A Potpourri of Small Intestinal

Neoplasms

Elizabeth Montgomery
 Objectives
To discuss common neoplasms of the small
bowel.
To review non-neoplastic lesions that can
mimic neoplasia
To review mast cell disorders and how they
affect the gastrointestinal tract.
To discuss some rare neoplasms to always
consider.
 Diagnosis???
Anyone want a special stain?
 Duodenal Well-differentiated
Neuroendocrine Tumors
(Carcinoids)

Can be easily missed and mistaken for

inflammation
Chromogranin stain
Chromogranin stain
A special variant of duodenal
neuroendocrine tumor

Somatostatinoma in patients with

neurofibromatosis (NF1)
Endocrine neoplasm in
NF1 patient - Duodenum
Duodenal “somatostatinoma” in NF
Psammoma-like calcifications
 Somatostatinoma on biopsy – Pitfall
is tubule formation and atypia

Dayal Y, Doos WG, O'Brien MJ, Nunnemacher G, DeLellis RA, Wolfe HJ. Psammomatous
somatostatinomas of the duodenum. Am J Surg Pathol. 1983 Oct;7(7):653-65.
Easy NET (carcinoid) – the very prominent endocrine
granules are a feature of ileal lesions
Zollinger-Ellison from a small bowel
viewpoint
 MEN-1
Gene: Tumor suppressor gene on
chromosome 11 (11q13)
Pituitary: Prolactinomas, mass effect
Parathyroid: Hyperparathyroidism,
nephrolithiasis
Pancreas-duodenum: Multicentric,
gastrinomas, ulcers (PanNETs are leading
cause of death)
 Gastrin Glucagon Insulin PP Somatostatin Unclassified

Ln metas

Endocrine tumors

> 5 mm

< 5 mm - 1 mm

< 1 mm - 0.5mm

Klöppel et al, < 0.5 mm

Am J Surg Pathol. 2008 Jul;32(7):1101-5.

Klöppel et al,
Am J Surg Pathol. 2008
Jul;32(7):1101-5
Gastrin
Pyloric Gland Adenoma

Small bowel
Brunner
glands
indicated
Let’s compare the duodenal
pyloric gland adenoma to a
duodenal tubular or
tubulovillous adenoma
 Reactive or neoplastic?
The mucin can be a clue
Reactive or neoplastic? The gastric
mucin can be a clue for reactive
Reactive or neoplastic? The
gastric mucin can be a clue
for reactive
Regular old
duodenal
adenoma
with lipid
“hang-up”
Regular old duodenal
adenoma with lipid
“hang-up” – PAS/AB
stain – note that the
material in the
cytoplasm is lipid not
mucin
Real or
Fake?
Metaplasia goes for fake
 Traditional Serrated Adenoma of Small Bowel

Seem to exist – more common than we have

noticed
Similar molecular profile to that of colorectal
lesions
Sporadic and FAP-associated
Rosty C, Campbell C, Clendenning M, Bettington M, Buchanan DD, Brown IS. Do
serrated neoplasms of the small intestine represent a distinct entity? Pathological findings
and molecular alterations in a series of 13 cases. Histopathology. 2015 Feb;66(3):333-
42.

Alruwaii ZI, Chianchiano P, Larman T, Wilentz A, Wood LD, Montgomery EA. Familial
Adenomatous Polyposis-associated Traditional Serrated Adenoma of the Small Intestine:
A Clinicopathologic and Molecular Analysis. Am J Surg Pathol. 2021 Dec 1;45(12):1626-
1632. PMID: 34232600.
Small
bowel
TSA
Small
bowel
TSA
 Adenoma or Reactive
Most cases can be resolved
If you do not know, do not pretend.
A diagnosis of ampullary adenoma can
prompt a Whipple operation – a bad thing if
the biopsy is only reactive
Report the case as “indefinite for adenoma”
– it is not so difficult to resample the area
 ?????? –
adenoma???? – do
not be afraid to
report as “indefinite”
 Ampullary “Mass”
An endoscopist saw a polyp in the
duodenum and performed a polypectomy
He thought the polyp was very firm and told
the pathologist that the pathologist should
diagnose cancer
Normal
ampulla
Small intestinal Biliary

