Anaplastic Carcinoma of the Pancreas Associated

Zeng-Gang Pan, Bo Wang
Department of Pathology, Creighton University Medical Center. Omaha, NE, USA
ABSTRACT
Context Anaplastic carcinoma of the
pancreas is a rare undifferentiated variant of
ductal adenocarcinoma, which commonly
displays sarcomatoid spindle-cell and
pleomorphic growth patterns. Anaplastic
carcinoma of the pancreas associated with
mucinous cystic neoplasm has rarely been
reported.
Case report Here we report a unique case of
an anaplastic carcinoma of the pancreas in
association with a mucinous cystadeno-
carcinoma in a 70-year-old woman. The
anaplastic component of this tumor is
predominantly composed of spindle cells and
highly pleomorphic cells that mimic a spindle
cell sarcoma. The spindle neoplastic cells
have strong expression of vimentin and mucin
1 and focal strong positivity of CK7 and
CK20. Scattered osteoclast-like giant cells are
admixed with the spindle cells with positivity
for CD68 but not epithelial or other
mesenchymal markers. Focal squamoid
differentiation is present. Adjacent to the solid
anaplastic tumor is a classic mucinous
cystadenocarcinoma, which has strong
reactivity to mucin 1, CA 19-9, epithelial
membrane antigen (EMA), CK19, CK8/18,
carcinoembryonic antigen and CK7. The peri-
cystic tissue and the septa consist of an
ovarian-type stroma that is strongly positive
for CD10. Focal areas with pancreatic
intraepithelial neoplasia IB (PanIN-IB)
changes are seen in the adjacent normal
pancreatic tissue.
Conclusion The anaplastic carcinoma of the
pancreas is of epithelial origin with various
microscopic features, and the scattered
osteoclast-like giant cells in the tumor are
reactive cells of histiocytic origin.
INTRODUCTION
Anaplastic carcinoma of the pancreas is a rare
pancreatic tumor of epithelial origin,
frequently showing various morphologies that
include pleomorphic epithelial cells and
relatively mononuclear spindle cells. Other
rare growth patterns have been reported,
including rhabdoid and squamous patterns.
Despite of many morphology changes, the
neoplastic cells usually have reactivity to
epithelial markers and vimentin, indicating an
epithelial origin with dedifferentiation.
Diagnosis of this type of tumor may be
challenging due to lack of the glandular
structures or other features that indicate a
direction of differentiation. However, it is
very important to recognize this distinct entity
because of the highly aggressive nature of this
type of tumor. In our report, this 70-year-old
woman had a pleomorphic anaplastic
carcinoma of the pancreas in adjacent to a
mucinous cystadenocarcinoma and a PanIN-
IB. A brief review of the literature is
included.

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CASE REPORT
A 70-year-old Caucasian female presented
with a two-month history of a funny taste in
the mouth, anemia, loss of appetite and a
weight loss of about 18 pounds. Past medical
history was significant for hypertension and
appendectomy. During this hospitalization, an
extensive workup showed a 6.0 cm right
breast mass, and an invasive ductal
adenocarcinoma was reported following a
biopsy. A further CT scan of the abdomen
Figure 1. a. CT scan of the abdomen reveals a large complex cystic and solid mass in the body and tail of the pancreas.
b. Gross specimen demonstrates a well-circumscribed tumor with a solid component and a polycystic component in the
body and tail of the pancreas. Microscopically, the solid component in the tumor consists of a variety of features: c.
mononuclear spindle cells; d. highly pleomorphic epithelial cells; e. scattered multinucleated osteoclast-like giant cells
with reaction to CD68 as indicated in the insert; f. squamoid differentiation.

