Atypical Proliferative Tumors Research Articles

New Achievements from Molecular Biology and Treatment Options for Refractory/Relapsed Ovarian Cancer-A Systematic Review.

Ovarian cancer (OC) has a high rate of mortality and is the fifth most common cause of death in females all over the world. The etiology is still unclear. Numerous factors such as smoking, obesity, and unhealthy diet may affect the risk of OC. Having a family history of breast and OC is one of the main risks for developing OC. Mutations of BRCA1/2 are associated with OC risk as well. The histopathological classification of OC reveals the four most common types: serous, clear cell, endometrioid, and mucinous; these are epithelial OC types, and other types are rare. Furthermore, OC can be subdivided into types I and II. Type I tumors are most probably caused by atypical proliferative tumors. Type II tumors include high-grade carcinoma of the serous type, carcinosarcoma, and carcinoma, which are not differentiated and generally originate from tubal intraepithelial carcinoma of the serous type. Typically, type I tumors are present in early stages, usually with good prognosis. Type II tumors are classified as high-grade tumors and are most often diagnosed at advanced FIGO stages with poor prognosis. High-grade serous OC accounts for 90% of serous OC. Tumor heterogeneity aggravates OC treatment. The standard care for primary epithelial ovarian cancer (EOC) is cytoreductive surgery followed by platinum-based chemotherapy. Neoadjuvant chemotherapy can be used in certain cases followed by cytoreductive surgery. The main prognostic factor is complete tumor resection. However, about 70% of patients relapse. Resistance to chemotherapeutic agents remains a major challenge in EOC treatment, in which many different factors are involved. In recent years, the examination of molecular parameters and their prognostic impact has become increasingly relevant in EOC, and furthermore, the use of immunotherapy has expanded the therapeutic range. As the clinical need is greatest for relapsed patients, this systematic review will focus on recent advances in molecular biology with prognostic and predictive markers and treatment options for recurrent/refractory OC. Inclusion criteria for the review: potential prospective or predictive biomarkers in preclinical or clinical use in relapsed and refractory OC, prognostic impact, clinical and preclinical trials, and immunotherapy. Exclusion criteria for the review: primary OC, no full text or abstract available, not the topic mentioned above, and text not available in English. Risk of bias: the included studies were evaluated descriptively for the topics mentioned above, and data were not compared with each other. The objective is to highlight the molecular mechanisms of the most promising targeted agents under clinical investigation to demonstrate their potential relevance in recurrent/refractory OC.

Prognostic relevance of autophagy-related markers p62, LC3, and Beclin1 in ovarian cancer

To analyze the expression of autophagy markers p62, LC3, and Beclin1 in ovarian cancer tissue and evaluate the prognostic potential of these markers. The study enrolled 328 patients: 122 with epithelial ovarian carcinoma, 42 with atypical proliferative tumor, and 164 with benign epithelial ovarian tumor. The expression of p62, LC3, and Beclin1 was analyzed in central and invasive tumor segments with immunohistochemistry combined with tissue microarray. The expression levels of the analyzed markers were correlated with relevant histopathology parameters. The expression of all analyzed markers was most remarkable in epithelial ovarian carcinoma. There was a strong positive correlation between the expressions of p62 and LC3, while these two markers negatively correlated with Beclin1. High-grade serous carcinoma had higher p62 and LC3 levels, and lower Beclin1 levels than other tumor types. This expression profile was also observed in more advanced tumor stages. Prominent p62 and LC3 expression in combination with weak Beclin1 expression in high-grade serous carcinoma indicates potential for the application of autophagy inhibitors in patients with this tumor subtype.

PD-L1 Expression in Different Segments and Histological Types of Ovarian Cancer According to Lymphocytic Infiltrate.

