Full text of DOI:10.1007/BF03343930

J. Endocrinol. Invest. 24: 802-805, 2001
CASE REPORT
An exception to the rule: Ectopic ACTH production from
functional neuroendocrine tissue in an ovarian dermoid cyst
J. Watson*, M. Taylor*, J. Pampiglione**, S. Rasbridge ***, and M. Armitage*
*Bournemouth Diabetes and Endocrine Centre; **Department of Obstetrics and Gynaecology; and
***Department of Histopathology, Royal Bournemouth Hospital, Bournemouth, U.K.
ABSTRACT. Ectopic ACTH production accounts
for 15% of Cushing’s syndrome presentations
and is characterized by the presence of an ex-
cess of ACTH precursors. However in the case
presented here ectopic ACTH production was
from functional pituitary tissue within an ovar-
ian dermoid cyst. Endocrine investigations
showed that the problem behaved more like
pituitary-dependent Cushing’s disease and this
is discussed. Furthermore, this case is one of
familial dermoid cysts, another unusual pheno-
menon.
(J. Endocrinol. Invest. 24: 802-805, 2001)
©2001, Editrice Kurtis
INTRODUCTION
We present here a case of ectopic ACTH produc-
tion by an ovarian dermoid cyst, which has been
proved to be an important exception to this def-
inition. Of further interest, this case is one of fa-
milial ovarian dermoid cysts, of which only 13 re-
ports have been previously published (5).
In recent years there have been exciting develop-
ments in the distinction of pituitary-dependent
Cushing’s syndrome from ectopic ACTH produc-
tion, namely the recognition of an excess of ACTH
precursor molecules from ectopic sources of
ACTH. These arise because of incomplete post-
translational processing of pro-opiomelanocortin
(POMC) (1).
CASE REPORT
Ectopic (non-pituitary) ACTH is responsible for
less than 15% of Cushing’s syndrome presenta-
tions. In such cases, this hormone is most com-
monly produced by carcinoma of the lung or
pancreas, although tumors diverse in origin have
been found to produce ACTH. Whilst important
biochemical differences have been previously
identified between pituitary-dependent and ec-
topic ACTH Cushing’s syndrome (Table 1), there
is considerable overlap. The combination of ac-
curate measurement of ACTH precursor molecu-
les by a two-site IRMA (2) and an IRMA for ACTH
(3) has lead to a suggested revision of the crite-
ria for ectopic ACTH syndrome diagnosis (Table
2) (4).
A 37-year-old Caucasian woman was referred by
her general practitioner with a 10-month history of
weight gain (18 kg), hirsutism, acne and secondary
amenorrhea. She had been started on 50-μg thy-
roxine daily because of suspected hypothyroidism,
although her thyroid function tests showed a free
thyroxine of 11 pmol/l (normal range 10-25 pmol/l)
and a thyroid stimulating hormone of 0.82 (normal
range 0.3-4.5 mU/l). More recently she had com-
plained of enuresis and stress incontinence. She
was a non-smoker and drank less than 10 units of
alcohol per week. Relevant family history included
the fact that her sister at the age of 36 years pre-
sented with a single (left) ovarian mass. Following
surgery, a struma ovarii was identified with im-
plants on the contralateral ovary and omentum
(Fig. 1).
On examination she had a classical cushingoid ap-
pearance. She was markedly hirsute with centripetal
obesity and wasting of the proximal muscles. A buf-
falo hump was present and she had thin, fragile skin
with a round face and high color. Her blood pres-
sure was 180/130 mmHg. Proximal myopathy was
Key-words: Ectopic ACTH, dermoid cyst, familial.
Correspondence: Dr. Mary Armitage, Consultant Physician, Royal Bourn-
emouth Hospital, Castle Lane East, Bournemouth BH7 7DW, U.K.
E-mail: mary.armitage@rbch-tr.swest.nhs.uk
Accepted January 16, 2001.
802

J. Watson, M. Taylor, J. Pampiglione, et al.
Table 1 - Biochemical criteria for ectopic ACTH syndrome (12).
