Home 
Prostate Cancer BJUI Mini Reviews - Paraneoplastic Cushing’s Syndrome in Prostate Cancer: A Difficult Management Problem
Prostate Cancer BJUI Mini Reviews - Paraneoplastic Cushing’s Syndrome in Prostate Cancer: A Difficult Management Problem | BJUI Mini Reviews - Paraneoplastic Cushing’s Syndrome in Prostate Cancer: A Difficult Management Problem |
|
|
|
|
|
| Tuesday, 11 March 2008 | ||
|
BJUI Mini Reviews - In this review, it is suggested that bilateral adrenalectomy at an early stage should be considered, possibly as a preliminary to anticancer treatments.
More BJUI Mini Reviews and Archives on UroToday.com
Please log-in or register in order to submit comments. Powered by AkoComment! |
||
![Paraneoplastic Cushing’s syndrome in prostate cancer:
a difficult management problem
Samantha Nimalasena, Alex Freeman* and Stephen Harland
Departments of Oncology and *Histopathology, University College London Hospital, London, UK
Accepted for publication 20 July 2007
normal range, despite previous castration.
The features of Cushing’s syndrome
contribute considerably to patients’
morbidity and probably to their mortality.
The syndrome is unlikely to be controlled
with inhibitors of steroid synthesis, and
chemotherapy is likely to be poorly
tolerated, resolving the syndrome in only a
few patients. We suggest that bilateral
adrenalectomy at an early stage should be
considered, possibly as a preliminary to
anticancer treatments
KEYWORDS
Cushing’s syndrome, prostate cancer,
paraneoplastic
Cushing’s syndrome associated with smallcell
de-differentiation of prostate cancer is
rare, but well described. The detection of
Cushing’s syndrome in a patient with
prostate cancer can be problematical, and
when occurring in prostate cancer nearly
always implies the development of smallcell
transformation. Testosterone levels in
these patients are likely to be in the
INTRODUCTION
Cushing’s syndrome associated with smallcell
differentiation of prostate cancer,
although rare, has been reported several times
but there is little advice on its management.
Many would regard the condition as a
‘premortem curiosity’. Such a view is a selffulfilling
prediction. In fact, anaplastic smallcell
carcinomas (SCCs) are sensitive to chemoand
radiotherapy and Cushing’s syndrome is
also amenable to treatment. Our experience is
probably typical, in that unfamiliarity with the
condition led to tardiness in diagnosis, and a
treatment choice that was probably not ideal.
Thus we feel that awareness of Cushing’s
syndrome should be increased in the
urological community, and in this review
highlight the special problem that it poses in
prostate cancer, suggesting a course of action
that might lead to greater success.
SMALL-CELL ANAPLASTIC CARCINOMA
OF PROSTATE
SCC, arising either de novo from the prostate
gland or from a pre-existing adenocarcinoma
of the prostate (Fig. 1), is one example of
extrapulmonary SCC and is now well
described [1–4]. In one series, four of 81
patients with extrapulmonary SCC had
disease arising from the prostate [5]. In 1984,
Schron
et al.
[6] reported three cases of
prostatic SCC; in all of these patients the
small-cell component in the prostate
carcinoma represented an aggressive
terminal phase of an otherwise regular
adenocarcinoma. They proposed that this was
a result of new clones showing differentiation
characteristics of small cells, rather than a
totally separate tumour [6].
In a review of 20 cases of SCC of the prostate
in one centre over a 23-year period, the
median survival was 5 months from the time
of diagnosis. The median age of the patients
at the time of diagnosis of SCC of the prostate
was 67 years, comparable to that of patients
diagnosed with adenocarcinoma of the
prostate [4]. Distant metastases occurred
frequently; common sites were pelvic lymph
nodes, liver, lungs and bone. In a few cases,
metastases were found in unusual sites, such
as omentum, vocal cords and periadrenal
tissue [4].
