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Undifferentiated carcinoma of the pancreas analysis of intermediate filament profile and Ki-ras mutations provides evidence of a ductal origin

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??????? ?? ?????????, ???. 185: 53?60 (1998)
UNDIFFERENTIATED CARCINOMA OF THE
PANCREAS: ANALYSIS OF INTERMEDIATE FILAMENT
PROFILE AND Ki-ras MUTATIONS PROVIDES
EVIDENCE OF A DUCTAL ORIGIN
???? ???????1, ????? ???????2, ???????? ?. ???????2 ??? ??????? ????????3*
1
Department of Pathology, Academic Hospital Jette, Free University of Brussels, Laarbeeklaan 101, B-1090 Brussels, Belgium
2
ICRF Oncology Unit, RPMS, Hammersmith Hospital, London W12 0NN, U.K.
3
Department of Pathology, University of Kiel, Michaelisstrasse 11, D-24105 Kiel, Germany
SUMMARY
Undifferentiated carcinomas and osteoclast-like giant cell tumours of the pancreas commonly contain foci of neoplastic ductal glands.
To test the hypothesis that undifferentiated carcinomas and osteoclast-like giant cell tumours have a ductal origin, the immunocytochemical cytokeratin pattern and the frequency and type of Ki-ras mutations at colon 12 were studied in a series of 17 undifferentiated
carcinomas and two osteoclast-like giant cell tumours. The cytokeratin features of undifferentiated carcinomas and osteoclast-like giant
cell tumours were compared with those found in 10 ductal adenocarcinomas, 20 acinar cell carcinomas, 25 neuroendocrine tumours, and
15 solid-pseudopapillary tumours. All undifferentiated carcinomas and osteoclast-like giant cell tumours stained with at least one
cytokeratin antibody, and 13/19 of them with antibodies against cytokeratins 7, 8, 18, and 19. The latter cytokeratins were expressed
in all ductal adenocarcinomas, but only in 15/20 acinar cell carcinomas, 2/25 neuroendocrine tumours, and 1/15 solid-pseudopapillary
tumours. In addition to cytokeratin, 15/19 undifferentiated carcinomas/osteoclast-like giant cell tumours were positive for vimentin.
Ki-ras mutations at codon 12 were found in 10 undifferentiated carcinomas and one osteoclast-like giant cell tumour from which DNA
could be successfully amplified. The Ki-ras mutation patterns were analysed in six tumours and corresponded to those typical of ductal
adenocarcinomas. In tumours with ductal and anaplastic components, both components revealed identical mutation patterns. From these
findings, it is concluded that both undifferentiated carcinomas and osteoclast-like giant cell tumours belong to the pancreatic tumours
that show a ductal phenotype. Since undifferentiated carcinomas and osteoclast-like giant cell tumours share the same cytokeratin and
Ki-ras features, they are probably derived from the same cell lineage. 1998 John Wiley & Sons, Ltd.
J. Pathol. 185: 53?60, 1998.
KEY WORDS?pancreatic
tumours; undifferentiated carcinoma; osteoclast-like giant cell tumour; cytokeratin pattern; vimentin; Ki-ras
mutation; ductal phenotype
INTRODUCTION
Undifferentiated carcinoma (UC) and osteoclast-like
giant cell tumour (OLGT) of the pancreas are rare
pancreatic neoplasms, with a reported incidence varying
from 2�to 12�per cent.1 While UC has an unfavourable prognosis, that of OLGT occasionally seems to be
much better. Because focal glandular elements are a
common component of both tumour types,2?4 it is
thought that they are of duct cell origin and represent a
variant of ductal adenocarcinoma of the pancreas.1,5,6
Other possibilities that have been discussed are an origin
from acinar cells, especially for OLGT,7 and a primarily
mesenchymal nature.3,8?10
Evidence of the ductal phenotype of the more
frequent adenocarcinoma of the pancreas can be found
in the histological and ultrastructural similarities
*Correspondence: Professor G. Kl鰌pel, Department of Pathology,
University of Kiel, Michaelisstrasse 11, D-24105 Kiel, Germany.
