Pancreatic Ductal Adenocarcinoma Features

General and Clinical Features

• Ductal adenocarcinoma makes up about 90% of all pancreatic malignancies.
• It is the fourth most common cause of cancer death in the United States.
• Pancreatic carcinomas share characteristics with tumors of the gallbladder, 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 known risk factor.
• The link between chronic pancreatitis and pancreatic cancer risk is difficult to confirm.
• Variations in pancreaticobiliary ductal anatomy may be related to carcinoma incidence.
• Diabetes incidence increases in patients with pancreatic carcinoma, usually shortly after diagnosis.
• Overproduction of IAPP by beta cells may contribute to diabetes.
• Presenting symptoms depend on cancer location and disease extent.
• Common symptoms include vague abdominal pain, nausea, and weight loss.
• Carcinoma in the head of the pancreas often causes progressive jaundice.
• Diagnosis is often late when tumors are relatively large (5 cm) and have spread beyond the pancreas (85% of cases).
• Small pancreatic carcinomas found incidentally at autopsy tend to be invasive with perineural spread.
• Carcinomas of the body and tail of the pancreas often metastasize before diagnosis.
• Deep venous thrombi occur in about 20% of patients.
• Tumor necrosis factor, interleukin-1, and interleukin-6 released by macrophages in tumor stroma may cause the syndrome.
• Tumor cells may produce procoagulant substances.
• About 10% of pancreatic cancers have an inherited component.
• Identified syndromes include:
  • Hereditary breast and ovarian cancer syndrome (BRCA2 mutation).
  • Familial atypical multiple mole melanoma syndrome (p16 gene mutation).
  • Peutz-Jeghers syndrome (STK11/LKB1 gene mutations).
  • Hereditary nonpolyposis colorectal cancer (DNA mismatch repair gene mutations).
  • Hereditary pancreatitis (PRSS1 gene mutations).

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 ductal adenocarcinomas are poorly delineated, fibrotic, and firm, with a yellow-gray cut surface.
• Difficult to distinguish tumor from adjacent chronic pancreatitis.
• Rarely, the tumor undergoes massive cystic degeneration.
• Duodenal wall invasion occurs in one-fourth of tumors arising from the pancreatic head.
• Involved pancreatic ducts may be dilated and plugged with necrotic tumor, or compressed/destroyed by tumor growth.
• Extrapancreatic extension is common, making it difficult to determine the origin of the tumor.
• Non-neoplastic pancreas adjacent to the tumor may show atrophy, chronic inflammation, fibrosis, and ductal dilation.
• Pancreatic intraepithelial neoplasia (PanIN) may also be present, especially in familial cases.

Microscopic Features

• Typical pancreatic ductal adenocarcinomas consist of infiltrating, haphazard glands and ducts with surrounding desmoplastic stroma.
• Can be well, moderately, or poorly differentiated, although this differentiation has limited prognostic significance.
• Poorly differentiated carcinomas have more nuclear pleomorphism, less glandular differentiation, solid growth areas, and easily identified mitoses.
• Well-differentiated tumors can be difficult to diagnose in biopsy specimens, requiring close attention to cytologic details.
• At low power, glands are often well-formed with a large lumen and lined by one or a few layers of cylindrical or cuboidal epithelium.
• High-power examination will show nuclear pleomorphism, variation in nuclear size, loss of polarity, prominent nucleoli, and mitotic activity.
• High degree of cytologic atypia and low level of architectural atypia is typical of tumors of the pancreaticobiliary region.
• Features useful in diagnosing carcinoma within small biopsy specimens include:
  • Glands outside the normal lobular architecture.
  • Glands immediately adjacent to muscular arteries.
  • Necrotic debris within gland lumens.
• Perineurial invasion is present in 90% of cases and is an important diagnostic sign.
• Benign epithelial inclusions have been observed in pancreatic nerves, and perineurial extension of islet cells can occur in chronic pancreatitis.
• Perineurial invasion by carcinoma can extend from the intrapancreatic nerves into the extrapancreatic neural plexus.
• Invasion of blood vessels, particularly veins, is seen with half of the tumors.
• Ducts surrounded by adipose tissue without intervening acini ("naked ducts") are highly indicative of malignancy.
• Non-neoplastic lobular tissue surrounding ductal adenocarcinoma may show alterations.
• Islet tissue is usually well preserved, but atrophic and hypertrophic changes can occur.
• Destruction of islet tissue mass can result in a subclinical or overt diabetic picture.
• Surrounding parenchyma may be destroyed due to ductal occlusion by invasive carcinoma and subsequent pancreatitis.
• Microscopic precursor lesions are classified as PanIN.
• These lesions are often adjacent to invasive ductal adenocarcinomas and have been identified in pancreata years before the development of invasive carcinoma.
• Molecular alterations in invasive ductal adenocarcinoma are present in PanIN.
• The prevalence of genetic alterations increases with the degree of morphologic atypia.
• Lesions formerly classified as PanIN-1 and PanIN-2 are now grouped as low-grade lesions.
• PanIN-3 is classified as a high-grade lesion.
• Both low-grade and high-grade PanIN can be found in the duct epithelium adjacent to carcinoma.
• The incidence of these lesions, particularly high-grade PanIN, is very low in control subjects.
• The presence of PanIN of any grade at a margin of resection for invasive ductal adenocarcinoma does not affect patient survival.

