The n e w e ng l a n d j o u r na l
Case Records of the Massachusetts General Hospital
From the Departments of Endocrinology
(J.C.P.), Radiology (M.M.), Hematology
Oncology (P.J.S.), and Pathology (R.I.W.),
Massachusetts General Hospital, and the
Departments of Endocrinology (J.C.P.),
Radiology (M.M.), HematologyOncology
(P.J.S.), and Pathology (R.I.W.), Harvard
Medical School both in Boston.
N Engl J Med 2015;373:2358-69.
DOI: 10.1056/NEJMcpc1506821
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of m e dic i n e
Founded by RichardC. Cabot
EricS. Rosenberg, M.D., Editor NancyLee Harris, M.D., Editor
JoAnneO. Shepard, M.D., Associate Editor AliceM. Cort, M.D., Associate Editor
SallyH. Ebeling, Assistant Editor EmilyK. McDonald, Assistant Editor
Case 38-2015: A 21-Year-Old Man
with Fatigue and Weight Loss
J.Carl Pallais, M.D., M.P.H., Micheal McInnis, M.D., PhilipJ. Saylor, M.D.,
and RoseannI. Wu, M.D., M.P.H.
Pr e sen tat ion of C a se
Dr. Gregory L. Hundemer (Medicine): A 21-year-old man was admitted to this hospital
because of fatigue, weight loss, and lesions in the lungs and liver on radiographic
imaging.
The patient had been in excellent health, running 3 to 5 miles daily and com-
peting in sports, until approximately 3 months before this admission, when in-
creasing fatigue occurred. During the next 6 weeks, his sleep requirement in-
creased from 8 to 20 hours per day. Approximately 2 months before this admission,
he was a passenger in a motor vehicle accident, after which he had an exacerbation
of chronic back pain that he had previously attributed to sports activities. He was
seen in a clinic of another hospital a few days later; a radiograph of the cervical
spine was normal. He took nonsteroidal antiinflammatory drugs as needed for pain.
One week later, he went to the emergency department of a second hospital because
of fatigue, low back pain, and bilateral swelling of the breast tissue. Testing for
Lyme disease was negative. He was advised to discontinue taking the workout sup-
plements (which contained creatine nitrate) that he had been taking for several
years. The next week, he returned to the second hospital because of worsening
symptoms; test results were reportedly unchanged. A muscle relaxant was admin-
istered, without improvement.
One month before this admission, anorexia, nausea, nonbilious nonbloody
vomiting, weight loss, intermittent chills, and anxiety occurred, followed by dys-
pnea with exertion and decreased exercise tolerance (i.e., exercise was limited to
walking several blocks before resting). On evaluation in the emergency department
of the second hospital 3 weeks before this admission, testing for Lyme disease was
negative; other test results are shown in Table1. The stool was positive for occult
blood, and urinalysis revealed trace protein, increased urobilinogen (2.0; reference
range, 0.0 to 1.0), and 9 red cells per high-power field (reference range, 0 to 5).
Diagnoses of anemia and hyperthyroidism were made. The patient was discharged
with instructions to see a gastroenterologist and an endocrinologist.
The next day, on evaluation in a gastroenterology clinic, the patient reported
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 Case Records of the Massachuset ts Gener al Hospital
fatigue, weight loss of 6 kg (from 82 kg to 76
kg), and hematochezia. The body-mass index
(BMI; the weight in kilograms divided by the
square of the height in meters) was 21.6. There
was abdominal guarding and tenderness in the
right lower quadrant, with no hepatomegaly or
splenomegaly. The stool was brown, with occult
blood. Four days later, upper and lower endoscopic
examinations revealed no active bleeding. Patho-
logical examination of bowel-biopsy specimens
was reportedly normal. Ten days later (6 days
before this admission), the patient was evaluated
by an endocrinologist. Thyroid scintigraphy re-
portedly showed elevated and diffuse uptake of
radioactive iodine. Therapy with methimazole and
propranolol was begun.
Two days before this admission, on return to
the gastroenterology clinic, the patient reported
persistent symptoms, as well as cough, sweats,
nocturia, dark urine, and intermittent tremors.
The temperature was normal, the blood pressure
118/50 mm Hg, the pulse 100 beats per minute,
and the BMI 20.0. Wasting of the facial muscle
was noted. The stool was positive for occult
blood. Therapy with ondansetron was begun.
The next day, the blood level of vitamin B12 was
normal; other test results are shown in Table1.
Computed tomography (CT) of the abdomen and
pelvis, performed at the second hospital with the
administration of oral contrast material, revealed
numerous pulmonary masses (up to 4 cm in
diameter) at the lung bases, hepatomegaly with
lesions in the liver (up to 13 cm by 9 cm), mas-
sive retroperitoneal lymphadenopathy, and gyne-
comastia. Because of these findings and at the
request of his family, the patient was referred to
this hospital.
On presentation, the patient reported fatigue
and anxiety, both of which had improved after
treatment with methimazole and propranolol.
He also reported persistent nausea, vomiting,
abdominal discomfort (which he rated at 3 on a
scale of 0 to 10, with 10 indicating the most
severe discomfort), dyspnea, and weight loss of
14 kg in the previous 2.5 weeks. Four years ear-
lier, he had had methicillin-resistant Staphylococ-
cus aureus preseptal cellulitis after trauma above
his right eye. Medications were methimazole,
propranolol, and ondansetron. He had no known
allergies. He lived with his family, attended col-
lege, and had jobs during vacation. He had chewed
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tobacco and drunk alcohol but had stopped doing
both 1 month before this admission; he reported
no use of intravenous illicit drugs. His mother
had Graves disease, his father had hypothyroid-
ism and hypertension, his maternal grandmoth-
er had diabetes mellitus, and his siblings were
healthy.
On examination, the patient appeared to be
fatigued. The vital signs were normal, and the
oxygen saturation was 100% while he was breath-
ing ambient air. There was tender gynecomastia
and inguinal lymphadenopathy on the right side;
the right testicle was larger than the left, with-
out tenderness or fluctuance. Hepatomegaly to
the umbilicus was present. The remainder of the
examination was normal, with no splenomegaly
or palpable lymphadenopathy. The activated par-
tial-thromboplastin time and plasma lactic acid
level were normal, as were blood levels of glu-
cose, total protein, albumin, globulin, phosphorus,
magnesium, calcium, alanine aminotransferase,
amylase, and lipase and results of renal-function
tests; other test results are shown in Table1. Ad-
ditional imaging studies were obtained.
Dr. Micheal McInnis: A chest radiograph showed
bilateral, well-circumscribed pulmonary nodules
and masses. Contrast-enhanced CT scans of the
chest, abdomen, and pelvis showed bilateral pul-
monary nodules and masses, with the greatest
distribution in the lower lung zones (Fig.1A).
No notable mediastinal or hilar lymphadenopa-
thy was present. Bilateral, symmetric gynecomas-
tia was observed (Fig.1B). Multiple heteroge-
neous masses, measuring up to 11 cm in longest
transverse dimension, were distributed through-
out the liver (Fig.1C). A necrotic retroperitoneal
nodal mass was observed in the interaortocaval
position, below the level of the renal hila (Fig.1D).
The third and fourth segments of the duodenum
were compressed and displaced anteriorly by the
retroperitoneal nodal mass. No other notable
retroperitoneal lymphadenopathy was present.
The remaining organs of the abdomen and pel-
vis were unremarkable. Ultrasonography of the
scrotum revealed an area of calcification (3 mm
by 4 mm by 2 mm) in the right lower testicle; the
right testis was 4.0 cm by 2.8 cm by 2.1 cm, and
the left testis was 3.7 cm by 2.6 cm by 2.0 cm.
Dr. Hundemer: The patient was admitted to this
hospital, and diagnostic procedures were per-
formed.
2359
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Laboratory Data.*

