Solid Tumors and Tumor-like Lesions of the Pancreas
Moderators: Ralph H. Hruban and Günter Klöppel
Section 2 -
Differential Diagnosis of Solid and Cystic Tumors of the Exocrine Pancreas
Dipartimento di Patologia, Università di Verona, Italy
Servizio di Anatomia Patologica
Ospedale Don Calabria, Negrar, Verona
Although ductal cells account for only 10-30% of the normal pancreatic
parenchyma, ductal adenocarcinoma comprises between 80 and 90% of all neoplasms of the exocrine pancreas
. With the exception of functioning endocrine neoplasms, characterised by a specific clinical
picture, the other pancreatic tumors manifest with either non-specific symptoms, or symptoms similar to
pancreatitis. Although a correct diagnosis is mandatory to plan the therapeutic approach and establish a
prognosis, accurate preoperative diagnosis of a pancreatic mass is very difficult to achieve. In several
cases, preoperative diagnosis can be established by ultrasonound (US)-guided fine needle aspiration
citology (FNAC) or, more rarely, by fine needle aspiration biopsy (FNAB)
 . These methods have a good
safety level but limited sensitivity. For these reasons, the majority of clinically and radiologically
suspicious masses, which are potentially resectable, are surgically treated and diagnosis can only be
established by pathological examination of the resected pancreas.
Ductal adenocarcinomas must be differentiated from other pancreatic non-adenocarcinomatous tumors
such as cystic tumors, solid-pseudopapillary tumors, and acinar cell carcinomas or pancreatic
non-neoplastic lesions such as chronic pancreatitis or lymphocytic pancreatitis . Adenocarcinoma of the
pancreas is generally detected at an advanced stage. Due to its silent course, late clinical
manifestation and rapid growth it has been considered the 'silent killer' . Early diagnosis is
mandatory to improve prognosis, although only 10-20% of patients initially present with a resectable
Surgery has achieved the aim of reducing postoperative mortality, but the local and distant
recurrence rate of resected pancreatic carcinomas is still relatively high with retroperitoneal tissue
infiltration as one of the principal causes of recurrence
In order to improve prognosis,
surgery has become more aggressive, including radical lymphadenectomy is some cases
principal aims of extended pancreaticoduodenectomy (PD) are disease staging, reduction of local and
regional recurrence, and, most importantly, better survival. Recent prospective randomized trials failed
to confirm their results with extended lymphadenectomy. In most of these studies there is a difference
between the two groups of patients but the difference has no statistically significance
The only patients who can benefit from extended lymphadenectomy are those who are R0, have pathologically
involved second echelon lymph nodes and has no visceral metastatic disease (M0). On the base of these
data, only 0.3% of patients can have putative survival benefit. The adequately powered randomized trials
to definitively address the potential benefit of extended lymphadenectomy are infeasible:the study would
require 202,000 patients in each study arm . In the update analysis of 5-years survival of Johns Hopkins's patients there is a trend toward
improved survival in patients with pancreatic adenocarcinoma in the radical group (13% versus 29%,
P=0.13). The Authors's hypothesis is that this trend may be largely accounted for by the higher
incidence of microscopically margin positive resections in the standard resection group (21%) compared
with a 5% incidence in the radical group (P = 0.002)
Specimens of resected pancreatic cancer are uncommon in the majority of pathology departments. The
anatomical complexity of a PD specimen is intriguing; therefore, accurate pathological evaluation of the
resected specimen is better achieved when there is a concerted effort among surgeons, pathologists, and
radiologists. Numeorus pathological criteria are prognostically important, however the pathologist must
focus on those with prognostic significance thatare useful in identifying patients who would benefit from
Histological Tumor Typing
Histological tumor typing should be performed according to the WHO classification . The great
majority of carcinomas are common type ductal adenocarcinoma that strongly resemble the appearance of
normal pancreatic and bile duct structures. The neoplastic cells, similar to ductal pancreatic cells,
produce mucin, and the mucin phenotype closely simulates that of the intralobular small ductules. Thus
MUC1, which is a marker of intralobular ductal cells, is consistently expressed, whereas MUC2, which is
not found in the normal pancreas, and MUC5AC, normally expressed by the gastric mucous surface cells, are
also lacking in cancer cells . Other duct cell markers that are typically found in adenocarcinomas
are the cytokeratins 7, 8, 18, 19 and occasionally 20, CA19.9, DUPAN-2, CEA and loss of DPC4
Ductal adenocarcinomas must be differentiated from other pancreatic malignancies such as acinar or
endocrine carcinomas. It is especially essential to identify mucinous-cystic neoplasms and
intraductal-papillary neoplasms because of their incomparably better prognosis. The 'cystic' variant of
ductal adenocarcinoma, due either to degeneration changes or to ectatic changes of the duct system, can
mimic the former two neoplasms.
