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A 61-year-old Caucasian woman with body mass index 30 kg/m2 was referred to the Department of Gynecology at the Västerås Hospital in Sweden for an asymptomatic abdominal mass above the pubic symphysis which had gradually increased over the month prior to presentation. Her surgical history was significant for a cesarian section through Pfannenstiel incision in 1981 and an abdominal supracervical hysterectomy for uterine fibroids via Joel-Cohen incision in 2010. There was no history of endometriosis. Her family history was negative for gynecological cancers. She had hormone replacement therapy administered by transdermal estradiol patch. She had reported normal Pap smears in the past.
On examination, there was a 10 cm area above the Pfannenstiel incision where the skin was thinner and purple-blue in color. On palpation there was a well-defined, 8 cm, tender, irreducible, solid mass with limited mobility.
The mass extended in the midline to the pubic symphysis while the Joel-Cohen incision was completely uninvolved. Transvaginal sonography showed normal ovaries, no ascites or any other abnormalities in the pelvis. Abdominal ultrasound revealed a 8×6 cm cystic lesion with fluid and small hyperechoic foci, extending from the subcutis to the peritoneum but not invading the abdominal cavity. Her vital signs were normal, as well as the C-reactive protein and the complete blood count. The serum level of CA 125 was marginally elevated (42 U/mL) while the serum levels of carcinoembryonic antigen were normal (2, normal range<6 µg/L).
Dr Svensson: based on the clinical presentation, what additional imaging would you recommend and what did it demonstrate?
A CT of the abdomen and pelvis was performed, which revealed an approximately 6×10 x 8 cm large subcutaneous midline mass with cystic components and heterogenous contrast enhancement located above the pubic symphysis. There was no suspicion of liver or lymph node metastasis. There was no ascites and no evidence of carcinomatosis ( Figure 1A ). The assessment was of a soft tissue tumor. A MRI scan of the lower abdomen showed normal ovaries, status post supracervical hysterectomy without evidence of malignancy, and a 6.5×11 x 7.5 cm large subcutaneous lobulated mass with solid and cystic components. The mass was located in and around the midline above the pubic symphysis and extended from the skin surface to the anterior abdominal wall with signs of infiltration of the rectus muscle but without invasion of the abdominal cavity. There was high signal in the cystic components in T1-weighted images possibly due to hemorrhagic content and heterogenous contrast enhancement in the solid components ( Figure 1B–D ). A CT scan of the thorax showed a 2 mm and a 7 mm nodule in the right lower lung lobe as well as a 7 mm nodule in the left lower lung lobe, which raised suspicion of metastasis. Notably, a review of previous CT scans of the abdomen that had been performed in September 2017 and January 2018 for uncomplicated diverticulitis, showed a 3×4 x 2 cm subcutaneous soft tissue mass partly containing fluid in the same place as the current finding. At that time it had raised no suspicion of malignancy. The location of the subcutaneous mass with proximity to the C-section scar, as well as the radiological features, were consistent with endometriosis-associated malignant tumor in the abdominal surgical scar. Other options considered in the differential diagnosis included serous adenocarcinoma or sarcoma.
Dr Giannakopoulos: Based on the information provided by the radiology report, what would be your diagnostic approach?
The patient was referred to the Sarcoma Cancer Centrum, Karolinska University Hospital in Stockholm for further investigation.
A fine-needle aspiration biopsy of the pelvic mass was performed. The tumor tissue, which was examined with hematoxylin-eosin (H&E) staining, showed papillary structures. The epithelial cells showed enlarged, clear cytoplasm when stained with H&E as well as hobnail cells containing bulbous, hyperchromatic, pleomorphic nuclei (Figure 2A ). Typical morphological epithelial features supported by cytokeratin AE and low molecular weight cytokeratin ck8/18 markers expression excluded sarcoma. Cytology examination was morphologically consistent with metastasis of malignant epithelial tumor, primarily of ovarian origin because of positive immunostaining for PAX8.
On return of the patient to the Department of Gynecology at the Västerås Hospital for further management, the assessment was made that the initial treatment should be primary debulking surgery. Lung biopsies could not be obtained due to the nodules size and were no longer indicated because they would not change the treatment strategy. The patient underwent abdominal surgery with an en bloc resection of the tumor including the overlying skin, part of the lower rectus muscle, as well as the part of the fascia and peritoneum that was located beneath the mass. Intra-operatively, both ovaries and fallopian tubes were macroscopically normal and there was no evidence of endometriosis. There was no suspicion of metastasis after examination of the entire abdominal cavity, including omentum, diaphragm, liver, intestine, and peritoneum. Visual and palpation assessment of the lymph node stations was negative for any suspicion of tumor. A cervical removal and a bilateral salpingo-oophorectomy was performed. The 10×7 cm defect that occurred after the resection of rectus muscle, was repaired using polypropylene surgical mesh.
