Could It Be a Neuroendocrine Tumor (NET)?

Could It Be a
Neuroendocrine Tumor (NET)?
Detecting the Differences,
Connecting the Clues
CELEBRATING
YEA R S
Committed to improving
knowledge and care in NETs
Contents
Introduction and Background
1
Common Manifestations of Carcinoid Syndrome
6
Focus on Diarrhea
9
Focus on Abdominal Pain
13
Focus on Flushing
15
Focus on Cardiac Disease
17
Other Symptoms and Manifestations
19
Diagnostics and Imaging
21
Expert Advisor Panel
24
References
24
There is limited published information on the differential
diagnosis of neuroendocrine tumors. Therefore, some of the
information in this brochure is based on expert opinion and
should be considered as background information only.
Introduction
and Background
6.00
600
Incidence of all malignant neoplasms
Incidence of neuroendocrine neoplasms
5.00
500
4.00
400
3.00
300
2.00
200
1.00
100
SEER9
SEER13
SEER17
0
04
20
00
20
95
19
90
19
85
19
19
19
80
73
75
0
19
Incidence per 100,000 for All Malignant Neoplasms
Incidence per 100,000 for Neuroendocrine Neoplasms
Introduction and Background
Year
Figure 1. Incidence has increased 5-fold from 1973-2004.1
Adapted with permission. ©American Society of Clinical Oncology. All rights reserved.
Yao JC et al. J Clin Cncol. 2008;26(18):3065.
1,200,000
1,100,000
103,312
Cases
65,836
Cases
32,353
Cases
28,664
Cases
21,427
Cases
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Neuroendocrine tumors (NETs) belong to the family
of neuroendocrine neoplasms that arise from dispersed
neuroendocrine cells found throughout the body.1
NETs commonly can be divided into 3 groups:
pancreatic neuroendocrine tumors (also known as
pancreatic islet cell tumors), NETs that arise from
the gastrointestinal (GI) tract (excluding the pancreas),
and NETs that arise from the bronchopulmonary system
(please refer to footnote).
The highest occurrence of NETs is in the GI tract
(67.5%) and the bronchopulmonary system
(25.3%). Within the GI tract, most NETs occur in
the small intestine (41.8%), rectum (27.4%), and
stomach (8.7%).2
NETs have the ability to secrete hormones and
peptides; depending on the secretory products,
different clinical syndromes can occur.3 Most NETs,
like other solid neoplasms, are clinically silent, eliciting
symptoms only as a consequence of tumor growth.
Incidence
1,141,407
Cases
100,000
Neuroendocrine Tumors
Figure 2. Neuroendocrine neoplasms are more common than
many GI malignancies.1,5
Source: Surveillance, Epidemiology, and End Results (SEER) data (1973-2004).
Yao JC et al. J Clin Oncol. 2008;26(18):3064.
Data from the Surveillance, Epidemiology, and End
Results (SEER) Program indicate that the diagnosed
incidence of all neuroendocrine neoplasms has
increased dramatically, with a 5-fold increase observed
in a 30-year period (1973-2004) (Figure 1).1 However,
the exact reasons for the increase remain unclear.
The trend in the incidence of these malignancies is
predicted to continue to rise.4
Prevalence
As of 2004, more than 100,000 people were suffering
with NETs, making them more common than many
other GI malignancies. In fact, the prevalence of NETs
exceeds that of stomach and pancreatic cancers
combined (Figure 2).1,5
This brochure uses the nomenclature established in the 2010 WHO Classification of Tumours of the Digestive System to classify different types of neuroendocrine neoplasms.6
The WHO naming convention categorizes these neoplasms into 2 groups:
• Well-differentiated grade 1 (G1) or grade 2 (G2) neuroendocrine tumors (NETs)
• Poorly differentiated grade 3 (G3) neuroendocrine carcinomas
The 2010 WHO guidelines also refer to a G1 NET as a “carcinoid,” although this term is still often used to denote a neoplasm of any grade that usually originates in the GI tract
as opposed to the pancreas.6,7
1
Introduction and Background (cont)
Most NETs
Classification
associated with
Neuroendocrine neoplasms can be classified by1:
carcinoid syndrome
• Embryonic site of origin (Figure 3)
originate in
• Histology – well-differentiated (G1 and G2) NETs, poorly differentiated (G3)
carcinomas, or undifferentiated neoplasms
the midgut.8
• Extent of disease – local, regional, and distant (metastatic) (Figure 4)
Other NETs
• Lungs
• Stomach
• First part of
duodenum
Pancreatic NETs
• Gastrinoma
• Insulinoma
• Glucagonoma
• Somatostatinoma
• VIPoma
• Pancreatic
polypeptidoma
• Second part of
duodenum
• Jejunum
• Ileum
• Right colon
• Transverse, left,
sigmoid colon
• Rectum
Figure 3. Classification of NETs by embryonic origin.9,10
Figure 4. Differing extent of
disease in NETs shown by
computed tomography.