23 Days before 1 Day before

Reference Range, Admission, Admission, On Admission,
Variable Adults Second Hospital Second Hospital This Hospital
Hematocrit (%) 41.053.0 (men) 31.5 26.9 27.3
Hemoglobin (g/dl) 13.517.5 (men) 10.5 8.6 8.8
White-cell count (per mm3) 450011,000 14,700 15,100 17,200
Differential count (%)
Neutrophils 4070 80 79.0
Lymphocytes 2244 8 8.8
Monocytes 411 12 10.1
Eosinophils 08 0 0.8
Basophils 03 0 0.4
Platelet count (per mm3) 150,000400,000 386,000 408,000
Mean corpuscular volume (m3) 80.0100.0 82.7 80.1 78.7
Erythrocyte count (per mm3) 4,500,000 3,360,000 3,470,000
5,900,000
Erythrocyte sedimentation rate 41 58 (ref 020)
(mm/hr)
Prothrombin time (sec) 11.014.0 14.3
Prothrombin-time international 0.91.1 1.1
normalized ratio
Sodium (mmol/liter) 135145 135 132
Potassium (mmol/liter) 3.44.8 4.6 4.2
Chloride (mmol/liter) 100108 102 97
Carbon dioxide (mmol/liter) 23.031.9 24 26.2
Alkaline phosphatase (U/liter) 45115 133 249 246
Aspartate aminotransferase (U/liter) 1040 39 62 51
C-reactive protein (mg/dl) 9.9 11.6 (ref <0.3)
Vitamin B12 (pg/ml) 672 (ref 211911)
Thyrotropin (U/ml) 0.405.00 <0.01 <0.01 <0.01
(ref 0.363.74)
Free thyroxine (ng/dl) 0.91.8 2.3 (0.761.46) 2.6 2.6
Triiodothyronine uptake (%) 36.0 (ref 3139)
Free triiodothyronine (pg/ml) 5.1 (ref 2.34.2)
Total triiodothyronine (ng/dl) 60181 224
Thyroid-stimulating immunoglobulins 1.3 Normal <1.0
index (index units)
Thyrotropin-binding inhibiting immuno 0.00 to 1.75 <1.00
globulins (IU/liter)
Antibodies to Borrelia burgdorferi Negative Negative
Luteinizing hormone (mIU/ml) 0.7 (ref 1.59.3)
Follicle-stimulating hormone (mIU/ml) <0.3 (ref 1.418.1)
Testosterone (ng/dl) 249836 338.7 (ref 241827) 753
Cortisol (g/dl) 25.7 at 9 a.m.
(ref 4.322.4)

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 Case Records of the Massachuset ts Gener al Hospital

Table 1. (Continued.)

23 Days before 1 Day before

Reference Range, Admission, Admission, On Admission,
Variable Adults Second Hospital Second Hospital This Hospital
Iron (g/dl) 45160 11 (ref 65175) 17
Iron-binding capacity (g/dl) 230404 147.0 (ref 250450) 126
Iron saturation (%) 7 (ref 2740)
Ferritin (ng/ml) 30300 770 (ref 22322) 824
Lactate dehydrogenase (U/liter) 110210 4720
Alpha-fetoprotein (nonmaternal) <7.9 <0.6
(ng/ml)
Prolactin (ng/ml) 0.115.2 34.3
CA 199 (U/ml) <35 6
Carcinoembryonic antigen (ng/ml) <3.4 3.0

* The term ref denotes the reference range at the other hospital. To convert the values for free triiodothyronine to nano
moles per liter, multiply by 0.1536. To convert the values for iron and iron-binding capacity to micromoles per liter,
multiply by 0.1791.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The
ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical condi
tions that could affect the results. They may therefore not be appropriate for all patients.

