Stomach 773
requires both BCL-10 and MLT, which work together in a
Lymphoma
Although extranodal lymphomas can arise in virtually
any tissue, they do so most commonly in the GI tract,
particularly the stomach. In allogeneic hematopoietic stem
cell and organ transplant recipients, the bowel is also the
most frequent site for Epstein-Barr virus-positive B-cell
lymphoproliferations. This preferential location is most
likely because the deficits in T-cell function caused by oral
immunosuppressive agents (e.g., cyclosporine) are greatest
at intestinal sites of drug absorption. Nearly 5% of all
gastric malignancies are primary lymphomas, the most
common of which are indolent extranodal marginal zone
B-cell lymphomas. In the gut these tumors are often referred
to as lymphomas of mucosa-associated lymphoid tissue (MALT),
or MALTomas. This and other lymphomas of the gut are
discussed in Chapter 13.
Pathogenesis.  Extranodal marginal zone B-cell lympho-
mas usually arise at sites of chronic inflammation. They can
originate in the GI tract at sites of preexisting MALT, such
as the Peyer patches of the small intestine, but more com-
monly arise within tissues that are normally devoid of
organized lymphoid tissue. In the stomach, MALT is induced,
typically as a result of chronic gastritis. H. pylori infection is
the most common inducer in the stomach and, therefore,
is found in association with most cases of gastric MALToma.
Remarkably, H. pylori eradication results in durable remis-
sions with low rates of recurrence in most MALToma
patients.
Three translocations are associated with gastric
MALToma, the t(11;18)(q21;q21) and the less common
t(1;14)(p22;q32) and t(14;18)(q32;q21). The t(11;18)(q21;q21)
translocation brings together the apoptosis inhibitor 2
(API2) gene on chromosome 11 with the “mutated in
MALT lymphoma,” or MLT, gene on chromosome 18. This
creates a chimeric API2-MLT fusion gene that encodes an
API2-MLT fusion protein. The t(14;18)(q32;q21) and t(1;14)
(p22;q32) translocations cause increased expression of
intact MALT1 and BCL-10 proteins, respectively.
Each of the three translocations has the same net effect,
the constitutive activation of NF-κB, a transcription factor
that promotes B-cell growth and survival. Antigen-
dependent activation of NF-κB in normal B and T cells
pathway downstream of the B- and T-cell antigen recep-
tors. Thus, H. pylori–induced inflammation may trigger
NF-κB activation through the MLT/BCL-10 pathway in
MALTomas that lack these translocations. Removal of this
stimulus may explain why these tumors tend to respond
to H. pylori eradication. In contrast, NF-κB is constitutively
active in tumors bearing translocations involving MLT
or BCL10, and H. pylori treatment is ineffective. Other
tumor characteristics, including invasion to the muscularis
propria or beyond and lymph node involvement, also cor-
relate with failure of H. pylori eradication to induce
remission.
As with other low-grade lymphomas, MALTomas can
transform into more aggressive tumors that are histologi-
cally identical to diffuse large B-cell lymphomas. This is
often associated with additional genetic changes, such as
inactivation of the tumor suppressor genes that encode
p53 and p16. As one might guess, MALTomas that have
undergone such transformation are not responsive to
H. pylori eradication.
  MORPHOLOGY
Histologically, gastric MALToma takes the form of a dense
lymphocytic infiltrate in the lamina propria (Fig. 17-19A).
Characteristically, the neoplastic lymphocytes infiltrate the
gastric glands focally to create diagnostic lymphoepithelial
lesions (Fig. 17-19A, inset). Reactive-appearing B-cell follicles
may be present, and, in about 40% of tumors, plasmacytic
differentiation is observed. At other sites GI lymphomas may
disseminate as discrete small nodules (Fig. 17-19B) or infiltrate
the wall diffusely (Fig. 17-19C).
Like other tumors of mature B cells, MALTomas express the
B-cell markers CD19 and CD20. They do not express CD5 or
CD10, but are positive for CD43 in about 25% of cases, an
unusual feature that can be diagnostically helpful. In cases
lacking lymphoepithelial lesions, monoclonality may be demon-
strated by restricted expression of either κ or λ immunoglobulin
light chains or by molecular detection of clonal IgH rearrange-
ments. Molecular analysis is being used increasingly to identify
tumors with translocations that predict resistance to therapy.
Clinical Features.  The most common presenting symp-
toms are dyspepsia and epigastric pain. Hematemesis,
melena, and constitutional symptoms such as weight
loss can also be present. Because gastric MALTomas
and H. pylori gastritis often coexist and have overlapping
clinical symptoms and endoscopic appearances, diagnostic
difficulties may arise, particularly in small biopsy
specimens.
Carcinoid Tumor
Carcinoid tumors arise from the diffuse components of
the endocrine system and are now properly referred to
as well-differentiated neuroendocrine tumors. The term carci-
noid, or “carcinoma-like,” was applied because these
tumors tend to have a more indolent clinical course than
GI carcinomas. Most are found in the GI tract, and more
than 40% occur in the small intestine (Table 17-6). The
tracheobronchial tree and lungs are the next most
774 C H A P T E R 17 The Gastrointestinal Tract

commonly involved sites. Gastric carcinoid tumors may be

associated with endocrine cell hyperplasia, autoimmune
chronic atrophic gastritis, MEN-I, and Zollinger-Ellison
syndrome. In addition to autoimmune chronic atrophic
gastritis, as already discussed, gastric endocrine cell hyper-
plasia has been linked to proton pump inhibitor therapy,
but the risk of progression to a neuroendocrine neoplasm
in this circumstance is extremely low.

  MORPHOLOGY
Grossly, carcinoids are intramural or submucosal masses that
create small polypoid lesions (Fig. 17-20A). In the stomach they
typically arise within oxyntic mucosa. At all GI sites, the overlying
mucosa may be intact or ulcerated, and in the intestines the
tumors may invade deeply to involve the mesentery. Carcinoids
tend to be yellow or tan in color and are very firm as a conse-
quence of an intense desmoplastic reaction, which may cause
kinking and obstruction of the bowel. Histologically, carcinoids
are composed of islands, trabeculae, strands, glands, or sheets
A B of uniform cells with scant, pink granular cytoplasm and a round
to oval stippled nucleus (Fig. 17-20). In most tumors there is
minimal pleomorphism, but anaplasia, mitotic activity, and
necrosis may be present in rare cases. Immunohistochemical
stains are typically positive for endocrine granule markers, such
as synaptophysin and chromogranin A.

Clinical Features.  The peak incidence of carcinoid tumors

is in the sixth decade, but they may appear at any age.
Symptoms are determined by the hormones produced. For
example, tumors that produce gastrin may cause Zollinger-
C Ellison syndrome, while ileal tumors may cause carcinoid syn-
Figure 17-19  Lymphoma. A, Gastric MALT lymphoma replacing much of the drome, which is characterized by cutaneous flushing,
gastric epithelium. Inset shows lymphoepithelial lesions with neoplastic  sweating, bronchospasm, colicky abdominal pain, diar-
lymphocytes surrounding and infiltrating gastric glands. B, Disseminated rhea, and right-sided cardiac valvular fibrosis. Carcinoid
lymphoma within the small intestine with numerous small serosal nodules.  syndrome occurs in fewer than 10% of patients and is
C, Large B-cell lymphoma infiltrating the small intestinal wall and producing caused by vasoactive substances secreted by the tumor into
diffuse thickening. the systemic circulation. When tumors are confined to the

Table 17-6  Features of Gastrointestinal Carcinoid Tumors

Feature Esophagus Stomach Proximal Duodenum Jejunum and Ileum Appendix Colorectum
Fraction of GI carcinoids <1% <10% <10% >40% <25% <25%
Mean patient age (yr) Rare 55 50 65 All ages 60
Location Distal Body and fundus Proximal third, Throughout Tip Rectum > cecum
peri-ampullary
Size Limited data 1-2 cm, multiple; 0.5-2 cm <3.5 cm 0.2-1 cm >5 cm (cecum);
>2 cm, solitary <1 cm (rectum)
Secretory product(s) Limited data Histamine, Gastrin, somatostatin, Serotonin, substance Serotonin, Serotonin,
somatostatin, cholecystokinin P, polypeptide YY polypeptide YY polypeptide YY
serotonin
Symptoms Dysphagia, Gastritis, ulcer, Peptic ulcer, biliary Asymptomatic, Asymptomatic, Abdominal pain,
weight incidental obstruction, obstruction, incidental weight loss,
loss, reflux abdominal pain metastatic disease incidental
Behavior Limited data Variable Variable Aggressive Benign Variable
Disease associations None Atrophic gastritis, Zollinger-Ellison None None None
MEN-I syndrome, NF-1,
sporadic
MEN-I, Multiple endocrine neoplasia type I; NF-1, neurofibromatosis type I.

A B
Figure 17-20  GI carcinoid tumor (neuroendocrine carcinoma). A, Gross cross-section of a submucosal tumor nodule. B, Microscopically the nodule is com-
posed of tumor cells embedded in dense fibrous tissue. C, In other areas, the tumor has spread extensively within mucosal lymphatic channels. D, High
magnification shows the bland cytology of carcinoid tumors. The chromatin texture, with fine and coarse clumps, is frequently described as a “salt and pepper”
pattern. Despite their innocuous appearance, carcinoids can be clinically aggressive. E, Electron microscopy reveals cytoplasmic dense core neurosecretory
granules.
intestine, the vasoactive substances released are metabo-
lized to inactive forms by the liver, a “first-pass” effect
similar to that exerted on oral drugs. This can be overcome
by a large tumor burden or, more commonly, when tumors
secrete hormones into a nonportal venous circulation. The
carcinoid syndrome is therefore strongly associated with
metastatic disease in the liver since the bioactive products
can be released directly into systemic circulation.
The most important prognostic factor for GI carcinoid
tumors is location.
• Foregut carcinoid tumors, those found within the stomach,
duodenum proximal to the ligament of Treitz, and
esophagus, rarely metastasize and are generally cured
by resection. This is particularly true for gastric carci-
noid tumors that arise in association with atrophic
gastritis, while gastric carcinoid tumors without predis-
posing factors are often more aggressive.
• Midgut carcinoid tumors that arise in the jejunum and
ileum are often multiple and tend to be aggressive. In
these tumors, greater depth of local invasion, increased
size, and the presence of necrosis and mitoses are associ-
ated with a worse outcome.
• Hindgut carcinoids arising in the appendix and colorec-
tum are typically discovered incidentally. Those in the
appendix occur at any age and are generally located
at the tip. These tumors are rarely more than 2 cm
in diameter and are almost always benign. Rectal carci-
noid tumors tend to produce polypeptide hormones
and, when symptomatic, present with abdominal pain
and weight loss. Because they are usually discovered
when small, metastasis of rectal carcinoid tumors is
uncommon.
Gastrointestinal Stromal Tumor
A wide variety of mesenchymal neoplasms may arise in
the stomach. Many are named according to the cell type
they most resemble; for example, smooth muscle tumors
are called leiomyomas or leiomyosarcomas, nerve sheath
tumors are termed schwannomas, and those resembling
glomus bodies in the nail beds and at other sites are termed
Stomach 775
C D E
glomus tumors. These are all rare and are discussed in
greater detail in Chapter 26. GI stromal tumor (GIST) is
the most common mesenchymal tumor of the abdomen,
with annual incidences between 11 and 20 per million
people. More than half of these tumors occur in the stomach.
The term stromal reflects historical confusion about the
origin of this tumor, which is now recognized to arise from
the interstitial cells of Cajal, or pacemaker cells, of the gas-
trointestinal muscularis propria.
Epidemiology.  Clinically silent, microscopic proliferations
that may represent precursors to GIST are present in 10%
to 30% of resected stomachs. These have a low mitotic
index and lack pleomorphism and other features suggest-
ing malignancy. The risk of of these benign proliferations
becoming a GIST is estimated to be 1 in 2000.
The peak age at which clinically evident GISTs are rec-
ognized is approximately 60 years, with fewer than 10%
occurring in individuals younger than 40 years of age. Of
the uncommon GISTs in children, some are related to the
Carney triad, a nonhereditary syndrome of unknown etiol-
ogy seen primarily in young females that includes gastric
GIST, paraganglioma, and pulmonary chondroma. There
is also an increased incidence of GIST in individuals with
neurofibromatosis type 1.
Pathogenesis.  Approximately 75% to 80% of all GISTs
have oncogenic, gain-of-function mutations in the recep-
tor tyrosine kinase KIT. Approximately 8% of GISTs
have mutations that activate a closely related receptor tyro-
sine kinase, platelet-derived growth factor receptor α
(PDGFRA). For unknown reasons, GISTs bearing PDGFRA
mutations are overrepresented in the stomach. KIT
and PDGFRA gene mutations are mutually exclusive,
reflecting their activities within the same signal transduc-
tion pathway. Germline mutations in these same genes are
present in rare familial GISTs, in which patients develop
multiple GISTs and may also have diffuse hyperplasia of
Cajal cells. Both sporadic and germline mutations result in
constitutively active KIT or PDGFRA receptor tyrosine
kinases and produce intra­cellular signals that promote
tumor cell proliferation and survival (Chapter 7). Some
GISTs without mutated KIT or PDGFRA have mutations in
776 C H A P T E R 17 The Gastrointestinal Tract

other genes that function in these pathways (NF1, BRAF,

HRAS, or NRAS). However, more common are mutations
in genes encoding components of the mitochondrial
succinate dehydrogenase complex (SDHA, SDHB, SDHC,
SDHD). These mutations, which cause loss of SDH func-
tion, are often inherited in the germline and confer an
increased risk for GIST and paraganglioma (Carney-
Stratakis syndrome, not to be confused with Carney triad);
with the second copy of the affected gene being either
mutated or lost in the tumor. The mechanisms by which
SDH mutations lead to GIST are unclear; one hypothesis is
that the accumulation of succinate leads to dysregulation
of hypoxia inducible factor-1α (HIF-1α), which results in
increased transcription of the vascular endothelial growth
factor (VEGF) and insulin-like growth factor-1 (IGF1R)
genes.
A
Mutation of KIT or PDGFRA is an early event in sporadic
GISTs and is detectable in lesions as small as 3 mm. Therefore,
KIT or PDGFRA mutations alone are insufficient for tumor-
igenesis. Changes associated with progression to overt
GIST are not well-defined, but loss or partial deletion of
chromosomes 14 and 22 is common and losses and gains
at other chromosomes also occur. In particular, deletion of
9p results in loss of the cell cycle regulator CDKN2A, a
tumor suppressor that is involved in many cancers. In
addition to potentially being related to progression,
increased numbers of chromosomal alterations correlate
with poor prognosis.

  MORPHOLOGY
B
Primary gastric GISTs can be quite large, as much as 30 cm in
diameter. They usually form a solitary, well-circumscribed,
fleshy mass (Fig. 17-21A) covered by ulcerated or intact mucosa
(Fig. 17-21B), but can also project outward toward the serosa.
The cut surface shows a whorled appearance. Metastases may
take the form of multiple serosal nodules throughout the peri-
toneal cavity or as one or more nodules in the liver; spread
outside of the abdomen is uncommon, but can occur. GISTs
composed of thin elongated cells are classified as spindle cell
type (Fig. 17-21C), whereas tumors dominated by epithelial-
appearing cells are termed epithelioid type; mixtures of the
two patterns also occur. The most useful diagnostic marker is
KIT, which is detectable in Cajal cells and 95% of gastric GISTs
by immunohistochemical stains.

