Adenocarcinoma

Definition

Malignant glandular neoplasm arising from the gastric foveolar epithelium, of intestinal or diffuse type, and generally poor prognosis.

Clinical Features

Symptoms:
- usually:
  - indicate advanced disease
  - vague and nonspecific, e.g.:
    - dyspepsia
    - weight loss
    - anemia
- may be obstruction relatively early if in cardiac or pyloric areas
Metastasis:
- sometimes first sign
- Trousseau's sign or Virchow's node:
  - isolated nodal metastasis in left supraclavicular region

Spread

Often invasion of:
- duodenum if in distal stomach25
- esophagus if in proximal stomach26
- mucosal and submucosal (Borrman's) lymphatic plexus of stomach:
  - can then spread to:
    - perigastric lymph nodes
    - periaortic lymph nodes
    - celiac axis-related lymph nodes27
Mucosal lymphangiectasia associated with regional lymph node metastases28
Serosal spread more common and greater if infiltrative rather than expanding type29
Local extension:
- omentum
- colon
- pancreas
- spleen
May be:
- invasion of blood vessel walls (vasculitis carcinomatosa)30

Metastases

Lymph Node Metastases

Tumors of distal third:
- high incidence of involvement of hepatoduodenal nodes31
Incidence influenced by detection method:
- significantly higher when:
  - comprehensive fat-clearing method32
  - sections evaluated immunohistochemically for keratin33,34
Diffuse permeation of lymphatic plexus of bowel:
- sometimes:
  - large bowel
    - almost exclusively diffuse type 35

Distant Metastases

Most frequent sites:
- liver:
  - often found unexpectedly at operation
  - more common with intestinal type:
    - particularly if highly cellular (medullary)36,37
  - occasionally grow in diffuse intrasinusoidal pattern and lead to hepatic failure 38
- peritoneum
- lung
- adrenal gland
- ovary:
  - bilateral ovarian metastases constitute majority of Krukenberg's tumors
- also uterine body and cervix39
Diffuse type:
- wider pattern of dissemination than intestinal type
- more frequent involvement of:
  - peritoneum
  - lungs
  - ovary36,40

Pathogenesis

Possibility of malignant transformation of gastric peptic ulcer controversial 41–44

Intestinal-type Adenocarcinoma

Practically all arise from generative or basal cells of foveolae:45
- thought to arise from metaplastic epithelium46
Usually:
- background chronic atrophic gastritis with intestinal metaplasia:
  - etiopathogenic link and relative risk for malignancy controversial47–51
- preceded by dysplasia, CIS, and superficial carcinoma 52,53
Exceptionally originate in:
- other epithelium-lined submucosal cysts in gastric wall 54,55
Closely related to environmental factors 56
Sometimes a genetic predisposition57
Hypochlorhydria:
- 85–90% of cases
- may precede gastric cancer by several years
- postulated that high intragastric pH promotes growth of bacteria that reduce dietary nitrate to nitrite and then convert dietary amines, in presence of nitrite, into carcinogenic N-nitroso compounds58
Associated with:
- pernicious anemia:
  - risk not high enough to justify surveillance if asymptomatic59
- H. pylori:
  - implicated as etiologic factor through its role in chronic gastritis60–63
  - Menétrier's disease
  - gastric peptic ulcer
  - gastric stump
  - irradiation and chemotherapy for other malignancies 64
  - esophageal squamous cell carcinoma65
  - EBV: 66,67
    - incidence:68,69
      - 16% in US 70–72
      - higher in men than women 71
    - usual if a lymphoepithelioma-like appearance
    - seems to be early event independent of:
      - bcl-2 expression
      - p53 accumulation72,73

Early Carcinoma

Genetic studies suggest true multicentricity:
- supporting theory of field cancerization 74

