Pancreatic Ductal Adenocarcinoma Features

General and Clinical Features

• Ductal adenocarcinoma accounts for about 90% of pancreatic malignancies
• It's the fourth most common cause of cancer death in the US
• Pancreas carcinomas share embryologic origin, differentiation pathways, population-related development, and microscopic features with tumors of the gallbladder, extrahepatic bile ducts, and ampulla of Vater
• Most patients are elderly, with a slight male predominance (1.6:1)
• Can occur in patients younger than 40
• Smoking is a risk factor
• Chronic pancreatitis may increase risk, but the cause-effect relationship is hard to confirm
• Variations in pancreaticobiliary ductal anatomy may relate to carcinoma incidence
• Increased diabetes incidence in patients with pancreatic carcinoma often develops shortly after cancer diagnosis, suggesting it's a secondary event
• Overproduction of IAPP by beta cells may contribute to diabetes

Location and Gross Features

• Pancreatic ductal carcinoma is located in the head of the pancreas in two-thirds of patients and in the body or tail in the other third
• Multiple tumors are found in a minority of cases
• Most are poorly delineated, fibrotic, and firm, with a yellow-gray cut surface
• It is frequently difficult to distinguish tumor from adjacent chronic pancreatitis grossly
• Rarely, the tumor undergoes massive cystic degeneration and thus may mimic other cystic pancreatic tumors
• Duodenal wall invasion occurs by direct extension in one-fourth of tumors arising from the pancreatic head
• Involved pancreatic ducts may become greatly dilated and plugged with necrotic tumor or compressed and even destroyed by tumor growth
• Extrapancreatic extension is common

Microscopic Features

• Typical pancreatic ductal adenocarcinomas consist of infiltrating, haphazard glands and ducts with surrounding desmoplastic stroma
• Can be stratified as well, moderately, or poorly differentiated
• Poorly differentiated carcinomas have more significant nuclear pleomorphism and less well-developed glandular differentiation, along with areas of solid growth and easily identified mitoses
• The glands are often well formed, have a large lumen, and are lined by one or a few layers of cylindrical or cuboidal epithelium
• High-power examination of the lining epithelium will show one or more features that, in this location, are indicative of malignancy: marked nuclear pleomorphism, variation in nuclear size, loss of polarity, prominent nucleoli, and mitotic activity
• Features useful in diagnosing carcinoma within small biopsy specimens include glands present outside the normal lobular architecture; the presence of glands immediately adjacent to muscular arteries; and necrotic debris within gland lumens
• Perineurial invasion, which is present in 90% of the cases, constitutes an additional important diagnostic sign
• Invasion of blood vessels, particularly veins, is seen with half of the tumors
• The presence of ducts surrounded by adipose tissue without intervening acini ("naked ducts") is also highly indicative of malignancy

Other Microscopic Types

• There are several patterns of ductal adenocarcinoma that do not differ significantly from the conventional type clinically or prognostically but do have distinctive morphologic features
• The foamy gland pattern has a deceptively benign appearance and may be confused with non-neoplastic mucinous ducts
• The large duct pattern has large, ectatic, or microcystic malignant glands, which may be mistaken for benign dilated glands or a lower-grade noninvasive cystic neoplasm, particularly if the cytologic features are bland
• The vacuolated pattern consists of irregular or cribriforming nests of cells with prominent large, empty vacuoles, which may contain debris or mucin
• Adenosquamous and squamous carcinoma have squamous elements that may range from benign-appearing to poorly differentiated or may show basaloid features
• Tumors should be at least squamous to warrant the designation of adenosquamous in the WHO 2010 classification
• Medullary carcinoma is similar to those found in the breast and GI tract, are sometimes multicentric, and are associated with wild-type (nonmutated) KRAS
• Colloid carcinomas are often associated with IPMNs or mucinous cystic neoplasms (MCNs) and have a more protracted clinical course than conventional ductal adenocarcinoma
• Poorly differentiated ductal adenocarcinomas may have a clear cell phenotype (which is immunoreactive for hepatocyte nuclear factor-1 beta) or may have oncocytic features
• Microadenocarcinoma represents instead a pattern of growth associated with an aggressive clinical course rather than a distinctive morphologic entity
• Tumors termed undifferentiated carcinomas of the pancreas include tumors previously classified as anaplastic carcinoma, sarcomatoid carcinoma, spindle cell carcinoma, pleomorphic carcinoma, carcinosarcoma, and undifferentiated carcinoma with osteoclast-like giant cells