Clinical Features.  Symptoms of GISTs at presentation may C

be related to mass effects. Mucosal ulceration can cause
blood loss, and approximately half of individuals with
GIST present with anemia or related symptoms. GISTs
may also be discovered as an incidental finding during
radiologic imaging, endoscopy, or abdominal surgery per-
formed for other reasons. Complete surgical resection is
the primary treatment for localized gastric GIST. The prog-
nosis correlates with tumor size, mitotic index, and loca-
tion, with gastric GISTs being less aggressive than those
arising in the small intestine. Recurrence or metastasis is
rare for gastric GISTs smaller than 5 cm but common for
mitotically active tumors larger than 10 cm. Many tumors
fall into an intermediate category where the malignant
potential of the lesion cannot be predicted with certainty
on the basis of histology alone.
Figure 17-21  GI stromal tumor. A, On cross-section a whorled texture is
evident within the white, fleshy tumor. B, The mass is covered by intact
mucosa. C, Histologically the tumor is primarily composed of bundles, or
fascicles, of spindle-shaped tumor cells. (Courtesy Dr. Christopher Weber,
The University of Chicago, Chicago, Ill.)
The molecular phenotype is an important consideration
in the treatment of patients with unresectable, recurrent, or
metastatic GISTs. Those with mutations in KIT or PDGFRA
often respond to the tyrosine kinase inhibitor imatinib. In
contrast, tumors without these mutations are generally
resistant. Further, specific KIT or PDGFRA mutations are
associated with different drug sensitivities. In treated
patients, development of imatinib-resistance is common.
 Small intestine and colon 777

This is due to secondary KIT or PDGFRA mutations.

therefore require more aggressive therapy than adenomas
Tumors with secondary mutations may respond to other
of the colon.
tyrosine kinase inhibitors as well as experimental therapies
that target other pathways.
■ Gastric adenocarcinoma incidence varies markedly with
geography. Individual tumors are classified according to
location, gross, and histologic morphology. Gastric tumors
with an intestinal histology tend to form bulky tumors
  KEY CONCEPTS and may be ulcerated, while those composed of signet-
ring cells typically display a diffuse infiltrative growth
Neoplastic and Non neoplastic proliferations pattern that may thicken the gastric wall without forming
of the stomach a discrete mass. Gastric adenocarcinomas are linked to
■ Ménétrier disease is a rare disorder caused by excessive H. pylori induced chronic gastritis.
secretion of transforming growth factor α (TGF-α) and
■ Primary gastric lymphomas are most often derived
characterized by diffuse foveolar hyperplasia and protein- from mucosa-associated lymphoid tissue (MALT), whose
losing enteropathy. development is induced by chronic gastritis that is most
■ Zollinger-Ellison syndrome is caused by gastrin-secreting often induced by H. pylori.
tumors that cause parietal cell hyperplasia and acid hyper
■ Carcinoid tumors (well-differentiated neuroendocrine
secretion; 60% to 90% of gastrinomas are malignant. tumors) arise from diffuse components of the endocrine
■ The majority of gastric polyps are inflammatory or system and are most common in the GI tract, particularly
hyperplastic polyps, reactive lesions that are associated the small intestine. Prognosis is based on location; tumors
with chronic gastritis. of the small intestine tend to be most aggressive, while
■ Fundic gland polyps occur sporadically, most often as a those of the appendix are typically benign.
consequence of proton pump inhibitor therapy, and in
■ Gastrointestinal stromal tumor (GIST) is the most
familial adenomatous polyposis (FAP) patients. common mesenchymal tumor of the abdomen, occurs
■ Gastric adenomas develop in a background of chronic most often in the stomach, and is related to benign pace-
gastritis and are particularly associated with intestinal maker cells, or interstitial cells of Cajal. Tumors generally
metaplasia and mucosal (glandular) atrophy. Adeno­ have activating mutations in either KIT or PDGFRA tyrosine
carcinoma is frequent in gastric adenomas, which kinases and respond to specific kinase inhibitors.
804 C H A P T E R 17 The Gastrointestinal Tract

Polyps
Polyps are most common in the colo-rectal region but may
occur in the esophagus, stomach, or small intestine. Most,
if not all, polyps begin as small elevations of the mucosa.
These are referred to as sessile, a term borrowed from bota-
nists who use it to describe flowers and leaves that grow
directly from the stem without a stalk. As sessile polyps
enlarge, proliferation of cells adjacent to the mass and the
­ effects of traction on the luminal protrusion, may combine
to create a stalk. Polyps with stalks are termed peduncu-
lated. In general, intestinal polyps can be classified as non-
neoplastic or neoplastic in nature. The most common
neoplastic polyp is the adenoma, which has the potential
to progress to cancer. The nonneoplastic polyps can be
further classified as inflammatory, hamartomatous, or
hyperplastic.

  Hyperplastic Polyps

Colonic hyperplastic polyps are benign epithelial prolif-
erations that are typically discovered in the sixth and
seventh decades of life. The pathogenesis of hyperplastic
polyps is incompletely understood, but they are thought to
result from decreased epithelial cell turnover and delayed
shedding of surface epithelial cells, leading to a “piling up”
of goblet cells and absorptive cells. It is now appreciated
that these lesions are without malignant potential. Their
chief significance is that they must be distinguished from
sessile serrated adenomas, that are histologically similar
but have malignant potential, as described later. It is also
important to remember that epithelial hyperplasia can
occur as a nonspecific reaction adjacent to or overlying any
mass or inflammatory lesion and, therefore, can be a clue
to the presence of an adjacent, clinically important lesion.

  MORPHOLOGY
Hyperplastic polyps are most commonly found in the left colon
and are typically less than 5 mm in diameter. They are smooth,
nodular protrusions of the mucosa, often on the crests of mucosal
folds. They may occur singly but are more frequently multiple,
particularly in the sigmoid colon and rectum. Histologically,
hyperplastic polyps are composed of mature goblet and absorp-
tive cells. The delayed shedding of these cells leads to crowding
that creates the serrated surface architecture that is the morpho-
logic hallmark of these lesions (Fig. 17-41). Serration is typically
restricted to the upper third, or less, of the crypt.

Inflammatory Polyps

Polyps that form as part of the solitary rectal ulcer syn-
drome are examples of purely inflammatory lesions.
Patients present with a clinical triad of rectal bleeding,
mucus discharge, and an inflammatory lesion of the ante-

rior rectal wall. The underlying cause is impaired relax-
ation of the anorectal sphincter that creates a sharp angle
at the anterior rectal shelf and leads to recurrent abrasion
and ulceration of the overlying rectal mucosa. An inflam-
matory polyp may ultimately form as a result of chronic
cycles of injury and healing. Entrapment of this polyp in

A adenomas. In addition, it is important to recognize these
B C
Figure 17-41  Hyperplastic polyp. A, Polyp surface with irregular tufting of
epithelial cells. B, Tufting results from epithelial overcrowding. C, Epithelial
crowding produces a serrated architecture when crypts are cut in
cross-section.
the fecal stream leads to mucosal prolapse. The distinctive
histologic features of a typical inflammatory polyp include
mixed inflammatory infiltrates, erosion, and epithelial
hyperpla­sia together with lamina propria fibromuscular
hyperplasia (Fig. 17-42).
A B
Figure 17-42  Solitary rectal ulcer syndrome. A, The dilated glands, proliferative epithelium, superficial erosions, and inflammatory infiltrate are typical of an
inflammatory polyp. However, the smooth muscle hyperplasia within the lamina propria suggests that mucosal prolapse has also occurred. B, Epithelial
hyperplasia. C, Granulation tissue-like capillary proliferation within the lamina propria caused by repeated erosion.
Small intestine and colon 805
Hamartomatous Polyps
Hamartomatous polyps occur sporadically or as compo-
nents of various genetically determined or acquired syn-
dromes (Table 17-10).
Although they were originally thought to be caused by
developmental abnormalities, it is now appreciated that
many hamartomatous polyp syndromes are caused by
germline mutations in tumor suppressor genes or proto-
oncogenes. Some of these syndromes are associated with
increased cancer risk, either within the polyps or at
other intestinal or extra-intestinal sites. Thus, in some ham-
artomatous polyp syndromes, the polyps can be consid-
ered to be pre-malignant, neoplastic lesions, much like
polyps because of associated extraintestinal manifestations
and the possibility that other family members are affected.
Several of these syndromes are discussed below, while
other syndromes are summarized in Table 17-10.
Juvenile Polyps
Juvenile polyps are focal malformations of the epithelium
and lamina propria. These may be sporadic or syndromic,
but the morphology of the two forms is often indistinguish-
able. The vast majority of juvenile polyps occur in children
younger than 5 years of age but they can present at older
ages as well. Most juvenile polyps are located in the rectum
and typically present with rectal bleeding. In some cases
intussusception, intestinal obstruction, or polyp prolapse
(through the anal sphincter) may occur.
Sporadic juvenile polyps are usually solitary lesions
and may also be referred to as retention polyps. In con­
trast, individuals with the autosomal dominant syndrome
of juvenile polyposis have from 3 to as many as 100
hamartomatous polyps and may require colectomy to
limit the chronic and sometimes severe hemorrhage asso­
ciated with polyp ulceration. A minority of patients also
have polyps in the stomach and small bowel that can
undergo malignant transformation. Pulmonary arteriove-
nous malformations and other congenital malformations
are recognized extraintestinal manifestation of juvenile
polyposis.
C
806 C H A P T E R 17 The Gastrointestinal Tract

Table 17-10  Gastrointestinal Polyposis Syndromes

Mean Age at Mutated Gene(s); Selected Extra-Gastrointestinal
Syndrome Presentation (yr) Pathway Gastrointestinal Lesions Manifestations
Juvenile polyposis <5 SMAD4,BMPR1A; Juvenile polyps; risk of gastric, small Congenital malformations, digital
TGF-β signaling intestinal, colonic, and pancreatic clubbing
pathway adenocarcinoma
Peutz-Jeghers syndrome 10-15 STK11; AMP Arborizing polyps; Small intestine > Pigmented macules; risk of colon,
kinase-related colon > stomach; colonic breast, lung, pancreatic, and
pathways adenocarcinoma thyroid cancer
Cowden syndrome, <15 PTEN: Hamartomatous/ inflammatory Benign skin tumors, benign and
Bannayan-Ruvalcaba-Riley PI3K/AKT pathway intestinal polyps, lipomas, malignant thyroid and breast
syndrome* ganglioneuromas lesions; no increase in GI cancers
Cronkhite-Canada syndrome >50 Nonhereditary, Hamartomatous polyps of stomach, Nail atrophy, hair loss, abnormal
unknown cause small intestine colon; abnormalities skin pigmentation, cachexia, and
in nonpolypoid mucosa anemia. Fatal in up to 50%.
Tuberous sclerosis TSC1 (hamartin), Hamartomatous polyps Mental retardation, epilepsy. facial
TSC2 (tuberin); angiofibroma, cortical (CNS)
mTOR pathway tubers, renal angiomyolipoma
Familial adenomatous
polyposis (FAP)
  Classic FAP 10-15 APC Multiple adenomas Congenital RPE hypertrophy
  Attenuated FAP 40-50 APC Multiple adenomas
  Gardner syndrome 10-15 APC Multiple adenomas Osteomas, thyroid and desmoid
tumors, skin cysts
  Turcot syndrome 10-15 APC Multiple adenomas Medulloblastoma, glioblastoma
  MYH-associated polyposis 30-50 MYH Multiple adenomas
CNS, Central nervous system; mTOR, mammalian target of rapamycin; RPE, retinal pigmented epithelium.
*Also called PTEN Hamartoma-Tumor Syndromes.

  MORPHOLOGY
Most juvenile polyps are less than 3 cm in diameter. They are
typically pedunculated, smooth-surfaced, reddish lesions  polyps and mucocutaneous hyperpigmentation. The
with characteristic cystic spaces apparent after sectioning.
Microscopic examination shows these cysts to be dilated
glands filled with mucin and inflammatory debris (Fig. 17-43).
The remainder of the polyp is composed of lamina propria
expanded by mixed inflammatory infiltrates. The muscularis
mucosae may be normal or attenuated.
Although the morphogenesis of juvenile polyps is in­
completely understood, it has been proposed that mucosal
hyperplasia is the initiating event. This hypothesis is
consistent with the discovery that mutations in pathways
that regulate cellular growth cause autosomal dominant
juvenile polyposis. The most common mutation identified
is of SMAD4, which encodes a cytoplasmic intermediate
in the TGF-β signaling pathway. BMPR1A, a kinase that is
a member of the TGF-β superfamily, may be mutated in
other cases (Table 17-10). However, these mutations
account for fewer than half of patients, suggesting that
other genes responsible for autosomal dominant juvenile
polyposis remain to be discovered.
Dysplasia is extremely rare in sporadic juvenile polyps.
In contrast juvenile polyposis syndrome is associated with
dysplasia, both within the juvenile polyps and in separate
adenomas. As a result, 30% to 50% of patients with juvenile
polyposis develop colonic adenocarcinoma by age 45.
Peutz-Jeghers Syndrome
This rare autosomal dominant syndrome presents at a
median age of 11 years with multiple GI hamartomatous
latter takes the form of dark blue to brown macules on the
lips, nostrils, buccal mucosa, palmar surfaces of the hands,
genitalia, and perianal region. These lesions are similar
to freckles but are distinguished by their presence in the
buccal mucosa. Peutz-Jeghers polyps can initiate intussus-
ception, which is occasionally fatal. Of greater importance,
Peutz-Jeghers syndrome is associated with a markedly increased
risk of several malignancies. Lifetime risk is approximately
40% for these, and regular surveillance is recommended
beginning at birth, for sex cord tumors of the testes; late
childhood for gastric and small intestinal cancers; and the
second and third decades of life for colon, pancreatic,
breast, lung, ovarian, and uterine cancers.
Pathogenesis.  Germline heterozygous loss-of-function
mutations in the gene STK11 are present in approximately
half of individuals with familial Peutz-Jeghers syndrome
as well as a subset of patients with sporadic Peutz-Jeghers
syndrome. You will recall from Chapter 7 that STK11 is a
tumor suppressor gene that encodes a kinase that regulates
cell polarization and acts as a brake on growth and ana-
bolic metabolism. As is common with other tumor sup-
pressor genes, the function of the second “normal” copy of
STK11 is often lost through somatic mutation in cancers
occurring in Peutz-Jeghers syndrome, providing an expla-
nation for the high risk of neoplasia in affected patients.
Importantly, colon cancers can also develop at sites without
Peutz-Jeghers polyps.
 Small intestine and colon 807

Neoplastic Polyps
Any neoplastic mass lesion in the GI tract may produce a
mucosal protrusion, or polyp. This includes adenocarcino-
mas, neuroendocrine (carcinoid) tumors, stromal tumors,
lymphomas, and even metastatic cancers from distant sites.
The most common neoplastic polyps are colonic adenomas, which
are precursors to the majority of colorectal adenocarcinomas.
Adenomas are intraepithelial neoplasms that range
from small, often pedunculated, polyps to large sessile
lesions. There is a small male predominance, and they
are present in approximately 30% of adults living in the
Western world by age 60. Because these polyps are precur-
sors to colorectal adenocarcinoma, it is recommended that
all adults in the United States undergo surveillance by age
50. Patients at increased risk, including those with a family
A
history of colorectal adenocarcinoma, are typically screened
colonoscopically at least 10 years before the youngest age
at which a relative was diagnosed. The preferred approach
to surveillance varies, but colonoscopy is most common.

