Pancreas exocrin

› Pancreatite acute

› Pancreatite cronice

› Afectiuni ereditare ale pancreasului

› Tumori pancreatice

Pancreas endocrin

› Diabetul zaharat

› Tumorile neuroendocrine PET-NET

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

Chirurg sau

Internist

Pancreatita cronica

durere abdominala trenanta

Medic de familie !

Eventual internist din policlinica

Tumori pancreatice

Nutritionist, medic de familie, endocrinolog, psihiatru, gastroenterolog

5

Necesita explorari

Uneori sofisticate

Necesara internare

De obicei

gastroenterolog

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

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): 3018-3026

European studies increase in the incidence rate of acute pancreatitis

922 patients with confirmed diagnosis of AP ( (2000–2009)in 1 hospital incidence rate varied from 24 to 35/100 000 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 956149,

Cauza › Pancreatita cronica

› Fibroza chistica

› Chirurgia pancreatica

Prevalenta 3,9/100.000 EU › 3,3/100.000 Franta

› 4,2 /100000 Germania

› 2,9/100000 Italia

› 3.0/100000 Spania

› 5,5/100000 UK

Mattson,Jakc Report 2005- Pancreatic exocrine insuffiency epidemiology

› 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

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)

Insuficienta pancreatica exocrina

Pancreatectomie

Rezectie

gastrica

Pancreatita

cronica

Pancreatita

acuta

Fibroza

chistica

“Pancreatita

senila”

Plenitudine Meteorism

Intoleranta

alimentelor

Steatoree

Pierdere in

greutate

Dispepsie

Malabsortie

Durere

abdominala

Greata / varsaturi Pierderea apetitului

PEI

Cauze

Indicatie

Semne

simptome

Pancreatita cronica

Incidenta PC este de 3,5 - 4 /

100 000 locuitori.

Prevalenta/Predominanta de

vârsta si sex: pancreatita

cronica afecteaza

preponderent barbatii în vârsta

de 35 - 45 ani (de 3 ori mai

frecventa decât la femei).

Forma usoara Forma severa Pseudochist

Recidiva

Restitutio ad integrum

PA

PC

PA Pancreatita acuta

PC Pancreatita cronica

Klöppel & Maillet, Hepatogastroenterol 38:408, 1991

14

INCIDENTA = 3-10 %ooo loc

PREVALENTA = 5.5-30 %ooo loc

!!Este in crestere

Variaza geografic

Tara Incidenta

/100 000 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):

469-77, 2002

Cehia 7.9 idem

Inciența este de 6-7 /100.000 locuitori în vest

80% sex masculin.

Vârsta medie depinde de etiologie,

› ~ 40-45 ani la PC alcoolică,

› ~ 25-30 la PC idiopatică,

› ~ 15-20 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

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

Benigne

Maligne

Epiteliale

Nonepiteliale

Exocrine

Endocrine

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

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

Sex Cancer Recorded deaths 2007 Predicted number of deaths 2012

Men

Stomach 37424 33926

colon and rectum 85244 89117

Pancreas 35022 39088

Lung 183019 183592

Prostate 68282 69960

Leukemias 21553 22320

All cancers (malignant and benign) 706619 717398

Women

Stomach 25060 21138

Colon and rectum 75294 73989

Pancreas 34965 38443

Lung 69115 78658

Breast 89012 88101

Uterus (cervix and corpus) 27393 26720

Leukemias 17884 18605

All cancers (malignant and benign)554515 565703

Malvezi M et al - Annals of Oncology 28 feb 2012

10th most frequent cancer

the 8th leading cause of cancer-related

death

Incidence

men: 7,3 – 8,7 per 100.000

women: 4,5 – 5,7 per 100.000

>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

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: 1049–57

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; 67:2664-70

**Farrow DC. Am J Epidemiol 1990; 132:423-31

***Gullo L. N Engl J Med 1994; 331:81-4

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

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

Press; 2000

successive accumulation of gene mutations

3 precursor lesions*:

› Primary histologic precursor of pancreatic cancer =

pancreatic intraductal neoplasia (PanIN)

PanIN 1a,b (minimally dysplastic epithelium)

** activation of the KRAS2 oncogene,

inactivation of the tumor-suppressor gene CDKN2A

inactivation of the tumor-suppressor genes TP53 and deleted in

pancreatic

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

Normal duct

Normal duct

PanIN Ia PanIN Ib PanIN II PanIN III

MCN low grade

IPMN low grade

Intermediate grade

High grade

Cancer

Jason Klapman. Cancer Control October 2008, Vol. 15, No. 4

Gene/ chromosomal region

(oncogenes and tumor supression)

% of tumors with genetic mutation

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%

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

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

Cancer Incidence

Oesophagus 578

Stomach 2650

Colorectum 4554

Liver 1279

Gallbladder 293

Pancreas 1682

Lung 8387

Prostate 3620

Cancer Incidence Oesophagus 103

Stomach 1351 Colorectum 4142 Liver 692

Gallbladder 355 Pancreas 1184 Breast 7929 Cervix uteri 3402 Corpus uteri 1208 Ovary 1686

Male Female both

Lung Breast Lung

Colorectum Colorectum Colorectum

Prostate Cervix uteri Breast

Stomach Lung Stomach

Bladder Ovary Prostate

Romania GLOBOCAN 2008

Statisitica MS – PCR in 2011 – 975 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 2012 – 81 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

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

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

Abord multidiscliplinar

Standardizarea diagnosticelor

APPR => registre pe domenii restranse

de cazuri

› Pancreatite ereditare

› Tumori pancreatice rare

› Tumori neuroendocrine (PET-NET)

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