TFF3 Expression as Stratification Marker in Borderline Epithelial Tumors of the Ovary.

Borderline tumors (BOT) of the ovary account for 10% to 20% of ovarian neoplasms. Like ovarian cancer, BOT encompass several different histological subtypes (serous, mucinous, endometrioid, clear cell, transitional cell and mixed) with serous (SBOT) and mucinous (MBOT) the most common. Current hypotheses suggest low-grade serous carcinoma may develop in a stepwise fashion from SBOT whereas the majority of high grade serous carcinomas develop rapidly presumably from inclusion cysts or ovarian surface epithelium. The pathogenesis of mucinous ovarian tumors is still puzzling. Molecular markers could help to better define relationships between such entities. Trefoil factor-3 (TFF3) is an estrogen-regulated gene associated with prognosis in different types of cancer. It has also been included in a recent marker panel predicting subtypes of ovarian carcinoma. We analyzed the expression of TFF3 by immunohistochemistry in a cohort of 137 BOT and its association with histopathological features. Overall expression rate of TFF3 was 21.9%. None of the BOT with serous and endometrioid histology displayed strong TFF3 expression. On the other hand, TFF3 was highly expressed in 61.4% of MBOT cases and 33.3% of BOT with mixed histology (P < 0.001) suggesting a potential function of the protein in that subtypes. Associations of TFF3 expression with FIGO stage and micropapillary pattern were significant in the overall cohort but confounded by their correlation with histological subtypes. The highly specific expression of TFF3 in MBOT may help to further clarify potential relationships of tumors with mucinous histology and warrants further studies.

Glandular neoplasms of the urachus: a report of 55 cases emphasizing mucinous cystic tumors with proposed classification.

Published experience remains limited for glandular neoplasms of the urachus, especially mucinous cystic tumors. We reviewed 55 glandular urachal neoplasms to evaluate their clinical features and histopathologic spectrum and to devise a classification system for the mucinous cystic forms. Within the 55 cases studied, we observed 2 groups with differing clinical, gross, and histopathologic features. The first group, invasive, noncystic adenocarcinomas (n=24), had clinicopathologic features in accord with the known spectrum of urachal adenocarcinoma (mean age 50 y, female:male ratio 1.7, with recurrence or death from disease in 9/16 cases over a 45 mo mean follow-up). The second group, mucinous cystic tumors (n=31), morphologically resembled mucinous cystic tumors of the ovary and appeared classifiable by the same approach (mean age 47 y, female:male ratio 1.4) and included mucinous cystadenoma (n=4), mucinous cystic tumor of low malignant potential (n=22, including 2 cases with intraepithelial carcinoma), and mucinous cystadenocarcinoma with microscopic (n=4) or frank invasion (n=1). Follow-up information was available for 13 patients with mucinous cystic tumors (mean 41 mo); we observed no local recurrence or distant metastasis. This experience suggests that there is a distinct group of glandular, cystic tumors of the urachus that is classifiable in a manner similar to ovarian neoplasms and that has a favorable prognosis after complete excision. As with cystic neoplasms of other organs, rigorous sampling is recommended to identify potentially small foci of carcinoma that could be missed by inadequate sampling. Accordingly, classification based on methods other than complete surgical excision may be hazardous.

Claudin-18 overexpression in intestinal-type mucinous borderline tumour of the ovary.

AIMS: Mucinous borderline tumours of the ovary are subclassified as intestinal-type (IMBT) and endocervical-like (EMBT), which differ in their clinicopathological features. In this study, we attempted to elucidate characteristics of the mucinous epithelium in each subtype. METHODS AND RESULTS: The expression of claudin-18, a marker of gastric differentiation, MUCs, CDX2, CK7, CK20, oestrogen receptor (ER), progesterone receptor (PgR), CA-125 and vimentin in IMBTs (n = 54), EMBTs (n = 25) and serous borderline tumours (SBTs) (n = 22) were compared by immunohistochemistry. Claudin-18 positivity was identified in 98% of the IMBTs, whereas only 4% of the EMBTs were claudin-18-positive. Expression of intestinal markers such as CDX2 and MUC2 was relatively infrequent in IMBTs (48% and 33%, respectively). Müllerian-lineage markers such as ER, PgR and vimentin were expressed rarely in IMBTs, while most EMBTs and SBTs were positive for these markers. Hierarchial clustering revealed a close association between EMBTs and SBTs, while IMBTs were clearly separate. CONCLUSIONS: Claudin-18 positivity is a specific phenotype that is characteristic of IMBTs. Frequent and diffuse expression of gastric markers, along with less frequent and usually focal expression of intestinal markers, suggests that IMBTs are essentially composed of gastrointestinal-type mucinous epithelium (gastric-type epithelium with a variable degree of intestinal differentiation).

