Development of clear cell carcinoma based on iatrogenic endometriosis - case series

Endometriosis is a chronic, inflammatory, estrogen-sensitive illness in which endometrium-like tissue exists outside the uterine cavity. This tissue will adhere to and invade other organs, most frequently the ovaries, the tubes, and the peritoneum. But not only pelvic — occasionally it will appear in distant organs like the lungs or even the brain. Endometriosis has been found to affect an estimated 10% of women of reproductive age whose quality of life is affected by the chronic pelvic pain, infertility, and other secondary symptoms. It is no longer considered a local disorder but now also a systemic disease with a global presentation [1–4]. Definition of endometriosis and its forms Endometriosis occurs in various forms, including: - peritoneal endometriosis, where lesions appear on the surface of the peritoneum; - ovarian endometriosis, characterized by endometrial cysts (so-called chocolate cysts); - deep infiltrating endometriosis, in which lesions penetrate deeper structures such as the intestines or bladder; - iatrogenic endometriosis, occurring in postoperative scars, e.g., after a cesarean section. Increase in cesarean sections and their consequences In recent decades, there has been a global increase in the number of cesarean sections. According to World Health Organization (WHO) data, currently, 1 in 5 (21%) births worldwide is performed via cesarean section. In Poland, the cesarean section rate was approximately 55% in 2019. The most common reason for choosing this method was a history of a previous cesarean section (34.23%). However, the high percentage of non-obstetric indications raises concerns: psychiatric (35.31%), with tokophobia being the most frequent; orthopedic (14.42%); and ophthalmological (11.73%) [5]. The increased number of cesarean sections results from various factors, such as: - changes in the approach to childbirth safety; - a rise in the number of complicated pregnancies; - preferences of both patients and doctors. Though the cesarean section is a life-saving procedure in a majority of cases, its overuse has grave health consequences. These are postoperative complications, wound healing issues, and even incidence of iatrogenic endometriosis in the postoperative scar [6–8]. Iatrogenic endometriosis Iatrogenic endometriosis — mechanisms of development A rare but becoming more well-known type of endometriosis that arises as a result of surgical procedures is called iatrogenic endometriosis. The transfer of endometrial cells into soft tissues during gynecological procedures, such cesarean sections, is one of the main processes of its development. The cells may implant and multiply under these circumstances, resulting in the development of endometrial lesions outside the uterus. The method by which endometriosis forms within a surgical scar is explained by a number of theories. The direct transplantation idea, which contends that endometrial pieces are moved and implanted in the surgical site during a cesarean section, is the most generally recognized. These cells proliferate and create ectopic endometrial foci when there are periodic hormonal fluctuations. Other ideas suggest that endometrial cells migrate through lymphatic or blood arteries, or that mesenchymal cells within the scar’s connective tissue undergo metaplastic change [9, 10]. Regardless of the mechanism of development, iatrogenic endometriosis presents a significant diagnostic and therapeutic challenge. Its occurrence is increasingly reported, correlating with the rising number of cesarean sections worldwide [11, 12]. The significance of surgical implantation of endometrial cells During a cesarean section or other surgical procedures, the anatomical barrier of the uterus is disrupted, creating conditions that facilitate the transplantation of endometrial cells into the tissues surrounding the wound. This process is further intensified by inflammation and factors that promote cellular adhesion. The presence of growth factors and angiogenesis within the scar may support the survival and proliferation of endometrial cells, ultimately leading to pathological changes in the soft tissues [13]. Endometriosis in the cesarean section scar — incidence rate Iatrogenic endometriosis in a cesarean section scar is relatively rare; however, its incidence