Pancreatic neoplasms are distinguished by their differentiation and phenotypic
characteristics. They are all properties that reflect the tendency, expressed in
different degrees in individual neoplasms, to differentiation in the direction
of one, or more, of the three epithelial structures that make up the normal
pancreas (ducts, acini, insule). This concept does not necessarily imply that
the phenotype of a neoplasm reflects its derivation from specific cells that
reside within these structures. In this regard, there is a large dichotomy
between the structural components and the incidence of the various tumor forms.
Ductal adenocarcinoma accounts for about 90% of the exocrine pancreatic
neoplasms, although the ductal system constitutes only a small part of the
pancreatic parenchyma (2-3%). Acinar carcinoma, on the other hand, represents
only 1% of all pancreatic neoplasms, even if the acinar epithelium constitutes
more than 80% of the entire pancreas structure.
Discrepancy that is now connected with the hypothesis that the different
neoplasies can derive from a single stem cell, endowed with multiple
differentiation potentialities. Suggestive hypothesis that would allow to
explain the ductility of the carcinogenetic process that often produces aberrant
differentiations, or the presence of mixed tumors with the proliferation of
different cell types. Another possibility is represented by the ability of
mature cells to transdifferentiate.
In this regard, research into experimental pancreatic adenocarcinomas is of
great importance: neoplasms that can be obtained both from acinar and insular
structures. At an initial proliferative phase, a proliferation of
tubulo-glandular complexes occurs. Cell differentiation does not represent, as
it was considered, a univocal and irreversible process while it is considered as
a dynamic / plastic process. The stem cell would not have a rigidly defined
identity, as it could be considered itself as a state of cellular
differentiation (concept of an optional stem cell). Even differentiated cells,
if properly stimulated, can assume the "role" of stem cells. All or most of the
pancreatic ductal cells can be considered potential-optional stem cells, with
the ability to re-enter the replicative cycle, to lose the differentiating
ductal markers, to temporarily activate the pancreatic Pdxl gene-cell gene and
subsequently to differentiate into cells endocrine or acinar. Obviously this
cell, peculiar for its capacity to proliferate, is the element on which oncogene
mutations can occur. Although the pancreas ductal segment may be considered the
major "reserve" of potential stem cells, the endocrine and acinar pancreatic
compart also have the capacity to de-differentiate and assume a ductal-like
tubular phenotype. Acine and endocrine cells in culture can trans-differentiate
into ductal cells, reactivate the Pdxl gene and subsequently give rise to
differentiated cells, both acinar and endocrine.
From these data it follows that a specific tumor "phenotype" does not
necessarily derive from a single type of cell.
In the pancreatic neoplasia, three groups are distinguished that have different
biological behavior:
- benign;
- uncertain (potential malignant behavior);
- malicious.
The classifications of diseases must always be considered useful tools of work,
but not at all rigid, stable and less definitive definitions.
They instead serve for:
- understand the pathogenesis;
- formulating the prognosis;
- program the therapy. They are also useful or necessary tools to promote the
adoption of a common "language", which is indispensable for facilitating the
communication of experiences among the most diverse operators.
For a better understanding of the various forms of cancer, so far known, in the
present discussion it was considered useful to adapt or "adapt" the
histopathological classification to the prevalent type of "clinical"
presentation as it is captured by radiological investigations, which very often
constitute the first document, somehow "morphological", of a clinical problem
that calls the attention of the doctor on the abdomen or more specifically on
the pancreas.
Pancreatic tumors were divided into two categories: 1) predominantly
solid-structure tumors; 2) cystic tumors.
Malignant epithelial tumor composed of muco-secreting glandular elements with
characters similar to normal pancreatic ductal structures. They are synonyms:
- ductal carcinoma;
- exocrine carcinoma;
- pancreatic carcinoma.
It represents about 90% of all pancreatic tumors and the fourth leading cause of
cancer death in Europe and the United States. The most affected age is between
60 and 70 years. The male sex predominates over the female sex with a variable
ratio from 2: 1 to 1.1: 1. The incidence of pancreatic cancer in Italy varies in
the different regions from 2 to 13 per 100,000 inhabitants.
Ductal adenocarcinoma of the pancreas has been called the "silent killer" due to
its silent development and subsequent explosive and highly lethal behavior.
Survival for pancreatic carcinoma worldwide is the lowest among the 60 most
common cancers. The most frequent and important symptom is pain; fatigue,
anorexia and weight loss characterize the advanced stage of the disease.
Obstructive jaundice is usually the debut sign of most pancreatic head cancers.
