**Multi-Disciplinary Management of Metastatic Pancreatic Cancer**

Marwan Ghosn\*, Colette Hanna and Fadi El. Karak *Faculty of Medicine, Saint-Joseph University, Beirut, Lebanon* 

### **1. Introduction**

196 Pancreatic Cancer – Clinical Management

Vandermeulen, E.P., Van Haken, H. & Vermylen, J. (1994). Anticoagulants and spinalepidural anesthesia. *Anesth Analg*, Vol. 79,No. 6, pp. 1165-77, ISSN 0003-2999 Verhofstad, H.J. & Hendriks, T. (1996). Complete prevention of impaired anastomotic

Zacharias, A.Z. & Habib, R.H. (1996). Factors predisposing to median sternotomy complications. *Chest*, Vol. 110, No. 5, pp. 1173-8, ISSN 0012-3692 WHO (2008). Scoping document for WHO treatment guideline on pain related to cancer,

Vol. 83, No. 12, pp. 1717-21, ISSN 0007-1323

Pain Guidelines

healing in diabetic rats requires preoperative blood glucose control. *Br J Surg,*

HIV and other progressive life-threatening illnesess in adult adopted in WHO steering group on pain guidelines, 14 October 2008. WHO Steereing Group on

> Pancreatic cancer (PC) is a devastating disease with the worst mortality rate and an overall 5-year survival rate lower than 5% (2% in distant cases; 9% in regional cases and 22% in localized cases). Although accounting for only 3% of all cancers, this disease is the fourth leading cause of death and represents 6 – 7 % of all cancer related deaths. In males, the incidence ASR is 8.2 and 2.7 and the mortality ASR is 7.9 and 2.5 in more developed areas and less developed areas, respectively.

> In females, the incidence ASR is 5.4 and 2.1 and the mortality ASR is 5.1 and 2.0 in more developed areas and less developed areas, respectively.

> We noticed that the incidence and the mortality rates are very close (*Jemal et al. 2011).* Also, the death rate is increasing from 9.28 per 100,000 in 1991 to 9.48 in 2006 with an absolute change of 0.2 (2.1%). *(Jemal et al. 2010).*

> In the United States, the overall incidence is about 8–10 cases per 100,000 persons/year and rises slowly over the years with 43 140 new cases in 2010.

> Pancreatic cancer remains one of the most difficult to treat due to late initial diagnosis and to intrinsic resistance to conventional treatments. About 50% of patients have distant disease at the time of diagnosis (locally advanced stage) and in 40% the tumor has spread (metastatic stage).

#### **2. Risk factors**

Risk factors have been identified, molecular pathogenesis has been elucidated, but advances in early detection and efficient treatments remain rather disappointing despite tremendous efforts.

Studies results show that long-term diabetes, even though risk diminishes over time, remains a risk factor for PC independent of obesity and smoking with a latency period of more than 5 years. Type 3 diabetes mellitus is an effect, and therefore a harbinger, of pancreatic cancer in at least 30% of patients *(Magruder JT et al, 2011; Li D et al. 2011).*

<sup>\*</sup> Corresponding Author

Multi-Disciplinary Management of Metastatic Pancreatic Cancer 199

pain, dyspepsia, nausea and depression. However, no early warning signs of pancreatic cancer have been established. As previously noted, long term diabetes is a risk factor thus diagnosis of pancreatic cancer should be considered in diabetic patients with continuous weight loss and abdominal symptoms. All patients for whom there is clinical suspicion of pancreatic cancer or evidence of dilated duct should undergo initial evaluation by dynamicphase CT scan. Subsequent decisions regarding diagnostic management and resectability should involve multidisciplinary consultation with reference to appropriate radiographic

1. Decisions about diagnostic management and resectability should involve multidisciplinary consultation with reference to appropriate radiographic studies to evaluate the extent of disease. Resections should be done at institutions that perform a

2. Imaging should include specialized pancreatic CT scan. CT should be performed according to a defined protocol such as triphasic cross-sectional imaging and thin slices. 3. The role of PET/CT scan remains unclear. PET/CT may be considered after formal pancreatic CT protocol in high risk patients to detect extra-pancreatic metastases. It is

5. EUS directed fine needle biopsy is preferable to a CT-guided FNA in patients with resectable disease because of lower risk of peritoneal seeding with EUS FNA when compared with the percutaneous approach. Biopsy proof of malignancy is not required before surgical resection and a non diagnostic biopsy should not delay surgical

6. Diagnostic staging with laparoscopy to rule out subradiologic metastases (especially for body and tall lesions) is used routinely in some institutions prior to surgery or chemoradiation or selectively in patients whoa re at higher risk for disseminated disease (borderline resectable disease, markedly elevated CA 19-9, large primary

7. Positive cytology from washings obtained at laparoscopy or laparotomy is equivalent to M1 disease. If resection has been done for such a patient, they should be treated as for

In 2010 new insights were added to the complex biology of pancreatic cancer offering new

The first comprehensive analysis of pancreatic tumors and their metastases describes the patterns of genomic instability and estimates the time from tumor initiation to metastatic

Genome-wide association studies point towards multiple common disease alleles with small effects influencing pancreatic cancer risk *(Petersen, G. M. et al. 2010; Low, S. K. et al. 2010).*

The ESPAC-3 trial reported that gemcitabine did not result in improved overall survival compared with fluorouracil plus folinic acid in patients with resected pancreatic cancer

studies to evaluate the extent of the disease *(Agarwal B et al, 2001. Johnson CD. 2010)* 

**The principles of diagnosis and staging are:** 

tumors or large regional lympnodes).

opportunities for early diagnosis and treatment.

spread to be at least 10 years *(Yachida, S. et al, 2010).*

M1 disease. **The key advances are:** 

*(Neoptolemos, J. P. et al. 2010).* 

large number (15-20) of pancreatic resections annually.

not a substitute for high quality contrast enhances CT scan.

4. Endoscopic Ultrasound (EUS) may be complementary to CT for staging.

resection when the clinical suspicion for pancreatic cancer is high.

After a pooled analysis of 14 cohort studies, a review study noted that, coffee consumption was inversely associated with pancreatic cancer (RR, 0.82; 95% CI, 0.69-0.95) *(Yu X et al, 2011).* 

Although there have not been a sufficient number of clinical trials, promising dietary factors to prevent pancreatic cancer include citrus fruits, flavonoids, curcumin, folate, and vitamin D. Phase II clinical trials of curcumin have shown encouraging chemoprotective effects in patients with pancreatic cancer and have determined that curcumin can be safely administrated to patients at oral doses up to 8 g/d.

Several flavonoids found in a variety of fruits and vegetables have also been shown to inhibit pancreatic cancer at various molecular targets including cell-cycle, Akt, NFkB, ERK, and many others. Currently, there is one on-going phase II clinical trial on the use of genistein in treating resectable pancreatic cancer patients. However, more clinical trials are needed to explore the efficacy and application of these factors in treating pancreatic cancer.

The use of citrus fruit extracts to treat pancreatic cancer has become of interest only in the past few years. Using citrus fruit extracts instead of individual compounds to treat pancreatic cancer is of great interest because it allows the use of low doses of multiple bioactive compounds and nutrients instead of large doses of single compounds, and therefore reducing the possibility of reaching toxic effects.

When comparing the inhibitory effects of different extraction methods of lime juice on pancreatic cancer, it was found that the methanol extract exhibited the highest inhibitory effect. Although the results from this study provide insight into the best options for extracting citrus fruits, more research needs to be conducted on various types of citrus fruits extracts and their mechanisms of action by which they affect pancreatic cancer.

Folate and vitamin D have good epidemiological evidence that shows that consumption of either of these nutrients leads to a reduced risk of pancreatic cancer. However, both of the nutrients have few experimental studies needed to help draw conclusions about either of their impacts on pancreatic cancer. *(Jodee Johnson et al. 2011).* 

The pooled data of 6 studies involving a total of 2335 patients suggests an association between infection with H. pylori and the development of pancreatic cancer ((AOR 1.38, 95% CI: 1.08-1.75; P=0.009*). (Trikudanathan G et al, 2011)* 

As is the case in other complex diseases, common, low-risk variants in different genes may act collectively to confer susceptibility to pancreatic cancer in individuals with repeated environmental exposures, such as smoking and red meat intake. Clarification of gene–gene and gene–environmental interaction is therefore indispensable for future studies. To address these issues, a rigorously designed molecular epidemiologic study with a large sample is desirable. *(Yingsong Lin et al, 2011.)* 

#### **3. Diagnosis**

Pancreatic cancer is usually detected at an advanced stage and responds poorly to treatment.

Ductal adenocarcinoma and its variants account for over 90% of pancreatic malignancies. The presenting symptoms of the disease can include weight loss, jaundice, floating stools,

After a pooled analysis of 14 cohort studies, a review study noted that, coffee consumption was inversely associated with pancreatic cancer (RR, 0.82; 95% CI, 0.69-0.95) *(Yu X et al,* 

Although there have not been a sufficient number of clinical trials, promising dietary factors to prevent pancreatic cancer include citrus fruits, flavonoids, curcumin, folate, and vitamin D. Phase II clinical trials of curcumin have shown encouraging chemoprotective effects in patients with pancreatic cancer and have determined that curcumin can be safely

Several flavonoids found in a variety of fruits and vegetables have also been shown to inhibit pancreatic cancer at various molecular targets including cell-cycle, Akt, NFkB, ERK, and many others. Currently, there is one on-going phase II clinical trial on the use of genistein in treating resectable pancreatic cancer patients. However, more clinical trials are needed to explore the efficacy and application of these factors in treating pancreatic cancer. The use of citrus fruit extracts to treat pancreatic cancer has become of interest only in the past few years. Using citrus fruit extracts instead of individual compounds to treat pancreatic cancer is of great interest because it allows the use of low doses of multiple bioactive compounds and nutrients instead of large doses of single compounds, and

When comparing the inhibitory effects of different extraction methods of lime juice on pancreatic cancer, it was found that the methanol extract exhibited the highest inhibitory effect. Although the results from this study provide insight into the best options for extracting citrus fruits, more research needs to be conducted on various types of citrus fruits

Folate and vitamin D have good epidemiological evidence that shows that consumption of either of these nutrients leads to a reduced risk of pancreatic cancer. However, both of the nutrients have few experimental studies needed to help draw conclusions about either of

The pooled data of 6 studies involving a total of 2335 patients suggests an association between infection with H. pylori and the development of pancreatic cancer ((AOR 1.38, 95%

As is the case in other complex diseases, common, low-risk variants in different genes may act collectively to confer susceptibility to pancreatic cancer in individuals with repeated environmental exposures, such as smoking and red meat intake. Clarification of gene–gene and gene–environmental interaction is therefore indispensable for future studies. To address these issues, a rigorously designed molecular epidemiologic study with a large sample is

Pancreatic cancer is usually detected at an advanced stage and responds poorly to

Ductal adenocarcinoma and its variants account for over 90% of pancreatic malignancies. The presenting symptoms of the disease can include weight loss, jaundice, floating stools,

extracts and their mechanisms of action by which they affect pancreatic cancer.

administrated to patients at oral doses up to 8 g/d.

therefore reducing the possibility of reaching toxic effects.

their impacts on pancreatic cancer. *(Jodee Johnson et al. 2011).* 

CI: 1.08-1.75; P=0.009*). (Trikudanathan G et al, 2011)* 

desirable. *(Yingsong Lin et al, 2011.)* 

**3. Diagnosis** 

treatment.

*2011).* 

pain, dyspepsia, nausea and depression. However, no early warning signs of pancreatic cancer have been established. As previously noted, long term diabetes is a risk factor thus diagnosis of pancreatic cancer should be considered in diabetic patients with continuous weight loss and abdominal symptoms. All patients for whom there is clinical suspicion of pancreatic cancer or evidence of dilated duct should undergo initial evaluation by dynamicphase CT scan. Subsequent decisions regarding diagnostic management and resectability should involve multidisciplinary consultation with reference to appropriate radiographic studies to evaluate the extent of the disease *(Agarwal B et al, 2001. Johnson CD. 2010)* 

#### **The principles of diagnosis and staging are:**


#### **The key advances are:**

In 2010 new insights were added to the complex biology of pancreatic cancer offering new opportunities for early diagnosis and treatment.

The first comprehensive analysis of pancreatic tumors and their metastases describes the patterns of genomic instability and estimates the time from tumor initiation to metastatic spread to be at least 10 years *(Yachida, S. et al, 2010).*

Genome-wide association studies point towards multiple common disease alleles with small effects influencing pancreatic cancer risk *(Petersen, G. M. et al. 2010; Low, S. K. et al. 2010).*

The ESPAC-3 trial reported that gemcitabine did not result in improved overall survival compared with fluorouracil plus folinic acid in patients with resected pancreatic cancer *(Neoptolemos, J. P. et al. 2010).* 

Multi-Disciplinary Management of Metastatic Pancreatic Cancer 201

The primary goals of treatment for advanced pancreatic cancer are palliation and improved survival. Although some effect on survival may be achieved, these benefits are usually limited to patients with adequate performance status (ECIG 0-2). Patients who present with very poor performance status may benefit from the administration of Gemcitabine, but comfort-directed measures are always paramount. Before initiating cytotoxic therapy, an open dialogue regarding the goals of treatment should take place, and adjunctive strategies should be discussed (including nonsurgical bypass, celiac block for pain; of note debilitated patients with advanced disease may have abrupt changes in clinical status. Therefore, if treatment is begun, it should proceed with close follow-up. Patients may experience sudden onset of bleeding or thromboembolism, rapidly escalating pain, biliary stent occlusion, cholangitis, or other infections. Moreover, clinically meaningful tumor progression may develop quickly, and tumor-related symptoms may be inappropriately attributed to chemotherapy or other causes. For instance, patients who complain of intractable nausea and vomiting may have gastric outlet obstruction rather than chemotherapy-induced emesis. Peritoneal carcinomatosis may manifest as ascites or in its more subtle form, as

Prior to approval of Gemcitabine, 5-FU was the most extensively evaluated agent for PC, either alone or in combination without survival advantage. Gemcitabine, with or without Erlotinib, has been the standard chemotherapy in APC. The FDA approval in 1997 was based on the results of the randomized trial where Gemcitabine was compared to 5-FU in previously untreated patients. Patients treated with Gemcitabine had a median survival of 5.65 months, compared to 4.41 months (p < 0.05) in those treated with 5-FU. Twenty-four percent of patients treated with gemcitabine were alive at 9 months, compared to 6% of patients treated with 5-FU. In addition, more clinically meaningful effects on disease-related symptoms were seen with gemcitabine (23.8%) than with 5-FU (4.8%). *(Burris HA 3rd, Moore* 

Platinum compounds have been widely evaluated. A pooled analysis of two randomized trials indicates that the combination of gemcitabine with a platinum analog such as oxaliplatin or cisplatin significantly improves progression-free (PFS) and overall survival (OS) when compared to gemcitabine alone (HR for PFS: 0.75 with p=0.0030; HR for OS: 0.64 with p=0.063 in favour of the GP combination). The benefit from combination therapy is predominantly detected in patients with a good performance status. *(V. Heinemann, Labianca* 

Among the numerous randomized phase III studies comparing gemcitabine as single agent to gemcitabine combined to a new agent, only the gemcitabine-erlotinib combination has shown a small, but statistical improvement in survival. A trend to better survival was also observed with a gemcitabine-capecitabine regimen. The use of low-weight heparin may be

The various combinations of new generation drugs showed 13% - 28.7 % RR with the Gemcitabine/Oxaliplatin, 8.2% - 17.3% with Gemcitabine alone, 12.8 % with Gemcitabine/CPT-11, 16% - 23% with Gemcitabine/Capecitabine, 22% with Oxaliplatin/Capecitabine and 10% with Oxaliplatin and 5-FU, 12.9% with Cisplatin / Gemcitabine, 13 % with Bevacizumab/Gemcitabine, 8.6 % with Erlotinib/Gemcitabine and

12.5 % with Cetuximab/Gemcitabine and 31% with the Folfirinox regimen.

**4.4 Chemotherapy for locally advanced and metastatic disease** 

abdominal bloating, decreased oral intake and constipation.

*MJ, Andersen J et al. 1997).* 

*R, Hinke A, Louvet C. et al. 2007).* 

of value to reduce venous thromboembolic events

Superior values for diagnostic performance were shown for MIC-1, PAM4, OPN, HSP27, TPS, TSGF, and CAM17.1 as individual markers. Panels of biomarkers comprised CA 19-9, MCSF, CEA, SAA, Haptoglobin, TSGF, CA 242, and HSP27. Individually or in concerted form, sensitivity and specificity ranged from 77 to 100% and 84-100%, respectively. While these markers show high screening potential for pancreatic cancer, standardized validation studies using multiplex assays are required to pave the way for clinical routine application *(Bünger S et al, 2011).* 

### **4. Treatment**

There is consensus on the fact that surgical removal of the tumor represents the best option for pancreatic cancer treatment; to be resectable, tumors need to be small and strictly localized to pancreas without invasion into surrounding organs and evidence of metastasis. However, only 15–20% of all patients are candidates for potentially curative surgery. Depending on the tumor localization, pancreaticoduodenectomy, distal or total pancreatectomy can be performed. However, even with an optimal curative surgery, metastases often occur. Median survival time without evidence of recurrent disease is 21.2 months after resection.

Systemic therapy is used in the adjuvant setting and in the management of locally advanced unresectable and metastatic disease.

#### **4.1 Neoadjuvant resectable / borderline resectable**

No standard treatment regimen currently exists for neoadjuvant resectable or borderline resectable pancreatic cancer. Neoadjuvant therapy for patients with resectable tumors should ideally be conducted on a clinical trial. Generally, use similar paradigms as for locally advanced unresectable disease:


Ideally, surgical resection should be atatempted 6 to 8 weeks following chemoradiation. Surgery can be performed after 8 weeks following chemoradiation however radiation induced fibrosis may potentially make surgery more difficult.

#### **4.2 Chemoradiation therapy for locally advanced disease**

Chemoradiation is a conventional option for the management of unresectable locorgeional pancreatic cancer, although the utility of chemoradiation in this population of patients is controversial.

#### **4.3 Post-operative adjuvant treatment**

Clinical trial preferred or Systemic Gemcitabine or 5-FU/Leucovorin before or after chemoradiation (fluoropyrimidine or gemcitabine based) or chemotherapy alone Gemcitabine (category 1) or 5-FU/Leucovorin (category 1) or Capeciatbine (Category 2B).

Superior values for diagnostic performance were shown for MIC-1, PAM4, OPN, HSP27, TPS, TSGF, and CAM17.1 as individual markers. Panels of biomarkers comprised CA 19-9, MCSF, CEA, SAA, Haptoglobin, TSGF, CA 242, and HSP27. Individually or in concerted form, sensitivity and specificity ranged from 77 to 100% and 84-100%, respectively. While these markers show high screening potential for pancreatic cancer, standardized validation studies using multiplex assays are required to pave the way for clinical routine application

There is consensus on the fact that surgical removal of the tumor represents the best option for pancreatic cancer treatment; to be resectable, tumors need to be small and strictly localized to pancreas without invasion into surrounding organs and evidence of metastasis. However, only 15–20% of all patients are candidates for potentially curative surgery. Depending on the tumor localization, pancreaticoduodenectomy, distal or total pancreatectomy can be performed. However, even with an optimal curative surgery, metastases often occur. Median survival time without evidence of recurrent disease is 21.2

Systemic therapy is used in the adjuvant setting and in the management of locally advanced

No standard treatment regimen currently exists for neoadjuvant resectable or borderline resectable pancreatic cancer. Neoadjuvant therapy for patients with resectable tumors should ideally be conducted on a clinical trial. Generally, use similar paradigms as for


Ideally, surgical resection should be atatempted 6 to 8 weeks following chemoradiation. Surgery can be performed after 8 weeks following chemoradiation however radiation

Chemoradiation is a conventional option for the management of unresectable locorgeional pancreatic cancer, although the utility of chemoradiation in this population of patients is

Clinical trial preferred or Systemic Gemcitabine or 5-FU/Leucovorin before or after chemoradiation (fluoropyrimidine or gemcitabine based) or chemotherapy alone Gemcitabine (category 1) or 5-FU/Leucovorin (category 1) or Capeciatbine (Category 2B).

*(Bünger S et al, 2011).* 

months after resection.

unresectable and metastatic disease.

locally advanced unresectable disease:

chemoradiation therapy.

**4.3 Post-operative adjuvant treatment** 

controversial.

**4.1 Neoadjuvant resectable / borderline resectable** 


induced fibrosis may potentially make surgery more difficult.

**4.2 Chemoradiation therapy for locally advanced disease** 

**4. Treatment** 

#### **4.4 Chemotherapy for locally advanced and metastatic disease**

The primary goals of treatment for advanced pancreatic cancer are palliation and improved survival. Although some effect on survival may be achieved, these benefits are usually limited to patients with adequate performance status (ECIG 0-2). Patients who present with very poor performance status may benefit from the administration of Gemcitabine, but comfort-directed measures are always paramount. Before initiating cytotoxic therapy, an open dialogue regarding the goals of treatment should take place, and adjunctive strategies should be discussed (including nonsurgical bypass, celiac block for pain; of note debilitated patients with advanced disease may have abrupt changes in clinical status. Therefore, if treatment is begun, it should proceed with close follow-up. Patients may experience sudden onset of bleeding or thromboembolism, rapidly escalating pain, biliary stent occlusion, cholangitis, or other infections. Moreover, clinically meaningful tumor progression may develop quickly, and tumor-related symptoms may be inappropriately attributed to chemotherapy or other causes. For instance, patients who complain of intractable nausea and vomiting may have gastric outlet obstruction rather than chemotherapy-induced emesis. Peritoneal carcinomatosis may manifest as ascites or in its more subtle form, as abdominal bloating, decreased oral intake and constipation.

Prior to approval of Gemcitabine, 5-FU was the most extensively evaluated agent for PC, either alone or in combination without survival advantage. Gemcitabine, with or without Erlotinib, has been the standard chemotherapy in APC. The FDA approval in 1997 was based on the results of the randomized trial where Gemcitabine was compared to 5-FU in previously untreated patients. Patients treated with Gemcitabine had a median survival of 5.65 months, compared to 4.41 months (p < 0.05) in those treated with 5-FU. Twenty-four percent of patients treated with gemcitabine were alive at 9 months, compared to 6% of patients treated with 5-FU. In addition, more clinically meaningful effects on disease-related symptoms were seen with gemcitabine (23.8%) than with 5-FU (4.8%). *(Burris HA 3rd, Moore MJ, Andersen J et al. 1997).* 

Platinum compounds have been widely evaluated. A pooled analysis of two randomized trials indicates that the combination of gemcitabine with a platinum analog such as oxaliplatin or cisplatin significantly improves progression-free (PFS) and overall survival (OS) when compared to gemcitabine alone (HR for PFS: 0.75 with p=0.0030; HR for OS: 0.64 with p=0.063 in favour of the GP combination). The benefit from combination therapy is predominantly detected in patients with a good performance status. *(V. Heinemann, Labianca R, Hinke A, Louvet C. et al. 2007).* 

Among the numerous randomized phase III studies comparing gemcitabine as single agent to gemcitabine combined to a new agent, only the gemcitabine-erlotinib combination has shown a small, but statistical improvement in survival. A trend to better survival was also observed with a gemcitabine-capecitabine regimen. The use of low-weight heparin may be of value to reduce venous thromboembolic events

The various combinations of new generation drugs showed 13% - 28.7 % RR with the Gemcitabine/Oxaliplatin, 8.2% - 17.3% with Gemcitabine alone, 12.8 % with Gemcitabine/CPT-11, 16% - 23% with Gemcitabine/Capecitabine, 22% with Oxaliplatin/Capecitabine and 10% with Oxaliplatin and 5-FU, 12.9% with Cisplatin / Gemcitabine, 13 % with Bevacizumab/Gemcitabine, 8.6 % with Erlotinib/Gemcitabine and 12.5 % with Cetuximab/Gemcitabine and 31% with the Folfirinox regimen.

