Endometriosis-Associated Neoplasms: A Review of Clinicopathologic Features and Common Diagnostic Challenges

Neoplastic potential of endometriosis is well established, albeit rare, and endometriosis-associated neoplasms are frequently encountered in clinical practice. Objective.— To summarize and review common diagnostic issues with endometriosis and endometriosis-associated neoplasms, as well as review clinical, pathologic, and molecular characteristics of these tumors and discuss differential diagnoses. Data Sources.— Literature review and cases from the authors’ personal practice. Conclusions.— Endometriosis-associated neoplasms are a frequently encountered heterogeneous group of ovarian neoplasms with some unifying features, including younger age and lower stage at presentation. The most common tumors are endometrioid carcinomas, clear cell carcinomas, and seromucinous borderline tumors. The diverse morphologic features and variant histologic patterns can significantly complicate interpretation and compromise reproducibility. This review offers a systematic approach in overcoming these diagnostic challenges that are facilitated by the integration of histologic, immunohistochemical, and molecular findings. Endometriosis, classically defined by the presence of endometrial glands and stroma in extrauterine locations, is a common, inflammatory, estrogen-dependent condition, seen in 10% to 15% of women in the reproductive age group.1,2 Endometriosis-associated neoplasms (EANs) are a rare complication of endometriosis seen in approximately 1% of these patients. They can occur at any site where endometriosis occurs but are most common in the ovary.2,3 The criteria for EANs, specifically carcinomas in the ovary, were suggested by Sampson4 and Scott5 and continue to be used in current practice. These include (1) the coexistence of carcinoma and endometriosis in the same ovary; (2) the presence of endometrioid stroma surrounding epithelial glands; (3) the exclusion of a metastatic tumor to the ovary; and (4) the presence of benign endometriosis histologically close to the tumor. Subsequently, additional tumors were defined as associated with endometriosis, even if endometriosis was not in close proximity to the tumor.4,5 Common sites of endometriosis and therefore potentially EANs are usually in the pelvis and include the ovary, fallopian tube, pelvic ligaments, cul-de-sac, cervix, vagina, bladder, ureter, bowel, lymph nodes, and other pelvic peritoneal sites. Other extrapelvic and unusual sites can be involved by endometriosis and can occasionally pose diagnostic difficulties.2 The most common EANs include endometrioid adenocarcinoma (EC) and clear cell carcinoma (CCC). Borderline counterparts of these tumors are uncommon. Benign and borderline seromucinous tumors are the third most common EANs. Other rare tumors associated with endometriosis include extrauterine endometrioid stromal sarcoma, Müllerian adenosarcoma, carcinosarcoma, and mesonephric-like carcinoma.2,3,6 EANs are usually seen in younger patients, tend to be low stage at presentation, and have an overall favorable outcome.6,7 While EANs share common molecular features with endometriosis, each of the EANs has additional distinct molecular signatures. This review offers a systematic overview of the benign morphologic alterations observed in endometriosis, paired with a comprehensive synthesis of the clinical, histopathologic, and molecular characteristics associated with both common and rare neoplasms arising in the context of endometriosis. ENDOMETRIOSIS: DIAGNOSTIC CHALLENGES Endometriosis, defined as the presence of ectopic endometrial tissue outside the uterus corpus, is usually easily identifiable owing to the presence of characteristic endometrioid glands and stroma associated with an infiltrate of hemosiderin-laden macrophages elicited by repeated episodes of bleeding. However, the absence of, or reactive and metaplastic changes in 1 or more components, can lead to underrecognition of endometriosis. Some of these changes are briefly discussed here (see supplemental digital content containing 7 figures at https://aplm.kglmeridian.com by clicking on the article title in the April 2026 table of contents). Polypoid Endometriosis Polypoid endometriosis is a rare polypoid, mass–like lesion protruding from mucosal or serosal surfaces or within endometriotic cysts that mimics a neoplasm on clinical, intraoperative, and gross examination. The most common sites of involvement are the colon and ovary. Other reported sites of involvement include uterine serosa, cervix, vagina, ureter, fallopian tube, omentum, bladder, paraurethral and paravaginal soft tissues, and retroperitoneum. Multiple site involvement may be seen. There is an association with exogenous hormones and hyperestrogenism. Microscopically, these lesions resemble endometrial polyps with endometrioid glands and stroma with thick-walled vessels and variable fibrosis of the stroma. The glandular component frequently shows metaplastic and hyperplastic changes. Lack of recognition of this entity as endometriosis may result in misinterpretation of the stromal cuff around the glands as periglandular stromal condensation of Müllerian adenosarcoma. In contrast to adenosarcoma, the stroma in polypoid endometriosis lacks atypia and/or mitotic activity, although reactive changes may make this distinction challenging.8,9 Stromal Endometriosis Stromal endometriosis or gland-poor endometriosis is defined as endometriosis composed almost entirely of endometrioid stroma with an absence of glands. It is usually seen in the pelvic peritoneal surfaces, cervix, ovary, and omentum. Stromal endometriosis is relatively common and is likely underrecognized. It may be mistaken for lymphoid aggregates or nonspecific stromal cell aggregates. In the peritoneum, stromal endometriosis is typically seen as small, well-circumscribed nodules or plaques, submesothelial in location with