Differ en t i a l Di agnosis The cause of gynecomastia can usually be de-

Dr. J. Carl Pallais: This 21-year-old man had pro-
gressive clinical deterioration over the course of
3 months, after relatively nonspecific symptoms
had developed. His most specific features were
gynecomastia, hyperthyroidism, and liver and lung
lesions and a large necrotic retroperitoneal nodal
mass on radiographic studies. I will first address
the possible causes of this patients gynecomas-
tia and hyperthyroidism, because these findings
preceded the imaging studies; then I will deter-
mine whether there is a unifying diagnosis to
explain his other findings.
Gynecomastia
Gynecomastia is caused by excess estrogen activity
relative to androgen activity at the level of the
breast.1,2 Breast tenderness is a feature found pri-
marily during the early proliferative stage of breast
enlargement, typically within the first 6 months of
the disease process, and is characterized by in-
flammation and stromal edema.1,2 In a 21-year-
old patient, gynecomastia would most likely be
caused by persistence of pubertal gynecomastia,
but the presence of tenderness in this patient
points toward an active process of recent onset,
requiring further investigation.1,2
termined by measuring levels of testosterone,
estrogen, luteinizing hormone, and human cho-
rionic gonadotropin (hCG). The presence of
normal hormone levels is indicative of idiopath-
ic gynecomastia, whereas the presence of low
testosterone levels suggests that hypogonadism
is the primary cause of gynecomastia.1,2 These
two relatively common causes of gynecomastia
can be ruled out by the results of the initial
laboratory evaluation, which included testoster-
one levels in the normal and high-normal range
and a suppressed level of luteinizing hormone.
Remaining considerations in this patient include
conditions associated with high-estrogen states
or an hCG-mediated process. Hyperthyroidism
can result in a hyperestrogenic state because of
the sequestration of testosterone by sex hormone
binding globulin and increased aromatase activ-
ity, but levels of luteinizing hormone are not
typically suppressed in hyperthyroid-mediated
gynecomastia.1,2 The low levels of luteinizing
hormone in this case suggest that the normal
and high-normal testosterone levels and the pre-
sumed elevation in estrogen are not physiologic
and are instead caused by circulating hCG, exog-
enous hormone intake, or a tumor that is able to
produce both testosterone and estrogens. In the

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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 1. CT Scans of the Chest, Abdomen, and Pelvis.

An axial image of the chest obtained at the lung window setting (Panel A) shows multiple bilateral pulmonary nod
ules and masses. An image obtained at the softtissue window setting (Panel B) shows bilateral gynecomastia (ar
rows). A contrastenhanced image of the upper abdomen (Panel C) shows multiple liver masses. Another image of
the abdomen (Panel D) shows a conglomerate, necrotic retroperitoneal nodal mass (asterisk).

absence of exogenous hormone intake, a hor- Hyperthyroidism

mone-altering tumor would be the most likely
cause of this patients gynecomastia and specific
biochemical profile (Fig. 2). Some adrenal carci-
nomas and benign testicular stromal tumors (tu-
mors of Leydig or Sertoli cells) have high aroma-
tase activity and can secrete both testosterone
and estrogens.1,2 Other tumors indirectly induce
testicular secretion of both estrogens and testos-
terone through the production of hCG, which
has a high affinity for the luteinizing hormone
receptor in Leydig cells.2-4 Germ-cell tumors are
the neoplasms that are most likely to secrete
hCG, but other nontrophoblastic tumors that
originate in the lungs, liver, stomach, or kidneys
have also been associated with ectopic hCG pro-
duction.4-6
This patient had several signs and symptoms of
hyperthyroidism, as well as elevated thyroid hor-
mone levels and a suppressed level of thyrotro-
pin; these findings confirm the diagnosis of
hyperthyroidism.7,8 The causes of hyperthyroid-
ism can be broadly divided into entities associ-
ated with increased uptake of radioactive iodine
and those associated with decreased uptake.
Thyroiditis, factitious or iatrogenic thyrotoxico-
sis, iodine-induced hyperthyroidism, and thyroid
hormonesecreting tumors are associated with
decreased uptake of radioactive iodine and can
be ruled out in this patient because of the find-
ing of increased uptake of radioactive iodine on
scintigraphy.7,8
Common causes of hyperthyroidism that re-

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 Case Records of the Massachuset ts Gener al Hospital

Hypothalamus
GnRH TRH

Pituitary

LH Thyrotropin
Tumor

Thyrotropin
LH receptor receptor
Testosterone hCG hCG T4 and T3
and estradiol

Gonads Thyroid

Hyperthyroidism

Gynecomastia Diffuse uptake of radioactive iodine

Figure 2. Pathogenesis of Human Chorionic GonadotropinMediated Gynecomastia and Hyperthyroidism.