The most important differential diagnosis of ductal carcinoma of the pancreatic head is that versus
ampullary and periampullary carcinomas. Ampullary carcinoma, which
represents 5% of all gastrointestinal tumors, but accounts for up to 36% of the surgically operable
pancreatoduodenal tumors, is a neoplasm centered in the region of the ampulla of Vater. The ampulla of
Vater is formed by three anatomical components: the ampulla (common channel), the intraduodenal portion
of the bile duct and the intraduodenal portion of the pancreatic duct. Thus, it may show intestinal or
pancreatobiliary morphology and immunophenotype
The unequivocable establishment of ampullary
origin is possible in small lesions by applying strict topographical criteria during the gross and
histological examination. The presence of 'preinvasive' modification in the anatomical structures of the
ampulla can help in establishing a differential diagnosis. Periampullary
carcinoma is a widely used term to define a heterogeneous group of neoplasms arising from the head
of the pancreas, the terminal common bile duct and duodenum. The clinical importance of differentiating
ampullary cancer from cancers arising from periampullary structures lies in the significant differences
in their resectability and prognosis. Unlike pancreatic carcinoma, allelic losses on chromosomal arms
17p and 18q are relatively frequent events in ampullary carcinoma, and chromosome 17p status and the
presence of microsatellite instability were found to be independent prognostic factors among ampullary
carcinomas at the same stage. DNA replication errors occur only in a small percentage of longterm
survivors pancreatic carcinomas, which are also characterized by wild-type K-ras gene status and a
medullary phenotype with poor differentiation and expanding pattern of invasion . Thus, the combined
use of T-stage and chromosome 17p status may help determine whether patients with ampullary cancer
require therapy other than surgical intervention
The other most important differential diagnosis is with nonneoplastic lesions mimicking solid
neoplasms of the pancreas. If we rule out the very unusual cases
most of the "solid" cases fell
in the category of the inflammatory and fibrosis conditions, correlated in different ways to chronic
pancreatitis (CP). The CPs which pose difficult differential diagnosis are not the classical severe CPs
with extensive calcifications and ductal dilatation , but those presenting with a pancreatic mass
The lesions which frequently present as tumor mass are the autoimmune pancreatitis
inflammatory pseudotumor  and the groove pancreatitis or paraduodenal pancreatitis
Resection Margins of Duodenectomy Specimens
Resection margins include the common bile duct and the pancreatic transection margin, both of which
are to be evaluated intraoperatively on frozen sections. Pathologists should concentrate on assessing
involvement of the retroperitoneal resection margin (peripancreatic adipose tissue behind the head of the
pancreas that is located dorsal and lateral to the superior mesenteric artery) and vascular structures
(the portal vein and/or mesenteric vessels), since this provides much more useful information relative to
prognosis and for management. The retroperitoneal margins should be inked with India ink, sectioned
perpendicularly and 4-5 successive, numbered specimens should be submitted for histological examination.
Segments of vessel resection should be separated submitted and entirely included so that tumor invasion
can be ascertained histologically.
For ductal adenocarcinomas the grade is an essential and independent prognostic factor  and should
be recorded according to the criteria of the WHO .
While invasiveness is always present in ductal adenocarcinoma and need only to be described in
relation to its growth (expanding or infiltrating), in other tumor, such as mucinous cystic tumors and
intraductal-papillary tumors, it is frequently absent or may be detected only focally detected.
