Research ArticleClinical Studies
Open Access

Mesonephric-like Adenocarcinoma of the Uterine Corpus: Clinicopathological and Prognostic Significance of L1 Cell Adhesion Molecule (L1CAM) Over-expression

SUHO PARK, YUNJOO CHO and HYUN-SOO KIM
Anticancer Research October 2023, 43 (10) 4559-4571; DOI: https://doi.org/10.21873/anticanres.16650

Abstract

Background/Aim: The expression of L1 cell adhesion molecule (L1CAM) in uterine mesonephric-like adenocarcinoma (MLA) remains understudied. Our aim was to explore the L1CAM expression in uterine MLA, delving into its clinicopathological implications and prognostic significance. Patients and Methods: We conducted L1CAM immunostaining in MLA, endometrioid carcinoma (EC), and serous carcinoma (SC), compared L1CAM expression across these histological types, and probed the relationship between L1CAM expression and the clinicopathological features and outcomes of patients with MLA. Results: High L1CAM expression was evident in 15 of 28 MLA cases (53.6%). This rate surpassed that of EC (7.5%) but was less than that of SC (78.9%). A high L1CAM expression correlated with initial distant metastasis, advanced initial stage, lung metastasis, and the recurrence of MLA. L1CAM-high MLA exhibited worse disease-free and overall survival than L1CAM-low MLA. Conclusion: L1CAM over-expression was observed in more than half of the MLA cases, and was associated with aggressive clinicopathological traits and adverse outcomes in patients with uterine MLA.

Key Words:

Endometrial carcinoma is the most common gynecological malignancy in the United States, with approximately 66,000 new cases reported annually (1-5). Notably, the number of new endometrial carcinoma cases is on a steady rise in the Republic of Korea (6). Currently, the determination of the histological type and grade of endometrial carcinoma is based on morphological traits (7-9). The most prevalent histological type is endometrioid carcinoma (EC), which constitutes approximately 80% of all endometrial carcinoma cases, followed by serous carcinoma (SC), clear-cell carcinoma, mixed carcinoma, carcinosarcoma, and undifferentiated carcinoma. While histological diagnosis of endometrial carcinoma is generally reproducible, high-grade endometrial carcinomas present significant inter- and intra-observer variability due to their overlapping histological features (10-15). Although morphological classification provides key prognostic information, the incorporation of molecular determinants can enhance its accuracy.

The Cancer Genome Atlas Research Network performed an extensive molecular analysis of 232 endometrial carcinoma cases and identified for the first time four molecularly classified groups (16). The Proactive Molecular Risk Classifier for Endometrial Cancer, a practical model for clinical application, delineated four subgroups—the DNA polymerase epsilon, catalytic subunit (POLE)-mutant group, harboring mutations in the exonuclease domain in exons 9-14 and showing very favorable outcomes; mismatch repair (MMR)-deficient group, showing the loss of expression of one or more MMR proteins; p53-abnormal group, demonstrating aberrant p53 immunostaining pattern, indicating pathogenic tumor protein (TP53) mutation; and no specific molecular profile (NSMP) group (3, 17, 18). The last category is characterized by the absence of specific molecular markers—POLE-wild type, TP53-wild type, and MMR-proficient. The NSMP group is heterogeneous and comprises a mixture of distinct groups characterized by different risk of recurrence and potential susceptibility to tailored treatments (19). Hence, more refined risk stratification for NSMP endometrial carcinoma has been proposed and is currently being examined in clinical studies.

L1 cell adhesion molecule (L1CAM), an immunoglobulin superfamily membrane glycoprotein, plays a crucial role in neurogenesis by regulating cellular adhesion and migration (20). In tumor cells, L1CAM facilitates the epithelial-mesenchymal transition, thereby enhancing cellular migration, invasion, and metastasis (21). Although L1CAM over-expression is strongly associated with mutant p53 expression patterns in endometrial carcinoma (17), evidence also suggests a p53-independent mechanism for L1CAM over-expression across multiple molecular groups (17). Notably, in NSMP endometrial carcinoma, L1CAM expression was found to further stratify tumors at a higher risk for poor outcomes. L1CAM over-expression signaled a reduced disease-free and overall survival period in the NSMP group (17).

Mesonephric-like adenocarcinoma (MLA) is a rare and recently recognized malignancy of the upper female genital tract (10-12, 15, 22-27). Uterine MLA shares morphological and immunophenotypical characteristics with mesonephric adenocarcinoma, originating from mesonephric remnants in the uterine cervix and vagina. MLA displays various architectural patterns and can closely resemble low-grade EC if the tumor predominantly exhibits well-formed tubular and glandular architectures, coupled with low-to-intermediate cytological atypia (22, 23, 25-29). Owing to its rarity, uterine MLA is often misdiagnosed by pathologists (10-13, 15). The clinical presentations, histological features, immunostaining results, and molecular findings of uterine MLA, as well as the difficulty in distinguishing it from other histological types of endometrial carcinoma, have recently been reported in the literature (10-13, 15, 30). As uterine MLA exhibits more aggressive behavior and worse prognosis than other endometrial carcinoma types, an accurate pathological diagnosis is critical for proper treatment (10, 15, 24).

While L1CAM has garnered attention as a noteworthy prognostic biomarker and potential therapeutic target in endometrial carcinoma (21, 31-34), L1CAM expression in uterine MLA has not been examined. This rare subtype of uterine carcinoma was only recently acknowledged in the 2020 World Health Organization (WHO) Classification (7). Consequently, it remains uncertain whether the immunohistochemical expression status of L1CAM bears any clinicopathological significance or prognostic implications for patients with uterine MLA. In this study, we aimed to assess the status of L1CAM expression and evaluate the prevalence of L1CAM over-expression in patients with uterine MLA. We also compared the L1CAM expression status of uterine MLA with that of common histological types of endometrial carcinoma, including EC and SC. Additionally, we sought to explore whether L1CAM over-expression is associated with the clinicopathological characteristics and outcomes of patients with uterine MLA.

Patients and Methods

Case selection and clinicopathological data collection. This study was approved by the Institutional Review Board of the Samsung Medical Center (protocol number: 2021-06-190). Between March 2019 and September 2022, we searched for data on consecutive endometrial carcinoma cases in the pathology databases of the Samsung Medical Center. Two board-certified gynecological pathologists reviewed all available hematoxylin and eosin-stained slides to confirm the histological types. Histologically, MLA (Figure 1A-D) is recognized by its diverse architectural patterns and the proliferation of closely packed small tubules with eosinophilic intraluminal secretions. This is accompanied by either characteristic immunophenotypes (at least one positive mesonephric marker and negative or focal positive for the estrogen receptor) or molecular confirmation (pathogenic Kirsten rat sarcoma viral oncogene homolog mutation) (7, 12, 14, 15, 22, 23, 27-29). EC (Figure 1E-G) is distinguished by confluent glandular proliferation featuring architectural abnormalities (complex papillary growth pattern, back-to-back arrangement, villoglandular structure, microacinar-like configuration, and solid architecture) and varying degrees of nuclear atypia (enlargement, rounding, loss of polarity, pleomorphism, and conspicuous nucleoli) (7, 14). SC (Figure 1H-J) is identified by its papillary, micropapillary, and solid architecture, high-grade nuclear atypia (notable pleomorphism, conspicuous nucleoli, and frequent mitotic figures), and aberrant p53 expression patterns (7, 35). Clinicopathological information was sourced from the electronic medical records and pathology reports.

