Microcystic, Elongated, And Fragmented Research Articles

Utility of immunocytochemistry in diagnosing abdominopelvic washings from patients undergoing radical surgery for endometrial cancer.

This study aimed to explore the efficacy of immunocytochemistry in diagnosing abdominopelvic washings (APWs) and evaluate the superiority of cytology combined with immunocytochemistry over cytology alone. Data on APW cytology and available cell blocks from patients who underwent radical surgery for endometrial cancer between January 2021 and December 2022 were reviewed. Cytology was re-evaluated according to a five-tier system. Immunocytochemistry analysis for targets such as Sry box transcription factor 1(SOX17), Paired box gene 2 (Pax-2) protein, Phosphatase and tensin (PTEN), and β-catenin was performed on each case with non-negative cytology. Mismatch repair (MMR) protein and P53 immunocytochemistry analyses were performed using cell blocks from cases with abnormal MMR or P53 expression in their primary lesion. The accuracies of cytology combined with immunocytochemistry and cytology alone were calculated. Overall, 126 patients were included in this study, 18 of whom demonstrated non-negative cytology of APW. Cell blocks were successfully prepared for 16 cases. SOX17 positivity was observed in 16 cases, including 1 of serous carcinoma, 1 of clear cell carcinoma, and 14 of endometrioid carcinoma (EC). Loss of Pax-2 and PTEN expression was observed in the APWs of the 14 patients with EC. MMR deficiency was noted in two patients with EC, and P53 mutation was noted in another two patients with EC. Compared with 10 metastatic carcinomas (10/18, 55.56%) diagnosed by cytology alone, 15 malignant APWs (15/18, 83.33%) were confirmed through combination cytology and immunocytochemistry. APWs were more likely to be observed in cases with more than half myometrial invasion than those with no or less than half myometrial invasion (P = 0.0067). The probability of malignant APW occurrence was slightly elevated in cases of EC exhibiting microcystic, elongated, and fragmented(MELF) infiltrative growth (P = 0.039). SOX17 is a useful Müllerian marker for distinguishing endometrial epithelium in APW. Loss of Pax-2 and PTEN expression offers evidence of metastatic endometrial carcinoma. Furthermore, positive APWs retained molecular features similar to primary lesions. The use of multiple immunocytochemical markers can effectively enhance the diagnostic efficiency of APWs.

Accuracy of MRI in predicting deep myometrial invasion in endometrial cancer and the influence of leiomyoma, adenomyosis and the microcystic elongated and fragmented tumour pattern.

The most common form of endometrial cancer is Type 1 endometrioid adenocarcinoma. Depth of myometrial invasion is the most important prognostic factor correlating with overall patient survival. The objective was to investigate how accurate magnetic resonance imaging (MRI) is in predicting the depth of myometrial invasion in preoperative assessment, and the influence of leiomyoma and/or adenomyosis, or microcystic, elongated and fragmented (MELF) pattern of invasion on MRI diagnostic performance. Retrospective audit of 235 endometrial cancer patients from the regional Gynaecology Oncology multidisciplinary meeting at Auckland City Hospital, between January 2020 and January 2021. Radiologist assigned stage was compared to histopathology. Presence of leiomyoma, adenomyosis andMELF pattern evaluated followed by analysis under a Biostatistician's supervision. Overall MRI diagnostic accuracy for depth of myometrial invasion was 86%. For deep myometrial invasion, MRI had a sensitivity of 72% and specificity 91%. Out of the misreported 32/235 cases, 16 demonstrated fibroids and/or adenomyosis leading to a sensitivity of 57% and specificity 93% for deep invasion, compared with 94% and 74% respectively in the population without, demonstrating statistical significance. Thirty seven cases with MELF pattern of invasion showed a sensitivity of 81% and specificity 80% for deep invasion, compared with 63% and 92% respectively in the group without, demonstrating no statistical significance. MRI assessment of the depth of myometrial invasion in endometrial cancer has high accuracy. In the presence of background uterine fibroids/adenomyosis, pre-operative MRI accuracy of evaluating deep invasion shows a statistically significant reduction.

