Gastric cancer

Gastric cancer
Ebers papyrus 1600 BC
Hippocrates 460-377 BC
Karkinos, karkinoma.

Gastric cancer
Claudius Galenus (131-201 AD)
from Pergamum (present Turkey)

Avicenna (Abn Ali Al Hosain Ibn Abdallah Ibn Sina) (980-1037) from Kharmaithen (Bokhara province, Persia)

Gastric cancer. What is the problem?

Gastric cancer is one the most common cancer, also one of the most common causes of overall cancer-related mortality worldwide. Geographic areas of highest incidence: Japan, Korea, South America, and Eastern Europe Prognosis depends on the developmental stage at diagnosis; 5-year survival rate is low (~20%). At early stage, GC is a treatable disorder, with 5year survival rate >90%.
Kikuchi et al.Survival after surgical treatment of early gastric cancer: surgical techniques and long-term survival. Langenbecks Arch Surg 2004; 389:69-74

The Ten Most Common Cancers in 1984, 2007 and projected to 2030
Number of Cases, UK
Cancer Site 1984 Cancer Site 2007 Cancer Site 2030

Lung Colorectum* Breast Stomach Prostate

43.049 29.216 26.600 13.329

Breast Lung Colorectum* Prostate Uterus Non-Hodgkin Lymphoma Malignant Melanoma Bladder Kidney Oesophagus

45.758 39.490 38.442 36.083

Prostate Colorectum* Breast Lung Malignant Melanoma

61.090 58.176 57.442 57.201

11.714

15.062

21.824

Bladder

11.629

10.928

Uterus Non-Hodgkin Lymphoma Kidney Bladder Pancreas

21.443

Uterus Pancreas Ovary Leukaemia

9.112 6.811 5.500 5.443

10.723 10.151 8.205 7.969

15.386 14.815 14.092 11.927

Prepared by Cancer Research UK using data sourced from M Mistry et al. Cancer incidence in the UK: Projections to the year 2030, Br J Cancer, 2011. (Vol 105) page 1795 1803

Overall epidemiology of oncology

Incidence of gastric cancer worldwide*
Western Eurpoe Eastern Europea Japan Australia/ N. Zealand China North Africa South Africa
Male Female Male Female Male Female Male Female 16.4 8.2 36.3 16.9 77.9 33.3 10.8 4.9

Male Female
Male Female Male Female

43.6 19.0
5.9 2.6 11.5 4.3

798 000 new cases in1990

*Incidence: new cases / 100,000 population / year

Central America North America

Male Female
Male Female

18.6 13.3
8.4 4.0

Parkin DM, et al. CA Cancer J Clin. 1999;49:33-64.

Stomach Cancer (ICD-10 C16), Males, World Age-Standardised Incidence and Mortality Rates, Regions of the World, 2008 Estimates

http://info.cancerresearchuk.org

Stomach Cancer (ICD-10 C16), Females, World Age-Standardised Incidence and Mortality Rates, Regions of the World, 2008 Estimates

http://info.cancerresearchuk.org

Overall epidemiology of oncology

Incidence of gastric cancer in USA

Age-standardised cancer incidence rate per 100,000 population, stomach cancer, by sex, EU countries, 2006 estimates
Lithuania Poland Estonia Romania Latvia Portugal Slovenia Hungary Bulgaria Slovakia Italy Greece EU Germany Czech Cyprus Spain Luxembourg Ireland Austria UK Malta Netherlands France Finland Belgium Sweden Denmark 0 5 10

Males Females

http://www.cancerresearchuk.org
15 20 25 30 35 40

Overall epidemiology of oncology

Age-related incidence of gastric cancer in USA

Hohenberg P and Gretschehel S. Lancet. 2003,362:305-315

Our situation:
Incidence of gastric cancer in Lithuania: 39.2/100 000 in 1982 27.4/100 000 in 1994
E.Stratilatovas, E.Sangaila.-Medicina.- 1996, 32 tomas, 10 priedas, p.137

28.9 (28.4)/100 000 in 1999 (2004) (male 36.7, female 21.1)

Pagrindiniai onkologins pagalbos rezultatai Lietuvoje. 1999 metai (2004). Lietuvos Kancerregistras. Vilnius, 2000 (2005),

Spain: 16.1 /100 000 in 1994

Monferrer-Guardiola-R et al.- An-Med-Interna. -1996 Feb; 13(2): 68-72

Our situation:
82% of GC is diagnosed at stage III and IV, just around 2 % at stage I.
J.Umbrasas, A.Bubnys, S.Jureviius. -Medicina.- 1996, 32 tomas, 10 priedas, p.144.

