Received: 20 December 2017 | Revised: 14 February 2018 | Accepted: 16 February 2018

DOI: 10.1002/dc.23920

ORIGINAL ARTICLE

Metastatic hepatocellular carcinoma diagnosed by fine needle

aspiration: A clinical and cytologic study

Lei Yan MD | Shriram Jakate MD | Vijaya Reddy MD | Paolo Gattuso MD

Department of Pathology, Rush University

Medical Center, Chicago, Illinois
Correspondence
Lei Yan, Department of Pathology, Jelke
579, Rush University Medical Center,
600 S. Paulina St., Chicago, Illinois 60612.
Email: lei_yan@rush.edu
Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths world-
wide. The clinical and cytological features of metastatic HCC have not been well established.
Methods: To determine the clinical and cytological features of metastatic HCC, we retrospectively
searched for all HCC metastasis diagnosed by fine needle aspiration or core biopsy.
Results: We found 12 bone metastases, 11 intra-abdominal, 4 lung, 3 soft tissue, and 2 lymph
node metastases from 32 patients. 7/12 bone metastases were vertebral body, 4 were pelvic
bone, and 1 case was humerus. 10/32 cases showed concurrent metastasis at a different location.
The average metastasis size was 40.9 mm. Tumor grades of HCC showed near equal distribution.
The following cytological features are most frequently associated with metastatic HCC: single
tumor cells (88.9%), cytoplasmic vacuolization (70.4%), trabecular pattern (70.4%), bare nuclei
(66.7%), prominent nucleoli (66.7%), tumor giant cells (44.4%), and traversing capillaries (44.4%)
and encased by endothelium (18.5%). Immunohistochemical stains of 12 cases showed the major-
ity were positive for E-Cadherin, Carcinoembryonic Antigen, and HepPar1. Negativity for CK7 and
CK20 is contributory to making the diagnosis.

Conclusion: The most frequent metastatic HCC diagnosed by FNA was from bone, especially the
vertebral body. The frequent cytomorphology and immunophenotype seen in primary HCC are
good diagnostic criteria for diagnosing metastatic HCC.

KEYWORDS
fine needle aspiration, FNA, HCC, metastatic hepatocellular carcinoma, metastasis

1 | INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common primary malig-
nancy of the liver. Globally, liver cancer was the fifth commonest can-
cer in 2012, accounting for 9.1% of all cancer deaths worldwide.1
Cirrhosis due to chronic hepatitis B (HBV) or hepatitis C (HCV) is the
2
leading risk factor for HCC. The disease burden is highest in areas
with endemic HBV infection, such as in the sub-Saharan Africa and
Eastern Asia.3 In the U.S., the most common etiology of HCC is HCV
hepatitis which has increased >10-folds since 1996. In an analysis of
4
National Cancer Institute Surveillance, Epidemiology and End Results
(SEER) Database of the National Cancer institute in the US, liver cancer
*The authors certify that they have no affiliations with or involvement in any
organization or entity with any financial interest or nonfinancial interest in the
subject matter or materials discussed in this manuscript. This study was not
supported by any grant or funding.
incidence rates increased by 3.1% per year from 2008 to 2012 in the
US.5 The overall 5-year survival is <12%, making HCC the fastest rising
cause of cancer-related death in the United States.6
Progress in diagnostic modalities, such as ultrasonography (US),
computed tomography (CT), magnetic resonance imaging, and digital
subtraction angiography has led to a better detection of patients with
early and small HCC. However, the best approach is still to detect HCC
early and by as noninvasive a technique as possible (such as triple-
phase dynamic imaging). Primary HCC can be diagnosed by noninvasive
approaches with serum a-fetoprotein (AFP) levels above 200 ng/mL
and/or a radiological imaging finding of tumor mass larger than 2.0 cm
in patients with chronic liver disease.7 However, if sampling is clinically
indicated, percutaneous FNA biopsy performed under CT or ultrasound
guidance has been adopted worldwide as a safe, efficient and minimally
invasive, low-cost outpatient procedure for the diagnosis of focal liver
lesions. The sensitivity and specificity of percutaneous FNA for

