Ca Pancreas Part -II

By-Dr Satyajeet RathGuide-Prof Kamal Sahni

Ca Pancreas is a systemic disease from the outset

• Disease diagnosed late in its natural history– No established screening strategy– 5 year survival less than 5%

• High frequency of systemic failures even after curative resection

• Subclinical metastasis present at the outset

Epidemiology• Pancreatic ductal adenocarcinoma (PDA)

– 12th most common cancer in the United States, – 4th most frequent cause of cancer-related death.

• The incidence , M:F = 1.3:1 , ↑ after 45 yrs of age

• Incidence in India : – 0.5-2.4 per 1,00,000 men– 0.2-1.8 per 1,00,000 women

• Incidence more in western and northern india•

Pancreaticcancerindia group

Disease 5-YEAR OS Median Survival

Localized disease 20 % 13-20 mnths

Locally advanced , unresectable disease 8-14 mnths

Metastatic disease < 2% 4-6 mnths

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11–30

Presentation – often locally advanced or metastatic

• Most adenoca present in periampullary region

( head , neck & uncinate process)• Present with• Obstructive jaundice with

pruritus• Dark urine • Clay-coloureed stools• Steatorrhea

• 15-20% may have recent onset of atypical diabetes mellitus

• Tumours of body and tail present when they are larger.• Back pain and weight loss

are common• Jaundice is a late

manifestation

• Tail Tumours may have left sided portal hypertension , upper GI bleed , splenomegaly

• 80% metastatic disease

• Pruritis – biliary duct obstruction• Steatorrhea - pancreatic duct obstruction,

• Positive physical findings, if any, generally reflect incurable disease.

• These may include a – palpable abdominal mass (i.e., pancreas, liver, or gallbladder due to biliary

obstruction), – ascites, – supraclavicular nodes, or – palpable rectal shelf (i.e., peritoneal seeding).; Blumer’s shelf– left cervical lymphadenopathy (Virchow's node), a – palpable gallbladder (Courvoisier's sign), and – migratory superficial thrombophlebitis (Trousseau's syndrome).

Contd..

Empiric Risk Counselling

• In familial pancreatic cancer kindreds (defined as a family with a pair of affected first-degree relatives), – the risk of pancreatic cancer increases with the number of affected first-degree

relatives – High-penetrance – Individuals with multiple affected first-degree relatives are at an appreciably

increased risk for pancreatic cancer

Associated Inherited Cancer Syndromes• Roughly 10% of PDAs are familial, and only 10% of the familial subgroup

are associated with a previously defined genetic syndrome.

*Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov 2012;2:41–46 .

•Hereditary breast and ovarian cancer is the most common familial syndrome

•Peutz-Jeghers syndrome confers the highest lifetime risk.

Screening

• There are currently no universal guidelines or proven strategies for screening high-risk individuals.

• There were two projects, but were inconclusive.– Cancer of the Pancreas Screening (CAPS) project – In persons with hereditary diseases

• There was consensus that EUS and MRI were the preferred surveillance strategies.

• Routine surveillance should be performed annually, and suspicious solid masses should be further evaluated by CT scanning.

• Screening should begin around 50 years of age.

*Canto MI, Hruban RH, Fishman EK, et al. Gastroenterology 2012;142:796–804.*Canto MI, Harinck F, Hruban RH, et al. Gut 2013;62:339–347.

• Main purpose of the workup is to - determine resectability, - establish a histologic diagnosis, - reestablish biliary-tract outflow, and - circumvent gastric outlet obstruction.

• Imaging – Abdominal USG– CT scan – EUS– Laparoscopy– MRI – upper GI Endoscopy– ERCP & MRCP

CT-guided biopsy.

• Laboratories: – CBC, LFT , KFT , RBS– CEA, – CA19-9, – amylase, – lipase, – LDH

Diagnostic Work Up

Abdominal USG

• Often the first approach used in attempting to identify the cause of abdominal pain or jaundice

• Signs of the presence of pancreatic tumor• Hypoechoic mass • dilatation of the pancreatic duct and CBD

• No characteristic signs for the different pancreatic lesions.

• Accuracy of conventional US for diagnosing pancreatic tumors is only 50–70% 

CT• The best initial imaging test for diagnosis and staging of pancreatic

cancer is contrast-enhanced, dual-phase, MDCT, with thin cuts through the pancreas.

• CT allows – assessment of the primary tumor, – local invasiveness, – liver metastases– regional lymph node involvement, and – peritoneal spread

• Sensitivity of helical CT for detecting ca pancreas : 85-95%. • Over 90% of patients deemed unresectable due to vascular

involvement by CT are truly inoperable at time of surgery.• CT can be utilized to facilitate fine-needle aspiration (FNA).

