Mesonephric-like Adenocarcinoma of the Uterine Corpus in a 28-Year-Old with Down Syndrome and Hypothyroidism: A Case Series of Three Patients and Literature Review

1. Introduction

Mesonephric-like adenocarcinoma (MLA) is an emerging subtype of gynecologic carcinoma that primarily involves the uterine corpus and, less frequently, the ovary. First characterized as a distinct entity by McFarland, Quick, and McCluggage in 2016 [1]and formally incorporated into the 2020 WHO Classification of Female Genital Tumors, MLA poses diagnostic challenges due to its rarity, morphologic heterogeneity, and overlap with other uterine carcinomas.

Histologically, MLA recapitulates features of mesonephric adenocarcinoma, including tubular, glandular, and solid growth patterns, often with eosinophilic luminal secretions. Immunohistochemically, MLA frequently expresses PAX8 and mesonephric-associated markers such as GATA3 and thyroid transcription factor 1 (TTF-1), while typically lacking strong, diffuse estrogen receptor (ER) and progesterone receptor (PR) expression. In contrast to true mesonephric adenocarcinomas of the cervix, MLA often arises in the endometrium or ovary and usually lacks demonstrable mesonephric remnants, supporting a Müllerian origin with mesonephric-like differentiation.

Molecular studies have shown that MLA is commonly driven by recurrent KRAS mutations, with additional alterations in genes such as PIK3CA, ARID1A, and CTNNB1 in a subset of cases. In contrast, mutations in PTEN, TP53, and SMARCA4 are generally less frequent, further distinguishing MLA from conventional endometrioid and serous endometrial carcinomas. These findings suggest that MLA represents a distinct molecular and morphologic pathway within the spectrum of Müllerian neoplasia.

Down syndrome is the most common chromosomal cause of intellectual disability worldwide and is associated with characteristic phenotypic features, immune dysregulation, and an altered cancer profile.[1] Individuals with Down syndrome exhibit an increased risk of hematologic malignancies, but a decreased risk of many solid tumors, including breast, lung, and prostate cancers.[2,3,4] However, the relationship between Down syndrome and rare gynecologic malignancies like MLA has not been previously described.

In this case series, we report three patients with MLA of the uterine corpus, all with documented hypothyroidism. One patient is, to our knowledge, the first reported individual with Down syndrome diagnosed with MLA. We correlate the clinical, histopathologic, and immunohistochemical findings of these cases with a literature review of approximately 200 reported MLA cases and discuss potential links between MLA, thyroid dysfunction, and genetic predisposition.

2. Materials and Methods

2.1. Study Design and Case Selection

This retrospective case series was conducted at a single academic medical center. Cases were identified through a review of the institutional pathology database over a defined study period. Inclusion criteria consisted of endometrial carcinomas with histopathologic and immunophenotypic features consistent with mesonephric-like adenocarcinoma (MLA). Cases with insufficient diagnostic material or incomplete immunohistochemical evaluation were excluded.

2.2. Clinical and Pathologic Data Collection

Clinical data extracted from the medical record included patient age, presenting symptoms, relevant medical history, imaging findings, treatment modality, and available follow-up information. Pathologic variables collected included tumor size, depth of myometrial invasion, histologic architecture, cytologic features, lymphovascular invasion, and pathologic stage when available.

2.3. Histopathologic Evaluation

Hematoxylin and eosin–stained slides from endometrial biopsies, curettage specimens, and hysterectomy specimens were reviewed by board-certified pathologists. Histologic features assessed included glandular architecture, nuclear atypia, mitotic activity, presence of solid growth, and cytoplasmic characteristics. Tumors were classified according to the current World Health Organization (WHO) classification of female genital tumors.

2.4. Immunohistochemistry

Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded tissue sections using standard laboratory protocols. Antibodies evaluated across cases included GATA3, TTF-1, ER, PR, p16, p53, Napsin A, glypican-3, AFP, CDX2, CD10, and calretinin, as clinically indicated. Immunoreactivity was assessed qualitatively and recorded as diffuse, patchy, focal, or negative.

2.5. Staging and Ancillary Studies

Pathologic staging was performed according to the American Joint Committee on Cancer (AJCC) 8th edition staging system and corresponding FIGO criteria when surgical specimens were available. Molecular or germline testing results, when performed, were recorded from clinical reports.

2.6. Ethical Approval

This study was conducted in accordance with institutional guidelines for retrospective studies. Institutional review board approval was obtained, with waiver of informed consent due to the retrospective nature of the study.

2.7. Use of Generative Artificial Intelligence

Generative artificial intelligence tools were used for language refinement and formatting assistance only. No GenAI tools were used for data generation, analysis, or interpretation.

3. Results

3.1. Cohort Characteristics

Three patients with endometrial mesonephric-like adenocarcinoma were identified. Patient ages ranged from 28 to 74 years. All patients presented with abnormal uterine bleeding, including heavy menstrual bleeding in premenopausal patients and postmenopausal bleeding in the postmenopausal patient. Two patients had a history of hypothyroidism. One patient had a prior history of breast carcinoma.