Local
Regional
Distant
Local disease: an isolated single focus of primary
NET in the small bowel (solid red arrow); regional
disease: a primary NET in the small bowel (solid red
arrow) with mesenteric spread (dashed red arrow);
distant disease: a primary NET in the small bowel
(solid red arrow) with mesenteric spread (dashed red
arrows) and liver metastasis (arrow head).
Images kindly provided by Dr James Yao (2008).
2
“I have often seen
Diagnosis and Prognosis
The diagnosis of NETs is often delayed (up to 5-7 years on average from onset
of symptoms), at which time the probability of metastatic disease is increased.11
The SEER database (1973-2004) indicates that 9% of tumors of the rectum have
metastasized at the time of diagnosis compared to 71% of tumors of the jejunum/
ileum (Figure 5). The data also show that 50% of NETs present with regional or
distant metastases at the time of diagnosis.1
patients who have been
labeled as having IBS,
IBD, menopause, or
even neuropsychiatric
disorders for quite a while
Extent of Disease (%)
before they finally get the
”
correct diagnosis.
Dr David C Metz
100
90
80
70
60
50
40
30
20
10
0
“NETs are cancers which
71%
92%
49%
29%
Rectum
Localized
Lung
Jejunum/Ileum
Regional
Distant
Figure 5. Disease extent on diagnosis of NETs varies according to site.
”
detected and treated early.
Dr Alexandria Phan
51%
Selected Sites of Location
can have a dramatically
improved prognosis if
9%
Adapted from Yao JC et al (selected sites with incidence >0.5 per 100,000).1
The median age of diagnosis for NETs of the rectum is 56 years, for NETs
of the lung is 64 years, and for NETs of the jejunum/ileum is 66 years.1
As with other malignant neoplasms, prognosis differs depending on histology
and disease extent. Reported 5-year survival rates range from 4% to 82%
(Table 1); the poorest prognosis is in poorly differentiated carcinomas with
metastatic disease.1 Urinary 5-hydroxyindoleacetic acid (5-HIAA) levels
≥150 mg/24 hours are associated with a median survival of less than 1 year.12
Table 1. Median duration of survival and 5-year survival rates decrease with the
degree of tumor differentiation and extent of disease.1
Local Disease
Regional Disease
Distant Disease
Survival duration, months
223
111
33
5-year survival, %
82
68
35
Survival duration, months
34
14
5
5-year survival, %
38
21
4
Well-differentiated NETs
Poorly differentiated neuroendocrine carcinomas
3
Introduction and Background (cont)
The 5-year survival
rates for NETs vary
depending on the site
and extent of disease.4
Overall, patients with grade 1 or grade 2 NETs with distant metastases have a
median survival of 33 months, and the 5-year survival probability for these patients
is only 35%.*1 However, the 5-year survival probability for certain NET patients
(grade 1 or grade 2) with distant metastases can be even worse – NET colon: 14%,
NET lung or pancreas: 27%.†1
*5-year survival probability based on patients diagnosed from 1973 to 2004.
†
5-year survival probability based on patients diagnosed from 1988 to 2004.
Carcinoid-related heart failure is the cause of death in approximately half of patients
with certain types of metastatic GI NETs. According to one hospital study of
121 patients with midgut NETs, other causes of death include cachexia (malnutrition,
dehydration, weight loss), liver insufficiency, pulmonary infection, and kidney failure.13
Symptoms
NETs can secrete hormones and peptides that may cause distinct clinical
syndromes, such as carcinoid syndrome. At least 13 gut neuroendocrine cells
exist, all of which secrete bioactive peptides or amines.11
Secretory tumors often do not produce noticeable symptoms, as the metabolic
products released are efficiently metabolized by the liver.14 However, when secreting
tumors metastasize to the liver (the most common site of metastasis;
see Figure 6), substances are released directly into systemic circulation,
circumventing hepatic metabolism.15
Carcinoid Syndrome
arcinoid syndrome is the primary clinical manifestation of NETs, occurring
C
in 8% to 35% of patients.15 Carcinoid syndrome is frequently associated
with neoplasms of the midgut, as these are the most common and
frequently metastasize.8
Carcinoid syndrome is caused by neurohormonal products released by the neoplasm,
including serotonin, corticotropin, histamine, dopamine, substance P, neurotensin,
prostaglandin, kallikrein, and tachykinin.14
150
135
Cases (N=146)
120
90
71
60
35
30
35
34
16
15
12
5
3
3
3
1
Liv
Re Mes er
tro en
pe ter
rit
y
on
eu
m
Pe Bon
rit e
on
eu
m
Ov
ar
y
Su Tho
pr ra
ac x
lav
icl
e
Re Sk
tro in
-o
rb
Ep ital
ica
rd
ial
Br
ea
st
Br
ain
0
Figure 6. Sites of metastatic dissemination of GI NETs.