Multi-Disciplinary Management of Metastatic Pancreatic Cancer 203

or IV toxicities were mild. The median time to progression and the median survival time

Results from the randomized phase III study PRODIGE 4/ACCORD 11 trial evaluating the regimen of FOLFORINOX vs. Gemcitabine alone in patients with APC and good performance status showed dramatic improvements in both progression-free survival (6.4 months vs. 3.3 months, p < 0.001) and median overall survival (11.1 months vs. 6.8 months, p < 0.001) in favor of the group receiving FOLFORINOX. Because of these strong results, NCCN classified FOLFORINOX as a category 1 recommendation for first-line treatment of

There are however some concerns about the toxicity of the FOLFORINOX regimen. The grade ¾ toxicities rates were 12.3% for diarrhea, 15.6% for nausea, 17.2% for vomiting, 24% for fatigue, 47.9% for neutropenia and 5.7% for febrile neutropenia. Despite the high level of

The high level of toxicity highlight the need to identify which patients will ultimately

Summary: Gemcitabine (with or without erlotinib or capecitabine) is still the reference treatment in patients with ECOG performance status 2. **Folfirinox** is a new more toxic and more efficient regimen that may be considered in patients with good performance status. There is a difficulty in improving outcomes in metastatic PC. This continues to be a field of intense interest and regimens that conclusively show benefit in this disease are likely to

Agarwal B et al, 2004. Endoscopic ultrasound guided fine needle aspiration and multidetector spiral CT in the diagnosis of pancreatic cancer. Am J gastroenterol; 99: 844 – 850. Bendell J. C. et al, 2011, Immediate impact of the FOLFIRINOX phase III data reported at the

Bernhard Jürg et al, 2008. Clinical Benefit and Quality of Life in Patients With Advanced

Bünger S et al, 2010. biomarkers for improved diagnostic of pancreatic cancer: a current

Burris HA 3rd et al, 1997. Improvements in survival and clinical benefit with gemcitabine as

Colucci Giuseppe et al, 2010. Randomized Phase III Trial of Gemcitabine Plus Cisplatin

Ghosn M et al, 2007. FOLFOX-6 combination as the first-line treatment of locally advanced and/or metastatic pancreatic cancer. Am J Clin Oncol, 30 (1): 15-20.

overview. J Cancer Res Clin Oncol. 2011 Mar; 137(3):375-89. .

2010 ASCO Annual Meeting on prescribing plans of American oncology physicians for patients with metastatic pancreas cancer (MPC). J Clin Oncol , 29 (suppl 4):

Pancreatic Cancer Receiving Gemcitabine Plus Capecitabine Versus Gemcitabine Alone: A Randomized Multicenter Phase III Clinical Trial. J Clin Oncol, 26 (22):

first-line therapy for patients with advanced pancreas cancer: a randomized trial. J

Compared With Single-Agent Gemcitabine As First-Line Treatment of Patients With Advanced Pancreatic Cancer: The GIP-1 Study. J Clin Oncol, 28: 1645 – 1651. Conroy T et al, 2011. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N

good performance status patients with either metastatic or locally advanced disease.

were 4 and 7.5 months respectively *(M. Ghosn et al, 2007).* 

toxicity, no toxic deaths have been reported.

benefit from this more aggressive approach.

**5. References** 

Abstr 286;

3695-3701;

Clin Oncol 1997, 15(6): 2403-13.

Engl J Med. May 12; 364(19):1817-25.

generate enthusiasm and rapid adoption into clinical practice.

The addition of Cisplatin, Bevacizumab, Cetuximab to Gemcitabine did not improve survival compared with patients treated with Gemcitabine alone in APC patients. The OS ranged between 5.8 and 9 months (table 1).

*(G. Stathopoulos, K. Syrigos, G. Aravantinos, et al. 2006; V. Heinemann, T. Hoehler, G. Seipelt et al. 2008; K. Song, Y. Do, H. Chang et al. 2008; M. Moore, D. Goldstein, J. Hamm et al. 2007; Hedy Lee Kindler et al. 2010; Philip A. Philip. 2010; Giuseppe Colucci et al. 2010; E. Popli, Y. Feng, J. Berlin et al. Phase III, 2009; Jürg Bernhard et al. 2008; J. C. Bendell, S. Britton, M. R. Green et al. 2011; P. E. Oberstein, M. Saif. First 2011).* 


Table 1. Summary of Results of some important Gemcitabine-based regimen

Oxaliplatin is one of the investigational active agents used in APC. With its synergistic effect, Oxaliplatin shows a higher RR when combined with other drugs. With 5-FU, preclinical data suggested synergistic efficacy which led to investigate the combination in many clinical trials. In a phase II trial in pancreatic cancer patients, this combination was explored and showed encouraging RR which deserve more evaluation *(M. Ducreux, 2004; C. Louvet, R. Labianca, P. Hammel et al. 2005; C. Louvet, T. Andre, G. Liedo et al. 2002).* 

Recent publication of the results of a phase II trial performed by our group and assessing the combination of the FOLFOX 6 regimen showed promising results (27.5% partial response and 34.5% stable disease resulting in tumor growth control in 62% of the patients). Grade III or IV toxicities were mild. The median time to progression and the median survival time were 4 and 7.5 months respectively *(M. Ghosn et al, 2007).* 

Results from the randomized phase III study PRODIGE 4/ACCORD 11 trial evaluating the regimen of FOLFORINOX vs. Gemcitabine alone in patients with APC and good performance status showed dramatic improvements in both progression-free survival (6.4 months vs. 3.3 months, p < 0.001) and median overall survival (11.1 months vs. 6.8 months, p < 0.001) in favor of the group receiving FOLFORINOX. Because of these strong results, NCCN classified FOLFORINOX as a category 1 recommendation for first-line treatment of good performance status patients with either metastatic or locally advanced disease.

There are however some concerns about the toxicity of the FOLFORINOX regimen. The grade ¾ toxicities rates were 12.3% for diarrhea, 15.6% for nausea, 17.2% for vomiting, 24% for fatigue, 47.9% for neutropenia and 5.7% for febrile neutropenia. Despite the high level of toxicity, no toxic deaths have been reported.

The high level of toxicity highlight the need to identify which patients will ultimately benefit from this more aggressive approach.

Summary: Gemcitabine (with or without erlotinib or capecitabine) is still the reference treatment in patients with ECOG performance status 2. **Folfirinox** is a new more toxic and more efficient regimen that may be considered in patients with good performance status. There is a difficulty in improving outcomes in metastatic PC. This continues to be a field of intense interest and regimens that conclusively show benefit in this disease are likely to generate enthusiasm and rapid adoption into clinical practice.

#### **5. References**

202 Pancreatic Cancer – Clinical Management

The addition of Cisplatin, Bevacizumab, Cetuximab to Gemcitabine did not improve survival compared with patients treated with Gemcitabine alone in APC patients. The OS

*(G. Stathopoulos, K. Syrigos, G. Aravantinos, et al. 2006; V. Heinemann, T. Hoehler, G. Seipelt et al. 2008; K. Song, Y. Do, H. Chang et al. 2008; M. Moore, D. Goldstein, J. Hamm et al. 2007; Hedy Lee Kindler et al. 2010; Philip A. Philip. 2010; Giuseppe Colucci et al. 2010; E. Popli, Y. Feng, J. Berlin et al. Phase III, 2009; Jürg Bernhard et al. 2008; J. C. Bendell, S. Britton, M. R. Green et al. 2011; P.* 

benefit ORR median

5FU + Gem 23.8% 6.9% 3.4 mo 6.7 mo Gem 4.8% 5.6% 2.2 mo 5.4 mo

Gem + Cisplatin 15.1% 12.9% 3.8 mo 7.2 mo Gem 23.0% 10.1% 3.9 mo 8.3 mo

Gem + Oxaliplatin 38.2% 26.8% 5.8 mo 9 mo Gem 26.9% 17.3% 3.7 mo 7.1 mo

Gemox ND 9.0% 2.7 mo 5.7 mo Gem fixed dose rate ND 10.0% 3.5 mo 6.2 mo Gem ND 6.0% 2.6 mo 4.9 mo

Gem + Platinum ND 22.0% 24 weeks 36 weeks Gem ND 14.0% 15 weeks 29 weeks

5FU/LV 62.0% 27.5% 4 mo 7.5 mo

Gem + Cetuximab 49.5% 12.5% 3.4 mo 6.3 mo Gem 44.1% 14.0% 3 mo 5.9 mo

Gem + Bevacizumab 13.0% 13.0% 3.8 mo 5.8 mo Gem 10.0% 10.0% 2.9 mo 5.9 mo

Gem + Erlotinib 57.5% 8.6% 3.75 mo 6.24 mo Gem 49.2% 8.0% 3.55 mo 5.91 mo

Oxaliplatin is one of the investigational active agents used in APC. With its synergistic effect, Oxaliplatin shows a higher RR when combined with other drugs. With 5-FU, preclinical data suggested synergistic efficacy which led to investigate the combination in many clinical trials. In a phase II trial in pancreatic cancer patients, this combination was explored and showed encouraging RR which deserve more evaluation *(M. Ducreux, 2004; C.* 

Recent publication of the results of a phase II trial performed by our group and assessing the combination of the FOLFOX 6 regimen showed promising results (27.5% partial response and 34.5% stable disease resulting in tumor growth control in 62% of the patients). Grade III

Gem + Capecitabine 26.0% ND ND ND Gem 25.0% ND ND ND

PFS

median survival

ranged between 5.8 and 9 months (table 1).

Reference Regimen Clinical

Gem + Oxaliplatin +

Table 1. Summary of Results of some important Gemcitabine-based regimen

*Louvet, R. Labianca, P. Hammel et al. 2005; C. Louvet, T. Andre, G. Liedo et al. 2002).* 

*E. Oberstein, M. Saif. First 2011).* 

Berlin et al. JCO 2002

Colucci et al. JCO 2010

Louvet et al. JCO 2005

Poplin et al. JCO 2009

Ghosn et al. Am J Clin Oncol

Bernhard et al. JCO 2008

Philip et al. JCO 2010

Kindler et al JCO 2010

Moore et al. JCO 2007

2007

Heinemann et al Ann Oncol 2007


**12**

*Iceland* 

**Pancreatic Cancer –**

Birgir Gudjonsson *MACP, FRCP, AGAF* 

*The Medical Clinic, Reykjavik,* 

**Clinical Course and Survival** 

The incidence of pancreatic carcinoma varies from 6-20/100.000 in different countries and ethnic groups, but is considered to be on the average 10/100.000 (Gudjonsson 1987) and causes a significant economic burden on health resources (Gudjonsson 1995, Du 2000).

Cancer of the pancreas is the 13th in frequency in the USA but fourth most frequent cause of death from cancer (Jemal 2010) fifth most frequent cause of death in Japan and sixth in

Adenocarcinoma constitutes 90% of pancreatic malignancies. Only 50% of patients in tumor

The cause of pancreatic cancer is unclear but it is more frequent among cigarette smokers.

Mutations in K-ras genes are found in up to 90% of cases of cancer of the pancreas but are not specific and are also found in patients with chronic pancreatitis. The suppressor genes p16 and p53 are inactivated and DPC4 deleted in 50% of cases of pancreatic cancer. (Cowgill

Patients may occasionally be under thirty years of age. Forty percent are between 60-70 years. Thirty percent are between 50-60 years old and twenty percent between 70-80 years

Majority of patients complain of weight loss which is on the average 10 kg. Most complain of pain, which may be deep seated, in a third of patients the pain radiates to the back, a fifth

experience relief by bending forward, and 10-15% it is worsened with eating.

registries had histologic confirmation (Gudjonsson 1987).

The disease is slightly more frequent among males than females.

Chronic pancreatitis leads to increased frequency.

**1. Introduction**

China.

**2. Genes** 

**3. Clinical features** 

old (Gudjonsson 1987).

**4. Clinical features** 

2003).


## **Pancreatic Cancer – Clinical Course and Survival**

Birgir Gudjonsson *MACP, FRCP, AGAF The Medical Clinic, Reykjavik, Iceland* 

#### **1. Introduction**

204 Pancreatic Cancer – Clinical Management

Heinemann V et al. 2007. Increased survival using platinum analog combined with

Jemal A et al. 2001.Global Cancer Statistics, Ca Cancer J Clin 2011, 61: 69 – 90) N Engl J Med.

Johnson J, de Mejia EG. Dietary factors and pancreatic cancer: The role of food bioactive

Johnson CD. Pancreatic carcinoma: devleoping a protocol for multidetecto row CT.

Kindler Hedy Lee et al, 2010. Gemcitabine Plus Bevacizumab Compared With Gemcitabine

Lin Y et al, 2011. An Overview of Genetic Polymorphisms and Pancreatic Cancer Risk in

Low SK et al, 2010. Genome-wide association study of pancreatic cancer in Japanese

Magruder JT et al. 2011. Diabetes and pancreatic cancer: chicken or egg? Pancreas, 40(3):339-

Moore M et al, 2007. Erlotinib plus gemcitabine compared with gemcitabine alone in

Oberstein PE, M. Saif. First-Line Treatment for Advanced Pancreatic Cancer. S from the

Philip A. Philip. Phase III Study Comparing Gemcitabine Plus Cetuximab Versus

Popli E et al, 2009. Phase III, Randomized Study of Gemcitabine and Oxaliplatin Versus

Song K et al, 2008. A phase II study of capecitabine plus gemcitabine in patients with locally

Stathopoulos S et al, 2006. A multicenter phase III trial comparing irinotecan-gemcitabine

locally advanced or metastatic pancreatic cancer. Br J Cancer, 95 (5):587-92.

Cooperative Oncology Group. J Clin Oncol, 27 (23): 3778-3785.

Institute of Canada Clinical Trials Group. J Clin Oncol, 25 (15): 1960 – 6 Neoptolemos JP et al, 2010. Adjuvant chemotherapy with fluorouracil plus folinic acid vs

patients with advanced pancreatic cancer: a phase III trial of the National Cancer

gemcitabine following pancreatic cancer resection: a randomized controlled trial.

"2011 ASCO Gastrointestinal Cancers Symposium". J Pancreas (Online) 2011,

Gemcitabine in Patients With Advanced Pancreatic Adenocarcinoma: Southwest Oncology Group–Directed Intergroup Trial S0205. J Clin Oncol 2010, 28 (22): 3605-

Gemcitabine (fixed-dose rate infusion) Compared With Gemcitabine (30-minute infusion) in Patients With Pancreatic Carcinoma E6201: A Trial of the Eastern

advanced or metastatic pancreatic cancer. Cancer Chemother Pharmacol 2008, 62

(IG) with gemcitabine (G) monotherapy as first-line treatment in patients with

control studies. Cancer Causes Control. 2011 Feb; 22(2):189-97.

Molecular Epidemiologic Studies. J Epidemiol; 21(1):2-12

population. PLoS ONE 2010 Jul 29; 5(7):e11824.

Plus Placebo in Patients With Advanced Pancreatic Cancer: Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol, 28 (22): 3617-3622. Li D et al, 2010. Diabetes and risk of pancreatic cancer: a pooled analysis of three large case-

Jemal Aet al, 2010. Cancer Statistics 2010, Ca Cancer J Clin, 60: 277 – 300.

compounds. Mol. Nutr. Food Res. 2011, 55, 58–73.

Ann Oncol, 19 (2): 340 – 7.

Radiology 2001: 220: 3- 4.

JAMA, 304, 1073–1081.

12(2):96-100.

(5): 763 – 8.

3610.

364(19):1817-25.

51).

gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study. Ann Oncol, 18 (10): 1652 – 9). Heinemann V et al., 2008. Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus

gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer.

> The incidence of pancreatic carcinoma varies from 6-20/100.000 in different countries and ethnic groups, but is considered to be on the average 10/100.000 (Gudjonsson 1987) and causes a significant economic burden on health resources (Gudjonsson 1995, Du 2000).

> Cancer of the pancreas is the 13th in frequency in the USA but fourth most frequent cause of death from cancer (Jemal 2010) fifth most frequent cause of death in Japan and sixth in China.

> Adenocarcinoma constitutes 90% of pancreatic malignancies. Only 50% of patients in tumor registries had histologic confirmation (Gudjonsson 1987).

> The cause of pancreatic cancer is unclear but it is more frequent among cigarette smokers. Chronic pancreatitis leads to increased frequency.

#### **2. Genes**

Mutations in K-ras genes are found in up to 90% of cases of cancer of the pancreas but are not specific and are also found in patients with chronic pancreatitis. The suppressor genes p16 and p53 are inactivated and DPC4 deleted in 50% of cases of pancreatic cancer. (Cowgill 2003).

#### **3. Clinical features**

The disease is slightly more frequent among males than females.

Patients may occasionally be under thirty years of age. Forty percent are between 60-70 years. Thirty percent are between 50-60 years old and twenty percent between 70-80 years old (Gudjonsson 1987).

#### **4. Clinical features**

Majority of patients complain of weight loss which is on the average 10 kg. Most complain of pain, which may be deep seated, in a third of patients the pain radiates to the back, a fifth experience relief by bending forward, and 10-15% it is worsened with eating.

Pancreatic Cancer – Clinical Course and Survival 207

Hepatomegaly may be present in over 50% of patients, 40% may have clinical jaundice, blood in stool may be found in one in four, abdominal mass found in one in five and ascites

Elevated alkaline phosfatase and gamma GT are the most frequent abnormalities or in close

Fasting hyperglycemia may be found in close to 60% of patients. Hyperbilirubinemia is

CA 19-9 may be elevated in 80-90% but is mainly of benefit in monitoring the progress of the

The main differential diagnosis are gastric pathology, i.e. cancer or ulcers, gallstones,

initially found in approximately 50%, anemia and elevated lipase in a third.

**5. Physical findings** 

in more than one in ten.

**6. Laboratory values** 

**7. Differential diagnosis** 

chronic pancreatitis, or ampullary ca.

Fig. 3. CT. Pancreatic cancer. Axial view.

disease.

to 80% of patients, while 60% have elevated SGOT.

Anorexia may be present in half of patients. A third may complain of vomiting. A third complain of acholic stools and dark urine. One in four may report jaundice (Gudjonsson 1987).

Fig. 1. Age distribution.

Duration of symptoms is variable but 40% have had symptoms less than 1 month, 20% 2 months and 10% 3 months.


Fig. 2. Duration of symptons.

### **5. Physical findings**

206 Pancreatic Cancer – Clinical Management

Anorexia may be present in half of patients. A third may complain of vomiting. A third complain of acholic stools and dark urine. One in four may report jaundice (Gudjonsson

Duration of symptoms is variable but 40% have had symptoms less than 1 month, 20% 2

1987).

Fig. 1. Age distribution.

months and 10% 3 months.

Fig. 2. Duration of symptons.

Hepatomegaly may be present in over 50% of patients, 40% may have clinical jaundice, blood in stool may be found in one in four, abdominal mass found in one in five and ascites in more than one in ten.

#### **6. Laboratory values**

Elevated alkaline phosfatase and gamma GT are the most frequent abnormalities or in close to 80% of patients, while 60% have elevated SGOT.

Fasting hyperglycemia may be found in close to 60% of patients. Hyperbilirubinemia is initially found in approximately 50%, anemia and elevated lipase in a third.

CA 19-9 may be elevated in 80-90% but is mainly of benefit in monitoring the progress of the disease.

### **7. Differential diagnosis**

The main differential diagnosis are gastric pathology, i.e. cancer or ulcers, gallstones, chronic pancreatitis, or ampullary ca.

Fig. 3. CT. Pancreatic cancer. Axial view.

Pancreatic Cancer – Clinical Course and Survival 209

Overall five-year survival is well below 1%. Close to 50% of patients with pancreatic adenocarcinoma will be dead within approximately 3 months, 65-70% within 6 months and 85-90% within 12 months, but an occasional patient may still survive 5 years with or without

The disease will cause pain and obstruction of the biliary and/or gastroduodenal system. A full 90% of patients will therefore primarily need palliation in the form of relief of pain and relief of the obstruction of the biliary and gastroduodenal system which may occur.

Fig. 5. Survival distribution.

Fig. 6. Survival curve.

resection.

Fig. 4. CT. Pancreatic cancer, Sagital view. Metastases in liver.

#### **8. Diagnostic procedure**

In non-jaundice patients it is appropriate to start with upper endoscopy or radiographic upper gastrointestinal studies. In a jaundiced patient ultrasound would establish or rule out gallstones, but also make large tumors and liver metastases obvious. Computerised Tomography, especially the helical form would best confirm the extent of tumor mass and growth beyond the boundaries of the gland. MRI, EUS or ERCP would further delineate the extent of the disease. Angiography and a PET scan are of lesser value (Bipat 2005).

Attempts should be made to obtain tissue diagnosis from the tumour mass or liver by Fine Needle Biopsy guided by CT, US or EUS.

#### **9. Prognosis, statistics**

Before doctors embark on attempts at vigorous curative therapy the documented course of this disease and survival statistics so far should be borne in mind (Gudjonsson 1987, 1995).

In 90% of cases it has been found that the disease has progressed beyond the boundaries of the gland to adjacent lymph nodes, liver, omentum, stomach or duodenum.

Fig. 4. CT. Pancreatic cancer, Sagital view. Metastases in liver.

In non-jaundice patients it is appropriate to start with upper endoscopy or radiographic upper gastrointestinal studies. In a jaundiced patient ultrasound would establish or rule out gallstones, but also make large tumors and liver metastases obvious. Computerised Tomography, especially the helical form would best confirm the extent of tumor mass and growth beyond the boundaries of the gland. MRI, EUS or ERCP would further delineate the

Attempts should be made to obtain tissue diagnosis from the tumour mass or liver by Fine

Before doctors embark on attempts at vigorous curative therapy the documented course of this disease and survival statistics so far should be borne in mind (Gudjonsson 1987, 1995). In 90% of cases it has been found that the disease has progressed beyond the boundaries of

extent of the disease. Angiography and a PET scan are of lesser value (Bipat 2005).

the gland to adjacent lymph nodes, liver, omentum, stomach or duodenum.

**8. Diagnostic procedure** 

**9. Prognosis, statistics** 

Needle Biopsy guided by CT, US or EUS.


Fig. 5. Survival distribution.

Overall five-year survival is well below 1%. Close to 50% of patients with pancreatic adenocarcinoma will be dead within approximately 3 months, 65-70% within 6 months and 85-90% within 12 months, but an occasional patient may still survive 5 years with or without resection.

Fig. 6. Survival curve.

The disease will cause pain and obstruction of the biliary and/or gastroduodenal system.

A full 90% of patients will therefore primarily need palliation in the form of relief of pain and relief of the obstruction of the biliary and gastroduodenal system which may occur.

Pancreatic Cancer – Clinical Course and Survival 211

up to 50% of cases (Z'graggen 2001). Biopsy proof should be mandatory before resections are performed. Radical cancer surgery of 6-10 hours duration for chronic pancreatitis is not

An occasional resected patient may certainly survive 5 years but will then most likely be

Half of those who survive 5 years after resections have recurrence of cancer (Conlon 1996). The post op course of resected patients is not smooth and they may need many readmissions to hospitals (Gudjonsson 1995, Reddy 2009). The value of resections as

Cancer of the pancreas is a very chemoresistant disease. Gemcitabine and 5 fluoruracil have been used in different forms in numerous trials of resected and nonresected patients and may add to quality of life and prolong life and exceptionally contribute to 5-year survival

Radiation therapy has been used pre- intra- and postoperatively in various forms alone or in

Bipat S, Phoa SSKS, Delden OMv, et. al. Ultrasonography, computed tomography and

Brooks J, Culebras JM. Cancer of the pancreas. Palliative operation, Whipple procedure, or

Conlon K, Klimstra DS, Brennan M. Long-term survival after curative resection for

Costamagna G, Pandolfini M. Endoscopic stenting for biliary and pancreatic malignancies. J

Du W, Touchette D, Vaitkevicus VK, et al. Cost analysis of pancreatic carcinoma treatment.

Gudjonsson B. Carcinoma of the pancreas: Critical analysis of costs, results of resections, and the need for standardized reporting. J Am Coll Surg 1995; 181:483-503.

Gudjonsson B. Cancer of the pancreas. 50 years of surgery. Cancer 1987; 60:2284-03.

Cowgill SM, Muscarella P. The genetics of pancreatic cancer. Am J Surg 2003; 186:279-286. Cress RD, Yin D, Clarke L, et al. Survival among patients with adenocarcinoma of the

magnetic resonance imaging for diagnosis and determining respectability of pancreatic adenocarcinoma: A meta-analysis. J Comput Assist Tomogr 2005;

pancreatic ductal adenocarcinoma: Clinicopathologic analysis of 5-year survivors.

pancreas: a population-based study (United States). Cancer Causes Control 2005;

conjunction with chemotherapy but has not had any significant effect on survival.

