Primary peritoneal clear cell carcinoma with metastasis mimicking ovarian carcinoma: a case report and literature review

A 48-year-old woman with no significant past medical or family history presented to a local clinic with acute lower abdominal pain. She had no prior history of hormone replacement therapy or endometriosis. Laboratory tests revealed elevated tumor markers, including CA 19–9 (777.3 U/mL) and CA 125 (242.9 U/mL), while CEA (1.3 ng/mL) and AFP (3.06 ng/mL) were within normal limits. Abdominal computed tomography (CT) revealed a 15 × 10 mm oval-shaped, subtly enhancing lesion in the pancreatic tail, raising suspicion for either pancreatic adenocarcinoma or an islet cell tumor. Additionally, a 70 × 65 × 35 mm well-defined, heterogeneously enhancing solid mass was noted in the left pelvic cavity, suspicious for a malignant pelvic tumor or metastasis. The patient was referred to a tertiary care center for further evaluation. Upon transfer, pelvic magnetic resonance imaging (MRI) revealed an 11 cm mixed cystic and solid mass in the left adnexa, with the solid component demonstrating heterogeneous enhancement and diffusion restriction, suggestive of ovarian malignancy (Fig.  1 ). Under the clinical impression of synchronous ovarian and pancreatic malignancies, the patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and distal pancreato-splenectomy. Intraoperatively, a large pelvic mass was identified within the pelvic peritoneum. Frozen section analysis performed during surgery initially suggested high-grade serous carcinoma of ovarian origin. A 2 cm encapsulated, well-demarcated mass was also identified in the pancreatic tail, adherent to the adjacent omentum, requiring adhesiolysis. However, both ovaries, fallopian tubes, and uterus appeared grossly unremarkable. Fig. 1 Pelvic MRI demonstrating a large mixed cystic and solid mass in pelvic cavity. A Sagittal view. B Coronal view showing heterogeneous enhancement and diffusion restriction within the solid component, suggestive of malignancy Pelvic MRI demonstrating a large mixed cystic and solid mass in pelvic cavity. A Sagittal view. B Coronal view showing heterogeneous enhancement and diffusion restriction within the solid component, suggestive of malignancy Gross pathological examination revealed a 12 × 11 × 3.5 cm pelvic mass with no apparent lesions in other gynecologic organs (Fig.  2 A-C). To exclude a gynecologic origin, both ovaries and fallopian tubes were entirely submitted and examined microscopically according to the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) protocol; however, no evidence of a primary tumor was identified. The pelvic mass was extensively sampled, with approximately 30 paraffin-embedded tissue blocks submitted for histologic evaluation. The pancreatic tail contained a 3 × 2.8 × 2.5 cm cystic lesion with a friable whitish intraluminal mass. A similar 1.3 × 1.1 cm cystic, friable whitish mass-forming lesion was identified within the splenic parenchyma. Microscopically, the pancreatic lesion was centered within the pancreatic parenchyma and demonstrated an infiltrative growth pattern. Tumor cells formed solid and sheet-like architectures with extensive necrosis and were observed dissecting through the pancreatic stroma, entrapping and partially replacing native pancreatic acini and ducts. The splenic lesion demonstrated a cystic change within the splenic parenchyma, containing a mass-forming papillary tumor. Tumor nests and glandular structures were present within the adjacent red pulp. Across all sites, the tumors shared identical histomorphological features. Tumor cells displayed round to oval nuclei with irregular contours, clear to eosinophilic cytoplasm, and moderate nuclear atypia. Mitotic activity was variable, and occasional eosinophilic hyaline globules were noted (Fig.  3 A, B). No lymphovascular or perineural invasion was identified. These findings collectively support true parenchymal involvement of both the pancreatic and splenic lesions. Fig. 2 Gross specimens of the resected tumors. A Pancreas: well-demarcated mass measuring approximately 2 cm, with solid and cystic components and hemorrhage. B Pelvic mass: irregularly shaped solid mass with a lobulated and uneven surface. C Uterus and adnexa: both ovaries and fallopian tubes appeared grossly unremarkable, except for a leiomyoma in the uterus; no primary tumor was identified Fig. 3 Histopathologic and immunohistochemical features of the peritoneal clear cell carcinoma. A Low-power view showing a predominantly solid and papillary architecture with necrosis (H&E, × 20). B High-power view demonstrating tumor cells with round to oval nuclei, clear to eosinophilic cytoplasm and moderate nuclear atypia (H&E, × 100). C , D Tumor cells show diffuse positivity for PAX8 (C, × 100) and HNF1β (D, × 100). E , F DNA mismatch repair analysis