Physiologic variations of serum tumor markers in gynecological malignancies during pregnancy: a systematic review

Tumor markers are biochemical substances found in the presence of cancer and produced either by the tumor itself or in response to (para)neoplastic conditions, such as inflammation. Tumor markers can be found in a variety of bodily fluids and tissues and include hormones and several subgroups of (glyco)proteins, such as oncofetal antigens (which are normally expressed during fetal life), enzymes and receptors. They are used for diagnosis, assessment of therapeutic efficacy, and detecting recurrence during follow-up. The most limiting factor in the clinical use of tumor markers is the lack of sensitivity and specificity because the majority of markers are tumor-associated rather than tumor-specific; elevated levels can occur in different types of malignancies as well as in benign and physiological conditions such as pregnancy [1]. Moreover, early diagnosis and treatment of recurrences that are solely detected by the use of tumor marker alone has not shown survival benefit [2].

It is estimated that one in 1,000 to 2,000 pregnant women are diagnosed with an intercurrent malignancy, at an average age of 33 years [3]. Moreover, a slowly rising incidence rate has been observed since the 1960s [4]. Breast cancer, hematological malignancies and cervical cancer are the most commonly encountered malignancies during pregnancy [3]. Pregnancy after oncologic treatment is also becoming more common, mainly due to advances in fertility-sparing treatment and improved prognosis [5]. Diagnosis and treatment of these two types of patients cannot always be extrapolated from the non-pregnant patient; this is also the case when interpreting tumor markers during pregnancy. Unawareness of pregnancy-related physiologic elevations of tumor markers may lead to the search for metastatic disease, using extensive and unnecessary diagnostic examinations that are costly and uncomfortable, and also expose the fetus to avoidable radiation.

At present, the number of studies conducted on serum tumor markers during pregnancy is limited. Our goal is to review existing publications on this topic, and also to provide an easily accessible table of reference values during pregnancy for the most common tumor markers used in cases of gynecological malignancies.

We focused on six tumor markers that are well-established in gynecological cancers and are used for breast cancer (carbohydrate antigen (CA) 15-3), cervical squamous cell cancer (squamous cell carcinoma antigen (SCC)), and ovarian cancer (CA 125 for epithelial ovarian tumors, inhibin B and anti-Müllerian hormone (AMH) for sex cord-stromal tumors, and lactate dehydrogenase (LDH) for germ cell tumors). We conducted a systematic literature search in MEDLINE to identify relevant publications from 1 January 1980 to 31 September 2011 in the English language. Additional publications were identified from the reference lists of relevant articles (Figure 1). The systematic search was conducted using the following medical subject headings (MeSH) terms, words and combinations of words: pregnancy AND CA 15-3, squamous-cell carcinoma antigen, CA 125, inhibin B, anti-Müllerian hormone, lactate dehydrogenase. Two investigators (SH and AL) independently identified potentially relevant articles using the title and the abstract. Eligibility criteria were as follows: firstly, when the maternal serum tumor marker was studied in healthy pregnant women without medical or obstetric confounding conditions, and secondly, if the gestational age was reported by trimester. For inhibin, we excluded older publications that used assays unable to differentiate between dimeric forms and thus were nondiscriminatory between inhibin A and B. Due to the diverse study designs and conditions and use of different assay methods with different intra-and inter-assay coefficients of variation, a meta-analysis was not possible.

α-fetoprotein and the β subunit of human chorionic gonadotropin are both substances that are abundantly present during gestation and have been extensively investigated. Reference values during pregnancy are available in most laboratories, hence we did not include these two markers in our review.

The database search provided 1,786 articles for the six tumor markers combined. After an initial review of the title and abstract, 54 articles appeared to be relevant and were retrieved to be reviewed in full. Twenty-six studies met our inclusion criteria and were included in the review. Table 1 provides a short summary of the general characteristics of the tumor markers (clinical use, molecular weight and production site). Definitions on the three trimesters of pregnancy varied between publications. The first trimester was defined as the period between the beginning of pregnancy up to 12 to 14 weeks' gestation; the second trimester was defined as the period from the end of the first trimester up to 24 to 28 weeks' gestation, after which began the third trimester until delivery. For each tumor marker, data were extracted from as many studies as possible. These ranges were combined to establish a normal reference range per trimester (Table 2). Cut-off values used in clinical oncology for non-pregnant adults are as stated in the publications and also listed in Table 2.

Although tumor markers are very commonly used in clinical practice, their relevance and reliability is frequently debated. Tumor markers mainly have a supportive function, even for the routine care of non-pregnant patients. The role of tumor markers is limited in cases of cancer during pregnancy, or pregnancy after cancer, mainly due to their low specificity rate. Elevations are not always correlated with the presence of malignancy but are more often associated with normal physiologic changes of pregnancy. Moreover, obstetrical complications can induce even more variations. For example, elevated CA 125 has been associated with imminent miscarriage [29], and LDH is known to increase in cases of severe preeclampsia and HELLP (hemolysis, elevated liver function tests, low platelets) [26]. Physicians and midwives caring for pregnant women are well aware that the reference ranges of various laboratory values differ during pregnancy [27, 30], and this should also be the case with tumor markers in pregnancy (Table 1). Here, we summarize and explain the physiology of elevated levels during pregnancy for CA 15.3, SCC and CA 125. Inhibin-B, AMH and LDH are not elevated during normal pregnancy.