Dr Badani de la Parra: please provide details of the pathology findings
On gross examination of the abdominal wall specimen, a prior scar in the central part of the incision was detected. On the cut section, the tumor consisted of a thick-walled multilocular large hemorrhagic cyst approximately 5 cm in diameter with solid and partially cystic area spreading to the resection line. Microscopically, the tumor was partially cystic with tumor cells forming papillary structures with enlarged, hyperchromatic nuclei and mitotic activity. Atypical clear cell and hobnail-type cells, as well as necrotic tissue, were also detected. Immunohistochemical analyses were positive for CA125, CK7, cytokeratin AE, p16, EMA, PAX8 and Napsin as well as partly positive for vimentin, cytokeratin 8/18, CD15, Ber-EP4 and HBME-1 (Figure 2B,C ). Immunostaining was negative for estrogen receptor, progesterone receptor (PR), WT1, p53, inhibin, CEA mono, calretinin, CK5/6 and D2-40 (Figure 2D).
The uterus, fallopian tubes, and ovaries were thoroughly examined, showing no sign of malignancy. Notably, there was no evidence of endometriosis in any of the specimens. Mesothelioma was ruled out both morphologically and because of the negative calretinin and D2-40. Renal clear cell carcinoma was also excluded, both clinically and radiologically. The overall morphology and immunophenotype indicated a primary peritoneal carcinoma, and more specifically, a primary peritoneal carcinoma of clear cell type.
Dr Giannakopoulos: What do we know about primary peritoneal carcinoma of clear cell type and treatment strategies?
Primary peritoneal carcinoma are rare with an incidence of 6.8 per million population 1 and were first reported in 1959 by Swerdlow. 2 These tumors commonly show serous histology but even other variants have been reported, such as mucinous, endometrioid, clear cell, Brenner, and mixed Müllerian tumors. 3 Primary peritoneal carcinoma mimic epithelial ovarian cancer due to the common embryologic origin from the Müllerian ductal system, and this is the reason why they have no major antigenic differentiation from epithelial ovarian cancer. Primary peritoneal carcinoma of clear cell type is extremely rare, accounting for approximately 3% of all primary peritoneal carcinoma. The most plausible theories regarding their pathogenesis appear to be a Müllerian metaplasia and a malignant transformation of endometriosis. 4 The Gynecologic Oncology Group (GOG) diagnostic criteria for primary peritoneal tumors, which may also be applied to primary peritoneal carcinoma of clear cell type, are as follows: bilateral ovaries should be normal in size or enlarged by a benign process, involvement in the extraovarian sites is greater than on the surface of either ovary. Microscopically, the ovarian findings can be one of the following: ovaries should not have evidence of disease, ovarian surface can be involved but without evidence of cortical invasion, and tumor may involve the ovarian surface and cortex but any tumor is less than 5×5 mm, and lastly, microscopically the tumor should be predominantly of a serous cell type that is similar or identical to ovarian serous papillary adenocarcinoma of any grade.3 Seventeen cases of primary peritoneal carcinoma of clear cell type have been reported in the English language literature ( online supplemental table 1 5 6). They are typically high-grade tumors with poor prognosis. The median age at diagnosis was 54 years (range 37–67), and the most common symptoms reported are abdominal distension, progressive abdominal pain, and a palpable pelvic mass. On imaging, the tumor presents as a single cystic mass with solid and/or papillary components having a median size of 7 cm (range 2–25). In eight cases (47%), endometriosis or adenomyosis were detected in the gynecological history or appeared as concurrent disease. CA125 at the time of diagnosis may be elevated as shown in these cases (median 76, range 28–2218 U/mL). In most cases, debulking surgery has been performed followed by chemotherapy (carboplatin and paclitaxel). In cases where there was residual primary tumor after surgery (three cases), all patients died of disease at 5–6 months. Leaving no residual primary tumor was associated with improved outcomes (median disease-free interval 13.5 months, range 5–32).
