The n e w e ng l a n d j o u r na l of
case records of the massachusetts general hospital
From the Division of Endocrinology, Dia-
betes, and Hypertension, the Department
of Medicine, Brigham and Women’s Hos-
pital (G.T.M.); the Departments of Radi-
ology (M.A.B.) and Pathology (C.-L.W.),
Massachusetts General Hospital; and the
Departments of Medicine (G.T.M.), Radi-
ology (M.A.B.), and Pathology (C.-L.W.),
Harvard Medical School.
N Engl J Med 2010;362:156-66.
Copyright © 2010 Massachusetts Medical Society.
156
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m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor
Case 1-2010: A 75-Year-Old Man with
Hypertension, Hyperglycemia, and Edema
Graham T. McMahon, M.D., M.M.Sc., Michael A. Blake, M.D.,
and Chin-Lee Wu, M.D., Ph.D.
Pr e sen tat ion of C a se
Dr. Jennifer L. Lyons (Medicine): A 75-year-old man was admitted to this hospital be-
cause of the recent onset of hypertension, hyperglycemia, and edema.
The patient had been in his usual state of health, with borderline hypertension
and glucose intolerance, until 11 days earlier, when at a routine visit to his internist,
the blood pressure was 171/75 mm Hg. The pulse was 73 beats per minute and
the weight 101 kg. The physical examination was normal. The serum levels of total
protein, albumin, globulin, bilirubin, alkaline phosphatase, cholesterol, lipids,
creatine kinase, iron, iron-binding capacity, ferritin, vitamin B12, free thyroxine
(T4), and total triiodothyronine (T3) and tests of liver function were normal; other
laboratory-test results are shown in Table 1. He was instructed to check his blood
pressure and serum glucose levels at home, and a follow-up appointment was
scheduled.
During the following week, the patient reported blood pressures from 160 to
186 mm Hg systolic and from 79 to 82 mm Hg diastolic, and a glucose level (accord-
ing to finger-stick testing after an overnight fast) of 170 to 286 mg per deciliter
(9.4 to 15.9 mmol per liter). He noted ankle swelling, weight gain of 4.5 kg, pain in
both calves that made it difficult to walk, and intermittent double vision. Two epi-
sodes of left-sided epistaxis occurred, which resolved spontaneously. The night
before admission, a frontal headache developed (rated 6 of 10 on a scale in which
10 is the most severe). He recorded a systolic blood pressure of 206 mm Hg. He came
to the emergency department of this hospital at 1:30 a.m.
The patient reported noticing pedal edema intermittently for 1 month, which had
increased during the previous week; one episode of hematuria had spontaneously
resolved. He did not have shortness of breath, orthopnea, paroxysmal nocturnal
dyspnea, fevers, chills, nausea or vomiting, lower abdominal pain, or bowel or uri-
nary symptoms. A diagnosis of hemochromatosis (homozygous C282Y mutation)
had been made 8 years earlier, after routine laboratory tests showed elevated levels
of serum iron and reduced iron-binding capacity, and was treated with regular
phlebotomy. A diagnosis of prostate cancer had been made 22 years earlier and
was treated with radical prostatectomy; pathological examination of the tissue
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The New England Journal of Medicine
 case records of the massachusetts gener al hospital

