Neurol Med Chir (Tokyo) 41, 406¿410, 2001

Metastatic Bronchogenic Carcinoma with Human
Chorionic Gonadotropin Production Manifesting
as Cerebellar Hemorrhage
—Case Report—
Hideki SAWA, Katsushi TAOMOTO, Norihiko TAMAKI*, Chiho OBAYASHI**,
and Ryuichiro NISHIMURA***
Departments of Neurosurgery and **Pathology, Hyogo Medical Center for Adults, Akashi, Hyogo;
*Department of Neurosurgery, Kobe University School of Medicine, Kobe;
***Hyogo Institute of Clinical Research, Akashi, Hyogo

Abstract
A 58-year-old male presented with a rare case of brain metastatic bronchogenic carcinoma with human
chorionic gonadotropin (hCG) production causing cerebellar hemorrhage with symptoms of nausea,
vomiting, and headache. Bronchogenic carcinoma manifesting as gynecomastia had been resected a
few months previously. Neurological examination revealed left cerebellar ataxia. Neuroimaging
showed multiple cerebellar metastases with cerebellar hemorrhage adjacent to the tentorium. Angiography demonstrated tumor staining fed by the hemispheric branch of the left posterior inferior cerebellar artery. Suboccipital craniectomy was performed. The left cerebellar hematoma was evacuated
and the tumor was partially removed to prevent massive intraoperative hemorrhage and avoid brain
stem injury. Histological examination showed the resected tumor was large cell carcinoma. hCG was
detected in the cerebrospinal fluid and was identified by immunohistochemical staining in tumor cells.
The primary lesion of bronchogenic carcinoma showed choriocarcinomatous change because the tumor
could produce hCG. The choriocarcinomatous cells with higher metastatic potential formed lesions in
the brain, and finally intratumoral hemorrhage occurred producing the rapid development of symptoms.
Key words: bronchogenic carcinoma,
metastatic brain tumor

cerebellar hemorrhage,

Introduction

cinoma producing hCG ectopically.

Case Report

Human chorionic gonadotropin (hCG) is a
glycoprotein hormone composed of a- and b-subunits which is normally produced by the trophoblastic tissue of pregnant women and secreted into the
blood and urine. Elevated serum levels of immunoreactive hCG or b-subunit of hCG (hCGb) are
often found in patients with various nontrophoblastic neoplasms, which are known as ectopic
hCG/hCGb-producing tumors.2,4,6–8,16,17) Germ cell
tumors and metastatic choriocarcinoma in the brain
produce hCG. We report a rare case of a cerebellar
tumor which presented as cerebellar hemorrhage
and was identified as a metastatic bronchogenic carReceived

February 19, 2001;

Accepted

human chorionic gonadotropin,

A 58-year-old man noted enlargement and pain in
the breast and a persistent cough in December 1997
for which he sought medical advice. Radiography of
the chest revealed a tumor on the right side thought
to be consistent with bronchogenic carcinoma. The
upper lobe and part of the lower lobe of the right
lung were resected in February 1998. Histological
examination revealed large cell carcinoma thought
to be the primary tumor. Laboratory studies revealed
the serum hCG level was 6.14 ng/ml preoperatively,
which decreased to 0.85 ng/ml postoperatively.
Metastases had spread to the lymph nodes of the
mediastinum, so 50 Gy of local fractionated irradia-

June 1, 2001

406

Metastatic Carcinoma Producing hCG

Fig. 1

Computed tomography scan demonstrating
a large left cerebellar hemorrhage and a
small right cerebellar hemorrhage with
deviation of the fourth ventricle to the right.

Fig. 2

Axial (left) and coronal (right) T1-weighted
magnetic resonance images obtained after
intravenous administration of gadoliniumdiethylenetriaminepenta-acetic acid, demonstrating slightly enhanced masses with
mixed intensity attached to the tentorium.