B
Figure 17-43  Juvenile polyposis. A, Juvenile polyp. Note the surface erosion
and cystically dilated crypts. B, Inspissated mucous, neutrophils, and inflam-
matory debris can accumulate within dilated crypts.

  MORPHOLOGY A

The polyps of Peutz-Jeghers syndrome are most common in

the small intestine, although they may occur in the stomach 
and colon, and, with much lower frequency, in the bladder and
lungs. Grossly, the polyps are large and pedunculated with a
lobulated contour. Histologic examination demonstrates a char-
acteristic arborizing network of connective tissue, smooth
muscle, lamina propria, and glands lined by normal-appearing
intestinal epithelium (Fig. 17-44). The arborization and presence
of smooth muscle intermixed with lamina propria are helpful in
distinguishing polyps of Peutz-Jeghers syndrome from juvenile
polyps.

Clinical Features.  Because the morphology of Peutz-

Jeghers polyps can overlap with that of sporadic hamarto-
matous polyps, the presence of multiple polyps in the
small intestine, mucocutaneous hyperpigmentation, and
a positive family history are critical to the diagnosis.
Detection of STK11 mutations can be helpful diagnostically
in patients with polyps who lack mucocutaneous hyper-
pigmentation. However, the absence of STK11 mutations
does not exclude the diagnosis, since mutations in other
presently unknown genes can also cause the syndrome.
B
Figure 17-44  Peutz-Jeghers polyp. A, Polyp surface (top) overlies stroma
composed of smooth muscle bundles cutting through the lamina propria. 
B, Complex glandular architecture and the presence of smooth muscle are
features that distinguish Peutz-Jeghers polyps from juvenile polyps. Compare
to Figure 17-42.
808 C H A P T E R 17 The Gastrointestinal Tract
While adenomas are less common in Asia, their frequency
has risen (in parallel with an increasing incidence of
colorectal adenocarcinoma) in these populations as Western
diets and lifestyles become more common.
Colorectal adenomas are characterized by the presence
of epithelial dysplasia. Consistent with their being precur-
sor lesions, the prevalence of colorectal adenomas corre-
lates with that of colorectal adenocarcinoma and the
distributions of adenomas and adenocarcinoma within
the colon are similar. Large studies have demonstrated that
regular surveillance colonoscopy and polyp removal
reduces the incidence of colorectal adenocarcinoma.
Despite this strong relationship, it must be emphasized
that majority of adenomas do not progress to become
adenocarcinomas. There are no tools presently available to
distinguish between adenomas that will or will not undergo
malignant transformation, and indeed it may be that trans-
formation is stochastic, being dependent on acquisition of
oncogenic mutations merely by chance. Most adenomas
are clinically silent, with the exception of large polyps that
produce occult bleeding and anemia and rare villous ade-
nomas that cause hypoproteinemic hypokalemia by secret-
ing large amounts of protein and potassium.
  MORPHOLOGY
Typical adenomas range from 0.3 to 10 cm in diameter and can
be pedunculated (Fig. 17-45A) or sessile, with the surface of
both types having a texture resembling velvet or a raspberry
(Fig. 17-45B). Histologically, the hallmark of epithelial dysplasia
is nuclear hyperchromasia, elongation, and stratification (see
Fig. 17-46C). These changes are most easily appreciated at the
surface of the adenoma and are often accompanied by promi-
nent nucleoli, eosinophilic cytoplasm, and a reduction in the
number of goblet cells. Notably, epithelial cells fail to mature as
they migrate from crypt to surface. Pedunculated adenomas
have slender fibromuscular stalks (Fig. 17-45C) containing
prominent blood vessels derived from the submucosa. The
stalk is usually covered by nonneoplastic epithelium, but dys-
plastic epithelium is sometimes present.
Adenomas can be classified as tubular, tubulovillous, or
villous based on their architecture. These categories, however,
A B
Figure 17-45  Colonic adenomas. A, Pedunculated adenoma (endoscopic view). B, Adenoma with a velvety surface. C, Low-magnification photomicrograph
of a pedunculated tubular adenoma.
have little clinical significance in isolation. Tubular adenomas
tend to be small, pedunculated polyps composed of rounded,
or tubular, glands (Fig. 17-46A). In contrast, villous adenomas,
which are often larger and sessile, are covered by slender villi
(Fig. 17-46B). Tubulovillous adenomas have a mixture of tubular
and villous elements. Although villous adenomas contain foci of
invasion more frequently than tubular adenomas, villous archi-
tecture alone does not increase cancer risk when polyp size is
considered.
Sessile serrated adenomas overlap histologically with
hyperplastic polyps, but are more commonly found in the right
colon. Despite their malignant potential, sessile serrated adeno-
mas lack typical cytologic features of dysplasia that are present
in other adenomas, prompting some to refer to these lesions
as sessile serrated polyps. Histologic criteria for these lesions
include serrated architecture throughout the full length of the
glands, including the crypt base, crypt dilation, and lateral
growth (Fig. 17-46D).
Intramucosal carcinoma occurs when dysplastic epithelial
cells breach the basement membrane to invade the lamina
propria or muscularis mucosae. Because functional lymphatic
channels are absent in the colonic mucosa, intramucosal car-
cinomas have little or no metastatic potential and complete
polypectomy is generally curative (Fig. 17-47A). Invasion
beyond the muscularis mucosae, including into the submucosal
stalk of a pedunculated polyp (Fig. 17-47B), constitutes invasive
adenocarcinoma and carries a risk of spread to other sites. In
such cases several factors, including the histologic grade of the
invasive component, the presence of vascular or lymphatic
invasion, and the distance of the invasive component from 
the margin of resection, must be considered in planning 
further therapy.
Although most colorectal adenomas are benign lesions,
a small proportion may harbor invasive cancer at the time
of detection. Size is the most important characteristic that cor-
relates with risk of malignancy. For example, while cancer is
extremely rare in adenomas less than 1 cm in diameter,
some studies suggest that nearly 40% of lesions larger than
4 cm in diameter contain foci of cancer. High-grade dys-
plasia is also a risk factor for cancer in an individual polyp,
C
 Small intestine and colon 809

Colorectal adenocarcinoma develops in 100% of

A B
untreated FAP patients, often before age 30 and nearly
always by age 50. As a result, prophylactic colectomy is
the standard therapy for individuals carrying APC muta-
tions. Colectomy prevents colorectal cancer, but patients
remain at risk for neoplasia at other sites. Adenomas may
develop elsewhere in the GI tract, particularly adjacent to
the ampulla of Vater and in the stomach.
FAP is associated with a variety of extraintestinal mani-
festations including congenital hypertrophy of the retinal
pigment epithelium, which can generally be detected
at birth, and therefore may be an adjunct to early screening.
Specific APC mutations have been associated with the
development of other manifestations of FAP and partly
explain variants such as Gardner syndrome and Turcot
syndrome (Table 17-11).
Some polyposis patients without APC loss have bi-allelic
mutations of the base-excision repair gene MYH (also
referred to as MUTYH). This autosomal recessive disorder
is termed MYH-associated polyposis. The colonic pheno-
type is similar to attenuated FAP, with polyp development
at later ages, the presence of fewer than 100 adenomas, and
the delayed appearance of colon cancer, often at ages of 50
or older. In addition, serrated polyps, often with KRAS

C D
Figure 17-46  Histologic appearance of colonic adenomas. A, Tubular
adenoma with a smooth surface and rounded glands. Active inflammation is
occasionally present in adenomas, in this case, crypt dilation and rupture can
be seen at the bottom of the field. B, Villous adenoma with long, slender
projections that are reminiscent of small intestinal villi. C, Dysplastic epithelial
cells (top) with an increased nuclear-to-cytoplasmic ratio, hyperchromatic
and elongated nuclei, and nuclear pseudostratification. Compare to the non-
dysplastic epithelium below. D, Sessile serrated adenoma lined by goblet
cells without cytologic features of dysplasia. This lesion is distinguished 
from a hyperplastic polyp by extension of the neoplastic process to 
the crypts, resulting in lateral growth. Compare to the hyperplastic polyp in
Figure 17-44A.

but does not confer an increased risk of cancer in other

polyps within the same patient.

Adenomatous Polyposis
Familial adenomatous polyposis (FAP) is an autosomal A
dominant disorder in which patients develop numer­
ous colorectal adenomas as teenagers. It is caused by
mutations of the adenomatous polyposis coli, or APC,
gene, which you will recall is a key negative regulator of
the Wnt signaling pathway (Chapter 7). Approximately
75% of cases are inherited, while the remaining appear to
be caused by de novo mutations.
At least 100 polyps are necessary for a diagnosis
of classic FAP, but as many as several thousand may be
present (Fig. 17-48). Except for their remarkable numbers,
these growths are morphologically indistinguishable from
sporadic adenomas. In addition, however, flat or depressed B
adenomas are also prevalent in FAP, and microscopic ade- Figure 17-47  Adenoma with intramucosal carcinoma. A, Cribriform glands
nomas, consisting of only one or two dysplastic crypts, interface directly with the lamina propria without an intervening basement
are frequently observed in otherwise normal-appearing membrane. B, Invasive adenocarcinoma (left) beneath a villous adenoma
mucosa. (right). Note the desmoplastic response to the invasive components.
810 C H A P T E R 17 The Gastrointestinal Tract

HNPCC is thought to account for 2% to 4% of all colorectal

A mismatch repair genes, but majority of patients with
B adenocarcinoma.
Figure 17-48  Familial adenomatous polyposis. A, Hundreds of small polyps
are present throughout this colon with a dominant polyp (right). B, Three
tubular adenomas are present in this single microscopic field.
mutations, are frequently present in MUTYH-associated
polyposis.
Hereditary Non-Polyposis
Colorectal Cancer
Hereditary non-polyposis colorectal cancer (HNPCC), also
known as Lynch syndrome, was originally described based
on familial clustering of cancers at several sites including
the colorectum, endometrium, stomach, ovary, ureters,
brain, small bowel, hepatobiliary tract, pancreas, and skin.
cancers, making it the most common syndromic form of
colon cancer. Colon cancers in HNPCC patients tend to
occur at younger ages than sporadic colon cancers and are
often located in the right colon (Table 17-11). Just as iden-
tification of APC mutations in FAP has provided molecular
insights into the pathogenesis of the majority of sporadic
colon cancers, unraveling the defects in HNPCC has shed
light on the mechanisms responsible for most of the remain-
ing sporadic cases. HNPCC is caused by inherited muta-
tions in genes that encode proteins responsible for the
detection, excision, and repair of errors that occur during
DNA replication (Chapter 7). There are at least five such
HNPCC have mutations in MSH2 or MLH1. Patients with
HNPCC inherit one mutant gene and one normal allele.
When the second copy is lost through mutation or epigen-
etic silencing, defects in mismatch repair lead to the accu-
mulation of mutations at rates up to 1000 times higher
than normal, mostly in regions containing short repeatings
sequences referred to as microsatellites. The human
genome contains approximately 50,000 to 100,000 micro-
satellites, which are prone to undergo expansion during
DNA replication and represent the most frequent sites of
mutations in HNPCC. The consequences of mismatch
repair deficiency and the resulting microsatellite insta­
bility are discussed next in the context of colonic
Adenocarcinoma
Adenocarcinoma of the colon is the most common malig-
nancy of the GI tract and is a major cause of morbidity
and mortality worldwide. In contrast, the small intestine,
which accounts for 75% of the overall length of the GI
tract, is an uncommon site for benign and malignant
tumors. Among malignant small intestinal tumors, adeno-
carcinomas and well-differentiated neuroendocrine (carci-
noid) tumors have roughly equal incidence, followed by
lymphomas and sarcomas.
Epidemiology.  Approximately 1.2 million new cases of
colorectal adenocarcinoma, and 600,000 associated deaths,
occur each year worldwide. Thus, colorectal adenocarci-
noma is responsible for nearly 10% of all cancer deaths. The

Table 17-11  Common Patterns of Sporadic and Familial Colorectal Neoplasia

Etiology Molecular Defect Target Gene(s) Transmission Predominant Site(s) Histology
Familial adenomatous APC/WNT pathway APC Autosomal dominant None Tubular, villous; typical
polyposis adenocarcinoma
MYH-associated polyposis DNA mismatch repair MYH Autosomal recessive None Sessile serrated adenoma;
mucinous adenocarcinoma
Hereditary nonpolyposis DNA mismatch repair MSH2, MLH1 Autosomal dominant Right side Sessile serrated adenoma;
colorectal cancer mucinous adenocarcinoma
Sporadic colon cancer APC/WNT pathway APC None Left side Tubular, villous; typical
(70%-80%) adenocarcinoma
Sporadic colon cancer DNA mismatch repair MSH2, MLH1 None Right side Sessile serrated adenoma;
(10%-15%) mucinous adenocarcinoma
Sporadic colon cancer Hypermethylation MLH1, BRAF None Right side Sessile serrated adenoma;
(5%-10%) mucinous adenocarcinoma