4
Adapted from Strosberg J et al.16
Based on market
research, it is estimated
that approximately 60%
of carcinoid patients visit
a gastroenterologist early
on in their disease.17
The most common signs and symptoms experienced by patients with carcinoid
syndrome are flushing, diarrhea, abdominal cramping, and cardiac disease caused
by valvular heart lesions (Table 2).7 Our expert panel (see page 24) suggests that
symptoms may be exacerbated by the 5 E’s: eating, epinephrine, emotion, ethanol,
and exercise.18,19
Because some of these features are nonspecific or easily overlooked, diagnosis
might be delayed for years.11 Increased awareness of carcinoid syndrome may
lead to earlier diagnosis and improved prognosis.12
Table 2. Frequency of signs and symptoms of carcinoid syndrome.
Symptoms of Carcinoid Syndrome and Their Frequency
Symptoms
Percentage of Patients with Symptoms
Flushing
94%
Diarrhea
78%
Heart valvular lesions
53%
Cramping
51%
Telangiectasia
25%
Peripheral edema
19%
Wheezing
19%
Cyanosis
18%
Arthritis
7%
Pellagra
7%
Adapted from Creutzfeldt W.7
The symptoms of carcinoid syndrome can have a major effect on quality of
life,15 and earlier diagnosis can help patient outcomes.12
NETs may be discovered incidentally; for example, appendiceal NETs may be
discovered during apparently routine appendectomy, and NETs of the rectum
or colon can be discovered in asymptomatic individuals during a screening
colonoscopy. However, because most NETs associated with carcinoid syndrome
are located in the small intestine, routine endoscopy will not discover them.
Points to consider
• NETs are solid neoplasms with variable
characteristics and prognosis
• Early diagnosis is important and may make
a difference in prognosis
• NETs should be managed by specialists
with experience in NETs
5
Common Manifestations Dry
Pinkish/Red
and
Purple
Flushing
Dry
Pinkish/Red
and
Purple
Flushing
Cardiac
Disease
Typically
Right-Sided
Valves
Cardiac
Disease
Typically
Right-Sided
Valves
6
of Carcinoid Syndrome
Common Manifestations
of Carcinoid Syndrome
Chronic
Watery Stools
Chronic
Watery Stools
Diarrhea
Diarrhea
Nocturnal
Incomplete
Response
to AntiDiarrheals
Abdominal
Pain
Intermittent
and Crampy
Intermittent
and Crampy
Pain
Associated
With
Diarrhea
Incomplete
Response
to AntiDiarrheals
Abdominal
Pain
Dull, Achy
and Colicky
Dull, Achy
and Colicky
Nocturnal
Pain
Associated
With
Diarrhea
7
Common Manifestations of
Carcinoid Syndrome
When GI symptoms predominate, many patients initially are misdiagnosed
with other GI conditions (Table 3).
Table 3. A number of GI disorders have at least 1 symptom also observed
in carcinoid syndrome.
Irritable bowel syndrome (IBS)20
Inflammatory bowel disease (IBD) – Crohn’s disease,21 ulcerative colitis22
Microscopic colitis23
Food intolerance/food allergy24
Bacterial overgrowth25
Celiac disease26
Hypersecretory states (eg, gastrinoma)27
Chronic pancreatitis28
Other cancers (eg, colon carcinoma, lymphoma)29
The aims of this brochure are to
• Provide a deeper understanding of the signs and symptoms of
carcinoid syndrome
• Help differentiate carcinoid syndrome from other GI diseases to
facilitate early diagnosis
8
Focus on Diarrhea
Chronic Diarrhea and Carcinoid Syndrome
Chronic diarrhea is present in up to 80% of patients with carcinoid syndrome.7,30
The pathophysiology of diarrhea in patients with carcinoid syndrome is poorly
understood. It may be caused by the increased secretion of neurohumoral
substances, such as serotonin, which alter enteric secretion and propulsion.31
Diarrhea
While chronic diarrhea is an important clue to help identify carcinoid syndrome,
patients may not report it adequately. A detailed history about the diarrhea, and
specific questioning about other possible manifestations of carcinoid syndrome
(eg, facial flushing), are required.
