Evaluation of pathology review at gynaecological oncology multidisciplinary team meetings: a 5-year prospective analysis of cases with major diagnostic discordance.

Multidisciplinary team meetings (MDTs) play an essential role in the management of patients with newly diagnosed and recurrent cancers, and often include review of pathology specimens that were initially assessed in external departments. Many studies have demonstrated a low but significant rate of diagnostic disagreement following such review but the pathological findings have seldom been detailed. We present a prospective 5-year study of all external cases reviewed at the Western Australian Gynaecological Oncology MDT focusing upon those cases with major diagnostic discordance likely to impact patient management. In total, 1275 cases were reviewed of which 132 (10.4%) were considered discordant including 48 (3.8%) with major discordance. Different interpretation of the presence and/or extent of tumour invasion accounted for a significant proportion of cases and in particular some adenocarcinoma and squamous carcinoma variants were initially reported to show only in situ or minimally invasive disease. Endometrial high-grade serous carcinoma was under-recognised and on occasion reassignment of tumour origin including metastasis to the gynaecological tract was facilitated by additional clinical information and supported by appropriate immunohistochemistry. This study supports the role of pathology review at MDTs and highlights problematic lesions that may merit a low threshold for additional opinion and ancillary studies.

Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss Are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer.

Purpose: Women with epithelial ovarian cancer generally have a poor prognosis; however, a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths.Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing.Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR deficiency and RB1 loss were correlated, and co-occurrence was significantly associated with prolonged survival.Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients. Clin Cancer Res; 24(3); 569-80. ©2017 AACRSee related commentary by Peng and Mills, p. 508.

Cervical carcinomas with a micropapillary component: a clinicopathological study of eight cases.

AIMS: Micropapillary carcinomas, or carcinomas with a micropapillary component, are well recognised in the breast and other anatomical sites. However, they have seldom been described in the cervix. In this article, we present a clinicopathological analysis of eight cervical tumours that showed at least a focal (≥5%) component of micropapillary carcinoma. METHODS AND RESULTS: The study group comprised eight cervical carcinomas (four adenocarcinomas and four adenosquamous carcinomas) with a micropapillary component. The median patient age was 41.5 years (range 27-65 years). At presentation, five patients were stage IB, two were stage IIB, and one was stage IV. The micropapillary component accounted for ≤25% of the tumour on initial biopsy or resection specimens in all but one case. Immunohistochemistry showed 'inside-out' (reverse polarity) mucin 1 staining along the cell membrane abutting the stroma. Four patients developed metastasis, all of whom showed a pure micropapillary pattern; this led to a misdiagnosis of an apparently independent peritoneal serous carcinoma in one case. All tumours showed diffuse p16 expression, and all three cases that were tested were positive for human papillomavirus (HPV) 18. Three of the six patients with at least 12 months of follow-up died of disease, and one is alive with distant metastasis. CONCLUSIONS: Usual-type (HPV-related) cervical carcinomas may show micropapillary differentiation, usually as a focal finding, and the cells show reverse polarity like similar tumours arising in other sites. Micropapillary cervical carcinoma appears to be a clinically aggressive malignancy, although this needs to be confirmed in larger studies.

Long-term survival of patients with mismatch repair protein-deficient, high-stage ovarian clear cell carcinoma.

AIMS: Gynaecological cancer patients with germline mutations appear to have a better prognosis than those with sporadic malignancies. Following the observation of long-term survival in a patient with stage III ovarian clear cell carcinoma (CCC) and possible Lynch syndrome (LS), DNA mismatch repair (MMR) protein immunohistochemistry was performed in a series of high-stage CCC and correlated with patient outcomes. METHODS AND RESULTS: Thirty-two consecutive cases of stage III/IV ovarian CCCs accessioned between 1992 and 2015 were examined. The tumours from two patients (6%), including the index case, showed loss of MSH2/MSH6 expression while MLH1/PMS2 staining was retained. The index patient subsequently developed colonic and rectal carcinomas that were also MSH2/MSH6-deficient, while the second patient had a genetically confirmed germline MSH2 mutation. All other tumours showed retained expression of the four MMR proteins. The two patients with MMR protein-deficient tumours were alive 160 months and 124 months following surgery, whereas the median survival of patients with MMR protein-intact CCCs was 11.8 months (75th and 25th percentiles of 8.1 months and 39.3 months, respectively), with 21 patients deceased due to tumour. CONCLUSIONS: Larger studies are required but high-stage, MMR protein-deficient CCCs may have a relatively favourable prognosis.

