SMALL INTESTINE

TUMOURS
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del corso Integrato Malattie dellapparato Gastroenterico e
Infettive.

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Achille PICH
Small intestine tumours
WHO Histological classification
Epithelial tumours
Benign
Malignant
Non-epithelial tumours
Benign
Malignant
Malignant lymphomas
Secondary tumours
Polyps
Adenoma
WHO histological classification
Epithelial tumours
Tubular
Villous
Tubulovillous
Intraepithelial neoplasia (dysplasia)
associated with chronic inflammatory diseases
- Low-grade glandular intraepithelial neoplasia
- High-grade glandular intraepithelial neoplasia
Carcinoma
Adenocarcinoma
Mucinous adenocarcinoma
Signet-ring cell carcinoma
Small cell carcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
Medullary carcinoma
Undifferentiated carcinoma
WHO histological classification
Epithelial tumours
Epithelial tumours
Carcinoid (well differentiated endocrine neoplasm)
Gastrin cell tumour, functioning
(gastrinoma) or non-functioning
Somatostatin cell tumour
EC-cell, serotonin-producing neoplasm
L-cell, glucagon-like peptide and
PP/PYY producing tumour
WHO histological classification
Epithelial tumours
Mixed carcinoid-adenocarcinoma
Gangliocytic paraganglioma
Others
WHO histological classification

Lipoma
Leiomyoma
Gastrointestinal stromal tumour
Leiomyosarcoma
Angiosarcoma
Kaposi sarcoma
Others
Non-epithelial tumours
WHO histological classification
Malignant Lymphomas
Immunoproliferative small intestine disease
(includes -heavy chain disease)
Western type B-cell lymphoma of MALT
Mantle cell lymphoma
Burkitt lymphoma
T-cell lymphoma
Others
- enteropathy associated
- unspecific
Diffuse large B-cell lymphoma
Burkitt-like / atypical Burkitt-lymphoma
WHO histological classification
Secondary tumours
Polyps
Hyperplastic (metaplastic)
Peutz-Jeghers
Juvenile
WHO histological classification
Adenoma
Small intestine tumours
WHO Histological classification
Epithelial tumours
Benign
Tubular
Villous
Tubulovillous
The frequency is minuscule.The duodenum and
jejunum are involved more often than the ileum.

They can be single or multiple, pedunculated or
sessile, and they have the microscopic appearance
of an adenomatous polyp (tubular adenoma),
villoglandular polyp (tubulovillous adenoma), or
villous adenoma.

Malignant transformation can occur in them; as
for their colorectal counterparts, the incidence of
this complication is greater if the lesions are
villous, large, or multiple.
Adenomas
Adenoma
Small intestine tumours
WHO Histological classification
Epithelial tumours
Benign
Tubular
Villous
Tubulovillous
Adenoma
Small intestine tumours
WHO Histological classification
Epithelial tumours
Benign
Tubular
Villous
Tubulovillous
Small intestine tumours
WHO Histological classification
Polyps
Hyperplastic (metaplastic)
Peutz-Jeghers
Juvenile
Small intestine tumours
WHO Histological classification
Polyps
Hyperplastic (metaplastic)
Peutz-Jeghers
Juvenile
Hamartomatous polyps of the jejunoileum are
usually seen as a component of the
Peutz-J eghers syndrome, a familial disorder
transmitted as a mendelian autosomal dominant
trait with variable degrees of penetrance.