Figure 1.
Figure 1.

Typical histological features of mesonephric-like adenocarcinoma (MLA; A-D), endometrioid carcinoma (EC; E-G), and serous carcinoma (SC; H-J). MLA is characterized by (A) architectural diversity, (B) compact proliferation of small tubules lined by cuboidal-to-short columnar epithelium, (C) low-to-intermediate-grade nuclear atypia including mild pleomorphism, occasional membrane irregularity, and inconspicuous nucleoli, and (D) hyaline-like, dense eosinophilic intraluminal secretions (blue arrows). Low-grade EC displays (E) glandular complexity and crowding with nuclear stratification, (F) proliferation of variable-sized and irregular-shaped endometrial glands, and (G) low-grade nuclear atypia. SC exhibits (H) proliferation of relatively well-formed papillae with floating cellular clusters and (I and J) high-grade nuclear atypia, including marked enlargement and pleomorphism, brisk mitotic activity, and occasional atypical mitoses (green arrows).

Immunohistochemical staining. Two board-certified gynecological pathologists selected the most representative slides per case. Tissue sections from the corresponding formalin-fixed, paraffin-embedded blocks were mounted onto SuperFrost Plus Microscope Slides (Thermo Fisher Scientific, Waltham, MA, USA), deparaffinized in xylene, and then rehydrated using an ethanol gradient. Immunohistochemical staining was carried out using a Bond-Max automated immunostainer (Leica Biosystems, Lincolnshire, IL, USA) and a Bond Polymer Refine Detection System (Leica Biosystems), as described previously (11, 30, 35-39). Following antigen retrieval, the slides were incubated with a primary antibody against L1CAM (dilution 1:100, clone EPR18998, Abcam, Waltham, MA, USA). After chromogenic visualization with 3,3′-diaminobenzidine-tetrahydrochloride-dihydrate, the slides were counterstained with hematoxylin, dehydrated, and mounted. Positive and negative controls were concurrently stained. Normal peripheral nerve tissue served as the positive control, while non-immune serum substitution for the primary antibody was used as a negative control, resulting in undetectable staining.

Immunohistochemical interpretation. Staining proportions were calculated in 5% increments over a 0-100% range (e.g., 0%, 1%, 5%, 10%, 15%, and 20%). High L1CAM expression or L1CAM over-expression was defined as moderate-to-strong staining intensity across ≥10% of the tumor area. Cases were then categorized into L1CAM-high (staining proportion ≥10%) and -low (staining proportion <10%) groups based on their expression status (17). In the case of heterogeneous L1CAM expression in the MLA, well-defined areas displaying alternative expression patterns were grouped into three distinct intratumoral heterogeneity patterns—concurrent positive and negative staining within glandular formations (intraglandular), whole glands or groups of glands (clonal), and larger tumor areas or compartments (compartmental) (40).

Statistical analysis. The Pearson chi-squared test, Fisher’s exact test, or linear-by-linear association test was employed to discern the difference in the frequency of high L1CAM expression among histological types and to investigate the correlation between L1CAM expression status and the clinicopathological features of patients with MLA. A one-way analysis of variance (ANOVA), followed by a post-hoc least significant difference (LSD) test, was used for comparing the mean values of L1CAM staining proportion among histological types. Univariate analysis of disease-free and overall survival rates was conducted to assess the prognostic implications of L1CAM over-expression in patients with MLA. Survival curves were generated using the Kaplan-Meier method, with the disparities in the Kaplan-Meier curves analyzed using the log-rank test. The Cox proportional hazards model (95% confidence interval) with the backward elimination method (stepwise withdrawal of non-significant variables with p≥0.05 from the model) was used for the multivariate analysis of disease-free and overall survival. All statistical analyses were conducted using IBM SPSS Statistics for Windows (version 23.0; IBM Corp., Armonk, NY, USA). Statistical significance was set at p<0.05.

Results

Baseline clinicopathological characteristics of patients with MLA, EC, or SC. The baseline clinicopathological characteristics of 32, 40, and 21 patients with MLA, EC, and SC, respectively, are summarized in Table I, alongside their disparities. Patients with SC (median age=65 years) were significantly older than those with MLA (median=60 years; p=0.020) or EC (median age=60.5 years; p=0.048). MLA more frequently extended into the uterine serosa (43.8%) than did EC (5.0%; p<0.001) and SC (9.5%; p=0.013). In contrast to EC, MLA more frequently involved the adnexa (31.3%) and pelvic wall (21.9%) (5.0% and 2.5%; p=0.004 and p=0.019, respectively). The differences in frequencies of adnexal and pelvic wall extensions between the MLA and SC groups were not statistically significant (p=0.362 and p=0.722, respectively). Distant metastases at initial diagnosis were detected in 31.3% and 14.3% of patients with MLA and SC, respectively, while no EC patients developed distant metastases (p<0.001 and p=0.037, respectively). The majority of EC patients (62.5%) had FIGO stage I tumors, whereas most MLA patients (26/32, 81.3%) had stage II-IV tumors. Approximately half of the SC cases (10/21, 47.6%) were diagnosed as stages IIIA-IV. Patients with MLA and SC demonstrated more advanced disease stages than those with EC (p<0.001 and p=0.032, respectively). Postoperative follow-up information was unavailable for two, three, and four patients in the MLA, EC, and SC groups, respectively. Twenty-three of the 30 patients with MLA experienced post-treatment recurrence, with the recurrence rate (76.7%) being higher than that in patients with EC (0/37, 0.0%; p=0.002) and SC (5/17, 29.4%; p=0.018).

View this table:
Table I.

Differences in baseline clinicopathological characteristics and L1 cell adhesion molecule (L1CAM) expression status among patients with uterine mesonephric-like adenocarcinoma (MLA), endometrioid carcinoma (EC), and serous carcinoma (SC).

Frequencies and patterns of L1CAM expression in uterine MLA. We conducted immunohistochemical staining for L1CAM on formalin-fixed, paraffin-embedded tissue blocks obtained from 28, 40, and 19 patients with MLA, EC, and SC, respectively. Tissue specimens for immunostaining were unavailable for four and two patients with MLA and SC, respectively. As shown in Table I, L1CAM over-expression was observed in 15 (53.6%) patients with MLA. Figure 2 shows representative photomicrographs displaying variable staining proportions for L1CAM immunoreactivity in MLA. More than half (15/28, 53.6%) of the MLA cases were classified as having L1CAM-high tumors. In particular, two cases of MLA exhibited 90% (Figure 2A) and 100% (Figure 2B) positivity. In ten MLA samples, 20-75% of the tumor cells expressed L1CAM (Figures 2C-E) with moderate to strong staining intensity. The remaining three MLA samples showed L1CAM immunoreactivity in 10% of tumor cells. Thirteen cases of MLA (46.4%) were classified as L1CAM-low tumors. Seven MLA samples were completely negative for L1CAM, whereas six expressed L1CAM in 1-5% of the tumor cells (Figure 2F). Intratumoral heterogeneity of L1CAM expression was observed in five L1CAM-high MLA samples. In two cases, the patterns of heterogeneous expression coexisted as clonal (Figure 2G) and compartmental (Figure 2H-I) heterogeneity. Isolated clonally heterogeneous expression was observed in two tumors, whereas zonal heterogeneity was observed in one tumor. In some MLA cases, L1CAM expression gradually varied across tumor tissues. A gradient was formed wherein the staining intensity and proportion of L1CAM-positive tumor cells gradually varied from one region to another. Heterogeneous L1CAM expression did not affect L1CAM over-expression frequency in uterine MLA.

