Is clear cell carcinoma of abdominal wall surgery scar associated with endometriosis a poor prognosis? A case report and literature review

Clear cell carcinoma of abdominal wall surgery scar is a rare condition that can have many potential causes, and its early diagnosis is dicult after undergoing obstetrical and gynecological surgery unless performing tumor biopsy. So far, about 45 cases have been reported in the literature. This paper provides a case report and literature review of clear cell carcinoma on abdominal wall surgical scar. We described the case of a 47-year-old woman reporting two lumps in the scar of abdomen. Her medical history was marked by a previous Caesarean section and two excisions of benign endometriosis nodules at the scar. Physical examination found a mass of about 6×5×5 cm on the left side of the scar with mucoid on the surface and a xed abdominal wall mass of about 10×10×8 cm in the 2 transverse ngers under the umbilicus. Histological examination proved a clear cell carcinoma result. The patient received tumor excision and rst-line chemotherapy with complete remission. A review of the literature showed that 91.3% of the cases had had a Caesarean section. Besides, approximately 34.2% of women died 5–48 months after diagnosis. The average age of women was 46.5 years and the average tumor size was 10 cm. in time and properly. Preoperative diagnosis is dicult and often incorrect, and there is no specic marker for malignant transformation. Treatment usually includes the prognosis is poor. abdominal wall endometriosis is very rare, including sarcomatoid degeneration [4], serous papillary carcinoma [5, 6], rhabdomyosarcoma [7] well as clear cell carcinoma (CCC). The most common histological type is CCC [8]. CCC caused by endometriosis is an invasive disease with a poor prognosis, with a 5-year survival rate of about 40% [8]. Diagnosis is challenging because the disease develops slowly and has no specic markers of malignant transformation.


Background
The incidence of scar endometriosis in abdominal surgery is between 0.03% and 1.08% in women undergoing pelvic surgery [1,2]. Abdominal wall endometriosis caused by incisions is an often neglected disease [3]. Scar endometriosis is usually caused by the implantation of endometrial tissue into the soft tissue of the abdominal wall during surgery. Symptoms of endometriosis in abdominal surgical scars in obstetrics and gynecology include slowly developing lumps in or near the scar, as well as pain and abdominal swelling during menstruation. However, malignant transformation of abdominal wall endometriosis is very rare, including sarcomatoid degeneration [4], serous papillary carcinoma [5,6], rhabdomyosarcoma [7] as well as clear cell carcinoma (CCC). The most common histological type is CCC [8]. CCC caused by endometriosis is an invasive disease with a poor prognosis, with a 5-year survival rate of about 40% [8]. Diagnosis is challenging because the disease develops slowly and has no speci c markers of malignant transformation.
Here we report a patient with CCC of the abdominal wall at the scar site of a previous Cesarean section (CS). Besides, we reviewed the existing English literature on transparent clear cell carcinoma caused by endometriosis in the abdominal wall and compared the clinical features of abdominal wall masses of different sizes.