Expression of hepatocyte nuclear factor 4 alpha in primary ovarian mucinous tumors.

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a member of the nuclear receptor superfamily and is expressed in several endodermal tissues. The aim of the present study was to examine the expression of HNF4 alpha on ovarian epithelial tumors with immunocytochemistry and immunohistochemistry using mAbs recognizing P1 and P2 promoter-driven HNF4 alpha. Ovarian mucinous adenoma, mucinous tumors of borderline malignancy, and mucinous adenocarcinoma had positive nuclear staining for HNF4 alpha (41/45, 91%). One-third (34%) of mucinous tumors had P1-positive staining and most had P1/P2-positive staining (93%). MUC2- and MUC5AC-positive staining was observed in 34% and 95% of mucinous tumors, respectively. The histological subtype of these mucinous tumors was not correlated with HNF4 alpha expression. On cytology it was found that cancer cells in the ascites from ovarian mucinous adenocarcinomas were HNF4 alpha positive, but tumor cells in ascites from other types of ovarian carcinomas were negative for HNF4 alpha. Thus, HNF4 alpha is demonstrated to be a useful marker for histological and cytological diagnosis of ovarian mucinous tumors.

Primary ovarian mucinous tumors with signet ring cells: report of 3 cases with discussion of so-called primary Krukenberg tumor.

The distinction between a primary ovarian mucinous carcinoma or even a borderline mucinous tumor and a metastatic mucinous carcinoma may be difficult. A constellation of clinical, gross pathologic and morphologic features is used in this distinction. One of the most important morphologic features suggesting a metastatic mucinous carcinoma in the ovary is the presence of signet ring cells; these are considered rare in primary ovarian mucinous tumors. In this study, we report 3 primary ovarian mucinous tumors with a component of signet ring cells. The tumors arose in patients aged 27, 55, and 60, were unilateral, confined to the ovary and stage IA. They ranged from 9 to 27 cm; 1 was grossly a multiloculated cystic lesion and 2 were cystic and solid. In one case, the neoplasm had the architecture of a mucinous adenofibroma but had frankly malignant cells lining glands and forming solid aggregates of cells. A second tumor also had the background of an adenofibroma. The third was mostly a mucinous cystadenoma. In one case, endometriosis was present in the same ovary; teratomatous elements were not identified in any case. Immunohistochemistry, performed in 2 cases, showed both to be diffusely positive with CK7 and CA19.9, including the signet ring cells. CK20 was positive in both cases (1 focal; 1 diffuse). Estrogen receptor and CA125 were diffusely positive and carcinoembryonic antigen and CDX2 focally positive in 1 case. Chromogranin and synaptophysin were negative. Investigations to exclude a gastrointestinal neoplasm in 2 cases were negative. Features favoring a primary rather than a metastatic neoplasm are unilateral tumor, low stage, background of adenofibroma or cystadenoma, associated endometriosis in 1 case and an absence of features which are characteristic of secondary mucinous carcinomas in the ovary, such as surface tumor deposits, a nodular growth pattern, and lymphovascular permeation. Immunohistochemistry is of limited value because of overlapping immunophenotype between a primary ovarian mucinous tumor and a metastasis from the stomach, pancreas, biliary tree, appendix, or colorectum, the most likely primary sites for a secondary exhibiting similar features. Our study illustrates that signet ring cells occur rarely in a primary ovarian mucinous tumor; even when conspicuous the features differ from those of the usual Krukenberg tumor. At least some cases of so-called primary Krukenberg tumor may be similar to our cases. However, the designation primary Krukenberg tumor should not be used as, apart from the signet ring cells, a resemblance to a "true" Krukenberg tumor of the secondary type is limited. The tumors should be classified according to the underlying background neoplasm with a notation concerning the signet ring cell component.

Nuclear morphometry and AgNOR quantification: computerized image analysis on ovarian mucinous tumor imprints.

