Pancreas exocrin. Pancreas endocrin. Pancreatite acute Pancreatite cronice Afectiuni ereditare ale pancreasului Tumori pancreatice

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2 Pancreas exocrin Pancreatite acute Pancreatite cronice Afectiuni ereditare ale pancreasului Tumori pancreatice Pancreas endocrin Diabetul zaharat Tumorile neuroendocrine PET-NET

3 Pancreas exocrin Pancreatite acute Pancreatite cronice Afectiuni ereditare ale pancreasului Tumori pancreatice Pancreas endocrin Diabetul zaharat Tumorile neuroendocrine PET-NET

4 Pancreatita acuta urgenta garda UPU Pancreatita cronica durere abdominala trenanta Medic de familie! Chirurg sau Internist Tumori pancreatice Eventual internist din policlinica Nutritionist, medic de familie, endocrinolog, psihiatru, gastroenterolog 4

5 Necesita explorari Uneori sofisticate Necesara internare De obicei gastroenterolog 5

6 Incidenta 4,9-35 %ooo /an In crestere in tarile europene Cauza majora de spitalizare in SUA Cauza = crester consum de alcool Mortalitate 5-17% Vege SS et al Gastrointestinal epidmiology 2007

7 Incidence of AP increased between 2000 and 2005 from 13.2 to 14.7 Incidence of AP for males increased from 13.8 to 15.2, for females from 12.7 to 14.2 Mortality for AP fluctuated between 6.9 and 11.7 per million persons/ year and was almost similar for males and females. Incidence and mortality of AP and CP increased markedly with age. CONCLUSION: Incidence of AP steadily increased. Mortality for AP remained fairly stable. Patient burden and health care costs probably will increase because of an ageing BW Ml Spanier et alworld J Gastroenterol 2013 May 28; 19(20):

8 European studies increase in the incidence rate of acute pancreatitis 922 patients with confirmed diagnosis of AP ( ( )in 1 hospital incidence rate varied from 24 to 35/ inhabitants annually. Mean age was 60 ± 16 years. 53% men and 47% women etiologies of AP were biliary stones in 60% and alcohol abuse in 19% of patients. severe in 50% and 43 Davor Stimac et al - Gastroenterology Research and Practice Volume 2013, Article ID ,

9 Cauza Pancreatita cronica Fibroza chistica Chirurgia pancreatica Prevalenta 3,9/ EU 3,3/ Franta 4,2 / Germania 2,9/ Italia 3.0/ Spania 5,5/ UK Mattson,Jakc Report Pancreatic exocrine insuffiency epidemiology

10 Loss of functioning parenchyma Chronic pancreatitis Cystic Fibrosis Tumours Resections secretion despite intact parenchyma Obstruction endogenous stimulation (coeliac, Crohns, DM) Asynchrony Gastric resections Short bowel syndrome Crohns, DM Enzyme inactivation Zollinger-Ellison syndrome

11 Prevalenta Creste cu varsta Mai mare la barbati Distributia pe sex si varsta difera f de etiologie Alcoolica mai frecv la Barbati Idiopatica si hiperlipemica la femei Fiborza chistica egala femei barbati Fibroza chistica mai frecv in primul an de viata Pancreatita cronica si chirurgie la varstnic Rothenbacher D, etal Scand J Gast 2005;40(6)

12 Insuficienta pancreatica exocrina Pancreatita cronica Pancreatita senila Pancreatita acuta Cauze Rezectie gastrica Fibroza chistica Pancreatectomie Indicatie PEI Plenitudine Meteorism Steatoree Dispepsie Semne simptome Greata / varsaturi Pierderea apetitului Malabsortie Intoleranta alimentelor Pierdere in greutate Durere abdominala