It was also evident that SCC of the prostate
tended to occur in association with, and
during the course of, progression of
prostatic adenocarcinoma. In some cases,
both components probably arise
simultaneously [4]. In 14 of the 20 cases,
prostatic adenocarcinoma preceded or
accompanied the SCC; in the remaining six
cases SCC was the only component present
at presentation [4]. As it is unusual to take
biopsies in a patient with metastatic
adenocarcinoma that has escaped endocrine
control, it is possible that the frequency of
transformation to the small-cell phenotype
is underestimated.
Immunostaining of these tumours for PSA
and the androgen receptor is negative, and
their proliferative activity is extremely high
[7]. This accords with their very aggressive
behaviour and the insensitivity to hormonal
therapy [7]. There can be a response to
chemotherapy [4,5], but these responses are
often transient [5].
DIAGNOSIS OF CUSHING’S SYNDROME IN
PROSTATE CANCER
Paraneoplastic Cushing’s syndrome in which
adrenocorticotropic hormone (ACTH), or
corticotrophin-releasing factor, is produced
by non-endocrine tumours is mostly
associated with SCC of the lung [8], but it has
also been described in medullary thyroid
cancer, nephroblastoma and gastrointestinal
adenocarcinomas [9]. It is not surprising that
the syndrome has also been described in SCC
of the prostate [1].
Recognising Cushing’s syndrome can be
problematical; patients with paraneoplastic
Cushing’s syndrome tend not to have
accelerated weight gain and centripetal fat
distribution [9]. In a patient with prostate
cancer clinicians should be alerted by the
occurrence of marked hypokalaemia, which is
present in 57% of patients with ectopic
Cushing’s syndrome [10]. Other indicators of
the diagnosis are muscular weakness in
the absence of spinal cord damage, and
generalized oedema. Whilst oedema of the
P A R A N E O P L A S T I C C U S H I N G ’ S S Y N D R O M E I N P R O S TAT E C A N C E R
©
2 0 07 T H E A U T H O R S
J O U R N A L C O M P I L A T I O N
©
2 0 07 B J U I N T E R N A T I O N A L
4 2 5
legs is common in prostate cancer, oedema of
the arms is not. The clinical and biochemical
features of two patients that we have
managed are shown in Table 1.
Once considered, the diagnosis of ectopic
ACTH as the cause of Cushing’s syndrome is
not usually problematical when the syndrome
develops rapidly in a patient with
carcinomatosis. Hypokalaemic alkalosis (K
+
<
3 mmol/L and HCO
3
>
30 mmol/L), serum
cortisol
>
800 nmol/L, ACTH
>
100 ng/L, a 24-h
urinary cortisol of
>
1300 nmol and no
suppression of ACTH after high-dose
dexamethasone, favour an ectopic over a
pituitary cause [11]. Inferior petrosal sinus
sampling to exclude a pituitary cause
(probably the definitive test at present) is
probably unnecessary. Detecting high
circulating levels of ACTH precursors shows
promise for identifying ectopic producers
[12]. Pentreotide scintigraphy, which
highlights somatostatin receptors, has been
used to detect ectopic ACTH-producing
tumours [13], but is helpful in only a few
cases [14]. A tissue diagnosis to confirm the
presence of small-cell histology is probably
desirable, although this morphology has been
present in all reported cases of Cushing’s in
prostate cancer.
TESTOSTERONE LEVELS
Cushing’s syndrome is a particularly
pernicious complication of prostate cancer, as
adrenal stimulation can produce testosterone
levels within the normal range, despite
medical or surgical castration (Table 1). This in
turn can cause stimulation of the hormonesensitive
component of the tumour. The
extent to which this feature increases the
morbidity, when the dominant component of
the tumour has small-cell histology, is
unknown.
MEDICAL TREATMENT FOR
THE ENDOCRINOPATHY
Several drugs are used in the medical
management of ectopic Cushing’s syndrome,
including octreotide (a modulator of ACTH
release) and the inhibitors of steroid
synthesis, aminoglutethimide, ketoconazole,
metyrapone and mitotane [15]; the last also
has anti-mitotic activity.
