balanced distribution of treatment commendations REF _Ref512519676 h * MERGEFORMAT Figure 23.
To be able to comment on a probable relation between age and subsequent treatment recommendation I would suggest conducting a larger study. One of the restrictions of this study lies in its´ limited covered time span and thereby its´ small size of population. Furthermore the analysis of patient data was performed retrograde using the existing patient records signifying the documentation of admission sheets and clinical examination were performed by multiple different doctors and varied in their extensiveness. As a result some parameters were not evaluated in all of the gastric cancer patients. A long-term study conducted on gastric cancer patients with a specific questionnaire as an addition to the general patient record would result in an even broader picture of patients with stomach malignancies.
5. Conclusion ACKNOWLEDGEMENTS This work was carried out in the Department of Internal Medicine II, Discipline of Gastroenterology at the “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania, under the supervision of Assist. Prof. Bogdan Miu?escu. REFERENCES