Other Microscopic Types

• Foamy gland pattern may be confused with non-neoplastic mucinous ducts.
• Large duct pattern may be mistaken for benign dilated glands or a lower-grade noninvasive cystic neoplasm.
• Vacuolated pattern consists of irregular or cribriforming nests of cells with prominent large, empty vacuoles.
• Micropapillary pattern resembles that in other anatomic sites and may have a signet ring cell component or features resembling colorectal adenocarcinoma.
• Adenosquamous and squamous carcinoma (more accurate term than mucoepidermoid carcinoma or adenoacanthoma).
• Tumors should be at least 30% squamous to warrant the designation of adenosquamous.
• Pure squamous cell carcinomas of the pancreas are exceedingly rare.
• Medullary carcinoma is similar to those found in the breast and GI tract, sometimes multicentric, and associated with wild-type KRAS.
• Some have microsatellite instability, similar to their colonic counterparts, and are associated with a family history of colon cancer.
• Colloid carcinomas are often associated with IPMNs or mucinous cystic neoplasms.
• Colloid carcinomas have a more protracted clinical course than conventional ductal adenocarcinoma and express markers of intestinal differentiation (CDX2, CK20, and MUC2).
• They are rarely associated with pseudomyxoma peritonei.
• It is postulated that the mucin in these tumors acts as a containment barrier.
• Poorly differentiated ductal adenocarcinomas may have a clear cell phenotype (immunoreactive for hepatocyte nuclear factor-1 beta) or oncocytic features.
• Hepatoid carcinomas of the pancreas are a rare and heterogeneous group of tumors that may have pure hepatoid differentiation or exist in association with other histologic types.
• These tumors are immunoreactive with Hep Par1, CD10, AFP, and polyclonal CEA.
• Microadenocarcinoma represents a pattern of growth associated with an aggressive clinical course rather than a distinctive morphologic entity.
• 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.
• The majority of the patients are above the age of 50 at the time of diagnosis, and there is a male predilection, with an extremely poor prognosis overall.
• Undifferentiated tumors with primarily anaplastic, spindled, or sarcomatoid morphology often contain heterologous elements.
• Immunohistochemically, stains for keratin, EMA, and CEA are typically positive in the obvious epithelial component and sometimes, but certainly not always, in the sarcoma-like areas.
• Undifferentiated carcinomas can be accompanied by areas of conventional ductal adenocarcinoma, or a pre-invasive neoplasm such as a mucinous cystic tumor or intraductal papillary mucinous tumor.
• Biphasic tumors with a sarcomatoid component and a separate glandular component may be termed carcinosarcomas.
• The presence in both components of the same KRAS mutations suggests a common origin.
• Undifferentiated carcinomas with osteoclast-like giant cells are usually large and hemorrhagic and have a dual population: relatively uniform spindle cells of mesenchymal appearance and atypical cytologic features alternate with multinucleated giant cells with an appearance and a histochemical profile indistinguishable from that of normal osteoclasts.

