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pancreatic cancer

Etiology: 1) ductal adenocarcinoma 90% 2) endocrine neoplasms 3) connective tissue neoplasm 4) acinar cell neoplasm 5) epidermoid neoplasm 6) mixed cell tumors 7) risk factors: a) diabetes mellitus type 2 - 10 mg/dL increase in fasting blood glucose associated with 14% increase in risk of pancreatic cancer [15] b) chronic pancreatitis* c) hereditary pancreatitis c) carcinogens 1] benzidine 2] cigarette smoking d) alcohol e) high-fat diet f) early adult obesity or excess weight [6] g) age >=50 years h) intraductal papillary mucinous neoplasms [3] i) intestinal infection with Malassezia [25] * regular aspirin use associated with reduced risk (RR=0.52) [14]; each year of low-dose aspirin associated with reduced risk (RR=0.94); speculation that effect of aspirin may be due to inhibition of COX2 [14] * dihydropyridine calcium channel blockers do not increase risk of pancreatic cancer [33] Epidemiology: 1) more common in men than women 2) generally presents between ages 60-80 3) 4th leading cause of cancer death in USA [5]; 3rd leading cause of cancer death [29] 4) 2-3 times higher incidence in persons born after 1990 than in older cohort [41] Pathology: - 80-90% of all pancreatic cancers are adenocarcinomas - only 2% of exocrine pancreatic tumors are benign - COX2 is upregulated in pancreatic cancer precursor lesions [14] - effects of invasive pancreatic cancer on celiac plexus can cause intractable pain [38] - Malassezia (especially, M globosa) travel from the gut through the sphincter of Oddi to the pancreas - in pancreatic cancer, M globosa is present in concentrations 3000 X its concentrations in normal or benignly inflamed pancreatic tissue [25] - Malassezia triggered tumor growth involves inflammation via activation of complement C3 [25] - pancreatic cancers produce relatively few neoantigens (antigens unique to the cancer) that are recognized by the immune system [34] - see Notes: & Clinical trials: below Genetics: - chromosomal inversion(s) found in nearly all metastatic pancreatic cancer [7] - telomeres are dysfunctional, control of cell cycle is lost - initiation of pancreatic cancer begin 15 years prior & metastasis 5 years prior to clinical presentation [7] - KRAS mutations in 90% [42] - defects in SMAD4 are a cause of pancreatic carcinoma - overexpression of: TM4SF5, LSM1 - implicated genes MLL4, WDR45, ANKRD37, IGF2BP3, MGAT4A, MGAT4B, AMIGO2, SULF1, HES2, ANLN, WIPI2, HCC1, TBRG1, ARID4B, LRRC26, OLFM4, PALLD, MTUS1, BCL9L, ARHGAP27, S100PBP, PTPRH, MUC17, NT5DC3, PEG10, ZNF146, CCKBR, CD97, PLXNB1, GNG7, RAB20, S100P, TSPAN8, BIRC5 Clinical manifestations: 1) generally presents late in the course of the disease 2) presenting signs & symptoms a) frequent 1] prodrome of malaise, anorexia & weight loss 2] upper abdominal pain, lumbar back pain 3] obstructive jaundice (lesion of head of pancreas) b) infrequent 1] glucose intolerance (diabetes mellitus) 2] palpable gallbladder (Courvoisier's sign) 3] migratory thrombophlebitis, superficial vein thrombosis (Trousseau's syndrome) 4] gastrointestinal hemorrhage 5] splenomegaly c) may present as depression 3) non-bacterial (thrombotic) 'marantic' endocarditis 4) hepatomegaly, ascites, abdominal mass 5) left supraclavicular adenopathy Laboratory: 1) non-specific elevations in serum transaminases, serum alkaline phosphatase, serum amylase may be present 2) complete blood count: anemia is variable 3) serum CA 19-9 > 800 ug/mL indicates a poor prognosis (tumor markers not used for diagnosis) [3] 4) germline testing for BRCA mutations & mismatch repair deficiency in all patients [3] 5) serum IgG4 6) investigational - a signature for pancreatic cancer based on microRNAs identified in the exomes shed from pancreatic cancers & cell-free DNA in blood - 90% accurate for stage I/II pancreatic cancer [39] - addition of serum CA 19-9 increases accuracy to 97% [39] - performance the same whether the tumor was in the head or tail of the pancreas [39] - licensed to Pharus Diagnostics for commercial development [39] 7) urine biomarker panel (LYVE1, REG1B & TFF1) alone & in combination with plasma CA19-9 cab detect pancreatic adenocarcinoma up to 2 years prior to diagnosis [24] 8) see ARUP consult [9] Special laboratory: - endoscopic retrograde cholangiopancreatography (ERCP) - ultrasound-guided biopsy with histopathology or cytology - endoscopic ultrasonography with fine-needle aspiration of pancreas for diagnostic confirmation if no metastases on abdominal CT [3] - recommended in patients with imaging characteristic of resectable pancreatic cancer [3] - surgical resection formerly recommended prior to histopathology for diagnosis [3] - percutaneous transhepatic cholangiopancreatography Radiology: 1) contrast-enhanced computed tomography (CT) imaging modality of choice [3] a) evaluation of pancreatic & bile ducts b) pancreatic mass, calcifications c) useful for staging d) 90% sensitivity for detecting pancreatic cancer [3] 2) magnetic resonance cholangiopancreatography if CT imaging negative - most sensitive test for small lesions 3) abdominal ultrasound, evaluation of pancreatic & bile ducts 4) 'double-duct' sign: - obstruction of both the pancreatic duct & bile duct 5) PET scan does not add value in staging or treatment survelliance [3] Differential diagnosis: - autoimmune pancreatitis - elevated IgG4 Complications: - pancreatic insufficiency Management: 1) geriatric assessment prior to palliative care consult in elderly [35,36,37] 2) palliative care consult for patients with newly diagnosed advanced cancer 3) neoadjuvant chemotherapy with or without radiation typically used for locally advanced pancreatic cancer - neoadjuvant FOLFIRINOX, losartan, followed by chemoradiotherapy for locally advanced pancreatic adenocarcinoma [24,30] - also see pancreatic adenocarcinoma 4) surgical resection affords the only hope of cure a) most lesions are non-resectable b) criteria for resection 1] tumor < 2 cm - 2.5 cm mass in head of pancreas is resectable [3] 2] absence of lymph node invasion 3] absence of mesenteric vasculature involvement 4] absence of metastases c) surgical procedures: 1] Whipple procedure 2] total pancreatectomy 3] survival is the same d) neoadjuvant chemoradiation - may improve survival [21] - does improve survival in borderline-resectable pancreatic cancer vs chemotherapy alone [27] 5) palliative surgery a) intraoperative chemical splanchnicectomy b) endoscopic biliary stent placement for obstructive jaundice c) expandable stent of gastrojejunostomy for relief of bowel obstruction d) celiac nerve block (celiac plexus neurolysis) when systemic analgesics are not effective 6) radiation therapy may have some role, but survival is unchanged - hypofractionated ablative radiation therapy following standard chemotherapy may be associated survival benefit in locally advanced, inoperable pancreatic cancer [28] 7) adjuvant chemotherapy seems to have some benefit a) gemcitabine plus daily oral erlotinib [5] for metastases b) gemcitabine for 6 months after surgical resection of pancreatic cancer improves 10 year disease-free survival from 6% to 14% [12] c) gemcitabine + capecitabine better than gemcitabine alone [3] d) nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 on days 1, 8, & 15 every 4 weeks [13] increases survival e) induction therapy with nab-paclitaxel + gemcitabine may confer survival advantage 8.8 vs 6. months in locally-advanced pancreatic cancer [20] 8) protocols include: a) FOLFIRINOX for metastatic disease [16] & for adjuvant chemotherapy after surgical resection [3,22] b) alternative gemcitabine + capecitabine (Xeloda) c) gemcitabine +/- nab-paclitaxel (GEM+NPTX) after surgical resection was the standard of care [12,13] d) FOLFIRINOX & GEM+NPTX with regimens with the best outcomes in Japan e) 5-fluorouracil f) 5-fluorouracil or gemcitabine with radiation therapy [3] 8) immunotherapy in pancreatic cancer works by recruiting & activating T cells that recognize tumor-specific antigens (still investigational) [10] 10) targeted therapies with receptor tyrosine kinase inhibitors plus immunotherapy may work synergistically [10] 11) metastatic recurrence in patients with good performance status treated with FOLFIRINOX [3,16] 12) pancrealipase for pancreatic insufficiency (see chronic diarrhea) 13) prognosis: a) 5 year survival < 6%; 10% [29] - may be up to 20% if localized disease [3] - gemcitabine may improve overall survival to 14% [12] b) median survival with metastatic disease 3-6 months c) median survival with locally unresectable disease is 1 year [3] d) poor survival mostly due to presentation & diagnosis at a late stage [29] 14) USPSTF recommends against screening for pancreatic cancer [23] - risk of pancreatic cancer associated with new onset hyperglycemia varies with race/ethnicity; screening is not recommended [26] - persons at high-risk for pancreatic cancer may benefit from early detection [29] - inherited predisposition to pancreatic cancer - new-onset diabetes mellitus - mucinous pancreatic cyst - chronic pancreatitis Clinical trials: - a personalized mRNA neoantigen vaccine created by sequenced DNA & RNA from resected pancreatic cancer as neoadjuvant therapy in combination with an immune checkpoint inhibitor & adjuvant chemotherapy eliminated the primary tumor in 8 of 16 patients [34] (see Notes:) - in these 8 patients, cytotoxic CD8 T-cells were produced that attacked the cancer neoantigens - in one patient micrometastases as well as primary tumor may bave been eliminated [34] Comparative biology: - C elegans exposed to urine of patients with early-stage pancreatic cancer show chemotaxis towards the urine vs controls [31] Notes: - pancreatic cancer expresses relatively few neoantigens (antigens unique to the cancer recognized by the immune system), thus immune checkpoint inhibitors that initiate a response to neoantigens perform poorly [34]

Related

cancer antigen CA 19-9 (carbohydrate antigen 19-9) in serum Courvoisier's sign Trousseau's syndrome; Trousseau's sign of malignancy; thrombophlebitis migrans

Specific

pancreatic adenocarcinoma

General

malignant neoplasm of digestive organs & peritoneum pancreatic neoplasm

Database Correlations

OMIM correlations

References

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