INTRODUCTION

Undifferentiated endometrial carcinoma (UEC) is defined as a malignant epithelial tumor that lacks definitive differentiation direction. It is classified as dedifferentiated endometrial carcinoma (DEC) when coexisting with a differentiated carcinoma component.[1] These rare malignancies account for approximately 2% of endometrial cancers and are characterized by high aggressiveness; the majority of patients (54%) present at an advanced stage, and 75% succumb to the disease, where even minimal undifferentiated components indicate a poor prognosis.[2] Fallopian tube malignancies, though rarer (1-2% of gynecologic cancers), frequently present diagnostic conundrums when coexisting with uterine tumors because of overlapping morphological features with metastatic lesions. The distinction between synchronous primaries and metastases in the uterus-adnexa tumor pairs remains clinically critical, with current criteria mainly based on anatomical distribution and traditional morphological analysis.

This case describes a rare DEC co-occurring with fallopian tube high-grade serous carcinoma (HGSC), a combination previously unreported. We achieved accurate diagnosis by combining morphology, immunohistochemistry (IHC), and next-generation sequencing (NGS) detection. Our findings enhance our understanding of DEC and identify the diagnostic key points for distinguishing between primary tumors and metastases. Results offer insights into clinical management and prognostic evaluation.

CASE REPORT

A 58-year-old woman presented with irregular vaginal bleeding for over 2 months. Her menstrual history was unremarkable, with a history of bilateral tubal ligation and no other significant medical conditions. Transvaginal ultrasound revealed endometrial thickening (1 cm) and intrauterine fluid. Pelvic magnetic resonance imaging demonstrated heterogeneous endometrial thickening with a small nodule exhibiting an abnormal signal in the uterine corpus and left lateral wall. Serum tumor markers (CA125) were within normal limits. Endometrial curettage histopathology indicated endometrioid carcinoma. Laparoscopic total hysterectomy, pelvic lymphadenectomy, and bilateral adnexectomy were then performed.

Gross examination identified a 1.2 cm × 0.6 cm irregular lesion (lesion 1) at the left uterine fundus, displaying a gray-white, poorly demarcated cut surface. The remaining endometrium appeared normal. The right fallopian tube measured 8 cm, with a 2.5 cm dilated ampulla containing a 1.3 cm × 1 cm mucosal lesion (lesion 2) exhibiting a rough, gray-white appearance.

Lesion 1 (Endometrial)

Histologically, the endometrial lesion showed fused glandular structures forming sieve-like patterns [Figure 1a], accompanied by mild-to-moderate cytologic atypia. Adjacent solid tumor sheets infiltrated the superficial myometrium. These cells displayed uniform morphology, high nuclear-cytoplasmic ratios, coarse chromatin, vesicular nuclei with small nucleoli, and frequent mitoses (>30/10 HPFs). Stromal lymphocytic infiltration was prominent [Figure 1b]. IHC was performed using automated platforms (Dako) with standardized protocols. Diffuse epithelial membrane antigen (EMA) [Figure 1c], paired box gene 8 (PAX8) [Figure 1d], and E-cadherin [Figure 1e] positivity in glandular regions were recorded, with focal EMA retention and loss of PAX8/E-cadherin in solid areas, suggesting divergent differentiation. The loss of nuclear MutL homolog 1(MLH1) [Figure 1f] and PMS1 homolog 2 (PMS2) [Figure 1g] in both components supports a microsatellite instability-high (MSI-H) phenotype.[3] Brahma-related gene 1 (BRG1) expression was retained in glandular regions but lost in solid areas [Figure 1h]. Additional IHC findings are summarized in Table 1a, supporting the diagnosis of DEC.

Figure 1: Pathological features of the uterine tumor. (a) Low-magnification view of a densely fused glandular area (red arrow) in the endometrium and a solid sheet-like area (black arrow) infiltrating the myometrium. (H&E staining, magnification, 20×, Scale bar: 1000 μm) (b) High-magnification view of the glandular area (red arrow) revealed mild to moderate atypia and sieve-like structures, while the solid area (black arrow) exhibited uniform cells with vesicular nuclei and focal rhabdoid-like features. (H&E staining, magnification, 200×, Scale bar: 100 μm). Immunohistochemical (magnification, 200×, Scale bar: 100 μm) analysis revealed differential expression patterns: (c) EMA, (d) PAX8, and (e) E-cadherin were strongly positive in glandular area but focally expressed (EMA) or negative (PAX8, E-cadherin) in solid area. (f) MLH1 and (g) PMS2 showed complete loss in both components, indicating mismatch repair deficiency. (h) BRG1 expression was retained in glandular area but lost in solid area. Scale bar: 100 μm. H&E staining: Hematoxylin-eosin staining, PAX8: Paired box gene 8, MLH1: MutL homolog 1, PMS2: PMS1 homolog 2, BRG1: Brahma-related gene 1.

