Immunohistochemical study of amylase in common epithelial tumors of the ovary

Cellular localization of amylase in various ovarian tumors was studied by the immunoperoxidase method using an antibody to human pancreatic amylase. Amylase was present in eight of 34 serous carcinomas and eight of 27 endometrioid carcinomas. However, only in one poorly differentiated serous carcinoma and two well-differentiated endometrioid carcinomas were a large number of amylase-reactive cells found. Five benign and three borderline serous tumors contained no amylase. Also, amylase was not detected in any of 34 mucinous tumors or five malignant clear cell tumors. The results obtained suggest that amylase will be a useful tumor marker, when present, for follow-up of endometrioid and serous carcinomas of the ovary.     

Carcinoembryonic antigen (CEA) and carbohydrate determinant 19-9 (CA 19-9) localization in 121 primary and metastatic ovarian tumors: an immunohistochemical study with the use of monoclonal antibodies

An immunoperoxidase study, using the Avidin-Biotin-Peroxidase complex method and the monoclonal antibodies, anti-carcinoembryonic antigen (CEA) and anti-carbohydrate determinant 19-9 (CA 19-9), was carried out on 108 common epithelial tumors of the ovary and 13 epithelial tumors metastatic to the ovary. Primary mucinous tumors were positive in 62% of the cases (benign, 15%; borderline, 80%; and carcinomatous, 100%) with anti-CEA. None of the serous tumors were positive with anti-CEA, but 27% (benign, 23%; borderline, 40%; and carcinomatous, 20%) were positive with anti-CA 19-9. With anti-CEA, 30% of the endometrioid carcinomas, 50% of the malignant mesodermal mixed tumors, 14% of the clear cell carcinomas, 36% of the Brenner tumors, and 83% of the metastatic carcinomas from the large intestine were positive. With anti-CA 19-9, 76% of the mucinous, 40% of the endometrioid, 25% of the malignant mesodermal mixed tumors, 57% of the clear cell carcinomas, 45% of the Brenner tumors, and all the metastatic carcinomas from the large intestine were positive. All the undifferentiated carcinomas were unreactive with both antibodies. Although neither CEA nor CA 19-9 is a specific marker for any type of ovarian tumor or for malignancy per se, the presence of the former antigen can be useful in differentiating serous from mucinous tumors. Moreover, demonstration of either antigen in a variety of tumors may indicate its potential value as a serum marker in monitoring the course of the patient.     

Subclassification of ovarian surface epithelial tumors based on correlation of histologic and molecular pathologic data.

Surface epithelial tumors are a large and heterogeneous group of neoplasms that are subclassified based on cell type and malignant potential. The objective of this review is to examine the correlations between recent molecular pathology data and the traditional histopathologic classification of surface epithelial tumors. By doing so, 6 distinct subsets of ovarian epithelial neoplasia can be identified with potential treatment implications 1. high-grade serous, high-grade endometrioid, and undifferentiated carcinomas; 2. low-grade serous carcinomas and serous borderline tumors; 3. mucinous carcinomas and mucinous borderline tumors of intestinal type; 4. low-grade endometrioid carcinomas and endometrioid borderline tumors; 5. clear cell carcinomas; and 6. transitional cell carcinomas.     

B7-H4 overexpression in ovarian tumors

OBJECTIVES: Despite great advances in therapeutic management, the mortality rate for ovarian cancer has remained relatively stable over the past 50 years. This study was designed to evaluate the expression of B7-H4 protein, recently identified as a potential molecular marker of breast and ovarian cancer by quantitative PCR analysis, in benign tumors, tumors of low malignant potential and malignant tumors of the ovary. METHODS: Archival formalin-fixed tissue blocks from serous, mucinous, endometrioid and clear cell ovarian tumors were evaluated by immunohistochemistry for the distribution of B7-H4 expression, and staining intensity was measured by automated image analysis. Univariate analyses were used to test for statistically significant relationships. RESULTS: B7-H4 cytoplasmic and membranous expression was detected in all primary serous (n = 32), endometrioid (n = 12), and clear cell carcinomas (n = 15), and in all metastatic serous (n = 23) and endometrioid (n = 7) ovarian carcinomas. By contrast, focal B7-H4 expression was detected in only 1/11 mucinous carcinomas. The proportion of positive cells and median staining intensity was greater in serous carcinomas than in serous cystadenomas or serous tumors of low malignant potential, and the differences were statistically significant (P < 0.0001 and P = 0.034, respectively). The median staining intensity was also significantly greater in endometrioid carcinomas than in endometriosis (P = 0.005). CONCLUSIONS: The consistent overexpression of B7-H4 in serous, endometrioid and clear cell ovarian carcinomas and the relative absence of expression in most normal somatic tissues indicates that B7-H4 should be further investigated as a potential diagnostic marker or therapeutic target for ovarian cancer.     