Diagnostic Cytopathology. 2018;1–6. wileyonlinelibrary.com/journal/dc V

C 2018 Wiley Periodicals, Inc. | 1
2 |
detection of liver malignancy are around 90% and 100%, respectively.8
In patients with primary liver cancer and AFP levels <200 ng/mL, per-
cutaneous FNA was found to have a sensitivity of 93.0% and a positive
predictive value of 100%.9 Cytologic features of primary HCC has been
well defined based on cellularity, cohesiveness, architecture pattern,
cellular characteristics, and presence of vascular component.10
Extrahepatic metastasis of HCC occurs in patients with advanced
stage intrahepatic tumor. 73.8% of the patients with extrahepatic
metastases have stage T3 or T4 tumor.11 The frequent metastatic sites
reported are lung, bone, lymph node, adrenal gland, and perito-
neum.12,13 In the published English literature, there are few studies
reporting the cytological features of extrahepatic metastasis of HCC.
The aim of this study is to determine the location, incidence, cytological
features and immunophenotype of metastatic HCC, and correlate with
primary tumor and clinical history.
2 | MATERIALS AND METHODS
2.1 | Study population
We conducted a retrospective study in patients with metastatic HCC
that were detected on imaging studies. A total of 32 patients who
were diagnosed with metastatic HCC by imaging (CT or US) guided
FNA or core biopsies from 1994 to 2016 were analyzed.
2.2 | Study design
The procedures were performed by experienced interventional radiol-
ogists at Rush University Medical Center, Chicago, Illinois. FNA was
performed using commercially available needles. The needle gauges
were at the radiologists’ discretion. For cases with on-site evaluation,
FNA smears were prepared and assessed for adequacy on site by a
cytotechnician/cytopathologist and subsequently confirmed by an
experienced cytopathologist. After tissue acquisition, the FNA speci-
mens were expressed onto a slide. Two slides were air-dried and pre-
pared with Diff-Quik stain for on-site analysis. Remaining FNA aspirate
was placed into a standard cytologic solution for thin prep Papanico-
laou stain and cell block preparation. Each pass was assessed immedi-
ately for cellular adequacy and a final diagnosis was determined after
review of all FNA material.
The FNA cytology and immunohistochemistry results were
retrieved from our pathology files. In total, 27 cases had available Diff-
quick smears, Thinpreps or cell blocks. Five cases had core biopsies
only without smears performed. Six of the 27 cases had Diff-quick
smears only. Four of the 27 cases had Diff-quick smears and Thinpreps
only. One of the 27 cases had Thinprep and cell block only. Four of the
27 cases had only cell blocks available. The distribution of specimen
preparation types is illustrated in Supporting Information Table S1. All
relevant clinical information including age, gender, HBV status, HCV
status, cirrhosis status, primary HCC tumor multiplicity, location of
metastasis, size of metastasis, histologic grade of primary tumor, imag-
ing studies, and clinical follow-up results were retrieved from patients’
YAN ET AL.
electronic medical record in EPIC (Epic Systems Corporation, Verona,
Wisconsin).
2.3 | Statistics
Frequencies and percentages were calculated for categorical variables.
v2 analysis was used to compare the association between categorical
variables and outcomes. The continuous variables were compared with
unpaired t test. A P values < .05 was considered significant and all sta-
tistical analyzes were conducted using GraphPad Prism 7 (GraphPad
Software, Inc., La Jolla, California).
This original research was approved by the local institutional ethics
committee. Only de-identified patient data was used in this study.
3 | RESULTS
A total of 32 patients who underwent imaging (CT or US) guided FNA
or core biopsy sampling of extrahepatic metastasis of HCC from 1994
to 2016 were analyzed. Twenty-four patients were male (75%) and 8
were female (25%). The mean age of patients was 58.7 years (range,
35–76). Six of 32 patients (18.7%) had metastatic HCC as the initial
presentation without a known history of primary liver malignancy at
the time of FNA cytology diagnosis. All of them were men with a mean
age of 58.1 (range, 46–76). In 26 of 32 patients (81.3%), a diagnosis of
primary HCC had been established by liver biopsy prior to the FNA
diagnosis at the metastasis site. Serum HBsAg was positive in 9.1% of
patients (2/22). Serum HCV Ab or HCV RNA was positive in 69.5% of
patients (16/23). Serum AFP was elevated in 76.2% of patients (16/
21). Available past medical history of cirrhosis was found in 58% of the
patients (18/31). Sixty-four percent of patients with primary HCC (16/
25) had multifocal tumor in the liver. Patient and lesion characteristics
are summarized in Table 1.
The most frequent locations of metastatic HCC diagnosed by FNA
were 12 bone (37.5%), 11 intra-abdominal (34.3%), 4 lung (12.5%), 3
soft tissue and musculoskeletal sites (9%), and 2 lymph node (6%).
Seven of 12 bone metastases involved the vertebral body (22% of total
cases). The rest of the bone involvements were 4 pelvic bones and 1
case to the humerus. The most frequent intra-abdominal metastatic
sites were omentum (3/11), peritoneum implants (2/11), pancreas (2/
11), and peripotal tissue (2/11). One of the two lymph node involve-
ment was to the mediastinal lymph node. The other nodal metastasis
was to the periportal lymph node. Ten of 32 patients with metastatic
HCC had concurrent metastasis at a different location. The anatomic
sites of the aspirates are listed in Table 2.
In all cases, the tumor cells resembled hepatocytes to some extent.
Eight of the 21 cases with histology archived were classified as well dif-
ferentiated, 6 cases were classified as moderately differentiated, and 6
were considered to be poorly differentiated. Two metastatic HCC had
histological subtype of fibrolamellar HCC. Histologic grades showed
near even distribution with 40% Grade 1 (8/20), 30% Grade 2 (6/20),
and 30% Grade 3 (6/20) and no stratification by gender, cirrhosis or
HCV status. The average size of metastasis was 40.9 mm (range, 6–
110 mm) and not stratified by locations or histologic grades. The most
YAN ET AL. | 3