There are many other causes of chronic diarrhea25; however, certain characteristics
may help to correctly identify carcinoid syndrome.
Dry
Pinkish/Red
and
Purple
Flushing
Chronic
Watery Stools
Diarrhea
Cardiac
Disease
Nocturnal
Incomplete
Response
to AntiDiarrheals
Typically
Right-Sided
Valves
9
Focus on Diarrhea (cont)
“A clue to carcinoid
Detecting the Differences
syndrome is that fasting
does not reduce the
Watery Stools Caused by Hypermotility
and Hypersecretion
diarrhea because the
The stools in diarrhea associated with carcinoid syndrome are watery and result
from intestinal hypermotility and hypersecretion.7
increased motility and
increased secretion are
”
independent of intake.
Patients with carcinoid syndrome show increased gut motility; von der Ohe et al
reported that the emptying rate of the proximal colon was approximately 6 times
faster, and that small bowel transit was approximately 2 times faster, in patients
with carcinoid syndrome compared with control subjects (Figure 7).30
Dr David C Metz
Copyright © (1993) Massachusetts Medical Society.
All rights reserved.
Figure 7. Carcinoid diarrhea causing rapid colonic transit of isotope.
In 2 hours, isotope has moved from cecum to rectum. Reproduced with permission from von der Ohe MR et al.30
The increase in gut motility in patients with carcinoid syndrome is likely to
be caused by serotonin, which is released as part of carcinoid syndrome14
and stimulates small bowel and colonic secretions and motility.12,31
10
“Nocturnal diarrhea is
a key clue to diagnosing
”
carcinoid syndrome.
Dr Rodney Pommier
Nocturnal Diarrhea
Limited information is
available in the literature
on nocturnal diarrhea in
carcinoid syndrome32;
however, our expert panel
reports that nocturnal
diarrhea is characteristic
of carcinoid syndrome
and can be a useful clue
to identifying patients.
Consider – Nocturnal
diarrhea may be observed
in other conditions (eg, IBD),
but is typically not seen in
IBS.25 If IBD is suspected
clinically, the patient will be
evaluated endoscopically
and/or radiologically.
Consider – There are many
other conditions that may also
have incomplete responses to
antidiarrheals.
Incomplete Response
to Antidiarrheals
Our expert panel suggests
that chronic diarrhea that
does not respond completely
to antidiarrheal medicines
(over-the-counter, antibiotics,
or prescription for IBS) should
raise the suspicion of possible
carcinoid syndrome.
11
Focus on Diarrhea (cont)
“If the usual
Focus on Diarrhea – Clues From
Clinical Practice
diagnostic tests
(ie, colonoscopy and
upper endoscopy with
the relevant biopsies) are
unrevealing, this should
raise the possibility of
carcinoid syndrome,
Carcinoid syndrome can be extremely difficult to recognize and diagnose.
Gastroenterologists frequently evaluate patients with chronic diarrhea and
see many more patients with IBD or IBS, for which carcinoid syndrome can
be mistaken.
Some differential characteristics of each condition that may isolate carcinoid
syndrome are shown in Table 4. Table 4 should be viewed as general clues only;
characteristics might not always be present.
Table 4. Characteristics of carcinoid syndrome, IBD, and IBS that may help
differentiate between conditions.
although it must be
Carcinoid
Syndrome
remembered that IBS is
far more common than
”
carcinoid syndrome.
IBD
Crohn’s
Disease
IBS
Description of stool
Mostly watery12
Could be watery,
could be mixed
with blood21
Bloody stools are
characteristic of
ulcerative colitis
during relapse*
Frequent, watery
(small quantity),
often with mucus
present35
Nocturnal diarrhea
Common*
Common33
Common
Uncommon25
Rectal bleeding
Uncommon*
Fairly
common34
A characteristic
feature34
Should
be absent*
Constipation
Uncommon*
Uncommon*
Common
(may alternate with
diarrhea)25
Dr David C Metz
Advanced midgut
tumor may
obstruct bowel
and cause
constipation*
Flushing
Common12
*Expert panel opinion.
“Uncommon” indicates this is not a classical symptom of the condition.
