Pancreatic cystadenocarcinoma is also classified as a proliferative cyst of the pancreas and can arise 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 in 1911 by Kaufman in a German journal and in 1834 by Lichenstem in an American journal. In 1963, Cullen identified 17 cases of pancreatic cystadenocarcinoma with complete and confirmable data among 2.4 million inpatient records at the Mayo Clinic. By 1984, Segessen's review of global medical literature revealed only slightly over 100 reported cases of pancreatic cystadenocarcinoma, with China's cases being sporadic individual reports or small case series.

bubble_chart Epidemiology

Pancreatic cystadenocarcinoma progresses slowly and has a low degree of malignancy. The tumor often appears benign in appearance, making it difficult to distinguish clinically. Even during surgery or pathological examination, it can be misdiagnosed due to its unique structure. The age of onset ranges from 20 to 80 years, with an average of about 60 years. The incidence is higher in women than in men, with a ratio of approximately 3:1. For details, see Table 1.

Table 1 Clinical data of 10 cases of pancreatic cystadenocarcinoma ^*

*Data from the First Affiliated Hospital of Beijing Medical University, Cancer Prevention and Treatment Research Institute of the Chinese Academy of Medical Sciences, Capital Hospital, and Union Hospital Affiliated to Tongji Medical College

bubble_chart Pathological Changes

1. General Morphology

Pancreatic cystadenocarcinoma originates from the mucous membrane epithelium of the major pancreatic ducts and can occur in any part of the pancreas, though it is more commonly found in the body and tail. According to 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), the tumors were located in the pancreatic head in 17.5%, the head in 1%, the body and tail in 81%, and were multifocal in 1%. The tumor size varies, with the smallest being only 2 cm (discovered during autopsy) and the largest capable of 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 tumor appears irregular, round, or lobulated in shape, with a complete membrane, smooth surface, and clear demarcation from the normal pancreas, without significant adhesion to surrounding organs. However, when the cancer reaches 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 walls and a smooth inner lining, possibly featuring scattered papillary or cauliflower-like projections. The cyst contains fluids of varying colors, turbidity, and viscosity, ranging from clear and transparent to mucinous, bloody, or old blood-like, and often includes necrotic tissue. The cyst does not communicate with the pancreatic duct, so measuring amylase levels in the cyst fluid usually does not show an increase.

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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 Stromal fibrosis is present, with vacuoles and chronic inflammatory cell infiltration, completely separated from the epithelial layer. Subepithelial hemorrhage, necrosis, or calcification may occur, 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, increased nuclear-to-cytoplasmic ratio; irregular nuclear size and shape; disordered nuclear arrangement with loss of polarity. ④ Some cases 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. Advanced-stage pancreatic cystadenocarcinoma mostly 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. Abdominal pain is usually not severe, with some patients only experiencing 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 are only incidentally diagnosed during laparotomy or autopsy. Strodel reported the clinical manifestations of 62 cases of pancreatic cystic cancer, as shown in Table 2.

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*Jiang Guangjie (review). Foreign Medical Sciences (Surgery), 1985, 5: 268

The size of the abdominal mass varies, 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. When secondary intracystic hemorrhage occurs, the mass may suddenly enlarge, with aggravated abdominal pain and obvious tenderness. Lai Chuanshan et al. reported 6 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, 3 cases with unbearable back pain were all diagnosed as cystadenocarcinoma. When the tumor infiltrates or compresses the common bile duct, obstructive jaundice may occur.

Because the symptoms and signs of pancreatic cystadenocarcinoma are often nonspecific, especially in the early stages when the mass is small, clinical diagnosis can be difficult. Many patients have had symptoms for months or even years before seeking medical attention, with some cases lasting as long as 15 years. Becker et al. reported that the duration of symptoms before a definitive diagnosis of pancreatic cystadenocarcinoma 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 of 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 as 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 calcification foci.