Migrant thrombophlebitis are found in 10-25% of patients both in the established
disease phase and in clinically silent tumors. The mechanisms involved in the
pathogenesis of thrombophlebitis are the release by the neoplasm of:
- tumor necrosis factors,
- platelet aggregating factors,
- substances with procoagulant activity, interleukin 1 and interleukin 6 by the
macrophages associated with the neoplasm.
In spite of the undoubted progress achieved in radiological diagnostic
techniques and the possibility of obtaining in many cases the pre-operative
morphological diagnosis with cytologic investigations carried out with
ultrasound-guided needle biopsies, the majority of pancreatic carcinomas at the
time of diagnosis show:
- diffusion to peripancreatic soft tissues;
- lymph node metastasis;
- haematogenous metastases (in the first instance hepatic).
The early diagnosis of carcinoma, before its extrapancreatic diffusion, is an
extremely important moment to improve its prognosis. Unfortunately, surgical
removal is only possible in a small percentage of patients (15-20%) and, in most
advanced carcinomas, conventional chemotherapy and radiotherapy, so far
attempted, have proved ineffective. The median survival is around 16 weeks from
the time of submission, while the five-year survival is less than 5%. In this
regard it should be recalled that the pathological re-evaluation (three distinct
pathologists experienced in pancreatic pathology), clinical and statistics of
the 4922 cases of pancreatic carcinoma - recorded from 1990 to 1996 in the
Finnish Cancer Registry -, indicated that only 89 patients had survived remotely
5 years from diagnosis. 45 of these cases (49%) were not ductal adenocarcinomas,
while in 18 no confirmed histological examination was performed. In the
remaining 26 patients for which histological examination was available,
diagnostic confirmation of adenocarcinoma was only formulated in 10 cases. From
the data of this research we can therefore deduce:
• the extreme aggressiveness of pancreatic carcinoma;
• the importance of a histological review of all pancreatic carcinomas in
patients who survived remotely.
Although the cause of pancreatic cancer remains unknown, there are numerous risk
factors identified for its development. Exposure to aromatic amines, cigarette
smoke (contains at least 30 different types of aromatic amines), diet rich in
meat, fish and fat (possible development of amines in the cooking process) as
well as alcohol abuse are among the factors that increase the risk of onset of
this neoplasia. The same factors are also implicated in the development of
chronic pancreatitis which, in turn, is considered one of the risk factors for
the development of carcinoma. The opinion about the causal role played by the
various forms of chronic pancreatitis is still controversial. It is in fact
difficult to determine whether the role of chronic pancreatitis is to favor the
development of carcinoma or if it represents an event secondary to the
carcinomatous obstruction of the ductal system, and therefore not causal.
However, there are no doubts regarding the role of chronic hereditary
pancreatitis, an autosomal dominant disease: the carriers of this disease, at
the age of 70, have a total risk estimated at around 40%, reaching values of
75% in patients with disease transmitted by the paternal route.
The role of insulin-resistant diabetes mellitus that appears in 70-80% of
patients with pancreatic cancer continues to be debated. In most of the patients,
diabetes usually coincides with or slightly precedes the diagnosis of carcinoma,
and is therefore likely to be considered an epiphenomena. This finding, however,
plays an important role because it can be considered, especially in patients
without a positive family history or risk factors for non-insulin-dependent
diabetes, an early sign of development of the neoplasm. Pancreatic cancer can
induce diabetes with different mechanisms: - tumor obstruction of the ductal
system and subsequent development of chronic pancreatitis; - direct carcinogenic
effect on the insulae; - production of diabetogenic factors. One of these, the 'islet
amyloid polypeptide ", capable of experimentally inducing insulin resistance, is
observed in high concentration in the serum of patients with pancreatic
carcinoma and decreases after the removal of the tumor. The regression of
diabetes, after removal of the tumor, however, does not represent a constant
element, most likely in relation to the severity of the insular alterations
being produced. According to some authors diabetes should instead be considered
as a factor capable of promoting the development of carcinoma, especially when
it has lasted for at least five years.
The carcinoma that develops in patients with long-term diabetes, or with a
history of family diabetes, occurs at a younger age of 4 years, prefers the
body-tail region and has a more aggressive histotype.
Abnormalities of the bilio-pancreatic junction, with the absence of a common
channel, may represent a favoring factor; also the annular pancreas, estimated
in 1 case on 6500 autopsies, but currently identified in 1 case in 1000
retrograde cholangi-wirsungografie (ERCP), is considered to cause the
development of carcinoma in the ventral portion of the pancreatic head, most
likely in relation to pancreatitis chronic that develops in this segment.
