Ampullary carcinoma

Dr .Touqeer Ahmed Siddiqui

Epidemiology,

Clinical manifestations,

Diagnosis and staging,

Treatment and prognosis.

Lay out

INTRODUCTION

INTRODUCTION

Ampullary carcinomas are defined as those that arise within the ampullary complex, distal to the confluence of the distal common bile duct and the pancreatic duct .

Difficult to distinguish a primary ampullary

carcinoma from other periampullary tumors preoperatively.

Prognosis better for ampullary carcinomas.

INTRODUCTION

 Neoplastic transformation more commonly

near the ampulla than at any other site in the small intestine. 

Both benign and malignant ampullary tumors can occur sporadically or in the setting of a genetic syndrome

 average age at diagnosis of sporadic ampullary carcinomas is 60 to 70 years old

EPIDEMIOLOGY AND BIOLOGIC BEHAVIOR

The histology of primary ampullary neoplasms more often

resembles that of adenomas and adenocarcinomas of intestinal origin rather than pancreaticobiliary origin.

In one study of 170 ampullary carcinomas, the most common histologic subtype was

intestinal (47 percent), followed by pancreatobiliary (24 percent),

poorly differentiated adenocarcinomas (13 percent), intestinal-mucinous (8 percent), and

invasive papillary (5 percent) 

EPIDEMIOLOGY AND BIOLOGIC BEHAVIOR

K-ras mutations are an early event in ampullary

carcinogenesis, with an incidence (37 percent) that is similar to that in colon cancer (up to 50 percent) .

Expression profiling of cyclooxygenase-2 (COX-2) by ampullary carcinomas is more consistent with a neoplasm of intestinal origin than pancreaticobiliary origin.

High COX-2 expression has been detected in 78 percent of ampullary carcinomas

EPIDEMIOLOGY AND BIOLOGIC BEHAVIOR

Subdividing adenocarcinomas of the ampulla of Vater according

to histologic subtype and immunohistochemical staining pattern into distinct subsets with differing biologic behavior has prognostic importance.

In a retrospective study of 208 patients treated for ampullary adenocarcinoma in Sydney, Australia,

those with a histomolecular pancreaticobiliary phenotype (CDX-negative, MUC1 positive) had a significantly worse outcome

than did those with an intestinal phenotype (CDX-positive, MUC1-negative), with median survival of 16 versus 116 months [22].

EPIDEMIOLOGY AND BIOLOGIC BEHAVIOR

When histomolecular phenotype was combined with the lymph node status,

three subsets of ampullary adenocarcinomas emerged with significantly different survival outcomes:

Patients with a node-negative, non-pancreaticobiliary histomolecular phenotype tumor had an excellent prognosis (five-year survival 88 percent).

Patients with a node-positive pancreaticobiliary phenotype had a poor prognosis (five-year survival 20 percent).

The remaining patients (node-positive non-pancreaticobiliary phenotype, node-negative pancreaticobiliary phenotype) had an intermediate prognosis (five-year survival 47 percent).

The results were comparable in two additional independent cohorts of 90 patients from Glasgow, Scotland, and 46 from Verona, Italy

EPIDEMIOLOGY AND BIOLOGIC BEHAVIOR

Most common presenting symptom of ampullary carcinoma is obstructive jaundice

(80 percent) 

 Additional symptoms may include diarrhea due to fat malabsorption (steatorrhea), mild weight loss, and fatigue.

Up to one-third of patients have chronic, frequently occult gastrointestinal blood loss with an associated microcytic anemia or heme-positive stools.

occasionally present with frank bleeding due to sloughing of the tumor, a condition exacerbated by the use of antiplatelet agents such as aspirin and clopidogrel.

In one report, nonspecific symptoms include abdominal pain (45 percent), fever (45 percent), mild nausea, and dyspepsia [25].

Large lesions may produce gastric outlet obstruction associated with severe nausea and vomiting

CLINICAL MANIFESTATIONS

The most commonly used staging system is the

tumor-node-metastasis (TNM) system of the combined AJCC (American Joint Committee on Cancer)/UICC (International Union Against Cancer) 

In the absence of metastases, the prognosis of an ampullary carcinoma depends primarily upon two factors:

the degree of local tumor invasion, as reflected by the T stage, and the presence of lymphatic spread, as reflected by the N stage

DIAGNOSIS AND STAGING

The diagnostic evaluation of a jaundiced

patient with a suspected malignant bile duct obstruction is designed to

eliminate benign tumors or gallstones from the differential,

to establish the extent of tumor invasion and spread.