OBJECTIVE: To determine the morphometric characteristics of nuclei and silver-stained nucleolar organizer regions (AgNORs) on cytologic imprints and their value in differential cytodiagnosis of benign, atypical proliferative (borderline) and malignant ovarian mucinous tumors. STUDY DESIGN: Forty-six mucinous ovarian tumor imprints (16 benign, 15 borderline, 15 malignant), were analyzed. Nuclear area, outline, "shape factor" and "form factor" were measured on Papanicolaou-stained smears. AgNOR quantification included 7 variables related to the number and area of single, cluster, total and relative AgNOR content per nucleus and the size distribution of AgNORs. RESULTS: Nuclear area and shape factor allowed distinguishing borderline and malignant tumors. The nuclear area in benign tumors was larger than that in borderline tumors; malignant tumors had the highest values. Single and cluster AgNORs were statistically significantly different in borderline tumors compared with malignant tumors, except for the cluster AgNOR area. The total AgNOR area, number and relative area increased from benign through malignant tumors, with statistically significant differences among all groups. By AgNOR size distribution, small AgNORs discriminate malignant from borderline and benign tumors. CONCLUSION: Combining nuclear morphometry and AgNOR analysis on cytologic imprints could be a diagnostically useful method in the assessment of mucinous ovarian tumors.

A review of mucinous cystic neoplasms of the pancreas defined by ovarian-type stroma: clinicopathological features of 344 patients.

INTRODUCTION: Despite formal definitions of mucinous cystic neoplasms (MCNs) and intraductal papillary neoplasms (IPMNs) by the World Health Organization (WHO) and Armed Forces Institute of Pathology (AFIP), several controversies with regard to MCNs remain. The aim of this review was to determine the clinicopathological features of MCNs defined by ovarian-type stroma (OS) as proposed by the WHO and AFIP and to compare them with MCNs defined by less stringent criteria. METHODS: A MEDLINE search was conducted to identify English-language articles on pancreatic MCNs from 1996 to 2005. Twenty-five studies were identified. The studies were divided into 2 groups: group A included 10 studies with 344 patients whereby the presence of OS was a criteria for the diagnosis of MCNs, and group B, included 15 studies comprising 761 patients whereby the presence of OS was not mandatory for the diagnosis of MCNs. RESULTS: Patients in group A (MCNs as defined by OS) were almost always female (99.7%), with a mean age of 47 (range, 18-95) years. MCNs were located predominantly in the body or tail of the pancreas (94.6%) and had a mean size of 8.7 cm (range, 0.6-35 cm); 76% were symptomatic, 6.8% demonstrated ductal communication, and 27% were malignant. At a mean follow-up of 57.5 (range, 1-264) months and 43 (range, 2-257) months after surgery, 97.9% of benign and 61.9% of malignant neoplasms were disease free, respectively. Patients in group B were older and had a higher proportion of males. Neoplasms were more evenly distributed in the pancreas, were smaller, communicated more frequently with the pancreatic duct, and were composed of a higher proportion of malignant tumors compared with group A. Their clinicopathological features were intermediate between those of group A and patients with IPMN. CONCLUSION: Pancreatic MCNs with OS have unique and distinct clinicopathological features. MCNs should be defined by the presence of OS, as it is the most reliable way of distinguishing MCNs from IPMN. Adoption of "looser" criteria will result in misclassification of some IPMNs as MCNs.

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.

Serous and mucinous borderline (low malignant potential) tumors of the ovary.

The prognosis for stage I serous borderline ovarian tumors (SBOTs) is thought to be excellent, despite rare, late recurrences. The behavior of advanced-stage SBOTs primarily depends on the invasiveness vs noninvasiveness of associated extraovarian implants. Pelvic and abdominal lymph node involvement and foci of microinvasion do not seem to adversely affect prognosis. Serous tumors with a micropapillary and/or cribriform growth pattern seem to be more frequently bilateral and exophytic and manifest at an advanced stage with a higher incidence of invasive implants than typical SBOTs. Molecular data suggest that such tumors may represent an intermediate stage in the typical SBOT-invasive low-grade serous carcinoma progression. Limited experience with endocervical (müllerian)-type mucinous borderline tumors shows a possible relation to SBOTs in clinicopathologic features and biologic behavior Intestinal-type mucinous borderline ovarian tumors (I-MBOTs) and well-differentiated mucinous carcinomas manifest at stage I in most cases; the prognosis is excellent. Mucinous tumors associated with pseudomyxoma peritonei are almost always secondary to similar tumors of the appendix or other gastrointestinal sites and should not be diagnosed as high-stage I-MBOTs. Rare primary ovarian mucinous tumors associated with pseudomyxoma peritonei are those arising in mature cystic teratomas. Advanced-stage ovarian mucinous carcinomas typically show frank, infiltrative-type invasion; the prognosis is poor.