WT1 is differentially expressed in serous, endometrioid, clear cell, and mucinous carcinomas of the peritoneum, fallopian tube, ovary, and endometrium.

The Wilms' tumor gene WT1 plays complex roles in the development of the organs of the genitourinary tract and mesothelium, as well as Wilms' tumors. Although its biologic role is still unclear, most serous carcinomas of the ovary and peritoneum, mesotheliomas, and Wilms' tumor have been shown to express WT1. A recent study, however, found no WT1 expression in serous carcinomas of the endometrium, suggesting that WT1 could be useful in identifying the primary site of serous carcinomas. We examined the expression of WT1 and p53 by immunohistochemistry in 69 cases of endometrial carcinoma (35 endometrioid, 18 clear cell, 16 serous), 68 cases of ovarian carcinoma (28 serous, 11 endometrioid, 18 clear cell, and 11 mucinous), 14 fallopian tube carcinomas (12 serous, 2 endometrioid), and 20 primary peritoneal serous carcinomas. WT1 nuclear reactivity of any extent and intensity was considered positive. Immunohistochemical stains were evaluated semiquantitatively using a four-tiered scale. Among endometrial carcinomas, WT1 immunoreactivity was seen in 10 of 16 serous, but in none of 35 endometrioid or 18 clear cell carcinomas. Among ovarian tumors, WT1 expression was seen in 24 of 28 serous and 4 of 18 clear cell carcinomas, but in none of 11 endometrioid and 11 mucinous tumors. All 12 serous carcinomas but none of 2 endometrioid carcinomas of the fallopian tube were positive for WT1. WT1 expression was seen in 19 of 20 serous primary peritoneal carcinomas. The difference in WT1 expression was highly significant between serous and other types of tumors in all sites (p<0.0001, chi-square test), although the level of WT1 expression was significantly different among serous carcinomas arising at different sites (p<0.0001, Kruskal-Wallis test). A significant positive correlation was found between the level of p53 and WT1 expression in all carcinomas combined (r = 0.3935, p<0.0001, Spearman test), but when only serous carcinomas were analyzed, the correlation between p53 and WT1 expression levels did not reach statistical significance. Our results suggest that WT1 expression in epithelial tumors of the female genital tract may be related to cell differentiation and histologic subtypes of carcinomas, rather than to primary site of origin.     

Tumor markers of epithelial ovarian neoplasms

Ninety-three formalin-fixed, paraffin-embedded surgical specimens from 69 ovarian tumors representing all five epithelial cell types were studied by immunohistochemistry, peanut and ulex lectin binding, and carbohydrate histochemistry. Carcinoembryonic antigen (CEA) was mostly noticeable in mucinous tumors (21 of 26). Glycogen was highly prevalent in clear cell (8 of 9) and endometrioid (4 of 6) carcinomas, in contrast to serous carcinomas (3 of 6), where it was only focally distributed, and was completely absent in all mucinous tumors. Among the different types of malignant tumors examined, mucinous carcinomas most frequently contained neutral mucins (6 of 8). In mucinous tumors, an increase in CEA content and a decrease in the total mucin secretion, particularly the strongly acidic sulfated group, were found to parallel the increased malignant potential of the tumor. Peanut and/or ulex lectin binding was a feature common to almost all epithelial neoplasms. Although peanut lectin showed a slightly higher affinity to serous and clear cell tumors, while ulex lectin was bound more to mucinous and endometrioid neoplasms, distribution of D-galactose and L-fucose does not have a diagnostic utility in these tumors. Placental lactogen was detected in 3 of 17 benign tumors and one of 19 tumors of low malignant potential (LMP). The beta subunit of hCG was found in one of 17 benign tumors, in 2 of 19 LMP tumors, and in 3 of 31 carcinomas.     