*Kinney T. Evidence-based imaging of pancreatic malignancies. Surg Clin North Am 2010;90(2):235–249.*Karmazanovsky G, et al. Pancreatic head cancer: accuracy of CT in determination of resectability. Abdom Imaging 2005;30(4):488–500.

EUS• In this procedure, an endoscope with an ultrasound transducer at its tip

is passed into the stomach and duodenum, where it provides high-resolution images of the pancreas and surrounding vessels.

• EUS facilitates FNA without exposing the peritoneum to potential tumor seeding, as may occur with CT-guided biopsy.

• Sensitivity for EUS is at least comparable to CT, with tumor detection reported as high as 97%.

• An advantage of EUS over CT is the ability to detect small lesions, which might not be well visualized on cross-sectional imaging.

• Interpretation of EUS is highly operator dependent.

*Hunt GC et al. Gastrointest Endosc 2002;55(2):232–237.

Contd..

• EUS is performed in conjunction with endoscopic retrograde cholangiopancreatography.

• This combined diagnostic approach allows for staging, therapeutic stenting of the common bile duct when indicated, and diagnostic FNA simultaneously.

• In a study by Rosch et al. , endoscopic ultrasound demonstrated greater sensitivity & specificity than for detecting pancreatic tumours

• For pancreatic tumors less than 2 cm, Yasuda et al. found that EUS had a detection rate of 100% , (ERCP: 57%, transabdominal ultrasound: 29%, CT: 29%, and angiography: 14%).

Brugge WR, Van Dam J. Pancreatic and biliary endoscopy. N Engl J Med 1999; 341(24):1808–1816.

Rosch T, et al. Endoscopic ultrasound in pancreatic tumor diagnosis. Gastrointest Endosc 1991;37(3):347–352.

EUS Abd. USG CT Scan

Sensitivity 99 67 77

Specificity 100 40 53

Staging Laparoscopy

• Advantages– For visualizing smaller hepatic and peritoneal implants– Avoids unnecessary laparotomies– Facilitates peritoneal washings and biopsy

• Recent meta-analysis :- adoption of staging laparoscopy and laparoscopic ultrasound will prevent up to 50% of patients from undergoing unnecessary laparotomy.1

1.Hariharan D, et al. Eur J Surg Oncol 2010;36(10):941–948.2.Fernandez-del Castillo C, Rattner DW, Warshaw AL et al.. Br J Surg 1995;82(8):1127–1129.

MRI• Advances in MRI, including high-resolution imaging, faster acquisition time,

three-dimensional (3D) reconstruction, functional imaging, and MR cholangiopancreatography(MRCP) have led to an improved ability of MRI to diagnose and stage pancreatic cancer.

• Advantages :– can be used in patients with poor renal function to assess the primary tumor and

determine resectability– identification of small foci of hepatic metastatic disease difficult to appreciate by CT– to further characterize ill-defined lesions seen on CT.2

– improve differentiation of a pancreatic cancer from chronic pancreatitis and offers simultaneous assessment of the pancreatic and bile ducts by heavily T2-weighted imaging (MRCP)

1.Bipat S, et al. Ultrasonography, computed tomography and magnetic resonance imaging for diagnosis and determining resectability of pancreatic adenocarcinoma: a meta-analysis. J Comput Assist Tomogr 2005;29(4):438–445.

2.Sica GT, Ji H, Ros PR. Computed tomography and magnetic resonance imaging of hepatic metastases. Clin Liver Dis 2002;6(1):165–179.

• The sensitivity of MRCP in a study of 124 patients was 84% with a specificity of 97% for pancreatic cancer.

ERCP• Role diminished in current

setting

• Most useful for palliating unresectable tumour that cause biliary obstruction

• Advantage of providing the opportunity both to • sample for cytology or

histology • to apply therapy via

biliary stenting for obstructive jaundice

• The sensitivity and specificity of ERCP (92%,96%) .

PET-CT• Initial studies showed that PET has a higher sensitivity, specificity, and

accuracy than CT in diagnosing pancreatic carcinomas.

• Lemke et al.1 evaluated 104 patients, with suspected pancreatic lesions. • Integrated PET-CT had a higher sensitivity for malignancy detection

than either PET or CT alone (96% vs. 84% vs. 77%) but did not improve specificity (64%).

• PET may also be a useful adjunct in the identification of benign versus malignant lesions and presence of metastatic disease.

• Although PET-CT may be useful in initial diagnosis, its role in determining resectability has been questioned as high metabolism can obscure peripancreatic planes.

1.Grassetto G, et al. Role of FDG-PET/CT in diagnosis, staging, response to treatment, and prognosis of pancreatic cancer. Am J Clin Oncol 2011;34(2):111–114.

Tumour Markers• CA19-9 :- a sialylated Lewis A blood group antigen commonly expressed and

shed in pancreatic and hepatobiliary disease • Concentration higher than 70 U/mL has a sensitivity of 70% and specificity of

87% for pancreatic cancer.