T AB LE 1 Patient and lesion characteristics

Total of patients (n 5 32) Percentage

Age, years
Mean 6 SD 58.7 6 11.4

Sex
Male 24 75%
Female 8 25%

Prior diagnosis of HCC 26/32 81.3%

Metastatic HCC at initial presentation 6/32 18.7%

Serum HBsAg 2/22 9.1%

HCVAb or HCV RNA 16/23 69.5%

Serum AFP 16/21 76.2%

History of cirrhosis 18/31 58%

Multifocal primary HCC 16/25 64%

frequent cytologic features associated with metastatic HCC are single
tumor cells (24/27 cases, 88.9%), trabecular pattern (19/27 cases,
70.4%), cytoplasmic vacuolation (19/27 cases, 70.4%), prominent
nucleoli (18/27 cases, 66.7%), bare nuclei (18/27 cases, 66.7%), tumor
giant cells (12/27 cases, 44.4%) (Figures 1–3), transgressing vessels
(12/27 cases, 44.4%), and peripheral endothelial cells (5/27 cases,
18.5%). Bile was seen within cells from only one case (1/27). Immuno-
histochemical stains of 12 cases helped in making the diagnosis of met-
astatic HCC. Immunostains showed the majority of metastatic HCC
were positive for E-Cadherin (91.6%), pericanalicular Carcinoembryonic
Antigen (CEA) (75%) and HepPar1 (87.5%). Negativity for CK7 and
disease. Percutaneous FNA biopsy performed under CT or ultrasound
guidance has been adopted worldwide as a safe, efficient and minimally
invasive, low-cost outpatient procedure for the diagnosis of focal
liver lesions.14 The sensitivity and specificity of percutaneous FNA
for detection of liver malignancy are around 90% and 100%,
respectively.15,16
HCCs are highly heterogeneous tumors with regard to differentia-
tion, histologic patterns and cell morphology. Cytologic features of pri-
mary HCC has been well characterized and include increased
cellularity, discohesiveness, architecture pattern (trabecular- sinusoidal,
pseudoacinar, and compact types), and abnormal cellular characteristics

CK20 was contributory to ruling out metastatic adenocarcinoma from (monomorphous population, increased nuclear-cytoplasmic ratio, nu-

respiratory and gastrointestinal primary.
4 | DISCUSSION
The incidence of HCC is rising in the West due to the increasing inci-
dence of hepatitis C virus infection and the nonalcoholic fatty liver
clear pleomorphism with irregular nuclear contours, prominent nucleoli,
bare nuclei, cytoplasmic vacuolation, and multinucleated tumor giant
cells). Vascular component, such as peripheral endothelium and travers-
ing endothelium (Figures 4 and 5), when present is a strong indicator of
HCC.10 The rapid on-site evaluation further increases the efficacy of