卵巢浆液性癌B7-H4的表达及临床病理意义

目的:探讨B7-H4在卵巢上皮性肿瘤浆液性癌中的表达及其临床病理意义。方法:用逆转录聚合酶链反应(RT-PCR)技术及免疫组织化学染色的方法检测6例良性卵巢上皮性肿瘤、10例交界性卵巢上皮性肿瘤、41例卵巢浆液性癌、5例内膜样癌、2例透明细胞癌和10例粘液性癌标本中B7-H4 mRNA及蛋白表达,并结合临床病理资料对其中41例卵巢浆液性癌中B7-H4蛋白的表达进行分析。结果:B7-H4 mRNA在74例卵巢上皮性肿瘤中均有表达,B7-H4蛋白在良性卵巢上皮性肿瘤、交界性卵巢上皮性肿瘤、恶性卵巢上皮性肿瘤中的表达阳性比例分别为2/6、6/10、52/58,恶性标本阳性率明显高于非恶性标本,差异有统计学意义(P<0.05);58例恶性卵巢上皮性癌标本中浆液性癌、内膜样癌、透明细胞癌、黏液性癌的B7-H4蛋白阳性比例分别为41/41、5/5、2/2、4/10,前三种病理类型B7-H4蛋白阳性率明显高于最后一种,且差异有统计学意义(P<0.05);41例卵巢浆液性癌标本中B7-H4蛋白阳性细胞比例在<10%,>10%~50%,>50~80%,>80~100%4组中的分布差异无显著性(P>0.05),且其蛋白表达与临床分期及病理分级有关(P<0.05),而与患者年龄、腹水细胞学、淋巴结转移无关(P>0.05)。结论:B7-H4在卵巢浆液性癌的高表达及其与临床分级分期的关系,提示其可能与肿瘤发生发展有关,可为卵巢恶性肿瘤诊断及治疗提供靶位点。     

Immunohistochemical localization of metallothionein in benign and malignant epithelial ovarian tumors

Abstract. McCluggage WG, Strand K, Abdulkadir A. Immunohistochemical localization of metallothionein in benign and malignant epithelial ovarian tumors.
Metallothioneins (MTs) are a group of low-molecular-weight proteins that are overexpressed in a variety of human neoplasms and are related to differentiation and prognosis in some tumor types. This study investigated immunohistochemically detectable metallothionein expression in benign and malignant ovarian surface epithelial tumors of serous, mucinous, and endometrioid types. MT expression was observed in 56% of carcinomas ( n = 139) and in 2% of benign neoplasms ( n = 81). Of the malignant tumors, MT expression was found in 68% of endometrioid, 56% of mucinous, and 52% of serous neoplasms. There was increased MT expression in grade 3 carcinomas (64%) as compared with grade 2 (60%) and grade 1 (23%). The overexpression of MT in malignant as opposed to benign ovarian surface epithelial tumors may suggest a role in tumorigenesis. Analogous to the situation in endometrial carcinomas, there is a tendency toward higher expression in poorly differentiated tumors. Whether high MT expression is an independent prognostic factor and increased expression indicates chemotherapy resistance in ovarian cancer, as has been previously suggested, should be determined by further studies.     

Ovarian mucinous and mixed epithelial carcinomas of mullerian (endocervical-like) type: a clinicopathologic analysis of four cases of an uncommon variant associated with endometriosis.