The secretion of human chorionic gonadotropin (hCG) from a nonseminomatous germcell tumor activates luteiniz
ing hormone (LH) receptors in testicular Leydig cells and promotes the secretion of both testosterone and estradi
ol, subsequently leading to the development of gynecomastia and the suppression of gonadotropinreleasing hor
mone (GnRH) and LH levels. Markedly elevated hCG levels also activate thyrotropin receptors in the thyroid,
resulting in diffuse uptake of iodine and increased synthesis and release of thyroid hormones (T4 and T3) and sub
sequently leading to the development of hyperthyroidism and the suppression of thyroidreleasing hormone (TRH)
and thyrotropin levels.

sult in increased uptake of radioactive iodine
include Graves disease and autonomous thyroid
nodules. Rare causes include hCG-secreting tu-
mors, thyroid-hormone resistance, and thyrotro-
pin-secreting pituitary adenomas. The diffuse
pattern of uptake of radioactive iodine that was
seen on scintigraphy in this case rules out au-
tonomous nodules, which are characterized by
focal uptake on thyroid scans.7,8
In the absence of a congenital receptor signal-
ing defect, diffuse uptake of radioactive iodine in
the thyroid points toward activation of the thy-
rotropin receptor in thyrocytes by one of three
ligands: thyrotropin, antithyrotropin receptor
autoantibodies, or hCG.7,8 This patient had sup-
pressed thyrotropin levels, a finding that rules
out thyroid-hormone resistance and thyrotropin-
secreting adenomas as possible causes. Both
binding and functional assays for antithyrotro-
pin receptor autoantibodies were negative in this
patient. In a patient with overt hyperthyroidism,
assays for antithyrotropin receptor autoanti-
bodies have excellent sensitivity and specificity
for Graves disease, and thus the negative tests
ultimately suggest that the activation of the thy-
rotropin receptor in this patient is caused by
hCG (Fig. 2).9,10
Human Chorionic Gonadotropin
In this patient with tender gynecomastia, a sup-
pressed level of luteinizing hormone, a high-
normal level of testosterone, hyperthyroidism
with a suppressed level of thyrotropin, elevated
and diffuse uptake of radioactive iodine on a

