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Objective: Most ovarian clear cell carcinomas are resistant to platinum-based chemotherapy, while a small subset shows a positive response. The aim of this study was to clarify the clinical, pathological and genetic characteristics of platinum-sensitive ovarian clear cell carcinomas., Methods: The study included 53 patients with stage III-IV ovarian clear cell carcinoma who had residual tumours after primary surgery and received platinum-based therapy between 2009 and 2018. A retrospective examination of platinum sensitivity was performed using the criterion of ≥6 months from the last day of first-line platinum therapy until recurrence/progression. Cases determined to be platinum-sensitive were subjected to immunohistochemical staining, genomic analyses using target sequencing (i.e. NCC Oncopanel) and homologous recombination deficiency (myChoice® HRD Plus) assays., Results: Of the 53 stage III-IV ovarian clear cell carcinoma cases, 11 (21%) were platinum-sensitive. These cases showed better progression-free and overall survival than platinum-resistant cases (hazard ratio = 0.16, P < 0.001). Among the seven sensitive cases whose tumour tissues were available for molecular profiling, five were pure ovarian clear cell carcinoma based on pathological and genetic features, whereas the remaining two cases were re-diagnosed as high-grade serous ovarian carcinoma. The pure ovarian clear cell carcinomas lacked BRCA1 and BRCA2 mutations, consistent with the absence of the homologous recombination deficiency phenotype, whereas two cases (40%) had ATM mutations. By contrast, the two high-grade serous ovarian carcinoma cases had BRCA1 or BRCA2 mutations associated with the homologous recombination deficiency phenotype., Conclusion: The subset of platinum-sensitive ovarian clear cell carcinomas includes a majority with pure ovarian clear cell carcinoma features that lack the homologous recombination deficiency phenotype., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: An effective treatment strategy for epithelial ovarian cancer (EOC) with homologous recombination (HR)-proficient (HRP) phenotype has not been established, although poly (ADP-ribose) polymerase inhibitors (PARPi) impact the disease course with HR-deficient (HRD) phenotype. Here, we aimed to clarify the cellular effects of paclitaxel (PTX) on the DNA damage response and the therapeutic application of PTX with PARPi in HRP ovarian cancer., Methods: Two models with different PTX dosing schedules were established in HRP ovarian cancer OVISE cells. Growth inhibition and HR activity were analyzed in these models with or without PARPi. BRCA1 phosphorylation status was examined in OVISE cells by inhibiting CDK1, which was reduced by PTX treatment. CDK1 expression was evaluated in EOC patients treated with PTX-based neoadjuvant chemotherapy., Results: PTX suppressed CDK1 expression resulting in impaired BRCA1 phosphorylation in OVISE cells. The reduced CDK1 activity by PTX could decrease HR activity in response to DNA damage and therefore increase the sensitivity to PARPi. Immunohistochemistry showed that CDK1 expression was attenuated in samples collected after PTX-based chemotherapy compared to those collected before chemotherapy. The decrease in CDK1 expression was greater with dose-dense PTX schedule than with the conventional PTX schedule., Conculsions: PTX could act synergistically with PARPi in HRP ovarian cancer cells, suggesting that the combination of PTX with PARPi may be a novel treatment strategy extending the utility of PARPi to EOC. Our findings provide cules for future translational clinical trials evaluating the efficacy of PTX in combination with PARPi in HRP ovarian cancer., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

