Download About 100 cases of small cell carcinoma

• Gastric cancer is the second most common type of cancer
worldwide
• The highest incidence of gastric cancer is in Asia, central
Europe, and South America
• In the United States, gastric cancer is the seventh most
frequent cause of cancer-related death
• Carcinomas of the gastric cardia now represent close to 30%
of all gastric cancers
• Early gastric cancer now represents close to 20% of all newly
diagnosed cancers in the United States, and up to 50% in
Japan.
PATHOGENESIS
• The carcinogenic process involves a progression from
• chronic gastritis to atrophy with hypochlorhydria or
achlorhydria, intestinal meta-plasia, dysplasia, and,
ultimately, adenocarcinoma. [10], [11]
• Intestinal metaplasia, and subsequently dysplasia and
early adenocarcinoma, develops initially in the neck
region of the antral or fundic glands of the stomach,
which supports the hypothesis that precursor cells are
located in this region. [
• Long-standing H. pylori infection induces
chronic gastritis that gradually results in
atrophy and intestinal metaplasia. [16], [17]
• There is a four- to ninefold increased risk of gastric
lesions in patients with H. pylori infection,
particularly if infection begins in early childhood. [18–
20]
• Chronic acid suppression also increases the risk
for development of atrophy in patients with H.
pylori gastritis.[21]
• For instance, cytotoxin-associated gene A (CagA)–
positive strains of H. pylori, which produce higher
levels of interleukin-8, elicit more intense
inflammation and are associated with an increased
risk of gastric carcinoma. [22]
• However, the majority of H. pylori–infected
individuals do not develop gastric cancer, and,
conversely,
• up to 20% of patients in whom gastric cancer
develops are H. pylori seronegative
• Diets rich in salt (dried and salted fish and meats,
soy sauce, smoked fish, pickled foods) and
containing low levels of micronutrients, vitamins,
and antioxidants[14] favor intraluminal formation of
genotoxic agents, such as specific N-nitroso
compounds (formed by nitrosation of ingested
nitrates), and have been found to be associated
with the development of gastric cancer
• the diffuse type is more common in younger
individuals and is observed with equal
incidence in both high- and low-risk
geographic regions.
• Its development is more regulated by genetic
factors than intestinal-type gastric cancer
HISTOLOGIC PRECURSORS OF GASTRIC CANCER
• In most instances, the development of gastric
adenocarcinoma represents the culmination of an
inflammation–metaplasia–dysplasia–carcinoma
sequence, known as the Correa cascade of
multistep gastric carcinogenesis. [32]
• Mucosal atrophy and intestinal metaplasia confer a
high risk for the development of gastric cancer;
however, gastric epithelial dysplasia (or adenoma,
if it is a polypoid lesion) represents a direct
neoplastic precursor lesion. [32], [33]
• The vast majority of gastric epithelial
dysplasias (or adenomas) have an
“intestinal” phenotype, resembling colonic
adenomas.
• Another, less common, histologic variant is
hyperplastic (type II) dysplasia.[34]
• Finally, the exceedingly rare tubule neck (or
globoid) dysplasia is believed to be a
precursor of diffuse-type gastric
carcinoma.[35]
EARLY GASTRIC CANCER
• Invasive adenocarcinomas confined to the mucosa
or submucosa, regardless of whether lymph node
metastasis is present, are defined as early gastric
cancer
• EGC represents between 15% and 21% of all newly
diagnosed gastric cancers, whereas in Japan it
accounts for over 50% of cases.[6–9]
• A higher prevalence of gastric cancer, more liberal
use of upper endoscopy and chromoendoscopy,
and differences in diagnostic criteria help explain
the differences between Western and Japanese
studies.
• Most EGCs are small, measuring between 2
and 5 cm, and are typically localized on the
lesser curvature around the angularis
region.[
• In 3% to 13% of patients, multiple primary
sites are present and this has been shown to
be associated with a worse prognosis
• vided into three types based on their
endoscopic appearance (Fig. 21-2):
protruding (type I), superficial (type II), and
excavating (type III).[
• Signet ring cell carcinoma (Fig. 21-4) and
poorly differentiated carcinoma represent
26% and 14% of cases, respectively, and are
usually depressed or ulcerated (types IIc and
III).[5], [6], [69] Diffuse-type EGCs tend to show
greater depths of invasion
ADVANCED GASTRIC CARCINOMA
• Advanced adenocarcinoma is defined as a tumor that
invades the gastric wall beyond the submucosa
• Approximately half of all gastric adenocarcinomas
measure between 2 and 6 cm in size, and
• 30% measure 6 to 10 cm in greatest dimension.
