VHJOE - Cystic Neoplasms of the Pancreas
Introduction
Cystic neoplasms of the pancreas are an uncommon, though increasingly reported, entity. They account for approximately 10% of all cystic lesions of the pancreas (1, 2), but only 1% of all pancreatic malignancies (2, 3). A classification of pancreatic cystic neoplasms is shown in Table 1.
http://www.vhjoe.org/index.php/vhjoe/article/view/3/4
Sunday, May 2, 2010
Mucinous nonneoplastic cyst of the pancreas: apomu... [Hum Pathol. 2010] - PubMed result
Mucinous nonneoplastic cyst of the pancreas: apomu... [Hum Pathol. 2010] - PubMed result
Abstract
Mucinous nonneoplastic cyst of the pancreas is a newly described and rare cystic lesion with unknown histogenesis. It is defined as a cystic lesion lined with mucinous epithelium, supported by hypocellular stroma and not communicating with the pancreatic ducts. It is very challenging to differentiate this lesion from other cystic mucinous neoplasms of the pancreas such as branch-duct intraductal papillary mucinous neoplasm by morphology. In this study, a total of 436 pancreatic specimens resected between 2002 and 2007 in our institution were reviewed. Fifteen (3.4%, 15/436) mucinous nonneoplastic cysts were identified. They included 3 males and 12 females, with a median age of 60 years. Forty-six percent of cases (7/15) occurred in pancreatic head, 27% (4/15) in neck, 7% (1/15) in body, and 20% (3/15) in tail. The size of lesions ranged from 0.5 to 3.5 cm in greatest dimension. In most cases (12/15, 80%), mucinous nonneoplastic cyst was associated or adjacent to acinar-ductal mucinous metaplasia. These morphologic data indicate that mucinous nonneoplastic cyst is not really a rare disease and may originate from acinar-duct mucinous metaplasia histogenestically. Furthermore, apomucin immunostains of mucinous nonneoplastic cyst showed MUC1 expressed in 27% (4/15) cases, MUC5AC in 67% (10/15 cases), and MUC2 was were negative in all cases, whereas intraductal papillary mucinous neoplasm (n = 17; 5 main duct type, 12 branch-duct type) showed focal and weak MUC1 positivity in 18% (3/17) cases, MUC2 positivity in 71% (12/17) cases, and all intraductal papillary mucinous neoplasm (17/17) were MUC5AC positive. The clonality assay with the HUMARA gene revealed that the mucinous nonneoplastic cysts were of polyclonal origin. For the first time, using HUMARA assay, we demonstrate the nonneoplastic nature of these cysts and further characterize morphologic and immunophenotypic properties that allow differentiation from intraductal papillary mucinous neooplasm. Copyright 2010 Elsevier Inc.
Abstract
Mucinous nonneoplastic cyst of the pancreas is a newly described and rare cystic lesion with unknown histogenesis. It is defined as a cystic lesion lined with mucinous epithelium, supported by hypocellular stroma and not communicating with the pancreatic ducts. It is very challenging to differentiate this lesion from other cystic mucinous neoplasms of the pancreas such as branch-duct intraductal papillary mucinous neoplasm by morphology. In this study, a total of 436 pancreatic specimens resected between 2002 and 2007 in our institution were reviewed. Fifteen (3.4%, 15/436) mucinous nonneoplastic cysts were identified. They included 3 males and 12 females, with a median age of 60 years. Forty-six percent of cases (7/15) occurred in pancreatic head, 27% (4/15) in neck, 7% (1/15) in body, and 20% (3/15) in tail. The size of lesions ranged from 0.5 to 3.5 cm in greatest dimension. In most cases (12/15, 80%), mucinous nonneoplastic cyst was associated or adjacent to acinar-ductal mucinous metaplasia. These morphologic data indicate that mucinous nonneoplastic cyst is not really a rare disease and may originate from acinar-duct mucinous metaplasia histogenestically. Furthermore, apomucin immunostains of mucinous nonneoplastic cyst showed MUC1 expressed in 27% (4/15) cases, MUC5AC in 67% (10/15 cases), and MUC2 was were negative in all cases, whereas intraductal papillary mucinous neoplasm (n = 17; 5 main duct type, 12 branch-duct type) showed focal and weak MUC1 positivity in 18% (3/17) cases, MUC2 positivity in 71% (12/17) cases, and all intraductal papillary mucinous neoplasm (17/17) were MUC5AC positive. The clonality assay with the HUMARA gene revealed that the mucinous nonneoplastic cysts were of polyclonal origin. For the first time, using HUMARA assay, we demonstrate the nonneoplastic nature of these cysts and further characterize morphologic and immunophenotypic properties that allow differentiation from intraductal papillary mucinous neooplasm. Copyright 2010 Elsevier Inc.
Pancreas, Mucinous Cystic Neoplasm: eMedicine Radiology
Pancreas, Mucinous Cystic Neoplasm: eMedicine Radiology
IPMT is a papillary neoplasm that arises within the MPD or its branches. The tumors hypersecrete mucin, which often leads to duct dilatation and/or chronic obstructive pancreatitis. IPMTs are premalignant and may histologically demonstrate areas ranging from hyperplasia to carcinoma within a single tumor. The tumors generally show intraluminal, longitudinal growth, but it is slow to invade periductal tissues radially and slow to metastasize. IPMTs are most commonly localized to the head of the pancreas, but they may occur at any site along the pancreatic ductal system. Ductal dilatation is often impressive and may mimic MCNs on CT scans.
Intraductal papillary mucinous neoplasm is recognized as predominantly a solid tumor with a central cyst. The cystic variety consists microscopically of cystlike spaces with papillary protrusions.
IPMT is a papillary neoplasm that arises within the MPD or its branches. The tumors hypersecrete mucin, which often leads to duct dilatation and/or chronic obstructive pancreatitis. IPMTs are premalignant and may histologically demonstrate areas ranging from hyperplasia to carcinoma within a single tumor. The tumors generally show intraluminal, longitudinal growth, but it is slow to invade periductal tissues radially and slow to metastasize. IPMTs are most commonly localized to the head of the pancreas, but they may occur at any site along the pancreatic ductal system. Ductal dilatation is often impressive and may mimic MCNs on CT scans.
Intraductal papillary mucinous neoplasm is recognized as predominantly a solid tumor with a central cyst. The cystic variety consists microscopically of cystlike spaces with papillary protrusions.
Modern Pathology - Mucinous Nonneoplastic Cyst of the Pancreas: A Novel Nonneoplastic Cystic Change?
Modern Pathology - Mucinous Nonneoplastic Cyst of the Pancreas: A Novel Nonneoplastic Cystic Change?
INTRODUCTION
Cystic tumors of the pancreas may be either neoplastic or nonneoplastic. The predominant neoplastic types are intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, serous cystic adenomas, and solid pseudopapillary neoplasms (1). The remaining cystic tumors (the term cystic tumor denotes any cystic lump, regardless of whether it is neoplastic or not) comprise neoplasms, such as acinar cystadenocarcinomas, cystic endocrine tumors, dermoid cysts, and ductal adenocarcinomas with cystic features (2, 3). They also include nonneoplastic lesions, such as lymphoepithelial cysts and other types that have been given various names but are poorly characterized (2, 4, 5, 6).
Recently, we observed a special type of cystic lesion of the pancreas composed of mucinous cells that were not supported by an ovarian-like stroma and did not show any obvious neoplastic potential. Here we report the clinicopathological features of a series of five cases of these recently observed, novel cystic lesions of the pancreas.
INTRODUCTION
Cystic tumors of the pancreas may be either neoplastic or nonneoplastic. The predominant neoplastic types are intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, serous cystic adenomas, and solid pseudopapillary neoplasms (1). The remaining cystic tumors (the term cystic tumor denotes any cystic lump, regardless of whether it is neoplastic or not) comprise neoplasms, such as acinar cystadenocarcinomas, cystic endocrine tumors, dermoid cysts, and ductal adenocarcinomas with cystic features (2, 3). They also include nonneoplastic lesions, such as lymphoepithelial cysts and other types that have been given various names but are poorly characterized (2, 4, 5, 6).
Recently, we observed a special type of cystic lesion of the pancreas composed of mucinous cells that were not supported by an ovarian-like stroma and did not show any obvious neoplastic potential. Here we report the clinicopathological features of a series of five cases of these recently observed, novel cystic lesions of the pancreas.
Jason - Cystic Lesion of the Pancreas: Case Presentation
A Young Woman With a Cystic Lesion of the Pancreas: Case Presentation
Case Presentation
A 41-year-old woman was referred for an abnormal gastroscopy. The patient had a history of gastroesophageal reflux disease. She had undergone upper endoscopy 1 week previously, and, at that time, was found to have extrinsic compression of the stomach. The patient has had no abdominal pain, nausea, vomiting, fever, chills, changes in bowel habits, or weight loss. She was referred to clinic for further evaluation.
Results of physical examination were unremarkable. Laboratory investigations showed normal hematology and chemistries, including serum amylase, lipase, and tumor markers.
Upper gastrointestinal endoscopy showed an extrinsic compression of the posterior wall of the gastric body (Figure 1). Computed tomography (CT) scan of the abdomen showed a 3-cm cystic lesion in the pancreas near the junction of the head and body (Figure 2). There was no other evidence of mass, adenopathy, or parenchymal pancreatic disease. The pancreatic and biliary ducts were normal. Intravenous contrast did not demonstrate any additional abnormality.
1. Is my cystic lesion neoplastic (15%) or nonneoplastic (no malignant potential 80% of all cysts) ?
- May be a Yes, because neoplastic cyst has 4 types: IPMN or IPMT (t for tumor) is one of them
2. Why is Jason's different from this lady's?
- Age,
- location is in the uncinated process (head and neck area),
- communicate with ductal system
3. How do I know Jason's is IPMN or IPMT? or MDE?
- MRI shows that the cyst is Multiloculated;
-MRI indicates that both the main and the branch ducts are dilated.
- communicates with ductal system
My symptoms
Recurrent, acute abdominal pain intermittently occured since a pancreatitis attach in 2002, for which I was hospitalized for a week at Huntington Methodist Memorial Hospital. Each time it started with sharp, cramping abdominal pain, followed with water like diarrhea; sometimes with vomiting. It subsided generally within 1 hour without any medication; I could go back to work the next day without feel anything.
I called 911 about once twice a year for this illness; and my wife took me to the emergency room for about one or two times a year. On average, it happened two to three times every year druing the last 9 years. The hospitals that I went are the Garfield Hospital, Monterey Park Hospital and Huntington Methodist Memorial Hospital
Management and Diagnostic Questions
What is your differential diagnosis of this patient's cystic lesion?
Most (70% to 80%) cystic lesions of the pancreas are nonneoplastic and have no malignant potential. These lesions are either pseudocysts complicating acute or chronic pancreatitis, or, rarely, true cysts. However, up to 15% of cystic lesions are neoplastic, with a variable propensity for malignancy. These cystic neoplasms are frequently misdiagnosed as pseudocysts, with potentially disastrous results.
Warshaw and colleagues[1] described cystic neoplasms of the pancreas in 67 patients seen between 1978 and 1989. Most of these lesions occurred in middle-aged women who presented with few symptoms. The average size of each lesion was 5 cm to 6 cm, and about 40% had been misdiagnosed as pseudocysts. Table 1 shows a simple classification scheme for cystic neoplasms of the pancreas. The 4 types most frequently encountered are:
1. mucinous cystic neoplasm (cancerous and noncancous),
2. serous cystadenoma,
3. papillary cystic neoplasm, and
4. intraductal papillary mucinous tumor.
Our patient has a relatively small lesion, which, on CT scan, has almost no solid component. She is young and may have a rare congenital cyst. Although, statistically, a pseudocyst is the most likely scenario, the absence of features suggestive of pancreatitis makes such a diagnosis less appealing. This patient may have a cystic neoplasm. Does accurate diagnosis make a difference in management?
How does definitive diagnosis affect management and outcome?
The mucinous cystic tumors (including mucinous cystic neoplasm, papillary cystic neoplasm, and intraductal papillary mucinous tumor) are all characterized by columnar epithelium lining the cystic spaces. These tumors may have frank malignancy at the time of diagnosis; all have malignant potential. These lesions must be resected. Serous cystadenomas have simple cuboidal cells lining the cysts and are generally not considered at risk for malignant progression. Pseudocysts and true cysts rarely need resection.