Similar polyps can also be present in the
stomach, duodenum, and large bowel, and the
patients have a typical pigmentation of the lips,
oral mucosa, digits, palms, and soles.
Peutz-Jeghers
Several cases of gastrointestinal
adenocarcinoma have been reported in
patients with Peutz-Jeghers syndrome.
Patients with Peutz-Jeghers syndrome
may also develop the distinctive ovarian
neoplasm known as sexcord tumor with
annular tubules so-called adenoma malignum
of uterine cervix, ovarian mucinous tumors,
breast carcinoma (often bilateral), and other
types of malignancy.
Small intestine tumours
WHO Histological classification
Epithelial tumours
Malignant
Carcinoma
Adenocarcinoma
Mucinous adenocarcinoma
Signet-ring cell carcinoma
Small cell carcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
Medullary carcinoma
Undifferentiated carcinoma
Adenocarcinoma of the small bowel is forty to
sixty times less common than its counterpart in the
large bowel.
Most patients are elderly, without sex predilection.

It is more common in the upper portions (40% to
50% of the cases occur in the duodenum, mostly in
the region of the ampulla).

Adenocarcinomas of the small bowel can occur in the Lynch
syndrome II, or as a complication of Peutz-Jeghers syndrome and
Crohn's disease, in bowel duplication, at ileostomy sites, in surgically
bypassed duodenum, and in association with Recklinghausen's
disease.

ADENOCARCINOMA
Gross anatomy

Duodenal carcinoma tends to have a papillary
configuration.

Adenocarcinomas located more distally usually
have a napkin-ring appearance and produce partial
intestinal obstruction with marked dilatation of the
proximal bowel; however, about 20% have a
predominantly polypoid or fungating appearance,
perhaps caused in some instances by their origins in
pre-existing adenomatous polyps or villous
adenomas. Occasionally these carcinomas present
as multiple tumors or in association with primary
malignant neoplasms in other sites.
Microscopy

These tumors are usually moderately or well-
differentiated adenocarcinomas.
Mucin production and CEA reactivity are the rule;
there may also be immunoreactivity for lysozyme,
suggesting focal differentiation toward Paneth cells.
In addition, it is common to find scattered
endocrine cells, particularly in ileal tumors. These
cells are positive for chromogranin and serotonin
and may show immunoreactivity for somatostatin, YY
peptide, neurotensin, glucagon, and glycentin.
Ultrastructurally, there is a prominent development of
microvilli.
Prognosis


At the time of diagnosis, the majority of the
tumors have extended deeply into the wall and may
have already metastasized to regional lymph nodes.

