IMR Press / EJGO / Volume 40 / Issue 4 / DOI: 10.12892/ejgo4553.2019
Open Access Original Research
Histopathologic features of advanced stage endometrial carcinoma
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1 Department of Pathology, The University of Eskisehir Osmangazi School of Medicine, Eskisehir, Turkey
Eur. J. Gynaecol. Oncol. 2019 , 40(4), 614–618; https://doi.org/10.12892/ejgo4553.2019
Revised: 10 January 2018 | Published: 10 August 2020
Abstract

Objectives: Four to six percent of endometrial cancer (EC) cases have been diagnosed at an advanced stage. The aim of the study is to show the role of immunohistochemistry in the new endometrial carcinoma classification. Materials and Methods: Twenty-nine advanced Stage EC cases which were admitted to the Eskisehir Osmangazi Hospital were included in the study. One grade 1, 18 grade 2, and ten grade 3 EC cases were detected. Ten EC cases showed focal or diffuse strong p53 expression and three cases had Lynch syndrome with the dual loss of MLH1 and PMS2. In those cases that were above 60-years-old, PTEN inactivation, loss of PAX-8, and strong p16 positivity were detected. Five cases had focal or complete e-cadherin loss or inactivation and ten cases had focal CDX-2 expression and/or β cathenin nuclear expression due to β-cathenin mutation. Results: Nine out of 22 cases who had deep myometrial invasion showed MELF pattern of myometrial invasion (p = 0.05). Fallopian tube involvements were associated with mild p53 positivity (p = 0.002) and peritoneal washing fluid positivities were correlated with serosal involvement (p = 0.013). Three cases (10.3%) showed recurrences and one case died from the disease during the study. Conclusions: Tubal endometriosis or adenomyomatous polyp were found in the other tube in ECs with tubal involvement and these case had superficial myometrial invasion. Strong p53 expression and Lynch syndrome coexisted with the e-cadherin and β-cathenin mutations in advanced stage ECs.

Keywords
Endometrial cancer
Immunohistochemistry
p53
MLH1
Advanced stage
Endometriosis
Introduction

Endometrial cancer (EC) is the most common neoplasm in female genital tract and occurs in both premenopausal and postmenopausal women. Type I and II ECs share many etiologic factors except estrogen dependency. The distribution of cases with respect to the stages are as following: 77.1% is in Stage I, 6.6% is in Stage II, 12,4 % is in Stage III, and 4% is in Stage IV in a large sample of ECs [1]. Stage I tumors have excellent prognosis. Recurrence rates are between 20% to 40% in type I ECs and type II ECs, respectively [2-4]. ECs had mutations in CTNNBI genes in 15-20% of the cases and some cases had also microsatellite instability. In type I tumors, mutations of PTEN, KRAS, PIK3CA, and loss of heterozygosity in cell cycle genes were also found [5]. Based on the recent integrated genomic data, EC can be classified into four prognostic molecular subtypes: (1) POLE ultra mutated tumors, (2) microsatellite unstable tumors (MSI), hypermutated, (3) copy number low, microsatellite stable tumors (MSS), and (4) copy number high, serous-like (mostly had TP53 mutations)[2].

The aim of this study is to define histopathologic features of advanced stage eEC by the aid of immunohistochemical stainings.

Materials and Methods

Twenty-nine advanced stage (Stage III-IV) EC cases which were histopathologically classified in the Eskisehir Osmangazi Hospital between January 2014 to July 2017 were included in the study. FIGO grade, myometrial invasion depth, pattern of myoinvasion, tubal involvement, serosal involvement, positivity of peritoneal washing fluid serology, cervical involvement, status of metastatic lymph node, and the presence of accompanying endometriosis were evaluated. All of the immunohistochemical (IHC) stainings which were applied to the EC cases had been recorded in computer-based patients’ pathology reports. The immunohistochemical studies were performed using a standard procedure on an automated immunostainer. Immunohistochemical studies were performed by using p53, MLH1, PMS2, MSH2, MSH6, PAX8, e-cadherin, β-cathenin, CDX2, estrogen receptor, progesterone receptor, p16, chromogranin, and CK19 antibodies. MLH1, PMS2, MSH2, and MSH6 were applied to ten of the EC cases. WT-1, calretinin, and PTEN were also used as primary antibodies if they were necessary for differential diagnosis. Appropriate positive controls were used for each antibody. The primary antibody was replaced with PBS as a negative control. Diaminobenzidine was used as chromogen. Finally, the sections counter was stained with Mayer’s hematoxylin, and the sections were dehydrated, cleared, and mounted.

