Mixed squamous and clear cell ovarian adenocarcinoma arising from endometriosis in a 71 year old patient

Alexandra Mills: Conceptualization, Writing – original draft. Mona Saleh: Conceptualization, Writing – original draft, Writing – review & editing. Faruk Erdem Kombak: Writing – original draft. Matthew Flint: Conceptualization, Writing – review & editing. Valentin Kolev: Writing – review & editing, Supervision.

A 71 year old Chinese G2P1 with history of hypertension and hyperlipidemia presented to her gynecologist with 10 days of non-radiating, sharp, right lower quadrant pain and one month of lower abdominal bloating. She had no postmenopausal bleeding, no changes in bowel movements, and no changes in urination. She had no history of abnormal pap smears and was a lifetime nonsmoker. Menarche was at age 15 and menopause at age 53. She had one vaginal delivery at age 26. She used oral contraceptive pills for 26 years and had no history of in vitro fertilization drug use or hormone replacement therapy. She never had abdominal or pelvic surgery. She had no family or personal history of breast or gynecologic cancer. A large pelvic mass was palpated on exam. CT imaging revealed a 22.5 cm × 14.0 cm × 20.9 cm cystic pelvic mass appearing to originate from the right ovary and extending to the midline ( Fig. 1 ). There was an irregular soft tissue component within the mass measuring 7.6 cm × 3.1 cm × 4.0 cm with calcifications and nodular septations. GI tract including pancreas appeared normal. Patient was then referred to gynecologic oncology. Lab work revealed an elevated CA 19–9 of 2,392.5 and elevated CA-125 of 211. CEA was within normal limits at 1.4. Because this constellation of findings was concerning for ovarian malignancy, exploratory laparotomy, total abdominal hysterectomy with bilateral salpingo-oophorectomy and staging was planned within two weeks. Fig. 1 Sagittal view of CT scan. Large cystic mass most likely arising from the right ovary extending to the mid abdomen measuring 22.5 × 14 × 20.9 cm. Sagittal view of CT scan. Large cystic mass most likely arising from the right ovary extending to the mid abdomen measuring 22.5 × 14 × 20.9 cm. Intraoperatively, a 25 cm cyst was found, originating from the right ovary. Pelvic washings were collected. The walls of the cyst were adherent to surrounding structures, notably the appendix, sigmoid colon, and right pelvic side wall. The cyst was drained in a contained manner, and the cyst walls were subsequently dissected from the appendix, sigmoid colon, and pelvic side wall. An appendectomy was performed along with cyst removal. There was no spillage of cyst contents into the abdomen. This mass was sent for frozen section, which revealed an invasive SCC. In order to mobilize the uterus, right ureterolysis was also performed, with noted vermiculation thereafter. The cyst, bilateral ovaries and tubes, and the uterus and cervix were removed. Omentectomy was performed through mobilization at the transverse colon for staging purposes. Finally, a right pelvic lymph node dissection was performed. Contralateral pelvic lymph node and para-aortic lymph node dissection were not performed because these procedures would add morbidity without change in management, given that patient would be receiving adjuvant chemotherapy given suspected aggressive histology of SCC. Hemostasis was achieved with 500 mL estimated blood loss. Postoperative course was uncomplicated. Pelvic washings were negative for malignant cells. Pathologic examination revealed FIGO stage IA ovarian cancer of the right ovary. Histology showed mixed carcinoma with a clear cell carcinoma component (25 %) and a squamous cell carcinoma component (75 %). The clear cell component showed positive staining for HNF1β and Napsin A. The squamous component showed intercellular bridges and keratin pearl formation ( Fig. 2 ). Due to the presence of an adjacent endometrioma, it was postulated that both these tumor components arose from antecedent endometriosis. The ovarian capsule was tumor-free and the bilateral Fallopian tubes, left ovary, right pelvic lymph nodes, omentum, and appendix were benign. Fig. 2 Ovarian squamous cell carcinoma. An irregular island of pleomorphic squamous cells, exhibiting intercellular bridges, focal keratin production and necrosis. (H&E, x200). Ovarian squamous cell carcinoma. An irregular island of pleomorphic squamous cells, exhibiting intercellular bridges, focal keratin production and necrosis. (H&E, x200). After presentation at institution-wide tumor board, conclusion was made that the presence of clear cell and squamous cell carcinoma classified this patient’s early stage ovarian cancer as high risk for recurrence, and she was recommended to undergo adjuvant treatment with carboplatin and paclitaxel every 3 weeks for 6 cycles. Routine pre-chemotherapy hepatitis serologies noted positive hepatitis B core antibody, and patient was begun on entecavir prior to initiation of chemotherapy. Patient adverse effects did not affect her activities of daily living. Patient underwent genetic testing that showed a variant of uncertain significance in adenomatous polyposis coli (APC) and epidermal growth factor receptor (EGFR) genes. At time of this submission, patient is 4 months from completion of adjuvant chemotherapy and has no evidence of disease based on physical exam and imaging. CA 19 9 normalized to 10, and CA 125 normalized to 14. Patient was continued on entecavir for 6 months following completion of chemotherapy to prevent hepatitis B flare-up.