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Table 1: IHC and NGS results of the uterine tumor and the right fallopian tube tumor.

(a) Immunohistochemical staining results Immunohistochemical marker Fused glandular area of uterine tumor Solid sheet-like area of uterine tumor Right fallopian tube tumor PCK Diffuse+ - N/A CK8/18 Diffuse+ - N/A EMA Diffuse+ Focal+ N/A Vimentin Partial+ Diffuse+ N/A E-cadherin + - N/A PAX8 + - + ER + - + PR + - N/A p53 20% Weak+ 20% Weak+ Diffuse Strong+ WT1 - - + p16 Speckled + - + Ki67 (LI) 30% 80% N/A MLH1 - - + PMS2 - - + MSH2 + + + MSH6 + + + BRG1 + - N/A INI1 + + N/A (b) NGS results Biomarker Fused glandular area of uterine tumor Solid sheet-like area of uterine tumor Right fallopian tube tumor KRAS/ERBB2 KRAS p.G12C KRAS p.G12C ERBB2 p.V777L PIK3CA PIK3CA p.H1047Y PIK3CA p.H1047Y - PTEN PTEN p.T319fs PTEN p.T319fs - TP53 TP53 p.R282W TP53 p.R282W TP53 p.C242Y SMARCA4 - SMARCA4 p.Q1569fs - - SMARCA4 p.L1161fs - NF1 - NF1 p.P678fs - MSI Status MSI-H MSI-H MSS TMB (mut/Mb) 23.93 25.92 2.99 Lesion 2 (Fallopian tube)

The tube lesion exhibited solid sheets and coarse papillary structures with sieve-like formations [Figure 2a]. Tumor cells demonstrated marked atypia, abundant mitoses, and absent stromal lymphocytes [Figure 2b]. IHC confirmed diffuse positivity for PAX8 [Figure 2c], Wilms tumor 1 (WT1) [Figure 2d], Tumor protein p53 (p53/TP53) [Figure 2e], and Cyclin-dependent kinase inhibitor 2A (p16) [Figure 2f], which are characteristic of HGSC.

Figure 2: Pathological features of the right fallopian tube tumor. (a) Low-magnification view showed tumor cells predominantly exhibiting large, solid, and blunt papillary growth patterns on the mucosal surface and within the lumen of the fallopian tube, with local glandular fusion forming sieve-like structures. (H&E staining, magnification: 20×, Scale bar: 1000 μm) (b) High-magnification view revealed severe cellular atypia and frequent mitotic figures in tumor cells. ( H&E staining, magnification: 200×, Scale bar: 100 μm). Immunohistochemical staining (magnification: 200×, Scale bar: 100 μm) showed diffuse positivity for (c) PAX8, (d) WT1, (e) p53, and (f) p16 in tumor cells. Scale bar: 100 μm. PAX8: Paired box gene 8, WT1: Wilms tumor 1, p53/TP53: Tumor protein p53, p16: Cyclin-dependent kinase inhibitor 2A, H&E staining: Hematoxylin-eosin staining.

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NGS profiling (Illumina NextSeq550, 520-gene panel)

NGS of lesion 1 identified shared Kirsten rat sarcoma viral oncogene homolog (KRAS), Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), Phosphatase and tensin homolog (PTEN), and TP53 mutations, MSI-H status, and a high tumor mutational burden (TMB-H) in glandular and solid components were noted. A SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutation was exclusively detected in the solid region [Table 1b], confirming a clonal origin. In lesion 2, NGS analysis identified a TP53 mutation (p.C242Y) and a V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) activating mutation (p.V777L), with microsatellite stable and low TMB (2.99 mutations/Mb). These molecular features, distinct from Lesion 1, confirmed a primary tubal origin.

Final pathological diagnoses included DEC (MSI-H subtype) of the endometrium (International Federation of Gynecology and Obstetrics [FIGO] stage IIC) and synchronous HGSC (SET subtype) of the right fallopian tube (FIGO stage IA). The patient underwent six cycles of TP chemotherapy (liposomal paclitaxel 240 mg + carboplatin 600 mg) and remained recurrence-free for 46 months postoperatively. The patient had no evidence of disease on quarterly gynecological ultrasonography and CA125 testing during the 1st year and biennially thereafter.