demonstrates retained MLH1 expression (E, × 100) but loss of MSH2 nuclear staining (F, × 100), indicating MMR deficiency Gross specimens of the resected tumors. A Pancreas: well-demarcated mass measuring approximately 2 cm, with solid and cystic components and hemorrhage. B Pelvic mass: irregularly shaped solid mass with a lobulated and uneven surface. C Uterus and adnexa: both ovaries and fallopian tubes appeared grossly unremarkable, except for a leiomyoma in the uterus; no primary tumor was identified Histopathologic and immunohistochemical features of the peritoneal clear cell carcinoma. A Low-power view showing a predominantly solid and papillary architecture with necrosis (H&E, × 20). B High-power view demonstrating tumor cells with round to oval nuclei, clear to eosinophilic cytoplasm and moderate nuclear atypia (H&E, × 100). C , D Tumor cells show diffuse positivity for PAX8 (C, × 100) and HNF1β (D, × 100). E , F DNA mismatch repair analysis demonstrates retained MLH1 expression (E, × 100) but loss of MSH2 nuclear staining (F, × 100), indicating MMR deficiency The specimens also lacked any histologic features suggestive of endometriosis, such as endometrial glands, stroma, or hemosiderin-laden macrophages. Immunohistochemical staining showed positivity for PAX8, CK7, and HNF1β, and negativity for CK20, p16, WT1, and calretinin (Fig.  3 C, D). p53 staining revealed a wild-type expression pattern. Immunohistochemical staining for PD-L1 was negative in the tumor cells. DNA mismatch repair (MMR) immunostaining demonstrated loss of nuclear expression of MSH2 and MSH6, while MLH1 and PMS2 remained intact, indicating MMR deficiency (Fig.  3 E, F). To exclude a gynecologic origin of the clear cell carcinoma, the ovaries, fallopian tubes, and uterus were serially and thoroughly sectioned for microscopic examination. However, no evidence of a primary tumor was identified. Next generation sequencing (NGS) of the tumor revealed loss of ARID1A, along with additional somatic mutations in PIK3CA H1047R and PIK3CA Q546L. Based on intraoperative findings, histopathological features, immunohistochemical profile and molecular characteristics by NGS, the final diagnosis was primary peritoneal clear cell carcinoma, with metastases to the pancreas and spleen, a highly unusual presentation. The patient was diagnosed with stage IVB primary peritoneal clear cell carcinoma, and the case was discussed at a multidisciplinary tumor board to determine the appropriate adjuvant treatment. The patient is scheduled to undergo six cycles of chemotherapy with gemcitabine and carboplatin.

Primary peritoneal clear cell carcinoma (PPCCC) is an exceptionally rare malignancy that closely resembles gynecologic epithelial cancers both clinically and histologically. While clear cell carcinoma (CCC) most commonly arises in the ovary or endometrium, its occurrence as a primary tumor in the peritoneum is exceedingly uncommon. Since its first description in 1990 [ 1 ], only a limited number of cases have been reported in the English literature [ 2 – 15 ]. Diagnosing PPCCC is challenging due to its overlapping morphological features with more common neoplasms originating from the ovary, endometrium and kidney. The pathogenesis of PPCCC remains poorly understood, though current hypotheses suggest possible origins from Müllerian metaplasia or malignant transformation of endometriosis [ 11 ]. However, many reported cases, including the present one, lack histological evidence of endometriosis or hormonal influence [ 1 , 2 , 7 , 9 , 11 , 13 – 15 ]. Given the rarity of reported cases, each new case provides valuable insights into the clinical and pathological spectrum of this underrecognized malignancy. Herein, we present a case of PPCCC in a 48-year-old woman without a history of endometriosis or hormone therapy, underscoring the diagnostic complexity and clinical significance of this unusual tumor.

Primary peritoneal clear cell carcinoma (PPCCC) is an exceptionally rare malignancy, and its diagnosis remains challenging due to its rarity and overlapping features with more common tumors at this site. In many cases, it may be under-recognized or misclassified as metastatic disease from the ovary or other organs. Therefore, complete exclusion of other potential primary sites is essential. In addition to characteristic histopathological features, immunohistochemistry plays a critical role in the differential diagnosis, helping to distinguish PPCCC from ovarian, renal, and mesothelial neoplasms. Proper identification of this rare malignancy plays a crucial role in achieving a precise diagnosis and informing appropriate treatment strategies. Given the aggressive behavior and poor prognosis associated with PPCCC, further studies are needed to better understand its molecular pathogenesis and to establish optimized treatment protocols to reduce mortality.