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revealed a large complex cystic and solid
mass measuring 10.4x8.3x6.6 cm in the body
and tail of the pancreas (Figure 1a). The
patient then underwent an exploratory
laparotomy
with
extensive
distal
pancreatectomy and splenectomy. During the
surgery, a local advanced tumor was resected
without evidence of systemic metastasis. The
patient’s condition remains controlled and
stable after four months following the
surgery.
Grossly, the specimen consists of a resected
spleen and a distal portion of the pancreas.
The spleen is unremarkable and free of tumor
invasion. The pancreatic specimen measures
14x12x9 cm, and the surface of the specimen
is smooth but distorted by multiple large
bulging nodules. Sectioning through the
pancreatic mass reveals a well-circumscribed
tumor with a solid component and a
multicystic component (Figure 1b). The solid
area of the tumor is pale tan and yellow
measuring 8.0x4.5 cm. The cysts contain
brown-tan cloudy gelatinous material with the
largest cyst measuring 4.0x3.5 cm.
Microscopically, the tumor has a relatively
well-demarcated pushing border with focal
invasion into the adjacent normal pancreatic
tissue. The tumor is restricted in the capsule
without evidence of infiltration to the major
pancreatic vessels or distant metastasis. The
solid area of the tumor consists of
mononuclear spindle cells and highly
pleomorphic epithelial cells with marked
mitotic index (Figure 1c, 1d). The tumor cells
are large with indistinct cell boarders and
moderate to abundant eosinophilic cytoplasm.
The nuclei are large, spindle, oval or round
with marked pleomorphism, hyperchromasia
and one or two conspicuous nucleoli (Figure
1d). Many bizarre giant tumor cells are seen,
and hemorrhage and necrosis are prominent in
the tumor. Occasional multinucleated
osteoclast-like giant cells are admixed with
the spindle tumor cells in focal areas (Figure
1e), and these osteoclast-like giant cells are
reactive to CD68 (Figure 1e insert). Nerve
invasion (Figure 2b and 2c) and squamoid
differentiation (Figure 1f) are identified.
There is no glandular differentiation in the
solid area of the tumor.
Figure 2. Immunostains of the anaplastic tumor. a.
CK7; b. CK20; c. MUC-1; d. Vimentin.

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The cysts in the tumor are lined with
mucinous epithelium with focal papillary
projections (Figure 3c). The lining epithelium
cells appear highly pleomorphic and atypical,
and a mucinous cystadenocarcinoma is
reported. A section of the tumor also
demonstrates a transition of the mucinous
cystadenocarcinoma (Figure 3a, upper left
and lower right; Figure 3b, lower right) and
the anaplastic tumor (Figure 3a, center; Figure
3b, upper left). The anaplastic component at
this point is negative for majority of the
markers that are detected in the lining
epithelium, including CK7 and CK8/18
(Figure 4b, lower right; 4c, upper left). The
peri-cystic tissue and the septa contain focal
calcifications and a distinctive ovarian-type
stroma, which is composed of dense spindle
cells with sparse cytoplasm and elongated
wavy nuclei.
A pancreatic intraepithelial neoplasia (PanIN-
IB, Figure 3d) is present in the duct of
adjacent normal pancreatic tissue. This lesion
consists of a papillary epithelium that is lined
by single layer of uniform columnar cells with
minimal atypia. The lining epithelial cells
contain abundant supranuclear mucin and
have basally located, round to oval uniform
nuclei that are oriented perpendicular to the
basement membranes.
Immunostains of the anaplastic carcinoma
demonstrate that the spindle and highly
pleomorphic tumor cells have strong
positivity of vimentin (Figure 2d) and mucin
1 (MUC-1) (Figure 2c), focal strong positivity
of CK7 (Figure 2a) and CK20 (Figure 2b),
and weak positivity of beta-catenin and p53.
The tumor cells are negative for cytokeratin
AE1/AE3 (CK AE1/AE3), CK5/6, CK8/18,
desmin and CD10. The scattered osteoclast-
Figure 3. a. This figure shows the transition of the mucinous cystadenocarcinoma (upper left and lower right) and the
anaplastic tumor (center). b. Higher power view of the lining epithelium of the cyst (lower right) and the anaplastic
tumor (upper left). c. Additional sections of the cyst reveals the lining mucinous epithelium with high grade dysplasia.
d. The PanIN-IB in the normal pancreatic tissue.

