Download Primary AdenosquamousCarcinoma of the Liver Which Produces

CASE REPORT
Primary AdenosquamousCarcinoma of the Liver Which
Produces Granulocyte-Colony-Stimulating Factor and
Parathyroid HormoneRelated Protein: Association
with Leukocytosis and Hypercalcemia
Tatsuhiko Hayashi, Akira Mizuki, Takuya Yamaguchi, Tasuku Hasegawa, Takamu Kunihiro,
Nobuhiro Tsukada, Kentaro Matsuoka*, Hideki Orikasa* and Kazuto Yamazaki*
Abstract
parathyroid hormone related protein (PTHrP) are responsible
A 55-year-old man was admitted to our hospital with
fever and vomiting. Abdominal computed tomography (CT)
revealed multiple low density masses in the liver. A diagnosis of primary adenosquamouscarcinoma of the liver was
confirmed by histological examination of a necropsy specimen. The present case showed leukocytosis and hypercalcemia with high levels of serum granulocyte-colony-stimu-
lating factor (G-CSF) and parathyroid hormone related
protein (PTHrP). Recent studies have shown that G-CSF
and PTHrPare responsible for the paraneoplastic syndromes with leukocytosis and hypercalcemia. The tumor
cells demonstrated positive cytoplasmic immunohistochem-
istry staining with anti-G-CSF and anti-PTHrP antibodies. This result suggested that the tumor produced G-CSF
and PTHrP.
(Internal
Medicine 40: 631-634, 2001)
Key words: primary
liver tumor, paraneoplastic syndrome,
cytokine
for these types of paraneoplastic syndromes. Wereport here a
rare case of primary adenosquamouscarcinoma of the liver
associated simultaneously with leukocytosis and hypercalcemia, with some discussion of the literature.
Case Report
A55-year-old manwas admitted to our hospital for a lowgrade fever and vomiting on June 5, 1999. He had no history of
blood transfusion. His family history was not contributory. On
physical examination, his body temperature was 37.8°C, his
blood pressure was 140/72 mmHg,and his pulse rate was 74/
min and regular. There was no jaundice. Cervical and supraclavicular lymph nodes were not palpable. Abdominal examination revealed a tender liver, extending seven finger-breadths
belowthe right costal margin. Therewasno ascites.
Table 1 shows the laboratory values on admission. Erythrocyte sedimentation rate (ESR) was 106 mm/h and C-reactive
protein (CRP) was 17 mg/dl. Total white blood cell (WBC)
count was 27,500/jil, absolute neutrophil (segment and bands)
count (ANC) was 23,500/|il (85.5%). Blast and immature cells
were not found in the peripheral blood. Blood chemistry was
within
Introduction
the normal range except for elevated
aspartate
amionotransferase
(AST) and alkaline phosphatase (ALP).
Hepatitis B viral surface antigen and hepatitis C viral antibody
were negative. The levels of serum a-fetoprotein (AFP) and
carcinoembryonic antigen (CEA) were within the normal range.
The levels of serum carbohydrate antigen 19-9 (199.7 U/ml,
normal range <37 U/ml) and squamous cell carcinoma related
antigen (6.6 ng/ml, normal range <1.5 ng/ml) were moderately
high. Protein induced by vitamin K antagonist-II (PIVKA-II)
was also elevated to 45 mAU/ml(normal range <40 mAU/ml).
There was markedly elevated ANC,although no evidence of
factor (G-CSF) and active infectious disease was found. His serum G-CSFwas el-
Adenosquamous carcinoma (ASC) is a tumor composed of
both squamouscell carcinoma and adenocarcinoma components. Primary adenosquamouscarcinoma of the liver is rare.