Although identification of a cystic lesion is relatively easy, the identification of a specific tumor type may be difficult. Clinical characteristics, such as sex of patient, size of cyst, location in the pancreas, and presence or absence of pain, do not help distinguish tissue types.[1]
What diagnostic modalities would provide a definitive diagnosis?
Specifically, what role do endoscopic ultrasound (EUS) and cyst aspiration play in the evaluation and management of cystic lesions of the pancreas? Abdominal ultrasound, CT, and magnetic resonance imaging may be used to differentiate between large (> 3 cm) cystic neoplasms and pseudocysts. Features that suggest a cystic neoplasm include multilocularity; thick, irregular walls and septae; and calcifications in the mass but not in the ducts. If a simple cyst communicates ( multilocularity <-> communication? - Jason )with the pancreatic duct on endoscopic retrograde cholangiopancreatography (ERCP), then a pseudocyst is suspected. However, these imaging techniques have not been adequately evaluated in assessing small lesions such as that seen in our patient. Table 2 shows that EUS and cyst aspiration may have a role in obtaining a definitive diagnosis for patients with cystic lesions of uncertain etiology.
EUS is useful for imaging the echo-architecture of a cystic mass in the pancreas and in predicting the probability of a cystic neoplasm.[2-5] Koito and coworkers[2] retrospectively evaluated the diagnostic accuracy of EUS in differentiating solitary pancreatic cystic tumors by comparing EUS diagnosis with histologic results in 52 resected specimens. In this study, the cut surfaces of the specimens were classified into 6 patterns (Figure 3). All nonneoplastic cysts were found to be either thin, septal type, or simple type; all neoplastic cysts belonged to the thick wall, tumor protruding, thick septal, or microcystic type. These investigators showed that EUS was able to accurately describe the internal architecture of pancreatic cystic tumors.
Hammel and associates[3] conducted a study to assess the diagnostic reliability of preoperative biochemical and tumor marker analysis in cyst fluid obtained by CT-guided fine-needle aspiration. Levels of serum amylase (upper limit of normal = 70 U/mL) and tumoral markers, including carcinoembryonic antigen (CEA; upper limits of normal = 5 ng/mL) and carbohydrate antigen 19.9 (CA 19-9; upper limit of normal = 37 U/mL), were measured in cyst fluid obtained preoperatively. The diagnosis of cystic neoplasms (7 serous cystadenomas and 12 mucinous tumors) was established by surgical specimen analysis. High CA 19-9 levels (> 50,000 U/mL) were indicative of mucinous tumors (75% sensitivity and 90% specificity). Low CEA levels (< 5 ng/mL) were indicative of serous cystadenomas (100% sensitivity and 86% specificity). High amylase levels (> 5000 U/mL) were indicative of pseudocysts (94% sensitivity and a 74% specificity).
Is surgery inevitable?
If there remains any diagnostic uncertainty after complete evaluation, all cystic lesions of the pancreas should be resected. Thus, unless there exists a set of diagnostic results that would virtually eliminate the possibility of a neoplasm with malignant potential, surgery should be done with the minimal evaluation.
In the case of the patient presented here, the physicians believed that EUS plus EUS-directed aspiration had the potential to provide sufficient information to allow surgery to be avoided. However, the patient was also presented with the alternative option of early operation. The patient elected to have the detailed evaluation.
Clinical Course and Outcome
The patient underwent EUS. Figure 4 shows the radial echo-image of the normal body of the pancreas and pancreatic duct. Figure 5 shows the radial echo-image of the cyst, which appears thin walled and has a thin septum (arrow).
Linear echo-endoscopy easily visualized the cyst (Figure 6) and was used to aspirate the cyst after the Doppler showed no blood flow (Figure 7). The fluid obtained by aspiration underwent cytologic examination and Figure 8 shows a low-power view of this cytology specimen.
Two types of cells are seen. The large, flat, pink epithelial cells were likely introduced into the specimen while sampling and the smaller blue cells are normal pancreatic duct cells. The specimen is not hypercellular and, therefore, is not likely to be from a neoplasm. Figures 9 and 10 are low- and high-powered views of the pancreatic ductal cells, respectively. There is no evidence of dysplastic or malignant cells.
Biochemical analysis of the cyst fluid revealed the following values: serum amylase > 100,000 U/mL; CEA = 2.2 ng/mL; CA 19-9 = 23 U/mL.
Taken together, the clinical information obtained from our patient, along with data presented in Table 2, suggest that our patient has a nonneoplastic cyst. By EUS, the cyst was either the simple type or thin-septal type, making neoplasia unlikely. By cytology, there was no evidence of neoplasia or malignancy. By biochemistry, mucinous tumor was unlikely and pseudocyst likely. The patient will have a repeat CT scan in 6 months.
Discussion
The case presented here helps us review some of the general principles regarding the diagnosis and management of cystic lesions of the pancreas.
It is important to distinguish a neoplastic cyst from a nonneoplastic cyst. Mucinous cystic tumors of the pancreas, including cystadenoma, cystadenocarcinoma, papillary cystic neoplasm, and mucinous ductal ectasia, have high malignant potential and should be resected.[6] Serous cystadenoma has a low malignant potential, as do true cysts and pseudocysts. EUS is useful for imaging the echo-architecture of a cystic mass in the pancreas and in predicting the probability of a cystic neoplasm. Cysts that are well defined, simple, uniloculated (single room - jason), or with thin septation are likely to be due to a nonneoplastic process. By contrast, complex cystic lesions with thick walls, thick septations, microcystic changes, or a solid lesion protruding into the cyst are more likely to be due to cystic pancreatic neoplasm.
Combined with clinical, radiologic, and echo-endoscopic data, cystic fluid analysis for amylase, CEA, and CA 19-9 levels may help provide an accurate diagnosis of cystic lesions of the pancreas. If there is any doubt regarding the nature of the lesion, surgical resection should be done.
Case Presentation
A 41-year-old woman was referred for an abnormal gastroscopy. The patient had a history of gastroesophageal reflux disease. She had undergone upper endoscopy 1 week previously, and, at that time, was found to have extrinsic compression of the stomach. The patient has had no abdominal pain, nausea, vomiting, fever, chills, changes in bowel habits, or weight loss. She was referred to clinic for further evaluation.
Results of physical examination were unremarkable. Laboratory investigations showed normal hematology and chemistries, including serum amylase, lipase, and tumor markers.
Upper gastrointestinal endoscopy showed an extrinsic compression of the posterior wall of the gastric body (Figure 1). Computed tomography (CT) scan of the abdomen showed a 3-cm cystic lesion in the pancreas near the junction of the head and body (Figure 2). There was no other evidence of mass, adenopathy, or parenchymal pancreatic disease. The pancreatic and biliary ducts were normal. Intravenous contrast did not demonstrate any additional abnormality.
1. Is my cystic lesion neoplastic (15%) or nonneoplastic (no malignant potential 80% of all cysts) ?
- May be a Yes, because neoplastic cyst has 4 types: IPMN or IPMT (t for tumor) is one of them
2. Why is Jason's different from this lady's?
- Age,
- location is in the uncinated process (head and neck area),
- communicate with ductal system
3. How do I know Jason's is IPMN or IPMT? or MDE?
- MRI shows that the cyst is Multiloculated;
-MRI indicates that both the main and the branch ducts are dilated.
- communicates with ductal system
My symptoms
Recurrent, acute abdominal pain intermittently occured since a pancreatitis attach in 2002, for which I was hospitalized for a week at Huntington Methodist Memorial Hospital. Each time it started with sharp, cramping abdominal pain, followed with water like diarrhea; sometimes with vomiting. It subsided generally within 1 hour without any medication; I could go back to work the next day without feel anything.
I called 911 about once twice a year for this illness; and my wife took me to the emergency room for about one or two times a year. On average, it happened two to three times every year druing the last 9 years. The hospitals that I went are the Garfield Hospital, Monterey Park Hospital and Huntington Methodist Memorial Hospital
Management and Diagnostic Questions
What is your differential diagnosis of this patient's cystic lesion?
Most (70% to 80%) cystic lesions of the pancreas are nonneoplastic and have no malignant potential. These lesions are either pseudocysts complicating acute or chronic pancreatitis, or, rarely, true cysts. However, up to 15% of cystic lesions are neoplastic, with a variable propensity for malignancy. These cystic neoplasms are frequently misdiagnosed as pseudocysts, with potentially disastrous results.
Warshaw and colleagues[1] described cystic neoplasms of the pancreas in 67 patients seen between 1978 and 1989. Most of these lesions occurred in middle-aged women who presented with few symptoms. The average size of each lesion was 5 cm to 6 cm, and about 40% had been misdiagnosed as pseudocysts. Table 1 shows a simple classification scheme for cystic neoplasms of the pancreas. The 4 types most frequently encountered are:
1. mucinous cystic neoplasm (cancerous and noncancous),
2. serous cystadenoma,
3. papillary cystic neoplasm, and
4. intraductal papillary mucinous tumor.
Our patient has a relatively small lesion, which, on CT scan, has almost no solid component. She is young and may have a rare congenital cyst. Although, statistically, a pseudocyst is the most likely scenario, the absence of features suggestive of pancreatitis makes such a diagnosis less appealing. This patient may have a cystic neoplasm. Does accurate diagnosis make a difference in management?
How does definitive diagnosis affect management and outcome?
The mucinous cystic tumors (including mucinous cystic neoplasm, papillary cystic neoplasm, and intraductal papillary mucinous tumor) are all characterized by columnar epithelium lining the cystic spaces. These tumors may have frank malignancy at the time of diagnosis; all have malignant potential. These lesions must be resected. Serous cystadenomas have simple cuboidal cells lining the cysts and are generally not considered at risk for malignant progression. Pseudocysts and true cysts rarely need resection.
Although identification of a cystic lesion is relatively easy, the identification of a specific tumor type may be difficult. Clinical characteristics, such as sex of patient, size of cyst, location in the pancreas, and presence or absence of pain, do not help distinguish tissue types.[1]
What diagnostic modalities would provide a definitive diagnosis?
Specifically, what role do endoscopic ultrasound (EUS) and cyst aspiration play in the evaluation and management of cystic lesions of the pancreas? Abdominal ultrasound, CT, and magnetic resonance imaging may be used to differentiate between large (> 3 cm) cystic neoplasms and pseudocysts. Features that suggest a cystic neoplasm include multilocularity; thick, irregular walls and septae; and calcifications in the mass but not in the ducts. If a simple cyst communicates ( multilocularity <-> communication? - Jason )with the pancreatic duct on endoscopic retrograde cholangiopancreatography (ERCP), then a pseudocyst is suspected. However, these imaging techniques have not been adequately evaluated in assessing small lesions such as that seen in our patient. Table 2 shows that EUS and cyst aspiration may have a role in obtaining a definitive diagnosis for patients with cystic lesions of uncertain etiology.
EUS is useful for imaging the echo-architecture of a cystic mass in the pancreas and in predicting the probability of a cystic neoplasm.[2-5] Koito and coworkers[2] retrospectively evaluated the diagnostic accuracy of EUS in differentiating solitary pancreatic cystic tumors by comparing EUS diagnosis with histologic results in 52 resected specimens. In this study, the cut surfaces of the specimens were classified into 6 patterns (Figure 3). All nonneoplastic cysts were found to be either thin, septal type, or simple type; all neoplastic cysts belonged to the thick wall, tumor protruding, thick septal, or microcystic type. These investigators showed that EUS was able to accurately describe the internal architecture of pancreatic cystic tumors.