Particular care should be taken to sample the tumor extensively, to ensure that invasive component is
detected. As additional features of the carcinomas, lymphatic, blood vessel and perineural invasion
should be recorded as well as the extent into the peripancreatic adipose tissue or into adjacent
Variants of Ductal Adenocarcinoma
- Mucinous noncystic carcinoma (colloid carcinoma) is composed of well
differentiated glands floating in abundant (>50%)
extracellular mucin . It has an incidence of
1-3% of all pancreatic cancers; the gender and age are similar to ductal carcinoma. Macroscopically, the
tumor is usually well demarcated. Microscopically, it is characterized by the presence of excessive
amounts of mucous in which epithelial components are found in at least some areas. The latter usually is
characterized by well differentiated cells, whereas signet ring cells are infrequently found. The
overwhelming majority of colloid carcinomas in the pancreas arise from preexisting intraductal papillary
mucinous neoplasms (IPMNs). When colloid tumors of the pancreas have been extensively sampled and
examined in their entirety a preexisting IPMNs have been found in all cases . The finding of a
colloid carcinoma in the pancreas should prompt the pathologist to search for an IPMN. The prognosis of
a colloid carcinoma is considered better than 'conventional' adenocarcinoma .
- Adenosquamous carcinoma is composed of a mixture of glandular and
squamous neoplastic cell component (>30%). Its incidence is 3-4% and the gender and age of these
patients are similar to those with ductal carcinoma. Microscopically, the adenocarcinomatous component
usually predominates over the squamous cell carcinoma component. It shows a high metastatic potential
and the prognosis is worse than that of 'conventional' adenocarcinoma . Molecular features have not
been reported so far. The existence of a 'pure' squamous pancreatic carcinoma is still debated. This
diagnosis should be made only after extensive sampling of the tumor to exclude the presence of a
malignant glandular component. The differential diagnosis versus metastatic squamous carcinoma is
essentially based on clinical information; the prognosis is fatal, with a 0% survival rate at 3 years
- Undifferentiated (anaplastic) carcinoma is composed of pleomorphic
large cells, giant cells and/or spindle cells . Its incidence is 5-7% of all pancreatic tumors; it
is more prevalent in males with an age peak in the seventh-ninth decades of life. Microscopically, the
tumor may reveal several subtypes. The frequency of a glandular component increases with the number of
tissue samples. It should be differentiated from sarcomas and metastatic undifferentiated carcinoma
(i.e. large cell lung carcinoma).
The behavior is poorer than 'conventional' adenocarcinoma .
- Undifferentiated carcinoma with osteoclast-like
giant cells is composed of malignant undifferentiated epithelial cells with round or
spindle-shaped cells associated with nonneoplastic osteoclast-like giant cells. The tumor, which
morphologically mimics a giant cell tumor of bone, may show osteoid or osseous formation. It is rare and
comprises less than 1% of all pancreatic cancers, with a prevalence in the sixth-seventh decade of life.
The epithelial nature of the neoplastic component is supported by the reactivity with the same
cytokeratin of conventional adenocarcinomas (CK7, 8, 18 and 19), identical KRAS mutations in their ductal components, whereas the reactive osteoclastic-like
giant cells express the leukocyte common antigen CD45, the MB1 and the histiocytic marker CD68 . The
ductal derivation of the neoplastic component is further supported by the detection of KRAS mutations identical to conventional adenocarcinomas. The clinical course is
extremely aggressive and most patients die within 1 year .
- Medullary carcinoma is, like their counterpart in the colorectum,
composed of polymorphous cells with a syncytial growth pattern, a high degree of nuclear polymorphism,
high mitotic rates and occasionally tumor infiltrating lymphocytes. The tumor cells are characterized by
a high mutation frequency in the mismatch repair genes (DNA replication error+) and by the absence of
K-ras mutations . Unlike medullary colorectal carcinoma, medullary
pancreatic carcinoma is not associated with a better prognosis; the 5-year survival rate is 13% .
- Other rare carcinomas: they include clear cell
ductal adenocarcinoma with a foamy gland pattern 
and mixed exocrine-endocrine carcinoma .
Precursors to the Invasive Pancreatic Carcinoma
Various non-invasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas;
identification of these non-invasive lesions offers the potential to cure early pancreatic cancers.
