Student Project

Tumor with Ectopic Production of Hormone

Colorectal Cancer
SGD B8
Denpasar, November 28,
2014

Chapter-1: Introduction
last of 20th century,
Lifestyle, lot of fast food, less
in physical activity

cancer incidence is expected to

increase by 100% to 180% in the
next 15 years due to increases in
life expectancy,

Metabolic
Disease

Health
Problems

Colorectal cancer is a type of

cancer is the third most in
Indonesia, the number of cases of
1.8/100,000 populations

Chapter-II: Content
Definiti
on
Epidemiolo
Epidemiolo
gy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Colorectal cancer (also

known as colon cancer,
rectal cancer or bowel
cancer) is the development
of cancer in the colon or
rectum (parts of the large
intestine)
Sign &
Sympotms

Is it urgent problems ?

Risk factors
Need To be
Consider
Colorectal cancer is a type of

Staging
number of colorectal cancer cases
in the United States for 2014 are
Preventi
cancer is the third most in
96,830
new cases of colon
Indonesia, the number of cases of
on
cancer 40,000 new cases of
Treatme
1.8 / 100,000 population
rectal cancer
nt
Prognos
1.
World Cancer Report 1.
2014.Stephen
World Health
Organization.
2014.
pp.Mellitus.Endicrinology
Chapter 5.5. ISBN 9283204298.
A. Brietzke,
MD, FACP,
FACE.
(2007) Vol 6 Part 3: 1-12.
2.

Mitrovic, B.; Schaeffer,

Riddell,
R. H.; Kirsch, R. (2012).
"Tumor
budding
in colorectal
to Vol. 51,
2. D. F.;
Troitza
K. Bratanova-Tochkova,
Haiying
Cheng,
Samira
Daniel, etcarcinoma:
al. DiabetesTime
(2002)

Chapter-II: Content
How Can it Developed ?

Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Most colorectal cancers develop slowly over several

years. Before a cancer develops, a growth of tissue or
tumor usually begins as a non-cancerous polyp on the
inner lining of the colon or rectum. A tumor is abnormal
tissue and can be benign (not cancer) or malignant
(cancer).

1.
2.

Produce the Ectopic

Hormone
? (2007) Vol 6 Part 3: 1-12.
Stephen A. Brietzke, MD, FACP, FACE.
Mellitus.Endicrinology

Troitza K. Bratanova-Tochkova, Haiying Cheng, Samira Daniel, et al. Diabetes (2002) Vol. 51,

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Ectopic Hormone From

Cancer Sel

Hormonal
Substance

Cancer Sel
Syndrome
1ST Type

2ND Type

The first is the production of a

The
second
type,is
the
hormonal substance by a cell
ectopic production of a
type that normally produces
hormone by a cell type that
the hormone ex. hormone
does not normally produce the
production by a parathyroid
hormonal
substance
or
produces(2007)
it normally
at very
1.cancer,
Stephenetc.
A. Brietzke, MD, FACP, FACE. Mellitus.Endicrinology
Vol 6 Part 3: 1-12.
2.
Troitza K. Bratanova-Tochkova, Haiying Cheng, Samira
Daniel, et al. Diabetes (2002) Vol. 51,
low levels.
Supplement 1: 83-90.

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Ectopic Hormone From Cancer Sel

Inappropriate secretion of ACTH, although uncommon, is an
important cause of morbidity and mortality in certain types of
Ectopic
malignancies, The most common cause of ectopic ACTH
ACTH
production is the expression of proopiomelanocortin (POMC) by a
Productio Colorectal tumor.
n
Acromegaly is a condition characterized by elevated growth
hormone and IGF-1 values, most commonly caused by a pituitary
Growth
tumor and gastric cancer. There are examples of GH production
Hormone and
by lung and gastric adenocarcinomas.
Prolactin
Prolactin

Cushing
Syndrome

1.
2.

Benign adenoma in the adrenal gland that produces too much

cortisol. Some patients have a similar condition known as
Cushing's disease, which is caused by a tumorin the pituitary
gland. Thetumor produces adrenocorticotropic hormone
(ACTH), which in turn signals the adrenal gland to produce
cortiso

Stephen A. Brietzke, MD, FACP, FACE. Mellitus.Endicrinology (2007) Vol 6 Part 3: 1-12.
Troitza K. Bratanova-Tochkova, Haiying Cheng, Samira Daniel, et al. Diabetes (2002) Vol. 51,

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

There are 2 kind of cushing syndrome :

Iatrogenic cushing's syndrome
More than 10 million Americans receive
pharmacologic doses of glucocorticoids
each year, so iatrogenic cushing's
syndrome must be more common
Ectopic ACTH syndrome
About 1 percent of patients with
colorectal cancer have ectopic ACTH
syndrome.

