Ordinary Ductal Adenocarcinoma Research Articles

Clinicopathologic Study of the MIB-1 Labeling Index (Ki67) and Postoperative Prognosis for Intraductal Papillary Mucinous Neoplasms and Ordinary Ductal Adenocarcinoma

Intraductal papillary mucinous neoplasms (IPMNs) are pathologically classified as IPMN with low- or intermediate-grade dysplasia, IPMN with high-grade dysplasia, and IPMN with an associated invasive carcinoma. A stepwise carcinogenic pathway has been considered for IPMN. However, it is not obvious when surgical resection should be performed for IPMN. We studied the MIB-1 labeling index in cases of IPMN and ordinary ductal adenocarcinoma (ODA). Moreover, IPMN with an associated invasive carcinoma was divided into 2, namely, carcinoma in situ and invasive components, and the respective MIB-1 labeling indexes were examined. The MIB-1 labeling index for IPMN with low- or intermediate-grade dysplasia (1.8%) was significantly lower than those for IPMN with high-grade dysplasia (14.2%), both the carcinoma in situ components (23.1%) and invasive components (19.2%) within the IPMN with an associated invasive carcinoma, and ODA (19.5%; P < 0.0001).The 5-year survival rates after resection were 100% for IPMN with low- or intermediate-grade dysplasia, 83.3% for IPMN with high-grade dysplasia, 53.8% for IPMN with an associated invasive carcinoma, and 10.3% for ODA. MIB-1 might be useful for the classification of malignant potential in IPMN. Intraductal papillary mucinous neoplasm should be surgically resected when the tumor is diagnosed as IPMN with high-grade dysplasia.

Pancreatic Carcinoma with Prominent Mucin Production: A Clinicopathologic and Immunohistochemical Study of 9 Cases

Pancreatic carcinoma occasionally associated with prominent mucin production and this type of tumor designated as PCM (pancreatic carcinoma with prominent mucin production) was diagnosed depends on subjective estimation of the amount of mucous area, and there has been no report on a quantitative evaluation of the amount of mucinous area in the tumor. To examine the feature of PCM, we analyzed 9 cases of PCM among 243 cases of pancreas carcinoma and evaluated the amount of mucin by imaging analysis. Morphologically, 5 cases were classified as intradactal papillary mucinous neoplasms (IPMN)-derived PCM and 4 cases were as ductal adenocarcinoma (DA)-derived PCM. Mucous composition was found to be more than 50% in all IPMN-derived PCM cases, and that was 40% - 50% in DA-derived PCM cases with one exception. IPMN-derived PCM cases showed expansive growth with pancreatic duct dilatation filled with mucin, while DA-derived PCM cases possessed mucin infiltration into interstitial tissue. Immunohisto-chemically, three of 4 DA-derived PCM cases were MUC1(–)/MUC2(+), and the results of expressions for p16 and Dpc4 suggesting that DA-derived PCM was similar to IPMN-derived PCM rather than ordinary DA. Survival rate of DA-derived PCM cases was lower than that of IPMN-derived PCM cases. We advocate that DA-derived PCM may constitute a borderline group between IPMN and ordinary DA.

Pancreatic intraductal papillary-mucinous neoplasms: a new and evolving entity

For a long time, intraductal tumors of the pancreas were neglected because they were misdiagnosed as mucinous cystadenocarcinoma, ordinary ductal adenocarcinoma, or chronic pancreatitis. Only in recent years have they been recognized as clinical and pathological entities. Most common are the intraductal papillary-mucinous neoplasms. Although they show an adenoma-carcinoma sequence, they have proved to have a more favorable prognosis than ductal adenocarcinoma, when resected in a preinvasive state. Recently, it has become clear that they constitute a heterogeneous group with at least four subtypes. Their stratification reveals that the various intraductal papillary-mucinous neoplasm subtypes have different biological properties with different prognostic implications.

