Gastro 48 Carcinoma stomach

• H. pylori
• Diet – High salt diet, smoked increases risk (high level of nitrates), Vegetables decrease risk
• Hereditary – E. cadherin gene mutation, FAP, Li Fraumeni (p-53), Lynch syndrome
• Other – Pernicious anemia, Polyp, PPI – secondary to atrophic gastritis

• If pedunculated – Endoscopic removal
• If >2cm , sessile, proven focus of invasive carcinoma – Excision
• Fundic polyp – Usually associated with PPI, regular surveillance only

• Type 0 (superficial) Typical of T1 tumors.
• Type 1 (mass) Polypoid tumors, sharply demarcated from the surrounding mucosa.
• Type 2 (ulcerative) Ulcerated tumors with raised margins  surrounded by a thickened gastric wall with clear margins.
• Type 3 (infiltrative ulcerative) - Ulcerated tumors with raised margins, surrounded by a thickened gastric wall without clear margins.
• Type 4 (diffuse infiltrative) Tumors without marked ulceration or raised  margins, the gastric wall is thickened and indurated and the margin is unclear.
• Type 5 (unclassifiable)  Tumors that cannot be classified into any of the  above types

• 
• [Reference: Japanese classification of gastric carcinoma: 3rd English edition]

• Type 0-I (protruding) - a Polypoid tumors.
• Type 0-II (superficial) -  Tumors with or without minimal elevation or depression relative to the surrounding mucosa.
• Type 0-IIa (superficial elevated) - a Slightly elevated tumors.
• Type 0-IIb (superficial flat) - Tumors without elevation or depression.
• Type 0-IIc (superficial depressed) - Slightly depressed tumors.
• Type 0-III (excavated) - Tumors with deep depression

• [Tumors with less than 3mm elevation are usually classified as 0-IIa, with more elevated tumors being classified as 0-I] 
• 

• Intestinal / Diffuse
• Environmental / Familial
• Gastric atrophy, intestinal metaplasia (arises in setting of well recognized pre-cancerous condition) / Blood group A
• Older age / Younger age
• Gland formation / Poorly differentiated signet ring cells
• Hematogenous spread / Transmural or lymphatic spread
• Microsatellite instability APC gene mutation / Decreased E-cadherein
• Prognosis is more favorable / Less favorable

• Adenocarcinoma, Adenosquamous, Squamous, Undifferentiated, Unclassified
• Adenocarcinoma types – Papillary, tubular, Mucinous, Poorly Cohesive (including signet ring cell carcinoma), and mixed adenocarcinoma [@ PTM²C]

Drop metastasis to ovaries

• Gastric carcinoma – 15 nodes
• Carcinoma colon - 12 nodes

• Type I – within 1-5 cm above GE junction
• Type II – from 1 cm above, 2 cm below
• Type III – Form 2-5 cm caudal to GE junction
• Type I and II – treated as Esophageal Ca, Type III treated as Gastric Ca

• 1- Right paracardial
• 2- Left paracardial
• 3- Lesser curvature
• 4- Greater curvature
• 4sa Short gastric
• 4sb Left gastroepiploic
• 4d Right gastroepiploic
• 5- Suprapyloric
• 6- Infrapyloric
• 7- Left gastric artery
• 8a Anterior common hepatic
• 8p Posterior common hepatic
• 9- Celiac artery
• 10- Splenic hilum
• 11p Proximal splenic
• 11d Distal splenic
• 12a Left hepatoduodenal ligament
• 12b, p Posterior hepatoduodenal
• 13- Retropancreatic
• 14v Superior mesenteric vein
• 14a Superior mesenteric artery
• 15- Middle colic
• 16al Aortic hiatus
• 16a2, b1 Para-aortic, middle
• 16b2 Para-aortic, caudal
• 19 - Infradiaphragmatic
• 20 - Esophageal hiatus of diaphragm
• 110 - Paraesophageal in lower thorax
• 111 - Supradiaphragmatic

(110 and 111 are in thorax)

6-8.

Single biopsy sensitivity – 70%, 7 biopsy – 98%

Total 5 layers

• First 3 layers – mucosa and submucosa (T1)
• 4th layer - Muscularis Propria (T2)
• 5th Layer – Serosa

• Tis Carcinoma in situ; intraepithelial tumor without invasion of the lamina propria
• T1 Tumor invades lamina propria, muscularis mucosae, or submucosa
• 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
• T4 Tumor invades serosa (visceral peritoneum) or adjacent structures
• T4a Tumor invades serosa (visceral peritoneum)
• T4b Tumor invades adjacent structures

• 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
• N3b Metastasis in 16 or more regional lymph nodes

M1 Distant metastasis

For clinical purpose, Carcinoma stomach is divided into

• Early gastric Ca - restricted to the mucosa or submucosa, irrespective of lymph node metastasis (T1, any N)
• Advanced gastric Ca – Involve muscular layer

In almost all patients

In the following condition, either EMR or ESD can be done.

• A differentiated-type adenocarcinoma
• Without ulcerative findings [UL(-)]
• Depth of invasion is clinically diagnosed as T1a and the diameter is ≤2 cm.