The prognosis mainly depends on the presence
or absence of regional lymph node involvement. In
one series, 88% of the patients with positive nodes
died of tumors, contrasted with 45% of those with
negative nodes.
TNM Clinical Classification
TX
Primary tumour cannot be assessed
T0
Lamina propria, muscularis mucosae or submucosa
T1a Lamina propria or muscularis mucosae
T1b Submucosa
T2
Muscularis propria
T3
Tumour invades into subserosa or into non-
peritonealized perimuscular tissue for 2 cm or less
T4
Tumour perforates visceral peritoneum or directly
invades other organs or structures (loops of small
intestine, mesentery, retroperitoneum for more than
2 cm) or pancreas
T - Primary Tumour
No evidence of primary tumour
T1
Tis Carcinoma in situ
TNM Clinical Classification
N0 No regional lymph node metastasis
N1
Metastasis in 1-3 regional lymph nodes
M0 No distant metastasis
M1 Distant metastasis
N - Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed
M - Distant Metastasis
MX Distant metastasis cannot be assessed
N2 Metastasis in 4 or more regional lymph nodes
STAGE GROUPING
Stage I
Stage IIB
Stage IIIB
Stage IV
T1,T2
T3
T4
Any T
Any T
Any T
N0
N0
N0
N1
N2
Any N
M0
M0
M0
M0
M0
M1
Stage 0 Tis N0 M0
Stage IIA
Stage IIIA
Small intestine tumours
WHO Histological classification
Epithelial tumours
Malignant
Carcinoma
Adenocarcinoma
Mucinous adenocarcinoma
Signet-ring cell carcinoma
Small cell carcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
Medullary carcinoma
Undifferentiated carcinoma
Small cell carcinoma is a rare type of small bowel
malignancy composed of small, round, or oval cells of
scanty cytoplasm and hyperchromatic nucleus.
The appearance is very similar to that of pulmonary
small cell carcinoma. As in the latter, dense core
granules of neurosecretory type can be identified
ultrastructurally and neuroendocrine markers
immunohistochemically. These tumors can present in a
pure form or mixed with ordinary adenocarcinoma.
They are deeply invasive, highly prone to
metastasize, and associated with a very poor prognosis.
SMALL CELL CARCINOMA
Small intestine tumours
WHO Histological classification
Epithelial tumours
Malignant
Carcinoma
Adenocarcinoma
Mucinous adenocarcinoma
Signet-ring cell carcinoma
Small cell carcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
Medullary carcinoma
Undifferentiated carcinoma
Small intestine tumours
WHO Histological classification
Epithelial tumours
Malignant
Carcinoma
Adenocarcinoma
Mucinous adenocarcinoma
Signet-ring cell carcinoma
Small cell carcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
Medullary carcinoma
Undifferentiated carcinoma
Small intestine tumours
WHO Histological classification
Epithelial tumours
Malignant
Carcinoma
Adenocarcinoma
Mucinous adenocarcinoma
Signet-ring cell carcinoma
Small cell carcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
Medullary carcinoma
Undifferentiated carcinoma
Small intestine tumours
WHO Histological classification
Epithelial tumours
Carcinoid (well differentiated endocrine neoplasm)
Gastrin cell tumour, functioning
(gastrinoma) or non-functioning
Somatostatin cell tumour
EC-cell, serotonin-producing neoplasm
L-cell, glucagon-like peptide and
PP/PYY producing tumour
CARCINOID
Carcinoid tumor is the generic term applied to low-
grade malignant neoplasms originating from the diffuse
endocrine system outside of the pancreas and the thyroid
C-cell.
They represent a group of neoplasms rather than a
single pathologic entity, as the digestive tract in general
and the small bowel in particular contain a large number
of endocrine types, any of which can be represented in
these neoplasms, singly or in combination.
Carcinoid tumor comprises about one third of all
neoplasms of the small bowel.
The majority occur in adults. Most are located
in the ileum (including Meckel's diverticulum),
followed in frequency by the jejunum and distal
duodenum. They are multiple in 15% to 35% of the
cases and are sometimes associated with malignant
gastrointestinal tumors of other microscopic types
or with tumors of endocrine differentiation in other
locations.
Grossly, they appear as nodules protruding
through the ileal mucosa.
Microscopically, the pattern is that of solid
masses of monotonous cells with small, round
nuclei; a moderate amount of finely granular
cytoplasm; and fine nucleoli. The mucosa is often
intact over the tumor. Infiltration of the submucosa
is the rule, and extension into the muscularis
externa is common.
Microscopic types
Based on their patterns of growth, carcinoid tumors may
be subdivided into several types:
A = insular (the most common form)
B = trabecular
C = glandular
D = undifferentiated
E = mixed
The various types correlate with behavioral differences.
Carcinoid tumors with a predominantly glandular pattern
are referred to as adenocarcinoids. On occasion, features
of endocrine and exocrine secretion can be seen in the
same cell (so-called amphicrine cell).
At the histochemical level, the tumor is argentaffin
(and therefore also argyrophilic).
Ultrastructurally, there are numerous dense-core
secretory granules.
Immunohistochemically, there is both epithelial and
neuroendocrine differentiation. The first is manifested by
keratin and CEA; the second by a series of "pan-endocrine"
markers, such as neuron-specific enolase, chromogranin,
synaptophysin, Leu7, PGP 9.5, and serotonin.
A variety of peptide hormones has also been
demonstrated in these tumors: substance P (the most
common), gastrin, somatostatin, glucagon, glycentin,
pancreatic polypeptide, bombesin, gastrin-releasing
peptide (GRP), and growth hormonereleasing factor (GRF).
Aneuploidy is present in over half of the ileal carcinoid
tumors.
SPREAD AND METASTASIS
Classic carcinoids are low-grade malignant neoplasms,
with a slow growth rate, but also are highly invasive and
can metastatize. Metastases occur most commonly in the
regional lymph nodes and liver (usually multiple), but also
in bone, skin, and thyroid.
TREATMENT AND PROGNOSIS
The primary treatment of carcinoid is wide surgical
removal of the primary tumor and its lymphatic drainage,
even in the presence of extensive liver metastasis. Solitary
liver metastases are also amenable to surgical excision.
The 5-year OS is between 50% and 65%, with a marked
difference between the tumors confined to the wall (85%
OS) and those invading the serosa or beyond (5% OS).
Large tumor size and CEA expression correlate with a more
aggressive course.
ASPETTI CLINICI DELLA SINDROME DA
CARCINOIDE
1. Disturbi vasomotori
Flushes cutanei e cianosi evidente (nella maggior parte dei pazienti)
2. Ipermotilit intestinale
Diarrea, crampi, nausea, vomito (nella maggior parte dei pazienti)
3. Attacchi asmatici broncocostrittivi
Tosse, sibili, dispnea (in un terzo dei pazienti)
4. Epatomegalia
nodulare, correlata a metastasi epatiche (in alcuni pazienti)
5. Fibrosi sistemica