nodular protrusion, termed micronodular stromal endometriosis. The cells resemble endometrial stromal cells in the proliferative phase with round-to-ovoid nuclei and indistinct cytoplasm. Spiral arteriole-like vessels engorged with red blood cells surrounded by whorled stromal cells are typical. There is usually associated mixed inflammation, reactive mesothelial hyperplasia, giant cell reaction or granuloma formation, hemosiderin pigment deposition and extravasated red blood cells, microcalcification, or myxoid change. Immunohistochemistry for CD10 and estrogen receptor (ER) can confirm the endometrioid nature of the stromal cells but is relatively nonspecific and can stain other Müllerian stromal cells. It is important to remember that in extrauterine low-grade endometrioid stromal sarcoma (LGESS) or metastatic uterine LGESS, neoplastic nodules identical to stromal endometriosis can be identified. However, in LGESS, there are usually grossly visible mass lesions and larger nodules of tumor with an obvious infiltrative pattern and/or lymphovascular invasion. In challenging cases, molecular studies for characteristic translocations of LGESS will be helpful.9–11 Another entity in the differential diagnosis of stromal endometriosis is Kaposi sarcoma (KS). In addition to contrasting clinical features, the cells in KS resemble fibroblasts and exhibit a fascicular arrangement with nuclear atypia, mitotic activity, and hyaline globules. Immunohistochemical stains can also help differentiate the 2 entities, with stromal endometriosis staining for CD10 and ER, and KS staining for human herpesvirus-8.9,11 Atypical Endometriosis The term atypical endometriosis has been used variably in literature for several lesions encompassing architectural complexity as well as variable degrees of cytologic atypia and is used to describe a spectrum of intermediary lesions between typical endometriosis and EANs. Architectural crowding resembling atypical hyperplasia or intraepithelial neoplasia in the endometrium is better described as an endometrioid borderline tumor. These lesions are commonly seen in association as well as in continuum with endometrioid carcinoma, and therefore, identification of such proliferations should prompt additional sampling to exclude an endometrioid carcinoma. Cytologic atypia in the epithelium of endometriotic cysts is a very common finding and can range from mild to severe with varying degrees of cellular stratification; a variety of metaplastic changes, including ciliated cell, clear cell, hobnail, squamous, and mucinous metaplasia; inflammatory and degenerative changes; and mitotic activity. The atypical cells have enlarged nuclei with prominent nucleoli, a low nuclear-to-cytoplasmic ratio, abundant clear-to-eosinophilic cytoplasm, hobnailing, and often demonstrate neutrophilic infiltration. There is associated reactive fibrotic stroma rather than endometrioid stroma, inflammation, hemorrhage, and hemosiderin-laden macrophages.2,9,12–15 This phenomenon is most likely secondary to repeated episodes of bleeding, has not been associated with increased risk of subsequent malignancy,12 and is best designated as “reactive changes” in the pathology report to prevent confusion among clinicians regarding recurrent and malignant potential. A recent report described 6 cases involving epithelial proliferations within the lining of endometriotic cysts, which were morphologically and immunophenotypically consistent with CCC. These lesions showed no evidence of stromal invasion and were classified as clear cell carcinoma in situ.16 Given that atypical endometriosis often appears in continuity with EC and CCC, it is crucial to thoroughly sample areas of atypical endometriosis to exclude the presence of an underlying malignancy. Although the precise malignant potential and ideal clinical approach for these lesions remain unclear, long-term follow-up data indicate low rates of recurrence and malignant transformation in patients with atypical endometriosis.17 Other Epithelial Changes in Endometriosis Metaplastic changes in endometriotic epithelial cells are common, found in up to two-thirds of cases in one study.18 These changes are similar to those seen in eutopic endometrium as well as in endometrioid carcinomas and include tubal (ciliated cell), eosinophilic, hobnail, squamous, clear cell, and mucinous metaplasia. Mucinous metaplasia can be of Müllerian type or, less commonly, intestinal type with goblet cells. In cecal and appendiceal endometriosis, replacement of endometriotic epithelium by intestinal-type epithelium may mimic an appendiceal mucinous neoplasm.19 Many of these metaplastic changes are seen in continuum with EANs, and the distinction between metaplasia and early neoplastic transformation is arbitrary and subjective. The presence of endometriotic stroma underneath metaplastic epithelium likely still represents metaplastic endometriosis. In many cases, it is not possible to ascertain whether these changes are reactive, degenerative, or a progression toward EAN.18 Stromal Changes in Endometriosis Smooth muscle metaplasia is common in endometriosis and has been reported in up to 18% of ovarian endometriotic cysts within the cyst wall.9,20 When florid (endomyometriosis), it can result in a firm mass resembling leiomyoma grossly or a uterus-like mass. Smooth muscle metaplasia in endometriosis should be distinguished from endometriosis involving indigenous smooth muscle, such as pelvic ligaments, and bowel or bladder walls, where the endometriosis induces reactive native smooth muscle proliferation, as seen in myometrial smooth muscle proliferation around foci of adenomyosis. The reactive smooth muscle proliferation can obscure endometriosis in such scenarios, and deeper levels may be needed to reveal the inciting endometriosis.15 Prominent myxoid change can be seen in the stroma where the stromal cells are separated by acellular stromal mucin, mimicking extravasated