Table 1. Laboratory Data.*

11 Days before On 2nd Hospital

Variable Reference Range, Adults† Admission Admission Day
Hematocrit (%) 41.0–53.0 (men) 42.2 40.0 37.0
Hemoglobin (g/dl) 13.5–17.5 (men) 14.9 14.6 13.5
White-cell count (per mm3) 4500–11,000 20,500 17,400 12,400
Differential count (%)
Neutrophils 40–70 83 87
Lymphocytes 22–44 13 8
Monocytes 4–11 4 5
Platelet count (per mm3) 150,000–400,000 278,000 146,000 138,000
Sodium (mmol/liter) 135–145 139 139 139
Potassium (mmol/liter) 3.4–4.8 3.5 2.6 2.5
Chloride (mmol/liter) 100–108 101 97 99
Carbon dioxide (mmol/liter) 23.0–31.9 25.3 26.5 32.9
Urea nitrogen (mg/dl) 8–25 21 26 27
Creatinine (mg/dl) 0.60–1.50 0.91 0.91 0.84
Estimated glomerular filtration rate (ml/min/1.73 m2) >60 >60 >60 >60
Glucose (mg/dl) 70–110 150 410 286
Glycated hemoglobin (%) 3.8–6.4 6.0 7.1
Calculated mean glucose (mg/dl) 126 157
Calcium (mg/dl) 8.5–10.5 8.7 8.0 7.8
Total 25-hydroxyvitamin D (ng/ml) 33–100 21
Prostate-specific antigen (ng/ml) <0.1 after radical prostatectomy; 17.02
<1.0 after other treatment
Thyrotropin (μU/ml) 0.40–5.00 0.21
N-terminal pro–B-type natriuretic peptide (pg/ml) 0–900 for age 50–75 yr 2350
Urinary microalbumin (mg/dl) 0.0–2.0 2.3 3.4
Urinary creatinine (mg/ml) Not provided 0.73 0.92
Microalbumin:creatinine ratio‡ <30 31.5 37.0

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter,
multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for calcium to millimoles
per liter, multiply by 0.250.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massa­
chusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may
therefore not be appropriate for all patients.
‡ The ratios were calculated as milligrams of microalbumin per gram of creatinine.

reportedly showed no evidence of lymph-node
metastases, but the serum level of prostate-spe-
cific antigen (PSA) did not fall to 0 after the op-
eration. Four years before admission, the serum
level of PSA was 21.0 ng per milliliter, and admin-
istration of bicalutamide was begun. Six months
later, the level of PSA was 2.3 ng per milliliter,
and 8 months before admission it was 8.75 ng per
milliliter. Bilateral adrenal nodules (2.1 cm by
1.8 cm on the left, and 2.3 cm by 1.1 cm on right)
had been present and stable in size on multiple
computed tomographic (CT) studies of the abdo-
men during the previous 6 years and were thought
to represent adenomas.
Bilateral thyroid adenomas had been present
for 15 years; 11 years before admission, a left thy­
roidectomy revealed a follicular adenoma. A nod-
ule on the right thyroid had been stable; 2 years
earlier, pathological examination of a specimen
from a fine-needle aspiration biopsy showed
benign follicular cells consistent with follicular
adenoma. He had a history of colonic adenomas,

