Primary diaphragmatic clear cell carcinoma associated with endometriosis: A case report and literature review

A 55-year-old postmenopausal woman, gravida 3, para 3 was found to have an asymptomatic right pleural effusion on routine chest radiography for periodic medical examination. She was admitted to a nearby general hospital for further examination of right pleural effusion. Unenhanced computed tomography (CT) showed a 5.5 × 4.8 cm round mass with heterogenous high density in the right diaphragm ( Fig. 1 A). Enhanced CT showed a cystic mass with enhanced papillary components, which had a fistula to the pleural cavity complicated with pleural effusion and passive atelectasis ( Fig. 1 B). Ultrasonography-guided percutaneous aspiration of the cystic mass was performed. The size of the mass was transiently reduced, but it immediately regrew. Fluid cytology analysis revealed neutrophil-dominant leukocytosis and no malignant cells. She was referred to our hospital for surgery. Fig. 1 A. Unenhanced computed tomography (CT) shows a round mass (arrow) with heterogenous high density in the right diaphragm. B. Enhanced CT with coronal reconstruction shows a cystic mass with enhanced papillary components (arrows), which had a fistula (arrowhead) to the pleural cavity complicated with pleural effusion and passive atelectasis. A. Unenhanced computed tomography (CT) shows a round mass (arrow) with heterogenous high density in the right diaphragm. B. Enhanced CT with coronal reconstruction shows a cystic mass with enhanced papillary components (arrows), which had a fistula (arrowhead) to the pleural cavity complicated with pleural effusion and passive atelectasis. On her past medical history, abdominal hysterectomy and bilateral salpingo-oophorectomy was performed for high-grade cervical intraepithelial neoplasia, uterine myoma, and bilateral ovarian endometriosis at our hospital 5 years ago. At that time, unenhanced CT scan was performed for screening of other diseases. Endometriosis in the right diaphragm was not identified on unenhanced CT images and during the surgery, However, on retrospective review of the unenhanced CT images, a nodular lesion with low density in the right diaphragm, consistent with diaphragmatic endometriosis ( Fig. 2 ) was detected. Fig. 2 Unenhanced computed tomography performed 5 years ago, shows a nodular lesion (arrow) with low density in the right diaphragm, consistent with diaphragmatic endometriosis. Unenhanced computed tomography performed 5 years ago, shows a nodular lesion (arrow) with low density in the right diaphragm, consistent with diaphragmatic endometriosis. Magnetic resonance imaging was performed during this admission. The cystic mass contained a serous fluid with low signal intensity on T1-weighted imaging and high signal intensity on T2-weighted imaging ( Fig. 3 A, B). The papillary components exhibited low signal intensity on T1-weighted imaging, high signal intensity on T2-weighted imaging, enhancement on gadolinium T1-weighted imaging, and high-signal restricted diffusion on diffusion-weighted imaging with apparent diffusion coefficient (ADC) mapping (mean ADC value 0.96 × 10 × 10–3 mm 2 /s) ( Fig. 3 A-E). T2*-weighted gradient echo imaging showed partial low signal intensity in the papillary components and cyst wall, which was suspected to represent hemosiderin deposition ( Fig. 3 F). Fig. 3 T1-weighted (A) and T2-weighted (B) imaging shows a cystic mass with papillary projection (arrows). The cystic mass contains serous fluid and exhibited low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. The papillary components exhibits enhancement on gadolinium T1-weighted imaging (C: arrow), and restricted diffusion on diffusion-weighted imaging (D: arrow) and apparent diffusion coefficient (ADC) map (E: arrow). The mean ADC value is 0.96x10 × 10–3 mm 2 /s. T2*-weighted gradient echo imaging (F) shows partial low signal intensity (arroehead) in the papillary components and cyst wall, which is suspected to be hemosiderin deposition. T1-weighted (A) and T2-weighted (B) imaging shows a cystic mass with papillary projection (arrows). The cystic mass contains serous fluid and exhibited low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. The papillary components exhibits enhancement on gadolinium T1-weighted imaging (C: arrow), and restricted diffusion on diffusion-weighted imaging (D: arrow) and apparent diffusion coefficient (ADC) map (E: arrow). The mean ADC value is 0.96x10 × 10–3 mm 2 /s. T2*-weighted gradient echo