mucin or, rarely, pseudomyxoma peritonei, leading to a misdiagnosis of mucinous adenocarcinoma. These changes mainly occur in the skin or soft tissue and are more common in pregnancy and puerperium. A diligent search for the epithelial element of endometriosis may aid in making the correct diagnosis, although the glands may be atrophic or attenuated secondary to hormone effects.15 Elastosis of endometriotic stroma can be extensive, giving the stroma a corpus albicans–like appearance; this finding is more common in the muscularis of hollow organs. Endometriotic lesions can also undergo extensive fibrosis of the stroma with adhesions to surrounding tissue and may show dystrophic calcifications.15 Pregnancy and exogenous progesterone treatment can lead to prominent decidualization of endometriotic stroma with glandular atrophy similar to that seen in the eutopic endometrium. Accompanying necrosis, edema, and lymphocytic infiltration may also be seen. Occasionally, the decidual cells may exhibit cytoplasmic vacuoles, resulting in a signet ring–like appearance mimicking metastatic signet ring cell adenocarcinoma, but negative keratin staining in the decidual cells can facilitate the correct diagnosis.15 Mesothelial Proliferation Associated With Endometriosis Peritoneal mesothelial hyperplasia is common, is usually minimal, and does not pose a diagnostic challenge. A wide variety of ovarian or peritoneal lesions, benign and malignant, may elicit reactive mesothelial proliferation in the peritoneum. However, exuberant and florid mesothelial hyperplasia involving the surface of the ovary is strongly associated with endometriosis. Endometriosis-associated mesothelial hyperplasia can also be seen on the surface of the fallopian tubes, the pelvic peritoneum, and the omentum. The mesothelial cell proliferations appear as innocuous epithelioid cells arranged in small tubules, papillae, nests, cords, or single cells, often embedded in reactive fibrous tissue. These hyperplastic proliferations may not be limited to the surface but can extend deep into the wall of the cysts and mimic an infiltrative pattern of malignancy within a desmoplastic stroma. Retraction artifact around the mesothelial cells may mimic lymphovascular invasion; at times, true lymphovascular invasion by hyperplastic mesothelial cells may be seen. These features could raise the possibility of several primary epithelial, mesothelial, as well as sex cord–stromal tumors. Awareness of this phenomenon in association with endometriosis is important to prevent diagnostic errors. Immunohistochemical staining with an epithelial and mesothelial marker can be used to confirm the mesothelial nature of these proliferations.9,21 Pseudoxanthomatous Salpingitis and Necrotic Pseudoxanthomatous Nodules Pseudoxanthomatous salpingitis of the fallopian tube, also known as pigmentosis tubae or pseudoxanthomatous salpingiosis, is an uncommon finding associated with pelvic endometriosis. The tubal mucosa may show chocolate-brown discoloration on macroscopic examination. On microscopic examination, the lamina propria of the tubal mucosa is typically engorged with foamy and pigmented histiocytes containing brown lipofuscin pigment and hemosiderin pigment, which is likely an inflammatory reaction to repeated episodes of endometriosis-derived bleeding.22 This needs to be distinguished from xanthogranulomatous salpingitis, where there are foamy vacuolated macrophages in a similar distribution, usually in the setting of pelvic inflammatory disease.22 Another entity seen associated with endometriosis is necrotic pseudoxanthomatous nodules of the peritoneum and ovaries, which are granulomatous nodules composed of a central focus of necrotic tissue with calcified debris surrounded by pseudoxanthoma cells and hyalinized tissue. These are seen distributed within the peritoneal cavity and within endometriotic cysts, typically in older patients. They are thought to represent an unusual reaction to endometriotic cyst contents and are a late manifestation of endometriosis. They can clinically mimic peritoneal or omental carcinomatosis.23 ENDOMETRIOSIS-ASSOCIATED NEOPLASMS Tumors arising in endometriosis are called EANs. The frequency of malignant transformation in endometriosis is estimated at 1.1% to 3%.24 It is possibly higher as tumors arising in endometriosis are likely to overrun and obliterate underlying endometriosis. The ovary is the most common site for EANs, accounting for about 75% of cases. EANs, however, can develop practically at any site where endometriosis is found. The common extraovarian sites include cul-de-sac, pelvic ligaments, fallopian tube, vagina, urinary bladder, colon and rectum, other pelvic peritoneal sites, scars, and omentum.2 Women with EANs tend to be younger with evidence of hyperestrogenism. EANs usually present earlier and have a more favorable prognosis than similar tumors unassociated with endometriosis.6,7 The histologic types of EANs are diverse and include epithelial, stromal, and mixed neoplasms. CCC and ovarian endometrioid adenocarcinoma (OEC) account for approximately two-thirds of all endometriosis-associated cases.24 While endometrioid carcinoma is the more common of the 2 entities, women who have ovarian CCC have a much higher frequency of coexistent pelvic endometriosis. Seromucinous neoplasms, most commonly borderline, are the third most common group of epithelial EANs. A mixture of these epithelial neoplasms can be seen in the setting of endometriosis. Stromal neoplasms thought to arise from the stromal component of endometriosis include low-grade endometrioid stromal sarcoma and adenosarcoma. Carcinosarcomas can also arise in endometriosis. Endometrioid Carcinoma Clinical Features Endometrioid epithelial tumors account for 2% to 4% of all ovarian tumors. Benign endometrioid adenofibromas and borderline endometrioid tumors are rare. OECs account for approximately 10% of all ovarian carcinomas.25,26 