These precursors include one microscopic lesion [ pancreatic intraepithelial neoplasias (PanINs) ], two
mass forming lesions [ intraductal papillary mucinous neoplasms (IPMNs) ] , and [ mucinous cystic
neoplasms (MCNs) ] . The ambiguity in the differential diagnosis between the two proliferative changes of
pancreatic ductal epithelium, PanINs and IPMNs, is still great.
1) Pancreatic intraepithelial neoplasia (PanIN): in the new guidelines for
their diagnosis PanIN is defined as a microscopic papillary or flat non-invasive epithelial neoplasm
arising in the pancreatic ducts. PanINs are characterized by columnar to cuboidal cells with varying
amounts of mucin and degrees of cytologic and architectural atypia. PanINs usually involve ducts <5mm
in diameter .
PanIN lesions (including lesions that were formerly known as ductal non-papillary or papillary
hyperplasia) characteristically occur in intralobular ducts, are undetectable macroscopically and are,
therefore, clinically silent. Early lesions, PanIn-1A and PanIN-1B, show minimal cytological and
architectural atypia lymphocytes. PanIn-2 lesions show mild to moderate cytological and architectural
atypia with frequent papillary formation. PanIN-3 lesions exibit severe cytological and architectural
atypia. PanIN lesions have been integrated into a tumor progression model for ductal carcinoma that
links the morphological changes in the duct epithelium with genetic alterations. The genetic profile of
PanINs show both activation of oncogenes and inactivation of tumor suppressor genes: activation of the
KRAS oncogene and inactivation of the tumor suppressor genes CDKN2A/p16, TP53/p53 and
Recent data show frequent up-regulation of foregut markers in early PanIN lesions and suggest that
PanIN development may involve Hedgehog-mediated conversion to a gastric epithelial differentiation
Data regarding the progression of the different types of PaIN lesions are still limited. PanINs-1 and
PanINs-2 are of unproven malignant potential and are generally not reported by pathologist in diagnosis.
PanIn-3 lesions must be recognized and reported in the pathology report.
2) Intraductal papillary-mucinous neoplasms (IPMNs) is a grossly visible
non-invasive, mucin-producing, predominantly papillary, or rarely flat, epithelial neoplasm arising from
the main pancreatic duct or branch ducts, with varying degrees of duct dilatation. IPMN usually produce
a lesion > 1 cm in diameter and include a variety of cell types with a spectrum of cytological and
The role of the macroscopic examination of the surgical resected specimen is to document the
intraductal growth of the lesion, the distribution and type of lesion and to search for invasive
carcinoma component. Macroscopically, two main types can be distinguished: ductectatic mucin-hypersectreting variant in which the dilated main duct or branch
ducts are filled wih tenacious mucin and the lining of the cysts is flat and smooth, and papillary-villous variant, characterized by nodular or papillary soft and friable
proliferation associated with mucous material within the dilated pancreatic duct. The polypoid
proliferations, along with the presence of mucing plugs, are responsible of the typical filling defects
seen at ERCP. IPMN can be further distinct into main-duct and branch-ducts types. The main-duct type prevalently involve the main duct, either
in diffuse or segmental manner. The great majority of cases arise in the main pancreatic duct of the
head of the pancreas and progress along the same duct with frequent involvement of the branch ducts. The
extension of the IPMN to the major and/or minor papilla creates the typical protrusion into the duodenum
that can be seen either at endoscopy or at US and CT.
IPMNs are graded according to the cytological and architectural atypia of the proliferating epithelium
into low-grade dysplasia (IPM-adenoma),
moderate dysplaia (IPM-borderline) andhigh-grade
Because the great variability within a tumor, it is important to emphasise the necessity of an
extensive tumor sampling in order to make the correct diagnosis and assess the presence of tumor
invasion, giving special emphasis to papillary proliferations, nodular areas and sclerotic areas. The
presence of carcinomatous stromal invasion characterizes the invasive
IPMN. Invasive IPMN is frequently characterized by the presence of
mucin-filled cystic spaces, partially lined by atypical cells and containing floating mucus-secreting
cells nuclei. This pattern of invasion, which has been called "muconodular"  assumes the appearance
of mucinous noncystic carcinomas (MNCC)
carcinoma . The overwhelming majority of
colloid carcinomas in the pancreas arise from preexisting IPMNs. When colloid tumors of the pancreas
have been extensively sampled and examined in their entirety a preexisting IPMNs have been found in all
cases , whereas, in less extensive pathological sampling, Adsay et al reported a 59% of association
with IPMNs . The finding of a colloid carcinoma in the pancreas should prompt the pathologist to
search for an IPMN. On the contrary, the presence of a glandular component which characterizes the
"tubular" pattern (similar to the usual ductal carcinoma) is infrequently encountered.