Current issues in the pathology of ovarian cancer.

The majority of primary ovarian tumors are histologically classified as surface epithelial-stromal neoplasms. The malignant potential of such neoplasms may be categorized, on the basis of the extent of epithelial proliferation and stromal invasion, as benign, borderline or malignant. Recent efforts to further classify the malignant potential of such neoplasms have produced a new system for the histologic grading of ovarian carcinoma as well as new potential histologic predictors of behavior, including micropapillary morphology and stromal microinvasion in serous tumors. Among mucinous ovarian neoplasms, new criteria have been proposed to distinguish primary ovarian from metastatic carcinomas; the distinction may be difficult but has great clinical significance. The origin of ovarian mucinous tumors associated with pseudomyxoma peritonei has been reassessed. Finally, recent pathologic findings from prophylactic salpingo-oophorectomy specimens in patients with hereditary risks for ovarian carcinoma have highlighted the additional risk for fallopian tube carcinoma and primary peritoneal carcinoma. Special processing of the pathologic specimens is required to detect early and minimal neoplasia in this setting. These current issues in the pathology of ovarian carcinoma and their clinical significance form the basis of this review.

The spectrum of pulmonary mucinous cystic neoplasia : a clinicopathologic and immunohistochemical study of ten cases and review of literature.

We describe 10 new cases and review 66 previously reported cases of primary pulmonary mucinous cystic neoplasia (PMCN). The 3 men and 7 women were 44 to 73 years old (mean, 60.0 years) at diagnosis. Lesions were found by chest radiograph (featuring a solitary, lobulated nodule with soft tissue density that enlarged slowly), or patients had major bronchial occlusion by mucus or hemoptysis. Tumors were well-circumscribed, lobulated soft masses with a central cavity filled with gray to greenish translucent mucus and were 1.5 to 5.5 cm in greatest dimension (mean, 3.3 cm). Microscopically, confluent lakes of mucin characterized all cases. Tumor epithelium ranged from bland to focal cytologic atypia to frankly malignant. The adjacent lung parenchyma was stretched, compressed, or showed an inflammatory reaction to dissected mucin. After 1- to 10-year follow-up (mean, 3.7 years), 3 patients died of metastasis and 1 of amitriptyline toxic effects; 6 were alive without tumor. Combined analysis of our cases and previously reported cases suggests a histologic spectrum from benign cystadenoma to mucinous cystic tumor with atypia to well-differentiated mucinous cystadenocarcinoma. The histomorphologic criteria derived from this analysis can help distinguish PMCN from other types of primary or metastatic mucinous tumors and predict outcome.

Mucinous borderline ovarian tumors: points of general agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior.

This report focuses on the borderline category of ovarian mucinous tumors and summarizes the points of general agreement and persistent controversies identified by experts in the field who participated in the Borderline Ovarian Tumor Workshop held in Bethesda, MD, in August 2003. Points of agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior are addressed for the following ovarian mucinous tumor categories: mucinous borderline ovarian tumor (M-BOT; synonymously referred to as atypical proliferative mucinous tumor of ovary or mucinous ovarian tumor of low malignant potential), M-BOT with intraepithelial carcinoma, and M-BOT with microinvasion. The morphologic spectrum of M-BOTs with regard to distinction from mucinous cystadenoma and the confluent glandular/expansile type of invasive mucinous carcinoma is also addressed. Non-ovarian mucinous tumors, including the secondary ovarian mucinous tumors associated with pseudomyxoma peritonei and metastatic mucinous carcinomas with a deceptive pattern of invasion, are recognized as tumors that can simulate primary M-BOTs. Improved classification of these mucinous tumors has clarifed the behavior of true M-BOTs by excluding these simulators from the M-BOT category.

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.

Histological classification of ovarian cancer.

The histology of ovarian tumors exhibits a wide variety of histological features. The histological classification of ovarian tumors by the World Health Organization (WHO) is based on histogenetic principles, and this classification categorizes ovarian tumors with regard to their derivation from coelomic surface epithelial cells, germ cells, and mesenchyme (the stroma and the sex cord). Epithelial ovarian tumors, which are the majority of malignant ovarian tumors, are further grouped into histological types as follows: serous, mucinous, endometrioid, clear cell, transitional cell tumors (Brenner tumors), carcinosarcoma, mixed epithelial tumor, undifferentiated carcinoma, and others. Clear cell and endometrioid carcinomas are highly associated with endometriosis. In stage distribution, serous carcinoma is found predominantly is stage III or IV. In contrast, clear cell and endometrioid carcinomas tend to remain confined to the ovary. Clear cell and endometrioid carcinomas may be unique histological types compared with serous carcinomas with respect to stage distribution and association with endometriosis.