Hammel and associates[3] conducted a study to assess the diagnostic reliability of preoperative biochemical and tumor marker analysis in cyst fluid obtained by CT-guided fine-needle aspiration. Levels of serum amylase (upper limit of normal = 70 U/mL) and tumoral markers, including carcinoembryonic antigen (CEA; upper limits of normal = 5 ng/mL) and carbohydrate antigen 19.9 (CA 19-9; upper limit of normal = 37 U/mL), were measured in cyst fluid obtained preoperatively. The diagnosis of cystic neoplasms (7 serous cystadenomas and 12 mucinous tumors) was established by surgical specimen analysis. High CA 19-9 levels (> 50,000 U/mL) were indicative of mucinous tumors (75% sensitivity and 90% specificity). Low CEA levels (< 5 ng/mL) were indicative of serous cystadenomas (100% sensitivity and 86% specificity). High amylase levels (> 5000 U/mL) were indicative of pseudocysts (94% sensitivity and a 74% specificity).
Is surgery inevitable?
If there remains any diagnostic uncertainty after complete evaluation, all cystic lesions of the pancreas should be resected. Thus, unless there exists a set of diagnostic results that would virtually eliminate the possibility of a neoplasm with malignant potential, surgery should be done with the minimal evaluation.
In the case of the patient presented here, the physicians believed that EUS plus EUS-directed aspiration had the potential to provide sufficient information to allow surgery to be avoided. However, the patient was also presented with the alternative option of early operation. The patient elected to have the detailed evaluation.
Clinical Course and Outcome
The patient underwent EUS. Figure 4 shows the radial echo-image of the normal body of the pancreas and pancreatic duct. Figure 5 shows the radial echo-image of the cyst, which appears thin walled and has a thin septum (arrow).
Linear echo-endoscopy easily visualized the cyst (Figure 6) and was used to aspirate the cyst after the Doppler showed no blood flow (Figure 7). The fluid obtained by aspiration underwent cytologic examination and Figure 8 shows a low-power view of this cytology specimen.
Two types of cells are seen. The large, flat, pink epithelial cells were likely introduced into the specimen while sampling and the smaller blue cells are normal pancreatic duct cells. The specimen is not hypercellular and, therefore, is not likely to be from a neoplasm. Figures 9 and 10 are low- and high-powered views of the pancreatic ductal cells, respectively. There is no evidence of dysplastic or malignant cells.
Biochemical analysis of the cyst fluid revealed the following values: serum amylase > 100,000 U/mL; CEA = 2.2 ng/mL; CA 19-9 = 23 U/mL.
Taken together, the clinical information obtained from our patient, along with data presented in Table 2, suggest that our patient has a nonneoplastic cyst. By EUS, the cyst was either the simple type or thin-septal type, making neoplasia unlikely. By cytology, there was no evidence of neoplasia or malignancy. By biochemistry, mucinous tumor was unlikely and pseudocyst likely. The patient will have a repeat CT scan in 6 months.
Discussion
The case presented here helps us review some of the general principles regarding the diagnosis and management of cystic lesions of the pancreas.
It is important to distinguish a neoplastic cyst from a nonneoplastic cyst. Mucinous cystic tumors of the pancreas, including cystadenoma, cystadenocarcinoma, papillary cystic neoplasm, and mucinous ductal ectasia, have high malignant potential and should be resected.[6] Serous cystadenoma has a low malignant potential, as do true cysts and pseudocysts. EUS is useful for imaging the echo-architecture of a cystic mass in the pancreas and in predicting the probability of a cystic neoplasm. Cysts that are well defined, simple, uniloculated (single room - jason), or with thin septation are likely to be due to a nonneoplastic process. By contrast, complex cystic lesions with thick walls, thick septations, microcystic changes, or a solid lesion protruding into the cyst are more likely to be due to cystic pancreatic neoplasm.
Combined with clinical, radiologic, and echo-endoscopic data, cystic fluid analysis for amylase, CEA, and CA 19-9 levels may help provide an accurate diagnosis of cystic lesions of the pancreas. If there is any doubt regarding the nature of the lesion, surgical resection should be done.
Pancreatic Surgery: Abstract and Introduction
Pancreatic Surgery: Abstract and Introduction
Introduction
Pancreatic surgery requires a detailed understanding of diseases and conditions of the pancreas and a multidisciplinary team dedicated to the care of pancreatic patients. A literature search on PubMed for pancreatic surgery revealed 1470 new publications the past year in the English literature. Some good news this year was revealed suggesting that the patients undergoing resection for pancreatic cancer may look forward to a 5-year survival rate of 35% - much higher than that reported in prior years. However, for surgical patients, obesity appears to engender a more aggressive malignancy. Unfortunately, each year the number of new cases of pancreatic cancer increases by 1000 to 1500 cases and now accounts for over 38 000 in the United States. In this review, we also highlight new reports on pancreatic endocrine neoplasms, cystic lesions of the pancreas, and both acute and chronic pancreatitis.
Introduction
Pancreatic surgery requires a detailed understanding of diseases and conditions of the pancreas and a multidisciplinary team dedicated to the care of pancreatic patients. A literature search on PubMed for pancreatic surgery revealed 1470 new publications the past year in the English literature. Some good news this year was revealed suggesting that the patients undergoing resection for pancreatic cancer may look forward to a 5-year survival rate of 35% - much higher than that reported in prior years. However, for surgical patients, obesity appears to engender a more aggressive malignancy. Unfortunately, each year the number of new cases of pancreatic cancer increases by 1000 to 1500 cases and now accounts for over 38 000 in the United States. In this review, we also highlight new reports on pancreatic endocrine neoplasms, cystic lesions of the pancreas, and both acute and chronic pancreatitis.
Mucinous Tumors of the Exocrine Pancreas: Intraductal Mucin-Hypersecreting Neoplasms
Mucinous Tumors of the Exocrine Pancreas: Intraductal Mucin-Hypersecreting Neoplasms
Intraductal mucin-hypersecreting neoplasms, also known as mucinous ductal ectasia (MDE), represent a form of pancreatic exocrine tumor previously confused with cystic neoplasms. This clinical entity, first described in 1982 by Ohhashi and colleagues, [3] was referred to as "mucin-producing intraductal tumor." The initial report described four patients with pancreatic carcinoma associated with unique clinical features distinct from the typical pancreatic ductal adenocarcinoma. Intraductal excretion of mucin resulted in diffuse dilatation of the main pancreatic duct and extrusion of mucus through a patulous ampullary orifice. The variety of terms subsequently used to describe MDE (Table 2) stems from a lack of understanding of this clinicopathologic entity. It seems likely, however, that various authors have focused on different stages in an adenoma-carcinoma sequence when choosing a descriptive diagnosis. [4] A recent study by Rivera et al [5] showed that intraductal papillary neoplasms with or without MDE represent a spectrum of main-duct papillary tumors ranging from adenoma to carcinoma. The authors therefore suggested the term intraductal papillary mucinous tumors (IPMTs) of the pancreas to encompass both tumors.
Little information is available on the epidemiology and etiology of IPMTs because they occur rarely and have been only recently recognized. The study by Rivera et al [5] suggested that cigarette smoking is a risk factor for IPMTs, which was also noted in a series based on all pancreatic cancers. [6] Data from animal models suggest that nitrosamines play a significant role in the etiology of both IPMTs and solid ductal adenocarcinomas. [7] IPMTs arise from the epithelial lining of the pancreatic ducts and progress along the duct system. Approximately 75% of the IPMTs arise from the main pancreatic duct within the head of the pancreas. Some IPMTs involve the ampulla of Vater and/or the minor papilla from where they protrude into the duodenum. The dilated duct segment contains a grossly visible papillary/villous tumor and/or viscous mucin. IPMTs may be benign, borderline, or malignant according to the differentiation of the proliferating columnar epithelial cells.
IPMTs occur mostly in men in the sixth to seventh decade (range = 40 to 85 years). The most common presenting symptom is abdominal discomfort associated with mild elevations of pancreatic serum enzymes mimicking chronic or relapsing pancreatitis. The history of pancreatitis or recurrent pancreatitis varies from 29% [5] to 80% [8] in the literature. These symptoms are more commonly observed in patients with mucinhypersecreting tumors and are most likely due to intermittent obstruction of the main pancreatic duct by plugs of viscous mucin or intraluminal tumor. Back pain (25%), jaundice (25%), weight loss (42%), steator-rhea (37.5%), and diabetes (37.5%) are among various presentations reported in one series. [5] In a recent report from our institution describing outcomes of 25 patients with IPMTs, [9] 52% of patients had acute relapsing pancreatitis with elevated pancreatic enzymes, 32% had pain with normal enzymes, 12% had weight loss with no pain, and 4% had incidental findings. Therefore, due to the indolent nature of these tumors and the limited awareness of this lesion among the medical community, a delay in diagnosis ranging from months to years is not uncommon.
Conventional imaging studies such as abdominal CT scanning and transabdominal ultrasonography reveal nonspecific changes that are indistinguishable from those of chronic pancreatitis, pancreatic pseudo-cysts, or nonmucinous producing cystic neoplasms. These studies typically demonstrate well-defined unilocular or multilocular cystic pancreatic masses and/or dilatation of the main pancreatic duct. The term cystic duct here would be a misnomer since these cystic structures represent dilated ductular structures. The cystic changes of IPMTs may occasionally be so extensive as that they are confused with a mucinous cystic neoplasm. An important distinction between the two lesions is that, in IPMTs, the "cysts" communicate with the duct system, whereas MCNs generally do not show any connection with the duct system.
Endoscopy and endoscopic retrograde pancreatography (ERP) are essential to clarify the diagnosis. The typical ERP reveals extreme dilatation along the entire length of the main pancreatic duct, with associated side branch ectasia, in the absence of a demonstrable pancreatic duct stricture that would explain the duct dilation (Fig 1). The cystically dilated portions of the duct are filled with mucus, and the dilation is the result of mucus obstruction. In a report by Cunningham and colleagues, [9] ERCP findings were patulous papilla (80%), visible mucin (84%), ductal filling defects (88%), and dilated pancreatic duct (100%), with whole pancreatic duct dilated in 64% and focal segmental dilation in 36%. Tissue specimens (aspiration cytology, brush cytology, or pancreatic biopsy) obtained endoscopically have a high false-negative rate but are helpful when positive.
(Enlarge Image)
Figure 1.
Endoscopic retrograde pancreatography demonstrates a diffusely dilated main pancreatic duct with filling defects and dilated irregular side branches consistent with mucinous ductal ectasia (MDE).
[ CLOSE WINDOW ]
Figure 1.
Endoscopic retrograde pancreatography demonstrates a diffusely dilated main pancreatic duct with filling defects and dilated irregular side branches consistent with mucinous ductal ectasia (MDE).
Pancreatoscopy may provide valuable information for the differential diagnosis of amorphous filling defects in the main pancreatic duct and may help to determine the extent of the pathology and the resection margin. Pancreatoscopy can be used to easily differentiate between an intraductal mass and mucin. Also, biopsies can be taken under direct vision from a suspicious mucosal lesion using the "mother-baby scope." [10] Although a diagnosis of malignancy can be obtained preoperatively, this usually does not substitute for surgical exploration and resection of the diseased segment based on frozen section results. In a series reporting on the results of 24 patients, [5] 20 (83%) were resectable. There were 9 pancreatoduodenectomies, 4 distal pancreatectomies, and 7 total pancreatectomies. The operation chosen is usually tailored to conform to the apparent distribution of the intraluminal tumor and not to the distribution of mucin. The inability to achieve histologically negative margins often leads to a total pancreatectomy. At final pathology, invasive adenocarcinoma was seen in 46% of the patients, carcinoma in situ was seen in an additional 24%, and low-grade dysplasia in 12% of the remaining patients. Despite the 88% prevalence of cancer in this series, the overall survival at a mean follow-up of 21 months was 81%. There were no recur-rences or new papillary growths in the pancreatic remnants. Four of the 24 patients had unresectable disease due to liver metastasis. The serum CA 19-9 value was helpful in predicting unresectability. Three of the 4 unresectable patients in this series had values higher than 2000 U/mL.
Cellier and colleagues [11] found invasive carcinoma in 43% of their patients and carcinoma in situ in 21%, with significantly poorer prognosis for patients with invasive carcinoma. The overall actuarial 3-year survival for patients with IPMTs was 83% in their series, whereas the overall recurrence-free 3-year survival was only 21% among patients with invasive disease. A review by Shyr et al [12] found a cumulative 5-year survival of 92% for 51 cases. In a study by Loftus and colleagues [13] involving 15 patients, 3 of 4 patients with malignant IPMTs died of metastatic disease, and 2 of 11 patients with benign disease died although with no evidence of tumor spread.