incidence of these tumors is highest in North America,
with the United States accounting for approximately 10%
of worldwide cases and cancer deaths. This represents
nearly 15% of all cancer-related deaths in the United States,
second only to lung cancer. Australia, New Zealand,
Europe, and, with changes in lifestyle and diet, Japan, also
have high incidences of colorectal adenocarcinoma. In con-
trast, rates are lower in South America, India, Africa, and
South Central Asia. Colorectal cancer incidence peaks at 60
to 70 years of age, with fewer than 20% of cases occuring
before age 50.
The dietary factors most closely associated with increased
rates of colorectal cancer are low intake of unabsorbable
vegetable fiber and high intake of refined carbohydrates
and fat. Although these associations are clear, the mecha-
nistic relationship between diet and risk remains poorly
understood. It is theorized that reduced fiber content leads
to decreased stool bulk and altered composition of the
intestinal microbiota. This change may increase synthesis
of potentially toxic oxidative by-products of bacterial
metabolism, which would be expected to remain in contact
with the colonic mucosa for longer periods of time as a
result of reduced stool bulk. High fat intake also enhances
hepatic synthesis of cholesterol and bile acids, which can
be converted into carcinogens by intestinal bacteria.
In addition to dietary modification, pharmacologic chemo-
prevention has become an area of great interest. Several
epidemiologic studies suggest that aspirin or other NSAIDs
have a protective effect. This is consistent with studies
showing that some NSAIDs cause polyp regression in FAP
patients in whom the rectum was left in place after colec-
tomy. It is suspected that this effect is mediated by inhibi-
tion of the enzyme cyclooxygenase-2 (COX-2), which is
highly expressed in 90% of colorectal carcinomas and 40%
to 90% of adenomas. COX-2 is necessary for production of
prostaglandin E2, which promotes epithelial proliferation,
NORMAL COLON MUCOSA AT RISK
Mucosa
Submucosa
Muscularis
propria
Germline (inherited) Methylation
or somatic (acquired) abnormalities
mutations of cancer Inactivation of
suppressor genes normal alleles
("first hit") ("second hit")
APC
APC at 5q21
b-catenin
Figure 17-49  Morphologic and molecular changes in the adenoma-carcinoma sequence. Loss of one normal copy of the tumor suppressor gene APC occurs
early. Individuals born with one mutant allele are therefore at increased risk of developing colon cancer. Alternatively, inactivation of APC in colonic epithelium
may occur later in life. This is the “first hit” according to the Knudson hypothesis (Chapter 7). The loss of the intact second copy of APC follows (“second hit”).
Other changes, including mutation of KRAS, losses at 18q21 involving SMAD2 and SMAD4, and inactivation of the tumor suppressor gene TP53, lead to the
emergence of carcinoma, in which further mutations occur. Although there seems to be a temporal sequence of changes, the accumulation of mutations,
rather than their occurrence in a specific order, is most critical.
Small intestine and colon 811
particularly after injury. Of further interest, COX-2 expres-
sion is regulated by TLR4, which recognizes lipopoly­
saccharide and is also overexpressed in adenomas and
carcinomas.
Pathogenesis.  Studies of colorectal carcinogenesis have
provided fundamental insights into the general mecha-
nisms of cancer evolution. These were discussed in Chapter
7; concepts that pertain specifically to colorectal carcino-
genesis will be reviewed here.
The combination of molecular events that lead to
colonic adenocarcinoma is heterogeneous and includes
genetic and epigenetic abnormalities. At least two genetic
pathways have been described. In simplest terms, these are
the APC/β-catenin pathway, which is activated in the classic
adenoma-carcinoma sequence; and the microsatellite insta-
bility pathway, which is associated with defects in DNA
mismatch repair and accumulation of mutations in micro-
satellite repeat regions of the genome (Table 17-11). Both
pathways involve the stepwise accumulation of multiple
mutations, but differ in the genes involved and the
mechanisms by which mutations accumulate. Epigenetic
events, the most common of which is methylation-induced
gene silencing, may enhance progression along either
pathway.
• The classic adenoma-carcinoma sequence, accounts
for up to 80% of sporadic colon tumors and typically
includes mutation of APC early in the neoplastic
process (Fig. 17-49). Both copies of the APC gene must
be functionally inactivated, either by mutation or epi-
genetic events, for adenomas to develop. APC is a key
negative regulator of β-catenin, a component of the Wnt sig-
naling pathway (Chapter 7). The APC protein normally
binds to and promotes degradation of β-catenin. With
loss of APC function, β-catenin accumulates and
ADENOMAS CARCINOMA
Protooncogene Homozygous loss of Additional mutations
mutations additional cancer Gross chromosomal
suppressor genes alterations
Overexpression of
COX-2
TP53 at 17p13
Telomerase,
K-RAS at 12p12 LOH at 18q21
Many genes
(SMAD 2 and 4)
812 C H A P T E R 17 The Gastrointestinal Tract
translocates to the nucleus, where it forms a complex
with the DNA-binding factor TCF and activates the
transcription of genes, including MYC and cyclin D1,
that promote proliferation. The critical role of β-catenin
in this pathway is demonstrated by the fact that many
colon cancers without APC mutations harbor β-catenin
mutations that allow them to avoid APC-dependent
degradation, thereby having the same impact as loss of
APC function. Additional mutations accumulate,
including activating mutations in KRAS that promote
growth and prevent apoptosis. The idea that mutation
of KRAS is a late event in carcinoma development is
supported by the observation that such mutations are
present in fewer than 10% of adenomas less than 1 cm
in diameter but are found in 50% of adenomas greater
than 1 cm in diameter and in 50% of invasive adenocar-
cinomas. Neoplastic progression is also associated with
mutations in other tumor suppressor genes such as
those encoding SMAD2 and SMAD4, which are effec-
tors of TGF-β signaling. Because TGF-β signaling nor-
mally inhibits the cell cycle, loss of these genes may
allow unrestrained cell growth. The tumor suppressor
gene TP53 is mutated in 70% to 80% of colon cancers,
but is uncommonly affected in adenomas, suggesting
that TP53 mutations also occur at later stages of tumor
progression. Loss of function of TP53 and other tumor
suppressor genes is often caused by chromosomal
deletions, supporting the idea that chromosomal insta-
bility is a hallmark of the APC/β-catenin pathway.
Alternatively, tumor suppressor genes may be silenced
by methylation of a CpG-rich zone, or CpG island, a 5′
region of some genes that frequently includes the pro-
moter and transcriptional start site. Expression of telom-
erase also increases as lesions become more advanced.
• In patients with DNA mismatch repair deficiency,
mutations accumulate in microsatellite repeats, a con-
dition referred to as microsatellite instability (MSI).
These are referred to as MSI high, or MSI-H, tumors.
Some microsatellite sequences are located in the coding
or promoter regions of genes involved in regulation of
cell growth, such as those encoding the type II TGF-β
receptor and the pro-apoptotic protein BAX (Fig. 17-50).
NORMAL COLON
Mucosa
Submucosa
Muscularis
propria
Germline (inherited) Alteration of second
or somatic (acquired) allele by LOH,
mutations of mismatch mutation, or
repair genes promoter methylation
MLH1, MSH2
(MSH6, PMS1, PMS2)
Figure 17-50  Morphologic and molecular changes in the mismatch repair pathway of colon carcinogenesis. Defects in mismatch repair genes result in micro-
satellite instability and permit accumulation of mutations in numerous genes. If these mutations affect genes involved in cell survival and proliferation, cancer
may develop.
Because TGF-β inhibits colonic epithelial cell prolifera-
tion, mutation of type II TGF-β receptor can contribute
to uncontrolled cell growth, while loss of BAX may
enhance the survival of genetically abnormal clones.
• A subset of microsatellite unstable colon cancers
without mutations in DNA mismatch repair enzymes
demonstrate the CpG island hypermethylation pheno-
type (CIMP). In these tumors, the MLH1 promoter
region is typically hypermethylated, thereby reducing
MLH1 expression and repair function. Activating
mutations in the oncogene BRAF are common in these
cancers. In contrast, KRAS and TP53 are not typically
mutated. Thus, the combination of microsatellite insta-
bility, BRAF mutation, and methylation of specific
targets, such as MLH1, is the signature of this pathway
of carcinogenesis.
• A small group of colon cancers display increased CpG
island methylation in the absence of microsatellite
instability. Many of these tumors harbor KRAS muta-
tions, but TP53 and BRAF mutations are uncommon.
In contrast, TP53 mutations are common in colon
cancers that do not display a CpG island methylator
phenotype.
While morphology cannot reliably define the underly-
ing molecular events that lead to carcinogenesis, certain
correlations have been associated with mismatch repair
deficiency and microsatellite instability. These molecular
alterations are common in sessile serrated adenomas and
cancers that arise from them. In addition, invasive carcino-
mas with microsatellite instability often have prominent
mucinous differentiation and peritumoral lymphocytic
infiltrates. These tumors, as well as those with a CpG island
hypermethylation phenotype, are frequently located in the
right colon. Tumors with microsatellite instability can be
recognized by the absence of immunohistochemical stain-
ing for mismatch repair proteins or by molecular genetic
analysis of microsatellite sequences. It is important to iden-
tify patients with HNPCC because of the implications for
genetic counseling, the elevated risk of a second malig-
nancy of the colon or other organs, and, in some settings,
differences in prognosis and therapy.
SESSILE SERRATED ADENOMA CARCINOMA
Microsatellite Accumulated mutations
instability/ in genes that regulate
"mutator growth, differentiation,
phenotype" and/or apoptosis
TGFβRII, BAX, BRAF,
TCF 4, IGF2R, others

A B
Figure 17-51  Colorectal carcinoma. A, Circumferential, ulcerated rectal
cancer. Note the anal mucosa at the bottom of the image. B, Cancer of the
sigmoid colon that has invaded through the muscularis propria and is present
within subserosal adipose tissue (left). Areas of chalky necrosis are present
within the colon wall (arrow).
  MORPHOLOGY
Overall, adenocarcinomas are distributed approximately
equally over the entire length of the colon. Tumors in the
proximal colon often grow as polypoid, exophytic masses
that extend along one wall of the large-caliber cecum and
ascending colon; these tumors rarely cause obstruction. In
contrast, carcinomas in the distal colon tend to be annular
lesions that produce “napkin-ring” constrictions and luminal
narrowing (Fig. 17-51), sometimes to the point of obstruction.
Both forms grow into the bowel wall over time. The general
microscopic characteristics of right- and left-sided colonic ade-
nocarcinomas are similar. Most tumors are composed of tall
columnar cells that resemble dysplastic epithelium found in
adenomas (Fig. 17-52A). The invasive component of these
tumors elicits a strong stromal desmoplastic response, which
is responsible for their characteristic firm consistency. Some
poorly differentiated tumors form few glands (Fig. 17-52B).
Others may produce abundant mucin that accumulates within
A B
Figure 17-52  Histologic appearance of colorectal carcinoma. A, Well-differentiated adenocarcinoma. Note the elongated, hyperchromatic nuclei. Necrotic
debris, present in the gland lumen, is typical. B, Poorly differentiated adenocarcinoma forms a few glands but is largely composed of infiltrating nests of tumor
cells. C, Mucinous adenocarcinoma with signet-ring cells and extracellular mucin pools.
Small intestine and colon 813
the intestinal wall, and these are associated with poor progno-
sis. Tumors may also be composed of signet-ring cells that are
similar to those in gastric cancer (Fig. 17-52C) or may display
features of neuroendocrine differentiation.
Clinical Features.  The availability of endoscopic screening
combined with the knowledge that most carcinomas arise
within adenomas presents a unique opportunity for cancer
prevention. Unfortunately, colorectal cancers develop
insidiously and may go undetected for long periods. Cecal
and other right-sided colon cancers are most often called to
clinical attention by the appearance of fatigue and weakness
due to iron deficiency anemia. Thus, it is a clinical maxim that
the underlying cause of iron deficiency anemia in an older
man or postmenopausal woman is GI cancer until proven
otherwise. Left-sided colorectal adenocarcinomas may produce
occult bleeding, changes in bowel habits, or cramping and left
lower quadrant discomfort.
Although poorly differentiated and mucinous histolo-
gies are associated with poor prognosis, the two most impor-
tant prognostic factors are depth of invasion and the presence of
lymph node metastases. Invasion into the muscularis propria
confers significantly reduced survival that is decreased
further by the presence of lymph node metastases (Fig.
17-53A). Metastases may involve regional lymph nodes,
lungs (Fig. 17-53B) and bones, but as a result of portal
drainage of the colon, the liver is the most common site of
metastatic lesions (Fig. 17-53C). The rectum does not drain
via the portal circulation, hence carcinomas of the anal
region that metastasize often circumvent the liver.
The prognostic factors were originally recognized by
Dukes and Kirklin and form the core of the TNM (tumor-
nodes-metastasis) classification (Table 17-12). The American
Joint Committee on Cancer (AJCC) staging system is com-
pared to the Astler-Coller modification of the Dukes system
in Table 17-13. Regardless of stage, it must be remem-
bered that some patients with small numbers of metastases
do well for years following resection of distant tumor
nodules.
Five-year survival rates vary widely worldwide. The
overall 5-year survival rate in the United States is 65%,
and ranges from 90% to 40% depending on stage. Survival
rates in Europe, Japan and Australia are similar, ranging
C
814 C H A P T E R 17 The Gastrointestinal Tract

Table 17-12  American Joint Committee on Cancer (AJCC) TNM

Classification of Colorectal Carcinoma
TNM
Tumor
Tis In situ dysplasia or intramucosal carcinoma
T1 Tumor invades submucosa
T2 Tumor invades into, but not through, muscularis propria
T3 Tumor invades through muscularis propria
  T3a Invasion < 0.1 cm beyond muscularis propria
  T3b Invasion 0.1 to 0.5 cm beyond muscularis propria
  T3c Invasion > 0.5 to 1.5 cm beyond muscularis propria
  T3d Invasion > 1.5 cm beyond muscularis propria
A B T4 Tumor penetrates visceral peritoneum or invades adjacent organs
  T4a Penetration into visceral peritoneum
  T4b Invasion into other organs or structures
Regional Lymph Nodes
NX Lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in one to three regional lymph nodes
  N1a Metastasis in one regional lymph nodes
  N1b Metastasis in two or three regional lymph nodes
  N1c Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized
pericolic or perirectal tissues without regional nodal metastasis
N2 Metastasis in four or more regional lymph nodes
  N2a Metastasis in four to six regional lymph nodes
  N2b Metastasis in seven or more regional lymph nodes
C
Distant Metastasis
Figure 17-53  Metastatic colorectal carcinoma. A, Lymph node metastasis.
MX Distant metastasis cannot be assessed
Note the glandular structures within the subcapsular sinus. B, Solitary sub-
M0 No distant metastasis
pleural nodule of colorectal carcinoma metastatic to the lung. C, Liver con-
M1 Distant metastasis
taining two large and many smaller metastases. Note the central necrosis
within metastases.
  M1a Metastasis confined to one organ or site
  M1b Metastases in more than one organ/site or the peritoneum

Table 17-13  Colorectal Cancer Staging Systems

from 60% (Switzerland, Japan) to (40%) Poland. Overall American Joint Committee   Astler-Coller Modification
survival rates are somewhat lower in other countries, on Cancer (AJCC) Stage of Dukes Classification
such as China, India, the Philippines, and Thailand (30% T N M
to 42%). Sadly, the 5-year survival rate in Gambia is I T1 N0 M0 A
only 4%. T2 N0 M0 B1
IIA T3 N0 M0 B2
IIB T4a N0 M0 B2
IIC T4b N0 M0 B3
  KEY CONCEPTS
IIIA T1-T2 N1/N1c M0 C1
Benign and malignant proliferative lesions T1 N2a M0 C1
of the colon IIIB T3, T4a N1 (any) M0 C2
■ Intestinal polyps can be classified as nonneoplastic T2, T3 N2a M0 C1/C2
or neoplastic. The nonneoplastic polyps can be further T1, T2 N2b M0 C1
defined as hyperplastic, inflammatory, or hamartomatous. IIIC T4a N2a M0 C2
T3, T4a N2b M0 C2
■ Hyperplastic polyps are benign epithelial proliferations
T4b N1, N2 M0 C3
most commonly found in the left colon and rectum. They
have no malignant potential, and must be distinguished IVA Any T Any N M1a D*
from sessile serrated adenomas. IVB Any T Any N M1b D*
■ Inflammatory polyps form as a result of chronic cycles of *Stages not included in original Dukes classification; added later for comparison with AJCC
staging.
injury and healing.
■ Hamartomatous polyps occur sporadically or as a part of

genetic diseases. The latter include juvenile polyposis are the precursors of colonic adenocarcinomas, is cyto-
and Peutz-Jeghers Syndrome, which are associated with logic dysplasia.
increased risk of malignancy. ■ In contrast to traditional adenomas, sessile serrated ade-

■ Benign epithelial neoplastic polyps of the intestines are nomas lack cytologic dysplasia and share morphologic
termed adenomas. The hallmark of these lesions, which features with hyperplastic polyps.
 815

■ Familial adenomatous polyposis (FAP) and hereditary

non-polyposis colorectal cancer (HNPCC) are the most
common forms of familial colon cancer.
■ FAP is caused by APC mutations. Patients typically have

more than 100 adenomas and develop colon cancer before

30 years of age.
■ HNPCC is caused by mutations in DNA mismatch repair

enzymes. HNPCC patients have far fewer polyps and

develop cancer at older ages than FAP patients but
younger ages than those with sporadic colon cancer.
■ FAP and HNPCC typify distinct pathways of neoplastic

transformation and progression that also contribute to

the majority of sporadic colon cancers.
■ Nearly all colonic cancers are adenocarcinomas. The two

most important prognostic factors are depth of invasion

and the presence or absence of lymph node metastases.