Histochemical and Immunohistochemical Features

• Most pancreatic ductal adenocarcinomas express cell surface-associated mucins, including MUC1, MUC3, MUC4, and MUC5AC
• The keratins expressed are those of simple epithelia such as 7, 8, 18, and 19 (as normal ductal cells), but also 20, 17, and occasionally cytokeratin 5/6
• Ductal adenocarcinomas also frequently express EMA, CEA, CA125, mesothelin, TAG72, DUPAN2, and CA 19-9
• A high proportion of ductal adenocarcinomas also contain a minor population of neoplastic cells that are immunoreactive with neuroendocrine markers, such as synaptophysin or chromogranin
• There is also frequent expression of the neural cell adhesion molecule N-CAM

Molecular Genetic Features

• The most commonly mutated genes include KRAS, CDKN2A (p16), TP53, SMAD4/DPC4, and MKK4
• Mutations of the KRAS oncogene are found in over 90% of the cases and represent an early genetic alteration
• Mutations of p16/CDKN2A, TP53, and SMAD4 occur in more than half of cases as well

Spread and Metastases

• Pancreatic ductal adenocarcinoma often spreads widely into the peripancreatic soft tissues
• Those located in the head may invade the duodenum (including the ampulla) and the common bile duct
• They also tend to surround the mesenteric vessels and the nerve plexus
• Nerve invasion has been correlated with expression of nestin in the tumor cells
• Ductal adenocarcinomas also metastasize to multiple lymph nodes located around the organ
• The most common sites of distant metastases are liver, peritoneum, lung, adrenal, bone, distant lymph node groups, skin, and central nervous system

Cytology

• Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has become the method of choice for the diagnosis of both solid and cystic pancreatic tumors, with a sensitivity of approximately 85% and a specificity of approximately 98%, exceeding that of brush cytology
• Cytologic specimens may also be used for a variety of ancillary studies useful to the diagnosis of pancreatic ductal adenocarcinoma, including immunohistochemistry for SMAD4 loss, mutational analysis for KRAS and p16, FISH (for a number of molecular abnormalities), and microRNA analysis

Surgical Exploration and Frozen Section

• At the time of exploration for a presumptive or confirmed diagnosis of carcinoma of the pancreas or ampullary region, the surgeon will search for evidence of metastatic disease in the peripancreatic nodes, liver, and peritoneum
• If the diagnosis has not been confirmed preoperatively, and a mass is palpated in the pancreas, a frozen section on a core needle biopsy or an intraoperative fine-needle aspiration will often be requested
• When the pancreatic head is biopsied, experience is required to avoid the common bile duct, the gastroduodenal artery, and the portal vein
• Frozen section interpretation of pancreatic lesions can be very difficult because of the well differentiated nature of many carcinomas on one hand, and the architectural distortion resulting from chronic pancreatitis on the other

Treatment

• Treatment of pancreatic adenocarcinoma may include surgery, chemotherapy, and radiation, depending on the stage of the tumor
• Surgery is considered to be the only curative treatment
• Adenocarcinomas without distant metastases are categorized as resectable, borderline resectable, or locally advanced
• Surgical approaches include the Whipple operation (pancreaticoduodenectomy), total pancreatectomy, and distal pancreatectomy for neoplasms of the distal body/tail, and it is recommended that 12-15 lymph nodes be resected for optimal pathologic staging
• Adjuvant chemotherapy may be given after surgery for resectable pancreatic cancer and may result in improved disease-free and overall survival
• The role of neoadjuvant chemotherapy in borderline resectable or locally advanced adenocarcinomas remains controversial
• Chemotherapy is the mainstay of therapy for patients with metastatic disease with a gemcitabine-based regimen