All the reported cases were in an advanced stage and had a
poor prognosis. On the other hand, it is well known that the
paraneoplastic syndromesof leukocytosis and hypercalcemia
sometimesoccur in malignancies. Thecoexistence of leukocytosis and hypercalcemia in certain cancers has been reported
( 14-1 8). Granulocyte-colony-stimulating
From the Department of Internal Medicine and *the Department of Pathology, Tokyo Saiseikai Central Hospital, Tokyo
Recieved for publication June 15, 2000; Accepted for publication December 1 8, 2000
Reprint requests should be addressed to Dr. Nobuhiro Tsukada, the Department of Internal Medicine, Tokyo Saiseikai Central Hospital, 1 -4- 1 7 Mita, Minatoku, Tokyo
Internal
108-0073
Medicine Vol. 40, No. 7 (July 2001)
631
Hayashi et al
Tablel. Laboratory Data on Admission
Erythrocyte
sedimentation rate
Hematology
White blood cell
Segment
Band
Lymphocyte
Monocyte
Eosinophil
Basophil
Red blood cell
1 06 mm/h Blood Chemistry
Total protein
6. 9 g/dl
27,500/^,1
Albumin
84%
Sodium
1.5%
Potassium
5 %
Chloride
6.5%
Calcium
3%
Blood urea nitrogen
0%
Creatinine
390x l 04/|al
Total bilirubin
2.9 g/dl
1 35 mEq//
3.6 mEq//
95 mEq//
1 2.6 mg/dl
1 2 mg/dl
0. 6 mg/dl
0.8 mg/dl
Hemoglobin
8.5 g/dl
Aspartate aminotransferase
Hematocrit
26.3 % Alanine aminotransferase
Platelet
493x 1 OVjxl
Lactate dehydrogenase
Serology
Alkaline
phosphatase
C-reactive protein
1 7 mg/dl
y-Glutamyltranspeptidase
Hepatitis B viral surface antigen
(-)
Cholinesterase
Hepatitis C viral antibody
(-)
Others
Tumor marker
G-CSF
oc-fetoprotein
1.2 ng/ml
PTHrP
Carcinoembryonic antigen
1.4 ng/ml
Intact PTH
Carbohydrate antigen 19-9
199.7 U//
Interleukinl a
SSC
6.6 ng/ml
Interleukinl p
PIVKA-II
45 mAU/ml
Interleukin-6
36 IU//
24 IU//
246 IU//
654 IU//
45 IU//
1 ,6 1 0 IU//
79 pg/ml
l O PMol//
6 pg/ml
10.5 pg/ml
<10 pg/ml
95.7
pg/ml
G-CSF: granulocyte-colony-stimulating
factor, PTHrP: parathyroid hormone related protein, intact PTH: intact
parathyroid hormone, SSC: squamous cell carcinoma related antigen, PIVKA-II: protein induced by vitamin K
antagonist
-II.
evated to 79 pg/ml (normal range <6-21 pg/ml). The serum
level of interleukin la (10.5 pg/ml, normal range <7.8 pg/ml)
and interleukin 6 (95.7 pg/ml, normal range <4 pg/ml) were
high, while interleukin lp (<10 pg/ml) was within the normal
range. On August 2, 1999, his serum level of calcium was elevated to 12.6 mg/dl and the serum level of PTHrP was high
( 10 PMol//, normal range <0.6 PMol//), while serum intact PTH
was low (6 pg/ml, normal range 10-65 pg/ml).
Computed tomograghy (CT) showed multiple nodules located in the anterior and medial segment of the liver (Fig. 1). A
fine-needle biopsy of the liver tumor revealed squamous cell
carcinoma. Since there wasno evidence of other primary sites,
a diagnosis of primary squamous cell carcinoma of the liver
was made. However, because of the rapid development of the
liver tumor, the patient died of liver failure 64 days after admission to the hospital. Uponautopsy, the liver weighed 4,300
g, and showed a solid whitish tumor, 5 cmin diameter, located
in the anterior segment of the liver, with diffuse small nodules
invading into two lobes (Fig. 2). Histologic examination revealed that the liver tumor was composedmainly of squamous
cell carcinoma and partly of focal areas of adenocarcinoma
(Fig. 3). No carcinomas were found in the gallbladder, stomach, pancreas or other organs. Finally, a diagnosis of primary
ASCwas confirmed. In addition, the tumor was immunostained
using antisera against G-CSF (Fig. 4) and PTHrP (Fig. 5). Some
tumor cells were positively stained. This demonstrated that the
tumor produced G-CSF and PTHrP.
632
Figure 1. Abdominal computed tomography scan showed multiple low density masses in the anterior and medial segment of
the liver.
Discussion
Adenosquamouscarcinoma (ASC) is a tumor which is composed of elements of both adenocarcinoma and squamous cell
carcinoma. Since the description of Pianzola and Drut in 1971
(1), only 34 cases (including the present case) of a primary
Internal
Medicine Vol. 40, No. 7 (July 2001)
G-CSFand Hepatic AdenosquamousCarcinoma
Figure 2. Uponautopsy, the liver demonstrated a solid whitish
tumor, 5 cm in diameter, located in the anterior segment, with
diffuse small nodule invasion into two lobes.
