Ovarian mesonephric-like adenocarcinoma mimicking serous carcinoma: A case report integrating cytologic, frozen, histological, immunohistochemistry, and molecular analyses

F.Z had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. W.L, S·H, X.Z. and L.Q contributed to drafting the manuscript and critically revising it for important intellectual content. F.Z and W.Z. reviewed, edited, and finalized the manuscript. All authors have read and approved the final version of the manuscript. The authors declare independence from the funders, and all final decisions regarding the research were made solely by the investigators without external influence.

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.

Ethical approval was waived by the International Peace Maternity and Child Health Hospital.

This work was partially sponsored by 10.13039/100007219 Natural Science Foundation of Shanghai ( 25ZR1401367 ).

N/A.

F, Z takes full responsibility as the guarantor for this study.

Mesonephric-like adenocarcinoma of the ovary is a rare malignancy that can sometimes closely mimic serous carcinoma, creating diagnostic pitfalls at cytology, frozen section, and routine histology. This case emphasizes the key distinguishing features of MLA: its varied architectural patterns and characteristic cytologic details, along with a mesonephric immunophenotype. As our understanding of MLA grows, including its molecular underpinnings, there is hope for more tailored treatments that improve outcomes for this aggressive tumor. Early and accurate diagnosis, combined with multidisciplinary management and consideration of novel targeted approaches, offers the best chance for patients affected by this “wolf in sheep's clothing.”

This case illustrates the prototypical features and diagnostic difficulties of mesonephric-like adenocarcinoma (MLA) of the ovary, with an emphasis on distinguishing this rare entity from serous carcinoma—both low-grade and high-grade types. The patient's initial misdiagnosis as serous carcinoma is not surprising given the overlapping clinical and pathologic presentation. Below, we discuss the comparative cytological, intraoperative (frozen), histological, immunohistochemical, and molecular characteristics of MLA versus serous carcinomas (summarized in Table 1 ), drawing from our case and the literature. Table 1 Distinguishing Features of Ovarian MLA vs. Serous Carcinoma (Low- and High-Grade). Table 1 Mesonephric-Like Adenocarcinoma (MLA) Low-Grade Serous Carcinoma (LGSC) High-Grade Serous Carcinoma (HGSC) Cytology Cohesive papillary clusters of tumor cells; monotonous oval nuclei with smooth contours, longitudinal grooves and pseudoinclusions (“thyroid-like” nuclei); high N:C ratio; necrosis usually minimal; no intracytoplasmic neutrophils (no “cannibalism”). Papillary clusters of relatively bland cells; mild nuclear atypia; can appear similar to MLA cytologically; rarely shows nuclear grooves; possible intracytoplasmic neutrophils in some cases (more common in endometrioid carcinoma cytology). Highly pleomorphic cells with irregular chromatin and macronucleoli; often occur singly or in disorderly clusters; abundant tumor diathesis (necrotic debris); markedly high N:C ratio and notable nuclear atypia. Histology Mixture of architectural patterns (tubular, papillary, retiform, glomeruloid, solid); no ciliated cells; often contains luminal eosinophilic colloid-like secretions (when present, characteristic for MLA); mild-to-moderate nuclear atypia. Typically arises from serous borderline tumor; predominantly papillary architecture; frequent calcified psammoma bodies; ciliated cells may present (tubal differentiation); mild-to-moderate nuclear atypia; slow growth but persistent disease common. Complex papillary, glandular, and solid growth; no ciliated cells (due to high-grade transformation); marked nuclear atypia and increased nuclear size variability; brisk mitotic activity; frequent necrosis; architecture often destructive infiltrative. Immunoprofile ER/PR negative; WT-1 negative (usually); GATA3 positive (diffuse); TTF-1 positive (diffuse); p53 wild-type; PAX8 positive; p16 often patchy (non-block). ER/PR positive (often strong); WT-1 positive; GATA3/TTF-1 negative; p53 wild-type; PAX8 positive; p16 usually patchy (non-block). ER positive (often); WT-1 positive (~90 %); GATA3/TTF-1 negative; p53 mutant; PAX8 positive; p16 typically diffusely positive (block-type). Molecular KRAS or NRAS mutations in ~80 % (most often KRAS codon 12); typically, no TP53 mutations (TP53 wild-type); no known BRAF V600E; low tumor mutational burden; microsatellite