Background and Objectives: Ovarian cancer is the leading cause of death among gynecological tumors. PD-1/PD-L1 immunoregulatory mechanism is activated in ovarian cancers. Lymphocyte infiltration is a significant factor that affects its expression. We analyzed the correlation between localization of lymphocytic infiltrate and PD-L1 expression in epithelial ovarian tumors. Materials and Methods: PD-L1 expression was analyzed in 328 subjects, 122 with epithelial ovarian carcinoma, 42 with atypical proliferative tumor, and 164 with benign epithelial ovarian tumor. Expression in central and invasive tumor parts in epithelial ovarian carcinoma was combined with the most pronounced lymphocyte reaction. Immunohistochemical analysis was performed using the tissue microarray and correlated with a set of histopathology parameters. Results: PD-L1 expression was most prominent in epithelial ovarian carcinoma with different levels of expression observed between invasive and central tumor segments. A high level of PD-L1 expression on tumor cells was more frequently present in the invasive than in the central tumor parts (p < 0.001) only in high-grade serous ovarian carcinoma (HGSC). There was no significant correlation between peritumoral lymphocytic infiltrate and PD-L1 expression regardless of tumor segment. In the central tumor parts of HGSC, there was a correlation of intratumoral lymphocytic infiltrate with a higher level of PD-L1 expression (p = 0.003). Conclusions: The most prominent PD-L1 expression was observed in the invasive tumor parts of HGSC. Only the central parts of the HGSC exhibited significant PD-L1 expression in association with considerable intratumoral lymphocytic infiltrate.

Long-term Behavior of Serous Borderline Tumors Subdivided Into Atypical Proliferative Tumors and Noninvasive Low-grade Carcinomas: A Population-based Clinicopathologic Study of 942 Cases.

Ovarian serous borderline tumors (SBTs) have been the subject of considerable controversy, particularly with regard to terminology and behavior. It has been proposed that they constitute a heterogenous group of tumors composed, for the most part, of typical SBTs that are benign and designated "atypical proliferative serous tumor (APST)" and a small subset of SBTs with micropapillary architecture that have a poor outcome and are designated "noninvasive low-grade serous carcinoma (niLGSC)". It also has been argued that the difference in behavior between the 2 groups is not due to the subtype of the primary tumor but rather the presence of extraovarian disease, specifically invasive implants. According to the terminology of the 2014 WHO Classification, typical SBTs are equivalent to APSTs and SBTs displaying micropapillary architecture are synonymous with niLGSC. In addition, "invasive implants" were renamed "low-grade serous carcinoma" (LGSC). The argument as to whether it is the appearance of the primary tumor or the presence of extraovarian LGSC that determines outcome remains unsettled. The current study was initiated in 2004 and was designed to determine what factors were predictive of outcome, with special attention to the appearance of the primary tumor (APST vs. niLGSC) and that of the extraovarian disease (noninvasive vs. invasive implants). Our study is population based, involving the entire female population of Denmark. None of the women in the study were lost to follow-up, which ranged up to 36 years (median, 15 y). All the microscopic slides from the contributing hospitals were rereviewed by a panel of 2 pathologists (R.V. and R.J.K.) who were blinded to the follow-up. After excluding those that were not SBTs by the pathology panel, as well as cases with a prior or concurrent cancer or undefined stage, 942 women remained, of which 867 were APSTs and 75 were niLGSCs. The median patient age was 50 years (range, 16 to 97 y). Eight hundred nine women (86%) presented with FIGO stage I disease, whereas 133 (14%) had advanced stage disease. Compared with APSTs, niLGSC exhibited a significantly greater frequency of bilaterality, residual gross disease after surgery, microinvasion/microinvasive carcinoma, advanced stage disease, and invasive implants at presentation (P-values <0.003). Because the cause of death is difficult to accurately ascertain from death certificates, we used development of invasive serous carcinoma as the primary endpoint as following development of carcinoma, the mortality is very high. In the entire cohort, subsequent development of carcinoma occurred in 4%, of which 93% were low grade and 7% high grade (median time, 10 y; range, up to 25 y). After adjusting for age at and time since diagnosis of APST or niLGSC, occurrence of subsequent carcinoma was significantly higher with niLGSC than APST among all stages combined (hazard ratio [HR]=3.8; 95% confidence interval [CI], 1.7-8.2). This difference was still significant for stage I but not advanced stage cases. Moreover, all-cause mortality was not statistically significantly different between APST and niLGSC. Of all women with advanced stage disease, 114 (86%) had noninvasive implants, whereas 19 (14%) were invasive. Noninvasive implants were significantly associated with subsequent development of carcinoma (HR=7.7; 95% CI, 3.9-15.0), but the risk with invasive implants was significantly higher (HR=42.3; 95% CI, 16.1-111.1). In conclusion, although invasive implants are the most important feature in predicting an adverse outcome, subclassification into APST and niLGSC is important as it stratifies women with respect to risk for advanced stage disease and invasive implants for all women and development of serous carcinoma for stage I cases.