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

A population based study in Denmark found

that the from 166 patients in an 11 year
period. Ninety nine patients had cushings
disease; 48 had adrenal dependent cushings
disease; 16 had ectopic corticotropin (ACTH).
This mean an incidence of 2 cases per 1
million inhabitants per year.
This study was in agreement with a similar
study conducted in Vizcya, Spain, in 1994. In
a Spanish population of 1.15 million, 49
patients were diagnosed with cushings
disease, yielding an incidence of 2.5 cases
per 1 million inhabitants per year.

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Bcl2A1
Bcl2A1

Mcl-1
Mcl-1

PUMA
PUMA

Translocation Bax into mitokondria

Translocationmembrane
Bax into mitokondria
membrane
Cleavage Bid and insertion Bad
Cleavage Bid and insertion Bad
Release

Release C
cytokrome
cytokrome C
Tomer C., Ioannis S.P. Ohad T., et al. Mutant p53 Prolongs NF-kB Activation and Promotes Chronic Inflammation and
Inflammation-Associated Colorectal Cancer. Cancer Cell 2013: 23(4); 634-646.
Mitchell S. C. The pathophysiology, clinical presentation, and diagnosis of colon cancer and adenomatous polyps. Med Clin
N Am 2005: 89(4); 142.

Chapter-II: Content
Definiti
on
Epidemiol

Apaf-1
Apaf-1

Epidemiol
ogy

Risk
Factor

Caspase
Apoptosom
Caspase9
Apoptosom
9

Pathogen
esis

Diagnos
is
Dif. Dx

ICAD
ICAD

Caspase Caspase3
3

Staging
Procaspase p21waf1

p53
type
wild
Procaspase9 type wild Release p21waf1
or cip1
p53
Preventi
9
or
cip1

Release C
cytokrome
Apoptosison
cell. This mechanism is not
Apoptosis
cytokrome C
Apoptosis
cell. This
Apoptosis
Treatme
cancer cell
happen
in mechanism
cancer cell. is not
cancer cell
happen in cancer cell.
Tomer
C.,
Ioannis
S.P.
Ohad
T.,
et
al.
Mutant
p53
NF-kB Activation and Promotes Chronic Inflammation
nt and Inflammation-Associated Colorectal Cancer. Prolongs
Cancer Cell 2013: 23(4); 634-646.
Prognos
Mitchell S. C. The pathophysiology, clinical presentation, and diagnosis of colon cancer and adenomatous
polyps. Med Clin N Am 2005: 89(4); 142.

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Colorectal cancer
Colorectal
cancer
cell
cell

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

POMC
POMC
Melanocyte
Melanocyte
stimulating
stimulating
hormone
hormone

Corticotropin
Corticotropin
releasing
releasing
hormone
hormone

ACTH
Staging
ACTH
Preventi
Ectopic production of ACTH hormone
on
Ectopic production of ACTH hormone
Treatme
nt
Prognos
Gomez R.T., Otero J.D., Escalada P.R., et al. Carcinoma of the colon associated to ectopic ACTH secretion. An Med Interna 2004: 19(10); 548549.

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Kaplan Meier plots for CSS according to p53 functionality
Treatme
Kaplan Meier plots for CSS according to p53 functionality
nt
Prognos
Arantza F.S., Giusi I.F., Wim E.C., et al. Integral analysis of p53 and its value as prognostic factor in sporadic colon cancer. BMC Cancer 2013:
13(6); 277-288.

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Mutp53 prolongs TNF- induced NF-B activation

Mutp53 prolongs TNF- induced NF-B activation
Tomer C., Ioannis S.P. Ohad T., et al. Mutant p53 Prolongs NF-kB Activation and Promotes Chronic Inflammation
and Inflammation-Associated Colorectal Cancer. Cancer Cell 2013: 23(4); 634-646

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Mutp53 mice are prone to DSS induced colon carcinoma

Mutp53 mice are prone to DSS induced colon carcinoma
Tomer C., Ioannis S.P. Ohad T., et al. Mutant p53 Prolongs NF-kB Activation and Promotes Chronic Inflammation
and Inflammation-Associated Colorectal Cancer. Cancer Cell 2013: 23(4); 634-646

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Anamnesis: Basic Four and sacred seven