Figure 2.
Figure 2.

L1 cell adhesion molecule (L1CAM) immunoreactivity in uterine mesonephric-like adenocarcinoma (MLA). (A and B) Very high L1CAM expression, with staining proportions of (A) 90% and (B) 100%. (C-E) Varying degrees of high L1CAM expression, with staining proportions of (C) 50%, (D) 30%, and (E) 20%. (F) Low L1CAM expression, with staining proportion of 1% (green arrows). (G-I) Intratumoral heterogeneity of L1CAM immunoreactivity. (G) Clonal heterogeneity, with scattered microscopic areas (yellow arrows) showing an abrupt transition from strong L1CAM expression to the absence of immunoreactivity. (H and I) Compartmental heterogeneity, with large areas (purple arrows) showing diffuse loss of tumor cell immunoreactivity.

Frequencies and patterns of L1CAM expression in endometrial EC and SC. High L1CAM expression was observed in two (5.0%) and 15 (78.9%) cases of endometrial EC and SC, respectively (Table I). Figure 3 depicts representative photomicrographs of L1CAM immunoreactivity in EC and SC. Most EC cases (33/40, 82.5%) showed a lack of L1CAM immunoreactivity (Figure 3A). Two L1CAM-high EC samples showed 10% and 15% positivity (Figure 3B). In contrast, most SC cases (14/19, 73.7%) displayed L1CAM over-expression, with 20-90% positivity (Figure 3D-E). Three of the four L1CAM-low SC samples were positive for L1CAM in 5% of tumor cells, and the remaining tumor was completely negative for L1CAM. Heterogeneous L1CAM expression was observed in 27.3% (9/33) of SC samples. Five and four patients with SC showed clonal and compartmental heterogeneity, respectively.

Figure 3.
Figure 3.

L1 cell adhesion molecule (L1CAM) immunoreactivity in endometrioid carcinoma (EC; A-C) and serous carcinoma (SC; D-E). (A and B) Low L1CAM expression in EC, with staining proportions of (A) 0% and (B) 5%. (C) High L1CAM expression in EC, with staining proportion of 15%. (D) Low L1CAM expression in SC, with staining proportion of 5%. (E) Very high L1CAM expression in SC, with staining proportion of 90%.

Differences in the frequency of L1CAM over-expression among MLA, EC, and SC. We analyzed the variance in the frequencies of L1CAM over-expression in MLA, EC, and SC (Table I). MLA and SC samples showed L1CAM over-expression more often than did EC samples (p<0.001). However, the frequency of L1CAM over-expression did not significantly differ between the MLA and SC groups (p=0.122). The average proportions of L1CAM staining in MLA, EC, and SC samples were 24.3 (standard deviation=29.6; range=0-100), 1.0 (standard deviation=3.0; range=0-15), and 28.7 (standard deviation=24.2; range=0-90), respectively. ANOVA with post hoc LSD test revealed that the L1CAM staining proportions of MLA and SC samples were significantly higher than those of EC (p<0.001, both), but the difference between MLA and SC samples was not statistically significant (p=0.464).

Clinicopathological significance of L1CAM over-expression in uterine MLA. Table II details the correlation between L1CAM expression status and the clinicopathological characteristics of patients with uterine MLA. L1CAM over-expression was significantly linked with four factors denoting the aggressive clinical behavior of uterine MLA—initial distant metastasis (p=0.006), lung metastasis (p=0.009), advanced initial stage (p=0.011), and post-treatment recurrence (p=0.033). Specifically, over half of the L1CAM-high MLA patients (9/15, 60.0%) presented with distant metastases at initial diagnosis, whereas only one of the 13 L1CAM-low patients showed initial distant metastases. Moreover, two-thirds of L1CAM-high MLA patients (10/15) experienced initial or recurrent lung metastases, while most L1CAM-low tumors (11/13, 84.6%) did not involve the lungs. All but one L1CAM-high MLA patient was diagnosed as having stage III-IV tumors. Four of the five uterine-confined (stage I-II) MLA patients had L1CAM-low tumors. Postoperative follow-up information was accessible for 14 and 12 patients with L1CAM-high and L1CAM-low MLAs, respectively. All L1CAM-high MLA patients experienced posttreatment recurrence. Although two-thirds of L1CAM-low MLA patients (8/12; 66.7%) relapsed after treatment, the difference in post-treatment recurrence frequency was statistically significant between the L1CAM-high and -low MLA cases (p=0.033). Additionally, L1CAM-high MLAs more frequently involved the uterine serosa (66.7% vs. 30.8%) and pelvic wall (40.0% vs. 7.7%) than did L1CAM-low tumors. However, these differences were not statistically significant (p=0.128 and p=0.084, respectively). Furthermore, there were no significant differences in age, parametrial extension, adnexal extension, and lymph node metastasis in relation to L1CAM expression status.

View this table:
Table II.

Association of L1 cell adhesion molecule (L1CAM) expression status with the clinicopathological characteristics of patients with uterine mesonephric-like adenocarcinoma.

Prognostic significance of L1CAM over-expression in uterine MLA. Table III summarizes the results of survival analysis in patients with uterine MLA. The univariate analysis revealed that pelvic wall extension (p<0.001), initial distant metastasis (p=0.002), and lung metastasis (p=0.001) were significant predictors of disease-free survival. The multivariate analysis revealed that pelvic wall extension (p=0.002) and initial distant metastasis (p=0.017) were statistically significant, establishing these parameters as independent predictors of diminished disease-free survival. The afore-mentioned three parameters were also significantly associated with overall survival (p<0.001, p=0.009, and p=0.002, respectively). However, the multivariate analysis revealed that none of these parameters independently predicted overall survival. Although the hazard ratios for pelvic wall extension and lung metastasis were estimated at 4.184 (95% confidence interval=0.928-18.852) and 7.966 (95% confidence interval=0.880-72.113), respectively, the results were not statistically significant (p=0.062 and p=0.065, respectively). As shown in Figure 4, patients with L1CAM-high MLA showed lower disease-free and overall survival rates than those with L1CAM-low MLA, but the differences were not statistically significant (p=0.064 and p=0.072, respectively). However, when seven of the 15 L1CAM-high MLA samples with staining proportions ≥50% were further classified as L1CAM-very high tumors, this subgroup had significantly worse disease-free and overall survival (p=0.017 and p=0.008, respectively) than L1CAM-low MLA patients (Figure 4C-D). The median disease-free and overall survival periods of L1CAM-very high MLA patients (2.5 and 25.4 months, respectively) were significantly shorter than those of patients with L1CAM-low MLA (25.0 and 66.4 months, respectively).