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 The n e w e ng l a n d j o u r na l
thyroid scan, and negative assays for antithyro-
tropin receptor autoantibodies, an hCG-mediat-
ed process should be considered as a possible
unifying diagnosis (Fig.2). The glycoprotein hor-
mone family of which hCG is a member also
includes thyrotropin, luteinizing hormone, and
follicle-stimulating hormone.11,12 These hormones
are closely related heterodimers, and all share
the same alpha subunit, which is noncovalently
bound to different beta subunits that determine
receptor specificity.11
Luteinizing hormone and hCG are highly
homologous and share the same receptor (the
LHhCG receptor). As compared with luteinizing
hormone, hCG has a considerably longer circu-
lating half-life and a more potent effect on the
LHhCG receptor, features that contribute to in-
creased aromatase activity in Leydig cells.2,3,11 The
net result of hCG stimulation is testicular pro-
duction of both testosterone and estradiol, with
subsequent inhibition of pituitary secretion of
luteinizing hormone; this biochemical profile is
consistent with the pattern that was seen in this
patient.
In addition, hCG has low affinity for the
thyrotropin receptor, and thyroid activity is cor-
related to hCG level.11,13-15 A very high hCG
level, which can be present in persons who are
pregnant or have certain tumors, may cause
clinical manifestations of hyperthyroidism. In
the absence of thyrotropin-receptor mutations,
the combination of frank hyperthyroidism and
undetectable thyrotropin levels is typically seen
only when hCG levels are higher than 50,000
IU per liter.16 Several case series involving preg-
nant patients and patients with hCG-secreting
tumors have shown that the prevalence of hy-
perthyroidism increases when the hCG level
rises above the threshold of 50,000 IU per liter
and that hyperthyroidism occurs in up to two
thirds of patients with hCG levels higher than
200,000 IU per liter.15-17 Therefore, in order to
suggest that hCG production is the mechanism
driving this patients hyperthyroidism, we must
assume that his hCG level is at least higher
than 50,000 IU per liter. Given that this patient
most likely meets this criterion and that the
hormone is presumably produced from a tumor,
we can now attempt to interpret the imaging
studies.
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of m e dic i n e
Retroperitoneal Lymphadenopathy
The differential diagnosis for a large retroperito-
neal nodal mass, one of the most prominent
features seen on the abdominal CT in this case,
can be broadly divided into infections, inflam-
matory diseases, and cancers.18 However, the
markedly elevated level of lactate dehydrogenase
(>10 times the upper limit of the normal range),
the presence of multiple lung and large liver le-
sions, and the rapid weight loss strongly suggest
cancer. Leukemia, lymphoma, and germ-cell tu-
mors account for nearly 50% of cancers in this
patients age group.19 All three categories of
cancer can be associated with markedly elevated
levels of lactate dehydrogenase, massive retro-
peritoneal lymphadenopathy, and rapid weight
loss. Because this patient also has gynecomastia
and hyperthyroidism, we should determine wheth-
er any of these tumors that are common in
young adults are also associated with high hCG
production.
The free beta subunit of hCG is expressed in
a large number of tumors and may serve as a
marker of advanced disease, but the intact hCG
molecule is produced at levels higher than the
threshold of 50,000 IU per liter in only very few
cancers. These include germ-cell tumors, molar
pregnancies, and rare tumors with trophoblastic
differentiation.6,20 Given the patients gynecomas-
tia, hyperthyroidism with negative assays for anti
thyrotropin receptor autoantibodies, and clinical
findings suggestive of cancer and given the tu-
mor epidemiology in this patients age group, it
is likely that he has an hCG-secreting germ-cell
tumor.
Germ-Cell Tumors
Germ-cell tumors are either pure seminomas or
nonseminomatous germ-cell tumors. Seminomas
do not commonly produce intact hCG, and if they
do, the levels are typically lower than 1000 IU per
liter.6,21-23 This patient was expected to have a
circulating hCG level of higher than 50,000 IU
per liter, and thus seminoma is an unlikely di-
agnosis. In contrast, approximately 20 to 40% of
nonseminomatous germ-cell tumors produce hCG,
and levels can exceed the threshold of 50,000 IU