T AB LE 2 The anatomic sites in 32 cases of metastatic HCC diag-

nosed by FNA

Site Total of biopsies (n 5 32) Percentage

Bone 12 37.5%
Vertebral body 7/12 22%
Pelvic bone 4/12 12.5%
Humerus 1/12 3%

Intra-abdominal 11 34.3%
Omentum 3/11 9.4%
Peritoneum 2/11 6.3%
Pancreas 2/11 6.3%
Periportal tissue 2/11 6.3%

Lung 4 12.5%

Soft tissue 3 9.4% FIGURE 1 Clusters of pleomorphic metastatic HCC cells in a

prominent trabecular pattern (Diff-Quick stain, 203) [Color figure
Lymph nodes 2 6.3%
can be viewed at wileyonlinelibrary.com]
4 |
FIGURE 2 Numerous naked tumor nuclei with nuclear
pleomorphism is characteristic of many metastatic HCCs (Diff-
Quick stain, 403) [Color figure can be viewed at wileyonlinelibrary.
com]
FNA by providing rapid Diff-Quik stained smears for assessment of
sample adequacy and triage of specimens for ancillary tests.
A number of antibodies are available for the comparative immuno-
histochemistry studies of primary and metastatic HCC of the liver.
Alpha-fetoprotein (AFP) expression in a tumor is highly specific for
hepatocellular differentiation (95% to 100%), if germ cell tumors can be
17
excluded. Hepatocytes express CK8, CK18, CAM 5.2, and AE1/3,
and are generally negative for CK7, CK19, and CK20.18 Cytoplasmic
and pericanalicular staining of CEA can be seen in about half of HCCs.
The sensitivity is high for well- and moderately differentiated HCC
(>80%) but low in poorly differentiated HCC (25% to 50%).19
Arginase-1 (Arg-1) is a binuclear manganese metalloenzyme that cata-
lyzes the hydrolysis of arginine to ornithine and urea. It functions as a
key enzyme in the urea cycle and is expressed in normal human liver
with a high degree of specificity. A study comparing the sensitivity of
arginase-1 and HepPar-1 in diagnosing HCC found that the sensitivities
of Arg-1 in well, moderately, and poorly differentiated HCCs to be
100%, 96.2%, and 85.7% respectively, slightly higher than the
FIGURE 3 Loose clusters of large anaplastic looking malignant
hepatocytes with associated multi-nucleated tumor giant cells
(Diff-Quick stain, 403) [Color figure can be viewed at wileyonlineli-
brary.com]
YAN ET AL.
FIGURE 4 Three dimensional cluster of metastatic HCC cells.
Note the high nuclear-to-cytoplasmic ratio of the HCC cells and
the flat endothelial wrapping cells at the periphery. (Papanicolaou
stain, 403) [Color figure can be viewed at wileyonlinelibrary.com]
sensitivities of HepPar-1 in corresponding categories (100%, 83.0%,
and 46.4%).20 A study performed on 1,240 surgical specimens and 62
liver FNA specimens demonstrated that Arg-1 had a similar sensitivity
and higher specificity in differentiating a non-HCC from HCC com-
pared with HepPar-1 and glypican-3 (100% vs. 97.4% and 96.7% in
specificity).21 Despite the available immunophenotypic markers, judi-
cious use of immunohistochemistry is imperative due to limited cell
block material.
Extrahepatic metastases of HCC are now observed more fre-
quently due to the improved diagnostic methods and the prolonged
survival of patients. Extrahepatic metastases of HCC have been
reported to occur in 14.0 to 36.7% of patients with HCC.17 In a study
of 482 patients with HCC, the most frequent metastatic sites were
reported to be lung (53.8%), bone (38.5%), lymph nodes (33.8%), adre-
nal glands (16.9%), and peritoneum (9.2%).11,12 Metastasis to spleen is
rare. Only a few cases have been reported in literature. Even fewer
cases were diagnosed by FNA cytology. Reported cytology of spleen
metastasis showed classic cytologic features of HCC and immunostain
FIGURE 5 Prominent transgressing vessels are characteristic of
HCC (Diff-Quick stain, 203) [Color figure can be viewed at
wileyonlinelibrary.com]
YAN ET AL.
pattern.22,23 Serous effusions in patients with HCC are common (about
30% of cases). HCC causes ascites by increasing portal pressure by
replacing liver parenchyma with tumor and/or leading to benign or
malignant thrombosis of the portal vein. However, the presence of
HCC in serous effusions is rarely encountered in clinical practice due to
the low incidence of peritoneal metastasis.24 A study of the incidence
