High‑grade corded and hyalinized endometrioid carcinoma with high microsatellite instability and STK11 mutation: A case report and literature review
- Authors:
- Published online on: June 10, 2025 https://doi.org/10.3892/ol.2025.15136
- Article Number: 389
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Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Corded and hyalinized endometrioid carcinoma (CHEC) is a rare histological variant of endometrioid carcinoma (EC). The presence of corded components within the hyalinized stroma, combined with histological changes typical of EC, contribute to its diagnosis. This distinctive morphology was initially described by Clement and Young (1) in a review in 2002. In 2005, Murray et al (2) analyzed the clinicopathological features of 31 similar cases and coined the term CHEC. To date, >60 cases with clinicopathological features of CHEC have been reported (2–7). The majority of these cases are classified as low-grade [International Federation of Gynecology and Obstetrics (FIGO) G1-G2] (8), with only seven cases exhibiting the high-grade component (FIGO G3) (5–7). Ladwig et al (5) revealed that low-grade CHEC shares similarity with classic EC, exhibiting β-catenin (CTNNB1; 7/7), PIK3CA(Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha, 6/7) and PTEN (6/7) mutations, with only one case of high-grade CHEC presenting with overexpression of p53 (1/7). Additionally, CHEC with high-grade components exhibits overexpression of p53 (2/5) and mismatch repair deficiency (MMRd; 3/5), while a unique case of CHEC with focal bizarre cells exhibited no specific molecular alterations (7). CHEC with high-grade components can be confused with carcinosarcoma, both in histological morphology and molecular phenotype, which poses a challenge for pathological diagnosis. The present study describes the case of a patient with high-grade CHEC and also provides a review of the relevant literature (5–7) to summarize the clinicopathological and molecular phenotypical features to prevent misdiagnoses.
Case report
A 38-year-old female patient was admitted to the Department of Gynecology at Shandong Provincial Hospital Affiliated to Shandong First Medical University in Jinan, China, in November 2023, with symptoms of intermittent vaginal bleeding and abdominal pain persisting for >3 months. She had irregular menstruation since menarche at the age of 18 years and had been receiving a combination of traditional Chinese and Western medicines since the age of 27 years. At the age of 31 years, the patient underwent endometrial curettage, which indicated atypical endometrial hyperplasia. Preoperative endometrial biopsy confirmed the diagnosis of carcinosarcoma. There was no reported family history of tumors. A gynecological B-mode ultrasound (transabdominal probe frequency, 3.5 MHz; depth 18 cm, focal zone set at the uterine corpus with medium gain adjustment) revealed the deep invasion of endometrial cancer into the myometrial layer and cervix, and MRI scans (3.0T, T2-weighted turbo spin-echo sequence: Repetition/Echo Time 4,000/100 msec, slice thickness 5 mm, Field of View 30 cm; diffusion-weighted imaging with b=1,000 s/mm2) confirmed the marked irregular thickening of the endometrium with invasion into the myometrium and cervix (Fig. 1A). Intraoperative frozen section analysis initially misdiagnosed the lesion as carcinosarcoma. The patient underwent a hysterectomy with bilateral salpingo-oophorectomy.
Upon a gross examination of radical hysterectomy specimens following surgery, the uterus was enlarged, presenting as a uniformly exophytic mass within the uterine cavity. The tumor was firm, with gray-white tissue diffusely invading the myometrium and the cervical stroma with a size of ~15×10×4 cm3 (Fig. 1B). The specimens were fixed in 10% neutral buffered formalin at 25°C for 24 h, sectioned at 4 µm thickness, stained with hematoxylin (5 min) and eosin (2 min at 25°C), and examined using an optical microscope. Under microscopic examination, two distinct morphological forms were evident. The majority of the tumor consisted of typical low-grade EC, while the corded components were embedded within the hyalinized stroma (Fig. 1E). The corded components were arranged in strips, small cell clusters and spindle cells, intermingling with the adenocarcinoma component. Locally, there was a transition between the two components (Fig. 1C and D). Additionally, areas of squamous/morular differentiation were observed. At a higher magnification, the nuclei of both the classic EC and corded components exhibited relatively consistent and mild to moderate dysplasia, with a limited number of mitotic figures (Fig. 1E). Notably, ~20% of the tumor displayed an increased density of spindle-shaped cells (Fig. 1F), and in some areas, a small amount of hyalinized stroma was visible. Moreover, a few glands and spindle cells fused with each other (Fig. 1G). In some regions, a uniformly pale or eosinophilic appearance is observed, often with well-demarcated borders, corresponding to ground pattern necrosis. Under a high-powered microscope, severe cell dysplasia was observed, and mitoses were visible (~50 cells/10 high-power fields; Fig. 1H). The histological classification revealed that 80% of the tumor was categorized as low-grade (FIGO G1)(8) and 20% as high-grade (FIGO G3). The tumor cells infiltrated more than half of the uterine wall and extended into the cervical stroma, without evident vascular invasion or metastasis into the pelvic lymph nodes.