60% patients exit wiithin the first year from diagnosis. Only 65% of all diagnosed GC cases are confirmed histologically.
E.Stratilatovas, E.Sangaila.-Medicina.- 1996, 32 tomas, 10 priedas, p.137.

Etiology
Genetic factors (5-10%):
Blood group A CDH1 gene mutations (E-cadherin) Exogenous factors (nutrition): High concentration of nitrates in smoked and salted products nitrates nitrites nitrozamines

Endogenous factors (infection):

achlorhydria promotes bacterial propagation in the stomach HP Chromic atrophic gastritis Status following gastric resection Adenomatous gastric polyposis (malignancy in 20%)

Risk factors for gastric cancer (US)

H. Pylori infection Age Male Vegetable-free and fruit-free diet Smoked, marinated and salted products in the diet Atrophic gastritis Intestinal metaplasia Pernicious anaemia (Addison-Biermer anaemia) Adenomatous gastric polyposis Family history of cancer Smoking Hypertrophic gastritis Familial adenomatous polyposis

Diagnosis
Optimal treatment of gastric cancer requires precise diagnosis of the developmental stage as the stage strictly determines the surgical approach: depending on the outspread of the process, the decision is made for a surgical intervention (either radical or palliative), or for a palliative non-surgical therapy.

Principles of decision-making
In cases with multiple primary neoplastic locuses, the deepest invasion into the gastric wall is taken into account.

When providing information on cancer, three major sources are being used:
clinical data surgical findings final data

Principles of decision-making
Once diagnosed, no findings can ever be changed or deleted
Any finding that cannot be ascertained unambiguously should be marked as undetermined.

Practical points in the diagnosis of gastric cancer

Clinical data Physical examination Diagnostic means: Endoscopy Biopsy Cytology Biochemical lab data Biological samples Other Surgical findings Clinical findings Inspection Palpation Diagnpstic means: Frozen cuts??? Punction needle biopsy Aspiration cytology Other F in a l d a t a Clinical data Surgical findings Histological results

A. Macroscopic findings
1. Position of the tumour
E

Stomach can be divided into

3 distinct parts:

D
C upper 1/3 M- intermediate 1/3 A - lower 1/3 E - oesophagus D - duodenum

M MA CMA CE AD

A. Macroscopic findings
2. Position of the tumour
In the transverse section, the stomach can be divided into 4 parts: Less- lesser curvature Gre greater curvature Ant anterior wall Post- posterior wall Less Post Ant Gre

A. Macroscopic findings
Location: Antrum Lesser curvature Cardia Other

- 35% - 30% - 25% - 10%

A. Macroscopic findings
Adenocarcinoma of the esophago-gastric junction
Tumours 5 cm above and 5 cm below The esophago-gastric junction Are classified by Siewert JR and Stein HJ (1998): Type Idistal esophageal; Type II centrum within the junction; Type III subcardiac tumour.

TNM Classification
(7th Edition, 2010)
Depth of tumor invasion (T) Tis: Carcinoma in situ - intraepithelial tumor without invasion of the lamina propria T1a : tumor invades lamina propria or muscularis mucosae T1b : tumor invades submucosa T2 : tumor invades muscularis propria T3 : tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures T4a : tumor invades serosa (visceral peritoneum) T4b : tumor invades adjacent structures

Structure of the stomach wall

A. Macroscopic findings
Early cancer - T1 cancer: infiltration of just the mucosa and submucosa layers, Muscularis propria intact. Advanced cancer: outspread of tumour beyond the submucosa layer.

A. Macroscopic findings
3. Macroscopic type

Type 1 : Polypoid tumors, sharply demarcated from the surrounding mucosa, usually attached on a wide base. Type 2 : Ulcerated carcinomas with sharply demarcated and raised margins. Type 3 : Ulcerated carcinomas without definite limits, infiltrating into the surrounding wall. Type 4 : Diffusely infiltrating carcinomas in which ulceration is usually not a marked feature. Type 5 : Non-classifiable carcinomas that cannot be classified into any of the above types.