Contract grant sponsor: Belgian National Fund for Scientific
Research (FGWO); Contract grant number: V41B-MW.D4738).
Contract grant sponsors: Deutsche Krebshilfe; Imperial Cancer
Research Fund; Medical Research Council; Mike Stone Cancer
Research Fund.
CCC 0022?3417/98/050053?08 $17.50
1998 John Wiley & Sons, Ltd.
between the neoplastic glands and the interlobular
pancreatic ducts. Further indications are that ductal
adenocarcinomas express the same set of cytokeratins
as the normal duct cells of the pancreas, namely cytokeratins (CKs) 7, 8, 18, and 19.11?14 Finally, ductal
adenocarcinomas are characterized by a high frequency
of mutation in the oncogene Ki-ras, a feature which is
absent or only rarely present in pancreatic neoplasms
with acinar or endocrine cell differentiation.15,16
In this study, we analysed a series of 17 UCs and two
OLGTs of the pancreas by means of immunocytochemistry and molecular biology. In particular, we looked for
evidence of their ductal origin and their relationship to
ductal adenocarcinoma. For this purpose, we compared
their intermediate filament expression with that of other
types of pancreatic tumours. We also investigated
whether the frequency of Ki-ras gene activation in UC is
similar to that of ductal adenocarcinomas.17?20
MATERIALS AND METHODS
We investigated a series of 17 UCs and two OLGTs of
the pancreas. The most important clinicopathological
findings are summarized in Table I. The age of the
Received 2 May 1997
Accepted 31 October 1997
54
A. HOORENS ET AL.
Table I?Clinicopathological findings in 19 patients with pancreatic undifferentiated carcinomas (UCs) or
osteoclast-like giant cell tumours (OLGTs)
Case No.
Age (years)/
sex/type of
resection
Pleomorphic
carcinoma type
44/F/W
44/F/W
44/M/W
46/M/W
53/M/A
55/M/W
58/M/W
62/M/W
63/F/A
65/F/T
71/M/W
71/M/A
73/M/W
78/M/A
86/F/A
91/F/A
96/F/A
44/F/W
57/M/A
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
OLGT
OLGT
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Site
(in pancreas)
Head
Head
Head
Head
Body
Head
Head
Head
Body?tail
Tail
Head
Body
Head?body
Tail
Head
Body
Tail
Head
Head?body
Size
(cm)
Ductal
component
755
644
544
321�554
21�1�32�2�32�2�764
554
642
875
988
644
443�554
655
655
665
+
+
+
+
+
+
+
+
+
+
+
+
F=female patient; M=male patient; A=autopsy; W=whipple resection; T=tail resection; + =present; =absent.
Table II?Antisera
Antigen
Keratins 1, 2, 5, 6, 7, 8, 11, 14, 16, 17, and 18
Keratins 8, 18, and 19
Keratin 7
Keratin 8
Keratin 18
Keratin 19
Vimentin (Vim)
CD45, leucocyte common antigen (LCA)
CD68
Antiserum
code
Working
dilution
Source
M (KL1)
M (CAM 5.2)
M (CK 7)
M (CK 8)
M (CK 18)
M (CK 19)
M
M
M (KP1)
1:500
1:10
1:100
1:100
1:10
1:20
1:20
1:50
1:500
Immunotech, Marseille, France
Becton Dickinson, Mountain View, CA, U.S.A.
Biogenex, San Ramon, CA, U.S.A.
Biogenex, San Ramon, CA, U.S.A.
Biogenesis, Bournemouth, U.K.
Dr Raemaekers, Nijmegen, The Netherlands
Boehringer, Mannheim, Germany
Dako, Glostrup, Denmark
Dako, Glostrup, Denmark
P=polyclonal; M=monoclonal.
patients ranged from 44 to 96 years (mean 63 years).