Ovarian sex cord-stromal tumors in patients with probable or confirmed germline DICER1 mutations.

The DICER1 gene encodes an endoribonuclease involved in the production of mature microRNAs which regulates gene expression through several mechanisms. Recent studies have demonstrated somatic mutations in DICER1 in approximately 60% of ovarian Sertoli-Leydig cell tumors. Furthermore, patients with germline mutations in DICER1 are predisposed to developing a range of rare neoplasms including ovarian sex cord-stromal tumors most of which have been classified as Sertoli-Leydig cell tumor. However, the histologic features of these tumors have not been reported in detail. We describe the morphologic and immunophenotypic findings of 4 sex cord-stromal tumors arising in patients with proven or likely germline DICER1 mutations including 3 individuals from 1 family. Three tumors showed similar appearances characterized by marked architectural and cytologic heterogeneity including sertoliform, juvenile granulosa cell tumor-like, and unclassifiable elements. The remaining case mainly showed heterologous mucinous epithelial and neuroendocrine differentiation with only a minor intermediate-grade Sertoli cell component. This tumor and one of the 3 former cases arose in related patients with identical germline DICER1 mutations indicating that additional factors influence tumor morphology. All tumors were positive for steroidogenic factor-1 and FOXL2 on immunohistochemical analysis, whereas there was more variable expression of inhibin, calretinin, CD56, CD99, and hormone receptors. The present small series suggests that some ovarian Sertoli-Leydig cell tumor associated with germline DICER1 mutations may show distinctive histologic features in particular admixed Sertoli cell and juvenile granulosa cell tumor-like features. Larger studies are required to establish whether heterologous elements are also a more common feature of these tumors.

Evaluation of fluorescence in-situ hybridization in monomorphic endometrial stromal neoplasms and their histological mimics: a review of 49 cases.

AIMS: To perform a population-based review of monomorphic endometrial stromal tumours and their histological mimics presenting over a 20-year period, including an evaluation of fluorescence in-situ hybridization (FISH) for the JAZF1 and YWHAE breakaparts. METHODS AND RESULTS: Forty-nine tumours were examined, comprising 13 histological mimics and 36 endometrial stromal tumours [six stromal nodules (ESNs), 25 low-grade stromal sarcomas (ESSs), and five monomorphic undifferentiated sarcomas (mUESs)]. Nine ESSs showed variant histological patterns, including smooth muscle, sex cord-like/glandular, fibrous or rhabdoid differentiation. Three ESSs were initially misclassified as benign uterine lesions, and, conversely, three benign mimics were originally reported as ESSs. One mUES showed a prominent pseudopapillary pattern. Fluorescence in-situ hybridization demonstrated JAZF1 breakaparts in five of six ESNs and 16 of 25 ESSs; however, only three of nine ESS variants were positive. YWHAE breakaparts were present in four of five mUESs. Analysis of a subsequent metastasis in the YWHAE breakapart-negative mUES demonstrated a YWHAE deletion. None of the histological mimics was positive in FISH analysis. Diffuse cyclin D1 expression was restricted to mUESs in this series. CONCLUSIONS: Endometrial stromal neoplasms continue to present diagnostic difficulty. Fluorescence in-situ hybridization analysis is helpful in distinguishing stromal tumours from their histological mimics and in distinguishing ESS from mUES.

ß-Catenin and E-cadherin expression in stage I adult-type granulosa cell tumour of the ovary: correlation with tumour morphology and clinical outcome.

