Pancreatic cancer basic and clinical parameters | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Pancreatic cancer basic and clinical parameters (EC, 2015)

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Encyclopedia of Cancer, 2015

Definition

Epithelial malignancies of the pancreatic gland that originate in more than 85% from ductal cells. In rare cases, tumors may also arise from acinar or endocrine cells.

Characteristics

Pancreatic adenocarcinoma is one of the most aggressive human malignancies reflected by a mortality rate which closely follows that of the incidence. Its incidence is steadily increasing, and today it is the fifth leading cause of cancer-related deaths in the western hemisphere. Most patients are diagnosed with pancreatic cancer in the late course of the disease with unspecific symptoms such as fatigue, weight loss, jaundice, and upper abdominal pain. At this stage pancreatic cancer frequently has invaded surrounding organs such as the duodenum and stomach and the retroperitoneal tissue and blood vessels (Fig. 1).

Lymph node metastases occur in most cases and reflect a high metastatic potential.

Most patients present between the fifth and eighth decade of life with a male/female ratio of ~1.5:1. The etiology of pancreatic cancer remains unclear. However, environmental factors such as cigarette smoking and a high-fat diet may predispose patients to the development of pancreatic malignancies. Chronic inflammatory diseases such as chronic pancreatitis might also increase the risk for pancreatic adenocarcinoma. Genetic factors, such as p16 germline mutations and mutations in the mismatch-repair system, may also increase the probability to develop pancreatic adenocarcinoma. However, less than 10% of patients belong to a hereditary pancreatic cancer syndrome.

Pathology

The most frequent site of pancreatic cancer is the head of the pancreatic gland (~60%). The remainder of cases arise in the body (15%) and the tail (5%) or disseminated throughout the pancreas (20%). The vast majority of pancreatic cancers are of ductal origin. Rarely, they originate from acinar or endocrine cells. Ductal adenocarcinoma of the pancreas are desmoplastic malignancies composed of mucin-producing glandular cells infiltrating a nonneoplastic stroma which accounts for more than 50% of the tumor tissue. In addition to the fibrocytic stroma, cancer cells are also admixed with inflammatory cells, including lymphocytes. The histological progression from benign to malignant pancreatic disease starts from fiat mucinous lesions to papillary lesions without atypia to lesions with atypia, to in situ carcinoma, and finally to infiltrating adenocarcinoma.

At the time of diagnosis, pancreatic cancer generally has invaded the peripancreatic fat tissue and lymph nodes or adjacent organs such as the duodenum, stomach, peritoneum, and vessels. Cancers restricted to the pancreatic gland are rare. In particular, carcinomas located in the body and tail are diagnosed at a more advanced stage due to unspecific symptoms. Sites of hematogenous metastasis formation are primarily the liver and rarely the lung. However, local tumor recurrence due to remaining microscopic tumor foci even in smaller tumors seems to be the determining factor for patient’s survival.

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Fig. 1. Abdominal magnetic resonance imaging (MRI) picture. The MRI depicts a huge mass in the upper abdomen that originates from the corpus of the pancreas

Staging

The UICC staging system is based on the size of the primary tumor (T), the extent of regional lymph node involvement (N), and the presence of metastases (M).

Primary tumor (T):

  • TX — Primary tumor cannot be assessed.
  • T0 — No evidence of primary tumor.
  • Tis — Carcinoma in situ.
  • T1 — Tumor ≤2 cm.
  • T2 — Tumor >2 cm.
  • T3 — Tumor beyond the pancreas but without involvement of the celiac axis or the superior misenteric artery.
  • T4 — Tumor involves the celiac axis or the superior misenteric artery. Regional lymph nodes (N):
  • NX — Regional lymph nodes cannot be assessed.
  • N0 — No regional lymph node metastasis.
  • N1 — Regional lymph node metastasis. Distant metastasis (M):
  • MX — Presence of distant metastasis cannot be assessed.
  • M0 — No distant metastasis.
  • M1 — Distant metastasis.

Genetics

An array of technologies has been applied to investigate relevant chromosomal and genetic changes in pancreatic cancer over the last couple of years. The detection of specific chromosomal changes and altered tumor suppressor genes and oncogenes has significantly improved our understanding of the development and progression of this dismal disease (Fig. 2).

