Keywords
clival tumor - hepatocellular carcinoma - ectopic pituitary adenoma -
α-fetoprotein - cancer of unknown primary site
Introduction
Liver cancer is sometimes called a silent killer because some patients have little to no early signs or symptoms. At times, metastatic
lesions are found before the primary lesion is diagnosed. In this case, the tumor
was first diagnosed as an atypical pituitary adenoma after the patient's first operation,
then grew rapidly and without any evidence of liver tumor on computed tomography (CT).
Following a second operation, we diagnosed the tumor as a clival metastasis of hepatocellular
carcinoma (HCC).
Case Report
The patient was a 76-year-old female, whose past medical history was significant for
hepatitis C virus (HCV), positivity without liver cirrhosis. She presented with right
abducens nerve (CN VI) palsy. Contrast-enhanced magnetic resonance imaging (MRI) and
CT scan showed a clival tumor with osteolysis and infiltration of the right cavernous
sinus ([Figs. 1] and [2]). All laboratory data were within normal limits, including liver function. We removed
the tumor using the right anterior petrosal approach. The tumor was hemorrhagic, so
we finished this operation as a subtotal removal. The specimen was negative for adrenocorticotropic
hormone, growth hormone, prolactin, thyroid-stimulating hormone, and follicle-stimulating
hormone/luteinizing hormone. The tumor was pathologically diagnosed as a pituitary
adenoma by three different pathologists ([Fig. 3]). The diagnosis was ultimately determined to be ectopic pituitary adenoma. Thirty-four
days after the operation, the patient presented at our hospital complaining of massive
bleeding from her nose. She had difficulty breathing, so she was intubated within
the outpatient clinic. MRI showed significant growth of the residual clival tumor
([Fig. 4]) and pathological diagnosis, so the patient was taken for contrast-enhanced whole-body
CT, which showed no evidence of tumor, including in the liver. ([Fig. 5]). We removed the tumor using an endoscopic transnasal transsphenoidal approach.
The tumor bled massively during surgery, necessitating the transfusion of 3,600 mL
of red blood cells (RBCs), 720 mL of fresh frozen plasma, and 400 mL of platelets.
Contrast-enhanced whole-body CT scanning was performed again 60 days after the first
operation and it showed a new enhanced liver mass ([Fig. 6]). Blood tests revealed significant elevation of α-fetoprotein (AFP), and protein induced by the absence of vitamin K or antagonists-II.
Immunostaining of the pathological specimen was positive for AFP ([Fig. 7]). K
i
-67 expression of the specimen was 20%, and it was the same in the first specimen.
We determined that the clival tumor was actually metastatic HCC. The residual tumor
rapidly increased in size following the second surgery ([Fig. 8A] and [B]). The right abducens nerve palsy remained unchanged during the course, whereas the
left abducens nerve palsy appeared 2 weeks following the second operation. The patient
died of liver failure 6 months after the first operation.
Fig. 1 Preoperative MRI, with contrast axial (A) and sagittal (B) sections demonstrating a contrast-enhanced clival tumor. MRI, magnetic resonance
imaging.
Fig. 2 Preoperative three-dimensional CT with contrast showing the clival tumor extending
laterally from the right cavernous sinus into the petrous apex. CT, computed tomography.
Fig. 3 Pathologic evaluation at ×40 magnification. The histologic section demonstrated anisonucleosis,
sheet-like proliferation, eosinophilic cytoplasm, and mitosis.
Fig. 4 MRI 34 days after the first operation with a contrast sagittal section, demonstrating
significant tumor growth. MRI, magnetic resonance imaging.
Fig. 5 Noncontrast whole-body CT imaging 1 day before the second operation did not reveal
any mass, including in the liver. CT, computed tomography.
Fig. 6 Contrast-enhanced whole-body CT scanning after the second operation showed an enhanced
liver mass. CT, computed tomography.
Fig. 7 During immunostaining, the pathological specimen was AFP positive. AFP, α-fetoprotein.
Fig. 8 CT immediately after the second operation (A) and one month after the second operation (B). CT, computed tomography.