Benign, borderline, and malignant endometrioid tumors are seen in the perimenopausal and postmenopausal age group with a mean age in the sixth decade of life.14,26 Most OECs are associated with endometriosis in the ipsilateral ovary or other pelvic sites.2,27 Patients with endometriosis-associated tumors are 5 to 10 years younger on average than patients without associated endometriosis. OECs present as a pelvic mass or are asymptomatic. Serum cancer antigen 125 (CA 125) is usually elevated.28 OECs are associated in 20% of cases with concurrent endometrial endometrioid carcinoma.2,14,27 OECs are seen in increased frequency in patients with Lynch syndrome. These patients tend to be of a younger age (usually <50 years), with synchronous endometrial endometrioid carcinoma in up to 80% of cases.27,28 Gross Appearance OECs are usually unilateral and average more than 10 cm in size. The cut surface is variably cystic or solid. Tumors arising in endometriotic cysts typically show polypoid masses protruding into the lumen of blood-filled cysts. Tumors with an adenofibromatous component tend to be solid with hemorrhage and necrosis. Histologic Features OECs show a wide range of morphologic variants similar to their endometrial counterparts. A background of cystic endometriosis, adenofibroma, and borderline tumors or a combination may be encountered. Most OECs are grade 1 or grade 2 tumors with a predominant glandular pattern, composed of back-to-back or cribriform glands or papillary structures lined by pseudostratified columnar cells, with well-defined luminal borders, and with minimal pleomorphism (Figure 1, A and B). Mitotic rate is typically low, with fewer than 12 mitotic figures per 10 high-power microscopic fields.14,29,30 Most tumors show an expansile or confluent pattern of invasion, with rare cases showing destructive or infiltrative invasion with a desmoplastic response.31 Squamous differentiation, mostly in the form of squamous morules, is seen in more than half the tumors27,29 and is a useful clue to endometrioid differentiation (Figure 1, C). Occasionally, squamous differentiation may present as spindle cells or with prominent glycogenation imparting a clear cell change. Rarely, the squamous component can be overtly malignant resembling invasive squamous cell carcinoma. Keratinization within the squamous component can elicit a foreign body giant cell reaction with granulomas dispersed within the peritoneum. It is important to note that keratin granulomas in the absence of viable endometrioid tumor cells do not affect staging and prognosis.9,14 Clear cell changes are common in OECs. These foci of clear cell change must be distinguished from CCC, based on characteristic architectural and cytologic features discussed later. Mucinous metaplasia can be seen in up to one-fourth of OECs and may be focal,27 or rarely, diffuse, resembling mucinous carcinoma (Figure 1, D). Other morphologic variants seen include extensive ciliated cell metaplasia, corded and hyalinized pattern, broad papillae resembling serous borderline tumors, and small nonvillous papillae.30 Prominent spindle cell change within the tumor may be a source of diagnostic confusion.32 Other uncommon morphologic variants in the ovary include OECs with sex cord-stromal–type pattern, resembling either an adult granulosa cell tumor or Sertoli cell tumor.33,34 These tumors show solid nests, tubules, cords, or trabecular patterns with relatively bland nuclear features, and occasional stromal luteinization that could lead to potential misinterpretation, particularly in the setting of intraoperative consultation. Grade 3 OECs can occasionally show significant pleomorphism and high mitotic activity and usually lack squamous differentiation. OECs may be associated with somatically derived yolk sac tumor (YST).2,9,14 Other rare associations include undifferentiated carcinoma and neuroendocrine carcinoma.2 Immunohistochemistry The typical immunoprofile of OECs is cytokeratin 7 (CK7) positive, epithelial membrane antigen (EMA) positive, paired box gene 8 (PAX8) positive, ER positive, and progesterone receptor (PR) positive. They usually show negativity or focal positivity for Wilms tumor 1 (WT1), while p16INK4a (p16) shows patchy staining, and p53 shows a wild-type staining pattern, features that help distinguish them from serous tumors. A subset of high-grade OECs can show aberrant p53 expression. Hepatocyte nuclear factor-1 beta (HNF1β) can show positivity in up to one-third of OECs, while Napsin A and α-methylacyl–coenzyme A racemase (AMACR) usually show negativity.30 As noted above, some OECs show DNA mismatch repair (MMR) loss, a subset of which are associated with Lynch syndrome.27,28 It is important to note some immunohistochemical pitfalls in OECs, including a lack of expression of Müllerian markers CK7, PAX8, and ER, and positive expression of cytokeratin 20 (CK20), caudal-type homeobox 2 (CDX2), and special AT-rich sequence–binding protein 2 (SATB2), which may lead to a potential misdiagnosis of metastatic colorectal carcinoma.9 Differential Diagnoses A broad spectrum of primary ovarian neoplasms and metastatic tumors may exhibit an endometrioid-like glandular architecture. Additionally, diverse metaplastic changes within OECs can complicate histologic interpretation. Grade 3 OECs often pose diagnostic challenges with high-grade serous carcinoma (HGSC) and undifferentiated carcinoma being common differential considerations. HGSCs may mimic glandular and solid growth patterns seen in OECs but typically demonstrate more pronounced nuclear atypia and pleomorphism. In cases exhibiting solid, pseudoendometrioid and transitional cell–like morphology, the atypia and mitotic activity may be subtle. Diagnostic features favoring OEC include the presence of endometriosis, adenofibromatous or borderline background, squamous metaplasia, and a WT1-negative, p53 wild-type staining pattern.35 Dedifferentiation within