Interessamento cardiaco
Ispessimento e stenosi valvolare tricuspidale e polmonare
Fibrosi endocardiaca, principalmente nel ventricolo destro
(nei carcinoidi bronchiali interessato quello sinistro)
Fibrosi retroperitoneale e pelvica
Placche collagene della pleura e dellintima
dellaorta
DUODENAL ENDOCRINE TUMOURS
Endoscopically, duodenal endocrine tumors appear as
smooth, round elevations, usually measuring between 5 and
20 mm in diameter.
Microscopically, they rarely have the features of classic
carcinoids. Many are composed of either G- or D-cells, as
demonstrated by their immunoreactivity for gastrin and
somatostatin, respectively. The G-cell tumors (gastrinomas)
may be associated with the Zollinger-Ellison syndrome and
MEN type I, whereas D-cell tumors (somatostatinomas) are
hormonally silent at the clinical level. Exceptionally,
duodenal endocrine tumors are of pancreatic B-cell type.
Metastases were present in 21% of the duodenal
endocrine tumors.
Small intestine tumours
WHO Histological classification
Epithelial tumours
Mixed carcinoid-adenocarcinoma
Gangliocytic paraganglioma
Others
GANGLIOCYTIC PARAGANGLIOMA
Gangliocytic paraganglioma (nonchromaffin
paraganglioma; paraganglioneuroma) occurs almost
exclusively in the second portion of the duodenum,
especially in the proximity of the ampulla of Vater.
The peculiar location of this tumor, its highly organoid
arrangement, and the striking predominance of PP cells
suggest that this lesion may represent a hamartomatous
process derived from the ventral primordium of the
pancreas.
Nearly all cases published so far have followed a benign
clinical course, but isolated instances associated with
lymph node metastases are on record.

Grossly, most lesions are small, pedunculated, and
submucosal, with frequent ulceration of the overlying
mucosa and bleeding.
Microscopically, three cell components are present:
(1) endocrine cells with a carcinoid-like appearance,
containing dense-core granules ultrastructurally and
exhibiting immunoreactivity for a variety of markers,
particularly pancreatic polypeptide (PP);
(2) isolated ganglion cells, immunoreactive for neuron-
specific enolase (NSE) and other neural markers; and
(3) spindle-shaped Schwann cells and/or sustentacular
cells, immunoreactive for S-100 protein.
Lipoma
Non-epithelial tumours
Small intestine tumours
WHO Histological classification

Leiomyoma
Gastrointestinal stromal tumour
Leiomyosarcoma
Angiosarcoma
Kaposi sarcoma
Others