Gross Pathology

Intestinal-type Adenocarcinoma

Wide variation
Many intermediate stages between two extremes of:
- fungating tumor growing mainly into lumen (Fig. 1
  Fig. 1: Gross appearance of gastric adenocarcinoma of polypoid type.
  )
- flat, ulcerated, and deeply invasive tumor growing through wall75,76 (Fig. 2
  Fig. 2: Gross appearance of gastric adenocarcinoma of ulcerative type showing marked resemblance to chronic peptic ulcer.
  )
Appearance:
- depends on:
  - relative amounts of mucin secreted
  - desmoplastic reaction
- may be:
  - fleshy
  - fibrous
  - gelatinous
Location:
- any area, in order of frequency:
  - anterior and posterior walls
  - lesser curvature
  - greater curvature77
Multiple in ≈6%78,79
Adjacent non-neoplastic mucosa often thickened:
- attributed to tumor production of epidermal growth factor 80

Diffuse-type Adenocarcinoma

Changes usually begin in prepyloric area
Often pyloric obstruction as wall becomes thickened and rigid (Fig. 3
Fig. 3: Typical gross appearance of diffuse carcinoma of linitis plastica type. Practically the entire wall of the stomach is involved by tumor. Note the prominence of rugal folds.
)
Sections of wall:
- marked submucosal fibrosis
- may be mucosal ulceration
- hypertrophic and segmented muscle:
  - by thin, parallel, grayish white, longitudinal lines:
    - continuous with foci of subserosal thickening
    - comb-like appearance

Early Carcinoma

At endoscopy:
- protruding or type I (polypoid, nodular, or villous)
- superficial or type II (elevated, flat, or depressed)
- excavated or type III
- combinations common81,82
Location:
- usually distal third 83,84
May be multicentric 5,85,86

Histopathology

Nearly all:
- composed of one or more of:
  - goblet cells 87
If in fundic area more likely to have invaded submucosa and beyond at surgery than those in pyloric area88

Intestinal-type Adenocarcinoma

Wide range of differentiation:
- correlates inversely with tumor size89
Better differentiated:
- cells usually:
  - columnar
  - mucin secreting (Fig. 4
    Fig. 4: Gastric adenocarcinoma of intestinal type.
    ):
    - amount variable
    - when abundant, often calcification
- occasionally so well differentiated simulates complete-type intestinal metaplasia90
- exceptionally ciliated91
Poorly differentiated:
- predominantly solid pattern92
Sometimes:
- metaplastic ossification
- easily identifiable Paneth cells:93
  - exceptionally predominant94,95
- scattered endocrine cells:
  - demonstrated with silver or immunohistochemical stains
- stroma heavily infiltrated by neutrophils or histiocytes (Fig. 5
  Fig. 5: Gastric adenocarcinoma accompanied by marked histiocytic reaction.
  )96

Diffuse-type Adenocarcinoma

Malignant cells:
- diffuse growth
- usually grow individually (Fig. 6
  Fig. 6: Diffuse type of gastric adenocarcinoma. An Indian file pattern of infiltration of the muscularis externa can be appreciated.
  )
Extensive fibrosis and inflammation
Often:
- entire wall involved
- mucosa less affected than deeper layers
  - though an intramucosal type of signet ring carcinoma occurs97
Rarely glandular formations
Mucin:
- most intracytoplasmic:
  - resulting in typical signet ring appearance (Fig. 7
    Fig. 7: Intracytoplasmic mucin droplet, as shown with Mayer's mucicarmine stain.
    )
- may be extracellular pools

Other Microscopic Types

Neuroendocrine Differentiation

Wide range in morphology and behavior98
Occasionally concurrent but independent adenocarcinoma (including ‘early’ carcinoma)99–101
Despite admixtures102,103
and overlaps most can be placed into one of following categories:
- most are in categories 3 or 4, i.e.:
  - small cell carcinoma
  - otherwise typical adenocarcinoma

1. Well-differentiated Neuroendocrine Tumor

Well differentiated
Slow growing
Traditionally known as carcinoid tumor
Composed of any of neuroendocrine cells of gastric mucosa