Cytogenetics

The application of modern fluorescence in situ hybridization (FISH) technologies such as comparative genomic hybridization (CGH) or spectral karyotyping (SKY) for the study of numerical and structural chromosomal aberrations has revealed new insights into pancreatic tumorigenesis. Pancreatic carcinoma cells have a surprisingly high degree of chromosomal instability but also have recurrent pattern of chromosomal alterations. Genetic losses usually involve chromosome arms and chromosomes 8p, 9p, 17p, 18q, 19p, and 21, whereas gains can be mapped to 3q, 5p, 7p, 8q, 12p, and 20q. These chromosomal regions are affected in up to 90% of pancreatic adenocarcinomas and correlate very well with those regions harboring oncogenes and tumor suppressor genes such as DPC4 at 18q, p16 at 9p, p53 at 17p, and Kras at 12p.

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Fig. 2. Schematic diagram of major pathways in the development of pancreatic adenocarcinomas which finally lead to the loss of cell cycle control

Oncogenes

The K-ras oncogene codes for a GTP-binding protein and plays a major role in pancreatic cancer. Activating point mutations of the K-ras oncogene occur in 70–90% of all ductal adenocarcinomas and are largely restricted to codons 12 and 13 of the K-ras gene at 12p12. Due to these mutations, the K-ras oncogene cannot be inactivated and the signal transduction pathway remains active stimulating proliferation and cellular transformation. K-ras mutations have been found in proliferative, noninvasive ductal lesions indicating that K-ras might play a role during early carcinogenesis. However, K-ras mutations have also been found in inflammatory and normal pancreatic tissue without neoplastic potential. This finding might limit the development of a gene-based test system using K-ras mutations as an indicator for neoplastic or malignant cells in pancreatic juice, blood, or stool of patients with pancreatic disease.

EGFR (epidermal growth factor receptor) and Her-2/neu (heregulin, neuregulin, or glial growth factor receptor) belong to the ERBB family. In normal pancreatic tissue and chronic pancreatitis, HER-2 expression remains unaffected, whereas in patients with pancreatic cancer, overexpression of HER-2 can be found in early morphologic duct lesions. Using immunochemistry, overexpression of HER-2 ranges from 21% to 80%, and only 27% of the immunohistochemical-positive cases showed amplification of HER-2 as detected by FISH.

The EGFR gene is located on chromosome 7p12. Expression of EGFR can be detected in about 50% of pancreatic carcinomas. EGFR expression seems to play an important role in the metastatic potential.

Tumor suppressor genes

The relevant tumor suppressor genes in pancreatic cancer are p53, p16, and DPC4.

p53 is a nuclear-binding protein that arrests cells at the G1/S checkpoint and also plays an important role in the induction of apoptosis after DNA damage. P53 resides on chromosome 17p13. It is inactivated by allelic loss and inactivating mutations in about 50% of pancreatic cancers. Therefore, loss of p53 function results in a disturbed cell cycle and loss of programmed cell death.

p16 has been identified at 9p21 and is inactivated in about 90% of pancreatic cancers via allelic loss; inactivating mutations and/or hypermethylation of the promoter has been found. p16 inhibits the promotion of the cell cycle by binding to the cyclin-CDK4 complex and preventing CDK4 activation of RB protein. Therefore, inactivation of p16 in pancreatic cancer dysregulates another relevant cell cycle checkpoint.

The tumor suppressor gene DPC4 is biallelically inactivated in about 50% of pancreatic cancers. Located on chromosome 18q, DPC4 codes for a peptide which is closely related to the MAD family of proteins (SMAD). These molecules play an integral part in the signal transduction from TGF-b superfamily cell surface receptors. Since it is known that TGF-b inhibits cell growth and proliferation, inactivation of DPC4 and loss of its inhibitory function may bestow a growth advantage upon cancer cells.