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 The n e w e ng l a n d j o u r na l
and 6 months before admission, a tubular ade-
noma with high-grade dysplasia had been re-
moved during colonoscopy, with no evidence of
residual adenoma on examination of another bi-
opsy specimen 6 weeks later. He had had hypo-
thyroidism since his thyroidectomy; he also had
gastroesophageal reflux disease, osteoporosis,
vitamin D deficiency, hyperlipidemia, migraine
headaches, allergic rhinitis, and depression relat­
ed to his wife’s recent illness and death. An epi-
sode of nephritis had occurred when he was in
his 20s, which had resolved without sequelae.
Five years before admission, a cardiac stress test
and echocardiogram had been normal. He had
had knee and bilateral cataract surgery. His par-
ents had died of congestive heart failure, and a
sister of nephritis; a grandfather had had throat
cancer, and a first cousin colon cancer; his chil-
dren and grandchildren were healthy.
The patient was retired from an office position
and had lived alone since his wife’s death 7 months
earlier. He drank alcohol rarely, had smoked
cigarettes for 10 years but stopped 40 years ear-
lier, and did not use illicit drugs or herbal sup-
plements. Medications included aspirin, loraze-
pam, bicalutamide, celecoxib, chondroitin sulfate,
glucosamine, levothyroxine, a multivitamin with-
out iron, cholecalciferol, and oxycodone–aceta­
minophen. He was allergic to doxazosin, prami­
pexole, and nicotinic acid.
On examination, the temperature was 36.6°C,
the blood pressure 186/79 mm Hg, the pulse 74
beats per minute, the respiratory rate 20 breaths
per minute, the weight 105 kg, and the oxygen
saturation 98% while the patient was breathing
ambient air. The jugular veins were distended to
8 cm when the head was elevated to 30 degrees.
There were mild expiratory wheezes diffusely and
minimal crackles at the both lung bases. The
first and second heart sounds were normal; a soft
systolic murmur (grade 1/6) was heard at the
right upper sternal border. Pulses were 2+ in
the carotid arteries and extremities; no bruits
were heard. There was mild bilateral gyneco-
mastia. The abdomen was soft, with no distention
or rebound tenderness. The liver measured 9 cm
in the midclavicular line. There was 2+ pitting
edema to the knees bilaterally. Funduscopic ex-
amination revealed sharp disks; visual acuity was
20/25 in the right eye and 20/100 in the left eye,
with no diplopia. There was a mild left facial
droop, and plantar responses were equivocal.
The remainder of the examination was normal.
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of m e dic i n e
Tests of coagulation and serum levels of phos-
phorus, magnesium, and lipase were normal;
other laboratory results are shown in Table 1.
Urinalysis revealed glucose 3+ and blood 1+
and was otherwise normal. An electrocardiogram
showed sinus rhythm, with nonspecific ST-seg-
ment and T-wave abnormalities. A chest radio-
graph was normal. CT of the abdomen after the
administration of intravenous contrast material
revealed multiple lesions in the liver (up to 2.5 cm
in diameter), which were hypodense relative to
the hepatic parenchyma after the administration
of intravenous contrast material, and a heman-
gioma in segment 6, which had not changed
from previous studies; bilateral adrenal nodules
had increased slightly in size from previous
studies (2.8 cm by 2.6 cm on the left, and 2.9 cm
by 1.8 cm on the right). The patient was admitted
to the hospital.
Insulin on a sliding scale, hydralazine, furo-
semide, and potassium chloride were adminis-
tered, and sodium was restricted. Laboratory-test
results showed no evidence of myocardial infarc-
tion. On the second day, the blood pressures
ranged from 138 to 175 mm Hg systolic and
from 64 to 79 mm Hg diastolic, and the weight
was 99 kg. CT of the chest performed without
the administration of contrast material revealed
two nodules in each lung, 2 to 4 mm in diameter,
and paratracheal and subcarinal lymph nodes,
0.8 to 1.0 cm in diameter, that had not been
present on a study 6 years earlier. Results of labo-
ratory tests are shown in Table 1. Other test re-
sults were pending.
On the third day, the blood pressure was
180/91 mm Hg. A diagnostic procedure was per-
formed.
Differ en t i a l Di agnosis
Dr. Graham T. McMahon: This 75-year-old man had
a recent onset of hypertension, edema, hypergly-
cemia, and hypokalemic metabolic alkalosis; a
rising level of PSA; and new liver lesions sugges-
tive of metastatic tumor.
The acute onset of hypertension in an older
patient warrants investigation. Acute, severe, or
refractory blood-pressure elevation suggests sec-
ondary hypertension. Pheochromocytoma and
hypothyroidism usually cause symptoms that this
patient did not have, such as palpitations and
constipation, respectively. Physical examination
can provide clues that may suggest renovascular
 case records of the massachusetts gener al hospital