The epithelial cells of ovarian mucinous carcinomas may sometimes appear similar to those of gastrointestinal or endocervical mucinous carcinomas, but most are composed of cells that do not suggest any particular derivation. We report four cases of mucinous ovarian carcinoma in which the cells were entirely or almost entirely endocervical-like. The patients' ages were 34, 43, 44, and 50 years. Two patients had bilateral tumors confined to the ovaries at initial staging; both also had synchronous endometrial carcinomas of the mucinous type. The two other patients had unilateral tumors, both with invasive metastases in the pelvis and abdomen at initial staging. In one of the latter cases a mullerian (endocervical-like) mucinous borderline tumor (MMBT) of the opposite ovary had been removed 5 years earlier, and in this case and two other cases the ovarian carcinomas had foci resembling MMBT, suggesting that they may be an invasive counterpart to these tumors. The six tumors ranged from 4 to 19 cm; five were grossly cystic with papillary or solid areas, and one was entirely solid. They were composed of closely packed glands, cysts, and cysts containing complex papillae. There was abundant intraglandular and intracystic mucin. The epithelial cells were well differentiated with infrequent mitoses and most were tall with mucinous cytoplasm resembling normal endocervical glandular cells. In three tumors there also were round to polygonal cells with eosinophilic cytoplasm; endometrioid foci were present in three tumors and a squamous focus was present in one. One tumor had a focally infiltrative growth pattern with a desmoplastic stromal reaction; the remaining five tumors had an exclusively confluent (expansile) pattern of invasion. Endometriosis was present in residual ovarian tissue adjacent to four tumors in three patients and had marked epithelial proliferation in three. All patients were treated postoperatively with chemotherapy and were without clinical recurrence with follow-up intervals of 8 months, 1.2 years, 2.9 years, and 3.8 years. By immunohistochemical analysis the neoplastic epithelium was positive for estrogen and progesterone receptor proteins, vimentin, and cytokeratin 7, and negative or only focally positive for carcinoembryonic antigen and cytokeratin 20, a profile that differs from that of the usual mucinous ovarian carcinoma and is supportive of a mullerian derivation. As with MMBTs, there was a strong association with endometriosis, and these tumors likely arise from endometriosis, possibly through an MMBT precursor in some cases. To better understand their clinicopathologic features and pathogenesis, this uncommon variant should be separated from the usual type in future studies of mucinous carcinomas of the ovary.     

p63 expression in epithelial ovarian tumors

Ovarian cancer is a highly lethal disease and its underlying biology is poorly understood. The p63 is a homologue gene of the tumor suppressor p53. p63 appears to be important for the development and differentiation of reproductive epithelium and interacts with p53 in human tumorigenesis. This study presents the immunoexpression of the p63 in benign and malignant epithelial ovarian tumors. We evaluated the p63 immunoexpression in 91 ovarian benign cystadenomas (29 mucinous and 62 serous) and in 29 ovarian malignant tumors (3 mucinous borderline, 3 serous borderline, 17 serous carcinomas, 2 endometrioid, 2 undifferentiated, 1 mucinous, and 1 clear-cell carcinoma) using a monoclonal antibody clone 4A4 (1:200), which recognizes all p63 variants. The tumors were considered p63 positive if 5% or more cells presented nuclear immunostaining. We observed 85.7% of positivity in benign tumors, 50% in borderline tumors, and 8.7% in invasive ovarian cancer (P < .0001). The benign serous cystadenomas were positive in 91.9% of cases and benign mucinous cystadenomas in 72.4% (P= .02). These data suggests an important role of p63 in the control of ovarian epithelium behavior. The p63 may be involved in the development of benign and malignant epithelial ovarian tumors.     

Correlation of multiple steroid receptors with histological type and grade in human ovarian cancer

One hundred eight human ovarian cancers were analyzed for estrogen (ER), progestin (PgR), and androgen (AR) receptors. The receptor levels were related to histological type and grade of the tumor. There were 103 common epithelial carcinomas subdivided into serous (36), endometrioid (36), mucinous (18), clear cell (5), malignant Brenner (3), mixed epithelial (2), and undifferentiated (3) types. Of the remaining five, four were sex cord-stromal tumors and there was a single case of germ cell tumor. ER was detected in 52%, PgR in 52%, and AR in 91% of the cases. There was no correlation between the presence of ER and AR and the tumor histology. The presence of PgR correlated with the grade of endometrioid carcinoma, while no clear correlation existed for the other tumor types. PgR was absent in the three undifferentiated carcinomas. Interestingly, high PgR levels were detected in the three granulosa cell tumors.     