AIMS: To study E-cadherin and ß-catenin expression in stage I adult-type granulosa cell tumours (AGCTs) and correlate the findings with tumour morphology and clinical outcome. METHODS AND RESULTS: The study group comprised 62 FIGO stage I AGCTs, including 48 stage IA and 14 stage IC cases. Fifty patients (80.6%) had negative clinical follow-up over periods from 3.0 to 19.2 years (median 6.4 years), and 12 patients (19.4%) developed metastases at intervals of 3.6-16.2 years (median 8.6 years). ß-Catenin and E-cadherin were expressed in 62 (100%) and 53 (85%) primary tumours, respectively, and staining was more consistent and intense in areas showing sex cord-like morphology. In contrast, diffuse tumour areas often showed weak or moderate staining (ß-catenin) or were negative (E-cadherin), and there was reduced expression of both proteins in luteinized cells. Reduced ß-catenin expression in primary tumours correlated with increased risk of recurrence (P = 0.002) and a shorter time interval to recurrence, whereas there was no correlation between E-cadherin staining and the risk of metastases. CONCLUSIONS: Localized variations in adhesion protein expression may partly explain the diverse morphological patterns exhibited by AGCT, and reduced ß-catenin staining in primary tumours may have value as an adverse prognostic factor.

Fallopian tube metastases of non-gynaecological origin: a series of 20 cases emphasizing patterns of involvement including intra-epithelial spread.

AIMS: To determine the frequency and distribution of Fallopian tube involvement in patients with ovarian metastases of non-gynaecological origin. METHODS AND RESULTS: All Fallopian tube tissue was processed for histological examination in a consecutive series of 31 patients with ovarian metastases of non-gynaecological origin. The most common primary sites were appendix (n = 10) colon (n = 7), stomach (n = 6) and breast (n = 4). Twenty cases (65%) showed at least one type of tubal spread. Mural involvement was most common (14 cases) but serosal, intra-vascular, intra-epithelial and intra-lumenal spread were also identified in 12, 9, 8 and 11 cases respectively. Intra-epithelial involvement was restricted to the fimbrial epithelium and mimicked tubal carcinoma in situ (CIS) architecturally. Pagetoid invasion was noted in two of the cases. CONCLUSIONS: The Fallopian tubes are commonly involved in patients who have neoplasms metastatic to the ovaries. Metastases may show a CIS-like pattern of intra-epithelial spread and therefore small serous CIS-type lesions may not represent proof of tubal tumour origin in patients who have high-stage pelvic serous carcinomas. The frequency of intra-lumenal tumour cells supports transtubal spread as a likely mechanism for mucosal involvement by metastatic tumours involving the lower genital tract.

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands.

Endometrial adenocarcinomas may show a distinctive pattern of invasion characterized by the presence of microcystic, elongated and fragmented glands, often most evident along the advancing tumor margin. Earlier, we have shown that these changes appear restricted to low-grade endometrioid carcinomas, many of which show focal mucinous differentiation and lymphovascular space invasion. However, the molecular alterations associated with this morphological alteration are not known. In this study, we have examined immunoreactivity for the cell cycle regulatory proteins cyclin D1, p16 and beta-catenin in 22 endometrial carcinomas, specifically comparing the results in conventional tumor areas and in foci in which the glands exhibited microcystic, elongated and fragmented appearances. The conventional neoplastic glands exhibited cyclin D1 and p16 expression in most cases, with >50% tumor cells positive in 8 cases and 11 tumors, respectively. Membranous expression of beta-catenin was usually preserved, with variable cytoplasmic and nuclear staining. Cyclin D1 and beta-catenin predominantly stained cells at the peripheral or basal aspect of the conventional glands, whereas p16 was more uniformly expressed centrally. Tumor foci composed of microcystic, fragmented and elongated glands showed strong expression of cyclin D1 and p16, sometimes in contrast to unstained contiguous or adjacent conventional neoplastic elements, and there was also loss or fragmentation of membranous beta-catenin staining. Intravascular tumor cells also expressed cyclin D1 and p16 and therefore the immunostains often highlighted subtle foci of lymphovascular invasion. The heterogeneous expression of cell cycle regulatory proteins within endometrial adenocarcinoma illustrates the importance of assessing microanatomical variations in immunoreactivity, particularly at the advancing margin of tumors. The upregulation of cyclin D1 and p16, together with loss of membranous beta-catenin expression in microcystic, fragmented and elongated glands, is similar to epithelial-mesenchymal transitions observed in other malignancies and suggests that this pattern of invasion represents an active rather than a degenerative cellular process.