is increasing along with the rising number of cesarean deliveries. It is estimated that scar endometriosis may occur in 0.2–0.45% of women following a cesarean section (as of 2010) [14]. However, more recent studies indicate an incidence rate close to 2% of cases [15]. It most commonly presents as a painful lump in the scar area, which may increase in size and intensify pain symptoms during the menstrual cycle. Despite its rare occurrence, this form of endometriosis poses a significant diagnostic and therapeutic challenge, requiring greater awareness among gynecologists and obstetricians [1, 16]. Malignant transformation of endometriosis in a cesarean section scar The malignant transformation of endometriosis is an uncommon but dangerous side effect of the condition. The emergence of malignant alterations in endometrial tissue beneath a postpartum cesarean section scar is a particularly alarming problem. Clear cell carcinoma (CCC) and endometrioid carcinoma are the most often seen histological types in these unusual sites among the cancers resulting from iatrogenic endometriosis. Several genetic and molecular alterations are involved in the multi-stage, intricate process of malignant transformation in scar endometriosis. The process of malignant transformation in endometriosis is not known. Still, it is seen that chronic inflammation, oxidative stress, and gene mutation are the most critical factors. DNA damage accumulation due to repeated hormonal fluctuations for extended periods, and due to inflammation by ectopic endometrial tissue within surgical scar sites, is the result. Endometrial cell survival and angiogenesis outside the uterine cavity are associated with growth factors and inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The most frequently reported genetic alterations involved in the malignant transformation of endometriosis include PTEN, ARID1A, KRAS, PIK3CA, and TP53 gene mutations. ARID1A loss-of-function mutations of the chromatin-modulating proteins are the most frequent known mutations in clear cell endometrium carcinoma and cancers of endometrial lesions. KRAS mutations also possess the potential to stimulate growth-promoting pathways, causing aggressive tumor development [17–20].

The aim of this work is to raise awareness among gynecologists and obstetricians about the long-term consequences of cesarean sections, particularly in the context of the development of iatrogenic endometriosis and its potential malignant transformation into clear cell carcinoma. This paper seeks to encourage reflection on the appropriateness of performing cesarean sections and to emphasize the need for more informed decision-making when it comes to choosing the method of delivery. Furthermore, the review nature of this analysis highlights the need for increased attention to this issue within the medical community, which may contribute to the development of more effective preventive, diagnostic, and therapeutic strategies.

This work presents a narrative review based on the analysis of existing studies regarding the development of clear cell carcinoma arising from iatrogenic endometriosis resulting from cesarean section. A search was conducted in medical databases such as PubMed, Embase, and Google Scholar to gather relevant publications. As of October 1, 2024, searching with the keywords “endometriosis,” “caesarean section,” and “clear cell carcinoma” yielded 44, 16, and 1130 records, respectively. For this review, 34 records were included, varying in quality and sample size, as well as additional 20 articles referenced in the introduction. The selected studies include case reviews and individual clinical cases that are statistically significant and directly related to the topic of clear cell carcinoma development due to iatrogenic endometriosis. This analysis provides a better understanding of the risks and long-term consequences of cesarean sections, particularly in the context of the possible malignant transformation of endometriosis.