This review provides an overview of the pathology of selected benign and malignant lesions of the female peritoneum and their often-encountered differential diagnoses. It includes endometriosis and its related lesions, endosalpingiosis, pseudomyxoma peritonei (PMP) and related ovarian/appendiceal pathology, and malignant and benign mesothelial tumors. The current terminology associated with PMP is also discussed., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate the presence of pathological residual tumor (pRT) in each initial disseminated site after neoadjuvant chemotherapy (NACT) to assess the appropriate surgical margins during interval debulking surgery (IDS) for a favorable prognosis., Methods: This prospective descriptive study included patients with stage IIIC-IV epithelial ovarian, fallopian tubal, and peritoneal cancer. One hundred eleven patients underwent diagnostic exploratory laparotomy, and their initial intra-abdominal dissemination statuses were recorded. Any tumor >1 cm in diameter found during the exploratory laparotomy was resected during IDS even if it was macroscopically invisible after NACT. The pRT rate after NACT and negative predictive value (NPV; probability that sites with macroscopically invisible tumors have no pRT) during IDS were assessed in each disseminated site., Results: A median of 5 NACT cycles were performed. Sites with a high incidence of pRT and low NPV included the rectosigmoid colon (71.4%, 38.6%), transverse mesentery (70.3%, 50.0%), greater omentum (68.3%, 51.7%), right diaphragm (61.9%, 48.1%), paracolic gutters (61.1%, 50.0%), and vesicouterine pouch (56.6%, 50.0%). Organs/tissues with a high incidence of pRT featured a low NPV. The median progression-free survival and overall survival in this cohort were 27.7 and 71.9 months, respectively., Conclusion: Even if a disseminated site >1 cm in diameter before NACT is invisible during IDS, microscopic disease remains present within it. The appropriate surgical margins for IDS with a favorable prognosis could be secured by resecting a lesion of >1 cm before NACT even if it is invisible during IDS., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Objective: Ovarian clear cell carcinoma (OCCC) is often resistant to conventional, standard chemotherapy using cytotoxic drugs. OCCC harbors a unique genomic feature of frequent (approximately 50%) ARID1A deficiency. The present study was performed to investigate standard chemotherapeutic options suitable for ARID1A-deficient OCCC patients., Methods: Drugs with selective toxicity to ARID1A-deficient OCCC cells were identified among six cytotoxic drugs used in standard chemotherapy for OCCC by employing multiple ARID1A-knockout cell lines and an OCCC cell line panel. Anti-tumor effects of drug treatment were assessed using a xenograft model. To obtain proof of concept in patients, seven OCCC patients who received single-agent therapy with gemcitabine were identified in a retrospective cohort of 149 OCCC patients. Patient samples and cases were analyzed for association between therapeutic response and ARID1A deficiency., Results: ARID1A-knockout and ARID1A-deficient OCCC cells had selective sensitivity to gemcitabine. IC50 values for gemcitabine of ARID1A-deficient cells were significantly lower than those of ARID1A-proficient cells (p = 0.0001). Growth of OCCC xenografts with ARID1A deficiency was inhibited by administration of gemcitabine, and gemcitabine treatment effectively induced apoptosis in ARID1A-deficient OCCC cells. Three ARID1A-deficient OCCC patients had significantly longer progression-free survival after gemcitabine treatment than four ARID1A-proficient OCCC patients (p = 0.02). An ARID1A-deficient case that was resistant to multiple cytotoxic drugs, including paclitaxel plus carboplatin in the adjuvant and etoposide plus irinotecan in the first-line treatment, exhibited a dramatic response to gemcitabine in the second-line treatment., Conclusion: ARID1A-deficient OCCC patients could benefit from gemcitabine treatment in clinical settings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology., Experimental Design: To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival ( N = 5) or had a very short time to progression ( N = 5)., Results: The majority of mixed OCCC ( N = 6, 85.7%) and a small proportion of pure OCCC ( N = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified samples were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS ( P = 0.0194 and 0.0395, respectively). Mutations in ARID1A, PIK3CA, PPP2R1A , and TP53 were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations., Conclusions: Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome., (©2019 American Association for Cancer Research.)