of serous fluid involvement in 44 cases of HCC with serous effusions
showed a low rate of serous effusions metastasis (about 5%, 2 of 44
25
cases) in patients with or without distant metastasis. In a study of
148 patients with extrahepatic metastatic HCC, the most frequent
locations of metastasis were reported to be lung (55%), the abdominal
26
lymph nodes (41%) and the bone (28%). Our experience with FNA in
diagnosing metastatic lesions is that it is being increasingly used as a
dual purpose procedure for correct localization of mass in less accessi-
ble locations such as the bones for core needle biopsies and for acquisi-
tion of cytology specimens. In the present study, the most frequent
locations included bone (37.5%), intra-abdominal (34.3%) and lung
(12.5%), coincided with the reported major metastatic locations with
the exception that very few of our FNAs were from the lung. This phe-
nomenon can be explained by the increasing use of wedge resection
by minimally invasive video-assisted thoracic surgery as a diagnostic
and treatment option. In a study of 20 patients with HCC bone metas-
tasis at initial presentation, the most common site of bone metastasis
was the vertebrae (60%), consistent with our findings in the present
study.27
In the present study, the cytological findings of HCC seen in the
extrahepatic metastatic sites were similar to those that had been found
in the primary HCC, such as trabecular pattern, single tumor cells, bare
nuclei, prominent nucleoli, cytoplasmic vacuolation, peripheral, and tra-
versing endothelium. Our findings confirmed that the same cytologic
criteria for primary HCC could be applied to the diagnosis of HCC at
metastatic sites. Our study showed that 81.3% of patients with meta-
static HCC had a primary HCC diagnosis. Fifty-eight percent of patients
with metastatic HCC had a history of cirrhosis and 76.2% of patients
had elevated AFP. These findings suggest that close correlation with
clinical information can help pathologist achieve an accurate diagnosis
of HCC at metastatic sites. Our data showed that the immunopheno-
type of metastatic HCC was similar to primary HCC in the liver. One
diagnostic challenge of evaluating cytology from a metastatic site is to
differentiate metastatic HCC from metastatic adenocarcinoma from
breast, prostate, lung, and gastrointestinal tract origins. If the patient
has a known primary and the aspirate demonstrates malignant cells,
comparing the FNA sample with available histologic or cytologic slides
from the original tumor can help establish a definitive diagnosis. Some-
times cytologic features may suggest a specific primary site. For exam-
ple, colorectal cancers often show glandular or tubular arrangement of
cells with oval or elongated nuclei with prominent nucleoli and vacuo-
lated cytoplasm. Intracytoplasmic mucin may be present. Extracellular
mucin and a dirty, necrotic background are characteristic. Colorectal
adenocarcinomas are negative for CK7 and positive for CD20 and
CDX2. Metastatic breast cancers may show variable ductal differentia-
tion or classic lobular carcinoma morphology. Sometimes cytoplasmic
lumen features can be identified. Positive immunostaining for ER, PR,
| 5
BRST-2 (GCDFP-15), mammaglobin, GATA-3 can help diagnose meta-
static carcinomas from breast origin. Metastatic prostate cancer fre-
quently displays micro-acini and prominent nucleoli. The tumors from
prostate origin are usually positive for prostate-specific antigen and
prostatic acid phosphatase. Metastatic adenocarcinoma from lung pri-
mary frequently shows acinar formation and lack of the trabecular pat-
tern of HCC. Cytoplasmic vacuoles and mucin are often present. Lung
adenocarcinoma cells are positive for CK7, TTF-1, and Napsin A. In
addition, immunostains for AFP and HepPar-1 can confirm the diagno-
sis of metastatic HCC. Immunostains for CK7 and CK20 which are neg-
ative in most HCC can help exclude a lung or gastrointestinal tract
primary. HCC frequently presents as large cells with abundant eosino-
philic cytoplasm which make oncocytic and granular tumors among the
