Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.

Now that more than two decades have passed since the first reports of intraductal papillary-mucinous neoplasms (IPMNs), it has become clear that IPMN consists of a spectrum of neoplasms with both morphological and immunohistochemical variations. At a meeting of international experts on pancreatic precursor lesions held in 2003, it was agreed that a consensus classification of IPMN subtypes should be established to enable a more detailed analysis of the clinicopathological significance of the variations. Based on our experience and on information from the literature, we selected representative histological examples of IPMNs and defined a consensus nomenclature and criteria for classifying variants as distinctive IPMN subtypes including gastric type, intestinal type, pancreatobiliary type, and oncocytic type. These definitions can be used for further analyses of the clinicopathological significance of the variations of IPMN.

Microdissection-based mutational genotyping of serous borderline tumors of the ovary.

Mutational changes in a number of genetic foci were studied in 12 serous borderline tumors (SBTs) of the ovary including 2 with a micropapillary pattern. The analysis was focused on chromosomal regions that have not been previously studied in these tumors. The findings were correlated with the morphology and the FIGO stage of the tumors. Six of the tumors were stage I, one was stage II, and five were stage III. Loss of heterozygosity analysis in each tumor was performed with a panel of 12 polymorphic markers on chromosomes 1p, 5q, 9p, 9q, 10q, and 17p. The ovarian tumors displayed allelic losses most frequently on 1p (83.3%), 9q (70%), and 17p (41.7%). In the extraovarian implants, allelic losses on 1p, 9q, and 17p were present in 66.7%, 75%, and 66.7% of cases respectively. In five of six cases, allelic losses were 88% concordant between multiple tumor sites. Only one case of stage III tumor displayed a discordant pattern of allelic loss at different tumor sites. Cumulative allelic losses did not show a statistically significant difference in stage I vs. higher stage disease. The pattern and cumulative allelic loss in the two cases with micropapillary architecture was similar to that of the other tumors. We report a high frequency of allelic loss on 1p and 9q that has not been previously reported in SBTs. Morphologically heterogenous areas including benign-appearing, typical borderline, and micropapillary areas had a similar pattern of allelic loss. Although the majority of SBTs seem to be monoclonal, a minor subset may be multiclonal in origin.

An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.

Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers. Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts. A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms. We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.

Micropapillary serous carcinoma of the ovary has distinct patterns of chromosomal imbalances by comparative genomic hybridization compared with atypical proliferative serous tumors and serous carcinomas.

Recent studies have subdivided serous borderline tumors into 2 categories: atypical proliferative serous tumors (APSTs), which have a relatively benign course, and micropapillary serous carcinomas (MPSCs), which behave like low-grade carcinoma. This study was undertaken to determine, using comparative genomic hybridization (CGH), whether cytogenetic changes support this hypothesis. Nine cases of APST, 10 of MPSC, and 11 of invasive serous carcinoma (SC) were analyzed by CGH. Tumor DNA was extracted from frozen or paraffin-embedded tissue from the primary ovarian tumor, using either sections with at least 70% tumor cells or tissue after relative enrichment by microdissection. Chromosomal imbalances were identified in 3 of 9 APST, 6 of 10 MPSC, and 11 of 11 SC. Three or more chromosomal imbalances were found in 0 of 9 APST, 4 of 10 MPSC, and 9 of 11 SC. Recurrent copy number alterations were grouped into 4 classes correlating with the different tumor types. Class I changes were present in APST and in MPSC or SC and included +8q (7 of 11 SC, 2 of 10 MPSC, 2 of 9 APST), -9p (5 of 11 SC, 0 of 10 MPSC, 1 of 9 APST), and +12 (+12p in 3/11 SC, +12 in 2 of 10 MPSC, +12 in 1 of 9 APST). Class II changes were found only in MPSC and SC, but not in APST. The most frequent examples were +3q (10 of 11 SC, 1 of 10 MPSC), -4q (5 of 11 SC, 1 of 10 MPSC), and -17p (5 of 11 SC, 1 of 10 MPSC). Class III changes were limited to SC, like -16q (7 of 11 SC) and -18q (6 of 11 SC). Class VI changes were unique to MPSC. Gain of 16p (3 of 10 MPSC) was the only aberration in this group. This aberration was not only unique to MPSC but was also the most frequent finding in MPSC. These data support the hypothesis that noninvasive serous tumors of the ovary can be subdivided into 2 categories: APST and MPSC. The number of imbalances in MPSC is substantially higher than in APST and lower than in SC. Some changes in MPSC are shared with SC and APST and others with SC only, suggesting that a subset of MPSC may represent a stage in progression from APST to SC. Other cases of MPSC with independent genetic alterations may represent another subset of tumors that are a distinct entity from APST and SC.

Refined diagnostic criteria for implants associated with ovarian atypical proliferative serous tumors (borderline) and micropapillary serous carcinomas.