2. Large Cell Neuroendocrine Carcinoma

Also known as:
- neuroendocrine carcinoma104–106
Obvious morphologic features of neuroendocrine differentiation:
- trabeculae
- rosettes
- insulae
- ultrastructurally dense-core secretory granules
- immunoreactivity for NSE and other neuroendocrine markers
Equally obvious atypical morphologic features:
- marked invasiveness
- necrosis
- mitotic activity
Probably heterogeneous group
Prognosis poor when features analogous to those of large cell neuroendocrine carcinoma of lung 104

3. Small Cell Carcinoma

Morphologically analogous to pulmonary counterpart
Very aggressive clinical course104

4. Otherwise Typical Adenocarcinoma

Diffuse or intestinal type, particularly diffuse type
Cells argyrophilic or have some other phenotypical attribute of neuroendocrine cells107–109
Rarely neuroendocrine cells recognized at H&E level because granules:
- brightly eosinophilic and resemble those of Paneth cells 110
Behave like ordinary adenocarcinomas
Dual chromogranin A and PCNA staining111 suggests that neuroendocrine cells represent terminally differentiated elements that do not replicate.

Adenosquamous and Squamous Cell Carcinoma

<1% of all gastric carcinomas112,113
Surrounded on all sides by gastric mucosa, particularly if pure squamous cell
If lower end of esophagus involved interpret as primary esophageal carcinoma with gastric extension
Behavior largely determined by widely variable degree of differentiation of glandular component 113
Most thought to be squamous cell carcinomas have minute glandular component114

Mucinous Carcinoma

Also known as:
- mucoid carcinoma
- gelatinous carcinoma
- colloid carcinoma
Prominent glandular formations
Mucin:
- abundant deposition
- mainly extracellular (Figs 8 and 9
  Fig. 8: Gross appearance of mucinous carcinoma of the stomach. The cut surface has a homogeneous gelatinous appearance.
  Fig. 9: Microscopic appearance of mucinous carcinoma of the stomach. In contrast to diffuse carcinoma, most of the mucin is located extracellularly.
  )
- distinct O-acylated form of sialomucin
- immunoreactive for MUC2115,116
Prognosis:
- not significantly different from ordinary adenocarcinoma 117,118

Hepatoid Adenocarcinoma

Glandular and hepatocellular differentiation with frequent admixtures 119,120
Also tubulopapillary pattern with clear cells:
- interpreted as representing enteroblastic differentiation 121
Nodular or massive pattern of growth
Cytoplasm:
- abundant:
  - glycogen
  - hyaline globules
Extensive venous invasion:
- sometimes to omental and mesenteric vessels in fashion resembling hepatocellular carcinoma122
Poor prognosis
Exceptionally a neuroendocrine component123
Canalicular pattern of staining with polyclonal CEA
Hep-Par-1 immunoreactivity usual124
AFP positivity ≈50% of cases125
Distinguish from otherwise typical gastric adenocarcinoma (without morphologically recognizable hepatoid features) that is immunoreactive for AFP125–127

Parietal Gland Carcinoma 128,129

Also known as oncocytic carcinoma
Growth:
- glandular, or
- solid:
  - can simulate lymphoma
Cytoplasm:
- granular (oncocytic) (Fig. 10
  Fig. 10: Parietal cell carcinoma of stomach. The cytoplasm of the tumor cells has an oncocyte-like quality.
  )
- stains for:
  - PTAH
  - Luxol fast blue130
Most distinctive features:
- seen ultrastructurally
- abundant mitochondria
- tubulovesicles
- intracellular canaliculi
- intercellular lumina filled with undulating microvilli
In future may be detected using parietal cell antibodies from patients with type A gastritis131
Occasionally focal parietal cell differentiation in an otherwise typical intestinal type132

