bubble_chart Overview

Pancreatic cystadenocarcinoma is also classified as a proliferative pancreatic cyst and can develop from the malignant transformation of pancreatic cystadenoma. This disease is extremely rare clinically, accounting for only 1% of pancreatic malignancies. The earliest documented reports of pancreatic cystadenocarcinoma were published by Kaufman in 1911 in a German journal and by Lichenstem in 1834 in an American journal. In 1963, Cullen identified 17 cases of well-documented and confirmed pancreatic cystadenocarcinoma out of 2.4 million inpatient records at the Mayo Clinic. By 1984, Segessen estimated that only slightly over 100 cases of pancreatic cystadenocarcinoma had been reported in medical literature worldwide, with sporadic individual or small case reports in China.

bubble_chart Pathological Changes

General Morphology

Pancreatic cystadenocarcinoma originates from the mucous membrane epithelium of the large pancreatic ducts and can occur in any part of the pancreas, but is more commonly found in the body and tail of the pancreas. A comprehensive report by Strodel on 62 cases of pancreatic cystic tumor diseases from the Mayo Clinic and the Armed Forces Institute of Pathology (AFIP) showed that the tumors were located in the pancreatic head in 17.5% of cases, the head in 1%, the body and tail in 81%, and were multifocal in 1%. The tumors vary in size, with the smallest being only 2 cm (discovered during autopsy) and the largest filling the entire abdominal cavity or even extending into the pelvic cavity; the average size is around 10 cm. Generally, tumors located in the head of the pancreas are smaller, while those in the body and tail are larger. The tumors appear irregular, round, or lobulated in shape, with a complete and smooth membrane, clearly demarcated from the normal pancreas, and no significant adhesion to surrounding organs. However, when the cancer is in an advanced stage and infiltrates or destroys surrounding tissues, it may form adhesions, become fixed, or even show obvious metastasis. Sometimes, the tumor surface may be surrounded by prominent varicose veins. The cut surface of the cystadenocarcinoma may be unilocular or multilocular, with unevenly thick cyst walls and a smooth inner lining that may have scattered papillary or cauliflower-like projections. The cysts contain fluids of varying colors, turbidity, and viscosity, ranging from clear and transparent to mucoid, bloody, or old blood, and often contain necrotic tissue. The cysts do not communicate with the pancreatic ducts, so measuring the amylase content in the cyst fluid usually does not show an increase.

Histological Features

The main histological changes of pancreatic cystadenocarcinoma include:

1. The cyst wall is composed of fibrous connective tissue, 0.1–0.2 cm thick, with inflammatory cell infiltration. Cancer cells may grow invasively into the stroma or infiltrate the islets, pancreatic ducts, and acini.
2. The stroma shows fibrosis, vacuoles, and chronic inflammatory cell infiltration, and is completely separated from the epithelial layer. Subepithelial hemorrhage, necrosis, or calcification may be observed, and these lesions are particularly prominent in cancerous areas.
3. The cyst wall is lined with tall columnar cells, which may form folds protruding into the cyst cavity. The cancer cells exhibit significant atypia: enlarged nuclei, thickened nuclear membranes, an increased nuclear-to-cytoplasmic ratio; irregular nuclear size and shape; and disordered nuclear arrangement with loss of polarity.
4. Some tumors exhibit a cystadenoma structure, with partial malignant transformation, often appearing as localized malignant foci in the cyst wall or septa. Therefore, during histopathological examination, multiple sampling and extensive sectioning are necessary to avoid misdiagnosis or missed diagnosis. In advanced stages, pancreatic cystadenocarcinoma often metastasizes to the liver.

bubble_chart Clinical Manifestations

The main symptoms of pancreatic cystadenocarcinoma are dull pain in the upper or middle abdomen or back pain, and an upper abdominal mass. The abdominal pain is usually not severe, with some patients experiencing only a sense of fullness or discomfort; other symptoms may include decreased appetite, nausea, indigestion, weight loss, jaundice, etc. A few patients may experience gastrointestinal bleeding. Some patients may have no complaints at all and the disease is only discovered incidentally during laparotomy or autopsy.

The abdominal mass varies in size, with smaller ones just palpable in the upper abdomen, while larger ones can fill the entire abdominal cavity or even extend into the pelvis. The mass is generally non-tender and may feel cystic or hard and solid. When secondary intracystic hemorrhage occurs, the mass may suddenly enlarge, with intensified abdominal pain and obvious tenderness. Lai Chuanshan et al. reported six cases of pancreatic cystic tumors in China, all of whom sought medical attention due to an upper abdominal mass and abdominal pain or back pain. Among them, three cases with unbearable back pain were all diagnosed as cystadenocarcinoma. When the tumor infiltrates or compresses the common bile duct, obstructive jaundice may occur.