stable; generally, no BRCA1/2 mutations or HR pathway defects. RAS/RAF pathway mutations in ~30–50 % of cases (KRAS ~30 %, BRAF ~10 %, NRAS ~ < 10 %); TP53 wild-type; may co-exist with serous borderline tumor sharing same mutations; microsatellite stable; often indolent but chemoresistant (some respond to hormonal therapy). Ubiquitous TP53 mutations; frequent BRCA1/2 mutations or homologous recombination defects; rare KRAS/NRAS mutations; highly aneuploid genome with complex structural variations; high genomic instability and copy number aberrations. Distinguishing Features of Ovarian MLA vs. Serous Carcinoma (Low- and High-Grade). On cytological examination (e.g. Pap smears, ascitic or washing fluids), MLA can closely mimic serous carcinoma, yet there are subtle differences. Both MLA and serous carcinoma (particularly low-grade serous carcinoma, LGSC) can shed cohesive clusters of tumor cells with papillary structures. In our case, the peritoneal washing cytology showed papillary cell clusters and high N:C ratio, which initially suggested a serous neoplasm. Serous carcinoma cells, especially of high-grade serous carcinoma (HGSC), tend to exhibit markedly pleomorphic nuclei with macronucleoli and irregular chromatin clumping. In contrast, MLA cells are often more monotonous with smooth nuclear contours. A striking feature in MLA cytology is the presence of nuclear grooves and pseudoinclusions, giving a thyroid-like appearance to nuclei. These were readily identified in our case ( Fig. 1 ) and are less typical in serous carcinoma cytology. HGSC cells usually show more prominent nucleoli and often occur in highly disordered clusters or singly with considerable pleomorphism, along with background necrosis (tumor diathesis). Meanwhile, MLA can have necrotic debris as well, but in reported series it was noted in only a minority of cases. Low-grade serous carcinoma cells, on the other hand, may appear relatively bland like MLA, sometimes forming three-dimensional clusters with mild atypia. One helpful distinction reported is that endometrioid or serous carcinoma cells (especially endometrioid) may show intracytoplasmic neutrophils or “cannibalism,” whereas MLA cells typically do not. Our patient's cytology was initially signed out as carcinoma NOS; retrospectively, the features were classic for MLA. Frozen section diagnosis of ovarian MLA can be tricky, as demonstrated by this case. At frozen, the tumor's low-grade histology (mainly papillary structures with bland nuclei) led to an interpretation of low-grade serous carcinoma. Low-grade serous carcinoma (LGSC) and MLA share several features: both can show papillae with fibrovascular cores, relatively uniform cells, and the absence of severe atypia. One distinguishing feature might be the luminal secretions often seen in MLA – thick eosinophilic colloid-like material – which are uncommon in serous tumors. In our frozen section, no obvious eosinophilic secretions were noted. Additionally, MLA's mixture of patterns (e.g., coexistence of tubular and glomeruloid structures) might be discernible only on well-fixed permanent sections [ 2 , 3 ]. In frozen sections, freezing artifacts can obscure fine architectural details, and limited sampling may further reduce the diagnostic accuracy during intraoperative evaluation. High-grade serous carcinoma (HGSC), if present, is usually easier to identify on frozen due to its high-grade cytology (marked pleomorphism, brisk mitoses, necrosis). Thus, the main frozen differential for MLA is often LGSC or even a borderline serous tumor. Consequently, a definitive classification is often deferred to permanent sections and ancillary studies, as it was in this case. The histologic overlap and differences between MLA and serous carcinoma are nuanced. Low-grade serous carcinoma of the ovary typically arises in association with serous borderline tumor and is characterized by micropapillary and hierarchically branching papillae, often with calcified psammoma bodies. The cells of LGSC have mild to moderate atypia, but importantly, LGSC almost always shows at least focal ciliated columnar cells, given its derivation from tubal (Müllerian) epithelium. MLA, conversely, shows no ciliated cells, and it often has a broader array of patterns beyond papillae [ 2 , 3 ]. In our case, the tumor exhibited extensive papillary architecture with psammoma bodies, closely mimicking a serous carcinoma. Some regions showed low-grade cytologic features resembling LGSC, whereas other foci, especially in a metastatic lymph node, displayed irregular nuclear contours and coarse chromatin reminiscent