Primary peritoneal carcinoma (PPC) is a rare epithelial malignancy characterized by predominant peritoneal disease with minimal or no ovarian involvement. Historically, the Gynecologic Oncology Group (GOG) proposed operational criteria to distinguish PPC from primary ovarian carcinoma, including normal-sized ovaries or only benign enlargement and peritoneal involvement exceeding ovarian surface disease [ 16 ]. However, advances in the understanding of pelvic high-grade serous carcinoma indicate that many tumors previously classified as primary peritoneal serous carcinomas likely arise from the distal fallopian tube, and thus the traditional concept of “primary peritoneal” origin has been substantially revised. In contrast, the histogenesis of primary peritoneal clear cell carcinoma (PPCCC) remains unclear, and a definitive tubal precursor lesion analogous to serous tubal intraepithelial carcinoma has not been established. PPCCC represents an exceedingly rare histologic subtype of PPC, accounting for approximately 3% of cases [ 17 ]. Histologically, it is indistinguishable from clear cell carcinomas (CCCs) of Müllerian origin, particularly those of the ovary and endometrium. Therefore, meticulous exclusion of other primary sites is essential for establishing a diagnosis. In the present case, serial sectioning and detailed histopathologic evaluation of the uterus, ovaries, and fallopian tubes revealed no evidence of a primary tumor. Although the possibility of a primary clear cell carcinoma arising from the fallopian tube was considered, comprehensive examination of both ovaries and fallopian tubes using the SEE-FIM protocol did not reveal any precursor or invasive lesions, supporting a primary peritoneal origin. While the molecular and pathogenetic mechanisms underlying PPCCC have not been fully elucidated, the most widely accepted hypotheses suggest either Müllerian metaplasia or malignant transformation of endometriosis [ 11 ]. However, extraovarian malignant transformation of endometriosis is extremely rare, occurring in only 1.6% of cases [ 18 ]. In previous reports, approximately one-third of patients with PPCCC had a history of endometriosis, and endometriotic foci were often found histologically [ 10 , 17 ]. In our case, however, extensive histologic sampling failed to demonstrate any features of endometriosis, such as endometrial-type glands or stroma, or hemosiderin-laden macrophages. A review of previously reported PPCCC cases is summarized in Table  1 , providing an overview of patient demographics, tumor location, history of endometriosis, molecular findings and clinical outcomes. Most cases involved women in their 40 s to 60 s, with endometriosis present in only a subset of cases, reflecting the heterogeneous pathogenesis of this malignancy. Our case shares similar histopathologic features but is distinguished by DNA mismatch repair deficiency and ARID1A loss on NGS, highlighting both overlapping and unique molecular characteristics. The differential diagnosis of CCC arising in the peritoneum includes high-grade serous carcinoma, malignant mesothelioma, and metastatic clear cell carcinomas from other organs, particularly the kidney. High-grade serous carcinoma is characterized by marked nuclear atypia, frequent mitotic figures, and a complex papillary or solid architecture [ 20 ]. In contrast, malignant mesothelioma often demonstrates relatively bland cytologic features and simple papillary formations lined by a single layer of uniform mesothelial cells. Despite morphologic overlap with CCC, these entities can usually be distinguished through a combination of histologic evaluation and imunohistochemical profiling. Among metastatic tumors, clear cell renal cell carcinoma (CCRCC), is an important consideration. CCRCC typically displays a nested-alveolar growth pattern with rich stromal vasculature, whereas Müllerian-type CCC is characterized by tubulocystic architecture, small rounded papillae, and hobnail cells [ 21 ]. Immunohistochemically, CCRCC is frequently negative for CK7, HNF1 beta, whereas CCCs of gynecologic origin are typically positive for these markers. In our case, the tumor showed diffuse CK7 and PAX8 positivity, along with HNF-1β positivity, and was negative for WT1. DNA mismatch repair (MMR) analysis revealed loss of nuclear expression of MSH2 and MSH6, while MLH1 and PMS2 remained intact, consistent with MMR deficiency. p53 staining showed a wild-type pattern. These findings collectively supported the diagnosis of gynecologic-type clear cell carcinoma of peritoneal origin. Table 1 Literature review for cases of clear cell carcinoma of peritoneum Authors Age Tumor location Endometriosis Treatment Stage Outcome Molecular characteristics Evans et al. [ 19 ] 54 Sigmoid mesocolon Yes DS + RT IIIB NA NA Lee