13 Pancreatita cronica PA Forma usoara Forma severa Pseudochist Recidiva Restitutio ad integrum PA Pancreatita acuta PC Incidenta PC este de 3,5-4 / locuitori. Prevalenta/Predominanta de vârsta si sex: pancreatita cronica afecteaza preponderent barbatii în vârsta de ani (de 3 ori mai frecventa decât la femei). PC Pancreatita cronica Klöppel & Maillet, Hepatogastroenterol 38:408, 1991

14 INCIDENTA = 3-10 %ooo loc PREVALENTA = %ooo loc!!este in crestere Variaza geografic Tara Incidenta / loc Sursa Japonia 5.7 JGastroenterol 38(4):315-26, 2003 Elvetia 1.6 Eur J Gastroenterol Hepatol.13(6):749-50, 2001 Finlanda 23 Pancreatology.2(5): , 2002 Cehia 7.9 idem 14

15 Inciența este de 6-7 / locuitori în vest 80% sex masculin. Vârsta medie depinde de etiologie, ~ ani la PC alcoolică, ~ la PC idiopatică, ~ la cei PC ereditară, ~ 10 ani la copii cu PC tropicală. Incidența este crescută la negri față de albi. James Jupp a,1, David Fine b,2, ColinD.Johnson c,*best Practice&ResearchClinicalGastroenterology24(2010)219e231

16 Etiologie. Consumul excesiv de alcool 70-85% Fumatul, l factor de risc extern cancerului pancreatic. Alte cauze rare de PC: hipercalcemia peste 12mg/dl (3mmol/l (1% din PC sunt datorate hiperpth, 7% din hiperpth au și PC). PC tropicală. PC genetică. PC autoimună PC obstructivă. PC idiopatică. 10% din cazurile de PC James Jupp a,1, David Fine b,2, ColinD.Johnson c,*best Practice&ResearchClinicalGastroenterology24(2010)219e231

17 Benigne Maligne Epiteliale Nonepiteliale Exocrine Endocrine

18 Epithelial tumours Benign Serous cystadenoma 8441/01 Mucinous cystadenoma 8470/0 Intraductal papillary-mucinous adenoma 8453/0 Mature teratoma 9080/0 Borderline (uncertain malignant potential) Mucinous cystic neoplasm with moderate dysplasia 8470/1 Intraductal papillary-mucinous neoplasm with moderate dysplasia Solid-pseudopapillary neoplasm 8452/1 Malignant Ductal adenocarcinoma 8500/3 Mucinous noncystic carcinoma 8480/3 Signet ring cell carcinoma 8490/3 Adenosquamous carcinoma 8560/3 Undifferentiated (anaplastic) carcinoma 8020/3 Undifferentiated carcinoma with osteoclast-like giant cells 8035/3 Mixed ductal-endocrine carcinoma 8154/3 Serous cystadenocarcinoma 8441/3 Mucinous cystadenocarcinoma 8470/3 non-invasive 8470/2 invasive 8470/3 Intraductal papillary-mucinous carcinoma 8453/3 non-invasive 8453/2 invasive (papillary-mucinous carcinoma) 8453/3 Acinar cell carcinoma 8550/3 Acinar cell cystadenocarcinoma 8551/3 Mixed acinar-endocrine carcinoma 8154/3 Pancreatoblastoma 8971/3 Solid-pseudopapillary carcinoma 8452/3 Others Non-epithelial tumours Secondary tumours

19 Primary Tumour (T) TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ T1 Tumour limited to the pancreas, 2 cm or less in greatest dimension T2 Tumour limited to the pancreas, more than 2 cm in greatest dimension T3 Tumour extends directly into any of the following: duodenum, bile duct, peripancreatic tissues3 T4 Tumour extends directly into any of the following: stomach, spleen, colon, adjacent large vessels4 Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis N1a Metastasis in a single regional lymph node N1b Metastasis in multiple regional lymph nodes Distant Metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis MI Distant metastasis Stage grouping Stage 0 Tis N0 M0 Stage I T1 N0 M0 T2 N0 M0 Stage II T3 N0 M0 Stage III T1 N1 M0 T2 N1 M0 T3 N1 M0 Stage IVA T4 Any N M0 Stage IVB Any T Any N M1