Epigenetic changes

Another cause of gene expression changes in the development of pancreatic cancer is DNA methylation. The methylation of the promoter regions of different genes (e.g., p16, RB, VHL, hMLH1, hMSH2) was also found in pancreatic carcinomas. Besides p16, the gene Preproenkephalin (ppENK), which has growth-inhibiting function, was found methylated in 90% of the pancreatic cancers. Methylation of genes with a significant role in carcinogenesis occurs early in cancer development. The methylation of p16 can be observed in up to 50% of such cancers. The number of methylated loci increases with the size of the tumor and the age of the patients. Nonneoplastic epithelium is not methylated.

Hereditary pancreatic cancer

Several family studies have suggested that between 5% and 10% of pancreatic cancer may have a hereditary basis. A predisposition to the development of pancreatic cancer has been shown for several genetic syndromes including hereditary pancreatitis, hereditary nonpolyposis colorectal cancer (HNPCC), and the familial atypical mole-malignant melanoma (FAMMM) syndrome.

Hereditary pancreatitis is an autosomal dominant disorder which is characterized by an early onset of age. Patients suffer from recurrent acute pancreatitis which leads subsequently to chronic pancreatitis carrying its significant risk factor for the development of pancreatic cancer. In the disorder, a mutation in the trypsinogen gene at 7q35 results in the inability to deactivate trypsin which results in autodigestion of pancreatic tissue.

Hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is another syndrome that predisposes individuals to pancreatic cancer. It is an autosomal transmitted disease, caused by germline mutations in the mismatch-repair system. Besides pancreatic cancer, patients also inherit a predisposition to other cancers, including colonic, breast, ovarian, and endometrial carcinomas.

Patients with the FAMMM syndrome have an elevated risk for the development of multiple atypical nevi, malignant melanomas, and pancreatic cancer. In a subset of patients, a germline mutation in the p16 tumor suppressor gene is implicated.

Diagnosis of pancreatic cancer

There are unfortunately no early signs or symptoms to identify pancreatic cancer as gastrointestinal obstruction and other compromising sequelae occur. Patients that are worked up for abdominal pain or jaundice suspicious for pancreatic cancer typically undergo the following diagnostic procedures.

Abdominal ultrasound

Transabdominal pancreatic ultrasonography (US) is performed using high-resolution real-time linear array or sector scanners combined with Doppler examination. The sensitivity of US in pancreatic cancer is as high as ~85%. Lesions in the head are more visible than lesions in the body or tail of the gland, due to intestinal gas. Computer tomography (CT) is clearly superior in terms of sensitivity and specificity compared to ultrasonography. In summary, US is a reliable screening method for the detection of pancreatic masses and liver metastases but is not recommended for examining patients if a malignant disease is strongly suspected.

Computed tomography (CT)

Current techniques including high-resolution spiral CT provide detailed images of the pancreas, the pancreatic and biliary duct system, the peripancreatic vessels, and the surrounding organs. Several studies have reported a sensitivity of 92% and a specificity of ~100% with spiral CT. However, only 65% of all tumors which were staged as resectable with spiral CT scans were actually candidates for resection. Therefore, laparotomy and surgical laparoscopy remain the only specific approaches to determine resectability.

Magnetic resonance imaging (MRI)

The importance of MRI in pancreatic cancer diagnostics, despite the advantage of avoiding ionizing radiation, is still to be determined. In most centers MRI is used to differentiate between malignant and benign disease when US or CT is equivocal or the administration of intravenous contrast agents is contraindicated.

Magnetic resonance cholangiopancreatography (MRCP)

Although the exact role of MRCP has not yet been determined, it has demonstrated its potential to display changes in the pancreatic duct pathology. MRCP and ERCP findings correlate with pathology in 80–90% of the cases.

Endoscopic retrograde cholangiopancreatography (ERCP)

Endoscopic techniques, such as ERCP, can be applied for diagnosis and interventional management for patients with pancreatic disorders with a sensitivity and specificity of 90%. Endoscopic pancreatographic features of malignant disease include stenosis or displacement of the pancreatic and bile duct (e.g., double duct sign), alteration of secondary branches, and extravasation of contrast dyes due to necrosis. An additional major role of ERCP is the opportunity to provide drainage of an obstructed common bile duct by facilitating the insertion of stents into the biliary system. Also tissue sampling can be performed during ERCP, using brush cytology, direct biopsy, endoscopic needle aspiration, and aspiration of pancreatic and bile fluid. The opportunity to obtain tumor material during endoscopic procedures might become an important step since molecular markers can be applied to these samples and might assist in the differential diagnosis of pancreatic disease.