DIAGNOSIS AND STAGING

A transabdominal ultrasound (US) is a reasonable first test in

patients presenting with obstructive jaundice, but it will generally not show the tumor.

Helical computed tomography (CT) scanning should be obtained to visualize the pancreas and surrounding structures.

Although its spatial resolution is inadequate to determine the degree of local tumor invasion, it is the most useful test to exclude the presence of distant metastases.

Endoscopic retrograde cholangiopancreatography (ERCP) is the

single most useful endoscopic study since it permits identification of the tumor, biopsy, and decompression, if needed.

While endoscopic ultrasonography (EUS) is as sensitive as ERCP and superior to CT and transabdominal US for detecting small ampullary tumors, it is typically not required for diagnosis.

It may have a role in preoperative staging but may result in over-staging.

As a result, we do not routinely employ EUS for the diagnosis and staging of ampullary carcinoma.

Liver biochemical tests — 

Blood chemistries cannot establish the diagnosis of ampullary carcinoma, but may reflect the presence of cholestasis when an ampullary neoplasm results in partial or complete biliary obstruction.

Patients generally have a cholestatic pattern of liver biochemical test abnormalities, although aminotransferases may also be elevated .

The prothrombin time may be elevated due to impaired absorption of fat-soluble vitamins including vitamin K .

Serum tumor markers — 

not specific for ampullary carcinomas and have limited diagnostic application.

Nevertheless, some ampullary cancers are associated with increased serum levels of carbohydrate antigen CA 19-9 and/or carcinoembryonic antigen (CEA) , and serial assay of these tumor markers may be useful for posttreatment follow-up.

 The outcome of resected ampullary cancer

depends upon

1. the extent of local invasion,

2. status of the surgical margins,

3. the presence or absence of nodal metastases

PROGNOSIS —

Histology Nodal metastases Obstructive jaundice  Intraoperative blood transfusion Tumor marker elevation 

Prognostic factors

 It can be difficult to distinguish a primary ampullary carcinoma

from other periampullary tumors (mainly pancreatic carcinoma or distal cholangiocarcinoma) preoperatively.

However, true ampullary cancers have a better prognosis than pancreatic head cancers or distal cholangiocarcinomas.

Resectability rates are higher, five-year survival rates are 30 to 50 percent in selected patients

with limited lymph node involvement.

Thus, an aggressive approach to diagnosis and treatment of periampullary tumors is needed to ensure that patients with these comparatively favorable cancers are treated optimally.

Treatment

TREATMENT FOR LOCALIZED

DISEASE — The only potentially curative treatment for ampullary carcinoma is surgical resection. Complete tumor resection with negative margins (R0 resection) is a prerequisite for cure.

Pancreaticoduodenectomy — Pancreaticoduodenectomy (Whipple operation) is considered the standard approach for ampullary cancer

Local resection — Many patients with ampullary

cancer are elderly and have significant comorbidities. This has generated interest in less aggressive surgical options, such as local resection or ampullectomy for selected patients

In the aggregate, the available data indicate that local resection is associated with lower morbidity than pancreaticoduodenectomy, but at the expense of higher recurrence rates and inferior survival, at least in the setting of invasive disease 

Early, low-grade tumors — In contrast to

pancreaticoduodenectomy, ampullectomy does not accomplish removal of the regional lymph nodes.

Because of the low rate of nodal metastases (less than 4 percent in most series), some have suggested that local resection is a reasonable approach for well-differentiated small (<6 mm) tumors that do not penetrate through the ampullary musculature (ie, Tis, T1, .

Minimally-invasive nonsurgical

therapies — Minimally invasive nonsurgical therapies for ampullary carcinoma include endoscopic snare resection, Nd:YAG laser ablation, and photodynamic therapy. The literature on these techniques in the setting of ampullary carcinoma is limited to single-case reports and small series.

Endoscopic snare resection (papillectomy) is an effective means of treating

ampullary adenomas.  Endoscopic papillectomy has been attempted in early stage (Tis, T1) well

differentiated ampullary cancers without angiolymphatic invasion  Endoscopic debulking has been used mainly preoperatively to permit stent

insertion and decompression of the biliary tree. 