Tissue sections were baked at 65°C for 1 h, followed by dewaxing in 100% xylene and rehydrated through graded ethanol series (100, 95, 80, 70%). After rinsing in PBS, antigen retrieval was performed using a pressure cooker with preheated retrieval buffer: sections were heated at full pressure for 3 min after boiling, cooled naturally, and washed in PBS. Endogenous peroxidase activity was blocked with 3% hydrogen peroxide (10 min; room temperature), followed by PBS rinsing. Primary antibodies: AE1/AE3, PAX-8, ER, PR, EMA and E-cadherin, β-catenin, CR, MLH1, MSH2, MSH6, PMS2, Ki-67, p53 (Zhongshan Golden Bridge Biotechnology) were applied and incubated overnight at 4°C in a humidified chamber. After PBS washing, universal secondary antibodies (rabbit/mouse IgG; 1:200 dilution, PV-9000, Zhongshan Golden Bridge Biotechnology) conjugated with horseradish peroxidase were incubated at 37°C for 30 min. DAB was applied for 4–6 min (room temperature), and reactions were stopped by rinsing under running water. Sections were counterstained with hematoxylin (1 min), differentiated in 1% acid alcohol (3 sec), blued in ammonia water (30 sec), dehydrated through graded alcohols (70–100 %), and mounted with neutral resin. Staining results were analyzed using Nikon Eclipse E600 light microscope (Nikon Corporation, Japan). Immunohistochemistry revealed that AE1/AE3, PAX-8, ER, PR, EMA and E-cadherin were positive in the low-grade EC, and β-catenin demonstrated membranous positivity (Fig. 2D; Table I). CR and α-inhibin were negative in the low-grade EC region, and the Ki-67 index was ~10% (Fig. 2E). In the low-grade corded components, PAX-8, CR and α-inhibin were positive, β-catenin displayed cytoplasmic and nuclear positivity (Fig. 2L) and AE1/AE3, EMA and E-cadherin were negative. The Ki-67 index of the low-grade corded region was 1% (Fig. 2E). MMR protein and wild-type p53 protein were found both in the low-grade EC and corded components. In the high-grade area, PAX-8 was weakly positive, β-catenin demonstrated nuclear positivity and the Ki-67 index was ~70%. AE1/AE3, EMA, E-cadherin, CR, α-inhibin, ER and PR were negative. The tumor cells exhibit wild-type p53 status, characterized by weak or absent nuclear staining, comparable with the pattern observed in normal cells. This aligns with our molecular testing results, which confirm the absence of pathogenic mutations in the TP53 gene. In addition, MMRd was detected in the high-grade tumor cells.