This group of neoplasms may also be subclassified on the basis of their morphology and mucin
immunophenotype: a) MUC2+/MUC1- gastrointestinal type with a good prognosis; b) MUC2-/MUC1+
pancreatobiliary with poorer prognosis and c) MUC2+/MUC1/MUC5AC+ gastric foveolar type with few or no
cellular atypia, and d)MUC1+/MUC2+ oncocytic types, which is not yet well characterized. The invasive
component, present in approximately one third of cases, shows either a tubular or a mucinous invasive
component. The tubular invasion pattern resembles the conventional ductal carcinoma, while the mucinous
pattern shows the features of colloid (mucinous noncystic) carcinoma. While the common MUC2+
gastrointestinal IPMNs can be considered the precursor of the MUC2+ mucinous noncystic carcinoma, the
MUC2-/MUC1+ pancreatobiliary IPMNs appear to have a close relationship to ductal carcinoma
The treatment of IPMN is the surgical resection. The extent of resection that is necessary should be
usually determined by histological examination of the margins on frozen sections. 
3) Mucinous cystic neoplasm (MCN) affect females almost exclusively,
predominantly involve the tail of the pancreas, do not communicate with the ductal system, and are
usually accompanied by the characteristics ovarian-type stroma
MCNs appear as a round mass with a smooth surface and a fibrous pseudocapsule with variable thickness
and frequent calcifications. The size of the tumor ranges from 2 to 35 cm at the most, with an average
size between 6 and 10 cm. The cut section shows either unilocular or multilocular tumor with cystic
spaces ranging from a few millimeters to several centimeters in diameter, containing either thick mucin
or a mixture of mucin and hemorrhagic-necrotic material. The internal surface of unilocular tumors is
usually smooth and glistening, whereas the multilocular tumors often show papillary projections and mural
Microscopically, the spectrum of differentiation ranges from histologically benign columnar epithelium
to severely atypical epithelium. MCNs are classified according to the degree of epithelial dysplasia
like IPMNs: adenoma, borderline and carcinoma. The presence of carcinomatous stromal invasion
characterizes the invasive mucinous cystadenocarcinoma. The invasive
component usually resembles the common ductal adenocarcinoma. However, MCCs with invasive adenosquamous
carcinoma, osteoclast-like giant cell or choriocarcinoma have been reported. Occasionally MCN shows
mural nodules with a sarcomatous stroma or an associated sarcoma.
As in the development of ductal carcinomas, the KRAS
mutations are early events, while TP53 and DPC4
gene inactivation are relatively late genetic alterations in the progression of noninvasive to invasive
Other Cystic Neoplasms
The category of cystic lesions of the pancreas includes cystic formations of different morphology,
pathogenesis and biology . Although these lesions are uncommon compared to solid tumors of the
pancreas, they constitute an important group of lesions with distinctive clinical and pathological
features. The therapeutic approach and the prognosis differ substantially, depending on the specific
diagnosis  The current interest in identifying cystic pancreatic lesions arises from their easier
recognition with modern imaging techniques, such as ultrasonography (US) and CT. They have been
encountered in 1.4% of all abdominal computer tomography (CT)
scans . The spectrum of pancreatic
tumors with cystic features is broad, and includes serous microcystic or oligocystic (macrocystic) tumor
solid pseudopapillary tumor with cystic degeneration (i.e., solid-cystic tumor} (44,46},
acinar cell cystadenocarcinoma
acinar cell cystadenoma , and endocrine tumor with cystic
Non-neoplastic cysts, such as congenital cysts ,
single true cysts ,
lymphoepithelial cysts ,
enterogenous cysts 
and endometrial cysts  are extremely rare, but an
exact estimation of their true prevalence is so far not available.