Since the symptoms and signs of pancreatic cystadenocarcinoma are mostly nonspecific, especially in the early stages when the mass is small, clinical diagnosis is often difficult. Many patients have had symptoms for months or even years before seeking medical attention, with some lasting as long as 15 years. Becker et al. reported that the duration of symptoms before a definitive diagnosis of pancreatic cystadenocarcinoma was made ranged from 7 months to 11 years, with an average of 22 months.

bubble_chart Auxiliary Examination

1. Laboratory tests: If the patient has elevated urine sugar and blood sugar, along with decreased glucose tolerance, it aids in establishing the diagnostic value for pancreatic lesions. According to Strodel's comprehensive report of 62 cases of pancreatic cystadenocarcinoma, 11% were accompanied by diabetes.
2. X-ray examination: On plain abdominal films, calcification shadows of the cyst wall may be observed, appearing round or crescent-shaped. Warshaw reported 67 cases of pancreatic cysts, among which 7 cases with calcification shadows were all pancreatic cystadenocarcinomas, whereas pancreatic pseudocysts, retention cysts, and cystadenomas mostly lacked calcifications.
   Upper gastrointestinal barium meal examination generally lacks specific diagnostic value. However, if there is enlargement of the duodenal loop or displacement of the stomach or transverse colon, it may help infer the location and size of the mass.
   Intravenous pyelography also lacks specific diagnostic value. By observing the direction of left kidney displacement and the degree of compression, the location, size, and growth direction of the mass can be assessed.
3. B-mode ultrasound: It can display the location and size of the tumor and its relationship with surrounding organs, helping to clarify whether the pancreatic mass is cystic or solid, the size and number of cystic cavities, the characteristics of cystic contents, cyst walls, and septa, providing crucial evidence for diagnosis and differential diagnosis.
4. Abdominal CT: It can more clearly display the location and size of the abdominal mass and its relationship with surrounding organs. CT can reveal whether the cyst is solitary or multilocular, with the latter often being a reliable sign of pancreatic cystadenoma or cystadenocarcinoma. CT can also indicate whether the cancer has metastasized to the liver or abdominal lymph nodes. If metastatic lesions are present, they support the diagnosis of pancreatic cystadenocarcinoma.
5. Selective celiac or superior mesenteric arteriography: It can determine the morphology, size, and organ of origin of the tumor. Since pancreatic cystadenocarcinomas have relatively rich blood supply, they can be distinguished from avascular pancreatic pseudocysts and poorly vascularized pancreatic cancers. The main arteriographic signs of pancreatic cystic tumors include: (1) Compression, displacement, twisting, stretching, and irregularity of large vessels around the lesion. (2) Rich blood supply, with hyperemia in the tumor area, manifested as contrast stagnation in capillaries. (3) Some vessels embedded in tumor tissue and infiltrated by the lesion suggest malignancy. (4) Arteriovenous shunting. (5) Impaired venous return. (6) Avascular or hypovascular areas do not completely rule out cystic tumors. Warshaw et al. performed arteriography on 11 cases of pancreatic cystadenocarcinoma, with only 2 showing rich blood supply, while among 10 cases of cystadenomas, only 4 had rich blood supply. Additionally, arteriography in 19 cases of cystic tumors showed poor vascularity.
6. Endoscopic retrograde cholangiopancreatography (ERCP): In diagnostically challenging cases, ERCP helps exclude chronic pancreatitis, pancreatic pseudocysts, and intraductal carcinoma, but it is not very helpful in distinguishing between cystadenocarcinoma and cystadenoma. Approximately 70% of pancreatic pseudocyst patients have communication between the pancreatic duct and the cyst, while pancreatic cancer may present as pancreatic duct stenosis or obstruction. Warshaw et al. reported that 50% of pancreatic cystadenocarcinoma patients had normal pancreatograms, while 33% showed the main pancreatic duct curved around the tumor in an arched shape.
   Mucinous ductal ectasia is a recently recognized precancerous lesion. When papillary hyperplasia occurs in the pancreatic duct and produces large amounts of mucus, the mucus filling the main pancreatic duct can induce obstructive pancreatitis. This lesion affects part or all of the pancreas, and further progression can lead to ductal dilation. During retrograde pancreatic duct cannulation, mucus outflow can be observed at the pancreatic duct orifice, while retrograde pancreatography can reveal these dilated pancreatic ducts.
7. Percutaneous fine-needle aspiration of pancreatic cysts: Through percutaneous fine-needle aspiration of pancreatic cysts, the cyst fluid is extracted to measure amylase, carcinoembryonic antigen (CEA), CA19-9, and for cytological examination, which aids in determining the nature of the cyst. The procedure can be guided by radiology, B-mode ultrasound, or CT, or performed via direct intraoperative aspiration. Pancreatic pseudocysts and retention cysts exhibit extremely high levels of amylase in the cyst fluid, whereas cystic tumors often show no elevation in amylase. In contrast, the CEA levels in the cyst fluid of pancreatic mucinous cysts (cystadenomas or cystadenocarcinomas) are significantly higher than those in pseudocysts and serous cysts. Ferrer reported a case of pancreatic cystadenocarcinoma where the plasma CEA level was 200μg/ml during laparotomy, which normalized after tumor resection, while the cyst fluid CEA was 100,000 times higher than normal plasma levels. Since CEA originates from mucus-secreting columnar epithelium, both cystadenomas and cystadenocarcinomas can produce large amounts of CEA, making it less useful for distinguishing between benign and malignant conditions.
   Recently, Rubin reported that measuring the expression of CA15-3 protein in cyst fluid can differentiate between benign and malignant pancreatic mucinous cystic tumors. CA15-3 is a mucoprotein weighing over 400KDa, found in milk fat globule membranes and various adenocarcinomas, including pancreatic cancer. The authors obtained pancreatic cyst fluid via percutaneous aspiration and measured CA15-3 concentrations using monoclonal antibodies 115-D8 and DF-3 in a radioimmunoassay. The normal range is 0–30 IU/ml. In six cases of pancreatic cystadenocarcinoma, the cyst fluid CA15-3 levels ranged from 40–392 IU/ml. Three cases of mucinous cystadenoma had an average of 4.7 IU/ml (0–14 IU/ml), five cases of serous cystadenoma averaged 9.2 IU/ml (0–32 IU/ml), and six cases of pseudocysts averaged 15.3 IU/ml (0–66 IU/ml). The latter three groups of benign pancreatic cystic lesions had a mean CA15-3 level of 10.6 IU/ml, significantly lower than that of pancreatic cystadenocarcinoma. Measuring cyst fluid CA15-3 demonstrated 100% sensitivity and 100% specificity (P<0.01）。