Mucinous noncystic (colloid) adenocarcinoma of the pancreas

To determine the clinicopathologic characteristics and the relationship between related gene expression and pathobiologic behavior of pancreatic mucinous noncystic adenocarcinoma. Among the 249 pancreatic carcinoma cases from the department files, 6 tumors were identified to meet the pathologic criteria of colloid carcinoma. Envision immunohistochemical staining technique was used to detect expression of p21(ras), p21(WAF1), p16, p33(ING1), p53, ATM, MDM2, PCNA, Cyclins (D1, D3, A, B and E). Intra- and extra- cellular mucin production were determined by AB-PAS staining. Clinically, all of 6 cases were followed to June, 2003. In all 6 cases, the tumors were located in the head of the pancreas and all displayed similar microscopic findings. Duodenal invasion was seen in 4 cases and perineural invasion was seen in 1 case. Tumor metastasis in the liver was seen in 2 cases and in the regional lymph nodes in 2 cases. Positive immunostaining was seen in 5 cases with p21(ras), 3 cases with p21(WAF1), 1 case with p16, 4 cases with p33(ING1), 2 cases with p53, 3 cases with ATM, 3 cases with MDM2, 6 cases with PCNA, 3 cases with cyclinA, 3 cases with cyclinD1, 4 cases with cyclinD3, 4 cases with cyclinB and 6 cases with cyclinE. Both extracellular and intracellular mucin was strongly positive for AB-PAS staining. Clinical follow-up found that 2 patients died of their tumors at 14 and 20 months. Three patients were alive after 28, 49 and 87 months of follow-up. One case were lost contact. Pancreatic mucinous noncystic adenocarcinoma has distinct morphologic features and biologic behavior. Multiple gene products including many cyclins may be involved in the pathogenesis of pancreatic colloid carcinoma. The tumor has an aggressive behavior with a high frequency of invasion and metastases, though the prognosis could be better than that of ordinary ductal adenocarcinoma of pancreas.

Colloid carcinoma of the pancreas

Pancreatic colloid carcinoma, also known as mucinous non-cystic carcinoma or gelatinous carcinoma, is a carcinoma of ductal origin, characterized morphologically by well-circumscribed pools of mucin that contain detached floating epithelial elements. Its distinction from conventional ductal adenocarcinoma is important because beyond the morphological dissimilarities, there are molecular and biologic differences between colloid and ordinary ductal carcinoma of the pancreas. Clinically, patients with colloid carcinoma often present with abdominal/epigastric pain and diarrhoea. They usually have larger tumours than ordinary ductal adenocarcinoma at presentation. Often, an associated intraductal papillary mucinous neoplasm is found. Macroscopically, colloid carcinoma is frequently well demarcated and characterized by gelatinous appearance. Microscopic examination reveals well-delineated mucin pools that contain detached and scanty malignant epithelial cells. In contrast with the mixed carcinomas, which may focally exhibit a similar pattern, pure mucinous carcinomas (those in which most of the tumour is composed of colloid pattern) seem to have a more indolent course with longer survival rates than conventional adenocarcinoma. Even in the presence of lymph node metastases, the patients can sometimes attain prolonged survival. There are certain characteristics of colloid carcinoma that are being recognized increasingly as the potential reasons for its distinctive clinicopathologic attributes. One distinctive feature of colloid carcinoma cells is that they exhibit altered cell polarity in which the secretory activity of the cell is manifested at its stroma-facing surfaces. In addition, it seems that production of MUC2 type mucin, which is specific for colloid carcinoma or its precursors, might act as a barrier limiting the growth and spread of the tumor and partially explaining the indolent nature of these cancers. The frequent association of colloid carcinoma with intraductal papillary mucinous neoplasms and also the observation that they share a similar profile of MUC1 and MUC2 expression have suggested that these neoplasms may be characterized by a different carcinogenetic pathway than ordinary ductal adenocarcinoma, which is believed to originate from pancreatic intraepithelial neoplasia.

Colloid (mucinous noncystic) carcinoma of the pancreas.