Objectives: The present study assessed whether human telomerase reverse transcriptase (TERT) promoter mutations mediate the increased mortality risk observed in patients with ovarian clear cell carcinoma (CCC) and characterized the pathologic features of TERT promoter mutation-associated ovarian CCC., Methods: The TERT promoter region in genomic DNA extracted from paraffin-embedded ovarian CCC specimens (n = 93) was bidirectionally sequenced., Results: A total of 24 TERT promoter mutations were identified among the analyzed CCC cases, of which 11 were known "hotspot" mutations whose frequency was increased in CCC cases with compared to without coexistent adenofibroma (P < .05). In contrast, the 14 (including three novel) identified uncommon site mutations were shown to be associated with a poor progression-free survival rate (P < .01)., Conclusions: The identified uncommon TERT promoter mutations exacerbate the poor prognosis characteristic of ovarian CCC cases, and the hotspot mutations appear to be a molecular feature of the adenofibroma-associated form of the disease.

Objective: Ovarian clear cell carcinoma (OCCC) frequently presents at an early stage. In stage I OCCC, the prognosis differs according to substage. In particular, predictive biomarkers and new treatment strategies are needed for stage IC2/IC3 disease. We investigated tumor biology and prognostic factors for stage I OCCC from a clinicopathological perspective, including the expression of ARID1A and IL-6, which are considered critical for OCCC carcinogenesis., Methods: A retrospective cohort study of 192 patients with stage I OCCC treated at a single institution was performed. We calculated overall survival (OS) with respect to 12 clinicopathological parameters that included the unique and diverse histological features of OCCC., Results: The estimated 5-year OS rate in patients with all stage I OCCC was 88.9% during a median of 91months of follow-up. The multivariate analysis indicated that substage classification and IL-6 expression status were associated with poor OS (p=0.010 and p=0.027, respectively). Loss of ARID1A expression had no impact on survival; however, it was associated with substage (p=0.001), capsule rupture status (p=0.011), and ascites cytology (p=0.016). No clear association was found between ARID1A and IL-6 expressions. Histological findings, including the presence of endometriosis, adenofibroma, architectural pattern, and tumor cell type, showed no prognostic effects., Conclusions: Both substage classification and IL-6 expression status may be independent prognostic factors in stage I OCCC. Therefore, IL-6 molecular stratification may be crucial in optimizing therapeutic strategies for early stage OCCC to improve survival., (Copyright © 2017 Elsevier Inc. All rights reserved.)

There has been significant progress in the understanding of the pathology and molecular biology of rare ovarian cancers, which has helped both diagnosis and treatment. This paper provides an update on recent advances in the knowledge and treatment of rare ovarian cancers and identifies gaps that need to be addressed by further clinical research. The topics covered include: low-grade serous, mucinous, and clear cell carcinomas of the ovary. Given the molecular heterogeneity and the histopathological rarity of these ovarian cancers, the importance of designing adequately powered trials or finding statistically innovative ways to approach the treatment of these rare tumors has been emphasized. This paper is based on the Rare Ovarian Tumors Conference for Young Investigators which was presented in Tokyo 2015 prior to the 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG)., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2017. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Aims: The carcinogenesis of ovarian clear cell carcinoma (CCC) has been hypothesized to comprise two different pathways: an adenofibroma-carcinoma sequence and an endometriosis-carcinoma sequence. However, the difference in the genetic basis of these two pathways remains unclear. Recent studies have suggested that an ARID1A mutation and the loss of the corresponding protein, BAF250a, are frequent events in CCC. Herein, we investigated the difference in the loss of BAF250a expression in adenofibroma-related CCC and endometriosis-related CCC., Methods and Results: In total, 93 cases of surgically treated CCC were evaluated. The presence of adenofibroma and endometriosis associated with carcinoma was determined by reviewing haematoxylin and eosin-stained slides for each case. BAF250a expression in carcinoma was examined immunohistochemically. The loss of BAF250a expression was detected in carcinomas in 50 of 93 (54%) cases, including five of 18 (28%) with adenofibroma alone, 30 of 45 (67%) with endometriosis alone, eight of 18 (44%) with both conditions and seven of 12 (58%) with neither condition. The loss of BAF250a expression was significantly less frequent in CCC cases with adenofibroma than in cases with endometriosis (P = 0.01, Fisher's exact test)., Conclusions: The action of ARID1A in carcinogenesis differs between adenofibroma-related CCC and endometriosis-related CCC., (© 2015 John Wiley & Sons Ltd.)