OECs must be distinguished from grade 3 OECs, as both may exhibit adjacent low-grade components. The dedifferentiated areas are typified by sheets of discohesive, high-grade monomorphic epithelioid or rhabdoid cells, often accompanied by necrosis, frequent mitoses, and loss of expression of keratins and Müllerian markers, as well as loss of SWItch/Sucrose Non-Fermentable (SWI/SNF) complex proteins. In contrast, grade 3 regions tend to be more cohesive and retain expression of keratins, PAX8, and hormone receptors.36 Mucinous tumors also mimic OECs. OECs may exhibit luminal mucin or extensive mucinous metaplasia, potentially mimicking mucinous borderline tumors or carcinomas. Conversely, mucinous neoplasms may show focal mucin depletion and resemble OECs. Most mucinous tumors show a spectrum of benign, borderline, and malignant changes within a single tumor and lack squamous differentiation, adenofibromatous, or endometriotic foci.37 Immunohistochemical profiles assist in differentiation: CK7+/ER+/PR+/PAX8+ supports endometrioid carcinoma, whereas CK7+/CK20+/CXD2+ with weak or absent ER and PAX8 expression favors a mucinous origin. Clear cell changes in OEC may occur from glycogenation within the squamous morules, secretory metaplasia of endometrioid epithelium, or nonspecific cytoplasmic vacuolation.38 These alterations are generally focal, with classic EC areas present. Cells in EC are more columnar and pseudostratified in contrast to the low cuboidal or polygonal cells of CCC, lack nuclear pleomorphism, and are diffusely positive for ER and PR in the low-grade component.27 Rarely, mixed OEC and CCC may coexist, particularly in the context of endometriosis and/or MMR deficiency.39 OECs may occasionally contain a spindle cell component that can mimic carcinosarcoma. These spindle cells typically merge with the epithelial elements and maintain a low-grade appearance. Both components share similar cytologic features and mitotic activity and express keratins, EMA, PAX8, ER, and PR.32 Rarely, a corded and hyalinized (CHEC) pattern with osteoid formation may also be seen in OECs, raising suspicion for carcinosarcoma. CHEC tumors feature low-grade spindled to epithelioid cells separately by hyalinized stroma into cords, often admixed with conventional EC areas.9 In contrast, true carcinosarcomas exhibit high-grade carcinoma and sarcoma components with anaplasia, show a sharp demarcation between the 2 components, lack hormone receptors, and are p53 aberrant. Sex cord–stromal tumors, mainly adult granulosa cell tumor or Sertoli cell tumor, are in the differential diagnosis for OECs that can occasionally display microglandular, tubular, or trabecular patterns within a solid background. Stromal condensation or luteinization resembling Leydig cells may further add to diagnostic confusion. However, OECs typically show more pronounced cytologic atypia. The presence of squamous elements, endometriosis, or adenofibromatous background supports OEC diagnosis. Serum inhibin levels and hormonal manifestations may aid in differentiation. Immunohistochemistry is pivotal: OECs with sex cord–stromal features exhibit an EMA+/CK7+/inhibin–/calretinin–/WT1–/steroidogenic factor 1 (SF1)– profile, whereas adult granulosa cell tumors, Sertoli cell tumors, and Sertoli-Leydig cell tumors show the opposite immunophenotype.34,40 The glandular or pseudoendometrioid variant of YST can closely resemble OEC. Diagnostic clues favoring YST include age less than 30 years, elevated serum α-fetoprotein (AFP) levels, presence of other YST patterns, and a Sal-like protein 4 (SALL4)+/glycipan3 (GPC3)+/CDX2+/villin+ and EMA−/CK7−/PAX8−/ER− immunoprofile. Rarely, YST may arise in association with OEC, representing a somatically derived YST in postmenopausal women. These tumors exhibit distinct components but show significant immunophenotypic overlap, with the YST component expressing keratins and PAX8 alongside YST markers.9,41 Such tumors are clinically aggressive and must be distinguished from conventional OEC.42 Distinguishing primary OEC from metastatic endometrioid carcinoma from the uterine corpus is of clinical significance. Approximately 20% of patients with OEC have concurrent endometrial carcinoma. Favorable outcomes in cases confined to both organs suggest independent primary tumors. Features supporting dual primary tumors include (1) low-grade histology at both sites; (2) histologic dissimilarity; (3) superficial myometrial invasion and lack of lymphovascular invasion; (4) large unilateral ovarian mass without surface involvement; and (5) ovarian endometriosis. Conversely, features favoring uterine metastasis to the ovary include (1) bilateral ovarian involvement; (2) surface involvement; (3) small ovaries with nodular growth pattern; (4) high-grade histology; and (5) deep myometrial invasion, lymphovascular invasion, or tubal involvement.14,43 Molecular analyses have demonstrated clonality in most cases.44 Metastatic human papillomavirus–associated endocervical adenocarcinoma may mimic OECs owing to its mucin-poor glandular morphology. Frequent apical mitosis and apoptosis, along with p16 and human papillomavirus positivity, aid in diagnosis. Notably, ovarian metastasis may be the initial presentation of an occult cervical tumor.45 Gastrointestinal tract carcinomas also frequently masquerade as primary ovarian neoplasms. Bilaterality, small tumor size, surface involvement, and advanced-stage disease suggest metastatic origin. Histologic features include nodular growth pattern with desmoplastic response, extensive lymphovascular invasion, garland necrosis, dirty necrosis within glands, hilar involvement, and signet ring cells.46 Immunohistochemistry panels including Müllerian and appropriate gastrointestinal tract markers are essential, though pitfalls associated with these markers as mentioned earlier must be considered.9 See the Table for further information on differential diagnoses. Behavior and