Gestational Renal Cell Cancer – An Update

Epidemiology

The diagnosis of malignancy during pregnancy is a rare occurrence, with an estimated incidence of 1 in 1,000 cases of cancer diagnosed before delivery. Among the gestational cancers, the most common types include breast cancer, lymphoma, and cervical cancer (7). Furthermore, approximately 5% of ovarian tumors detected during pregnancy are found to be malignant in nature (9). Limited published data are available regarding pregnancy complicated by lung cancer. A retrospective study published in 2013 identified only 60 cases of gestational lung cancer (10). Gestational urinary tract cancers are even rarer, with RCC being the most commonly diagnosed urological cancer during pregnancy (8). In the general population, RCC accounts for approximately 3% of all malignancies. Despite the trend of women giving birth at later ages, the incidence of gestational RCC remains low (11). The increased incidental detection of this clinical entity is postulated to be associated with the routine use of ultrasonography in modern antenatal care (12). Fetal metastasis occurred mainly in patients with placental metastases of melanoma and lung cancer primaries and was associated with a dismal prognosis (13).

Based on our analysis of the reported cases of gestational RCC in the literature since 2004 (Table I), the median age at diagnosis is 33. The age range spans from 20 the youngest to 52 years the oldest diagnosed patients. Additionally, our findings indicate that gestational RCC is most frequently diagnosed during the second trimester.

Etiology

Several risk factors have been identified as contributing to the development of RCC. Some of these risk factors are non-modifiable, such as increased age and being male. However, there are also modifiable risk factors, including obesity, smoking, and hypertension (14).

Obesity has been identified as a significant risk factor associated with RCC. In the prospective VITAL study conducted by Macleod et al., individuals with morbid obesity [Body Mass Index (BMI) of 35 kg/m2 or higher] had a 71% increased risk of developing RCC compared to those with a normal body weight (BMI below 25 kg/m2). The hazard ratio (HR) was 1.71, with a confidence interval (CI) of 1.06 to 2.79 for BMI of 35 kg/m² or higher compared to BMI below 25 kg/m² (15). Additionally, a quantitative analysis of 14 studies examining the relationship between obesity and RCC risk demonstrated that the risk increases by 7% per unit increase in BMI (16). The interplay between obesity and cancer pathogenesis has long been investigated, although the biological mechanisms behind this association remain unclear. It is thought that cell proliferation, angiogenesis and survival are driven by cellular pathways, which are activated by raised circulating levels of hormones, such as gonadal steroids, adipokines and insulin-like growth factors (17).

It is hypothesized that reproductive and hormonal factors during gestation may also contribute to the development of RCC, although the exact underlying mechanisms are not fully understood. The gestational period is characterized by elevated levels of progesterone and estrogen. Cohort studies have demonstrated associations between parity (number of pregnancies) and the risk of RCC (18, 19). It has long been recognized that estrogen and progesterone receptors are present on both normal and malignant cells (20).

During pregnancy, significant physiological changes occur in renal physiology. For instance, the glomerular filtration rate and renal plasma flow increase by approximately 50% and 80%, respectively, compared to pre-pregnancy levels. Physiological hydronephrosis, caused by fluid retention, is a common occurrence. Additionally, the renin-angiotensin-aldosterone system undergoes upregulation (21). The renin-angiotensin-aldosterone system gene polymorphism has been proposed to play a role in the increased risk of renal carcinogenesis and the development of RCC (22). Overall, these changes may render the nephrons more vulnerable to circulating carcinogens.

Clinical Presentation

The clinical presentation of RCC during pregnancy is typically asymptomatic and often discovered incidentally during routine abdominal ultrasonography, which has become a standard practice in obstetric clinical care (23). In cases where symptoms are present, flank pain is the primary complaint associated with RCC. This may be followed by hematuria and hypertension upon clinical examination. The classical triad of pain, palpable mass, and hematuria is less common and tends to occur only in advanced stages of the disease (12). It is important to recognize that these symptoms can be similar to those caused by normal physiological changes and pregnancy-related disorders. Nonetheless, it is crucial for healthcare professionals to consider potential neoplastic causes of these symptoms, as it enables timely diagnosis and facilitates early initiation of treatment (11). We have identified only one reported case of Wunderlich syndrome due to gestational RCC. The patient presented with intense abdominal pain, and upon clinical examination, she exhibited hemodynamic instability (24).