View this table:
Table III.

Association of L1 cell adhesion molecule (L1CAM) expression status with the outcomes of patients with uterine mesonephric-like adenocarcinoma.

Figure 4.
Figure 4.

Kaplan-Meier plots for disease-free and overall survival of patients with uterine mesonephric-like adenocarcinoma (MLA) according to L1 cell adhesion molecule (L1CAM) expression status. Patients with L1CAM-high (≥10%) uterine MLA showed worse (A) disease-free and (B) overall survival than those with L1CAM-low (<10%) tumors, but the differences were not statistically significant (p=0.064 and p=0.072, respectively). When the patients with tumors showing staining proportion ≥50% were further classified as the L1CAM-very high group, both (C) disease-free and (D) overall survival probabilities of this group were significantly lower than those of the L1CAM-low group (p=0.017 and p=0.008, respectively).

Discussion

To our best knowledge, this is the first study to investigate the expression status of L1CAM in uterine MLA and juxtapose the L1CAM immunoreactivity of uterine MLA with that of endometrial EC and SC. We found that the frequency of L1CAM over-expression in MLA and SC was notably higher than that in EC. In line with this, the average values of L1CAM staining proportions in MLA and SC samples were also significantly higher than those in EC samples. Nevertheless, the disparities in over-expression frequency and L1CAM positivity between MLA and SC samples were not statistically significant. In addition, we explored the clinicopathological and prognostic implications of L1CAM expression in uterine MLA. Our data suggested that L1CAM over-expression significantly correlated with initial distant metastasis, lung metastasis, advanced initial stage, and post-treatment recurrence. The survival analysis indicated that patients with L1CAM-very high (staining proportion ≥50%) MLA had significantly worse disease-free and overall survival than those with L1CAM-low tumors. These findings reinforce the notion that L1CAM over-expression is linked to aggressive clinicopathological features and unfavorable outcomes in patients with uterine MLA.

L1CAM expression has been consistently reported to be associated with aggressive clinical behavior and is of great significance in predicting poor outcomes in endometrial carcinoma (32, 41, 42). Huszar et al. (42) observed that L1CAM is not expressed in the normal endometrium and the vast majority of ECs but is strongly expressed in SCs. In cases with mixed endometrioid and serous histology, the latter component showed diffuse and strong positivity for L1CAM, whereas the former component showed negative or weakly positive staining. Consistent with these data, Geels et al. (41) and van der Putten et al. (32) reported that L1CAM over-expression is associated with a higher histological grade, non-endometrioid histology, advanced stage, lymphovascular space invasion, lymph node metastasis, and distant recurrence. Furthermore, L1CAM expression is a strong prognostic marker of EC. Although EC is usually negative for L1CAM, a small subset of ECs over-express L1CAM (12). Patients with L1CAM-positive EC exhibit poor prognosis, even in the early stages. In a study by Zeimet et al. (43), 51.4% of L1CAM-positive EC patients developed tumor recurrence, whereas only 2.9% of L1CAM-negative EC patients developed tumor recurrence. Kommoss et al. (44) documented that L1CAM is a significant independent prognostic factor for disease-specific survival, with a hazard ratio of 5.98. Although the frequency of L1CAM over-expression in low-risk endometrial carcinoma was lower than that in the intermediate- and high-intermediate-risk tumors, the adverse prognostic significance of L1CAM positivity was maintained in the low-risk subgroup analysis. A recent meta-analysis by Guo et al. (21) concluded that L1CAM over-expression in endometrial carcinoma is correlated with adverse clinicopathological parameters and decreased overall and disease-free survival, with hazard ratios of 2.87 and 3.32, respectively.

MLAs frequently go unrecognized due to their morphological features mirroring those of the more prevalent histological types of endometrial carcinoma, including EC and SC. Distinguishing MLAs from these types is crucial, as MLAs tend to have a worse prognosis than that of other endometrial carcinomas. In our recent study, wherein we explored seven cases of MLA (45), over half of the uterine MLAs (4/7) were diagnosed at an advanced stage. Every patient (7/7) exhibited deep myometrial invasion and LVSI, and more than half (4/7) developed metastases within eight months post-surgery. All patients with early-stage tumors (3/3) experienced local recurrence and metastasis within 14 months post-surgery. MLA was more frequent and had a shorter time to recurrence than did FIGO grade 1, 2, and 3 ECs (29, 45). Univariate and multivariate analyses revealed mesonephric-like histology as an independent risk factor for adverse patient outcomes (24). Similarly, a recent multi-institutional study by Pors et al. (29) reported that over half of uterine and ovarian MLAs were present at stage II or higher. Furthermore, over half of the patients with MLA developed recurrence, most commonly at distant sites, with a distinct propensity for recurrence in the lungs. Most uterine MLAs (63.6%) recurred in the lungs, while fewer ovarian MLAs (25.0%) recurred in the lungs.

Among the four molecular subgroups of EC, the p53-abnormal group was highly associated with L1CAM positivity. Kommoss et al. (17) reported that 81.8% (45/55) of p53-abnormal endometrial carcinoma tissues over-expressed L1CAM. However, more than half (52/97, 55.7%) of the L1CAM-positive endometrial carcinomas displayed a wild-type p53 expression pattern (the NSMP subgroup), which indicated that the NSMP group could be further stratified according to L1CAM expression status. L1CAM-positive NSMP endometrial carcinomas had higher histological grade (grade 3) and FIGO stage (II-IV) than the L1CAM-negative NSMP tumors. Although the vast majority of NSMP endometrial carcinomas is low-grade EC, the NSMP subgroup also encompasses any histological type of endometrial carcinoma (46), accounting for 28% of high-grade ECs (18), 40% of clear cell carcinomas (18), 25% of undifferentiated/dedifferentiated carcinomas (18), 14% of carcinosarcomas (47), 36% of endometrial neuroendocrine carcinomas (26), and almost all uterine MLAs (10, 11, 13, 22, 23, 27-29). At the molecular level, most uterine MLAs are associated with activating KRAS mutations but not with MMR-deficient or POLE-mutant signatures (25). The wild-type p53 immunostaining pattern in the uterine MLA also suggested the absence of an p53-abnormal signature. Therefore, uterine MLAs appear to belong to the NSMP subgroup. However, because the biological behavior of uterine MLA is consistently described as aggressive (11, 24, 29), the inclusion of this entity in the high-risk non-endometrioid group appears to be justified.