3.2. Clinical and Imaging Findings

Pelvic imaging demonstrated endometrial abnormalities in two cases, including a hypervascular uterine mass and a focal endometrial lesion. One patient had no discrete mass identified on ultrasound despite significant clinical symptoms. Severe anemia was present in two patients at presentation, requiring transfusion in one case.

3.3. Histopathologic Findings

Endometrial sampling demonstrated crowded, back-to-back glands with high nuclear-to-cytoplasmic ratios, hyperchromatic nuclei, and variable mitotic activity across all cases. Focal solid growth and clear cell–like cytoplasmic changes were observed in select cases. Initial diagnostic interpretations included high-grade endometrial adenocarcinoma or hyperplasia in some cases, prompting further immunophenotypic evaluation.

3.4. Immunophenotypic Profile

All tumors demonstrated an immunoprofile supportive of mesonephric-like adenocarcinoma. GATA3 and/or TTF-1 expression was identified in all cases, with staining patterns ranging from patchy to focal. Estrogen and progesterone receptor expression was absent or limited, with one case showing patchy ER and PR positivity. Napsin A expression was variable. p53 demonstrated wild-type staining patterns in evaluated cases. The combined morphologic and immunophenotypic findings supported the final diagnosis of MLA in all patients (Figure 1 and Figure 2).

3.5. Surgical Pathology, Treatment, and Outcomes

Two patients underwent total hysterectomy with bilateral salpingo-oophorectomy. One tumor demonstrated deep myometrial invasion and was staged as pT1b pN0 pMNa, corresponding to FIGO stage II. Peritoneal washings were negative for malignant cells. One patient received neoadjuvant carboplatin and paclitaxel. One patient pursued conservative management with levonorgestrel-releasing intrauterine device placement due to fertility preservation considerations. Available staging, treatment, and outcome data are summarized in Table 1.

A PubMed search of mesonephric-like adenocarcinoma revealed 256 papers of which 51 cases of mesonephric-like adenocarcinoma was included in our study comprising approximately 200 MLA cases. Comorbidity reporting was inconsistent: only 32.5% (65/200 cases) had comorbidity reports. No comorbidity data available in 135/200 cases (67.5%). Table 2 shows a summary of the reported cases, immunohistochemical profile, FIGO stage at diagnosis, and the associated molecular findings.

The literature strongly supports a Müllerian origin: among the 65 cases with available data, 86% were associated with Müllerian lesions, especially endometriosis and adenomyosis as seen in Table 3.

4. Discussion

Mesonephric-like adenocarcinoma occupies a unique niche within gynecologic pathology, combining morphologic and immunophenotypic features of mesonephric adenocarcinoma with a likely Müllerian origin. While no true mesonephric duct remnants are present, these tumors closely resemble mesonephric adenocarcinomas by their morphology and immunohistochemistry staining patterns, and are characterized by joint endometrial and mesonephric differentiation.[55] Similar to mesonephric adenocarcinomas, MLA tumors generally present as hormone receptor negative (though may be focally positive for estrogen, as observed in our third case presentation), but are positive for PAX-8, TTF-1, and GATA-3.[56,57] Unlike mesonephric adenocarcinomas, the primary site of this malignancy appears to be restricted to the uterus and ovaries and frequently coexists with other Müllerian lesions, including endometrioid adenocarcinoma, endometrioid adenofibroma, and endometriosis. These associations, together with its PAX8 positivity and characteristic KRAS-driven molecular profile, support the concept of a Müllerian-derived carcinoma undergoing mesonephric-like differentiation.

The origin of MLA is still controversial, primarily because of its rarity and shortage of literature, but some of the recent evidence suggests that it may originate from the Müllerian epithelium. For example, these tumors often coexist with other Mullerian neoplasms. Molecular data indicates an association with KRAS and PIK3CA mutations; however, mutations in PTEN, p53, and SMARCA4 have not been commonly observed.[58] The embryologic context provides a useful framework. The mesonephric (Wolffian) duct gives rise to the epididymis, vas deferens, and seminal vesicles in males, while regressing in females, leaving behind occasional mesonephric remnants in the cervix and uterine ligaments. These remnants can give rise to mesonephric hyperplasia and mesonephric adenocarcinoma. In contrast, the paramesonephric (Müllerian) ducts form the fallopian tubes, uterus, cervix, and upper vagina.[59]MLA appears to arise from Müllerian-derived epithelium that acquires a mesonephric-like immunophenotype (GATA3 and TTF-1 positivity, ER/PR negativity), resulting in a lesion that mimics mesonephric carcinoma but lacks true mesonephric rests.

Our three cases are concordant with previously described MLA in several respects: all showed TTF-1 positivity, two showed GATA3 expression, and all had limited or absent diffuse ER/PR expression. Morphologically, they demonstrated crowded glands with high-grade cytologic atypia and, in one case, clear cell-like changes, highlighting the potential for diagnostic confusion with endometrioid or clear cell carcinoma. Two of the three tumors were initially misclassified, emphasizing the need for heightened awareness and appropriate immunohistochemical workup, particularly in hormone receptor–negative endometrial carcinomas with unusual morphology.