Diagnosis and Imaging

The selection of imaging modalities during gestation is generally limited. In non-pregnant patients, RCC diagnosis is typically suggested by an ultrasound scan, followed by computed tomography (CT) for further evaluation of the tumor’s local invasiveness, lymph node involvement, and distant metastases. To achieve accurate staging, a contrast-enhanced CT of the chest, abdomen, and pelvis is performed (25). However, due to the potential teratogenic effects of ionizing radiation from CT imaging, its use is avoided during pregnancy. Teratogenic risks associated with CT imaging include central nervous system defects, intrauterine growth restriction, and congenital malformations (26). Consequently, CT imaging is contraindicated during gestation.

Ultrasound has been extensively utilized during pregnancy for many years, and no adverse maternal or perinatal outcomes have been reported (27). It is typically the preferred imaging modality for obstetric examinations and suspected non-emergency acute abdominal or pelvic conditions (28). Magnetic resonance imaging (MRI) is also considered safe throughout all stages of pregnancy (29). However, caution is advised when using the MRI intravenous contrast agent gadolinium during gestation due to its ability to cross the blood-placenta barrier. Limited evidence suggests that its use may increase the risk of rheumatological, inflammatory, and infiltrative dermatological conditions, as well as stillbirth or neonatal death (30). In the cases presented in Table I, ultrasonography was the primary diagnostic method, supplemented by abdominal MRI. MRI can offer additional insights into the tumor type, invasiveness, and local progression.

The differential diagnosis for suspected RCC encompasses a broad range of possibilities, including benign, inflammatory, and other malignant lesions. In most cases, imaging alone is usually sufficient for the diagnosis of suspected RCC. The literature indicates that preoperative biopsy of renal masses for confirmation of diagnosis during gestation is rare (23, 31, 32). Tumor core biopsy can offer high sensitivity and specificity in confirming histopathological malignancy. Biopsy may be considered when a renal mass has an indeterminate primary origin and is suspected to be metastatic, complicated by tumor seeding or hemorrhage, or before initiating ablative therapy (25). However, limited evidence exists regarding the safety of ultrasound-guided renal biopsy during pregnancy. In general, the consensus aligns with the guidance for the general population, where the final histopathological diagnosis relies on examination of surgical specimens.

Management

Due to the rarity of RCC presentation during gestation and the variability in case complexity, there are currently no standardized treatment guidelines for the management of gestational RCC. While certain management patterns exist, each case should be approached on an individual basis, guided by a multidisciplinary team. This team typically consists of specialists from urology, oncology, neonatology, obstetrics and gynecology, and psychology. The decisions made in the management process will not only impact the prognosis of the mother but also the development of a healthy fetus. Surgical resection remains the primary treatment option, while active surveillance may also be considered.

When contemplating surgical intervention for gestational RCC, it is crucial to consider additional clinical factors compared to non-pregnant patients. The aim is to minimize the risk of teratogenicity and potential interruption of pregnancy. These factors include the selection of the surgical procedure, approach, timing of intervention, and patient positioning during surgery. Several variables can influence the decisions in designing an individually tailored management plan, such as the gestational age at the time of diagnosis, oncological risk, and the experience of the surgical team.

First, determining the optimal timing of surgical intervention is crucial. This decision relies on assessing the oncological behavior of the tumor and considering the respective neonatal survival rates for each trimester (11). RCC is estimated to have a growth rate of 0.4 cm per year, with a relatively low tumor volume doubling time of around 500 days (33, 34). It has been widely recognized that if RCC is diagnosed during the first trimester, surgery should not be delayed, despite the potential risks of spontaneous abortion or congenital abnormalities (35). In cases where RCC is identified early in gestation, termination of the pregnancy may also be an option prior to surgery (36).