As of 2019, only 36 cases of ovarian SCC had been reported in the English language literature ( Koufopoulos et al., 2019 ). Most cases of squamous cell carcinoma (SCC) are due to metastasis or due to secondary transformation of mature cystic teratomas (MCTs), Brenner tumors, or foci of transformation within endometriomas ( Zhang & Ma, 2020 ). Secondary transformation of an MCT occurs when the ectodermal germ layer of a cystic teratoma undergoes metaplasia. 80 % of ovarian SCC’s are from these transformations ( Maharjan, 2019 , Hackethal et al., 2008 ). Another common transformation occurs within an endometrioma, which is the posited mechanism in this patient. Ectopic endometrial tissue on or within the ovary has been rarely reported to undergo malignant transformation, resulting in ovarian SCC within, or in a background of, endometriosis ( Koufopoulos et al., 2019 ). Ovarian SCC that originates from endometriosis likely comes about through neoplastic squamous transformation of the endometrial-type epithelium ( Acien et al., 2010 ). It has been suggested that ovarian SCC that originates in endometriosis tends to carry a worse overall survival than ovarian SCC that presumably transforms from a dermoid cyst ( Acien et al., 2010 ). Fifteen of these rare cases were reported as of 2009 ( Torre et al., 2018 , Acien et al., 2010 , Xu and Li, 2018 ). HPV and cervical dysplasia have also been associated with SCC of the ovary ( Hackethal et al., 2008 , Mai et al., 1996 , Wu et al., 2003 ). Retrospective reviews of SCC cases have shown 27–40 % of women with primary squamous cell carcinomas of the ovary have had previous or current cervical intraepithelial neoplasia (CIN) or vulvar intraepithelial neoplasia (VIN) ( Koufopoulos et al., 2019 , Park et al., 2010 , Xi et al., 2022 ). The proposed mechanism of ovarian carcinoma in the setting of HPV infection include contiguous spread from cervix to ovary, angioinvasion from the cervix, and the “field effect” through which simultaneous HPV infection of similar tissue can trigger synchronous transformation to primary squamous cell carcinoma at distinct sites ( Koufopoulos et al., 2019 , Mai et al., 1996 , Park et al., 2010 ). Worsened outcomes for patients are in part due to the insidious and nonspecific onset of symptoms, thereby delaying initial diagnosis. The most common presenting symptom of primary ovarian SCC is new onset abdominal pain ( Koufopoulos et al., 2019 , Acien et al., 2010 ). Ovarian cancer has been mistaken for pelvic inflammatory disease (PID) due to similarities in hypogastric, suprapubic, and lower quadrant tenderness evolving over weeks-months ( Acien et al., 2010 ). Suspicion for malignancy should be high in all older women presenting with vague abdominal pain, distention, or palpable adnexal masses. SCC in particular is locally aggressive and commonly adheres to or invades adjacent structures including the uterus, colon, appendix, kidney, ureters, and pelvic side wall ( Park et al., 2010 ). As a result, presenting symptoms may include vaginal bleeding, rectal bleeding, weight loss, constipation, urinary retention, fever, or cough ( Koufopoulos et al., 2019 ). Serologic analysis may show elevated CA125 and SCC antigen and can be useful for raising suspicion of SCC in the setting of an adnexal mass ( Xi et al., 2022 ). Surgical intervention in the form of cytoreduction, hysterectomy, bilateral salpingo-oophorectomy, and omentectomy is almost always recommended as the first step in management of resectable suspicious ovarian masses. Grossly, these tumors may appear necrotic, of mixed solid and cystic material, and can be adhered to surrounding structures, as in our case ( Koufopoulos et al., 2019 , Acien et al., 2010 ). Surgical resection of the appendix, colon, bladder, kidneys, omentum, ureters, or pelvic side wall may be necessary in these cases ( Koufopoulos et al., 2019 ). Although lymph node biopsy is frequently done for staging purposes, data has shown that lymphadenectomy carries no survival benefit. Average survival with and without lymphadenectomy are