Accurate distinction of clear cell carcinoma (CCC) from endometrioid carcinoma (EC) has important clinical implications, but, not infrequently, EC demonstrates clear cell change (EC-CC), mimicking CCC. We examined whether a panel of immunomarkers can help distinguish between these tumors. Sixty-four CCCs (40 ovarian and 24 uterine), 34 ECs (21 ovarian and 13 uterine), and 34 EC-CCs (6 ovarian and 28 uterine) were stained for HNF1β, BAF250a, Napsin A, ER, and PR. Intensity and extent of immunoreactivity was assessed. Fifty-seven of 64 (89%) CCCs, 14/34 (41%) EC-CCs, and 16/34 (47%) ECs expressed HNF1β, and 56/64 (88%) CCCs, 4/34 (12%) EC-CCs, and 1/34 (3%) ECs stained for Napsin A. Most CCCs demonstrated at least moderate and diffuse staining for both markers, whereas only focal and weak expression was identified in most EC-CC/EC. Compared to HNF1β, Napsin A showed increased specificity (93.0% vs. 55.9%, P<0.0001) and similar sensitivity (87.5% vs. 89.1%) in distinguishing CCC from EC-CC/EC. Thirteen of 64 (20%) CCCs, 6/34 (18%) EC-CCs, and 2/34 (6%) ECs showed loss of BAF250a. ER was expressed by 10/64 (16%) CCCs, 30/34 (88%) EC-CCs, and 33/34 (97%) ECs, whereas PR positivity was identified in 9/64 (14%) CCCs, 26/34 (77%) EC-CCs, and 33/34 (97%) ECs. The majority of EC and EC-CC demonstrated diffuse staining for ER/PR, whereas most CCCs showed very focal positivity. There is a statistically significant difference in HNF1β, Napsin A, ER, and PR immunoexpression between CCC and EC/EC-CC, with Napsin A being a more specific marker for CCC than HNF1β. Overall, the immunoprofile of EC-CC is more comparable to that of EC than CCC. The use of a panel of immunostains can help distinguish EC-CC from CCC.

Background: To achieve optimal cytoreduction for advanced-stage ovarian cancer, modified posterior exenteration is the most frequently performed bowel surgery. We assessed the extents of tumor spreading in the rectosigmoid wall and pelvic side wall in modified posterior exenteration specimens during primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy, and compared the validity of selecting this surgical procedure in the patients undergoing PDS with that in the patients undergoing IDS., Methods: Clinicopathological data from consecutive patients who had undergone a modified posterior exenteration for primary ovarian, tubal, and peritoneal cancer at our institution between April 2008 and March 2013 was retrospectively reviewed., Results: A total of 75 patients (38 in PDS and 37 in IDS) were included in this study. Tumor involvement of the rectosigmoid was histopathologically confirmed in 65% of the specimens. Though the extent of tumor spreading in the rectosigmoid was deeper in PDS than in IDS, the frequency of tumor involvement of the rectosigmoid in patients who had undergone modified posterior exenteration during PDS was equivalent to that in the IDS group. Lateral tumor spreading to the side wall(s) was histopathologically confirmed in 53% of the patients in whom a pelvic side wall resection had been performed., Conclusions: During both PDS and IDS for ovarian cancer presenting with tumor involvement of the cul-de-sac, close inspection and palpation by gynecologic oncologists may enable the extent of tumor spreading in the pelvis to be estimated, enabling valid decisions as to whether an en bloc resection of the pelvic tumors together with the rectosigmoid and the pelvic side wall might or might not be appropriate.