20 Malvezi M et al - Annals of Oncology 28 feb 2012 Sex Cancer Recorded deaths 2007 Predicted number of deaths 2012 Men Stomach colon and rectum Pancreas Lung Prostate Leukemias All cancers (malignant and benign) Women Stomach Colon and rectum Pancreas Lung Breast Uterus (cervix and corpus) Leukemias All cancers (malignant and benign)

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22 10th most frequent cancer the 8th leading cause of cancer-related death Incidence men: 7,3 8,7 per women: 4,5 5,7 per >95% of patients are dying of their disease No survival increases have been observed in the last years S. Cascinu et al. Annals of Oncology 21 (Supplement 5): v55 v58, 2010

23 Demographic factors Old age (most reliable and important predictor) Sex (more common in males than in females) Ethnic origin (mortality highest in black populations) Genetic factors and medical conditions Family history (one first degree 2,3 fold increased risk) Hereditary pancreatitis Hereditary non-polyposis colorectal cancer Ataxia-telangiectasia Peutz-Jeghers syndrome (132 fold increased risk) Familial breast cancer (BRCA2 mutations) Familial atypical multiple mole melanoma (germline mutations in p16) Chronic pancreatitis (2% per decade) Diabetic mellitus Gastrectomy Deficiency in carcinogen metabolism and DNA repair Environmental and lifestyle factors Cigarette smoking Occupational exposures Low dietary intake of fruits and vegetables Food preparation and cooking methods (grilling or charring confers the highest risk) James L Abbruzzese et al. Lancet 2004; 363:

24 Enviromental factors cigarette smoking* RR = at least 1,5 especially in smokers with GSTT1 (homozygous deletions of gene glutathione S-transferase T1) risk level returns to baseline by 15 years after cessation dietary** excessive fat or meat diabetes mellitus*** diagnosed within the preceding two years associated with obesity *Ghadirian P. Cancer 1991; 67: **Farrow DC. Am J Epidemiol 1990; 132: ***Gullo L. N Engl J Med 1994; 331:81-4

25 Normal pancreas has 3 types of epithelial cells Acinar cells 80% Ductal cells 10-15% Endocrine cells - <5% 95% of neoplasms arise from the exocrine elements - ductal and acinar cells Ductal adenocarcinoma = 85% to 90% of pancreatic tumors Localization: 60-70% head, 5-10% body,10-15% tail

26 Benign Serous cystadenoma Mucinous cystadenoma Intraductal papillary mucinous adenoma Mature cystic teratoma Borderline (uncertain malignant potential) Mucinous cystic tumor with moderate dysplasia Intraductal papillary mucinous tumor with moderate dysplasia Solid-pseudopapillary tumor Malignant Ductal adenocarcinoma Osteoclast-like giant cell tumor Serous cystadenocarcinoma Mucinous cystadenocarcinoma (noninvasive or invasive) Intraductal papillary mucinous carcinoma (noninvasive or invasive) Acinar cell carcinoma Pancreatoblastoma Solid-pseudopapillary carcinoma Miscellaneous carcinomas Hamilton SR, Aaltonen LA. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC

27 successive accumulation of gene mutations 3 precursor lesions*: Primary histologic precursor of pancreatic cancer = pancreatic intraductal neoplasia (PanIN) PanIN 1a,b (minimally dysplastic epithelium) pancreatic ** activation of the KRAS2 oncogene, inactivation of the tumor-suppressor gene CDKN2A inactivation of the tumor-suppressor genes TP53 and deleted in cancer 4 (DPC4, also known as the SMAD4 PanIN 2,3 (severe dysplasia) Mucinous cystic neoplasm (MCN) intraductal pancreatic mucinous neoplasm (IPMN) * Jason Klapman. Cancer Control October 2008, Vol. 15, No. 4 ** Feldmann G. J Hepatobiliary Pancreat Surg 2007;14:224-32