The male to female ratio was 11:8. In 11 patients a
laparotomy was performed, which led to a Whipple
resection in ten patients and a tail resection in
one patient. Autopsy specimens were available from
eight patients. For purposes of comparison, we
investigated a series of 10 ductal adenocarcinomas,
20 acinar cell carcinomas, 25 neuroendocrine
tumours (12/25 malignant and 9/25 functioning), and 15
solid-pseudopapillary tumours.
The tumour specimens were fixed in 10 per cent
formaldehyde, except for five samples which were
fixed in Bouin?s solution. Four-micrometre-thick serial
sections were cut from paraffin-embedded tissue blocks
(1?5 per specimen, mean 2). The first two sections
were stained with haematoxylin and eosin (H&E)
and periodic acid?Schiff with diastase pretreatment.
1998 John Wiley & Sons, Ltd.
Immunocytochemical analysis was carried out on
subsequent sections by means of the streptavidin?
biotin?peroxidase complex method. The sections were
stained with the primary antisera listed in Table II.
Peroxidase
staining
was
done
using
3,3diaminobenzidine tetra-hydrochloride (0� per cent
w/v) and hydrogen peroxide (0� per cent w/v) in
phopshate-buffered saline (PBS) buffer. For antigen
retrieval of CKs 7, 8, 18, and 19, deparaffinized sections
were pretreated with 0�per cent trypsin (Sigma) for
1?10 min. Sections from normal pancreas (n=5) were
used as positive controls for the antisera against
intermediate filaments and neuroendocrine markers.
All 19 tumours were examined for abnormalities in
Ki-ras at codon 12. In all tumours with a ductal
component, Ki-ras codon 12 was analysed in two different tumour areas, a region with ductal structures and a
??????? ?? ?????????, ???. 185: 53?60 (1998)
55
UNDIFFERENTIATED CARCINOMA OF THE PANCREAS
Fig. 1?DNA from the microdissected tissue samples was amplified with the primers K12S and K12ABstNI, and then
digested with BstNI and run in 2�per cent Nusieve/1 per cent agarose gel. Undigested PCR product is a fragment of
157 bp, while BstNI digestion produces a fragment of 143 bp in Ki-ras 12 mutant DNA and a fragment of 114 bp in
Ki-ras 12 wild-type DNA. Samples 1a, 14, and 15 have homozygous mutant Ki-ras and samples 19, 8a/b, 16a/b, and
2a/b have heterozygous mutant Ki-ras patterns
region with a pleomorphic, undifferentiated phenotype.
For detection of Ki-ras mutations, genomic DNA was
extracted from sections cut from paraffin-embedded
tissue blocks as described by Levi et al.21 Briefly, 10 靘
sections were made from each block. The area of interest
was microdisected with sterile scalpels and 18-gauge
needles, placed in a sterile Eppendorf tube, dewaxed in
two changes of warm xylene, and washed twice in
alcohol before drying. The tissue was then resuspended
in digestion buffer (50 m? Tris?HCl, 1 m? EDTA, 0�per cent Tween 20, pH 8� containing 0�mg/ml proteinase K (Sigma Chemical Co., St Louis, MO, U.S.A.)