In the past, colloid (mucinous noncystic) carcinoma (CC) of the pancreas had been included under the category of ordinary ductal adenocarcinoma, a tumor with a dismal prognosis, or was frequently misdiagnosed as mucinous cystadenocarcinoma. The clinicopathologic features of CC have not yet been well characterized, because most cases on record have been parts of studies on either mucinous cystic neoplasms (MCN) or intraductal papillary mucinous neoplasms (IPMN), with which colloid carcinomas are frequently associated. To determine the clinicopathologic characteristics of CC, 17 pancreatic tumors composed predominantly (>80%) of CC (defined as nodular extracellular mucin lakes with scanty malignant epithelial cells) and in which the invasive carcinoma measured larger than 1 cm were studied. Ten of these were originally classified as mucinous ductal adenocarcinoma and four as mucinous cystadenocarcinoma. The mean age of the patients was 61 years; 9 were men and 8 were women. The mean size of the CC was 5.3 cm (range, 1.2-16 cm). In more than half of the patients, CC represented the invasive component of an IPMN (in nine cases) or MCN (in one case). The tumors were composed of well-defined pools of mucin with sparse malignant cells in various patterns of distribution. Signet-ring cells floating in the mucin (but not as individual cells infiltrating stroma, a characteristic finding of signet-ring cell adenocarcinomas) were commonly identified and were prominent in five cases. Perineurial invasion was noted in six cases and regional lymph node metastases in eight. Mutation in codon 12 of the k-ras gene was detected in only 4 of 12 cases studied and p53 mutation in 2 of 9. Immunohistochemical and histochemical mucin stains suggested luminalization of the basal aspects of the cells. Five-year survival was 57%. At an overall mean follow up of 57 months, 10 patients were alive with no evidence of disease (median, 79 mos), including four with lymph node metastasis, three others with perineurial invasion, and another with vascular invasion. Four patients died of disease (18, 18, 25, and 26 mos), and three died of thromboembolism (with persistent disease) at 2, 5, 10 months. All seven patients who died with or of tumor had undergone incisional biopsy of the tumor either before the operation or intraoperatively, whereas none of the patients who were alive had incisional biopsy. When compared with 82 cases of resectable ordinary ductal adenocarcinoma on whom follow-up and staging information was complete, it was found that the patients with CC present with larger tumors (p = 0.03) but lower stage (p = 0.01). The prognosis of CC is significantly better: 2-year and 5-year survival are 70% versus 28% and 57% versus 12%, respectively (p = 0.001). In conclusion, pancreatic CC may occur with or without an identifiable IPMN and MCN component, and should be distinguished from mucinous cystadenocarcinoma, ordinary ductal adenocarcinoma, and signet-ring cell adenocarcinoma. CC of the pancreas is associated with a significantly better prognosis than ordinary ductal adenocarcinoma. In addition to its distinctive morphologic and clinical characteristics, CC of the pancreas also appears to have a low incidence of mutation in codon 12 of the k-ras gene. In cases with a clinical suspicion of colloid carcinoma, the possibility that an incisional biopsy may contribute to thromboembolic complications or even dissemination of the tumor may need to be considered. The luminalization of the basal aspects of the tumor cells may be the cause of stromal mucin accumulation that characterizes colloid carcinoma and may act as a containing factor.

Foamy gland pattern of pancreatic ductal adenocarcinoma: a deceptively benign-appearing variant.