disease, coarctation of the aorta, sleep apnea, and

Cushing’s syndrome. A laboratory evaluation may A
be necessary to rule out primary hyperaldosteron­
ism or primary hyperparathyroidism among oth-
ers.1 In this case, mineralocorticoid excess and
volume expansion are suggested by hypertension
that is accompanied by edema, jugular venous
distention, hypokalemia, and an elevated level of
basic natriuretic peptide. Glucocorticoid excess
is suggested by the presence of hyperglycemia
and neutrophilia. In high concentrations, cortisol
or its metabolites may induce volume retention
by overwhelming 11β-hydroxysteroid dehydroge-
nase type 2 and activating the mineralocorticoid
receptor. B
May we review the imaging studies?
Dr. Michael A. Blake: CT of the abdomen ob-
tained with the administration of intravenous
contrast material on admission (Fig. 1A) shows
multiple new, low-density lesions throughout the
liver, which are highly suggestive of metastatic
disease. The adrenal glands are enlarged, and the
adrenal nodules (Fig. 1B) are bigger than they
were on a scan obtained 2 years earlier. Exami-
nation of the pelvis was interpreted as showing
no changes from previous examinations. Chest
CT at the level of the thyroid gland shows evi- C
dence of the previous left hemithyroidectomy.
There is heterogeneity of the remaining right
lobe, which was stable in appearance and had
been previously sampled, with no evidence of
malignant conditions. Near the level of the hila,
four new pulmonary nodules were noted, 5 mm
or less in diameter, that were suggestive of meta-
static disease (Fig. 1C).
Dr. McMahon: In endocrine disorders, the pace
of the presentation can be an important indica-
tor of the relative benignity of the underlying
disease. In addition, pattern recognition is an Figure 1. Imaging Studies on Admission.
important component of endocrinologic diagno- An axial CT scan of the abdomen obtained after the ad-
sis, since most hormonal disorders present with ministration of contrast material (Panel A) shows mul-
diffuse metabolic and clinical derangements (Ta- tipleICM
low-density
AUTHOR lesions (arrows) with slightly
McMahon RETAKEirregular
1st
walls throughout the liver, features suggestive of metas-
ble 2), as in this case.2 The rapid onset of hyper- REG F FIGURE 1a-c 2nd
tases.
CASEThe TITLE
adrenal glands are enlarged (Panel B), and 3rd
tension and metabolic changes and the presence adrenal nodules (arrows) are bigger thanRevised
the EMail they were
Line 4-C
of new liver lesions raise the specter of paraneo- 2 years
Enon earlier. An image
ARTIST: mst from a chest CT scanSIZEwith a
H/T H/T
plastic Cushing’s syndrome, with severe hyper- lungFILL
window (Panel C) shows two of the new 16p6
Combo bilateral,
cortisolemia. small (5 mm or less in diameter),
AUTHOR, noncalcified nodules
PLEASE NOTE:
(arrows) thathas
Figure arebeen
suggestive of metastases.
redrawn and type has been reset.
Please check carefully.
Cushing’s Syndrome
Cushing’s syndrome results from sustained hy- JOB: 36202 ISSUE: 1-14-09
percortisolemia. The most common cause is ad- disease) accounts for approximately 70% of en-
ministration of exogenous glucocorticoids. Secre- dogenous cases; adrenal tumors and the ectopic
tion of corticotropin from the pituitary (Cushing’s production of corticotropin each account for ap-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Selected Endocrine Paraneoplastic Syndromes.

Clinical Presentation Hormone Most Common Responsible Tumors

Cushing’s syndrome Corticotropin or corticotropin-releasing Small-cell carcinoma of the lung, carcinoid tu-
hormone mors, medullary thyroid carcinoma, pheo-
chromocytoma
Hypercalcemia Parathyroid hormone–related peptide Squamous-cell carcinoma of the lung, skin, head
and neck; renal carcinoma; carcinoid tumors
1,25-Dihydroxycholecalciferol Lymphomas
Acromegaly Growth hormone Carcinoma of the lung, lymphoma
Growth hormone–releasing hormone Small-cell carcinomas, carcinoid, pancreatic
endocrine tumors
Gynecomastia Human chorionic gonadotropin Carcinomas of the lung, bladder, or kidney
Hyponatremia Arginine vasopressin Small-cell carcinoma of the lung, carcinomas
of the head and neck
Hypoglycemia Insulin-like growth factors Epithelial and mesenchymal tumors, hepato-
cellular carcinoma
Hypertension Renin Wilms’ tumor; sarcomas; carcinomas of the
lung, ovary, liver, pancreas
Zollinger–Ellison syndrome Gastrin Pancreatic endocrine tumors, ovarian cancers