Histochemical and Immunohistochemical Features

• Most pancreatic ductal adenocarcinomas express cell surface-associated mucins, including MUC1, MUC3, MUC4, and MUC5AC.
• Glycoprotein MUC1 is expressed in over 80% of conventional invasive ductal carcinomas and in a similar percentage of high-grade PanIN.
• Ductal adenocarcinomas express keratins 7, 8, 18, and 19, but also 20, 17, and occasionally cytokeratin 5/6.
• Cytokeratin 20 is expressed less frequently in pancreatic ductal than in ampullary adenocarcinomas.
• CK20 expression may be strong and diffuse in pancreatic colloid carcinomas, as they express markers of intestinal differentiation.
• Ductal adenocarcinomas also frequently express EMA, CEA, CA125, mesothelin, TAG72, DUPAN2, and CA 19-9.
• Ducts in cases of chronic pancreatitis also exhibit immunoreactivity for many of these markers, thus greatly diminishing their differential diagnostic utility.
• CEA, TAG72, and CA125 are not typically expressed in non-neoplastic ducts.
• 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.
• These molecular alterations are typical of pancreatic ductal adenocarcinoma and distinguish them at a molecular level from other pancreatic neoplasms.
• Patients with chronic pancreatitis, but lacking microscopic features of invasive or in situ adenocarcinoma or ductal atypia, often have KRAS mutations in the non-neoplastic epithelium.
• DPC4 is inactivated in approximately half of pancreatic ductal carcinomas but practically never in benign conditions.
• Although Lynch syndrome patients have a seven- to eightfold increase in pancreatic ductal adenocarcinoma, MSI does not appear to play a significant role in sporadic ductal adenocarcinomas.
• The rare cases of pancreatic carcinoma that are MSI-high tend to have the medullary phenotype.
• These tumors typically do not have KRAS mutations but commonly exhibit mutations in the BRAF gene, a downstream component of the KRAS pathway.

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.
• Lymph node metastases may occur very early in the course of the disease, even in T1 and T2 tumors.
• The most common sites of distant metastases are liver, peritoneum, lung, adrenal, bone, distant lymph node groups, skin, and central nervous system.
• Sometimes, a distant nodal metastasis (particularly in the supraclavicular region) is the first manifestation of pancreatic carcinoma.

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, and microRNA analysis.
• EUS-FNA can also successfully identify cystic lesions such as IPMNs and mucinous cystic tumors.
• Cyst fluid can be analyzed for CEA and CA 19-9.

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, and typically a frozen section will be requested if a lesion at any of these sites is encountered.
• 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.
• One should search for perineurial invasion and also evaluate carefully the cytologic features of the glandular formations.
• When examining sections from the terminal portion of the common bile duct or the ampullary region, one should be careful not to misinterpret accessory pancreatic ducts or periluminal sacculi of Beale as malignant.
• If all of these precautions are heeded, the accuracy of the intraoperative frozen section diagnosis is very high, and the percentage of cases in which the diagnosis needs to be deferred is low.

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.
• Surgical outcomes tend to correlate strongly with the volume of cases encountered by both the surgeon and the institution.
• Adjuvant chemotherapy may be given after surgery for resectable pancreatic cancer and may result in improved disease-free and overall survival.
• The median overall survival remains at only 20-22 months.
• The role of neoadjuvant chemotherapy in borderline resectable or locally advanced adenocarcinomas remains controversial.
• Chemotherapy is the mainstay of therapy for the majority of patients who present with metastatic disease, typically with a gemcitabine-based regimen.
• The advantages of adding radiation to a chemotherapy regimen remain controversial.
• Patients requiring palliative care may benefit from surgical, radiologic, or endoscopic interventions for gastric, small bowel, or biliary obstruction.
• Tumors treated with modern preoperative neoadjuvant chemoradiation regimes often show fibrosis and extensive necrosis.
• Almost 10% in some large centers performed for the clinical impression of pancreatic carcinoma will reveal only non-neoplastic disease upon microscopic examination of the resected specimen; a significant number of these cases are ultimately diagnosed as autoimmune pancreatitis.

Prognosis

• Stage is the most important prognostic determinator.
• Pancreatic adenocarcinoma is staged using the tumor-node-metastasis classification.
• Tumors are often clinically staged using contrast-enhanced CT scan, which is about 80% accurate.
• 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.
• Tumor size, node status, and distant metastases are independent predictors of survival.
• Other adverse prognostic factors include high tumor grade, markedly elevated serum CA 19-9, persistently elevated CA 19-9 postoperatively, and positive resection margins.
• SMAD4 gene inactivation is associated with a worse prognosis.