A. Macroscopic findings
3. Macroscopic type (Bormann) Type 1
Type 2 Type 3 Type 4

Histological forms
Adenocarcinoma: Papillary adenocarcinoma Tubular adenocarcinoma:
Well-differentiated type Moderately differentiated type

Poorly differentiated adenocarcinoma

Solid type Non-solid type

Signet-ring cell carcinoma Mucinous adenocarcinoma Special types Adenosquamous carcinoma Squamous cell carcinoma Carcinoid tumor

Histological forms
Adenocarcinoma:
Papillary adenocarcinoma Tubular adenocarcinoma:
Well-differentiated type Moderately differentiated type

Special types
Adenosquamous carcinoma Squamous cell carcinoma Carcinoid tumor

Poorly differentiated adenocarcinoma

Solid type Non-solid type

Signet-ring cell carcinoma Mucinous adenocarcinoma

Grading
Grading refers to the appearance of the cancer cells under the microscope. Grade 1 (low-grade) - The cancer cells tend to grow slowly, look quite similar to normal cells (are well differentiated) and are less likely to spread than higher grades. Grade 2 (moderate-grade) - The cells look more abnormal and are slightly faster growing. Grade 3 (high-grade) - The cancer cells tend to grow more quickly, look very abnormal (are poorly differentiated) and are more likely to spread than lowgrade cancer cells. Grade 4 undifferentiated cells

Growth patterns
Laurens classification by growth patterns (1965) : Intestinal: expansively (polypoid-like) growing
tumour with clear-cut borders

Diffuse: infiltrating growth, without clear-cut

borders. Peculiar form: Linitis plastica; prognosis unfavourable due to metastases to lymphatic nodes.

Laurens classification
Intestinal
More common in endemic regions

Diffuse
More common in regions of low incidence

Related to gastric atrophy

Glandular formation, intestinal metaplasia

Related to blood group A

Poorly differentiated, signetring-type

Male>female
Hematogenic spread In relation with the age

Female>male
Lymphogenic spread More common at young age

Diffuse type signet-ring cancer

A. Macroscopic findings
4. Lymphatic nodes
4.1. Regional lymphatic nodes (stations)
No. 1 Right paracardial LN No. 2 Left paracardial LN No. 3 LN along the lesser curvature No. 4sa LN along the short gastric vessels No. 4sb LN along the left gastroepiploic vessels No. 4d LN along the right gastroepiploic vessels No. 5 Suprapyloric LN No. 6 Infrapyloric LN No. 7 LN along the left gastric artery No. 8 LN along the common hepatic artery (Anterosuperior and poeterior group) No. 9 LN around the celiac artery No. 10 LN at the splenic hilum No. 11 LN along the splenic artery No. 12 LN in the hepatoduodenal ligament No. 13 LN on the posterior surface of the pancreatic head No. 14v LN along the superior mesenteric vein No. 14a LN along the superior mesenteric artery No. 15 LN along the middle colic vessels No. 16a1 LN in the aortic hiatus No. 16a2 LN around the abdominal aorta (from the upper margin of the celiac trunk to the lower margin of the left renal vein) No. 16b LN around the abdominal aorta (to the aortic bifurcation) No. 17 LN on the anterior surface of the pancreatic head No. 18 LN along the inferior margin of the pancreas No. 19 Infradiaphragmatic LN No. 20 LN in the esophageal hiatus of the diaphragm

A. Macroscopic findings
4. Lymphatic nodes
4.1. Regional lymphatic nodes

Grouping (Compartments) of lymph nodes The regional lymph nodes are classified into three groups depending upon the location of the primary tumor This grouping system is based on the results of studies of lymphatic flow at various tumor sites, together with the observed survival associated with metastasis at each nodal station.

4.2.Location of regional lymphatic nodes

4.2. Location of regional lymphatic nodes

4.2. Location of regional lymphatic nodes

4.2. Location of regional lymphatic nodes

TNM Classification
(7th Edition, 2010)
Extent of lymph node metastasis (N) N0: no regional lymph node metastasis. (A designation of pN0 should be used if all examined lymph nodes are negative, regardless of the total number removed and examined) NX: regional lymph nodes cannot be assessed N1 : metastasis in 1-2 regional lymph nodes N2 : metastasis in 3-6 regional lymph nodes N3a : metastasis in 7-15 regional lymph nodes N3b: metastases in 16 or more regional lymph nodes

Metastasis
Direct invasion Lymph node dissemination
Blood spread

Intraperitoneal colonization

Macroscopic findings
5. Metastatic spread of gastric cancer
Liver Peritoneum Omentum Lungs Mesenterion Pancreas Adrenal glands 38-54% 17-24% 13-21% 12-22% 9% 7-29% 5-15%

Karpeh MS, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001:1092-1126.