and incubation at 37C overnight. Nucleic acid was
purified by organic extraction with phenol/chloroform
and then chloroform. The nucleic acid was then ethanolprecipitated, washed, and dried before dissolving in
200 靗 of Tris?EDTA buffer. Ten microlitres of sample
DNA solution was used for each polymerase chain
reaction (PCR) amplification. Genomic DNA was
amplified in a volume of 100 ml containing 75 m? KCl,
10 m? Tris?HCl (pH 8�, 1�m? MgCl2, 0�m? of
each of four dNTPs (Pharmacia, Piscataway, NJ,
U.S.A.), 0�靏 of a pair of primers (K12F:
5-CATGTTCTAATATAGTCACA-3,
K12A1:
5-CGTCAAGGCACTCTTGCC-3), and 1 unit of Taq
DNA polymerase (Perkin Elmer Cetus Corp., Norwalk,
CT, U.S.A.). The conditions for the PCR using a
thermal cycler (Perkin Elmer Cetus) were as follows:
95C for 5 min for initial denaturation, 35 cycles of 94C
for 30 s, annealing for 45 s at 42C, and extension at
72C for 30 s. The efficiency of amplification was
checked by electrophoresis of an aliquot of each reaction
in agarose gel before single-strand conformation polymorphism (SSCP) analysis was performed. 0�靗 of this
product mix was taken as template for a further ten
cycles of amplification in 20 靗 of reaction mix prepared
in the same proportions as the initial amplification
except for the addition of 1 霤i of 32P-�-dATP. Two
microlitres of the radioactively labelled product was
loaded on a 6 per cent non-denaturing acrylamide gel
with 10 per cent glycerol and run at 4 W overnight at
1998 John Wiley & Sons, Ltd.
room temperature. In addition, mutations at codon 12
of the Ki-ras oncogene were detected by the method of
Levi et al.,21 in which mismatched primers (Fig. 1) are
used in the PCR to create restriction fragment length
polymorphisms (RFLPs). Samples were screened for the
presence or absence of the wild-type sequence by BstNI
digestion of DNA produced by amplification with primers K12S and K12ABstNI. Twenty microlitres of the
100 靗 PCR was digested with the restriction enzyme
BstNI (Promega Ltd, Southampton, U.K.). The reaction
conditions adhered to the supplier?s recommendations.
The DNA was then electrophoresed through 2�per cent
Nusieve/1 per cent agarose gel and the ethidium
bromide-stained gel was photographed using an ultraviolet light transilluminator and a gel documentation
system (UltraViolet Products, Cambridge, U.K.). Those
samples in which a mutant sequence was suspected were
further investigated by cloning the cold PCR products in
pBluescript. A single-stranded template was obtained
by phage rescue. It was sequenced in an automatic
sequencing machine (Applied Biosystems ABI 373,
Norwalk, CT, U.S.A.).
RESULTS
Histological findings
All UCs exhibited pleomorphic cells growing in
poorly cohesive sarcomatoid formations, supported by a
scanty fibrous stroma. Mononuclear tumour cells were
admixed with bizarre, mononucleated or multinuclear
giant cells. All cells had hyperchromatic nuclei and
usually eosinophilic cytoplasm. In seven tumours the
multinucleated neoplastic giant cells were very abundant
and prominent (Fig. 2). Four tumours contained areas
with small and more spindle-shaped tumour cells (Fig.
3). In 12 tumours, either single (five cases) or multiple
foci of neoplastic duct-like structures were found.
Scattered areas of necrosis were present in about half
of the cases. Mitoses were always very abundant. The
two OLGTs displayed numerous benign-appearing
??????? ?? ?????????, ???. 185: 53?60 (1998)
56
A. HOORENS ET AL.
Fig. 2?Undifferentiated carcinoma of the pancreas showing abundant
pleomorphic neoplastic giant cells (H&E, 120)
Fig. 3?Undifferentiated carcinoma of the pancreas. Pleomorphic
tumour cells next to an area with spindle-shaped cells (H&E, 120)
osteoclast-like giant cells, which were scattered
among pleomorphic mononuclear tumour cells and
spindle-shaped fibroblast-like cells.
additionally positive for CKs 7 and/or 19. None of the
ductal adenocarcinomas or acinar cell carcinomas
showed positively for vimentin.
In the series of 25 neuroendocrine neoplasms, 23/25
tumours were positive for CK 8 and 25/25 for CK 18.
Only two cases were faintly positive for CK 7, and 10/25
tumours expressed CK 19. One of the 25 tumours was
positive for vimentin. We found no correlation between
positivity for CK 7 or 19 and malignancy or functional
state.