of HGSC. Notably, our tumor lacked the eosinophilic, colloid-like secretions sometimes described in MLA; serous carcinomas may have intraluminal debris or calcifications, but they do not produce true colloid-like secretions. MLA can also be mistaken for a FIGO grade 1 endometrioid carcinoma due to tubular patterns and mild atypia (especially in uterine cases). However, MLA lacks squamous differentiation and does not exhibit the intratumoral neutrophils (“cannibalism”) often seen in endometrioid carcinoma. Immunohistochemistry is often the decisive factor in differentiating MLA from other carcinomas. As demonstrated in our case, MLA exhibits a mesonephric immunoprofile: typical ER/PR-negative, p53 wild-type, and positive for markers such as GATA3 and/or TTF-1. In contrast, serous carcinoma generally lacks GATA3 and TTF-1 expression. LGSC usually retains Müllerian marker expression – the majority of LGSCs are ER and PR positive (often strongly so, since hormonal therapy is sometimes effective for them). LGSC is also usually positive for WT-1 (because serous tumors, derived from tubal/Müllerian epithelium, express WT-1). HGSC is almost always p53 mutant; WT-1 and p16 strongly positive; ER positive to some extent. Our case's IHC profile (ER/PR negative, p53 wild, diffuse TTF-1/GATA3 positive) is virtually impossible for a serous carcinoma to achieve, sealing the diagnosis of MLA. One point of caution is the WT-1 staining: MLA is classically WT-1 negative, but there have been occasional reports of WT-1 reactivity in MLA, which likely represent an anomalous expression or heterogeneity within the tumor. This underscores that single-marker immunoreactivity (like WT-1) should not automatically equal a serous carcinoma diagnosis if other features point away. Therefore, the combination of markers is critical. In practice, when confronted with an unusual ovarian carcinoma, a panel including ER, PR, WT-1, p53, GATA3, TTF-1, and PAX8 can usually classify the tumor: MLA will emerge as ER/PR negative, PAX8 positive, p53 wild, GATA3/TTF-1 positive; serous carcinoma (especially HGSC) will be ER and WT-1 positive, p53 mutant, and GATA3/TTF-1 negative; endometrioid carcinoma will be ER/PR positive, usually GATA3/TTF-1 negative, etc. Immunoprofiles thus provide a powerful tool to avoid misdiagnosis. In our patient's case, the IHC results redirected us from an initial impression of serous carcinoma to the correct diagnosis of MLA. The molecular profile of MLA further differentiates it from serous carcinoma and has potential therapeutic relevance. MLA is characterized by frequent RAS mutations (e.g., KRAS mutations in over 80 % of cases [ 2 , [16] , [17] , [18] ]), whereas high-grade serous carcinoma (HGSC) almost invariably harbors TP53 mutations (often with BRCA1/2 alterations) and only rarely has RAS mutations. Low-grade serous carcinoma (LGSC) shares involvement of the RAS pathway (KRAS mutations in ~30 % of cases, with other cases featuring BRAF or NRAS mutations [ 19 ]), which can cause diagnostic overlap with MLA. In our case, the presence of a KRAS p.G12V mutation alongside the histology and immunoprofile clinched the diagnosis of MLA. Additionally, our tumor was microsatellite-stable with a low tumor mutational burden, consistent with prior reports that MLA is MMR-proficient and not hypermutated. From a therapeutic perspective, the molecular makeup of MLA suggests that conventional chemotherapy (as used for high-grade serous carcinoma) might not be as effective, given MLA's low proliferative index and distinct biology. The discovery of KRAS mutations in the majority of MLAs is notable because it provides a rationale for targeted therapy. A recent phase II/III trial demonstrated significantly improved progression-free survival with the MEK inhibitor trametinib in recurrent LGSC compared to standard chemotherapy [ 20 ]. By analogy, an MLA harboring a KRAS mutation could potentially respond to MEK inhibitors or other targeted agents affecting the MAPK pathway. There is already interest in exploring such targeted approaches in MLA, especially for patients with advanced or recurrent disease that is not TP53-mutated (and thus may not respond to platinum as robustly as HGSC would). Mesonephric-like adenocarcinoma is an aggressive tumor. Despite their often relatively bland histology, MLAs behave more like high-grade carcinomas clinically. Uterine MLAs tend to present at advanced stage and have high rates of distant lung metastases; ovarian MLAs also often present with extra-ovarian spread, as in this case (Stage IIIC) [ 21 , 22 ]. The largest series to date suggest