TNM Classification
(7th Edition, 2010) Distant metastases (M) M0 : No distant metastases, M1 : Distant metastases
Sister Mary Joseph nodle, Blumers shelf, Krukenburg tumour

Stage 0 Tis N0 M0 Stage I A T1 N0 M0 Stage IB T2 N0 M0 T1 N1 M0 Stage IIA T3 N0 M0 T2 N1 M0 T1 N2 M0 Stage IIB T4a N0 M0 T3 N1 M0 T2 N2 M0 T1 N3 M0

Macroscopic findings Surgical classification of stages (7th edition, 2010)

Stage IIIA T4a N1 M0 T3 N2 M0 T2 N3 M0 Stage IIIB T4b N0-1 M0 T4a N2 M0 T3 N3 M0 Stage IIIC T4a N3 M0 T4b N2-3 M0 Stage IV Any T Any N M1

Clinical manifestation
Signs and Symptoms
Early Gastric Cancer Asymptomatic or silent Peptic ulcer symptoms Nausea or vomiting Anorexia Early satiety Abdominal pain Gastrointestinal blood loss Weight loss
Dysphagia 80% 10% 8% 8% 5% 2% <2% <2%

<1%

Signs and Symptoms

Advanced Gastric Cancer Weight loss Abdominal pain Nausea or vomiting Anorexia Dysphagia Gastrointestinal blood loss Early satiety Peptic ulcer symptoms Abdominal mass or fullness Asymptomatic or silent 60% 50% 30% 30% 25% 20% 20% 20% 5% <5%

Duration of symptoms Less than 3 month 40% 3-12 months 40% Longer than 12 month 20%

Laboratory tests
Iron deficiency anemia

Fecal occult blood test (FOBT) Tumor markers (CEA, Ca19-9)

Endoscopic diagnosis
In patients with signs and symptoms suggestive of GC, and/or with compatible risk factors or paraneoplastic conditions, the diagnostic procedure of choice could be an endoscopic examination
The diagnostic criteria for early or advanced gastric cancer under endoscopy are based on the JRSGC and Bormanns classification

Endoscopic features of gastric cancer

Radiologic diagnosis
For reasons of cost and availability, radiography may sometimes be the first diagnostic procedure performed Classic radiography signs of malignant gastric ulcer
asymmetric/distorted ulcer crater ulcer on the irregular mass irregular/distorted mucosal folds adjacent mucosa with obliterated /distorted area gastricae nodularity, mass effect, or loss of distensibility

Radiologic diagnosis
Distal GC

Proximal GC

Linitis plastica

Detection of early gastric cancer

Endoscopic screening
general population or high risk persons

Careful observation Japan is the only country that had conducted large
nationwide mass population screening of asymptomatic individuals for gastric malignancy

Surgical treatment
Approaches

Intraluminal endoscopy Laparoscopy Laparotomy Thoraco-laparotomy Others

Treatment
Surgical resection
EMR Adjuvant therapy

Palliative therapy

Surgical treatment
Operative procedures Mucosectomy Wedge resection Segmental resection Proximal gastrectomy Pylorus preserving gastrectomy Distal (subtotal) gastrectomy Total gastrectomy Combined resection

Surgical interventions Gastrectomy

Surgical treatment R0 resection

Which is the sufficient extent of gastrectomy (resection)? How extensive should be the lymphadenoctomy?

Surgical treatment. Radicality

R0 resection indicates a microscopically margin-negative resection, in which no gross or microscopic tumor remains in the primary tumor bed. R1 resection indicates the removal of all macroscopic disease, but microscopic margins are positive for tumor. R2 indicates gross residual disease with gross residual tumor that was not resected (primary tumor, regional nodes, and macroscopic margin involvement).

Surgical interventions
Harvesting of lymphatic nodes
D1: 1st compartment of lymph nodes D2: 1st and 2d compartments of lymph nodes D3: all stations of lymph nodes should be removed

Regional lymph node group according to the location of tumor.

Sasako M et al. Jpn. J. Clin. Oncol. 2010;40:i28-i37

The Author (2010). Published by Oxford University Press. All rights reserved

Nodal dissection for patients with gastric cancer: a randomized controlled trial.

Sasako M et al. Jpn. J. Clin. Oncol. 2010;40:i28-i37

The Author (2010). Published by Oxford University Press. All rights reserved

B. Surgical interventions 2. Combined resections

All resections performed in combination with the main tumour (spleen, liver, colon transversum and its mesenterion, gall-bladder, pancreas, adrenal glands, ovarian, etc.) are called combined resections *Resections of omentum major or minor, anterior
mesenterion of the large intestine, abdominal part of esophagus, or the initial part of duodenum are not included in this category.