Novel diagnostic and therapeutic approach is needed (Yokoyama 2009).

total pancreatectomy. Am J Surg 1977; 131:516-519.

reported over and over in the literature (Gudjonsson 2009).

True cure of pancreatic cancer after resection is exceptional.

justified.

palliation is unproven.

**11. Chemotherapy** 

(Neoptolemos 2004).

**12. References** 

29:438-445.

17:403-409.

Ann Surg 1996; 23:273-279.

Cancer 2000; 89: 1917-24.

Clin Gastroenterol 2004; 38:59-67.

### **10. Operative findings**

Earlier on approximately 80% of patients would have had a surgical laparotomy after imaging studies and in a third of those only a biopsy would have been feasible. Half of those operated on would have had a biliary bypass performed and some of those also a gastric bypass with 5-10% undergoing only a gastric bypass (Brooks 1976).

Now laparoscopy is increasingly used to stage the extent of disease and obtain a biopsy (Nagorney 1999). Either method would reveal that in 2/3 of established cases the tumor would be located in the head of the pancreas and one third in the body and/or tail and have progressed beyond the boundaries of the pancreas. Only about 10% of patients are resectable.

Jaundice will be a significant problem in these patients as the disease progresses. Advances in endoscopic palliative therapy have been significant and stents can now be inserted by skilled hands endoscopically or transhepatically in the biliary system but are associated with complications and primarily have role in those patients who have a short term prognosis (Costamagna 2004).

Many patients will still have laparotomy but are then found to be unresectable. A surgical biliary bypass is then advisable and an operative bypass of the hepatic or common duct is preferred over the gallbladder (Nagorney 1999). If there is no gastric outlet obstruction at that stage the value of a prophylactic gastric bypass is debated but it is well documented that a significant number of those patients who have longer prognosis and initially have only a biliary bypass will later develop gastroduodenal obstruction and will need a second intervention (Gudjonsson 1987).

When a gastroduodenal obstruction occurs later in patients with biliary endoscopic stents, operative gastrojejunostomy may be required, but progress continues in both laparoscopic gastrojejunostomies and also insertion of duodenal stents (Maetani 2004).

Pain is in most cases a major problem. If a laparotomy is performed an intraoperative chemical neurolytic splanchnic block should be done (Lillemoe 1999).

In non-operated patients progress is being made in performing percutaneous, transthoracic (thoracoscopic) splanchnicectomy and endoscopic ultrasonographic splanchnic plexus blocks.

The value of a laparotomy should not be underestimated as by then biopsy, biliary-, gastroduodenalbypass and splanchnic resection can be accomplished (Mann 2009).

Resection is claimed by many to be the only chance of "cure", but is only applicable in 10% of cases. Survival statistics based only on resected patients with actuarial methods and significant censoring are misleading (Yeo 1995, Gudjonssn 2009).

Resections were initially fraught with a high mortality rate but that has certainly decreased at the relatively few centres with high volume, though morbidity is still high.

The poor results of resections is not surprising considering that even in those who are considered resectable, 20-50% of resection margins are positive for cancer (Willet 1993) and nodes are positive in up to 80% of cases and tumor cells can be found in the bone marrow in up to 50% of cases (Z'graggen 2001). Biopsy proof should be mandatory before resections are performed. Radical cancer surgery of 6-10 hours duration for chronic pancreatitis is not justified.

An occasional resected patient may certainly survive 5 years but will then most likely be reported over and over in the literature (Gudjonsson 2009).

Half of those who survive 5 years after resections have recurrence of cancer (Conlon 1996). The post op course of resected patients is not smooth and they may need many readmissions to hospitals (Gudjonsson 1995, Reddy 2009). The value of resections as palliation is unproven.

True cure of pancreatic cancer after resection is exceptional.

#### **11. Chemotherapy**

210 Pancreatic Cancer – Clinical Management

Earlier on approximately 80% of patients would have had a surgical laparotomy after imaging studies and in a third of those only a biopsy would have been feasible. Half of those operated on would have had a biliary bypass performed and some of those also a gastric

Now laparoscopy is increasingly used to stage the extent of disease and obtain a biopsy (Nagorney 1999). Either method would reveal that in 2/3 of established cases the tumor would be located in the head of the pancreas and one third in the body and/or tail and have progressed beyond the boundaries of the pancreas. Only about 10% of patients are

Jaundice will be a significant problem in these patients as the disease progresses. Advances in endoscopic palliative therapy have been significant and stents can now be inserted by skilled hands endoscopically or transhepatically in the biliary system but are associated with complications and primarily have role in those patients who have a short term prognosis

Many patients will still have laparotomy but are then found to be unresectable. A surgical biliary bypass is then advisable and an operative bypass of the hepatic or common duct is preferred over the gallbladder (Nagorney 1999). If there is no gastric outlet obstruction at that stage the value of a prophylactic gastric bypass is debated but it is well documented that a significant number of those patients who have longer prognosis and initially have only a biliary bypass will later develop gastroduodenal obstruction and will need a second

When a gastroduodenal obstruction occurs later in patients with biliary endoscopic stents, operative gastrojejunostomy may be required, but progress continues in both laparoscopic

Pain is in most cases a major problem. If a laparotomy is performed an intraoperative

In non-operated patients progress is being made in performing percutaneous, transthoracic (thoracoscopic) splanchnicectomy and endoscopic ultrasonographic splanchnic plexus

The value of a laparotomy should not be underestimated as by then biopsy, biliary-,

Resection is claimed by many to be the only chance of "cure", but is only applicable in 10% of cases. Survival statistics based only on resected patients with actuarial methods and

Resections were initially fraught with a high mortality rate but that has certainly decreased

The poor results of resections is not surprising considering that even in those who are considered resectable, 20-50% of resection margins are positive for cancer (Willet 1993) and nodes are positive in up to 80% of cases and tumor cells can be found in the bone marrow in

gastroduodenalbypass and splanchnic resection can be accomplished (Mann 2009).

at the relatively few centres with high volume, though morbidity is still high.

gastrojejunostomies and also insertion of duodenal stents (Maetani 2004).

chemical neurolytic splanchnic block should be done (Lillemoe 1999).

significant censoring are misleading (Yeo 1995, Gudjonssn 2009).

bypass with 5-10% undergoing only a gastric bypass (Brooks 1976).

**10. Operative findings** 

resectable.

blocks.

(Costamagna 2004).

intervention (Gudjonsson 1987).

Cancer of the pancreas is a very chemoresistant disease. Gemcitabine and 5 fluoruracil have been used in different forms in numerous trials of resected and nonresected patients and may add to quality of life and prolong life and exceptionally contribute to 5-year survival (Neoptolemos 2004).

Radiation therapy has been used pre- intra- and postoperatively in various forms alone or in conjunction with chemotherapy but has not had any significant effect on survival.

Novel diagnostic and therapeutic approach is needed (Yokoyama 2009).

#### **12. References**


Cowgill SM, Muscarella P. The genetics of pancreatic cancer. Am J Surg 2003; 186:279-286.


**13**

*USA* 

**Endoscopic Management of Pancreatic Cancer:** 

Pancreatic cancer is the fourth leading cause of cancer death in the U.S. According to the Surveillance Epidemiology and End Results (SEER) program, the median age at diagnosis between 2003-2007 was 72 years of age, and the incidence of new cases diagnosed during this period in all races was 13.3 per 100,000 men and 10.5 per 100,000 women. The median age at death for pancreatic cancer during the same period was 73 years of age, and the mortality rate for all races was 12.3 per 100,000 men and 9.4 per 100,000 women. Pancreatic cancer has a 22.5% 5-year survival rate when localized to the pancreas at diagnosis, and it decreases to 1.9% when metastasized. The lifetime risk to develop pancreatic cancer is 1.41%, and it is the same for men and women. (National Cancer Institute, 2011) Different types of pancreatic cancers originate from different type of pancreatic cells. About 95% of pancreatic cancers originate from exocrine cells. Of these, the most common is pancreatic adenocarcinoma (about 95%). Other less common types of exocrine tumors are: adenosquamous carcinomas, squamous cell carcinomas, giant cell carcinomas, intraductal papillary mucinous neoplasms (IPMN), mucinous cystadenocarcinoma, pancreatoblastoma, cystadenocarcinoma and pseudopapillary tumors. About 5% of pancreatic cancers originate from endocrine cells, and are known as pancreatic neuroendocrine tumors (NETs). Each of these tumors is named according to the hormone they produce: insulinomas, glucagonomas, gastrinomas, somatostatinomas, VIPomas. (American Cancer Society, 2011) Cystic pancreatic lesions are common and have a wide range of malignant potential. These lesions include, but are not limited to, serous cystadenomas (low potential for malignancy), mucinous cystic neoplasms, and IPMN. Based on the degree of dysplasia, these neoplasms are classified into benign (adenomatous), low-grade malignant (borderline) and malignant (carcinoma in situ and

Pancreatic cancer must be managed with a multidisciplinary approach. Endoscopy has a primary role in the diagnosis and staging of pancreatic cancer. Endoscopic ultrasound (EUS) is the most frequently used modality for this purpose. Treatment with curative intention involves surgery, with adjuvant therapy (chemotherapy and/ or radiation) in some cases. Most cases are diagnosed when curative resection is not possible. Technologic developments have introduced new endoscopic approaches to the palliation of these

**1. Introduction** 

invasive cancer). (Brugge et al, 2004)

advanced cases.

**From Diagnosis to Palliative Therapy** 

Erika Madrigal and Jennifer Chennat

*University of Chicago,* 

Gudjonsson B. Pancreatic cancer: survival, errors and evidence. Eur J Gastroenterol Hepatol 2009; 21: 1379-1382.

Lillemoe KD. Palliation of pain: Operation. J Gastrointest Surg 1999; 3:345-347.


Jemal A, Siegel R, Xu J, et al. Cancer Statistics, 2010. CA: A Cancer J Clin 2010; 60:277-300.

### **Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy**

Erika Madrigal and Jennifer Chennat *University of Chicago, USA* 

#### **1. Introduction**

212 Pancreatic Cancer – Clinical Management

Gudjonsson B. Pancreatic cancer: survival, errors and evidence. Eur J Gastroenterol Hepatol

Lee JK, Kim AY, Kim PN, et al. Prediction of vascular involvement and respectability by

Lockhart AC, Rothenberg ML, Berlin JD. Treatment for pancreatic cancer: Current therapy

Maetani I, Tada T, Ukita T, et al. Comparison of duodenal stent placement with surgical

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Nagorney DM, et al. Management of unresectable pancreatic duct cancer. The SSAT, AGA, AASLD, ASGE, AHPBA concensus panel. J Gastrointest Surg 1999; 3:331-332. Neoptolemos JP, Stocken DD, Friess H, et al. A randomised trial of chemotherapy after

Reddy DM, Townsend Jr, Kuo Y-F, et al. Readmission after pancreatectomy for pancreatic cancer in Medicare patients. J Gastrointest Surg 2009; 13: 1963-1975. Willett CG, Lewandrowski K, Warshaw AL, et al. Resection margins in carcinoma of the

Yeo CJ, Pitt HA, Cameron JL, et al. Pancreaticoduodenectomy for cancer of the head of the

Yokoyama Y, Mimura Y, Nagino M. Advances in the treatment of pancreatic cancer:

Z'graggen K, Centeno BA, Fernandez-del Castillo C. Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients. Surgery 2001; 129:537-546.

resection of pancreatic cancer. N Engl J Med 2004; 350: 1200-1210.

pancreas: 201 patients. Ann Surg 1995; 221:721-733.

multidetector-row CT versus MR imaging with MR angiography in patients who underwent surgery for resection of pancreatic ductal adenocarcinoma. Eur J

gastrojejunostomy for palliation in patients with duodenal obstruction caused by

procedure as effective palliation for unresectable malignant disease. ANZ J Surg

head of the pancreas: Implications for radiation therapy. Ann Surg; 1993; 217:144-

limitations of surgery and evaluation of new therapeutic strategies. Surg Today

Jemal A, Siegel R, Xu J, et al. Cancer Statistics, 2010. CA: A Cancer J Clin 2010; 60:277-300.

Lillemoe KD. Palliation of pain: Operation. J Gastrointest Surg 1999; 3:345-347.

and continued progress. Gastroenterology 2005; 128:1642-1654.

pancreaticobiliary malignancies. Endoscopy 2004; 36:73-78.

2009; 21: 1379-1382.

2009; 79: 471-475.

2009; 39: 466-475.

148.

Radiology 2010; 73: 310-316.

Pancreatic cancer is the fourth leading cause of cancer death in the U.S. According to the Surveillance Epidemiology and End Results (SEER) program, the median age at diagnosis between 2003-2007 was 72 years of age, and the incidence of new cases diagnosed during this period in all races was 13.3 per 100,000 men and 10.5 per 100,000 women. The median age at death for pancreatic cancer during the same period was 73 years of age, and the mortality rate for all races was 12.3 per 100,000 men and 9.4 per 100,000 women. Pancreatic cancer has a 22.5% 5-year survival rate when localized to the pancreas at diagnosis, and it decreases to 1.9% when metastasized. The lifetime risk to develop pancreatic cancer is 1.41%, and it is the same for men and women. (National Cancer Institute, 2011) Different types of pancreatic cancers originate from different type of pancreatic cells. About 95% of pancreatic cancers originate from exocrine cells. Of these, the most common is pancreatic adenocarcinoma (about 95%). Other less common types of exocrine tumors are: adenosquamous carcinomas, squamous cell carcinomas, giant cell carcinomas, intraductal papillary mucinous neoplasms (IPMN), mucinous cystadenocarcinoma, pancreatoblastoma, cystadenocarcinoma and pseudopapillary tumors. About 5% of pancreatic cancers originate from endocrine cells, and are known as pancreatic neuroendocrine tumors (NETs). Each of these tumors is named according to the hormone they produce: insulinomas, glucagonomas, gastrinomas, somatostatinomas, VIPomas. (American Cancer Society, 2011) Cystic pancreatic lesions are common and have a wide range of malignant potential. These lesions include, but are not limited to, serous cystadenomas (low potential for malignancy), mucinous cystic neoplasms, and IPMN. Based on the degree of dysplasia, these neoplasms are classified into benign (adenomatous), low-grade malignant (borderline) and malignant (carcinoma in situ and invasive cancer). (Brugge et al, 2004)

Pancreatic cancer must be managed with a multidisciplinary approach. Endoscopy has a primary role in the diagnosis and staging of pancreatic cancer. Endoscopic ultrasound (EUS) is the most frequently used modality for this purpose. Treatment with curative intention involves surgery, with adjuvant therapy (chemotherapy and/ or radiation) in some cases. Most cases are diagnosed when curative resection is not possible. Technologic developments have introduced new endoscopic approaches to the palliation of these advanced cases.

Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 215

utility in the diagnosis of pancreatic cancer and other gastrointestinal malignancies, as it

EUS is contraindicated in those circumstances where the lesion cannot be clearly visualized, presence of an interposed vessel in the path between the needle and the target lesion,

allows the etiological diagnosis by tissue acquisition by fine needle aspiration (FNA).

Fig. 2. FNA of a lymph node found during diagnostic EUS in 59 year-old male with

Radial and curve linear array echoendoscopes are available for EUS. Radial echoendoscopes provide a circumferential view at right angle to the shaft of the scope, similar to those provided by CT. The linear array echoendoscope generates longitudinal sector images parallel to the axis of the endoscope giving a 120° to 180° scanning view. The linear echoendoscope also has an instrument channel that ranges in size (2.0 to 3.8mm) and allows not only histological biopsies to be taken by FNA, but also therapeutic interventions that will be discussed later in this chapter. (Yamao et al, 2009; Hawes & Fockens, 2006) EUS-FNA needles can be locked in a fixed position on the echoendoscope and advanced into the lesion by the endoscopist under ultrasonographic guidance. Needle sizes available are 19, 22 and 25 gauge, and allow for a depth of penetration of up to 10cm. A 19 gauge trucut needle is also commercially available and allows for the specimens to be processed for immunohistochemical and gene analysis. (Yamao et al, 2009) The 25 gauge needle has the

metastatic pancreatic adenocarcinoma.

bleeding diathesis and risk of tumor seeding. (Yamao et al, 2009)

This chapter will cover the endoscopic technology currently available for diagnosis, staging and palliation of pancreatic cancer. Promising interventional techniques for the diagnosis and palliation of this neoplasia are currently under development and improvement and will also be discussed here.

#### **2. Diagnosis and staging**

The imaging modalities involved in the diagnosis and staging of pancreatic cancer include Computed Tomography (CT), Magnetic Resonance Imaging (MRI), EUS and Endoscopic Retrograde Cholangiopancreatography (ERCP). Only the endoscopic modalities, EUS and ERCP, will be reviewed here.

Fig. 1. 55 year-old male with a pancreatic mass found in abdominal CT during work up of abdominal pain and weight loss. EUS revealed a 2.5cm mass located at the neck of the pancreas.

EUS is a combination of endoscopy and intraluminal ultrasound that allows the introduction of high frequency ultrasound waves in the gastrointestinal tract to visualize the wall and adjacent structures. It is considered the procedure of choice for the diagnosis and staging of pancreatic cancer. High resolution endosonographic images can be obtained due to the short distance between the probe and the target lesion. It has become an accepted modality for the diagnosis of pancreato-biliary diseases. (Yamao et al, 2009) EUS has great

This chapter will cover the endoscopic technology currently available for diagnosis, staging and palliation of pancreatic cancer. Promising interventional techniques for the diagnosis and palliation of this neoplasia are currently under development and improvement and will

The imaging modalities involved in the diagnosis and staging of pancreatic cancer include Computed Tomography (CT), Magnetic Resonance Imaging (MRI), EUS and Endoscopic Retrograde Cholangiopancreatography (ERCP). Only the endoscopic modalities, EUS and

Fig. 1. 55 year-old male with a pancreatic mass found in abdominal CT during work up of abdominal pain and weight loss. EUS revealed a 2.5cm mass located at the neck of the

EUS is a combination of endoscopy and intraluminal ultrasound that allows the introduction of high frequency ultrasound waves in the gastrointestinal tract to visualize the wall and adjacent structures. It is considered the procedure of choice for the diagnosis and staging of pancreatic cancer. High resolution endosonographic images can be obtained due to the short distance between the probe and the target lesion. It has become an accepted modality for the diagnosis of pancreato-biliary diseases. (Yamao et al, 2009) EUS has great

also be discussed here.

**2. Diagnosis and staging** 

ERCP, will be reviewed here.

pancreas.

utility in the diagnosis of pancreatic cancer and other gastrointestinal malignancies, as it allows the etiological diagnosis by tissue acquisition by fine needle aspiration (FNA).

EUS is contraindicated in those circumstances where the lesion cannot be clearly visualized, presence of an interposed vessel in the path between the needle and the target lesion, bleeding diathesis and risk of tumor seeding. (Yamao et al, 2009)

Fig. 2. FNA of a lymph node found during diagnostic EUS in 59 year-old male with metastatic pancreatic adenocarcinoma.

Radial and curve linear array echoendoscopes are available for EUS. Radial echoendoscopes provide a circumferential view at right angle to the shaft of the scope, similar to those provided by CT. The linear array echoendoscope generates longitudinal sector images parallel to the axis of the endoscope giving a 120° to 180° scanning view. The linear echoendoscope also has an instrument channel that ranges in size (2.0 to 3.8mm) and allows not only histological biopsies to be taken by FNA, but also therapeutic interventions that will be discussed later in this chapter. (Yamao et al, 2009; Hawes & Fockens, 2006) EUS-FNA needles can be locked in a fixed position on the echoendoscope and advanced into the lesion by the endoscopist under ultrasonographic guidance. Needle sizes available are 19, 22 and 25 gauge, and allow for a depth of penetration of up to 10cm. A 19 gauge trucut needle is also commercially available and allows for the specimens to be processed for immunohistochemical and gene analysis. (Yamao et al, 2009) The 25 gauge needle has the

Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 217

2010; Yasuda et al, 1988; DeWitt et al, 2004; Chhieng et al, 2002; Eloubeidi & Tamhane, 2005) The operating characteristics of EUS-FNA of solid pancreatic masses in 547 patients were: sensitivity 95%, specificity 92%, positive predictive value 98% and negative predictive value 80%, with and overall accuracy of 94.1%. (Eloubeidi et al, 2007) Such accuracy numbers allow for preoperative counseling of patients, minimizing surgeon's operative time in cases of unresectable disease, and avoiding surgical biopsies in those with inoperable disease, also allowing for conservative management of patients with benign pathology results. (Eloubeidi

To compare the diagnostic yield and complication rates of 22 gauge and 25 gauge needles during EUS-FNA of solid pancreatic masses, a group prospectively randomized 131 patients with suspected pancreatic lesions. (Siddiqui et al, 2009) EUS-FNA with 22 gauge needle was performed in 64 patients and 25 gauge needle was used in 67 patients. Overall, cytology was diagnostic in 120 of 131 patients (91.6%): 87.5% with 22 gauge and 95.5% with 25 gauge. The difference was not statistically different (p=0.18) but there was a trend toward a higher accuracy with the 25 gauge. A similar number of passes was performed in both groups and

The 19 gauge Trucut biopsy needle contains an 18mm long specimen tray that acquires larger tissue samples while preserving tissue architecture to allow histologic examination. (Levy, 2007) It was introduced in 2002 and overcomes certain limitations of the FNA needle: certain tumors (stromal tumors, lymphomas and well-differentiated pancreatic tumors) are difficult to diagnose based on cytology alone and the diagnosis accuracy relies on immediate review of the specimen for sampling adequacy by an on-site cytopathologist. When used in conjunction with an echoendoscope, these large caliber needles procure larger specimens for histopathological analysis by means of EUS trucut needle biopsy (EUS-TNB). (Varadarajulu et al 2004) A tissue core sample has several advantages: better distinction between well-differentiated adenocarcinoma and chronic pancreatitis, which accounts for both false-positive and false-negative FNA results; appropriate cellular sub-typing and architectural analysis in the diagnosis of lymphoma, as well as use of special stains, all of which are of limited usefulness with FNA specimens; and elimination of the need for a cytopathologist to assess specimen adequacy, thereby reducing duration and cost of the procedure. (Larghi et al, 2004) A pilot study for the 19 gauge Trucut needle included 18 patients undergoing EUS-FNA and EUS-TNB of different lesions (11 mediastinal masses, 3 pancreatic masses, 3 gastric tumor/ cyst/ lymphoma, and 1 adrenal mass). There was no significant difference in the adequacy of the specimens for evaluation (83% vs. 100% adequate specimens in EUS-TNB and EUS-FNA respectively), or in the diagnostic accuracy of EUS-TNB from EUS-FNA (78% vs. 89% respectively). Two complications were encountered: one patient required surgery for mediastinitis and another patient was managed conservatively for immediate bleeding. (Varadarajulu et al 2004) A group in London prospectively evaluated the safety and accuracy of EUS-FNA alone vs. combined EUS-FNA and EUS-TNB (EUS-FNA/TNB). (Wittmann et al 2006) A total of 159 patients underwent EUS-FNA alone (lesions < 2cm) or the combination of both modalities (lesions of 2cm or more). Adequate samples were obtained in 91%, 88% and 97% by EUS-FNA, EUS-TNB and EUS-FNA/TNB respectively. From the pancreas (n = 83), adequate samples were obtained by FNA in 94% and by TNB in 81%, compared with 87% and 92% from nonpancreatic sites (n = 76) respectively. Overall accuracy for EUS-FNA alone was 77%, for

et al, 2007)

no complications were reported in either arm.

advantage of being more flexible and passes through the tissue more easily, however is less echogenic and can be more difficult to visualize during FNA. In the other hand, the stiffness of the 22 gauge needle produces less distortion and probably allows for firmer pressure to be applied. (Hawes, 2010a)

Fig. 3. 55 year-old male with pancreatic neck mass. EUS-FNA was performed and cytology was consistent with adenocarcinoma.