Polycythemia Erythropoietin Leiomyoma, renal-cell carcinoma, hepatocellu-

lar carcinoma

proximately 15% of cases.3 The clinical and labo-
ratory features of Cushing’s syndrome overlap
with many other medical conditions, and very
few patients fulfill the classic presentation of
facial rounding, weight gain, striae, hirsutism,
hypertension, and muscle weakness. The major-
ity of patients have abnormal glucose tolerance,
but edema and hypokalemic alkalosis, as seen in
this patient, occur in only a minority. This pa-
tient had gynecomastia, which is not typical in
Cushing’s syndrome but can be a manifestation
of hypogonadism or a consequence of hyper­
estrogenemia from a hormonally active tumor.
Gynecomastia occurs in approximately 10% of
men treated with bicalutamide.
The diagnosis of Cushing’s syndrome requires
the confirmation of hypercortisolism, generally
with the measurement of 24-hour urinary corti-
sol excretion, measurement of midnight salivary
cortisol levels, or both. Autonomous production
of cortisol can be demonstrated with the use of
a dexamethasone (1-mg) suppression test. Once
hypercortisolism is established, a corticotropin
level of more than 20 pg per milliliter (4.4 pmol
per liter) suggests corticotropin dependency; a
level below 5 pg per milliliter (1 pmol per liter)
suggests an adrenal source. When corticotropin
dependency is established, magnetic resonance
imaging can identify pituitary tumors approxi-
mately 60% of the time.4
The patient’s left-sided facial droop and left-
sided epistaxis are not readily attributable to a
benign pituitary adenoma. Nevertheless, pituitary
enlargement in response to a tumor that produces
corticotropin-releasing hormone or a primary be-
nign or malignant pituitary tumor could account
for some of the patient’s visual symptoms.
The standard method for differentiating be-
tween Cushing’s disease and the ectopic produc-
tion of corticotropin involves venous sampling
from the inferior petrosal sinus. Cushing’s dis-
ease is the most likely diagnosis if the sinus-to-
peripheral-vein ratio of plasma corticotropin is at
least 2:1 before or at least 3:1 after injection of
corticotropin-releasing hormone during sampling
from the inferior petrosal sinus. Ectopic produc-
tion of corticotropin is implicated if 8 mg of
dexamethasone does not suppress the plasma
cortisol level, although this test lacks sensitivity.
Adrenal Nodules
The accelerated development of Cushing’s syn-
drome in a patient with known adrenal tumors
introduces the differential diagnosis of adreno-
cortical carcinoma. Adrenal tumors, adrenal hy-
perplasia, and primary pigmented nodular adre-

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 case records of the massachusetts gener al hospital

nocortical disease can all lead to Cushing’s
syndrome, although the presentation of these
conditions tends to be gradual.
Adrenocortical carcinoma is very rare, with an
annual incidence of approximately two cases per
1 million population.5 Of the 60% of adrenocor-
tical carcinomas that are functional (i.e., hor-
mone-secreting), 45% secrete both androgens
and glucocorticoids; the rest secrete glucocorti-
coids alone (45%), androgens alone (10%), or,
rarely, aldosterone (<1%).2 The clinical manifes-
tations of hormone excess in adrenocortical car-
cinomas are rapidly progressive, as in this case.
Imaging can be helpful in differentiating be-
nign from malignant adrenal masses. Low atten-
uation on a CT scan obtained without the ad-
ministration of contrast material suggests a
substantial lipid content that is most consistent
with adrenal adenoma. Adrenal adenomas also
tend to wash out at least 60% of the contrast
material within 15 minutes after contrast ad-
ministration.6 Adrenal cancers generally have an
irregular appearance, high attenuation, and rapid
growth. None of these are apparent in this case,
and the relative stability of this patient’s tumors
in recent years makes a diagnosis of adrenocor-
tical cancer unlikely. It is more likely that the
recent bilateral adrenal enlargement in this case
is due to either adrenal metastases or adrenal
hyperplasia in response to corticotropin than to
the development of hormonally active adrenal
nodules.
The Ectopic corticotropin syndrome
Cushing’s syndrome was first reported in 1928 in
a patient with small-cell lung cancer7; in the
1960s, corticotropin was shown to be the link
between tumors (benign and malignant) and
Cushing’s syndrome.8 In patients with cancer,
Cushing’s syndrome generally develops quickly
and is associated with extremely high levels of
corticotropin and severe hypercortisolemia. Meta-
bolic abnormalities tend to predominate in the
clinical presentation, as in this case. Hypokalemia
is present in approximately 70% of patients with
Cushing’s syndrome and is related to the degree
of hypercortisolemia.9 The physical phenotype of
Cushing’s disease (i.e., facial fullness, a dorsocer­
vical fat pad, and striae) may be absent in patients
with ectopic corticotropin production, since these Though the differential diagnosis remains broad,
signs take weeks or months to develop. Pigmen- this patient’s clinical picture, particularly the
tation appears to be common in patients with acute nature of the presentation, is most consis-
small-cell lung cancer, and neuropsychiatric ab-
normalities have a particular association with
neuroendocrine tumors.
Small-cell lung cancers, bronchial carcinoids,
thymic tumors, islet-cell tumors of the pancreas,
medullary thyroid carcinomas, and pheochromo-
cytomas have all been associated with ectopic
corticotropin secretion. The source of ectopic
corticotropin remains unidentified in approxi-
mately 10% of patients with the syndrome, but
that percentage has declined with improvements
in imaging.10
Colon and Thyroid Carcinomas
The patient had a colonic lesion with high-grade
dysplasia. Although metastatic colonic adenocar-
cinoma has been associated with the ectopic cor-
ticotropin syndrome, these cases are rare.11,12
The patient also had follicular nodules of the thy-
roid. In contrast to medullary thyroid carcino-
mas,13 follicular adenomas and follicular carci-
nomas have not been associated with the ectopic
corticotropin syndrome.
Prostate cancer
This patient had a history of prostate cancer and
progressive elevation in his serum PSA level, de-
spite treatment with the androgen-receptor block-
er bicalutamide. Small-cell neuroendocrine carci-
noma accounts for only 1 to 2% of prostatic
carcinomas,14 and prostatic tumors account for
less than 2% of cases of the ectopic corticotro-
pin syndrome.9 Neuroendocrine cells are found
throughout the prostate and can secrete various
active compounds including corticotropin, sero-
tonin, chromogranin A, neuron-specific enolase,
bombesin, calcitonin, and parathyroid-hormone–
related protein. Neuroendocrine differentiation
in prostate cancer has been reported to occur in
patients treated with androgen ablation15 and
carries a poor prognosis.14 Case reports of pa-
tients with ectopic corticotropin syndrome due to
prostatic neuroendocrine carcinoma suggest that
edema and hypokalemia are common and widely
metastatic disease is present at diagnosis; the
level of PSA is variably elevated.16-22
Sum m a r y