Clinical case analysis The characterization of patients included in the case study is presented in Table 1 [21–54]. | Table 1. The description contains basic information about the patients described by the researchers. When presenting the column titled “Imaging study used to assess and diagnose the lesion”, the authors used abbreviations for imaging techniques: MRI (magnetic resonance imaging), CT (computed tomography), PET/CT (positron emission tomography/computed tomography), and USG (ultrasonography) | |||||||| | Case studied | Age | Amount of preformed cesarean sections | Years since last cesarean section | Reported symptoms | Time from symptoms appearance to diagnosis [months] | Imaging study used to assess and diagnose the lesion | Greater size of registered change [cm] | Follow-up | | Giannella et al., 2020 [21] | 45 | 2 | 13 | Mass effect in the area of the scar, pelvic pain, menstrual pain, scars tenderness | 3 | MRI, CT, biopsy | 18 | Death after 7 months | | Dobrosz et al., 2014 [22] | 42 | 1 | 17 | Presence of nodules in the scar, menstrual pain | – | USG | 8 | No long-term follow-up data | | Ijichi et al., 2014 [23] | 60 | 2 | 35 | Presence of nodules in the scar | 48 | MRI, biopsy | 4.3 and 3.3 | Death after 15 months | | Hashemi et al., 2021 [24] | 53 | 3 | 23 | Mass effect in the area of the scar, scars tenderness, bleeding from a scar | 3 | CT, biopsy | 9.1 | Death after 20 months | | Hashemi et al., 2021 [24] | 58 | 3 | 20 | Mass effect in the area of the scar, hernia | 2 | CT | 12 | No long-term follow-up data | | Wei et al., 2017 [25] | – | 1 | 18 | Ulceration in the area of the scar, irregular menstruation, mass effect in the area of the scar | 2 | CT | 7 and 6.3 | No long-term follow-up data | | Liu et al., 2022 [26] | 48 | 2 | 22 | Mass effect in the area of the scar, menstrual pain | 24 | CT, biopsy | 13 | No long-term follow-up data | | Alberto et al., 2006 [27] | 38 | 1 | 11 | Mass effect in the area of the scar, scars tenderness | 6 | USG, MRI | 5 | No long-term follow-up data | | Mert et al., 2012 [28] | 42 | 2 | – | Mass effect in the area of the scar, pelvic pain | – | CT, USG, biopsy | 11.4 | No long-term follow-up data | | Mert et al., 2012 [28] | 52 | 2 | – | Mass effect in the area of the scar | 12 | CT, biopsy | 7.5 | No long-term follow-up data | | Petit et al., 2023 [29] | 45 | 2 | – | Mass effect in the area of the scar, scars tenderness | – | Biopsy, MRI, PET/CT | 15 | No long-term follow-up data | | Bellalah et al., 2022 [30] | 52 | 2 | 1 | Mass effect in the area of the scar, scars tenderness | – | MRI | 20 | No long-term follow-up data | | Marques et al., 2017 [31] | 47 | 3 | 17 | Pelvic pain, mass effect in the area of the scar | 3 | CT | 11 | No long-term follow-up data | | Ferrandina et al., 2016 [32] | 44 | 1 | 9 | Mass effect in the area of the scar | – | PET/CT, MRI | 20 | Death after 3 months | | Shalin et al., 2012 [33] | 47 | 4 | – | Scars tenderness, presence of nodules in the scar, pelvic pain | 10 | Biopsy | 6 | No long-term follow-up data | | Colarossi et al., 2021 [34] | 52 | 2 | 17 | Presence of nodules in the scar | 1 | Biopsy | 6.6 | No long-term follow-up data | | Lai et al., 2019 [35] | 52 | 2 | 19 | Mass effect in the area of the scar, ulceration in the area of the scar | – | – | 17.5 | No long-term follow-up data | | Lai et al., 2019 [35] | 56 | 2 | 33 | Mass effect in the area of the scar | – | – | 6.5 | No long-term follow-up data | | Lai et al., 2019 [35] | 56 | 1 | 21 | Mass effect in the area of the scar | – | – | 12 | No long-term follow-up data | | Lai et al., 2019 [35] | 55 | 3 | 24 | Mass effect in the area of the scar | – | – | 12.5 | Death after 5 months | | Lai et al., 2019 [35] | 45 | 3 | 20 | Ulceration in the area of the scar, scar tenderness | – | – | 4.8 | No long-term follow-up data | | Bourdel et al., 2010 [36] | 43 | 2 | 15 | Mass effect in the area of the scar | 9 | MRI | 9 | Death after 22 months | | Schnieber et al., 1986 [37] | 40 | 1 | 15 | Presence of nodules in the scar | 24 | – | 7 | Death after 18 months | | Hitti et al., 1996 [38] | 46 | 2 | 12 | Pelvic pain | 12 | – | 6 | Death after 30 months | | Miller et al., 1998 [39] | 38 | 1 | 2 | Ulceration | – | – | 4 | Surviving more than 5 years | | Park et al., 1999 [40] | 54 | 2 | 24 | Mass effect in the area of the scar | – | CT | 5 | No long-term follow-up data | | Ishida et al., 2003 [41] | 56 | 2 | 20 | Mass effect in the area of the scar | 7 | CT, biopsy | 10 | Death after 14 months | | Sergent et al., 2006 [42] | 45 | 2 | 23 | Presence of nodules in the scar, mass effect in the area of the scar | 36 | MRI | 20 | Death after 6 months | | Razzouk et al., 2007 [43] | 46 | 2 | 24 | Mass effect in the area of the scar, pelvic pain | – | USG, MRI | 20 | Death after 6 months | | Bats et al., 2008 [44] | 38 | 1 | 13 | Mass effect in the area of the scar | – | MRI | 11 | Death after 6 months | | Williams et al., 2009 [45] | 55 | 1 | 17 | Presence of nodules in the scar, pelvic pain, menstrual pain, scars tenderness | – | MRI | 5 | No long-term follow-up data | | Yan et al., 2011 [46] | 41 | 2 | – | Mass effect in the area of the scar | – | CT | 9 | Death after 11 months | | Aust et al., 2015. [47] | 47 | 1 | 16 | Mass effect in the area of the scar | 6 | PET | 10 | No long-term follow-up data | | Liu et al., 2014 [48] | 39 | 1 | 5 | Presence of nodules in the scar, scar tenderness | 4 | CT | 6 | Death after 12 months | | Riuz et al., 2015 [49] | 41 | 1 | 20 | Presence of nodules in the scar, pelvic pain | 12 | – | 15 | No long-term follow-up data | | Riuz et al., 2015 [49] | 41 | 1 | 20 | Presence of nodules in the scar, scar tenderness | 9 | – | 19 | No long-term follow-up data | | Sosa-Durán et al., 2015 [50] | 45 | 3 | – | Mass effect in the area of the scar | 6 | – | 9 | No long-term follow-up data | | Gentile et al., 2018. [51] | 42 | 1 | 5 | Mass effect in the area of the scar, pelvic pain | 8 | – | 10 | No long-term follow-up data | | Rivera et al., 2019 [52] | 48 | 3 | 20 | Scar tenderness, mass effect in the area of the scar | – | CT | 7 | No long-term follow-up data | | Lopes et al., 2019 [53] | 48 | 1 | 18 | Scar tenderness, mass effect in the area of the scar | 3 | MRI, CT | 10.5 | No long-term follow-up data | | Behbehani et al., 2019 [54] | 48 | 1 | 5 | Pelvic pain, presence of nodules in the scar | 5 | MRI | 7 | No long-term follow-up data | | CT — computed tomography; MRI — magnetic resonance imaging; PET/CT — positron emission tomography/computed tomography; USG — ultrasonography | Basic characteristics of the patients In our review, we included 41 patients diagnosed with endometriosis in the cesarean section scar. The average age of the patients at the time of hospitalization and the start of the diagnostic process was 48 (47.65) years. The average number of previous cesarean sections among the patients was 2 (1.88), with the highest number recorded for a patient who had undergone 4 cesarean sections. Time of detection of scar endometriosis The average time from the last cesarean section to the detection of endometrial changes in the scar was 18 (17.67) years. The shortest time for the development of changes was 1 year, while in the longest case, the diagnosis was made after 35 years from the last cesarean section. Clinical symptoms The patients had different symptoms, the most common of which was a growing mass in the lower abdominal wall at or in the vicinity of a cesarean section scar, present in 38.4% of the cases. The other common symptoms were less common. Cessation scar tenderness and the presence of nodules in the scar were observed in 16.4% of the cases investigated, being the second most common symptom. Pelvic pain was found in 13.7% of the patients in the review. The other symptoms, listed in order of frequency, were ulceration near the scar in 5.5%, severe menstrual pain in 5.5%, and other symptoms (like bleeding from the cesarean scar, abnormal menstruation, and hernias) in 4.1% of patients. Diagnostic methods and therapeutic options It took an average of 13 (13.39) months from the start of symptoms to the diagnosis. A uncommon but serious side effect of scar endometriosis is malignant transformation, which indicates that women with a history of cesarean sections should have routine follow-up exams. Imaging methods like computed tomography (CT) and magnetic resonance imaging (MRI), which enable the evaluation of the lesion’s size and possible metastases, provide the foundation for diagnosing changes inside the scar. It should be mentioned that the patients in this analysis are from different nations and have varied methods for diagnosing endometriosis. To diagnose the illness, the authors used a variety of techniques in most of the instances. MRI is the main diagnostic technique for suspected endometriosis-related abnormalities. The fact that many of the patients reported mass effect symptoms and changes visible within the scar, indicating an advanced stage of endometriosis development in the scar, should be taken into consideration when evaluating the research team’s findings. This led the researchers to perform