 

Nodules and Tumors
Hepatic masses may come to attention for a variety of
reasons. They may generate epigastric fullness and dis-
comfort or be detected by routine physical examination or
radiographic studies for other indications. Hepatic masses
include nodular hyperplasias and true neoplasms.
Nodular Hyperplasias
Solitary or multiple hyperplastic hepatocellular nodules
may develop in the noncirrhotic liver. Two such conditions
are focal nodular hyperplasia and nodular regenerative hyper-
plasia. The common factor in both types of nodules seems
to be either focal or diffuse alterations in hepatic blood
supply, arising from obliteration of portal vein radicles and
compensatory augmentation of arterial blood supply.
  MORPHOLOGY
Focal nodular hyperplasia appears as a well-demarcated but
poorly encapsulated nodule, ranging up to many centimeters in
diameter (Fig. 18-51A). It presents as a spontaneous mass
lesion in an otherwise normal liver, most frequently in young to
middle-aged adults. The lesion is generally lighter than the sur-
rounding liver and is sometimes yellow indicating steatosis.
Typically, there is a central gray-white, depressed stellate scar
from which fibrous septa radiate to the periphery.
The central scar contains large vessels, usually arterial, that
typically show fibromuscular hyperplasia with eccentric or con-
centric narrowing of the lumen. The radi­ating septa show vari-
able ductular reactions along septal margins. The parenchyma
between septa is comprised of normal hepatocytes separated
A B
Figure 18-51  Focal nodular hyperplasia. A, Resected specimen showing lobulated contours and a central stellate scar. B, Low-power micrograph showing a
broad fibrous scar with hepatic arterial and bile duct elements and chronic inflammation present within parenchyma that lacks normal architecture due to
hepatocyte regeneration.
The liver and bile ducts 867
by thickened sinusoidal plates (Fig. 18-51B). The vascular lesion,
congenital or acquired, is probably the initiating insult. Resulting
areas of hypoperfused parenchyma collapse to become the
septa, while hyperperfused regions undergo hyperplasia.
Nodular regenerative hyperplasia denotes a liver entirely
transformed into nodules—grossly similar to micronodular
cirrhosis—but without fibrosis. Microscopically, plump hepato-
cytes are surrounded by rims of atrophic hepatocytes. Nodular
regenerative hyperplasia can lead to the development of
portal hypertension and occurs in association with conditions
affecting intrahepatic blood flow, including solid-organ (particu-
larly renal) transplantation, hematopoetic stem cell transplanta-
tion, and vasculitis. It also occurs in HIV-infected persons and
in association with rheumatologic diseases such as SLE. Most
such patients are asymptomatic and the condition is found at
autopsy.
Benign Neoplasms
Cavernous hemangiomas, blood vessel tumors identical
to those occurring elsewhere, are the most common
benign liver tumors (Chapter 11). They appear as discrete
red-blue, soft nodules, usually less than 2 cm in diameter,
generally located directly beneath the capsule. Histolog­
ically, the tumor consists of vascular channels in a bed of
fibrous connective tissue (Fig. 18-52). Their chief clinical
significance is that they might be mistaken radiographi-
cally or intraoperatively for metastatic tumors.
Hepatocellular Adenomas
Benign neoplasms developing from hepatocytes are
called hepatocellular adenomas (Fig. 18-53). They may be
detected incidentally with abdominal imaging or when
they cause abdominal pain from their rapid growth,
causing pressure on the liver capsule, or following hemor-
rhagic necrosis as the lesion outstrips its blood supply.
Rupture of hepatocellular adenomas may lead to intraab-
dominal bleeding that is a surgical emergency. Three large
subtypes have been defined on the basis of molecular anal-
ysis and associated clinical and pathologic findings, each
868 C H A P T E R 18 Liver and Gallbladder
Figure 18-52  Hemangioma. Blood-filled vascular channels separated by a
dense fibrous stroma.
with a different relative risk of malignant transformation.
Both oral contraceptives and anabolic steroids are associ-
ated with the development of these adenomas. In fact
before the advent of oral contraceptives, hepatocellular
adenomas were virtually unknown. The risk of developing
these tumors is increased 30-40 fold in users of oral contra-
ceptives. The highest risk is from prolonged use of estrogen
rich oral contraceptives. If surgery is not possible or is ill-
advised, cessation of exposure to sex hormones often can
lead to full regression.
Pathogenesis.  Three large subtypes have been defined on
the basis of molecular analysis and associated clinical and
pathologic findings, each with a different relative risk of
malignant transformation.
HNF1-α Inactivated hepatocellular adenomas. Ninety
percent of these tumors have inactivating mutations
of HNF1-α that are somatic, while 10% have germline
mutations. HNF1-α encodes a transcription factor.
Heterozygous germline mutations are responsible for
A B
Figure 18-53  Liver cell adenoma. A, Resected specimen presenting as a pendulous mass arising from the liver. B, Microscopic view showing cords of hepa-
tocytes, with an arterial vascular supply (arrow) and no portal tracts.
autosomal dominant MODY-3 (maturity onset diabetes of
the young, type 3). Patients with MODY-3 who develop
hepatocellular adenomas have acquired a second somatic
mutation. These lesions are most commonly found in
women. Oral contraceptive pills are implicated in some.
β-Catenin Activated Hepatocellular Adenomas. Activat­ing
mutations of β-catenin are associated with neoplasia and
malignancy in many organs. In the liver they may give rise
to hepatocellular adenomas that are considered at
very high risk for malignant transformation and should be
resected even when asymptomatic. They are associated
with oral contraceptive and anabolic steroid use. They are
found in men and women.
Inflammatory hepatocellular adenomas. These lesions are
found in both men and women and are associated with
non-alcoholic fatty liver disease; thus, their incidence
seems to be increasing. They have a small but definite risk
of malignant transformation and should probably be
resected even when asymptomatic. They are characterized
by activating mutations in gp130, a co-receptor for
IL-6, that lead to constitutive JAK-STAT signaling and
overexpression of acute phase reactants, which you will
recall are normally upregulated in systemic inflammatory
states. As will be discussed later, IL-6 mediated JAK-STAT
signaling has also been linked to the pathogenesis of hepa-
tocellular carcinoma, and undoubtedly explains the inflam-
matory background that characterizes this subtype of
hepatocellular adenoma. Ten percent of inflammatory
hepatocellular adenomas also have concomitant β-catenin
activating mutations and these tumors have a higher risk
of malignant transformation.
  MORPHOLOGY
The tumors resulting from HNF1-α mutations are often fatty
and devoid of cellular or architectural atypia. They have almost
no risk of malignant transformation. Liver fatty acid binding
protein (LFABP), a downstream regulated protein of HNF1-α,
is constitutively expressed in all normal hepatocytes, but is
 The liver and bile ducts 869

A B

Figure 18-54  Molecular subtypes of hepatocellular adenoma. A, HNF1α-

inactivated hepatocellular adenoma. Liver fatty acid binding protein
(LFABP, expression of which depends on HNF1α) is absent in the tumor
by immunostain and present in nearby normal hepatocytes (lower left). 
B, An hepatocellular adenoma with β-catenin mutation. Note nuclear
immunostaining for the mutant protein in some tumor hepatocytes (com-
pared to other tumor hepatocytes that maintain normal membranous
staining). C, Inflammatory hepatocellular adenoma. There is marked up-
regulation of C-reactive protein in neoplastic hepatocytes, compared to
the highly variable and usually low-level expression in adjacent hepatic
C parenchyma. (Immunostain with DAB [brown] and hematoxylin counter-
stain.) (A, Courtesy Dr. Valerie Paradis, Beaujon Hospital, Paris, France.)

absent in these tumors due to the inactivating mutation of Malignant Tumors

HNF1-α. Thus, immunostaining for LFABP demonstrating its
Malignant tumors occurring in the liver can be primary or
absence in the tumor is diagnostic of the mutation (Fig. 18-54A).
metastatic. Most of the discussion in this section deals with
β-Catenin mutated hepatocellular adenomas often have
primary hepatic tumors. Most primary liver cancers arise
a high degree of cytologic or architectural dysplasia or even
from hepatocytes and are termed hepatocellular carcinoma
overt areas of hepatocellular carcinoma. Immunostain for
(HCC). Much less common are carcinomas of bile duct
β-catenin usually shows nuclear translocation indicative of
origin, cholangiocarcinomas.
its activated state (Fig. 18-54B). This change is diagnostic.
Before embarking on a discussion of the major forms of
Glutamine synthetase, a target of beta-catenin, (normally only
malignancy affecting the liver, a rare form of primary liver
positive in perivenular hepatocytes) is also diffusely positive in
cancer, hepatoblastoma deserves a brief discussion.
these tumors, a change that may be seen even when the acti-
vating β-catenin mutation doesn’t result in nuclear staining. In Hepatoblastoma
such tumors, molecular analysis is necessary for definitive
Hepatoblastoma is the most common liver tumor of early
confirmation.
childhood. It is rarely occurs over the age of 3 years.
Inflammatory hepatocellular adenomas. Unlike the other
Its incidence, which is increasing, is approximately 1 to 2
hepatocellular adenomas, which are comprised of only hepato-
in 1 million births. Two primary anatomic variants are
cytes and vessels with minor amounts of stroma, these lesions
recognized:
characteristically have in addition areas of fibrotic stroma,
mononuclear inflammation, ductular reactions, dilated sinu-
soids, and telangiectatic vessels. Most of these tumors over­
• The epithelial type, composed of small polygonal fetal
cells or smaller embryonal cells forming acini, tubules,
express acute phase reactants such as C-reactive protein 
or papillary structures vaguely recapitulating liver
and serum amyloid A (Fig. 18-54C). These molecules may
development (Fig. 18-55)
also be elevated in the serum. 10% of these HCAs that also
have β-catenin activating mutations and, as would be anti­ • The mixed epithelial and mesenchymal type, which contains

foci of mesenchymal differentiation that may consist
cipated, also show increased nuclear levels of b-catenin by
of primitive mesenchyme, osteoid, cartilage, or striated
immunohistochemistry.
muscle
870 C H A P T E R 18 Liver and Gallbladder

incidence areas. The reason for the gender imbalance is not

known. Worldwide, liver cell cancer is the fifth leading
cause of death in males.

Pathogenesis.  Chronic liver diseases are the most

common setting for emergence of HCC. While usually
identified in a background of cirrhosis, cirrhosis per se is
not a premalignant lesion. Indeed, cirrhosis is not required
for hepatocarcinogenesis (Fig. 18-56). Rather, progression
to cirrhosis and hepatocarcinogenesis take place in parallel
over years to decades.
The most important underlying factors in hepatocar-
cinogenesis are viral infections (HBV, HCV) and toxic
injuries (aflatoxin, alcohol). Thus where HBV and HCV
are endemic, there is a very high incidence of HCC.
Co-infection further increases risk. In Africa and Asia, afla-
toxin, produced by Aspergillus species, is a mycotoxin that
Figure 18-55  Hepatoblastoma. The photograph shows proliferating hepato-
contaminates staple food crops. Aflatoxin metabo­lites are
blasts consisting mostly of round “epithelial” type cells. present in the urine of affected individuals as are aflatoxin-
albumin adducts in serum. This helps to identify the popu-
lations at risk and confirm the important influence of
A characteristic feature of hepatoblastomas is the
frequent activation of the WNT signaling pathway. This
occurs by a variety of mechanisms involving mutations
in molecules downstream of WNT signaling, including
mutations in APC gene. Patients with Familial adenoma-
tous polyposis frequently develop hepatoblastomas. Spo­
radic cases have activation of the beta-catenin signaling
through other mechanisms. Chro­mosomal abnormalities
are common in hepatoblastomas, and FOXG1, a regulator
of the TGF-β pathway, is highly expressed in some tumors.
Hepatoblastoma may be associated Beckwith-Wiedemann
syndrome as well. The treatment is sugical resection and
chemotherapy. Untreated, the tumor is usually fatal within
a few years, but therapy has raised the 5-year survival A
to 80%.

Hepatocellular Carcinoma (HCC)

Worldwide, HCC (also known erroneously as hepatoma)
accounts for approximately 5.4% of all cancers, but its inci-
dence varies widely in different parts of the world. More
than 85% of cases occur in countries with high rates of chronic
HBV infection. The highest incidences of HCC are found
in Asian countries (southeast China, Korea, Taiwan) and
sub-Saharan African countries. In these locales, HBV is
transmitted vertically and, as already discussed, the carrier
state starts in infancy. The peak incidence of HCC in these
areas is between 20 and 40 years of age, and in almost
50% of cases, the tumor appears in the absence of cirrhosis.
As discussed later, many of these populations are exposed
to aflatoxin, which is also a carcinogen (Chapter 7). The
risk of HCC is decreasing in China, Singapore and
Hong Kong, most likely due to institution of hepatitis B
vaccination.
In Western counties, the incidence of HCC is rapidly increas-
ing, largely owing to the hepatitis C epidemic. It tripled in the
United States in recent decades, but it is still eightfold to
30-fold lower than the incidence in some Asian countries. B
In Western populations, HCC rarely manifests before the
Figure 18-56  Hepatocellular carcinoma. A, Liver removed at autopsy showing
age of 60, and, in almost 90% of cases, the malignancy a unifocal neoplasm replacing most of the right hepatic lobe. B, Malignant
emerges after cirrhosis becomes established. There is a pro- hepatocytes growing in distorted versions of normal architecture, including
nounced male preponderance throughout the world, about large pseudoacinar spaces (malformed, dilated bile canaliculi) and thickened
3 : 1 in low-incidence areas and as high as 8 : 1 in high hepatocyte trabeculae.
 The liver and bile ducts 871

aflatoxin for hepatocarcinogenesis. Aflatoxin also syner-
gizes with HBV (perhaps also with HCV) to increase risk
further. Alcohol is another toxin which probably, by itself,
is a risk factor for HCC, but it also synergizes with HBV
and HCV, and even, possibly, cigarette smoking.
Metabolic diseases such as hereditary hemochromatosis
and α1AT deficiency markedly increase the risk of HCC.
Wilson disease probably does so with much less frequency.
Of probably greater import is the metabolic syndrome
associated with obesity, diabetes mellitus, and non-
alcoholic fatty liver disease, all of which increase the risk
of HCC.
No single, universal sequence of molecular or genetic
alterations leads to emergence of HCC. Activation of
β-catenin and inactivation of p53 are the two most common early
mutational events. Activating β-catenin mutations are iden-
tified in up to 40% of persons with HCC. These tumors are
more likely to be unrelated to HBV and to demonstrate
genetic instability. Inactivation of p53 is present in up to
60% of HCC cases. These tumors are strongly associated
with aflatoxin. Neither of these alterations, however, is
found in premalignant lesions.
Recent evidence has provided some novel insights into
the role of HBV, HCV, alcoholic liver disease and other
states of chronic inflammation in the pathogenesis of HCC.
Traditional thinking has been that cycles of cell death and
regeneration in chronic inflammatory states increases the
risk of mutations in regenerating hepatocytes. But the
precise molecular mechanisms of such changes have
remained obscure. More recent studies implicate a role for
signaling through the IL-6/JAK/STAT pathway in the cau-
sation of HCC. IL-6 is an inflammatory cytokine that is
overproduced in many chronic hepatitides. Based on some
preliminary experiments, it has been proposed that IL-6
can suppress hepatocyte differentiation and promote their
proliferation by regulating the function of the transcription
factor HNF4-α. In keeping with this, hepatic carcinogene-
sis can be suppressed by uncoupling HNF4-α from the
control of IL-6, in experimental animals. More studies are
needed to determine the significance of IL-6/HNF4-α sig-
naling axis in human HCC.
Precursor Lesions of HCC
Several cellular and nodular precursor lesions to HCC
have been identified (Table 18-12). Hepatocellular ade­
noma has already been discussed, in particular those with
β-catenin activating mutations. In chronic liver disease
there are cellular dysplasias, called large cell change and
small cell change (Fig. 18-57). These may be found at any
stage of chronic liver disease, before or after development
of cirrhosis, and serve as markers in biopsy specimens to
indicate which patients need more aggressive cancer sur-
veillance. Small cell change is thought to be directly premalig-
nant. Large cell change is at least a marker of increased risk of
HCC in the liver as a whole, but in hepatitis B they may also be
directly premalignant.
Dysplastic nodules are usually detected in cirrhosis, either
radiologically or in resected specimens (including explants).
These are nodules that have a different appearance from
the surrounding cirrhotic nodules (Fig. 18-58). The differ-
ences are in size or vascular supply (increasingly arterial
with increasingly high grade, a defining feature in contrast
radiologic studies) or other aspects of appearance (color,
texture). Low-grade dysplastic nodules, may or may not