Extrauterine adenomyoma with atypical (symplastic) smooth muscle cells: a report of 2 cases.

Adenomyomas are circumscribed tumorlike masses most often involving the uterus and consisting of endometrioid glands, stroma, and smooth muscle tissue. They are uncommon in extrauterine sites and in this situation it may be unclear whether such lesions represent foci of endometriosis with marked smooth muscle hyperplasia/metaplasia, uteruslike mass lesions, or leiomyomas with entrapped endometriotic glandular and stromal elements. In this report 2 cases of extrauterine adenomyoma are presented in which the smooth muscle component showed focal atypical (symplastic) cytologic appearances.

Intraoperative assessment of clear cell carcinoma of the ovary.

Frozen section is a reliable technique in gynecologic pathology and is widely used to guide intraoperative management in patients presenting with ovarian masses. However, there are limited data regarding the diagnostic accuracy of frozen section in specific subtypes of ovarian neoplasia. Our impression that primary clear cell carcinoma (CCC) causes disproportionate diagnostic difficulty led us to review the intraoperative and final histopathologic reports from a consecutive series of 44 CCC that were subject to frozen-section assessment and to compare the results with a similar number of primary serous and endometrioid carcinomas. The original intraoperative slides from those CCC with discordant diagnoses were also reviewed. Review of the diagnostic reports showed that CCC was less frequently specifically identified than serous or endometrioid carcinomas on frozen section (44% cases compared with 55% and 65%, respectively), although the differences were not statistically significant. Difficulties in distinguishing primary ovarian carcinoma from tumors metastatic to the ovary occurred in a minority of cases of all histologic subtypes, but was slightly more frequent in CCC. Two CCC were misdiagnosed as borderline epithelial tumors and 1 case as a dysgerminoma. Review of the frozen-section slides from the CCC with discrepant intraoperative diagnoses showed features suggestive or indicative of the correct diagnosis in 7 (39%) of 18 cases.

Intraoperative assessment of ovarian tumors: a 5-year review with assessment of discrepant diagnostic cases.

Frozen section is often requested in the intraoperative assessment of patients, presenting with ovarian masses, to provide guidance for appropriate surgical management. To assess the accuracy of frozen section and identify causes of diagnostic error, we reviewed 914 consecutive ovarian frozen sections performed over a 5-year period in 2 laboratories; one of which provides a general surgical pathology service and, the other, a specialist gynecologic pathology service. Cases, in which there were significant diagnostic discrepancies between the intraoperative and the final histological diagnoses, were reviewed. The series included 552 benign lesions (60.4%), 96 borderline (atypical proliferating) epithelial tumors (10.5%), and 266 malignancies (29.1%). The overall accuracy of frozen section diagnosis was 95.3%. There were 43 cases with diagnostic discrepancy; 20 (3.8% cases) of which were reported in the specialist laboratory and 23 (5.9% cases) in the general laboratory. Underdiagnosis of tumor type accounted for 32 of 43 discrepant cases and was most frequent in borderline mucinous tumors. The most common cause of overdiagnosis was the misinterpretation of serous cystadenofibroma as borderline serous tumor. Slide review of the 41 assessable cases indicated that sampling error, pathologist misinterpretation, and suboptimal slide preparations contributed to misdiagnoses in 17, 23, and 9 tumors, respectively (in 9 cases, 2 factors were contributory), whereas no specific error was identified in the remaining case. Technical factors and pathologist misinterpretation were more common in the general pathology laboratory. This study confirms that ovarian frozen section is a generally reliable technique, but there are problematic areas, particularly involving the assessment of borderline tumors.