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 The n e w e ng l a n d j o u r na l
tent with a diagnosis of metastatic neuroendo-
crine cancer complicated by ectopic corticotropin
syndrome. While awaiting the results of hormonal
testing and medically stabilizing the patient, I
would obtain a biopsy specimen of one of the
liver lesions to confirm the diagnosis.
Dr. Nancy Lee Harris (Pathology): Dr. Lyons, would
you tell us what the clinical thinking was?
Dr. Lyons: Our suspicion was high for Cush-
ing’s syndrome due to carcinoma metastatic to
the liver. The initial workup included diagnostic
testing for Cushing’s syndrome, including mea-
surement of urinary free cortisol and salivary
cortisol levels, and then we arranged for a liver
biopsy.
Cl inic a l Di agnosis
Metastatic neuroendocrine carcinoma (most like-
ly of prostatic origin), with the ectopic corticotro-
pin syndrome.
Dr . Gr a h a m T. M c M a hon’s
Di agnosis
Metastatic neuroendocrine carcinoma (most like­
ly of prostatic origin), with the ectopic corticotro-
pin syndrome.
Pathol o gic a l Discussion
Dr. Chin-Lee Wu: A fine-needle aspiration of the
liver was performed (Fig. 2). On the cores of liver
tissue, small groups of malignant tumor cells
were seen in lymphatic channels. The tumor cells
are small and round with scant cytoplasm, ill-
defined cell borders, hyperchromatic nuclei with
finely granular chromatin, nuclear molding, and
inconspicuous nucleoli. On immunohistochemi-
cal staining, the tumor cells expressed the epi-
thelial marker cytokeratin, thyroid transcription
factor 1 (TTF-1), and the neuroendocrine marker
chromogranin A; many cells expressed cortico­
tropin, evidence that they are the source of ecto-
pic corticotropin hormone. The tumor cells were
negative for PSA.
Small-cell carcinoma is an aggressive neuro­
endocrine cancer most commonly seen in the
lung, but it can also arise in extrapulmonary
organs, including the prostate.20,23,24 In some pa-
tients who have had a conventional adenocarci-
noma of the prostate, the disease may recur as a
small-cell carcinoma after hormonal therapy and
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of m e dic i n e
present with a paraneoplastic syndrome.25,26 Ap-
proximately half the cases of small-cell carci-
noma of the prostate express TTF-1, a protein
that is frequently expressed in thyroid and pul-
monary tumors, including non–small-cell car-
cinomas.20,23 Prostate markers such as PSA are
usually not expressed in the small-cell carcinoma
of the prostate.20,23,25
In summary, the pathological diagnosis is
metastatic small-cell carcinoma. The origin of
the tumor cannot be determined on the basis of
the pathological findings alone. However, eval-
uation did not reveal pulmonary or other extra-
pulmonary cancers. Thus, the combined patho-
logical and clinical features are most consistent
with small-cell carcinoma of prostatic origin.
Dr. Blake: CT scans of the pelvis performed
1 month after admission show a mass in the re-
gion of the pelvis that is consistent with recurrent
prostatic cancer (Fig. 3A). Although the pelvic
CT scan on admission was initially reported as
showing no change from previous studies, in
retrospect, this mass was present but was par-
tially obscured by streak artifact from surgical
clips. An 18F-fluorodeoxyglucose (FDG) positron-
emission tomographic scan (Fig. 3B) obtained
1 month later showed intense uptake of FDG in
the liver metastases; there was also intense up-
take in bony metastases that was not apparent
on the initial CT scan. The adrenal masses
showed only mild FDG uptake, suggesting that
the increase in their size may have been due to
the influence of corticotropin, as proposed by
Dr. McMahon.
discussion of m a nagemen t
Dr. McMahon: Medical management of hypercor-
tisolemia is often necessary in preparation for
surgery or for palliation. The principal treat-
ments are metyra­pone and ketoconazole.27 Me-
tyrapone would need to be used cautiously in this
case, since inhibition of 11β-hydroxylase may in-
crease androgen levels in the presence of an ele-
vated corticotropin level. Ketoconazole may be
especially appropriate for a patient with prostate
cancer, since it should reduce androgen produc-
tion in the adrenal gland.28 Other drugs include
aminoglutethimide,29 mitotane,29,30 mifepristone,
and somatostatin analogues.31 Surgical adrena-
lectomy is occasionally necessary if excision of
the corticotropin-producing tumor is either im-
possible or not curative.
 case records of the massachusetts gener al hospital