Prior to the development of EUS-FNA, pancreatic FNA or core biopsy were performed either during surgery or percutaneously under US or CT guidance. Intra-operative sampling considerably increases the operating time, and the percutaneous approach has reported sensitivity of about 80%, but at the expense of possible needle-track seeding. (Bret et al, 1986; Ferrucci et al, 1979; Smith et al, 1980; Caturelli et al, 1985) EUS-FNA is associated with high rates of adequate tissue sampling and diagnostic accuracy. A prospective study in 457 patients undergoing EUS-FNA in 554 lesions revealed a sensitivity, specificity, and accuracy of 92%, 93%, and 92% for lymph nodes, 88%, 95%, and 90% for extraluminal masses, and 61%, 79% and 67% for gastrointestinal wall lesions, respectively. (Wiersema et al, 1997) DeWitt summarized the reports of multiple authors on FNA of pancreatic tumors and reported the accuracy, sensitivity and specificity to be 88%, 85% and 98%, respectively in among nearly 1700 patients (DeWitt, 2006, as cited in Hawes & Fockens, 2006). Summarizing the results of 23 studies including 1,096 patients over a 21-year period, the sensitivity of EUS for the detection of a pancreatic mass was in the range of 85-100%. (Al-Haddad & Eloubeidi,

advantage of being more flexible and passes through the tissue more easily, however is less echogenic and can be more difficult to visualize during FNA. In the other hand, the stiffness of the 22 gauge needle produces less distortion and probably allows for firmer pressure to

Fig. 3. 55 year-old male with pancreatic neck mass. EUS-FNA was performed and cytology

Prior to the development of EUS-FNA, pancreatic FNA or core biopsy were performed either during surgery or percutaneously under US or CT guidance. Intra-operative sampling considerably increases the operating time, and the percutaneous approach has reported sensitivity of about 80%, but at the expense of possible needle-track seeding. (Bret et al, 1986; Ferrucci et al, 1979; Smith et al, 1980; Caturelli et al, 1985) EUS-FNA is associated with high rates of adequate tissue sampling and diagnostic accuracy. A prospective study in 457 patients undergoing EUS-FNA in 554 lesions revealed a sensitivity, specificity, and accuracy of 92%, 93%, and 92% for lymph nodes, 88%, 95%, and 90% for extraluminal masses, and 61%, 79% and 67% for gastrointestinal wall lesions, respectively. (Wiersema et al, 1997) DeWitt summarized the reports of multiple authors on FNA of pancreatic tumors and reported the accuracy, sensitivity and specificity to be 88%, 85% and 98%, respectively in among nearly 1700 patients (DeWitt, 2006, as cited in Hawes & Fockens, 2006). Summarizing the results of 23 studies including 1,096 patients over a 21-year period, the sensitivity of EUS for the detection of a pancreatic mass was in the range of 85-100%. (Al-Haddad & Eloubeidi,

be applied. (Hawes, 2010a)

was consistent with adenocarcinoma.

2010; Yasuda et al, 1988; DeWitt et al, 2004; Chhieng et al, 2002; Eloubeidi & Tamhane, 2005) The operating characteristics of EUS-FNA of solid pancreatic masses in 547 patients were: sensitivity 95%, specificity 92%, positive predictive value 98% and negative predictive value 80%, with and overall accuracy of 94.1%. (Eloubeidi et al, 2007) Such accuracy numbers allow for preoperative counseling of patients, minimizing surgeon's operative time in cases of unresectable disease, and avoiding surgical biopsies in those with inoperable disease, also allowing for conservative management of patients with benign pathology results. (Eloubeidi et al, 2007)

To compare the diagnostic yield and complication rates of 22 gauge and 25 gauge needles during EUS-FNA of solid pancreatic masses, a group prospectively randomized 131 patients with suspected pancreatic lesions. (Siddiqui et al, 2009) EUS-FNA with 22 gauge needle was performed in 64 patients and 25 gauge needle was used in 67 patients. Overall, cytology was diagnostic in 120 of 131 patients (91.6%): 87.5% with 22 gauge and 95.5% with 25 gauge. The difference was not statistically different (p=0.18) but there was a trend toward a higher accuracy with the 25 gauge. A similar number of passes was performed in both groups and no complications were reported in either arm.

The 19 gauge Trucut biopsy needle contains an 18mm long specimen tray that acquires larger tissue samples while preserving tissue architecture to allow histologic examination. (Levy, 2007) It was introduced in 2002 and overcomes certain limitations of the FNA needle: certain tumors (stromal tumors, lymphomas and well-differentiated pancreatic tumors) are difficult to diagnose based on cytology alone and the diagnosis accuracy relies on immediate review of the specimen for sampling adequacy by an on-site cytopathologist. When used in conjunction with an echoendoscope, these large caliber needles procure larger specimens for histopathological analysis by means of EUS trucut needle biopsy (EUS-TNB). (Varadarajulu et al 2004) A tissue core sample has several advantages: better distinction between well-differentiated adenocarcinoma and chronic pancreatitis, which accounts for both false-positive and false-negative FNA results; appropriate cellular sub-typing and architectural analysis in the diagnosis of lymphoma, as well as use of special stains, all of which are of limited usefulness with FNA specimens; and elimination of the need for a cytopathologist to assess specimen adequacy, thereby reducing duration and cost of the procedure. (Larghi et al, 2004) A pilot study for the 19 gauge Trucut needle included 18 patients undergoing EUS-FNA and EUS-TNB of different lesions (11 mediastinal masses, 3 pancreatic masses, 3 gastric tumor/ cyst/ lymphoma, and 1 adrenal mass). There was no significant difference in the adequacy of the specimens for evaluation (83% vs. 100% adequate specimens in EUS-TNB and EUS-FNA respectively), or in the diagnostic accuracy of EUS-TNB from EUS-FNA (78% vs. 89% respectively). Two complications were encountered: one patient required surgery for mediastinitis and another patient was managed conservatively for immediate bleeding. (Varadarajulu et al 2004) A group in London prospectively evaluated the safety and accuracy of EUS-FNA alone vs. combined EUS-FNA and EUS-TNB (EUS-FNA/TNB). (Wittmann et al 2006) A total of 159 patients underwent EUS-FNA alone (lesions < 2cm) or the combination of both modalities (lesions of 2cm or more). Adequate samples were obtained in 91%, 88% and 97% by EUS-FNA, EUS-TNB and EUS-FNA/TNB respectively. From the pancreas (n = 83), adequate samples were obtained by FNA in 94% and by TNB in 81%, compared with 87% and 92% from nonpancreatic sites (n = 76) respectively. Overall accuracy for EUS-FNA alone was 77%, for

Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 219

between malignant and benign PETs. (Ishikawa et al, 2010) This group retrospectively studied 62 pathologically confirmed PETs found in 41 patients who had undergone EUS, multiphasic multidetector computed tomography (MDCT) and transabdominal ultrasound (US). Contrast-enhanced EUS had 95% sensitivity in identifying PETs compared with 80% with MDCT and 45% with US. Heterogeneous ultrasonographic texture was the most significant factor for malignancy. It was also noted that when contrast was used with EUS, PETs showed contrast enhancement except in areas of hemorrhage or necrosis. The optimal use of elastography and contrast enhanced EUS would be to define an optimal target area

Cystic pancreatic lesions are commonly found nowadays given the development and availability of different imaging tests that are often performed for unrelated reasons. Cystic lesions are sometimes difficult to diagnose. Cross-sectional imaging is often non-diagnostic due to the small size of the cystic lesions. EUS has become useful for the diagnosis of these lesions as it provides high resolution images and allows the performance of FNA of the cystic fluid for cytology and tumor marker determinations. A large, prospective multicenter study looking at the imaging, cyst fluid cytology and cyst fluid tumor markers found that

Fig. 4. The picture demonstrates one of the multiple peri-pancreatic lymph nodes found in a patient with metastatic pancreatic adenocarcinoma. The largest measured 25mm. FNA of the lymph node was performed and cytology was consistent with poorly differentiated

adenocarcinoma.

within a pancreatic mass to maximize the cytologic yield. (Hawes, 2010)

EUS-TNB alone 73% and for EUS-FNA/TNB 91% (p = 0.008). For pancreatic sampling, the accuracy of FNA alone was 77%, for TNB alone was 56% and for FNA/TNB 83%. For nonpancreatic sampling, the accuracy for EUS-FNA alone was 78%, for EUS-TNB alone 83% and for EUS-FNA/TNB 95% (p = 0.006). The complication rate was 0.6% (one patient with moderate self-limited abdominal pain and another patient with bile leak requiring endoscopic stent replacement). Another group prospectively enrolled 247 patients to determine factors predicting a positive diagnostic yield and the safety of EUS-TBN. (Thomas et al, 2009) The lesions sampled were in the pancreas (113), esophagogastric wall (34), and extrapancreatic areas (100; 52 of those were lymph nodes). The overall accuracy was 75%. The overall complication rate was 2% (bronchopneumonia, minor hemoptysis, minor hematemesis, mucosal tear, retropharyngeal abscess) with no procedure-related deaths. A higher diagnostic yield was found when the lesion was approached through the stomach and when more than two passes were made. With the aim of comparing EUS-FNA using 25 gauge and 22 gauge needles with the EUS guided 19 gauge Trucut needle in solid pancreatic mass, a group in Japan prospectively enrolled 24 patients. (Sakamoto et al, 2009) The 25 gauge EUS-FNA was technically easier and obtained superior overall diagnostic accuracy, especially in lesions of the pancreas head and uncinate process. Overall accuracy for the 25 gauge, 22 gauge and Trucut needle was 91.7%, 79.7% and 54.1%, respectively. Accuracy for cytological diagnosis irrespective the site of lesions with 25 gauge, 22 gauge and Trucut needles was 91.7%, 75% and 45.8%, respectively. For uncinate masses, it was 100%, 33.3%, and 0% respectively.

Most endosonographers consider EUS-FNA the procedure of choice for sampling of pancreatic masses, however, EUS-TNB has a role in selected settings. The most clear advantage of EUS-TNB over EUS-FNA is in the diagnosis of disorders for which histology is necessary and cytology is inadequate, such as autoimmune pancreatitis and chronic 'nonspecific' pancreatitis. For other pancreatic disorders including cystic pancreatic tumors, islet cell tumors, secondary metastatic solid pancreatic tumor, and primary solid pancreatic tumors, EUS-TNB and EUS-FNA have often complementary roles. (Levy, 2007)

Pancreatic masses found in the background of chronic pancreatitis present a particular challenge to endoscopists. Better methods to detect pancreatic tumors in this setting and to better target the fine needle aspiration within a pancreatic mass to optimize sampling are needed. The development of image enhancing techniques and/or the use of contrast agents may fulfill these needs. Elastography is a method for real-time evaluation of tissue stiffness. Elastography uses a hue color map (red-green-blue) to display tissue stiffness: hard or stiff tissue is shown in dark blue, medium hard tissue areas in cyan, intermediate hardness tissue areas in green, medium soft tissue areas in yellow and soft tissue in red. (Hawes, 2010) A group from Spain reported the use of EUS elastography for the characterization of solid pancreatic masses in 130 patients and compared them with 20 normal controls. Four elastographic patterns were described, with high concordance among the 2 blinded investigators. A green-predominant pattern (homogeneous or not) excluded malignancy with high accuracy whereas a blue-predominant pattern (homogeneous or heterogeneous) supported a malignancy diagnosis. Sensitivity, specificity and overall accuracy for the diagnosis of malignancy were 100%, 85.5% and 94% respectively. (Iglesias-Garcia et al, 2009) A Japanese group investigated the usefulness of EUS combined with contrast enhancement in the preoperative localization of pancreatic endocrine tumors (PET) and the differentiation

EUS-TNB alone 73% and for EUS-FNA/TNB 91% (p = 0.008). For pancreatic sampling, the accuracy of FNA alone was 77%, for TNB alone was 56% and for FNA/TNB 83%. For nonpancreatic sampling, the accuracy for EUS-FNA alone was 78%, for EUS-TNB alone 83% and for EUS-FNA/TNB 95% (p = 0.006). The complication rate was 0.6% (one patient with moderate self-limited abdominal pain and another patient with bile leak requiring endoscopic stent replacement). Another group prospectively enrolled 247 patients to determine factors predicting a positive diagnostic yield and the safety of EUS-TBN. (Thomas et al, 2009) The lesions sampled were in the pancreas (113), esophagogastric wall (34), and extrapancreatic areas (100; 52 of those were lymph nodes). The overall accuracy was 75%. The overall complication rate was 2% (bronchopneumonia, minor hemoptysis, minor hematemesis, mucosal tear, retropharyngeal abscess) with no procedure-related deaths. A higher diagnostic yield was found when the lesion was approached through the stomach and when more than two passes were made. With the aim of comparing EUS-FNA using 25 gauge and 22 gauge needles with the EUS guided 19 gauge Trucut needle in solid pancreatic mass, a group in Japan prospectively enrolled 24 patients. (Sakamoto et al, 2009) The 25 gauge EUS-FNA was technically easier and obtained superior overall diagnostic accuracy, especially in lesions of the pancreas head and uncinate process. Overall accuracy for the 25 gauge, 22 gauge and Trucut needle was 91.7%, 79.7% and 54.1%, respectively. Accuracy for cytological diagnosis irrespective the site of lesions with 25 gauge, 22 gauge and Trucut needles was 91.7%, 75% and 45.8%, respectively. For uncinate masses, it was 100%, 33.3%,

Most endosonographers consider EUS-FNA the procedure of choice for sampling of pancreatic masses, however, EUS-TNB has a role in selected settings. The most clear advantage of EUS-TNB over EUS-FNA is in the diagnosis of disorders for which histology is necessary and cytology is inadequate, such as autoimmune pancreatitis and chronic 'nonspecific' pancreatitis. For other pancreatic disorders including cystic pancreatic tumors, islet cell tumors, secondary metastatic solid pancreatic tumor, and primary solid pancreatic

Pancreatic masses found in the background of chronic pancreatitis present a particular challenge to endoscopists. Better methods to detect pancreatic tumors in this setting and to better target the fine needle aspiration within a pancreatic mass to optimize sampling are needed. The development of image enhancing techniques and/or the use of contrast agents may fulfill these needs. Elastography is a method for real-time evaluation of tissue stiffness. Elastography uses a hue color map (red-green-blue) to display tissue stiffness: hard or stiff tissue is shown in dark blue, medium hard tissue areas in cyan, intermediate hardness tissue areas in green, medium soft tissue areas in yellow and soft tissue in red. (Hawes, 2010) A group from Spain reported the use of EUS elastography for the characterization of solid pancreatic masses in 130 patients and compared them with 20 normal controls. Four elastographic patterns were described, with high concordance among the 2 blinded investigators. A green-predominant pattern (homogeneous or not) excluded malignancy with high accuracy whereas a blue-predominant pattern (homogeneous or heterogeneous) supported a malignancy diagnosis. Sensitivity, specificity and overall accuracy for the diagnosis of malignancy were 100%, 85.5% and 94% respectively. (Iglesias-Garcia et al, 2009) A Japanese group investigated the usefulness of EUS combined with contrast enhancement in the preoperative localization of pancreatic endocrine tumors (PET) and the differentiation

tumors, EUS-TNB and EUS-FNA have often complementary roles. (Levy, 2007)

and 0% respectively.

between malignant and benign PETs. (Ishikawa et al, 2010) This group retrospectively studied 62 pathologically confirmed PETs found in 41 patients who had undergone EUS, multiphasic multidetector computed tomography (MDCT) and transabdominal ultrasound (US). Contrast-enhanced EUS had 95% sensitivity in identifying PETs compared with 80% with MDCT and 45% with US. Heterogeneous ultrasonographic texture was the most significant factor for malignancy. It was also noted that when contrast was used with EUS, PETs showed contrast enhancement except in areas of hemorrhage or necrosis. The optimal use of elastography and contrast enhanced EUS would be to define an optimal target area within a pancreatic mass to maximize the cytologic yield. (Hawes, 2010)

Cystic pancreatic lesions are commonly found nowadays given the development and availability of different imaging tests that are often performed for unrelated reasons. Cystic lesions are sometimes difficult to diagnose. Cross-sectional imaging is often non-diagnostic due to the small size of the cystic lesions. EUS has become useful for the diagnosis of these lesions as it provides high resolution images and allows the performance of FNA of the cystic fluid for cytology and tumor marker determinations. A large, prospective multicenter study looking at the imaging, cyst fluid cytology and cyst fluid tumor markers found that

Fig. 4. The picture demonstrates one of the multiple peri-pancreatic lymph nodes found in a patient with metastatic pancreatic adenocarcinoma. The largest measured 25mm. FNA of the lymph node was performed and cytology was consistent with poorly differentiated adenocarcinoma.

Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 221

3cm of its length and a higher prevalence for the presence of side branches in the narrowed portions if the main pancreatic duct. (Nishino et al, 2010) The pancreatographic features suggestive of pancreatic cystic neoplasms include displacement of the pancreatic duct, pancreatic duct strictures, and the degree of pancreatic ductal obstruction. In the case of IPMN, the main pancreatic duct may be dilated diffusely or in a segment fashion depending on the volume of mucus produced, the presence of ductal obstruction and the presence and distribution of intraductal tumors. Enlargement of the main pancreatic duct is a frequent pancreatographic abnormality in IPMN, present in about 77% of patients; side branch ectasia or cystic dilation occurs in about 51% of the cases. (Telford & Carr-Locke, 2002)

Pancreatic juice and mucus can be aspirated directly from the pancreatic duct during ERCP, either by catheter or pancreatoscopy. Stimulation of pancreatic exocrine secretion by administration of secretin may improve the diagnostic yield. The samples are sent for cytology, as well as analysis of mucin, tumor marker levels, and amplification of molecular abnormalities. (Telford & Carr-Locke, 2002) Examination of the pancreatic juice collected during cannulation yielded positive results in 52.3% of pancreatic cancer patients. Higher positive rates were obtained when washing with saline (63.2%) and aspirating after secretin stimulation (51.3%), as well as in cases of pancreatic head cancer (70.6%). (Kameya et al, 1981) For IPMN, the specificity of the cytology of the pancreatic juice is 100%, and the sensitivity is 62.2% when collected by pancreatoscopy and 38.2% when collected by catheter.

Brush cytology of pancreatic duct strictures or elevated intraductal lesions during ERCP has a sensitivity and specificity to detect malignancy of 48-76% and 100%, respectively, and accuracy of 70-76.4%. (Telford & Carr-Locke, 2002; Chen 2007; Ferrari et al, 1994; Vandervoort et al, 1999; Uchida et al, 2007) Accuracy may be influenced by location of sampling within the pancreas, technical errors and interpretation of the sample. (Chen 2007) Strictures located at the head and body of the pancreas usually yield high rates of positive cytology. The diagnostic yield is overall enhanced by concomitant brushing of pancreatic and bile duct strictures. (McGuire et al, 1996) A retrospective study evaluating the diagnostic yield of combining EUS-FNA with brushing cytology during the work up of pancreatic cancer revealed that the combined use of these two modalities provides a better diagnostic yield in pancreatic adenocarcinoma than either one alone. The sensitivity, specificity and accuracy were 69.2, 93.8, and 77.3% for EUS-FNA alone, 50.8, 100, and 67% for brushing cytology alone, and 84.6, 100, and 89.7% for combination of EUS-FNA with brushing cytology. (Jing et al, 2009) A recent study to determine whether KRAS (protooncogene) mutations could be identified in pancreatobiliary stricture brushings and to compare the performance characteristics of KRAS mutation analysis to cytology and fluorescence in situ hybridization (FISH) for detection of carcinoma revealed that combined KRAS mutation and FISH analysis appear to increase the cancer detection rate in patients with pancreatobiliary strictures. The KRAS mutation and polysomic FISH (positive) results were identified in 69% and 63% pancreatic adenocarcinoma specimens, respectively, with a combined sensitivity of 86%. (Kipp et al, 2010) In the case of cysts, a new through the needle cytological brush system (Echo-Brush) seeks to solve the poor cellularity typically obtained by EUS-FNA. This system consists in the introduction of the brush through a 19 gauge EUS needle after aspiration of the cyst fluid. The brush is used to scrub the cystic wall and is processed as standard brushing. Studies have had conflicting results. A group from Spain found that the brush was superior to the aspirated fluid for detecting diagnostic cells but

(Chen 2007; Yamaguchi et al, 2005)

the cystic fluid CEA (using a cutoff value of 192 ng/ mL) was able to differentiate mucinous vs. nonmucinous cystic lesions with an accuracy of 79%, which was significantly higher than the accuracy of EUS morphology (51%) or fluid cytology (59%) (p<0.05). (Brugge et al, 2004b)

Staging of pancreatic malignancy is done according to the American Joint Committee for Cancer (AJCC) Staging TNM classification. This describes the tumor extension (T), lymph node (N) and distant metastases (M) of tumors, respectively. Accuracy of the T staging by EUS ranges from 63% to 94% and nodal (N) staging ranges from 41% to 86%, (DeWitt et al, 2004; Palazzo et al, 1993; Gress et al, 1999; Rivadeneira et al, 2003) which is superior to CT and trans abdominal ultrasound. (Palazzo et al, 1993; Gress et al, 1999; Rivadeneira et al, 2003; Agarwal et al, 2004) Comparative studies between EUS and cross-sectional imaging have generally shown that EUS is superior for local tumor staging (T and N) in esophageal, pancreatic and rectal cancer, but CT is still necessary for full assessment of metastatic disease. (Hawes, 2010) EUS, however, can be of value when evaluating for metastases. Part of the liver can be visualized by EUS and suspected metastatic lesions can be sampled. Celiac lymph nodes can also be biopsied if appearing suspicious and ascites can be aspirated and sent for cytology to assess for peritoneal metastases. (Al-Haddad & Eloubeidi, 2010)

EUS is associated with a low rate of complications. A study in 322 patients and 345 lesions revealed an overall complication risk of 1.6%. This study involved pancreatic EUS-FNA in 248 cases (134 solid lesions and 114 cystic lesions) and complications were observed in 4 (1.2%) patients with pancreatic cystic lesions (acute pancreatitis in 3, and aspiration pneumonia in 1). No complications resulted from FNA of solid pancreatic lesions. (O'Toole et al, 2001) Despite the low complication risk, life threatening complications have been sporadically reported: fulminant cholangitis after FNA of a liver metastasis and uncontrolled bleeding from a pseudoaneurysm after pancreatic FNA, (Erickson, 2004) massive bleeding from a gastric GIST (Inoue et al, 2006) and acute portal vein thrombosis after FNA of pancreatic cancer. (Matsumoto et al, 2003) A prospective cohort study in 355 patients evaluated the frequency of major complications following EUS-FNA of solid pancreatic masses and found major complications in 2.54% with acute pancreatitis developing in 3 patients (0.85%). (Eloubeidi et al, 2006)

ERCP played a major role in the diagnosis of pancreatic disease since its development in the late 1960s. However, the introduction and advances of imaging studies, especially MRCP, have shifted the ERCP applications toward therapeutic interventions. ERCP is seldom performed for diagnostic purposes, but it provides detailed opacification of the main and branch ducts (pancreatogram). The morphologic changes in the ductal system usually correlate with histologic changes. This is limited in the case of cysts that do not communicate with the pancreatic duct. ERCP also allows collection of pure pancreatic juice for cytology and gene analysis, brush cytology, biopsy of the pancreatic duct, and introduction of baby scopes or ultrasonic probes into the pancreatic duct for pancreatoscopy and intraductal ultrasound (IDUS), respectively. (Fujita et al, 2004)

Pancreatography can suggest the diagnosis of pancreatic cancer. A Japanese study comparing the pancreatographic findings of autoimmune pancreatitis and cancer revealed that an obstructed main pancreatic duct and an upstream duct dilation to a diameter greater than 4mm were significantly more common in cancer cases; meanwhile, autoimmune pancreatitis had a higher prevalence of narrowing of the main pancreatic duct for more than

the cystic fluid CEA (using a cutoff value of 192 ng/ mL) was able to differentiate mucinous vs. nonmucinous cystic lesions with an accuracy of 79%, which was significantly higher than the accuracy of EUS morphology (51%) or fluid cytology (59%) (p<0.05). (Brugge et al,