Table 18-12  Precursor Lesions of Hepatocellular Carcinoma and Cholangiocarcinoma

Hepatocellular Carcinoma Cholangiocarcinoma
Intraductal
Low Grade High Grade Mucinous Papillary
Hepatocellular Small Cell Large Cell Dysplastic Dysplastic Cystic Biliary
Adenoma Change Change Nodule Nodule BilIN-3 Neoplasm Neoplasia
Focality in liver Single or multiple Diffuse Diffuse Single or Single or Diffuse or Single Focal or
(adenomatosis) multiple multiple multifocal diffuse
Premalignant Yes Yes In some HBV* Uncertain* Yes Yes Yes Yes
Association Rare Common Common Usual Usual Sometimes No No
with
cirrhosis
Commonly NAFLD, Sex HBV, HCV, HBV, HCV, HBV, HCV, HBV, HCV, PSC, None None
associated hormone Alcohol, Alcohol, Alcohol, Alcohol, Hepatolithiasis,
diseases exposures NAFLD, NAFLD, NAFLD, NAFLD, Liver flukes
Glycogen storage A1AT, A1AT, HH A1AT, HH A1AT, HH
diseases HH, PBC PBC PBC PBC
Occurrence Occasional No No No No Yes Yes Yes
without
identified
predisposing
condition
Need for ± depending on Yes Yes Yes Yes Yes No Yes
surveillance presence of
cancer predisposing
screening condition
*While these are not certain to be directly premalignant, they are always at least an indication of increased risk for malignancy in the liver as a whole.
BilIN-3, Biliary intraepithelial neoplasia, high grade; NAFLD, nonalcoholic fatty liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; A1AT, α1-antitrypsin deficiency; HH, hereditary hemochromatosis;
PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.
872 C H A P T E R 18 Liver and Gallbladder

normal distribution. Thus, the blood supply remains a mix of

portal venous and hepatic arterial blood. High grade dysplas-
tic nodules have cytologic (e.g., small cell change) or architec-
tural features (occasional pseudoglands, trabecular thickening)
suggestive of, but still insufficient for diagnosis of overt HCC.
Such atypia often presents as a subnodule within the larger
nodule. Portal tracts are fewer in these higher grade nodules
and arteries feeding the growing lesion gradually come to pre-
dominate over the portal veinous flow. Overt HCC may then
arise within the dysplastic nodules (Fig. 18-58B), eventually
overgrowing it.
Overall, HCC may appear grossly as (1) a unifocal
(usually large) mass, (2) multifocal, widely distributed
A nodules of variable size, or (3) a diffusely infiltrative

B
Figure 18-57  A, Large cell change. Large hepatocytes with large, often atypi-
cal nuclei are scattered among normal-size hepatocytes with round, typical
nuclei. B, Small cell change. The abnormal cells have a high nuclear-to-
cytoplasmic ratio and are separated by thickened plates. Normal-appearing
hepatocytes are in the lower right corner. (Courtesy Dr. Young Nyun Park,
Yonsei Medical College, Seoul, South Korea.)

undergo transformation to higher grade lesions, but they

at least indicate a higher risk for HCC in the liver as a
whole. High-grade dysplastic nodules are probably the most
A
important primary pathway for emergence of HCC in viral
hepatitis and alcoholic liver disease. Subnodules of HCC
are often found in high-grade dysplastic nodules in biopsy
or resection specimens.

  MORPHOLOGY
Large cell change shows scattered hepatocytes, usually near
portal tracts or septa, that are larger than normal hepatocytes
and with large, often multiple, often moderately pleomorphic
nuclei; however, the nuclear-cytoplasmic ratio is normal since
both nuclei and the cell as a whole become larger (Fig. 18-57A).
In small cell change the hepatocytes have high nuclear-
cytoplasmic ratio and mild nuclear hyperchromasia and/or pleo-
morphism (Fig. 18-57B). Hepatocytes exhibiting small cell B
change often form tiny expansile nodules within a single paren-
chymal lobule. Figure 18-58  A, Hepatitis C–related cirrhosis with a distinctively large
Low-grade dysplastic nodules are devoid of cytologic or nodule (arrows). Nodule-in-nodule growth suggests an evolving cancer.
architectural atypia, but have been shown to be clonal and are B, Histologically the region with in the box in A shows a well-differentiated
hepatocellular carcinoma (HCC) (right side) and a subnodule of moderately
probably neoplastic, rather than simply large cirrhotic nodules.
differentiated HCC within it (center, left). (Courtesy Dr. Masamichi Kojiro,
Portal tracts are still present within these nodules, often in near
Kurume University, Kurume, Japan.)
 The liver and bile ducts 873

cancer, permeating widely and sometimes involving the entire

liver. All three patterns may cause liver enlargement. The dif-
fusely infiltrative tumor may blend so imperceptibly into a back-
ground of cirrhosis that it might not be apparent by imaging,
even though most of the liver is replaced. HCCs may be pale
compared to surrounding liver or they may have a variegated
appearance reflecting different differentiation states (white when
there is abundant stroma, yellow when fatty change predomi-
nates, green when well-differentiated malignant hepatocytes
make abundant bile).
Intrahepatic metastases, by either vascular invasion or
direct extension, become more likely once tumors reach 3 cm
in size. These metastases are usually small, satellite tumor
nodules around the larger, primary mass. The vascular route is
also the most likely route for extrahepatic metastasis, especially
by the hepatic venous system. Hematogenous metastases,
especially to the lung, tend to occur late in the disease.
Occasionally, long, snakelike masses of tumor invade the portal
vein (causing portal hypertension) or inferior vena cava. The
latter can even extend into the right side of the heart. Lymph
node metastases are less common routes of extrahepatic
spread. If venous invasion is identified in HCC-bearing explanted
livers at the time of transplantation, tumor recurrence is likely to
occur in the transplanted liver due to seeding of circulating
tumor cells in the transplant recipient. Such lesions may appear
months after the operation.
HCCs range from well-differentiated to highly anaplastic
lesions. The better differentiated HCCs are comprised of 
cells that look much like normal hepatocytes and grow in struc-
tures that are distortions of normal: thickened trabecular 
structures (recapitulating liver cell plates) or pseudoglandular Figure 18-59  Fibrolamellar carcinoma. A, Resected specimen showing a well
structures that are poorly formed, ectatic bile canaliculi  demarcated nodule. B, Microscopic view showing nests and cords of
(Fig. 18-56). malignant-appearing, oncocytic hepatocytes separated by dense bundles of
A distinctive variant of HCC is fibrolamellar carcinoma, collagen.
constituting less than 5% of HCCs. 85% occur under the age
of 35 years and without gender predilection or identifiable pre-
disposing conditions. It usually presents as single large, hard
Most valuable for detection of small tumors are imaging
“scirrhous” tumor with fibrous bands coursing through it.
studies: ultrasonography to identify distinctive nodules of
Microscopically, they are composed of well-differentiated cells
all kinds, and computed tomography and magnetic reso-
rich in mitochondria (oncocytes) growing in nests or cords
nance imaging with vascular/contrast studies. The increas-
separated by parallel lamellae of dense collagen bundles (hence
ing arterialization in the process of conversion from high
the name) (Fig. 18-59).
grade dysplastic nodule to early HCC and then to fully
developed HCC, form the basis of diagnostic imaging.
HCC, even when small, has such characteristic vascular
Clinical Features.  The clinical manifestations of HCC are changes that imaging can be diagnostic.
seldom characteristic and, in the Western population, often The natural course of HCC involves the progressive
are masked by those related to the underlying cirrhosis or enlargement of the primary mass until it disturbs hepatic
chronic hepatitis. In areas of high incidence such as tropical function or metastasizes to the lungs or to other sites.
Africa, in particular where aflatoxin exposure is common, Death usually occurs from (1) cachexia, (2) gastrointestinal
patients usually have no clinical history of liver disease, or esophageal variceal bleeding, (3) liver failure with
although cirrhosis may be detected at autopsy. In both hepatic coma, or, rarely, (4) rupture of the tumor with
populations most patients have ill-defined upper abdomi- fatal hemorrhage. The 5-year survival of large tumors
nal pain, malaise, fatigue, weight loss, and sometimes is dismal, the majority of patients dying within the first
awareness of hepatomegaly or an abdominal mass or 2 years.
abdominal fullness. Jaundice, fever, and gastrointestinal or With implementation of screening procedures and
esophageal variceal bleeding are inconstant findings. advances in imaging, the detection of HCCs less than
Laboratory studies may be helpful but are rarely con- 2 cm in diameter has increased in countries where such
clusive. Rising or elevated levels of serum α-fetoprotein are facilities are available. These small tumors can be removed
found in 50% of persons with advanced HCC. However, it surgically or ablated (e.g., through embolization or with
is insensitive as a screening test for premalignant or early microwave radiation or freezing) with good outcomes.
lesions as these usually do not produce particularly high Radiofrequency ablation is used for local control of large
levels of the protein. tumors, and chemoembolization can also be used.
874 C H A P T E R 18 Liver and Gallbladder

Cholangiocarcinoma (CCA)
Cholangiocarcinoma (CCA), the second most common
primary malignant tumor of the liver after HCC, is a
malignancy of the biliary tree, arising from bile ducts
within and outside of the liver. It accounts for 7.6% of
cancer deaths worldwide and 3% of cancer deaths in the
United States. However, in some regions of Southeast Asia
such as northeastern Thailand, Laos, and Cambodia where
infestation with liver flukes is endemic, cholangiocarci-
noma is more common than hepatocellular carcinoma.
All risk factors for cholangiocarcinomas cause chronic
inflammation and cholestasis, which presumably promote
occurrence of somatic mutations or epigenetic alterations A
in cholangiocytes. The risk factors include infestation
by liver flukes (particularly Opisthorchis and Clonorchis
species), chronic inflammatory disease of the large bile
ducts, such as primary sclerosing cholangitis, hepatolithia-
sis, and fibropolycystic liver disease. It should be noted
that patients with hepatitis B and C, and non alcoholic fatty
liver disease, not only have a higher risk of developing
HCC, but also of cholangiocarcinoma. Globally, cholangio-
carcinomas are most often sporadic and not associated
with any preexisting condition.
Cholangiocarcinoma may be either intrahepatic or
extrahepatic. The extrahepatic forms include perihilar
tumors known as Klatskin tumors, which are located at the
junction of the right and left hepatic ducts. Fifty percent to
60% of all cholangiocarcinomas are perihilar (Klatskin)
tumors, 20% to 30% are distal tumors, arising in the
common bile duct where it lies posterior to the duodenum. B
The remaining 10% are intrahepatic. Regardless of site, the
prognosis is dismal, with survival rates of about 15% at 2
years after diagnosis for extrahepatic tumors. The median
time from diagnosis to death for intrahepatic CCAs is 6
months, even after surgery because intrahepatic CCAs are
not usually detected until late in their course. They come
to the attention because of obstruction of bile flow or as a
symptomatic liver mass. In contrast, hilar and distal tumors
present with symptoms of biliary obstruction, cholangitis,
and right upper quadrant pain.
Premalignant lesions for cholangiocarcinoma are
also known, the most important of which are biliary
intraepithelial neoplasias (low to high grade, BilIN-1, -2,
or -3). BilIN-3, the highest grade lesion, incurs the highest
risk of malignant transformation. More rare are mucinous
cystic neoplasms and intraductal papillary biliary neoplasia
(Table 18-12).
C
Figure 18-60  Cholangiocarcinoma. A, Multifocal cholangiocarcinoma in a
  MORPHOLOGY liver from a patient with infestation by the liver fluke Clonorchis sinensis.
B, Invasive malignant glands in a reactive, sclerotic stroma. C, Perineural
Extrahepatic cholangiocarcinomas are generally small
invasion by malignant glands, forming a wreathlike pattern around the central,
lesions at the time of diagnosis as they rapidly cause obstructive trapped nerve. (A, Courtesy Dr. Wilson M.S. Tsui, Caritas Medical Centre,
features. Most tumors appear as firm, gray nodules within the Hong Kong.)
bile duct wall; some may be diffusely infiltrative lesions; others
are papillary, polypoid lesions. Intrahepatic cholangiocarcino-
mas occur in the noncirrhotic liver (Fig. 18-60) and may track
along the intrahepatic portal tract system creating a branching moderately differentiated with clearly defined glandular/tubular
tumor within a portion of the liver. Alternatively, a massive tumor structures lined by malignant epithelial cells (Fig. 18-60B). They
nodule may develop. typically incite marked desmoplasia. Lymphovascular invasion
Regardless of site, cholangiocarcinomas are typical adeno- and perineural invasion (Fig. 18-60C) are both common, each
carcinomas. They often produce mucin. Most are well- to  a path to extensive intrahepatic and extrahepatic metastases.