The occurrence of regional variations in immunohistochemical expression within the same tumor is called intratumoral heterogeneity (48). Intratumoral heterogeneity mirrors subclonal diversity and may affect treatment response. Differential expression of biomarkers within the same tumor has been described in various human malignancies, including endometrial carcinoma (48-53). To our best knowledge, the intratumoral heterogeneity of L1CAM in uterine MLA has not been studied. We showed intratumoral heterogeneity of L1CAM expression using whole-section immunostaining in five of the 15 (33.3%) L1CAM-high MLA samples. The distribution of heterogeneous L1CAM expression in patients with uterine MLA presents clonal and compartmental heterogeneity. There was no significant tendency for intratumoral heterogeneity to be observed more frequently in the tumor center, periphery, or invasive front. In this study, as intratumoral heterogeneity of L1CAM expression was detected only in L1CAM-high MLA samples, we were unable to assess the clinicopathological or prognostic value of heterogeneous L1CAM expression in patients with uterine MLA. Nonetheless, intratumoral heterogeneity holds importance because prognostic predictions hinge on the expression of immunomarkers. Specifically, L1CAM is a negative prognostic factor for endometrial carcinoma. It is essential to acknowledge that this phenomenon can lead to varying L1CAM expression statuses to circumvent false-positive or false-negative results.

In conclusion, our study revealed that over half of the MLA cases exhibited L1CAM over-expression. We noticed intratumoral heterogeneity of L1CAM expression in a small subset of cases, but this did not influence the frequency of L1CAM over-expression. We found that both MLA and SC samples over-expressed L1CAM more frequently than did EC samples. Still, there was no significant difference in the frequency of L1CAM over-expression between MLA and SC. Similarly, the L1CAM staining proportions in MLA and SC samples significantly surpassed those in EC, but the variance in staining proportion between MLA and SC samples was not statistically significant. L1CAM over-expression in uterine MLA significantly correlated with four parameters indicative of its aggressive clinical behavior—initial distant metastasis, lung metastasis, advanced initial stage, and post-treatment recurrence. Uterine MLA patients exhibiting staining proportions of 50% or more (L1CAM-very high tumors) had notably poorer disease-free and overall survival than those with L1CAM-low MLAs. These findings suggest that L1CAM over-expression is linked to aggressive clinicopathological features and poor patient outcomes in uterine MLA. Further studies are required to elucidate the clinicopathological and prognostic significance and molecular mechanism of L1CAM over-expression in larger MLA patient cohorts.

Acknowledgements

This work was supported by Samsung Medical Center Grant (SMO1230291) and the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (2023R1A2C2006223).

Footnotes

  • Authors’ Contributions

    All Authors made substantial contributions to the conceptualization and design of this study; the acquisition, interpretation, and validation of the data; drafting and critical revision of the manuscript; and final approval of the version to be published.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest or financial ties related to this study.