To avoid incomplete dissection, ESD rather than EMR should be performed.

• Tumors clinically diagnosed as T1a and
• (a) Of differentiated-type, UL(-), but[2 cm in diameter.
• (b) Of differentiated-type, UL(?), and B3 cm in diameter.
• (c) Of undifferentiated-type, UL(-), and B2 cm in diameter.

• Make border of lesion using Electrocautery
• Submucosal injection of epinephrine with indigo caramine – Hydrodissection of Lesion
• Insulation of tipped knife to remove the lesion by dissecting the submucosal plane deep to the tumor to remove in en bloc

For T1 tumors - 2 cm

T2 or deeper tumors with an expansive growth pattern (types 1 and 2) - 3cm

Infiltrative growth pattern (types 3 and 4)- 5 cm

Tumors invading the esophagus - 5-cm margin is not necessarily

Always confirm with frozen section.

• Total gastrectomy - Total resection including the cardia and pylorus
• Distal gastrectomy - Stomach resection including pylorus but cardia preserved. 
• The standard surgical procedurefor clinically node-positive (cN+) or T2-T4a tumors is either total or distal gastrectomy.
• Distal gastrectomy is selected when a satisfactory proximal resection margin can be obtained.
• Total gastrectomy - lesions in the upper third
• Subtotal gastrectomy - lesions in the lower two-thirds
• Pancreatic invasion by tumor requiring pancreatico-splenectomy necessitates total gastrectomy regardless of the tumor location.
• Total gastrectomy with splenectomy should be considered for tumors that are located along the greater curvature and harbor metastasis to no. 4sb lymph nodes, even if the primary tumor could be removed by distal gastrectomy.
• For adenocarcinoma located on the proximal side of the esophagogastric junction, esophagectomy and proximal gastrectomy with gastric tube reconstruction should be considered, similarly to surgery for esophageal cancer

Tumors of the proximal stomach that do not invade the esophagogastric junction (EGJ) can be approached by either a total gastrectomy or a proximal subtotal gastrectomy. Total gastrectomy is preferred by most surgeons for the following two reasons:

• ●The Roux-en-Y reconstruction performed during total gastrectomy is associated with an extremely low incidence of reflux esophagitis (2 percent). In comparison, approximately one-third of patients develop reflux esophagitis after a proximal subtotal gastrectomy
• ●Proximal subtotal gastrectomy may leave behind lymph nodes along the lesser curvature of the stomach, which is the most common site of nodal metastases.

• Japanese guidelines
• In total gastrectomy
• D0 - Lymphadenectomy less than D1
• D1 - 1-7
• D1+ - D1 + 8a,9,11p
• D2 - D1 + 8a,9,10,11p,11d,12a.

For tumors invading the esophagus, D1+ includes:No. 110, D2 includes No. 19, 20, 110 and 111

• In Distal gastrectomy -
• D0 - Lymphadenectomy less than D1
• D1 - 1,3, 4sb, 4d, 5,6,7
• D1+ - D1 + 8a,9
• D2 - D1 + 8a,9,11p,12a

A. Standard gastrectomy – It involves resection of at least two-thirds of the stomach with a D2 lymph node dissection.

B Non-standard gastrectomy - the extent of gastric resection and/or lymphadenectomy is altered according to tumor stages.

1) Modified surgery The extent of gastric resection and/or lymphadenectomy is reduced (D1, D1+, etc.) compared to standard surgery.

2) Extended surgery

-  Gastrectomy with combined resection of adjacent involved organs.

- Gastrectomy with extended lymphadenectomy exceeding D2.

Palliative surgery -  Surgery to relieve symptoms (bleeding or obstruction) may then be considered an option, and palliative gastrectomy or gastrojejunostomy is selected depending on the resectability of the primary tumor and/or surgical risks.

Reduction surgery - The role of gastrectomy is unclear in patients with metastatic gastric cancer in the absence of urgent symptoms such as bleeding or obstruction. Reduction surgery aims to prolong survival or to delay the onset of symptoms by reducing tumor volume

• – Total gastrectomy Total resection of the stomach including the cardia and pylorus.
• – Distal gastrectomy Stomach resection including the pylorus. The cardia is preserved. In the standard gastrectomy, two-thirds of the stomach is resected.
• – Pylorus-preserving gastrectomy (PPG) Stomach resection preserving the upper third of the stomach and the pylorus along with a portion of the antrum.
• – Proximal gastrectomy Stomach resection including the cardia (esophagogastric junction). The pylorus is preserved.
• – Segmental gastrectomy Circumferential resection of the stomach preserving the cardia and pylorus.
• – Local resection.
• – Non-resectional surgery (bypass surgery, gastrostomy, jejunostomy).