Approximately 10% of pancreatic carcinomas develop in genetically predisposed
patients, with an incidence 13 times higher than the general population. Unlike
other hereditary family carcinomas, such as colon and breast cancer, carcinoma
of the hereditary pancreas shows a low penetrance (<10%) and does not differ
from sporadic carcinoma due to the age of onset.
Hereditary pancreatic carcinoma appears to be extremely polymorphic and may be
associated with various familial genetic syndromes:
• Hereditary colorectal carcinoma not associated with polyposis (HNPCC) or Lynch
type II syndrome, with germinal mutations in DNA coupling repair genes, hMSH2,
hMLHl. The relative risk is 4.46;
• hereditary carcinoma of the breast and ovary, with mutations of the BRCA2
gene;
• Peutz-Jeghers syndrome, with germline mutations of the STK11 / LKB1 gene;
• Syndrome of dysplastic nevus and melanoma, but limited to families with
functional defect of the pl6INK4 protein;
• Hereditary pancreatitis, with mutation of the cationic gypsum-geno gene
(PRSS1), with a risk 53 times higher.
In a screening study conducted on 38 patients with familial pancreatic
carcinoma, and performed with echoendo-scopic studies, and in positive cases
with needle aspiration, ERCP and TAC, 6 pancreatic masses were found, with a
diagnosis rate of clinically relevant lesions 5.3% (2 out of 38), equal to the
percentage of false positive cases (2 out of 38). Histological examination of
the operating parts revealed ductal carcinoma, patient still alive 5 years after
surgery, an intraductal mucinous papillary neoplasm, two serous cystadenomas and
two non-tumor masses.
The most important radiological examinations are represented by transabdominal
ultrasound or transduodenal echoendoscopy, TAC, MRI and ERCP. The appearance is
that of a mass of relatively small dimensions (2-4 cm at the head, larger at the
tail), with infiltrative margins, of an inhomogeneous and usually hypoechoic
appearance. Signs of important accessory are the stenosis and dilatation of the
duct of Wirsung and the choledochus and, in the more advanced stages, the
infiltration of the vascular pedicle, the retroperitoneum, the presence of
enlarged lymph nodes and hepatic metastases. Serum tumor markers, such as CA19-9
and CEA, are frequently increased in pancreatic carcinoma, but do not show
sufficient sensitivity and specificity. The application of new serum markers,
used alone as osteopontin or in combination with CA 19-9 as the MIC-1 (serum
inhibiting cytokine-1 of macrophages), appears to be promising.
Of the many genes involved in pancreatic carcinogenesis, none has proved
reliable in screening patients.
Although from a meta-analysis on all studies published between 1988 and 2003, on
mutations of K-ras in hyperplastic and dysplastic pancreas lesions, reclassified
according to the nomenclature of pancreatic intraepithelial neoplasia (Panin),
there would seem to be a correlation between mutations of K-ras and ductal
carcinoma. In patients with pancreatic cancer the incidence of K-ras mutations
correlates with the severity of dysplasia: 36%, 44%, and 87% in lesions
respectively PanlN-1A, 1B, and 2-3 (P <.001) . Patients with chronic
pancreatitis lasting longer than three years have a mutation rate of K-ras of
10%. The correlation between the incidence of K-ras mutations with the degree of
dysplasia in Panin lesions and the duration of disease in chronic pancreatitis
underscores the importance of these gene modifications in the development of
pancreatic carcinoma. However, the clinical use of the research of mutations of
K-ras carried out on serum, duodenal juice, pancreatic juice and faeces has
proved to be insufficiently sensitive.
Proteomic analysis studies of pancreatic juice in patients with pancreatic
cancer have recently detected a total of 170 distinct proteins with a
significant difference compared to healthy subjects. Among these were known
proteins such as CEA, MUC1 and others never identified in pancreatic juice as
the pg% tumor-associated tumor antigen, arurocidin and PAP-2, a protein with 85%
homology with HIP protein / PAP superexpressed in pancreatic, hepatic,
intestinal carcinoma and in chronic pancreatitis.
The discovery of new tumor markers, using the analysis method of gene expression
(SAGE), comparing all the overexpressed or under-expressed genes in pancreatic
cancer compared to normal, proceeds at such speed that it is extremely difficult
to keep up and even more difficult is the task of validating its clinical
utility.
In two thirds of cases the carcinoma is located at the head of the pancreas and,
in a third, in the body-tail. The involvement of the whole organ and the
multifocal presentation are a rarity. At the time of diagnosis, the average size
of the carcinoma of the head is significantly lower (2-3 cm) than those of the
body-tail (5-7 cm). Carcinoma is usually characterized by a solid mass, with
infiltrative margins, whitish complexion and hard-ligneous consistency.
