Pancreatic Adenocarcinoma: Update on Neoadjuvant and Adjuvant Treatment
Pathogenesis
Pancreatic neoplasms can be benign or malignant and thus a tissue histologic diagnosis is paramount. Pancreatic adenocarcinomas with exocrine features represent more than 95% of all pancreatic neoplasms, with only 5% arising from the endocrine pancreas (ie, neuroendocrine tumors). Pancreatic neuroendocrine tumors and pancreatic adenocarcinoma must be distinguished histologically because treatment of the 2 neoplasms is completely different. Other malignant pancreatic tumors are signet ring cell carcinoma, adenosquamous carcinoma, undifferentiated (anaplastic) carcinoma, and mucinous noncystic (colloid) carcinoma; the latter tumor has a better prognosis.12 It is essential to characterize and distinguish among benign cystic neoplasms, as some require surgical resection due to the risk of malignant transformation. IPMN, pancreatic intraepithelial neoplasia, and mucinous cystic neoplasms are thought to be premalignant lesions of invasive ductal adenocarcinomas, and the pathological report should highlight the degree of dysplasia for adequate risk stratification.13 This information could be the deciding factor in whether a pancreatectomy is recommended by a multidisciplinary team.
Most pancreatic cancers harbor activating or silencing genetic mutations, and multiple combinations of altered genes can be detected by next-generation sequencing (average of 63 genetic alterations per cancer).14 Mutational activated KRAS is the most frequent (> 90%) genetic alteration in pancreatic cancer, even in early neoplastic precursors (IPMN > 75%). KRAS is a highly complex, dynamic proto-oncogene involved in signaling of various receptor kinases such as the epidermal growth factor receptor and the insulin-like growth factor receptor-I. It also engages in canonical downstream effector pathways, mainly Raf/MEK/ERK, PI3K/PDK1/Akt, and the Ral guanine nucleotide exchange factor pathway, which drive much of the pathogenesis of malignancy. These pathways lead to sustained proliferation, metabolic reprogramming, anti-apoptosis, remodeling of the tumor microenvironment, evasion of the immune response, cell migration, and metastasis. An activating point mutation in codon G12 is the most common (98%) locus of KRAS mutation in pancreatic adenocarcinoma, but all drugs targeting this mutation have failed in clinical practice.15 Additionally, inactivation of tumor suppressor genes such as p53, DPC4 (SMAD4/MADH4), CDKN2A (p16/MTS1), and BRCA2 can be found in 75%, 30%, 35%, and 4% of pancreatic adenocarcinoma cases, respectively.14 Another pancreatic cancer hallmark is inactivation of DNA damage repair genes, which include MLH1 and MSH2.16
Diagnosis and Staging
Case Presentation
A 71-year-old male veteran with no significant past medical history other than hypertension and hyperlipidemia and an excellent performance status presents to the emergency department after noticing a yellowish skin and sclera color. He denies weight loss, abdominal pain, or any other pertinent symptom or sign. Physical examination reveals a healthy developed man with yellowish discoloration of the skin and sclera and a soft, nontender benign abdomen; physical examination is otherwise unremarkable. Laboratory evaluation reveals a direct bilirubin level of 4.5 mg/dL and normal values for complete blood count and renal, liver, and coagulation panels. Abdominal and pelvis computed tomography (CT) with intravenous contrast shows a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein, which remains patent. Follow-up endoscopic ultrasound (EUS) confirms an irregular mass at the head of the pancreas measuring 3.2 × 2.6 cm with sonographic evidence suggesting invasion into the portal vein. During the procedure, the bile duct is successfully stented, the mass is biopsied, and bile duct brushing is performed. Pathology report is consistent with pancreatic adenocarcinoma.
- What is the typical presentation of pancreatic cancer?
The most common symptoms of pancreatic cancer at the time of presentation include weight loss (85%), asthenia/anorexia (86%), and/or abdominal pain (79%).17 The most frequent signs are jaundice (55%), hepatomegaly (39%), and cachexia (13%). Courvoisier sign, a nontender but palpable distended gallbladder at the right costal margin, is neither sensitive nor specific for pancreatic cancer (13% of cases). Trousseau syndrome, a superficial thrombophlebitis, is another classic sign that reflects the hypercoagulable nature of pancreatic cancer (3% of cases).17 The pathophysiology of this syndrome is not completely understood, but it may occur secondary to the release of cancer microparticles in the blood stream which in turn stimulate the coagulation cascade. Other nonspecific symptoms are dark urine, nausea, vomiting, diarrhea, steatorrhea, and epigastric and back pain. Because symptoms early in the course of the disease are nonspecific, pancreatic cancer is typically diagnosed late, after the cancer has invaded local structures or metastasized. The initial presentation varies depending on tumor location, with 70% of pancreatic head malignancies presenting with jaundice and pain correlating to an advanced stage.18 Although data supporting an association between new-onset diabetes mellitus and pancreatic cancer are inconclusive, pancreatic cancer should still be a consideration in patients with new-onset diabetes mellitus and other symptoms such as pain and weight loss. Early signs of incurable disease include a palpable mass, ascites, lymphadenopathy (classic Virchow node), and an umbilical mass (Sister Mary Joseph node). Incidentally discovered pancreatic masses on imaging are rare, but the incidence is increasing due to frequent imaging for other reasons and improved diagnostic techniques.