Ampulla
 Ampulla
Ampulla itself is often a source of difficulty
since normal to have ampullary glands are
interspersed with disorganized bundles of
smooth muscle.
When inflammation is a feature, great
caution is advised. The ampulla is not
typically biopsied without a compelling
reason since pancreatitis may be a severe
consequence of performing such biopsies.
Ampullary
biopsy
Ampullary Surface
– No goblet cells
 Small Bowel Adenocarcinomas
Adenocarcinomas are the most common primary
malignancies of the small intestine (30-50% of
small bowel malignancies).
However, primary adenocarcinomas are still rare
lesions accounting 2% of gastrointestinal (GI tract)
tumors for 1% of GI tract cancer deaths.
Older adults (median 67 years), male
predominance, more common in African
Americans than Caucasians.
Sporadic ileal
adenocarcinoma
 Small Bowel Adenocarcinomas
Majority sporadic and share with sporadic
colorectal adenocarcinomas both clinical risk
factors and development from adenomatous
polyps.
Remaining minority syndromic - polyposis
syndromes (primarily familial adenomatous
polyposis [FAP] but also hereditary nonpolyposis
colon carcinoma syndrome (HNPCC, Lynch
syndrome), Peutz-Jeghers’ syndrome, and juvenile
polyposis syndrome), Crohn’s disease, gluten-
sensitive enteropathy, ileostomy, and ileal
conduits.
Small bowel adenocarcinoma in a patient
with familial adenomatous polyposis/FAP
Carcinoma
associated
with Peutz-
Jeghers
syndrome
Carcinoma associated with Peutz-
Jeghers syndrome
 Interesting Lynch Syndrome Variant
Small bowel adenomas and carcinomas are
a feature of Lynch syndrome
Biallelic mismatch repair deficiency
syndrome/constitutional mismatch repair
deficiency
Tends to be found in populations with
consanguity
Small Bowel Adenocarcinomas
Greatest risk of small intestinal
adenocarcinomas with FAP.
Relative risk of duodenal adenocarcinoma is
striking (relative risk, about 330)
Ampullary adenocarcinoma (relative risk,
about 124).
Risk of small intestinal adenocarcinoma in
Crohn’s disease and celiac disease are
each about 50-100 fold.
 Small Bowel Adenocarcinomas
Most common in the duodenum, with 65 percent
periampullary, prevalence decreases progressively
through the rest of the small intestine.
Important exception to the proximal location
Crohn's disease - 70 percent of adenocarcinomas
are ileal, corresponding to the primary site of the
inflammatory process in this disease.
Small Bowel Adenocarcinomas
Main differential diagnosis - metastatic
disease- small intestine is the most common
GI site for metastatic disease.
*******Metastases outnumber primary
adenocarcinoma by 2 fold.
KY Bilimoria, DJ Bentrem, JD Wayne, CY Ko, CL Bennett, MS Talamonti. Small bowel cancer in the United
States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg, 249 (1) (2009),
pp. 63-71

G Disibio, SW French Metastatic patterns of cancers: results from a large autopsy study. Arch Pathol Lab
Med, 132 (6) (2008), pp. 931-939.

SC Kadakia, A Parker, L Canales Metastatic tumors to the upper gastrointestinal tract: endoscopic
experience. Am J Gastroenterol, 87 (10) (1992), pp. 1418-1423
Features Favoring Metastasis/Direct Spread

1. The presence of multiple lesions

2. The absence of a precursor adenoma
3. A histologic appearance of tumor being “bottom
heavy” or encroaching from below
4. Lack of ulceration.