• Only 15% of gastric carcinomas are larger than 10 cm
at the time of diagnosis.[5]
• Multiple adenocarcinomas are detected in 5% of
patients.[61], [79]
• exophytic, ulcerated, infiltrative, or combined.
• Cytologically, a combination of gastric foveolar,
intestinal, and endocrine cell types usually
constitutes at least a portion of all tumors.
• G type (gastric phenotype; MUC5AC+ and/or
MUC6+; MUC2− and CD10−), type I (intestinal
phenotype; MUC2+ and/or CD10+; MUC5AC− and
MUC6−), GI type (gastric and intestinal), and N type
(null phenotype).
LAURÉN CLASSIFICATION
• intestinal,
• diffuse, and
• indeterminate/unclassified types.
• The relative frequencies are 50% to 67% for the intestinal
type, 29% to 35% for the diffuse type, and 3% to 21% for
the indeterminate/unclassified type. [90]
•
WHO INTESTINAL TYPE
• Papillary adenocarcinoma
•
Tubular adenocarcinoma
• A higher rate of lymph node metastases
has been reported for papillary
adenocarcinoma
• Diffuse type
• Signet ring cell carcinoma
•
Mucinous adenocarcinoma
• Diffuse-type adenocarcinomas are
composed of mostly single, or small, nests
of neoplastic cells that diffusely infiltrate
the gastric wall.
• This type is found most commonly in the
gastric body and in younger patients.
• Although also associated with H. pylori
infection, the carcinogenetic sequence of
the diffuse type of gastric cancer is not well
characterized
• Pure signet ring cell carcinomas are included in
the diffuse type (Fig. 21-11). They are
characterized by the presence of infiltrating
single cells containing distended cytoplasm and
compressed, eccentrically displaced nuclei that
form a crescent shape.
• Gland formation is not a normal component of
this tumor. It grows in cords, tight clusters, and
solid sheets
• By consensus, over 50% of the tumor should
be composed of signet ring cells to warrant
this designation.
• Other variants have also been observed,
such as tumors that contain cells resembling
histiocytes, deeply eosinophilic cells with
neutral mucin, and anaplastic cells with little,
or no, intracellular mucin[1] (Fig. 21-12).
Mitoses are typically less numerous than in
the glandular type of diffuse gastric
carcinoma.
• Also included in the diffuse type are
mucinous adenocarcinomas, in which
pools of extracellular mucin comprise at
least 50% of the tumor volume; these
represent 10% of all gastric
carcinomas.[86]
• The cellular component may be formed
of glands, or of irregular clusters of
cells that float freely in the extracellular
mucin
• Undifferentiated carcinomas
• Adenosquamous carcinoma
• Squamous carcinoma
•
Small cell carcinoma
•
Others[*]
SUBTYPES OF GASTRIC ADENOCARCINOMA
• This subtype, also known as medullary
carcinoma or lymphoepithelioma-like
carcinoma, is characterized by the presence of
prominent lymphoid infiltration of the stroma.
• More than 80% of gastric carcinomas with
lymphoid stroma (GCLS) are associated with
Epstein-Barr virus (EBV) infection.[100]
• The prognosis of GCLS is considered
better than that of ordinary
adenocarcinomas, with survival rates
close to 77% after 5 years, although this
is somewhat controversial. [5], [105], [110]
HEPATOID AND Α-FETOPROTEIN–PRODUCING
CARCINOMAS
• This subtype of gastric carcinoma is
particularly aggressive, showing a 5-year
survival rate of only 12
ADENOSQUAMOUS AND SQUAMOUS CELL
CARCINOMA
• Adenosquamous carcinoma, which accounts
for 0.5% of all gastric cancers, is defined as a
tumor in which the neoplastic squamous
component comprises at least 25% of the
tumor volume.[8], [116]
• These tumors are usually deeply penetrating
and associated with lymphovascular invasion,
and carry a relatively poor prognosis
• For tumors of the cardia region,
caudal extension of a primary
esophageal squamous cell
carcinoma should be excluded.