Napsin A is a reliable marker for pulmonary adenocarcinoma and is expressed in a subset of ovarian clear cell carcinomas (O-CCCs), endometrial (EM) CCCs, and endometrioid carcinomas (EC). We investigated napsin A levels in O-CCC and EM-CCC and compared these with levels in other nonmucinous ovarian carcinomas and EM-EC, respectively. Napsin A, thyroid transcription factor (TTF)-1, paired box (PAX) 8, and cancer antigen (CA) 125 expression was evaluated in 111 ovarian and uterine carcinoma cases (22 O-CCC, 15 EM-CCC, 13 ovarian EC (O-EC), 39 high-grade serous carcinoma [HGSC], and 22 EM-EC) using immunohistochemistry. Napsin A immunoreactivity was observed in 21 (95.5%) of 22 O-CCC and 10 (66.7%) of 15 EM-CCC cases but was rare in O-EC and EM-EC (7.7% and 4.5%) and undetectable in HGSC cases. Thyroid transcription factor 1 was not expressed in O-CCC but was detected in 1 (6.7%) of 15 EM-CCC, 3 (23.1%) of 13 O-EC, 2 (5.1%) of 39 HGSC, and 1 (4.5%) of 22 EM-EC cases. All 111 cases examined were positive for PAX8, whereas 3 (20.0%) of 15 of EM-CCC and 1 (4.5%) of 22 EM-EC cases were negative for CA125. There were no napsin A/TTF-1 double-positive cases, except for 1 EM-CCC, in which cells had a focal expression pattern. All napsin A- and/or TTF-1-positive cases expressed PAX8 and CA125. In conclusion, napsin A is frequently expressed in O-CCC and EM-CCC, rarely in O-EC and EM-EC, and never in HGSC cases. These findings confirm the importance of using a panel of antibodies that includes napsin A, TTF-1, and PAX8 when evaluating metastatic carcinomas of unknown origin, particularly when gynecologic and pulmonary adenocarcinomas are included in the differential diagnosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: CD147 is a membrane glycoprotein that is expressed in various cancer cells and is involved in tumor invasion and metastasis by inducing stromal fibroblastic cells to produce matrix metalloproteinases. This study was carried out to evaluate the correlation between CD147 expression and various clinicopathologic parameters, including histological grade and prognosis in a small sample set of human ovarian cancer patients., Material and Methods: Paraffin-embedded surgical tissue samples from 25 patients with ovarian serous and endometrioid adenocarcinoma were stained with anti-CD147 antibody (monoclonal antibody 12C3: MoAb 12C3) for immunohistochemical analysis., Results: CD147 protein was expressed in 84.0% (21 of 25 cases) of cancerous lesions, but not in normal lesions. CD147 expression by ovarian cancer cells was inversely correlated with overall survival. There was no correlation between CD147 expression and histological grade., Conclusions: These results suggest that measurement of CD147 expression may enhance the understanding of the pathophysiology of epithelial ovarian cancer., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Choriocarcinoma is a highly malignant tumor of trophoblastic origin. Most cases occur in association with preceding gestational events. However, on very rare occasions, nongestational choriocarcinoma arises from germ cell or trophoblastic differentiation in different types of carcinoma. This article reports the case of a 58-year-old woman with primary nongestational choriocarcinoma of the uterus that developed 19 years after her final pregnancy and 4 years after menopause. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. Histopathological examination showed choriocarcinoma of the uterus without components of other germ cell tumors. Karyotype analysis of the tumor cells demonstrated XX. We confirmed its nongestational origin by DNA polymorphism analysis at 15 short tandem repeat loci. After surgery, the patient was given four courses of combination chemotherapy. She is still alive and there has been no evidence of recurrence 3 years after surgery.