The topic of surgical intervention during the second trimester of gestation remains a subject of controversy. Some authors advise against surgery during this period, citing the risks of uterine contractions, miscarriage, and hypotension due to intraoperative hemorrhage. Such complications can impede uteroplacental perfusion and result in fetal distress (1/6). Consequently, surgery may be deferred until the 28th week of gestation to allow for fetal lung maturation (23). However, some experts propose that the second trimester is the optimal time for surgery, as the risk of uterine interruption and pre-term labor increases as gestation progresses (37). Interestingly, most of the reported cases in the literature underwent surgical resection during the second trimester (Table II).

If RCC is detected during the third trimester, surgical resection can be performed simultaneously with a cesarean section (23). Alternatively, if the diagnosis is made close to the expected delivery date, postponing surgery until after spontaneous vaginal delivery is an option, although careful consideration of oncological tumor progression is necessary (37). The growth rate of RCC during pregnancy appears to vary, with reports in the literature documenting both rapid tumor growth and fatal outcomes (31, 38). Consequently, if an active surveillance or watchful waiting approach is chosen, close monitoring becomes essential to detect any signs of rapid tumor growth and initiate timely intervention as needed. Overall, the optimal timing of surgery, particularly in the second trimester, lacks consensus in the literature, emphasizing the need for an individualized approach.

Once the timing of the surgery has been determined, the appropriate approach for nephrectomy, either radical or partial, can be chosen based on the size of the tumor. For T1 tumors, it is recommended to perform a partial nephrectomy, while for T2 and larger tumors, a radical nephrectomy is advised. These procedures can be conducted using different techniques, including open, laparoscopic, or robotic-assisted approaches. In recent years, there has been a noticeable shift from open to laparoscopic techniques in non-obstetric surgery during gestation. This shift offers several advantages, regardless of whether the transperitoneal or retroperitoneal approach is used. These benefits include improved recovery, reduced post-operative pain, decreased incidence of postoperative ileus, and overall shorter hospital stays (39).

However, it is important to exercise caution when performing laparoscopic procedures during gestation. There is a potential for iatrogenic complications arising from direct trauma to the fetus and uterus caused by laparoscopic instruments. Therefore, ensuring safe laparoscopic access becomes crucial, and this can be achieved using the Hasson technique. The initial trocar placement and subsequent port placement should be adjusted based on the size of the uterus (40). Moreover, the use of carbon dioxide insufflation carries certain risks, including fetal acidosis and potential compromise of maternal cardiac output and uteroplacental perfusion due to increased intra-abdominal pressures. To mitigate these risks, it is recommended to monitor maternal end-tidal carbon dioxide levels through capnography, aiming for concentrations below 35 mmHg. Additionally, regular assessment of maternal arterial blood gases is advised to prevent fetal hypercapnia (41). Furthermore, maintaining intra-abdominal pressures below 12 mmHg can help reduce the side effects associated with carbon dioxide pneumoperitoneum (40).

When considering a minimally invasive surgical approach for resecting RCC, the transperitoneal approach or the retroperitoneal approach can be used. The transperitoneal approach provides a larger operative space, allowing for better instrument angulation and maneuverability. It also offers improved anatomical orientation, making it the preferred method for anterior and lateral renal tumors (6, 40, 42). However, there is a risk of uterine irritation due to the required bowel mobilization to expose the renal hilum. The retroperitoneal approach offers a smaller operative space, especially when considering the carefully controlled pneumoperitoneal pressure (43). However, it provides a more direct access to the kidney and renal hilum, avoiding the need for bowel mobilization and reducing the likelihood of uterine irritation (42). This approach is suitable for posteriorly located tumors (6, 40, 42). In cases where there is limited anatomical space, a robotic-assisted retroperitoneoscopic approach can provide added precision without the necessity of bowel mobilization and pneumoperitoneum (44).