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like giant cells are strongly reactive to CD68
(Figure 1e, insert) but negative for epithelial
markers. The lining epithelium of the mucinous
cystadenocarcinoma shows strong positivity for
CA 19-9 (Figure 4a), CK7 (Figure 4b), CK8/18
(Figure 4c), CK19 (Figure 4d) and MUC-1
(Figure 4e). The stroma of the cystic septa is
strongly positive for CD10 (Figure 4f).
Ultrastructurally, the neoplastic cells have
variable sizes and shapes with prominent
nucleoli but no predominance of any specific
cytoplasmic organelles. Cytogenetic analysis
did not reveal any detectable numerical or
structural chromosomal anomaly.
Figure 4. Immunostains of the mucinous cystadenocarcinoma. a. CA 19-9; b. CK7; c. CK8/18; d. CK19; e. MUC-1; f.
CD10 of the peri-cystic stroma. The anaplastic component showed in panel b. (lower right) and panel c. (upper left) is
negative for CK7 and CK8/18.

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DISCUSSION
Anaplastic carcinoma of the pancreas is a rare
aggressive pancreatic tumor and accounts for
2-7% of all pancreatic cancers with a male
predominance [1, 2]. A number of terms have
been used to describe this type of tumor,
including
pleomorphic
carcinoma,
sarcomatoid carcinoma, anaplastic and undif-
ferentiated carcinoma. Anaplastic carcinomas
of the pancreas are more common in older
men with an age peak in the seventh-ninth
decades of life. The clinical symptoms
include loss of weight, fatigue, loss of
appetite, abdominal pain, nausea, vomiting
and diarrhea [1, 2, 3]. Our patient had many
of these classic symptoms.
This tumor may occur in the head, body and
tail of the pancreas. Three major histological
subtypes have been described, spindle cell
carcinoma, pleomorphic carcinoma and round
cell carcinoma (Table 1). Anaplastic
carcinomas with other very rare features have
been reported, including two cases with
rhabdoid features [5, 11] and one with
squamous features [15]. Despite of various
morphology changes, the neoplastic cells
usually have reactivity to epithelial markers
Table 1. A summary of the microscopic and immunohistochemistry features of the reported anaplastic
adenocarcinomas in the English literature.
Author, year
Gender/age
Histology
Immunostains and cytogenetics
Nojima, et al.
1993 [4]
2 cases
Anaplastic carcinomas with
sarcomatoid cells, adenocarcinomatous
elements and osteoclast-like giant cells.
In both cases, spindle cells express vimentin
and cytokeratin, and osteoclast-like cells
express CD68 but not cytokeratins
Nishihara, et al.
1997 [5]
F/52 years Anaplastic carcinoma with rhabdoid
features and a mucinous
cystadenocarcinoma
Epithelial membrane antigen (EMA) and
vimentin positive
Motoo, et al.
1997 [6]
M/75 years Anaplastic carcinoma with sarcomatoid
change and neoplastic cyst formation
Epithelial marker positive in the sarcomatoid
component
Lane, Sangüeza
1997 [7]
F/25 years Anaplastic carcinoma in association
with a mucinous cystic neoplasm,
borderline-type
-
Molberg, et al.
1998 [8]
5F/4M
Mean 67 year
Anaplastic tumor with ovoid or spindle
mononuclear cells and osteoclast-like
giant cells
6/9 cases positive for epithelial markers.
Osteoclast-like cells CD68 positive and
cytokeratin negative in all cases
Hoorens, et al.
1998 [9]
17 cases
-
All cases positive for epithelial markers.
K-ras mutations in 10 cases
Higashi, et al.
1999 [10]
1 case
Anaplastic carcinoma with sarcomatoid
feature
Sarcomatoid cells are positive for
cytokeratin AE1/AE3, EMA, MUC-1-
apomucin-related antigen (ARA) and CA 19-
9 and negative for vimentin, desmin, and
myoglobin
Kuroda, et al.
2000 [11]
F/68 years Anaplastic carcinoma with rhabdoid
features
-
Paal, et a l.
2001 [1]
10F/25M
Mean 63 year
Anaplastic carcinomas with
pleomorphic cells or spindle cells
27 cases positive for epithelial markers.
K-ras mutations in 12 cases.
Yonemasu, et al.
2001 [12]
8 cases
-
7 cases had loss of E-cadherin expression
with impaired alpha-and beta-catenin
expressions.
Chadha, et al.
2004 [13]
F/74 years
Pleomorphic anaplastic carcinoma
Positive for cytokeratin.
Sawai, et al.
2005 [14]
M/77 years
Anaplastic tumor with squamous
features
Strong reactivity for cytokeratin, smooth
muscle alpha-actin (SMA), vimentin,
neuron-specific enolase (NSE), and S-100