Increasing expression of extracellular matrix metalloprotease inducer in ovary tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters.

Ovary cancer invasion is responsible for both local tissue destruction and distant metastasis. Invasion is largely mediated by matrix metalloproteases that are thought to be induced by tumor cell-derived extracellular matrix metalloprotease inducer (EMMPRIN) in surrounding fibroblasts. We hypothesized that EMMPRIN isoverexpressed in ovary tumors. Immunohistochemical analysis of EMMPRIN was performed in tissue microarrays of ovary neoplasms including 84 cases of serous adenocarcinoma, 23 cases of mucinous adenocarcinoma, 10 cases of endometrioid adenocarcinoma, 12 cases of yolk sac tumor, 12 cases of clear cell carcinoma, 8 cases of dysgerminoma, 8 cases of granulosa cell tumor, 6 cases of transitional cell carcinoma, and 6 cases of Brenner tumor. All malignant ovary tumors showed significant immunohistochemical expression of EMMPRIN. The EMMPRIN scores in malignant ovary tumors were significantly higher than their nontumor counterparts (313+/-28 for serous adenocarcinoma; 308+/-25 for mucinous adenocarcinoma; 187+/-19 for endometrioid adenocarcinoma; 265+/-23 for yolk sac tumors; 87+/-13 for clear cellcarcinoma; 126+/-15 for dysgerminoma; 243+/-26 for granulosa cell tumor; 87+/-16 for transitional cell carcinoma). The EMMPRIN score was significantly higher in serous adenocarcinomas than in serous adenomas and serous borderline tumors and was correlated with nodal stage. Our findings show for the first time that EMMPRIN is overexpressed in all malignant ovary tumors.     

Benign and malignant serous and endometrioid epithelium in the omentum.

OBJECTIVES: Benign and malignant serous and endometrioid epithelial proliferations are found in the omentum, where their presence may be interpreted either as metastases from Müllerian tumors elsewhere or as primary peritoneal tumors. The present study was undertaken in an attempt to gather data that might help resolve the issue. METHODS: The ratios of serous epithelium to endometrioid epithelium in the omentum, in both the benign and malignant states, were determined for cases from January 1985 to July 1997 and January 1991 to December 1997, respectively. RESULTS: In ovarian carcinoma, the ratio of malignant serous epithelium to endometrioid epithelium involving the omentum is 15:1. This is comparable to the ratio of benign serous epithelium to endometrioid epithelium in the omentum, which is 10:1. The ratio of primary peritoneal serous carcinoma to endometrioid carcinoma is 10.5:1. CONCLUSION: It seems not reasonable that endometrioid carcinoma of the ovary is 15 times less likely to metastasize to the omentum than its serous counterpart. The ratio, however, is not unreasonable if endometrioid and serous carcinomas arise from preexisting endometrioid or serous epithelium. We conclude that serous and endometrioid carcinomas may arise primarily in the omentum and, in at least some cases, may derive from their benign counterparts.     

Histologic subtypes and laterality of primary epithelial ovarian tumors

OBJECTIVES: To determine if the likelihood of bilateral primary ovarian tumors differs by histologic subtype. METHODS: Using data collected by the Surveillance Epidemiology and End Results (SEER) program, the analysis included 22,328 women 25-84 years of age who were diagnosed with a borderline or malignant epithelial ovarian tumor during 1992-2000, categorized as to laterality and histologic subtype. RESULTS: Malignant serous tumors were bilateral in 57.5% of cases. Corresponding figures for mucinous, clear cell, endometrioid and other epithelial tumors were 21.3%, 13.3%, 26.8%, and 35.6%, respectively. Borderline serous tumors were bilateral in 29.8% of the cases compared to only 7.0% of mucinous tumors. The tendency for serous tumors to present as bilateral was consistent across all categories of race, age, and stage. CONCLUSIONS: Serous tumors of the ovary are more commonly bilateral than ovarian tumors of other histologic subtypes. The reasons for this tendency remain to be determined.     

KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants

OBJECTIVE: Mutations of BRAF, a downstream mediator of K-RAS, have been described in serous borderline tumors of the ovary. Data concerning other types of ovarian tumors are scarce. Therefore, we assessed KRAS and BRAF mutation in a series of more than 100 different ovarian tumors. METHODS: Paraffin-embedded material, including invasive carcinomas, borderline tumors, benign lesions and implants, was used. BRAF codon 600 in exon 15 and K-RAS codon 12 in exon 2 were analysed. RESULTS: 92 cases (92%), including all serous carcinomas (100%), did not show a mutation of BRAF. Eight cases (8.0%), including five serous borderline tumors (31.25%), contained a mutation. In all serous borderline tumors, codon 600 was affected. The remaining three cases were invasive carcinomas of endometrioid (mutation on codon 600), mucinous (mutation on codon 600) and clear cell (mutation on codon 615) subtype. There was no BRAF mutation in mucinous borderline tumors. Regarding K-RAS, 89 cases (87.25%) did not show an aberration. The 11 positive borderline tumors (10.7%) were of serous (22.2%) and of mucinous type (46.6%). There was a KRAS mutation in a serous and a mucinous invasive carcinoma each. BRAF and K-RAS mutations were mutually exclusive and not seen in implants. CONCLUSION: Mutation of either K-RAS or BRAF is frequent in borderline tumors but is not found in invasive serous carcinomas and is very rare in other invasive subtypes. This supports the notion of different pathological pathways. For the development of extraovarian implants, further studies are observed.     

Neutral endopeptidase/CD10 expression in the stroma of epithelial ovarian carcinoma.

This study investigated the immunohistochemical expression and localization of neutral endopeptidase (NEP) (CD10), which plays a functional role by degrading bioactive peptides, in ovarian tumors. In normal ovaries and benign cystadenomas, NEP was not detected in any epithelial or stromal cells. In borderline tumors, NEP was detected in the stromal cells in 6 of 7 serous tumors, but not in those from mucinous tumors. In ovarian carcinomas, NEP in the stromal cells was observed in 13 of 20 serous, 8 of 10 endometrioid, and 7 of 10 clear-cell adenocarcinomas. NEP was weakly detected in only 1 of 9 mucinous adenocarcinomas. The staining intensity of stromal NEP was decreased in grades 2 and 3 serous carcinomas compared with that in grade 1 serous carcinomas. In conclusion, NEP was specifically expressed in the stroma of borderline and malignant ovarian tumors, but not in adenomas. Furthermore, stromal NEP was downregulated as the histological grade advanced. These results suggest that NEP may play a role in the regulation of neoplastic transformation and tumor differentiation in epithelial ovarian carcinomas.     

Mucinous ovarian tumors of Mullerian-type: an analysis of 17 cases including borderline tumors and intraepithelial, microinvasive, and invasive carcinomas.

Mullerian-type mucinous tumors (MMTs) of the ovary are characterized by a papillary architecture similar to that of serous tumors and a content of endocervical-like mucinous epithelium. The latter may be admixed with other mullerian-type epithelia, including those of serous, endometrioid, and squamous types, and indifferent eosinophilic epithelial cells. We analyzed 17 MMTs, including 12 borderline tumors, 2 intraepithelial carcinomas, 2 microinvasive carcinomas, and 1 invasive carcinoma. Fourteen of 16 tumors (88%) with available staging were stage I; the remaining two cases (both borderline) were stage IIa and IIIc. Endometriosis was identified in eight cases (47%). Only two patients (12%) had bilateral tumors, a frequency of bilaterality lower than in previous studies. Five patients (31%) had conservative treatment consisting of a cystectomy or unilateral salpingo-oophorectomy. All patients had a favorable outcome, with no recurrences or disease-related deaths, regardless of the presence of high mitotic index, intraepithelial carcinoma, microinvasion, bilaterality, conservative treatment, or advanced stage. This indolent behavior of MMTs is similar to that previously reported, but additional cases of invasive carcinomas in this category are needed to better define their outcome.     