  • Received July 12, 2023.
  • Revision received August 3, 2023.
  • Accepted August 4, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Miyamoto M,
    2. Hada T,
    3. Ishibashi H,
    4. Iwahashi H,
    5. Kakimoto S,
    6. Suzuki R,
    7. Sakamoto T,
    8. Matsuura H,
    9. Tsuda H,
    10. Takano M
    : A new model to improve the prediction of prognosis of endometrial carcinoma by combining traditional classification with the presence of tumor-infiltrating lymphocytes. Anticancer Res 41(2): 1047-1053, 2021. DOI: 10.21873/anticanres.14861
    OpenUrlAbstract/FREE Full Text
    1. Hecking T,
    2. Thiesler T,
    3. Halbe J,
    4. Otten L,
    5. Recker F,
    6. Gevensleben H,
    7. MÜller T,
    8. Schiller C,
    9. Egger EK,
    10. Fimmers R,
    11. Stope MB,
    12. Kristiansen G,
    13. Mustea A
    : Programmed cell death ligand-1 (PDL-1) correlates with tumor infiltration by immune cells and represents a promising target for immunotherapy in endometrial cancer. Anticancer Res 42(3): 1367-1376, 2022. DOI: 10.21873/anticanres.15606
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Loukovaara M,
    2. Pasanen A,
    3. Bützow R
    : Molecular classification of endometrial carcinoma: a clinically oriented review. J Clin Pathol 75(11): 731-738, 2022. DOI: 10.1136/jclinpath-2022-208345
    OpenUrlAbstract/FREE Full Text
    1. Siegel RL,
    2. Miller KD,
    3. Jemal A
    : Cancer statistics, 2019. CA Cancer J Clin 69(1): 7-34, 2019. DOI: 10.3322/caac.21551
    OpenUrlCrossRefPubMed
  5. ↵
    1. Jumaah AS,
    2. Al-Haddad HS,
    3. Salem MM,
    4. McAllister KA,
    5. Yasseen AA
    : Mismatch repair deficiency and clinicopathological characteristics in endometrial carcinoma: a systematic review and meta-analysis. J Pathol Transl Med 55(3): 202-211, 2021. DOI: 10.4132/jptm.2021.02.19
    OpenUrlCrossRefPubMed
  6. ↵
    1. Goulder A,
    2. Gaillard SL
    : Molecular classification of endometrial cancer: entering an era of precision medicine. J Gynecol Oncol 33(3): e47, 2022. DOI: 10.3802/jgo.2022.33.e47
    OpenUrlCrossRefPubMed
  7. ↵
    1. WHO Classification of Tumors Editorial Board
    1. WHO Classification of Tumours
    : Female Genital Tumours. Fifth Edition. Lyon, WHO Classification of Tumors Editorial Board (eds.), 2020.
    1. Murali R,
    2. Soslow RA,
    3. Weigelt B
    : Classification of endometrial carcinoma: more than two types. Lancet Oncol 15(7): e268-e278, 2014. DOI: 10.1016/s1470-2045(13)70591-6
    OpenUrlCrossRefPubMed
  9. ↵
    1. Jung HJ,
    2. Lee SY,
    3. Hong JH,
    4. Chun YK
    : Interobserver diagnostic reproducibility in advanced-stage endometrial carcinoma. J Pathol Transl Med 55(1): 43-52, 2021. DOI: 10.4132/jptm.2020.10.04
    OpenUrlCrossRefPubMed
  10. ↵
    1. Kim H,
    2. Na K,
    3. Bae GE,
    4. Kim HS
    : Mesonephric-like adenocarcinoma of the uterine corpus: Comprehensive immunohistochemical analyses using markers for mesonephric, endometrioid and serous tumors. Diagnostics (Basel) 11(11): 2042, 2021. DOI: 10.3390/diagnostics11112042
    OpenUrlCrossRefPubMed
  11. ↵
    1. Sohn J,
    2. Lee Y,
    3. Kim HS
    : Endometrioid carcinomas of the ovaries and endometrium involving endocervical polyps: Comprehensive clinicopathological analyses. Diagnostics (Basel) 12(10): 2339, 2022. DOI: 10.3390/diagnostics12102339
    OpenUrlCrossRefPubMed
  12. ↵
    1. Koh HH,
    2. Park E,
    3. Kim HS
    : Mesonephric-like adenocarcinoma of the ovary: clinicopathological and molecular characteristics. Diagnostics (Basel) 12(2): 326, 2022. DOI: 10.3390/diagnostics12020326
    OpenUrlCrossRefPubMed
  13. ↵
    1. Na K,
    2. Kim HS
    : Clinicopathologic and molecular characteristics of mesonephric adenocarcinoma arising from the uterine body. Am J Surg Pathol 43(1): 12-25, 2019. DOI: 10.1097/PAS.0000000000000991
    OpenUrlCrossRefPubMed
  14. ↵
    1. Park S,
    2. Bae GE,
    3. Kim J,
    4. Kim HS
    : Mesonephric-like differentiation of endometrial endometrioid carcinoma: Clinicopathological and molecular characteristics distinct from those of uterine mesonephric-like adenocarcinoma. Diagnostics (Basel) 11(8): 1450, 2021. DOI: 10.3390/diagnostics11081450
    OpenUrlCrossRefPubMed
  15. ↵
    1. Park S,
    2. Park E,
    3. Kim HS
    : Mesonephric-like carcinosarcoma of the uterine corpus: Clinicopathological, molecular and prognostic characteristics in comparison with uterine mesonephric-like adenocarcinoma and conventional endometrial carcinosarcoma. Cancer Genomics Proteomics 19(6): 747-760, 2022. DOI: 10.21873/cgp.20357
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Cancer Genome Atlas Research Network,
    2. Kandoth C,
    3. Schultz N,
    4. Cherniack AD,
    5. Akbani R,
    6. Liu Y,
    7. Shen H,
    8. Robertson AG,
    9. Pashtan I,
    10. Shen R,
    11. Benz CC,
    12. Yau C,
    13. Laird PW,
    14. Ding L,
    15. Zhang W,
    16. Mills GB,
    17. Kucherlapati R,
    18. Mardis ER,
    19. Levine DA
    : Integrated genomic characterization of endometrial carcinoma. Nature 497(7447): 67-73, 2013. DOI: 10.1038/nature12113
    OpenUrlCrossRefPubMed
  17. ↵
    1. Kommoss FK,
    2. Karnezis AN,
    3. Kommoss F,
    4. Talhouk A,
    5. Taran FA,
    6. Staebler A,
    7. Gilks CB,
    8. Huntsman DG,
    9. Krämer B,
    10. Brucker SY,
    11. McAlpine JN,
    12. Kommoss S
    : L1CAM further stratifies endometrial carcinoma patients with no specific molecular risk profile. Br J Cancer 119(4): 480-486, 2018. DOI: 10.1038/s41416-018-0187-6
    OpenUrlCrossRefPubMed
  18. ↵
    1. Travaglino A,
    2. Raffone A,
    3. Mollo A,
    4. Borrelli G,
    5. Alfano P,
    6. Zannoni GF,
    7. Insabato L,
    8. Zullo F
    : TCGA molecular subgroups and FIGO grade in endometrial endometrioid carcinoma. Arch Gynecol Obstet 301(5): 1117-1125, 2020. DOI: 10.1007/s00404-020-05531-4
    OpenUrlCrossRefPubMed
  19. ↵
    1. Ravaggi A,
    2. Capoferri D,
    3. Ardighieri L,
    4. Ghini I,
    5. Ferrari F,
    6. Romani C,
    7. Bugatti M,
    8. Zanotti L,
    9. Vrede S,
    10. Tognon G,
    11. Pijnenborg JMA,
    12. Sartori E,
    13. Calza S,
    14. Bignotti E,
    15. Odicino F
    : Integrated biomarker analysis reveals L1CAM as a potential stratification marker for no specific molecular profile high-risk endometrial carcinoma. Cancers (Basel) 14(21): 5429, 2022. DOI: 10.3390/cancers14215429
    OpenUrlCrossRefPubMed
  20. ↵
    1. Van Gool IC,
    2. Stelloo E,
    3. Nout RA,
    4. Nijman HW,
    5. Edmondson RJ,
    6. Church DN,
    7. Mackay HJ,
    8. Leary A,
    9. Powell ME,
    10. Mileshkin L,
    11. Creutzberg CL,
    12. Smit VTHBM,
    13. Bosse T
    : Prognostic significance of L1CAM expression and its association with mutant p53 expression in high-risk endometrial cancer. Mod Pathol 29(2): 174-181, 2016. DOI: 10.1038/modpathol.2015.147