that MLA outcomes are poorer than those of grade-matched endometrial carcinomas; one study found MLA had outcomes similar to Grade 3 endometrioid carcinoma and worse than Grade 1–2 endometrioid carcinoma [ 23 ]. There is no consensus yet on the optimal treatment of MLA, but most patients receive surgery followed by platinum-based chemotherapy (by analogy to high-grade Müllerian carcinoma). Our patient was started on adjuvant chemotherapy (carboplatin and paclitaxel) after recovery from surgery. Given the KRAS mutation, enrollment in a clinical trial for MEK inhibitor therapy is being considered if she has residual or recurrent disease. Close surveillance is warranted, as MLA has a propensity for early relapse and distant metastasis (particularly to the lungs). At the time of this report, the patient has remained free of recurrence during one year of follow-up. In summary, our case highlights the importance of considering mesonephric-like adenocarcinoma in the differential diagnosis of ovarian carcinomas that histologically resemble low-grade and high-grade serous or endometrioid carcinoma yet have unusual features. The integration of morphology, immunoprofile, and molecular findings is essential for correct diagnosis. Pathologists should be aware of MLA and apply an appropriate panel of stains in suspicious cases – doing so can uncover this rare entity that might otherwise be mislabeled as a common tumor. Correct identification of MLA has significant implications: it alerts the clinical team to the tumor's aggressive behavior and the potential need for innovative therapy. It also prevents misclassification that could skew treatment (for example, avoiding hormonal therapies that would be ineffective in an ER-negative tumor like MLA).

Mesonephric carcinomas of the female genital tract are thought to arise from remnants of the mesonephric (Wolffian) ducts, classically occurring in the cervix and rarely in the upper gynecologic tract. In 2016, McFarland et al. first delineated mesonephric-like adenocarcinoma (MLA) as a distinct entity: an adenocarcinoma of the uterine corpus or ovary that histologically resembles mesonephric carcinoma but arises in locations without mesonephric remnants. Since then, fewer than 200 cases have been reported in the literature – approximately 115 in the uterus and 39 in the ovary as of 2021, underscoring the rarity of this tumor, especially in the ovary [ 1 ]. This entity has been included in the 5th edition World Health Organization (WHO) classification of female genital tumors. MLA poses a diagnostic challenge because its morphology is diverse and overlaps with other tumor types. Within a single tumor, MLA can exhibit mixtures of small tubular glands, ductal/glandular patterns, papillary structures, solid sheets, trabecular cords, retiform (sieve-like) networks, and even glomeruloid bodies [ 2 , 3 ]. Crucially, MLA lacks squamous, mucinous, or ciliated cell differentiation and is not associated with mesonephric remnants or hyperplasia, helping to distinguish it from true mesonephric carcinoma of the cervix [ 1 ]. Beyond histology, MLA can readily mimic common ovarian carcinomas on cytology. Tight papillary cell clusters with overlapping, grooved nuclei can lead to a cytologic impression of serous carcinoma, as occurred in our case. Moreover, the bland cytologic appearance and mixed papillary/tubular architecture often result in an indeterminate or “low-grade carcinoma” label on intraoperative frozen section, delaying the definitive classification of MLA until permanent sections and immunostains are available. Awareness of these pitfalls is essential for both cytopathologists and frozen-section pathologists. Immunohistochemically, the unique immunoprofile of MLA (GATA3/TTF-1–positive, ER/PR-negative, p53-wild, WT-1–negative) is a key to diagnosis [ [4] , [5] , [6] , [7] , [8] ]. Molecularly, MLA is characterized by a high frequency of KRAS mutations, reported in over 80 % of cases [ [9] , [10] , [11] ]. MLA of the ovary is a rare tumor that can masquerade as more common ovarian carcinomas. Careful attention to histological patterns, heightened suspicion on cytology, and recognition of frozen-section limitations, followed by judicious use of immunohistochemistry and targeted molecular testing, are essential for accurate diagnosis. We present a case of ovarian MLA in a 41-year-old female that was initially interpreted as serous carcinoma, and we discuss the features that distinguish MLA from both low-grade and high-grade serous carcinoma. This case report has been reported in line with the SCARE checklist [ 12 ].