per liter. Most nonseminomatous germ-cell tu-
mors are composed of a mix of different cell types,
including elements of seminoma, choriocarcino-
 Case Records of the Massachuset ts Gener al Hospital
ma, teratoma, yolk-sac tumor, and embryonal
cancers. Choriocarcinoma elements are the most
aggressive and the most often associated with
high secretion of hCG and no production of al-
pha-fetoprotein.17,21-23
Although approximately 10% of germ-cell
tumors are extragonadal, the radiographic find-
ing of a right testicular lesion in this patient most
likely points to the source of his metastatic tu-
mor. Testicular germ-cell tumors have a charac-
teristic pattern of spread, and the interaortocaval
distribution of this patients retroperitoneal lymph-
adenopathy further supports a right testicular
origin of the tumor.21 The presence of both liver
and lung lesions and the markedly elevated lac-
tate dehydrogenase level indicate that this patients
germ-cell tumor is in the high-risk category.22
High-risk germ-cell tumors are associated with
hCG levels of higher than 50,000 IU per liter and
thus can account for the observed hormonal im-
balance.
In fact, one of the first patients in whom hCG
was shown to cause hyperthyroidism had fea-
tures similar to those seen in this patient, in-
cluding a testicular nonseminomatous germ-cell
tumor with tender gynecomastia, retroperitone-
al lymphadenopathy, lung metastases, and a very
high level of hCG.24 Since then, approximately 5%
of patients with disseminated nonseminomatous
germ-cell tumors have been found to have hyper-
thyroidism due to high hCG levels. Furthermore,
patients with nonseminomatous germ-cell tu-
mors and frank hyperthyroidism have much higher
levels of hCG, higher levels of lactate dehydroge-
nase, and lower levels of alpha-fetoprotein than do
patients with nonseminomatous germ-cell tumors
and normal thyroid function; this most likely
indicates that the patients with hyperthyroidism
have a greater amount of choriocarcinoma ele-
ments.17 Occasionally, persons with very high
hCG levels have been noted to have hemorrhage
from metastatic sites of choriocarcinoma, a fea-
ture that is referred to as the choriocarcinoma
syndrome and may explain this patients intesti-
nal bleeding.25 In order to establish the diagnosis
of a nonseminomatous germ-cell tumor, I would
review the imaging studies with the help of an
interventional radiologist to determine which of
the numerous lesions would have a high diagnos-
tic yield and be safe for biopsy.
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Dr. Eric S. Rosenberg (Pathology): Dr. Roy, what
was your impression when you initially evaluated
this patient?
Dr. Lipi Roy (Medicine): When we considered
this patients combination of hyperthyroidism,
gynecomastia, multiple pulmonary and hepatic
nodules, and a massive retroperitoneal nodal mass,
we were very concerned that he might have a
germ-cell tumor. As part of his initial workup,
we performed a test for hCG; the level was
higher than 1,000,000 IU per liter, thus making
choriocarcinoma our leading diagnostic consid-
eration. At that point, our next step was to ask for
input from the oncology and urology services to
determine the best options for obtaining a patho-
logical diagnosis.
Cl inic a l Di agnosis
Metastatic germ-cell tumor.
J. C a r l Pa l l a iss Di agnosis
Metastatic nonseminomatous germ-cell tumor
(with prominent choriocarcinoma elements) caus-
ing hCG-mediated hyperthyroidism and gyneco-
mastia.
Pathol o gic a l Discussion
Dr. Roseann I. Wu: The diagnostic procedures
were a fine-needle aspiration and core biopsy of
the liver. The specimen submitted for examina-
tion showed a poorly differentiated carcinoma
(Fig.3A), with a mix of mononuclear tropho-
blasts and large, multinucleated syncytiotropho-
blasts (Fig.3B). The diagnosis of choriocarcinoma
is primarily based on the presence of intermixed
mononuclear trophoblasts and syncytiotropho-
blasts, a finding that distinguishes this tumor
from other germ-cell tumors with only scattered
syncytiotrophoblasts. Hemorrhage and necrosis
are commonly seen in patients with choriocarci-
noma because of the tumors angioinvasive nature.
Results of immunohistochemical staining for
hCG and GATA3 support the diagnosis (Fig.3C
and 3D).26
In men, especially young men, choriocarcinoma
is usually detected as a component of a testicular
mixed germ-cell tumor and is exceedingly rare
2365
 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. Liver-Biopsy Specimens.