1. Present illness
a. Onset
b. Location
c. Chronology
d. Quantity
e. Quality
f. Factor aggravate and extenuate
g. Accompanying symptoms
2. Past illness
3. Family history
4. Social history

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Common symptom of colorectal cancer

are:
Abdominal cramps
A change in bowel habits (either
constipation or diarrhea)
Blood in stools
Narrow stool
Unexplained weight loss
Fatigue
Loss of appetite

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

The symptoms of ectopic ACTH are as below:

Weak muscle
Fluid retention
Increased skin pigmentation
Diabetes
Increased blood pressure
Increased blood glucose
Increased urination
Anxiety
Fatigue round, red and full face (moon face)
Purple mark called striae on skin of abdomen,
thighs and breast
Collection of fat between the shoulder and
above the collar bone

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Moon face

Multiple striae on skin

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

If patient is suspected with colorectal

cancer after anamnesis and physical
examination, then further tests are
needed for confirmation such as:
Colonoscopy
Sigmoidoscopy
Biopsy
MRI, CT scan
Fecal Occult Blood Testing
Tumor Marker test

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Urine level of free cortisol

Dexamethasone
Suppression Test
Plasma Concentration of
ACTH

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Stage-0
The tumor is very small,
in the inner part of colon
& rectum. The therapy
can be surgery

Stage-1
The tumor cells invade
into the other layer of
the intestine but not out
of the colon

Stage-2
spread out of the colon
and rectum but do not
reach the lymph node.

Stage-4
Stage-3
The tumor cells
tumor cells
have been
have spread out
spread into the
into the nearest
other organs
lymph node but
such as liver
do not reach the
and lung. The
other organs.
possible
The possible
therapies are
therapies are
surgery,
surgery,
chemotherapy,
chemotherapy,
L. P. Fielding, P. A. Arsenault, P. H. Chapuis, dkk. 1991. Clinicopathological staging for colorectal cancer: An
radiation, and
and radiation.
International Documentation System (IDS) and an International Comprehensive Anatomical Terminology (ICAT).

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

Depends on tumor size, stage of

diagnosis, location of the tumor, risk of
the cancer returning and physical health
of the patient. There are 3 types of
treatments:
a) Surgery helps to relieve symptoms
b) Chemotherapy-shrink
tumors,
relieve symptoms and help people
live longer. 2 types of chemotherapy:
1) Adjuvant chemotherapy and 2)
Neoadjuvant chemotherapy

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

c) Biological therapy - uses the

immune system to fight cancer.
1) to help lessen the side effects
of other treatments by using
natural body substances.
2) drugs to strengthen the
bodys immune system and
boost its own defences.
3) Common
drugss:
bevacizumab (Avastin) and
cetuximab (Erbitux).

Chapter-II: Content
Definiti
on
Epidemiol
Epidemiol
ogy

Risk
Factor

Pathogen
esis

Diagnos
is
Dif. Dx

Staging
Preventi
on
Treatme
nt
Prognos

With prompt and appropriate treatment,

the prognosis for a person with colorectal
cancer is hopeful. The survival rate for
people with colorectal cancer depends
on the extent of the cancer at the time of
diagnosis and the individuals response
to treatment.
Several factors determine how well a
person will do after treatment for
colorectal cancer. They include: Stage of
the cancer, The number of lymph glands
involved, If the cancer has spread to
other organs, and Quality of the surgery

Chapter-III: Conclusion

Chapter-III: Conclusion

Case Study-1
NI Tsabedze, C Ray, M Hale. Ectopic
ACTH syndrome: a clinical
challenge. JEMDSA 2011;16(2):107110

History
A 29-year-old woman with a six-month
history of human immunodeficiency virus
(HIV)
infection
on
highly
active
antiretroviral
therapy
(HAART)
was
referred to endocrinology unit.
Her presenting complaints were a onemonth history of malaise and fatigue,
emotionally labile, dyspnea with poor
effort tolerance, recent weight gain
and darkening of her skin.

Physical Exam
Normotensive Cushingoid young woman with central
obesity and moon facies.
Purple striae over her flanks and thighs.
Facial acne
Bruising on her forearms
Hyperpigmentation of her extensor surfaces on her
upper and lower limbs.
A significant right inguinal lymph node was
palpable, which was fixed and nontender.
On rectal examination a worrying ulcer was noted on
her anus.
Thyroid examination was normal.