Ovarian Seromucinous (Endocervical-Type Mucinous and Mixed Cell-Type) Tumor: A Case Report

Summary Objective Ovarian tumors are commonly encountered in clinical practice. Epithelial ovarian cancers account for the majority of female ovarian neoplasms. Some uncommon ovarian mucinous tumors have recently been termed “seromucinous” tumors because they exhibit both serous and mucinous features. Case Report A 27-year-old female patient presented with a 2-month history of a palpable abdominal mass. Ultrasonography and computed tomography revealed a huge multilocular, solid pelvic cyst. Following staging surgery, pathological sections showed that the tumor was composed of a mixture of endocervical-type mucinous, serous, endometrioid, squamous, and undifferentiated cells. An ovarian seromucinous tumor was diagnosed. The neoplastic cells were located mainly within the ovarian epithelium with only focal stromal invasion. Metastatic implants were found in the pelvic peritoneum. The patient received six courses of chemotherapy after surgery and has been regularly followed. Conclusion Seromucinous tumors can be classified from atypical proliferative tumors to invasive carcinomas. Death related to this kind of tumor is rare. The tumors are not common, and their clinical behavior is not as aggressive as other types. Prognostic factors have been studied, including morphologic cellular atypia, tumor necrosis, mitotic index, and depth of tumor invasion. Adjuvant therapy is necessary for patients with poor prognostic factors.

Diagnostic criteria and behavior of ovarian seromucinous (endocervical-type mucinous and mixed cell-type) tumors: atypical proliferative (borderline) tumors, intraepithelial, microinvasive, and invasive carcinomas.

Ovarian endocervical-type (müllerian) mucinous tumors and tumors composed of a mixture of endocervical-type mucinous, serous, endometrioid, squamous, and indifferent cells with abundant eosinophilic cytoplasm reported to date have been primarily limited to borderline and microinvasive types, with only one report of a disease-related death. The clinicopathologic features of 54 endocervical-type and mixed cell-type mucinous tumors, defined as tumors with papillary architecture resembling serous tumors but containing endocervical-type mucinous epithelium, were evaluated. Thirty-four tumors (64%) were classified as atypical proliferative (borderline) tumors based on the absence of stromal invasion and the absence of micropapillary architecture measuring >5 mm. Five tumors (9%) qualified as intraepithelial carcinoma based on the presence of marked cytologic atypia or a complex cribriform growth pattern involving the epithelium covering the surface of papillae or lining cystic spaces. Eight tumors (15%) with stromal invasion < or =5 mm were classified as microinvasive carcinoma. Seven tumors (13%) with either stromal invasion (five tumors) or micropapillary architecture measuring >5 mm (two tumors) were classified as carcinoma. Sixteen tumors (30%) were bilateral, and endosalpingiosis was identified in 41% of cases. Serous-type differentiation was present in all cases. Of the 29 patients with atypical proliferative tumors, intraepithelial carcinomas, and microinvasive carcinomas for whom follow-up was available, there were no disease-related deaths. In contrast, of the seven patients whose tumors had either stromal invasion or micropapillary architecture >5 mm, two stage III patients died of disease (one with frank invasion and one with a micropapillary tumor that lacked stromal invasion). One other stage III patient with a noninvasive micropapillary carcinoma was alive with disease at 84 months. The remaining four patients (three stage I and one stage III) were alive with no evidence of disease. In summary, most endocervical-type atypical proliferative tumors are stage I and benign. The presence of either intraepithelial carcinoma or microinvasion has no adverse effect on behavior. Rare endocervical-type mucinous tumors demonstrate histologically malignant features and aggressive behavior that warrant designation as carcinoma. As with serous tumors, micropapillary architecture without frank invasion in endocervical-type mucinous tumors is associated with disease recurrence and death when presenting as advanced-stage disease. All the tumors in this study were composed of a heterogeneous population of cells, consisting mainly of serous (ciliated) and endocervical-type mucinous cells. In addition, they all contained endometrioid-type cells, hobnail cells, and indifferent cells with abundant eosinophilic cytoplasm to a varying degree. Accordingly, it appears that tumors that feature endocervical-type mucinous cells are rarely if ever pure but almost invariably of mixed cell type. Despite containing mucinous epithelium, the papillary architecture, serous-type differentiation, association with endosalpingiosis, frequent bilaterality, size, and clinical behavior of endocervical-type mucinous tumors closely resemble serous tumors. We therefore recommend the term "seromucinous" for these tumors, which acknowledges both their serous and mucinous features.

Serous borderline tumors of the ovary: a long-term follow-up study of 137 cases, including 18 with a micropapillary pattern and 20 with microinvasion.