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and vimentin, indicating an epithelial origin
with dedifferentiation. Anaplastic carcinomas
of pancreas in association with mucinous
cystic neoplasm were rarely reported although
the mucinous cystic neoplasm may be a
precursor lesion. Only two cases were
reported in the English literatures, one
cystadenocarcinoma [5] and the other one
borderline type [7].
Interestingly, many of the anaplastic
carcinomas contain osteoclast-like giant cells.
There has been some disagreement regarding
to the origin of these osteoclast-like giant
cells in pancreatic tumor, and the proposed
origins of the osteoclast-like giant cells
include neoplastic epithelial cells, neoplastic
mesenchymal cells and reactive mesenchymal
cells. Many studies have shown that these
giant cells highly express CD68 and lysozyme
without reactivity to epithelial markers [4, 8],
and they have similar morphological features
to the osteoclast-like giant cells in the bone.
There findings suggest a histiocytic origin of
these giant cells and they may be reactive
cells in the pancreatic tumor. However, when
the pancreatic tumor has prominent
osteoclast-like giant cells, it may belong to
another distinct rare entity of pancreatic
carcinoma, named undifferentiated carcinoma
with osteoclast-like giant cells.
The tumor in our case has a solid component
with a predominance of spindle neoplastic
cells with admixture of highly pleomorphic
epithelial cells. Immunohistochemically, the
spindle cells have strong reactivity to MUC-1
and vimentin with focal strong positivity for
CK7 and CK20, indicating an epithelial origin
of these spindle cells. The tumor also has
focal squamoid differentiation. Interestingly,
a large mucinous cystadenocarcinoma is
present in our case. The mucinous cystadeno-
carcinoma highly expresses MUC-1, CA 19-
9, epithelial membrane antigen (EMA),
CK19, CK8/18, carcinoembryonic antigen
(CEA) and CK7, and the cystic septa consist
of a CD10 positive ovarian-type stroma. This
type of mucinous cystadenocarcinomas
almost always occurs in the female. In our
case, the scattered osteoclast-like giant cells
have strong reaction to CD68 but not
epithelial markers, which further suggests that
they are reactive cells of histiocytic origin.
Focal PanIN-IB is also noted in the adjacent
normal pancreatic tissue.
Most anaplastic carcinomas of the pancreas
harbor activating point mutations in the codon
12 of K-ras oncogene. In pancreatic tumors
with ductal and anaplastic components, both
components reveal identical point mutation of
the K-ras oncogene, indicating that the
anaplastic carcinoma may arise from the
ductal carcinoma. It has been postulated that
mutations of the K-ras oncogene occur at
early stages of PanIN progression, and
inactivation of the p16 tumor suppressor gene
occurs at intermediate stages, and the
inactivation of the p53SMAD4 (DPC4), and
BRCA 2 tumor suppressor genes occur at late
stages of malignant transformation [15].
PanIN is a common lesion in normal elderly
adults, and the PanIN-IB in our case may be
an incidental finding.
Anaplastic pancreatic carcinoma is an
aggressive neoplasm with a worse prognosis
than poorly differentiated ductal adeno-
carcinoma of the pancreas. The 3-year
survival rate is lower than 3%, with an
expectation of 10 to 20 months. Compared
with poorly differentiated pancreatic ductal
adenocarcinoma, anaplastic carcinoma has a
loss or impaired expression of surface
adhesion molecules, including E-cadherin,
alpha- and beta-catenin [12], which may
explain some of the aggressive natures of this
tumor. Interestingly, the tumor in our case is
pathologically and clinically not as aggressive
as those described in the literature in spite of
its large size and typical anaplastic features.
The tumor is locally restricted without
evidence of extensive invasion or distant
metastasis, and the patient is stable after the
surgery. Possible explanation is that this
tumor may not acquire enough cellular and
molecular alterations for its invasion and
distant metastasis.
Received July 9
th
, 2007 - Accepted September
6
th
, 2007

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Keywords Carcinoma; Cystadenocarcinoma,
Mucinous; Pancreas
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
Bo Wang
Department of Pathology
Creighton University Medical Center
Omaha, NE 68131
USA
 
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