407

middle cerebellar peduncle and right middle cerebellar peduncle adjacent to the tentorium (Fig. 1).
The lesion appeared as high signal intensity with irregular low signal intensity on T1- and T2-weighted
magnetic resonance imaging with slight enhancement around the lesion after administration of
gadolinium (Fig. 2). Left vertebral angiography
demonstrated tumor staining fed by the hemispheric
branch of the left posterior inferior cerebellar artery.
A midline suboccipital craniectomy was performed. The tense dura was opened, revealing
subarachnoid hemorrhage on the posterior lateral
surface of the left cerebellar hemisphere. The
subarachnoid hemorrhage was removed by suction
to reveal a reddish-brown, soft tumor. The tumor
was removed by Cavitron ultrasonic surgical aspirator in spite of considerable bleeding from the tumor.
An associated large hematoma was aspirated. The
anterior superior portion of the tumor was strongly
adherent to the tentorium. The residual tumor was
removed piece by piece using tumor forceps. The
medial portion of the tumor that had infiltrated the
brain stem could not safely be removed.
Histological examination of the resected specimen revealed that much of the tumor was necrotic.
Surviving portions appeared to be undifferentiated
large cell carcinoma of the same morphology as the
original lung tumor, and was regarded as metastatic
(Fig. 3). However, re-examination of the original
tumor revealed scattered syncytiotrophoblastic-like
giant cells. Similar cells were gathered around the
vessels in the cerebellar tumor. Immunohistochemical study showed that antibody against hCG stained
the cytoplasm of these cells (Fig. 4). This finding was
consistent with the high level of hCG in the
cerebrospinal fluid (37.5 ng/ml), collected during the
operation.
Postoperatively, his cerebellar signs and symptoms were improved. Whole brain irradiation was
planned as adjuvant treatment, but was not performed because the patient suffered ileus of
unknown etiology. The patient died in July 1998 of
progressive cachexia. Autopsy was not permitted.

Discussion
tion therapy was given.
The patient complained of vertigo and subsequent
mild headache in April 1998. On admission, the
patient complained of nausea and vomiting. His vertigo worsened gradually, so the patient was admitted
to our hospital in June 1998.
Neurological examination found left cerebellar
ataxia. Computed tomography revealed high- and
low-density areas in the left cerebellar hemisphere to

Neurol Med Chir (Tokyo) 41, August, 2001

Brain tumor is an important cause of spontaneous,
nontraumatic, intracranial hemorrhage not due to
cerebral aneurysm, vascular malformation, or
hypertensive cerebrovascular disease.10,11,13,14,18)
Hypertension and coagulopathy are thought to be
risk factors of intratumoral hemorrhage in some
cases, but the etiologies of intratumoral hemorrhage
are often considered to be endothelial proliferation

408

H. Sawa et al.

Fig. 4

Fig. 3

Photomicrographs of the metastatic tumor
showing cerebellar tumor tissue composed
of undifferentiated large cells with abundant vessels (upper) and syncytiotrophoblastic-like giant cells (middle). Photomicrograph of the primary lesion demonstrating syncytiotrophoblastic-like giant
cells scattered among undifferentiated
large cells (lower). HE stains, ×400.

Photomicrograph
showing
immunohistochemical staining for human chorionic
gonadotropin in the cytoplasm of the syncytiotrophoblastic-like giant cells. Nuclei
are stained by hematoxylin. ×400.

with vascular obliteration, vessel compression,
and/or distortion due to rapid tumor growth, vessel
necrosis, invasion of vessel walls by the tumor,
and/or increased venous pressure associated with
increased intracranial pressure.9–15,19) The histological features of tumors that bleed microscopically or
macroscopically include tumor necrosis as well as
the vascular changes of vessel-wall hyalinization, degeneration or necrosis of vessel walls, thrombosis,
and the presence of many thin-walled fragile vessels
and ruptured vessels. Hemorrhage from tumors is
also believed to be influenced by treatment, disturbance of venous drainage, or rapid tumor necrosis.
Hemorrhage from a brain tumor was confirmed
clinically, surgically, or at autopsy in 94 of 1861
cases (5.1%) treated during the past 18 years.18)
Hemorrhage was seen in 49 of 311 pituitary
adenomas (15.8%) and in 45 of 1550 other brain
tumors (2.9%).18) The rates of hemorrhage from
primary and metastatic brain tumors were both
2.9%. Among primary brain tumors, malignant
glioma, oligodendroglioma, and germ cell tumors
have the highest risk of hemorrhage.10,18) Among
metastatic brain tumors, choriocarcinoma, malignant melanoma, bronchogenic carcinoma, and renal
cell carcinoma frequently develop significant
hemorrhage.10,11,13,14,18) Both primary and metastatic
choriocarcinomas very frequently show hemorrhage. Such hemorrhage is considered to be due to
the inherent propensity of trophoblasts to specifically invade and destroy vessel walls.14,18) In our case,
the primary lesion in the lung was considered to ex-