major differential diagnoses. Thyroid, salivary gland, and kidney are the
most common primaries that present as oncocytic or granular lesions
which are diagnostic challenges cytologist may encounter in practice.
€rthle cell carcinoma is a close imitator of HCC at metastatic loca-
Hu
tions with similar cytologic features, such as granular cytoplasm, round
nuclei, single prominent nucleoli and transgressing vessels. Papillary
thyroid carcinoma oncocytic variant may show focal papillary structures
and typical papillary features such as intranuclear inclusions, nuclear
grooves, and psammomatous calcifications. In both situations immuno-
staining positivity for thyroglobulin, TTF-1 and CK7 can help pinpoint a
thyroid primary. Oncocytic variant of medullary thyroid carcinoma usu-
ally shows more size and shape pleomorphism than HCC on cytology.
The presence of amyloid material and positivity for neuroendocrine
markers and calcitonin are diagnostic of medullary carcinoma. Onco-
cytic carcinoma is a very rare tumor and can be from salivary gland,
breast, or renal primaries. Oncocytic carcinoma frequently shows
marked nuclear atypia and huge nucleoli. Immunohistochemical stains
for antimitochondrial antibody and P63 can help differentiate from
metastatic HCC. Malignant granular cell tumor can be from soft tissue,
thyroid, breast or gastrointestinal primaries and usually carries a poor
prognosis. Cytologic features include singly cells, abundant granular
debris in the background and many naked nuclei. Malignant granular
cell tumor shows immunohistochemical positivity for S-100 and vimen-
tin. In addition, electron microscopy can help differentiate these various
oncocytic/granular neoplasms by identifying the cytoplasmic granular-
ities, such as smooth endoplasmic reticulum in HCC, increased mito-
chondria in oncocytic carcinoma and increased lysosomes in malignant
granular cell tumor.
Limitations of this study include that only a subset of the cases
studied have all three types of cytology specimens (Diff-quick smear,
Thinprep and cell block) which can influence the statistical accuracy of
the most frequent cytologic features presented by metastatic HCC. In
addition, it is known that smear preparations fixed in alcohol and
stained with Pap stain can greatly facilitate the evaluation of the pres-
ence of traversing vessels and encasing endothelial cells. The lack of
this preparation type at our institution may have made recognition of
the above mentioned features more difficult.
In summary, the most frequent location of metastatic HCC diag-
nosed by FNA was from the bone, especially the vertebral bodies. A
biopsy diagnosis of HCC in the liver may precede the diagnosis at a
6 |
metastatic site. The frequent cytomorphology and immunophenotype
seen in primary HCC are good diagnostic criteria for metastatic HCC.
Fine needle aspiration is an effective technique to diagnose metastatic
HCC, especially when it is used in conjunction with ancillary studies.
OR CID
Lei Yan MD http://orcid.org/0000-0001-7385-1242
R E FER E NCE S
[1] Ferlay J, Shin H, Bray F, Forman D, Mathers C, Parkin DM. GLOBO-
CAN 2008, cancer incidence and mortality worldwide: IARC Cancer-
Base No. 10 [Internet]. Lyon, France: International Agency for
Research on Cancer. 2010:2.
[2] Bosch FX, Ribes J, Cleries R, Díaz M. Epidemiology of hepatocellular
carcinoma. Clin Liver Dis. 2005;9:191–211.
[3] McGlynn KA, London WT. The global epidemiology of hepatocellu-
lar carcinoma: present and future. Clin Liver Dis. 2011;15:223–243.
[4] Kanwal F, Hoang T, Kramer JR, et al. Increasing prevalence of HCC
and cirrhosis in patients with chronic hepatitis C virus infection.
Gastroenterology. 2011;140:1182,1188. e1.
[5] Ryerson AB, Eheman CR, Altekruse SF, et al. Annual report to the
nation on the status of cancer, 1975–2012, featuring the increasing
incidence of liver cancer. Cancer. 2016;122:1312–1337.
[6] Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma:
consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–S6.
[7] Chan SL, Mo F, Johnson PJ, et al. Performance of serum
a-fetoprotein levels in the diagnosis of hepatocellular carcinoma in