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Fig. 3. Pylorus-preserving pancreatectomy (PPPD). (a) Intra-abdominal situs before surgical resection – areas in orange color mark the organs which will be removed. (b) Intra-abdominal situs after resection according to PPPD

Therapy of pancreatic cancer

Although there has been considerable progress in the biological understanding and diagnostic tools of pancreatic cancer, the neoplasms continue to have one of the poorest prognoses of all human cancers. Surgical resection of small tumors is the only option for curative treatment. The 5-year survival is below 5%, and due to advanced tumor stage at the time of diagnosis, therapies remain palliative for the vast majority of patients. Five-year survival rates increase to 30% when tumors smaller than 2 cm are resected.

Surgical technique is dependent on location of the tumor and includes local excision in papillary tumors and left hemipancreatectomy in tumors of the pancreatic tail.

However, the majority of pancreatic cancers are located in the pancreatic head on which two methods of resection are most commonly employed. The classical method, the Whipple-Kausch pancreatectomy, involves en bloc removal of (i) the distal third of the stomach and the right half of the greater omentum,

(ii) the gall bladder including the distal bile duct system, (iii) the duodenum and the proximal 10 cm of the jejunum, (iv) the head and parts of the body of the pancreas, and (v) the peripancreatic and hepatoduodenal lymph nodes. The surgical therapy of choice and modern technique is the so-called the pylorus-preserving pancreatectomy (PPPD). Instead of resection of the distal stomach, the pylorus is attached directly to a jejunal loop in PPPD (see Fig. 3). It remains unclear if either method is superior, but advocates of PPPD claim better nutritional outcomes and shorter operative times compared to standard Whipple-Kausch pancreatectomy. Therefore, the PPPD is considered as state of the art in the major surgical centers in Europe.

In patients with advanced disease, multidisciplinary approaches are needed involving the surgeon, endoscopist, and radiologist to optimize palliative therapy in the setting of a limited life expectancy. Operative bypasses including choledochojejunostomies and gastroenterostomies have many advantages and remain as highly acceptable choices in the management of terminal disease. Nonoperative stenting should be reserved for elderly patients or patients with very advanced disease who are poor operative candidates.

The resistance of pancreatic cancer to adjuvant, neoadjuvant, and palliative chemoand/or radiotherapy has remained a consistent disappointment over the last decades. Trials with gemcitabine, a cytidine analogue, have shown a decrease of disease-related symptoms thus benefiting patient’s quality of life and have resulted in very modest prolongation in survival. Recently, oral 5-FU (capecitabine) has been added to gemcitabine and some oncologists recommend additionally EGFR blockers. Overall, there are no convincing data about any drugs significantly increasing patient’s survival. Such results emphasize the importance of developing new diagnostic methods of pancreatic cancer to allow surgical resection at an earlier tumor stage.

References

Baumgart M, Heinmцller E, Horstmann O et al (2005) The genetic basis of sporadic pancreatic cancer. Cell Oncol 27:3–13

Evans DB, Abbruzzese JL, Rich TA (1997) Cancer of the pancreas. In: DeVita VT, Hellmann S, Rosenberg S (eds) Cancer: principles and practice of oncology, 5th edn. Lippincott, Philadelphia

Hruban RH, Yeo CJ, Kern SE (1998) Pancreatic cancer. In: Vogelstein B, Kinzler KW (eds) The genetic basis of human cancer. Mc Graw Hill, New York

Klцppel G (1997) Pathology and classification of tumors of the exocrine pancreas. In: Trede M, Carter DC (eds) Surgery of the pancreas. Churchill Livingstone, Edinburgh

Trede M, Carter JD (1997) The surgical options for pancreatic cancer. In: Trede M, Carter DC (eds) Surgery of the pancreas. Churchill Livingstone, Edinburgh

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