Prognosis

• Stage is the most important prognostic determinator
• Pancreatic adenocarcinoma is staged using the tumor-node-metastasis classification (AJCC classification scheme in North America)
• Median overall survival is approximately 4 months
• Overall survival ranges from approximately 40% (stage I) to 8% (stage IV) at 1 year, to 12% (stage 1) and 0.7% (stage IV) at 5 years
• Other adverse prognostic factors include high tumor grade, markedly elevated serum CA 19-9, persistently elevated CA 19-9 postoperatively, and positive resection margins

Pancreatic Ductal Adenocarcinoma (PDAC) - Mucins

• MUC1: Expressed in over 80% of conventional invasive ductal carcinomas and high-grade PanIN
• MUC2: More commonly expressed in intraductal papillary carcinomas, mucinous (colloid) carcinomas, ampullary carcinomas, and colorectal carcinomas.
• MUC3, MUC4, MUC5AC: Also expressed in pancreatic ductal adenocarcinomas
• MUC6: Expressed in approximately one-third of ductal adenocarcinomas

Pancreatic Ductal Adenocarcinoma (PDAC) - Cytokeratins

• Simple Epithelia Keratins (7, 8, 18, 19): Expressed as in normal ductal cells.
• Other Keratins (20, 17, occasionally 5/6): Can also be expressed
• Cytokeratin 20: Expressed less frequently in pancreatic ductal than in ampullary adenocarcinomas
• Strong and diffuse expression in pancreatic colloid carcinomas

Pancreatic Ductal Adenocarcinoma (PDAC) - Other Markers

• EMA, CEA, CA125, Mesothelin, TAG72, DUPAN2, CA 19-9: Frequently expressed
• Neuroendocrine Markers (Synaptophysin, Chromogranin): A minor population of neoplastic cells within ductal adenocarcinomas may be immunoreactive with these
• N-CAM: Frequent expression
• Hep Par1, CD10, AFP, Polyclonal CEA: Hepatoid carcinomas of the pancreas are immunoreactive with these
• HNF-1 beta: Clear cell phenotype of poorly differentiated ductal adenocarcinomas is immunoreactive for this.
• CDX2, CK20, MUC2: Colloid carcinomas express these markers of intestinal differentiation

Pancreatic Ductal Adenocarcinoma (PDAC) - SMAD4 (DPC4)

• Loss of DPC4 protein (detected by immunohistochemistry) in the ductal epithelium of a pancreatic biopsy specimen is strongly suggestive of carcinoma.
• Positive staining does not rule out malignancy

Pancreatic Ductal Adenocarcinoma (PDAC) - Nestin

• Expression of nestin in tumor cells has been correlated with nerve invasion

PDAC - Commonly Mutated Genes

• KRAS:
  • Mutated in over 90% of cases
  • Represents an early genetic alteration
  • Not specific for malignancy; can be seen in chronic pancreatitis without dysplasia
  • Exception: Wild-type (non-mutated) KRAS is often seen in medullary carcinomas
• CDKN2A (p16):
  • Mutated in more than half of cases
• TP53:
  • Mutated in more than half of cases
• SMAD4/DPC4:
  • Mutated in more than half of cases
  • Protein product (DPC4) is inactivated in approximately half of PDACs
  • Loss of DPC4 protein (detected by immunohistochemistry) is strongly suggestive of carcinoma
• MKK4:
  • Mutated in a significant proportion of cases

PDAC - Concepts

• Genetic Progression: The search for genetic alterations in the invasive component and precursor lesions (PanINs) has provided key information on the genetic progression of pancreatic carcinoma
• The prevalence of genetic alterations increases with the degree of morphologic atypia in PanINs
• KRAS Mutation Utility: While KRAS mutations are common in PDAC, their presence in non-neoplastic epithelium in chronic pancreatitis limits their diagnostic utility in histologic or cytologic material
• DPC4 (SMAD4) Inactivation: Since DPC4 is inactivated in approximately half of pancreatic ductal carcinomas but practically never in benign conditions, the immunohistochemical absence of the protein product is strongly suggestive of carcinoma
• MSI (Microsatellite Instability): MSI does not appear to play a significant role in sporadic PDAC
• Lynch Syndrome: Patients with Lynch syndrome have an increased risk of PDAC