Focal or diffuse strong p53 expression were accepted as positive staining in this study. One to 10% of tumor cells with weak or moderate intensity of p53 expression accepted as wild type expression. PAX-8, MLH1, PMS2, MSH2, and MSH6 staining were evaluated as negative or positive. The percentage of staining was evaluated in the other immunohistochemical stains.

Results

The patients’ ages ranged from 39 to 85 (mean; 59, median; 62) years. Eleven (38%) cases were under 60 years and 18 (62%) cases were above 60 years. Of the 29 cases,20 (69%) cases had EC at tubal segments, 14 (48%) cases had cervical stromal involvement and six (21%) cases had extrauterine disease, five (17%) cases had metastatic lymph nodes. Peritoneal washing fluid was positive in five (17%) cases. Among 29 cases, one case was grade 1, 18 (62%) cases were grade 2, ten (35%) cases were grade 3. One case of mixed endometrioid serous carcinoma (MEC) coexisting with synchronous serous tubal carcinoma at the fimbrial end, two cases of grade 3 EC arising in adenofibroma, two cases of Stage IIIa EC arising in adenomyomatous polyp, and one case of dedifferentiated carcinoma were detected. One EC case was in Stage IIIa and associated with ovarian granulosa cell tumor in Stage IC were observed. There were three cases that were under 60-years-old with superficial myometrial invasion and these cases were associated with endometriosis.

Recurrence was observed in three (10.3%) cases and one vaginal, one cervical lymph node metastasis, and one urinary bladder metastasis were observed. Vaginal recurrence was observed in a grade 2, Stage IIIa EC case originated in adenomyomatous polyp and there was also cervical mucosal involvement. One patient who was diagnosed as MEC originating in adenomyomatous polyp associated with serosal and tubal involvement died from disease.

Immunohistochemistry exhibited T cell factor/APC/β-cathenin pathway involvement in ten (34.4%) cases. In these cases, CDX2 or p63 positive squamous differentiation areas showed decreased estrogen and progesterone receptors, CK19 expression, and/or β-cathenin nuclear expression and these features were compatible with β-cathenin mutation [6]. Two cases showed additional chromogranin expression, 50% and 70%, respectively. One case showed e-cadherin inactivation with additional 80% CDX2 expression due to β-catenin mutation. Recurrence was observed in urinary bladder after 11 months. Focal or complete loss of membranous e-cadherin expression was observed in five cases: one of these cases had grade 1 EC showing also 70% chromogranin expression (Figure 1). Three cases had an additional 5%, 30%, and 50% chromogranin expression. One case had an additional strong p53 positivity and associated with ovarian, tubal and cervical endometriosis, and omental vascular thrombosis. Ten (34.5%) cases had focal or diffuse strong p53 expression (serous-like ECs, one case MEC arising in adenomyomatous polyp, one case of MEC associated with synchronous serous tubal carcinoma, and two cases of carcinoma arising in adenofibroma).

Figure 1.

— Focal loss of membraneous e-cadherin expression in grade 1, Stage IIIa EC arising in an adenomyomatous polyp (e-cadherin immunohistochemistry).

Among 29 cases, six (20.7%) patients had additional immunohistochemical abnormalities, that had a strong p53 positivity (three cases) and dual loss of MLH1 and PMS2 (three cases). One of the Lynch syndrome cases had Stage IV disease showing dual MLH1 and PMS2 loss, and β-cathenin mutation was associated with 27 metastatic lymph nodes. This case showed recurrence in a cervical lymph node after 16 months. The second case with an omental involvement, had β-cathenin mutation and Lynch syndrome as shown in Figures 2 and 3.

Figure 2a.

— MLH1 loss of tumor cells. Lymphocytes around the tumor express the MLH1 antibody (MLH-1 immunohistochemistry).