Upper gastrointestinal barium meal examination generally lacks specific diagnostic value, but 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, but the direction of displacement and degree of compression of the left kidney can provide insights into the location, size, and growth direction of the mass.

3. B-mode ultrasound examination:

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 contents of the cyst, and the structural and morphological features of the cyst wall and its septa. This provides important 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, it supports the diagnosis of pancreatic cystadenocarcinoma.

5. Selective celiac arteriography or superior mesenteric arteriography:

It can determine the morphology, size, and organ of origin of the tumor. Since pancreatic cystadenocarcinoma has a relatively rich blood supply, it can be differentiated from avascular pancreatic pseudocysts and poorly vascularized pancreatic cancers. The main angiographic signs of pancreatic cystic tumors include: ① Compression, displacement, distortion, stretching, and irregularity of large blood vessels around the lesion area. ② Rich blood supply, with congestion in the tumor area, manifested as stasis of contrast medium in capillaries. ③ Some blood vessels embedded in the tumor tissue and infiltrated by the lesion suggest the possibility of malignancy. ④ Arteriovenous shunting. ⑤ Obstruction of venous return. ⑥ Avascular or hypovascular areas in the lesion do not completely rule out cystic tumors. Warshaw et al. performed arteriography on 11 cases of pancreatic cystadenocarcinoma, only 2 of which had rich blood supply, while among 10 cases of cystadenomas, only 4 had rich blood supply; the remaining 19 cases of cystic tumors showed hypovascularity on arteriography.

6. Endoscopic retrograde cholangiopancreatography (ERCP):

In cases of diagnostic difficulty, ERCP can help exclude chronic pancreatitis, pancreatic pseudocysts, and intraductal carcinoma, but it is not very helpful in differentiating between cystadenocarcinoma and cystadenoma. Approximately 70% of pancreatic pseudocyst patients have communication between the pancreatic duct and the cyst; pancreatic cancer may present as stenosis or obstruction of the pancreatic duct. Warshaw et al. reported that 50% of pancreatic cystadenocarcinoma patients had normal pancreatic duct images, while 33% had 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 a large amount 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 and contrast imaging, mucus outflow can be observed at the pancreatic duct orifice, and the dilated pancreatic ducts can be visualized on retrograde pancreatograms.

7. Percutaneous fine-needle aspiration of pancreatic cyst fluid for examination:

Transmission from one meridian to another. Fine-needle aspiration of pancreatic cysts, extracting cystic fluid to measure amylase, carcinoembryonic antigen (CEA), CA19-9, and perform cytological examination, aids in distinguishing the nature of the cyst. Aspiration can be guided by radiology, B-mode ultrasound, or CT, or performed directly during surgery. The amylase content in pancreatic pseudocysts and retention cysts is extremely high, whereas it is often not elevated in cystic tumors. The CEA level in the cystic fluid of pancreatic mucinous cysts (cystadenoma or cystadenocarcinoma) is significantly higher than that in pseudocysts and serous cysts. Ferrer reported a case of pancreatic cystadenocarcinoma where the plasma CEA was 200μg/ml during laparotomy, which normalized after tumor resection, and the cystic fluid CEA was 100,000 times higher than normal plasma levels. Since CEA originates from mucus-secreting columnar epithelium, both cystadenoma and cystadenocarcinoma can produce large amounts of CEA, making it less useful in distinguishing benign from malignant lesions.