Lymphoepithelioma-like Carcinoma

Undifferentiated carcinoma with intense lymphoid infiltration
Morphologically resembles homonymous tumor of upper respiratory tract
Usually EBV present133–136
Probably related (or similar morphologically) to gastric (medullary) carcinoma with lymphocytic infiltration137–141

Sarcomatoid Carcinoma

Also known as carcinosarcoma
Dual composition:
- epithelial elements:
  - may contain neuroendocrine cells 142
- sarcoma-like spindle cell component:143–145
  - may contain heterologous elements such as skeletal muscle and bone 146
Much less common in stomach than in esophagus.
Variant in which epithelial component appears benign designated adenosarcoma147

(Adeno)carcinoma With Rhabdoid Features

Very rare
Solid growth pattern
Cytoplasm:
- eosinophilic inclusion-like material displaces and indents nucleus148
Coexpress keratin and vimentin
Very aggressive149

Gastric Carcinoma With Osteoclast-Like Giant Cells

Growth pattern:
- solid, or
- cribriform
Scattering of multinucleated cells with histiocytic markers150

Early Carcinoma

Differentiation varies:
- better differentiated (compared with poorly differentiated):
  - more vascularized
  - higher association with H. pylori151,152
Deep mucosal component underlying carcinoma:
- often cystic dilatation of glands 153
Histochemically gastric or intestinal phenotype154,155

Special Stains and Immunohistochemistry

Acid mucosubstance:
- features analogous to those of intestinal-type mucins 156,157
- various alterations of sialylation 158
Acidic or neutral type mucin:
- secreted by diffuse-type carcinoma
- within cytoplasm of signet ring cell
- sometimes neutral type predominates159
Main mucin types expressed:
- MUC1:
  - intestinal type
- MUC5AC:
  - diffuse type:
  - prevalent if antral
- MUC2:
  - mucinous type160,161
  - greater amounts if in cardia 162
Usually reactivity for:
- keratin:
  - usually simple epithelium type (low molecular weight)
  - sometimes those of normal squamous epithelia such as CK13 and 16163
  - CK7/CK20 patterns vary
    - generally ≈70% CK7+ and 20% CK20+164
  - sometimes coexpression with vimentin:165
    - particularly if diffuse type
- epithelial membrane antigen
- CEA166
- MI (a mucin antigen) and cathepsins D and E (an aspartic proteinase):
  - as expression of differentiation toward foveolar cells167,168
Markers of specific gastric differentiation include gastric proteases, e.g.:
- chymosin 169–171
Reactivity for lysozyme:
- may be abortive expression of Paneth cell differentiation 172,173
Often positivity for:
- α1-antitrypsin
- α1-antichymotrypsin
- α2-macroglobulin
Reactivity to hCG:
- in ≈10–50%174–176
- should not be equated with rare gastric choriocarcinoma
Other substances detected:
- pancreatic secretory trypsin inhibitor (PSTI)177
- lactoferrin178
- hormone receptors179,180
- hormone receptor-related proteins p52 and ERD5 181
- epidermal growth factor (EGF) and EGF receptor (suggesting autocrine mechanism for tumor growth)182
- immunoglobulin and secretory component183
- villin184
- α-catenin185
- enzymes superoxide dismutase and aromatase186,187
- CDw75 antigen 188
- CD44189
- placental alkaline phosphatase190
- HLA-DR antigen:
  - especially intestinal type191
- PTH-related protein:
  - especially if heterotopic ossification in primary lesion or metastases192
- basement membrane components:
  - e.g. laminin and type IV collagen:
  - more commonly intestinal than diffuse type193

Diagnosis

Categories (Table 1)