Endocervical Adenocarcinoma Showing Microcystic, Elongated, and Fragmented (MELF) Pattern of Stromal Invasion: A Single-Institutional Analysis of 10 Cases with Comprehensive Clinicopathological Analyses and Ki-67 Immunostaining.

Microcystic, elongated, and fragmented (MELF) pattern of invasion has seldom been documented in endocervical adenocarcinoma (EAC). The aim of this study was to analyze the clinicopathological characteristics of EAC showing MELF pattern. We collected the clinicopathological information of 10 cases of EAC with the MELF pattern and conducted polymer-based immunostaining for Ki-67 (dilution 1:200, clone MIB-1) on these cases. Ki-67 expression was assessed using the average estimation within the hotspot method. All tumors were human papillomavirus-associated EAC with Silva pattern C. All except one tumor exceeded 3 cm in size. Five tumors involved the entire thickness of the cervical stroma, and four tumors extended into the parametrium. Lymphovascular space invasion was identified in six cases. Two patients developed metastatic recurrences in the para-aortic lymph nodes and lungs, respectively. The MELF area showed significantly lower Ki-67 labelling index than that of a conventional tumor area. We confirmed our previous observation that the MELF area displayed lower proliferative activity than the conventional tumor area of EAC. We also demonstrated that patients with EAC showing MELF pattern had several adverse clinicopathological characteristics reflecting aggressive behavior. On the other hand, since the frequencies of post-operative recurrence and disease-related mortality that occurred during the follow-up period were relatively low, further investigations are warranted to clarify the prognostic value of MELF pattern in EAC patients.

Molecular Classification of Endometrial Endometrioid Carcinoma With Microcystic Elongated and Fragmented Pattern.

The studies on the molecular classification of endometrioid carcinoma (EC) with microcystic, elongated, and fragmented (MELF) pattern invasion are limited. In this study, 77 cases of ECs with MELF patterns in Chinese women were collected. The molecular classification of the fifth edition of the World Health Organization was used to classify the molecular subtypes using immunohistochemistry staining (mismatch repair [MMR]-immunohistochemistry: MSH2, MSH6, MLH1, and PMS2; p53) and Sanger sequencing targeted POLE . The results showed that the prevalence of the 4 molecular subtypes in EC with MELF pattern was 6.5% (5/77) for POLE mutation, 20.8% (16/77) for MMR deficient, 11.7% (9/77) for p53-mutant, and 61.0% (47/77) for no specific molecular profile. The clinicopathological characteristics of each subtype were compared. The p53-mutant and no specific molecular profile subgroups were associated with higher International Federation of Gynecology and Obstetrics stage and International Federation of Gynecology and Obstetrics grade, deeper myometrial invasion, lymphovascular space invasion, lymph node metastasis, and absence of tumor-infiltrating lymphocytes, whereas the POLE mutation and MMR deficient subgroups were associated with lower aggressive features and prominent tumor-infiltrating lymphocytes. Progression-free survival showed that the p53-mutant and no specific molecular profile subgroups had a poorer prognosis than the POLE mutation and MMR deficient subgroups. However, lymph node metastasis was an independent factor associated with a higher risk of disease recurrence in multivariate analysis. In conclusion, ECs with MELF patterns can be divided into 4 molecular subtypes with discrepancies in aggressive clinicopathological characteristics and tumor-infiltrating lymphocytes. Molecular classification has clinical significance in a morpho-molecular approach for ECs with MELF patterns.

Microcystic, elongated and fragmented (MELF) pattern in endometrial carcinoma: clinicopathologic analysis and prognostic implications.