Pathologic diagnosis of pancreatic adenocarcinoma is frequently a challenge, particularly in small biopsies, frozen sections, and in metastatic foci. Here we report a deceptively benign-appearing and morphologically distinctive pattern of ductal adenocarcinoma with prominent microvesicular cytoplasm, giving the cells a foamy appearance similar to that described in the prostate (Am J Surg Pathol 1996;20:419). This variant, which we refer to as foamy gland pattern (FGP), was frequently misdiagnosed in frozen sections or biopsies and its pathologic stage underestimated in surgical specimens. Histologically, the diagnostic features were: (1) white and crisply foamy, "microvesicular" cytoplasm; (2) often basally located and compressed, hyperchromatic nuclei reminiscent of endocervical glands (and so-called "adenoma malignum") or gastric foveolar glands; (3) irregular nuclear contours forming wrinkled (raisinoid) nuclei in some areas; and (4) a distinctive chromophilic condensation of the cytoplasmic material in the luminal aspect of the cells forming a brush border-like zone (BLZ). Histochemically, this BLZ was positive for mucicarmine, alcian blue, and high iron diamine, but not PAS. The remainder of the cytoplasm was negative for all these stains. In contrast, benign mucinous ducts, which constitute the major differential diagnosis, had more homogeneous acidophilic cytoplasm, lacked BLZ, and showed cytoplasmic staining with PAS. Immunohistochemically, the tumor cells were diffusely and strongly positive for CEA and cytokeratin 8 whereas B72.3 staining was focal and weak. MUC1 staining was largely confined to the BLZ. MUC2 was negative. P53 staining was detected in 16 of the 20 cases studied and was strong and diffuse in five. K-ras mutation was detected in 6 of 8 cases studied. The clinical findings in the 20 patients in this study (4 pure and 16 mixed with usual ductal carcinoma) did not appear to differ significantly from those of ordinary ductal adenocarcinoma of the pancreas. Eleven patients were men and nine were women; the mean age was 62 years and the mean tumor size was 4.4 cm. Follow-up information was available in 17 patients of whom 7 were alive at an average follow up of 23 months (range, 7-104 mos), and 10 were dead of disease at a median follow up of 15 months (range, 4-42 mos). The median survival of the four patients with pure FGP was 18 months. The median survival did not appear to be significantly longer than that of the patients with resectable ordinary ductal adenocarcinoma in the authors' experience (109 patients, median survival of 12 mos, p = 0.48). In conclusion, foamy gland pattern of invasive pancreatic ductal carcinoma is morphologically distinctive and is prone to misdiagnosis as a benign process. The pathologic stage is often underestimated as a result of the lack of its recognition and misinterpretation as mucinous ducts. Careful attention to its microscopic features is adequate for accurate diagnosis. Histochemical and immunohistochemical stains are useful in confirming the diagnosis of malignancy in challenging cases.

Clinical and pathologic correlation of 84 mucinous cystic neoplasms of the pancreas: can one reliably differentiate benign from malignant (or premalignant) neoplasms?

To determine whether the long-term behavior of cystic mucinous neoplasms of the pancreas could be predicted using a novel, precisely defined classification of benign mucinous cystadenomas, noninvasive proliferative cystic mucinous neoplasms, and invasive mucinous cystadenocarcinomas. The primary interest was to obtain long-term follow-up after complete resection to determine the recurrence rates based on this objective classification. Current understanding is that all cystic mucinous neoplasms of the pancreas are potentially malignant and that mucinous cystadenomas, when completely removed, are biologically benign. Cystadenocarcinomas are thought to be less aggressively malignant than ordinary ductal adenocarcinoma, but reported recurrence rates vary widely and are unpredictable. All patients who underwent "curative" resection for cystic mucinous neoplasms at Mayo Clinic Rochester from 1940 to 1997 were identified. All available pathology slides, gross specimens, and clinical records were reviewed, eliminating patients with inadequate documentation. Neoplasms were reclassified as mucinous cystadenomas, noninvasive proliferative mucinous cystic neoplasms, or invasive cystadenocarcinomas based on specific histologic criteria. Of 84 patients (70 women, 14 men) with cystic mucinous neoplasms of the pancreas, 54 were classified as cystadenomas, 23 as noninvasive proliferative cystic mucinous neoplasms, and only 7 as cystadenocarcinomas. Recurrent disease developed in none of the 77 patients without invasion, but 5 of the 6 patients surviving resection for cystadenocarcinomas died of recurrent cystadenocarcinoma within 5 years. When the neoplasm is completely resected and subjected to adequate histopathologic examination based on these objective criteria, absence of tissue invasion predicts a curative operation and detailed follow-up may be unnecessary. In contrast, a histologic diagnosis of invasive cystadenocarcinoma portends a dismal prognosis, similar to that of typical ductal adenocarcinoma of the pancreas.