Figure 4. Immunostaining of the tumor tissue with monoclonal
anti -G-CSF antibodies demonstrated positive cytoplasmic stain-
Figure 3. Microscopic findings of the tumor obtained from the
autopsy showed both squamous cell carcinoma and adenocarcinomacomponents. HEstain, x75.
Figure 5. Immunostaining of the tumor tissue with monoclonal
anti-PTHrP antibodies demonstrated positive cytoplasmic staining
of the tumor cells. Avidin-biotin peroxidase complex method,
xl50.
liver tumorwith similar composite histology of areas of adenocarcinoma and squamouscell carcinoma, such as ASC,
mucoepidermoidcarcinoma or adenoacanthoma, have been
reported (2-4). Amongthose 34 cases, ASC was found in only
26 cases, including the present case, with definitive histological studies. This histologic type of hepatic ASCis not consistently found in a particular site within the liver and shows no
evidence of being related to hepatitis virus. ASC typically develops in the gallbladder, the extrahepatic bile duct, or the pan-
creas, but rarely in the liver. The diagnosis of primary ASCof
the liver should be madewhenboth malignant squamousand
glandular elements are present, and primary cancers of the gallbladder, pancreas, extrahepatic bile duct, or lungs should be
ruled out. ASCof the liver is currently assumed to originate
Internal
Medicine Vol. 40, No. 7 (July 2001)
ing of the tumor cells. Avidin-biotin
xl50.
peroxidase complex method,
from the intrahepatic bile duct. This tumor is considered to be
a subtype of cholangiocarcinoma,whichis not a commontype
of liver malignancy. However, the histogenesis of the tumor is
still largely unknown.Someinvestigators support the theory
that the tumor might develop by transformation of pre-existing
adenocarcinoma in the transitional areas between adenocarcinoma and squamous cell carcinoma (5, 6). Concerning the
pathogenesis, somereports have demonstrated that ASCis associated with hepatolithiasis
(7, 8) or hydatid cysts (1, 9) which
have been proposed as etiological factors. But the present case
did not have these complications.
It is well known that both leukocytosis and hypercalcemia
are considered to be paraneoplastic syndromes associated with
633
Hayashi et al
a variety of malignancies. Recently, it has been reported that
G-CSFis responsible for this kind of paraneoplastic syndrome.
More than 200 cases of G-CSF-producing tumors have been
reported since Asano et al (10) reported the first case of a patient with lung cancer in 1977. The present case had associated
leukocytosis, even in the absence of active infectious diseases,
and had an elevated level of serum G-CSF. Positive staining of
the tumor cells by immunohistochemistry with monoclonal anti-
carcinoma of the liver resected by right trisegmentectomy: Report of a
case and review of the literature. J Gastroenterol 32: 843-847, 1997.
3) Miki M, Mizuno Y, Yamaguchi T, et al. Adenosquamous carcinoma of the
liver associated with high fever and hypercalcemia. Nippon Shokakigeka
Gakkai Zasshi 31: 1559, 1998 (in Japanese).
4) Kurashita Y, Okushima N, Isa T, et al. A case of adenosquamous carcinoma of the liver presenting as liver cystadenocarcinoma. Nippon
Shokakibyo Gakkai Zasshi 96: A264, 1999 (in Japanese).
5) Barr RJ, Hancock DE. Adenosquamous carcinoma of the liver. Gastroen-
Concerning the biological relationship of G-CSF and tumor
growth, it has been reported that G-CSFalso stimulates
nonhematopoietic tumor cells. G-CSF-producing tumor cells
expressed a G-CSFreceptor which induces tumor cell growth
by G-CSFvia the autocrine pathways (1 1). For this reason GCSF-producing tumors usually grow rapidly and the prognosis
is extremely unfavorable. Recent studies have shownthat the
G-CSF producing tumor is a multi-cytokine-producing
tumor
which secretes IL-1 and IL-6 in addition to G-CSF(12). IL-1
levels may exceed those of G-CSFand IL-6. The present case
also showed elevated serum levels of IL-1 and IL-6. This suggests that IL-1 mayplay an important role in the regulation of
G-CSF and IL-6 production in this G-CSF producing hepatic
nomaof the liver. Acase report and review of the literature.
terology
69: 1326-1330,
1975.