Case Presentation
A 47-year-old woman, grava 4, para 3, abortion 1, presented with two big abdominal masses, which were gradually enlarging after 2 previous excisions of an endometriotic nodule in a CS scar. This patient underwent a CS in 2001 due to fetal distress and transverse position. The CS procedure was successful, with no postoperative discomfort such as abdominal pain, abdominal distension, and the menstruation is regular. Early in 2017, she noticed a small mass of about 1 cm in right lower abdominal scar without menstrual period pain and itching. She underwent abdominal endometriosis mass resection in May 2017. During the operation, the boundary between the mass and abdominal wall tissue was not clear, and a mesh was placed to repair the abdominal wall. The mass containing chocolate-like uid with a hard texture. The pathology of the nodule was reported as endometriosis with decidual degeneration. The mass in the abdominal wall is consistent with the adenomatoid tumor. Microscopically, a large amount of dilated cystic cavity was seen in the brous tissue, which was lined with a single layer of epithelium, which was at or cuboidal cells, and interstitial mucus degeneration. Immunohistochemical stains included CKp (+), CK7 (+), ER (+), PR (-), CK (5/6), CR (+/-), D2-40 (+/-), CD34 (-), Ki-67-LI (10%).
At the beginning of 2018, the patient again realized that she could touch the mass in the right lower abdominal scar, which was about 3 cm in size. During exercise, the lower abdomen occasionally felt slight pain, relieved with rest, and had nothing to do with the menstrual cycle. The abdominal mass gradually increased. In November 2019, she underwent excision of abdominal wall endometriosis and mesh repair because of abdominal wall mass. Postoperative pathology showed that endometriosis with deciduous degeneration. She was then given a subcutaneous injection of Leuprorelin for the purpose of preventing recurrence. However, the size of the right lower abdominal mass remained enlarged, and a similar painless mass, about 2×1×1 cm, was also found in the scar of the left lower abdominal CS in April 2020. She didn't experience any pain at the scar during menstruation. She did not visit a doctor until the mass gradually enlarged and protruded the abdominal epidermis with broken ulcer and mucous bloody secretions in September 2020. She was then referred to our hospital for further management. At this time, physical examination revealed a 12 cm transverse shape of the CS scar of the lower abdomen. A purplish-black mass of about 6×5×5 cm can be seen on the left side of the scar with mucoid on the surface. A hard mass of about 10×10×8 cm can be palpated in the 2 transverse ngers under the umbilicus. Pelvic examination showed a normal-sized uterus and lateral adnexa. A biopsy from the mass in combination of immunohistochemical examination con rmed a pathology of endometriosis-associated CCC.
The preoperative pelvic magnetic resonance imaging (MRI) showed that the parenchyma of the tumor showed equal T1 and long T2 signal intensity, with a clear boundary, and the larger one was 6.2x3.6x4.2 cm (Fig. 1A-C). No obvious enhancement was found on contrast-enhanced scan after injection of contrast agent. There was no abnormality in the uterus, bilateral adnexa, and no enlarged lymph nodes in the pelvis. Ultrasound scan showed normal liver, spleen, pancreas, kidneys, and no mass in the abdominal cavity. Hence, a multidisciplinary team including dermatology, gynecologic oncology, gastrointestinal glandular surgery, and plastic surgery department made a treatment plan for the patient preoperatively. During operation, gross complete excision with a surgical margin of 1 cm beyond the lesion of the abdominal wall including the rectus abdominis muscle, together with an abdominal wall reconstruction was performed ( Fig. 2A-C, Fig. 3A, Fig. 4A and B). It can be seen that the tumor in ltrated part of the fascia and rectus abdominal tissue, the bottom of the tumor reached the peritoneum and protruded to the abdominal cavity, and part of the omentum majus, intestine adhered to the peritoneum. No abnormality was found in the uterus and bilateral adnex, omentum and intestine. The pelvic lymph nodes were not enlarged. After separating the abdominal wall mass, the defect of fascia, rectus abdominis, and peritoneum on the right side of the wound could be seen, with an area of 15X13cm. Considering the large defect of rectus abdominis and peritoneum, mesh repair was performed ( Fig. 3B.C). Hysterectomy and bilateral salpingo-oophorectomy were not performed. The operation time was 300 minutes, of which 160 minutes were resected and 140 min was reconstructed. There were no intraoperative complications. The blood loss was estimated to be 200 mL. Pathologic examination of resected abdominal wall lesion showed CCC under the background of endometriosis with clear resection margins (Fig. 5). The patient was referred to plastic surgery for further care due to the huge surgical wound for 18 days. Chemotherapy with paclitaxel liposome and carboplatin regimen was conducted on day 19 and she was discharged on postoperative day 20. A month later, she returned to the hospital on time for chemotherapy, with no signs of recurrence. She is still closely followed up during the preparation of the manuscript.