Staging of pancreatic malignancy is done according to the American Joint Committee for Cancer (AJCC) Staging TNM classification. This describes the tumor extension (T), lymph node (N) and distant metastases (M) of tumors, respectively. Accuracy of the T staging by EUS ranges from 63% to 94% and nodal (N) staging ranges from 41% to 86%, (DeWitt et al, 2004; Palazzo et al, 1993; Gress et al, 1999; Rivadeneira et al, 2003) which is superior to CT and trans abdominal ultrasound. (Palazzo et al, 1993; Gress et al, 1999; Rivadeneira et al, 2003; Agarwal et al, 2004) Comparative studies between EUS and cross-sectional imaging have generally shown that EUS is superior for local tumor staging (T and N) in esophageal, pancreatic and rectal cancer, but CT is still necessary for full assessment of metastatic disease. (Hawes, 2010) EUS, however, can be of value when evaluating for metastases. Part of the liver can be visualized by EUS and suspected metastatic lesions can be sampled. Celiac lymph nodes can also be biopsied if appearing suspicious and ascites can be aspirated and sent for cytology to assess for peritoneal metastases. (Al-Haddad & Eloubeidi, 2010)

EUS is associated with a low rate of complications. A study in 322 patients and 345 lesions revealed an overall complication risk of 1.6%. This study involved pancreatic EUS-FNA in 248 cases (134 solid lesions and 114 cystic lesions) and complications were observed in 4 (1.2%) patients with pancreatic cystic lesions (acute pancreatitis in 3, and aspiration pneumonia in 1). No complications resulted from FNA of solid pancreatic lesions. (O'Toole et al, 2001) Despite the low complication risk, life threatening complications have been sporadically reported: fulminant cholangitis after FNA of a liver metastasis and uncontrolled bleeding from a pseudoaneurysm after pancreatic FNA, (Erickson, 2004) massive bleeding from a gastric GIST (Inoue et al, 2006) and acute portal vein thrombosis after FNA of pancreatic cancer. (Matsumoto et al, 2003) A prospective cohort study in 355 patients evaluated the frequency of major complications following EUS-FNA of solid pancreatic masses and found major complications in 2.54% with acute pancreatitis

ERCP played a major role in the diagnosis of pancreatic disease since its development in the late 1960s. However, the introduction and advances of imaging studies, especially MRCP, have shifted the ERCP applications toward therapeutic interventions. ERCP is seldom performed for diagnostic purposes, but it provides detailed opacification of the main and branch ducts (pancreatogram). The morphologic changes in the ductal system usually correlate with histologic changes. This is limited in the case of cysts that do not communicate with the pancreatic duct. ERCP also allows collection of pure pancreatic juice for cytology and gene analysis, brush cytology, biopsy of the pancreatic duct, and introduction of baby scopes or ultrasonic probes into the pancreatic duct for pancreatoscopy

Pancreatography can suggest the diagnosis of pancreatic cancer. A Japanese study comparing the pancreatographic findings of autoimmune pancreatitis and cancer revealed that an obstructed main pancreatic duct and an upstream duct dilation to a diameter greater than 4mm were significantly more common in cancer cases; meanwhile, autoimmune pancreatitis had a higher prevalence of narrowing of the main pancreatic duct for more than

developing in 3 patients (0.85%). (Eloubeidi et al, 2006)

and intraductal ultrasound (IDUS), respectively. (Fujita et al, 2004)

2004b)

3cm of its length and a higher prevalence for the presence of side branches in the narrowed portions if the main pancreatic duct. (Nishino et al, 2010) The pancreatographic features suggestive of pancreatic cystic neoplasms include displacement of the pancreatic duct, pancreatic duct strictures, and the degree of pancreatic ductal obstruction. In the case of IPMN, the main pancreatic duct may be dilated diffusely or in a segment fashion depending on the volume of mucus produced, the presence of ductal obstruction and the presence and distribution of intraductal tumors. Enlargement of the main pancreatic duct is a frequent pancreatographic abnormality in IPMN, present in about 77% of patients; side branch ectasia or cystic dilation occurs in about 51% of the cases. (Telford & Carr-Locke, 2002)

Pancreatic juice and mucus can be aspirated directly from the pancreatic duct during ERCP, either by catheter or pancreatoscopy. Stimulation of pancreatic exocrine secretion by administration of secretin may improve the diagnostic yield. The samples are sent for cytology, as well as analysis of mucin, tumor marker levels, and amplification of molecular abnormalities. (Telford & Carr-Locke, 2002) Examination of the pancreatic juice collected during cannulation yielded positive results in 52.3% of pancreatic cancer patients. Higher positive rates were obtained when washing with saline (63.2%) and aspirating after secretin stimulation (51.3%), as well as in cases of pancreatic head cancer (70.6%). (Kameya et al, 1981) For IPMN, the specificity of the cytology of the pancreatic juice is 100%, and the sensitivity is 62.2% when collected by pancreatoscopy and 38.2% when collected by catheter. (Chen 2007; Yamaguchi et al, 2005)

Brush cytology of pancreatic duct strictures or elevated intraductal lesions during ERCP has a sensitivity and specificity to detect malignancy of 48-76% and 100%, respectively, and accuracy of 70-76.4%. (Telford & Carr-Locke, 2002; Chen 2007; Ferrari et al, 1994; Vandervoort et al, 1999; Uchida et al, 2007) Accuracy may be influenced by location of sampling within the pancreas, technical errors and interpretation of the sample. (Chen 2007) Strictures located at the head and body of the pancreas usually yield high rates of positive cytology. The diagnostic yield is overall enhanced by concomitant brushing of pancreatic and bile duct strictures. (McGuire et al, 1996) A retrospective study evaluating the diagnostic yield of combining EUS-FNA with brushing cytology during the work up of pancreatic cancer revealed that the combined use of these two modalities provides a better diagnostic yield in pancreatic adenocarcinoma than either one alone. The sensitivity, specificity and accuracy were 69.2, 93.8, and 77.3% for EUS-FNA alone, 50.8, 100, and 67% for brushing cytology alone, and 84.6, 100, and 89.7% for combination of EUS-FNA with brushing cytology. (Jing et al, 2009) A recent study to determine whether KRAS (protooncogene) mutations could be identified in pancreatobiliary stricture brushings and to compare the performance characteristics of KRAS mutation analysis to cytology and fluorescence in situ hybridization (FISH) for detection of carcinoma revealed that combined KRAS mutation and FISH analysis appear to increase the cancer detection rate in patients with pancreatobiliary strictures. The KRAS mutation and polysomic FISH (positive) results were identified in 69% and 63% pancreatic adenocarcinoma specimens, respectively, with a combined sensitivity of 86%. (Kipp et al, 2010) In the case of cysts, a new through the needle cytological brush system (Echo-Brush) seeks to solve the poor cellularity typically obtained by EUS-FNA. This system consists in the introduction of the brush through a 19 gauge EUS needle after aspiration of the cyst fluid. The brush is used to scrub the cystic wall and is processed as standard brushing. Studies have had conflicting results. A group from Spain found that the brush was superior to the aspirated fluid for detecting diagnostic cells but

Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 223

Cancer detection rate can be improved by techniques that allow better visualization, such as narrow-band imaging (NBI) or by developing techniques that image the lesion at microscopic level, such as confocal laser microscopy. NBI during pancreatoscopy has been shown to provide better visualization of vascular pattern and tumor vessels than conventional white light. (Iqbal & Stevens, 2009) Some authors have reported the ability of NBI to identify both the surface structure and mucosal vessels as good as, or even better than, conventional white light, regardless of benign or malignant etiology. (Itoi et al, 2009) The use of a confocal microscope enables subsurface in vivo histological assessment during ongoing endoscopy. This technology also requires the application of a flourophore for mucosal fluorescence imaging. Endomicroscopic images can be acquired after intravenous application of fluorescein, which also makes the blood vessels clearly visible. The use of this technology in the investigation of biliary pathologies has escalated since the introduction of a flexible probe-based confocal laser endomicroscopy (pCLE) system. Certain hallmarks and patterns have been identified to differentiate benign from malignant epithelium. (Meining, 2009) The experience in pancreatic pathologies is more limited and developing. A group was able to use pCLE to detect and further differentiate pancreatic strictures such as IPMN. (Meining et al, 2009) The use of this technology may be helpful to clarify location and types of IPMN for a targeted surgical resection. Confocal endomicroscopy is being developed further and a new miniprobe small enough to be introduced through a 22 gauge puncture needle was developed. Feasibility studies to evaluate the ability of this needle-based confocal laser endomicroscopy (nCLE) for in vivo histology of various organs, including pancreas, have been carried in animal models with good results. (Becker et al, 2010; Mennone & Nathanson, 2011) A multicenter trial assessing the use of nCLE in humans is

Endoscopy has no role in the treatment of pancreatic cancer, as the only definite treatment is surgical resection when the disease is diagnosed in early stages. For advanced cases, palliation is indicated and endoscopy plays an important role. The procedures currently performed for palliation of pancreatic cancer involve stent placement for the drainage of biliary or pancreatic duct obstruction by ERCP or under EUS guidance, celiac plexus neurolysis (CPN), injection of anti-tumor agents, and implantation of fiducial markers to guide radiation therapy. Other experimental procedures are being developed to evaluate the role of EUS in the application of radiofrequency ablation (RFA) and photodynamic therapy

ERCP for drainage of biliary obstruction is the most commonly performed endoscopic procedure for palliation of pancreatic cancer. Endoscopic treatment of these malignant biliary obstructions is often successful in alleviating symptoms such as jaundice and pruritus, reducing the incidence of cholangitis, and increasing biliary drainage so that hepatically metabolized chemotherapeutic agents can be offered. (Rogart, 2010) The first biliary stents available were made of polyethylene (plastic), and had the drawback of occlusion with sludge in about 30% of cases, resulting in recurrence of symptoms and development of cholangitis. Self-expanding metal stents (SEMS) had previously been used for vascular and urethral indications, and were later developed for biliary applications. Initial non-comparative studies reported an occlusion rate of SEMS of 10-18%. In 1992, the

currently being carried.

(PDT).

**3. Therapeutic Interventions** 

didn't reach statistical significance (73% vs. 36%, p=0.08). In terms of mucinous cells, the yield of the cytobrush was significantly higher (50% vs. 18%, p=0.016). (Sendino et al, 2010) A group from the United Kingdom evaluating the management of cystic pancreatic lesions reported a similar cellularity yield between the FNA group and the brushing group (61.9% and 55.0%, respectively). Greater proportion of patients with malignant cystic lesions diagnosed by EUS sampling were in the brushing group, but this did not reach significance (50% in the brushing group vs. 20% in the FNA group, p=0.524). (Thomas et al, 2010)

Random transpapillary biopsies of the pancreatic duct can be obtained in the presence of a stricture or an elevated lesion. The specificity for the detection of malignancy approaches 100%, but the sensitivity is variable, ranging from 57% to 100%. The accuracy of these biopsies increases when performed during pancreatoscopy. (Telford & Carr-Locke, 2002; Chen, 2007)

Pancreatoscopy is the endoscopy of the pancreatic duct, and it is performed using a motherbaby scope system: a thin endoscope (baby scope) is introduced into the pancreatic duct through the working channel of the duodenoscope (mother scope). This technique has some limitations for small size pancreatic ducts: the wider the scope diameter, the better the quality of images; the tip-bending system, useful for observing the tortuous pancreatic ductal lumen, increases the size of the scope; the use of irrigation and suction system is needed to achieve a good endoscopic view, but also increases the size of the scope. Given these size limitations, the investigation of IPMN is the best indication for the use of pancreatoscopy. (Fujita et al, 2004) The insertion of the pancreatoscope is facilitated by the frequently enlarged papillary orifice present in IPMN. Pancreatoscopy in this condition allows for endoscopic diagnosis in 67% to 83%, (Nguyen et al, 2009) differentiation of a filling defect seen in pancreatography as mucus, tumor or stone, identification of malignant features, endoscopic biopsy, and determination of disease extent. Clusters of papillary projections in IPMN rising <3mm above the ductal surface can represent hyperplasia or adenoma with different degrees of dysplasia. In the other hand, adenocarcinoma is typically polypoid and protrudes >3mm into the ductal lumen. Diffuse hyperemia or distinct vessels may also be observed and are also considered high-risk features. (Telford & Carr-Locke, 2002) The cancer detection rate by pancreatoscopy-guided sampling has a sensitivity of 62.5%, specificity 100%, positive predictive value 100%, and negative predictive value 70.7%. (Iqbal & Stevens, 2009) Despite the usefulness of this diagnostic tool, pancreatoscopy requires expensive, very fragile equipment and two experience endoscopists to operate it. Hence, it is not performed often. (Telford & Carr-Locke, 2002)

IDUS uses a thin caliber (approximately 2mm in diameter) ultrasound probe with highfrequency ultrasound (12-30 MHz). For pancreatic IDUS, the ultrasonic probe is advanced into the pancreatic duct over a guidewire during an ERCP. However, in some situations it is not possible for even a thin caliber prove to pass a stenotic site caused by a mass in the pancreatic duct. (Fujita et al, 2004) A study comparing the detection rates of different imaging technologies in patients with mucin-producing tumors revealed a detection rate of 21% for CT, 29% for ultrasound, 83% for pancreatoscopy, 86% with EUS, and 100% for IDUS. (Chen, 2007) IDUS is useful in assessing the indications for surgery by revealing mural nodules in mucinproducing tumors, evaluating the feasibility of partial resection of the tumor, locating multiple lesions in pancreatic islet-cell cancer, and differentiating benign from malignant cases of localized stenosis of the main pancreatic duct. (Furukawa et al, 1997)

Cancer detection rate can be improved by techniques that allow better visualization, such as narrow-band imaging (NBI) or by developing techniques that image the lesion at microscopic level, such as confocal laser microscopy. NBI during pancreatoscopy has been shown to provide better visualization of vascular pattern and tumor vessels than conventional white light. (Iqbal & Stevens, 2009) Some authors have reported the ability of NBI to identify both the surface structure and mucosal vessels as good as, or even better than, conventional white light, regardless of benign or malignant etiology. (Itoi et al, 2009)

The use of a confocal microscope enables subsurface in vivo histological assessment during ongoing endoscopy. This technology also requires the application of a flourophore for mucosal fluorescence imaging. Endomicroscopic images can be acquired after intravenous application of fluorescein, which also makes the blood vessels clearly visible. The use of this technology in the investigation of biliary pathologies has escalated since the introduction of a flexible probe-based confocal laser endomicroscopy (pCLE) system. Certain hallmarks and patterns have been identified to differentiate benign from malignant epithelium. (Meining, 2009) The experience in pancreatic pathologies is more limited and developing. A group was able to use pCLE to detect and further differentiate pancreatic strictures such as IPMN. (Meining et al, 2009) The use of this technology may be helpful to clarify location and types of IPMN for a targeted surgical resection. Confocal endomicroscopy is being developed further and a new miniprobe small enough to be introduced through a 22 gauge puncture needle was developed. Feasibility studies to evaluate the ability of this needle-based confocal laser endomicroscopy (nCLE) for in vivo histology of various organs, including pancreas, have been carried in animal models with good results. (Becker et al, 2010; Mennone & Nathanson, 2011) A multicenter trial assessing the use of nCLE in humans is currently being carried.

#### **3. Therapeutic Interventions**

222 Pancreatic Cancer – Clinical Management

didn't reach statistical significance (73% vs. 36%, p=0.08). In terms of mucinous cells, the yield of the cytobrush was significantly higher (50% vs. 18%, p=0.016). (Sendino et al, 2010) A group from the United Kingdom evaluating the management of cystic pancreatic lesions reported a similar cellularity yield between the FNA group and the brushing group (61.9% and 55.0%, respectively). Greater proportion of patients with malignant cystic lesions diagnosed by EUS sampling were in the brushing group, but this did not reach significance

Random transpapillary biopsies of the pancreatic duct can be obtained in the presence of a stricture or an elevated lesion. The specificity for the detection of malignancy approaches 100%, but the sensitivity is variable, ranging from 57% to 100%. The accuracy of these biopsies increases when performed during pancreatoscopy. (Telford & Carr-Locke, 2002;

Pancreatoscopy is the endoscopy of the pancreatic duct, and it is performed using a motherbaby scope system: a thin endoscope (baby scope) is introduced into the pancreatic duct through the working channel of the duodenoscope (mother scope). This technique has some limitations for small size pancreatic ducts: the wider the scope diameter, the better the quality of images; the tip-bending system, useful for observing the tortuous pancreatic ductal lumen, increases the size of the scope; the use of irrigation and suction system is needed to achieve a good endoscopic view, but also increases the size of the scope. Given these size limitations, the investigation of IPMN is the best indication for the use of pancreatoscopy. (Fujita et al, 2004) The insertion of the pancreatoscope is facilitated by the frequently enlarged papillary orifice present in IPMN. Pancreatoscopy in this condition allows for endoscopic diagnosis in 67% to 83%, (Nguyen et al, 2009) differentiation of a filling defect seen in pancreatography as mucus, tumor or stone, identification of malignant features, endoscopic biopsy, and determination of disease extent. Clusters of papillary projections in IPMN rising <3mm above the ductal surface can represent hyperplasia or adenoma with different degrees of dysplasia. In the other hand, adenocarcinoma is typically polypoid and protrudes >3mm into the ductal lumen. Diffuse hyperemia or distinct vessels may also be observed and are also considered high-risk features. (Telford & Carr-Locke, 2002) The cancer detection rate by pancreatoscopy-guided sampling has a sensitivity of 62.5%, specificity 100%, positive predictive value 100%, and negative predictive value 70.7%. (Iqbal & Stevens, 2009) Despite the usefulness of this diagnostic tool, pancreatoscopy requires expensive, very fragile equipment and two experience endoscopists to operate it.

IDUS uses a thin caliber (approximately 2mm in diameter) ultrasound probe with highfrequency ultrasound (12-30 MHz). For pancreatic IDUS, the ultrasonic probe is advanced into the pancreatic duct over a guidewire during an ERCP. However, in some situations it is not possible for even a thin caliber prove to pass a stenotic site caused by a mass in the pancreatic duct. (Fujita et al, 2004) A study comparing the detection rates of different imaging technologies in patients with mucin-producing tumors revealed a detection rate of 21% for CT, 29% for ultrasound, 83% for pancreatoscopy, 86% with EUS, and 100% for IDUS. (Chen, 2007) IDUS is useful in assessing the indications for surgery by revealing mural nodules in mucinproducing tumors, evaluating the feasibility of partial resection of the tumor, locating multiple lesions in pancreatic islet-cell cancer, and differentiating benign from malignant cases of

Hence, it is not performed often. (Telford & Carr-Locke, 2002)

localized stenosis of the main pancreatic duct. (Furukawa et al, 1997)

(50% in the brushing group vs. 20% in the FNA group, p=0.524). (Thomas et al, 2010)

Chen, 2007)

Endoscopy has no role in the treatment of pancreatic cancer, as the only definite treatment is surgical resection when the disease is diagnosed in early stages. For advanced cases, palliation is indicated and endoscopy plays an important role. The procedures currently performed for palliation of pancreatic cancer involve stent placement for the drainage of biliary or pancreatic duct obstruction by ERCP or under EUS guidance, celiac plexus neurolysis (CPN), injection of anti-tumor agents, and implantation of fiducial markers to guide radiation therapy. Other experimental procedures are being developed to evaluate the role of EUS in the application of radiofrequency ablation (RFA) and photodynamic therapy (PDT).

ERCP for drainage of biliary obstruction is the most commonly performed endoscopic procedure for palliation of pancreatic cancer. Endoscopic treatment of these malignant biliary obstructions is often successful in alleviating symptoms such as jaundice and pruritus, reducing the incidence of cholangitis, and increasing biliary drainage so that hepatically metabolized chemotherapeutic agents can be offered. (Rogart, 2010) The first biliary stents available were made of polyethylene (plastic), and had the drawback of occlusion with sludge in about 30% of cases, resulting in recurrence of symptoms and development of cholangitis. Self-expanding metal stents (SEMS) had previously been used for vascular and urethral indications, and were later developed for biliary applications. Initial non-comparative studies reported an occlusion rate of SEMS of 10-18%. In 1992, the

Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 225

first prospective randomized clinical trial reporting the patency and cost-effectiveness of SEMS vs. plastic stents was published: the median patency of the stent was significantly prolonged in patients with metal stent compared with those with a polyethylene stent (273 days vs. 126 days, p=0.006), and the incremental cost-effectiveness analysis showed that initial placement of a SEMS results in a 28% decrease of endoscopic procedures. (Davids et al, 1992) Since the introduction of biliary SEMS, several groups have concluded that their placement represent a cost-saving strategy, as plastic stents are associated with higher risk of recurrent biliary obstruction, which translates into additional procedures, hospitalizations, etc. (Arguedas et al, 2002; Kaassis et al, 2003; Moss et al, 2006) There was initial concern on the possibility of interfering with subsequent pancreaticoduodenectomy after biliary metal stent placement in patients with uncertain surgical status or with resectable masses, but this has not been well substantiated. There are actually some reports on the cost-benefit that these stents offer to these patients, as well as the longer patency rate, need for fewer procedures and fewer episodes of cholangitis. (Rogart, 2010; Wasan et al, 2005; Chen et al, 2005; Boulay et al, 2010) In addition, insertion of SEMS is advised as the treatment of biliary SEMS occlusion, as it provides longer patency and survival, decreases the number of subsequent procedures by 50% (compared to plastic stents) and is cost-

However, technical failure during ERCP is encountered in up to 10% of cases due to various factors including duodenal obstruction, anatomical variations, periampullary diverticulum and tightness of the stricture. In these cases, percutaneous transhepatic biliary drainage (PTBD) and surgical drainage are options available. The technical success rate for PTBD placement is 90% if the intrahepatic system is dilated and 70% in a non-dilated system. The morbidity is 7% and the mortality is 5%, and it is contraindicated in the presence of ascites and coagulopathy. Surgical drainage, although a possibility, is associated with high morbidity and mortality rates (66% and 32%, respectively), as the patients in need for this procedure are usually very deconditioned. Hence, the drainage of the biliary system using a transgastric or transduodenal approach under EUS guidance has been introduced with a reported technical success rate of 92%. Once the common bile duct (CBD) is localized from the duodenal bulb or the intrahepatic system is visualized from the stomach, the biliary system is accessed under EUS guidance and a stent is deployed under fluoroscopic guidance to form a choledochoduodenostomy or a hepaticogastrostomy, respectively. The reported technical success rate for hepaticogastrostomy is 90-100% and the clinical success rate is 75-100%. The complication rate associated with EUS-guided biliary drainage is 19%, with 8% being due to focal biliary peritonitis. Other complications include bleeding, pneumoperitoneum, infection caused by stent occlusion/migration, and death. (Ramesh & Varadarajulu, 2008; Irisawa et al 2009) Plastic stents are the most commonly used during this approach; however, transduodenal and transgastric placement of self-expandable metal stents (SEMS) for palliation of malignant biliary obstruction has been reported and some authors report antegrade placement achieving transpapillary or, in case of post-surgical anatomy, transanastomotic placement. (Siddiqui et al, 2011; Nguyen et al, 2010; Artifon et al, 2010)

EUS-guided pancreatic duct drainage can also be accomplished. There are two techniques: 1) transmural drainage of the main pancreatic duct; and 2) rendezvous approaches for ERCP assistance of transpapillary drainage. (Irisawa et al, 2009) The main indication for the pancreatic duct drainage is to alleviate pain caused by pancreatic ductal obstruction

effective. (Rogart et al, 2008)

Fig. 5. 59 year-old male with biliary obstruction secondary to pancreatic head mass (adenocarcinoma). An ERCP was performed and a distal common bile duct stricture can be appreciated in the left image. The patient had metastatic disease, and a SEMS was placed for palliation of jaundice and pruritus.

effective. (Rogart et al, 2008)

224 Pancreatic Cancer – Clinical Management

Fig. 5. 59 year-old male with biliary obstruction secondary to pancreatic head mass

palliation of jaundice and pruritus.