Recently, Rubin reported that measuring the expression of CA15-3 protein in cystic fluid can differentiate between benign and malignant pancreatic mucinous cystic tumors. CA15-3 is a mucoprotein exceeding 400KDa, found in milk fat globule membranes and various adenocarcinomas, including pancreatic cancer. The authors performed percutaneous aspiration of pancreatic cystic fluid and used monoclonal antibodies 115-D₈ and DF-3 radioimmunoassay to measure CA_15-3 levels. The normal range is 0–30 IU/ml; in 6 cases of pancreatic cystadenocarcinoma, the cystic fluid CA_15-3 levels were 40–392 IU/ml. The average levels were 4.7 IU/ml (0–14 IU/ml) in 3 cases of mucinous cystadenoma, 9.2 IU/ml (0–32 IU/ml) in 5 cases of serous cystadenoma, and 15.3 IU/ml (0–66 IU/ml) in 6 cases of pseudocysts. The average CA_15-3 level in these three groups of benign pancreatic cystic lesions was 10.6 IU/ml, significantly lower than the average in pancreatic cystadenocarcinoma. Measuring cystic fluid CA_15-3 to differentiate benign from malignant pancreatic cystic lesions showed a sensitivity of 100% and specificity of 100% (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, the possibility of 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 definitive diagnosis and the choice of 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, intraoperative findings of normal pancreatic tissue around the cyst and no significant adhesions highly suggest the possibility of a cystic tumor. 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 cystadenomas are 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 presence of cancerous structures. In several large case reports abroad, there are patients with cystadenomas that progressed to cystadenocarcinoma after incomplete resection or drainage. Prostin reported one case where, over a 10-year period, continuous observation of three resection specimens and their sinus tissues revealed the progression from a completely benign cystadenoma to the formation of papillary structures, atypical cells, irregular glandular arrangements, 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 classify these tumors as benign cystadenomas or malignant cystadenocarcinomas based solely on the histological presence of cancer. This is because, in a large cyst, benign and malignant factors may coexist and be scattered in distribution, and without sufficient specimens and serial sections, the true nature of the lesion cannot be fully 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 found. 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 tumor site and part of the surrounding normal pancreas, is the only effective treatment for this disease. Since most pancreatic cystadenocarcinomas exhibit mild adhesion and can be easily separated even with significant adhesion, 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 lesion's location and extent, the relationship between the tumor and adjacent organs, and the degree of metastasis and infiltration, different surgical approaches may be chosen, such as simple cyst enucleation, distal pancreatectomy with splenectomy, pancreaticoduodenectomy, or total pancreatectomy. During surgery, efforts should be made to keep the cyst intact, as rupture of the cyst wall may lead to intraperitoneal implantation 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 instead of radical resection in cases where the latter could have been achieved with effort. ② Diagnosing the condition as pancreatic pseudocyst, retention cyst, or cystadenoma based solely on limited intraoperative frozen section examination of cyst tissue, and consequently performing internal or external drainage. Both domestic and international literature report cases where pancreatic pseudocysts or cystadenomas progressed to cystadenocarcinoma after incomplete resection or drainage. The possibility that some of these patients already had cancer at the initial surgery but were misdiagnosed cannot be ruled out. Therefore, for pancreatic cystic masses of uncertain nature, especially mucinous cysts, they should be managed according to the principles of pancreatic cystadenocarcinoma treatment, with resection of the mass and part of the surrounding pancreatic tissue. Internal or external drainage should never be performed casually 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. Results from Mayo Clinic's 20 cases of pancreatic cystadenocarcinoma showed 5-year survival rates of 68% and 14% for radical resection and palliative resection, respectively. In Warren's report of 17 cases, the 5-year and 10-year survival rates after surgical resection were 38% and 23%. For patients with recurrence or metastasis after tumor resection, reoperation 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 shows chronic pancreatitis changes, with duct obstruction and frequent association with 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. The ducts and acini may dilate due to obstruction, and the cystic cavities are relatively small, with no inflammatory cell infiltration in the cyst wall. The cyst wall is lined by 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 shows positive silver staining, while the latter two are also silver-positive. Cystadenomas lined by columnar epithelium have a higher potential for malignant transformation, and papillary cystadenoma can be regarded as a precancerous lesion. When cystadenoma undergoes malignant transformation, there is significant papillary hyperplasia, marked cellular atypia, enlarged and hyperchromatic nuclei, increased mitotic figures, pathological mitosis, 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 and form a cystic structure. However, such cysts are usually not large, and the cystic cavity communicates with the duct. The cyst contains bloody or clear thin fluid, along with pancreatic enzymes.