Bellizzi AM, Montgomery EA, Hornick JL. American Registry of Pathology Expert
Opinions: Evaluation of poorly differentiated malignant neoplasms on limited samples -
Gastrointestinal mucosal biopsies. Ann Diagn Pathol. 2020;44:151419.
 Sarcomatoid
carcinoma
involving small
bowel mucosa
 Sarcomatoid
carcinoma involving
small bowel mucosa
Keratin Cam
5.2
Colon carcinoma colonizing small bowel
Colon cancer colonizing small bowel
CK7
CK20 –
SATB2 is
similarly
helpful
Unauthorized glands in ampulla
Pancreas cancer
spread to ampulla
 Small Bowel Adenocarcinomas,
Immunohistochemistry
We have found DPC4 (smad4)
antibodies helpful in identifying some
cases of pancreatic carcinomas since
about 60% of pancreatic carcinomas
show loss of this marker in their nuclei
whereas this is relatively uncommon in
colorectal and small intestinal
adenocarcinomas.
SMAD4/
DPC4
 This
metastatic
melanoma is
very easy to
diagnose
 But
please
always
check
lacteals
Is this a carcinoid (neuroendocrine tumor)?
Melan-A
If you check lacteals, you
will not miss this
metastatic breast cancer
Pancreatic ductal
carcinoma “colonizing”
the duodenum
Pancreatic ductal
carcinoma “colonizing”
the duodenum
Pancreatic ductal
carcinoma “colonizing”
the duodenum
Pancreatic ductal
carcinoma “colonizing” the
duodenum, CDX2 staining
Pancreatic ductal
carcinoma “colonizing” the
duodenum, CDX2 staining
Mucinous neoplasms on duodenal
biopsies
You CANNOT tell if they are
pancreatobiliary CARCINOMAs or
“mucinous neoplasms” extending onto the
duodenal surface and you should not try or
you will be wrong sometimes
Your report should express the need to
correlate with imaging – similar operations
will be performed as long as the surgeon
has a neoplastic diagnosis!
Ampullary biopsy;
mucinous neoplasm
 The Joy of Mast Cells
“Mastocytic enterocolitis”
Systemic mastocytosis
Mast cell activation syndrome

A little knowledge is a dangerous thing

 Mastocytic Enterocolitis
First reported by Jakate et al
Jakate S, Demeo M, John R, Tobin M, Keshavarzian A. Mastocytic enterocolitis: increased mucosal
mast cells in chronic intractable diarrhea. Arch Pathol Lab Med. 2006 Mar;130(3):362-7. PubMed
PMID: 16519565.

Authors counted mast cells in patients with diarrhea

prominent irritable bowel syndrome and compared the
counts in patients without it and found counts greater than
20/hpf in many of the patients. The patients responded to
H1 and H2 receptor antagonists with or without mast cell
mediator release inhibitor . There were poor controls.\

This paper led to lots and lots of mast cell stains in normal
mucosa
 Mastocytic Enterocolitis
Has been essentially debunked
Best paper for this:
Doyle LA, Sepehr GJ, Hamilton MJ, Akin C, Castells MC, Hornick JL. A
clinicopathologic study of 24 cases of systemic mastocytosis involving
the gastrointestinal tract and assessment of mucosal mast cell density
in irritable bowel syndrome and asymptomatic patients. Am J Surg
Pathol. 2014 Jun;38(6):832-43. PubMed PMID: 24618605; PubMed
Central PMCID: PMC4086834.
We will circle back to these data.
What is Systemic Mastocytosis?
Clonal neoplastic proliferation of mast cells
that involves one or more organ systems.
Different subtypes recognized by distribution
of disease and clinical manifestations.
Most commonly involves the skin (urticaria
pigmentosa (UP), and much less commonly
telangiectasia macularis eruptiva perstans,
diffuse cutaneous mastocytosis, or solitary
mastocytoma.
 Systemic Mastocytosis,
Extracutaneous
Bone marrow is most frequently involved.
Gastrointestinal (GI) tract involvement is
increasingly recognized
Many patients with mastocytosis, even
without apparent GI involvement, have
significant GI symptoms, such as abdominal
pain, nausea, and diarrhea, thought in most
cases to be due to the release of mast cell
mediators such as histamine and
leukotrienes.
 GI Mastocytosis
In patients with involvement of the GI tract,
symptoms may also be due to direct
infiltration of the mucosa by mast cells, with
resultant malabsorption and/or enhanced
local effects of mediator release.
The frequency of GI symptoms in patients
with systemic mastocytosis (SM) is
estimated at 70% and in patients with UP
(without known GI involvement), 25%.
Normal colon, from
polyp screening patient
KIT stain
Normal
colon
Systemic
mastocytosis
Systemic
mastocytosis
Systemic mastocytosis – note
background eosinophils – definition
– aggregates of > 15 mast cells
Systemic
mastocytosis,
easy case
Systemic mastocytosis- top part of lamina
propria is too pale, bottom appears normal
Systemic mastocytosis, sneaky case – note the rinds of lesional cells cuffing the
basement membranes
Systemic
mastocytosis,
CD117/KIT
 What is Mast Cell Activation Syndrome?