A 41-year-old woman (gravida 2, para 2) presented in December 2023 with right lower quadrant abdominal pain. Pelvic ultrasound on 12/11/2023 revealed a complex right adnexal mass. Subsequent MRI on 20/12/2023 demonstrated a cystic mass with septations located posterior to the uterus, raising suspicion for an endometriosis-related ovarian tumor. An ill-defined lesion in the posterior uterine wall was also noted, favored to be benign but not definitively excluding malignancy. Imaging additionally showed postoperative changes in the uterus with adenomyosis, and adhesions between the left posterior uterine serosa and pelvic wall, as well as between the anterior uterine wall and bladder, features consistent with endometriosis. Tumor markers (CA-125, HE4, CEA) assayed on 02/01/2024 were within normal limits. Given the imaging findings, the patient underwent a diagnostic dilatation and curettage (D&C) on 07/03/2024. Histologic evaluation of the endometrial curettage showed atypical glandular cells concerning for a high-grade papillary carcinoma (favoring serous carcinoma). The patient was referred to our institution for definitive surgical management, which was performed on 11/03/2024. The patient's history included two Cesarean sections (in 2005 and 2008) and a tubal ligation (2008). She had multiple laparoscopic surgeries for endometriotic ovarian cysts (2019 and 2022) and underwent a localized sclerotherapy procedure in 2023 for an endometriotic lesion. A levonorgestrel intrauterine device (Mirena) was placed in 2019 for endometriosis management and removed in 2023. She had also received gonadotropin-releasing hormone (GnRH) analog therapy in the past for endometriosis. There was no history of any other malignancies. The patient underwent an exploratory laparotomy with the intent of tumor debulking. Intraoperatively, dense pelvic adhesions from endometriosis were noted. A 6 cm right ovarian mass was identified, which was adherent to the pelvic sidewall. The uterus appeared enlarged and was embedded in adhesions to the bowel and bladder. Multiple tumor implants were observed on the peritoneal surfaces and rectosigmoid serosa. The surgeon performed a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, pelvic and para-aortic lymph node dissection, and resection of visible peritoneal and bowel serosal tumor implants for optimal cytoreduction. During surgery, peritoneal washing fluid was collected for cytological analysis, and a frozen section was requested on a portion of the ovarian mass to guide intraoperative management. The peritoneal washing fluid was positive for malignant cells. Smears revealed highly cellular samples with numerous three-dimensional clusters of epithelial cells. The cell clusters had a papillary architecture with crowded, overlapping cells and irregular, scalloped borders. Many clusters showed cells with longitudinal nuclear grooves and occasional intranuclear pseudoinclusions, imparting a striking resemblance to papillary thyroid carcinoma cells. Occasional rosette-like microacinar arrangements and loose discohesive single cells were also present in the background. The tumor cell nuclei were relatively small, round to oval, with hyperchromatic to pale “ground-glass” chromatin. The cytoplasm was scant, yielding a high nuclear-to-cytoplasmic ratio. No cilia or significant intracytoplasmic mucin was seen in the cells. Rare cells exhibited elongated (spindle) nuclei, and focal necrotic debris (tumor diathesis) was noted. These cytologic features raised the possibility of a malignancy with papillary differentiation; an initial interpretation favored a diagnosis of adenocarcinoma, possibly a serous carcinoma, given the papillary clusters and absence of obvious endometrioid features. No benign mesothelial cell clusters with endometriosis were identified in the sample, and the cytologic differential diagnosis included low-grade serous carcinoma or a metastatic endometrial carcinoma. The cytologic diagnosis was reported as “malignant cells present, consistent with carcinoma.” ( Fig. 1 ). Fig. 1 Cytopathology of the ovarian mesonephric-like adenocarcinoma in