(adenocarcinoma). An ERCP was performed and a distal common bile duct stricture can be appreciated in the left image. The patient had metastatic disease, and a SEMS was placed for first prospective randomized clinical trial reporting the patency and cost-effectiveness of SEMS vs. plastic stents was published: the median patency of the stent was significantly prolonged in patients with metal stent compared with those with a polyethylene stent (273 days vs. 126 days, p=0.006), and the incremental cost-effectiveness analysis showed that initial placement of a SEMS results in a 28% decrease of endoscopic procedures. (Davids et al, 1992) Since the introduction of biliary SEMS, several groups have concluded that their placement represent a cost-saving strategy, as plastic stents are associated with higher risk of recurrent biliary obstruction, which translates into additional procedures, hospitalizations, etc. (Arguedas et al, 2002; Kaassis et al, 2003; Moss et al, 2006) There was initial concern on the possibility of interfering with subsequent pancreaticoduodenectomy after biliary metal stent placement in patients with uncertain surgical status or with resectable masses, but this has not been well substantiated. There are actually some reports on the cost-benefit that these stents offer to these patients, as well as the longer patency rate, need for fewer procedures and fewer episodes of cholangitis. (Rogart, 2010; Wasan et al, 2005; Chen et al, 2005; Boulay et al, 2010) In addition, insertion of SEMS is advised as the treatment of biliary SEMS occlusion, as it provides longer patency and survival, decreases the number of subsequent procedures by 50% (compared to plastic stents) and is cost-

However, technical failure during ERCP is encountered in up to 10% of cases due to various factors including duodenal obstruction, anatomical variations, periampullary diverticulum and tightness of the stricture. In these cases, percutaneous transhepatic biliary drainage (PTBD) and surgical drainage are options available. The technical success rate for PTBD placement is 90% if the intrahepatic system is dilated and 70% in a non-dilated system. The morbidity is 7% and the mortality is 5%, and it is contraindicated in the presence of ascites and coagulopathy. Surgical drainage, although a possibility, is associated with high morbidity and mortality rates (66% and 32%, respectively), as the patients in need for this procedure are usually very deconditioned. Hence, the drainage of the biliary system using a transgastric or transduodenal approach under EUS guidance has been introduced with a reported technical success rate of 92%. Once the common bile duct (CBD) is localized from the duodenal bulb or the intrahepatic system is visualized from the stomach, the biliary system is accessed under EUS guidance and a stent is deployed under fluoroscopic guidance to form a choledochoduodenostomy or a hepaticogastrostomy, respectively. The reported technical success rate for hepaticogastrostomy is 90-100% and the clinical success rate is 75-100%. The complication rate associated with EUS-guided biliary drainage is 19%, with 8% being due to focal biliary peritonitis. Other complications include bleeding, pneumoperitoneum, infection caused by stent occlusion/migration, and death. (Ramesh & Varadarajulu, 2008; Irisawa et al 2009) Plastic stents are the most commonly used during this approach; however, transduodenal and transgastric placement of self-expandable metal stents (SEMS) for palliation of malignant biliary obstruction has been reported and some authors report antegrade placement achieving transpapillary or, in case of post-surgical anatomy, transanastomotic placement. (Siddiqui et al, 2011; Nguyen et al, 2010; Artifon et al, 2010)

EUS-guided pancreatic duct drainage can also be accomplished. There are two techniques: 1) transmural drainage of the main pancreatic duct; and 2) rendezvous approaches for ERCP assistance of transpapillary drainage. (Irisawa et al, 2009) The main indication for the pancreatic duct drainage is to alleviate pain caused by pancreatic ductal obstruction

Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 227

with chronic pancreatitis for pain control. (Ramesh & Varadarajulu, 2008) Significant reduction of pain scores 12 weeks after CPN was observed in 30 patients with advanced intra-abdominal malignancy, while 91% of these patients required same or less pain medication and 88% of patients had persistent improvement in their pain score. (Wiersema et al, 1996) Similarly, in another study of 58 patients with unresectable pancreatic cancer, EUS-guided CPN lowered pain scores in 78% at 2 weeks and a sustained response was noted until 24 weeks. (Naresh et al, 2001) The most commonly reported complications after CPN are orthostatic hypotension in 10-15% and transient diarrhea in 9%. (Gunaratnam et al, 2001) Recently, a retrospective analysis to determine predictors of response to CPN in a cohort of 64 patients with pancreatic cancer revealed that visualization o the celiac ganglia was the best predictor of response: patients with visible ganglia were >15 times more likely

Percutaneous ethanol injection is an effective treatment for cystic and solid lesions in the liver. Successful ethanol ablation of cysts in the thyroid, parathyroid, kidneys, and spleen have been reported with minimal side effects. EUS offers minimally invasive access to perform ablation of pancreatic lesions. This EUS-guided ablative therapy may have important clinical applications in the treatment of solid (adenocarcinomas, neuroendocrine tumors) and cystic pancreatic lesions (mucinous cystic neoplasm, IPMN), especially in nonoperative candidates. A pilot study in porcine models showed that ethanol injection into normal porcine pancreas results in focal inflammation, necrosis and fibrosis at the injection site. (Aslanian et al, 2005) Another pilot study reported the safety and feasibility in humans, after 25 patients underwent ethanol lavage of different cystic pancreatic lesions (mucinous cystic neoplasms, IPMNs, serous cystadenomas, and pseudocysts) with no side effects or complications reported in short and long-term follow up. (Gan et al, 2005) The approach to this technique involves aspirating the cyst content with a 22 gauge needle until collapse is achieved. Ethanol is then injected into the cyst, and the cyst is lavaged for 3 to 5 min. The cystic lesion is finally drained of fluid at the conclusion of the lavage. (Trevino & Varadarajulu, 2011) Studies in animals have revealed that EUS-guided injection of ethanol into the pig pancreas results in a localized concentration-depended tissue necrosis without complications, with a visible necrotic area of 20.8mm (+/- 4.3mm) after injection of 40% to 100% ethanol. (Matthes et al, 2007) A small study demonstrated no cyst recurrence by CT after a median follow up of 26 months (including suspected mucinous cysts). However, longer follow up is still needed before considered these patients cured. (DeWitt et al, 2010) The main potential problem of EUS-guided ethanol ablation is the risk of acute pancreatitis due to diffusion of alcohol outside the lesion into the main pancreatic duct and/or the

EUS-guided fine needle injection (FNI) has been proposed as a new technique for delivery of anti-tumor agents for patients with locally advanced malignancy. Few small size studies (8-37 patients) have been published, reporting the safety and feasibility of direct injection of different agents, such as allogenic mixed lymphocyte culture or cytoimplant (cytokine production within a tumor may lead to regression by host immune mechanisms, and cytoimplants produce such a cytokine response), ONYX-015 (adenovirus that selectively replicates and kills malignant cells) and TNFerade [replication-deficient adenovector containing the human tumor necrosis factor (TNF)-α gene, regulated by radiation-inducible promoter Egr-1]. The commonly reported side effects are low grade fever without

to respond (p < 0.001). (Ascunce et al, 2011)

pancreatic parenchyma. (Giovannini, 2007)

associated with chronic pancreatitis and other inflammatory processes. For this reason, this will not be discussed further in this chapter.

Fig. 6. 40 year-old female with locally advanced pancreatic cancer and severe abdominal pain with poor response to narcotics. Patient had EUS guided CPN. Celiac axis is localized under EUS (left image) and absolute alcohol was then injected to both sides of the celiac axis (seen as a white cloud surrounding the aorta in the right image) .

Pain is reported in the majority of patients with advanced pancreatic cancer (90%), and effective pain control can be achieved in 70-90% of these patients with CPN. (Ramesh & Varadarajulu, 2008; Puli et al, 2009; Kaufman et al, 2010) This procedure entails the injection of absolute alcohol under EUS guidance to destroy the sympathetic plexus near the celiac axis. A similar technique involving the injection of triamcinolone is performed in patients

associated with chronic pancreatitis and other inflammatory processes. For this reason, this

Fig. 6. 40 year-old female with locally advanced pancreatic cancer and severe abdominal pain with poor response to narcotics. Patient had EUS guided CPN. Celiac axis is localized under EUS (left image) and absolute alcohol was then injected to both sides of the celiac axis

Pain is reported in the majority of patients with advanced pancreatic cancer (90%), and effective pain control can be achieved in 70-90% of these patients with CPN. (Ramesh & Varadarajulu, 2008; Puli et al, 2009; Kaufman et al, 2010) This procedure entails the injection of absolute alcohol under EUS guidance to destroy the sympathetic plexus near the celiac axis. A similar technique involving the injection of triamcinolone is performed in patients

(seen as a white cloud surrounding the aorta in the right image) .

will not be discussed further in this chapter.

with chronic pancreatitis for pain control. (Ramesh & Varadarajulu, 2008) Significant reduction of pain scores 12 weeks after CPN was observed in 30 patients with advanced intra-abdominal malignancy, while 91% of these patients required same or less pain medication and 88% of patients had persistent improvement in their pain score. (Wiersema et al, 1996) Similarly, in another study of 58 patients with unresectable pancreatic cancer, EUS-guided CPN lowered pain scores in 78% at 2 weeks and a sustained response was noted until 24 weeks. (Naresh et al, 2001) The most commonly reported complications after CPN are orthostatic hypotension in 10-15% and transient diarrhea in 9%. (Gunaratnam et al, 2001) Recently, a retrospective analysis to determine predictors of response to CPN in a cohort of 64 patients with pancreatic cancer revealed that visualization o the celiac ganglia was the best predictor of response: patients with visible ganglia were >15 times more likely to respond (p < 0.001). (Ascunce et al, 2011)

Percutaneous ethanol injection is an effective treatment for cystic and solid lesions in the liver. Successful ethanol ablation of cysts in the thyroid, parathyroid, kidneys, and spleen have been reported with minimal side effects. EUS offers minimally invasive access to perform ablation of pancreatic lesions. This EUS-guided ablative therapy may have important clinical applications in the treatment of solid (adenocarcinomas, neuroendocrine tumors) and cystic pancreatic lesions (mucinous cystic neoplasm, IPMN), especially in nonoperative candidates. A pilot study in porcine models showed that ethanol injection into normal porcine pancreas results in focal inflammation, necrosis and fibrosis at the injection site. (Aslanian et al, 2005) Another pilot study reported the safety and feasibility in humans, after 25 patients underwent ethanol lavage of different cystic pancreatic lesions (mucinous cystic neoplasms, IPMNs, serous cystadenomas, and pseudocysts) with no side effects or complications reported in short and long-term follow up. (Gan et al, 2005) The approach to this technique involves aspirating the cyst content with a 22 gauge needle until collapse is achieved. Ethanol is then injected into the cyst, and the cyst is lavaged for 3 to 5 min. The cystic lesion is finally drained of fluid at the conclusion of the lavage. (Trevino & Varadarajulu, 2011) Studies in animals have revealed that EUS-guided injection of ethanol into the pig pancreas results in a localized concentration-depended tissue necrosis without complications, with a visible necrotic area of 20.8mm (+/- 4.3mm) after injection of 40% to 100% ethanol. (Matthes et al, 2007) A small study demonstrated no cyst recurrence by CT after a median follow up of 26 months (including suspected mucinous cysts). However, longer follow up is still needed before considered these patients cured. (DeWitt et al, 2010) The main potential problem of EUS-guided ethanol ablation is the risk of acute pancreatitis due to diffusion of alcohol outside the lesion into the main pancreatic duct and/or the pancreatic parenchyma. (Giovannini, 2007)

EUS-guided fine needle injection (FNI) has been proposed as a new technique for delivery of anti-tumor agents for patients with locally advanced malignancy. Few small size studies (8-37 patients) have been published, reporting the safety and feasibility of direct injection of different agents, such as allogenic mixed lymphocyte culture or cytoimplant (cytokine production within a tumor may lead to regression by host immune mechanisms, and cytoimplants produce such a cytokine response), ONYX-015 (adenovirus that selectively replicates and kills malignant cells) and TNFerade [replication-deficient adenovector containing the human tumor necrosis factor (TNF)-α gene, regulated by radiation-inducible promoter Egr-1]. The commonly reported side effects are low grade fever without

Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 229

Varadarajulu, 2008) Further application of this technique has been impeded because of the lack of a retractable needle electrode array to ablate large areas. This was overcome by the development of a retractable umbrella-shaped electrode array that has delivered effective

coagulation necrosis of large areas in the porcine model. (Varadarajulu et al, 2009)

Fig. 7. 66 year-old male with locally advanced, non resectable, pancreatic cancer that underwent EUS-guided of fiducials in the pancreatic head for stereotactic radiotherapy. A 5cm pancreatic head mass was identified by EUS (left image), followed by placement of a

total of 9 gold fiducials into the inferior and superior aspects of the tumor under

fluoroscopy (right image)

leukocytosis, nausea, abdominal pain and elevated liver enzymes and bilirrubin. No pancreatitis has been reported, but few cases of sepsis and two cases of duodenal perforation occurred prior to the institution of prophylactic antibiotic and due to the rigid endoscope tip during transduodenal approach, respectively. These studies revealed partial response or at least tumor stabilization. Perhaps combination of systemic chemotherapy and/or radiation with EUS-FNI would improve outcomes. This field will continue to expand with the refinement of echoendoscopes, delivery systems and novel local antitumor agents. (Trevino and Varadarajulu, 2010; Klapman & Chang, 2005; Verna & Dhar, 2008; Chang, 2006)

Implantation of fiducial markers to facilitate stereotactic radiotherapy and radioactive seeds for brachytherapy can be performed under EUS guidance. Fiducials can be placed into tumors to enable higher doses of targeted radiotherapy while sparing adjacent healthy tissue with low risk of complications. This technique has a reported technical success rate of 84-94%, and its direct impact on patient management is promising but still under clinical investigation. A total of 3-6 gold fiducials are placed within the tumor in different planes under EUS guidance. Immediate complications are uncommon and involve needle malfunction and minor bleeds with no significant drop in hemoglobin. Although fiducials can spontaneously migrate from the initial injection site, the reported rate of migration is low (7%), and no migration-related complications have been documented. (Ramesh & Varadarajulu, 2008; Park et al, 2010; Sanders et al, 2010) The EUS-guided placement of fiducials has traditionally involved the use of 19 gauge needles. However, a recently published case series reported the feasibility of using a 22 gauge needle, which may permit greater access when compared to a 19 gauge needle technique. (Ammar et al, 2010) Brachytherapy is a useful method for local control of malignant tumors, including pancreas. After the placement of the radioactive seeds, the tissue is exposed to steady radiation, leading to localized ablation and avoiding the radiation of normal tissues surrounding the malignant lesion. EUS-guided brachytherapy has been performed to place radioactive iodine seeds into the locally advanced pancreatic tumor mass, with significant improvement in pain scores and also improvement in performance status scores. When assessing the tumor response, an 80% rate of positive response (decrease in tumor size) or stable disease has been reported. Hematologic toxicity is usually mild, but includes neutropenia, thrombocytopenia, and anemia. Other reported complications reported less frequently are pancreatitis and pseudocyst formation. (Sun et al, 2006) Small size studies have demonstrated the technical feasibility of EUS-guided implantation of radioactive seeds in pancreatic tumors, and the technique appears to be well tolerated. (Ramesh & Varadarajulu, 2008; Sun et al, 2006) However, larger studies evaluating this technique and its role in a multimodality approach in combination with chemotherapy and/ or external beam radiation are needed.

Radiofrequency ablation (RFA) is a well-established procedure that provides palliation for various malignant diseases. RFA causes a relatively predictable zone of coagulation necrosis by intense tissue heating. Accurate and precise targeting of the tumor is important to maximize the yield and minimize the morbidity. (Klapman & Chang, 2005) This technique is emerging as one of the safest and most predictable for thermal tumor ablation and is traditionally administered with percutaneous or surgical approaches. (Verma & Dhar, 2008) The feasibility and effectiveness of EUS-guided RFA has been evaluated in animal models and the probe is deployed by a 19 gauge needle inducing coagulative necrosis. (Ramesh &

leukocytosis, nausea, abdominal pain and elevated liver enzymes and bilirrubin. No pancreatitis has been reported, but few cases of sepsis and two cases of duodenal perforation occurred prior to the institution of prophylactic antibiotic and due to the rigid endoscope tip during transduodenal approach, respectively. These studies revealed partial response or at least tumor stabilization. Perhaps combination of systemic chemotherapy and/or radiation with EUS-FNI would improve outcomes. This field will continue to expand with the refinement of echoendoscopes, delivery systems and novel local antitumor agents. (Trevino

Implantation of fiducial markers to facilitate stereotactic radiotherapy and radioactive seeds for brachytherapy can be performed under EUS guidance. Fiducials can be placed into tumors to enable higher doses of targeted radiotherapy while sparing adjacent healthy tissue with low risk of complications. This technique has a reported technical success rate of 84-94%, and its direct impact on patient management is promising but still under clinical investigation. A total of 3-6 gold fiducials are placed within the tumor in different planes under EUS guidance. Immediate complications are uncommon and involve needle malfunction and minor bleeds with no significant drop in hemoglobin. Although fiducials can spontaneously migrate from the initial injection site, the reported rate of migration is low (7%), and no migration-related complications have been documented. (Ramesh & Varadarajulu, 2008; Park et al, 2010; Sanders et al, 2010) The EUS-guided placement of fiducials has traditionally involved the use of 19 gauge needles. However, a recently published case series reported the feasibility of using a 22 gauge needle, which may permit greater access when compared to a 19 gauge needle technique. (Ammar et al, 2010) Brachytherapy is a useful method for local control of malignant tumors, including pancreas. After the placement of the radioactive seeds, the tissue is exposed to steady radiation, leading to localized ablation and avoiding the radiation of normal tissues surrounding the malignant lesion. EUS-guided brachytherapy has been performed to place radioactive iodine seeds into the locally advanced pancreatic tumor mass, with significant improvement in pain scores and also improvement in performance status scores. When assessing the tumor response, an 80% rate of positive response (decrease in tumor size) or stable disease has been reported. Hematologic toxicity is usually mild, but includes neutropenia, thrombocytopenia, and anemia. Other reported complications reported less frequently are pancreatitis and pseudocyst formation. (Sun et al, 2006) Small size studies have demonstrated the technical feasibility of EUS-guided implantation of radioactive seeds in pancreatic tumors, and the technique appears to be well tolerated. (Ramesh & Varadarajulu, 2008; Sun et al, 2006) However, larger studies evaluating this technique and its role in a multimodality approach in combination with chemotherapy and/ or external beam

Radiofrequency ablation (RFA) is a well-established procedure that provides palliation for various malignant diseases. RFA causes a relatively predictable zone of coagulation necrosis by intense tissue heating. Accurate and precise targeting of the tumor is important to maximize the yield and minimize the morbidity. (Klapman & Chang, 2005) This technique is emerging as one of the safest and most predictable for thermal tumor ablation and is traditionally administered with percutaneous or surgical approaches. (Verma & Dhar, 2008) The feasibility and effectiveness of EUS-guided RFA has been evaluated in animal models and the probe is deployed by a 19 gauge needle inducing coagulative necrosis. (Ramesh &

and Varadarajulu, 2010; Klapman & Chang, 2005; Verna & Dhar, 2008; Chang, 2006)

radiation are needed.

Varadarajulu, 2008) Further application of this technique has been impeded because of the lack of a retractable needle electrode array to ablate large areas. This was overcome by the development of a retractable umbrella-shaped electrode array that has delivered effective coagulation necrosis of large areas in the porcine model. (Varadarajulu et al, 2009)

Fig. 7. 66 year-old male with locally advanced, non resectable, pancreatic cancer that underwent EUS-guided of fiducials in the pancreatic head for stereotactic radiotherapy. A 5cm pancreatic head mass was identified by EUS (left image), followed by placement of a total of 9 gold fiducials into the inferior and superior aspects of the tumor under fluoroscopy (right image)

Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 231

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#### **4. Conclusion**

Endoscopy is a constantly evolving field with a major role in the diagnosis of pancreatic cancer as well as palliation of advanced cases. Pancreatic cancer must be managed with a multidisciplinary approach. EUS is the most frequently used modality for the diagnosis and staging of pancreatic cancer. Treatment with curative intention involves surgery, with the use of adjuvant therapy (chemotherapy and/ or radiation) in some cases. Most cases are diagnosed when curative resection is not possible and different endoscopic approaches can be used in a palliative attempt for symptomatic relieve of pain, jaundice or obstruction.

#### **5. References**


Another experimental technique is photodynamic therapy (PDT), which involves the systemic administration of a photosensitizing agent, followed by placement of lightdiffusing photodynamic fibers into the target malignant tissue. This is usually accomplished percutaneously, but it has recently been placed endoscopically with EUS guidance in the pancreas of porcine models. (Verma & Dhar, 2008) In animal models, the EUS-guided PDT

These two EUS-guided ablative techniques, RFA and PDT, have only been performed in animal models and further studies in the safety and efficacy in humans are needed before

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Hawes RF, P. Endosonography. Elsevier, 2006.

Endosc 2009;70:1101-8.

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Endoscopic Management of Pancreatic Cancer: From Diagnosis to Palliative Therapy 235

Siddiqui UD, Rossi F, Rosenthal LS, Padda MS, Murali-Dharan V, Aslanian HR. EUS-guided

Smith FP, Macdonald JS, Schein PS, Ornitz RD. Cutaneous seeding of pancreatic cancer by

Society AC. Learn About Cancer. Pancreatic Cancer. http://www.cancer.org/Cancer/ PancreaticCancer/DetailedGuide/pancreatic-cancer-what-is-pancreatic-cancer,

Sun S, Xu H, Xin J, Liu J, Guo Q, Li S. Endoscopic ultrasound-guided interstitial

Telford JJ, Carr-Locke DL. The role of ERCP and pancreatoscopy in cystic and intraductal

Thomas T, Bebb J, Mannath J, Ragunath K, Kaye PV, Aithal GP. EUS-guided pancreatic cyst brushing: a comparative study in a tertiary referral centre. JOP 2010;11:163-9. Thomas T, Kaye PV, Ragunath K, Aithal G. Efficacy, safety, and predictive factors for a

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Varadarajulu S, Fraig M, Schmulewitz N, Roberts S, Wildi S, Hawes RH, Hoffman BJ,

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Wasan SM, Ross WA, Staerkel GA, Lee JH. Use of expandable metallic biliary stents in

Wiersema MJ, Vilmann P, Giovannini M, Chang KJ, Wiersema LM. Endosonography-

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Nguyen-Tang T, Binmoeller KF, Sanchez-Yague A, Shah JN. Endoscopic ultrasound (EUS)-

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**14**

*Italy* 

**Role of Guided –** 

*Hospital of Piacenza,* 

**Fine Needle Biopsy of the Pancreatic Lesion**

Pancreatic cancer (PC) is the fifth leading cause of cancer death in the United States, with

Survival in patients with untreated pc is very poor, the one year survival rate is 19% and the

It must be emphasized that the majority of patients with pancreatic cancer are diagnosed in the metastatic phase; however when complete surgical resection with margin negative and node negative is possible, it offers the best opportunity for long survival or even cure, with 5-year survival approaching 40% when performed at specialized center. (Sohn et al, 2000). Epithelial neoplasia of pancreas can be divided into those with predominantly exocrine

Neoplasia of exocrine differentiation can be further subdivided into solid and cystic tumors; the majority of malignancies of the pancreas are solid infiltrating ductal adenocarcinomas.

About 80% of pancreatic malignancies are ductal adenocarcinomas, of which approximately

A variety of uncommon types of pancreatic carcinoma have been described, including acinar, adenosquamous, anaplastic, papillary, mucinous and microadenocarcinomas, each of which composes less than 5% of the total. All of these have similarly poor prognoses and are treated in a similar fashion. Also uncommon are mucinous cystic neoplasms (cystadenoma/cystadenocarcinoma) of the pancreas, which occur most frequently in the

Clinical behavior can be difficult to predict pathologically, leading some to conclude that all

Other rare neoplasms include pancreatoblastomas, most of which occur in children, primary

middle-aged women, and these are tipically located in the tail of the pancreas.

mucinous cystic neoplasms of pancreas have malignant potential.

28,000 to 30,000 number of deaths annually (American Cancer Society,2002).

differentiation and those with endocrine differentiation.

70% occur in the head of the pancreas.

lymphoma of the pancreas and metastasis.

5- year survival rate is 4% for all stages combined (American Cancer Society,2002).