Serous Cystic Tumors of the Pancreas
Serous cystic tumors are formed by glycogen-rich, PAS-positive epithelial cells which produce serous
fluid, and are characterized by the absence of atypia and indolent course. They can be subdivided:
Identifying a pancreatic mass as a SCN on imaging is important because in this tumor, surgical
resection is only necessary when the tumors are symptomatic and the benefits of the operation outweighs
the risk or to prevent the development of complications such as erosion into adjacent organs, hemorrhage,
biliary and gastroinstestinal obstructions
- Microcystic or classic type:t he most common form; the tumors appear
as relatively well circumscribed with multi-lobular margins, formed by innumerable cysts (sponge-like
appearance), which range from 1 mm to 5mm in diameter with central stellate scar.
- Macrocystic or oligocystic type: characterized by a small number of
locules, less demarcated than the microcystic variant and frequent extension of the cysts into the
adjacent pancreatic parenchyma. The cut surface shows the presence of a countable number of cysts
(oligocystic) or sometimes a single cyst (unilocular) with a variable diameter of 2 to 15 cm. The
oligocystic variant characteristically lacks a central scar
Correct diagnosis of macrocystic
serous adenoma is of the utmost importance, since surgical resection may not be necessary.
- Solid serous adenoma: a rare lesion, usually of small size that can
be easilly confused radiologically with pancreatic endocrine tumor.
- Serous tumors associated with von Hippel-Lindau syndrome (VHL):
characterized by multiple, diffusely distributed microcystic and macrocystic lesions.
- Serous cystadenocarcinomas: the histological features are similar to
the benign forms, but are characterized by aggressive growth with perineural and perivascular invasion,
involvement of regional lymph nodes and adjacent organs such as stomach and liver .
Solid Pseudo-Papillary Neoplasm (SPN)
SPN of the pancreas, which represents less than 1% of all pancreatic neoplasms, is a distinctive
low-grade malignancy that primarily occurs in young women and is composed of monomorphous, small sized
non-cohesive cells . It has been rarely reported in older women, males and in extrapancreatic sites
Macroscopically, SPNs are frequently large, round, well-circumscribed masses and show variable
proportions of solid and cystic areas filled with hemorrhagic fluid and necrotic debris. At the extreme
ends of the spectrum of macroscopic appearances, some cases can be exclusively solid (usually the smaller
lesions), whereas others (usually the larger tumors) may be entirely cystic and the lesion easily
mistaken for a pseudocyst.
Microscopically, the tumors are composed of a mixture of solid and cystic areas, usually surrounded by
a fibrous capsule. The tumor cells, collected in solid areas or lining pseudopapillae, are monomorphous
with round to oval nuclei and eosinophilic, granular cytoplasms. PAS-positive globules, stromal myxoid
degeneration, necrotic changes with foam cells and hemorrhage are characteristically present. Mitotic
figures are virtually absent with a low proliferative fraction.
Clinically and radiologically, the differential diagnosis of exclusively solid SPTs, lacking
degenerative changes, with endocrine tumors is not possible. The immunophenotype is well characterized:
the neoplastic cells express NSE, CD56, CD10, vimentin, a-1-antitrypsin and a-1-antichimotrypsin, whereas
the immunoreactivity for a broad spectrum keratin markers is usually negative as well as for chromogranin
A. The nuclear positivity for beta-catenin has been reported in near all cases
SPTs have not
been shown the molecular changes reported in ductal adenocarcinomas, such as mutations in the p53, KRAS, DPC4 and p16 genes
Despite their large size, intrapancreatic SPN are cured by complete surgical resection . However,
proximately 15% of patients with SPN develop metastatic disease, mostly involving the liver or
peritoneum. However, even in the presence of disseminated disease, the clinical course is usually
protracted and only a few patients died of metastasizing tumor
M orphologically, it remains
difficult to predict the behavior of these tumors, which can display in some regions the typical
histologic features of SPN . The recognition of a diffuse growth pattern, extensive tumor necrosis, significant nuclear atypia,
an unusually high mitotic rate may be useful in the prediction of potentially more aggressive SPNs .
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