    OpenUrlCrossRefPubMed
  21. ↵
    1. Guo M,
    2. Gong H,
    3. Nie D,
    4. Li Z
    : High L1CAM expression predicts poor prognosis of patients with endometrial cancer: A systematic review and meta-analysis. Medicine (Baltimore) 100(13): e25330, 2021. DOI: 10.1097/MD.0000000000025330
    OpenUrlCrossRefPubMed
  22. ↵
    1. Mirkovic J,
    2. Sholl LM,
    3. Garcia E,
    4. Lindeman N,
    5. Macconaill L,
    6. Hirsch M,
    7. Dal Cin P,
    8. Gorman M,
    9. Barletta JA,
    10. Nucci MR,
    11. Mccluggage WG,
    12. Howitt BE
    : Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract. Mod Pathol 28(11): 1504-1514, 2015. DOI: 10.1038/modpathol.2015.103
    OpenUrlCrossRefPubMed
  23. ↵
    1. Mirkovic J,
    2. McFarland M,
    3. Garcia E,
    4. Sholl LM,
    5. Lindeman N,
    6. MacConaill L,
    7. Dong F,
    8. Hirsch M,
    9. Nucci MR,
    10. Quick CM,
    11. Crum CP,
    12. McCluggage WG,
    13. Howitt BE
    : Targeted genomic profiling reveals recurrent KRAS mutations in mesonephric-like adenocarcinomas of the female genital tract. Am J Surg Pathol 42(2): 227-233, 2018. DOI: 10.1097/pas.0000000000000958
    OpenUrlCrossRefPubMed
  24. ↵
    1. Euscher ED,
    2. Bassett R,
    3. Duose DY,
    4. Lan C,
    5. Wistuba I,
    6. Ramondetta L,
    7. Ramalingam P,
    8. Malpica A
    : Mesonephric-like carcinoma of the endometrium. Am J Surg Pathol 44(4): 429-443, 2020. DOI: 10.1097/pas.0000000000001401
    OpenUrlCrossRefPubMed
  25. ↵
    1. Horn L,
    2. Höhn AK,
    3. Krücken I,
    4. Stiller M,
    5. Obeck U,
    6. Brambs CE
    : Mesonephric-like adenocarcinomas of the uterine corpus: report of a case series and review of the literature indicating poor prognosis for this subtype of endometrial adenocarcinoma. J Cancer Res Clin Oncol 146(4): 971-983, 2020. DOI: 10.1007/s00432-019-03123-7
    OpenUrlCrossRefPubMed
  26. ↵
    1. Howitt BE,
    2. Dong F,
    3. Vivero M,
    4. Shah V,
    5. Lindeman N,
    6. Schoolmeester JK,
    7. Baltay M,
    8. MacConaill L,
    9. Sholl LM,
    10. Nucci MR,
    11. McCluggage WG
    : Molecular characterization of neuroendocrine carcinomas of the endometrium. Am J Surg Pathol 44(11): 1541-1548, 2020. DOI: 10.1097/pas.0000000000001560
    OpenUrlCrossRefPubMed
  27. ↵
    1. Pors J,
    2. Ho J,
    3. Prentice L,
    4. Thompson E,
    5. Cochrane D,
    6. Gibbard E,
    7. Huntsman D,
    8. Gilks B,
    9. Hoang LN
    : c-KIT analysis and targeted molecular sequencing of mesonephric carcinomas of the female genital tract. Am J Surg Pathol 44(4): 495-502, 2020. DOI: 10.1097/pas.0000000000001403
    OpenUrlCrossRefPubMed
    1. Kolin DL,
    2. Costigan DC,
    3. Dong F,
    4. Nucci MR,
    5. Howitt BE
    : A combined morphologic and molecular approach to retrospectively identify KRAS-mutated mesonephric-like adenocarcinomas of the endometrium. Am J Surg Pathol 43(3): 389-398, 2019. DOI: 10.1097/pas.0000000000001193
    OpenUrlCrossRefPubMed
  29. ↵
    1. Pors J,
    2. Segura S,
    3. Chiu DS,
    4. Almadani N,
    5. Ren H,
    6. Fix DJ,
    7. Howitt BE,
    8. Kolin D,
    9. McCluggage WG,
    10. Mirkovic J,
    11. Gilks B,
    12. Park KJ,
    13. Hoang L
    : Clinicopathologic characteristics of mesonephric adenocarcinomas and mesonephric-like adenocarcinomas in the gynecologic tract: a multi-institutional study. Am J Surg Pathol 45(4): 498-506, 2021. DOI: 10.1097/PAS.0000000000001612
    OpenUrlCrossRefPubMed
  30. ↵
    1. Choi S,
    2. Na K,
    3. Kim S,
    4. Kim H
    : Dedifferentiated mesonephric-like adenocarcinoma of the uterine corpus. Anticancer Res 41(5): 2719-2726, 2021. DOI: 10.21873/anticanres.15053
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Suh DH,
    2. Kim MA,
    3. Kim HS,
    4. Chung HH,
    5. Park NH,
    6. Song YS,
    7. Kang SB
    : L1 cell adhesion molecule expression is associated with pelvic lymph node metastasis and advanced stage in diabetic patients with endometrial cancer: a matched case control study. J Cancer Prev 19(3): 231-239, 2014. DOI: 10.15430/JCP.2014.19.3.231
    OpenUrlCrossRefPubMed
  32. ↵
    1. van der Putten LJ,
    2. Visser NC,
    3. van de Vijver K,
    4. Santacana M,
    5. Bronsert P,
    6. Bulten J,
    7. Hirschfeld M,
    8. Colas E,
    9. Gil-Moreno A,
    10. Garcia A,
    11. Mancebo G,
    12. Alameda F,
    13. Trovik J,
    14. Kopperud RK,
    15. Huvila J,
    16. Schrauwen S,
    17. Koskas M,
    18. Walker F,
    19. Weinberger V,
    20. Minar L,
    21. Jandakova E,
    22. Snijders MP,
    23. van den Berg-van Erp S,
    24. Matias-Guiu X,
    25. Salvesen HB,
    26. Amant F,
    27. Massuger LF,
    28. Pijnenborg JM
    : L1CAM expression in endometrial carcinomas: an ENITEC collaboration study. Br J Cancer 115(6): 716-724, 2016. DOI: 10.1038/bjc.2016.235
    OpenUrlCrossRefPubMed
    1. Klat J,
    2. Mladenka A,
    3. Dvorackova J,
    4. Bajsova S,
    5. Simetka O
    : L1CAM as a negative prognostic factor in endometrioid endometrial adenocarcinoma FIGO Stage IA-IB. Anticancer Res 39(1): 421-424, 2019. DOI: 10.21873/anticanres.13128
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Asano H,
    2. Hatanaka KC,
    3. Matsuoka R,
    4. Dong P,
    5. Mitamura T,
    6. Konno Y,
    7. Kato T,
    8. Kobayashi N,
    9. Ihira K,
    10. Nozaki A,
    11. Oku A,
    12. Matsuno Y,
    13. Hatanaka Y,
    14. Watari H
    : L1CAM predicts adverse outcomes in patients with endometrial cancer undergoing full lymphadenectomy and adjuvant chemotherapy. Ann Surg Oncol 27(7): 2159-2168, 2020. DOI: 10.1245/s10434-019-08103-2
    OpenUrlCrossRefPubMed
  35. ↵
    1. Jeong SY,
    2. Cho Y,
    3. Ryu J,
    4. Choi J,
    5. Hwang J,
    6. Kim B,
    7. Lee Y,
    8. Kim H,
    9. Lee J
    : Establishment and preclinical application of a patient-derived xenograft model for uterine cancer. Gynecol Oncol 162(1): 173-181, 2021. DOI: 10.1016/j.ygyno.2021.04.028
    OpenUrlCrossRefPubMed
    1. Koh HH,
    2. Jung YY,
    3. Kim HS
    : Clinicopathological characteristics of gastric-type endocervical adenocarcinoma misdiagnosed as an endometrial, ovarian or extragenital malignancy, or mistyped as usual-type endocervical adenocarcinoma. In Vivo 35(4): 2261-2273, 2021. DOI: 10.21873/invivo.12499
    OpenUrlAbstract/FREE Full Text
    1. Choi S,
    2. Lee YJ,
    3. Choi Y,
    4. Kim M,
    5. Kim HJ,
    6. Kim JE,
    7. Oh S,
    8. Chae SW,
    9. Cha HJ,
    10. Jo JC
    : Prognostic significance of BLK expression in R-CHOP treated diffuse large B-cell lymphoma. J Pathol Transl Med 56(5): 281-288, 2022. DOI: 10.4132/jptm.2022.07.26
    OpenUrlCrossRefPubMed
    1. Jung H,
    2. Yun BS,