Surgical results
Mean 5-year survival is 25% - 38.2%.
Dietl F., Rumpf K.D. Zentralbl-Chir. 1995; 120(10): 800-3 Oertli D. et al. Schweiz-Med-Wochenschr. 1994 Jun 4; 124(22): 945-52

Surgical results Early cancer

N*=1137, N*=126, N*=294 In cases of mucosal cancer invasion (T1a), l/n mts can be found in 2.6-3.1-4% of cases. In cases of submucosal invasion (T1b), l/n mts can be found in 9,5-16.4-18,4% of cases. Mucosal cancer <10 mm was not accompanied by l/n mts L/m mts are more common in diffuse as compared to intestinal cancer type (p<0,01)
Namieno T. et al., 1996; Zhu Z. et al., 1995; Shimoyama S et al., 2002

Surgical results
Early cancer: 5-year survival rate
67% of operated cases
Cohen M.M., Zoeter M.A., Loar C. Surg-Endosc. 1994 Aug; 8(8): 862-6

82%of operated cases

Dietl F., Rumpf K.D. Zentralbl-Chir. 1995; 120(10): 800-3

96% (mucose invasion), 86% (submucose invasion)Austria!

Jatzko G., Lisborg P.H., Klimpfinger M. Jpn-J-Clin-Oncol. 1992 Feb; 22(1): 26-9

98% (n0), 92% (n+) N=621; 10 years - 97,4% (n0), 87,2% (n+) Seto Y. et al. World J.Surg. , 1997, 21, 186-190

Surgical results
Early cancer
L/n metastases have been found in 63 (10.1%) out of 621 patients.
In cases of invasion into 1, 2, 3, 4 and more l/n, 5 (10)year survival change as folows:
90.0% (70.7%) 92.9% (84.8%) 92.3% (83.1%) 74.0% (55.2%)
Seto Y. et al. World J.Surg. , 1997, 21, 186-190

Early gastric cancer (EGC)

EGC mucosal and submucosal cancer, regardless the invasion to regional l/n or distant metastases. T1cancer according to TNM classification: tumour invasion to mucose and/or muscularis mucosa (M), or submucose (SM) layer. SM1 is defined as invasion <0,5 mm from muscularis mucosae SM2 is defined as invasion>= 0,5 mm from muscularis mucosae

Morphologic EGC classification

Japanese Research Society for Gastric Cancer
Type I protruded (polypoid) type Type II - superficial type Type II a - elevated lesion
Type IIb - flat lesion Type II c - superficially depressed lesion Type III - excavated lesion

Strategy of gastric cancer treatment

Gotoda T. Gastric Cancer. 2007, 10: 1-11

Gastric cancer

Lymphatic nodes

Peritoneum, blood circulation

Localised disorder Systemic disorder

Early stage

Advanced cancer

Endoscopic m/sbm resection Adjuvant chemoterapy Laparoscopic surgery Surgical treatment Gastrectomy + L/n resection

Guidelines for endoscopic EGC resection.

Gotoda T et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 2000; 3:219-25

Depth
Histology

Mucose cancer Submucose cancer ulcer (+) ulcer(-)

20 20< 30 30<

SM1 30

SM2 any size

Differentiated

Undifferentiated

Eligible for EMR Extended ESD criteria

Surgery Surgery for consideration

Endoscopic mucosal resection

Gastric cancer lesion confined to mucosa layer

Endoscopic ultrasound (EUS) is helpful in stageing GC

EMR

http://www.city.gifu.lg.jp/c/Files/1/11020088/img/emr.gif

Kitano S et al. Laparocopic EGC surgical resection Europ J Gastroenterol and Hepatol 2006; 18:8

Laparoscopic borderline resection

Kitano S et al. Laparocopic EGC surgical resection Europ J Gastroenterol and Hepatol 2006; 18:8

Intragastric mucal or partial resection

Conclusions
Most patients (80%) are hospitalized with gastric cancer stage III-IV, and this determines the treatment results; thus, the most important task is to improve the means for early diagnostics. The incidence of laparotomies is 16%, therefore, in cases of suspected outspread cancer, the initial recommended intervention is diagnostic laparoscopy.

Conclusions
The treatment of gastric cancer is still contraversial:
Whenever neoadjuvant treatment did not prove effective,postoperative combined chemotherapy also did not provide much hope in clinical trials.

The use of intraoperative chemotherapy and immunotherapy still requires more scientific data.

Current needs
Implementation of biomarkers in clinical practice Sanation of precancer conditions Up-to-date diagnostics and staging Maintainance of curability principles. Auditing