**1. Introduction** 

**2. Histology** 

Luigi Cavanna, Roberto Di Cicilia, Elisabetta Nobili, Elisa Stroppa, Adriano Zangrandi and Carlo Paties

*Oncology – Hematology and Pathology Departments,* 


## **Role of Guided – Fine Needle Biopsy of the Pancreatic Lesion**

Luigi Cavanna, Roberto Di Cicilia, Elisabetta Nobili, Elisa Stroppa, Adriano Zangrandi and Carlo Paties *Oncology – Hematology and Pathology Departments, Hospital of Piacenza, Italy* 

#### **1. Introduction**

236 Pancreatic Cancer – Clinical Management

Yamaguchi T, Shirai Y, Ishihara T, Sudo K, Nakagawa A, Ito H, Miyazaki M, Nomura F,

Yamao K, Bhatia V, Mizuno N, Sawaki A, Shimizu Y, Irisawa A. Interventional endoscopic

Yasuda K, Mukai H, Fujimoto S, Nakajima M, Kawai K. The diagnosis of pancreatic cancer

pancreatoscopy. Cancer 2005;104:2830-6.

ultrasonography. J Gastroenterol Hepatol 2009;24:509-19.

by endoscopic ultrasonography. Gastrointest Endosc 1988;34:1-8.

Saisho H. Pancreatic juice cytology in the diagnosis of intraductal papillary mucinous neoplasm of the pancreas: significance of sampling by peroral

> Pancreatic cancer (PC) is the fifth leading cause of cancer death in the United States, with 28,000 to 30,000 number of deaths annually (American Cancer Society,2002).

> Survival in patients with untreated pc is very poor, the one year survival rate is 19% and the 5- year survival rate is 4% for all stages combined (American Cancer Society,2002).

> It must be emphasized that the majority of patients with pancreatic cancer are diagnosed in the metastatic phase; however when complete surgical resection with margin negative and node negative is possible, it offers the best opportunity for long survival or even cure, with 5-year survival approaching 40% when performed at specialized center. (Sohn et al, 2000).

> Epithelial neoplasia of pancreas can be divided into those with predominantly exocrine differentiation and those with endocrine differentiation.

> Neoplasia of exocrine differentiation can be further subdivided into solid and cystic tumors; the majority of malignancies of the pancreas are solid infiltrating ductal adenocarcinomas.

#### **2. Histology**

About 80% of pancreatic malignancies are ductal adenocarcinomas, of which approximately 70% occur in the head of the pancreas.

A variety of uncommon types of pancreatic carcinoma have been described, including acinar, adenosquamous, anaplastic, papillary, mucinous and microadenocarcinomas, each of which composes less than 5% of the total. All of these have similarly poor prognoses and are treated in a similar fashion. Also uncommon are mucinous cystic neoplasms (cystadenoma/cystadenocarcinoma) of the pancreas, which occur most frequently in the middle-aged women, and these are tipically located in the tail of the pancreas.

Clinical behavior can be difficult to predict pathologically, leading some to conclude that all mucinous cystic neoplasms of pancreas have malignant potential.

Other rare neoplasms include pancreatoblastomas, most of which occur in children, primary lymphoma of the pancreas and metastasis.

Role of Guided-Fine Needle Biopsy of the Pancreatic Lesion 239

that 1) imaging techniques can suggest the suspicion of PPL, however are unable to distinguish PPL from pancreatic adenocarcinoma, 2) histological diagnosis can be easily obtained by percutaneous Us-guided tissue core biopsy 3)surgery can be avoided both for diagnosis and therapy, but the treatment of choice of PPL may only be evaluated on a larger

Metastases to the pancreas are rare; in a survey of 4,955 autopsies (Adsay et al., 2004) a rate of metastasis to the pancreas of 3,83% was described and a significantly different distribution of metastatic neoplasms, with lung and gastrointestinal tumors comprising by

In a retrospective review of 1,172 pancreatic endoscopic ultrasound-guided fine-needle aspiration biopsy , 25 cases (2,1%) had a confirmed diagnosis of pancreatic metastasis.

This included 12 cases of renal cell carcinoma, 3 (12%) melanomas, 3 (12%) small cell

Four cases (16%) had no prior history of malignancy; the average time of diagnosis of

Immunohistochemistry and special stains were performed in 22 (88%) and 9 (36%) cases

Staging procedures include US, CT scanning, MRI, and EUS. A diagnostic laparoscopy may also be performed to detect peritoneal disease that is not visible radiologically. Regardless of these studies, an accurate histologic diagnosis is necessary to distinguish benign disease from carcinoma, islet cell tumors, and retroperitoneal lymphomas, because of the major therapeutic and prognostic differences among these disease entities. Criteria for surgical resection include

Intraoperative needle biopsy of the pancreas has been performed with the fine-needle aspiration biopsy (FNAB) technique since the 1960's (Moossa & Altorki, 1983) and with the core tissue biopsy technique since 1970's (Ingram et al., 1978) subsequently ultrasound , computed tomography and endoscopic ultrasound became available to evaluate and characterize pancreatic masses and above all to guide a needle for the biopsy, avoiding the costs, morbidity and mortality of a major surgical procedure performed only to obtain a

For many years percutaneous US and /or CT guided biopsy was routinely performed in situations in which a pancreatic biopsy was necessary, in 2002 the American Joint Committee on cancer has selected endoscopic ultrasound guided FNAB as "the procedure of

However, as recently reported, local expertise in and the availability of EUS and interventional radiology may determine the first procedure selected for a cytohistological

absence of metastatic disease and absence of invasion of prominent local blood vessels.

tissue sample for a cytohistological diagnosis (Civardi et al.,1986; Turner et a.l, 2010).

In these metastatic tumors involving the pancreas 20 (80%) of the lesions were solitary.

series of patients (Arcari et al., 2005).

carcinomas and 7 (28%) other malignancies.

**4. Staging of pancreatic cancer (table 1)** 

pancreatic metastasis was 5.3 years.

**5. Guide for pancreatic biopsy** 

choice" if available (Greene et al., 2002).

diagnosis for a pancreatic mass (Zamboni et al., 2010 ).

respectively (Gilbert et al., 2011).

far the largest proportion.

#### **3. Diagnosis of pancreatic neoplasia**

Currently, imaging modalities for detection of pancreatic masses include ultrasonography (US), computed tomography (CT) scan, magnetic resonance imaging (MRI)/ magnetic resonance cholangiopancreatography, endoscopic ultrasonography (EUS).

In clinical practice differential diagnosis of pancreatic masses is frequently a clinical challenge; often therapeutic decision in this context is mainly based on the ability to perform a diagnosis of malignancy or to exclude malignancy (Tamm & Charnsangavej, 2001).

It is well known that ductal adenocarcinoma is the most frequent cause of pancreatic mass, however other neoplasms such as lymphoma, metastasis, cystic tumors or benign conditions as chronic pancreatitis with different prognosis and treatment options can arise within the pancreas (Iglesias et al., 2010).

A pathologic diagnosis becomes therefore relevant for an adequate therapeutic strategy (Cohen et al., 2000).

At least 80% of the patients with suspected pancreatic cancer, have unresectable disease at diagnosis because of locoregional involvement or distant metastases , and it as been reported that only 7% of the patients have a tumour that is confined within the pancreas (National Cancer Institute, 2007).

Patients with suspected pancreatic cancer and imaging studies suggesting resectable tumour should undergo directly to surgery since no histologic diagnosis confirmation is required prior to surgical exploration unless neoadjuvant therapy is indicated (Zamboni et al., 2010).

As a matter of fact preoperative cytohistological diagnosis may risk dissemination of cancer cells, or developing complications (bleeding, pancreatitis, pancreatic leak) that can delay surgery and increase costs.

On the other hand a negative biopsy results in a patient with a high suspicion of cancer neoplasm that is not of help, due to a high possibility of a false negative result (Tillou et al., 1996).

Patients with metastatic or locally advanced but unresectable disease at imaging studies should undergo biopsy prior chemotherapy or radiation since a cytohistological diagnosis is recommended before initiating a cytostatic therapy coherently with the National Comprehensive Cancer Network (NCCN) guidelines for suspected pancreatic cancer. (Hartwig et al, 2009; Itani et al., 1997) Biopsies allow a cytohistological diagnosis and can differentiate pancreatic cancer between primary pancreatic lymphoma (Arcari et al., 2005), metastasis or benign focal lesion such as focal pancreatitis.

#### **3.1 Primary pancreatic lymphoma and pancreatic metastasis**

Primary pancreatic lymphoma (PPL) is a very rare disease, representing fewer than 2% of extra-nodal malignant lymphoma and 0,5% of all pancreatic masses (Arcari et al., 2005).

Fewer than 150 cases of PPL have been reported in the literature in English. Imaging techniques such as Us and CT scan can suggest a diagnosis of PPL but a cyto-hystological examination is mandatory for diagnosis and treatment planning of patients with suspicious PPL. Our group reported five cases of PPL and reviewing the literature it was concluded

Currently, imaging modalities for detection of pancreatic masses include ultrasonography (US), computed tomography (CT) scan, magnetic resonance imaging (MRI)/ magnetic

In clinical practice differential diagnosis of pancreatic masses is frequently a clinical challenge; often therapeutic decision in this context is mainly based on the ability to perform

It is well known that ductal adenocarcinoma is the most frequent cause of pancreatic mass, however other neoplasms such as lymphoma, metastasis, cystic tumors or benign conditions as chronic pancreatitis with different prognosis and treatment options can arise within the

A pathologic diagnosis becomes therefore relevant for an adequate therapeutic strategy

At least 80% of the patients with suspected pancreatic cancer, have unresectable disease at diagnosis because of locoregional involvement or distant metastases , and it as been reported that only 7% of the patients have a tumour that is confined within the pancreas

Patients with suspected pancreatic cancer and imaging studies suggesting resectable tumour should undergo directly to surgery since no histologic diagnosis confirmation is required prior to surgical exploration unless neoadjuvant therapy is indicated (Zamboni et al., 2010). As a matter of fact preoperative cytohistological diagnosis may risk dissemination of cancer cells, or developing complications (bleeding, pancreatitis, pancreatic leak) that can delay

On the other hand a negative biopsy results in a patient with a high suspicion of cancer neoplasm that is not of help, due to a high possibility of a false negative result (Tillou et al.,

Patients with metastatic or locally advanced but unresectable disease at imaging studies should undergo biopsy prior chemotherapy or radiation since a cytohistological diagnosis is recommended before initiating a cytostatic therapy coherently with the National Comprehensive Cancer Network (NCCN) guidelines for suspected pancreatic cancer. (Hartwig et al, 2009; Itani et al., 1997) Biopsies allow a cytohistological diagnosis and can differentiate pancreatic cancer between primary pancreatic lymphoma (Arcari et al., 2005),

Primary pancreatic lymphoma (PPL) is a very rare disease, representing fewer than 2% of extra-nodal malignant lymphoma and 0,5% of all pancreatic masses (Arcari et al., 2005).

Fewer than 150 cases of PPL have been reported in the literature in English. Imaging techniques such as Us and CT scan can suggest a diagnosis of PPL but a cyto-hystological examination is mandatory for diagnosis and treatment planning of patients with suspicious PPL. Our group reported five cases of PPL and reviewing the literature it was concluded

metastasis or benign focal lesion such as focal pancreatitis.

**3.1 Primary pancreatic lymphoma and pancreatic metastasis** 

a diagnosis of malignancy or to exclude malignancy (Tamm & Charnsangavej, 2001).

resonance cholangiopancreatography, endoscopic ultrasonography (EUS).

**3. Diagnosis of pancreatic neoplasia** 

pancreas (Iglesias et al., 2010).

(National Cancer Institute, 2007).

surgery and increase costs.

1996).

(Cohen et al., 2000).

that 1) imaging techniques can suggest the suspicion of PPL, however are unable to distinguish PPL from pancreatic adenocarcinoma, 2) histological diagnosis can be easily obtained by percutaneous Us-guided tissue core biopsy 3)surgery can be avoided both for diagnosis and therapy, but the treatment of choice of PPL may only be evaluated on a larger series of patients (Arcari et al., 2005).

Metastases to the pancreas are rare; in a survey of 4,955 autopsies (Adsay et al., 2004) a rate of metastasis to the pancreas of 3,83% was described and a significantly different distribution of metastatic neoplasms, with lung and gastrointestinal tumors comprising by far the largest proportion.

In a retrospective review of 1,172 pancreatic endoscopic ultrasound-guided fine-needle aspiration biopsy , 25 cases (2,1%) had a confirmed diagnosis of pancreatic metastasis.

This included 12 cases of renal cell carcinoma, 3 (12%) melanomas, 3 (12%) small cell carcinomas and 7 (28%) other malignancies.

In these metastatic tumors involving the pancreas 20 (80%) of the lesions were solitary.

Four cases (16%) had no prior history of malignancy; the average time of diagnosis of pancreatic metastasis was 5.3 years.

Immunohistochemistry and special stains were performed in 22 (88%) and 9 (36%) cases respectively (Gilbert et al., 2011).

#### **4. Staging of pancreatic cancer (table 1)**

Staging procedures include US, CT scanning, MRI, and EUS. A diagnostic laparoscopy may also be performed to detect peritoneal disease that is not visible radiologically. Regardless of these studies, an accurate histologic diagnosis is necessary to distinguish benign disease from carcinoma, islet cell tumors, and retroperitoneal lymphomas, because of the major therapeutic and prognostic differences among these disease entities. Criteria for surgical resection include absence of metastatic disease and absence of invasion of prominent local blood vessels.

#### **5. Guide for pancreatic biopsy**

Intraoperative needle biopsy of the pancreas has been performed with the fine-needle aspiration biopsy (FNAB) technique since the 1960's (Moossa & Altorki, 1983) and with the core tissue biopsy technique since 1970's (Ingram et al., 1978) subsequently ultrasound , computed tomography and endoscopic ultrasound became available to evaluate and characterize pancreatic masses and above all to guide a needle for the biopsy, avoiding the costs, morbidity and mortality of a major surgical procedure performed only to obtain a tissue sample for a cytohistological diagnosis (Civardi et al.,1986; Turner et a.l, 2010).

For many years percutaneous US and /or CT guided biopsy was routinely performed in situations in which a pancreatic biopsy was necessary, in 2002 the American Joint Committee on cancer has selected endoscopic ultrasound guided FNAB as "the procedure of choice" if available (Greene et al., 2002).

However, as recently reported, local expertise in and the availability of EUS and interventional radiology may determine the first procedure selected for a cytohistological diagnosis for a pancreatic mass (Zamboni et al., 2010 ).

Role of Guided-Fine Needle Biopsy of the Pancreatic Lesion 241

Prior to perform the biopsy, a pancreatic lesion can be studied with conventional US, Doppler US, and CT, to evaluate the content of the lesion and to select the best route for

In clinical practice when liver metastases are present in patients with suspected pancreatic cancer, the biopsy can be done in the liver metastasis, if safer for the patient and easier for

Computed tomography allows optimal visualization of the lesion and is superior to US in large fat patients , however radiation dose and the procedure length are the major limits of

CT fluoroscopy can reduce procedure length because it allows a fast reconstruction of images, with a continuous update and the possibility of controlling acquisition and

In addiction CT fluoroscopy allows visualizing the needle track from the entry point to the

Over the past decade, EUS has proven to be one of the most significant advantages in gastrointestinal endoscopy (Turner et al., 2010; Erickson, 2004) Since its introduction, EUS has offered improved accessibility to small pancreatic lesions, and its usefulness as a

Since it was first reported in (Chang et al, 1994), EUS-guided FNAB of the pancreas has become a popular technique for the diagnosis and staging of cystic and solid lesions of the

Thus, this diagnostic modality has become important in the management of patients with

The relative diagnostic accuracy, safety and cost of US and CT-guided FNAB favor their use over EUS-FNAB for the diagnosis of unresectable pancreatic tumors. (Zamboni et al., 2010 ;

A randomized controlled trial EUS-FNAB and US/CT-FNAB failed to observe any statistically significant difference between the endoscopic and percutaneous approach in the

Several authors support the use of EUS-FNAB over percutaneuos approach because of the lower risk of seeding (Gilbert et al, 2001; Turner et al, 2010). In a review of 1406 cases with advanced pancreatic cancer who underwent nonsurgical biopsy (percutaneous-guided or EUS-guided sampling) were compared with cases who did not undergo biopsy, without observing any difference in overall median survival, so it was concluded that the risk of

diagnostic tool has greately changed the therapeutic approach to pancreatic masses.

visualizing images in the room while performing the examination.

target, allowing faster and more efficient procedure (Zamboni et al., 2010).

pancreas because it is relatively safe and accurate (Carrara et al., 2010;).

symptomatic or incidentally discovered pancreatic masses.

diagnosis of pancreatic malignancy (Horwhat et al.,2006).

**5.4.1 US, CT, or EUS for guide pancreatic FNAB** 

biopsy, avoiding vessels and pleura.

**5.3 Computed tomography** 

CT -guided pancreatic biopsy.

**5.4 Endoscopic ultrasound** 

Levy, 2006).

the psysician.


Table 1. Staging of pancreatic carcinoma

#### **5.1 Methods of percutaneous guided biopsy**

Patient preparation before any type of invasive procedure includes ruling out coagulation disorders with laboratory tests and obtaining written informed consent for the biopsy. Local anesthesia (lidocaine) is not routinely performed. (Zamboni et al., 2010; Civardi et al., 1986).

#### **5.2 Percutaneous ultrasound**

In the past for performing abdominal US-guided FNAB the "free-hand" technique was utilized (Civardi et al., 1986; Bret et al., 1982; Livraghi, 1984) subsequently puncturing probe became available and two types of probes are commonly used for interventional procedures: probes with lateral support and probes with noncontinuous crystals and central support; the former allow only oblique needle tracks, whereas the latter allow both vertical and oblique tracks.

Prior to perform the biopsy, a pancreatic lesion can be studied with conventional US, Doppler US, and CT, to evaluate the content of the lesion and to select the best route for biopsy, avoiding vessels and pleura.

In clinical practice when liver metastases are present in patients with suspected pancreatic cancer, the biopsy can be done in the liver metastasis, if safer for the patient and easier for the psysician.

#### **5.3 Computed tomography**

240 Pancreatic Cancer – Clinical Management

T1 Tumor limited to the pancreas 2 cm or less in greatest dimension T2 Tumor limited to the pancreas more than 2 cm in greatest dimension T3 Tumor extends beyond the pancreas but without involvement of celiac

T4 Tumor involves the celiac axis or the superior mesenteric artery

axis or the superior mesenteric artery

Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB T2 N0 M0 Stage IIA T3 N0 M0 Stage IIB T1-3 N1 M0 Stage III T4 Any N M0 Stage IV Any T Any N M1

Patient preparation before any type of invasive procedure includes ruling out coagulation disorders with laboratory tests and obtaining written informed consent for the biopsy. Local anesthesia (lidocaine) is not routinely performed. (Zamboni et al., 2010; Civardi et al., 1986).

In the past for performing abdominal US-guided FNAB the "free-hand" technique was utilized (Civardi et al., 1986; Bret et al., 1982; Livraghi, 1984) subsequently puncturing probe became available and two types of probes are commonly used for interventional procedures: probes with lateral support and probes with noncontinuous crystals and central support; the former allow only oblique needle tracks, whereas the latter allow both vertical and oblique

(unresectable primary tumor)

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis

MX Distant metastasis cannot be assessed

**Prymary Tumor (T)**

Tis In situ carcinoma

**Regional Lymph Nodes (N)**

**Distant Metastasis (M)**

**Stage grouping**

M0 No distant metastasis M1 Distant metastasis

Table 1. Staging of pancreatic carcinoma

**5.2 Percutaneous ultrasound** 

tracks.

**5.1 Methods of percutaneous guided biopsy** 

TX Primary tumor cannot be assessed T0 No evidence of primary tumor

> Computed tomography allows optimal visualization of the lesion and is superior to US in large fat patients , however radiation dose and the procedure length are the major limits of CT -guided pancreatic biopsy.

> CT fluoroscopy can reduce procedure length because it allows a fast reconstruction of images, with a continuous update and the possibility of controlling acquisition and visualizing images in the room while performing the examination.

> In addiction CT fluoroscopy allows visualizing the needle track from the entry point to the target, allowing faster and more efficient procedure (Zamboni et al., 2010).

#### **5.4 Endoscopic ultrasound**

Over the past decade, EUS has proven to be one of the most significant advantages in gastrointestinal endoscopy (Turner et al., 2010; Erickson, 2004) Since its introduction, EUS has offered improved accessibility to small pancreatic lesions, and its usefulness as a diagnostic tool has greately changed the therapeutic approach to pancreatic masses.

Since it was first reported in (Chang et al, 1994), EUS-guided FNAB of the pancreas has become a popular technique for the diagnosis and staging of cystic and solid lesions of the pancreas because it is relatively safe and accurate (Carrara et al., 2010;).

Thus, this diagnostic modality has become important in the management of patients with symptomatic or incidentally discovered pancreatic masses.

#### **5.4.1 US, CT, or EUS for guide pancreatic FNAB**

The relative diagnostic accuracy, safety and cost of US and CT-guided FNAB favor their use over EUS-FNAB for the diagnosis of unresectable pancreatic tumors. (Zamboni et al., 2010 ; Levy, 2006).

A randomized controlled trial EUS-FNAB and US/CT-FNAB failed to observe any statistically significant difference between the endoscopic and percutaneous approach in the diagnosis of pancreatic malignancy (Horwhat et al.,2006).

Several authors support the use of EUS-FNAB over percutaneuos approach because of the lower risk of seeding (Gilbert et al, 2001; Turner et al, 2010). In a review of 1406 cases with advanced pancreatic cancer who underwent nonsurgical biopsy (percutaneous-guided or EUS-guided sampling) were compared with cases who did not undergo biopsy, without observing any difference in overall median survival, so it was concluded that the risk of

Role of Guided-Fine Needle Biopsy of the Pancreatic Lesion 243

**(%) guidance needle** 

**size authors** 

(1998)

(2008)

(2002)

(2008)

(2005)

(2006)

(2010)

et al (2007)

Zamboni (2005)

**accuracy** 

510 87 100 95 US 21-22 Di Stasi et al

267 81 - - US 22 Bhatia et al

222 89 98 91 US 22 (20,25) Garre Sanchez

104 77.9 100 81.7 US - Volmar et al;

70 80 100 81 CT/US - Mallery et al

50 78.6 100 82 CT - Volmar et al

36 62 100 72 CT/US 20-22 Horwhat et al

545 99.4 - 99.4 US 21-22 Zamboni et al

pancreas. Retrieval rate, sensitivity, specificity, and overall diagnostic accuracy of the whole series, by three different bioptic procedures (cytology, histology and cytology plus histology) were evaluated. The reliability of ultrasound-guided fine needle biopsy to allow a correct diagnosis in the different pancreatic pathologies was calculated for cytology, histology, and cytology plus histology, retrieval rate values were: 94%, 96%, and 97%; sensitivity was: 87%, 94%, and 94%, specificity:100%; and diagnostic accuracy: 91%, 90% and

In a series of 545 US-guided FNAB, 93,4% procedures were diagnostic, with an overall 99,4%

The largest series reporting in the literature percutaneous FNAB of pancreatic masses show sensitivities ranging between 62% and 93%, accuracies between 72% and 94%. The majority of percutaneous FNAB are ultrasound guided, and the needle size range from 21 to 22 G

FNAB cytology of pancreatic cancer are reported in figure 1 a , b, 2 a, b, 3 a, b;

Table 2. Sensitivity, specificity, accuracy method of guidance and needle size (gauge) of

percutaneous fine needle aspiration biopsy of pancreatic masses

sensitivity and 99.4% accuracy (Zamboni et al., 2010).

59 93 100 93 US 22 Matsubara et al

**N° of patients** 

95%, respectively.

(Tab 2).

**sensitivity (%)** 

**specificity (%)** 

seeding is remote. (Hernandez et al., 2009). It was reported that the risk of seeding can be related to the number of needle passes: more number of needle passes more risk of seeding (Civardi et al., 1986; Fornari et al., 1989).

It must be emphasized that one-site cytopathological evaluation can improve the diagnostic yield of guided FNAB and can reduce the number of needle passes (Garcia et al., 2011).

A review of 182 patients undergoing EUS-guided FNAB of solid pancreatic lesions over a 2 years study period was reported (Garcia et al., 2011). Sample were either evaluated on site by a cytopathologist or processed by the endoscopist and sent to the pathology department for evaluation.

Diagnostic accuracy for malignancy, number of needle passes, adequate – specimen collection rate, cytological diagnosis , and final diagnosis and complications rate according to the presence or absence of on-site cytopathologist were evaluated.