MRCP has emerged as a new noninvasive technology to assess both pancreatic and bile ducts without the use of contrast material or endoscopy. A study by Koito and colleagues [14] compared MRCP to ERCP in the diagnosis of mucin-hypersecreting tumors of the pancreas. MRCP showed cystic dilated branches of the pancreas better than ERCP. The numbers of nodules or septa that were detectable by MRCP and ERCP were similar. The authors concluded that MRCP appears to be more effective than ERCP for the detection of intraductal cystic lesions of mucin-producing pancreatic tumors. Because some of these tumors are not malignant and do not require surgery, MRCP offers a less invasive alternative to ERCP for follow-up studies. In the study by Yamaguchi et al, [15] the details of cystic lesions of the branch ducts (eg, mural nodule, communication with main pancreatic duct) were more clearly demonstrated by ERCP than by MRCP. ERCP was clear-ly superior in demonstration of normal main pancreatic duct and its branches. These two studies suggest that both ERCP and MRCP are complementary studies that are helpful in the diagnosis and follow-up of patients with IPMTs.
Cellier and colleagues [11] reported on the role of EUS in assessing tumor extension and invasion in patients with IPMTs (Fig 2). They demonstrated that the sensitivity and specificity of EUS for invasive malignancy were 78% and 75%, respectively. The overall accuracy of EUS in assessing tumor invasiveness was 76%. The accuracy for EUS using the GF-UM-3 and GF-UM-20 was 82% and 70%, respectively. This compares with an accuracy of 76% and 79% for CT and ERCP, respectively. The accuracy of EUS in assessing tumor extension was 62% overall and varied from 63% to 60% when using the GFUM-3 and GF-UM-20 instrument systems (Olympus Optical Co, Tokyo, Japan), respectively. Endoluminal endosonography using the UM-3R ultrasonic probe is a useful adjunct in the diagnosis of malignancy in patients with IPMTs. Inui and colleagues [16] studied 9 patients with IPMTs. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for differentiation of malignant and benign design were 85.7%, 88.9%, 90.5%, 60.0%, and 96.9%, respectively. None of the patients developed acute pancreatitis, but high serum amylase levels were detected in 10% of the patients.
(Enlarge Image)
Figure 2.
EUS revealed a markedly dilated pancreatic duct with no mural vegetations. CBD = common bile duct, PD = pancreatic duct.
Intraductal mucin-hypersecreting neoplasms, also known as mucinous ductal ectasia (MDE), represent a form of pancreatic exocrine tumor previously confused with cystic neoplasms. This clinical entity, first described in 1982 by Ohhashi and colleagues, [3] was referred to as "mucin-producing intraductal tumor." The initial report described four patients with pancreatic carcinoma associated with unique clinical features distinct from the typical pancreatic ductal adenocarcinoma. Intraductal excretion of mucin resulted in diffuse dilatation of the main pancreatic duct and extrusion of mucus through a patulous ampullary orifice. The variety of terms subsequently used to describe MDE (Table 2) stems from a lack of understanding of this clinicopathologic entity. It seems likely, however, that various authors have focused on different stages in an adenoma-carcinoma sequence when choosing a descriptive diagnosis. [4] A recent study by Rivera et al [5] showed that intraductal papillary neoplasms with or without MDE represent a spectrum of main-duct papillary tumors ranging from adenoma to carcinoma. The authors therefore suggested the term intraductal papillary mucinous tumors (IPMTs) of the pancreas to encompass both tumors.
Little information is available on the epidemiology and etiology of IPMTs because they occur rarely and have been only recently recognized. The study by Rivera et al [5] suggested that cigarette smoking is a risk factor for IPMTs, which was also noted in a series based on all pancreatic cancers. [6] Data from animal models suggest that nitrosamines play a significant role in the etiology of both IPMTs and solid ductal adenocarcinomas. [7] IPMTs arise from the epithelial lining of the pancreatic ducts and progress along the duct system. Approximately 75% of the IPMTs arise from the main pancreatic duct within the head of the pancreas. Some IPMTs involve the ampulla of Vater and/or the minor papilla from where they protrude into the duodenum. The dilated duct segment contains a grossly visible papillary/villous tumor and/or viscous mucin. IPMTs may be benign, borderline, or malignant according to the differentiation of the proliferating columnar epithelial cells.
IPMTs occur mostly in men in the sixth to seventh decade (range = 40 to 85 years). The most common presenting symptom is abdominal discomfort associated with mild elevations of pancreatic serum enzymes mimicking chronic or relapsing pancreatitis. The history of pancreatitis or recurrent pancreatitis varies from 29% [5] to 80% [8] in the literature. These symptoms are more commonly observed in patients with mucinhypersecreting tumors and are most likely due to intermittent obstruction of the main pancreatic duct by plugs of viscous mucin or intraluminal tumor. Back pain (25%), jaundice (25%), weight loss (42%), steator-rhea (37.5%), and diabetes (37.5%) are among various presentations reported in one series. [5] In a recent report from our institution describing outcomes of 25 patients with IPMTs, [9] 52% of patients had acute relapsing pancreatitis with elevated pancreatic enzymes, 32% had pain with normal enzymes, 12% had weight loss with no pain, and 4% had incidental findings. Therefore, due to the indolent nature of these tumors and the limited awareness of this lesion among the medical community, a delay in diagnosis ranging from months to years is not uncommon.
Conventional imaging studies such as abdominal CT scanning and transabdominal ultrasonography reveal nonspecific changes that are indistinguishable from those of chronic pancreatitis, pancreatic pseudo-cysts, or nonmucinous producing cystic neoplasms. These studies typically demonstrate well-defined unilocular or multilocular cystic pancreatic masses and/or dilatation of the main pancreatic duct. The term cystic duct here would be a misnomer since these cystic structures represent dilated ductular structures. The cystic changes of IPMTs may occasionally be so extensive as that they are confused with a mucinous cystic neoplasm. An important distinction between the two lesions is that, in IPMTs, the "cysts" communicate with the duct system, whereas MCNs generally do not show any connection with the duct system.
Endoscopy and endoscopic retrograde pancreatography (ERP) are essential to clarify the diagnosis. The typical ERP reveals extreme dilatation along the entire length of the main pancreatic duct, with associated side branch ectasia, in the absence of a demonstrable pancreatic duct stricture that would explain the duct dilation (Fig 1). The cystically dilated portions of the duct are filled with mucus, and the dilation is the result of mucus obstruction. In a report by Cunningham and colleagues, [9] ERCP findings were patulous papilla (80%), visible mucin (84%), ductal filling defects (88%), and dilated pancreatic duct (100%), with whole pancreatic duct dilated in 64% and focal segmental dilation in 36%. Tissue specimens (aspiration cytology, brush cytology, or pancreatic biopsy) obtained endoscopically have a high false-negative rate but are helpful when positive.
(Enlarge Image)
Figure 1.
Endoscopic retrograde pancreatography demonstrates a diffusely dilated main pancreatic duct with filling defects and dilated irregular side branches consistent with mucinous ductal ectasia (MDE).
[ CLOSE WINDOW ]
Figure 1.
Endoscopic retrograde pancreatography demonstrates a diffusely dilated main pancreatic duct with filling defects and dilated irregular side branches consistent with mucinous ductal ectasia (MDE).
Pancreatoscopy may provide valuable information for the differential diagnosis of amorphous filling defects in the main pancreatic duct and may help to determine the extent of the pathology and the resection margin. Pancreatoscopy can be used to easily differentiate between an intraductal mass and mucin. Also, biopsies can be taken under direct vision from a suspicious mucosal lesion using the "mother-baby scope." [10] Although a diagnosis of malignancy can be obtained preoperatively, this usually does not substitute for surgical exploration and resection of the diseased segment based on frozen section results. In a series reporting on the results of 24 patients, [5] 20 (83%) were resectable. There were 9 pancreatoduodenectomies, 4 distal pancreatectomies, and 7 total pancreatectomies. The operation chosen is usually tailored to conform to the apparent distribution of the intraluminal tumor and not to the distribution of mucin. The inability to achieve histologically negative margins often leads to a total pancreatectomy. At final pathology, invasive adenocarcinoma was seen in 46% of the patients, carcinoma in situ was seen in an additional 24%, and low-grade dysplasia in 12% of the remaining patients. Despite the 88% prevalence of cancer in this series, the overall survival at a mean follow-up of 21 months was 81%. There were no recur-rences or new papillary growths in the pancreatic remnants. Four of the 24 patients had unresectable disease due to liver metastasis. The serum CA 19-9 value was helpful in predicting unresectability. Three of the 4 unresectable patients in this series had values higher than 2000 U/mL.
Cellier and colleagues [11] found invasive carcinoma in 43% of their patients and carcinoma in situ in 21%, with significantly poorer prognosis for patients with invasive carcinoma. The overall actuarial 3-year survival for patients with IPMTs was 83% in their series, whereas the overall recurrence-free 3-year survival was only 21% among patients with invasive disease. A review by Shyr et al [12] found a cumulative 5-year survival of 92% for 51 cases. In a study by Loftus and colleagues [13] involving 15 patients, 3 of 4 patients with malignant IPMTs died of metastatic disease, and 2 of 11 patients with benign disease died although with no evidence of tumor spread.
MRCP has emerged as a new noninvasive technology to assess both pancreatic and bile ducts without the use of contrast material or endoscopy. A study by Koito and colleagues [14] compared MRCP to ERCP in the diagnosis of mucin-hypersecreting tumors of the pancreas. MRCP showed cystic dilated branches of the pancreas better than ERCP. The numbers of nodules or septa that were detectable by MRCP and ERCP were similar. The authors concluded that MRCP appears to be more effective than ERCP for the detection of intraductal cystic lesions of mucin-producing pancreatic tumors. Because some of these tumors are not malignant and do not require surgery, MRCP offers a less invasive alternative to ERCP for follow-up studies. In the study by Yamaguchi et al, [15] the details of cystic lesions of the branch ducts (eg, mural nodule, communication with main pancreatic duct) were more clearly demonstrated by ERCP than by MRCP. ERCP was clear-ly superior in demonstration of normal main pancreatic duct and its branches. These two studies suggest that both ERCP and MRCP are complementary studies that are helpful in the diagnosis and follow-up of patients with IPMTs.
Cellier and colleagues [11] reported on the role of EUS in assessing tumor extension and invasion in patients with IPMTs (Fig 2). They demonstrated that the sensitivity and specificity of EUS for invasive malignancy were 78% and 75%, respectively. The overall accuracy of EUS in assessing tumor invasiveness was 76%. The accuracy for EUS using the GF-UM-3 and GF-UM-20 was 82% and 70%, respectively. This compares with an accuracy of 76% and 79% for CT and ERCP, respectively. The accuracy of EUS in assessing tumor extension was 62% overall and varied from 63% to 60% when using the GFUM-3 and GF-UM-20 instrument systems (Olympus Optical Co, Tokyo, Japan), respectively. Endoluminal endosonography using the UM-3R ultrasonic probe is a useful adjunct in the diagnosis of malignancy in patients with IPMTs. Inui and colleagues [16] studied 9 patients with IPMTs. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for differentiation of malignant and benign design were 85.7%, 88.9%, 90.5%, 60.0%, and 96.9%, respectively. None of the patients developed acute pancreatitis, but high serum amylase levels were detected in 10% of the patients.
(Enlarge Image)
Figure 2.
EUS revealed a markedly dilated pancreatic duct with no mural vegetations. CBD = common bile duct, PD = pancreatic duct.
Mucinous Tumors of the Exocrine Pancreas: Intraductal Mucin-Hypersecreting Neoplasms
Mucinous Tumors of the Exocrine Pancreas: Intraductal Mucin-Hypersecreting Neoplasms
IPMTs may be benign, borderline, or malignant according to the differentiation of the proliferating columnar epithelial cells
www.medscape.com
From Cancer Control: Journal of the Moffitt Cancer Center
Mucinous Tumors of the Exocrine Pancreas
Mohamad A. Eloubeidi, MD, MHS, and Robert H. Hawes, MD, From the Division of Gastroenterology/Hepatology and the Digestive Disease Center at the Medical University of South Carolina, Charleston, South Carolina. Dr. Eloubeidi is currently at the University of Alabama at Birmingham.
