Diffuse Cirrhosis-like Hepatocellular Carcinoma - Rush University ...

Jakate et al Am J Surg Pathol Volume 34, Number 7, July 2010
or detection of HCC; (3) serum AFP values; (4) pre-OLT
imaging results; (5) gross photograph and/or gross
description of the explanted liver, specifically the size
ranges and distribution of cirrhotic-like abnormal pale
or cholestatic nodules; (6) detailed review of the routine
formalin-fixed, paraffin-embedded, and hematoxylin
and eosin stained 4 mm thick microscopic sections; (7)
immunohistochemical studies on formalin-fixed and
paraffin-embedded representative sections of the tumor
for the following markers: CD10, CD34, HepPar-1,
Ki-67, cytokeratins 7 and 19, AFP, glypican-3, and
ubiquitin; and (8) available follow-up including recurrence
of HCC in the graft. The demographic, clinical,
pathologic, and follow-up information was collected from
individual sites. All microscopic sections were reviewed by
4 participating pathologists as a panel with concurrence
of findings.
Macroscopically, the livers were examined and
sampled for microscopic evaluation according to the
individual medical center’s protocol. At all places, the
livers were thinly sliced at approximately 0.5 cm intervals
and random protocol sections from both lobes were
taken, a minimum of 5 and a maximum of 14. In all cases,
abnormal appearing cholestatic or pale nodules were
documented for their size range and extent, and
additional sections (5 to 10) from these abnormal nodules
were taken. Formalin-fixed paraffin-embedded sections
were processed, embedded, cut at 4 mm, and stained
routinely with hematoxylin and eosin. The sections were
examined microscopically with emphasis on presence of
HCC in random sections of cirrhotic nodules, differentiation,
and additional histologic tumor characteristics.
Immunohistochemical studies were performed on one
representative tumor bearing section for the following
markers: CD10 (Leica Microsystems, Bannockburn, IL),
HepPar-1 (Cell Marque, Rocklin, CA), CD34 (Cell
Marque, Rocklin, CA), Ki-67 (Dako, Carpinteria, CA),
cytokeratin 19 (Cell Marque, Rocklin, CA), cytokeratin 7
(Cell Marque, Rocklin, CA), AFP (Cell Marque, Rocklin,
CA), glypican-3 (Cell Marque, Rocklin, CA), and
ubiquitin (Invitrogen, Carlsbad, CA). Cytokeratins 7 and
19 were performed to determine if there was admixed
cholangiocarcinoma component. In patients where follow
up was available, it was studied for tumor recurrence,
metastases and graft and patient survival.
RESULTS
Clinical Features
The patient demographic data included 9 males and
1 female in the age range of 35 to 80 years with the mean
age of 61 years. All 10 patients had cirrhosis from varying
etiologies [3 hepatitis C virus (HCV), 3 alcoholic hepatitis,
1 hepatitis B virus (HBV), 1 autoimmune, and 2 mixed
HCV/alcoholic hepatitis and hemochromatosis/HCV].
All patients met the clinical and laboratory criteria for
OLT qualification and underwent OLT without pretransplant
diagnosis of HCC. In particular, HCC appeared
clinically silent and without stigmata such as rapid weight
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loss, tumor-related ascites or hepatomegaly, palpable
mass, or evidence of metastases. In all 10 cases, the first
suspicion of diffuse HCC ensued after the explanted liver
was examined grossly and cut surfaces showed abnormal
appearing pale and/or cholestatic cirrhotic-like nodules
scattered among the cirrhotic nodules.
Serology
The AFP values were below 20 ng/mL in 7 patients
and increased in only 3 patients at 144, 150, and 252
ng/mL, respectively. In these cases, HCC was clinically
suspected but as imaging studies did not identify a mass,
these raised values were regarded as nonspecific and
related to chronic liver disease.
Imaging
The ultrasonography performed on 6 of 10 cases
showed normal hepatic echogenicity, diffuse coarseness
compatible with cirrhosis, and no focal lesions. There was
trace ascites or perihepatic fluid. The other 4 cases had
dynamic imaging-CT of the abdomen with and without
contrast and/or MR with and without gadolinium. In 2
of these 4 cases, small lesion(s), 1000 in numbers)
and diffusely scattered throughout the liver sometimes
occupying up to 50% of the total volume (Fig. 1). Some
cirrhotic nodules were partially pale suggestive of partial
involvement of cirrhotic nodule by tumor (Fig. 2). In 2 of
10 cases, the nodules were fewer, about 20, and more
localized within the liver (Fig. 3). Aggregate tumor sizes
were estimated between 5 and 23 cm. There was no
necrosis and no tumor was grossly seen to invade the
vessels or the bile ducts.
Histologic Features
Representative sections from all cases were reviewed
and the tumor nodules in each case were classified and
graded according to the World Health Organization
criteria. 4 There was general uniformity of grade among
multiple nodules in each individual patient. Almost all
tumor nodules were either moderately or well-differentiated
carcinoma of hepatocellular origin and often
showed pseudoglandular pattern (Fig. 4A). Corresponding
well with the macroscopically visible pallor and/or
cholestasis, the tumor cells frequently showed ballooning
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