Prognostic Factors Stage is the most important prognostic factor in OEC.2,25 The International Federation of Gynecology and Obstetrics (FIGO) grading system applied to endometrial endometrioid adenocarcinoma is applicable to OEC and is based on the amount of glandular/solid nonsquamous component in a tumor (grade 1 tumors have ≤5%, grade 2 tumors have 6%–50%, and grade 3 tumors have >50% solid architecture).2 FIGO grading has been found to correlate with survival on univariate analyses for all tumors.47 A confluent or expansile pattern of invasion has been associated with a good prognosis, compared to a destructive pattern of invasion.31 Clear Cell Carcinoma Clinical Features CCC accounts for about 10% of all ovarian cancers in the Western world, and up to 25% of ovarian cancers in Japan.2,48,49 These tumors are seen in a wide age range from teens to the postmenopausal age group, with a mean age in the sixth decade of life.50 Patients usually present with a pelvic mass and modest elevations in serum CA 125 levels. There is often a history of antecedent or concurrent endometriosis. CCC is associated with a higher incidence of venous thromboembolic events and with paraneoplastic hypercalcemia.51,52 CCC is seen in patients with Lynch syndrome.53 Gross Appearance CCC is usually unilateral and ranges widely in size (mean, 13.0 cm). The cut surface shows variable proportions of solid and cystic components. In cystic tumors, the carcinoma may present as solid fleshy mural nodules protruding into a blood-filled endometriotic cyst. The solid component may be a solid carcinoma or a background adenofibroma.2,14,30,50 Histologic Features CCC of the ovary characteristically shows a variable admixture of tubulocystic, papillary, and solid architectural patterns. The papillae of CCC are small and rounded with prominent stromal hyalinization or myxoid change. The papillae are lined by flattened cuboidal or “hobnail” cells arranged in a monolayer with minimal pseudostratification (Figure 2, A). Occasionally the presence of broader papillae or micropapillary tufting may mimic a borderline tumor. The tubulocystic pattern ranges from large, dilated ectatic cysts lined by deceptively bland epithelium to small, round glandular structures (Figure 2, B). The solid component is composed of nests and sheets of cells with prominent cell borders. The cells are cuboidal, with hyperchromatic nuclei and show markedly variable pleomorphism ranging from mild to severe within the same tumor (Figure 2, C). Cytoplasm ranges from scant to absent in the tubulocystic component to abundant clear or eosinophilic cytoplasm—the so-called oxyphilic CCCs.54 Mitotic activity can be variable within the tumor but is usually low. Other encountered features of CCC include hyaline globules, colloid-like luminal secretions, nuclear pseudoinclusions, psammomatous calcifications, and signet ring–like cells. A prominent stromal lymphoplasmacytic infiltrate may be noted.2,14 Tumors with diffuse intratumoral stromal inflammation and peritumoral lymphocytes were more frequently associated with MMR loss.55 An adenofibromatous component resembling clear cell adenofibroma or borderline tumor can be seen in up to one-third of cases30,50,54,56 (Figure 2, D). Immunohistochemistry CCC shows a Müllerian phenotype and is typically CK7 and PAX8 positive, and CK20 and CDX2 negative. Of the CCC-specific markers—HNF1β, Napsin A, and AMACR—HNF1β is the most sensitive stain but lacks specificity. Napsin A and AMACR are relatively specific but not very sensitive and are therefore helpful only when showing positivity. ER, PR, and WT1 typically show negativity in CCC. p53 shows aberrant expression in approximately 25% of cases, and p16 shows block positivity in about 20% of cases.30,57 CCC shows loss of MMR proteins and association with Lynch syndrome in up to 17% of CCCs.55 Therefore, immunohistochemistry for MMR proteins is recommended in all cases of CCC. Differential Diagnoses The diagnosis of CCC can be challenging. As the presence of clear cells is not specific to CCC, there is always a potential for overdiagnosis of CCC. The plethora of architectural and cytologic features of CCC can potentially mimic many primary and metastatic tumors of the ovary, especially during intraoperative consultation. Other Müllerian tumors, like high-grade serous carcinomas, can show similar architectural patterns and clear cells, particularly post neoadjuvant chemotherapy. However, they typically present with high-stage disease, tend to have diffuse high-grade nuclear features with nuclear stratification and a high mitotic rate, and show abnormal p53 expression with WT1+/Napsin A−/AMACR−/HNF1β− immunophenotype.58 Papillary CCC can mimic serous borderline tumor, especially if the atypia and pleomorphism are not prominent. Focal high-grade nuclear features, presence of endometriosis, and a WT1−/ER−/Napsin A+ immunoprofile would help make the diagnosis.56 The presence of a prominent inflammatory infiltrate in a solid CCC may raise the possibility of dysgerminoma. Features that favor CCC include older age group, lack of elevated serum lactate dehydrogenase levels, presence of endometriosis and other patterns of CCC, and a CK7+/EMA+/CD117−/octamer-binding transcription factor 3/4(OCT3/4)− immunoprofile.14 There is potentially considerable histologic overlap between CCC and YST with solid and papillary architecture with clear monolayered cells lining papillae, hyalinization, and hyaline globules. YST is seen in younger patients with elevated serum AFP levels, and other patterns of YST, such as microcystic, reticular, or hepatoid patterns, typically coexist. YST, in contrast to CCC, is SALL4+/GPC3+/CDX2+/ER−/PR−/PAX8−.30 CK7 and EMA usually show patchy positivity in YST. In older patients, YSTs may be somatically derived and mixed with other epithelial tumors, including CCC, with an overlap of immunophenotypes.59 Steroid cell tumors of the ovary are in the