12
Ulcerative Colitis
Dry
Focus on Abdominal Pain
Pinkish/Red
and
Purple
Chronic
Flushing
Watery Stools
Abdominal pain is
Abdominal Pain and Carcinoid Syndrome
present in 40% to 51%
Abdominal pain in carcinoid
36
syndrome is intermittent
Cardiac
7
and crampy, andDisease
occurs
in approximately
40% to 51% of patients.7,14
of patients.7,14
Nocturnal
Typically
Abdominal
Pain
Intermittent
and Crampy
Dull, Achy
and Colicky
Pain
Associated
With
Diarrhea
Our expert panel says that
in carcinoid syndrome,
abdominal pain or
discomfort may be due
to gut hypermotility,
obstructive-type symptoms or, rarely, tumor intussusception. Pain may also be due
to serosal involvement of the tumor or to stretching of the liver capsule because of
large hepatic metastases.
Abdominal Pain
Abdominal
Right-Sided pain is a
Valves
nonspecific
symptom with
many different potential
causes. Because patients
describe pain in different
ways, diagnosis can be
extremely difficult. Pain
may also be vague12
and may be misdiagnosed
as IBS.
Detecting the Differences
Diagnosing abdominal pain associated with carcinoid syndrome is difficult, as there
are no real distinguishing factors. Not all characteristics of abdominal pain listed on
the following page will be present in a patient, and the pain may have none of these
characteristics – it may just be described as “vague.”
Dry
Pinkish/Red
and
Purple
Chro
Flushing
Diarrh
Cardiac
Disease
Typically
13
Focus on Abdominal Pain (cont)
Consider – Abdominal
cramping associated with
bloating is typical of IBS.20
Abdominal cramping is
also observed in IBD.21,22
Intermittent Crampy Pain
Pain associated with carcinoid syndrome is usually intermittent36
and crampy.7
In IBS, abdominal pain or discomfort is typically improved or
relieved with defecation20; our expert panel suggests that this
is not typically the case in carcinoid syndrome.
Dull, Achy, and Colicky Pain
Pain in carcinoid syndrome has been variously described as dull,
achy,37 and colicky.12
Pain Associated With Diarrhea
Pain associated with diarrhea in carcinoid syndrome may be colicky12
and may not be relieved with defecation.
Focus on Abdominal Pain – Clues From
Clinical Practice
Abdominal pain associated with carcinoid syndrome can be extremely difficult
to recognize and correctly diagnose; abdominal pain is common in other more
prevalent GI disorders, such as IBD and IBS.
Some differential characteristics of abdominal pain in each condition are given
in Table 5 and may help to isolate carcinoid syndrome. Table 5 should be viewed
as general clues only; characteristics might not always be present.
Table 5. Characteristics of carcinoid syndrome, IBD, and IBS that may help
differentiate between conditions.
Carcinoid
Syndrome
Key describing features
of abdominal pain
Intermittent36 and
crampy7 occurring
in episodes;
often dull, achy37
and colicky12
Pain relieved upon
defecation
Uncommon*
Bloating
Uncommon*
IBD
Ulcerative Colitis
Usually
intermittent
and colicky*
Abdominal pain
varies34 and is not a
major feature*
Recurrent
abdominal pain or
discomfort20
Variable*22
Common20
Uncommon*
Common20,35
Can occur*
Can occur if
mesenteric
involvement and
partial obstruction*
14
IBS
Crohn’s
Disease
*Expert panel opinion.
“Uncommon” indicates this is not a classical symptom of the condition.
Focus on Flushing
Flushing occurs in
Flushing and Carcinoid Syndrome
over 90% of patients
Flushing is the most common symptom of carcinoid syndrome and occurs in more
than 90% of patients.12
with carcinoid syndrome.12
Dry
Flushing
Pinkish/Red
and
Purple
Characteristically dry38 and usually pink
to red in color, flushing typically affects
the face, neck, and upper trunk.12,14
The typically dry nature of flushing
in carcinoid syndrome is a good
distinguishing clue for this symptom.
Our expert panel suggests that flushing
episodes may be exacerbated by the
5 E’s: eating, epinephrine, emotion,
ethanol, and exercise.18,19 The specific
cause of flushing in carcinoid syndrome
is unknown, although it has been
shown to be preceded
Chronic by a rise in
39
substance P.
