Case 2 -
Metastatic Hepatocellular Carcinoma from an Occult Primary
Charles D. Sturgis
Evanston Northwestern Healthcare
Northwestern University Feinberg School of Medicine
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The patient was a 77 year-old female with no prior
history of malignancy. She presented with neck pain and new onset right arm paralysis. MRI of the
cervical spine revealed an abnormal diminished signal intensity in the right pedicle and lamina of C6
with a noted 4 x 4 x 3.6 cm soft tissue mass. The mass showed epidural extension into the spinal canal
and neural foramen. Digital photomicrographs were taken from microscope slides prepared following
image-guided biopsy of the spinal mass.
consistent with hepatocellular primary
Cytologic Diagnosis of Hepatic primary:
Five digital images were provided for review. Image
one (20X Diff Quik) demonstrates a hemodiluted background without necrosis or diathesis. A flat,
cohesive group of lesional cells is noted in the center of the field. The cells are round to polygonal
with moderately abundant granular cytoplasm and indistinct cytoplasmic borders at this magnification. In
image two (40X Papanicolaou) a three dimensional aggregate of neoplastic cells is seen. The cells have
abundant coarsely granular eosinophilic cytoplasm and somewhat better defined cell borders than in the
low power Diff Quik image. Nucleoli are visible. Small flattened cells with tapered nuclei are noted at
the peripheral edges of the cell cords. The fragment is at least six cells in thickness from side to
side. The digital image numbered as three (40X Diff Quik) emphasizes the abundance of cytoplasm in some
of the lesional cells with focal dark blue-black globular pigment material as well as focal coarse
eosinophilic cytoplasmic globules. Binucleation is present. In the high power image number four (60X
Papanicolaou), the polygonal shapes of the lesional cells becomes more obvious. Moderately abundant
coarsely granular cytoplasm and nucleoli are key features of this small cohesive lesional cell group.
The block from this case was paucicellular. Image five (60X Hematoxylin and Eosin) shows erythrocytes
and a small aggregate of lesional cells, one with an intranuclear cytoplasmic invagination. Subsequent
immunohistochemical studies performed on the cell block revealed the lesional cells to be immunoreactive
(positive) for pan-cytokeratin, cytokeratin 7, and the hepatocyte antigen HepPar 1 / HSA. The lesional
cell groups were nonreactive (negative) for cytokeratin 20, estrogen receptor, and thyroid transcription
Cytologic and Clinical Follow-up:
Following the image-guided cervical
spine needle aspiration, the patient underwent additional imaging and additional laboratory testing. Her
serum alpha-fetoprotein (AFP) was measured at 17.1 ng/ml (upper limit of normal range 8 ng/ml). Other
tumor markers including CEA were within normal limits. Computerized tomographic studies of the chest,
abdomen and pelvis demonstrated a 1 cm partially calcified incidental right thyroid nodule, a 5 cm
heterogeneously enhancing mass within the right hepatic lobe, multiple bilateral 2 to 4 mm lung nodules
and colonic diverticulosis. The thyroid nodule was needle aspirated under ultrasound guidance resulting
in a diagnosis of "benign thyroid nodule." The liver mass was also needle aspirated under ultrasound
guidance yielding 13 direct smears and a cell block. The liver lesion was diagnosed as "hepatocellular
carcinoma" based on morphology alone.
Cases of metastatic adenocarcinoma arising from clinically
occult primary sites are seen with some frequency by practicing cytopathologists. Metastatic deposits
from occult primary solid tumors are encountered in the context of needle aspiration biopsies of lymph
nodes, lung, liver, adrenal, bone, soft tissue, skin, brain, and other body sites. As expected,
epidemiologically "common" occult primary tumors are those that most typically lead to metastatic
disease. Adenocarcinomas are the most usual malignancies to give rise to metastatic deposits from
unknown origins, and the most frequent primary sites (when discoverable) are lung, large bowel and the
In postmenopausal females, breast and gynecologic tract primary
tumors should be added to the list. In males, the prostate gland may be considered as a common primary
site. Even with highly cellular samples and quality immunocytochemical analyses, there are instances in
which a primary source simply cannot be accurately pinpointed. Inability to specifically label a
metastatic focus as being derived from a certain site is most common in poorly differentiated / high
grade neoplasms and in those cases in which the burden of metastatic disease is widespread, involving
multiple anatomic sites.