Other Primary Hepatic Malignant Tumors
Other primary liver malignancies are rare, but noteworthy.
Some tumors show combined hepatocellular and cholangiocar-
cinoma, suggesting an origin from a multipotent stem cell.
Mucinous cystic neoplasms and intraductal papillary biliary
neoplasia may occur as in situ lesions or as invasive
cholangiocarcinoma.
Angiosarcoma of the liver resembles those occurring
elsewhere and has historical associations with vinyl chlo-
ride, arsenic, or Thorotrast (Chapters 9 and 11), although
with reduced exposures to these compounds in recent
decades, this malignancy is becoming very rare. Epithelioid
hemangioendothelioma, another form of endothelial malig-
nancy, has a much more variable prognosis than the
almost uniformly fatal angiosarcoma. Hepatic lymphomas
are primarily diseases of middle aged men and are seen,
albeit rarely, in association with hepatitis B and C, HIV,
and PBC. Most are diffuse large B-cell lymphomas, followed
by MALT lymphomas. Hepatosplenic delta-gamma T cell
lymphoma, most common in young adult males, has a pre-
dilection for hepatic and splenic sinusoids as well as the
marrow.
Metastasis
Involvement of the liver by metastatic malignancy is far
more common than primary hepatic neoplasia. Although
the most common primary sources are the colon, breast,
lung, and pancreas, any cancer in any site of the body may
spread to the liver. Typically, multiple nodular metastases
are found that often cause striking hepatomegaly and
replace much of the normal liver parenchyma. The liver
weight can exceed several kilograms. Metastasis may also
appear as a single nodule, in which case it may be resected
surgically. Always surprising is the amount of metastatic
involvement that may be present in the absence of clinical
or laboratory evidence of hepatic functional insufficiency.
Often the only telltale clinical sign is hepatomegaly.
However, with massive destruction of liver substance or
direct obstruction of major bile ducts, jaundice and eleva-
tions of liver enzymes may appear.
GALLBLADDER
Gallbladder 875
  KEY CONCEPTS
Liver Tumors
■ The liver is the most common site of metastatic cancers
from primary tumors of the colon, lung, and breast.
■ Hepatocellular adenomas are benign tumors of neoplas-
tic hepatocytes. Most can be subclassified on the basis of
molecular changes:
■ HNF1-α inactivated adenomas, with virtually no risk of
malignant transformation, often associated with oral
contraceptive pill use or in individuals with MODY-3
■ β-Catenin activated adenoma, with mutations in the
β-catenin gene leading to marked atypia and associated
with a very high risk for malignant transformation
■ Inflammatory adenomas, the hallmark of which is
up-regulation of C-reactive protein and serum amyloid
A (often derived from gp130 mutations); 10% of these
have concomitant β-catenin activating mutations. Risk
for malignant transformation is intermediate.
■ The main primary malignancies are HCCs and cholan-
giocarcinomas; HCCs are by far the most common.
■ HCC is a common tumor in regions of Asia and Africa,
and its incidence is increasing in the United States.
■ The main etiologic agents for HCC are chronic hepatitis
B and C, alcoholic cirrhosis, non-alcoholic fatty liver
disease, and hemochromatosis. In the Western popula-
tion, about 90% of HCCs develop in cirrhotic livers; in
Asia, almost 50% of cases develop in noncirrhotic livers.
■ The chronic inflammation and cellular regeneration
associated with viral hepatitis or the activation of IL-6/
JAK STAT pathway may be predisposing factors for the
development of carcinomas.
■ HCCs may be unifocal or multifocal, tend to invade
blood vessels, and recapitulate normal liver architecture
to varying degrees.
■ Cholangiocarcinoma is endemic in areas where liver flukes
such as Opisthorchis and Clonorchis species are endemic.
Chronic inflammatory diseases of bile ducts are also risk
factors. The tumors may arise from extra hepatic or intrahe-
patic bile ducts. They have uniformly poor prognosis.
 Gallbladder 879

Carcinoma
Carcinoma of the gallbladder is the most common malig-
nancy of the extrahepatic biliary tract. Approximately
6,000 new cases of gallbladder cancer are diagnosed each
year in the United States. There are wide variations in the
incidence of gallbladder cancer worldwide, with some
regions such as Chile, Bolivia and Northern India, harbor-
ing the highest numbers of cases. Even within the United
  States, areas with large numbers of Native American or
Hispanic populations, such as the southwest, have a higher
incidence of gallbladder cancer than the rest of the country.
  Gallbladder cancer is at least twice as common in women than
in men; this gender disparity can be several fold greater in
regions of highest incidence. The overwhelming majority
of patients are diagnosed at an advanced, surgically unre-
sectable, stage, and the mean 5-year survival for these
patients remains at less than 10%.

Pathogenesis.  The most important risk factor for gallbladder

  cancer (besides gender and ethnicity) is gallstones which are
present in 95% of cases. However, it should be noted that
only 1-2% of patients with gallstones develop gallbladder
cancer. In Asia, chronic bacterial or parasitic infections
have been implicated as risk factors, and the coexistence
of gallstones with gallbladder cancer is much lower.
Nonetheless, the common thread that ties gallstones or
chronic infections together with gallbladder cancer is
chronic inflammation. Gallbladder cancers harbor recur-
rent molecular alterations that might be “actionable”
targets of therapy. One example is the oncoprotein ERBB2
(Her-2/neu) that is overexpressed in a third to two-thirds
of cases, and therefore might be targeted with small mol-
ecule inhibitors or monoclonal antibodies. Recent deep
sequencing of gallbladder cancers has revealed mutations
880 C H A P T E R 18 Liver and Gallbladder
of chromatin remodeling genes such as PBRM1 and MLL3
in up to a quarter of cases. These could potentially provide
targets for therapy.
  MORPHOLOGY
Carcinomas of the gallbladder show two patterns of growth:
infiltrating and exophytic. The infiltrating pattern is more
common and usually appears as a poorly defined area of diffuse
mural thickening and induration. Deep ulceration can cause
direct penetration into the liver or fistula formation to adjacent
viscera into which the neoplasm has grown. These tumors are
scirrhous and have a very firm consistency. The exophytic
pattern grows into the lumen as an irregular, cauliflower mass,
but at the same time invades the underlying wall (Fig. 18-65A).
Most carcinomas of the gallbladder are adenocarcino-
mas. Some of the carcinomas are papillary in architecture and
are well to moderately differentiated; others are infiltrative and
poorly differentiated to undifferentiated (Fig. 18-65B). About
5% are squamous cell carcinomas or have adenosquamous
differentiation. A minority may show carcinoid or a variety of
mesenchymal features (car­cinosarcoma). Papillary tumors gen-
erally have a better progno­sis than other tumors. By the time
these neoplasms are discovered, most have invaded the liver
centrifugally, and many have extended to the cystic duct and
adjacent bile ducts and portal-hepatic lymph nodes. The peri-
toneum, gastrointestinal tract, and lungs are common sites of
seeding.
A
B fibroblastic cells of the liver with inflammatory, fibrosing, and neoplastic
Figure 18-65  Gallbladder adenocarcinoma. A, The opened gallbladder con-
tains a large, exophytic tumor that virtually fills the lumen. B, Malignant glands
are seen infiltrating a densely fibrotic gallbladder wall.
It is not uncommon to find preneoplastic (dysplastic) lesions
in the epithelium adjacent to invasive cancer, or in gallbladders
with long-standing cholelithiasis. These are nearly always flat
dysplasias, with varying grades of cellular atypia, including
carcinoma-in-situ. Although polypoid adenomas of the gallblad-
der have been reported, these are uncommon precursors to
invasive adenocarcinomas, and harbor distinct genetic
alterations.
Clinical Features.  Preoperative diagnosis of carcinoma of
the gallbladder is the exception rather than the rule, occur-
ring in fewer than 20% of patients. Presenting symptoms
are insidious and typically indistinguishable from those
associated with cholelithiasis: abdominal pain, jaundice,
anorexia, and nausea and vomiting. Early detection of the
tumor may be possible in patients who develop a palpable
gallbladder and acute cholecystitis before extension of the
tumor into adjacent structures, or when the carcinoma is
an incidental finding during a cholecystectomy for symp­
tomatic gallstones. Surgical resection, often including adja-
cent liver, is the only effective treatment, when possible,
but chemotherapy regimens are also used.
  KEY CONCEPTS
Diseases of the Gallbladder
■ Gallbladder diseases include cholelithiasis and acute and
chronic cholecystitis and gall bladder cancer.
■ Gallstones are common in Western countries. The great
majority are cholesterol stones. Pigmented stones con­
taining bilirubin and calcium are most common in Asian
countries.
■ Risk factors for the development of cholesterol stones are
advancing age, female gender, estrogen use, obesity, and
heredity.
■ Cholecystitis almost always occurs in association with
cholelithiasis, although in about 10% of cases it occurs in
the absence of gallstones. Gall stones are also a risk factor
for gall bladder cancer.
■ Acute calculous cholecystitis is the most common reason
for emergency cholecystectomy.
■ Gall bladder cancers are associated with gall stones in the
vast majority of cases. Typically they are detected late
because of non specific symptoms and hence carry a poor
prognosis.
SUGGESTED READINGS
Mechanisms of Liver Injury and Repair
Gouw ASW, Clouston AD, Theise ND: Ductular reactions in human
livers: diversity at the interface. Hepatology 54:1853, 2011. [A review
of ductular reactions, the stem cell response of human livers in all liver
diseases, that are related to mechanisms of regeneration, fibrogenesis and
neoplasia.]
Kocabayoglu P, Friedman SL: Cellular basis of hepatic fibrosis and its
role in inflammation and cancer. Front Biosci (Schol Ed) 5:217, 2013.
[Interweaving what is known about hepatic stellate cells and other myo-
disease processes.]
Iwaisako K, Brenner DA, Kisseleva T: What’s new in liver fibrosis?
The origin of myofibroblasts in liver fibrosis. J Gastroenterol Hepatol
27(Suppl 2):65, 2012.
 Nonneoplastic cysts 889

Nonneoplastic Cysts
  A variety of cysts can arise in the pancreas. Most are non-
neoplastic pseudocysts (discussed later), but congenital
cysts and neoplastic cysts also occur.

Congenital Cysts
  Congenital cysts are unilocular, thin-walled cysts that are
believed to result from anomalous development of the
pancreatic ducts. They range in size from microscopic
lesions to 5 cm in diameter, and are lined by a glistening,
uniform cuboidal epithelium or, if the intracystic pressure
is high, by a flattened and attenuated cell layer. Congenital
cysts are enclosed in a thin, fibrous capsule and are filled
with a clear serous fluid. Congenital cysts may be sporadic,
or part of inherited conditions such as autosomal-dominant
polycystic kidney disease (Chapter 20) and von Hippel-Lindau
disease (Chapter 28). Cysts in the kidney, liver, and pan-
creas frequently coexist in polycystic kidney disease. In
von Hippel-Lindau disease vascular neoplasms are found
in the retina and cerebellum or brain stem in association
with congenital cysts (and also neoplasms) in the pancreas,
liver, and kidney.

Pseudocysts
Pseudocysts are localized collections of necrotic and hem-
orrhagic material that are rich in pancreatic enzymes and
lack an epithelial lining (hence the prefix “pseudo”).
Pseudocysts account for approximately 75% of cysts in the
pancreas. They usually arise following a bout of acute pan-
creatitis, particularly one superimposed on chronic alco-
holic pancreatitis. Traumatic injury to the pancreas can also
give rise to pseudocysts.
890 C H A P T E R 19 The Pancreas
A
B
Figure 19-7  Pancreatic pseudocyst. A, Cross-section revealing a poorly
defined cyst with a necrotic brown-black wall. B, The cyst lacks a true epi-
thelial lining and instead is lined by fibrin and granulation tissue.
  MORPHOLOGY
Pseudocysts are usually solitary and may be situated within the
pancreas, or, more commonly, in the lesser omental sac or in
the retroperitoneum between the stomach and transverse colon
or between the stomach and liver. They can even be subdia-
phragmatic (Fig. 19-7A). Pseudocysts are formed when areas
of intrapancreatic or peripancreatic hemorrhagic fat necrosis
are walled off by fibrous tissue and granulation tissue (Fig.
19-7B). They range in size from 2 to 30 cm in diameter.
While many pseudocysts spontaneously resolve, they
may become secondarily infected, and larger pseudocysts
may compress or even perforate into adjacent structures.
Neoplasms
A broad spectrum of exocrine neoplasms arises in the pan-
creas. Such neoplasms may be cystic or solid; some are
benign, while others are among the most lethal of all malig-
nancies. Neuroendocrine tumors also occur in the pancreas
and are discussed in Chapter 24.
Cystic Neoplasms
Cystic neoplasms are diverse tumors that range from
harmless benign cysts to lesions that may be precursors
A
B
Figure 19-8  Serous cystic neoplasm (serous cystadenoma). A, Cross-section
through a serous cystic neoplasm. Only a thin rim of normal pancreatic
parenchyma remains. The cysts are relatively small and contain clear, straw-
colored fluid. B, The cysts are lined by cuboidal epithelium without atypia.
to invasive, potentially lethal, cancers. Only 5% to 15% of
all pancreatic cysts are neoplastic (most are pseudocysts;
see the previous section), and cystic neoplasms make up
fewer than 5% of all pancreatic neoplasms. Serous cystic
neoplasms are entirely benign, whereas others, such as
intraductal papillary mucinous neoplasms and mucinous
cystic neoplasms, are precancerous. Recent whole-exome
sequencing has identified genetic alterations specific for
each type of cystic neoplasm.
Serous cystic neoplasms are multicystic neoplasms that
usually occur in the tail of the pancreas. The cysts are small
(1 to 3 mm), lined by glycogen-rich cuboidal cells, and
contain clear, thin, straw-colored fluid (Fig. 19-8). They
account for about 25% of all cystic neoplasms of the pan-
creas. These neoplasms arise twice as often in women as in
men and typically present in the sixth to seventh decade
of life with nonspecific symptoms such as abdominal pain.
Many are now being detected incidentally during imaging
for another indication. Serous cystic neoplasms, called
serous cystadenomas, are almost always benign and, if
small, can be safely observed. Surgical resection is curative
in the vast majority of patients. Inactivation of the VHL
tumor suppressor gene is the most common genetic abnor-
mality in serous cystic neoplasms.
Close to 95% of mucinous cystic neoplasms arise in
women, and, in contrast to serous cystic neoplasms, they

B distending the main pancreatic duct. B, The neoplasm involves the main
Figure 19-9  Pancreatic mucinous cystic neoplasm with low-grade dysplasia.
A, Cross-section through a mucinous multiloculated cyst in the tail of the
pancreas. The cysts are large and filled with tenacious mucin. 
B, The cysts are lined by columnar mucinous epithelium, and a dense
“ovarian” stroma is noted.
can be precursors to invasive carcinomas. These neoplasms
usually arise in the tail of the pancreas and present as pain-
less, slow-growing masses. The cystic cavities are larger
than those in serous cystic neoplasms. They are filled with
thick, tenacious mucin and lined by a columnar mucin-
producing epithelium associated with a dense stroma
similar to ovarian stroma (Fig. 19-9). Up to one third of
surgically resected mucinous cystic neoplasms harbor an
associated invasive adenocarcinoma. While surgical resec-
tion is curative for noninvasive mucinous cystic neoplasms,
half of patients with an invasive carcinoma arising in a
mucinous cystic neoplasm will die of their disease. Early
detection and treatment before an invasive cancer develops
is therefore critical. The KRAS oncogene and the TP53 and
RNF43 tumor suppressor genes are frequently mutated in
these neoplasms.
Intraductal papillary mucinous neoplasms (IPMNs) are
mucin-producing neoplasms that involve the larger ducts
of the pancreas. In contrast to mucinous cystic neoplasms,
IPMNs arise more frequently in men than in women, and
they involve the head of the pancreas more often than the
tail. Ten to twenty percent are multifocal. Two features are
Neoplasms 891
B
Figure 19-10  Intraductal papillary mucinous neoplasm. A, Cross-section
through the head of the pancreas showing a prominent papillary neoplasm
pancreatic duct (left) and extends down into the smaller ducts and ductules
(right).
useful in distinguishing IPMNs from mucinous cystic neo-
plasms: (1) absence of the dense “ovarian” stroma seen in
mucinous cystic neoplasms and (2) involvement of a pan-
creatic duct (Fig. 19-10). Just as with mucinous cystic neo-
plasms, IPMNs can progress to an invasive cancer. Early
detection and treatment of IPMNs before they progress to
an invasive cancer is therefore critical. Frequent mutations
in the GNAS and KRAS oncogenes and the TP53, SMAD4,
and RNF43 tumor suppressor genes have been reported in
these neoplasms.
The unusual solid-pseudopapillary neoplasm is seen mainly
in young women. These large, well-circumscribed malig-
nant neoplasms have solid and cystic components filled
with hemorrhagic debris. The neoplastic cells grow in solid
sheets or, as the name suggests, as pseudopapillary projec-
tions, and often appear to be poorly cohesive. These neo-
plasms often cause abdominal discomfort because of their
large size. Of note, this neoplasm is virtually always associ-
ated with hyperactivation of the Wnt signaling pathway
due to acquired activating mutations of the CTNNB1
(β-catenin) oncogene. Surgical resection is the treatment of
choice. Although some solid-pseudopapillary neoplasms
are locally aggressive, most patients are cured following
complete surgical resection of the neoplasm.
892 C H A P T E R 19 The Pancreas