Watery Stools
Nocturnal
Incomplete
Response
to AntiDiarrheals
Typically
Right-Sided
Valves
Detecting the Differences
Clues from
Clinical
Practice
Flushing in carcinoid syndrome may vary from person
to person and may have
Abdominal
Intermittent
similar characteristics to menopausal
“hot flashes,” making
Pain diagnosis difficult in
and Crampy
some cases.39
Dry Flushing
Flushing in carcinoid syndrome
is characteristically dry38 – in
women, this helps distinguish it
from menopausal hot flashes,
which are often associated
with perspiration.40
Dull, Achy
and Colicky
Pain – If flushing
Consider
Associated
With
is not associated
with
Diarrhea
perspiration, consider
carcinoid syndrome.
15
Flushing
Diarrhea
Focus on Flushing (cont)
Pink/Red or Purple in Color, Affecting the Face,
Neck, and Upper Trunk
Consider – Hot flashes
in menopause may be
associated with reddened
skin color.
Flushing in carcinoid syndrome is typically pink to red in color and
generally affects the face, neck, and upper trunk,12,14 fading from the
center to the periphery.12 Flushing may also be purplish, and may affect
the limbs.14
Association With Transient Hypotension,
Headache, Bronchoconstriction, and Palpitations
Consider – Menopausal
hot flashes are not
associated with a fall
in blood pressure.40
T ransient hypotension, headache, and bronchoconstriction may
coincide with flushing in patients with carcinoid syndrome,12,14
particularly in patients with NETs arising in the lungs, thymus, stomach,
and duodenal.41 Our experts suggest that palpitations may coincide
with flushing in these patients.
Focus on Flushing – Clues From
Clinical Practice
Although the relationship between flushing and other symptoms is variable,39
association of flushing with these symptoms is a good clue that a patient may
have carcinoid syndrome.
Some potential differential characteristics of flushing in carcinoid syndrome
compared with menopause are presented in Table 6. Table 6 should be viewed
as general clues only; characteristics might not always be present.
Table 6. Characteristics of flushing in carcinoid syndrome and menopause.
Typical Carcinoid Syndrome
Atypical Carcinoid
Syndrome (usually found
in foregut tumors)
Menopausal Hot Flashes
Type
Dry38
Dry38
Associated with perspiration40
Color
Pink to red12,14
Purplish14
Red39
Duration
Few minutes to 30 minutes,
occur several times a day9,14
Hours14
A few minutes, can occur
many times a day39
Location
Face, upper trunk12,14
Face, upper neck, limbs14
Face, neck, chest39
May coincide with hypotension
and bronchoconstriction12,14
Frequently associated with
telangiectasia, and may
coincide with hypotension
and bronchoconstriction14
Not associated
with telangiectasia
or hypotension39
No obvious triggers14
Stress, ethanol, hot drinks39
Associated
symptoms
Possible
triggers
16
Alcohol or tyramine-containing
foods, such as chocolate, walnuts,
and bananas14 (also the 5 E’s:
eating, epinephrine, emotion,
ethanol, exercise18,19)
Focus on Cardiac Disease
Heart failure from
Cardiac Disease and Carcinoid Syndrome
cardiac diseases causes
Cardiac disease is one of the most serious aspects of carcinoid syndrome,
occurring in approximately two thirds of patients.9 Heart failure is
responsible for approximately one third to one half of carcinoid syndrome
deaths, and 10% to 20% of patients with carcinoid syndrome already have
heart disease at presentation.9,11,12
carcinoid syndrome.12
The development of carcinoid heart disease leads to poorer prognosis
(Figure 8).42 This highlights the fact that carcinoid syndrome should be
managed with a multidisciplinary approach.
100
90
No Cardiac
Involvement
80
70
Survival %
up to 50% of deaths in
60
50
n=51
40
30
Carcinoid Heart
Disease
20
P=0.0003
n=73
10
0
0
1
2
3
Years
4
5
6
Figure 8. Effect of carcinoid heart disease on survival in NETs patients.
Cardiac Disease
Adapted from Pellikka PA et al.42
17
Focus on Cardiac Disease (cont)
Heart disease in
Detecting the Differences
carcinoid syndrome
Right-Side Involvement
typically involves
right-sided valves.
8
Cardiac manifestations usually develop late in the carcinoid syndrome disease
process,12 when the right side of the heart is exposed to high levels of serotonin
and other vasoactive substances released from hepatic metastases.43 This
exposure is believed to result in fibrotic damage of the right-heart endocardium
and pulmonary and tricuspid valves. The results are the thickening, retraction,
and fixation of the pulmonary and tricuspid valves, leading to valvular
dysfunction (stenosis and insufficiency) and, eventually, right-sided heart
failure.8,15,43 Carcinoid heart disease has been shown to be related to increased
levels of urinary 5-HIAA.42,44
Left-sided heart disease is infrequent, but it has been observed in some
patients15,43 (typically in those with bronchial tumors that release products into
the pulmonary veins).