Mucinous cystic neoplasm (mucinous cystadenocarcinoma of low-grade malignant potential) of the pancreas: a clinicopathologic study of 130 cases.

Mucinous cystic neoplasms (MCNs) of the pancreas are uncommon tumors. The classification and biologic potential of these neoplasms remain the subject of controversy. Attempts to classify these tumors in a similar manner to ovarian MCNs remains controversial, as even histologically benign-appearing pancreatic MCNs metastasize and are lethal. One hundred thirty cases of MCNs were identified in the files of the Endocrine Pathology Tumor Registry of the Armed Forces Institute of Pathology from the years 1979 to 1993. The pathologic features, including hematoxylin and eosin staining, histochemistry, immunohistochemistry (IHC), cell cycle analysis, and K-ras oncogene determination were reviewed. These findings were correlated with the clinical follow-up obtained in all cases. There were 130 women, aged 20-95 years (mean age at the outset, 44.6 years). The patients had vague abdominal pain, fullness, or abdominal masses. More than 95% of the tumors were in the pancreatic tail or body and were predominantly multilocular. The tumors ranged in size from 1.5 to 36 cm in greatest dimension, with the average tumor measuring >10 cm. A spectrum of histomorphologic changes were present within the same case and from case to case. A single layer of bland-appearing, sialomucin-producing columnar epithelium lining the cyst wall would abruptly change to a complex papillary architecture, with and without cytologic atypia, and with and without stromal invasion. Ovarian-type stroma was a characteristic and requisite feature. Focal sclerotic hyalinization of the stroma was noted. This ovarian-type stroma reacted with vimentin, smooth muscle actin, progesterone, or estrogen receptors by IHC analysis. There was no specific or unique epithelial IHC. K-ras mutations by sequence analysis were wild type in all 52 cases tested. Ninety percent of patients were alive or had died without evidence of disease (average follow-up 9.5 years), irrespective of histologic appearance; 3.8% were alive with recurrent disease (average 10 years after diagnosis); and 6.2% died of disseminated disease (average 2.5 years from diagnosis). Irrespective of the histologic appearance of the epithelial component, with or without stromal invasion, pancreatic MCNs should all be considered as mucinous cystadenocarcinomas of low-grade malignant potential. Pancreatic MCNs cannot be reliably or reproducibly separated into benign, borderline, or malignant categories.

Progress in the study of pancreatic cancer and its pathology.

Recent advances in diagnostic techniques allow detection of relatively small ductal cancers and mucinous cystic neoplasms of the human pancreas. The histopathological characteristics of a series of such small pancreatic carcinomas encountered in our hospital were: 1) all were invasive ductal carcinomas accompanied by fibrosis, 2) four of seven carcinomas were thought to originate in the branch ducts, 3) no precancerous lesions were found, and 4) lymph node metastasis was detected in only one patient. Mucinous cystic neoplasms were of two types: megacystic and ductectatic. The megacystic type is the classical mucinous cystic neoplasm. The ductectatic type is characterized by the presence of multilocular cysts (reminiscent of bronchiectasia of the lung), and papillary proliferation of the lining epithelium-differing from typical ductal carcinomas as well as from megacystic lesions in terms of morphological features, intrapancreatic location, patient age, and sex. The ductectatic type occurs exclusively in the head and body of the pancreas, and is found predominantly in aging males.

[Mucosecretory and papillary intraductal tumors of the pancreas: clinicopathological considerations and radiological aspects including computed tomography symptomatology]. / Tumeurs intracanalaires mucosecretantes et papillaires du pancreas: considerations clinico-pathologiques et aspects radiologiques comprenant la semiologie tomodensitometrique.

Intraductal papillary-mucinous tumor of the pancreas (IPMT) is an uncommon entity, defined as an intraductal papillary proliferation of mucin-producing epithelial cells. Since the original description of the disease by Ohhashi in 1982, the definition and the classification of the disease has remained confused until the recently published classification of the World Health Organisation (WHO). The purpose of this article is therefore to report the clinico-pathological features of IPMT according to the WHO classification, to illustrate the radiological features especially the computed tomographic signs and to discute of the treatment.