The natural history of serous borderline tumors (SBTs) of the ovary varies considerably. A group of investigators have proposed that a small subset of SBTs with a micropapillary architecture and an allegedly higher incidence of invasive peritoneal implants should be designated "micropapillary serous carcinomas." Based on the overall favorable prognosis of the nonmicropapillary SBTs, these investigators have recommended abandoning the borderline category of serous tumors, restricting them to benign (benign and typical SBTs) and malignant types; other investigators, however, are in favor of retaining the original grouping, designating borderline tumors with a micropapillary pattern as such instead of designating them carcinomas. We have reviewed the clinicopathologic records of 137 patients with ovarian SBTs and obtained follow-up information on 106 of them ranging from 1 to 18 years (mean 7 years). Of the 21 patients with stage I tumors who had conservative surgical treatment, only two (9.5%) were subsequently found to have tumor in the contralateral ovary. Both were successfully managed by reoperation alone. Forty-five stage I patients had procedures that included bilateral oophorectomy, and two of them (4.4%) had a pelvic recurrence, which was fatal in one patient (whose tumor had been understaged) and occurred on multiple occasions in the other patient, finally transforming into invasive carcinoma; that patient survived. Of the 45 stage II-IV patients, only the six (13%) with invasive implants had an unfavorable outcome: three died of tumor (from 7 to 9.3 years), and the other three were alive with progressive disease from 5 to 10 years. Solid epithelial nests or small papillae surrounded by clefts and micropapillary architecture were found more often in invasive than in noninvasive implants. However, the only feature specifically associated with a poor outcome was obvious destructive invasion of the underlying tissue. Among the 137 SBTs, we identified 18 cases of serous borderline tumors with a micropapillary pattern (SBT-MP) (so-called "micropapillary carcinoma") and 20 cases of SBT with microinvasion (SBT-Minv) (three of which were also micropapillary). We compared the two groups of tumors with the remaining 102 cases of typical SBTs (which lacked micropapillary pattern and microinvasion). Of the 17 patients with SBT-MP and follow-up data, only the one patient with invasive implants had an unfavorable outcome; similarly, of the two patients with SBT-Minv and an unfavorable outcome, one had invasive implants and the other had been incompletely staged. SBTs have a very favorable prognosis, but complete surgical staging and prolonged follow-up are advised because pelvic recurrence and occasionally transformation to invasive carcinoma may occur. Designation of SBTs as "atypical proliferative tumors" is not recommended because it discourages complete surgical staging and follow-up. Advanced stage tumors with noninvasive implants are common, characteristically behave in a benign fashion, and can be safely treated conservatively. The rare SBTs associated with invasive implants are almost always fatal. SBT-MP and SBT-Minv are much closer in their biologic behavior to SBTs than to serous carcinomas. The micropapillary pattern alone does not imply an unfavorable prognosis; only micropapillary tumors associated with invasive implants behave aggressively.

A clinicopathologic analysis of atypical proliferative (borderline) tumors and well-differentiated endometrioid adenocarcinomas of the ovary.

Atypical proliferative (borderline) endometrioid tumors (APTs) and well-differentiated endometrioid carcinomas of the ovary constitute a spectrum of morphologically diverse proliferative tumors. There is currently no agreement on the criteria for distinguishing them. We report the clinicopathologic features of 56 proliferative endometrioid tumors focusing on the criteria for invasion, the clinical significance of microinvasion and cytologic atypia, and prognosis. Endometriomas, adenofibromas, adenosarcomas and moderately to poorly differentiated carcinomas were excluded, as were patients with concurrent endometrioid carcinoma of the endometrium. The tumors were classified as atypical proliferative tumor (APT) (33 tumors), APT with intraepithelial carcinoma (high-grade cytology in a tumor lacking stromal invasion) (three tumors), APT with microinvasion (invasion <5 mm) (five tumors), and invasive carcinoma (invasion > or = 5 mm) ( 15 tumors). All tumors were confined to the ovary (stage I). In 50 patients, the tumor involved one ovary, and in three patients, the tumors were bilateral. The predominant growth pattern was adenofibromatous in 29 tumors and glandular or papillary in 27 tumors. In 8 (24%) of 41 APTs, areas of benign adenofibroma were identified, and in 13 (87%) of 15 carcinomas, areas of associated APT were identified. Stromal invasion was manifested by confluent glandular growth in all 15 invasive carcinomas and all tumors with microinvasion. Destructive infiltrative growth was also present in 2 (13%) of 15 carcinomas. Confluent glandular growth was the most common manifestation of stromal invasion and therefore served as the best criterion for the diagnosis of carcinoma. Squamous differentiation was observed in 24 tumors, and mucinous differentiation was seen in 20 tumors and was most often seen in APTs. Endometriosis was present in 14 patients with APTs and one patient with carcinoma. Four patients had hyperplasia or atypical hyperplasia of the endometrium. One patient with an APT had a concurrent peritoneal serous neoplasm. Twenty-one patients had available clinical follow-up. Twenty (95%) of 21 patients, including six with invasive carcinoma, two with microinvasion, one with intraepithelial carcinoma, and 11 with APT were alive with no evidence of disease with a mean follow-up of 47 months. One patient with carcinoma had recurrent tumor after 46 months and was alive 40 months after resection of the recurrent tumor. In this large series of proliferative endometrioid tumors, all were stage I and only one patient had a recurrence. Most carcinomas contained evidence of a precursor APT, and in some APTs, an associated benign adenofibroma was identified. Microinvasion or intraepithelial carcinoma occurred in 19% of APTs. This finding likely reflects the various stages of endometrioid carcinogenesis in the ovary. For clinical management, we suggest that these tumors be divided into two categories-APTs and well-differentiated carcinoma-because based on the available data, cytologic atypia and microinvasion appear not to affect the prognosis.

Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas.

Histologic criteria for the distinction of ovarian mucinous borderline tumors (MBTs) from invasive mucinous carcinomas (MUCCAs) and the definitions of intraepithelial (noninvasive) carcinoma and microinvasion are controversial. Accurate assessment of the behavior of these tumors has been obscured by inclusion of cases of pseudomyxoma peritonei (PMP), an entity of extraovarian origin, and misclassification of the ovarian tumors in PMP and metastatic mucinous carcinomas (METCAs) as either advanced-stage MBTs or primary ovarian MUCCAs. One hundred thirty-six intestinal-type ovarian mucinous tumors without PMP were evaluated for the presence of stromal invasion, marked cytologic atypia, epithelial stratification of more than three cell layers, and necrosis. Criteria for the diagnosis of MBT, MBT with intraepithelial carcinoma, MBT with microinvasion (MIBT), MUCCA, and METCA were established and correlated with behavior. Twenty-three (59%) of 39 patients whose tumors had stromal invasion of more than 5 mm died of disease. Stromal invasion of more than 5 mm was the sole feature that correlated with a poor prognosis. In the absence of this feature, marked cytologic atypia, epithelial stratification of more than three layers, microinvasion (<5 mm), or necrosis did not have an adverse effect on survival. Tumors were classified as MBT (n = 65; 48%) based on absence of stromal invasion, regardless of degree of cytologic atypia or epithelial stratification; of these, 28 (43%) qualified as intraepithelial carcinoma based on epithelial stratification of more than three cell layers or marked cytologic atypia. Tumors with stromal invasion of less than 5 mm were classified as MIBT (n = 8; 6%). Tumors with stromal invasion of more than 5 mm were classified as MUCCA (n = 24; 18%). Tumors with a nodular pattern of stromal invasion, morphology inconsistent with ovarian origin, or a primary site elsewhere were classified as METCA (n = 35; 26%). Four tumors could not be definitively classified. Of the 86 cases with follow-up (median, 33 months) all MBTs (n = 44) and MIBTs (n = 6) were stage I, with 5-year survival rates of 100%. MUCCAs (n = 17) that were stage I had a 5-year survival rate of 91%; all patients with advanced-stage MUCCA died of disease. Five-year survival rate for METCAs (n = 19) was 11%. METCAs were more common than MUCCAs but can mimic MUCCAs and MBTs clinically and histologically. In the absence of a primary site elsewhere, METCA should be strongly suspected when there is bilateral surface involvement and a characteristic nodular pattern of invasion. It is important to recognize this pattern because 5-year survival rate for METCA (11%) was substantially less than that of MUCCA (all stages, 51%) and MBT (100%). Because all MBTs, regardless of degree of atypia or stratification, were stage I and benign, we prefer to designate them as atypical proliferative mucinous tumors. Marked cytologic atypia, epithelial stratification of more than three layers, and microinvasion (<5 mm) had no effect on the behavior of MBT. Noninvasive mucinous tumors with marked cytologic atypia or excessive epithelial stratification can be interpreted as atypical proliferative tumors with intraepithelial carcinoma and those with microinvasion can be designated as atypical proliferative tumors with microinvasion; these tumors appear to represent transitional stages in ovarian mucinous carcinogenesis.