28 Normal duct PanIN Ia PanIN Ib PanIN II PanIN III Cancer MCN low grade Normal duct Intermediate grade High grade IPMN low grade Jason Klapman. Cancer Control October 2008, Vol. 15, No. 4

29 Gene/ chromosomal region (oncogenes and tumor supression) K-ras (12p) >90% p16 CDKN2A (9p) >95% PK53 (17p) 50%-70% SMAD4/DPC4 (18q) 55% AKT2 (19q) 10%-20% MYB (6q) 10% AIB1 (20q) 10% BRCA2 (13q) 7%-10% LKB1/STK11 (19p) <5% MKK4 (17p) <5% TGF-β-R1 (9q) or TGF-β-R2 (3p) <5% RB1 (13q) <5% % of tumors with genetic mutation Modified from Hruban RH, Wilentz RE. The pancreas. In: Kumar V, Abbas AK, Fausto N, editors. Robbins and Cotran pathologic basis of disease. 7th ed. Philadelphia: Elsevier; 2005

30 Oncogenes K-ras present in 90% of cancers frequency of mutations = extent of dysplasia Can be detected in chronic pancreatitis without neoplasia Tumor suppressor genes TP53 mutations chromosomal instability cancer P16 mutation associated with FAMMM syndrome (melanoma and pancreatic cancer) associated with decreased survival DPC4 = effect on cell cycle regulation and cell differentiation Other: up-regulation of EGF, telomere shortening

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32 Cancer Incidence Oesophagus 578 Stomach 2650 Colorectum 4554 Liver 1279 Gallbladder 293 Pancreas 1682 Lung 8387 Prostate 3620

33 Cancer Incidence Oesophagus 103 Stomach 1351 Colorectum 4142 Liver 692 Gallbladder 355 Pancreas 1184 Breast 7929 Cervix uteri 3402 Corpus uteri 1208 Ovary 1686

34 Male Female both Lung Breast Lung Colorectum Colorectum Colorectum Prostate Cervix uteri Breast Stomach Lung Stomach Bladder Ovary Prostate Romania GLOBOCAN 2008

35 Statisitica MS PCR in cazuri = 4,8 %ooo locuitori Studii Diculescu et al Romanian J gastroenterol 2005 studiu de cohorta PAC 62 pacienti sp Elias Hajjar N et al Chirurgia pacienti Chirurgie 3 Cluj Hecser L et al Rom J Legal Med2009 case reports PAC Diaconu B J Gastrointest Liver Disease 2009 SPINK 1 mutatie in 94 pac cu PCR

36 Cauze Raportarea in functie de ICM/DRG modifica formularea diagnostica Raportarea in teritoriu deficitara Patologie complexa ce implica multe esaloane medicale ( primara, secundara tertiare) fiecare cu raportari diferite

37 Dezavantaje Simptomatologia in patologia pancreatica apare de f multe ori f tardiv in stadii avansate Diagnosticul se bazeaza pe explorari imagistice sofisticate inabordabila pt metode de screening Avantaje Pancreatitele acute se interneaza doar in spitalele de urgenta Rata incidentei in tumorile maligne pancreatica este practic egala cu cea a mortalitatii Putine cazuri de Pancreatite cronice

38 Abord multidiscliplinar Standardizarea diagnosticelor APPR => registre pe domenii restranse de cazuri Pancreatite ereditare Tumori pancreatice rare Tumori neuroendocrine (PET-NET)

39 Incidenta pancreatitelor acute este in crestere in tarile occidentale ( si la noi?) Cunoasterea corecta a abordarii PAC poate salva vieti Pancreatitele cronice sunt subdiagnosticate si subestimate Tumorile pancreatice sunt in crestere si nu sunt metode de screening eficient actual

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