imaging (F) shows partial low signal intensity (arroehead) in the papillary components and cyst wall, which is suspected to be hemosiderin deposition. Based on these serial images, malignant transformation of diaphragmatic endometriosis was suspected. Open abdominal surgery was performed, and right diaphragmatic cystic mass with a fistula to the pleural cavity was found. The mass adhered to the liver, but the adhesion was easily removed. Combined resection of the mass and part of the diaphragm, and repair of the diaphragmatic defect using a Gore-tex mesh were performed. Endometriosis implants were detected on the pelvic peritoneum during the surgery. Histopathological examination revealed papillary structures and hemosiderin deposition in papillary components and cyst wall ( Fig. 4 A). The papillary structures were lined by columnar or hobnail cells with clear cytoplasm and nuclei of various sizes ( Fig. 4 B), and the tumor cells invading a diaphragmatic muscle. In immunohistochemistry analysis the tissue was hepatocyte nuclear factor 1 beta (HNF1β)-positive and estrogen receptor-negative. Thus, clear cell carcinoma (CCC) was diagnosed. Moreover, endometrial glands and endometrial stroma were detected in the cyst wall ( Fig. 4 C), resulting in a diagnosis of endometriosis. Based on histopathology and serial imaging, a primary diaphragmatic CCC associated with endometriosis was diagnosed. Fig. 4 Histopathological examination, Hematoxylin and eosin (H&E) staining. A. Low-power of view (x5). reveals papillary structures and hemosiderin deposition in the papillary components and cyst wall. B. On high-power of view (x200), the papillary structures are lined by columnar or hobnail cells with clear cytoplasm and nuclei of various sizes, resulting in a diagnosis of clear cell carcinoma. C. On high-power of view (x100), endometrial glands and endometrial stroma are detected in the cyst wall, resulting in a diagnosis of endometriosis. Histopathological examination, Hematoxylin and eosin (H&E) staining. A. Low-power of view (x5). reveals papillary structures and hemosiderin deposition in the papillary components and cyst wall. B. On high-power of view (x200), the papillary structures are lined by columnar or hobnail cells with clear cytoplasm and nuclei of various sizes, resulting in a diagnosis of clear cell carcinoma. C. On high-power of view (x100), endometrial glands and endometrial stroma are detected in the cyst wall, resulting in a diagnosis of endometriosis. She received six courses of TC adjuvant chemotherapy (paclitaxel 180 mg/m 2  and carboplatin AUC 6 mg/m × minute) at 3-week intervals and is alive without evidence of disease 15 months after the surgery.

Mitsuru Matsuki: Conceptualization, Writing - original draft. Isao Numoto: Data curation. Takefumi Hamakawa: Data curation. Kazunari Ishii: Writing - review & editing. Takaaki Chikugo: Data curation.

Written informed consent was obtained from the patient to publish this data.

Endometriosis is characterized by the extrauterine growth of endometrial glandular epithelial and stromal cells. It is commonly located in the pelvic cavity including the ovaries, uterosacral ligaments, and pouch of Douglas, and more rarely in remote locations such as the abdominal peritoneum, diaphragm, pericardium, pleura, lung, and brain. It affects 10% of all women of reproductive age, and 30% of infertile women. It is a benign chronic gynecological disease and is clinically associated with dysmenorrhea, dyspareunia, pelvic pain, and infertility. Its etiology is yet to be clearly elucidated, but it is considered to involve a combination of anatomical, hormonal, immunological, reactive, estrogenic, genetic, epigenetic, and environmental factors. With regard to pathogenesis, Sampson’s retrograde menstruation theory that endometriosis originates from implantation and invasion of menstrual endometrial cells due to reflux through the fallopian tubes into the peritoneal cavity is widely accepted. And the Coelomic metaplasia theory postulates that endometriosis originates from the metaplasia of specialized cells that are present in the mesothelial lining of the visceral and abdominal peritoneum. Diaphragmatic endometriosis is rare, and it usually occurs in the right side of the diaphragm. The higher prevalence in the right diaphragm supports Sampson’s retrograde menstruation theory. On the left side of the pelvis, the sigmoid colon covers part of the left adnexa and is fixed to the pelvic side wall by adhesions. Conversely the right