The sequencing analysis utilized the NEBNext Ultra II DNA Library Prep Kit (Catalogue No. E7645L; New England Biolabs, USA) for library preparation. Sample quality was verified using an Agilent 4200 TapeStation System with High Sensitivity D1000 ScreenTape (Agilent Technologies) to ensure DNA integrity (DIN ≥7.0) and tumor cell content (≥20%). Sequencing was performed on Illumina platforms (NovaSeq 6000/NextSeq 500/MiSeq/iSeq 100) with paired-end 150-bp reads, employing the NovaSeq 6000 S4 Reagent Kit (Catalogue No. 20028312; Illumina, USA). The final library was quantified to 1.8 nM using a Qubit 4.0 Fluorometer (Thermo Fisher Scientific) and KAPA Library Quantification Kit (Roche). Data analysis utilized BWA-MEM v0.7.17 for alignment, GATK v4.2.6.1 for variant calling, ANNOVAR (2023-05 -01) for annotation, and IGV v2.12.3 for visualization, ensuring stringent quality metrics (Q30: 93.95%, average depth: 824×). Next-generation sequencing was performed to assess microsatellite instability (MSI) and a tumor panel (typically covering 30–50 genes) was used, including DNA polymerase ε, catalytic subunit (POLE), TP53, PIK3CA, CTNNB1 and serine/threonine kinase 11 (STK11), for detection of mutations in the low- and high-grade regions. Both the low- and high-grade components exhibited mutations in CTNNB1 (exon 3; Fig. 3A and B) and PIK3CA (exon 21; Fig. 3C and D; Table II). POLE mutations were not identified in either low- or high-grade CHEC. Furthermore, only the high-grade region components had high MSI (MSI-H), whereas the low-grade components exhibited no special molecular profile (NSMP). STK11 mutation was identified exclusively in the high-grade region, located in exon 9, involving a change from C to T at base 1,217 of the encoded protein (Fig. 3E). Conversely, the STK11 mutation was not detected in the low-grade region. Protein-protein interaction (PPI; dataset obtained from the STRING database (string-db.org/) analysis of STK11 revealed a potential downstream network (Fig. 3F).
Pathological diagnosis of CHEC was confirmed, with 20% of the region classified as high-grade (FIGO G3). The FIGO stage was classified as IIA. Following the surgical procedure, the patient underwent three cycles of chemotherapy with lomustine at 240 mg/cycle and carboplatin at 600 mg/cycle, administered every 4 weeks. The patient underwent pelvic CT scans every 6 months, with tumor marker assessment (including CA-125) performed at the 12-month mark. If elevated, CA-125 levels were monitored every 3 months. No recurrence was detected during the 16-month follow-up period.
Discussion
To date, 62 cases of CHEC have been reported (2–7); patients with CHEC are typically younger compared with those with conventional EC with a median age at diagnosis of ~49.8 years compared to 61 years for conventional EC (9). CHEC exhibits characteristic structural features, consisting of a combination of classical EC structures and corded structures with hyalinized degeneration, which are merged together. The corded component accounts <5->90% of the tumor, with the majority being low-grade (FIGO G1 or G2) and FIGO stage I (68%). Notably, the majority of the patients with CHEC survived and remained disease-free at the last follow-up (70%). Therefore, CHEC is a subtype of low-grade EC exhibiting a favorable prognosis, and the prognostic outcome of CHEC is comparable to conventional low-grade EC (10). However, seven cases of CHEC with high-grade components have been reported, which exhibit MMR deficiency, p53 abnormalities, and/or poor prognosis (5–7), in which the EC and/or corded components exhibit marked heterogeneity and moderate to severe atypia. These features suggest a high degree of tumor complexity, as observed in the present case.
The present study reviewed eight cases (including the present case) of CHEC with high-grade components (Table III). The median age of the patients in these cases was 59 years (range, 34–71 years), similar to that of conventional EC but older than that of low-grade CHEC patients. Notably, 5/8 cases were classified as FIGO stage I, 1/8 as FIGO stage II and 2/8 as FIGO stage III. All eight cases had traditional EC components, 3/8 cases exhibited low-grade EC, 2/8 exhibited high-grade EC and 3/8 displayed both high- and low-grade EC (Table III). Furthermore, 7/8 cases exhibited squamous/morular differentiation and there was marked variation in the proportion of corded and hyalinized components with a median of 27.5% (range, 15.0–90%). In the previously reported cases (5–7), the corded component was consistently characterized by moderate to severe dysplasia. Similarly, in the present case, the corded and hyalinized degeneration components displayed both low- and high-grade elements. Within the low-grade region, the cells exhibited mild characteristics, with minimal mitoses and a Ki-67 index of 1%. High-grade corded components displayed marked heterogeneity, characterized by pronounced cellular pleomorphism, visible mitotic figures and necrosis. Intravascular tumor thrombi were found in only 1/8 cases. Notably, despite the presence of a high-grade component, all patients eligible for a follow-up examination (6/8) experienced disease-free survival.
