Correlation Between Histopathologic Features And β-HCG Levels in the Event of Hydatidiform Mole

ABSTRACT


INTRODUCTION
A hydatidiform mole, more commonly known as a molar pregnancy, is a pregnancy which characterized by abnormal trophoblast growth. In a hydatidiform mole, the structure formed by the trophoblast is chorionic villi which has bubbles-shaped like grapes. Based on genetic and pathological differences, hydatidiform mole can be divided into two subtypes, that are complete and partial hydatidiform mole. 1 Compared with other gestational trophoblastic diseases, hydatidiform mole is the most common type. In general, the incidence of hydatidiform mole in Asia and Latin America is higher than in western countries. The incidence in Europe and the United States is 1-2 per 1000 pregnancies, while the incidence in Southeast Asia is eight times higher. The incidence of hydatidiform mole in Indonesian hospitals is higher than other countries, which is 1 per 40 pregnancies. It shows that hydatidiform mole is an important disease in Indonesia. 1,2 Many patients with molar pregnancy are concerned that their condition could affect their reproductive health. Several studies have found that a patient with a hydatidiform mole, especially a complete mole, has a 10-20 times greater risk of mole recurrence than the general population. It can be concluded that 2% of hydatidiform mole patients could have an abnormal pregnancy after evaluation. To improve postevaluation reproductive health, we have to know the factors that have correlation with the patient's reproductive performance. In patients with hydatidiform mole, there are several clinical characteristics that can indicate a high risk of developing malignancy and affecting reproductive performance. One of them is the increase of β-hCG levels, conditions that can interrupt hypothalamic-pituitary-ovarian system so may produce different pregnancy outcomes. These clinical symptoms are related to the excessive proliferation of syncytiotrophoblast cell which causes the chorionic villi has hydrophilic degeneration which can be observed on histopathologic features and also has secondary effect of exceeding uterine size for gestational age. 1,2 This research aims to reveal the correlation of histopathologic feaures with β-hCG levels in hydatidiform mole patients so that it can be used as a screening to detect hydatidiform mole malignancy. 3 This study is an analytic observational study with a cross sectional design to see the correlation of histopathologic features with β-hCG levels in hydatidiform mole patients through secondary data.

Statistical analysis
The data analysis used chi-square to see the correlation between histopathologic features and β-hCG levels in hydatidiform mole patients. A p-value <0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) versions 17 for Windows.

RESULTS
Patients with hydatidiform mole from the Hasanuddin University Hospital from 2014 to 2019 were 12 samples and from Dr. Wahidin Sudirohusodo had 40 samples. So the total samples of this research are 52 samples. The minimum number of samples is determined by the Slovin formula. The results of minimum sampling are 46 respondents from 52 total population. However, only 28 samples had β-hCG levels and histopathologic features for analysis. Patient data was analyzed in two phases. At first β-hCG levels were divided in two categories: <100.000 mIU/mL and >100.000 mIU/mL. Next histopathological features of villi that has hydrophilic degeneration were divided in four categories: 10-25%, 25-50%, 50-75%, >75%. And then histopathological features of the proliferating trophoblast were divided I two categories: hypoproliferation and hyperproliferation.  Table 5.1 shows the correlation between β-hCG levels and the histopathologic of villi that has hydrophilic degeneration. There were 10 respondents who have β-hCG levels <100.000 mIU/mL, including 3 people whose villi had 10-25% hydrophilic degeneration, 3 people whose villi had 25-50% hydrophilic degeneration, no person whose villi had 50-75% hydrophilic degeneration and 4 people whose villi had >75% hydrophilic degeneration. There were 18 respondents who had β-hCG levels >100.000 mIU/mL, which no people whose villi had 10-25% hydrophilic degeneration, 1 person whose villi had 25-50% hydrophilic degeneration, 6 people whose villi had 50-75% hydrophilic degeneration, and 11 people whose villi had >75% hydrophilic degeneration. The result of statistic tests using the chi square test is p value (0.008) < 0.05, which means there is a correlation between the levels of β-hCG and the histopathologic features of villi that has hydrophilic degeneration.

