Solid Tumors and Tumor-like Lesions of the Pancreas
Moderators: Ralph H. Hruban and Günter Klöppel
Section 1 -
Ductal Adenocarcinoma of the Pancreas and Its Variants
Ralph H. Hruban
Professor of Pathology and Oncology
The Sol Goldman Pancreatic Cancer Research Center
The Johns Hopkins Medical Institutions
Baltimore, MD USA
Infiltrating ductal adenocarcinoma of the pancreas (pancreatic cancer) is one of the most lethal of
all of the solid malignancies. World-wide it is estimated that 227,000 will die from pancreatic cancer
. These numbers will only grow as the population ages.
Pancreatic cancer can be hard on the pathologist. The stakes are high and the diagnoses
are difficult. Both the life expectancy and the most appropriate treatment for a patient diagnosed with
chronic pancreatitis differ significantly from the life expectancy and appropriate treatment for a
patient diagnosed with pancreatic cancer. Yet, in some cases, it can be extremely difficult, if not
impossible, to distinguish pathologically between a benign reactive gland of chronic pancreatitis and an
infiltrating gland of well-differentiated pancreatic cancer.
In this lecture we will discuss well-defined morphologic criteria that can be used to differentiate
between neoplastic and reactive glands. In addition, the clinical characteristics, morphologic spectrum,
and grading of infiltrating ductal adenocarcinoma will be presented. Emphasis will be placed on
precursor lesions because these lesions can mimic infiltrating cancer, and because a better understanding
of these lesions offers the best hope for treating pancreatic neoplasia before an incurable invasive cancer develops.
Infiltrating ductal adenocarcinoma of the pancreas is an invasive malignant epithelial neoplasm with
glandular (ductal) differentiation and without a predominant component of any other type of carcinoma
Grossly, most infiltrating ductal adenocarcinomas form poorly-defined firm fibrotic masses. They are
white-yellow, and they obscure the normal lobular architecture of the pancreas . This latter feature
can be very helpful in distinguishing between chronic pancreatitis and infiltrating ductal
adenocarcinoma. Some cancers undergo central necrosis and these cancers can form gross cysts. Cysts may
also be found adjacent to the carcinoma due to localized dilatation of obstructed ducts (retention cysts)
Microscopically, as defined above, infiltrating ductal adenocarcinoma of the pancreas are
invasive malignant epithelial neoplasms with glandular (ductal) differentiation and without a predominant
component of any of the other carcinoma types . The degree of gland formation can vary from
well-formed glands, to partially formed glands, to focal intracellular mucin production by poorly
oriented cells infiltrating singly, to solid sheets of neoplastic cells . Several features can be
used to distinguish between benign reactive glands and infiltrating ductal adenocarcinoma, and most of
these boil down to location, location, location (Table 1). In evaluating the location of a duct, recall
that non-neoplastic glands, even when there is severe chronic pancreatitis, form predictable lobular
units. The ducts are towards the center of the lobular unit and are surrounded by grape-like clusters of
acini. The first feature useful in establishing a diagnosis of pancreatic
cancer is that pancreatic carcinoma infiltrates in a haphazard pattern. The glands violate the lobular
architecture, and are strewn in the parenchyma without rhyme or reason. Second, and this really is a manifestation of the first feature, is that
neoplastic glands can be found adjacent to muscular arteries without intervening pancreatic parenchyma
. By contrast, in the non-neoplastic pancreas, muscular arteries run at the periphery of the lobules
separated from the ducts by pancreatic parenchyma. The third and fourth features are that glands will be found where they simply don't belong.