To assess the clinical value of microcystic, elongated, and fragmented (MELF) pattern in Chinese patients with endometrial endometrioid carcinoma. A total of 189 patients with endometrial endometrioid carcinoma were retrospectively analyzed in Peking University Third Hospital from January 2017 to December 2019. We analyzed the association of MELF pattern with the histopathologic data and prognosis of the patients, while immunohistochemistry was performed. The frequency of MELF pattern was 17.99% (34/189). MELF pattern was associated significantly with tumor size, myometrial invasion, histological grade, International Federation of Gynecology and Obstetrics stages, lymphovascular space invasion, and lymph node metastasis. According to multivariate logistic regression analysis, lymphovascular space invasion [95% confidence interval 1.021-48.485, P = .048] was a significant predictor of lymph node involvement. However, MELF pattern was not a significant predictor (95% confidence interval 0.054-2.279, P = .400). Loss of expression for mismatch repair proteins was observed in 10 MELF + cases (29.41%) and 54 MELF- cases (34.84%), respectively. All patients were followed up for 36.8 ± 8.9 months (18-54 months). Only 1 patient with MELF pattern was diagnosed with vaginal recurrence 28 months after the surgery. MELF pattern was associated with adverse histologic findings in endometrial endometrioid carcinomas. However, MELF pattern was statistically not a valuable predictor of lymph node metastasis and it needs more studies to show whether MELF pattern has an impact on the prognosis of patients with endometrial endometrioid carcinoma. MELF pattern may be important for identifying those patients who need comprehensive staging surgery.

Endometrial carcinomas with dyshesive, eosinophilic, and vacuolated (histiocyte-like) tumor cells: a reactive-like phenotype associated with aggressive behavior.

Herein, we present a clinicopathological and molecular analysis of four cases of endometrial carcinoma (EC) diffusely exhibiting dyshesive cells with wide eosinophilic and vacuolated cytoplasm (histiocyte-like tumor cells, HLTCs). We compared these HLTCs to similar cells found in microcystic, elongated and fragmented (MELF) pattern (n = 20) or after neoadjuvant chemotherapy (NAC) (n = 5). The four cases were endometrioid, serous, clear cell, and gastric-type; all were at FIGO stage ≥ III. HLTCs showed an epithelial Müllerian phenotype and at least focal CK20, HNF1β, and CK5/6 expression, with aberrant e-cadherin and β-catenin expression; two cases were MMR-deficient, and one was p53-abnormal; all were POLE wild type. MELF-associated and NAC-associated HLTCs showed similar morphological/immunophenotypical features. However, MELF-associated HLTCs were mainly intraglandular and inflammation-associated, did not form a distinct tumor component, and showed no relationship with lymph node metastases. In conclusion, different histotypes of EC may show a prominent HLTC component, which shows peculiar morphological/immunophenotypical features and appears associated with aggressive behavior.

L1CAM Expression in Microcystic, Elongated, and Fragmented (MELF) Glands Predicts Lymph Node Involvement in Endometrial Carcinoma.

Simple SummaryL1CAM overexpression (≥10%) and the microcystic, elongated, and fragmented (MELF) pattern of invasion have previously been assessed as prognostic factors in endometrial carcinoma. We aimed to assess the relationship between L1CAM expression, MELF glands, and lymph node involvement in endometrial carcinoma, as all these factors are related to epithelial-to-mesenchymal transition. We evaluated L1CAM expression in 58 cases of uterine-confined, low-grade endometrioid carcinomas. We found that most cases (65.5%) expressed L1CAM in a limited manner to MELF glands. Cases with L1CAM expression in ≥10% of the MELF component showed a significantly higher tendency to lymph node spread (p < 0.001), even when adjusted for lymphovascular space invasion, depth of myometrial invasion and p53/mismatch repair status. On this account, L1CAM expression in the MELF component may stratify the prognosis and management in patients with uterine-confined, low-grade carcinomas.In endometrial carcinoma, both L1CAM overexpression and microcystic, elongated and fragmented (MELF) patterns of invasion have been related to epithelial-to-mesenchymal transition and metastatic spread. We aimed to assess the association between L1CAM expression, the MELF pattern, and lymph node status in endometrial carcinoma. Consecutive cases of endometrial carcinoma with MELF pattern were immunohistochemically assessed for L1CAM. Inclusion criteria were endometrioid-type, low-grade, stage T1, and known lymph node status. Uni- and multivariate logistic regression were used to assess the association of L1CAM expression with lymph node status. Fifty-eight cases were included. Most cases showed deep myometrial invasion (n = 42, 72.4%) and substantial lymphovascular space invasion (n = 34, 58.6%). All cases were p53-wild-type; 17 (29.3%) were mismatch repair-deficient. Twenty cases (34.5%) had positive nodes. No cases showed L1CAM positivity in ≥10% of the whole tumor. MELF glands expressed L1CAM at least focally in 38 cases (65.5%). L1CAM positivity in ≥10% of the MELF component was found in 24 cases (41.4%) and was the only significant predictor of lymph node involvement in both univariate (p < 0.001) and multivariate analysis (p < 0.001). In conclusion, L1CAM might be involved in the development of the MELF pattern. In uterine-confined, low-grade endometrioid carcinomas, L1CAM overexpression in MELF glands may predict lymph node involvement.