The positioning of a pregnant patient during surgery is a critical aspect to consider. As the pregnancy progresses beyond the first trimester, the growing size of the uterus exerts pressure on the inferior vena cava when the patient is in a supine position. This pressure can result in reduced venous return, leading to decreased cardiac output and compromised uteroplacental perfusion. To address this, it is recommended that nephrectomies for both right and left-sided renal masses be performed with the patient positioned in a minimum of a 15-degree left lateral tilt. This tilt helps alleviate the pressure on the inferior vena cava, allowing for adequate venous return (45).

After undergoing surgical intervention for localized or locoregional RCC, adjuvant therapy may be considered for non-pregnant patients. One notable option is the use of adjuvant sunitinib, a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor (VEGF), which has demonstrated improvement in disease-free survival (46). However, it is important to note that despite its approval by the US Food and Drug Administration (FDA), sunitinib has not received approval from the European Medicines Agency (EMA). Additionally, preliminary animal studies have indicated a risk of teratogenicity, and there have been no completed investigations on the effects of sunitinib during pregnancy (47). Therefore, it is advisable to avoid the use of sunitinib during pregnancy.

Currently, the selection of first-line systemic anti-cancer therapy for metastatic RCC depends on the individual risk of the patient, which can be determined using various prognostic models (25). It is important to note that none of these models or risk stratification tools consider the risk of pregnancy and its impact on prognosis. Once again, this highlights the rarity of gestational RCC diagnosis and management. First-line treatment options typically include VEGF-TKIs, such as sunitinib and pazopanib, as well as immunotherapy options, such as the combination of nivolumab/ipilimumab, and avelumab/axitinib (48). In 2007, a phase 3 trial demonstrated that previously untreated patients with metastatic RCC who received sunitinib experienced longer progression-free survival compared to those treated with interferon alfa, which had already been approved by the US FDA since 1992 (49). Pazopanib received approval from the US FDA in October 2009 for treating advanced or metastatic RCC based on encouraging results from a phase III randomized clinical trial (50). However, the inhibition of multiple targets by pazopanib can lead to various adverse events (51). In 2018, the CheckMate 214 trial revealed that the combination of nivolumab and ipilimumab provided superior efficacy and overall survival benefits compared to sunitinib as a first-line treatment for intermediate- or poor-risk advanced clear-cell RCC (52). Similarly, the JAVELIN Renal 101 trial examined the effectiveness of initial treatment in patients with advanced RCC. The study revealed that individuals who received a combination of avelumab and axitinib exhibited extended progression-free survival and a higher objective response rate compared to those treated with sunitinib (53). However, it is crucial to be aware that TKIs can cross the placental barrier throughout gestation and affect molecular pathways involved in normal fetal physiological development, potentially leading to embryo-toxicity (54). The available data on the use of TKIs and other immunotherapy treatments during pregnancy are limited, emphasizing the need for caution. Therefore, if metastatic RCC is diagnosed, systemic anti-cancer therapy can be considered after the termination of pregnancy.

In managing gestational RCC, it is crucial to consider not only the surgical and obstetric aspects but also the psychological well-being of the mother. The combination of pregnancy and a new cancer diagnosis can give rise to conflicting emotions. Within a short period, the pregnant patient must make informed treatment decisions that have implications not only for their long-term health but also for the well-being of their unborn child. In this context, the members of the multidisciplinary team play a vital role in supporting the pregnant patient, ensuring the optimization of the decision-making process while upholding the fundamental ethical principle of patient autonomy (55).

Prognosis

The prognosis for gestational RCC is generally favorable and comparable to that of non-pregnant patients (11). In most cases, healthy newborns are delivered. However, to establish the prognosis of metastatic gestational RCC, further reporting and international collaboration are necessary, as there are currently no completed relevant investigations in this area.