  KEY CONCEPTS The epithelial cells in PanIN show dramatic telomere

shortening. A critical shortening of telomere length
■ Virtually all serous cystic neoplasms are benign. in PanIN may predispose these lesions to accumulate
■ Intraductal papillary mucinous neoplasms and mucinous progressive chromosomal abnormalities and to develop
cystic neoplasms are curable noninvasive cystic neoplasms invasive carcinoma (Chapter 7).
that can progress to incurable invasive carcinoma. Based on these observations, a model for progression of
■ Each of the major cystic neoplasms has a relatively spe-
PanINs has been proposed (Fig. 19-12).
cific mutational profile.
Pathogenesis
Multiple genes are somatically mutated or epigenetically
Pancreatic Carcinoma silenced in each pancreatic carcinoma, consistent with their
stepwise evolution from precursor lesions, and the pat-
Infiltrating ductal adenocarcinoma of the pancreas, more terns of genetic alterations in pancreatic carcinoma as
commonly known as pancreatic cancer, is the fourth a group differs from those seen in other malignancies.
leading cause of cancer deaths in the United States, trail- Molecular alterations in pancreatic carcinogenesis are sum-
ing only lung, colon, and breast cancers, and has one of marized in Table 19-3 and include the following:
the highest mortality rates of any cancer. It was estimated
that in 2013 pancreatic cancer would strike approximately KRAS.  KRAS (chromosome 12p) is the most frequently
44,000 Americans, virtually all of whom would die of their altered oncogene in pancreatic cancer, with activating
disease. The 5-year survival rate is dismal, less than 5%. point mutations being present in 90% to 95% of cases.
These point mutations result in constitutive activation of
Precursors to Pancreatic Cancer
Invasive pancreatic cancers are believed to arise from
well-defined noninvasive precursor lesions in small ducts
referred to as pancreatic intraepithelial neoplasia (PanIN,
Fig. 19-11). Just as there is a progression in the colorectum
from nonneoplastic epithelium to adenoma to invasive car-
cinoma (Chapters 7 and 17), there is a progression in the
pancreas from nonneoplastic epithelium to PanIN to inva-
sive carcinoma. The PanIN-invasive carcinoma sequence is
supported by the following observations:
• The genetic and epigenetic alterations identified in
PanIN are similar to those found in invasive cancers
(described later).
• PanIN is often found in pancreatic parenchyma adjacent

to infiltrating carcinoma.
• PanIN precedes the development of invasive cancer in
genetically engineered mouse models of pancreatic
cancer.
• Isolated case reports have documented individuals with

PanIN who later developed an invasive pancreatic Figure 19-11  Pancreatic intraepithelial neoplasia grade 3 (PanIN-3) involving
cancer. a small pancreatic duct.

NORMAL PanIN-1A PanIN-1B PanIN-2 PanIN-3 INVASIVE

CARCINOMA

Telomere shortening Inactivation of CDKN2A Inactivation of TP53,

SMAD4,
Activating KRAS mutations BRCA2

Figure 19-12  Model for the progression from normal ducts (far left) through PanINs (center) to invasive carcinoma (far right). It is postulated that telomere
shortening and mutations of the oncogene KRAS occur early, that inactivation of the CDKN2A tumor suppressor gene that encodes the cell cycle regulator
p16 sta occurs in intermediate grade lesions, and that the inactivation of the TP53, SMAD4, and BRCA2 tumor suppressor genes occur in higher grade
(PanIN-3) lesions. It is important to note that while there is a general temporal sequence of changes, the accumulation of multiple mutations is more important
than their occurrence in a specific order. (Adapted from Wilentz RE, et al: Loss of expression of DPC4 in pancreatic intraepithelial neoplasia: evidence that
DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000;60:2002.)
 Neoplasms 893

Table 19-3  Somatic Molecular Alterations in Invasive growth, inducing cell death (apoptosis) or causing cellular
Pancreatic Adenocarcinoma senescence (Chapter 7).
Percentage
of Carcinoma Other Genes.  A growing number of less common, but
Chromosomal with Genetic nonetheless important, genetic loci have been reported to
Gene Region Alteration Gene Function be damaged in pancreatic cancer (Table 19-3).
Oncogenes
DNA Methylation Abnormalities.  Several DNA methyla-
KRAS 12p 90 Growth factor signal
transducer tion abnormalities also occur in pancreatic cancer. Hyper-
methylation of the promoter of several tumor suppressor
AKT2 19q 10-20 Growth factor signal
transducer
genes, including CDKN2A, is associated with transcrip-
tional silencing of these genes and loss of their function.
MYB 6q 10 Transcription factor
NCOA3/AIB1 20q 10 Chromatin regulator Gene Expression.  In addition to DNA alterations, global
MAP2K4/MKK4 17p 5 Growth factor signal analyses of gene expression have identified several path-
transducer ways that seem to be abnormally active in pancreatic
Tumor Supprossor and DNA Repair Genes cancers. These pathways and their downstream conse-
p16/CDKN2A 9p 95 Negative cell-cycle
quences are potential targets for novel therapies and may
regulator form the basis of future screening tests. For example, the
Hedgehog signaling pathway has been shown to be acti-
TP53 17p 50-70 Response to DNA
damage
vated in pancreatic cancer and represents a potential thera-
peutic target.
SMAD4 18q 55 TGFβ pathway
GATA-6 18q 10 Transcription factor Epidemiology and Inheritance.  Pancreatic cancer is pri-
RB 13q 5 Negative cell-cycle marily a disease of older adults, with 80% of cases occur-
regulator ring in people aged 60 to 80 years. It is more common in
STK11 19p 5 Regulation of cellular blacks than in whites, and it is slightly more common in
metabolism individuals of Ashkenazi Jewish descent.
ATM 11q 5 DNA damage response The strongest environmental influence is cigarette
smoking, which is believed to double the risk of pancreatic
ARID1A 1p 4 Chromatin regulator
cancer. Even though the magnitude of this increased risk
TGFBR1 9q 2 TGFβ pathway is not great, the impact of smoking on pancreatic cancer is
TGFBR2 3p 2 TGFβ pathway significant because of the large number of people who
smoke. Consumption of a diet rich in fats has also been
implicated, but less consistently. Chronic pancreatitis and
KRAS, which is a small, GTP-binding protein that nor- diabetes mellitus are both risk factors for, and complica-
mally participates in signaling events downstream of tions of, pancreatic cancer. In an individual patient it can
growth factor receptors with intrinsic tyrosine kinase activ- be difficult to sort out whether chronic pancreatitis is the
ity (Chapters 1 and 7). KRAS signaling activates a number cause of pancreatic cancer or an effect of the disease, since
of downstream pathways that augment cell growth and small pancreatic cancers may block the pancreatic duct and
survival, most notably the MAPK and PI3K/AKT path- produce chronic pancreatitis. A similar argument applies
ways (Chapter 7). to the association of diabetes mellitus with pancreatic
cancer, in that diabetes may develop as a consequence of
CDKN2A.  The CDKN2A gene (chromosome 9p) is inacti- pancreatic cancer and new-onset diabetes mellitus in an
vated in 95% of pancreatic cancers, making it the most older patient may be the first sign that the patient has
frequently inactivated tumor suppressor gene in these pancreatic cancer.
tumors. This complex locus encodes two tumor suppressor Familial clustering of pancreatic cancer has been
proteins (Chapter 7): p16/INK4a, a cyclin-dependent reported, and a growing number of inherited genetic
kinase inhibitor that antagonizes cell cycle progression, defects are recognized to increase pancreatic cancer risk
and ARF, a protein that augments the function of the p53 (Table 19-4). Germline BRCA2 mutations account for
tumor suppressor protein. approximately 10% of pancreatic cancer cases in Ashkenazi
Jews. Patients with these mutations may not have a family
SMAD4.  The SMAD4 tumor suppressor gene (chromo- history of breast or ovarian cancers. Germline mutations in
some 18q) is inactivated in 55% of pancreatic cancers. CDKN2A are associated with pancreatic cancer and are
SMAD4 encodes a protein that plays an important role in almost always observed in individuals from families with
signal transduction from the TGF-β family of cell surface an increased incidence of melanoma, which also frequently
receptors. SMAD4 is only rarely inactivated in other cancer harbors CDKN2A loss-of-function mutations.
types.
  MORPHOLOGY
TP53.  Inactivation of the TP53 tumor suppressor gene
Approximately 60% of cancers of the pancreas arise in the head
(chromosome 17p) occurs in 70% to 75% of pancreatic
of the gland, 15% in the body, and 5% in the tail; in 20% the
cancers. This gene encodes p53, a nuclear DNA-binding
neoplasm diffusely involves the entire gland. Carcinomas of the
protein that can respond to DNA damage by arresting cell
894 C H A P T E R 19 The Pancreas

Table 19-4  Inherited Predisposition to Pancreatic Cancer

Increased Risk of
Risk of Pancreatic
Pancreatic Cancer by
Disorder Gene Cancer (Fold) Age 70 (%)
Peutz-Jeghers STK11 130 30-60
syndrome
Hereditary PRSS1, SPINK1 50-80 25-40
pancreatitis
Familial atypical CDKN2A 20-35 10-17
multiple-mole
melanoma
syndrome
Strong family history   Unknown 14-32 8-16
(3 or more A
relatives with
pancreatic cancer)
Hereditary breast and Multiple, including 4-10 5
ovarian cancer BRCA1, BRCA2,
PALP2, BRCA2
Hereditary Multiple, including 8-10 4
non-polyposis MLH1, MSH2
colorectal cancer (2p21)
(HNPCC)

pancreas are usually hard, stellate, gray-white, poorly defined

masses (Fig. 19-13A).
The vast majority of carcinomas are ductal adenocarcinomas B
that recapitulate to some degree normal ductal epithelium by
Figure 19-13  Carcinoma of the pancreas. A, A cross-section through the tail
forming glands and secreting mucin. Two features are charac- of the pancreas showing normal pancreatic parenchyma and a normal pan-
teristic of pancreatic cancer; it is highly invasive (even “early” creatic duct (left), an ill-defined mass in the pancreatic substance (center)
invasive pancreatic cancers extensively invade peripancreatic with narrowing of the pancreatic duct, and dilatation of the pancreatic duct
tissues), and it elicits an intense host reaction in the form of upstream (right) from the mass. B, Poorly formed glands are present in
dense fibrosis (“desmoplastic response”), described later. densely fibrotic stroma within the pancreatic substance; some inflammatory
Most carcinomas of the head of the pancreas obstruct the cells are also present.
distal common bile duct as it courses through the head of the
pancreas. As a consequence there is marked distention of 
the biliary tree in about 50% of patients with carcinoma of the marked degree of desmoplasia can hinder the interpretation 
head of the pancreas, and most develop jaundice. In marked of diagnostic biopsies, as much of the tissue present is
contrast, carcinomas of the body and tail of the pancreas nonneoplastic. Perineural invasion within and beyond the organ
do not impinge on the biliary tract and hence remain is common, as are lymphatic and large vessel invasion.
silent for some time. They may be quite large and most Less common morphologic variants of pancreatic cancer
are widely disseminated by the time they are discovered. include adenosquamous carcinomas, colloid carcinoma, hepa-
Pancreatic cancers often grow along nerves and invade  toid carcinoma, medullary carcinoma, signet-ring cell carcinoma,
into blood vessels and the retroperitoneum. They can directly undifferentiated carcinoma, and undifferentiated carcinoma with
invade the spleen, adrenals, transverse colon, and stomach. osteoclast-like giant cells.
Peripancreatic, gastric, mesenteric, omental, and portohepatic
lymph nodes are frequently involved. Distant metastases occur,
principally to the liver and lungs.
Clinical Features.  From the preceding discussion it should
Microscopically, there is no difference between carcinomas
be evident that carcinomas of the pancreas remain silent
of the head of the pancreas and those of the body and tail of
until they invade into adjacent structures. Pain is usually
the pancreas. The appearance is usually that of a moderately
the first symptom, but by the time pain appears these cancers
to poorly differentiated adenocarcinoma forming abor-
are usually beyond cure. Obstructive jaundice is associated
tive tubular structures or cell clusters and showing an
with most cases of carcinoma of the head of the pancreas,
aggressive, deeply infiltrative growth pattern (Fig. 19-13B).
but it rarely draws attention to the invasive cancer soon
The malignant glands are poorly formed and are usually lined
enough. Weight loss, anorexia, and generalized malaise and
by pleomorphic cuboidal-to-columnar epithelial cells. Well-
weakness tend to be signs of advanced disease. Migratory
differentiated carcinomas are the exception. As noted earlier, a
thrombophlebitis, known as the Trousseau sign, occurs in
characteristic feature of these cancers is that they elicit an
about 10% of patients and is attributable to the elaboration
intense desmoplastic reaction with dense stromal fibrosis. The
of platelet-activating factors and procoagulants from the
 Suggested readings 895

carcinoma or its necrotic products (Chapter 4). On a sad

note, Armand Trousseau (1801-1867, physician at Hotel
Dieu, Paris), for whom this sign is named, correctly sus-
pected that he had carcinoma when he developed spontane-
ously appearing and disappearing (migratory) thromboses.
The course of pancreatic carcinoma is typically brief and
progressive. Despite the tendency of lesions of the head of
the pancreas to obstruct the biliary system, fewer than 20%
of pancreatic cancers overall are resectable at the time of
diagnosis. Most have invaded vessels and other structures
that cannot be removed surgically, or have metastasized to
distant organs. There has long been a search for tests that
could be useful in the early detection of pancreatic cancer.
Serum levels of several antigens (e.g., carcinoembryonic
antigen and CA19-9 antigen) are often elevated in
individuals with pancreatic cancer. These markers, while
useful in following an individual patient’s response to
treatment, are relatively nonspecific and also lack the sen-
sitivity needed to be used as tests to screen the wider popu-
lation. Several imaging techniques, such as endoscopic
ultrasonography and computed tomography, have proved
of great value in establishing the diagnosis once it is sus-
pected, but are also not useful as screening tests.

  KEY CONCEPTS
■ Cigarette smoking is the leading preventable cause of pan-
creatic cancer.
■ Pancreatic cancer is one of the most aggressive of the

solid malignancies.
■ Many invasive pancreatic cancer arises from histologically

well-defined precursor lesions called pancreatic intraepi-

thelial neoplasia (PanIN).
■ Ductal adenocarcinomas elicit an intense desmoplastic

response.
■ The genes most frequently mutated or otherwise altered in

pancreatic cancer include KRAS, p16/CDKN2A, TP53, and

SMAD4
■ Clinically, most patients present with abdominal pain and

weight loss, sometimes accompanied by jaundice and

deep vein thrombosis, and succumb to the disease within
1 to 2 years.

Acinar Cell Carcinoma

Like normal acinar cells, acinar cell carcinomas form
zymogen granules and produce exocrine enzymes such as
trypsin and lipase. Fifteen percent of individuals with
acinar cell carcinoma develop the syndrome of metastatic
fat necrosis caused by the release of lipase into the
circulation.

Pancreatoblastoma
Pancreatoblastomas are rare neoplasms that occur primar-
ily in children aged 1 to 15 years. They have a distinct
microscopic appearance consisting of squamous islands
admixed with acinar cells. They are malignant neoplasms,
but survival is better with these tumors than it is for pan-
creatic ductal adenocarcinomas.