Microcystic elongated and fragmented (MELF) pattern of invasion: Molecular features and prognostic significance in the PORTEC-1 and -2 trials

ObjectiveMicrocystic, elongated fragmented (MELF) pattern of myometrial invasion is a distinct histologic feature occasionally seen in low-grade endometrial carcinomas (EC). The prognostic relevance of MELF invasion was uncertain due to conflicting data, and it had not yet appropriately been studied in the context of the molecular EC classification. We aimed to determine the relation of MELF invasion with clinicopathological and molecular characteristics, and define its prognostic relevance in early-stage low/intermediate risk EC. MethodsSingle whole tumor slides of 979 (85.8%) out of 1141 (high)intermediate-risk EC of women who participated in the PORTEC-1/−2 trials were available for review. Clinicopathological and molecular features were compared between MELF invasion positive and negative cases. Time-to-event analyses were done by Kaplan-Meier method, log-rank tests and Cox’ proportional hazards models. ResultsMELF invasion was found in 128 (13.1%) cases, and associated with grade 1–2 histology, deep myometrial invasion and substantial lymph-vascular space invasion (LVSI). 85.6% of MELF invasion positive tumors were no-specific-molecular-profile (NSMP) EC. NSMP EC with MELF invasion were CTNNB1 wild type in 92.2% and KRAS mutated in 24.4% of cases. Risk of recurrence was lower for MELF invasion positive as compared to MELF invasion negative cases (4.9% vs. 12.7%, p = 0.026). However, MELF invasion had no independent impact on risk of recurrence (HR 0.65, p = 0.30) after correction for clinicopathological and molecular factors. ConclusionsMELF invasion has no independent impact on risk of recurrence in early-stage EC, and is frequently observed in low-grade NSMP tumors. Routine assessment of MELF invasion has no clinical implications and is not recommended.

Clinicopathologic association and prognostic impact of microcystic, elongated and fragmented pattern invasion, combined with tumor budding in endometrioid endometrial cancer.

As a special invasive pattern seen in low-grade endometrial carcinoma, microcystic, elongated and fragmented (MELF) pattern is related to lymph node metastasis. Tumor budding (TB) is another histological marker in many cancers associated with tumor aggressiveness. Herein, we evaluated the impact of MELF pattern combined with TB about clinicopathological features and prognosis in endometrioid endometrial cancer (EEC). To verify the relationship between the two morphological markers and microsatellite status in EEC, the primary mismatch repair (MMR) proteins were detected by immunohistochemistry. One hundred and seventy-two cases of ECC diagnosed between 2011 and 2016 were reviewed with a median follow up of 47.5months. MELF pattern and TB were examined on all H&E-stained slides. Primary MMR proteins (MLH1, MSH2, MSH6, and PMS2) were also detected. Based on MELF pattern and TB, 172 patients were divided into the following four groups: MELF(-)/TB(+) (n=41), MELF(+)/TB(-) (n=15), MELF(+)/TB(+) (n=20), and MELF(-)/TB(-) (n=96). Adverse pathological features were observed in the MELF(+)/TB(+) group: 70% presented deep muscular infiltration, 65% were lymphovascular space invasion, and 25% suffered lymph node metastasis. The proportion of MMR deficient in MELF(+)/TB(-) group was the highest (66.7%). The progression-free survival (PFS) and overall survival (OS) among the four groups were significantly different. MELF(+)/TB(+) group showed the worst PFS and OS. As univariate and multivariate survival analyses revealed, the combination of MELF pattern and TB was confirmed as an independent predictor of poor prognosis. Our research demonstrates that MELF pattern combined with TB, as an independent predictor of adverse outcome, is associated with adverse pathological features, which facilitates better understanding of EEC tumor behavior and more precise prognosis without additional medical expense.

Clinicopathological Prognostic Parameters of Endometrioid Endometrial Carcinomas.

