Serous Morphology Research Articles

Malignant mixed Müllerian tumor: Analysis of 21 cases at tertiary care rural hospital

Introduction: Malignant mixed Müllerian tumor (MMMT)/carcinosarcoma is an exceptionally rare tumor, representing just 1%–5% of all gynecological malignancies, but leading to 15% of gynecological malignancy-related deaths, with an occurrence of <2/1,00,000 women/year. Material and Methods: Twenty-one patients with MMMT of the uterus accounting for 1.7% of total uterine malignancies were included in the study. The histologic subtypes of the carcinoma and sarcoma components were examined and recorded. The proportions of carcinoma and sarcoma components were semi-quantitatively evaluated and recorded within the primary tumor site in the hysterectomy specimen. Among the metastatic sites and recurrent tumors, the histologic component (carcinoma vs. sarcoma) was evaluated. Results: Of these 21 cases, the carcinomatous component was further subtyped as 11 cases with endometrioid morphology, four cases each of clear cell and serous morphology, and two cases had undifferentiated epithelial component. Most of the tumors had carcinomatous components and 55% of tumors were high grade. Prognostic factors include the presence of bleeding (P = 0.05) which is associated with poor outcomes. Other known prognostic factors like myometrial invasion (P = 0.46) and stage of disease (P = 0.86) did not show any prognostic significance in present study. Conclusions: The elderly age, higher stage, and a poorly differentiated tumor are associated with poor outcomes. Utmost efforts should be made to educate women in early cancer detection by creating awareness on risk factors and symptoms. Study on the trends of gynecological cancers is essential to plan and evaluate cancer control programs.

The Prognostic Effect of HER2 Gene Amplification in High-Grade Endometrial Carcinomas and its Correlation with Protein Overexpression.

Introduction. New therapeutic agents and biomarkers are needed for the treatment of aggressive endometrial cancer subtypes. Recently, HER2 has been recommended to be tested routinely in serous endometrial cancers. The aim of this study is to investigate the correlation between HER2 (ERBB2) protein overexpression and HER2 gene amplification and the relationship of HER2 gene amplification with prognosis in cancers with serous morphology. In addition, the concordance of HER2 testing in paired curettage and hysterectomy specimens is also investigated. Methods. Twenty five serous carcinomas and 8 carcinosarcomas with a serous morphology were included in the study. HER2 staining was performed on whole tissue sections by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). The system, which was proposed by Fader et al was used to evaluate the stainings. Results. Protein overexpression was detected in 27.3% (n = 9) of the cases, and gene amplification in 30.3% (n = 10). A significant positive correlation was found between the two methods (P < .0001). HER2 IHC revealed a heterogeneous staining pattern, such as intense complete membranous in solid areas, and basolateral in papillary and glandular areas. HER2 gene amplification was significantly associated with shorter overall (P = .005) and disease-free (P = .014) survival. The concordence of the results in curettage and hysterectomy specimens was also significantly high. Conclusion. HER2 is an important prognostic and predictive marker for endometrial cancers with serous morphology. HER2 IHC/ISH testing can be performed by using diagnostic curettage specimens which contain enough viable tumor cells. However, pathologists should be aware of the intratumoral heterogeneity for HER2 staining.

Endocervical neoplasia: Pathologic updates in diagnosis and prognosis.

The diagnosis of adenocarcinoma of the uterine cervix can be challenging due to the varied histologic types different etiologies and their associated biologic behaviors and corresponding clinical management implications. To address these issues a new classification system has been developed and is introduced in the most recent edition of the WHO Classification of Female Genital Tumors. This system is based on morphology and the relationship with human papillomavirus (HPV). All the tumors are now classified into HPV-associated (HPVA) and HPV-independent (HPVI). In addition there are diagnostic pathology related advancements which are able to predict prognosis such as the incidence of lymph node metastasis and the tumor recurrence. These advances include cancer invasive patterns tumor nuclear grade and the status of necrotic tumor debris. This review will discuss endocervical adenocarcinomas (EAC) including their precursors in association with HPV. Instead of discussing each histologic type of ECA individually we group all EACs into four categories based on their dominant growth patterns including glandular papillary mucin producing and solid microscopic appearances. Differential diagnosis and diagnostic pitfalls are addressed in each category. The glandular growth pattern is the most common. In this category location is important to be considered for the differential. The mucin-producing group is comprised by HPVA and HPVI tumors and the differential diagnosis should include metastatic mucinous carcinomas. Serous carcinoma of the uterine cervix no longer exists; however the terminology serous-like adenocarcinoma has been designated to tumors with the serous morphology that are HPV positive. We include this tumor in the papillary architecture category. A solid growth pattern can be found in multiple histologic types of EAC and most of them behave aggressively. Histopathologic parameters with prognostic relevance are also briefly discussed.

HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology.

Uterine carcinosarcoma (UCS) is an aggressive malignancy with few treatment options. A recent clinical trial has shown an increase in progression-free survival in patients with human epidermal growth factor receptor 2 (HER2)-positive serous endometrial carcinomas treated with anti-HER2-targeted therapies. Few studies have evaluated HER2 expression/amplification in UCS. Similar to serous endometrial carcinoma, the majority of UCS have TP53 mutations and a serous epithelial component, suggesting that UCS may show similar rates of HER2 positivity and therapeutic response. Therefore, we evaluated HER2 expression/amplification in a cohort of UCS over a 5-year period. HER2 immunohistochemistry (IHC) and chromogenic in situ hybridization were performed on tissue microarray and whole tissue sections and scored according to the most recent clinical trial recommendations. Three of 48 UCS (6%) had strong (3+) HER2 IHC expression, and 3 cases (6%) were equivocal (2+). Seven cases (15%) had HER2 amplification by chromogenic in situ hybridization, including all 3 with overexpression and 2 that were equivocal by IHC. Mismatch repair (MMR) protein, p53, and programmed cell death-ligand 1 (PD-L1) expression status was obtained from prior whole section analyses. All HER2-positive cases had a serous morphology and aberrant p53 expression. Only minimal PD-L1 expression was seen in the HER2-positive cases, and none had MMR loss. A subset of UCS with serous morphology have overexpression and/or amplification of HER2, which may predict response to HER2-targeted therapies. HER2-positive UCS may be less susceptible to immune checkpoint inhibition as they uncommonly show MMR deficiency and/or strong PD-L1 expression. Thus, HER2-targeted therapies could be of clinical utility in a subset of UCS without other adjuvant treatment options.

An international, multicenter, real-world analysis of epithelial ovarian cancer treatment and outcomes.

5531 Background: Few major studies have examined and compared the management and outcomes of patients from diagnosis to death between countries. We have established an international collaboration across Europe and South Korea to compare treatment and outcomes in Epithelial Ovarian Cancer (EOC). Methods: Patients diagnosed with EOC between January 2012 and December 2018 (age ≥18), were included for analysis. Data from medical records from five European and a single South Korean treatment centre were extracted, standardised to a common data model and analysed at each centre using a common script developed in R. Time to each progression/recurrence event (defined as time to next treatment) and overall survival have been estimated using Kaplan Meier methodology and outcomes stratified by categories of interest. Changes in the use of anti-cancer therapies over time and the incidence of BRCA mutations and incidence/timing of second breast cancers have also been examined. Results: A total cohort of 2925 patients was identified with a median age at each centre of 53 to 67 years. Advanced disease (FIGO stage III - IV) (range 57% to 84%) and high-grade serous morphology (38% to 70%) were most common at each centre. The timing of surgery (primary, interval debulking or delayed) and the proportion of patients undergoing surgery varied with stage. Patients with stage I disease where most likely to undergo surgery (range 73% to 100%) and stage IV the least (range 39% to 84%). Median overall survival for high grade serous cancers ranged from 1.9 to 4.9 years, and for the whole cohort from 2.1 to 5.5 years. Median time to next treatment at first relapse for the whole cohort ranged from 14 to 22 months. Second breast cancers were noted in 6 to 17% of patients and the majority of these occurred before the diagnosis of EOC at a median time of 96 to 118 months prior to diagnosis of EOC. Additional data on treatment pathways, BRCA status and outcomes by line of therapy for each centre will be presented. Conclusions: Preliminary analysis of results across this network suggests a variation in patient populations between sites and substantial differences in both treatments and outcomes. The establishment of a common data model and the use of a common analytic script between sites across six different countries allows for detailed exploration of the factors influencing differences in patient management and treatment outcomes in ovarian cancer patients.