• Drawbacks of using CA19-9 as a diagnostic marker. – It may be elevated in

• Benign conditions such as pancreatitis, poorly controlled diabetes, choledocholithiasis and cholangitis

• Malignant conditions such as biliary tract cancers, some colon cancers

– up to 10% of pancreatic cancer do not synthesize CA19-9 even in advanced stages.

• Clinical utility – has prognostic value– used for surveillance for recurrence after treatment– Highly significant predictor of OS in resected ca pancreas ( RTOG 97-04 )

Summary of Diagnosis

• High-resolution pancreatic CT and EUS remain the current standard for diagnosis and staging of pancreatic malignancies.

• Staging laparoscopy is useful in assessing for intraperitoneal and liver disease.

• MRI and PET-CT are emerging technologies that require further investigation.

Perez & Brady , Principles and Practice of Radiation Oncology, 6th edition

StagingSTAGING (AJCC 7th Ed., 2010): PANCREATIC CANCER

• The definition of TNM and anatomic stage/prognostic groupings has not changed from the sixth edition (2002) for exocrine pancreas.

• Pancreatic neuroendocrine tumors (including carcinoid tumors) are now staged by a single pancreatic staging system.

• For practical purposes, tumors are generally classified as – Resectable (Stage I, II), – Unresectable (Stage III), and – Metastatic (Stage IV).

TNM Staging

T 1 : Tumour limited to pancreas, 2 cm or less in greatest dimensionT 2 : Tumour limited to pancreas, more than 2 cm in greastest dimension

T 3 : Tumour extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery

T 4 : Tumour involves the celiac axis or the superior mesenteric artery ( unresectable primary tumour )

Lymphatic spread

Lymphatic spread

• Pancreas head cancers metastasize frequently to the superior pancreatic and posterior pancreaticoduodenal lymph nodes, and they can also involve inferior pancreatic and anterior pancreaticoduodenal lymph nodes.

Pathways of spread

• Retroperitoneal organ• Close anatomic relationship to stomach, duodenum, jejunum ,

kidneys, spleen, celiac trunk, SMA, CBD and portal vein.• >85% ca pancreas will have extended into adjacent organs and

lymph nodes allowing early metastasis

• The peritoneum and liver are the most frequent metastatic sites. • Extraabdominal metastasis is frequently to lungs.

• Malignancies metastasizing to Pancreas include – Breast– Lung– Colon/Rectum– Stomach– Melanoma

Gunderson & Tepper , Clinical Radiation Oncology,3rd edition

Pathologic Classification

• The classification and nomenclature of pancreatic epithelial neoplasms has been reviewed by Klimstra et al.

• Broadly three types : ductal adeno ca, neuroendocrine & cystic neoplasms.• Ductal adenocarcinoma

• >90% of pancreatic cancers with a 4% 5-year survival • worst of any cancer

• Ductal adenocarcinomas most commonly arise from the periampullary region

2.Michelassi F, et al.. Ann Surg 1989;210(4):544–556.1.Klimstra DS, Pitman MB, Hruban RH. et al Arch Pathol Lab Med 2009;133:454–464

Tumours of the Pancreas• Exocrine / Non endocrine – Benign or Malignant• Endocrine

• Exocrine Malignant

• Pancreatic Ductal adenoca

Less common Pancreatic Ca

• Acinic cell ca• Pancreatoblastoma• Intraductal Papillary

Mucinous Neoplasms• Mucinous Cystic

Neoplasms• Solid-Pseudopapillary

Neoplasms(Hamoudi or Franz tumors)

• Exocrine Benign

• adenoma• Cystadenoma• Lipomas• Fibromas• Haemingoma• lymphangioma • Neuromas

• extremely rare

• Neuro endocrine tumours

• Insulinoma• Gastrinoma• Glucagonoma• Somatostatinoma• VIPoma

• less common than non-endocrine tumours

• generally benign sometimes multiple

PDA – Pancreatic Ductal Adeno ca• Characteristics –

– molecular heterogeneity, – a tendency for perineural invasion, in almost all cases (much more frequently than in other

common adenocarcinomas like colon and breast). – Microscopic vessel and – lymphatic invasion are common, and – tumor necrosis is frequently present.

• Genetic Alterations commonly seen– Oncogenic Kras is altered in more than 90% of PDAs– CDKN2A (p16) is inactivated in roughly 95% of PDAs– TP53 mutations - 75%– SMAD4/DPC4 inactivation in 50% of PDAs

• Immunohistochemical markers typically seen include cytokeratins (e.g., 7, 8, 13, 18, 19), CA19-9, B72.3, CA-125, and DUPAN-2.

