Growth kinetics of renal tumours during pregnancy in patients with hereditary renal cancer syndromes

Active surveillance with delayed intervention is a pertinent consideration for small renal masses, showing non-inferior outcomes to direct surgical intervention in select patients [1]. Current AUA and European Association of Urology guidelines favour active surveillance with periodic clinical/imaging studies for non-infiltrative small renal masses of low complexity, and for elderly patients with comorbid conditions and limited life expectancy [2, 3]. Potential triggers for intervention include tumour size >3 cm, fast tumour growth rate (GR; >0.50 cm/year), and clinical or pathological progression [2]. In sporadic RCC, tumour GRs have been shown to vary based on histology, with clear cell RCC growing faster than papillary and chromophobe RCC [4]. However, substantial GR heterogeneity is noted within the same histological subtype, reflecting the importance of underlying host and tumour biology [4]. When accounting for histological and genetic correlates in a cohort of patients with hereditary RCC syndromes, GR tends to vary clinically and statistically based on alterations at the gene level. Notably, renal tumours exhibit a GR of 0.37 cm/year in von Hippel–Lindau disease (VHL; VHL-deficient), 0.10 cm/year in Birt-Hogg-Dubé syndrome (BHD; FLCN-deficient), and 0.60 cm/year in BAP1-deficient RCC [5]. Across the hereditary RCC syndromes, faster GRs were noted in younger cohorts, with the fastest GR seen in patients aged <42 years [5]. This important difference, coupled with the earlier onset of renal tumours, poses a challenge in managing patients with hereditary RCC syndromes. A particularly vulnerable cohort is women of childbearing age with hereditary (or sporadic) RCC who present with renal tumours before or during pregnancy. Women experience variations in sex hormones and glucocorticoids, among others, during menstruation, pregnancy, and menopause. Oestrogen and androgenic signalling have been implicated in carcinogenesis due to their regulation of apoptosis, angiogenesis, and cellular proliferation pathways [6, 7]. A recent study found that parity and reproductive organ surgeries may be associated with a higher risk of developing RCC after menopause; however, it is unclear how these hormonal changes affect the growth and/or invasiveness of preexisting, early-onset renal tumours [8]. Infrequent case reports indicate a favourable prognosis of women with renal tumours during pregnancy, but there are no uniform criteria or recommendations for management. Thus, despite its rare occurrence, the management of RCC during pregnancy remains an unmet clinical need. We evaluated tumour growth kinetics and pathological correlates in patients with hereditary RCC syndromes who had renal tumours during pregnancy and were prospectively followed between 2009 and 2022 at the National Institutes of Health. Hereditary RCC syndromes offer an optimal population for such investigations due to their genetically defined nature and applicability to sporadic RCC [5]. Furthermore, while sporadic RCC more commonly presents in males than females, hereditary RCC affects both equally. Tumour sizes were measured before, during, and after pregnancy from cross-sectional abdominal imaging using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 (Fig. 1A–C). Tumour GRs (cm/year) were calculated before, during, and after pregnancy. Inclusion in this study required the availability of at least two renal imaging scans prior to the woman's last menstrual period, one scan either during pregnancy or shortly after delivery, and at least one scan within 1 year of the previous pregnancy/post-delivery scan to allow for calculation of GR pre-, during and post-pregnancy. Three patients with VHL (n = 9 tumours) and one patient with BHD (n = 1 tumour) met these criteria and were analysed. Upon eventual resection, VHL tumours were of grade 2 clear-cell pathology and the BHD tumour was of hybrid oncocytic pathology. Among VHL tumours, the median pre-pregnancy size was 1.8 cm and the median post-pregnancy size was 2.9 cm. The median GR was 0.72 cm/year (Fig. 1D). All patients had at least one tumour that reached the clinically relevant threshold size of 3 cm during or in the months after pregnancy. The median (interquartile range [IQR]) pre-pregnancy GR for VHL tumours was 0.28 (0.00–0.63) cm/year, the median (IQR) GR during pregnancy for VHL tumours was 0.72 (0.61–0.91) cm/year, and the median (IQR) GR after pregnancy for VHL tumours was 0.36 (0.00–0.79) cm/year. The BHD tumour exhibited a GR of 0.12 cm/year during pregnancy (Fig. 1D). Of the VHL tumours, 6/9 (67%) had a >100% increase in GR during pregnancy vs before pregnancy, and 5/9 (56%) VHL tumours had a >40% decrease in GR after pregnancy vs during pregnancy. Among VHL tumours, the median change in tumour size when comparing the first post-pregnancy size to the final size during pregnancy was 0.0 cm. These data indicate that renal tumours behave heterogeneously during pregnancy based on pathology. The BHD hybrid oncocytic tumour tracked during pregnancy showed a comparable growth rate to that reported in the literature (0.12 and 0.10 cm/year, respectively). However, this was not the case with VHL clear-cell RCC tumours. The GRs measured before and after pregnancy were comparable to those reported in the literature, but they increased considerably during pregnancy. The GRs of VHL tumours during pregnancy more than doubled the pre-/post-pregnancy GR (0.72 vs ~0.3 cm/year, respectively), and exceeded the GR threshold for potential intervention described in current guidelines (0.50 cm/year) [2]. Interestingly, a general plateau in tumour size was observed in the immediate post-partum period, following the increased growth during pregnancy. These findings suggest a potential role for reproductive hormonal and physiological changes in promoting RCC growth and/or progression. This hypothesis-generating study is not without limitations. While the inclusion of four patients is a testament to the rare occurrence of renal masses detected during pregnancy, the small sample size limits the generalisability of our findings. Nevertheless, to our knowledge, this is the largest single cohort of pregnant patients with renal masses described to date. Further studies are necessary to improve our understanding of the effects of pregnancy on sporadic or hereditary renal cancer. With regards to the management of hereditary RCC during pregnancy, our institutional practice is to advocate for close follow-up of renal masses in the peri- and post-partum periods. In patients who are planning for pregnancy and are found to harbour a renal tumour(s), we recommend evaluation of renal tumour size and GR. Additionally, the patient should be informed of the oncological risks associated with a potentially fast tumour growth. From here, shared decision making should be pursued based on patient preferences, the timing desired for pregnancy (if not already pregnant), and imaging findings in the pre- and post-partum period. Early intervention should be taken into consideration for patients who harbour masses approaching 3 cm, especially if they are endophytic in nature. These novel findings will help inform the management of early-onset RCC in women of childbearing age who are planning to become or are already pregnant. None.