Dr Henning: What options for adjuvant therapy would you consider for this patient?
The final diagnosis was primary peritoneal carcinoma of clear cell type, FIGO stage IV. At primary surgery, the tumor in the abdominal wall was resected. Although there is no evidence-based treatment for primary peritoneal carcinoma of clear cell type, management is similar to that of advanced epithelial ovarian carcinoma with surgical cytoreduction, where possible, and adjuvant chemotherapy with intravenous carboplatin (area under the curve (AUC) 5 or 6) and intravenous paclitaxel(175 mg/m2) administered every 3 weeks. It should be noted that the clear cell histology may have a lower response rate than the serous adenocarcinomas. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, may be added to the combination of paclitaxel and carboplatin if there is no response to the treatment or in cases of recurrence. 3 In cases of symptomatic pelvic metastases, radiation therapy may be taken into consideration since clear cell tumors can be radiosensitive. 7 Lastly, immunotherapy has shown promising signs of efficacy for clear cell ovarian cancer in small studies, therefore is considered to be off-label treatment strategy. 8
In July 2020, 10 weeks after surgery, a CT scan of the chest, abdomen, and pelvis was performed before starting chemotherapy, revealing progression of the suspected lung metastasis as well as enlarged inguinal lymph nodes. Positron emission tomography (PET) confirmed these findings. A BRCA gene test was negative.
The patient started adjuvant chemotherapy with paclitaxel (175 mg/m2) and carboplatin (AUC 5) every 3 weeks with evaluation of CA125 at each cycle and a CT scan of chest, abdomen, and pelvis after four cycles. At completion of these first four cycles, serum CA125 levels had risen from 181 to 2493 U/mL with progression of inguinal lymph node metastases on CT scan and PET while showing radiological stability of the lung metastases. At this point, bevacizumab was added (two cycles) and then it was administered alone as maintenance treatment with significant decrease of CA125 (754 U/mL). Due to continued progression of the inguinal node metastases, bevacizumab was stopped so that the patient could receive palliative pelvic beam radiotherapy (10 treatments, 3 Gray each for a total of 30 Gray). Thereupon, the patient resumed the maintenance therapy with bevacizumab and completed 15 cycles with 3-week intervals. A CT scan showed progression of the lung metastases and emergence of para-aortic lymph node metastases. Thus, adjuvant chemotherapy was resumed, this time with liposomal doxorubicin (30 mg/m2) and carboplatin (AUC 5) every 4 weeks with CT evaluation scan after three cycles. On completion of this regimen, a CT scan of chest, abdomen, and pelvis was performed (March 2022), revealing continued slow progression of the lung metastases and marginal increase of the inguinal lymph node metastases. Given the slow progression a new CT scan is planned for June 2022.
Primary peritoneal carcinoma of clear cell type is a rare condition sharing common presenting symptoms with epithelial ovarian cancer. The etiology is unknown. The presence of an irreducible, solid mass in the abdominal wall and the absence of abnormalities in the pelvis on clinical examination, the elevated CA125, as well as the atypical single cystic mass on imaging, raise suspicion of primary peritoneal carcinoma. The cytologic examination and the diverse immunohistochemical analyses on biopsies from the pelvic mass lead to the primary diagnosis of primary peritoneal carcinoma of clear cell type. An extensive panel of primary antibodies can be used for the immunohistochemical analysis of these tumors. 4 Molecular analysis was not performed in this case but it has been described that this type of tumor can display deletion in ARID1A, two germline mutations in MKI67 and BRCA2, as well as somatic mutations in GSDMB and KMT2C. 4
The final diagnosis is obtained on examination of the surgical specimen after surgery. Radical surgical resection of the primary tumor may be an important factor affecting disease-free survival. Thereupon, as primary peritoneal carcinoma of clear cell type mimic the epithelial ovarian cancer in many aspects, adjuvant chemotherapy with paclitaxel and carboplatin have been used in almost all cases described in the literature. However, no evidence-based treatment approach is available.
Patient consent for publication
Participants gave informed consent to participate in the study before taking part.
Contributors NG: conceptualization of the study design, acquisition of patient consent, medical record review, literature search, analysis and interpretation of data, writing the manuscript. LH: gynecologic oncologist who supervised and critically revised the text regarding the treatment of the patient. JBdP: provided the images and answered the questions related to the pathology issues. AS: provided the images and answered the questions related to the radiology issues. CR: Contributed to study design, supervision, and critical review of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.