Although epidemiologically common adenocarcinomas are the tumors most frequently
encountered in the work up of metastases from unknown primaries, rarities make for good stories. A
veritable treasure trove of unexpected and occult metastatic malignant neoplasms has been reported
popping up in the bones of the cervical spine (as in the hepatocellular carcinoma in the current case).
This list includes but is not limited to such infrequently encountered entities as pituitary carcinoma,
glioblastoma multiforme, malignant meningioma, chordoma, renal cell carcinoma, sebaceous carcinoma,
carcinoid tumor of the testis, and paraganglioma.
Occult thyroid carcinomas presenting as
cervical spine disease also exist.
When a history of primary malignancy at another body
site is not provided, the cytologist starts at the beginning with light microscopic evaluation. Time
invested with a critical "reading of the slides" can pay the largest dividends.
Diagnosing a hepatocellular carcinoma presenting as a cervical spine mass is akin
to standing behind a one-way glass and picking a Hobbit out of a lineup of felon cytopathologists. If
one doesn't think to put Hobbits in the differential diagnosis, then the wrong "criminal" may go free.
Critically interpreting the slides and keeping an open mind makes all of the difference in fingering the
correct culprit. The cytomorphologic features of metastatic hepatocellular carcinoma are essentially the
same as those of primary hepatoma. Classical architectural / low power features of hepatocellular
carcinoma include complex branching and anastomosing thick trabeculae with sharp borders and endothelial
appliques. Traversing capillary-sized blood vessels are often noted, and acinar formations are possible.
Cellular / high power features include morphologic similarities to non-neoplastic hepatocytes such as
polygonal-shaped cells with distinct cell borders and dense granular cytoplasm. Central round nuclei
with prominent nucleoli are typical. Low grade lesions and their metastases are typically monotonous
with increased nuclear /cytoplasmic ratios. Binucleation and intranuclear inclusions are common. Bile
pigment may be seen, as can intracytoplasmic hyaline globules.
Of note, not all primary and secondary hepatoid epithelial malignancies are truly derived
from hepatocytes, and endothelial investiture surrounding trabeculae of malignant cells is not entirely
specific for hepatocellular carcinoma. Hepatoid morphologies have been reported in (among others) cases
of pancreatic adenocarcinoma, gastric adenocarcinoma, ovarian adenocarcinoma, adenocarcinoma of the lung,
yolk sac tumor and immature teratoma.
The floating island pattern of neoplastic
epithelial cells surrounded by appliques of intimately adherent flattened endothelial cells can be seen
in adrenal cortical carcinomas and occasionally in other highly vascular tumors such as renal cell
carcinoma and tumors derived from neuroendocrine tissues. In a sense, a critical review of the
cytomorphology of a metastatic carcinoma may lead one to the diagnosis of a hepatoid malignancy, but
ancillary testing will likely be pursued to confirm the cytologic impression whenever possible. In
addition to correlating morphology with immunocytochemistry and imaging studies, measurement and tracking
of certain serum tumor markers may be of value in discerning primary sites. Serum alpha-fetoprotein, an
oncofetal antigen, is frequently used for screening patients suspected of harboring hepatocellular
carcinoma in high risk populations. Although this serum marker is elevated in approximately 70% of
patients with hepatoma, it is not entirely specific and can be elaborated by germ cell neoplasms, solid
tumors of the lung and endometrium and by hepatoblastoma.
In addition, mildly to
moderately elevated serum levels of alpha-fetoprotein have been reported in hepatic inflammatory
Multiple cases of hepatocellular carcinoma either presenting with or rapidly developing
metastatic disease to the spine, neck, head and upper thorax are known in the world's literature.