High-grade CHEC poses a challenge for differential diagnoses of carcinosarcoma and dedifferentiated carcinoma. Carcinosarcoma was diagnosed at both the biopsy and in the analysis of the frozen sections in the present case study. Following surgery, morphological analysis revealed classic low-grade CHEC, with high-grade epithelioid cells arranged in cords with a hyalinized stroma. The high-grade corded component was superficially located, merged with the endometrioid component and accompanied by prominent squamous differentiation with nuclear expression of β-catenin with a CTNNB1 mutation. However, no p53 upregulation was observed, which could have aided with differential diagnosis.
Common gene mutations in endometrial cancer include PTEN (82%), PIK3CA (54%), AT-rich interaction domain 1A (54%), PIK3R1 (36%) and CTNNB1 (34%). (11). In the present case, PIK3CA and CTNNB1 mutations were found in both high- and low-grade CHEC. Notably, MSI-H and the STK11 mutation were found only in high-grade CHEC. Previously, there have been increasing reports of STK11 gene mutations occurring in EC (12–14), which may be associated with the malignant progression of EC. Based on the present case, STK11 may be associated with the high-grade transformation of CHEC.
According to The Cancer Genome Atlas, EC is classified into four molecular subtypes: ‘POLE-mut’ in the presence of POLE mutation, ‘MMRd’ in the absence of POLE mutations but with MMRd, ‘p53abn’ with an aberrant p53 expression in the absence of POLE mutations and MMRd and ‘NSMP’ as POLE-wild-type, MMR-proficient and p53-wild-type (15). In the pooled high-grade CHEC cases, the molecular subtypes observed were p53abn (3/8), MMRd (4/8) and NSMP (1/8), with no POLE-mut cases. The association of p53abn with a worse prognosis of patients with EC further supports the hypothesis that high-grade CHEC is a more malignant tumor. High-grade CHEC with p53abn typically exhibits more aggressive biological behaviors. Additionally, p53abn tumors are associated with genomic instability, leading to enhanced resistance to standard chemotherapy, a higher risk of recurrence and reduced progression-free and overall survival (16,17). Notably, all three cases with p53 overexpression were FIGO stage I, potentially due to the early stage of the cancer and possibly other favorable factors in those individual cases. This does not necessarily contradict the overall trend, and the available follow-up information did not indicate a worse prognosis compared with the non-p53abn type. However, all three p53abn cases were FIGO stage 1 and had relatively short follow-up periods, necessitating larger case series and longer follow-up for further investigation. MMRd was present in 4/8 cases, which suggests the need for germline and MSH1 promoter hypermethylation testing in combination with family history, to differentiate between Lynch syndrome associated-EC vs. sporadic EC (18). Immunotherapy is generally beneficial for MMRd tumors (19). The present case exhibited MMRd based on molecular detection and MLH1 and PMS2 protein deficiency based on immunohistochemistry only in the high-grade region. Further genetic testing confirmed that the low-grade region belonged to the NSMP subtype. While it has been hypothesized that high-grade CHEC should be treated as an aggressive tumor (20), the limited number of high-grade CHEC cases necessitates the collection of more cases to investigate prognosis and the efficacy of immunotherapy.
In the present study, the molecular analysis detected mutations in STK11 in the high-grade component of CHEC. STK11 encodes the liver kinase B1 (LKB1) protein, which serves a key role in transmitting signal events by phosphorylating downstream molecules, such as STE20-Related Adaptor (STRAD), PTEN and p21/CDK inhibitor 1A (15,21). The STK11 gene is involved in essential cellular functions, including regulation of the cell cycle, angiogenesis and the DNA damage response (22,23). STK11 mutations are commonly associated with Peutz-Jeghers syndrome, characterized by pigmented skin and oral lesions, as well as gastrointestinal polyps (24,25). Individuals with this syndrome are at a 10–18-fold greater risk of developing tumors, particularly gastrointestinal tumors, and may also develop tumors in other sites, such as the breast, uterus, ovary, testes and pancreas (26,27). The present patient lacked a history of mucosal melanosis and gastrointestinal polyps but had a prolonged medication history. Alterations in the STK11 gene may co-occur with high-grade CHEC, possibly contributing to the aggressive nature of these tumors (12).