peritoneal washing fluid. (A, B) Pap-stained cytology smears showing tight, three-dimensional clusters of glandular cells with papillary configurations. The cell groups have overlapping nuclei with longitudinal grooves (arrowheads) and occasional intranuclear pseudoinclusions, closely mimicking papillary thyroid carcinoma nuclei. (C) High-power view highlighting the monotonous, small to medium-sized tumor cells with scant cytoplasm and hyperchromatic nuclei. (D) Occasional rosette-like microacinar structures (circle) are formed by the tumor cells. (E) Loosely discohesive single tumor cells are present in the background. (F) Rare foci show nuclear feathering at the edges of cell clusters (arrow) with scattered apoptotic debris. Fig. 1 Cytopathology of the ovarian mesonephric-like adenocarcinoma in peritoneal washing fluid. (A, B) Pap-stained cytology smears showing tight, three-dimensional clusters of glandular cells with papillary configurations. The cell groups have overlapping nuclei with longitudinal grooves (arrowheads) and occasional intranuclear pseudoinclusions, closely mimicking papillary thyroid carcinoma nuclei. (C) High-power view highlighting the monotonous, small to medium-sized tumor cells with scant cytoplasm and hyperchromatic nuclei. (D) Occasional rosette-like microacinar structures (circle) are formed by the tumor cells. (E) Loosely discohesive single tumor cells are present in the background. (F) Rare foci show nuclear feathering at the edges of cell clusters (arrow) with scattered apoptotic debris. An intraoperative frozen section of the right ovarian mass was performed on a representative slice of the tumor. The frozen section revealed a malignant epithelial neoplasm with papillary and glandular architecture. The tumor cells on frozen sections had relatively uniform, mildly to moderately atypical nuclei and scant cytoplasm. Some papillary structures with fibrovascular cores were present. No areas of obvious high-grade nuclear atypia or necrosis were identified on the frozen section ( Fig. 2 ). The differential diagnosis on frozen was between a low-grade serous carcinoma, endometrioid carcinoma, and other low-grade glandular neoplasms. Given the patient's history and the cytologic findings, the frozen-section pathologist favored a diagnosis of “low-grade carcinoma, serous carcinoma cannot be excluded.” The possibility of an unusual carcinoma was not recognized at frozen diagnosis due to the bland cytology and papillary architecture. The surgeon proceeded with full staging and tumor debulking based on the confirmation of malignancy. Fig. 2 Histopathologic features of endometriosis and ovarian mesonephric-like adenocarcinoma (MLA). (A) Endometriosis involving the ovary with characteristic glandular epithelium and surrounding stromal components, suggesting a possible association between endometriosis and the development of MLA. (B) Intraoperative frozen section at low magnification demonstrating prominent papillary architecture supported by delicate fibrovascular cores, closely resembling low-grade serous carcinoma. (C—F) Medium to high magnification images of MLA reveal complex growth patterns, including glandular, retiform, and papillary architectures. Tumor cells exhibit mild to moderate nuclear atypia with overlapping nuclei, finely dispersed “ground-glass” chromatin, and an absence of marked nuclear pleomorphism or prominent nucleoli. (G) Low magnification view of metastatic MLA within a lymph node, illustrating nodal tumor involvement. (H) High-power image of nodal metastasis highlighting increased nuclear atypia and irregular nuclear contours that mimic high-grade serous carcinoma. Psammoma bodies are also identified (arrow). Fig. 2 Histopathologic features of endometriosis and ovarian mesonephric-like adenocarcinoma (MLA). (A) Endometriosis involving the ovary with characteristic glandular epithelium and surrounding stromal components, suggesting a possible association between endometriosis and the development of MLA. (B) Intraoperative frozen section at low magnification demonstrating prominent papillary architecture supported by delicate