Published cases of hepatoma presenting with vertebral, cranial, parotid gland and chest wall metastases
highlight myriad possible anatomic starting points for the cytologic work up of
A retrospective Taiwanese series of 395 individuals with pathologically
verified hepatocellular carcinoma demonstrated that 20 (5%) of the patients had bone metastases at
initial presentation and that in this subset of patients the most common initial presentation was with a
spinal lesion with neurologic compression.  Acutely symptomatic epidural hematoma arising in
association with metastatic disease has also been reported as the presenting symptom of an otherwise
unknown hepatoma. 
As hepatocellular carcinoma can present with variable symptoms and as non-hepatocellular
carcinomas may appear hepatoid by light microscopy, ancillary testing of tumor tissue is generally
undertaken when cellularity allows. Ancillary testing of hepatocellular carcinomas can be of great
importance not only in metastatic foci but also in the work up of liver masses proper, as the liver is a
common site for metastatic tumors from neoplasms that are primary to other organs and as metastatic
disease to the liver is far more common that primary liver carcinoma in North America.  In
the future, quantitative polymerase chain reaction methodologies and serial analysis of gene expression
based on classification maps may allow pathologists to identify malignancies of unknown origin without
reliance upon the art of cytomorphologic interpretation.  Until that time, we in diagnostic
anatomic pathology will likely continue to rely upon algorithms centered around glass slide based
immunohistochemical and immunocytochemical testing. Published algorithms for the workup of metastatic
adenocarcinoma of unknown primary are helpful; however, these treatises typically focus on "standard" or
"frequently encountered" primaries such as a panel including CA125, CDX2, cytokeratins 7 and 20, estrogen
receptor, gross cystic disease fluid protein 15, lysozyme, mesothelin, prostate specific antigen, and
thyroid transcription factor 1 that is promoted for separating breast, colon, lung, ovary, pancreas,
prostate, and stomach cancers.  OCT4 is a relatively new marker that is reported to be
sensitive and specific for metastatic germ cell tumors and might be of value in ruling out one of these
lesions with a hepatoid phenotype.  Pertinent positive markers for hepatocellular carcinoma
include pancytokeratin and cytokeratin Cam5.2. Many hepatocellular carcinomas express cytokeratins 8 and
18, as is the case with benign hepatocytes. Approximately 90% of hepatomas are immunoreactive with
HepPar1, while approximately 40% are immunoreactive for alpha-fetoprotein. Alpha-1-antitrypsin
positivity is noted in 50% of hepatocellular carcinomas. The majority of hepatomas are nonreactive with
antibodies to cytokeratins 7 and 20; however, the pattern of 7 and 20 expression is highly variable.
Monoclonal CEA is typically negative in hepatocellular carcinomas; however, polyclonal CEA antibodies are
known to decorate these lesions with a canalicular pattern of staining roughly 70% of the time. Markers
such as CD34 may prove useful in highlighting wrapping endothelial cells. It is important to note that
IHC results must be interpreted in combination with the overall morphology and with thought given to the
larger context of the clinical setting.
For cytodiagnosticians, the challenge of finding an occult primary site based on studies
of cells harvested from a metastatic deposit is akin to solving a complicated puzzle based on synthesis
of data points taken from combined clinical, radiographic, cytomorphologic, cytochemical, and
immunocytochemical correlations. It should be emphasized that behind each one of these challenging
puzzles sits a patient. In most instances, the answer to the puzzle will determine the specific
patient's treatment. Noticeably varied interventions result from the wording of cytopathology reports.
The cytopathology report may trigger initiation of systemic anticancer therapies, administration of
targeted radiation, surgery, radio frequency ablation or pain management and hospice referral depending
upon the label given to the metastatic deposit and the likely primary source. Empirical chemotherapy
with platinum-containing regimens has been shown to benefit some patients who present with metastatic
disease from unknown primary sites.  If given choices, certainly all patients would prefer
specific therapies targeting specific diseases over "blanket" approaches to bad situations. One
retrospective study of patients with cervical spine metastases from tumors of unknown primary source
showed that detection of the primary tumor was the only factor that significantly influenced patient
survival.  Looking carefully at every brush stroke on the cytopathology slides allows us to
envision the most complete pictures, and seeing the big picture may make all of the difference for a
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