DISCUSSION

The simultaneous detection of tumors in the uterine cavity and fallopian tube necessitated clarification of their histological types and whether they were of primary or metastatic origin. This case highlights synchronous primaries: An endometrial DEC and a fallopian tube HGSC. The uterine tumor exhibited two distinct growth patterns: A fused glandular area consistent with low-grade endometrioid carcinoma and a solid sheet-like area lacking differentiation. The latter required the exclusion of poorly differentiated EC, mucinous carcinoma, neuroendocrine carcinoma, undifferentiated carcinoma, undifferentiated sarcoma, and high-grade endometrial stromal sarcoma. IHC revealed that focal EMA expression but absent epithelial markers (including Pan cytokeratin, Cytokeratin 8/18, E-cadherin) and neuroendocrine markers, ruling out the solid-growth pattern of endometrioid carcinoma, mucinous carcinoma, and neuroendocrine carcinoma. Negative stromal markers (Cluster of differentiation 10, Cyclin D1, SMA, and Desmin) excluded uterine sarcoma. Furthermore, the presentations of this case do not fit with those of malignant mesodermal mixed tumors, which typically consist of high-grade carcinoma components. In addition, BRG1 loss supported undifferentiated carcinoma. The diagnosis of DEC is well-supported by the findings combined with the concurrent low-grade endometrioid carcinoma.

Mutually exclusive inactivation of SWI/SNF core subunits SMARCA4 (encoding the BRG1 protein) and SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily B, member 1 (SMARCB1) (encoding the integrase interactor 1 [INI1] protein) drives undifferentiated carcinogenesis, with SMARCA4 inactivation being more common.[4] Our molecular analyses confirmed SMARCA4 frameshift mutations (p.Q1569fs and p.L1161fs), causing BRG1 loss, reinforcing its pathogenic role. These findings underscore the clinical importance of BRG1/INI1 immunohistochemistry when encountering poorly cohesive and undifferentiated morphologies, particularly given the aggressive nature and dismal prognosis associated with SWI/ SNF-deficient carcinomas.[5] Furthermore, molecular profiling is employed for synchronous uterine/adnexal tumors to distinguish primary lesions from metastases; it is crucial for prognosis, given the favorable outcomes associated with early-stage disease.[6] This patient shows no recurrence to date, which may be related to the earlier stage of the disease.

The tumor in the right fallopian tube exhibited solid, glandular, and transitional cell-like growth patterns on microscopy. Its morphology partially overlaps with that of endometrial tumors. The selection of IHC markers such as PAX8 and WT1 prioritized specificity for Müllerian origin and serous differentiation. The tumor diffusely expressed PAX8, WT1, p53, and p16, which is the classic immunophenotype of HGSC. NGS revealed that two lesions had different molecular pathological features with KRAS, PIK3CA, and PTEN mutations in the uterine cavity tumor, while an ERBB2 mutation in the right fallopian tube. This further confirmed that both tumors were primary.

Synchronous endometrial-adnexal malignancies typically involve the endometrium and ovary, with concurrent fallopian tube involvement being rare.[7] Terzakis et al.[8] described an endometrial endometrioid adenocarcinoma with coexisting fallopian tube adenocarcinoma papillary serous type. While dual primaries usually show low-grade endometrial histology, synchronous high-grade uterine/adnexal malignancies are considered monoclonal.[9] Our case exhibited discordant high-grade carcinomas (endometrial cavity and fallopian tube), challenging this paradigm. Furthermore, it represents a unique DEC/SET-subtype HGSC co-occurrence arising from distinct Müllerian sites (endometrium vs. fallopian tube) with divergent molecular profiles, underscoring the necessity of combined histo-genomic analysis for accurate diagnosis.

In this case, the two lesions exhibited distinct stromal characteristics: The uterine tumor displayed abundant lymphocytes, contrasting with minimal infiltration in the fallopian tube. This result may be related to MSI-H in the uterine cavity tumor inducing the body’s immune response, leading to an increase in tumor-infiltrating lymphocytes. Furthermore, MSI-H endometrial carcinomas have a higher TMB, which can significantly increase the number of neoantigens, facilitating the induction of anti-tumor immune responses in the body. Clinical trials (e.g., KEYNOTE-158) demonstrate durable responses to immune checkpoint inhibitors in MSI-H cases, though early-stage disease in this patient precluded immunotherapy. Nevertheless, MSI-H testing remains crucial for advanced disease management.