Characterization of invasive peritoneal implants from patients with noninvasive serous ovarian tumors has important prognostic and treatment implications, but the criteria for distinguishing invasive and noninvasive implants vary among investigators and can be difficult to apply. The authors studied 148 implants from 60 patients, 33 with primary atypical proliferative serous tumor, and 27 with primary noninvasive micropapillary serous carcinoma, with a mean follow-up of 62 months (median follow-up, 52 months). Previously reported and newly proposed histologic features for implant classification were evaluated and correlated with clinical outcome. Three criteria were applied for the diagnosis of "invasive" implants: invasion of underlying normal tissue, micropapillary architecture, and solid epithelial nests surrounded by clefts. Implants displaying any one of these three features were classified as "invasive," whereas those lacking all three features were classified as "noninvasive." Sixty-six implants were invasive and 82 were noninvasive. Of the 31 patients with invasive implants, six were dead of disease (DOD), 13 were alive with progressive disease (AWPD), and 12 were alive with no evidence of disease (NED). Of the 29 patients with noninvasive implants, two were DOD, one was dead of uncertain causes, one was AWPD, and 25 were alive with NED. Eighty-nine percent of invasive implants had a micropapillary architecture and 83% had solid epithelial nests surrounded by clefts. A minority of invasive implants (14% of those with underlying normal tissue) demonstrated invasion of normal underlying tissue. Nuclear atypia, mitoses, calcification, necrosis, and identification of individual cells "infiltrating" the stroma did not correlate with implant type. The proposed criteria permitted recognition of implants that correlated strongly with adverse outcome. Sixty-one percent of patients with implants displaying any one of the three features used to diagnose invasive implants were AWPD or DOD compared with 10% of patients whose implants lacked these features (p = 0.00001). Because implants associated with an adverse outcome can be identified before they invade underlying normal tissue, the term invasive implant to describe them is inaccurate and misleading. These implants resemble patterns of growth in micropapillary serous carcinoma of the ovary and the recurrent tumor that is obvious carcinoma. Accordingly, we propose that these extraovarian lesions be designated "well-differentiated serous carcinoma."

Villoglandular adenocarcinoma of the endometrium: a clinicopathologic study of 61 cases: a gynecologic oncology group study.

Papillary endometrioid or villoglandular adenocarcinoma (VGA) is a relatively common type of endometrial adenocarcinoma, but studies describing its behavior have yielded conflicting results. Patients with a component of VGA were identified in a review of 819 women entered in a Gynecology Oncology Group Study (Protocol 33) of clinical stages I and II endometrial adenocarcinoma. Cases with coexisting foci of serous or clear cell carcinoma were excluded from further consideration. Of the 61 cases that formed the study sample, there were 24 with pure villoglandular differentiation and 37 who were admixed with typical endometrioid adenocarcinoma (EA). The general clinicopathologic features of patients with pure and mixed VGA are compared with 469 patients with pure EA. The VGAs were better differentiated (grade 1 or 2--97% of VGA versus 74% EA, p = 0.001). but they were not significantly different with respect to median age, depth of invasion, or frequency of nodal spread. Six of the 61 patients with VGA died of their tumor. The disease-specific survival rate at 3 years for VGA is 94% (95% confidence interval: 0.88-0.99) compared with 88% (95% CI: 0.86-0.91) for EA. Two of the patients who died had pure villoglandular tumors and four had mixed villoglandular and endometrioid carcinoma. In view of the frequent admixture of VGA and EA and their generally similar biological characteristics, with a prognosis similar to that of typical EA, we conclude that VGA should be considered a variant of EA.

Subclassification of serous borderline tumors of the ovary into benign and malignant types. A clinicopathologic study of 65 advanced stage cases.

Poor outcome in serous borderline tumors (SBT) of the ovary is limited to patients with advanced stage disease. This study was designed to determine whether there are histologic features among advanced-stage SBTs (International Federation of Gynecology and Obstetrics [FIGO] stages II and III) that predict behavior. The 65 cases in the study were divided into three groups: typical SBTs, with noninvasive implants (51 cases), SBTs with invasive implants (three cases), and a recently described tumor, designated micropapillary serous carcinoma (MPSC) (11 cases), a proliferative serous ovarian neoplasm that often lacks destructive infiltrative growth but appears to behave as a low-grade invasive carcinoma. When the tumor lacks infiltrative growth, as it did in the 11 cases in this series, it qualifies as a borderline tumor. After censoring nontumor deaths, the 5- and 10-year actuarial survival rates were 98% for SBTs with noninvasive implants, 33% for SBTs with invasive implants, and 81% at 5 years and 71% at 10 years for MPSCs. The mean follow-up was 100 months. Two (4%) of 51 patients with SBTs with noninvasive implants subsequently developed invasive carcinoma, and one (2%) died of carcinoma. In contrast, two (67%) of three women with SBTs accompanied by invasive implants developed invasive carcinoma, and both died of disease. Finally, of the 11 patients with MPSC, seven (64%), all of whom had invasive implants, developed recurrences of invasive carcinoma and/or died of tumor. MPSCs had significantly higher rates of mortality (p < 0.001) and recurrence as invasive carcinoma (p < .002) than SBTs with noninvasive implants. The recognition that SBTs can be divided into benign and malignant subtypes provides the basis for replacing the borderline category. The benign subgroup is composed of typical SBTs, including those with noninvasive implants for which the term atypical proliferative serous tumor is appropriate. In contrast, tumors displaying a micropapillary growth pattern (MPSC) and SBTs with invasive implants should be classified as carcinomas and treated accordingly.