Neurol Med Chir (Tokyo) 41, August, 2001

Metastatic Carcinoma Producing hCG
hibit choriocarcinomatous change because the
tumor produced hCG. Apparently the tumor had
metastasized to the cerebellum, then intratumoral
hemorrhage produced the rapid evolution of symptoms.
Ectopic hCG production in carcinomas had been
considered rare, but newer immunohistochemical
methods have shown that some carcinomas can unexpectedly produce hCG.2,4,6–8,16,17) hCG production
in cases of bronchogenic carcinoma that also gave
rise to gynecomastia is rarely reported.5,21) However,
12% of patients with lung cancer had elevated levels
of immunoreactive hCG/hCGb, but the increase in
immunoreactive hCG/hCGb in the serum was
mainly attributable to free hCGb, not to intact hCG
composed of a- and b-subunits.21) In our case, both
intact hCG and free hCGb were examined in the serum using the same methods, finding that the main
hCGb-related molecule was intact hCG but not free
hCGb. The biological activity of hCG is displayed
through the a- and b-subunits and is consistent with
the clinical finding of tumor-associated gynecomastia in our patient. However, most patients do not
show gynecomastia even when the serum level of
immunoreactive hCG/hCGb is highly elevated. This
is understandable given that immunoreactive
hCG/hCGb in the serum exclusively represents free
hCGb, which does not show binding activity with
the gonadotropin receptor.
Ectopic production of intact hCG or free hCGb
mainly occurs in the large cell carcinoma and
adenocarcinoma types of bronchogenic carcinoma.1,3,7,20) Previous immunohistochemical studies on
hCG/hCGb-producing bronchogenic carcinomas
demonstrated that localization of immunoreactive
hCG/hCGb was usually associated with syncytiotrophoblastic giant cells scattered among the
non-trophoblastic carcinoma cells. This finding may
indicate that the non-trophoblastic carcinoma
retrodifferentiated to choriocarcinoma. In our case,
localization of immunoreactive hCG/hCGb was
recognized in the syncytiotrophoblastic-like giant
cells scattered among the undifferentiated large cell
carcinoma cells in the primary lesion of the lung.
Syncytiotrophoblastic-like giant cells were observed
near the hemorrhagic and necrotic areas of the
metastatic lesion. The choriocarcinomatous cells
with higher metastatic potential formed the lesion in
the brain. Ectopic hCG-producing carcinoma has a
very poor prognosis.4,6,16) The hCG-producing cells
are preferentially localized to the deep, most invasive, and highly proliferating tumor areas.4) There is
a significant correlation with high-grade and advanced-stage ectopic hCG-producing transitional
carcinoma of the bladder. A patient with maxillary

Neurol Med Chir (Tokyo) 41, August, 2001

409

squamous cell carcinoma ectopically producing
hCGb developed diffuse pulmonary metastases, liver
and splenic metastases, as well as brain metastasis
in spite of chemotherapy and died of distant disease
less than one year after the initial treatment.16)
Therefore, hCG-producing carcinoma can be expected to metastasize and progress rapidly. Our patient
died 6 months after the initial diagnosis of bronchogenic carcinoma.
Brain tumors manifesting as cerebral hemorrhage
have a poor outcome. Survival time might be
prolonged if the brain metastasis can be identified
before cerebellar hemorrhage occurs. Our patient
suffered cerebellar symptoms of headache and vertigo before the cerebellar hemorrhage, so we suggest
that careful neurological examination is necessary
in patients with ectopic hCG-producing carcinomas
to prevent the serious complication of intratumoral
hemorrhage in brain metastases.

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Address reprint requests to: H. Sawa, M.D., Department of
Neurosurgery, Hyogo Medical Center for Adults,
13–70 Kitaoji–cho, Akashi, Hyogo 673–0021, Japan.

Neurol Med Chir (Tokyo) 41, August, 2001