Essentially these patients have activated

mast cells that are not neoplastic and have
the same symptoms as people with systemic
mastocytosis
Conditions such as chronic infections,
autoimmune conditions, physical urticarias,
and certain neoplasms may display release
of mast cell mediators, which can be defined
as “secondary mast cell activation”
 How is Mast Cell Activation Syndrome
Diagnosed

Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma
Rep. 2013 Feb;13(1):10-8. doi: 10.1007/s11882-012-0326-8. Review. PubMed PMID: 23212667; PubMed Central PMCID: PMC3545645.
 More recent guidelines
Also did not include GI biopsies:

Weiler CR, Austen KF, Akin C, et al. AAAAI

Mast Cell Disorders Committee Work Group
Report: Mast cell activation syndrome
(MCAS) diagnosis and management. J
Allergy Clin Immunol. 2019;144(4):883-896.
 Mast Cell Activation Syndrome
In a 2011 study of mast cell activation
syndrome (Hamilton et al), there was no
significant difference in the numbers of
intestinal mucosal mast cells between
affected patients and healthy control
subjects.
We avoid honoring requests for mast cell
counts in normal-appearing samples.
Doyle LA, Sepehr GJ, Hamilton MJ, Akin C, Castells MC, Hornick JL. A
clinicopathologic study of 24 cases of systemic mastocytosis involving the
gastrointestinal tract and assessment of mucosal mast cell density in
irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol.
2014 Jun;38(6):832-43. PMID: 24618605; PubMed Central PMCID:
PMC4086834.
 Two cautions
1.Johncilla M, Jessurun J, Brown I, et al. Are
Enterocolic Mucosal Mast Cell Aggregates
Clinically Relevant in Patients Without
Suspected or Established Systemic
Mastocytosis?. Am J Surg Pathol.
2018;42(10):1390-1395.
2. Hereditary Alpha-Tryptasemia can
produce mast cell clusters in the tips of villi
 Sample Note
NOTE: A CD117 immunostain shows a normal distribution and density of mast cells.
There are no features of systemic mastocytosis. So called "mastocytic enterocolitis" has
been called into question together with the utility of mast cell counts in histologically
unremarkable samples. We would also note that mast cell activation syndrome is not
diagnosed on GI biopsies but that some patients whose samples contain clusters of mast
cells can be shown to have hereditary Alpha-Tryptasemia.

Hamilton MJ, Zhao M, Giannetti MP, Weller E, Hufdhi R, Novak P, Mendoza-Alvarez LB, Hornick J, Lyons JJ, Glover SC, Castells MC,
Pozdnyakova O. Distinct Small Intestine Mast Cell Histologic Changes in Patients With Hereditary Alpha-tryptasemia and Mast Cell Activation
Syndrome. Am J Surg Pathol. 2021 Jul 1;45(7):997-1004. PMID: 33481382.

Weiler CR, Austen KF, Akin C, et al. AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS)
diagnosis and management. J Allergy Clin Immunol. 2019;144(4):883-896.

Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation syndrome: a newly recognized disorder with systemic
clinical manifestations. J Allergy Clin Immunol. 2011 Jul;128(1):147-152.e2. PubMed PMID: 21621255.

Doyle LA, Sepehr GJ, Hamilton MJ, Akin C, Castells MC, Hornick JL. A clinicopathologic study of 24 cases of systemic mastocytosis involving
the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg
Pathol. 2014 Jun;38(6):832-43. PubMed PMID: 24618605; PubMed Central PMCID: PMC4086834.
 Another Caution – My Dirty Laundry
A young male patient presented with
vomiting and a duodenal mass was biopsied
in about 2005
Small bowel biopsy from a
mass; 22 year old male
This is a pankeratin; the lesion
was CK7+, CK20-
 Report
“Poorly differentiated carcinoma involving
the small intestine. Please correlate with
imaging to address the possibility of other
disease sites”
 Long Delay Until Correct Diagnosis

This was an embryonal carcinoma

Another embryonal carcinoma that
even suggests an in situ component
Another young male patient
with duodenal mass

Had been reported as Ewing’s

sarcoma of the duodenum
 Case
Was diagnosed as Ewing’s/PNET based on
some CD99 labeling
CD117
SALL4
OCT4
 Lesson learned
This was a seminoma
A tiny testicular primary was detected on
ultrasound
 Small bowel
Remember that lesions from other sites
outnumber small bowel primary neoplasms
by 2 fold
Consider reparative lesions before
diagnosing adenomas
Thank you