Abstract
Background/Aim: Endometriosis is a common disorder in reproductive-age women leading to a broad range of symptoms and is associated with a higher risk for endometrioid ovarian carcinoma. Case Report: We report the case of a 55 year-old woman with previously undiagnosed endometriosis presenting with a large mediastinal cancer of unknown primary (CUP) and synchronous Union Internationale Contre le Cancer (UICC) stage II rectal adenocarcinoma. Histopathologically the mediastinal tumor resembled endometrial carcinoma and laparoscopically endometriotic lesions on the patient’s peritoneum were detected. The patient was treated with neoadjuvant carboplatin and paclitaxel, followed by resection of the mediastinal tumor. After recovery, the patient received neoadjuvant short-course radiation to the rectal adenocarcinoma, which was resected afterwards. No primary endometrial carcinoma was found in the uterus, leading to the most likely conclusion that the mediastinal tumor derived from an extragenital endometriotic lesion. Conclusion: Although rare, cases of degeneration of endometriosis have been described. In this case not only the localization of endometriosis was uncommon, but also its malignant transformation and synchronous diagnosis of a rectal adenocarcinoma, complicating diagnosis, and treatment of the patient. This rare case highlights the importance of diagnosing and treating patients with CUP or multiple malignancies at large interdisciplinary centers to reach the best possible outcome.
Endometriosis is a common and most likely underdiagnosed disorder characterized by the presence of endometrium-like tissue found outside the uterus with an estimated prevalence of 10% among reproductive-age women. Unspecific and variable symptoms, as well as lack of awareness and specific biomarkers complicate timely diagnosis, the gold standard for which is laparoscopic visualization and histologic confirmation (1). Symptoms range from dysmenorrhea, pelvic pain, dyspareunia, dyschezia, and dysuria to fatigue and infertility, however asymptomatic courses are also possible (1, 2). The proposed pathogenic theories of endometriosis include retrograde menstruation, coelomic metaplasia which describes transformation of peritoneal mesothelium into glandular endometrium, Müllerian remnants and lymphatic or vascular metastasis (1, 2). By now it is understood that endometriosis is not a localized disorder limited to the pelvis, but rather a systemic one (3). For extragenital endometriosis, locations as far from the pelvis as the brain have been described (4, 5). Therapeutic options range from hormonal treatment and surgery to complementary treatments, such as analgesia, pelvic physical therapy, and cognitive behavioral therapy, and should be applied according to the severity of symptoms, location of the lesions, and age and preference of the patient. Generally, treatment requires multidisciplinary expertise, especially when multiple organ systems are affected (1). Although very rare, an association of endometriosis with a higher risk for ovarian cancer, especially endometrioid and clear cell carcinoma, has been identified (2, 6, 7). No significant association between endometriosis and endometrial carcinoma has been found (6, 7). Endometrial carcinoma is a common gynecological malignancy for which obesity and metabolic syndrome are risk factors. Since most patients are diagnosed at an early stage due to early symptom onset, surgery is the first treatment option for the majority of patients. In advanced or recurrent disease, systemic treatment becomes necessary, first line chemotherapy being carboplatin combined with paclitaxel (8, 9). For patients unfit for platinum-based chemotherapy, endocrine therapy is an alternative, while the checkpoint-inhibitors pembrolizumab and dostarlimab can be used in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors as a second-line treatment (8, 10).
We report the case of a 55-year-old woman with two synchronous primary malignancies: rectal adenocarcinoma and a mediastinal tumor, which most likely was an endometrial carcinoma on the grounds of an extragenital endometriotic lesion. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. This retrospective review of patient data did not require ethical approval in accordance with local guidelines.
Case Report
In August 2021, a 55-year-old female patient presented to her primary care physician with thoracic pain that had been persisting over some weeks. A computed tomography (CT) of the thorax revealed a large mediastinal mass (Figure 1). The patient was referred to our clinic, where a CT guided biopsy of the tumor was performed. The histological examination revealed fibrous soft tissue with infiltration by a moderately differentiated, microsatellite-stable adenocarcinoma. Because of immunohistochemical positivity for PAX8, estrogen and progesterone receptor, as well as vimentin, a primary tumor in the internal genital organs, especially an endometrial carcinoma, was considered most likely (Figure 2).