Perineural and vascular invasion are both features of an invasive adenocarcinoma. Benign glands abutting
a nerve have been reported in very rare instances of severe chronic pancreatitis, but true perineural
invasion is virtually diagnostic of invasive pancreatic cancer . One feature of vascular invasion
that should be noted is that when pancreatic cancer infiltrates into vessels it has a tendency to grow
along the intimal surface of the vessel. In these instances the malignant glands lining the intima of
the vessel can mimic a low-grade pancreatic intraepithelial neoplasia (PanIN) lesion. The fifth feature is called the "4 to 1 rule." The nuclei in non-neoplastic glands
tend to be uniform, and in a single gland the area of the nuclei do not vary by more then 4 to 1. By
contrast, significant nuclear pleomorphism can be seen in ductal adenocarcinomas, and the finding of
nuclei in a single gland varying by more than 4 to 1 is indicative of a malignancy. Necrotic debris
within the lumen of a gland is the sixth feature to support a diagnosis of
pancreatic cancer. The seventh feature is incomplete lumina- that is lumina
which are not completely lined by an epithelial layer such that the luminal contents appear to directly
touch the stroma. I find the eighth feature, a gland directly touching fat
without intervening stroma, difficult to apply. The ninth and final feature
is the immunolabeling profile. The expression of the DPC4/MADH4 gene
product, dpc4, is completely lost in slightly more than half of infiltrating ductal adenocarcinomas, and
cancers express carcinoembryonic antigen (CEA). By contrast the vast majority of non-neoplastic glands
have intact (normal) labeling for dpc4 and most do not express CEA. When rigorously applied, these nine
features form a solid foundation for one of the most difficult differential diagnosis in surgical
pathology, namely chronic pancreatitis versus pancreatic cancer.
Special stains and immunohistochemical labeling can help in the evaluation of suspected infiltrating
ductal adenocarcinoma. Most adenocarcinomas of the pancreas express mucin and therefore stain with
periodic acid-Schiff stain and this staining is diastase resistant. They also stain with the mucicarmine
stain. Most express the cytokeratins (CK)
7, 8, 13, 18 and 19 (2). CK 17 is expressed by 50% of
infiltrating ductal adenocarcinoma, and CK 20 by <20%. The majority also express carcinoembryonic
antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), B72.3 (TAG-72), CA 125, and DUPAN 2. Most express
MUC1 (a pan-epithelial mucin), MUC3, MUC4, and MUC5AC (a gastric foveolar mucin)
. A minority express
MUC6 (a pyloric-gland mucin), and <10% MUC2.
Pancreatic Intraepithelial Neoplasia
Microscopic precursor lesions, known as pancreatic intraepithelial neoplasia, have been
recognized for over a century. Recent molecular studies have helped solidify the importance of these
lesions as precursors to invasive pancreatic cancer. PanINs are a hot topic because they suggest that it
should be possible to detect and treat these non-invasive precursor lesions before an incurable invasive
cancer develops. PanINs are defined as neoplastic epithelial proliferations in the smaller caliber
pancreatic ducts, and PanINs were divided into three grades based on the degree of architectural and
nuclear atypia present . Just as there is a progression in the colorectum from adenoma, to adenoma
with dysplasia, to invasive cancer, so too is there a histologic and genetic progression from PanIN-1, to
PanIN-2, to PanIN-3, to invasive ductal adenocarcinoma in the pancreas .
PanINs are often encountered at surgical margins. Although there is scant evidence-based medicine to
guide us, it is generally agreed that no therapy is needed for PanIN-1 or PanIN-2 at a margin . There
have been isolated case reports of PanIN-3 lesions which progressed to invasive ductal adenocarcinomas.
Therefore the resection of additional pancreatic parenchyma to achieve a margin free of PanIN-3 may be
warranted in some instances. When deciding whether or not to take an additional margin, it would be wise
to first consider the patient's clinical situation. If the patient has a large invasive cancer with
multiple lymph node metastases, then their invasive cancer posses a significantly greater threat to their
life than a PanIN-3 . By contrast, if it is a young patient with a potentially curable pancreatic
cancer, the resection of additional parenchyma to achieve a margin free of PanIN-3 may be recommended
Variants of Adenocarcinoma
Adenosquamous carcinoma is a malignant epithelial neoplasm with
significant components of both glandular and squamous differentiation . At least 30% of the neoplasm
should have squamous differentiation . The two components can be intimately admixed, or they can be
topographically separate within the neoplasm (2). Adenosquamous carcinoma is an extremely aggressive
Colloid carcinoma is an infiltrating adenocarcinoma
characterized by mucin producing neoplastic epithelial cells suspended ("floating") in large pools of
The colloid component should comprise at least 80% of the neoplasm . Most
colloid carcinomas arise in association with an IPMN, and these IPMNs usually exhibit intestinal type
Hepatoid carcinoma is a malignant epithelial neoplasm with significant
hepatocellular differentiation . Only a few cases have been reported and most also have areas with a
more common direction of differentiation, particularly ductal adenocarcinoma. .
