Clear cell carcinoma arising from abdominal wall endometriosis is a highly aggressive, rare cancer with a propensity to recur or metastasize. (5) Approximately thirty cases have been described worldwide since it was first reported by Sampson in 1925. (6) In general, malignant transformation of endometriosis is highly unusual and approximately 0.7-1.0% of women diagnosed with endometriosis develop an endometriosis-related neoplasm. (2) According to Taburiaux et al, malignant transformation of abdominal wall endometriosis develops twenty-one years after initial uterine surgery, while the average age at diagnosis is forty-seven years. (7)
Malignant endometriosis typically affects the ovary while, extra-gonadal malignant endometriosis may involve the colon, rectovaginal septum, and vaginal walls. (8, 9) Rarely, the abdominal wall is implicated. The most common histologic subtype of extra-gonadal malignant endometriosis is endometrioid carcinoma (69.1%) followed by sarcoma (25%) and clear cell carcinoma (4.5%). (10) However, when malignant endometriosis involves the abdominal wall, the predominant histological subtype observed is clear cell carcinoma (66%) followed by endometrioid carcinoma (24%). (10) Clear cell carcinoma arising from abdominal wall endometriosis is similar to clear cell carcinoma of the endometrium, ovary, vagina, and cervix. These cancers are deeply invasive and carry a poor prognosis. (11)
The pathogenesis of malignant transformation of endometriosis remains unelucidated, however, certain studies implicate oxidative stress according to a two-step process in endometriotic carcinogenesis. (12) Firstly, fluid in endometriotic cysts contains elevated levels of iron which may form reactive oxygen species and promote oxidative stress. (13) Oxidative stress may lead to epigenetic alterations and aberrant DNA methylation which predispose susceptible cell populations to malignant transformation. (14) In the second step, cancer progression occurs due to antioxidant production which prolongs the survival of affected cell populations, thus promoting carcinogenesis. (12, 13)
Several risk factors have been described for the malignant transformation of endometriosis. These include hyperestrogenism, endometriosis diagnosed at an early age, women with long-standing endometriosis, ovarian endometriomas, and endometriosis associated with infertility. (15) Additionally, carcinogens like dioxin, and genetic anomalies involving the loss of heterozygosity on chromosome 4, may be implicated. (8)
Clear cell carcinoma of the abdominal wall presents as an abdominal mass that develops adjacent to a previous surgical scar. (10, 16) The tumor often involves the rectus abdominis muscle and may protrude into the abdominal cavity as noted in the second case described. (17) Abdominal pain is commonly reported and may occur as the tumor invades nearby anatomical structures. Additionally, premenopausal women may experience cyclical abdominal pain which reflects the presence of hormonally active endometriotic foci. (18) A diagnostic dilemma often arises in the evaluation of women with clear cell carcinoma of the abdominal wall. This clinical entity may be mistaken for various benign causes of an abdominal wall mass such as an abscess, hernia, lipoma, hematoma, or lymphadenopathy. (19) Hence, for the generalist, a thorough evaluation should entail a detailed gynaecological history and examination, imaging studies, and biopsy as the clinical suspicion for an endometriosis-related neoplasm may be low. (16)
Currently, there are no pathognomonic biochemical markers for malignant endometriosis. The cancer antigen, CA-125, is a non-specific biomarker elevated in both ovarian malignancy and advanced endometriosis. (10) Thus, a considerable increase in CA-125 concentrations may increase the suspicion of malignancy. (20) Imaging modalities such as CT and magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis are important to delineate the disease extent, invasion into adjacent structures, metastasis, exclude benign causes of an abdominal wall mass, and plan surgical intervention. (6)
The diagnosis of clear cell carcinoma is confirmed on histopathology. Histologically, clear cell carcinoma exhibits papillary, tubulocystic, or solid patterns. (11) Other common histologic findings include intraluminal mucin, intracytoplasmic vacuoles, eosinophilic hyaline mucin, and stromal hyalinization. (11) Moreover, immunohistochemistry may demonstrate positive stains for HNF-1B, Napsin-A, AMACR, CK-7, and p53. (21) Of significance, in 1925, Sampson defined three criteria for confirming the diagnosis of neoplastic transformation of endometriosis: 1. evidence of endometriosis in proximity to the tumor, 2. absence of another primary site tumor, and 3. histological evidence consistent with an endometrial origin. (3) Scott et al added a fourth criterion in 1953: morphological demonstration of benign endometriosis contiguous with malignant tissue. (22) In both cases described, histopathology fulfilled Sampson’s three criteria and Scott’s fourth criterion thus confirming an endometriosis-related clear cell carcinoma.
The management of clear cell carcinoma arising from abdominal wall endometriosis consists of cytoreductive surgery with considerations for adjuvant chemotherapy. (10) Surgical intervention necessitates wide excision of the abdominal wall tumor to achieve healthy margins, hysterectomy, bilateral salpingo-oophorectomy, and abdominal wall reconstruction. (10, 16) According to Ferrandina et al, a bilateral salpingo-oophorectomy, and endometrial biopsy should be performed to exclude other primary tumor sites. (23) Lymph node dissection is considered when pre-operative imaging demonstrates suspicious nodes or nodal involvement. (24) A prosthetic mesh or in some cases, a pedicle-skin-muscle flap, is used for abdominal wall repair and reinforcement depending on the extent of surgical resection. (23)
Due to the limited publications on this clinical entity, there are no clearly established protocols regarding adjuvant treatment. (5) However, clear cell carcinoma arising from abdominal wall endometriosis appears to respond to adjuvant platinum-based chemotherapy. (16) The combination of carboplatin (AUC 5-6) and paclitaxel (175mg/m2) used for six cycles demonstrates efficacy in treatment, and this combination is better tolerated and less toxic compared to the use of doxorubicin, carboplatin, and paclitaxel triple therapy. (6, 25, 26). Despite the use of adjuvant chemotherapy, disease recurrence or progression may still occur, as noted in our study. (5) Adjuvant radiotherapy may be considered, particularly in cases with a suboptimal response to chemotherapy. (16) However, reports indicating successful outcomes with radiotherapy are scarce, and there are no standardized treatment protocols available.
Clear cell carcinoma of the abdominal wall is associated with a poor prognosis. (11) Patients often encounter disease recurrence or progression. Lymph node metastasis is common and particularly involves the inguinal lymph nodes since the superficial abdominal wall lymphatics drain towards the superficial inguinal nodes. (27) Due to the rarity of cases, an evaluation of prognostic factors is also challenging. According to Taburiaux, the median survival time is approximately 30 months. (7) Patients should be followed-up indefinitely and this should involve regular pelvic and rectal examinations, regional lymph node examinations, serum CA-125 measurements, and imaging for suspected recurrence.
In conclusion, clear cell carcinoma arising from the malignant transformation of abdominal wall endometriosis is a rare and aggressive cancer associated with a poor prognosis. This condition may be easily mistaken for many benign causes of an abdominal wall mass. Hence, clinicians must be suspicious of malignancy in patients with a history of abdominal surgery and long-standing endometriosis. Until treatment protocols are established, cytoreductive surgery with abdominal reconstruction and adjuvant chemotherapy utilizing platinum-based compounds appear to improve outcomes. Adjuvant radiotherapy should be considered in select cases with a suboptimal response to adjuvant chemotherapy.