Figure 2b.

— EC metastasis in omentum showing strong keratin expression (keratin immunohistochemistry).

In three cases above 60 years, PTEN inactivation, loss of PAX-8 (85y), and strong p16 positivity due to aging were detected. There were two PAX8 negative and strong p53 positive case and one of them was 44-years-old.

Statistical inference was based on Pearson Chi Square test. Twenty-two (75.9%) cases had deep myometrial invasion and MELF pattern of myometrial invasion was observed in nine (31%, p = 0.05) cases. Fallopian tube involvement was associated with mild p53 positivity (p = 0.002, Table 1) and peritoneal washing fluid positivity was correlated to serosal involvement (p = 0.013, Table 2). Six cases had endometriosis. Of the endometriosis cases, three cases were under 60 years and had superficial myometrial invasion. Endometriosis was associated with the cases under 60-years-old and there was superficial myometrial involvement (p = 0.018 and p = 0.01, respectively, Tables 3 and 4).

Table 1Comparison of fallopian tube involvement and p53 IHC in ECs.
Fallopian tube involvement P53 Total p value
Negative Positive
Negative 2 7 9 0.002
Positive 17 3 20
Total (29 cases) 19 10 29
Table 2Comparison of positive peritoneal fluid serology and serosal involvement.
Serosal involvement Peritoneal fluid cytology Total p value
Negative Positive
Negative 20 1 21 0.013
Positive 4 4 8
Total (29 cases) 24 5 29
Table 3Comparison of age in ECs associated with endometriosis.
Age Endometriosis Total p value
Positive Neg.
<60 5 6 11 0.018
>60 1 17 18
Total 6 23 29
Table 4Comparison of myometrial invasion degree in ECs associated with endometriosis.
Myometrial invasion Endometriosis Total p value
Neg. Positive
>1/2 2 5 7 0.001
<1/2 21 1 22
Total 23 6 29
Discussion

In this study, IHC was applied to all EC cases after definition of morphological features. IHC provides important clues to define primary tumor side, synchronous malignancies, to discriminate the tumoral cells among the spilling fallopian tube cells /or peritoneal fluid cells, and to find the cause of the aggressive behavior [6-13]. P53 overexpression was correlated with high nuclear grade and positive p53 staining was suggested to be an aggressive behavioral indicator for ECs [14,15]. Rossi et al. [16] showed that 52.2% of 69 mixed endometrial carcinomas had Stage III-IV disease. MECs having a type 2 component larger than 5% represent more aggressive outcomes and worse prognoses due distant metastases. In this study, pure endometrioid carcinomas showed weak or moderate heterogenous p53 staining and this finding was observed in less than 10% of tumor cells. This result was evaluated as wild type p53 staining due to acute stress. Ten of 29 Stage III-IV ECs, exhibited focal or diffuse p53 overexpression due to chronic stress and this was the cause of more aggressive behavior [17-19]. In type I tumors mutations of PTEN, KRAS, PIK3CA, and CTNNBI genes were frequently found and microsatellite instability coexisted in some early or advanced stages of ECs [5]. Kato et al. [20] showed that isolated loss of PMS2 IHC expression is frequently caused by heterogenous MLH1 promotor hypermethylation. Billingsley et al. [21] detected POLE mutations in microsatellite stable (MSS) and unstable tumors (MSI) at similar frequencies, 5.9% and 5.2%, respectively and they found 25% of ECs with MSI, but lacking MLH1 methylation, are POLE-ultramutated. Loss of heterozygosity in cell cycle genes were also found in EC. P16 is a tumor suppressor gene. Horre et al. [22] showed that p16 immunostaining with mosaic pattern was seen in all cases with endometrial tubal metaplasia. Simon et al. [23] demonstrated that the presence of typical and atypical tubal metaplasia did not increase the risk of developing endometrial hyperplasia and endometrial cancer at long-term follow-up. These cases showed focal Ki-67 positivity and focal weak to mild p53 expression; however TERT expression was observed in only uterine serous carcinoma cases. While PAX-8, a Müllerian differentiation factor, is highly expressed in ovarian carcinomas, in endometrium cancers it may result in staining at lower levels, even with complete loss [24]. In this study there were two PAX-8 negative but p53 positive EC cases. Further studies are necessary to better clarify PAX-8 negative and p53 positive endometrial carcinoma cases for diagnosis of Li-Fraumeni syndrome.