differential diagnosis for CCC as they may have clear cytoplasm and some degree of pleomorphism, but typically lack the tubulocystic and papillary patterns of CCC and have a distinct immunophenotype. Metastatic tumors with clear cells like clear cell renal cell carcinoma can be differentiated from CCC by clinical history and use of appropriate immunostains. Behavior and Prognostic Factors Stage is the most important prognostic factor in CCC according to multiple studies. Low-stage CCC confined to the ovary with no surface involvement has an excellent prognosis. High-stage CCC has a worse prognosis owing to poor response of these tumors to platinum-based chemotherapy.50,60,61 Several grading schemes have been proposed and used, but do not show prognostic significance.50,62 CCC is considered a high-grade tumor. Two distinct pathways of CCC development have been proposed on the basis of histology: (1) an adenofibromatous type that develops from noncystic endometriosis with an associated adenofibromatous background; and (2) a cystic type that develops from an endometriotic cyst without an associated adenofibromatous background.63 There is no current consensus on the prognostic significance of the presence of background endometriosis64–67 or an adenofibromatous component.68,69 Improved survival in women with MMR-deficient high-stage CCCs compared to those with MMR-intact tumors was found in one study.70 Seromucinous Neoplasms Ovarian seromucinous tumors were introduced in the 2014 World Health Organization classification with benign, borderline, and malignant categories.71 This nomenclature replaced the previously used Müllerian mucinous, endocervical mucinous, and mixed epithelial tumors. Borderline seromucinous tumors are most common, with rare reports of benign cystadenomas and cystadenofibromas. Few studies reported seromucinous carcinomas72; however, subsequent reproducibility analyses showed poor interobserver agreement in the diagnosis of these tumors.73 In addition, most of these carcinomas showed an immunohistochemical and molecular overlap with endometrioid carcinomas. Owing to lack of distinct immunophenotypic and genotypic signatures, the seromucinous carcinoma category was discontinued and is now considered a subtype of endometrioid carcinoma.2,9 Clinical Features Seromucinous borderline tumors (SMBTs) are seen in patients in the fourth and fifth decades of life. These tumors are bilateral in up to 40% of patients, and 30% to 50% are associated with endometriosis.74 Gross Appearance SMBTs are usually up to 10 cm in size with a smooth external surface. They are typically unilocular with papillary or polypoid projections of the borderline component on the inner surface of the cyst. The cyst wall is often fibrous and thickened with hemorrhagic, serous, mucinous, or mucopurulent contents.2,9,75 Histologic Features SMBTs are composed of bulbous and edematous or fibrotic papillae with hierarchical branching (Figure 3, A). Neutrophilic infiltration of the stroma and epithelium is characteristic, and often prominent. The low-power architecture resembles serous borderline tumor; however, the lining cells show significant stratification and tufting and are composed of variable epithelial cells including endocervical-type mucinous, serous, endometrioid, clear cells, squamoid cells, and indifferent eosinophilic cells (Figure 3, B). Rarely, goblet cells may also be seen. These cells vary markedly in proportion. Microinvasion in SMBTs is uncommon2,9,75 (Figure 3, C). A collision of endometrioid borderline and SMBT can be seen in the background of endometriosis (Figure 3, D). Areas transitioning to endometrioid carcinoma can be identified. These tumors can also coexist with CCCs owing to the common pathogenesis and association with endometriosis.76 Occasionally, high-grade carcinomas that lack morphologic appearance of endometrioid or CCCs may be seen in association with SMBTs. Immunohistochemistry SMBTs show a Müllerian immunophenotype of CK7+/ER+/PR+/PAX8+/CK20−/CDX2−, similar to endometrioid tumors. They are typically negative or focally positive for WT1 and lack aberrant p53 expression.9,75 Unlike OECs and CCCs, they are not reported to be associated with loss of MMR proteins or with Lynch syndrome. Behavior and Prognostic Factors Most of these tumors present as FIGO stage I with very few reports of extraovarian disease. The few patients with advanced-stage disease have also been reported to have an excellent outcome.2,75 Molecular Findings in Endometriosis and Associated Epithelial Neoplasms The most frequent genomic alterations in EANs are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, which frequently co-occur. Mutations in ARID1A lead to a loss of BRG-associated factor 250a (BAF250a) protein expression.14,30 Other mutations in the PI3K pathway and the SWI/SNF complex that have been reported include ARID1B, phosphoinositide-3-kinase regulatory subunit (PIK3R), mesenchymal-epithelial transition (MET), AKT serine/threonine kinase 2 (AKT2), SWI/SNF-related BAF chromatin remodeling complex subunit ATPase 4 (SMARCA4), and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 (SMARCD3).14 Endometriotic foci that are associated with carcinoma show a high mutational burden. These molecular alterations are generally absent in eutopic endometrium, suggesting that the process of neoplastic transition begins with endometriosis. The hypoxic microenvironment within endometriotic cysts and the presence of already-mutated epithelia lay a fertile ground for the development of EANs. There is significant overlap in the molecular events that have been identified in EANS, although the frequencies differ. The most common recurring events in CCC include mutations in the ARID1A gene (50%) and mutations of the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene (30%–40%), telomerase reverse transcriptase (TERT) promoter (16%), DNA MMR proteins (5%–10%), MET amplification (37%), and