• Gastric squamous cell carcinomas
are often diagnosed at a late stage,
and their prognosis is generally
poor, despite response to
chemotherapy
CARCINOSARCOMA
• Gastric carcinosarcomas are rare tumors
composed of varying amounts of
adenocarcinomatous and sarcomatous elements.
• Sarcomatous elements may consist of
uncommitted cells or demonstrate light
microscopic or immunohistochemical features of
chondrosarcoma, osteosarcoma,
rhabdomyosarcoma, or leiomyosarcoma
differentiation.[60,130–132]
• Tumors with adenosquamous and neuroendocrine
components have also been reported. [133–135]
• Most gastric carcinosarcomas are large
polypoid tumors and are associated
with a poor outcome.[136]
• A single case of gastric adenosarcoma
composed of benign tubular and cystic
glands embedded in an otherwise
typical leiomyosarcoma stroma has
been reported.[137]
SMALL CELL CARCINOMA
• About 100 cases of small cell carcinoma (oat
cell carcinoma or neuroendocrine carcinoma)
have been reported in the stomach. [138]
Because these tumors are frequently
diagnosed at an advanced stage, the
prognosis is generally quite poor, with most
patients dying within 1 year of diagnosis. [139],
[140] However, long-term survival can be
observed with aggressive adjuvant
therapy.[141]
• Immunohistochemically, carcinoembryonic
antigen (CEA) is usually negative,[142]
whereas neuron-specific enolase (NSE) and
chromogranin A are often positive; electron
microscopy can help demonstrate the
characteristic neurosecretory granules in
these tumors
PARIETAL CELL CARCINOMA AND ONCOCYTIC CARCINOMA
• Rare examples of parietal cell carcinoma
have been reported. These tumors are
composed of solid sheets of polygonal
cells with abundant, finely granular,
eosinophilic cytoplasm that stains with
phosphotungstic acid–hematoxylin.
GASTRIC MUCOEPIDERMOID AND PANETH CELL CARCINOMAS
• Very few of these tumors have been reported. Mucoepidermoid carcinomas show a mixture of
mucusproducing and squamous epithelium. [150], [151]
One case has been shown to arise from submucosal
ectopic glands.[151] The prognosis is reportedly poor.
A few Paneth cell carcinomas have been reported as
well. These are characterized by tumors with a
predominance of cells with Paneth cell differentiation,
characteristically showing eosinophilic cytoplasmic
granules that are positive for lysozyme by
immunohistochemistry.[146], [147]
METASTATIC CARCINOMAS
• Metastases to the stomach are uncommon. They are
reported in less than 5.4% of individuals in autopsy
series of patients with cancer. [155], [156]
• They can be completely asymptomatic, [157] or
present clinically as a large bleeding ulcer
mimicking a primary carcinoma (39% of cases), or
as submucosal tumor (51% of cases).[156]
• When diagnosed endoscopically, 65% to 80% of
gastric metastases are solitary lesions.
• In some studies, there is a predilection for
involvement of the middle and proximal stomach
• Malignant melanoma and lung and breast
carcinomas are the most commonly reported
primaries.[156], [158], [159]
• However, primary tumors originating from the
kidney, pancreas, esophagus, skin, testis, cervix,
and colon have been reported as well.[155], [156]
• In 50% of cases, concomitant metastases are noted
in other organs.[160]
• In patients with metastasis, infiltration of the deep
layers of the gastric wall, combined with a reactive
hyperplastic appearance of the overlying mucosa,
may mimic benign hypertrophic gastritis.
• Metastatic lobular breast carcinoma deserves
special attention because its typical single-file
growth pattern can resemble diffuse-type
carcinoma, signet ring cell carcinoma, or linitis
plastica.
• an immunohistochemical profile consisting of
gross cystic disease fluid protein-15 (GCDFP-15),
estrogen and progesterone receptors, and CK-7 (all
positive in breast carcinoma) and CK-20 (negative
in breast carcinoma) has been noted to be useful in
establishing a correct diagnosis. [161–163]
• More recently, negativity for CDX2, MUC2, MUC5AC,
MUC6, and DAS-1 (negative in breast and variably
positive in gastric cancer) has been shown to be
useful in diagnosing metastatic breast
carcinoma.[161], [164], [165]