Table 1. Classifications of gastric carcinoma

	Bormann, 1926209	Type I (polypoid)
		Type II (fungating)
		Type III (ulcerated)
		Type IV (infiltrative)
	Stout (Atlas of Tumor Pathology), 195376	Fungating
		Penetrating
		Spreading
		Superficial spreading
		Linitis plastica
		No special type
	Lauren, 1965210	Intestinal
		Diffuse
	Ming, 1977211	Expanding
		Infiltrative
	Japanese Society for Gastric Cancer, 1981212	Papillary
		Tubular
		Poorly differentiated
		Mucinous
		Signet ring
	World Health Organization, 2000213	Adenocarcinoma, intestinal type
		Adenocarcinoma, diffuse type
		Papillary adenocarcinoma
		Tubular adenocarcinoma
		Mucinous adenocarcinoma
		Signet ring cell carcinoma
		Adenosquamous carcinoma
		Squamous cell carcinoma
		Small cell carcinoma
		Undifferentiated carcinoma
		Others

Intestinal-type adenocarcinoma:214
- most common (53%)
- predominates in high-risk areas
- decline in incidence in US and England47,215–217
Diffuse-type adenocarcinoma:218,219
- less common (33%)
- if signet ring cells categorize as signet ring carcinoma rather than mucinous (mucoid) carcinoma
Rest are heterogeneous in composition 220

Early Carcinoma

Confined to mucosa or mucosa and submucosa (Fig. 14
Fig. 14: Early gastric carcinoma limited to the mucosal layer of the organ.
):
- not extending into muscularis externa
- regardless of status of regional lymph nodes5,221–224
- usually intestinal type
- sometimes:
  - mucinous 225,226
Name inaccurate because not related to duration of lesion:
- also known as:
  - microinvasive cancer8,227
- subdivided into:
  - small
    - 6–10 mm in greatest diameter 228,229
Form limited to mucosa:
- intramucosal carcinoma
- separate from severe dysplasia–CIS:
  - based on invasion through glandular basement membrane into lamina propria
- not always easy to determine

Other investigations

Radiography usually demonstrates tumor:
- in ≈10% impossible to determine whether benign or malignant
Mass screening, endoscopy, cytology, and biopsy
- identifies up to 33% of early cases 194–197

Cytologic diagnosis

Traditionally vigorous lavage by saline or Ringer's of empty stomach:
- accurate results if symptomatic 198,199
- disappointing results in high-risk patients as screening test 200,201
Flexible fiberoptic gastroscopy (Figs 11–13
Fig. 11: Cytologic appearance of reactive (reparative) atypia.
Fig. 12: Cytologic appearance of intestinal-type gastric adenocarcinoma.
Fig. 13: Cytologic appearance of diffuse-type gastric adenocarcinoma.
):
- direct-vision gastric biopsy:
  - accuracy 78%202
- brush cytology203–205
  - accuracy 85%202
- gastric lavage cytology under direct vision:
  - accuracy 96%202
Selective chymotrypsin lavage method under fluoroscopy:206
- combined cytology and biopsy
False-negative diagnoses with biopsies:
- most often ulcerating type
- inversely related to number of specimens207
- greater rate with diffuse than intestinal type
Immunocytochemical staining for ras oncogene p21 may prove useful208

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Adenocarcinoma

Differential diagnosis in biopsy:
- severe dysplasia
- reactive or otherwise non-neoplastic conditions that may simulate malignancy such as:
  - bizarre epithelial atypia associated with chemotherapy or radiochemotherapy230,231
  - degenerative changes associated with erosion and regeneration:
    - striking background eosinophilia 232
  - plump reactive mesenchymal cells related to granulation tissue232
  - cohesive clusters of pyloric cells with glassy cytoplasm:
    - resembles signet ring carcinoma
  - polyvinylpyrrolidone storage disease:233
    - resembles signet ring carcinoma
  - gastric xanthoma:
    - resembles signet ring carcinoma

Diffuse-type Adenocarcinoma

One of most difficult problems in frozen section material
May be misinterpreted as benign due to:
- small size of tumor cells
- lack or inconspicuousness of glandular formations
- marked inflammatory and desmoplastic reaction
May simulate malignant lymphoma due to:
- diffuse pattern of growth
- round shape of cells and their nuclei