DISCUSSIONS
The normal placenta consists of trophoblastic cells classified according to their location and cytological shape. Trophoblast cells that grow with chorionic villi are called chorionic villi, while trophoblasts that enter and are found in the decidua, myometrium, and placental blood vessels are called extravillous trophoblasts. Trophoblast is divided into three types namely cytotrophoblast, syncytiotrophoblast, and intermediate trophoblast. The syncytiotrophoblast produces hCG on the 12th day of gestation. Early in normal pregnancy, the serum hCG concentration increases rapidly as the trophoblast increases in size. 4 Classification of hydatidiform mole is associated with the risk of postmolar gestational trophoblastic neoplastic neoplasia (GTN) and clinical management. The type of hydatidiform mole that is distinguished is usually based on histopathology. The classic histological features of a complete hydatidiform mole (CHM) are villous hydrops (widespread cavitation), trophoblastic proliferation (circumferential distribution, hyperplasia and cytologic atypia), intermediate trophoblast and marked cytological atypia. 5 The significant histologic features that can distinguish complete hydatidiform mole (CHM) from partial hydatidiform mole (PHM) were central cistern, trophoblastic proliferation, trophoblastic atypia, two populations of villi, presence of fetal vessels and scalloped border. Howat et al. (1993) reported important features in differentiating CHM from PHM were atypical patterns of trophoblastic hyperplasia with circumferential and multifocal patterns. While Ishikawa (Ishikawa et al.,2009) found that the shape of villi and predominance villi with hydropic change were useful to differentiate complete hydatidiform mole from partial hydatidiform mole. The insignificant pathological morphologies that distinguished CHM from PHM in this study were hydropic villi and trophoblastic inclusions which were similar to previous studies (Paradinas et al., 1996;Ishikawa et al., 2009). However, histological criteria for diagnosis type hydatidiform mole are subjective and difficult to imitate. 6 From a previous study, 72 patients with hydatidiform mole who were treated at the Obstetrics and Gynecology Section of Dr. Wahidin Sudirohusodo Hospital Makassar from January 2002 to December 2005, they were 43 patients who had the sample criteria. The results showed that there were 10 patients with hydatidiform mole in the first trimester (23.3%) which 3 people with low β-hCG levels (7.0%), 4 people with normal β-hCG levels (9.3%) and 3 people with high β-hCG levels (7.0%). In the second trimester there were 33 people (76.7%) with low β-hCG 8 people (18.6%), normal β-hCG 13 people (39.5%), high β-hCG 12 people (27.9%). 6 This shows that β-hCG levels are also influenced by gestational age. However, in this study, it was not categorized based on gestational age. There may be samples with low β-hCG levels or <100,000 mIU/mL due to gestational age in the early trimester, not because partial hydatidiform mole. 7 Research from the Department of Obstetrics and Gynecology, Faculty of Medicine, Padjajaran University, Dr Hasan Sadikin Hospital, Bandung, said that there was a correlation between preevacuated β-hCG levels, histopathologic features, and lutein cysts with β-hCG performance in patients with hydatidiform mole who progressed to PTG and returned to normal. 8 The study explained that there are three risk factors that support the diagnosis of a hydatidiform mole in patient, they are β-hCG levels, histopathologic features of villi that has hydrophilic degeneration, and trophoblast proliferation. 8 This is what supports this research.

Correlation of β-hCG levels with histopathologic features of villi that has hydrophilic degeneration
As we know, a normal pregnancy must consist of mother element which will form the embryonal part (child) and the father element which is needed to form the extraembryonic part (placenta, amniotic fluid, etc.). Because there is no maternal element, in a complete hydatidiform mole there is no embryonal (fetus) part, there is only a pathological extraembryonic part in the form of chorionic villi that become hydrophilic degeneration like grapes and in partial hydatidiform mole, some immature villi relative normal and some villi enlarged with hydrophilic degeneration. 9 Hydatidiform moles are divided into 2; partial and complete moles, where partial moles have normal β-hCG levels or <100.000 and have normal chorionic villi or partially hydrophilic degeneration whereas in complete moles, β-hCG levels > 100,000 and have chorionic villi that are almost entirely hydrophobic degeneration. 10,11 From this study, it can be seen that 10 patients with β-hCG levels <100.000 mIU/mL had chorionic villi which 6 people had partial hydrophilic degeneration and 4 patients had complete hydrophilic degeneration, 18 patients with β-hCG levels >100.000mIU/mL had chorionic villi which 1 person had partial hydrophilic degeneration and 17 people had complete hydropic degeneration.

Correlation of β-hCG levels with histopathologic features of trophoblast proliferation
On research of Obstetrics and Gynecology Department, Faculty of Medicine, Padjadjaran University, Dr Hasan Sadikin Hospital, Bandung, the trophoblast proliferation was divided into 2 categories, they were hyperproliferation and hypo proliferation and it was found that complete hydatidiform mole which has high levels of β-hCG >100.000 mIU/mL in 21 of 23 samples and 14 of 23 samples with histopathological features of hyperproliferation. 8 From this study it can also be seen that 10 patients with β-hCG levels <100.000 mIU/mL which 8 patients had hypoproliferative trophoblast features and 2 patients with hyperproliferative trophoblast, while 18 patients with β-hCG levels >100.000 mIU/mL which 3 people had hypoproliferative trophoblast features and 15 people had hyperproliferation trophoblast features.
Meanwhile, there is a gap where complete hydatidiform mole patients should have β-hCG levels > 100.000 mIU/mL, histopathologic features of villi are all hydrophobic degeneration, and hyperproliferation trophoblast. However, in this study, there were some samples that deviated from having β-hCG levels > 100,000 mIU/mL with histopathologic features of the villi only partially hashydrophilic degeneration and hypoproliferation trophoblasts. 11,12 High levels of β-hCG which give a low value because the sensitivity of the hCG test is set in the range of 27.300 to 233.000 at 8-11 weeks of gestation. Laboratory errors can occur when the β-hCG level is more than 500,000 mIU/mL. Level measurement β-hCG which is found to be falsely low reading can appear in patients with hydatidiform mole, where this phenomenon is called the high dose hook effect. Several things that cause a high dose hook effect include the measurement of ferritin by immunoassay, prolactin, thyrotropin, CA 125, and prostate-specific antigen. High dose hook effect occurs whenever there is an inordinate amount of substance measured by immunoassay that causes incomplete antibody-antigen binding. 12

CONCLUSION
There is a correlation between β-hCG levels and the histopathologic features of villi that had hydrophilic degeneration. The higher the level of β-hCG, the more villi had hydrophilic degeneration. There is also correlation between β-hCG levels and histopathologic features of proliferating trophoblasts. The higher the level of β-hCG, the trophoblast become hyperproliferation.