Investigations on the prognostic role of prostaglandin, retinoic acid, prenylation, carbonyl, and lipid synthesis pathways showed their important roles to controlling cells during inflammation, proliferation, differentiation, apoptosis, mutagenesis, and carcinogenesis. As a product of prostaglandin pathway cox-2 and estrogen, progesterone and progesterone metabolites have important effects on inflammation and differentiaton [25,26]. Sinreih et al. [26] examined correlations between gene expessions, demograpic characteristics, and histopathologic findings in ECs by STAR (steroidogenic acute regulatory protein), AKR1B1 and AKR1B10 (aldo-keto reductase 1B10), and revealed STAR and AKR1B10 were significantly decreased in high-grade vs. low-grade ECs tumors. Lower levels of STAR might lead to a decrease de-novo steroid hormone synthesis with the effect on cholesterol transportation through the mitochondrial membrane and this resulted in a decrease of tumor differentiation. Lower levels of AKR1B10 may result in diminished elimination of toxic electrophilic carbonyl compounds in high-grade endometrial cancer.

In recent years, studies about myoinvasive patterns of EC have pointed that lymphovascular space involvement mostly occurs in the microcystic elongated fragmented pattern (MELF) [27-30]. Joehlin-Price et al. [31] reported 16 cases of lymph node metastases in 464 consecutive case of FIGO grade 1 EC. After an average of 26 months follow-up, 4.3% of patients showed recurrences. In this group, 45% of cases had isolated vaginal recurrences and 55% had extravaginal recurrences. In a multicentric study, 67 recurrent low-grade only surgically-treated EC cases had relapses in vagina (47.8%), in peritoneum (28.4%), in lymph nodes (9%), and showed hematogenous metastases (14.9%). These results demonstrated that lymphovascular space involvement and patient age are important risk factors for giving adjuvant therapy in grade 2 ECs [32]. In this study, 10.3% of the cases showed recurrences during the study. Sanci et al. [33] observed a recurrence rate between 15.8% and 19.4% in grade I-II ECs with MELF type of myoinvasion and the other types of myoinvasion, respectively (p > 0.05). In this study, among 22 ECs with deep myometrial invasion, nine ECs had MELF pattern of myoinvasion and it was statistically significant (p = 0.05).

Fallopian tube is an important channel for EC to spread to the peritoneum. Fallopian tube sampling according to SEE-FIM protocol is necessary for the true histopathologic classification of EC cases. Intraluminal tumor cells within the fallopian tube are associated with-high grade carcinoma and positive peritoneal cytology [34,35]. In this study, most of the ECs (85%) with fallopian tube involvement had wild type p53 expression (p = 0.002) and peritoneal washing fluid positivity was correlated with serosal involvement (p= 0.013). There were six endometriosis cases in this study and endometriosis was found to be associated with the cases under 60 years and superficial myometrial involvement (p = 0.018 and p = 0.01, respectively). Endometrial cancer arising in adenomyomatous polyp has distinct tumor characteristics and poor survival outcome compared with EC coexisting with adenomyomatous polyp [36]. In this study, two ECs arising in adenomyomatous polyp and three endometriosis cases located in the fallopian tube had tubal metastases, and four out of five cases had metastases in the other fallopian tube. A case of MEC arising in adenomyomatous polyp had also tubal tumoral involvement and died from disease.

In this immunohistochemical study, MELF pattern of myoinvasion, p53 overexpression, Lynch syndrome, and Li-Fraumeni syndrome (i.e. PAX-8 negativity coexisted with p53 overexpression?), loss of PTEN expression, focal or complete loss of e-cadherin expression, and beta-catenin mutation associated with neuroendocrine differentiation, strong p16 expression was observed in the advanced stage of endometrial carcinoma cases. This study showed that the cases with fallopian tube endometriosis and ECs arising in adenomyomatous polyp imposed important risks for the development of tubal metastases under 60-years-old.

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