Laser ablation offers the potential for control of local tumor growth in patients who are unfit for more aggressive therapy. In one such series of 12 patients with ampullary cancer, duodenal obstruction was relieved in one, and the longest survival was 36 months (median 21 months) [45].

●Compared with laser ablation, photodynamic therapy (PDT) eradicates local tumor with less surrounding tissue destruction. PDT uses a photosensitizing drug (a hematoporphyrin derivative, Photofrin®), which is disproportionately retained by malignant tissue after intravenous administration.

Pancreaticoduodenectomy rather than local resection for most patients with

invasive ampullary carcinomas (Grade 1B).

Local ampullary excision rather than pancreaticoduodenectomy for patients with noninvasive ampullary tumors.

Ampullectomy is also a reasonable approach for poor surgical candidates who have a well-differentiated T1 tumor that is less than 6 mm in size (based upon endoscopic ultrasound [EUS]).

However, a more aggressive surgical approach is preferred for patients who are candidates for pancreaticoduodenectomy because of better outcomes.

Nonsurgical treatment modalities (ie, endoscopic snare resection, laser ablation, photodynamic therapy) provide palliative rather than curative benefit for patients with ampullary carcinoma.

These methods should be restricted to patients who are not operative candidates and those who refuse surgery.

Primary treatment

 There is no consensus regarding the optimal management

of patients after resection of an ampullary adenocarcinoma.

There are scant data to guide adjuvant treatment decisions, and the true benefit of such therapy remains uncertain.

Nevertheless, many clinicians, treat these patients in a similar manner as those with resected pancreatic head adenocarcinomas.

Offer adjuvant therapy to all patients with resected ampullary cancer stage IB or higher

Adjuvant therapy —

European clinicians

ESPAC-1 trial, showed that 5-FU-containing chemotherapy (but not chemoradiotherapy) prolongs survival in resected pancreatic cancer.

German CONKO trial showing a survival benefit from adjuvant gemcitabine in the same patient population,

preliminary report of the ESPAC-3 trial, suggesting a potentially clinically meaningful but statistically insignificant improvement in overall survival with adjuvant gemcitabine or leucovorin-modulated 5-FU in ampullary cancer,

most use chemotherapy alone after resection of an ampullary neoplasm.

The approach differs in Europe and in the United States:

The American approach more often includes

chemoradiotherapy as well as adjuvant chemotherapy.

The approach differs in Europe and in the United States:

Recommended approach

•Eligible patients should be encouraged to enroll in clinical trials evaluating the potential benefits of chemotherapy and/or chemoradiotherapy as well as new therapies.

•Off-protocol, combination of concurrent chemoradiotherapy and chemotherapy for patients with resected ampullary cancers stage IB or higher ,rather than observation alone (Grade 2C).

During the concurrent chemoradiotherapy portion, prefer infusional 5-FU, and use gemcitabine alone for the chemotherapy portion.

The optimal way to sequence 5-FU-based chemoradiotherapy and gemcitabine

 chemotherapy is unclear.

An acceptable regimen is that used in the RTOG 9704 trial , which consists of three weekly doses of gemcitabine alone (1000 mg/m2 per week), followed by chemoradiotherapy using concurrent infusional 5-FU.

Although the RTOG trial used 250 mg/m2 daily continuously, many clinicians, consider this too toxic and use 225 mg/m2 daily, five days per week.

Following chemoradiotherapy and starting three to five weeks later, three months of single agent gemcitabine are given.

An alternative approach that is often used for pancreatic cancer is to administer all six months of chemotherapy upfront and to pursue concurrent fluoropyrimidine-based chemoradiotherapy only for patients who remain free of metastatic disease.

 Distinction as to whether periampullary tumors are of intestinal,

biliary, or pancreatic origin is particularly important in patients with metastatic disease as the approach differs.

The optimal regimen for systemic therapy of true ampullary tumors has not been established.

Based upon the results of the ABC trial, the combination of gemcitabine plus cisplatin is a reasonable approach for patients who are able to tolerate it.

Others use a single agent gemcitabine initially ,followed by an oxaliplatin-based regimen, or vice versa, in a manner similar to treatment of pancreatic cancer.

Metastatic disease

 The results of clinical trials are not definitive,

and there is no consensus regarding the optimal management of patients after resection of an ampullary cancer.

Recommendations for management of ampullary carcinoma are not included in published guidelines from either the NCCN or ESMO .

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