Posted: 09/01/2000; Cancer Control. 2000;7(5) © 2000 H. Lee Moffitt Cancer Center and Research Institute, Inc.
Abstract and Introduction
Abstract
Background: Mucin-producing cystic neoplasms of the pancreas account for 1% of all malignant tumors of the pancreas. They include mucinous cystic neoplasms (MCNs) and mucinous ductal ectasia (MDE), also known as intraductal mucin-hypersecreting neoplasms.
Methods: This review focuses on the clinical presentation, the role of diagnostic imaging modalities, and cyst fluid analysis preoperatively in the differentiation between these tumors and other nonneoplastic cysts of the pancreas.
Results: MCNs and MDE evolve from pancreatic duct epithelium, produce an abundance of mucin, and are considered premalignant or malignant. While MCNs affect primarily middle-aged women with lesions occurring predominantly in the body and tail of the pancreas, MDE affects primarily men in the sixth or seventh decade with lesions more often located in the head of the pancreas.
Conclusions: All mucin-producing cystic tumors of both types require surgical resection because they are frankly malignant or premalignant. Survival rates of both tumors are better than those reported for ductal cell carcinomas. Future studies are needed to improve the accuracy of diagnosing these tumors preoperatively.
Introduction
Cystic abnormalities of the pancreas encompass a wide variety of lesions ranging from the nonmalignant pseudocyst to neoplastic lesions (Table 1). [1] Cystic neoplasms of the pancreas are rare, accounting for 10%-13% of pancreatic cysts and 1% of pancreatic carcinomas. [2] Cystic neoplasms of the pancreas include serous cystadenomas, papillary cystic tumors, cystic islet cell tumors, mucinous cystic neoplasms (MCNs [cystadenomas and cystadenocarcinomas]), and intraductal mucin-hypersecreting pancreatic neoplasms, also known as mucinous ductal ectasia (MDE). Better detection rates of these distinct clinical entities have resulted from recent advances in pancreatico-biliary imaging, including endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), endoscopic ultra-sonography (EUS), computed tomography (CT), and ultrasonography. MCNs and MDE have received much attention due to the possibility of confusing them with benign pseudocysts and the potential for cure if diagnosed and managed appropriately.
MCNs and MDE evolve from pancreatic duct epithelium, produce an abundant amount of mucin, and are considered premalignant or malignant. While MCNs affect primarily middle-aged women with lesions occurring predominantly in the body and tail of the pancreas, MDE affects primarily men in the sixth and seventh decade with lesions more often located in the head of the pancreas.
Intraductal Mucin-Hypersecreting Neoplasms
Intraductal mucin-hypersecreting neoplasms, also known as mucinous ductal ectasia (MDE), represent a form of pancreatic exocrine tumor previously confused with cystic neoplasms. This clinical entity, first described in 1982 by Ohhashi and colleagues, [3] was referred to as "mucin-producing intraductal tumor." The initial report described four patients with pancreatic carcinoma associated with unique clinical features distinct from the typical pancreatic ductal adenocarcinoma. Intraductal excretion of mucin resulted in diffuse dilatation of the main pancreatic duct and extrusion of mucus through a patulous ampullary orifice. The variety of terms subsequently used to describe MDE (Table 2) stems from a lack of understanding of this clinicopathologic entity. It seems likely, however, that various authors have focused on different stages in an adenoma-carcinoma sequence when choosing a descriptive diagnosis. [4] A recent study by Rivera et al [5] showed that intraductal papillary neoplasms with or without MDE represent a spectrum of main-duct papillary tumors ranging from adenoma to carcinoma. The authors therefore suggested the term intraductal papillary mucinous tumors (IPMTs) of the pancreas to encompass both tumors.
Little information is available on the epidemiology and etiology of IPMTs because they occur rarely and have been only recently recognized. The study by Rivera et al [5] suggested that cigarette smoking is a risk factor for IPMTs, which was also noted in a series based on all pancreatic cancers. [6] Data from animal models suggest that nitrosamines play a significant role in the etiology of both IPMTs and solid ductal adenocarcinomas. [7] IPMTs arise from the epithelial lining of the pancreatic ducts and progress along the duct system. Approximately 75% of the IPMTs arise from the main pancreatic duct within the head of the pancreas. Some IPMTs involve the ampulla of Vater and/or the minor papilla from where they protrude into the duodenum. The dilated duct segment contains a grossly visible papillary/villous tumor and/or viscous mucin. IPMTs may be benign, borderline, or malignant according to the differentiation of the proliferating columnar epithelial cells.
IPMTs occur mostly in men in the sixth to seventh decade (range = 40 to 85 years). The most common presenting symptom is abdominal discomfort associated with mild elevations of pancreatic serum enzymes mimicking chronic or relapsing pancreatitis. The history of pancreatitis or recurrent pancreatitis varies from 29% [5] to 80% [8] in the literature. These symptoms are more commonly observed in patients with mucinhypersecreting tumors and are most likely due to intermittent obstruction of the main pancreatic duct by plugs of viscous mucin or intraluminal tumor. Back pain (25%), jaundice (25%), weight loss (42%), steator-rhea (37.5%), and diabetes (37.5%) are among various presentations reported in one series. [5] In a recent report from our institution describing outcomes of 25 patients with IPMTs, [9] 52% of patients had acute relapsing pancreatitis with elevated pancreatic enzymes, 32% had pain with normal enzymes, 12% had weight loss with no pain, and 4% had incidental findings. Therefore, due to the indolent nature of these tumors and the limited awareness of this lesion among the medical community, a delay in diagnosis ranging from months to years is not uncommon.
Conventional imaging studies such as abdominal CT scanning and transabdominal ultrasonography reveal nonspecific changes that are indistinguishable from those of chronic pancreatitis, pancreatic pseudo-cysts, or nonmucinous producing cystic neoplasms. These studies typically demonstrate well-defined unilocular or multilocular cystic pancreatic masses and/or dilatation of the main pancreatic duct. The term cystic duct here would be a misnomer since these cystic structures represent dilated ductular structures. The cystic changes of IPMTs may occasionally be so extensive as that they are confused with a mucinous cystic neoplasm. An important distinction between the two lesions is that, in IPMTs, the "cysts" communicate with the duct system, whereas MCNs generally do not show any connection with the duct system.
Endoscopy and endoscopic retrograde pancreatography (ERP) are essential to clarify the diagnosis. The typical ERP reveals extreme dilatation along the entire length of the main pancreatic duct, with associated side branch ectasia, in the absence of a demonstrable pancreatic duct stricture that would explain the duct dilation (Fig 1). The cystically dilated portions of the duct are filled with mucus, and the dilation is the result of mucus obstruction. In a report by Cunningham and colleagues, [9] ERCP findings were patulous papilla (80%), visible mucin (84%), ductal filling defects (88%), and dilated pancreatic duct (100%), with whole pancreatic duct dilated in 64% and focal segmental dilation in 36%. Tissue specimens (aspiration cytology, brush cytology, or pancreatic biopsy) obtained endoscopically have a high false-negative rate but are helpful when positive.
Figure 1. Endoscopic retrograde pancreatography demonstrates a diffusely dilated main pancreatic duct with filling defects and dilated irregular side branches consistent with mucinous ductal ectasia (MDE).
Pancreatoscopy may provide valuable information for the differential diagnosis of amorphous filling defects in the main pancreatic duct and may help to determine the extent of the pathology and the resection margin. Pancreatoscopy can be used to easily differentiate between an intraductal mass and mucin. Also, biopsies can be taken under direct vision from a suspicious mucosal lesion using the "mother-baby scope." [10] Although a diagnosis of malignancy can be obtained preoperatively, this usually does not substitute for surgical exploration and resection of the diseased segment based on frozen section results. In a series reporting on the results of 24 patients, [5] 20 (83%) were resectable. There were 9 pancreatoduodenectomies, 4 distal pancreatectomies, and 7 total pancreatectomies. The operation chosen is usually tailored to conform to the apparent distribution of the intraluminal tumor and not to the distribution of mucin. The inability to achieve histologically negative margins often leads to a total pancreatectomy. At final pathology, invasive adenocarcinoma was seen in 46% of the patients, carcinoma in situ was seen in an additional 24%, and low-grade dysplasia in 12% of the remaining patients. Despite the 88% prevalence of cancer in this series, the overall survival at a mean follow-up of 21 months was 81%. There were no recur-rences or new papillary growths in the pancreatic remnants. Four of the 24 patients had unresectable disease due to liver metastasis. The serum CA 19-9 value was helpful in predicting unresectability. Three of the 4 unresectable patients in this series had values higher than 2000 U/mL.
Cellier and colleagues [11] found invasive carcinoma in 43% of their patients and carcinoma in situ in 21%, with significantly poorer prognosis for patients with invasive carcinoma. The overall actuarial 3-year survival for patients with IPMTs was 83% in their series, whereas the overall recurrence-free 3-year survival was only 21% among patients with invasive disease. A review by Shyr et al [12] found a cumulative 5-year survival of 92% for 51 cases. In a study by Loftus and colleagues [13] involving 15 patients, 3 of 4 patients with malignant IPMTs died of metastatic disease, and 2 of 11 patients with benign disease died although with no evidence of tumor spread.
MRCP has emerged as a new noninvasive technology to assess both pancreatic and bile ducts without the use of contrast material or endoscopy. A study by Koito and colleagues [14] compared MRCP to ERCP in the diagnosis of mucin-hypersecreting tumors of the pancreas. MRCP showed cystic dilated branches of the pancreas better than ERCP. The numbers of nodules or septa that were detectable by MRCP and ERCP were similar. The authors concluded that MRCP appears to be more effective than ERCP for the detection of intraductal cystic lesions of mucin-producing pancreatic tumors. Because some of these tumors are not malignant and do not require surgery, MRCP offers a less invasive alternative to ERCP for follow-up studies. In the study by Yamaguchi et al, [15] the details of cystic lesions of the branch ducts (eg, mural nodule, communication with main pancreatic duct) were more clearly demonstrated by ERCP than by MRCP. ERCP was clear-ly superior in demonstration of normal main pancreatic duct and its branches. These two studies suggest that both ERCP and MRCP are complementary studies that are helpful in the diagnosis and follow-up of patients with IPMTs.
Cellier and colleagues [11] reported on the role of EUS in assessing tumor extension and invasion in patients with IPMTs (Fig 2). They demonstrated that the sensitivity and specificity of EUS for invasive malignancy were 78% and 75%, respectively. The overall accuracy of EUS in assessing tumor invasiveness was 76%. The accuracy for EUS using the GF-UM-3 and GF-UM-20 was 82% and 70%, respectively. This compares with an accuracy of 76% and 79% for CT and ERCP, respectively. The accuracy of EUS in assessing tumor extension was 62% overall and varied from 63% to 60% when using the GFUM-3 and GF-UM-20 instrument systems (Olympus Optical Co, Tokyo, Japan), respectively. Endoluminal endosonography using the UM-3R ultrasonic probe is a useful adjunct in the diagnosis of malignancy in patients with IPMTs. Inui and colleagues [16] studied 9 patients with IPMTs. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for differentiation of malignant and benign design were 85.7%, 88.9%, 90.5%, 60.0%, and 96.9%, respectively. None of the patients developed acute pancreatitis, but high serum amylase levels were detected in 10% of the patients.
Figure 2. EUS revealed a markedly dilated pancreatic duct with no mural vegetations. CBD = common bile duct, PD = pancreatic duct.
Mucinous Cystic Neoplasms
Cystic pancreatic neoplasms consist of a heterogeneous group of pathologic entities, which share only cystic appearance on abdominal imaging and a predilection for female gender. The most common cystic pancreatic neoplasms are MCNs and serous cystadenomas. These two entities account for more than 75% of the cystic pancreatic neoplasms. Other less common cystic pancreatic neoplasms include papillary cystic tumors, cystic neuroendocrine tumor, cystic teratoma, lymphangioma, hemangioma, and paraganglioma.