Computed tomography (CT) and positron emission tomography (PET)-CT images before treatment start. Left: Transverse view of the mediastinal tumor in the CT scan. Right: Sagittal view of the mediastinal and the rectal tumor in the PET-CT scan.
Adenocarcinoma with immunohistochemical expression of markers typical for Mullerian origin of the primary tumor. In (A), H&E stain reveals a moderately differentiated adenocarcinoma. Immunohistochemistry shows strong nuclear expression of PAX8 (B) and progesterone receptor (C) and negative staining for SATB2 (D).
In the transvaginal ultrasound exam, the uterus and the ovaries did not appear suspicious, so a 18F-FDG positron emission tomography-computed tomography (PET/CT) was performed to locate the primary tumor of the mediastinal cancer of unknown primary (CUP). In the PET/CT, the mediastinal mass showed increased metabolic activity, furthermore a tumor in the dorsal rectum was detected, which also displayed increased metabolic activity (Figure 1). Through a rectoscopy and magnetic resonance imaging (MRI), the tumor was located 8 cm proximal of the anal verge and classified as T2N2. The histological examination of the tumor tissue confirmed the diagnosis of microsatellite-stable rectal adenocarcinoma. However, the histology did not match the histology of the mediastinal tumor and a gastroscopy and colonoscopy had no remarkable findings except the already known rectal adenocarcinoma. Furthermore, elevated levels of CA15-3, CA19-9, and CA125 were measured.
Due to the histological results of the CUP, a hysteroscopy with curettage and a laparoscopic adnexectomy were performed, despite the inconspicuous transvaginal sonography. The diagnostic laparoscopy revealed endometriosis lesions in the peritoneum. In the histological examination of the gathered tissue, no malignant cells were detected, so the patient ultimately presented to our oncological outpatient clinic with a mediastinal CUP and rectal adenocarcinoma. Further discussion with the pathologists confirmed that neither a renal cell carcinoma nor a gastrointestinal tumor or a malignancy of the thyroid were likely primary tumors of the mediastinal CUP. Since endometrial carcinoma was histologically the most probable diagnosis of the mediastinal CUP, no primary carcinoma was found in the uterus, and the patient had endometriosis, malignant transformation of an ectopic endometriosis lesion in the mediastinum was considered. The case was discussed in our interdisciplinary tumor conference and with the mediastinal tumor predominantly determining the prognosis of the patient, a chemotherapy with carboplatin and paclitaxel was recommended first. After two treatment cycles, the CT staging showed a size decrease in the mediastinal tumor, whereas the rectal carcinoma seemed to remain stable. A third treatment cycle with carboplatin and paclitaxel was conducted, during which the patient was evaluated for a possible resection of the mediastinal tumor. An MRI of the heart revealed no significant cardiac infiltration by the tumor and the mass was deemed resectable by the visceral surgeons. The surgical tumor resection with subtotal pericardial and diaphragmatic resection and reconstruction, as well as partial resection of two ribs and the sternum, took place in February 2022 after three cycles of neoadjuvant chemotherapy. The resection margins were confirmed to be tumor free by the pathologist during surgery. Further histologic evaluation of the tumor continued to favor a gynecologic carcinoma due to positivity for PAX8, CK7, and progesterone, as well as SATB2 negativity. We ordered a next generation sequencing analysis for the resected tissue, since the remaining amount of initial biopsy material was not sufficient. However, only sparse amounts of vital tumor cells were found after neoadjuvant therapy and the analysis was not successful. To complete the perioperative systemic therapy, three more cycles of carboplatin and paclitaxel would have been desirable next, however due to the so far untreated rectal adenocarcinoma, we decided to start the patient on tamoxifen as anti-hormonal bridging treatment until adjuvant chemotherapy was feasible. Six weeks after the resection of the mediastinal tumor, a short-course radiation with 25 gray in 5 fractions was applied to the rectal adenocarcinoma. With the histology of the mediastinal tumor hinting towards an endometrial carcinoma, the laparoscopic low anterior resection with protective ileostomy was combined with a laparoscopic hysterectomy. The postoperative tumor classification of the rectal adenocarcinoma was ypT3, ypN0 (0/21 LK), L0, V0, Pn0, R0, G2 with a Dworak regression grade of 1. Interestingly, no malignancy was found in the hysterectomy specimen. Our interdisciplinary tumor conference recommended follow-up care visits in regard to the rectal adenocarcinoma, and completion of systemic treatment for the endometrial carcinoma with three adjuvant cycles of carboplatin and paclitaxel. At the time of submission, the patient has completed the six-month follow-up with the CT scan and laboratory assessments showing no evidence of disease.