not statistically significantly different ( Koufopoulos et al., 2019 ). Surgical specimens may have histology consistent with squamous cell carcinoma including pathognomonic findings of intercellular bridges and keratin pearls ( Koufopoulos et al., 2019 ). Other phenotypes include papillary structures, polypoid histology, cystic findings and necrosis ( Koufopoulos et al., 2019 ). Immunohistochemistry can reveal molecular signatures including p16, hMLH1, hMSH2, hMSH6, PMS2 ( Xi et al., 2022 ). In this case report, the patient had expression of HNF1β and Napsin A, both markers associated with ovarian clear cell carcinoma ( Chandra et al., 2021 , Travaglino et al., 2022 ). There were additionally foci of vimentin expression, a marker that correlates with the epithelial to mesenchymal transition and tumor aggressiveness. Following surgical resection, adjuvant therapy may be offered. However, due to the small number of primary ovarian SCC cases, there is not a robust body of evidence for specific regimens postoperatively. The National Comprehensive Cancer Center (NCCN) does not provide guidelines for squamous cell carcinomas of the ovary ( Armstrong et al., 2022 ). Most are managed with the same guidelines as other ovarian cancers. Most studies recommend that high grade serous ovarian carcinomas stage 1C or greater be treated with platinum-based chemotherapy and paclitaxel ( Gadducci et al., 2021 , Koufopoulos et al., 2019 , Hackethal et al., 2008 , Xu and Li, 2018 ), but National Comprehensive Cancer Center (NCCN) guidelines recommend that more aggressive histologies, of which clear cell carcinoma is one, also be treated adjuvantly with platinum-based chemotherapy. A systematic review in 2012 by Winter-Roach et al showed that adjuvant platinum-based chemotherapy is effective in prolonging survival of the majority of patients with IA disease with well-differentiated, encapsulated unilateral disease ( Winter-Roach et al., 2012 ). Table 1 contains shows published cases of ovarian SCC and the treatments thereof. Out of the 21 case reports reviewed, all underwent some form of cytoreductive surgery. All except 1 case received adjuvant treatment, 2 received radiotherapy ( Tetu et al., 1987 , Sharma et al., 2015 ), and the remainder received adjuvant chemotherapy. Most patients who received specified chemotherapy were treated with platinum-based regimens. Those with stage IA disease, such as our patient, were dead of disease at 6 months (without any adjuvant chemotherapy) ( McCullough et al., 1946 ), and alive without disease progression at 6 months ( Maharjan, 2019 ). Table 1 Review of ovarian squamous cell carcinoma in the literature. Author Year Age Pathology FIGO Stage Surgical Intervention Chemotherapy Outcome McCullough (1946) 1946 – SCC within endometriotic cyst Stage IA BSO N/A DOD at 6 months Tetu et al. (1987 ) 1987 45 Ovarian SCC after TAH for endometriosis Stage III, grade 3 Tumor reduction * Chemotherapy * DOD at 5 months Naresh et al. (1991 ) 1991 62 Ovarian SCC associated with endometrioma TAH, LSO, debulking of R ovarian mass, partial omentectomy Multiagent chemotherapy DOD at 2 months Campagnutta et al. (1994 ) 1994 Ovarian SCC associated with endometrioma RH Radiotherapy DOD at 11 months Eltabbakh et al. (1998 ) 1998 31 Ovarian SCC associated with endometrioma Stage IV Cytoreductive surgery Paclitaxel-cisplatin 12 cycles (every 4 weeks) Alive without disease progression at 24 months Ohtani et al. (2000 ) 2000 53 Well-moderately differentiated SCC with focal endometriosis RH, BSO, low anterior colectomy POMB (cisplatin, vincristine, mitomycin C, bleomycin) 2 cycles; paclitaxel-carboplatin 5 weekly cycles Reduction in tumor volume by 78 % at 2 months Balat et al. (2001 ) 2001 40 Bilateral primary ovarian SCC TAH, BSO, PLND, infracolic omentectomy, appendectomy, right nephrectomy multiagent-chemotherapy DOD at 24 months Chien et al. (2005 ) 2005 63 High-grade SCC Stage IV, grade 3 TAH, BSO, bilateral PLND, tumor resection, omentectomy Paclitaxel-cisplatin 6 cycles DOD at 7 months Amjad and Pal (2008 ) 2008 31 Well