G-CSFantibodies revealed that the tumor cells produce G-CSF. 6) Hamaya K, Nose S, Mimura T, Sasaki K. Solid adenosquamous carci-
tumor.
Jpn 41:
834-840,
1991.
Acta Pathol
7) Hu TJ, Chen MF, Jan YY, Chen TJ. Adenosquamous carcinoma of the
liver. Report of two cases. Chang Keng I Hsueh ll: 152-159, 1988.
8) Horiuchi T, Sakaguchi M, Oka S, et al. A case report of adenosquamous
carcinoma of the liver with hepatolithiasis.
Nippon Shokakigeka Gakkai
Zasshi 24: 880-884, 1991 (in Japanese).
9) Tokunaga S, Matsuo T, Shimokawa I, et al. An autopsy case of adenosquamous carcinoma of the liver. Shokakigeka 8: 1657-1660, 1985 (in
Japanese).
10) Asano S, Urabe A, Okabe T, Sato N, Kondo Y. Demonstration of
granulopoietic factors in the plasma of nude mice transplanted with a
human lung cancer and in the tumor tissue. Blood 49: 845-852, 1977.
1 1) Tachibana M, Miyakawa A, Tazaki H, et al. Autocrine growth of transitional cell carcinoma of the bladder induced by granulocyte-colony stimulating factor. Cancer Res 55: 3438-3443, 1995.
12) Suzuki A, Takahashi T, Okuno Y, et al. IL-1 production as a regulator of
G-CSF and IL-6 production in CSF-producing cell lines. Br J Cancer 65:
Furthermore, hypercalcemia also occurred in the present
515-518,
1992.
case. His serum PTHrPlevels were elevated. PTHrPhas been
13)
Broadus
AE,
Ikeda K, et al. Humoral hypercalcemia of canidentified as a major causative peptide for hypercalcemia in cer. IdentificationManginof M,
a novel parathyroid hormone-like peptide. N Engl J
malignancies (13). The immunohistochemistry study of the Med 319: 556-563, 1988.
present tumor tissue demonstrated positive staining for PTHrP. 14) Yoneda T, Nishimura R, Kato I, Ohmae M, Takita M, Sakuda M. FreThis suggests that the tumor produces PTHrPwhich is respon- quency of the hypercalcemia-leukocytosis syndrome in oral malignansible for hypercalcemia. The concomitant existence of leuko- cies. Cancer 68: 617-622, 1991.
cytosis and hypercalcemia has been reported in cancers of the 1 5) Yazawa S, Toshimori H, Nakatsuru K, Katakami H, Takemura J, Matsukura
S. Thyroid anaplastic carcinoma producing granulocyte-colony-stimulatoral mucosa (14), thyroid (15), lungs (16), gallbladder (17),
ing factor and parathyroid hormone-related protein. Intern Med34: 584588,
1995.
and cholangiocarcinoma (18). It is still uncertain whether leukocytosis and hypercalcemia are complicated randomly or if 16) Sakamoto A, Katakami H, Mukae H, et al. Simultaneous production of
there are some factors commonlyregulating them. IL-l is a parathyroid hormone-related protein (PTHrP) and granulocyte-colonyfactor (G-CSF)in lung cancer patient with hypercalcemia
osteoclast-activating
factor which causes hypercalcemia syn- stimulating
and leukocytosis.
Nippon Kyobu Shikkan Gakkai Zasshi 33: 34-38, 1995
ergistically
with PTHrP (19). IL- 1 is also a hemopoetin- 1 , which
Japanese).
potentiates G-CSF-induced leukocytosis. Sato et al (19) re- 17)(in Kuroki
M, Uto H, Ido A, et al. A case of gallbladder cancer producing
ported that IL-1a has dual effects on the development of leu- granulocyte-colony-stimulating
factor and possible parathyroid hormone
kocytosis and hypercalcemia. However, the detailed mecha- related protein. Nippon Shokakibyo Gakkai Zasshi 97: 478-483, 2000
Japanese).
nism of hypercalcemia-leukocytosis syndromeis not clear. In 18)(in Aizawa
M, Koshiyama H, Inoue D, et al. Postoperative aggravation of
order to elucidate it, further investigation will be necessary.
hypercalcemia-leukocytosis syndromein a case of squamouscell type
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