Papanicolaou staining of the fineneedle aspirate (Panel A) shows a cluster of mediumtolarge malignant cells with
a moderate amount of granular cytoplasm, irregular and hyperchromatic nuclei, and distinct nucleoli; a mitotic fig
ure is present (arrow). Hematoxylin and eosin staining of the corebiopsy specimen (Panel B) shows normal liver
parenchyma and a biphasic tumor composed of mediumsized polygonaltoround mononuclear cells with vesicular
topale chromatin (mononuclear trophoblasts) and admixed multinucleated cells with abundant eosinophilictovac
uolated cytoplasm (syncytiotrophoblasts). Immunohistochemical staining for hCG (Panel C) shows diffuse staining,
a finding that is most likely a result of the patients high serum hCG levels; the staining is strongest in the multinu
cleated cells. Results of staining for nuclear GATA3 (Panel D) support the trophoblastic differentiation of the tumor.
At a higher magnification, hematoxylin and eosin staining (Panel E) shows the intermixed components of the tumor
adjacent to normal liver.

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 Case Records of the Massachuset ts Gener al Hospital

in its pure form. This patients liver biopsy shows

A
only choriocarcinoma at this metastatic site
(Fig. 3E). Another diagnostic possibility is em-
bryonal carcinoma, which is not typically associ-
ated with syncytiotrophoblasts, is negative for
hCG, and is usually composed of pleomorphic
cells with vesicular nuclei. Carcinomas with tro-
phoblastic differentiation typically have a com-
ponent with the classic features of carcinoma.
There are no morphologic features to suggest
other cancers, such as lymphoma.