All but three solid-pseudopapillary tumours were
positive for vimentin, while cytokeratin expression was
found in only six tumours (Table III). None of the
tumours stained for CD45 (LCA) or CD68.
Immunocytochemical findings
Normal pancreatic duct cells contained CKs 7, 8, 18,
and 19, while normal acinar cells and pancreatic
endocrine cells were only positive for CKs 8 and 18.
All 17 UCs and two OLGTs were positive for at least
one of the antisera directed against various cytokeratins.
KL1, which is a broad spectrum keratin marker, stained
18/19 tumours. The one tumour that was KL1-negative
was positive for CK 7. All but two tumours stained for
CAM 5�(which detects CKs 8, 18, and 19), while CK 7
was found in 18 tumours (Table III and Fig. 4). In 15
tumours (including one of the two OLGTs), the neoplastic cells were also positive for vimentin (Fig. 5). Among
the tumour cells, there were usually macrophages which
were labelled by the markers LCA and CD68, in
addition to vimentin. In the two OLGTs, the nonneoplastic osteoclast-like cells stained for vimentin,
LCA and CD68. The LCA staining was in a fine
submembranous pattern.
All but one ductal adenocarcinoma were positive for
CKs 7, 8, 18, and 19. The 20 acinar cell carcinomas
stained positively for CKs 8 and 18, but 18 cases were
1998 John Wiley & Sons, Ltd.
Molecular analysis
PCR failed repeatedly on samples from eight patients
(cases 3, 5, 6, 9, 11, 12, 13, and 19), but was successful in
11 cases (cases 1, 2, 4, 7, 8, 10, 14, 15, 16, 17, and 18), six
of which also contained a ductal component (cases 1, 2,
4, 8, 16, and 18). SSCP analysis was able to identify only
one case with a possible abnormality (case 4). By means
of RFLP, however, it was possible to demonstrate
mutations of codon 12 in all 11 cases in which DNA was
successfully amplified (Fig. 1). Automatic sequencing of
PCR fragments of exon 1 was successful in six of these
??????? ?? ?????????, ???. 185: 53?60 (1998)
57
UNDIFFERENTIATED CARCINOMA OF THE PANCREAS
Table III?Cytokeratin and vimentin expression in pancreatic tumours
Tumour
type
KL1
CAM
5.2
CK 7
CK 8
CK 18
CK 19
Vim
Undifferentiated carcinoma
Ductal carcinoma
Acinar cell carcinoma
Neuroendocrine tumours
Solid-pseudopapillary tumours
18/19
10/10
20/20
25/25
6/15
17/19
10/10
20/20
25/25
1/15
18/19
10/10
15/20
2/25
1/15
13/19
9/10
20/20
23/25
2/15
15/19
10/10
20/20
25/25
1/15
17/19
10/10
15/20
10/25
2/15
15/19
0/10
0/20
1/25
12/15
Fig. 4?Undifferentiated carcinoma of the pancreas. Both neoplastic
ductal structures and anaplastic tumour cells stain positively for CK 19
(120)
11 cases (cases 1, 2, 4, 14, 15, and 18). In two cases each,
the mutations were G to C transversion at position 1, G
to T transversion at position 1, and G to A transversion
at position 2. In all cases with a ductal component in
which a mutation was found, it was identical in both the
undifferentiated component and the ductal component.
DISCUSSION
Undifferentiated or anaplastic carcinoma (UC) of the
pancreas is an uncommon tumour with a poor prognosis.1,5,22 Because of its sarcomatoid appearance, electron