Pelvic HGSC with the SET subtype typically occurs with a higher proportion of breast cancer susceptibility gene 1 and breast cancer susceptibility gene 2 (BRCA1/2) mutations and is associated with homologous recombination deficiency (HRD).[10] In this case, the fallopian tube HGSC displayed SET morphology but lacked BRCA1/2 mutations, limiting polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) utility. This underscores the need for molecular stratification beyond histology. It is still recommended that BRCA1/2 or HRD testing for non-classical HGSC morphologies (including the SET subtype) identifies potential beneficiaries of PARPi.

The rarity of uterine-fallopian tube synchronous primaries limits this study’s generalizability. Karnezis et al.[4] identified mismatch repair deficiency as the genomic background in 73% of SMARCA4-deficient and 50% of SMARCB1-deficient undifferentiated tumors, with our case additionally suggesting potential MSI-H-associated SMARCA4 defects. Notably, DEC demonstrates heterogeneous molecular subtypes with undefined mechanisms and the prognostic significance of SMARCA4 and TP53 mutations in MSI-H tumors remains unclear. Future studies should focus on constructing SMARCA4-deficient EC in vitro models to elucidate the mechanistic link between SWI/SNF inactivation and MSI-H. Furthermore, functional analyses of PARPi sensitivity in SET subtype cancers without BRCA mutations may refine treatment strategies.

SUMMARY

This case highlights the diagnostic challenge of synchronous primaries. Integrating histopathology, immunohistochemistry, and molecular profiling is essential for distinguishing between primary/metastatic lesions and guiding therapy and prognostic evaluation. The endometrial MSI-H status suggests potential immunotherapy responsiveness, while the SET subtype of HGSC necessitates BRCA/HRD testing even in morphologically atypical cases. This report reinforces the value of advanced diagnostics in improving patient outcomes.

AVAILABILITY OF DATA AND MATERIALS

The data that support the findings of this study are available from the corresponding author upon reasonable request.

ABBREVIATIONS

ALK: Anaplastic lymphoma receptor tyrosine kinase

BRCA1/2: Breast cancer susceptibility gene 1 and breast cancer susceptibility gene 2

BRG1: Brahma-related gene 1

CD10: Cluster of differentiation 10

CD34: Cluster of differentiation 34

CD56: Cluster of differentiation 56

CgA: Chromogranin A

CK8/18: Cytokeratin 8/18

DEC: Dedifferentiated endometrial carcinoma

EMA: Epithelial membrane antigen

ER: Estrogen receptor

ERBB2: V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2

FIGO: International federation of gynecology and obstetrics

H&E staining: Hematoxylin-eosin staining

HGSC: High-grade serous carcinoma

HRD: Homologous recombination deficiency

IHC: Immunohistochemistry

INI1: Integrase interactor 1

Ki67 (LI): Ki67 (labeling index)

KRAS: Kirsten rat sarcoma viral oncogene homolog

MLH1: MutL homolog 1

MSH2: MutS homolog 2

MSH6: MutS homolog 6

MSI: Microsatellite instability

MSI-H: Microsatellite instability-high

MSS: Microsatellite stable

NF1: Neurofibromin 1

NGS: Next-generation sequencing

PAX8: Paired box gene 8

PCK: Pan cytokeratin

p16: Cyclin-dependent kinase inhibitor 2A

p53/TP53: Tumor protein p53

PARP: Poly adenosine diphosphate-ribose polymerase

PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha

PMS2: PMS1 homolog 2

PR: Progesterone receptor

PTEN: Phosphatase and tensin homolog

SMARCA4: SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4

SMARCB1: SWI/SNF related, matrix associated, actindependent regulator of chromatin, subfamily B, member 1

SMA: Smooth muscle antibody

Syn: Synaptophysin

TMB: Tumor mutational burden

UEC: Undifferentiated endometrial carcinoma

WT1: Wilms tumor 1

AUTHOR CONTRIBUTIONS

QC: Writing introduction and case discussion, editing, and reviewing; XTZ: Writing case presentation, editing, and reviewing; DJL: Providing immunohistochemical staining imaging; SG: Contributing in writing introduction, the pathological findings and case discussion, editing, and reviewing; BXH: Review and editing. All authors meet the authorship status of ICMJE.