Immunohistochemical demonstration of pancreatic secretory trypsin inhibitor in gynecologic tumors

Pancreatic secretory trypsin inhibitor (PSTI) is a specific trypsin inhibitor secreted by the acinar cells of the pancreas. Serum levels of immunoreactive PSTI have been reported elevated in patients with various malignancies including gynecologic tumors. The immunohistochemical localization of PSTI is studied in the comparison with argyrophilia and amylase immunoreactivity on 100 ovarian tumors, 35 endometrial carcinomas, and 34 cervical carcinomas. PSTI was noted in 19 of 85 common epithelial tumors of the ovary, being most frequently in mucinous tumors and less in endometrioid, but only occurred in immature pancreatic tissue of 1 of 15 germ cell tumors tested. In the uterus, 5 of 19 adenocarcinomas of the endometrium and 3 of 10 adenocarcinomas of the cervix were positive for PSTI immunoreactivity. PSTI was found more frequently in the tumors with argyrophil cells, especially of type I, but was related to the intestinal metaplasia and exocrine secretion rather than argyrophilia itself, judging from the different localization of PSTI and argyrophilic granules. No relationship was observed between amylase and PSTI immunoreactivity.     

Molecular pathology of epithelial ovarian cancer

Ovarian cancer is the most lethal gynaecological malignancy and it most commonly occurs in postmenopausal women. Ninety per cent of ovarian cancers are derived from the ovarian surface epithelium and these neoplasms are classified into serous, mucinous, endometrioid, clear-cell and transitional-cell types. The molecular pathology of ovarian carcinomas is heterogeneous and involves various putative precursor lesions and multiple pathways of development. The most common subtype, high-grade serous carcinoma, is characterized by p53 mutations, and BRCA1 and/or BRCA2 dysfunction. It most likely arises from epithelium within inclusion cysts or from the surface of the ovary. In contrast, low-grade serous carcinomas are characterized by KRAS or BRAF mutations and appear to arise via an adenoma-borderline-carcinoma sequence. Similarly, mucinous carcinomas have KRAS mutations and probably develop via an adenoma-borderline-carcinoma sequence. Low-grade endometrioid carcinomas, however, are characterized by mutations in PTEN and CTNNB1, and microsatellite instability, and may arise from ovarian endometriosis or borderline endometrioid tumours. High-grade endometrioid carcinomas have similar changes to high-grade serous carcinomas. Clear-cell carcinomas are characterized by mutations of TGFbetaR2 and over-expression of HNF-1beta, and probably arise from ovarian endometriosis. The molecular changes in transitional-cell carcinomas of the ovary remain largely unknown. The identified molecular changes and pathways of development in epithelial ovarian cancer will facilitate the rationalized development of new diagnostic modalities and tailored therapies for this malignancy.     

Immunohistochemical demonstration of HNK-1-defined antigen in gynecologic tumors with argyrophilia

Gynecologic tumors with argyrophilia were tested immunohistochemically for reactivity with monoclonal antibody HNK-1, which detects normal and neoplastic cells derived from the neuroectodermal and the amine-precursor-uptake and decarboxylation (APUD) systems. The tumors included six small cell carcinomas and four adenocarcinomas of the cervix; 23 adenocarcinomas of the endometrium (13 with type I and 10 with type II argyrophil cells); and 11 mucinous tumors (three benign, three borderline, and five malignant), eight endometrioid carcinomas (four with type I and four with type II argyrophil cells), and two carcinoid tumors (one insular and one strumal) of the ovary. HNK-1 reactive cells were found in almost every category of tumor: in four small cell carcinomas and two adenocarcinomas of the cervix; 11 adenocarcinomas of the endometrium (eight with type I and three with type II argyrophil cells); and four mucinous (two benign and two borderline), two endometrioid (one with type I and one with type II argyrophil cells), and two carcinoid tumors of the ovary. These cells corresponded to at least some of the type I argyrophil cells in endometrial and ovarian endometrioid carcinomas and to similar cells in mucinous and carcinoid tumors of the ovary and small cell carcinoma and adenocarcinoma of the cervix. However, the remaining type I and similar argyrophil cells and almost all type II argyrophil cells were HNK-1 negative, and some of the nonargyrophil tumor cells were HNK-1 positive. Although the significance of such discrepancies in reactivity with HNK-1 antibody remains unknown, the present results suggest that some of the gynecologic tumors with argyrophilia are related to APUDomas.