Discussion of M a nagemen t
B
Dr. Philip J. Saylor: On the basis of this patients
initial evaluation, he received a diagnosis of a
stage IIIC nonseminomatous germ-cell tumor
(with a tumornodemetastasis, with blood tu-
mor markers, classification of TXN3M1bS3). His
primary tumor was either in the region of the
right testicular calcification or the retroperito-
neal nodal mass. Because choriocarcinoma has
a propensity to metastasize to the central ner-
vous system, the patient underwent magnetic
resonance imaging of the head, which was un-
remarkable.
Prognosis associated with metastatic germ- C
cell tumors is based on the presence or absence
of three clinical factors that are indicative of
poor prognosis: a primary mediastinal tumor,
elevated tumor markers above specific thresholds
after orchiectomy, and nonpulmonary visceral
metastases. This patient had a poor prognosis,
which was indicated by an hCG level substan-
tially higher than the threshold of 50,000 IU per
liter (which was unlikely to drop after orchiectomy)
and by the presence of nonpulmonary visceral
(liver) metastases. Long-term survival among pa-
tients with a poor prognosis is approximately 50%.
Figure 4. Orchiectomy Specimen.
Most men with stage II or III germ-cell tu-
The gross orchiectomy specimen (Panel A) shows
mors (metastatic to nodes or elsewhere) undergo a subcentimeter tantowhite discoloration (arrow),
orchiectomy for tissue diagnosis and removal of with associated firm calcification. Hematoxylin and
cancer from what is considered to be a sanctuary eosin staining of this area (Panel B) shows a small
site, which is not well managed by systemic nodule with bland glandular epithelium, a finding
consistent with a teratoma. Hematoxylin and eosin
therapy. In this case, the absence of a clinically
staining of an adjacent area (Panel C) shows a fi
obvious testicular primary tumor and the pres- brous scar with associated intratubular calcifica
ence of marked functional decline due to sys- tions, a finding consistent with regressed germcell
temic disease argued for systemic therapy from tumor.
the outset.

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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

Standard chemotherapy for a patient with
stage IIIC cancer and a poor prognosis consists
of four cycles of a cisplatin-based triplet regimen.
Given that this patient had substantial lung in-
volvement and was likely to need surgery in the
future, we chose to treat him with VIP (etopo-
side [VP-16], ifosfamide, and cisplatin) to avoid
the long-term risk of pulmonary fibrosis that is
associated with bleomycin.
The patients hCG level and radiographic fea-
tures responded dramatically to therapy but did
not normalize. The hCG level fell from higher
than 1,000,000 IU per liter at baseline to 105.3 IU
per liter after four cycles of VIP. The patient un-
derwent salvage therapy with TIP (paclitaxel, if-
osfamide, and cisplatin) for two cycles, followed
by stem-cell mobilization and two courses of high-
dose chemotherapy with autologous stem-cell res-
cue. At that time, the patient also underwent
radical right inguinal orchiectomy.
Dr. Wu: A specimen was obtained during the
right orchiectomy (Fig.4A). Microscopic exami-
nation shows a small teratoma (Fig.4B) and fi-
brous scar (Fig.4C). In some orchiectomy speci-
mens, metastatic choriocarcinoma appears only
as a regressed germ-cell tumor.27,28 Choriocarci-
noma is the germ-cell tumor that is most likely
to have spontaneous regression because of its
aggressive nature and tendency to outgrow the
blood supply, but regression can be seen in semi-
nomas and embryonal carcinomas. No viable
choriocarcinoma was seen in the orchiectomy
specimen from this patient.
Dr. Rosenberg: Dr. Chu, would you tell us what
happened with this patient?
Dr. Edward W. Chu (Medicine): The patient had
no surgical complications of the right radical
orchiectomy. After the surgery, he started a sub-
sequent regimen of chemotherapy with gem-
citabine and oxaliplatin. At the time of this
conference, the patient has completed two cycles
of this new regimen. Unfortunately, repeat tests
for hCG have not shown any further improve-
ment. Although the patients prognosis is poor
overall, he has shown considerable improvement
since his initial presentation over a year ago.
A nat omic Di agnose s
Metastatic choriocarcinoma involving the liver.
Testicular teratoma with a focus of calcifica-
tion consistent with a regressed germ-cell tumor.
Fina l Di agnosis
Metastatic choriocarcinoma.
This case was presented at Medical Grand Rounds.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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