Using the STRING database, the hub genes of STK11 were identified in the PPI network (Fig. 3D). LKB1 forms heterotrimers with STRAD and calcium binding protein 39 (CAB39) (28), which enhances the phosphorylation activity of LKB1 and regulates signaling pathways in vivo, such as the AMP-activated protein kinase (AMPK) pathway (29). CAB39-like protein, an analogue of CAB39, interacts with the LKB1-STRAD complex to activate and phosphorylate AMPKα/β (30). PTEN and STK11 serve different functions; however, PTEN can interact with LKB1 and is affected by the phosphorylation of LKB1 (31). Axin 1 (AXIN1) is associated with the AMPK signaling pathway (32,33), although AXIN1 and STK11 do not directly interact, they collaboratively regulate cellular processes through integrated networks involving metabolic regulation (AMPK/mTOR), proliferative signaling (Wnt/β-catenin), and stress response pathways to suppress abnormal cell proliferation. Loss of function in the protein can disrupt the balance of these pathways, leading to dysregulation that drives tumor growth (34). LKB1 is a primary upstream regulator of AMPK. It directly phosphorylates the α-subunit at a critical site (Thr172), activating AMPK in response to low energy states (35). By contrast, p21 is activated by LKB1 (36), which prevents cells from entering the S-phase by inhibiting CDK activity, thereby inhibiting cell proliferation (37). In CHEC, STK11 mutations disrupt LKB1 tumor-suppressive roles in metabolism, proliferation, and genomic stability. These aberrations synergize with CTNNB1/PIK3CA mutations to drive malignant progression (38). Further investigations are needed to explore this association.
Immunohistochemical and molecular analyses have demonstrated that almost all low-grade CHEC cases exhibit widespread nuclear β-catenin expression (10). However, a noticeable decrease in nuclear β-catenin positivity was demonstrated in high-grade CHEC cases (5/8 cases exhibited nuclear positivity) and only 2/8 cases of high-grade CHEC exhibited CTNNB1 mutations. The present study solely assessed hotspot mutations within exon 3. Hence, the potential occurrence of other hotspot mutations or alterations in the Wnt/β-catenin pathway cannot be ruled out (7). Thus, a greater number of cases and further molecular tests are required.
In conclusion, the present study described a patient with CHEC with a high-grade component, molecularly classified as MSI-H and accompanied by mutations in PIK3CA, CTNNB1 and STK11. The selection of different differentiation regions of the tumor for immunohistochemistry and molecular detection may yield different results, which will impact the treatment of patients. Therefore, it is important to consider the selection of tumor regions for molecular detection. Due to the rarity of high-grade CHEC and potential for diagnostic confusion, additional comprehensive studies involving larger cohorts should be performed in the future.
Acknowledgements
Not applicable.
Funding
The present study was supported by the National Natural Science Foundation of China (grant no. 82201293).
Availability of data and materials
The data generated in the present study may be found in the Mendeley Data database under accession number 10.17632/fjhp6pwjwp.1 or at the following URL: https://data.mendeley.com/datasets/fjhp6pwjwp/1.
Authors' contributions
ZX and FC wrote the manuscript and performed the literature review. FC analyzed and interpretated the data. YY and ZX constructed figures and performed the pathology review. ZC and HC made substantial contributions to conception and design and revised the manuscript. All authors have read and approved the final manuscript. ZX and FC confirm the authenticity of all the raw data.
Ethics approval and consent to participate
The present study was reviewed and approved by the Biomedical Research Ethic Committee of the Shandong Provincial Hospital Affiliated to Shandong First Medical University (approval no. SWYX2024-572), dated October 2024.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the present case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
CHEC |
corded and hyalinized endometrioid carcinoma |
|
MSI-H |
high microsatellite instability |
|
POLE |
polymerase ε, catalytic subunit |
|
MMRd |
mismatch repair deficiency |
|
STK11 |
serine/threonine kinase 11 |
|
NSMP |
no special molecular profile |
|
LKB1 |
liver kinase B1 |
|
STRAD |
STE20-Related Adaptor |
|
CAB39 |
calcium binding protein 39 |
|
AMPK |
AMP-activated protein kinase |
|
PI3KCA |
Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit α |
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