We report a case of sex cord tumor with annular tubules featuring a giant multilocular cyst, grossly similar to cystadenoma, in the ovary of an 8.5 year old girl. Estrogen-related symptoms, including precocious puberty and irregular uterine bleeding, immediately improved after tumor resection., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Apart from typical yolk sac tumors, ovarian tumors with elevated alfa-fetoprotein (AFP) are uncommon and the differential diagnosis needs to consider the hepatoid pattern of a yolk sac tumor, hepatocellular carcinoma metastatic to the ovary, hepatoid carcinoma, and other epithelial ovarian tumors. We report here an AFP-producing ovarian tumor with uncertain pathological diagnosis, which was extremely responsive to chemotherapy. A 59-year-old Japanese woman presented with lower abdominal distension and was found to have a left ovarian mass on pelvic examination and magnetic resonance imaging (MRI) scan. Laboratory tests showed serum AFP, 73 687 ng/ml; carbohydrate antigen 125 (CA125), 1599 U/ml; and carcinoembryonic antigen (CEA), 13.9 ng/ml. Total hysterectomy with bilateral salpingo-oophorectomy, partial omentectomy, and low anterior resection of the rectum was performed, without any residual macroscopic tumor. Microscopically, the tumor was characterized by a hepatoid carcinomatous component composed of solid sheets of large eosinophilic cells with pleomorphic nuclei. The pathological stage was pT2N0M0. Tumor cells were diffusely immunoreactive for AFP and cytokeratin (CAM5.2), but monoclonal CEA and CA19-9 were focally positive in the cytoplasm, while CA125 was negative. The patient was treated postoperatively with three cycles of chemotherapy consisting of bleomycin, etoposide, and cisplatin; with this regimen, serum AFP decreased to 16 ng/ml from 12 600 ng/ml just before the initiation of chemotherapy. The patient received secondary cytoreductive surgery of systemic lymphadenectomy, which revealed no evidence of residual tumor.

We developed mitochondrial (MT) scoring system based on MT ultrastructural findings in association with response to chemotherapy in ovarian cancer (OC). Ultrathin sections of MT prepared from 28 OC patients before chemotherapy were examined by electron microscopy. Platinum-sensitive ovarian carcinoma cell line 2008 and its resistant variant C13 were used as control cells. Seven independent MT features including, diameter, pattern of cresta structure, electron density, distribution-density and -pattern, ratio of minimal/maximal diameter and MT architecture were examined and were assigned a score between 0 and 2. Twenty-eight cases were primary advanced OC, including 4 recurrent cases. Nine cases were chemosensitive while 19 were resistant. Univariate and multivariate analysis in each factor showed good correlation to chemosensitivity for 2 factors of electron density, distribution pattern. Total score of these 2 factors in 9 sensitive cells was 1.44+/-0.41 (M +/- SE) and was 3.58+/-0.18 in 19 resistant cells (P<0.001). Receptor operative characteristics (ROC) analysis revealed that total 'cut-off' score was 3 point (P<0.05; AUC=0.84). In conclusion, this MT scoring system was excellently correlated to response regardless of histopathologic findings and this strongly suggests that the system is deemed to be of great value as biomarker for the chemosensitivity in OC.

Ovarian mucinous borderline tumor of müllerian type (MMBT) and mixed epithelial borderline tumor of müllerian type (MEBT) are uncommon subtypes of ovarian surface epithelial tumors. Both are often associated with endometriosis, but their histogenesis is still debated. We have noticed occasional foci of subepithelial cuboidal cells resembling uterine cervical reserve cells (RCs) in MMBTs/MEBTs, which have not been documented in the literature to the best of our knowledge. This study was carried out to identify the presence of RC-like cells (RCLCs) in MMBTs/MEBTs and their immunohistochemical features in comparison to those of cervical RCs. We analyzed 10 consecutive cases of RC-like MMBTs/MEBTs, 6 of which were associated with endometriosis. Immunohistochemistry was performed for p63, cytokeratin 34BE12, cytokeratin 17 (CK17), and low-molecular cytokeratin CAM5.2. In 9 of 10 cases, RCLCs were appreciated in hematoxylin-eosin stain, although their amount in the tumor varied from case to case. Immunohistochemically, RCLCs were positive for p63 in 9 cases. They were positive for both 34BE12 and CK17 and were very weakly positive or negative for CAM5.2 in 8 cases. This immunohistochemical profile is similar to that seen in the cervical RCs. Reserve cell-like cells were also found in the foci of endometriosis coexisting with MMBTs/MEBTs in 1 of 5 cases examined. We draw attention to the existence of the RCLCs in MMBTs/MEBTs and in endometriosis. Their similarity to the cervical RCs may indicate their potential role as precursor cell that may subsequently differentiate into different müllerian cell types, thus merit further study.