Lab test

No

Test

Value

Normal Value

Serum Potassium 2.3 mmol/l

(hypokalae
mic)

Serum
Bicarbonate

39 mmol/l

C-reactive
Protein

4.1 mg/l

< 1 mg/l

Normochromic
macrocytic
anemia wth MCV

110.3 fl

79.1-98.9 fl

White blood cell

count

4.4 x 109/l
(neutrophils
80.8%)

4 11 x 109 / l

Absolute CD4
count

81 x 106 /l

Random serum
cortisol

ACTH level

742 ng/l

Urinary
cortisol

2691
nmol/24 h

3.3-5.3 mmol/l
Lab Test

2069 nmol/l

18-29 mmol/l

500-1200 x 106 /l
120-620 nmol/l
< 46 ng/l
80-590 nmol/24 h

 Thyroid
function
tests,
serum
aldosterone,
alpha
foetoprotein,
luteinising
hormone,
folliclestimulating hormone, Liver function
tests, urea and creatinine
Normal limit

Imaging
CT scan of the
abdomen
revealed a locally
invasive rectal
tumor
An
obstructive
rectal tumor was
identified
by
sigmoidoscopy
and biopsy was
taken

Histopathology
Histopathological
examination
showed
ulceration of the squamous epithelium
Extensive infiltration of the perianal soft
tissue by discohesive nests of small cells with
hyperchromatic nuclei having finely stippled
chromatin
with
a
salt-and-pepper-like
appearance .
Small, eosinophilic nucleoli were present.
The cells also had a moderate amount of pale
staining cytoplasm. Occasional mitoses were
identified together with focal necrosis.

Immunohistochemistry showed paranuclear, dotlike, positive staining for the pankeratins MNF 116
and AE1/3, together with positive cytoplasmic
staining for synaptophysin, chromogranin A and
ACTH in the malignant cells.

Diagnosis and treatment

This patient can be diagnosed as an
ectopic ACTH production caused by
neuroendocrine carcinoma
Neuroendocrine carcinoma can be
confirmed by imaging and histology
examination.
It is unclear whether HIV infection
itself has a direct effect on the
development of anal cancer

The ectopic ACTH production can be

seen by:
Random serum cortisol was in excess
of 2 069 nmol/l
Adrenocorticotropic hormone (ACTH)
significantly increased at 742.0 ng/l
(normal < 46 ng/l)
Failed cortisol suppression test

Ectopic hormone production confirmed

by:
Immunohistochemistry examination
that show ACTH in the malignant
cells
Patients physical appearance
is
Cushing syndrome appearance that
caused by high ACTH level that made
high cortisol level.
labile emotion can be caused by high
cortisol level.

Treatment and prognosis

Hypokalemic still occur despite
aggressive potassium replacement
therapy.
Despite aggressive supportive and
specific therapy, the disease course
was complicated by nosocomial
sepsis and septic shock, temperature
spikes, hypotension and the patient
eventually succumbed

Case Study-2

R Sehgal, W Mchayleh, et al. Journal of

Oncology. Adenocarcinoma of Colon
Presenting as Cushings Syndrome . 2010

A 35-year-old woman present with 1 month

history of abdominal pain, weight gain (20
lbs, a body mass index of 36 kg/sqm), facial
puffiness, lower extremity edema, and
weakness.
Non Obstructing Mass in the
Colonoscopy

Cecum

biopsy

poorly differentiated
adenocarcinoma

computed tomography scan of

the abdomen and pelvis

multiple bilobar liver metastases

Worsening symptom acne extending onto

upper chest, facial hair, darkening of skin,
frequent
bowel
movements,
enlarged
supraclavicular and dorsocervical fat pads, and
purple striae,
light headedness, decreased
libido, and increased depression.

Pictures

Physical Exam and

Laboratory data

Pulse rate 68x/minute

ACTH 420 pg/mL

Blood pressure 170/94

ACTH 582 pg/mL (at 6 AM)

cortisol of 73 g/dL (at 11 AM)

potassium 1.7 mg/dL, potassium

2.7 mEq/L (with supplementation)

cortisol 136 g/dL (at 11 PM)

Blood Glucose 254 mg/dL

cortisol 151 g/dL (at 6 AM),

24 hours urine free cortisol 21,135

g/d

8 mg overnight dexamethasone suppression test failed

to suppress cortisol (138.9 g/dL).
Diagnosis ectopic ACTH production from colon cancer
Biochemical features alterations in serum ACTH,
cortisol, glucose, potassium, and urinary cortisol levels.

Treatment
ACTH supression
therapy
Systemic
chemotherapy
Metyrapone and
etomidate were
used during this
period for
treatment of
hypercortisolism

A right
hemicolectomy and
intrabdominal
lavage
perforated cecum
and intraabdominal
abcess