Plasma potassium <3.0 mmol/l
Manchester), are shown in Table 3. Corticotropin-
releasing factor, measured in a peripheral blood
sample, was low at 0.472 ng/l (Prof. Lowry, Uni-
versity of Reading). Androgen production was al-
so elevated with suppression of gonadotropins
and estradiol. Pituitary computed tomography
(CT) scan showed a normal sized sella turcica that
was partially empty. There was no identifiable tu-
mor within the very small pituitary gland. Ab-
dominal CT scan showed normal adrenal archi-
tecture, the glands were not enlarged. However,
there were two, large masses arising from the
pelvis. Both were fat-filled and had evidence of
calcification within. In the right mass there was al-
so a solid area. An abdominal X-ray showed sev-
eral teeth in the left abdominal mass. These find-
ings were consistent with dermoid cysts arising
from the ovaries.
Plasma bicarbonate >3.0 mmol/l
Serum cortisol at 09:00 h or midnight >800 nmol/l
Urinary free cortisol >1300 nmol/24 h
Plasma ACTH>22 pmol/l
High-dose dexamethasone suppression test: no suppression
Corticotropin-releasing hormone test: no response
Table 2 - Revised criteria for ectopic ACTH precursor syndrome (1).
Plasma ACTH>139 pmol/l
ACTH precursor/ACTH ratio >48
Following her presentation, she was started on an
increasing dose regimen of metyrapone to 500 mg
3 times daily. Urinary cortisol fell to 266 nmol/l and
her blood pressure improved. The above investi-
gation results were awaited. A provisional diagno-
sis of ACTH production by an ovarian dermoid cyst
was made.
The patient underwent total abdominal hysterec-
tomy with bilateral salpingo-oophorectomy. At
surgery both ovaries were replaced by cystic mass-
es (Fig. 2). The tumors were benign cystic teratomas
(dermoid cysts) both containing cutaneous adipose
and glial tissue. The left tumor also contained foci
of thyroid tissue whilst the right ovarian cyst had
neuroendocrine tissue. Immunohistochemical stains
for ACTH were positive in this epithelium, consis-
tent with it being the source of ACTH secretion (Fig.
3). The uterus was atrophic with evidence of tumor
spread.
also noted. Visual fields were normal to confronta-
tion. Gynecological examination revealed a right-
sided ovarian mass; the left ovary could not be
clearly identified.
Initial investigations showed hypokalemia with 3.1
mmol/l serum potassium. There was no evidence
of diabetes mellitus. Twenty-four-hour urinary cor-
tisol measurements were unequivocally elevated
at 1832 and 1730 nmol/24 h (normal range 28-221
nmol/24 h). Hypercortisolemia and elevated lev-
els of ACTH were confirmed. Levels of ACTH and
ACTH precursors (POMC and pro-ACTH), measu-
red by a two-site IRMA (Dr. White, University of
The post-operative course was uneventful. She was
maintained on 30-mg hydrocortisone daily. She lost
13 kg and was normotensive at her first review one
month later. Hirsutism was much improved, as was
her complexion and proximal myopathy. Repeat
investigations revealed normal electrolytes with
suppressed cortisol production (09:00 h cortisol 15
nmol/l). Urinary free cortisol remained normal (105
nmol/ 24 h) and ACTH was undetectable at that
time. Although she had some difficulty in reducing
her steroids initially, these have now been stopped.
A recent synacthen test showed a good response
with the cortisol level rising from 236 nmol/l to 838
nmol/l. She remains on estrogen replacement with
no evidence of osteoporosis on DEXA scanning
and has normal thyroid function. There continues
to be no evidence of hypercortisolism 3 years af-
ter surgery.
Fig. 1 - Light micrograph of index case’s sister. At operation a
cystic ovary measuring 160x110x80 mm was removed. Histo-
logically it was a monodermal ovarian cyst consisting of thyroid
tissue with colloid containing follicles. It was cytologically be-
nign. Here the right ovary is shown with several small nodules
of implanted thyroid tissue at the surface. Omental implants
were also present.
803

Ovarian dermoid cyst producing ACTH
Table 3 - Results of two-site IRMA of ACTH and ACTH precursors.