Discussion
The diagnosis of malignant transformation of abdominal endometriosis is still a challenge for gynecologists. There are no characteristic symptoms and markers in the process of carcinogenesis. The best treatment for malignant transformation of abdominal endometriosis is not clear. We searched the articles published from September 1986 to December 2020 by Medline and EMBASE, and the search words were combined into medical subject entries. The keywords used for the search are as follows: "abdominal wall endometriosis" and "clear cell carcinoma". All relevant articles were retrieved and the list of relevant references was systematically reviewed to determine further reports that could be included in this analysis. Besides, reviews of cancer and endometriosis published over the same period were reviewed and their reference lists were searched for potential additional studies. We used SPSS 23.0 statistical software for statistical analysis. The unpaired t-test of continuous variables and the chi-square test of classi ed variables were used in the comparison between groups. GraphPad's Kaplan-Meier estimation was used for survival analysis.
Finally, we included 45 patients in our systematic retrospective analysis, including 44 from the literature review and 1 from our organization. All of them reported that endometriosis was associated with malignant transformation of the surgical scar. The characteristics of the patients are shown in Table  1. As shown in Fig. 6, it is more common than previously reported, especially if we consider the increasing rate of CS in western countries [9]. The average age of the patients at the time of diagnosis was 46.5 years (range from 37 to 60), which was consistent with the retrospective analysis of Endometriosis-associated malignant transformation in an abdominal surgical scar by Mihailovici et al. [8]. Fifteen cases (33.3%) had a history of endometriosis and 28 cases (62.2%) had never been diagnosed with endometriosis before admission (2 cases were not clear). The average delay from the rst operation to diagnosis was 17.9 years (standard deviation 6.6). CCC is related to uterine surgery, mainly the CS. Forty-two cases (91.1%) had at least one CS, of which 15 cases had 2 CS s, 6 cases had 3 CSs, and 4 cases (8.9%) had undergone other gynecological operations, usually CS ( Table  2). At least one excision of scar endometriosis was performed in 9 cases, including our case.  Because some literature did not specify the time of the events, the results of the delay from st gynecological surgery,onset of symptoms, and follow-up time only counted the cases with speci c years.
As for tumor markers, CA 125 was detected in 24 cases before the operation. 14 cases were in the normal range (0-35U/mL), 10 cases were higher than the normal range, and the highest was 3157.9U/mL [10]. The preoperative detection of CEA,7 was in the normal range in 9 cases, above the normal range in 2 cases, up to 96.5 µg/L [11]. CA 199 was detected in 12 cases before treatment, and above the normal range in 4 cases, up to 222 µg/L [12]. (Table S1) Table 3. The most common histological type is CCC, in 43 cases (95.6%), followed by CCC with endometrioid carcinoma in 2 cases (4.4%). Of these, only 22 cases (51.2%) found coexisting endometriosis implants (Table 3). In these cases, additional samples for a thorough search for residual lesions of endometrial glands were not all successful. In 1925, Sampson [13] put forward the criteria for the diagnosis of malignant transformation of endometriosis: (a) benign and neoplastic endometrial tissue were shown in the tumor at the same time; (b) histology was compatible with the origin of the endometrium; (c) no other primary tumor sites were found. Besides, Scott proposed the fourth criterion in 1953 [14], that was, (d) the morphological manifestation of benign endometriosis adjacent to malignant tissue is a prerequisite for judging malignant tumors originating from endometriosis. In the current situation, the rst three criteria of the reported cases have been met, but the fourth criteria may not be met, which may be the result of the complete replacement of normal tissue due to the proliferation of a large number of tumors. Because some literature did not specify the pathological characteristics of lumps, the results of Pathological characteristics of lumps only counted the cases with speci c results.
Also, we classi ed the tumor into large masses and small masses by 10 cm in diameter. The correlation between mass size and clinical features was shown in Table 4. The results suggested that patients with abdominal masses larger than 10 cm had more symptoms of abdominal pain before admission than those with small masses, and complained more about the pain caused by palpable masses (P = 0.015). There was no signi cant difference in other characteristics (P > 0.05). In terms of treatment, four patients received preoperative neoadjuvant chemotherapy (mainly platinum-based) [15][16][17][18], and one of them did not consider radical surgery because of the rapid progression of multiple metastases throughout the body [15]. Six patients were trying to treat vaginal estradiol medroxyprogesterone injection, leuprolide acetate, gestrinone, riptorelin, leiprim [10,[19][20][21][22], including