Recent work has highlighted the value of treating cardiac disease aggressively,
including valve replacements, given the slow rate of tumor bulk progression
in many patients.45
Focus on Cardiac Disease – Clues From
Clinical Practice
The fact that carcinoid heart disease usually involves the right-sided valves14
can help differentiate it from cardiac disease due to other causes.
Carcinoid heart disease can be diagnosed with 2-dimensional echocardiographic
and Doppler examinations, which assess the severity of valvular stenosis and
regurgitation.44 A combination of tricuspid and pulmonary lesions is characteristic
of carcinoid heart disease.
18
Other Symptoms
and Manifestations
Episodes of
Wheezing and Carcinoid Syndrome
bronchoconstriction
Wheezing and bronchospasm
are characteristic of carcinoid
syndrome. Wheezing is present
in up to 19% of patients with
carcinoid syndrome.7 Episodes of
bronchoconstriction are usually
associated with flushing.14
are usually associated
with flushing.14
Consider – Wheezing is also
a symptom of asthma. Some
of the characteristics that
distinguish asthma include
coughing; trouble breathing;
chest tightness; symptoms that
occur or worsen at night; and
symptoms that are triggered by
cold air, exercise, or exposure to
allergens.46 Lung function tests
can be used to identify asthma.
Peripheral Edema and Carcinoid Syndrome
In addition to the leading symptoms discussed in earlier sections, peripheral
edema is present in approximately 1 in 5 patients with carcinoid syndrome.7
Other Symptoms
19
Other Symptoms and
Manifestations (cont)
Skin Changes and Carcinoid Syndrome
Skin changes in carcinoid syndrome occur in a small number of patients and
include telangiectasia,39 cyanosis,47 and rarely pellagra.8
Telangiectasia
Telangiectasia is the most notable of the skin changes. It occurs with repeated
flushing over a prolonged period,39 particularly in patients with NETs arising in
the lungs, thymus, stomach, and duodenal.41 Telangiectasia is characterized as
red/purple spots on the skin39 (Figure 9).
Image kindly supplied by Dr Rodney Pommier (2009).
Figure 9. A patient with telangiectasia.
Telangiectasia is noticeably present on the malar region of the face and other regions of the body, including
the forehead, lower neck, presternal area of the chest, and dorsa of the hands.
Cyanosis
Cyanosis (bluish color of the skin) results from increased amounts of reduced or
desaturated hemoglobin in the blood.48
Pellagra
Pellagra is caused by niacin deficiency, which occurs when tryptophan is diverted
from niacin synthesis to serotonin production. Pellagra in carcinoid syndrome
manifests as symptoms of scaly brown patches on the legs, and is associated
with a fiery-red tongue and mental status changes.12
20
Diagnostics and Imaging
In cases of suspected NETs associated with carcinoid syndrome, diagnosis can be
confirmed using circulating biochemical tumor markers and imaging techniques.
Biochemical Markers
Testing of biochemical markers, such as chromogranin A (CgA) and
5-hydroxyindoleacetic acid (5-HIAA), can be used to establish diagnosis
and/or monitor the progression of disease.
Chromogranin A
Despite certain limitations, CgA is considered the best overall circulating NET
biomarker. It is elevated in up to 90% of patients with NETs,49-52 and levels are
independent of hormone secretion.51 CgA levels have been shown to reflect tumor
mass and may be correlated with reduced survival times.49 Note that elevations
in CgA can be seen in other conditions, such as renal or hepatic failure, and slight
elevations in CgA may be seen in IBD.53 CgA levels can also be elevated by protonpump inhibitors and certain other therapies.52 When interpreting CgA blood levels,
the clinician should keep in mind that results may vary between laboratories,54
and confirmatory testing is required before making a diagnosis of NET.52
5-Hydroxyindoleacetic acid
5-HIAA, a metabolite of serotonin, acts as a good biomarker for tumor secretory
activity, which is measured in a 24-hour urine specimen.55,56 Elevations in 5-HIAA
may be predictive of reduced survival57 and progressive carcinoid heart disease.43
Reductions in 5-HIAA are correlated with relief of carcinoid symptoms.58 It is
important to note that certain serotonin-rich foods (eg, bananas, tomatoes,
avocados, plantain, plums, pineapples, eggplant, and walnuts) can increase urinary
5-HIAA levels and should be avoided prior to specimen collection (Figure 10).9
5-HIAA is a useful diagnostic test for NETs associated with carcinoid syndrome.