A salient finding in our series is the consistent presence of hypothyroidism in all three patients. However, our systematic review of ~200 published MLA cases did not identify thyroid dysfunction as a recurrent or well-described comorbidity. This discrepancy likely reflects incomplete reporting rather than absence of disease, as 67.5% of published cases lacked any comorbidity information. Thus, although endocrine abnormalities were observed in our cohort, their significance remains speculative. In contrast, the literature strongly supports a Müllerian origin: among the 65 cases with available data, 86% were associated with Müllerian lesions, especially endometriosis and adenomyosis as seen in Table 3.

This trend reinforces the proposal that MLA arises from Müllerian epithelium undergoing mesonephric-like differentiation. While causality cannot be inferred from observational data, thyroid hormone pathways intersect with cell proliferation, metabolism, and immune regulation, any of which could hypothetically influence tumor biology in susceptible tissues. Our findings reinforce the need for systematic evaluation of thyroid status in larger MLA cohorts and for mechanistic studies exploring thyroid–tumor crosstalk.

The most novel aspect of our series is the occurrence of MLA in a young woman with Down syndrome. Down syndrome is characterized by trisomy 21, involving the Down Syndrome Critical Region with genes such as ETS2, RCAN1, and DYRK1A that modulate immune function and carcinogenesis. Epidemiologic studies consistently show an increased risk of hematologic malignancies in individuals with Down syndrome but a reduced incidence of many solid tumors, suggesting complex, context-dependent roles for chromosome 21–encoded genes in tumorigenesis.

Down syndrome is the most prevalent genetic culprit of intellectual disability globally. The addition of part or an entire twenty-first chromosome is associated with numerous consequences, including loss of muscle tone, craniofacial abnormalities, delays in speech and language development, and learning impairment. Triploidy of chromosome 21 is also associated with immunodeficiency: children with Down syndrome are more susceptible to infections, especially respiratory infections.[60] An area on chromosome 21 of particular interest is commonly called the Down Syndrome Critical Region (DSCR), and includes 33 genes believed to be responsible for many of the abnormalities seen in patients with Down syndrome. Particularly, genes on the DSCR including protein-encoding genes for the erythroblast transformation-specific 2 protein (ETS2), regulator of calcineurin 1/calcipressin-1 (RCAN1), and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), are all being studied for their suspected tumor-suppressing roles.[61,62] There are numerous studies describing the relationship between Down syndrome and malignancy. These studies describe a positive correlation between Down syndrome and hematologic malignancies and negative correlation between patients and solid tumor malignancies, specifically breast, lung, and prostate.[61,63,64]However, there is also literature describing young patients with Down syndrome acquiring rare solid tumor malignancies, which demands further investigation.[65] To date, MLA has not been described in patients with Down syndrome. The coexistence of MLA, Down syndrome, and hypothyroidism in our first case may represent coincidence; however, it also raises the hypothesis that immune dysregulation, endocrine disturbance, and trisomy 21–related gene dosage effects could converge to alter the risk profile for rare Mullerian neoplasms. Larger datasets and molecular profiling will be required to test this hypothesis.

5. Conclusions

Mesonephric-like adenocarcinoma is an uncommon and diagnostically challenging uterine malignancy that often mimics endometrioid carcinoma on initial evaluation. In this case series, all three patients presented with abnormal uterine bleeding and shared overlapping histopathologic and immunohistochemical features characteristic of MLA, including TTF-1 positivity and relative absence of hormone receptor expression. The consistent presence of hypothyroidism across all cases reinforces previously suggested endocrine associations and supports the need for further investigation into thyroid dysfunction as a potential contributing factor in MLA pathogenesis.

Notably, we report the first known case of MLA occurring in a patient with Down syndrome. Although a causal relationship cannot be established from a single case, the finding raises the possibility of an underlying genetic susceptibility, potentially involving chromosome 21–associated pathways, and highlights an area for future research. As recognition of MLA continues to expand, heightened awareness of its morphologic spectrum, immunophenotype, and possible molecular underpinnings will be essential for improving diagnostic accuracy and optimizing patient outcomes.

Our case series and literature review of approximately 200 reported MLA cases confirms several key themes:

• MLA is uncommon but likely underrecognized.
• It often presents at an early stage but carries a higher risk of recurrence and metastasis than low-grade endometrioid carcinoma.
• KRAS mutations are highly prevalent; additional alterations in PIK3CA, ARID1A, and CTNNB1 occur in a subset. These observations suggest important prognostic and therapeutic implications, including potential eligibility for targeted therapies directed at KRAS or PI3K/AKT/mTOR pathway alterations.
• The immunophenotypic pattern of PAX8+/TTF-1+/GATA3+/ER– (or ER-focal) is highly characteristic but not entirely specific.
• Endocrine comorbidities, including hypothyroidism, appear in case reports and small series, though systematic data remains limited. Recognition of these associations can improve diagnostic accuracy and promote further research into molecular and endocrine pathways underlying MLA pathogenesis.