Ovarian mucinous tumour arising in mature cystic teratoma and associated with pseudomyxoma peritonei: report of two cases and comparison with ovarian involvement by low-grade appendiceal mucinous tumour.

AIMS: It is currently accepted that primary ovarian tumours rarely, if ever, give rise to mucinous ascites/pseudomyxoma peritonei (PMP) which most commonly results from the intra-abdominal spread of an appendiceal mucinous neoplasm. However, primary ovarian mucinous tumours of appendiceal type arising within mature cystic teratomas appear to represent an exception to this rule. In this report two further examples of this rare tumour are described, and the immunohistological phenotype including expression of MUC proteins is compared with secondary ovarian involvement by low-grade appendiceal mucinous neoplasm. METHODS: Two cases of ovarian mucinous tumour associated with mature cystic teratoma and PMP are described. The tumours were examined immunohistochemically for expression of cytokeratin (CK)7, CK20, carcinoembryonic antigen (CEA), CDX-2, MUC2, MUC5AC and MUC6. The results were compared with four cases of ovarian neoplasia secondary to primary appendiceal low-grade mucinous tumour. RESULTS: The ovarian mucinous tumours associated with mature cystic teratomas were morphologically similar to those secondary to appendiceal neoplasia. They comprised irregularly distributed glands and cysts lined by tall, mucin-rich epithelial cells exhibiting focal villoglandular architecture and low grade cytological atypia. The immunophenotype of the teratoma-associated tumours and those secondary to appendiceal neoplasia was identical: there was strong and diffuse expression of CK20, CEA, CDX-2, MUC2 and MUC5AC with no reactivity for the other antisera tested. CONCLUSIONS: PMP associated with primary ovarian neoplasia is rare, and probably restricted to mucinous tumours arising in mature cystic teratomas. The immunohistological findings in this study further support the view that such tumours exhibit a lower gastrointestinal and, more specifically, appendiceal phenotype. Careful examination and sampling of the ovaries may be required to demonstrate the teratomatous component of these tumours.

Accuracy of frozen section in distinguishing primary ovarian neoplasia from tumors metastatic to the ovary.

Frozen section is widely used in the intra-operative assessment of patients with ovarian tumors. The diagnosis of malignancy is usually straightforward but in some cases it may be difficult to distinguish whether tumors are of ovarian origin or represent matastases from other sites. Recently, Seidman and colleagues presented a simple algorithm based on tumor size and unilateral versus bilateral involvement to aid in intra-operative assessment of ovarian mucinous neoplasms. In this study we have reviewed the accuracy of frozen section in distinguishing primary ovarian malignancies from tumors metastatic to the ovaries encountered in two hospitals over a 5-year period. The algorithm was also applied to our cases retrospectively irrespective of histological type. Nine hundred fourteen ovarian frozen sections were performed in the study period including 266 cases with a final diagnosis of malignancy. Thirty-seven malignancies (13.9%) were of metastatic origin (exclusing one lymphoma), 21 of which (58.8%) were correctly identified on frozen section. In 5 additional cases metastatic origin was included in the differential diagnosis while a primary ovarian tumor was favored un 11 cases (29.7%). Application of the algorithm to the metastatic tumors led to correct classification in 26/33 (78.8%) assessable cases. Conversely, 195/228 primary ovarian malignancies were correctly identified intra-operatively but the possibility of extra-ovarian malignancy was considered or not excluded in 33 cases (14.5%). Application of the algorithm to the latter problematic primary ovarian tumors overall was not helpful in distinguishing primary or metastatic origin. However if only low-grade primary adenocarcinomas were considered then 10/12 assessable cases were correctly assigned. In conclusion frozen section is only moderately successful in distinguishing primary ovarian malignancies fron tumors metastatic to the ovaries. The simple algorithm proposed by Seidman and colleagues for assessment of ovarian mucinous tumors is helpful and can be applied to low-grade adenocarcinomas of other histological types.