A significantly higher number of needle passes was performed when an on-site cytopathologist was not available (3.5+- 1.0 vs 2.0+-0.7; p< 0.001). The presence of an on-site cytopathologist was associated with a significant lower number of inadequate samples (1.0 vs 12.6%; p=0.002) and a significantly higher diagnostic sensivity (96.2 vs 78.2%; p=0.002), and overall accuracy (96.8 vs 86.2%; p=0.013) for malignancy (Garcia et al., 2011).

Already, in 1988 our group reported the value of rapid staining and assessment of percutaneous ultrasound-guided fine needle aspiration biopsy in a series of 160 patients. (Civardi et al., 1988) The total series of FNAB had a sensitivity of 95.6%, a specificity of 100% and an overall accuracy of 97.3%.

The cumulative accuracy after each pass was calculated: a significant increase in diagnostic accuracy was found only after the second pass, the third and the fourth passes gave little further improvement. These results indicate that a rapid evaluation of the aspirated material during US-guided FNAB can reduce the number of punctures needed per case resulting in less disconfort and, probably a reduced likelihood of complications for the patient.

It must be emphasized that in this study the same physicians that performed the US-FNAB performed also the rapid staining evaluation for the adequacy avoiding the cytopathologist, minimizing the costs and improving the educational benefit of physicians. (Civardi et al., 1988).

#### **5.4.2 Type of needle and results of guided biopsy**

Biopsies of the pancreas can be performed with needle ranging in size from 18 to 25 gauge (G). Aspiration biopsies for cytological evaluation are performed with fine-needle (< 1mm in external diameter : from 20 to 25 G), cutting needle are used to obtain tissue cores, which allow hystopathological evaluation , these needle ranging in size from 18 to 23 G.

In table 2 are reported the results of sensitivity, specificity, overall accuracy, method of guidance, needle size of percutaneous pancreatic fine-needle aspiration biopsy.

Our group (Di Stasi et al., 1998) in a multicenter study reviewed 510 patients who had a final diagnosis available and who had undergone ultrasound-guided fine needle biopsy of the

seeding is remote. (Hernandez et al., 2009). It was reported that the risk of seeding can be related to the number of needle passes: more number of needle passes more risk of seeding

It must be emphasized that one-site cytopathological evaluation can improve the diagnostic yield of guided FNAB and can reduce the number of needle passes (Garcia et al., 2011).

A review of 182 patients undergoing EUS-guided FNAB of solid pancreatic lesions over a 2 years study period was reported (Garcia et al., 2011). Sample were either evaluated on site by a cytopathologist or processed by the endoscopist and sent to the pathology department

Diagnostic accuracy for malignancy, number of needle passes, adequate – specimen collection rate, cytological diagnosis , and final diagnosis and complications rate according

A significantly higher number of needle passes was performed when an on-site cytopathologist was not available (3.5+- 1.0 vs 2.0+-0.7; p< 0.001). The presence of an on-site cytopathologist was associated with a significant lower number of inadequate samples (1.0 vs 12.6%; p=0.002) and a significantly higher diagnostic sensivity (96.2 vs 78.2%; p=0.002),

Already, in 1988 our group reported the value of rapid staining and assessment of percutaneous ultrasound-guided fine needle aspiration biopsy in a series of 160 patients. (Civardi et al., 1988) The total series of FNAB had a sensitivity of 95.6%, a specificity of 100%

The cumulative accuracy after each pass was calculated: a significant increase in diagnostic accuracy was found only after the second pass, the third and the fourth passes gave little further improvement. These results indicate that a rapid evaluation of the aspirated material during US-guided FNAB can reduce the number of punctures needed per case resulting in

It must be emphasized that in this study the same physicians that performed the US-FNAB performed also the rapid staining evaluation for the adequacy avoiding the cytopathologist, minimizing the costs and improving the educational benefit of physicians. (Civardi et al.,

Biopsies of the pancreas can be performed with needle ranging in size from 18 to 25 gauge (G). Aspiration biopsies for cytological evaluation are performed with fine-needle (< 1mm in external diameter : from 20 to 25 G), cutting needle are used to obtain tissue cores, which

In table 2 are reported the results of sensitivity, specificity, overall accuracy, method of

Our group (Di Stasi et al., 1998) in a multicenter study reviewed 510 patients who had a final diagnosis available and who had undergone ultrasound-guided fine needle biopsy of the

and overall accuracy (96.8 vs 86.2%; p=0.013) for malignancy (Garcia et al., 2011).

less disconfort and, probably a reduced likelihood of complications for the patient.

allow hystopathological evaluation , these needle ranging in size from 18 to 23 G.

guidance, needle size of percutaneous pancreatic fine-needle aspiration biopsy.

to the presence or absence of on-site cytopathologist were evaluated.

(Civardi et al., 1986; Fornari et al., 1989).

and an overall accuracy of 97.3%.

**5.4.2 Type of needle and results of guided biopsy** 

for evaluation.

1988).


Table 2. Sensitivity, specificity, accuracy method of guidance and needle size (gauge) of percutaneous fine needle aspiration biopsy of pancreatic masses

pancreas. Retrieval rate, sensitivity, specificity, and overall diagnostic accuracy of the whole series, by three different bioptic procedures (cytology, histology and cytology plus histology) were evaluated. The reliability of ultrasound-guided fine needle biopsy to allow a correct diagnosis in the different pancreatic pathologies was calculated for cytology, histology, and cytology plus histology, retrieval rate values were: 94%, 96%, and 97%; sensitivity was: 87%, 94%, and 94%, specificity:100%; and diagnostic accuracy: 91%, 90% and 95%, respectively.

In a series of 545 US-guided FNAB, 93,4% procedures were diagnostic, with an overall 99,4% sensitivity and 99.4% accuracy (Zamboni et al., 2010).

The largest series reporting in the literature percutaneous FNAB of pancreatic masses show sensitivities ranging between 62% and 93%, accuracies between 72% and 94%. The majority of percutaneous FNAB are ultrasound guided, and the needle size range from 21 to 22 G (Tab 2).

FNAB cytology of pancreatic cancer are reported in figure 1 a , b, 2 a, b, 3 a, b;

Role of Guided-Fine Needle Biopsy of the Pancreatic Lesion 245

Fig. 2. a. FNAB of pancreatic moderately differentiated pancreatic adenocarcinoma.

Fig. 2. b. Clusters of cells with some acinar arrangement. PAP x 400

MMG x 200

Fig. 1. a. FNAB of pancreatic well-differentiated adenocarcinoma, (a) relatively mild nuclear atypia, but nuclear crowding. MGG x 200

Fig. 1. b. Well evident microglandular arrangement. PAP x 400

Fig. 1. a. FNAB of pancreatic well-differentiated adenocarcinoma, (a) relatively mild nuclear

atypia, but nuclear crowding. MGG x 200

Fig. 1. b. Well evident microglandular arrangement. PAP x 400

Fig. 2. a. FNAB of pancreatic moderately differentiated pancreatic adenocarcinoma. MMG x 200

Fig. 2. b. Clusters of cells with some acinar arrangement. PAP x 400

Role of Guided-Fine Needle Biopsy of the Pancreatic Lesion 247

Fig. 4. a. FNAB of pancreatic mass showing metastatic melanoma large cells. MGG x 400

Fig. 4. b. Immunocytochemical HMB-45 positivity consistent with metastatic melanoma X 400

and FNAB cytology of pancreatic metastasis is reported in figure 4 a, b.

Fig. 3. a. FNAB of pancreatic poorly differentiated pancreatic adenocarcinoma, a cluster of cancer cells. MGG x 400

Fig. 3. b. Cancer cells with strong reactivity to CK 7 antiboby. X 400

Fig. 3. a. FNAB of pancreatic poorly differentiated pancreatic adenocarcinoma, a cluster of

Fig. 3. b. Cancer cells with strong reactivity to CK 7 antiboby. X 400

cancer cells. MGG x 400

and FNAB cytology of pancreatic metastasis is reported in figure 4 a, b.

Fig. 4. a. FNAB of pancreatic mass showing metastatic melanoma large cells. MGG x 400

Fig. 4. b. Immunocytochemical HMB-45 positivity consistent with metastatic melanoma X 400

Role of Guided-Fine Needle Biopsy of the Pancreatic Lesion 249

Fig. 5. a. Tissue core biopsy of a pancreatic mass. H&E X 20

Fig. 5. b. Diffuse large B-cell Lymphoma CD20 positive. X 400


Sensitivity, specificity, accuracy method of guidance and needle size of percutaneous tissue core biopsy of pancreatic masses are reported in table 3.

Table 3. Sensitivity, specificity, accuracy method of guidance and needle size (gauge) of percutaneous tissue core biopsy of pancreatic masses

372 CT-guided pancreatic biopsies with a 18 G cutting needle showed 90% sensitivity and accuracy (Karlson et al., 1996); similar results were reported in a series of 212 US guided percutaneous tissue core pancreatic biopsies, with 86% sensitivity and accuracy (Paulsen et al., 2006).

The largest series in the literature on percutaneous tissue core biopsy of pancreatic lesions report sensitivities and accuracies between 86% and 100% (Tab 3). Tissue core biopsy of primary pancreatic lymphoma and metastatic adenocarcinoma are reported in fig 5 a b and 6 a b c. Percutaneous core biopsy of pancreatic lesions is considered sensitive, safe and accurate (Zanaboni et al., 2010) however this procedure may have a higher complication rate than percutaneous FNAB (Fornari et al., 1989).

At our institution we routinely use FNAB with 22G needles when a pathologic diagnosis of pancreatic mass is required while tissue core biopsy with 20G or 21G needles is reserved when cytological diagnosis is inadequate or when lymphoma is suspected on cytological evaluation (Arcari et al., 2005) Fig 5 a, b.

Sensitivity, specificity, accuracy method of guidance and needle size of percutaneous tissue

accuracy (%)

372 90 - 90 CT 18 Amin et al

100 90 - - US - Karlson et al

92 92.5 100 93.3 US 18 Paulsen et al

50 90.4 - 92 US - Elvin et all

18 100 1 100 CT 18 Paulsen et al

Table 3. Sensitivity, specificity, accuracy method of guidance and needle size (gauge) of

372 CT-guided pancreatic biopsies with a 18 G cutting needle showed 90% sensitivity and accuracy (Karlson et al., 1996); similar results were reported in a series of 212 US guided percutaneous tissue core pancreatic biopsies, with 86% sensitivity and accuracy (Paulsen et

The largest series in the literature on percutaneous tissue core biopsy of pancreatic lesions report sensitivities and accuracies between 86% and 100% (Tab 3). Tissue core biopsy of primary pancreatic lymphoma and metastatic adenocarcinoma are reported in fig 5 a b and 6 a b c. Percutaneous core biopsy of pancreatic lesions is considered sensitive, safe and accurate (Zanaboni et al., 2010) however this procedure may have a higher complication rate

At our institution we routinely use FNAB with 22G needles when a pathologic diagnosis of pancreatic mass is required while tissue core biopsy with 20G or 21G needles is reserved when cytological diagnosis is inadequate or when lymphoma is suspected on cytological

percutaneous tissue core biopsy of pancreatic masses

than percutaneous FNAB (Fornari et al., 1989).

evaluation (Arcari et al., 2005) Fig 5 a, b.

guidan ce

needle

size authors

(2006)

Matsubara et al (2008)

Jennings et al (1989)

(1996)

(2006)

(1990)

(2006)

core biopsy of pancreatic masses are reported in table 3.

specificity (%)

212 86 100 86 US 21

142 90.9 - 92.6 US -

sensitivity (%)

N° of patients

al., 2006).

Fig. 5. a. Tissue core biopsy of a pancreatic mass. H&E X 20

Fig. 5. b. Diffuse large B-cell Lymphoma CD20 positive. X 400

Role of Guided-Fine Needle Biopsy of the Pancreatic Lesion 251

Since it was developed endoscopic ultrasound-guided fine needle aspiration biopsy has been widely used and has been adapted for gastrointestinal and perigastrointestinal lesions. A medical literature review to evaluate the role of EUS-FNAB for diagnosis of pancreatic masses showed a 78-95% sensitivity, 75-100% specificity, 98-100% positive predictive value

**N of patients Sensitivity % Specificity % Accuracy% Needle size Authors** 

583 84 86 84 22-26 Siddiqui

100 78 75 78 22 Touchefeu

182\* 78.2-96.2\* 98.4 86.2-96.8\* 22 Garcia

737 77 99 80 22-25 Turner

207 92.6 88.6 91.8 22 Klimet

Table 4. Sensitivity, specificity, accuracy needle size of endoscopic-guide pancreatic biopsy

\* The presence of an on site-cytopathologist was associated with a significantly higher diagnostic

et al (2011)

et al (2009)

et al (2011)

et al (2010)

et al(2010)

Fig. 6. c. Estrogen receptor positive neoplastic cells. X100

and a 78-95% accuracy (Yoshinaga et al, 2011) (Tab 4).

sensitivity and overall accuracy for malignancy.

Fig. 6. a. Tissue core biopsy of a pancreatic mass. H&E x 20

Fig. 6. b. Histology shows metastasis from endometrial adenocarcinoma. H&E X 100

Fig. 6. a. Tissue core biopsy of a pancreatic mass. H&E x 20

Fig. 6. b. Histology shows metastasis from endometrial adenocarcinoma. H&E X 100

Fig. 6. c. Estrogen receptor positive neoplastic cells. X100

Since it was developed endoscopic ultrasound-guided fine needle aspiration biopsy has been widely used and has been adapted for gastrointestinal and perigastrointestinal lesions.

A medical literature review to evaluate the role of EUS-FNAB for diagnosis of pancreatic masses showed a 78-95% sensitivity, 75-100% specificity, 98-100% positive predictive value and a 78-95% accuracy (Yoshinaga et al, 2011) (Tab 4).


\* The presence of an on site-cytopathologist was associated with a significantly higher diagnostic sensitivity and overall accuracy for malignancy.

Table 4. Sensitivity, specificity, accuracy needle size of endoscopic-guide pancreatic biopsy

Role of Guided-Fine Needle Biopsy of the Pancreatic Lesion 253

Bhatia P, Srinivasan R, Rajwanshi A, et al (2008) 5 Year review and reappraisal of

Bret PM, Fond A, Bretagnolle M, et al. (1982) Une technique simple de guidage des Ponctions Percutanees Par l'echographie en temps reel. J Radiol ; 63 : 363-365. Carrara S, Arcidiacono PG, Mezzi G,et al, (2010). Pancreatic Endoscopic Ultrasound-guided

Chang KJ, Albers CG, Erickson RA, et al (1994). Endoscopic ultrasound-guided fine needle

Civardi G, Fornari F, Cavanna L et al. (1988) Value of rapid Staining and Assessment of Ultrasound-guided Fine Needle Aspiration Biopsies. Acta Cytologica 32;4. Civardi G, Fornari F, Cavanna L, et al (1986). Ultrasonically guided fine needle aspiration

malignancies. European Journal of Cancer & Clinical Oncology; 2: 225-227.

Cohen SJ, Pinover WH, Watson JC et al. (200) Pancreatic cancer. Curr TRat Options Oncol;

Di Stasi M, Lencioni R, Solmi L, et al (1998) Ultrasound-guided fine needle biopsy of pancreatic masses: results of a multi center study. Am J Gastroenterol 93:1329-1333 Elvin A, Andersson T, Scheibenpflug L, et al (1990) Biopsy of the pancreas with a biopsy

Fornari F, Civardi G, Cavanna L et al. (1989) Complications of ultrasonically guided fine-

literature. The Cooperative Study Group. Scand J Gastroenterol 24(8):949-55 Garcia JI, Larino-Noia J, Abdulkader I et al. Quantitative endoscopic ultrasound

Garcia JI, Dominguez-Munoz E, Abdulkader I et al. (2011) Influence of On-Site Cytopathology

Hartwig W, Schneider L, Diener MK, et al (2009) Preoperative tissue diagnosis for tumours

Hernandez LV, Bhutani MS, Eisner M et al. (2009) Non-surgical tissue biopsy among

Horwhat JD, Paulson EK, McGrath K, et al. (2006)A randomized comparison of EUS-guided

Ingram DM, Sheiner HJ, Shilkin KB. (1978) Operative biopsy of the pancreas using the

Itani KM, Taylor TV, Green LK. Needle biopsyfor suspicious lesions of the head of the pancreas: pitfalls and implications for therapy. J Gastrointest Surg 1997; 1: 337-341

patients with advanced pancreatic cancer: effect on survival. Pancreas 38(3):289-292

FNA versus CT or US-guided FNA for the evaluation of pancreatic mass lesions.

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needle abdominal biopsy. Results of a multicenter Italian study and review of the

elastography: an accurate method for the differentiation of solid pancreatic masses.

Evaluation on the Diagnostic Accuracy of Endoscopic Ultrasound-Guided Fine Needle Aspiration (EUS-FNA) of Solid Pancreatic Masses. Am J Gastroenterol. Garre Sanchez MC, Rendon Unceta P, Lopez Cano A, et al (2007) Ultrasound-guided biopsy of the pancreas: a multicenter study. Rev Esp Enferm Dig 99:520-524 Gilbert CM, Monaco SE, Cooper ST, Khalbuss WE. (2011) Endoscopic ultrasound-guided fineneedle aspiration of metastases to the pancreas: a sudy of 25 cases. Cyjournal 2011; 8:1 Greene F, Fritz A, Balch C et al. (2002) Exocrine pancreas. Cancer Staging Handbook.

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Fine Needle Apiration: Complication rate and clinical course in a single centre. Dig

biopsy (UG-FNAB): a useful technique for the diagnosis of abdominal

#### **6. Complications of pancreatic biopsy**

US, EUS or CT guided fine-needle biopsy are considered to be a low risk procedure.

Interventions with needle with a larger diameter seem cause more complications.

The major complication of pancreatic biopsy can be hemorrhage, needle track seeding and pancreatitis.

Our group (29) reported the complications following 10.766 US-guided fine-needle abdominal biopsies. The mortality was 0.018%: the two reported deaths were due to hemoperitoneum and occurred in patients with hepatocellular carcinoma arizing in cirrotic liver.

The biopsy of pancreatic carcinoma was more dangerous for needle –track seeding (five of eight reported cases), however, it has been reported that peritoneal carcinomatosis may occur more frequently in patients who undergo percutaneous FNAB compared with those who have FUS-FNAB for the diagnosis of pancreatic cancer (Micames et al, 2003).

#### **6.1 Conclusions**

There is consensus in the literature of the appropriateness of obtaining a cytohystological diagnosis in patients with unresectable pancreatic neoplastic lesion, prior to initiate chemotherapy and/or radiation.

Although the American Joint Committeee on Cancer has selected EUS-guided FNAB as the procedure of choice, if available, we recall that there is wide variability in the world on the modalities for guide biopsy (US ; CT ; EUS) and for needle biopsy choice (FNAB or tissue core biopsy).

There is a consensus that local expertise, the availability of EUS and interventional percutaneous procedures may determine the choice for pancreatic biopsy.

In agreement with other authors (Zamboni et al., 2010) at our institution , in the appropriate setting, percutaneous US-guided FNAB is considered the first invasive approach of obtaining tissue diagnosis confirmation in patients with unresectable lesions.

However, guided FNAB or guided tissue core biopses remain invasive procedures and must be performed when informations so obtained benefits the patient.

#### **7. Acknowledgments**

Authors thanks Michela Monfredo, Gabriele Cremona and MariaRosa Cordani for the important support.

#### **8. References**

Adsay NV, Adea A, Basturk O, Kilnc N, Nassar H, Cheng JD. Secondary tumours of the pancreas: An analisys of a surgical and autopsy database and review of the literature. Virchows Arch 2004; 444:527-35.

American Cancer Society. (2002) Facts and figures. Atlanta, GA: American Cancer Society.


The major complication of pancreatic biopsy can be hemorrhage, needle track seeding and

Our group (29) reported the complications following 10.766 US-guided fine-needle abdominal biopsies. The mortality was 0.018%: the two reported deaths were due to hemoperitoneum and

The biopsy of pancreatic carcinoma was more dangerous for needle –track seeding (five of eight reported cases), however, it has been reported that peritoneal carcinomatosis may occur more frequently in patients who undergo percutaneous FNAB compared with those who have FUS-

There is consensus in the literature of the appropriateness of obtaining a cytohystological diagnosis in patients with unresectable pancreatic neoplastic lesion, prior to initiate

Although the American Joint Committeee on Cancer has selected EUS-guided FNAB as the procedure of choice, if available, we recall that there is wide variability in the world on the modalities for guide biopsy (US ; CT ; EUS) and for needle biopsy choice (FNAB or tissue

There is a consensus that local expertise, the availability of EUS and interventional percutaneous

In agreement with other authors (Zamboni et al., 2010) at our institution , in the appropriate setting, percutaneous US-guided FNAB is considered the first invasive approach of obtaining

However, guided FNAB or guided tissue core biopses remain invasive procedures and must be

Authors thanks Michela Monfredo, Gabriele Cremona and MariaRosa Cordani for the

Adsay NV, Adea A, Basturk O, Kilnc N, Nassar H, Cheng JD. Secondary tumours of the

Arcari A, Anselmi E, Bernuzzi P, et al (2005). Primary pancreatic lymphoma. Report of five

American Cancer Society. (2002) Facts and figures. Atlanta, GA: American Cancer Society. Amin Z, Theis B, Russel RC, et al (2006) Diagnosing pancreatic cancer: the role of percutaneous

pancreas: An analisys of a surgical and autopsy database and review of the

US, EUS or CT guided fine-needle biopsy are considered to be a low risk procedure. Interventions with needle with a larger diameter seem cause more complications.

occurred in patients with hepatocellular carcinoma arizing in cirrotic liver.

FNAB for the diagnosis of pancreatic cancer (Micames et al, 2003).

procedures may determine the choice for pancreatic biopsy.

tissue diagnosis confirmation in patients with unresectable lesions.

performed when informations so obtained benefits the patient.

literature. Virchows Arch 2004; 444:527-35.

biopsy and Ct. Clin Radiol 61:996-1002

cases. Haematologica; 90: (3) e23-e26.

**6. Complications of pancreatic biopsy** 

pancreatitis.

**6.1 Conclusions** 

core biopsy).

**7. Acknowledgments** 

important support.

**8. References** 

chemotherapy and/or radiation.


**15**

*Romania* 

**Coagulation Disorders in**

A. Albu, D. Gheban, C. Grad and D.L. Dumitrascu

*University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca,* 

The association between cancers and thrombosis is well known for a long period of time. In 1865 Armand Trousseau noted for the first time that unexpected or migratory thrombophlebitis could be a sign of an undiagnosed visceral malignancy (Trousseau, 1865). Some years later it is said that he observed this complication on himself in the context of an

The risk of developing thrombosis in cancer patients is considered to be increased 2- 7 fold compared with persons without cancer (Bloom et al, 2005; Heit et al, 2004). This risk is dependent on many factors. According to the type of tumor, the risk is thought to be the highest in tumors of the ovary, pancreas and central nervous system. Also the extent of the tumor, the presence of metastasis, age, immobility and the type of therapy increase this risk. Surgery for cancers (Rahr & Sørensen, 1992) and chemotherapy (Levine, 1997) are both associated with an important risk of venous thrombosis and embolism. In a large casecontrol study that included 3220 patients with cancer, it was reported an overall 7 times increased risk for venous thrombosis that depend on type of cancer and time since the cancer diagnosis. A very high relative risk was found for gastrointestinal, lung and hematological malignancies. Advanced stage of disease was associated with a further

Patients with cancer who develop venous thromboembolism have a poor prognosis than those without this vascular complication. The risk of recurrent thromboembolism and death from any cause is greater than three fold in patients with cancer compared to those without

Epidemiological studies looking for the incidence of cancer in patients with thromboembolic events found out that in 15-20% of patients, thromboses were associated with malignancy

The association of cancer and thrombosis raises two distinct problems. On one hand, the diagnosis of thrombosis in one patient may represent, in some situations, a sign of an occult malignancy. On the other hand, a patient with cancer may develop some time, in the evolution of his malignant disease, a thromboembolic event, which may worsen his

occult gastric cancer that cased his death (Khorana, 2003).

**1. Introduction** 

increase in risk (Blom et al, 2005).

malignancy (Levitan et al, 1999).

(Er & Zacharsky, 2006).

**Pancreatic Cancer** 

Jennings PE, Donald JJ, Coral A, et al (1989) Ultrasound –guided core biopsy. Lancet 1:1369-1371