fibrovascular cores, closely resembling low-grade serous carcinoma. (C—F) Medium to high magnification images of MLA reveal complex growth patterns, including glandular, retiform, and papillary architectures. Tumor cells exhibit mild to moderate nuclear atypia with overlapping nuclei, finely dispersed “ground-glass” chromatin, and an absence of marked nuclear pleomorphism or prominent nucleoli. (G) Low magnification view of metastatic MLA within a lymph node, illustrating nodal tumor involvement. (H) High-power image of nodal metastasis highlighting increased nuclear atypia and irregular nuclear contours that mimic high-grade serous carcinoma. Psammoma bodies are also identified (arrow). The ovarian tumor measured 5.8 cm in greatest dimension and was primarily solid-cystic with papillary excrescences. Histologically, it displayed a mixture of architectural patterns. In most areas, the tumor exhibits a papillary growth pattern in a fibrous stroma with scattered psammoma bodies, reminiscent of serous carcinoma, including both low-grade and high-grade, whereas the retiform glandular architecture also resemble endometrioid carcinoma whereas there is no area of squamous differentiation, or ciliated (tubal-type) cells identified anywhere in the tumor. Lacking mesonephric remnants in the surrounding ovarian tissue and non-hilum limited location, against Wolffian tumor. On higher magnification, the tumor cells are characterized by cuboidal to low columnar nuclei, with scant to moderate amphophilic cytoplasm and moderate nuclear atypia. Occasional longitudinal nuclear grooves were observed, and nuclear overlapping was common (especially in the papillary areas), mirroring the cytologic findings. Occasional intranuclear pseudoinclusions were noted. Mitotic activity was low (approximately 3–5 mitoses per 10 high-power fields in the most proliferative areas). Significant nuclear features or tumor giant cells were absent. The ovarian cortex adjacent to the tumor showed fibrosis and endometriotic foci, indicating the tumor arose in a background of endometriosis (a scenario documented in some MLA cases) [ [13] , [14] , [15] ] ( Fig. 2 ). The tumor extensively involved the ovarian surface and capsule and demonstrated widespread intra-abdominal spread at diagnosis. Metastatic carcinoma was present on the serosal surface of the uterus and infiltrated the underlying myometrium, consistent with direct extension. The contralateral (left) ovary and fallopian tube were grossly unremarkable, but microscopic foci of tumor were found on the serosa of the left adnexa and within the left fallopian tube fimbria. Tumor deposits were also present on the pelvic peritoneum and omentum, and on the serosal surface of the rectosigmoid colon. One pelvic (left obturator) lymph node out of 7 resected was positive for metastatic carcinoma, and one right para-aortic lymph node (out of 1) was positive. All other lymph nodes were negative. The cervix was free of tumor, and no mesonephric remnants were identified in the cervix or uterus. These findings confirmed stage IIIC disease (FIGO 2014) of Müllerian origin (ovarian primary with metastases). Given the unusual histology, a panel of immunohistochemical (IHC) stains was performed on the ovarian tumor to clarify its classification. The tumor cells were diffusely positive for mesonephric markers: GATA3 was diffusely nuclear positive in the majority of tumor cells, and TTF-1 (thyroid transcription factor-1) was likewise diffusely positive. They were diffusely negative for estrogen receptor ( ER ) and progesterone receptor ( PR ), confirming a non-Müllerian phenotype. They showed diffuse strong nuclear positivity for PAX8 , consistent with a gynecologic origin. CD10 highlighted luminal surfaces of the glands focally. Calretinin was negative. WT-1 (Wilms tumor 1) immunostain, typically positive in serous carcinomas, is negative in this case, consistent with the unusual finding of MLA. p16 showed a patchy staining often seen in MLA. p53 immunohistochemistry revealed a wild-type pattern : the tumor cell nuclei showed variable moderate intensity staining in a non-overlapping (mosaic) distribution, with scattered unstained cells and no evidence of the uniform strong staining or total absence that would indicate a TP53 mutation. The immunoprofile (ER/PR negative, p53 wild-type, GATA3/TTF-1 positive, WT-1 negative, PAX8 positive) supported the diagnosis of mesonephric-like adenocarcinoma and helped exclude it's morphologic mimics such as low-grade serous carcinoma and endometrioid carcinoma (which would usually be ER/PR positive and GATA3/TTF-1 negative) or high-grade serous carcinoma (which would typically show mutant p53, strong WT-1 and GATA3/TTF-1 negative). ( Fig. 3 ). Fig. 3 Immunohistochemical profile of the ovarian mesonephric-like adenocarcinoma. (A) GATA3 immunostain is diffusely positive in the tumor cell nuclei, consistent with mesonephric differentiation. (B) TTF-1 is strongly and diffusely nuclear-positive in the carcinoma cells, supporting a mesonephric-like origin. (C) Estrogen receptor (ER) is completely negative in the tumor. (D) Progesterone receptor (PR) is also entirely negative in the tumor. (E) PAX8 highlights the nuclei of the tumor cells, confirming gynecologic origin. (F) WT-1 is negative in the tumor cells, which helps distinguish MLA from serous carcinoma (nearly all serous carcinomas are WT-1 positive). (G) p16 shows a patchy (non-block) positive staining pattern, whereas high-grade serous carcinomas typically show diffuse strong p16 positivity. (H) p53 demonstrates a wild-type (normal) expression pattern with heterogeneous nuclear staining and no uniform overexpression or complete absence; this finding supports TP53 wild-type status and differentiates the tumor from a high-grade serous carcinoma, which would usually show a mutant p53 pattern. Fig. 3 Immunohistochemical profile of the ovarian mesonephric-like adenocarcinoma. (A) GATA3 immunostain is diffusely positive in the tumor cell nuclei, consistent with mesonephric differentiation. (B) TTF-1 is strongly and diffusely nuclear-positive in the carcinoma cells, supporting a mesonephric-like origin. (C) Estrogen receptor (ER) is completely negative in the tumor. (D) Progesterone receptor (PR) is also entirely negative in the tumor. (E) PAX8 highlights the nuclei of the tumor cells, confirming gynecologic origin. (F) WT-1 is negative in the tumor cells, which helps distinguish MLA from serous carcinoma (nearly all serous carcinomas are WT-1 positive). (G) p16 shows a patchy (non-block) positive staining pattern, whereas high-grade serous carcinomas typically show diffuse strong p16 positivity. (H) p53 demonstrates a wild-type (normal) expression pattern with heterogeneous nuclear staining and no uniform overexpression or complete absence; this finding supports TP53 wild-type status and differentiates the tumor from a high-grade serous carcinoma, which would usually show a mutant p53 pattern. Molecular testing was performed on the ovarian tumor. Targeted next-generation sequencing (NGS) of a 50-gene solid tumor panel identified a missense mutation in KRAS (exon 2, codon 12, p.G12V). No mutations were detected in BRAF , NRAS , PIK3CA , PTEN , CTNNB1 , TP53 , or BRCA1/2 . The tumor mutational burden (TMB) was low at 0.56 mutations per megabase, and microsatellite instability testing was negative (MSI-stable). No pathogenic variants were found in a limited germline analysis, and in particular no Lynch syndrome-associated mutations were present. The presence of a solitary KRAS mutation with otherwise “quiet” (mutation-sparse) genomic profile is characteristic of MLA. These molecular results further supported the MLA diagnosis and provided a potential therapeutic target. The low TMB and MSS status indicated that immunotherapy (checkpoint inhibitors) would likely be of limited benefit. Mesonephric-like adenocarcinoma of the right ovary, FIGO stage IIIC. The tumor involved the right fallopian tube and uterine serosa with focal myometrial invasion. Metastatic carcinoma was present in the omentum, pelvic peritoneum, rectosigmoid serosa, left adnexal serosa, left obturator lymph node (1/7), and right para-aortic lymph node (1/1).

The authors declare no conflict of interest.