However, 5-HIAA is less reliable than CgA in the detection of NETs located in the
rectum and colon.55
Bananas
Tomatoes
Walnuts
Figure 10. Examples of serotonin-rich foods.
Diagnostics
and Imaging
21
Diagnostics and Imaging (cont)
Imaging
There are multiple imaging techniques available to help diagnose, stage, and
monitor the progression of NETs (Table 7).
Table 7. Application of imaging techniques to detect and monitor NETs.
Method
Description
Octreoscan
A unique molecular imaging agent for the scintigraphic localization of primary and
metastatic NETs bearing somatostatin receptors.59 The most sensitive imaging
technique for GI NETs (86%-95% sensitivity)59
Spect/CT hybrid
imaging in SRS with triplephase CT scanning
Functional anatomical mapping may improve reporting
accuracy for SRS60
CT/MRI
Well-established tools for the identification of NETs that provide
important means of initial localization of NETs and/or metastases
when suspected9,61
Endoscopic ultrasound
Highly sensitive for detection of NETs in the stomach and the duodenum9
Capsule endoscopy
Has potential for imaging of the small intestine in carcinoid patients9
MIBG scintigraphy
May be used as an adjunct to assist in determining location and
extent of tumor62
™
PET
May be useful for identifying small NETs and detecting metastases. Newer forms
of PET using a gallium-68 (68Ga)-labeled somatostatin analog (SSA) or
11
C-labeled and 18F-labeled amine precursors are being investigated11
CT, computed tomography; MIBG, iodine-131 metaiodobenzylguanidine; MRI, magnetic resonance imaging;
PET, positron emission tomography; SPECT, single-photon emission computed tomography; SRS, somatostatin
receptor scintigraphy.
No imaging technique is 100% sensitive, and multiple techniques may need to be
used in combination to detect small, biochemically diagnosed tumors11 – even then,
tumors may not be detected.
Octreoscan is a trademark of Covidien AG or one of its affiliates.
22
“NETs in the intestinal
Images
tract present as
submucosal nodules on
Figure 11. Image of a gastric NET.
endoscopic examination.
Image kindly supplied by Dr Jeffrey H Lee.
They usually involve
the deep mucosa and
submucosa. However,
they can grow into the
Figure 12. Image of NET in the duodenal bulb.
muscularis propria,
Image kindly supplied by Dr Jeffrey H Lee.
involving the entire wall
thickness. Endoscopic
ultrasound examination
can accurately assess the
”
depth of infiltration.
Figure 13. NET involving the ampulla.
Image kindly supplied by Dr Jeffrey H Lee.
Dr Jeffrey H Lee
Figure 14. Endosonographic image of hypoechoic
submucosal tumor extending through the muscularis
propria layer in the duodenal bulb. Arrows indicate the
muscularis propria layer and NET.
Image kindly supplied by Dr Jeffrey H Lee.
Figure 15. Abdominal CT scan of a patient with a small
primary tumor in the terminal ileum showing large
metastasis to lymph node at the root of the mesentery
with surrounding desmoplastic reaction.
Image kindly supplied by Dr Rodney Pommier.
Figure 16. Intraoperative view of large metastasis to
lymph node at the root of the mesentery in a carcinoid
patient with liver metastases and 5-mm primary tumor
in the ileum. The fourth portion of the duodenum is to
the right of the nodal metastasis.
Image kindly supplied by Dr Rodney Pommier.
23
Expert Advisor Panel
We would like to acknowledge the advice and guidance of our panel of expert
advisors (in alphabetical order):
• Dr Jeffrey H Lee, MD Anderson Cancer Center, Houston, Texas
• Dr David C Metz, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania
• Dr Alexandria Phan, MD Anderson Cancer Center, Houston, Texas
• Dr Rodney Pommier, Oregon Health and Science University,
Portland, Oregon
We would also like to thank our peer reviewers:
• Dr Colin W Howden, Northwestern University, Feinberg School of Medicine,
Chicago, Illinois
• Dr Larry Kvols, H. Lee Moffitt Cancer Center & Research Institute,
Tampa, Florida
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25
Dry
Pinkish/Red
and
Purple
Chronic
Flushing
Watery Stools
Diarrhea
Nocturnal
Incomplete
Response
to AntiDiarrheals
Cardiac
Disease
Typically
Right-Sided
Valves
Abdominal
Pain
Intermittent
and Crampy
Dull, Achy
and Colicky
Novartis Pharma AG
CH-4002 Basel, Switzerland
© Novartis 2013
1/13
Pain
Associated
With
Diarrhea
G-NEA-1054527
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936-1080