microscopy and/or immunocytochemistry are required
1998 John Wiley & Sons, Ltd.
to demonstrate the tumour?s epithelial nature. A further,
though inconsistent, indication of its epithelial origin is
that neoplastic glandular elements and duct-like structures may be observed in some of the tumours. The
tumour is therefore considered to be a variant of ductal
adenocarcinoma.1,5,23 A similar histogenetic origin
has been discussed for the osteoclast-like giant cell
tumour (OLGT) of the pancreas, since it also may
contain a ductal component.2?4,24 However, it has also
been reported that the neoplastic cells in OLGT do
not stain for cytokeratin and also do not show any
evidence of epithelial differentiation by electron
microscopy.3,9 Against the background of these
conflicting results, we conducted a study to analyse the
cell lineage pattern in UC and OLGT and to test them
for Ki-ras codon 12 activation, a well-known feature of
ductal adenocarcinoma.25
Our results provide strong evidence of a ductal origin
of UC and OLGT. Firstly, we found that more than
two-thirds of the UCs and OLGTs stained for antibodies directed against CKs 7, 8, 18, and 19 of Moll
et al.?s catalogue.26 This CK pattern characterizes the
pancreatic duct cell system and also ductal
adenocarcinoma.11?13,27,28 Secondly, in all tumours of
our series in which we were able to perform a molecular
analysis (ten of 17 UCs and one of two OLGTs), a
Ki-ras point mutation at codon 12 was demonstrated,
confirming recently published data.29,30
In the normal pancreas, ductal cells contain CKs 7, 8,
18, and 19, while acinar cells and endocrine cells express
only CKs 8 and 18.11?13,28 In addition to CKs 7, 8, 18,
and 19, some duct cells may also stain for CKs 4, 5, 14,
and 17.12,1428 Pancreatic tumours with a ductal phenotype express the same set of CKs as the normal
duct cells, i.e., predominantly CKs 7, 8, 18, and
19.11?13,27,28,31 Expression of additional CKs, such as
CK 14, may be observed in pancreatic carcinomas with
a squamous component,12 and CK 20, a relatively new
member of this class of intermediate filaments,32 seems
to be only exceptionally expressed in ductal adenocarcinomas of the pancreas.32 Since, with five exceptions, the
17 UCs of our series reacted with antibodies against the
four ?ductal? CKs, i.e., CKs 7, 8, 18, and 19, we conclude
that the majority of UCs adhere to the phenotype of
ductal adenocarcinoma. This also holds true for the two
OLGTs examined, since they both displayed a ductal
CK pattern.
The neoplastic counterparts of pancreatic acinar or
endocrine cells, acinar cell carcinomas and neuroendocrine tumours, only partly matched the CK pattern of
??????? ?? ?????????, ???. 185: 53?60 (1998)
58
A. HOORENS ET AL.
Fig. 5?Osteoclast-like giant cell tumour. (a) Neoplastic cells stain for cytokeratin (KL1). Stromal cells and osteoclast-like giant cells remain
unstained. (b) Neoplastic cells as well as non-neoplastic stromal cells and osteoclast-like giant cells stain for vimentin (200)
the respective normal cells. They almost all stained for
CKs 8 and 18, but some were additionally positive for
CKs 7 and/or 19. In acinar cell carcinomas, CK 7 and/or
CK 19 reactivity was seen in two-thirds of the tumours,
while in endocrine tumours, CK 7 was only expressed in
two cases and CK 19 in ten tumours. This deviation
from the normal CK pattern, which may be attributed to
the loss of cellular differentiation in these neoplasms,
shows that pancreatic tumours with either a ductal,
acinar, or endocrine phenotype cannot be distinguished
from each other on the basis of their reactivity with CK
7, 8, 18, or 19 with certainty in all cases. Additional tests
are necessary to make this distinction. We therefore also
tested the UCs and OLGTs of our series for the neuroendocrine marker synaptophysin and the pancreatic
enzymes trypsin and lipase15,33,34 and obtained negative
results (data not shown). These data further support the
ductal origin of UC and OLGT of the pancreas.