Medullary carcinoma is a malignant epithelial neoplasm characterized by
poor differentiation, pushing borders, a syncytial growth pattern and necrosis . Most are
microsatellite instable (MSI+), and immunolabeling will often reveal the loss of the expression of one of
the DNA mismatch repair proteins, Mlh1 and Msh2 . Patients with medullary cancers are more likely to
have a family history of cancer.
Signet ring carcinoma is a malignant epithelial neoplasm in which the
predominant component is composed of infiltrating round non-cohesive (isolated) cells containing
intracytoplasmic mucin . Metastases from a breast or gastric primary should be ruled out before
making the diagnosis of a signet ring carcinoma primary to the pancreas.
Undifferentiated carcinoma is anepithelial
neoplasm with a significant component showing no glandular structures or other features to indicate a
definite direction of differentiation . The neoplastic cells range from pleomorphic epithelioid
mononuclear cells containing abundant eosinophilic cytoplasm admixed with bizarre frequently
multinucleated giant cells, to relatively monomorphic spindle cells . As one would expect, these are
extremely aggressive almost uniformly fatal malignancies.
The undifferentiated carcinoma with osteoclast-like giant cells is a
malignant epithelial neoplasm composed of reactive multinucleated giant cells admixed with atypical
neoplastic mononuclear cells . These neoplasms often arise in association with an adenocarcinoma or
mucinous cystic neoplasm.
TABLE 1: H and E features useful in distinguishing
benign glands and invasive adenocarcinoma+
| ||Benign gland ||Invasive Carcinoma|
|Haphazard growth pattern ||No ||Yes|
|Glands adjacent to vessels ||No ||Yes|
|Perineural invasion ||No ||Yes|
|Intravascular invasion ||No ||Yes|
|Nuclear variation > 4 to 1 ||No ||Yes|
|Intraluminal necrosis ||Usually no ||Often|
|Incomplete glands ||No ||Often|
|Gland touching fat ||No ||Yes|
+Adapted from 
- Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001; 94(2):153-156.
- Hruban RH, Klimstra DS, Pitman MB. Atlas of tumor pathology. Tumors of the pancreas. Fourth Series ed. Washington, DC: Armed Forces Institute of Pathology, 2006.
- Sharma S, Green KB. The pancreatic duct and its arteriovenous relationship: an underutilized aid in the diagnosis and distinction of pancreatic adenocarcinoma from pancreatic intraepithelial neoplasia. A study of 126 pancreatectomy specimens. Am J Surg Pathol 2004; 28(5):613-620.
- Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett E, Goodman SN et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001; 25(5):579-586.
- Maitra A, Fukushima N, Takaori K, Hruban RH. Precursors to invasive pancreatic cancer. Adv Anat Pathol 2005; 12(2):81-91.
- Adsay NV, Pierson C, Sarkar F, Abrams J, Weaver D, Conlon K et al. Colloid (mucinous noncystic) carcinoma of the pancreas. Am J Surg Pathol 2001; 25(1):26-42.
- Seidel G, Zahurak M, Iacobuzio-Donahue CA, Sohn TA, Adsay NV, Yeo CJ et al. Almost all infiltrating colloid carcinomas of the pancreas and periampullary region arise from in situ papillary neoplasms: a study of 39 cases. Am J Surg Pathol 2002; 26(1):56-63.
- Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA et al. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity. Am J Pathol 2000; 156(5):1641-1651.