differentiated ovarian SCC Stage IIIc TAH, BSO, PLND, PALND, supracolic TAH, BSO, sigmoid colectomy, terminal ileostomy, total omentectomy, small bowel resection Cisplatin-etoposide 3 months DOD at 3 months Park et al. (2010 ) 2010 76 Well differentiated invasive ovarian SCC Stage IIc, grade 1 TAH, BSO, PLND, PALND, supracolic omentectomy, appendectomy Paclitaxel and platinum-based chemotherapy 5 cycles Alive without disease progression at 90 months Park et al. (2010 ) 2010 48 Invasive ovarian SCC Stage IV, grade 3 TAH, BSO, PLND, PALND, supracolic omentectomy, appendectomy, debulking Paclitaxel and platinum-based chemotherapy 3 cycles Alive without disease progression at 9 months Acien et al. (2010 ) 2010 46 Primary, moderately differentiated ovarian SCC associated with endometriosis Stage IV TAH,BSO, recto-sigmoidectomy, infracolic omentectomy, appendectomy, peritoneal wall biopsies Paclitaxel-carboplatin 1 cycle DOD at 70 days Yamakawa et al. (2011 ) 2011 45 Moderately differentiated ovarian SCC Stage IIIc RH, BSO, PLND, PALND, rectal serosa tumor resection, omentectomy Paclitaxel-carboplatin 6 cycles, paclitaxel weekly 5 cycles, irinotecan-mitomycin 3 cycles every 2 weeks DOD at 16 months Baughn et al. (2011 ) 2011 58 Moderately differentiated invasive ovarian SCC arising in continuity w/benign mucinous cyst TAH, BSO, PLND, PALND, omentectomy Paclitaxel-carboplatin 3 cycles Alive without disease progression at 6 months Park and Bae (2015 ) 2015 46 Pure ovarian SCC Stage IVB TAH, BSO, segmental sigmoid resection Paclitaxel-carboplatin 6 cycles. Topotecan-cisplatin 3 cycles. Etoposide-ifosfamide 3 cycles DOD at 12 months Nakamura et al. (2015 ) 2015 71 Pure ovarian SCC Stage IIb Initial: RSO, uterine wall tumor resection. Post-chemo: TAH, LSO, PLND, PALND, partial omentectomy Paclitaxel-carboplatin 2 cycles monthly; irinotecan 3 weekly cycles; Post-surgery: irinotecan 3 weekly cycles Alive without disease progression at 18 months Sharma et al. (2015 ) 2015 66 Moderately differentiated ovarian SCC Stage IIIC TAH, BSO, infracolic omentectomy, removal of right parietal wall mass Radiation therapy with cisplatin DOD at 2 months Srivastava et al. (2017 ) 2017 30 Pure ovarian SCC Stage IIIc TAH, LSO, debulking of residual tumor, infra-colic omentectomy, ileal resection Paclitaxel-cisplatin 7 cycles DOD at 12 months Mimura et al. (2017 ) 2017 50 Pure ovarian SCC Stage IIB En-bloc TAH, BSO, rectosigmoid colectomy, infracolic omentectomy, PLND, PALND Paclitaxel-carboplatin Alive without disease progression at 7 months Xu and Li (2018 ) 2018 43 Poorly differentiated ovarian SCC TAH, BSO, omentectomy Paclitaxel-cisplatin (peritoneal injection) 3 cycles; paclitaxel-cisplatin (IV) 2 cycles; cisplatin-doxorubicin-cyclophosphamide 2 cycles DOD at 16 months Maharjan (2019 ) 2019 43 Moderately differentiated SCC arising from mature cystic teratoma Stage IA TAH, BSO Carboplatin-based chemotherapy Alive without disease progression at 6 months This study 2023 71 Mixed ovarian carcinoma with clear cell carcinoma component (25 %) and SCC component (75 %) Stage IA RH, BSO, PLND, appendectomy, omentectomy Paclitaxel-carboplatin, 6 cycles Alive without disease progression at 8 months Key: TAH = total abdominal hysterectomy; RH = radical hysterectomy; PALND = para-aortic lymph node dissection; PLND = pelvic lymph node dissection; BSO = bilateral salpingo-oophorectomy; RSO = right salpingo-oophorectomy; LSO = left salpingo-oophorectomy; B/L = bilateral; Q3W = every 3 weeks; DOD = dead of disease. * Data obtained from Acien et al. Review of ovarian squamous cell carcinoma in the literature. Key: TAH = total abdominal hysterectomy; RH = radical hysterectomy; PALND = para-aortic lymph node dissection; PLND = pelvic lymph node dissection; BSO = bilateral salpingo-oophorectomy; RSO = right salpingo-oophorectomy; LSO = left salpingo-oophorectomy; B/L = bilateral; Q3W = every 3 weeks; DOD = dead of disease. Data obtained from Acien et al. Despite these interventions, prognosis of ovarian cancer remains poor ( Amjad & Pal, 2008 ). A SEER study in 