biopsies of changes that were superficially located. Thus, with a frequency of 28.3%, imaging procedures like MRI and CT were the most often employed diagnostic methods in the data that were reported. Biopsies came next with 26.1%, followed by ultrasound with 10.9% and positron emission tomography combined with computed tomography (PET/CT) with 6.5%, in lower amounts. Our research team collated the magnitude of the alterations noted by the researchers with reference to imaging investigations in the case review. There were three instances where the lesion’s maximum dimension reached 20 cm, with the average lesion size being 10.39 cm. Patient survivability The available data on survival rates for patients with iatrogenic endometriosis resulting from a cesarean section procedure suggest poor prognosis. Over a 5-year survival period was recorded in only one case, published in 1990. In contrast, 13 of the analyzed cases reported patient deaths. In the remaining 27 cases, follow-up data describing the long-term outcomes of the patients were missing. Among this group, 8 patients were reported to survive more than a year after diagnosis, but lack of further data prevented the determination of whether they survived beyond 5 years, as the authors did not conduct such long-term observations. These results indicate the high aggressiveness of the disease and emphasize the need for early diagnosis and effective therapeutic strategies in cases of iatrogenic endometriosis transforming into a malignant cancer, such as CCC.

CCC arising in a cesarean section scar is a rare but highly aggressive complication of iatrogenic endometriosis. With the increasing number of cesarean deliveries worldwide, this condition poses a serious health risk for women undergoing the procedure. Literature cases report a poor prognosis, short survival time, and limited treatment. CCC developing in scar endometriosis tends to be diagnosed at an advanced stage, and treatment becomes challenging, with extremely low survival rates for patients. One of the biggest challenges in CCC in a cesarean section scar is its late diagnosis. Most women neglect initial symptoms, such as painful nodules in the scar, so there are diagnostic delays. Unfortunately, the lack of early screening and low awareness of this complication among gynecologists and obstetricians additionally increase the risk of not noticing pathological changes. Our analysis shows that in most cases, patients were diagnosed more than a decade after their cesarean section, meaning the disease may have been developing silently for years. The outlook for individuals with CCC in a cesarean section scar is very bad. There were very few patients in the described cases who lived for more than five years. The high death rate is essentially due to the impossibility of effective treatment — at the moment of cancer diagnosis at these late stages, metastases are generally present, and the treatments available, like surgery and chemotherapy, do not always demonstrate the necessary results.

These findings ought to make doctors more prudent when assessing the requirement for cesarean sections (C-sections). At a period of increasing medicalization of delivery and increasingly C-sections performed without clear-cut medical indications, one must remember that every surgery carries risks — some that may not emerge for decades. CCC in a cesarean scar is one of the most dangerous but widely overlooked complications with possibly catastrophic consequences. To this end, further research needs to be performed to increase the information regarding the mechanisms of the malignant transformation of iatrogenic endometriosis and to provide more effective diagnostic and therapeutic means. Education of both the patients and the physicians regarding the late complications of C-sections would also be helpful in the reduction of the number of unnecessary operations and therefore in the reduction of CCC in endometriosis. Article information and declarations Author contributions Conceptualization, investigation, data curation, writing review and editing — MS; conceptualization, writing review and editing — SS, NL; corresponding author, writing review and editing — KN; supervisor, project administration — AD-C. Funding Authors declare no funding. Conflict of interest Authors declare no conflict of interest. Supplementary material None.