Carcinoma in advanced stages of disease may have an uneven and sometimes "cystic"
appearance. This aspect can originate either from regressive changes of the
tumor itself (necrosis and haemorrhage), or from the presence, intra or
peritumoral, of retention cysts (secondary to obstruction of the ductal system).
Such cystic modifications may erroneously make these ductal carcinomas be
considered as "cystadenocarcinomas" or "intraductal carcinomas".
Carcinoma of the pancreatic head, more frequently located in the anterior
portion than in the uncinate process, is usually associated with stenosis of the
terminal choledochus (jaundice) and of the Wirsung duct (chronic obstructive
pancreatitis). In advanced stages it can extend to the papilla of Vater and
infiltrate the duodenum. The carcinoma of the body and of the round tail instead
of invaderp the retroperitoneum, the stomach, the colon, the omentum, the spleen
and the adrenals.
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Carcinoma mucinoso, non cistico |
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Differential ductal adenocarcinoma |
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Poorly differentiated ductal adenocarcinoma |
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Carcinoma, anaplastic variant |
The main histopathological features of pancreatic carcinoma are represented by:
- presence of infiltrating duct-like structures;
- rich desmoplastic stromal component;
- frequent perineural invasion.
The glandular component traces, to varying degrees, the characters of the
columnar epithelium of the pancreatic ducts, but does not possess distinctive
characteristics with respect to the neoplastic glandular component that
originates from the biliary system and from the structures of the papilla of
Vater. The neoplastic epithelial component can be organized into tubular,
cribriform, papillary and other aspects.
The grading of the neoplasm, based on cytoarchitectonic criteria, foresees three
grades:
- G1, presence of well differentiated glandular structures;
- G2, presence of moderately differentiated glandular structures;
- G3, presence of poorly differentiated glandular structures, mucoepidermoid
differentiation or pleomorphic structures. The presence of a desmoplastic
reaction gives the neoplasia a woody consistency and in particular cases a "scar"
appearance. Desmoplasia induces a considerable reduction of the vascular bed,
which is one of the useful signs for the differential radiological diagnosis of
normal tissue and carcinoma. Character that, in clinical practice, is made less
evident by the concomitant fibrous changes that occur in the peri-tumoral
pancreatic parenchyma (chronic obstructive pancreatitis).
Dense fibrous tissue consists predominantly of type I and IV collagen,
fibronectin and, more rarely, type III collagen. The neoplastic infiltration in
perineural spaces is another very characteristic aspect of ductal carcinoma,
being found in 70% -88% of cases.
The most relevant immunohistochemical characters trace the ductal cell phenotype,
with the positivity for CEA, CA 19-9, DUPAN-2, for cytokeratins 7,8,18,19 and
only rarely for cytokeratin 20. In particular , tumor cells of ductal carcinoma
express MUCl-positivity and MUC2-negativity. MUC1 is normally expressed in
normal intralobular pancreatic ducts, whereas MUC2 is absent in both major and
interlobular pancreatic ducts. Positivity for MUC5AC, a marker of gastric mucin
and absent in normal pancreatic ducts, can be considered a sign of
trans-differentiation of gastric ductal pancreatic neoplasia.
Histological variants. Those neoplasms with a minimal component of classical
ductal adenocarcinoma are considered; clinical features and survival are
overlapping.
These variants are essentially represented by:
- non-cystic mucinous carcinoma, characterized by a massive production of mucus
and by an intraductal mucinous papillary component, more or less evident;
- adenosquamous carcinoma, characterized by mixed aspects of adenocarcinomatosis
and squamous carcinoma, with frequent sarcomatous-like areas;
- anaplastic carcinoma, characterized by variable histological aspects with
presence of giant cells, pleomorphs;
- giant cell carcinoma of the osteoclastic-like type characterized by the
presence of numerous giant multinucleated cells, similar to osteoclasts;
- clear cell carcinoma, composed predominantly of pleomorphic cells with a clear
cytoplasm rich in glycogen;
- mixed ductal-endocrine carcinoma, characterized by the presence of a glandular
component which, at the immunohistochemical investigations for endocrine markers,
shows a conspicuous presence of endocrine elements strictly connected to the
ductal cells, positive vice versa for the mucins. The endocrine component, by
definition, must represent at least one third of the neoplasm (most classic
ductal adenocarcinomas have a sparse endocrine component, which is not
sufficient to classify it as a mixed tumor);
- carcinoma with morphological characters of the "medullary" type, characterized
by expansive growth, by marked peritumoral inflammatory infiltrate and by
instability of microsatellites.
Differential diagnosis of adenocarcinoma
ductal of greater clinical impact arises with:
- chronic pancreatitis (in its various forms);
- the tumors of the papilla of Vater (better prognosis).