• 1. Mobilization of the greater curvature with detachment of omentum from transverse colon and mesocolon and division of left gastroepiploic vessels
• 2. Infrapyloric mobilization with ligation of right gastroepiploic vessels and dissection of station 6 lymph nodes up with specimen
• 3. Suprapyloric mobilization with ligation of right gastric vessels in the porta hepatis and dissection of the station 5 lymph nodes up with specimen
• 4. Duodenal Transection (GIA Stapler)
• 5. D2 lymphadenectomy with dissection of the porta hepatis (Station 12), common hepatic artery (Station 8), left gastric artery (station 7), celiac axis (Station 9), and splenic artery(Station 11 ), and ligation of left gastric vessels
• 6. Gastric transection
• 7. Reconstruction by loop or Roux-en-Y gastrojejunostomy

• Similar follow up in early and advanced gastric cancer -
• ●History and physical examination every three to six months for years 1 to 2, every 6 to 12 months for years 3 to 5, and then annually
• ●Complete blood count and chemistry profile as indicated
• ●Radiologic imaging or endoscopy as clinically indicated
• ●Monitor for nutritional deficiency in surgically resected patients and treat as indicated

National Comprehensive Cancer Network (NCCN) recommend that D2 lymph node dissection is preferred over a D1 dissection.

From Japanese study, D2 lymph node dissection is likely oncologically superior, must be performed in safe manner. In absence of tumor invasion, spleen should be spared during gastrectomy.

D1 versus D2 dissection Trials

MRC trial - no difference in recurrence free or overall survival between D1 vs D2 dissection

Dutch D1D2 trial - lower recurrance rate and disease free survival at 15 yr follow up in D2 group, no difference in overall survival, possibly due to perioperative mortality

Japanese trial - increase survival in D2 group with no increased or minimal increase in morbidity

Roux loop at least 50 cm to prevent reflux oesophagitis.

• Removal of the inner peritoneal surface of the bursa omentalis
• For tumors penetrating the serosa of the post gastric wall with the aim of removing microscopic tumor deposits in lesser sac

Southwest oncology group – Surgery Vs Surgery + 5-FU + Radiotherapy

CLASSIC Trial – Gastrectomy (D2) Vs Gastrectomy + eight 3-week cycles of Capecitabine + Oxaliplatin. Chemotherapy group better outcome. Stopped early

ARTIST Trial – Whether the addition of Adjuvant radiotherapy would be benefitial in patients undergoing D2 gastectomy and chemotherapy

MAGIC Trial – In stage II or higher gastric Ca, Comparision of Perioperative (pre+postoperative) chemotherapy Vs Operation alone. Better with chemotherapy group.

[@ aRtist trial for Radiotherapy, classiC, magiC trial for Chemotherapy)

French Trial (FFCD) – Similar to MAGIC Trial

MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. 

Study was done by Cunningham et al in London and the results was published in NEJM 2006. 

The trial compared perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer. 

Eligibility criteria - Patients of any age who had a WHO performance status of 0 or 1 were eligible if they had histologically proven adenocarcinoma of the stomach or lower third of the esophagus that was considered to be stage II (through the submucosa) or higher, with no evidence of distant metastases, or locally advanced inoperable disease, as evaluated by computed tomography, chest radiography, ultrasonography, or laparoscopy. 

• 453 patients were randomized
• – ECF > Surgery > ECF
• – Surgery

Epirubicin, cisplatin, plus infusional fluorouracil (FU; ECF) regimen. Three cycles prior to resection and three cycles after surgery.

Conclusion: Perioperative ECF decreases tumor size and stage and improves both overall and disease free survival

• Critiques
• – Tumor heterogeneity - 25 % of patients had esophageal and GE junction tumors
• – Treatment toxicity - Only 42 % of the patients in the perioperative group completed all protocol treatments, 34 % of the patients who completed preoperative chemotx + surgery did not undergo postop chemotx
• – Inadequate staging - Only 70 % of the patients had their tumor size recorded prior to surgery, No EUS, no laparoscopy
• – No radiation, older generation drugs

Despite the impressive results of the trial, neoadjuvant chemotherapy with an ECF regimen has not been adopted as standard of care.

• Combination of -
• Tegafur (prodrug of 5-fluorouracil)
• gimeracil (Gimestat), and
• oteracil (Otastat) potassium

S-1-based chemotherapy and the combination of S-1 and cisplatin are the most reasonable first-line standards for unresectable advanced gastric cancer in Japan

• HER2 positive:
• Trastuzumab-containing regimen

• HER2-negative gastric cancer:
• S1 + Cisplatin combination is standard based on the results of SPIRITS trial and JCOG 9912 trial
• Capecitabine + cisplatin combination is currently one of standard based on ToGA trial and AVAGAST trial
• S-1, cisplatin and docetaxel (DCS regimen) is currently on investigational treatment

• Bleeding or obstruction - pallative resection
• If growth is not resectable - pallative gastrojejunostomy to relief gastric outlet obstruction.
• For inoperable gastroesophageal junction growth:
• • Stenting or recanalization with laser may be helpful
• • Alternatively esophagojejunostomy and gastric exclusion may be done
• Perforation – Closure with Healthy omentum

The overall five-year survival rate for treated EGC in most modern era series is over 90 percent

Recurrence of 40-80%, most recurrences in first 3 years in advanced gastric ca