Lipoma

Gastrointestinal stromal tumour
Leiomyosarcoma
Angiosarcoma
Kaposi sarcoma
Others
Non-epithelial tumours
Small intestine tumours
WHO Histological classification
Leiomyoma

Lipoma
Leiomyoma
Gastrointestinal stromal tumour

Angiosarcoma
Kaposi sarcoma
Others
Non-epithelial tumours
Small intestine tumours
WHO Histological classification
Leiomyosarcoma
Small intestine tumours
WHO Histological classification
Malignant Lymphomas
Immunoproliferative small intestine disease
(includes -heavy chain disease)
Western type B-cell lymphoma of MALT
Mantle cell lymphoma
Burkitt lymphoma
T-cell lymphoma
Others
enteropathy associated
unspecific
Diffuse large B-cell lymphoma
Burkitt-like / atypical Burkitt-lymphoma
Immunoproliferative small intestine
disease (includes -heavy chain disease)
Immunoproliferative small intestinal disease (IPSID),
Mediterranean lymphoma, and Middle Eastern lymphoma
is a B-cell lymphoma relatively common among non-
European Jews, Arabs in the Middle East, and the black
population of South Africa.
Patients often have a short history of diarrhea and
malabsorption, but the mucosa is not completely flat in
most cases.
The involvement centers in the distal portions of the
duodenum and the upper jejunum.
Microscopy
The low-grade form (by far the most common) shows a
heavy mature or only slightly immature lymphoplasmacytic
infiltration. This is associated with the presence of
monoclonal alpha heavy chains of immuno-globulins in
their cytoplasm, as well as in the serum and urine, hence
the alternate designation alpha chain disease.
It has been speculated that this lymphoplasmacytic
infiltration is originally reactive in nature and represents a
response to a continuous antigenic stimulus of possible
infectious nature (some cases respond to tetracycline).
The high-grade form of the disease, which is usually
preceded and accompanied by the low-grade form, shows
microscopic appearance of highly pleomorphic large cell
lymphoma.
The MALT concept
Mucosa-associated lymphoid tissue (MALT) is the
term proposed by Isaacson et al. for the component of
the immune system that has evolved to protect the
freely permeable surface of the gastrointestinal tract
and other mucosal membranes directly exposed to the
external environment.
This comprises lymphoid nodules (which in the
ileum form the Peyer's patches), lymphocytes and
plasma cells in the lamina propria, and intraepithelial
lymphocytes.
The lymphomas arising from it ("MALTomas") have
propensity to involve other mucosal sites, which has
been explained by the normal homing pattern of MALT
lymphocytes.
Western type B-cell lymphoma
of MALT
Represent most of B-cell lymphomas of the small bowel.
The low-grade form is not as common as it is in the
stomach. Its gross, microscopic, and immunohisto-
chemical features are similar to those of its gastric
counterpart. The key features are the predominance of
small lymphoid cells (either centrocyte-like or
monocytoid B cells), the formation of lymphoepithelial
lesions, and the presence of reactive follicles.
The high-grade form of this tumor may be seen in
association with the low-grade form or in its absence.
This is a large cell lymphoma of large cell type, often
associated with plasmacytoid forms.
Mantle cell lymphoma
MCL is a B-cell lymphoma that tipically involves both
spleen and intestine and may present as an isolated mass
or multiple polyps (multiple lymphomatous polyposis).
The polyps range in size from 0.5 to 2 cm. The
architecture is most frequently diffuse, but a nodular and
a less common true mantle-zone pattern are also seen.
The lymphoma cells are small to medium sized. They
are mature B-cells and express both CD19 and CD20, with
the characteristic coexpression of CD5 and CD43. Bcl-1
(cyclin D1) is found in virtually all cases within the nuclei.
MCL is an aggressive lymphoma, which typically
presents in advanced stage.
Burkitt lymphoma
Burkitt lymphoma occurs in two major forms.
1) Endemic Burkitt is found primarily in Africa and
typically presents in the jaw, orbit or paraspinal region, and is
strongly associated with Epstein-Barr virus (EBV).
In other endemic regions however, it is relatively common for
Burkitt lymphoma to present in the small intestine, usually
involving the ileum, with preferential localization to the ileo-
caecal region. In parts of the Middle East, primary gastro-
intestinal Burkitt lymphoma is a common disease of children.
2) Sporadic or non-endemic Burkitt lymphoma is a rare
disease, not associated with EBV infection, that frequently
presents as primary intestinal lymphoma. Burkitt lymphoma
is also seen in the setting of HIV infection when it often
involves the gastrointestinal tract.
The histology in all cases is identical and is characterized
by a diffuse infiltrate of medium-sized cells with round to
oval nuclear outlines, 2-5 small but distinct nucleoli and a
small amount of intensely basophilic cytoplasm. Numerous
mitotic figures and apoptotic cells are present.