et al. [ 1 ] 67 Pelvic cavity No DS + TAHBSO IIIB NA NA Tziortzioti et al. [ 7 ] 62 Peritoneum and omentum No DS + TAHBSO + OM + CT IIIA DOD at 6 mo NA Ichimura et al. [ 6 ] 45 Pelvic cavity Yes DS + TAHBSO + CT NR ROD at 32 mo NA Hama et al. [ 5 ] 53 Peritoneum Yes DS + BSO + CT IIIB DOD at 5 mo NA Terada et al. [ 13 ] 49 Gastric peritoneal, splenic hilus No DS IIIB NED at 6 mo NA Takano et al. [ 14 ] 53 Upper abdomen and omentum No DS + CT IIIC DOD at 5 mo NA Takano et al. [ 14 ] 66 Omentum and peritoneum No DS + TAHBSO + OM + LND + CT IIIC NED at 20 mo NA Matsuo et al. [ 4 ] 37 Abdominal scar Yes DS + CT IIIB ROD at 18 mo NA Muezzinoglu et al. [ 3 ] 54 Abdomen Yes DS + TAHBSO + CT IIIC NED at 12 mo NA Johnson et al. [ 2 ] 54 Proximal vagina and vaginal cuff No CT + RT IIB ROD at 4 mo NA Shigeta et al. [ 10 ] 59 Douglas pouch Yes DS + TAHBSO + LND + CT IIB NED at 5 mo NA Peiro et al. [ 11 ] 48 Peritoneum No TAHBSO + OM + CT IIIC NED at 28 mo ARID1A loss Giannakopoulos et al. [ 15 ] 61 Peritoneum No DS III NED at 2 mo Alves et al. [ 9 ] 34 Peritoneum No TAH + LND + OM + CT IIIA DOD at 24 mo BRCA1A unknown significance Present case 48 Pelvic peritoneum No TAHBSO + CT IVB NED at 1 mo ARID1A loss PIK3CA H1047R Literature review for cases of clear cell carcinoma of peritoneum ARID1A loss PIK3CA H1047R The identification of MMR deficiency carries important clinical implications. Loss of MSH2 and MSH6 expression raises the possibility of an underlying Lynch syndrome, warranting further genetic counseling and germline testing. Moreover, MMR deficiency has been associated with increased tumor mutational burden and may confer potential responsiveness to immune checkpoint inhibitors, even in malignancies such as clear cell carcinoma that are often considered chemoresistant. Recent molecular studies have provided insights into the genetic alterations associated with ovarian CCCs, with frequent mutations reported in ARID1A, PIK3CA, and KRAS [ 22 ]. Peiró et al. [ 11 ] also described a pathogenic deletion in ARID1A and additional somatic mutations in GSDMB and KMT2C in a case of PPCCC. In our case, molecular analysis revealed ARID1A loss, consistent with the findings reported by Peiró et al. [ 11 ]. In addition, NGS identified a PIK3CA H1047R mutation, expanding the molecular profile of PPCCC in this patient. PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a variety of cancers, including breast, endometrial, and cervical cancers. The H1047R mutation is known to be oncogenic. Preclinical data suggest that tumor harboring these PIK3CA mutations may be sensitive to isoform-selective PIK3CA inhibitors such as RLY-2608, highlighting a potential targeted therapy approach [ 23 , 24 ]. While data on PPCCC remain scarce, these overlapping molecular features suggest a potential shared pathogenesis with ovarian CCC, underscoring the importance of further molecular investigations to better characterize this rare malignancy. Moreover, the identification of potentially actionable mutations emphasizes the role of comprehensive molecular profiling in guiding future research and individualized therapeutic strategies [ 22 , 25 , 26 ]. Clinically, PPCCC typically presents with abdominal pain, ascites, and a pelvic mass, as was observed in our patient [ 10 ]. While the majority of reported cases remain confined to the peritoneal cavity, distant metastases beyond the peritoneal cavity has been documented in the skin and brain [ 9 ]. In our case, metastatic involvement of the pancreas and spleen indicated advanced disease (FIGO stage IVB), highlighting the aggressive clinical behavior and poor prognosis often associated with PPCCC. Current treatment strategies for PPCCC are not well established due to its rarity and are generally extrapolated from protocols for epithelial ovarian carcinoma, including cytoreductive surgery followed by platinum-based chemotherapy. Despite such treatment, outcomes remain suboptimal, with frequent early recurrence and limited response to standard regimens. Immune checkpoint inhibitors targeting the PD-1/PD-L1 have been explored in CCC subtypes and have shown limited efficacy. Although our case was negative for PD-L1 expression, the presence of MMR deficiency may still provide a rationale for considering immunotherapy in the event of disease progression or recurrence. In conclusion, PPCCC is a rare and aggressive malignancy that poses significant diagnostic and therapeutic challenges. Accurate diagnosis requires thorough histologic, immunohistochemical, and clinical evaluation to exclude more common primary sites. This case contributes to the limited body of literature and highlights the need for further research into the pathogenesis, molecular characteristics, and potential targeted therapies for this underrecognized malignancy.