In one study, short-term octreotide treatment
caused a significant initial response (
>
30%
decrease in serum cortisol, ACTH and
cortisoluria) in 24 of 38 (64%) patients with
ectopic ACTH/corticotropin-releasing
hormone Cushing’s syndrome. Long-term
treatment caused a persistent response
(
>
30% decrease in cortisol, ACTH and
cortisoluria for
>
3 months) in 10 of 14
patients [13]. However, that series included
only two cases of anaplastic SCC, where the
syndrome is often fulminant. A 30% decrease
in corticosteroid and testosterone levels is
unlikely to produce a clinical benefit when the
pretreatment levels are very high.
Of more relevance is a series of 15 patients
with metastatic cancer (nine with small-cell
lung cancer) treated with ketoconazole [16].
In the context of patients with prostate
cancer, ketoconazole also has the advantage
of reducing testosterone synthesis. Although
10 of the 15 patients in that study had
amelioration of the symptoms, including five
with a complete biochemical response, the
median duration of response was only
25 days [16].
It is possible that potent inhibitors of 17
α
-
hydroxylase/C17–21 lyase, of which
abiraterone is the first drug, will improve the
efficacy of medical treatment, but there is no
information on this [17].
CHEMOTHERAPY
Extrapulmonary SCC, like the more common
pulmonary form, frequently responds
temporarily to chemotherapy [5], and this
approach, by reducing tumour load, might be
FIG. 1.
Histological specimen of SCC of the prostate.
Haematoxylin and eosin,
×
400.
TABLE 1
Features of paraneoplastic Cushing’s syndrome in two patients treated at the authors’
institution. Patient 1 had locally advanced prostate cancer initially treated with radical radiotherapy, and
had disease recurrence on androgen suppression therapy for 26 months. Patient 2 had metastatic
prostate cancer to the bone, and was on androgen suppression for 10 months
Feature
Patient
1 2
Age, years 64 52
Clinical Fatigue, leg and arm
oedema
Muscle weakness,
bilateral leg and arm
oedema
Serum:
K
+
on admission, mmol/L (normal 3.5–5.2) 2.7 1.7
cortisol, nmol/L (normal 171–536) 2370 2392
ACTH, ng/L (normal
<
46) 241 1064
testosterone, nmol/L (normal 9.8–25) 21.0 12.7
Treatment given Ketoconazole, metyrapone Ketoconazole, octreotide,
flutamide, ‘ECarboF’*
chemotherapy
Normalization of cortisol? No No
Castrate levels of testosterone? No No
Survival after diagnosis of Cushing’s, months 3.5 1
Histological findings at post mortem Disseminated SCC arising
from de-differentiation
of prostatic
adenocarcinoma
Anaplastic SCC in
prostate, liver and
bone
*Epirubicin, carboplatin, 5-fluorouracil.
N I M A L A S E N A
E T A L .
©
2 0 07 T H E A U T H O R S
4 2 6
J O U R N A L C O M P I L A T I O N
©
2 0 07 B J U I N T E R N A T I O N A L
considered an effective treatment for
Cushing’s syndrome. However, this will only
apply to the most chemosensitive tumours;
ACTH, cortisol and testosterone levels can be
increased 10 times, and in this situation,
tumour shrinkage of
>
90% will be required to
normalise the endocrine status.
The experience with Cushing’s syndrome
associated with anaplastic SCC of the
bronchus is probably relevant (note the
differing significance of testosterone
elevations). The presence of Cushing’s
syndrome has been found to be an
independent negative prognostic factor [18].
Complications of chemotherapy are common;
non-neutropenic sepsis is frequent and
survival is poor (Table 2) [18–21], and in
particular, complete resolution of Cushing’s
syndrome is infrequent.