patients with a hepatic mass. HPB. 2014;16:366–372.
[8] Wang P, Meng Z, Chen Z, et al. Diagnostic value and complications
of fine needle aspiration for primary liver cancer and its influence
on the treatment outcome—a study based on 3011 patients in
China. Eur J Surg Oncol. 2008;34:541–546.
[9] Chen Q, Cheng C, Chen H, et al. Effectiveness and complications of
ultrasound guided fine needle aspiration for primary liver cancer in
a Chinese population with serum a-fetoprotein levels 200 ng/ml-a
study based on 4,312 patients. PLoS One. 2014;9:e101536.
[10] Wee A. Fine needle aspiration biopsy of hepatocellular carcinoma
and hepatocellular nodular lesions: role, controversies and approach
to diagnosis. Cytopathology. 2011;22:287–305.
[11] Natsuizaka M, Omura T, Akaike T, et al. Clinical features of hepato-
cellular carcinoma with extrahepatic metastases. J Gastroenterol
Hepatol. 2005;20:1781–1787.
[12] Uchino K, Tateishi R, Shiina S, et al. Hepatocellular carcinoma with
extrahepatic metastasis. Cancer. 2011;117:4475–4483.
[13] Serra K, Llatjos R, Catala I, Gornals JB. Adrenal metastasis of hepa-
tocellular carcinoma diagnosed by endoscopic ultrasound-guided
fine-needle aspiration of the right adrenal gland. Rev Esp De Enferm
Dig. 2017;109:378–379.
[14] Conrad R, Castelino-Prabhu S, Cobb C, Raza A. Cytopathologic diag-
nosis of liver mass lesions. J Gastrointest Oncol. 2013;4:53–61.
YAN ET AL.
[15] Hertz G, Reddy VB, Green L, et al. Fine-needle aspiration biopsy of
the liver: A multicenter study of 602 radiologically guided FNA.
Diagn Cytopathol. 2000;23:326–328.
[16] Kuo F, Chen W, Lu S, Wang J, Eng H. Fine needle aspiration cyto-
diagnosis of liver tumors. Acta Cytol. 2004;48:142–148.
[17] Lau SK, Prakash S, Geller SA, Alsabeh R. Comparative immunohisto-
chemical profile of hepatocellular carcinoma, cholangiocarcinoma,
and metastatic adenocarcinoma. Hum Pathol. 2002;33:1175–1181.
[18] Maeda T, Adachi E, Kajiyama K, Takenaka K, Sugimachi K, Tsu-
neyoshi M. Spindle cell hepatocellular carcinoma: a clinicopathologic
and immunohistochemical analysis of 15 cases. Cancer. 1996;77:
51–57.
[19] Wang L, Vuolo M, Suhrland MJ, Schlesinger K. HepPar1, MOC-31,
pCEA, mCEA and CD10 for distinguishing hepatocellular carcinoma
vs. metastatic adenocarcinoma in liver fine needle aspirates. Acta
Cytol. 2006;50:257–262.
[20] Yan BC, Gong C, Song J, et al. Arginase-1: a new immunohisto-
chemical marker of hepatocytes and hepatocellular neoplasms. Am J
Surg Pathol. 2010;34:1147–1154.
[21] Timek DT, Shi J, Liu H, Lin F. Arginase-1, HepPar-1, and Glypican-3
are the most effective panel of markers in distinguishing hepatocel-
lular carcinoma from metastatic tumor on fine-needle aspiration
specimens. Am J Clin Pathol. 2012;138:203–210.
[22] Duggal R, Garg M, Kalra N, Srinivasan R, Chawla Y. Spleen metasta-
sis from hepatocellular carcinoma: report of a case with diagnosis
by fine needle aspiration cytology. Acta Cytol. 2010;54:783–786.
[23] Fujimoto H, Murakami K, Nosaka K, Arimizu N. Splenic metastasis
of hepatocellular carcinoma. Accumulation of Tc-99m HDP. Clin
Nucl Med. 1992;17:99–100. Feb
[24] Falconieri G, Zanconati F, Colautti I, Dudine S, Bonifacio-Gori D, Di
Bonito L. Effusion cytology of hepatocellular carcinoma. Acta Cytol.
1995;39:893–897.
[25] Heagley D, Gates JP, Schein C, Kluskens L, Reddy V, Gattuso P.
Serous fluids involved by hepatocellular carcinoma: A review. Am J
Clin Pathol. 2012;138:A266.
[26] Katyal S, Oliver IIIJH, Peterson MS, Ferris JV, Carr BS, Baron RL.
Extrahepatic metastases of hepatocellular carcinoma. Radiology.
2000;216:698–703.
[27] Liaw C, Ng K, Chen T, Liaw Y. Hepatocellular carcinoma presenting
as bone metastasis. Cancer. 1989;64:1753–1757.
SUP POR TI NG INFOR MATION
Additional Supporting Information may be found online in the sup-
porting information tab for this article.
How to cite this article: Yan L, Jakate S, Reddy V, Gattuso P.
Metastatic hepatocellular carcinoma diagnosed by fine needle
aspiration: A clinical and cytologic study. Diagnostic Cytopathol-
ogy. 2018;00:1–6. https://doi.org/10.1002/dc.23920