side of the pelvis has no such protective barrier, therefore on that side menstrual blood is carried away to the right subphrenic space by the flow of peritoneal fluid. Catamenial pneumothorax and hemothorax can be caused. Typical symptoms of diaphragmatic endometriosis include chest pain, dyspnea, epigastric pain, shoulder pain, and upper abdomen pain. The symptoms are usually periodic, but some patients have continual symptoms that are not associated with the menstrual cycle. Moreover, it is often asymptomatic as it was in the present case. On CT imaging, it often appears as a nodular or plaque-type lesion in the right diaphragm, as it was in the present case ( Posniak et al., 1990 ). On T1-weighted magnetic resonance imaging the lesion often demonstrates hyperintensity, reflecting hemorrhage. In the treatment, medical treatment is the first line for symptomatic cases. Surgery is indicated in the symptomatic patients with failure of medical treatment. For some groups, it is recommended that asymptomatic implants incidentally founded during laparoscopy must be treated to avoid, theoretically, a progression to deep endometriotic nodules. It was reported that the rates of synchronous endometriosis in conjunction with ovarian cancer were reportedly 40.6% in patients with CCC and 23.1% in patients with endometrioid carcinoma ( Jimbo et al., 1997 ). In another report, endometriosis was identified in the final pathology reports in 51% of patients with CCC and 43% with endometrioid carcinoma ( Stamp et al., 2016 ). It has been suggested that hemosiderin, heme, or iron deposition trigger oxidative stress in patients with endometriosis, and the oxidative stress may contribute to subsequent carcinogenesis of endometriosis ( Kobayashi et al., 2009 ). Endometriosis-associated ovarian carcinogenesis is considered to involve aberrant expression of the AT-rich interactive domain-containing protein 1A (ARID1A) tumor suppressor gene, and driver genes including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and Kirsten rat sarcoma viral oncogene homologs (KRAS) ( Anglesio et al., 2017 ), which are promoted under oxidative stress. HNF1β appears to play a key role in anti-oxidative defense mechanisms. Overexpression of HNF1β is evident in nearly all CCCs, it may play a role in the development of CCCs in stressful environments, and it can be used as a biomarker to assist the histopathological diagnosis of CCC ( Shigetomi et al., 2012 ). The origin of CCCs in the peritoneum and diaphragm is currently thought to be associated with Müllerian metaplasia and endometriosis. To our knowledge 15 cases of primary peritoneal or diaphragmatic CCCs have previously been reported, and they are summarized in Table 1 ( Terada and Kawaguchi, 2005 , Takano et al., 2009 , Fujiu et al., 2010 , Harimoto et al., 2018 , Shigeta et al., 2014 , Insabato et al., 2015 , Peiro et al., 2020 ). Only two cases of diaphragmatic CCC were identified ( Fujiu et al., 2010 , Harimoto et al., 2018 ). The mean age of the patients was 55 years (range 45–67 years), and 6/15 cases had a history of endometriosis or adenomyosis, or concurrent endometriosis and adenomyosis. In treatment, it is reported that TC (paclitaxel and carboplatin) adjuvant chemotherapy after debulking surgery can be effective. Table 1 Summary of primary peritoneal and diaphragmatic clear cell carcinomas reported in the literature. Case Authors Age Past history or concurrence of endometriosis or adenomyosis Serum CA125 (U/mL) Tumor size Location Peritoneal dissemination CT findings MR findings Macroscopic findings Coexistent endometriosis with CCC on the histopatlogy Treatment Outcome 1 Evans et al. 54 Ov EM, AM NA 18 × 13 cm Sigmoid mesocolon No Multilocular cyst with nodules NA Multilocular cyst with nodules No DS followed by RT NA 2 Lee et al. 67 None 2218 6 cm Abdomen, Pelvs Yes NA NA NA No DS with TAH + BSO NA 3 Tziortzioti et al. 62 None 313.9 0.5–2 cm Subdiaphragm, Abdomen, Omentum Yes NA NA NA No DS with TAH + BSO, CTx DOD at 6 months 4 Ichimura et al. 45 Ov EM 28 NA Pelvis No Cyst with solid components NA NA No DS with TAH + BSO, CTx RD at 32 months 5 Hama et al. 53 EM 467 NA Pelvis, Liver surface Yes Cystic mass with solid coponents Multicystic mass with hemorrhage and heterogenous solid protrusions NA No DS and BSO DOD at 5 months 6 Terada et al. 49 None NA 3 cm, 2 cm Greatur curvature of the stomach, Splenic hilus No NA NA Cystic tumor with solid and papillary components No DS DOD at 6 months 7 Takano et al. 53 None 467 13 × 5 