Ovarian cancer in Western Australia (1982-1998): trends in surgical intervention and relative survival.

OBJECTIVES: We aimed to review the utilisation and trends in surgical procedures for the primary management of ovarian cancer and the survival outcomes of patients surgically treated in Western Australia. METHODS: The population-based Western Australia Data Linkage System was used to link hospital morbidity and mortality data for all women diagnosed with malignant primary ovarian cancer in the State Cancer Registry in the period 1982-1998. Poisson regression was used to analyse trends in surgical procedure rates. Logistic regression examined the likelihood of having a surgical procedure in the periods 1988-1993 and 1994-1998 compared with 1982-1987. Relative survival was used to adjust survival estimates for other causes of death occurring in the general female population. RESULTS: There were 1,126 women who underwent a primary surgical procedure for ovarian cancer in Western Australia in the period 1982-1998. Women were more likely to undergo surgery in 1994-1998 (87.8%) compared with 1988-1993 (76.8%), but there was no difference when compared to 1982-1987 (89.2%) (P = 0.62). The likelihood of using specific surgical procedures to treat ovarian cancer increased for all but total abdominal hysterectomy. Bilateral salpingo-oophorectomy was 3.7 times more likely to be performed and omentectomy 5 times more likely to be performed in 1994-1998 compared with 1982-1987. The median length of hospital stay decreased from 15 to 12 days and emergency admissions decreased from 26.5 to 15.4% over the three time periods. Thirty-two percent of women were readmitted within 30 days of separation from their primary surgery, 23% of which were for the same-day treatment with either chemotherapy or radiotherapy. A 15% increase in relative survival was observed between the periods 1982-1997 (38.8%) and 1994-1998 (53.5%).Conclusion. CONCLUSION: Surgery remains a cornerstone in the primary management of ovarian cancer. There have been dramatic shifts in surgical practice in Western Australia, with more women undergoing certain surgical procedures today than they were 20 years ago. Coupling the increasing surgical trends are improved outcomes. Fewer women are presenting as an emergency, the length of hospital stay has been reduced, and survival outcomes have shown a significant improvement.

Ovarian cancer in Western Australia (1982-98): incidence, mortality and survival.

OBJECTIVES: To investigate the trends in incidence and mortality and estimate survival for women diagnosed with ovarian cancer in Western Australia. CASE SELECTION AND METHODS: There were 1,336 women diagnosed with ovarian cancer in 1982-98. Age-standardised rates were calculated by the direct method. Age-period and age-cohort models were analysed by Poisson regression. The Kaplan-Meier method was used to estimate survival and Cox proportional hazards regression evaluated the relative risk of dying. RESULTS: Trends in age-adjusted incidence and mortality rates showed little changed over the three time periods of diagnosis. A significant birth cohort effect showed a peak in the risk in the 1924 (mid-year) cohort followed by a general decrease in both incidence and mortality risk. Survival at five years was 34% (95% CI 31.3-36.5) overall, but was only 27% (95% CI 17.4-36.7) among women with stage III and IV disease. Aboriginal women showed a risk of dying twice that of non-Aboriginal women. CONCLUSIONS: The birth cohort analysis of ovarian cancer proved better at explaining disease trends than was time period of diagnosis. Survival continues to be poor, but Aboriginal women and those with serous and unspecified adenocarcinoma tumours fair much worse. IMPLICATIONS: As the leading cause of death from a gynaecological malignancy, ovarian cancer is of public health importance. Historical trends in birth rates and the use of oral contraceptives help to explain at least some of the observed birth cohort trends in this study. In the long term, an effective diagnostic technique needs to be developed or this disease will continue to be diagnosed at an advanced stage when treatment options for cure are limited.