CONCLUSION
The severity of Cushing’s syndrome in cases
associated with anaplastic SCC, the negative
effect of the syndrome on tolerance to
chemotherapy, and the poor endocrine
response to currently available medical
treatment, lead us to propose early bilateral
adrenalectomy. Anaplastic SCC is an
aggressive condition and usually there is a
desire to start chemotherapy as soon as
possible. Furthermore, a patient’s state of
health might make surgery an undesirable
option. However, our limited experience
suggests that a trial of medical therapy is
likely to lead to a situation where surgery is
the only option that will effectively resolve
the hypercortisolaemic state, and that by this
time the patient’s condition will have
deteriorated so that even a laparoscopic
operation is no longer feasible. Arguably, the
effect of Cushing’s syndrome on testosterone
levels makes early control of the syndrome in
prostate cancer imperative. Whether early
adrenalectomy would permit patients to
tolerate chemotherapy better, and to obtain
worthwhile remissions of their cancers,
remains to be confirmed.
CONFLICT OF INTEREST
None declared.
REFERENCES
1
Vuitch MF, Mendelsohn G.
Relationship
of ectopic ACTH production to tumour
differentiation: a morphologic and
immunohistochemical study of prostatic
carcinoma with Cushing’s Syndrome.
Cancer
1981;
47
: 296–9
2
Haukaas SA, Halvorsen OJ, Nygaard SJ,
Paus E.
Cushing’s syndrome in prostate
cancer. An aggressive course of prostatic
malignancy.
Urol Int
1999;
63
: 296–9
3
Di Sant
¢
Agnese PA.
Neuroendocrine
differentiation in carcinoma of the
prostate. Diagnostic, prognostic and
therapeutic implications
Cancer
1992;
70
:
254–68
4
Tetu B, Ro JY, Ayala AG, Johnson DE,
Logothetis CJ, Ordonez NG.
Small cell
carcinoma of the prostate. Part I. A
clinicopathologic study of 20 cases.
Cancer
1987;
59
: 1803–9
5
Galanis E, Frytak S, Lloyd RV.
Extrapulmonary small cell carcinoma.
Cancer
1997;
79
: 1729–36
6
Schron DS, Gipson T, Mendelsohn G.
The histogenesis of small cell carcinoma
of the prostate: An immunohistochemical
study.
Cancer
1984;
53
: 2478–80
7
Helpap B, Kollermann J.
Undifferentiated carcinoma of the
prostate with small cell features:
immunohistochemical subtyping and
reflections on histogenesis.
Virchows Arch
1999;
434
: 385–91
8
Meador CK, Liddle GW, Island DP
et al.
Cushing’s syndrome in patients with
tumours arising from ‘nonendocrine’
tissue.
J Clin Endocrinol Metab
1962;
22
:
693–703
9
Rickman T, Garmany R, Doherty T,
Benson D, Okusa MD.
Hypokalaemia,
metabolic alkalosis and hypertension:
Cushing’s syndrome in a patient with
metastatic prostate adenocarcinoma.
Am
J Kid Dis
2001;
37
: 838–46
10
Torpy DJ, Mullen N, Ilias I, Nieman LK.
Association of hypertension and
hypokalaemia with Cushing’s syndrome
caused by ectopic ACTH secretion.
Ann NY
Acad Sci
2002;
970
: 134–44
11
Teves DA.
Clinical approach of Cushing’s
Syndrome resulting from ACTH producing
metastatic neuroendocrine tumour.
Endocrinologist
2005;
516
: 401–4
12
Oliver RL, Davis JR, White A.
Characterisation of ACTH related peptides
in ectopic Cushing’s syndrome.
Pituitary
2003;
6
: 119–26
13
De Herder WW, Lamberts SW.
Is there a
role for somatostatin and its analogues in
Cushing’s syndrome?
Metabolism
1996;
45
(Suppl. 1): 83–5
14
Isidori AM, Kaltsas GA, Pozza C
et al.
The
ectopic adrenocorticotrophin syndrome:
clinical features, diagnosis and long term
follow-up.