The prominent starry-sky appearance is caused by benign
phagocytic histiocytes engulfing the nuclear debris resulting
from apoptosis.
It is a mature B-cell lymphoma and the neoplastic
cells express pan-B-cell antigens CD19, CD20, CD22, and
CD79. In approximately 60-80% of cases, the neoplastic
cells co-express CD10, but fail to express CD5 or CD23.
Surface immunoglobulin expression is moderately intense
and is nearly always IgM with either kappa or lambda light
chain restriction.
The growth fraction, as assessed by Ki-67 or the
paraffin equivalent MIB-1, is typically in excess of 90% of
tumour cells. Burkitt lymphoma cells uniformly fail to
express bcl-2.
Burkitt-like lymphomas with dual translocation of
both bcl-2 and c-myc oncogenes have a markedly
shortened overall survival.
Prognostic factors

The main determinants of clinical outcome in small
intestinal lymphomas are histological grade, stage, and
resectability.
Advanced age at diagnosis, an acute presentation with
perforation, and the presence of multifocal tumours have
an adverse impact on survival.
The behaviour of diffuse large B-cell lymphoma is not
affected by the presence of a low-grade MALT component.
The expression of bcl-2 protein and the presence of TP53
mutations may adversely affect outcome in this group, but a
systematic study of small intestinal lymphomas is lacking.
T-cell malignant lymphomas are rare (5% of all GI
lymphomas); they represent, in most instances, a compli-
cation of long-standing celiac sprue or related
malabsorption syndrome. These are called enteropathy-
associated T-cell lymphomas. T-cell lymphomas not
associated with malabsorption also occur.
The affected bowel is often dilated and oedematous,
and shows multiple circumferential ulcers.
The histological appearences are variable, the most
frequent type is composed of highly pleomorphic, medium
to large cells, followed by a type that shows a morphology
most consistent with anaplastic large cell lymphoma.
T- cell lymphoma
Prognosis and predictive factors

The clinical course is very unfavorable due to complications
from peritonitis and malnutrition and later from progressive
disease typically characterized by intestinal recurrences.
The malabsorption due to underlying coeliac disease is
detrimental to these patients, particularly when recovering
from surgery or receiving multiagent chemotherapy.
Consequently, only one half of the patients is amenable to
chemotherapy and only a proportion of these is able to
finish the complete course.
The overall median survival is only 3 months, and 5-year
survival ranges from 8-25%. The small group of long-term
survivors usually received chemotherapy and none had a
previous diagnosis of coeliac disease.
Small intestine tumours
WHO Histological classification
Secondary tumours
Metastatic tumors can involve the small
bowel, often in the form of multiple polypoid
tumors. The lesions may result in obstruction or
perforation, necessitating palliative resection.



The most common types of primary tumor
are malignant melanoma, carcinoma from lung
and breast, and choriocarcinoma