Ovarian mucinous tumor of gastric and intestinal type associated with Peutz-Jeghers syndrome: in situ hybridization study of apomucin gene transcripts

Occurrence of mucinous tumors is favored by Peutz-Jeghers syndrome (PJS). A case of bilateral ovarian mucinous tumor associated with ovarian mature teratoma occurring in a 22-year-old woman with PJS was reported. Tumor cells included 5 cell types: tall columnar mucinous pale cells with neutral mucins; goblet cells with acidic nonsulfated mucins; non mucinous columnar cells; mucinous cuboidal cells lining small glands; endocrine cells. Expression of the MUC2, MUC3, MUC5AC and MUC6 genes was demonstrated by in situ hybridization according to cell type. Some atypia and numerous mitotic figures were observed in basal glands. Diagnosis was ovarian borderline mucinous tumor with gastric and intestinal phenotype associated with PJS.     

Brenner tumours of the ovary: a study of the histology, immunohistochemistry and cellular DNA content in benign, borderline and malignant ovarian tumours

Brenner tumours are now generally regarded as being of ovarian epithelial origin. Most have a limited growth potential and are benign. For this reason they are usually found incidentally at hysterectomy. In common with other epithelial ovarian tumours there is a histopathological spectrum of appearances ranging from benign through borderline to invasive malignancy. In this series all 54 tumours were graded according to the degree of cytological atypia, presence of mitoses and tumour necrosis. Heterogeneity of DNA content was observed in the higher grade tumours, two of the four being diploid and two being aneuploid (all benign tumours being diploid). The presence of aneuploidy correlated with the histological features and a poor clinical prognosis. Immunohistochemical staining for keratoprotein was found to be of limited value in the diagnosis of Brenner tumours and their metastases.     

Serous borderline tumours of the ovary

Serous borderline tumours of the ovaryIn this Expert Opinion we have invited articles from two leading groups, to discuss serous borderline tumours (serous tumours of low malignant potential) of the ovary from their own perspectives. Controversy remains over heterogeneity within this group of tumours and their relationship to ovarian cancer. Our authors discuss the histopathological classification of these tumours in relation to morphological appearances, molecular and clinical data. The significance of a micropapillary pattern is discussed, and issues related to extra-ovarian implants.     

Quantitation of borderline and malignant mucinous ovarian tumours

Discrimination between borderline and malignant mucinous ovarian tumours is a well-known diagnostic problem. In order to obtain objective reproducible and consistent features for differential diagnosis, 32 quantitative microscopical features were assessed in 10 benign, 10 borderline and 22 malignant mucinous ovarian tumours. There were many significant differences between the three groups, but using multivariate analysis there was 93% agreement between the histopathological assessment of these sections and the qualitative analyses. The following features were useful in the quantitative classification: the mean area, the mean perimeter and the mean of the short axis of the nucleus; the volume percentage of the epithelium; the mitotic activity. In three cases, there was a difference between the original histopathological and computer classification. It was debatable whether the original diagnosis was correct, and therefore, all the cases were independently reassessed blind by three pathologists. Their diagnoses lend strong support to the computer classification in two of the three cases. The computer classification seems therefore to be even better than 93%. The present quantitative techniques are inexpensive, relatively easy to use, and, we believe, have a useful place in diagnostic histopathology.     

Ultrastructure of the benign and borderline Brenner tumours

One benign Brenner tumour and one Brenner tumour of borderline malignancy were investigated by electron microscopy. The cells of the benign Brenner tumour nests and the cells in the borderline tumour were similar in ultrastructure. The intercellular spaces were large and reinforced by a moderate number of desmosomes. The nuclei were round or oval. The nuclear membrane was irregular in shape with deep infoldings corresponding to the characteristic nuclear groovings seen by light microscopy. Only few secreting cells could be found in the benign of Brenner tumour. The cystic cavities of the borderline Brenner tumour were lined by nonciliated secreting and ciliated nonsecreting cells. The secretory granules were PAS-positive and diastaseresistant. The granules stained homogeneously and strongly with the PASM-method at the electron microscopical level indicating the presence of 1.2-hydroxyl groups. The Brenner tumours have many similarities to the transitional epithelium and to the Muellerian-derived tubular structures. The findings support the theory that Brenner tumours are of coelomic origin and develop by direct metaplasia from the ovarian surface epithelium.     

Neuroendocrine cells in cystic mucinous tumours of the ovary

This histogenesis of cystic mucinous ovarian tumours is still controversial. It has been proposed that these neoplasms may arise from metaplastic ovarian surface epithelium. Others have suggested that these tumours represent monophyletic (intestinal) types of teratoma. Against this background we have studied the presence of different types of neuroendocrine cells in a series of cystic mucinous ovarian tumours. Argyrophil neuroendocrine cells were found almost exclusively in tumours which were histologically classified as borderline or low-grade mucinous carcinomas, whereas these cells were very rare in mucinous cystadenomas and in grade III and IV carcinomas. Several gut peptide hormones could be demonstrated in these cells, but only in borderline tumours and low-grade mucinous carcinomas. Mucin histochemistry did not reveal characteristic patterns in these neoplasms. The results confirm that with regard to the presence of endocrine cells the epithelium of borderline mucinous cystadenomas and mucinous cystadenocarcinomas bears strong resemblance to intestinal epithelium. These findings do not rule out the possibility that these tumours arise by metaplasia from ovarian germinal epithelium but are equally compatible with a teratomatous origin. The epithelium of most benign mucinous cystadenomas resembles that of ovarian inclusion cysts.     

Fertility determinants after conservative surgery for mucinous borderline tumours of the ovary (excluding peritoneal pseudomyxoma)

BACKGROUND The aim of this study was to define determinants of fertility in patients treated conservatively for mucinous borderline ovarian tumours (MBOTs), and to compare outcomes after salpingo-oophorectomy or cystectomy. METHODS This was a retrospective cohort study of fertility results in a series of patients treated conservatively for MBOTs and desiring pregnancy. Conservative surgery was defined as preservation of the uterus and ovarian tissue in one or both adnexa(e). Fertility results were compared with patients who had undergone a cystectomy or a (salpingo-)oophorectomy. Only patients with a minimum of 1 year of follow-up were included. Epidemiological, surgical, histological parameters and other prognostic factors for fertility results were investigated. RESULTS A group of 31 patients who had been treated conservatively between 1997 and 2004 and who desired pregnancy were investigated. Patients were treated by unilateral salpingo-oophorectomy (USO) (n = 19) or cystectomy (n = 12). The 5-year recurrence-free survival rate was higher in the USO group compared with the cystectomy group (94.7 versus 49.1%, P = 0.041). Among the 31 women, 12 had become pregnant. The 5-year probabilities of pregnancy were comparable between the cystectomy and salpingo-oophorectomy groups (41.8 and 45.9%, respectively, P= 0.66). None of the other factors studied (epidemiological, surgical and histological parameters) were associated with fertility results. CONCLUSIONS The use of salpingo-oophorectomy rather than cystectomy should be preferred during conservative surgery for patients with MBOTs because it decreases the risk of recurrence and does not impair fertility.     

RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary

Mucinous carcinomas represent a distinct morphological subtype which can arise from several organ sites, including the ovary, and their genetic characteristics are largely under‐described. Exome sequencing of 12 primary mucinous ovarian tumours identified RNF43 as the most frequently somatically mutated novel gene, secondary to KRAS and mutated at a frequency equal to that of TP53 and BRAF. Further screening of RNF43 in a larger cohort of ovarian tumours identified additional mutations, with a total frequency of 2/22 (9%) in mucinous ovarian borderline tumours and 6/29 (21%) in mucinous ovarian carcinomas. Seven mutations were predicted to truncate the protein and one missense mutation was predicted to be deleterious by in silico analysis. Six tumours had allelic imbalance at the RNF43 locus, with loss of the wild‐type allele. The mutation spectrum strongly suggests that RNF43 is an important tumour suppressor gene in mucinous ovarian tumours, similar to its reported role in mucinous pancreatic precancerous cysts. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

O-acylated sialic acid variants in mucinous tumours of the ovary

Summary O-acylated sialic acid variants (site 8) can be demonstrated histochemically by the PB/KOH/PAS method. They are secreted by goblet cells of the lower gastrointestinal tract, by colorectal adenocarcinomas, and by their metastases. Since the metastases are positive only when the primary tumour is positive, O-acylated sialomucins can be considered to be specific markers of colorectal adenocarcinomas if identified in metastases of a tumour of unknown origin. In our histochemical study we evaluated 29 mucinous cystomas of the ovary (23 benign and 6 malignant). We found that six cases were positive to PB/KOH/PAS. The positivity was observed in a limited number of cells and only in areas which presented an intestinal type epithelium. It was also more evident in malignant cystomas than in benign ones. We therefore think that the PB/KOH/PAS positivity can not only be considered a marker of colorectal adenocarcinomas, but also of all neoplasms which originate from an intestinal epithelium or appear to an intestinal type epithelium.This work is partially supported by the M.P.I. (40%)     

The prognostic significance of grading in borderline mucinous tumors of the ovary

Fifty-three stage I borderline mucinous tumors of the ovary were placed into four histologic grades according to a simple system of grading based on degree of cell layering, nuclear characteristics, and mitotic count. Three patients died of recurrence and spread of their tumors. All three patients had grade 4 tumors, suggesting that there may be some prognostic value in grading borderline mucinous ovarian tumors.     

Endocervical-like mucinous borderline tumors of the ovary: clinicopathological features and electron microscopic findings

Endocervical-like mucinous borderline tumor (EMBT) is a distinct entity of the ovary that seems to be underrecognized. It occurs with relatively high frequency in Japanese women. Compared with intestinal-type mucinous borderline tumor (IMBT), more frequent bilateral occurrence, paucilocular cysts, association with endometriosis, absence of pseudomyxoma but possible association of peritoneal implants and lymph node metastases, and lower mortality rate are the characteristic features. Histologically, it consists of a mixture of two types of epithelium, tall columnar mucinous cells and stratified eosinophilic cells. Electron microscopy revealed that they were endocervical glandlike mucinous cells and ciliated columnar epithelium reminiscent of the fallopian tube. As the mixture of EMBT and serous borderline tumor (seromucinous borderline tumor) occurs, these findings may show that the tumor shows MÜllerian origin with two-way differentiation, or differentiation toward endocervical glands with metaplastic features as seen in reactive endocervical lesions.     

Expression of the pro-opiomelanocortin gene in lung neuroendocrine tumours: In situ hybridization and immunohistochemical studies

Neuroendocrine tumours of the lung may be associated with the ectopic adrenocorticotrophin (ACTH) syndrome and may synthesize and secrete ACTH-related peptides in the absence of the syndrome. However, immunocytochemical analysis may not confirm these biochemical findings, particularly in small cell carcinoma, which is poorly granulated. To investigate further the morphological evidence for expression of the pro-opiomelanocortin (POMC) gene in neuroendocrine lung tumours, we have examined a series of 46 small cell carcinomas and 13 carcinoid tumours of the lung by in situ hybridization for POMC mRNA using a digoxigenin-labelled oligoprobe. We have compared the findings with the immunocytochemical detection of ACTH and β-endorphin. In situ hybridization was positive in 15 of 46 small cell carcinomas (33 per cent) and in 8 of 13 carcinoid tumours (62 per cent). Immunocytochemical staining was positive in only one carcinoid tumour. These in situ hybridization studies have corroborated biochemical data indicating POMC gene expression in a high proportion of lung neuroendocrine tumours. This suggests that the low levels of expression detected by immunocytochemistry may be due to low levels of hormone storage. Multivariate analysis showed a weak negative association between POMC expression and survival in small cell carcinomas, although this did not reach statistical significance.     

Ovarian borderline tumours: a review with comparison of serous and mucinous types

Ovarian borderline tumours are relatively uncommon but not rare neoplasms. A large majority are of serous or mucinous type with other morphological variants being much more uncommon. In this review, the clinicopathological features of ovarian borderline tumours are discussed, concentrating on serous and mucinous neoplasms. Other morphological types are briefly discussed. A comparison is made between serous and mucinous borderline tumours which exhibit marked differences with regards to incidence of bilaterality, surface involvement, extraovarian spread, lymph node involvement, risk of malignant progression and prognosis. It has been suggested that the category of borderline tumour be abandoned for both serous and mucinous neoplasms but this terminology is useful for both types but for different reasons, namely the significant risk of extraovarian disease in serous borderline tumours and the large size and heterogeneity of mucinous borderline tumours which can result in an invasive focus being undetected by the pathologist.     

Tropoelastin gene expression in the developing vascular system of the chicken: an in situ hybridization study

Temporal and spatial patterns in the accumulation of Tropoelastin (TE) mRNA during development of the chick embryo were established by in situ hybridization. Radiolabeled oligonucleotide probes of high specific activity were hybridized to serial sections of the cardiovascular system from embryonic day 3.5 (ED 3.5) to ED 19. Tropoelastin mRNA was observed as early as ED 3.5 in the dorsal part of the arterial trunk. During septation varying levels of TE mRNA were seen in the pulmonary trunk, the aorta and the aorticopulmonary septum. Thereafter TE mRNA levels increased up to ED 12, and the appearance of message was distributed distally in the walls of developing arteries. From ED 4.5 on, we found a decreasing proximo-distal gradient of the hybridization signal along the trunks and later along the main arteries (longitudinal gradient), and a radial gradient through the arterial vessel wall with the highest levels of TE mRNA in the outer layers of the media. Both gradients persisted in all major arterial vessels except in the proximal systemic and pulmonary trunks, where the original radial gradient was inverted or locally bimodal during the second half of development. The valvular region of aortic and pulmonary trunks showed particularly striking patterns of TE mRNA distribution, notably a prominent label on the endothelial cell layer on aortic and pulmonary valves. Outside the cardiovascular system, TE mRNA was mainly present in prochondral or perichondral cells in trachea and growing skeleton, and in the gap of growing joints. In kidney or nephric primordia, TE mRNA was only detectable in the wall of renal arteries. A hybridization signal was observed on mesenchyme of pulmonary septae at ED 16. Our results suggest a complex regulation of elastin gene expression during development, particularly within the proximal regions of the large arterial vessels.     

Ovarian borderline tumours and carcinomas: an update

In the 5^th edition of the World Health Organization (WHO) Classification of Female Genital Tumours, published in 2020, the emphasis on accurate diagnosis of ovarian borderline tumours and carcinomas based on cell type (histotype) continues. The different histotypes of ovarian epithelial tumours are not just morphological variants of the same disease but are different diseases, associated with critically important differences in precursor lesions, risk factors, patterns of spread, molecular pathology and response to treatment. Thus accurate histopathological diagnosis remains the cornerstone of patient care. This review provides an overview of recent advances in our understanding of this important family of tumours and provides guidance on how to translate this information into practice.     

High frequency of beta-catenin mutations in borderline endometrioid tumours of the ovary

Some low-grade endometrioid carcinomas arise from a background of endometrioid tumours of borderline malignancy. To determine the molecular mechanisms involved in the initiation of endometrioid carcinoma, the present study investigated whether the genetic alterations reported in these tumours (mutations in PTEN, KRAS, and beta-catenin genes, and microsatellite instability) are already present in endometrioid tumours of borderline malignancy. Eight endometrioid tumours of borderline malignancy were studied. By immunohistochemistry, beta-catenin was expressed in the nuclei of all tumours, suggesting the presence of stabilizing beta-catenin mutations. By mutational analysis, five different beta-catenin mutations were found in seven of eight cases (90%), affecting codons 32, 33, and 37. In contrast, only one tumour harboured a PTEN mutation, which affected codon 130. Neither KRAS mutations nor microsatellite instability was detected. A review of the literature indicated that beta-catenin mutations are characteristic of well-differentiated endometrioid carcinomas, since they were present in nearly 60% of grade I but in less of 3% of grade III tumours. In conclusion, the present study identifies beta-catenin mutation as a nearly constant molecular alteration in borderline endometrioid tumours, whereas PTEN and KRAS mutations and microsatellite instability are very infrequent. The findings in the present study, and previously reported data, strongly suggest that beta-catenin mutation is an early event in endometrioid ovarian carcinogenesis, and that it is involved in the development of low-grade endometrioid tumours.