J Clin Endocrinol Metab
2006;
91
: 371–7
15
Niemann LK.
Medical therapy of
Cushing’s disease.
Pituitary
2002;
5
: 77–
82
16
Winquist EW, Laskey J, Crump M,
Khamsi F, Shepherd FA.
Ketoconazole in
the management of paraneoplastic
Cushing’s syndrome secondary to ectopic
adrenocorticotrophin production.
J Clin
Oncol
1995;
13
: 157–64
17
Attard G, Yap TA, Reid AH
et al.
Phase I
study of continuous oral dosing of an
irreversibleCYP17 inhibitor, abiraterone
(A), in castration refractoryprostate
cancer (CRPC) patients (p) incorporating
theevaluation of androgens and steroid
metabolites in plasmaand tumor. ASCO
Annual Proceedings Part I.
J Clin Onc
2007;
25
(18S): 5063
18
Dimopoulos MA, Fernandez JF, Samaan
NA, Holoye PY, Vassilopoulou-Sellin R.
Paraneoplastic Cushing’s syndrome, an
adverse prognostic factor in patients who
die early with small cell lung cancer.
Cancer
1992;
69
: 66–71
19
Delisle L, Boyer MJ, Warr D
et al.
Ectopic
corticotrophin syndrome and small cell
carcinoma of the lung. Clinical features,
outcome and complications.
Arch Intern
Med
1993;
153
: 746–52
TABLE 2
Outcomes in Cushing’s syndrome associated with small-cell lung cancer
Reference
No. of
patients
Hormone levels
normalized, n
Median
survival Comments
[18] 11 – 12 days Patients selected by death within 90 days
[19] 14 3 5.5 months Infections very common; 3–4 infective deaths
[20] 23 2 3.6 months High rate of chemotherapy complications.
Tumour response rate only 46%
[21] 10 3 4 months Non-neutropenic infections common
P A R A N E O P L A S T I C C U S H I N G ’ S S Y N D R O M E I N P R O S TAT E C A N C E R
©
2 0 07 T H E A U T H O R S
J O U R N A L C O M P I L A T I O N
©
2 0 07 B J U I N T E R N A T I O N A L
4 2 7
20
Shepherd FA, Laskey J, Evans WK, Goss
PE, Johansen E, Khamsi F.
Cushing’s
syndrome associated with ectopic
corticotrophin production and small cell
lung cancer.
J Clin Oncol
1992;
10
:
21–7
21
Collichio FA, Woolf PD, Brower M.
Management of patients with small cell
carcinoma and the syndrome of ectopic
corticotropin secretion.
Cancer
1994;
73
:
1361–7
Correspondence: Samantha Nimalasena,
Oncology, University College London Hospital,
Euston Road, London NW1 2PQ, UK.
e-mail:
<script language='JavaScript' type='text/javascript'>
<!--
var prefix = 'ma' + 'il' + 'to';
var path = 'hr' + 'ef' + '=';
var addy33726 = 'samanthan' + '@';
addy33726 = addy33726 + 'doctors' + '.' + 'org' + '.' + 'uk';
document.write( '<a ' + path + '\'' + prefix + ':' + addy33726 + '\'>' );
document.write( addy33726 );
document.write( '<\/a>' );
//-->\n </script><script language='JavaScript' type='text/javascript'>
<!--
document.write( '<span style=\'display: none;\'>' );
//-->
</script>This email address is being protected from spam bots, you need Javascript enabled to view it
<script language='JavaScript' type='text/javascript'>
<!--
document.write( '</' );
document.write( 'span>' );
//-->
</script>](http://urotoday.com/images/stories/bjui_feb2008_cover.gif)
| < Prev | Next > |
|---|
|
UroToday, 1802 Fifth Street, Berkeley CA 94710 510.540.0930 (fax), info@urotoday.com ISSN 1939-4810
Privacy Policy | © 2008 UroToday ® All Rights Reserved |