MCNs are the most common cystic pancreatic neoplasms.[17,18] Eighty percent of MCNs occur in women with a mean age at presentation of 54 years. Abdominal pain, weight loss, early satiety, nausea and vomiting are among the most frequently reported symptoms. Twenty percent of MCNs and 50% of serous cystadenomas are asymptomatic and are discovered incidentally during laparotomy or radiological evaluation performed for an unrelated problem. Most MCNs consist of large loculi (macrocystic) filled with thick mucoid material. The walls are dense and fibrous and may even be calcified. Histologic evaluation reveals mucin-producing epithelial cells lining the cyst, but denudation of large areas of epithelium is common. In general, cystic tumors of the pancreas are distinguished from pseudo-cysts by the presence of solid components, septa, and loculations on CT scan and extracorporeal ultrasonography.[19] Calcifications can be seen in one third of cystic tumors and, unlike calcifications, are seen with pseudocysts arising from chronic pancreatitis. They never form part of the pseudocyst wall.
Misdiagnosis of a cystic neoplasm as a pancreatic pseudocyst either delays appropriate resection or leads to performance of an inappropriate procedure in as many as 37% of cases. [18] A thorough clinical history might provide some clues as to the nature of the pancreatic cystic lesion and might minimize confusion between these two entities. While a pseudocyst usually develops in the setting of chronic pancreatitis or following an episode of acute necrotizing pancreatitis, neoplastic cysts arise de novo. In rare instances, however, cystic tumors can cause acute pancreatitis due to obstruction of the pancreatic duct. While an elevated serum amylase supports the diagnosis of a pseudocyst, a normal value provides no discriminatory information. Cysts whose fluid is low in amylase are almost always neoplastic.
Identifying cystic lesions on the basis of imaging modalities is difficult, especially for solitary unilocular cysts. The diagnostic accuracy of cytology obtained by CT-guided aspiration is limited due to the difficulty in finding diagnostic cells, but the overall accuracy is 67% for malignant cysts and 40% for mucinous cysts. [20] To improve the diagnostic yield of cyst fluid analysis, both the physical characteristics of cyst fluid and other tumor markers in the cyst fluid have been studied (Table 3). The fluid within MCNs is more viscous than within serous cystadenomas. Carcinoembryonic antigen (CEA) appears to be the most useful marker for detecting MCNs. [21] Other markers such as CA-72-4 and CA 15-3 appear better at discerning benign from malignant lesions. [22]
The role of EUS in differentiating benign cystic lesions from malignant ones has been recently clarified. Koito and colleagues [23] used EUS to classify 52 cystic lesions according to the wall and septa characteristics. All nonneoplastic tumors belonged to the thin septa type or simple type, and all malignant tumors belonged to the thick wall, tumor-protruding, thick septal, or microcystic type. The accuracy of EUS for differentiating tumors, as classified by two independent EUS observers blinded to the pathologic specimens, was estimated at 96% and 92%. Ikeda and coworkers [24] reported EUS criteria for follow-up of small pancreatic cysts (87.1% <2 cm) of unknown etiology. The cysts were classified as (1) a clear thin wall, (2) smooth contour, (3) round or oval shape, (4) no septum or nodule, (5) asymptomatic, and (6) no findings of chronic pancreatitis. After a follow-up of 3 years, 30 (97%) of 31 cases appeared to be nonprogressive. Following resection, the enlarging lesion was found to be a retention cyst. Sugiyama and colleagues [25] were able to reliably distinguish MCNs from intraductal papillary tumors by using a combination of EUS, ERCP, MRCP, and CT. EUS and MRCP demonstrated septa within cysts and mural nodules more accurately than ultrasonography, CT, and ERCP. EUS was significantly superior to ultrasonography, CT, and ERCP for the detection of mural nodules.
The presence of mural nodules suggests malignancy in both cystic tumor types. EUS therefore facilitates the diagnosis of serous cystadenomas, mucinous cyst-adenomas, and cystadenocarcinomas when microcysts, vegetation of the wall of a macrocyst, limited invasion of the pancreas due to the presence of vegetation, or a localized thickening of the wall of the cystic lesion are detected (Fig 3). Moreover, when faced with diagnostic uncertainty, EUS allows sampling of cystic fluid material for biochemical analysis and evaluation of the mucins and tumor markers (Figs 3 and 4). In a study by Mallery et al, [26] the use of EUS-guided fine-needle aspiration (FNA) with cyst fluid analysis in pancreatic cystic lesions was evaluated in 20 patients. In addition to cytology, cyst fluid was sent for mucin staining and tumor markers (CEA, CA 125, CA 19-9, CA 72-4, CA 15-3, and tissue polypeptide antigen). Positive cytology or an elevated level of a tumor marker had an accuracy of 86%, a sensitivity of 83%, a specificity of 88%, a positive predictive value of 83%, and a negative predictive value of 88% for diagnosing a cystic neoplasm. Two patients developed self-limited pancreatitis, and no patients developed any infectious complications. Other groups [27] have encountered infectious complications up to 14% when aspirating pancreatic cystic lesions with EUS-guided FNA. Because of the potential risk of infection, our current practice is to administer antibiotics prior to aspirating a cystic lesion of the pancreas. A multicenter study is underway to evaluate the role of EUS-guided FNA in determining the nature of cystic pancreatic lesions preoperatively.
Figure 3. EUS revealed a complex cystic lesion with multiple thin septa. EUS-guided FNA revealed markedly elevated CEA and CA 19-9 and low amylase. Pathology revealed a mucinous (macrocystic) cystadenoma.
Figure 4. Transgastric aspiration of a large simple cyst under EUS guidance (arrow = needle, arrowhead = cyst).
Treatment of cystic pancreatic neoplasms depends on the tumor's size, location, type, and extent. The prognosis depends on the tumor type and the resectability of the lesion. MCNs should be resected according to standard oncologic principles. The prognosis for completely resected MCNs is excellent, with a 5-year survival rate of more than 50% reported for malignant lesions. Long-term survival is possible in patients with cystadenocarcinomas, so these patients should undergo resection with the intent to cure even if a large tumor or local extension is found. In a series by Warshaw et al [18] of 42 patients with MCNs, 64% were found to be malignant. Sixty three percent of mucinous adenocarcinomas were judged to be resectable, and 22% had nonlocal metastases. Overall, 76% of patients with mucinous carcinomas resected with curative intent were alive, without evidence of recurrent dis-ease, at a follow-up ranging from 6 months to 10 years. All patients with unresectable local or metastatic cancer died of their disease at an average of 4 months after having followed a rapid downhill course similar to that of unresectable pancreatic adenocarcinoma. In a review of 21 cases of cystadenocarcinomas, Hodgkin-son and colleagues [28] noted a 5-year survival rate of 68% after complete excision compared with a 14% rate for those who had partial excision. Delcore and colleagues [29] reported 90% long-term disease-free survival among 10 patients with resectable mucinous cystadenocarcinomas, whereas 3 patients who underwent palliative resection died within 9 months. These two studies emphasize the prognosis and survival in these patients; localized and therefore resectable cystadenocarcinomas are highly curable, while those with distant spread have a dismal prognosis similar to patients with ductal adenocarcinoma.
Conclusions
Mucinous-producing neoplasm of the pancreas, IPMTs and MCNs, are two distinct clinical entities, and they present a diagnostic and therapeutic challenge. They behave in an indolent manner, with frequent overlap of symptoms and radiological appearance with pancreatic cysts, pseudocysts, or malignancy. Both IPMTs and MCNs originate in the pancreatic duct epithelium, produce mucin, demonstrate a papillary growth pattern, and are considered to be premalignant or malignant at the time of diagnosis. Both lesions are less aggressive biologically than ductal adenocarcinoma, and they appear to infiltrate peripancreatic tissue and metastasize to lymph nodes or adjacent structures late in the course of the disease. IPMTs are located primarily in the head of the pancreas, predominantly affect elderly men, and present with acute or recurrent pancreatitis symptoms. MCNs are more likely to develop in the body or tail, are more commonly seen in women of middle age, and present with symptoms referable to a mass effect on adjacent structures. To diagnose these lesions preoperatively, a high index of suspicion is needed; factors that should heighten the suspicion include the presence of a cystic structure of the pancreas on abdominal imaging, the absence of a history of pancreatitis in a patient with a cystic lesion of the pancreas, and the presence of exuding mucus from the major or minor papilla and the amorphous filling defects in an elderly patient undergoing ERCP. Cyst fluid aspiration and analysis preoperatively are helpful in differentiating between malignant and benign neoplasms. Both lesions are managed by surgical resection because the opportunity for cure is high in the absence of metastatic disease. Future studies are needed to improve the accuracy of diagnosing these tumors preoperatively.
[ CLOSE WINDOW ]
References
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Acknowledgments
Appreciation is expressed to Mrs. Linda McDaniel for her assistance in reproducing the figures shown in this manuscript.
Cancer Control. 2000;7(5) © 2000 H. Lee Moffitt Cancer Center and Research Institute, Inc.
© Copyright by H. Lee Moffitt Cancer Center & Research Institute. All rights reserved.
IPMTs may be benign, borderline, or malignant according to the differentiation of the proliferating columnar epithelial cells
www.medscape.com
From Cancer Control: Journal of the Moffitt Cancer Center
Mucinous Tumors of the Exocrine Pancreas
Mohamad A. Eloubeidi, MD, MHS, and Robert H. Hawes, MD, From the Division of Gastroenterology/Hepatology and the Digestive Disease Center at the Medical University of South Carolina, Charleston, South Carolina. Dr. Eloubeidi is currently at the University of Alabama at Birmingham.
Posted: 09/01/2000; Cancer Control. 2000;7(5) © 2000 H. Lee Moffitt Cancer Center and Research Institute, Inc.
Abstract and Introduction
Abstract
Background: Mucin-producing cystic neoplasms of the pancreas account for 1% of all malignant tumors of the pancreas. They include mucinous cystic neoplasms (MCNs) and mucinous ductal ectasia (MDE), also known as intraductal mucin-hypersecreting neoplasms.
Methods: This review focuses on the clinical presentation, the role of diagnostic imaging modalities, and cyst fluid analysis preoperatively in the differentiation between these tumors and other nonneoplastic cysts of the pancreas.
Results: MCNs and MDE evolve from pancreatic duct epithelium, produce an abundance of mucin, and are considered premalignant or malignant. While MCNs affect primarily middle-aged women with lesions occurring predominantly in the body and tail of the pancreas, MDE affects primarily men in the sixth or seventh decade with lesions more often located in the head of the pancreas.
Conclusions: All mucin-producing cystic tumors of both types require surgical resection because they are frankly malignant or premalignant. Survival rates of both tumors are better than those reported for ductal cell carcinomas. Future studies are needed to improve the accuracy of diagnosing these tumors preoperatively.
Introduction
Cystic abnormalities of the pancreas encompass a wide variety of lesions ranging from the nonmalignant pseudocyst to neoplastic lesions (Table 1). [1] Cystic neoplasms of the pancreas are rare, accounting for 10%-13% of pancreatic cysts and 1% of pancreatic carcinomas. [2] Cystic neoplasms of the pancreas include serous cystadenomas, papillary cystic tumors, cystic islet cell tumors, mucinous cystic neoplasms (MCNs [cystadenomas and cystadenocarcinomas]), and intraductal mucin-hypersecreting pancreatic neoplasms, also known as mucinous ductal ectasia (MDE). Better detection rates of these distinct clinical entities have resulted from recent advances in pancreatico-biliary imaging, including endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), endoscopic ultra-sonography (EUS), computed tomography (CT), and ultrasonography. MCNs and MDE have received much attention due to the possibility of confusing them with benign pseudocysts and the potential for cure if diagnosed and managed appropriately.
MCNs and MDE evolve from pancreatic duct epithelium, produce an abundant amount of mucin, and are considered premalignant or malignant. While MCNs affect primarily middle-aged women with lesions occurring predominantly in the body and tail of the pancreas, MDE affects primarily men in the sixth and seventh decade with lesions more often located in the head of the pancreas.