Ovarian small cell carcinoma of hypercalcemic type is a rare neoplasm that typically occurs in young females. We describe three cases of ovarian small cell carcinoma of hypercalcemic type occurring in patients aged 24, 37, and 25 years. The first patient had stage IIc disease and had primary surgery with a left salpingo-oophorectomy and omentectomy, followed by chemotherapy with cisplatin and etoposide. Upon a second relapse, pelvic lymphadenectomy was performed, followed by chemotherapy with docetaxel. She is alive for 4 years without any recurrence after the initial treatment. In vitro drug-sensitivity assay revealed the tumor cells were sensitive to taxane and resistant to irinotecan. The second patient had stage III disease and had primary debulking surgery with bilateral salpingo-oophorectomy, simple hysterectomy, omentectomy, low-anterior resection, and lymphadenectomy, followed by chemotherapy with paclitaxel and carboplatin. Four months after the initial treatment she relapsed and died. The tumor cells were sensitive to platinum, taxane, and doxorubicin, but resistant to irinotecan. The third patient had stage III disease and had right salpingo-oophorectomy, omentectomy, and lymphadenectomy, followed by chemotherapy with cisplatin, cyclophosphamide, and doxorubicin. She relapsed 4 months after completing the chemotherapy and died 5 months after secondary debulking surgery. The tumor cells were sensitive to platinum, taxane, and doxorubicin, but resistant to irinotecan. The drug-sensitivity assays suggested that a non-irinotecan, taxane-containing combination might have been suitable as first-line chemotherapy for these patients. However, an effect of such a regimen was seen in only one patient with early-stage disease, and this questions the validity of chemosensitivity testing.

Multiagent chemotherapy for small cell carcinoma of the ovary (SCCO) may contribute to the prolonged survival of young women who are suffering from this disease, even in the advanced stage with remaining tumor, although the rarity of SCCO complicates the generalization of chemotherapy agents and operation methods for this disease. A 24-year-old patient with SCCO FIGO stage IIC is alive after recurrences and chemotherapy including cisplatin + etoposide after the first operation and docetaxel for the second recurrence. She is now doing well with no evidence of disease more than 4 years after the first operation and 2 years after docetaxel treatment. This may be the first report describing the use of docetaxel that may be included in multiagent chemotherapy.