Vimentin expression is absent in pancreatic acinar
cell carcinomas. It is a very rare finding in pancreatic
ductal adenocarcinomas13 or neuroendocrine tumours
(one tumour in our series), but is common in solidpseudopapillary tumours,35,36 in which CK expression
appears to be rather the exception. Positivity for vimentin is also a frequent finding in our series of UCs and
OLGTs, being observed in 75 per cent of cases. This
finding has been interpreted as an indication of a
1998 John Wiley & Sons, Ltd.
mesenchymal origin of the tumour cells.3,8,10 Expression
of vimentin in carcinomas is, however, a well-known
phenomenon in other anaplastic carcinomas, such as
anaplastic thyroid or hepatocellular carcinomas.10,28,37
The expression of vimentin in UC and OLGT of the
pancreas cannot therefore be considered as evidence of a
primarily mesenchymal nature of the tumour. The discrepancy between our findings and reports in which
OLGTs were found to be positive only for vimentin and
to lack any CK staining may be attributed to the failure
of the antiserum or the technique used to detect CK,
rather than to the lack of CK expression. In our study,
we found that proper immunocytochemical recognition
of some CKs required digestive treatment of the sections
prior to staining.
Ki-ras mutation at codon 12 is a feature of ductal
adenocarcinomas of the pancreas, occurring in 80?100
per cent of the cases.16,25 In other pancreatic tumours
with a ductal phenotype, such as intraductal papillary
mucinous tumour, Ki-ras mutations are found in a
varying frequency.38 In contrast, pancreatic tumours
with an acinar or endocrine phenotype almost always
lack Ki-ras mutations.15,39 Our results in UC and OLGT
confirm the data of two recently published studies,29,30
in that they reveal the same high rate of Ki-ras mutations as in ductal adenocarcinoma.16,25 In addition, we
found that in the four cases in which we were able to test
??????? ?? ?????????, ???. 185: 53?60 (1998)
UNDIFFERENTIATED CARCINOMA OF THE PANCREAS
a microdissected focus with ductal differentiation for
Ki-ras mutations and compare its Ki-ras pattern with
that of the adjacent undifferentiated part of the tumour,
the same mutation pattern was present in both components. Finally, the spectrum of mutations detected, i.e.,
GGT to TGT, GGT to CGT, and GGT to GAT,
corresponds to that most frequently found in ductal
adenocarcinoma series.16 On the basis of these findings
and the CK features already discussed, we therefore
conclude that pancreatic UCs and OLGTs are derived
from ductal adenocarcinomas. Further support for this
conclusion is provided by the finding that UCs may stain
for pancreatic and gut-type antigens, which are also
found in ductal adenocarcinomas.40
It is still controversial whether UC and OLGT are two
separate entities or belong to one group of tumours. In
the new WHO classification, they are viewed as two
categories.23 Apart from the assumed mesenchymal
nature of OLGT, the notion exists that UC and OLGT
might differ in biology because OLGT has a potentially
better prognosis. Our findings, however, lead us to
believe that UC and OLGT are derived from the same
cell lineage and therefore have a common origin. OLGT
may be regarded as a variant of UC distinguished by a
special response of non-neoplastic giant cells to poorly
differentiated epithelial tumour cells. The non-neoplastic
nature of the giant cells has been established in several
previous reports.3,4,41 The identification as cells of the
mesenchyme system with features of osteoclast cells is
based on the positive labelling with vimentin and mononuclear phagocytic markers such as CD68 and CD45
(common leukocyte antigen). Why some of the OLGTs
seem to have a much better prognosis than UCs is not
known,42 but it may be related to the response of the
infiltrating non-neoplastic giant cells to tumour cells.
ACKNOWLEDGEMENTS
Anne Hoorens and G黱ter Kl鰌pel were supported
by a grant from the Belgian National Fund for Scientific
Research (FGWO; V4/B?MW.D4738); Klaus Prenzel
by a grant from Deutsche Krebshilfe; and Nicholas
Lemoine by grants from the Imperial Cancer Research
Fund, Medical Research Council, and the Mike Stone
Cancer Research Fund. We thank Mrs N. Buelens for
technical assistance and Mrs K. Dege for secretarial
work and helpful English corrections. We are also
grateful to the many colleagues who provided material
and clinical data for this study.
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