cm Between liver and disphargm, Omentum, Abdomen Yes NA NA NA No DS DOD at 5 months 8 Takano et al. 66 None 347 20 × 15 cm Omentum No NA Cystic and solid mass NA No DS with TAH + BSO, omentectomy, lymph node dissection, CTx NED at 20 months 9 Muezzinoglu et al. 54 pEM 42.3 25 × 25 × 4 cm Abdomen No NA Cystic mass with solid nodules Mulicystic tumor with papillary structures and solid nodules Yes DS with TAH + BSO, CTx NED at 12 months 10 Johnson et al. 54 None NA 5.6 × 3.7 × 3.5 cm Pelvis No Soft tissue mass NA NA No CTx and RTx RD (bone and liver) 11 Shigeta et al. 59 AM, pEM 76 7 cm Pelvis No NA Heterogenous tumor Multilocular cystic tumor with solid components No DS with TAH + BSO, PLD, CTx NED at 5 months 12 Insabato et al. 49 None NA 9.5 × 9 × 7 cm Adherent to the ileum No Solid and cystic mass NA Microcystc and solid tumor No DS with left oophorectomy RD at 6 months(Inguinal lymphnode), NED at 5 months after second surgery and CTx 13 Peiro et al. 48 None 57 25 × 15 cm Abdomen No Cystic mass wth papillary projection NA Multilocular cystic tumor with papillary components No DS with T1H + BSO + omentectomy RD at 8 months (peritoneum), stable at 28 months after initial surgery by CTx 14 Fujiu et al. 65 Ov EM 48 2.5 cm Right diaphragm No Thick-walled cystic mass with peripheral enhancement Thick-walled cystic mass with peripheral enhancement Thick-walled unilocular cyst with protruded components No DS RD at 12 months (lung) 15 Harimoto et al. 55 None NA 3 cm Right diaphragm No Lobulated cystic mass Lobulated cystic mass Lobulated cystic tumor with protruded components and intracystic hemorrhage No DS NA 16 Present case 55 Ov EM, pEM 40 5.5 × 4.8 cm Right diaphragm No Cyst with solid and papillary components Cyst with solid and papillary components Cyst with solid and papillary components Yes DS and Cx NED at 15 months Ov EM, ovarian endometriosis; pEM, peritoneal endometriosis; AM, adenomyosis; CCC, clear cell carcinoma; NA, not available DS, debulking surgery; TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; CTx, chemotherapy; RTx, radiotherapy; DOD, death of disease; NED, no evidence of isease; RD, recurrence of disease. Summary of primary peritoneal and diaphragmatic clear cell carcinomas reported in the literature. Ov EM, ovarian endometriosis; pEM, peritoneal endometriosis; AM, adenomyosis; CCC, clear cell carcinoma; NA, not available DS, debulking surgery; TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; CTx, chemotherapy; RTx, radiotherapy; DOD, death of disease; NED, no evidence of isease; RD, recurrence of disease. On imaging, most appeared as unilocular or multilocular cystic masses with solid or papillary components, which is similar to malignant transformation of ovarian endometriosis ( Tanaka et al., 2000 , Takeuchi et al., 2006 ). In the present case, T2*-weighted gradient echo images showed partial low signal intensity in the papillary components and cyst wall, reflecting hemosiderin deposition. Such findings can be useful in the detection of the coexistence of endometriosis with hemosiderin deposition ( Tanaka et al., 2000 , Takeuchi et al., 2006 ). In conclusion, we report a first case of histologically proven primary diaphragmatic CCC associated with endometriosis. Imaging showed a cystic mass with papillary components in the right diaphragm. T2*-weighted gradient echo imaging detected hemosiderin deposition caused by the coexistent endometriosis. When these characteristic imaging features are encountered, a detailed medical history should be determined and the possibility of concurrent endometriosis or adenomyosis should be investigated, as should the potential existence of diaphragmatic endometriosis in previous images.

Endometriosis is commonly located in the pelvic cavity including the ovaries, uterosacral ligaments, and pouch of Douglas, and diaphragmatic endometriosis is rare. It was reported that ovarian endometriosis was associated with an increased risk of malignant transformation developing clear cell carcinoma (CCC) and endometrioid carcinoma ( Jimbo et al., 1997 , Stamp et al., 2016 ). Previously, only two reports of primary diaphragmatic CCC were reported, but coexistent endometriosis was not histologically proven ( Fujiu et al., 2010 , Harimoto et al., 2018 ). We herein report a first case of histologically proven primary diaphragmatic CCC associated with endometriosis that presented characteristic imaging findings with radiologic–pathologic correlation.

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.