    3. Jung YY,
    4. Kim HS
    : Dissecting gonadoblastoma of the ovary coexistent with an atypical endometriotic cyst: Incidental detection in cystectomy specimen of a woman with 46,XX karyotype. Diagnostics (Basel) 12(3): 660, 2022. DOI: 10.3390/diagnostics12030660
    OpenUrlCrossRefPubMed
  39. ↵
    1. Chang S,
    2. Choi YL,
    3. Shim HS,
    4. Lee GK,
    5. Ha SY, Korean Cardiopulmonary Pathology Study Group
    : Usefulness of BRAF VE1 immunohistochemistry in non-small cell lung cancers: a multi-institutional study by 15 pathologists in Korea. J Pathol Transl Med 56(6): 334-341, 2022. DOI: 10.4132/jptm.2022.08.22
    OpenUrlCrossRefPubMed
  40. ↵
    1. Joost P,
    2. Veurink N,
    3. Holck S,
    4. Klarskov L,
    5. Bojesen A,
    6. Harbo M,
    7. Baldetorp B,
    8. Rambech E,
    9. Nilbert M
    : Heterogenous mismatch-repair status in colorectal cancer. Diagn Pathol 9: 126, 2014. DOI: 10.1186/1746-1596-9-126
    OpenUrlCrossRefPubMed
  41. ↵
    1. Geels YP,
    2. Pijnenborg JM,
    3. Gordon BB,
    4. Fogel M,
    5. Altevogt P,
    6. Masadah R,
    7. Bulten J,
    8. van Kempen LC,
    9. Massuger LF
    : L1CAM expression is related to non-endometrioid histology, and prognostic for poor outcome in endometrioid endometrial carcinoma. Pathol Oncol Res 22(4): 863-868, 2016. DOI: 10.1007/s12253-016-0047-8
    OpenUrlCrossRefPubMed
  42. ↵
    1. Huszar M,
    2. Pfeifer M,
    3. Schirmer U,
    4. Kiefel H,
    5. Konecny GE,
    6. Ben-Arie A,
    7. Edler L,
    8. Münch M,
    9. Müller-Holzner E,
    10. Jerabek-Klestil S,
    11. Abdel-Azim S,
    12. Marth C,
    13. Zeimet AG,
    14. Altevogt P,
    15. Fogel M
    : Up-regulation of L1CAM is linked to loss of hormone receptors and E-cadherin in aggressive subtypes of endometrial carcinomas. J Pathol 220(5): 551-561, 2010. DOI: 10.1002/path.2673
    OpenUrlCrossRefPubMed
  43. ↵
    1. Zeimet AG,
    2. Reimer D,
    3. Huszar M,
    4. Winterhoff B,
    5. Puistola U,
    6. Abdel Azim S,
    7. Müller-Holzner E,
    8. Ben-Arie A,
    9. Van Kempen LC,
    10. Petru E,
    11. Jahn S,
    12. Geels YP,
    13. Massuger LF,
    14. Amant F,
    15. Polterauer S,
    16. Lappi-Blanco E,
    17. Bulten J,
    18. Meuter A,
    19. Tanouye S,
    20. Oppelt P,
    21. Stroh-Weigert M,
    22. Reinthaller A,
    23. Mariani A,
    24. Hackl W,
    25. Netzer M,
    26. Schirmer U,
    27. Vergote I,
    28. Altevogt P,
    29. Marth C,
    30. Fogel M
    : L1CAM in early-stage Type I endometrial cancer: Results of a large multicenter evaluation. J Natl Cancer Inst 105(15): 1142-1150, 2013. DOI: 10.1093/jnci/djt144
    OpenUrlCrossRefPubMed
  44. ↵
    1. Kommoss F,
    2. Kommoss F,
    3. Grevenkamp F,
    4. Bunz A,
    5. Taran F,
    6. Fend F,
    7. Brucker SY,
    8. Wallwiener D,
    9. Schönfisch B,
    10. Greif K,
    11. Lax S,
    12. Staebler A,
    13. Kommoss S
    : L1CAM: amending the “low-risk” category in endometrial carcinoma. J Cancer Res Clin Oncol 143(2): 255-262, 2017. DOI: 10.1007/s00432-016-2276-3
    OpenUrlCrossRefPubMed
  45. ↵
    1. Kim HG,
    2. Kim H,
    3. Yeo MK,
    4. Won KY,
    5. Kim YS,
    6. Han GH,
    7. Kim HS,
    8. Na K
    : Mesonephric-like adenocarcinoma of the uterine corpus: Comprehensive analyses of clinicopathological, molecular, and prognostic characteristics with retrospective review of 237 endometrial carcinoma cases. Cancer Genomics Proteomics 19(4): 526-539, 2022. DOI: 10.21873/cgp.20338
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Arciuolo D,
    2. Travaglino A,
    3. Raffone A,
    4. Raimondo D,
    5. Santoro A,
    6. Russo D,
    7. Varricchio S,
    8. Casadio P,
    9. Inzani F,
    10. Seracchioli R,
    11. Mollo A,
    12. Mascolo M,
    13. Zannoni GF
    : TCGA molecular prognostic groups of endometrial carcinoma: Current knowledge and future perspectives. Int J Mol Sci 23(19): 11684, 2022. DOI: 10.3390/ijms231911684
    OpenUrlCrossRefPubMed
  47. ↵
    1. Travaglino A,
    2. Raffone A,
    3. Gencarelli A,
    4. Mollo A,
    5. Guida M,
    6. Insabato L,
    7. Santoro A,
    8. Zannoni GF,
    9. Zullo F
    : TCGA classification of endometrial cancer: the place of carcinosarcoma. Pathol Oncol Res 26(4): 2067-2073, 2020. DOI: 10.1007/s12253-020-00829-9
    OpenUrlCrossRefPubMed
  48. ↵
    1. Nassar A,
    2. Radhakrishnan A,
    3. Cabrero IA,
    4. Cotsonis GA,
    5. Cohen C
    : Intratumoral heterogeneity of immunohistochemical marker expression in breast carcinoma. Appl Immunohistochem Mol Morphol 18(5): 433-441, 2010. DOI: 10.1097/pai.0b013e3181dddb20
    OpenUrlCrossRefPubMed
    1. Kahn AM,
    2. Golestani R,
    3. Harigopal M,
    4. Pusztai L
    : Intratumor spatial heterogeneity in programmed death-ligand 1 (PD-L1) protein expression in early-stage breast cancer. Breast Cancer Res Treat 201(2): 289-298, 2023. DOI: 10.1007/s10549-023-06977-1
    OpenUrlCrossRefPubMed
    1. He X,
    2. Zhao D,
    3. Zhang X,
    4. Ma Y,
    5. Zhang R,
    6. Huang Z,
    7. Wang G,
    8. Guo G,
    9. Wang W,
    10. Wen Y,
    11. Zhang L
    : Intrinsic immunogenic tumor cell death subtypes delineate prognosis and responsiveness to immunotherapy in lung adenocarcinoma. Biology (Basel) 12(6): 808, 2023. DOI: 10.3390/biology12060808
    OpenUrlCrossRefPubMed
    1. Ghosh D,
    2. Hsu J,
    3. Soriano K,
    4. Peña CM,
    5. Lee AH,
    6. Dizon DS,
    7. Dawson MR
    : Spatial heterogeneity in cytoskeletal mechanics response to TGF-β1 and hypoxia mediates partial epithelial-to-meshenchymal transition in epithelial ovarian cancer cells. Cancers (Basel) 15(12): 3186, 2023. DOI: 10.3390/cancers15123186
    OpenUrlCrossRefPubMed
    1. Bian S,
    2. Wang Y,
    3. Zhou Y,
    4. Wang W,
    5. Guo L,
    6. Wen L,
    7. Fu W,
    8. Zhou X,
    9. Tang F
    : Integrative single-cell multiomics analyses dissect molecular signatures of intratumoral heterogeneities and differentiation states of human gastric cancer. Natl Sci Rev 10(6): nwad094, 2023. DOI: 10.1093/nsr/nwad094
    OpenUrlCrossRefPubMed
  53. ↵
    1. Wątor G,
    2. Seweryn M,
    3. Kapusta P,
    4. Świrta J,
    5. Wałęga P,
    6. Barczyński M,
    7. Wołkow PP
    : Intratumor heterogeneity in colorectal cancer: Distribution of tumor suppressor gene variants with regard to patient lymph node status. Clin Genet, 2023. DOI: 10.1111/cge.14388
    OpenUrlCrossRef
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Mesonephric-like Adenocarcinoma of the Uterine Corpus: Clinicopathological and Prognostic Significance of L1 Cell Adhesion Molecule (L1CAM) Over-expression
SUHO PARK, YUNJOO CHO, HYUN-SOO KIM
Anticancer Research Oct 2023, 43 (10) 4559-4571; DOI: 10.21873/anticanres.16650
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords