Epithelial mucosubstances and argyrophil cells in Brenner tumours

Brenner tumours of various degree of malignancy were investigated by histochemical methods. The cells lining the cystic cavities in the benign Brenner tumours contained various amounts of PAS-positive, diastase resistant secretory material mixed with small amounts of sulpho- and carboxymucin. The borderline and malignant tumours contained more acidic mucins than the benign tumours. All tumours contained glycogen. Argyrophil and argentaffin cells have not earlier been detected in the Brenner tumours but in this study they were detected in twelve of the 18 Brenner tumours. These cells were not proliferating and therefore Brenner tumour should not be included in the group of APUDomas.     

Proliferating Brenner tumour of ovary--a case report

Transitional cell tumours or Brenner tumours of ovary are uncommon neoplasms. Out of all the Brenner tumours less than 2% are either proliferating or malignant type. Borderline or malignant tumours occur in women who are on an average 10 years older than those with benign tumours. It is essential to categorise these tumours as benign, borderline or malignant type as the biologic behaviour and choice of surgery differs in all of the three categories. The gross and microscopic findings of a proliferating brenner tumour are reported here.     

Differential diagnosis, prognostic factors, and clinical treatment of proliferative Brenner tumor of the ovary

Brenner tumors are rare ovarian tumors displaying benign, borderline or proliferative, and malignant variants. The case of a 63-year-old woman with a proliferative Brenner tumor is presented and the histomorphological differential diagnosis of this tumor entity is compared to that of its benign and malignant counterparts. Light microscopy, immunohistochemistry, and electron microscopy were performed to allow discrimination from the other subtypes. Despite a considerable overlap of pathological features the differential diagnosis of proliferative Brenner tumor could be established. Electron microscopy allowed assessment of characteristic infoldings of the nuclear membrane that proved to be a valuable ultrastructural criterion. Considering that the vast majority of Brenner tumors are benign, precise identification of the small proportion of malignant tumors allows the extent of surgical therapy to be adapted.     

Differential Diagnosis,Prognostic Factors,and Clinical Treatment of Proliferative Brenner Tumor of the Ovary

Brenner tumors are rare ovarian tumors displaying benign, borderline or proliferative, and malignant variants. The case of a 63-year-old woman with a proliferative Brenner tumor is presented and the histomorphological differential diagnosis of this tumor entity is compared to that of its benign and malignant counterparts. Light microscopy, immunohistochemistry, and electron microscopy were performed to allow discrimination from the other subtypes. Despite a considerable overlap of pathological features the differential diagnosis of proliferative Brenner tumor could be established. Electron microscopy allowed assessment of characteristic infoldings of the nuclear membrane that proved to be a valuable ultrastructural criterion. Considering that the vast majority of Brenner tumors are benign, precise identification of the small proportion of malignant tumors allows the extent of surgical therapy to be adapted.     

p63 expression in ovarian tumours: a marker for Brenner tumours but not transitional cell carcinomas

AIMS: To investigate p63 expression in ovarian neoplasms. METHODS AND RESULTS: Immunohistochemistry using an antibody that detects all p63 isoforms was performed on 103 primary ovarian neoplasms of different histological types. Diffuse nuclear immunoreactivity of p63 was demonstrated in the 17 benign and five borderline Brenner tumours. Only one of the six malignant Brenner tumours displayed p63 expression. p63 immunoreactivity was absent in all the ovarian transitional cell carcinomas (TCC), but was demonstrated extensively in TCCs of the urinary bladder. Besides focal p63 expression in epidermal basal cells of immature and mature teratomas, all other ovarian lesions were devoid of p63 expression. p63 expression was also demonstrated in cervical transitional cell metaplasia and Walthard cell nests of fallopian tubes. CONCLUSIONS: Expression of p63 protein is apparently cell lineage specific and in ovarian neoplasms is confined to benign and borderline Brenner tumours. The loss of expression in malignant Benner tumours suggests a role for p63 in Brenner carcinogenesis. The distinct patterns of p63 expression in TCCs in the ovary and urinary bladder may help in their differential diagnosis.     

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.     

Mucin gene transcripts in benign and borderline mucinous tumours of the ovary: an in situ hybridization study

Mucinous tumours of the ovary are characterized by mucin-secreting cells exhibiting a variable endocervical, intestinal, gastric or pancreatobiliary phenotype as ascertained by microscopy, electron microscopy, histochemistry or immunohistochemistry. The molecular mechanisms underlying the tumourigenesis process are not well understood. The mucin glycoproteins expressed by ovarian mucinous tumours have not been fully characterized, but mucins are known to be implicated in tumour progression in various epithelial neoplasms. The purpose of this study was to evaluate the expression of mucin genes (MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC6) in ovarian mucinous tumour cells, to relate MUC gene expression to the histological diagnosis, and to compare the expression patterns with those observed in normal tissues. The expression of mucin genes was evaluated by in situ hybridization in 21 mucinous tumours (11 adenomas and ten borderline tumours). Heterogeneity of expression correlated with morphological heterogeneity. Intense expression of the MUC5AC gene, suggesting a gastric surface cell phenotype, was demonstrated in 18/21 tumours (86%). Goblet cells expressing the MUC2 gene and columnar cells expressing the MUC3 gene were consistent with an intestinal phenotype, which was observed in 15 tumours (71%) including nine adenomas and six borderline tumours. Major expression of MUC4 and MUC5B consistent with an endocervical phenotype was observed in seven benign (64%) and three borderline (30%) tumours. In all, the MUC profiles suggested gastrointestinal-type cells in 13 cases (62%), gastric-type cells in five cases (24%), and intestinal-type cells in two cases (one benign, one borderline) (9%); the results were inconclusive in one borderline tumour (5%). It is concluded that gastric and, to a lesser degree, intestinal differentiation are early and almost constant events in ovarian mucinous tumourigenesis.     

Hyaline globules in ovarian tumours

Hyaline eosinophilic globules have so far been described in a restricted variety of tumour types. We have noted their presence in a variety of gynaecological malignancies, in particular mixed Müllerian tumours and other epithelial ovarian tumours. We therefore studied their incidence and distribution in a series of malignant, borderline and benign epithelial ovarian tumours, and endometrial and endocervical adenocarcinomas. Hyaline eosinophilic globules were found in all 30 mixed Müllerian tumours from various sites in the female genital tract, 22 of 30 clear cell carcinomas, seven of 30 serous, two of 30 mucinous, and one of 30 endometrioid carcinomas examined, and were also seen in metastases from these tumours. They were present in only two of 25 borderline serous, one of 25 borderline mucinous tumours, and in four of 50 benign serous and one of 50 benign mucinous tumours. The globules were not found in any of 25 Brenner tumours examined, nor in 30 endometrial or 30 endocervical adenocarcinomas. The globules were periodic acid–Schiff positive after diastase, stained positively with PTAH, and were immunoreactive for α-1-antitrypsin. This study therefore demonstrates that eosinophilic globules are not specific for any particular tumour. However, their frequency in malignant mixed Müllerian tumours suggests that this diagnosis should be carefully excluded whenever these globules are present in epithelial tumours of the female genital tract.     

Neurosecretory cells of the lamina propria of the appendix and their possible relationship to carcinoids

Carcinoid tumours of the appendix are generally thought to be derived from enterochromaffin cells; in-situ abnormalities of these cells are, however, rarely observed in the mucosal epithelium. One hundred appendices, removed consecutively at surgery, were stained with an alcian blue-PAS diastase-lead haematoxylin sequence and, in 69, cells were found in the lamina propria with a cellular and architectural morphology identical to those of an archetypal appendiceal carcinoid tumour. These cells appeared to contain neurosecretory granules, were diazo-positive and showed argentaffinity. They were further characterized by the localization of cytoplasmic neurone specific enolase and the presence of neurosecretory granules was confirmed by electron microscopy. These cells are designated subepithelial neurosecretory cells (SNC). It is suggested they are an integral component of the subepithelial nervous plexus and are the progenitors of appendiceal carcinoid tumours. A neuroectodermal origin of the SNC—and hence appendiceal carcinoid tumours—is proposed.     

Expression of BRCA1 protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and allelic loss of the BRCA1 gene

BRCA1 is a putative tumour suppressor gene responsible for a hereditary ovarian cancer syndrome. To clarify the possible involvement of BRCA1 in the development of sporadic ovarian neoplasms, this study analysed the immunohistochemical expression of BRCA1 protein in normal ovarian surface epithelium and 119 epithelial ovarian tumours (19 benign, 24 borderline, and 76 malignant tumours). Loss of heterozygosity (LOH) of BRCA1 was examined using three microsatellite markers to analyse the relationship between BRCA1 expression and alterations of the BRCA1 gene. Methylation of the BRCA1 promoter was also analysed by methylation-specific PCR. In ovarian carcinomas showing heterogeneous expression of BRCA1 protein in the same tumour, LOH and methylation status were analysed using microdissection techniques. Finally, the relationship of BRCA1 expression or its genetic alteration to clinicopathological parameters and patient survival was analysed. Ovarian surface epithelial cells expressed BRCA1 protein. Decreased expression of BRCA1 was found in 16% of benign tumours, 38% of borderline tumours, and 72% of carcinomas. LOH of BRCA1 was demonstrated in no benign tumours, 15% of borderline tumours, and 66% of carcinomas. Methylation of BRCA1 was not detected in benign or borderline tumours, but was present in 31% of carcinomas. Reduced expression of BRCA1 correlated with the presence of gene methylation. The frequency of BRCA1 methylation and LOH was higher in serous carcinomas than in other types. In one of the three serous carcinomas that showed heterogeneous expression of BRCA1, BRCA1-positive borderline-like tumour cells were LOH-positive and methylation-negative, whereas adjacent BRCA1-negative carcinoma cells were LOH-positive and methylation-positive. The prognosis of carcinoma patients did not correlate with BRCA1 expression or genetic status. These findings suggest that reduced expression of BRCA1 protein along with genetic and epigenetic changes of the BRCA1 gene play an important role in the development of sporadic ovarian carcinomas, particularly those of serous histology.     

Metallothionein expression and nuclear size in benign,borderline, and malignant serous ovarian tumours

Metallothioneins (MTs) are low-molecular-weight proteins involved in metalloregulatory functions such as cell proliferation, growth, and differentiation. In recent years, MT expression has been linked with carcinogenesis, resistance to cancer therapy, and tumour progression. However, the significance of MT expression in ovarian cancers is at present inadequately documented. In this study, MT immunohistochemistry was performed in 12 benign, 14 borderline, and eight malignant serous tumours of the ovary. The intensity of the immunostaining was evaluated by image analysis. There was a significantly higher number of MT-immunopositive cells in the multilayered epithelial cells of borderline serous tumours (atypical proliferative serous tumours) than in the single layered epithelial cells within the same tumour, and in the single cell layer of benign serous tumours. There was no difference in the expression of MTs in the single layered tumour cells of benign and borderline serous tumours. Significantly higher numbers of MT-immunopositive cells were observed in both the single and the multilayered epithelial cells of serous carcinomas, the highest number being observed in the multiple layers of serous carcinomas. The positively stained malignant tumour cells in both single and multiple layers were larger than the negatively stained cells in benign, borderline, and malignant serous ovarian tumours. There was moderate to intense staining. These findings indicate that there is increased expression of MTs in the progression of malignancy, which could be used as a marker in grading the three groups of ovarian serous tumours and for determining prognosis. Copyright © 1999 John Wiley & Sons, Ltd.     

A pulmonary mucinous cystic tumour of borderline malignancy

We report a well-documented case of pulmonary mucinous cystic tumour of borderline malignancy involving the left lower lobe. The lesion was found incidentally by chest radiograph and CT scan with a provisional diagnosis of bronchioloalveolar carcinoma. The tumour was 4 cm in its greatest dimension, cystic and filled with gelatinous mucus. Microscopically, the neoplastic mucinous epithelium was composed of cuboidal cells with focally nuclear stratification and mild to moderate nuclear atypia. The patient has remained free from recurrence or metastases for 6 years. Pulmonary mucinous cystic tumour of borderline malignancy is a rare, recently described neoplasm, which spans a spectrum of tumours with malignant potential. The recent World Health Organization classification of lung tumours does not recognize this entity, which has a very good prognosis, and as such should be distinguished from classic pulmonary adenocarcinoma. Histological diagnosis can be difficult to distinguish from cystic bronchioloalveolar carcinoma or metastatic mucinous adenocarcinoma.     

Neurohormonal peptide immunoreactive cells in mucinous cystadenomas and cystadenocarcinomas of the ovary

Summary In 144 benign mucinous cystadenomas of the ovary, 33 mucinous cystadenomas of borderline malignancy and 64 mucinous cystadenocarcinomas, the incidence of tumours containing argyrophil (and probably endocrine) cells was 18%, 33%, and 53%, respectively. The results of a semiquantitative assessment of the number of argyrophil cells in each individual tumour indicates that the greatest numbers occurred in the cystadenocarcinomas. As, however, the tumour cell density was larger in the cystadenocarcinomas than in the cystadenomas, and as the argyrophil cells often had a patchy distribution in the tumour epithelium, the incidence figures are unreliable. In addition, visualization of the argyrophil cells depends on an adequate fixation which is difficult to achieve in the routine processing of large tumour specimens.Many argyrophil cells in the cystadenocarcinomas displayed immunoreactivity with antisera raised against gastro-entero-pancreatic (GEP) neurohormonal peptides. In ten such tumours immunohistochemical evidence was obtained for the presence of the following neurohormonal peptides in the tumour cells: somatostatin, glucagon, gastrin/CCK, neurotensin, and enkephalin. Four of these ten cystadenocarcinomas were multihormonal, in that three contained two cell populations storing GEP neurohormonal peptides, and one tumour even three such populations. In the benign cystadenomas, however, no immunoreactive tumour cells were found. In those of borderline type, only two harboured immunoreactive cells. In both cases the tumour cells stored gastrin/CCK.The general appearance of the epithelium in the mucinous tumours — a continuous single-cell layer of mucin-producing cells intermingled with argyrophil cells of open type — and the spectrum of neurohormonal peptides observed, indicate an origin from the foregut endoderm.This investigation was supported by grants from the Swedish Medical Research Council (Projects No. 4X-4499 and 12X-718), the Swedish Cancer Society (Project No. 805), the Cancer Research Fund of Malmö General Hospital, and the Medical Faculty at the University of Lund     

Expression of a homeobox gene (SIX5) in borderline ovarian tumours

AIMS: To assess the expression of SIX5 (a homeobox gene) mRNA in surface coelomic epithelium, endocervical epithelium, Fallopian tube epithelium, and benign, borderline, and malignant epithelial ovarian tumours. METHODS: 10 normal premenopausal ovaries, 10 normal Fallopian tubes, 10 normal cervices, 10 normal postmenopausal ovaries, 10 benign epithelial ovarian tumours, 10 malignant epithelial ovarian tumours, and 40 borderline epithelial ovarian tumours were studied retrospectively. The tissues had been fixed in formalin and embedded in paraffin wax. The tumours had previously been typed into mucinous, serous, or mixed tumours and assigned to the borderline category according to the FIGO/WHO criteria. Expression was assessed by in situ binding of SIX5 specific sense and antisense riboprobes. Hybridization of the riboprobes was detected using a standard immunohistochemical technique and the results correlated with expression in the normal epithelium of the endocervix, Fallopian tube, surface coelomic epithelium, and ovarian tumours. RESULTS: Expression of SIX5 mRNA was demonstrated in normal Fallopian tube epithelium and normal endocervical epithelium. SIX5 mRNA was not detected in normal ovarian epithelial tissue at any of the times studied during the menstrual cycle. Expression of SIX5 was not shown in benign epithelial ovarian tumours or in any of the malignant epithelial ovarian tumours. In 31 of 37 borderline epithelial ovarian tumours (84%), SIX5 expression was found in the epithelial cells. CONCLUSIONS: SIX5 expression is present in the normal epithelium throughout most of the female reproductive tract, suggesting it may have a role in maintaining epithelial differentiation in these tissues. SIX5 expression appears to be restricted to borderline epithelial ovarian tumours and may be a marker of epithelial differentiation in these tumours; thus borderline ovarian tumours may not be part of a continuum of disease between benign and malignant epithelial ovarian tumours. Further investigation of expression of SIX5 may clarify the molecular processes that promote differentiation of the ovarian surface epithelium.     

Primary retroperitoneal mucinous cystadenocarcinoma in a male patient

Primary retroperitoneal mucinous cystadenocarcinomas (PRMCs) are rare. This is the first reported case in the literature in English of PRMC in a man. The 64-year-old man presented with a large retroperitoneal cystic tumour measuring 24 x 20 x 16 cm3, which was removed intact. Areas ranging from a benign mucinous cyst to borderline mucinous tumour to mucinous cystadenocarcinoma were observed on microscopy. Strong patchy staining for cytokeratins 7 and 20 and strong diffuse staining for MUC2 and MUC5AC core peptides, similar to staining patterns in ovarian mucinous tumours, were shown in the benign and atypical epithelium. Staining for CA19.9 and carcinoembryonic antigen was also shown by both components. The theory of its origin from the mucinous metaplasia of peritoneal (mesothelial) inclusion cysts, rather than from ectopic ovarian tissue or ovarian teratomas, is supported by the occurrence of such a tumour in a male patient.     

Malignant transformation of mucinous ovarian cystadenomas of intestinal epithelial type

We studied 116 benign and 18 borderline malignant mucinous ovarian cystadenomas. Their epithelial lining was compared with normal epithelium of the uterine cervix and that of the small and large intestines, by both light and electron microscopy as well as histochemically. This morphological and histochemical analysis enabled us to subdivide mucinous cystadenomas into cervical, mixed and intestinal epithelial types. The epithelial cells of intestinal type tumours exhibited histochemical reactions very similar to, or identical with, those found in both immature and mature cells of intestinal mucosa. Malignant transformation was found in intestinal type mucinous cystadenomas only. Ultrastructural investigations of six neoplasms (four of intestinal and two of cervical epithelium type) confirmed the results found with the light microscope.     

Clonality analysis of combined Brenner and mucinous tumours of the ovary reveals their monoclonal origin

The derivation of ovarian intestinal‐type mucinous tumours is not well established. Some are derived from teratomas but the origin of the majority is not clear. It has been recently proposed that the non‐germ cell group may be derived from Brenner tumours, as the association of a mucinous tumour with a Brenner tumour is frequently observed. In order to explore the histogenesis of these neoplasms, we undertook a clonality analysis of the two components of ten combined Brenner and mucinous tumours using a human androgen receptor gene (HUMARA) assay. All eight informative cases of ten showed a concordant X‐chromosome inactivation pattern between the two tumour components, indicative of a shared clonal origin (p = 0.0039). Microsatellite genotyping in five of the combined tumours displayed an identical heterozygous pattern with paired Fallopian tube tissue, indicative of a somatic cell origin. In addition, paired box protein 8, a highly sensitive Müllerian epithelial marker, was not detected by immunohistochemistry in either tumour component in any of the ten tumours, suggesting that this subset of mucinous tumours does not originate from Müllerian‐derived epithelium. In conclusion, this study demonstrates that in combined mucinous and Brenner tumours, there is a shared clonal relationship between the two different tumour components and suggests that some pure mucinous tumours may develop from a Brenner tumour in which the Brenner tumour component becomes compressed and obliterated by an expanding mucinous neoplasm. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Unusual presentation of benign cystic brenner tumor with exuberant psammomatous calcifications

Transitional cell tumors of the ovary comprise about 1% to 2% of all ovarian neoplasms. Most of these tumors are benign Brenner tumors and account for about 5% of benign surface epithelial-stromal tumors. Spicules of calcifications are found in the stroma of about 50% of benign Brenner tumors. Although diagnostic challenges might occur more frequently with either of the borderline or malignant Brenner tumors, this problem is not that common when diagnosing a benign Brenner tumor. This study reports a case of benign Brenner tumor with exuberant dystrophic calcifications that obscured most of the epithelium and posed a diagnostic challenge in differentiating it from the more common malignant counterparts such as serous carcinoma and specifically psammocarcinoma.     

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.