90. Serous borderline paraovarian tumor: a rare presentation in an adolescent girl

<h3>Background</h3> Borderline serous ovarian tumors represent less than 1% of all ovarian tumors in children and adolescents. Even more rare are serous borderline paratubal tumors. There are a few case reports of this rare tumor in the adult literature, but to our knowledge we report the youngest patient with a serous borderline paratubal tumor. <h3>Case</h3> A 17 year-old girl presented with progressive weight gain and lower abdominal distension over a three month period. She also reported intermittent crampy suprapubic abdominal pain as well as irregular menses and increasing fatigue. Workup revealed a 19 × 15 × 10 cm mass adjacent to the left ovary. Laboratory evaluation was remarkable only for a mild elevation in LDH (641). She underwent laparoscopic, ovarian sparing resection of a paratubal cyst. Final pathology was consisted with a serous borderline tumor without invasion or microinvasion. Cytology from the cyst fluid also showed "atypical cells with serous morphology." She had an uneventful post operative course, her LDH levels normalized, and she is currently being followed with serial ultrasounds and LDH levels. <h3>Comments</h3> Serous borderline paratubal tumors are extremely rare tumors, usually occurring in young women. There are only scant case reports in the adult literature and this is the first reported case in an adolescent to our knowledge. These tumors generally present as early stage and have good clinical outcomes. Continued reporting is essential to ensure a better understanding of these tumors.

PD-L1 and Mismatch Repair Status in Uterine Carcinosarcomas.

Uterine carcinosarcomas have few adjuvant treatment options. Programmed cell death ligand-1 (PD-L1) expression in these tumors may predict response to checkpoint inhibitor therapies. An increase in PD-L1 expression has been shown in endometrial carcinomas with mismatch repair (MMR) deficiencies; however, few studies have evaluated PD-L1 expression in uterine carcinosarcomas. We examined PD-L1 expression in 41 cases of uterine carcinosarcoma using combined positive scores (CPS) and tumor proportion scores (TPS), and correlated with MMR status, p53 expression, and epithelial histotype. In addition to confirming the diagnosis of carcinosarcoma, the epithelial components were stratified based on endometrioid versus serous histology. Thirty-three cases (80%) were positive for PD-L1, defined as a CPS score of ≥1 or a TPS score of ≥1%. Twelve cases (29%) showed high expression of PD-L1, defined as a CPS score of ≥10 or a TPS score of ≥10%. The majority of the morphologically adjudicated carcinosarcomas had a serous epithelial component (83%) rather than endometrioid (17%), which was reinforced by aberrant p53 staining predominantly within cases with serous morphology. The majority of carcinosarcomas showed at least focal PD-L1 expression, predominantly in tumor-associated immune cells. Carcinosarcomas with endometrioid morphology were significantly more likely to have high-level PD-L1 (5/7 vs. 7/34; P=0.015). MMR-deficient carcinosarcomas were also more likely to have high-level PD-L1 (2/3 vs. 10/28); however, this did not reach statistical significance (P=0.2) and overall MMR-deficiency was uncommon (3 cases, 7%). These findings suggest that PD-L1 may be additive to MMR testing as a predictive biomarker for checkpoint inhibitor vulnerability in carcinosarcomas.

Mismatch Repair Deficiency in Uterine Carcinosarcoma: A Multi-institution Retrospective Review.

Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is recommended in endometrial carcinomas as a screening test for Lynch syndrome, and mismatch repair deficiency (MMRd) is reported in ∼30% of cases. However, few studies have evaluated the rate of MMR loss in uterine carcinosarcomas. A 5-year retrospective database search of uterine carcinosarcomas was performed at 3 academic institutions. The histologic diagnoses, type of carcinoma present, and MMR IHC interpretations were confirmed by a gynecologic pathologist. One hundred three cases of uterine carcinosarcomas with available MMR IHC results were identified. Ninety-nine cases (96%) showed intact expression and 4 cases (4%) showed loss of MLH1/PMS2. All MMRd carcinosarcomas identified in this series had an endometrioid carcinomatous component and wild-type p53 expression. In contrast, the majority of MMR intact carcinosarcomas had a serous morphology and aberrant p53 expression. Three additional cases initially diagnosed as carcinosarcoma also revealed MMRd; however, given the lack of clear mesenchymal differentiation, these cases were reclassified as dedifferentiated endometrial carcinomas and were subsequently excluded from the carcinosarcoma category. No cases of Lynch syndrome were identified among carcinosarcoma patients, as all 4 MMRd cases were due to somatic MLH1 hypermethylation. In summary, we found that the rate of MMRd is markedly lower in uterine carcinosarcoma when compared with endometrial carcinoma. In the setting of MMR loss, a diagnosis of dedifferentiated carcinoma should be considered as almost half of the MMRd tumors which were called carcinosarcomas initially were reclassified as dedifferentiated on review. However, given the interobserver variability in the classification of carcinosarcoma versus dedifferentiated carcinoma a universal screening approach that includes uterine carcinosarcoma is still recommended.

VEGF Expression to Support Targeted Therapy in Ovarian Surface Epithelial Neoplasms.

Vascular Endothelial Growth Factor (VEGF), a promoter of angiogenesis, is a promising target for anti-angiogenic therapy in ovarian cancer. In our study, we examined the expression of VEGF in the spectrum of epithelial ovarian neoplasms (benign, borderline and malignant) by Immunohistochemistry (IHC). Diagnosing ovarian epithelial neoplasms, examining the expression of VEGF in benign, borderline and malignant neoplasms and correlating it with histological grade and stage of malignant cases. This is a cross-sectional, observational study where, total of 50 cases of surface epithelial ovarian neoplasms were examined for expression of VEGF by IHC. Scoring for VEGF expression was done for each case. A total of 42 of the 50 cases (84%) showed VEGF expression. Out of the 42 positive cases, 19 were high VEGF expressors and 23 were low VEGF expressors. VEGF expression was significantly higher in carcinomas as compared to benign and borderline neoplasms (p=<0.001). All neoplasms of serous morphology were positive for VEGF. High VEGF expression was significantly associated with high grade (p=0.003) and stage (p=0.001) of disease. Ovarian surface epithelial neoplasms significantly express VEGF. Though, some VEGF expression was noted in benign and some borderline neoplasms, high VEGF expression was noted only in carcinomas and one case of borderline serous papillary tumour. Thus, these results suggest that epithelial ovarian tumours are candidates for VEGF targeting therapy as most of them are dependent on VEGF for progression.

Prognostic significance of immunohistochemical markers in endometrial cancer treated with chemotherapy

e16551 Background: The proportion of patients receiving chemotherapy for endometrial cancer is increasing both in the adjuvant and advanced setting. The literature describes many prognostic immunohistochemical factors in early stage endometrial cancer, the majority of whom will not receive chemotherapy. The aim of this study was to describe the biomarker expression for endometrial tumours treated with chemotherapy and to assess what constitutes a favourable and unfavourable profile for this patient group. Methods: For a subset of patients with either endometrioid, serous or a mixed mullerian morphology treated with chemotherapy at our centre between 1996 and 2008 an immunohistochemical profile of 14 biomarkers was studied (ERα, Erβ1, Erβ2, PR, PRB, P53, Rb, E-cad, MDM2, MIB-1, E2F1, p16, p13, and p21). A univariate analysis using cox regression of potential prognostic factors was then carried out. Results: In total 199 patients received chemotherapy for endometrial cancer over the 12 year period studied. Two year survival from commencement of chemotherapy for patients receiving adjuvant treatment was 45.2% and palliative treatment 28.1%. The commonest histological subtypes were endometrioid adenocarcinoma (40%), serous carcinoma (24.1%) and mixed mullerian tumours (14.6%). For the subset of 35 patients 38.2% of patients had positive immunohistochemical staining for ERα, 53% for PR, 73.5% for p16, and 94% for E2F1. Good prognosis was predicted by the strength of staining for E2F1 (HR 0.757, CI 0.216/0.902, p = 0.025) and poor prognosis by p16 (HR 1.470, CI 1.040/2.077, p = 0.029). Conclusions: Positive staining for ERα and PR was of similar frequency to previous studies of early stage endometrial cancer and did not significantly influence prognosis. Good prognosis correlated with E2F1 expression and poor prognosis with p16. A greater proportion of patients had serous morphology compared to published series of early stage endometrial cancer. Further study of prognostic factors in larger numbers of patients and built into prospective randomised trials may allow the creation of a prognostic model and guide the development of future clinical trials of targeted therapy. No significant financial relationships to disclose.