CA 15-3 is a well-characterized immunoassay that allows the detection of the mucin (MUC)-1 antigen. MUC-1 is part of the family of membrane-bound mucins, large glycoproteins, and their expression is frequently elevated in breast cancer cells. Elevated levels can be found in the serum of over 70% of patients with advanced breast cancer [31]. Conflicting data on the possible fetoplacental origin of CA 15-3 are reported. CA 15-3 concentrations in amniotic fluid and/or umbilical cord blood were analyzed and remained very low throughout pregnancy [32‐34]; the authors concluded that the combination of an elevated maternal CA 15-3 and low levels in amniotic fluid and umbilical cord blood indicate that the antigen is not produced by the fetus, placenta or decidual tissue, and therefore, could not be considered as an oncofetal antigen [32‐35]. However, MUC-1 has been detected in trophoblastic tissue even very early in pregnancy; placental expression increases as the pregnancy progresses and it is highly expressed throughout the third trimester [36, 37]. Several authors have hypothesized that CA 15-3 elevations in maternal serum may result from the proliferation of maternal mammary gland epithelium late in pregnancy, with enhanced secretion of mucin, as opposed to placental transfer of the mucin [9, 10, 35]. Botsis et al. [8], and also Ercan et al. [11], asserted that CA 15-3 is independent of gestation and remains a reliable tumor marker for breast cancer during pregnancy. This statement is not in accordance with most other studies as found in this review. Although the reported values during pregnancy are only moderately elevated, we believe that caution is warranted, and a higher cut-off value would facilitate interpretation during pregnancy.

Elevated SCC serum levels are found in between 57% and 70% of women with a primary squamous cell carcinoma of the cervix. Elevated levels are also found in between 24% and 53% of patients with squamous cell carcinomas of the head and neck, esophagus, and lung, and also in between 8% and 42% of patients with adenocarcinomas of the ovary and uterus [38]. SCC is probably a marker of cellular differentiation for squamous cells, as the incidence of elevated serum levels is higher in women with grade 1 (78%) and grade 2 (67%) carcinomas than in those with grade 3 tumors (38% )[38]. Sarandakou et al. sampled maternal serum, umbilical cord blood and amniotic fluid during delivery of 56 full-termed pregnancies [39]; they found a high incidence of SCC levels above the cut-off value of ≤2.5 µg/L (30% in maternal serum and 75% in umbilical cord blood). The levels found in amniotic fluid were extremely high (median 710 µg/L; range 30 to 7,692 µg/L), which led the authors to conclude that SCC is an oncofetal antigen [39]. The analysis of in vitro culture of amnion cells and amniotic membranes revealed no accumulation of SCC in the supernatant, and no mRNA expression of SCC was found in the amnion, the cord or the placenta using a northern blot with a cDNA probe of SCC [40]. Therefore, it is more likely that the fetus, and not the placenta, is the origin of SCC found in amniotic fluid, but this remains to be confirmed.

CA 125 is used for monitoring non-mucinous epithelial ovarian cancer [7, 41]. Of patients with ovarian carcinoma, 82% have CA 125 levels >35 U/mL, compared with 1% of apparently healthy non-pregnant individuals. During pregnancy, CA 125 is present in relatively high concentrations in decidual cells, amniotic fluid and amnion cells, and significantly lower levels are found in umbilical cord blood, suggesting that decidua and amnion cells (and not the fetus) produce and secrete CA 125 into the amniotic fluid [39, 41, 42]. Interestingly, the molecular weight of CA 125 identified in pregnancy was significantly higher than that observed in ovarian cancer, suggesting a different production and/or metabolism of CA 125 glycoprotein for different tissues [35]. The large molecular weight of CA 125 in the fetoplacental unit prevents the passage of the antigen through the basal membranes. Therefore, a large difference exists between amniotic fluid and maternal serum concentrations of CA 125; disruption of the basal membranes can cause a higher permeability from the fetoplacental unit into the maternal circulation [39]. Higher maternal serum CA 125 levels in the first trimester can be explained by the process of trophoblast invasion in the decidua during placentation. Higher levels in the third trimester, and more particularly in the puerperium, can be caused by detachment of the placenta from the uterus, during which time decidual CA 125 might reach the maternal circulation [10].

In persisting adnexal masses during pregnancy, expert ultrasonographic assessment plays a pivotal role in estimating the risk of malignancy, and planning conservative management for an adnexal mass that is probably benign versus surgical treatment during pregnancy for an adnexal mass that has malignant characteristics [43, 44]. Ovarian cancer during pregnancy is very rare and has an estimated incidence of 1 in 12,000 to 47,000 pregnancies [43]. When uncertainty remains towards the type of adnexal mass, despite expert evaluation, tumor markers might be important to help formulate the differential diagnosis. From the data presented, it is clear that the usefulness of CA 125 in pregnant women must be carefully considered, as it is evident that maternal serum CA 125 concentrations are influenced by pregnancy, especially during the first trimester. Thus, an adjusted cut-off level should be established in order to interpret CA 125 levels in pregnant patients [35]. Inhibin B and AMH are both serum markers for granulosa cell tumors. Granulosa cell tumors represent about 5% of all primary ovarian neoplasms, and the juvenile type has a higher incidence in children and young women. Currently, there is no evidence-based preference to use inhibin B or AMH as tumor marker in the non-pregnant patient [45]. During pregnancy, an apparent increase in inhibin B immunoreactivity may reflect some cross-reaction with inhibin A. Consequently, it is to be expected that AMH measurements are more reliable during pregnancy than inhibin B.

Based on this review, we can conclude that CA 125 values can be raised during pregnancy and both CA 15.3 and SCC levels generally remain below the cut-off values, although higher levels are not uncommon. Inhibin B, AMH and LDH levels are not elevated in maternal serum during normal pregnancy. Despite its aforementioned limitations, the reference table we have assembled provides a quick reference for gynecological tumor markers during pregnancy.