Ca pancreas part diagnosis and workup

1. Ca Pancreas Part -II
By-Dr Satyajeet Rath
Guide-Prof Kamal Sahni

2. 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

3. 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

4. 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

5. • 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..

6. 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

7. 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.

8. •Hereditary breast
and ovarian cancer
is the most common
familial syndrome
•Peutz-Jeghers
syndrome confers
the highest lifetime
risk.

9. 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.

10. • 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

11. 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%

12. 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.

13. 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.

14. 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

15. 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.

16. 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.

17. 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%) .

18. 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.

19. 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 )

20. 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

21. Staging
STAGING (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).

22. TNM Staging

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

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

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

26. Lymphatic spread

27. 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.

28. 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

30. 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

31. 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

32. 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.

33. 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.

34. 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

35. 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.

36. 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.

37. 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.

38. * 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

39. 1.Pancreas ;Volume 39, Number 6, August 2010
2.Hochwald SN et al. J Clin Oncol. 2002;20:2633Y2642.
Grading of Pancreatic Neuroendocrine tumours

40. 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

41. 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

42. Thank You