Serous Intraepithelial Carcinoma Arising in an Endometrial Polyp: A Proposal for Modification of Terminology

Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States, most frequently presenting in postmenopausal women. Two major subtypes of endometrial adenocarcinoma are now well recognized. The more common (type 1) has an endometrioid morphology with several variants. The far more aggressive subtype (type II) that accounts for only 10% of cases more frequently displays a serous morphology, but may have pure clear cell differentiation. We present here an interesting aspect of the type II carcinoma manifested in a case we recently received for consultation at the Department of Pathology, Yale New Haven Hospital. Seven slides were available for review from a 67-year-old woman, who had undergone a total hysterectomy and bilateral salpingo-oophorectomy. An endometrial polyp (Figure 1) was the major finding. Within the polyp, a high-grade malignant serous epithelium focally replaced the surface epithelium and superficial glands of the endometrial polyp (Figure 2). Despite the absence of any myometrial invasion, endocervical mucosal involvement without stromal invasion was identified (Figure 3). The non-neoplastic endometrium was atrophic. The neoplastic cells were immunoreactive for p53 (Figure 4) and showed a high mitotic index on Ki-67 immunostain, supporting the morphologic impression. The clinical, morphologic examination, and immunohistochemical profile were classic for the so-called endometrial intraepithelial carcinoma (EIC).

Early molecular changes in endometrial cancer

Endometrial carcinoma (EC) is currently divided into two major types, Type I and II, based on clinicopathological parameters. Type I carcinomas are associated with a hyperestrogenic state and account for approximately 85% of ECs. Type I carcinomas are low-grade, indolent tumors of endometrioid histology. In contrast, Type II tumors are estrogen independent and arise in the setting of atrophy. They are poorly differentiated tumors and most commonly demonstrate a serous morphology. Molecular genetic studies over the past decade have shown that the two tumor types evolve via distinct pathogenetic pathways(1). The most frequent early molecular genetic alterations in Type I tumors are mutations in the PTEN tumor suppressor gene and KRAS oncogene and microsatellite instability (MI). Molecular genetic studies have shown that PTEN and KRAS mutations are present in complex atypical hyperplasia (CAH), the direct precursor to endometrioid carcinoma. In addition, methylation of the hMLH1 gene, which is thought to result in MI, has also been documented in CAH. In addition, it has been consistently reported that there is a statistically significant association between PTEN mutations and MI in Type I tumors, however the biological significance of the association remains unclear(2). More recently mouse models have further supported a central and early role for the PTEN gene and MI in the development of Type I EC. One hundred percent of Pten heterozygous female mice spontaneously develop complex atypical hyperplasia. The lesions begin to develop at about 16 weeks and increase in number and size with age. By 10 months of age approximately 20% develop carcinoma. The invasive lesions are histologically very similar to well-differentiated endometrioid carcinoma often demonstrating mucinous and squamous metaplasia as seen in primary human endometrioid carcinoma. In order to explore the relationship of MI and PTEN mutations, Pten heterozygous, Mlh1 null mice were generated. Mice of this genotype have an accelerated onset of lesions and an increase in the frequency of invasion at a young age(3). This mouse model should provide a system in which the association of these two common molecular alterations can be studied and the relationship between genetic alterations and hormonal influences can be addressed. Although there have been fewer studies on Type II tumors, mutations in P53 have been found in 75% of endometrial intraepithelial carcinomas, the putative precursor to serous carcinoma, and in 90% of serous carcinomas. Additional studies are clearly needed to uncover the other common alterations in this uncommon, but aggressive, form of endometrial carcinoma.