2020 compared squamous cell carcinoma of the ovary with high grade serous adenocarcinoma of the ovary. Median survival of SCC was 26 months compared to 50 months with serous carcinoma ( Zhang & Ma, 2020 ). Notably, although 1–2 year survival for ovarian SCC was half that of serous carcinoma, by 5 years, survival actually slightly favored SCC, suggesting an early increase in mortality but longer survival for those who are caught early ( Zhang and Ma, 2020 ). In another study of 32,185 women diagnosed with high grade serous ovarian carcinoma and squamous cell carcinoma of the ovary from 2000 to 2017, SCC presented earlier in the disease course but had decreased overall survival than its more common high grade serous counterpart ( Amjad & Pal, 2008 ). Of these over 32,000 cases, only 206 were SCC, further reinforcing the rarity of this subtype of ovarian cancer and the limitations that exist in finding sufficient evidence to support treatment recommendations. Risk factors associated with worse disease outcome included older age, larger tumor size, bilaterality, and more advanced FIGO stage at time of diagnosis ( Zhang & Ma, 2020 ). This case represents one of a very limited number of reports of ovarian SCC. In this case, keratinizing squamous cell carcinoma component was found to comprise 75 % of the ovarian tumor, with the remaining 25 % clear cell carcinoma. Unlike 80 % of ovarian SCCs, this was not transformed within a mature cystic teratoma but rather from antecedent endometriosis. This patient came to attention early on in the disease process with histology revealing FIGO stage 1A cancer. Resection with clear margins was achieved and subsequent management included a standard ovarian cancer carboplatin/paclitaxel regimen necessitated by the presence of high risk components on histology. Ovarian SCC represents a rare and aggressive histology that does not currently have an established standard of care treatment. Based on our review of the literature, we would recommend treating these patients with initially cytoreductive surgery if the chance of optimal cytoreduction is high. Thereafter, even in stage IA disease, we would recommend treatment with adjuvant platinum-based chemotherapy and close surveillance. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ovarian cancer is the second most common malignancy of the female reproductive tract in the United States. Subtypes are divided into germ cell cancers (10 %), stemming from the oocyte, and epithelial cell cancers (90 %), which are more common in later life and are associated with poor prognosis due to late diagnoses and nonspecific clinical presentations ( Torre et al., 2018 ). Epithelial cell cancers are thought to arise from extraovarian tissues that embed in the ovary and undergo malignant transformation ( Torre et al., 2018 ). This includes Fallopian tube epithelial deposition that causes serous carcinoma, transitional epithelium from the tubo-peritoneal junction causing mucinous carcinoma, and endometriomas on the ovary leading to clear cell carcinoma, adenocarcinoma, and rarely, squamous cell carcinoma ( Torre et al., 2018 ). Ovarian Squamous Cell Carcinoma (SCC) is a rare form of ovarian cancer that comprises less than 1 % of all ovarian cancer diagnoses. Ovarian SCC most often arises from malignant transformation of one cell layer in a mature cystic teratoma ( Roxburgh and Glasspool, 2014 , Gadducci et al., 2021 ). Less commonly, they arise from an endometrioma or Brenner tumor ( Srivastava et al., 2017 ). The rarest form of SCC is a pure ovarian SCC, of which only 30 cases have been reported ( Srivastava et al., 2017 ). Regardless of etiology, squamous cell carcinoma of the ovary carries a particularly poor prognosis with median survival time of only 26 months, compared to the more common high grade serous ovarian adenocarcinoma, which has median survival of 50 months ( Zhang & Ma, 2020 ). Pathologic findings suggestive of ovarian SCC necessitate staging and aggressive management at time of diagnosis.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.