our case, but the effect was not satisfactory. Surgery is the main treatment for the most of patients. The rst-stage operation was performed based on extensive resection of the tumor and extensive abdominal tissue. Two cases were not treated surgically because of multiple metastases throughout the body and the rapid progression of the disease [15,23]. Due to the extent of the fascia defect, 22 patients (47.8%) used mesh to reconstruct the abdominal wall (including our case]. Other regular operations include hysterectomy (27 cases, 60.0%) and/or salpingectomy (29 cases, 64.4%), and / or lymph node dissection (14 cases, 30.4%) and/or omental resection (15 cases, 33.3%). Although radical surgery is a major part of the treatment of all patients, our case did not performe hysterectomy and bilateral salpingo-oophorectomy plus pelvic lymphadenectomy, because no signs of the above organs were involved. Another reason is that we plan to perform postoperative radiotherapy for the patient after chemiotherapy. The follow-up adjuvant therapy is mainly chemotherapy, usually platinum and paclitaxel drugs. Twenty-nine cases (64.4%) received 1-9 cycles of adjuvant chemotherapy. However, due to the poor individual characteristics and compliance, adverse reactions, or partial reactions to the treatment, the treatment is interrupted and the e cacy of chemotherapy is di cult to evaluate. Only 16 patients (34.8%) received radiotherapy after surgery and chemotherapy (Table S1).
The above patients obtained the latest clinical follow-up information currently available, and eventually, 38 patients were able to know the outcome (Table S1). The follow-up time of the above patients ranged from 1 to 60 months, with an average of 15.0 months. 34.2% of women (13/38) died between 5 and 48 months after diagnosis. As shown in the Kaplan-Meier survival curve (Fig. 7), the median survival time is 48 months and the ve-year survival rate is 35%. Seventeen patients were reported to relapse. The sites of recurrence were local (5 cases), lymphatic metastasis (3 cases, all inguinal lymph nodes) [15,20,24], distant metastasis (4 cases of liver, 2 cases of lung, 2 cases of brain, and 2 cases of bone). Univariate Cox regression model showed that the prognosis of patients with metastasis (17 cases, 17/37, Of the 38 cases with a speci c follow-up period, one death was excluded because it was not known whether there was metastasis.) was worse than that without metastasis (20 cases, 20/37), as shown by Kaplan-Meier curve (Fig. 8), suggesting that metastasis invasion is a poor prognostic factor affecting patient survival. This is consistent with Taburiaux's study [25].
At present, there is no multicenter RCT in the study of abdominal CCC. However, we can put forward some general directions for future treatment and research, and emphasize several ndings that seem to appear from our data: (a) abdominal wall scar CCC appears in relatively young women and is an invasive disease with a poor prognosis, with a 5-year survival rate of about 35%. (b) it is an iatrogenic disease of abdominal wall scar formation after gynecological surgery, and CS is the most common. (c) the progression of the disease was slow, and the average time of diagnosis was 17.9 years after the rst gynecology and obstetrics operation. In this case, it often relapses to benign nodules of endometriosis, and sometimes patients undergo repeated surgery. (d) the size of the tumor was large at the time of diagnosis, and most of them needed extensive surgical repair of abdominal wall defects. (e) the use of progesterone or gonadotropin-releasing hormone analogs (GnRH-a) before surgical treatment is limited to the number of cases, and the effects are not clear.
The limitation of the review lies in the rarity of the disease, resulting in data collection based only on case reports, with heterologous information from different specialties. This leads to a lack of useful data, which limits statistical analysis. Although we have carried out a lot of statistical analysis, no clear results have been obtained. However, the results of this analysis can guide us to better understand the CCC risk factors and optimal treatment of abdominal wall endometriosis.

Conclusion
The transformation of abdominal endometriosis to CCC is a rare and little-known complication, but invasive surgical resection with a safe margin in combination with lymph node dissection is still the most effective and survival treatment. The role of adjuvant therapy is still unclear, so further research is needed to assess the long-term bene ts. Our case did not undergo radical hysterectomy and lymphadenectomy because there was no local, lymph node and distant metastasis, and planned follow-up radiotherapy and chemotherapy. Of course we need to long term and closely follow up to investigate if lymphatic metastasis and distant metastasis occurred, including liver, lung, brain and bone metastasis. Ethics approval and consent to participate Approval of the Ethics Committee of the First A liated Hospital of Guangxi Medical University was obtained for this study, and the patient signed informed consent form.

Consent for publication
The patient signed consent for publication.

Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated. (C).Surgical suture.