Winter JM, Cameron JL, Campbell KA, et al. 1423 J Gastrointest Surg 2006;10:1199–1210. Rozenblum E, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 1997;57(9):1731–1734.

PDA• PDA development follows an adenoma to carcinoma

sequence, similar to colon cancer.

Cho KR, Vogelstein B. Genetic alterations in the adenoma—carcinoma sequence. Cancer 1992;70:1727–1731.

Cystic neoplasms of Pancreas

• 5-15% of pancreatic cystic lesions are neoplastic• Can be Serous or Mucinous • Most serous cystic neoplasms are benign• Mucinous cystic neoplasms are more frequently malignant• Both are more common in women• Mucinous cystadenoca – better prognosis

Gunderson & Tepper , Clinical Radiation Oncology,3rd edition

Intraductal Papillary Mucinous Neoplasms

• Intraductal papillary mucinous neoplasms (IPMN) are mucin-producing cystic neoplasms that arise from pancreatic ducts.

• IPMNs are the most common pancreatic cystic neoplasms

• develop in roughly 1% to 5% of the general population.

• Good prognosis compared to typical pancreatic malignancies

• The Sendai guidelines recommend resection for IPMNs that are either symptomatic, >3 cm in diameter, contain solid components (e.g., mural nodules), have malignant cells on cytology, or involve the main pancreatic duct.

*Shi C, Hruban RH. Intraductal papillary mucinous neoplasm. Hum Pathol 2012;43:1–16.

*Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR Am J Roentgenol 2008;191:802–807.

Pancreatoblastoma• Most common pancreatic malignancy in children• Usually occurs in the first 8 years of life.

• Associated with – Beckwith-Wiedmann – Familial adenomatous polyposis syndromes.

• Elevated levels of serum α-fetoprotein

• Cures are often achievable with resection in children• About one-third of patients present with metastatic disease. • Cases have been reported in adults as well, with survival after

resection that is comparable to conventional PDA.

Salman B, Brat G, Yoon YS, et al. The diagnosis and surgical treatment of pancreatoblastoma in adults: a case series and review of the

literature. J Gastrointest Surg 2013;17:2153–2161.

Endocrine pancreatic cancers• The classification of pancreatic neuroendocrine tumors (PNET) is challenging

because of the heterogenous biology of this tumor type. – United States (AJCC 7th ed. 2010, same as exocrine pancreatic cancer) – Europe (European Neuroendocrine Tumor Society [ENETS]).

• Slow growing and therefore carry much better prognosis.

• Pancreatic NET– 30-40% associated with symptoms of hormone hypersecretion– 60-70% “non-functioning”

• Commonly mutated genes included – MEN1 (44% of PNETs), – chromatin remodeling genes (43%: DAXX and ATRX), and – mTOR pathway genes (15%: phosphatase and tensin homolog [PTEN], PIK3CA, and TSC2).

*Ellison TA, Wolfgang CL, Shi C, et al. A single institution’s 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. Ann Surg 2014;259:204–212.

* Familial syndromes associated with the development of PNETs include -multiple endocrine neoplasia 1 (MEN1 gene), -von Hippel-Lindau disease (VHL), -neurofibromatosis (NF1), and -tuberous sclerosis (TSC1 or TSC2).

Pancreatic Endocrine Neoplasms

1.Pancreas ;Volume 39, Number 6, August 20102.Hochwald SN et al. J Clin Oncol. 2002;20:2633Y2642.

Grading of Pancreatic Neuroendocrine tumours

Insulinoma• Whipple’s Triad:

• symptoms of hypoglycemia during fasting or exercise• serum glucose <45mg/dL during symptoms• relief of symptoms with administration of glucose

• Definitive test is 72-hour fast with measurement of insulin and glucose• 75% of patients develop symptoms and GB<40 within 24 hours• insulin:glucose ratio >0.4 is indicative of insulinoma

• Elevated c-peptide proinsulin levels are confirmatory along with screening for antiinsulin antibodies, sulfonylureas

• 10% are malignant, indicated by metastases• Metastases usually to regional peripancreatic lymph nodes, liver

*Whipple AO. The surgical therapy of hyperinsulinism. J Int Chir 1938;3:237–276

Gastrinoma : ZE diagnosis

• Zollinge Ellision Triad : Gastrinoma give rise to ZE Syndrome which consist of triad – hypersecretion of gastric acid– severe peptic ulceration – presence of non-beta cell tumour of the pancreas or duodenum

• Localization with somatostatin receptor scintigraphy (SRS)

• Elevated serum gastrin level, elevated basal acid secretory rate both suggest possible gastrinoma

• Secretin stimulation test– discontinue acid-inhibitory medication– basal serum gastrin levels– 2 U/kg of secretin IV bolus, then serum gastrin measured at 2, 5, 10, and 20 minutes

later– Positive response is gastrin >200pg/mL above basal level

Thank You