Gastric Ulcer

Methods To Make Differential Diagnosis

Radiographic examination alone:
- subject to error234,235
Radiographic, endoscopic, and pathologic (biopsy and/or cytology) techniques combined:
- accuracy approaches 100%
Frozen section at operation if in cardiac region because:
- increased risk of malignancy
- surgical therapy varies
If in midportion of distal half of stomach and no evidence of neoplastic spread beyond stomach:
- probably best to resect without gastrotomy and biopsy
- extent of excision differs little if benign or malignant

Staging/grading

Primary Tumor (T)

.
* A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T3. The adjacent structures of the stomach include spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. * Intramural extension to the duodenum or esophagus is classified by depth of the greatest invasion in any of these sites, including the stomach.
	TX	Primary tumor cannot be assessed
	T0	No evidence of primary tumor
	Tis	Carcinoma in situ: intraepithelial tumor without invasion of lamina propria
	T1	Tumor invades lamina propria or submucosa
	T2	Tumor invades muscularis propria or subserosa*
	T2a	Tumor invades muscularis propria
	T2b	Tumor invades subserosa
	T3	Tumor invades serosa (visceral peritoneum) without invasion of adjacent structures,*
	T4	Tumor invades adjacent structures,*

Regional Lymph Nodes (N)

.
* A designation of pN0 should be used if all examined lymph nodes are negative, regardless of total number removed and examined.
	NX	Regional lymph node(s) cannot be assessed
	N0	No regional lymph node metastasis*
	N1	Metastasis in 1–6 regional lymph nodes
	N2	Metastasis in 7–15 regional lymph nodes
	N3	Metastasis in >15 regional lymph nodes

Distant Metastasis (M)

.

	MX	Distant metastases cannot be assessed
	M0	No distant metastasis
	M1	Distant metastasis

Stage Grouping

.

	Stage 0	Tis	N0	M0
	Stage IA	T1	N0	M0
	Stage IB	T1	N1	M0
		T2a/b	N0	M0
	Stage II	T1	N2	M0
		T2a/b	N1	M0
		T3	N0	M0
	Stage IIIA	T2a/b	N2	M0
		T3	N1	M0
		T4	N0	M0
	Stage IIIB	T3	N2	M0
	Stage IV	T4	N1–3	M0
		T1–3	N3	M0
		Any T	Any N	M1

Genetics

Type	Name	Comment
gene	E-cadherin	Germline truncating mutations
gene	b-catenin	Mutation resulting in loss of b-catenin protein
gene	p53	Overexpression
gene	CDKN2A	Loss of p16 protein

Aneuploidy:
- much higher incidence in intestinal type than in diffuse type 236
AgNOR counts higher in adenocarcinoma than in dysplasia, but overlap237,238
Microsatellite instability (MSI):
- ≈20% of cases in US 239,240
- associated with:
  - lower stage 241
  - lymphocyte-rich gastric carcinoma242
Accumulation of p53:
- ≈50% of cases:243
  - primarily:
    - intestinal type
    - advanced stages of mixed glandular and diffuse types244,245
APC gene:
- somatic mutations:
  - 4% of gastric adenocarcinomas
    - in contrast to 76% in adenomas or flat dysplasia 246
    - suggests not significant in progression from adenoma to carcinoma.
ras p21 product:
- overexpressed in:
  - dysplasia
  - intestinal metaplasia
  - adenocarcinoma of both major microscopic types247,248
c-erbB-2 protein:
- membrane immunostaining:
  - 5–15% of cases 249,250
Loss of p16 (CDKN2A gene product):
- most common if:
  - associated with EBV 251
Apoptosis-regulating proteins:
- such as bcl-2 and Bax
- more commonly expressed in intestinal type than diffuse type240,252
Cyclin D1:
- overexpression:
  - common 253
  - more frequent with intestinal type253
Telomerase:
- upregulation:
  - common
  - may play role in development254,255