ACTH (pmol/l)
ACTH precursors (pmol/l)
Ref. range 5-40 pmol/l
ACTH precursors/ACTH ratio
Pituitary Cushing’s range 2-12
Ref. range <18 pmol/l
Ectopic ACTH syndrome range 7-316
(Southampton assay) 27
(Manchester assay) 23
111
4.83
DISCUSSION
ACTH. In ectopic ACTH production, this process-
ing is deranged, giving rise to an excess of ACTH
precursors compared to ACTH i.e. a high ACTH
precursors/ACTH ratio. Stewart et al. found that in
the ectopic ACTH syndrome the ratio was high (me-
dian 48, range 7-316), compared to patients with
pituitary-dependent Cushing’s disease (median 4,
range 2-12) and controls (median 3, range 1-10) (1).
The ACTH precursor/ACTH ratio in this case is in
the pituitary-dependent Cushing’s range, indicat-
ing correct, pituitary-like processing of POMC.
Another exception has proved to be corticotroph
macroadenomas, representing up to 20% of pa-
tients with pituitary-dependent Cushing’s syndrome
(13). Gibson et al. demonstrated impaired POMC
processing in these tumors, the median ACTH pre-
cursor/ACTH ratio was again grossly elevated at 28
(range 15-181) (14).
Finally, this case is unusual because of the relative
rarity of familial dermoid cysts, although the tumors
themselves represent 10-20% of all ovarian tumors.
This phenomenon has been reported on only 12
occasions to date, which relate to 34 cases (5).
Interestingly in Kim et al.’s report, familial teratomas
are more often bilateral (46 vs 25%) in non-familial
cases (5). Dermoid cysts occur following self-fertil-
Theoretically a dermoid cyst, or cystic teratoma can
contain any body tissue, although ectodermal tis-
sue predominates. It is surprising therefore that so
few cases of tumors containing anterior pituitary
have been reported (6-11). An even rarer phe-
nomenon is the secretion of pituitary hormones in
active amounts (9). Two case reports of Cushing’s
syndrome secondary to teratomas have been pre-
viously described (10, 11). The former did not es-
tablish the definite presence of a pituitary tumor but
the latter demonstrated a chromophobe adenoma
that stained histochemically for ACTH. The case pre-
sented here using modern investigation techniques
demonstrates active pituitary tissue which is cor-
rectly processing ACTH. Thus it is an exception to
the diagnosis of ectopic ACTH production.
Biochemical criteria for ectopic ACTH-induced
Cushing’s syndrome have included ACTH>100 ng/l
(12). However, it has subsequently been demon-
strated that “ACTH precursors characterize the ec-
topic ACTH syndrome” (1), as ACTH levels can
overlap between pituitary-dependent and ectopic
ACTH-induced Cushing’s disease. POMC is modi-
fied in the pituitary in a co-ordinated fashion to pro-
duce pro-ACTH, ꢀ-LPH, N-POMC, ꢀ-endorphin and
Fig. 2 - Macroscopic appearances of the bilateral ovarian cysts
with fallopian tubes, uterus and cervix attached. Both ovaries
were replaced with cystic masses (right 155x130x95 mm, left
150x80x90 mm).
Fig. 3 - Light micrograph of right ovary; decalcified section
showing neuroendocrine tissue with resemblance of the carci-
noid tumor. Immunostaining was positive for ACTH.
804

J. Watson, M. Taylor, J. Pampiglione, et al.
8. Fenoglio C., Tlasma G., Habif G.
ization of a single germ cell (parthenogenesis) af-
ter the first meiotic division (15). It has been pro-
posed that mutant genes may affect the normal
process of meiosis and predispose to their forma-
tion (16). In a transgenic mouse study targeted
over-expression of bcl-2 in the ovaries of these an-
imals lead to an increased susceptibility to the for-
mation of benign cystic ovarian teratoma (17). This
needs further clarification and work such as the
Linkage Consortium for testicular teratomas may
answer this question in the future.
Pituitary containing benign teratoma of the ovary in a
patient with metastatic breast cancer: a case report.
Diagn. Histopathol. 1982, 5: 143-150.
9. Palmer P.E., Bogojavlensky S., Bhan A.K., Scully
R.E.
Prolactinoma in wall of ovarian dermoid cyst with
hyperprolactinemia.
Obstet. Gynaecol. 1990, 75: 540-543.
10. Kronke E., Parade G.
Morbus Cushing bei ovarial teratoma.
Z. Clin. Med. 1938, 134: 698-718.
11. Axiotis C.A., Lippes H.A., Merino M.J., Kinder B.
Corticotroph cell pituitary adenoma within an ovar-
ian teratoma.
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