Discussion
The pathologic similarity of HCC and atypical pituitary adenoma, as well as the fact
that the clival metastasis tumor grew before the CT scan revealed liver HCC, complicated
the diagnostic process in this patient. Our patient's tumor was initially diagnosed
as an ectopic pituitary adenoma. Histopathologic appearance of HCC varies greatly
from patient to patient. The most common histologic growth patterns include trabecular-resembling
normal liver tissue, pseudoglandular, or acinar with possible bile or fibrin content,
and solid.[1] Solid-type HCC could closely resemble pituitary adenoma on pathological imaging.
A side-by-side comparison of pathological images of a solid-type HCC and a diffuse-type
pituitary adenoma is presented in [Table 1].[2]
[3]
[4] HCC and pituitary adenomas are distinguishable via immunostaining, such as hepatocyte
and AFP but immunostaining is only performed when it is considered necessary.
Table 1
A histopathological image comparison of HCC (solid-type) and pituitary adenoma (diffuse-type)
|
Solid-type HCC
|
Diffuse-type pituitary adenoma
|
|
Morphologic features
|
Diffuse proliferation
Trabecular arrangement
Inconspicuous sinusoids
|
Diffuse proliferation
Fibrous component in the stroma
Formation of new blood vessels
|
|
Hematoxylin and eosin stain
|
Eosinophilic
|
Eosinophilic basophilic
|
|
K
i
67
|
0.1–89%
|
1–23%
|
|
Anisonucleosis
|
(+)
|
(+∼ − )
|
|
Mitosis
|
(+)
|
(+∼ − )
|
|
Immunostaining
|
Hepatocyte, AFP
|
PRL, ACTH, TSH, GH, none
|
Abbreviations: ACTH, adrenocorticotropic hormone; AFP, α-fetoprotein; GH, growth hormone; HCC, hepatocellular carcinoma; PRL, prolactin; TSH,
thyroid-stimulating hormone.
When we operated on this patient the second time, the CT scan showed no liver masses.
Metastatic tumors diagnosed prior to primary tumors are called cancer of unknown primary
site (CUP). CUP accounts for 3 to 5% of all tumor diagnoses. Eighty percent of all
patients diagnosed with CUP have a poor prognosis and a median overall survival of
6 months. It is possible that the progression of CUP parallels the primary tumor,
and CUP metastases are an early event in tumor development.[5] In this case, the liver tumor grew rapidly over a short time, suggesting that the
tumor was highly malignant. The clival metastasis was an early HCC progression event,
and the metastasis grew more rapidly than the primary site. When cancer is diagnosed
as CUP, repeat CT, positron emission tomography, and serum tumor markers are recommended
to find the true primary cancer.[5]
Ectopic pituitary adenoma was the suspected diagnosis after the first operation. The
location of the tumor itself did not exclude a diagnosis of ectopic pituitary adenoma.
Karras et al reported an ectopic pituitary adenoma that involved the entire clivus,
laterally extended to the petroclival junction, and bilaterally invaded the cavernous
sinuses, with further bilateral encasement of the internal carotid arteries without
direct extension into the sella.[6] The clinical course of this case is quite different from that of a patient with
ectopic pituitary adenoma. First, we encountered massive bleeding from the tumor during
each operation, and during the second operation the patient needed transfusions. Second,
there was rapid tumor regrowth. The size of the residual tumor doubled in approximately
1 month. Third, the patient demonstrated spontaneous and idiopathic hemorrhaging from
her nose. The volume of the hemorrhage was so large that the patient required intubation.
Typically, patients with ectopic pituitary adenomas present as asymptomatic or with
focal neurological deficits.[6] The clinical course of this patient indicated the tumor was aggressive and could
be malignant.
Conclusion
Solid-type HCC can appear pathologically similar to a pituitary adenoma. It is difficult
to diagnose a clival metastasis of HCC from preoperative images if the tumor is a
potential CUP. When we doubt a histopathological diagnosis, it is important to compare
the pathological diagnosis with the patient's clinical course.