A B

C D

E F

Figure 2. Liver-Biopsy Specimen.

A biopsy of the liver (Panel A, hematoxylin and eosin) reveals a cluster of tumor cells in a lymphatic channel
of liver parenchyma. The tumor cells are small and round with scant cytoplasm, hyperchromatic nuclei, a high
ICM cell
nucleus:cytoplasm ratio, and ill-defined AUTHOR
borders.McMahon RETAKE
Immunostaining shows 1st tumor cells are diffusely posi-
that the
FIGURE 2nd
REG F (Panel
tive for the epithelial marker cytokeratin B) 2a-f
and negative for the prostate marker prostate-specific antigen
CASEcells 3rd
(Panel C) and that many of the tumor TITLE
express the neuroendocrine marker chromogranin
Revised A (Panel D), as well
EMail
as corticotropin (Panel E) and thyroid transcription factor 1Line 4-C
(Panel F).
Enon ARTIST: mst SIZE
H/T H/T
FILL Combo 33p9
AUTHOR, PLEASE NOTE:
Dr. Harris: I would like to ask been redrawn syndrome
Dr.hasGeoffrey
Figure wasreset.
and type has been confirmed by markedly elevated
Please check carefully.
Walford from Endocrinology and Dr. Atish Choud­ urinary free cortisol, late-night salivary cortisol,
hury from Medical Oncology JOB: to discuss
36202 their and serum ISSUE: corticotropin
1-14-09 levels. Insulin, spirono­
management of this patient’s disease. lactone, and antihypertensive medications were
Dr. Geoffrey A. Walford (Endocrinology): The used to manage hyperglycemia, hypokalemia,
diagnosis of corticotropin-dependent Cushing’s and hypertension, respectively. Treatment with

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 3. Follow-up Imaging Studies.