bubble_chart Diagnosis

Pancreatic cystic carcinoma lacks characteristic symptoms and signs, and clinically mainly manifests as an upper abdominal mass and varying degrees of abdominal pain or back pain. For patients with no history of abdominal trauma or pancreatitis, and whose B-ultrasound and CT scans suggest a cystic mass possibly originating from the pancreas, this disease should be considered. Reasonable selection of the aforementioned laboratory testing methods can help further clarify pancreatic cysts and their nature.

Whether the diagnosis is confirmed preoperatively or not, intraoperative exploration is crucial, as it directly relates to further confirming the diagnosis and selecting the surgical approach. Special attention should be paid to differentiating this disease from pancreatic pseudocysts and cystadenomas. Pancreatic cystadenocarcinoma and pseudocysts share many similarities in clinical manifestations and general auxiliary examinations. Approximately one-third of pancreatic cystic lesions are misdiagnosed as pseudocysts, and even intraoperative frozen biopsy results are not entirely reliable, with a misdiagnosis rate of up to 20%. Therefore, for patients suspected of having pancreatic pseudocysts but with no history of pancreatitis, trauma, alcoholism, or biliary tract disease, and whose intraoperative findings show normal pancreatic tissue around the cyst without significant adhesions, the possibility of a cystic tumor should be highly suspected. If suspicious tumor areas with cauliflower-like or papillary features are found on the inner wall of the cyst, multiple repeated biopsies should be performed to further establish the diagnosis of pancreatic cystadenocarcinoma.

Pancreatic mucinous cystadenoma is also very similar in terms of age of onset, gender, clinical manifestations, lesion distribution, and gross features. Moreover, cystadenomas have a significant tendency for malignant transformation, and current clinical and radiological examinations cannot provide an accurate preoperative diagnosis. Therefore, whether a pancreatic cystic tumor is benign or malignant generally depends solely on the histological detection of cancerous structures. In several large case series reported abroad, there have been patients with cystadenomas that progressed to cystadenocarcinoma after incomplete resection or drainage. Prostin reported one case where, over a 10-year period, sequential observations from three resection specimens and sinus tissue revealed the progression from a completely benign cystadenoma to papillary formation, atypical cell appearance, irregular gland arrangement, and finally the development of cystadenocarcinoma with invasive growth into the stomach, spleen, and transverse mesocolon. Compagno pointed out that it is impossible to strictly categorize these tumors as benign cystadenomas or malignant cystadenocarcinomas based solely on the histological presence or absence of cancer. This is because, in a large cyst, benign and malignant elements may coexist and be scattered in distribution, and without sufficient specimens and serial sections, the true nature of the lesion cannot be adequately reflected. The author's pathological study of 41 cases of pancreatic mucinous cystic tumors showed that 34 cases (83%) exhibited varying degrees of malignancy, with two cases requiring examination of 47 and 66 specimens, respectively, before cancer was detected. Therefore, Compagno believes that no pancreatic mucinous cystic neoplasm is truly benign, and all such lesions should be regarded as malignant.