AKT2 amplification (14%). The principal molecular alterations in OEC include mutations in catenin beta-1 (CTNNB1) (38%–50%), PIK3CA gene (30%–40%), ARID1A (30%), Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (20%), phosphatase and tensin homolog (PTEN) (20%), DNA MMR proteins (12%–20%), and protein phosphatase 2 scaffold subunit alpha (PPP2R1A) (12%). Seromucinous neoplasms primarily show mutations in KRAS (70%), ARID1A (30%), PIK3CA gene (37%), and PTEN (20%).14 Rare Endometriosis-Associated Neoplasms Rare tumors associated with endometriosis include endometrioid stromal sarcomas, Müllerian adenosarcoma, and carcinosarcoma. Few cases of mesonephric-like adenocarcinoma associated with endometriosis have been recently described. As these tumors are more commonly uterine in origin, a primary uterine tumor always needs to be ruled out before presuming an extrauterine origin in endometriosis. Endometrioid Stromal Sarcoma Primary LGESS has been well documented in extrauterine sites where endometriosis typically occurs and thus can cause variable signs and symptoms depending on the site of involvement. Histology is identical to uterine LGESS, with sheets of bland monotonous tumor cells resembling cells of proliferative-phase endometrial stroma with interspersed, characteristic spiral arteriole-like vessels. Several variant morphologies have been reported that, in addition to the unusual and unexpected location of the tumor, can cause diagnostic challenges. As in the uterus, these tumors are diffusely positive for CD10, ER, and PR.77 Rare cases of high-grade endometrioid stromal sarcoma have been reported. The extrauterine tumors show similar molecular profiles to their uterine counterparts. Extrauterine LGESS follows an indolent course despite most cases presenting at higher stages.77 Müllerian Adenosarcoma Primary ovarian Müllerian adenosarcoma is histologically identical to its uterine counterpart. It shows the characteristic biphasic, phyllodes-like pattern of uterine adenosarcoma. Benign glands lined by endometrioid or serous-type epithelium are surrounded by periglandular condensation of the sarcomatous stroma, which results in intraglandular polypoid projections. Sarcomatous overgrowth, sex cord elements, and heterologous stromal elements can be seen. Ovarian adenosarcomas have a more aggressive course than their uterine counterparts.78 Carcinosarcoma Primary ovarian carcinosarcomas, similar to uterine carcinosarcomas, are clinically aggressive tumors with poor prognosis, regardless of association with endometriosis. As in the uterus, they show bulky polypoid tumors with variable high-grade epithelial and sarcomatous components. There is extraovarian spread at diagnosis in most cases.79 The presence of a sarcomatous component in metastatic sites has been shown to be an adverse prognostic factor. Mesonephric-like Carcinoma Mesonephric-like carcinomas, resembling mesonephric carcinomas of the uterine cervix, can be seen as primary tumors at other sites of the female genital tract, including the ovary, where it has been associated with endometriosis. As in the cervix, these tumors show varied architecture, including papillary, tubular, and solid patterns. Colloid-like material may be present within tubules. The cells are atypical with angulated, vesicular nuclei with nuclear overlapping and frequent mitoses. They show a PAX8+/GATA-binding protein 3 (GATA3)+/thyroid transcription factor 1 (TTF-1)+/ER−/PR− immunophenotype and usually harbor KRAS mutations. As at other sites, these tumors show aggressive behavior with high stage at presentation and a propensity for pulmonary recurrence.80,81 CONCLUSIONS EANs represent a diagnostically challenging subset of gynecologic tumors. Despite their rarity, their frequent encounter in clinical practice, particularly in younger patients, demands heightened awareness and diagnostic precision. The morphologic diversity and overlapping histologic features of these neoplasms complicate reproducibility and interpretation. A systematic approach that integrates histopathologic evaluation with immunohistochemical and molecular profiling is essential to navigate these challenges. Ovarian endometrioid carcinoma. A, Low-grade carcinoma showing confluent invasion within an endometriotic cyst. B, Low-grade carcinoma with glandular pattern and minimal nuclear atypia. C, Tumor with squamous morules. D, Tumor with extensive mucinous metaplasia (hematoxylin-eosin, original magnifications ×20 [A], ×100 [B], and ×200 [C and D]). Figure 2. Clear cell carcinoma. A, Papillary architecture with stromal hyalinization and single flat-to-cuboidal atypical cells lining papillae. B, Tubulocystic pattern with dilated tubules lined by deceptively benign-appearing flattened cells and hobnail cells. C, Solid architecture with clear cytoplasm and prominent nuclear pleomorphism. D, Rare example of clear cell carcinoma arising in an adenofibroma and borderline tumor (hematoxylin-eosin, original magnifications ×100 [A through D]). Figure 3. Seromucinous borderline tumor. A, Broad papillae showing hierarchical branching and tufting. B, High magnification highlighting different epithelial types, including serous, mucinous, and eosinophilic cells along with neutrophilic infiltration. C, Tumor with microinvasion. D, Mixed seromucinous and endometrioid borderline tumor (hematoxylin-eosin, original magnifications ×10 [A], ×200 [B], ×100 [C], and ×40 [D]). Contributor Notes Corresponding author: Ramya P. Masand, MD, Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX-77030 (email: [email protected]). Supplemental digital content is available for this article at https://aplm.kglmeridian.com by clicking on the article title in the April 2026 table of contents. The authors have no relevant financial interest in the products or companies described in this article. Presented in part at the 11th Princeton Integrated Pathology Symposium; May 4, 2024; Plainsboro, New Jersey.