Discussion
We report on a patient with both a common and a rare tumor that were diagnosed simultaneously. What seems striking about this case is the accumulation of unlikely and unfortunate occurrences, leading to a complex diagnostic and therapeutic situation: diagnosis of stage II rectal adenocarcinoma only two years after a screening colonoscopy, extragenital endometriosis located in the mediastinum, and the following malignant transformation thereof.
Manifestation of endometriosis outside of the pelvis or abdomen is generally a rare condition (11); however distant localizations of endometriotic lesions, such as the brain and thorax have been reported (4, 5, 11, 12). While various pathogenetic theories have been proposed for endometriosis, it may be that not one single theory can sufficiently explain all characteristics and occurrences of endometriosis, but rather that different pathological mechanisms influenced by a complex interplay of epigenetic, genetic, hormonal and inflammatory factors may account for the multi-faceted disorder (13). The theory of retrograde menstruation is a widely accepted pathomechanism especially explaining pelvic endometriosis, and has been supported by studies in animals (14). The proposed clockwise flow of peritoneal fluid containing endometrial cells leads to them reaching the right diaphragm and attaching to it, congenital or acquired fenestration would then allow for migration of the cells to the thoracic cavity. The falciform ligament obstructing the flow of the peritoneal fluid to the left hemidiaphragm would explain the right-sided predominance of catamenial pneumothorax occurrences (11). Since in the case described in this report the mediastinal tumor was located on the right side, this may have been a possible mechanism of its development. However, the theory of retrograde menstruation cannot explain cases of cerebral endometriosis, endometriosis in patients with Mayer-Rokitansky-Küster-Hauser syndrome or even in men taking high doses of estrogen (14), therefore other theories, such as metaplasia, lymphatic or vascular benign metastasis of endometrial stem cells need to be explored further as well (15).
Although it is rare with occurrence in <1% of cases, endometriotic lesions harbor the potential for malignant transformation (14). Most of these cases develop from endometriosis of the ovary, leading to an association of endometriosis with a higher risk for endometrioid ovarian cancer. Rare occasions of malignant transformation of extra-pelvic endometriosis, such as in the liver or the urinary bladder have been reported (16, 17).
Theories for the emergence of cancers of unknown primaries include malignant cells spreading to distant sites and leading to metastases before the development of a detectable primary tumor, transformation of mobile cells into a malignant stage at the primary site, or the tumor microenvironment favoring the outgrowth of tumor cells at the metastatic site and abrogating their growth at the primary site (18). While none of these theories can be excluded in this case, three criteria for diagnosis of a malignancy developed from an endometriotic lesion are proven endometriosis close to the tumor, no other primary tumor, and the tumor being histologically consistent with an endometriosis origin (14). Since all three criteria were fulfilled in our patient, endometrial carcinoma arising from endometriosis seems the most likely explanation for the mediastinal CUP.
The complexity of the patient`s clinical situation required the involvement and expertise of multiple disciplines: oncology, pathology, radiology, visceral and thoracic surgery, gynecology, and radiotherapy. This rare case highlights the importance of patients with CUP or multiple malignancies, especially patients of young age, to be diagnosed and treated at large interdisciplinary centers to reach the best outcome.
Acknowledgements
The Authors thank the hospital staff involved in the patient’s care and the patient for allowing us to share details on the case.
Footnotes
Authors’ Contributions
All Authors were involved in the treatment of the patient. K.D. summarized the case and wrote the first version of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received January 14, 2023.
- Revision received January 26, 2023.
- Accepted January 27, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.