120 Krukenberg tumors were analyzed with emphasis on their wide microscopic spectrum and resultant problems in differential diagnosis. The patients ranged from 13 to 84 years (average, 45 years) with 43% of them under 40 years. Abdominal swelling or pain usually accounted for the clinical presentation, but 17 had abnormal vaginal bleeding, 4 had virilization, and 4 had hirsutism without virilization. Ascites was present in 43% of the cases. Sixty-three percent of the tumors were documented to be bilateral, but both ovaries were not always removed or rigorously examined microscopically. The mean diameter of the tumors was 10.4 cm, and they typically had intact, bosselated external surfaces without adhesions. The sectioned surfaces were typically solid and firm to edematous to gelatinous; one third of the tumors also had cysts. Microscopic examination showed great variation from case to case and within individual neoplasms. Multiple nodules separated by normal stroma were seen in small neoplasms and focally in many larger ones. The tumors were often more cellular at their periphery and edematous to gelatinous centrally. An irregular distribution of cellular and less cellular areas often imparted a pseudolobular pattern. The cellularity of the stroma ranged from densely cellular to paucicellular; the latter regions ranged from edematous to mucoid. The overall morphology varied according to the prominence of signet-ring cells, extracellular mucin, edema, and various epithelial patterns. Signet-ring cells were numerous in most neoplasms (and by definition occupied at least 10% of the neoplasm) but were often absent or inconspicuous in significant areas of them. The signet-ring cells typically had modest but sometimes copious amounts of pale to basophilic cytoplasm; occasionally, it was eosinophilic. The signet-ring cells varied widely in their arrangement, growing singly, in clusters, forming confluent masses or pseudo-tubular arrays or lining part of all of a true tubule. Small glands and tubules were common, often resembling microcysts (when the lining cells were flattened) or Sertoli tubules; mucinous glands and cysts and medium-sized to large intestinal-type glands were also relatively common, particularly the latter. Extracellular mucin was often conspicuous and, when associated with scant acellular collagenous stroma, gave a distinctive appearance referred to by us as "feathery degeneration." Stromal luteinization was present in the tumors of the 8 pregnant patients and was seen in 14% of the nonpregnant patients. Unusual features that complicated the microscopic picture included diffuse sheets or other arrangements of mucin-free indifferent cells, squamous cells, clear cells, transitional cells, and corded, trabecular, and insular patterns. Vascular space invasion was common. Two thirds of the primary carcinomas were detected synchronously with, or subsequent to, detection of the Krukenberg tumor compounding the diagnostic difficulty posed by the cases. Two thirds of the primary tumors were in the stomach; other primary sites in order of frequency were appendix, colon, breast, small intestine, rectum, gallbladder, and urinary bladder. Our observations emphasize that the microscopic spectrum of the Krukenberg tumor is broader that often presented in the literature, in particular tubules, glands, and cysts often being present, and the wide pathologic differential diagnosis is discussed.

Fifty cancers, seven borderline tumors, and two adenomas of the ovary were immunohistochemically examined for alteration of p53 to clarify its clinical significance. Nuclear accumulation of p53 protein was detected in 60% of the cancers, but in none of the borderline tumors or adenomas. No significant correlation was found between aberrant expression of p53 and clinical stage or histological type. DNA aneuploidy was significantly more common and the Ki-67 index was significantly higher in the cancers with altered p53 protein than in those without it. There was a concordant expression level of p53 in primary and matched metastatic lesions in all twelve pairs of cancers examined. These findings suggest that alteration of p53 protein is an event that occurs in the development of cancer, but not of borderline tumors of the ovary, and that it occurs before metastasis and remains unchanged thereafter.

The correlation between histological subtype [endodermal sinus (ES), polyvesicular vitelline (PV), glandular (G) and hepatoid (H) subtypes] and the prognosis of pure yolk sac tumours (YSTs) of the ovary was investigated. From 1964 to 1989, 35 patients with YSTs were treated with primary surgery and adjuvant chemotherapy. The prevalence of histological subtypes was as follows: 14 patients had a single subtype, either ES (12) or G (2); 12 patients had two subtypes, ES+G (4), ES+PV (3), ES+H (4) or G+H (1); six patients had three subtypes, ES+P+H (4) or ES+G+H (2); and three patients had all four subtypes. Multivariate analysis showed that important predictors were FIGO stage, chemotherapeutic regimen and residual tumour size. However, for stage I, multivariate analysis showed that the histological subtype was a superior predictor to the subclassification of FIGO stage I, age or chemotherapeutic regimen (P = 0.03). Kaplan-Meier analysis showed that YSTs composed of an admixture of three or four subtypes was associated with a better prognosis than those composed of one or two subtypes (P < 0.01), other variables being constant.