Context.-Metastatic disease is the most critical determinant of resectability of pancreatic cancer and accounts for the poor outcome of patients with this disease. Thus, a better understanding of metastatic pancreatic cancer will afford new opportunities for therapeutic intervention. Objective.-To summarize and discuss the current understanding of the clinical and molecular features of metastatic pancreatic cancer. Data Sources.-Published literature on advanced stage pancreatic cancer, pancreatic cancer metastasis, and autopsy findings in patients with pancreatic cancer. Conclusions.-In the clinical setting, it can be difficult to distinguish a metastatic pancreatic carcinoma from primary neoplasms in the liver, lung, or ovary. However, immunolabeling for DPC4 protein as part of a diagnostic panel is useful for making this distinction. Emerging data from a variety of investigators now indicate that overexpression of EphA2, loss of DPC4 and MKK4, and aberrant activation of the Hedgehog signaling pathway are associated with metastatic propensity of pancreatic cancers, providing novel therapeutic targets for the most lethal stage of this disease.
The Pathology and Genetics of Metastatic Pancreatic Cancer Shinichi Yachida, MD, PhD; Christine A. Iacobuzio-Donahue, MD, PhD ● Context.—Metastatic disease is the most critical deter- Conclusions.—In the clinical setting, it can be difﬁcult minant of resectability of pancreatic cancer and accounts to distinguish a metastatic pancreatic carcinoma from pri- for the poor outcome of patients with this disease. Thus, a mary neoplasms in the liver, lung, or ovary. However, im- better understanding of metastatic pancreatic cancer will munolabeling for DPC4 protein as part of a diagnostic pan- afford new opportunities for therapeutic intervention. el is useful for making this distinction. Emerging data from a variety of investigators now indicate that overexpression Objective.—To summarize and discuss the current un- of EphA2, loss of DPC4 and MKK4, and aberrant activation derstanding of the clinical and molecular features of met- of the Hedgehog signaling pathway are associated with astatic pancreatic cancer. metastatic propensity of pancreatic cancers, providing Data Sources.—Published literature on advanced stage novel therapeutic targets for the most lethal stage of this pancreatic cancer, pancreatic cancer metastasis, and au- disease. topsy ﬁndings in patients with pancreatic cancer. (Arch Pathol Lab Med. 2009;133:413–422) P ancreatic cancer is the fourth leading cause of cancer- related mortalities in the United States. In the year 2008 in the United States, an estimated 37 680 patients will genetics of advanced stage pancreatic cancer including re- cent advances that may lead to novel treatments for this most lethal stage of the disease. be diagnosed with pancreatic cancer, and 34 290 patients will die of their disease.1 These unfortunate statistics re- GROSS FEATURES ﬂect the advanced stage at which most patients with pan- Distant metastases are a frequent occurrence in patients creatic cancer are diagnosed and the paucity of effective with pancreatic cancer.9–12 The most common site of dis- chemotherapeutic regimens for advanced disease.2–4 Thus, tant metastasis found at autopsy is the liver, followed by a better understanding of the factors that contribute to the peritoneum, lung and pleura, bones, and adrenal pancreatic cancer progression and metastasis is critical in glands (Figure 1).9–12 However, metastatic pancreatic can- combating this disease. cer has been reported in virtually every organ site, includ- Contrary to early pancreatic carcinogenesis,5 the pa- ing the brain, diaphragm, gallbladder, heart, small and thology and molecular features of advanced stage pancre- large intestines, kidneys, ovaries, pericardium, seminal atic cancers are relatively unexplored. As a result, little is vesicles, skin, stomach, spleen, testis, thyroid gland, uri- known about the mechanisms responsible for uncon- nary bladder, and uterus.9,10,12 Calculations based on esti- trolled local growth and metastatic spread, the very pro- mates of tumor doubling times indicate that occult liver cesses ultimately responsible for most pancreatic cancer– metastases are often present at the time of pancreatecto- related deaths.6 This is underscored by the fact that unlike my.13 Even small ( 2 cm) pancreatic cancers are associ- advanced stage colorectal cancers in which the primary ated with metastases,10 suggesting metastatic propensity cancer and/or liver metastases are commonly resected for is rapidly acquired during pancreatic carcinogenesis and clinical beneﬁt and are thus available for medical research, progression. Consistent with this notion, molecular anal- the management of advanced stage pancreatic cancer of- yses indicate micrometastases are frequently present with- ten does not include surgical resection.7,8 in the peritoneal cavity and bone marrow of patients with A better understanding of the clinical, genetic, and mo- potentially resectable pancreatic cancer.14–16 lecular features of metastatic pancreatic cancer will afford Although the liver is the most common site of distant novel areas for therapeutic intervention. Toward this goal, metastasis, up to one-third of patients do not have hepatic we provide a review of the literature on the pathology and metastases at autopsy. In these patients, the lungs and ab- dominal lymph nodes are the most common sites of me- Accepted for publication November 4, 2008. tastasis possibly due to hepatofugal portosystemic shunt- From The Johns Hopkins Medical Institutions, The Sol Goldman Pan- ing (ie, ﬂow directed away from the liver to the systemic creatic Cancer Research Center, Baltimore, Maryland. circulation) induced by splenic vein obstruction or to the The authors have no relevant ﬁnancial interest in the products or presence of aggressive features of the primary carcino- companies described in this article. Reprints: Christine A. Iacobuzio-Donahue, MD, PhD, The Johns ma.9–11 Mao et al10 found that carcinomas of the body and/ Hopkins Medical Institutions, Department of Pathology, Division of or tail of the pancreas are more frequently associated with Gastrointestinal/Liver Pathology, 1550 Or
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