Early Carcinoma

Abnormalities in DNA ploidy as common as in advanced carcinomas262–264

Management

Gastrectomy:
Extended lymph node dissection:
- no convincing evidence that this increases survival272
Radiation therapy:
- little response
Chemotherapy:273,274
- relatively unresponsive
Frozen section at operation may be performed at:
- edge of perforated ulcers
- surgical margins
- enlarged regional nodes
- liver nodules or peritoneal implants

Prognosis

In US disappointingly poor:
- overall survival rate 4–13%275–278
Rate better in:
- Japan279:
  - 5-year survival rates:
    - 46% for advanced carcinoma
    - 89% for early carcinoma280
- England273,275
Different survival rates may result from:
- intrinsic differences in growth patterns 281
- different criteria in differential diagnosis between severe dysplasia and carcinoma278

Early Carcinoma

5-year survival rate following resection:
- 80–95%
- high even when nodal metastases8
Local recurrence:
- very low incidence282
- related to:
  - lymph vessel invasion
  - ulceration
  - tumor size283
Progresses to advanced carcinoma if not treated by gastrectomy284

Prognostic Factors

Age:
- grim if young, possibly because:
  - delay in diagnosis
  - higher percentage of diffuse type285,286
Tumor stage:
- greatest significance 287
- incorporates:
  - depth of invasion:
    - greater chance of metastases if deeper288–290
    - significantly associated with survival independently of lymph node status 291
  - lymph node status:
    - directly related to gross appearance of tumor:
    - much lower if polypoid and largely intraluminal than if growing primarily within wall292
- seems to be relationship between prognosis and surface area of any serosal invasion293
Location within stomach:
- distal half of stomach in 80% of 5-year survivors
- cardia, fundus, or esophagogastric junction – practically no long-term survivors276
Tumor margins:
- pushing or expanding border favorable294
- diffuse infiltration associated with decreased survival rate295–299
Tumor size:
- better prognosis if small, but linked to depth of penetration 279
Microscopic type and grading:
- intestinal type better than diffuse type294,300–302
- little correlation once special types excluded
- a new grading system that combines intracellular mucin content and tubular differentiation (Goseki's grading) may be related to survival 303
- proposed grouping for prognosis in decreasing order of malignancy:
  - high grade:
    - adenosquamous, anaplastic, and small cell neuroendocrine
  - diffuse and mixed
  - cohesive:
    - glandular and solid304
Inflammatory reaction:
- between tumor and normal tissue
- often associated with degenerative changes in tumor
- good prognostic sign299,305
- also claimed for abundant S-100 protein-positive Langerhans’ cells in advanced carcinoma 306
Perineurial invasion:
- poorer prognosis307
Surgical margins:
- early recurrence expected if carcinoma found at limit of excision279
Regional lymph node involvement:
- 5-year survival rate:
  - >50% if lymph nodes negative
  - <10% if nodal involvement295,308
- number of nodes more important than nodal stage 309
- immunohistochemically detected micrometastases may carry some prognostic significance310,311
Type of surgery:
- may be best survival with radical subtotal gastrectomy (22.1%)276
- may be better survival with radical lymphadenectomy than standard lymphadenectomy312
DNA ploidy and cell proliferation:
- may be reliable prognostic indicators313–318
c-erbB-2 protein overexpression:
- an independent indicator of poor prognosis 319–322
p53 protein overexpression:
- may be decreased survival 323,324
Cathepsins:
- increasing levels of cathepsin D associated with poorer survival 325
- high expression of cathepsins B and L related to greater tumor capacity for invasion and metastases326
p27Kip1 expression:
- said to indicate reduced survival327
Loss of Fhit protein:
- may indicate poor prognosis328
T antigen expression:
- said to correlate with depth of invasion and metastatic spread329

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Last updated: 19 Mar 2006