An axial image from a pelvic CT scan obtained after the administration of intravenous contrast material shows a
mass (Panel A, arrow) in the region of the prostate that is highly suggestive of a prostatic tumor. The lesion was
ICM
present on admission but was not recognizedAUTHOR McMahon
because RETAKE
of streak artifact from 1st
the surgical clips. An axial image from
REG F FIGURE 3a-d 18 2nd
a positron-emission tomographic scan after the administration of F-fluorodeoxyglucose 3rd
(FDG) shows intense up-
CASE
take of FDG in the liver metastases (PanelTITLE
B, arrows) and in a bony metastasis in the spine (arrowhead). Neither of
Revised
EMail Line 4-C
the adrenal masses show significant uptake, suggesting that their increase in SIZE
size may have been due to the influ-
Enon ARTIST: mst H/T H/Tmethylene diphosphonate bone scan (poste-
ence of corticotropin. Coronal images from a technetium-99m–labeled 33p9
FILL Combo
rior view) (Panel C) and a CT scan displayed on bone windows (Panel D), both obtained 3 months later while the
patient was receiving chemotherapy, show multiple AUTHOR, PLEASE
abnormal NOTE:
foci of radiotracer uptake (arrows) in the bones corre-
Figure has been redrawn and type has been reset.
sponding to sclerotic lesions (arrows) on the CT scan,
Pleasefeatures consistent with bony metastases.
check carefully.

JOB: 36202 ISSUE: 1-14-09

ketoconazole and, later, metyrapone was begun levels fell to values at the low end of the normal
to reduce the synthesis of cortisol. The patient range, and prednisone was begun to prevent the
had a good response to this regimen. Cortisol expected hypoadrenalism. Edema of the lower

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 case records of the massachusetts gener al hospital

extremities resolved, and he was able to discon-
tinue insulin, spironolactone, and antihyperten-
sive agents.
Dr. Atish Choudhury (Oncology): The standard
first-line palliative chemotherapy regimen for
small-cell carcinoma is carboplatin and etopo-
side, which was initiated while the patient was
in the hospital. Soon after the initiation of che-
motherapy, the corticotropin level decreased to
normal levels. The patient’s blood pressure, ede-
ma, and levels of blood sugars and electrolytes
all improved toward normal.
Approximately 3 months later, after four cy-
cles of chemotherapy, restaging by means of CT
scans showed that the liver metastases and pul-
monary nodules had decreased in size. Ketocona­
zole and metyrapone were discontinued. Despite
resolution of visceral disease, the bony disease
progressed.
Dr. Blake: A bone scan with technetium-99m–
labeled methylene diphosphonate (Fig. 3C) and
a CT scan displayed on bone windows (Fig. 3D)
were obtained after the patient had received the
four cycles of chemotherapy. Multiple abnormal
foci of radiotracer uptake in the bones corre-
spond to newly seen sclerotic lesions on the CT
scan, features consistent with bony metastases.
Dr. Choudhury: We suspected that the visceral
disease and the bony disease may represent two
different processes, with the bony disease repre-
senting progression of his original prostatic ad-
enocarcinoma in the bone. Although his PSA
level had been rising while he was taking bicalu-
tamide at initial presentation, we thought that
the progression of his prostatic adenocarcinoma
while his corticotropin levels were high could
have been related to excessive adrenal production
of androgens, which would have overwhelmed
the ability of bicalutamide to inhibit their action.
After the corticotropin level normalized, we re-
started bicalutamide and initiated treatment with
a gonadotropin-releasing hormone agonist (leu-
prolide); the PSA level decreased from 17 to 2 ng
per milliliter.
Unfortunately, despite an excellent initial re-
sponse to chemotherapy, the small-cell cancer
recurred within 2 months after completion of six
cycles of therapy; also, levels of corticotropin and
cortisol rose and symptoms recurred. At this
time, the patient elected not to pursue further
therapy, and he died in the hospital in the com-
pany of family members, approximately 7 months
after the diagnosis.
Dr. Richard J. Lee (Medical Oncology): The pa-
tient expressed gratitude before his death that
he was to be the subject of a case history, so that
others could learn from his experience.
A nat omic a l Di agnosis
Secondary Cushing’s syndrome due to metastatic
small-cell carcinoma of prostatic origin.
Presented at the Medicine Case Conference, February 27, 2009.
Dr. Wu reports being listed as a coinventor on patents related
to the diagnosis of prostate cancer; as of publication, these patents
have not been licensed. No other potential conflict of interest
relevant to this article was reported.
We thank Drs. Robert E. Singer (Internal Medicine), Richard J.
Lee (Medical Oncology), and Giuseppe Barbesino (Endocrinology)
for their assistance in preparing the case presentation.

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