bubble_chart Treatment Measures

1. Surgical resection of pancreatic cystadenocarcinoma, including the portion of normal pancreas where the tumor is located, is the only effective treatment for this disease. Since most pancreatic cystadenocarcinomas exhibit mild adhesion, and even significant adhesion can be easily separated, radical resection should generally be attempted unless the cancer has metastasized extensively, the patient's overall condition is extremely poor, or vital organs are involved. Depending on the location and extent of the lesion, the relationship between the tumor and adjacent organs, and the degree of metastasis and infiltration, different surgical approaches may be selected, such as simple cyst enucleation, distal pancreatectomy with splenectomy, pancreaticoduodenectomy, or total pancreatectomy. During the procedure, every effort should be made to keep the cyst intact, as rupture of the cyst wall may lead to intraperitoneal seeding metastasis.
2. Common mistakes in the treatment of pancreatic cystadenocarcinoma include: (1) Overestimating the difficulty of tumor resection, leading to palliative resection or cyst drainage in cases where radical resection could have been achieved with effort. (2) Relying solely on frozen section examination of a small amount of cyst tissue to hastily diagnose the condition as pancreatic pseudocyst, retention cyst, or cystadenoma, and consequently performing internal or external drainage. Both domestic and international literature document cases where pancreatic pseudocysts or cystadenomas progressed to cystadenocarcinoma after incomplete resection or drainage. The possibility cannot be ruled out that some of these patients already had cancer at the time of initial surgery, but it went undetected. Therefore, for pancreatic cystic masses of uncertain nature, especially mucinous cysts, they should be managed according to the treatment principles for pancreatic cystadenocarcinoma, with resection of the mass and part of the surrounding pancreatic tissue. Internal or external drainage should never be performed lightly for pancreatic cystadenocarcinoma, as this not only fails to achieve the goal of surgical treatment but also increases the risk of cyst infection and delays the opportunity for radical surgery.
3. Pancreatic cystadenocarcinoma is insensitive to both chemotherapy and radiotherapy.

bubble_chart Prognosis

The prognosis for surgically resected pancreatic cystadenocarcinoma is generally favorable, with long-term survival rates significantly better than those for pancreatic cancer. A study of 20 patients with pancreatic cystadenocarcinoma at Mayo Clinic showed that the 5-year survival rates for radical resection and palliative resection were 68% and 14%, respectively. In another report by Warren involving 17 patients, the 5-year and 10-year survival rates after surgical resection were 38% and 23%, respectively. For patients who experience recurrence or metastasis after tumor resection, re-resection should be attempted if the patient's condition permits, as some may still achieve satisfactory outcomes.

bubble_chart Differentiation

1. Retention cyst: Generally unilocular, without a membrane, and usually small in size, with the characteristic of sometimes enlarging and sometimes shrinking. The cyst wall is lined by a single layer of cuboidal or flattened epithelium, and the surrounding tissue often exhibits chronic pancreatitis, with duct obstruction frequently accompanied by pancreatic lithiasis. The cystic fluid contains minimal inflammatory exudate, but pancreatic amylase often shows a strongly positive reaction.
2. Cystadenoma: Contains fibrous tissue septa and a membrane, which may undergo hyaline degeneration and calcification. The adjacent pancreatic tissue may atrophy due to compression, and ducts and acini may dilate due to obstruction. The cystic cavities are relatively small, with no inflammatory cell infiltration in the cyst wall. The lining epithelium consists of a single layer of flattened, cuboidal, or tall columnar cells. Cystadenomas lined by flattened epithelium should be differentiated from lymphangiomas or capillary hemangiomas; the former is positive for silver staining, while the latter two are also positive. Cystadenomas lined by columnar epithelium have a higher potential for malignant transformation, and papillary cystadenoma can be considered a precancerous lesion. When cystadenoma undergoes malignant transformation, there is significant papillary hyperplasia, marked cellular atypia, enlarged and hyperchromatic nuclei, increased mitotic figures, pathological mitoses, glandular wall sharing, and back-to-back arrangements, all of which are malignant features.
3. Pancreatic cancer: When pancreatic cancer obstructs the pancreatic duct, the distal duct may dilate into a cystic form. However, such cysts are generally not large, and the cystic cavity communicates with the duct. The cyst contains bloody or clear, thin fluid, along with pancreatic enzymes.