Intraductal Mucin-Hypersecreting Neoplasms
Intraductal mucin-hypersecreting neoplasms, also known as mucinous ductal ectasia (MDE), represent a form of pancreatic exocrine tumor previously confused with cystic neoplasms. This clinical entity, first described in 1982 by Ohhashi and colleagues, [3] was referred to as "mucin-producing intraductal tumor." The initial report described four patients with pancreatic carcinoma associated with unique clinical features distinct from the typical pancreatic ductal adenocarcinoma. Intraductal excretion of mucin resulted in diffuse dilatation of the main pancreatic duct and extrusion of mucus through a patulous ampullary orifice. The variety of terms subsequently used to describe MDE (Table 2) stems from a lack of understanding of this clinicopathologic entity. It seems likely, however, that various authors have focused on different stages in an adenoma-carcinoma sequence when choosing a descriptive diagnosis. [4] A recent study by Rivera et al [5] showed that intraductal papillary neoplasms with or without MDE represent a spectrum of main-duct papillary tumors ranging from adenoma to carcinoma. The authors therefore suggested the term intraductal papillary mucinous tumors (IPMTs) of the pancreas to encompass both tumors.
Little information is available on the epidemiology and etiology of IPMTs because they occur rarely and have been only recently recognized. The study by Rivera et al [5] suggested that cigarette smoking is a risk factor for IPMTs, which was also noted in a series based on all pancreatic cancers. [6] Data from animal models suggest that nitrosamines play a significant role in the etiology of both IPMTs and solid ductal adenocarcinomas. [7] IPMTs arise from the epithelial lining of the pancreatic ducts and progress along the duct system. Approximately 75% of the IPMTs arise from the main pancreatic duct within the head of the pancreas. Some IPMTs involve the ampulla of Vater and/or the minor papilla from where they protrude into the duodenum. The dilated duct segment contains a grossly visible papillary/villous tumor and/or viscous mucin. IPMTs may be benign, borderline, or malignant according to the differentiation of the proliferating columnar epithelial cells.
IPMTs occur mostly in men in the sixth to seventh decade (range = 40 to 85 years). The most common presenting symptom is abdominal discomfort associated with mild elevations of pancreatic serum enzymes mimicking chronic or relapsing pancreatitis. The history of pancreatitis or recurrent pancreatitis varies from 29% [5] to 80% [8] in the literature. These symptoms are more commonly observed in patients with mucinhypersecreting tumors and are most likely due to intermittent obstruction of the main pancreatic duct by plugs of viscous mucin or intraluminal tumor. Back pain (25%), jaundice (25%), weight loss (42%), steator-rhea (37.5%), and diabetes (37.5%) are among various presentations reported in one series. [5] In a recent report from our institution describing outcomes of 25 patients with IPMTs, [9] 52% of patients had acute relapsing pancreatitis with elevated pancreatic enzymes, 32% had pain with normal enzymes, 12% had weight loss with no pain, and 4% had incidental findings. Therefore, due to the indolent nature of these tumors and the limited awareness of this lesion among the medical community, a delay in diagnosis ranging from months to years is not uncommon.
Conventional imaging studies such as abdominal CT scanning and transabdominal ultrasonography reveal nonspecific changes that are indistinguishable from those of chronic pancreatitis, pancreatic pseudo-cysts, or nonmucinous producing cystic neoplasms. These studies typically demonstrate well-defined unilocular or multilocular cystic pancreatic masses and/or dilatation of the main pancreatic duct. The term cystic duct here would be a misnomer since these cystic structures represent dilated ductular structures. The cystic changes of IPMTs may occasionally be so extensive as that they are confused with a mucinous cystic neoplasm. An important distinction between the two lesions is that, in IPMTs, the "cysts" communicate with the duct system, whereas MCNs generally do not show any connection with the duct system.
Endoscopy and endoscopic retrograde pancreatography (ERP) are essential to clarify the diagnosis. The typical ERP reveals extreme dilatation along the entire length of the main pancreatic duct, with associated side branch ectasia, in the absence of a demonstrable pancreatic duct stricture that would explain the duct dilation (Fig 1). The cystically dilated portions of the duct are filled with mucus, and the dilation is the result of mucus obstruction. In a report by Cunningham and colleagues, [9] ERCP findings were patulous papilla (80%), visible mucin (84%), ductal filling defects (88%), and dilated pancreatic duct (100%), with whole pancreatic duct dilated in 64% and focal segmental dilation in 36%. Tissue specimens (aspiration cytology, brush cytology, or pancreatic biopsy) obtained endoscopically have a high false-negative rate but are helpful when positive.
Figure 1. Endoscopic retrograde pancreatography demonstrates a diffusely dilated main pancreatic duct with filling defects and dilated irregular side branches consistent with mucinous ductal ectasia (MDE).
Pancreatoscopy may provide valuable information for the differential diagnosis of amorphous filling defects in the main pancreatic duct and may help to determine the extent of the pathology and the resection margin. Pancreatoscopy can be used to easily differentiate between an intraductal mass and mucin. Also, biopsies can be taken under direct vision from a suspicious mucosal lesion using the "mother-baby scope." [10] Although a diagnosis of malignancy can be obtained preoperatively, this usually does not substitute for surgical exploration and resection of the diseased segment based on frozen section results. In a series reporting on the results of 24 patients, [5] 20 (83%) were resectable. There were 9 pancreatoduodenectomies, 4 distal pancreatectomies, and 7 total pancreatectomies. The operation chosen is usually tailored to conform to the apparent distribution of the intraluminal tumor and not to the distribution of mucin. The inability to achieve histologically negative margins often leads to a total pancreatectomy. At final pathology, invasive adenocarcinoma was seen in 46% of the patients, carcinoma in situ was seen in an additional 24%, and low-grade dysplasia in 12% of the remaining patients. Despite the 88% prevalence of cancer in this series, the overall survival at a mean follow-up of 21 months was 81%. There were no recur-rences or new papillary growths in the pancreatic remnants. Four of the 24 patients had unresectable disease due to liver metastasis. The serum CA 19-9 value was helpful in predicting unresectability. Three of the 4 unresectable patients in this series had values higher than 2000 U/mL.
Cellier and colleagues [11] found invasive carcinoma in 43% of their patients and carcinoma in situ in 21%, with significantly poorer prognosis for patients with invasive carcinoma. The overall actuarial 3-year survival for patients with IPMTs was 83% in their series, whereas the overall recurrence-free 3-year survival was only 21% among patients with invasive disease. A review by Shyr et al [12] found a cumulative 5-year survival of 92% for 51 cases. In a study by Loftus and colleagues [13] involving 15 patients, 3 of 4 patients with malignant IPMTs died of metastatic disease, and 2 of 11 patients with benign disease died although with no evidence of tumor spread.
MRCP has emerged as a new noninvasive technology to assess both pancreatic and bile ducts without the use of contrast material or endoscopy. A study by Koito and colleagues [14] compared MRCP to ERCP in the diagnosis of mucin-hypersecreting tumors of the pancreas. MRCP showed cystic dilated branches of the pancreas better than ERCP. The numbers of nodules or septa that were detectable by MRCP and ERCP were similar. The authors concluded that MRCP appears to be more effective than ERCP for the detection of intraductal cystic lesions of mucin-producing pancreatic tumors. Because some of these tumors are not malignant and do not require surgery, MRCP offers a less invasive alternative to ERCP for follow-up studies. In the study by Yamaguchi et al, [15] the details of cystic lesions of the branch ducts (eg, mural nodule, communication with main pancreatic duct) were more clearly demonstrated by ERCP than by MRCP. ERCP was clear-ly superior in demonstration of normal main pancreatic duct and its branches. These two studies suggest that both ERCP and MRCP are complementary studies that are helpful in the diagnosis and follow-up of patients with IPMTs.
Cellier and colleagues [11] reported on the role of EUS in assessing tumor extension and invasion in patients with IPMTs (Fig 2). They demonstrated that the sensitivity and specificity of EUS for invasive malignancy were 78% and 75%, respectively. The overall accuracy of EUS in assessing tumor invasiveness was 76%. The accuracy for EUS using the GF-UM-3 and GF-UM-20 was 82% and 70%, respectively. This compares with an accuracy of 76% and 79% for CT and ERCP, respectively. The accuracy of EUS in assessing tumor extension was 62% overall and varied from 63% to 60% when using the GFUM-3 and GF-UM-20 instrument systems (Olympus Optical Co, Tokyo, Japan), respectively. Endoluminal endosonography using the UM-3R ultrasonic probe is a useful adjunct in the diagnosis of malignancy in patients with IPMTs. Inui and colleagues [16] studied 9 patients with IPMTs. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for differentiation of malignant and benign design were 85.7%, 88.9%, 90.5%, 60.0%, and 96.9%, respectively. None of the patients developed acute pancreatitis, but high serum amylase levels were detected in 10% of the patients.
Figure 2. EUS revealed a markedly dilated pancreatic duct with no mural vegetations. CBD = common bile duct, PD = pancreatic duct.
Mucinous Cystic Neoplasms
Cystic pancreatic neoplasms consist of a heterogeneous group of pathologic entities, which share only cystic appearance on abdominal imaging and a predilection for female gender. The most common cystic pancreatic neoplasms are MCNs and serous cystadenomas. These two entities account for more than 75% of the cystic pancreatic neoplasms. Other less common cystic pancreatic neoplasms include papillary cystic tumors, cystic neuroendocrine tumor, cystic teratoma, lymphangioma, hemangioma, and paraganglioma.
MCNs are the most common cystic pancreatic neoplasms.[17,18] Eighty percent of MCNs occur in women with a mean age at presentation of 54 years. Abdominal pain, weight loss, early satiety, nausea and vomiting are among the most frequently reported symptoms. Twenty percent of MCNs and 50% of serous cystadenomas are asymptomatic and are discovered incidentally during laparotomy or radiological evaluation performed for an unrelated problem. Most MCNs consist of large loculi (macrocystic) filled with thick mucoid material. The walls are dense and fibrous and may even be calcified. Histologic evaluation reveals mucin-producing epithelial cells lining the cyst, but denudation of large areas of epithelium is common. In general, cystic tumors of the pancreas are distinguished from pseudo-cysts by the presence of solid components, septa, and loculations on CT scan and extracorporeal ultrasonography.[19] Calcifications can be seen in one third of cystic tumors and, unlike calcifications, are seen with pseudocysts arising from chronic pancreatitis. They never form part of the pseudocyst wall.
Misdiagnosis of a cystic neoplasm as a pancreatic pseudocyst either delays appropriate resection or leads to performance of an inappropriate procedure in as many as 37% of cases. [18] A thorough clinical history might provide some clues as to the nature of the pancreatic cystic lesion and might minimize confusion between these two entities. While a pseudocyst usually develops in the setting of chronic pancreatitis or following an episode of acute necrotizing pancreatitis, neoplastic cysts arise de novo. In rare instances, however, cystic tumors can cause acute pancreatitis due to obstruction of the pancreatic duct. While an elevated serum amylase supports the diagnosis of a pseudocyst, a normal value provides no discriminatory information. Cysts whose fluid is low in amylase are almost always neoplastic.
Identifying cystic lesions on the basis of imaging modalities is difficult, especially for solitary unilocular cysts. The diagnostic accuracy of cytology obtained by CT-guided aspiration is limited due to the difficulty in finding diagnostic cells, but the overall accuracy is 67% for malignant cysts and 40% for mucinous cysts. [20] To improve the diagnostic yield of cyst fluid analysis, both the physical characteristics of cyst fluid and other tumor markers in the cyst fluid have been studied (Table 3). The fluid within MCNs is more viscous than within serous cystadenomas. Carcinoembryonic antigen (CEA) appears to be the most useful marker for detecting MCNs. [21] Other markers such as CA-72-4 and CA 15-3 appear better at discerning benign from malignant lesions. [22]
The role of EUS in differentiating benign cystic lesions from malignant ones has been recently clarified. Koito and colleagues [23] used EUS to classify 52 cystic lesions according to the wall and septa characteristics. All nonneoplastic tumors belonged to the thin septa type or simple type, and all malignant tumors belonged to the thick wall, tumor-protruding, thick septal, or microcystic type. The accuracy of EUS for differentiating tumors, as classified by two independent EUS observers blinded to the pathologic specimens, was estimated at 96% and 92%. Ikeda and coworkers [24] reported EUS criteria for follow-up of small pancreatic cysts (87.1% <2 cm) of unknown etiology. The cysts were classified as (1) a clear thin wall, (2) smooth contour, (3) round or oval shape, (4) no septum or nodule, (5) asymptomatic, and (6) no findings of chronic pancreatitis. After a follow-up of 3 years, 30 (97%) of 31 cases appeared to be nonprogressive. Following resection, the enlarging lesion was found to be a retention cyst. Sugiyama and colleagues [25] were able to reliably distinguish MCNs from intraductal papillary tumors by using a combination of EUS, ERCP, MRCP, and CT. EUS and MRCP demonstrated septa within cysts and mural nodules more accurately than ultrasonography, CT, and ERCP. EUS was significantly superior to ultrasonography, CT, and ERCP for the detection of mural nodules.
The presence of mural nodules suggests malignancy in both cystic tumor types. EUS therefore facilitates the diagnosis of serous cystadenomas, mucinous cyst-adenomas, and cystadenocarcinomas when microcysts, vegetation of the wall of a macrocyst, limited invasion of the pancreas due to the presence of vegetation, or a localized thickening of the wall of the cystic lesion are detected (Fig 3). Moreover, when faced with diagnostic uncertainty, EUS allows sampling of cystic fluid material for biochemical analysis and evaluation of the mucins and tumor markers (Figs 3 and 4). In a study by Mallery et al, [26] the use of EUS-guided fine-needle aspiration (FNA) with cyst fluid analysis in pancreatic cystic lesions was evaluated in 20 patients. In addition to cytology, cyst fluid was sent for mucin staining and tumor markers (CEA, CA 125, CA 19-9, CA 72-4, CA 15-3, and tissue polypeptide antigen). Positive cytology or an elevated level of a tumor marker had an accuracy of 86%, a sensitivity of 83%, a specificity of 88%, a positive predictive value of 83%, and a negative predictive value of 88% for diagnosing a cystic neoplasm. Two patients developed self-limited pancreatitis, and no patients developed any infectious complications. Other groups [27] have encountered infectious complications up to 14% when aspirating pancreatic cystic lesions with EUS-guided FNA. Because of the potential risk of infection, our current practice is to administer antibiotics prior to aspirating a cystic lesion of the pancreas. A multicenter study is underway to evaluate the role of EUS-guided FNA in determining the nature of cystic pancreatic lesions preoperatively.
Figure 3. EUS revealed a complex cystic lesion with multiple thin septa. EUS-guided FNA revealed markedly elevated CEA and CA 19-9 and low amylase. Pathology revealed a mucinous (macrocystic) cystadenoma.
Figure 4. Transgastric aspiration of a large simple cyst under EUS guidance (arrow = needle, arrowhead = cyst).
Treatment of cystic pancreatic neoplasms depends on the tumor's size, location, type, and extent. The prognosis depends on the tumor type and the resectability of the lesion. MCNs should be resected according to standard oncologic principles. The prognosis for completely resected MCNs is excellent, with a 5-year survival rate of more than 50% reported for malignant lesions. Long-term survival is possible in patients with cystadenocarcinomas, so these patients should undergo resection with the intent to cure even if a large tumor or local extension is found. In a series by Warshaw et al [18] of 42 patients with MCNs, 64% were found to be malignant. Sixty three percent of mucinous adenocarcinomas were judged to be resectable, and 22% had nonlocal metastases. Overall, 76% of patients with mucinous carcinomas resected with curative intent were alive, without evidence of recurrent dis-ease, at a follow-up ranging from 6 months to 10 years. All patients with unresectable local or metastatic cancer died of their disease at an average of 4 months after having followed a rapid downhill course similar to that of unresectable pancreatic adenocarcinoma. In a review of 21 cases of cystadenocarcinomas, Hodgkin-son and colleagues [28] noted a 5-year survival rate of 68% after complete excision compared with a 14% rate for those who had partial excision. Delcore and colleagues [29] reported 90% long-term disease-free survival among 10 patients with resectable mucinous cystadenocarcinomas, whereas 3 patients who underwent palliative resection died within 9 months. These two studies emphasize the prognosis and survival in these patients; localized and therefore resectable cystadenocarcinomas are highly curable, while those with distant spread have a dismal prognosis similar to patients with ductal adenocarcinoma.
Conclusions
Mucinous-producing neoplasm of the pancreas, IPMTs and MCNs, are two distinct clinical entities, and they present a diagnostic and therapeutic challenge. They behave in an indolent manner, with frequent overlap of symptoms and radiological appearance with pancreatic cysts, pseudocysts, or malignancy. Both IPMTs and MCNs originate in the pancreatic duct epithelium, produce mucin, demonstrate a papillary growth pattern, and are considered to be premalignant or malignant at the time of diagnosis. Both lesions are less aggressive biologically than ductal adenocarcinoma, and they appear to infiltrate peripancreatic tissue and metastasize to lymph nodes or adjacent structures late in the course of the disease. IPMTs are located primarily in the head of the pancreas, predominantly affect elderly men, and present with acute or recurrent pancreatitis symptoms. MCNs are more likely to develop in the body or tail, are more commonly seen in women of middle age, and present with symptoms referable to a mass effect on adjacent structures. To diagnose these lesions preoperatively, a high index of suspicion is needed; factors that should heighten the suspicion include the presence of a cystic structure of the pancreas on abdominal imaging, the absence of a history of pancreatitis in a patient with a cystic lesion of the pancreas, and the presence of exuding mucus from the major or minor papilla and the amorphous filling defects in an elderly patient undergoing ERCP. Cyst fluid aspiration and analysis preoperatively are helpful in differentiating between malignant and benign neoplasms. Both lesions are managed by surgical resection because the opportunity for cure is high in the absence of metastatic disease. Future studies are needed to improve the accuracy of diagnosing these tumors preoperatively.
[ CLOSE WINDOW ]
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Acknowledgments
Appreciation is expressed to Mrs. Linda McDaniel for her assistance in reproducing the figures shown in this manuscript.
Cancer Control. 2000;7(5) © 2000 H. Lee Moffitt Cancer Center and Research Institute, Inc.
© Copyright by H. Lee Moffitt Cancer Center & Research Institute. All rights reserved.
Mucinous Tumors of the Exocrine Pancreas: Intraductal Mucin-Hypersecreting Neoplasms
Mucinous Tumors of the Exocrine Pancreas: Intraductal Mucin-Hypersecreting Neoplasms
IPMTs occur mostly in men in the sixth to seventh decade (range = 40 to 85 years). The most common presenting symptom is abdominal discomfort associated with mild elevations of pancreatic serum enzymes mimicking chronic or relapsing pancreatitis. The history of pancreatitis or recurrent pancreatitis varies from 29% [5] to 80% [8] in the literature. These symptoms are more commonly observed in patients with mucinhypersecreting tumors and are most likely due to intermittent obstruction of the main pancreatic duct by plugs of viscous mucin or intraluminal tumor. Back pain (25%), jaundice (25%), weight loss (42%), steator-rhea (37.5%), and diabetes (37.5%) are among various presentations reported in one series. [5] In a recent report from our institution describing outcomes of 25 patients with IPMTs, [9] 52% of patients had acute relapsing pancreatitis with elevated pancreatic enzymes, 32% had pain with normal enzymes, 12% had weight loss with no pain, and 4% had incidental findings. Therefore, due to the indolent nature of these tumors and the limited awareness of this lesion among the medical community, a delay in diagnosis ranging from months to years is not uncommon.
Conventional imaging studies such as abdominal CT scanning and transabdominal ultrasonography reveal nonspecific changes that are indistinguishable from those of chronic pancreatitis, pancreatic pseudo-cysts, or nonmucinous producing cystic neoplasms. These studies typically demonstrate well-defined unilocular or multilocular cystic pancreatic masses and/or dilatation of the main pancreatic duct. The term cystic duct here would be a misnomer since these cystic structures represent dilated ductular structures. The cystic changes of IPMTs may occasionally be so extensive as that they are confused with a mucinous cystic neoplasm. An important distinction between the two lesions is that, in IPMTs, the "cysts" communicate with the duct system, whereas MCNs generally do not show any connection with the duct system.
IPMTs occur mostly in men in the sixth to seventh decade (range = 40 to 85 years). The most common presenting symptom is abdominal discomfort associated with mild elevations of pancreatic serum enzymes mimicking chronic or relapsing pancreatitis. The history of pancreatitis or recurrent pancreatitis varies from 29% [5] to 80% [8] in the literature. These symptoms are more commonly observed in patients with mucinhypersecreting tumors and are most likely due to intermittent obstruction of the main pancreatic duct by plugs of viscous mucin or intraluminal tumor. Back pain (25%), jaundice (25%), weight loss (42%), steator-rhea (37.5%), and diabetes (37.5%) are among various presentations reported in one series. [5] In a recent report from our institution describing outcomes of 25 patients with IPMTs, [9] 52% of patients had acute relapsing pancreatitis with elevated pancreatic enzymes, 32% had pain with normal enzymes, 12% had weight loss with no pain, and 4% had incidental findings. Therefore, due to the indolent nature of these tumors and the limited awareness of this lesion among the medical community, a delay in diagnosis ranging from months to years is not uncommon.
Conventional imaging studies such as abdominal CT scanning and transabdominal ultrasonography reveal nonspecific changes that are indistinguishable from those of chronic pancreatitis, pancreatic pseudo-cysts, or nonmucinous producing cystic neoplasms. These studies typically demonstrate well-defined unilocular or multilocular cystic pancreatic masses and/or dilatation of the main pancreatic duct. The term cystic duct here would be a misnomer since these cystic structures represent dilated ductular structures. The cystic changes of IPMTs may occasionally be so extensive as that they are confused with a mucinous cystic neoplasm. An important distinction between the two lesions is that, in IPMTs, the "cysts" communicate with the duct system, whereas MCNs generally do not show any connection with the duct system.
Pancreatic cysts: Tests and diagnosis - MayoClinic.com
Pancreatic cysts: Tests and diagnosis - MayoClinic.com
In some cases, the location of the cyst in your pancreas — along with your age and sex — can help doctors pinpoint what type of cyst you have.
1. Mucinous cystadenoma. These cysts are usually located in the body or tail of the pancreas and occur most often in middle-aged women. They are precancerous, and some may already be cancerous when discovered. Larger cysts are more likely to be cancerous.
2. Mucinous duct ectasia. More common in men, these cysts consist of dilated ductal segments, usually within the head of the pancreas. Also known as intraductal papillary mucinous neoplasms, these growths are often cancerous.
3. Serous cystadenoma. These growths can become large enough to displace nearby organs, causing such symptoms as abdominal pain and a feeling of fullness. They occur most frequently in middle-aged women and become cancerous only rarely.
4. Papillary cystic tumor. The least common of the nonpseudocysts, papillary cystic tumors — also known as papillary cystic neoplasm or solid and pseudopapillary neoplasm — occur most often in young women and are usually located in the body or tail of the pancreas. They are usually cancerous.
Islet cell tumors, also known as neuroendocrine tumors, are less common. Normally, the pancreas's islet cells produce insulin and other hormones. Islet cell tumors can also produce these hormones.
In some cases, the location of the cyst in your pancreas — along with your age and sex — can help doctors pinpoint what type of cyst you have.
1. Mucinous cystadenoma. These cysts are usually located in the body or tail of the pancreas and occur most often in middle-aged women. They are precancerous, and some may already be cancerous when discovered. Larger cysts are more likely to be cancerous.
2. Mucinous duct ectasia. More common in men, these cysts consist of dilated ductal segments, usually within the head of the pancreas. Also known as intraductal papillary mucinous neoplasms, these growths are often cancerous.
3. Serous cystadenoma. These growths can become large enough to displace nearby organs, causing such symptoms as abdominal pain and a feeling of fullness. They occur most frequently in middle-aged women and become cancerous only rarely.
4. Papillary cystic tumor. The least common of the nonpseudocysts, papillary cystic tumors — also known as papillary cystic neoplasm or solid and pseudopapillary neoplasm — occur most often in young women and are usually located in the body or tail of the pancreas. They are usually cancerous.
Islet cell tumors, also known as neuroendocrine tumors, are less common. Normally, the pancreas's islet cells produce insulin and other hormones. Islet cell tumors can also produce these hormones.
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