Endometrioid endometrial carcinomas (EEC) are common malignant lesions of the female genital tract, with incidence and risk factors that raise issues to improve histopathological prognostic factors. The study included 50 EEC cases, for which the clinicopathological parameters represented by age, risk factors, tumor grade, histological differences, invasion pattern, tumor stage and association of endometrial hyperplasia were analyzed statistically. The results indicated the predominance of EEC in the 7th decade of life, with associated risk factors (78%), more frequently well differentiated (52%), with no other specifications related to differentiation (NOS, 60%), with irregular invasion pattern (66%) in<50% of the myometrial wall (48%). Irregular pattern, microcystic, elongated, and fragmented (MELF) pattern and myoinvasion associated with vascular invasion (MVI) pattern were significantly associated with high grade and advanced stage tumors. With the exception of EEC-NOS and squamous differentiation, all other tumors were associated with low grade (G1). In this study there was a tendency to associate the age group of 60-69 years with the presence of endometrial hyperplasia and with high grade and advanced stage. Apart from the high grade and advanced stage, in the aggressive profile of the EEC can be included as the clinicopathological parameters the 7th decade of life and the irregular, MELF and MVI invasion patterns.

Is microcystic, elongated, and fragmented pattern of myometrial invasion in endometrioid endometrial carcinoma associated with survival?

Microcystic, elongated, and fragmented (MELF) pattern is one of the myometrial invasion patterns in endometrioid endometrial carcinoma (EEC), and it has been associated with poor prognostic parameters, especially lymphovascular space invasion (LVSI) and lymph node metastasis (LNM). This study aims to represent the frequency of MELF pattern in EEC and the relationship between MELF pattern with clinicopathological parameters, overall survival (OS), and disease-free survival (DFS). In this retrospective cohort study, we examined 233 patients with EEC diagnoses with the result of a total hysterectomy and bilateral salpingo-oophorectomy between 2009 and 2014. The association of MELF pattern with risk factors such as stage, recurrence, and survival was analysed statistically with the comparison of MELF positive and negative cases. MELF pattern was seen in 21.8% of all cases (51/233) and 23% of grade 1-2 cases (50/217). The MELF pattern showed a significant difference among patients when they were compared according to advanced age (≥60) (p = 0.022), LVSI (p = 0.021), deep myometrial invasion (p < 0.01), LNM (p = 0.027), and advanced FIGO stage (p = 0.043). MELF pattern was a predictive factor of LNM in univariate logistic regression analysis but did not show significance in multivariate analysis. The Kaplan-Meier survival analysis showed that MELF positive cases had reduced OS (66.7% vs 79.7% p = 0.003) and DFS (66.7% vs 77.5% p = 0.017) rates. In the univariate analyses, MELF pattern was an independent prognostic factor on OS and DFS along with other parameters, while it was not observed to maintain this effect in the multivariate analyses. This study is one of the largest series examining the relationship between MELF pattern of myometrial invasion and survival, and our results represented that the MELF pattern is associated with the worse clinical outcome since it is associated with lymphovascular space invasion, deep myometrial invasion, lymph node metastasis, and reduced overall survival and disease-free survival rates. Although the presence of MELF pattern is not reported in routine practice, it may be used as an indicator that will help predict a worse outcome.

PATTERNS OF MYOINVASION IN ENDOMETRIOID ADENOCARCINOMA OF ENDOMETRIUM

Objective: To assess the patterns of myoinvasion of endometrial endometrioid adenocarcinoma, their frequencies in our hospital and to correlate these patterns with survival.&#x0D; Study Design: Retrospective observational study.&#x0D; Place and Duration of Study: Department of Pathology, Shaukat Khanum Memorial Cancer Hospital &amp; Research Centre, Lahore, from Aug 2019 to Apr 2020.&#x0D; Methodology: All cases of endometrial endometrioid adenocarcinoma between 2015 and 2017 were retrieved from the archives, independently reviewed by two researchers, all key reporting parameters recorded in addition to the pattern of myoinvasion as per their operational definitions described by Cole and Quick. The follow-up of 3-5 years was obtained from archives and through telephonic contact for outside hospital patients. Disease free survival and relapse-associated mortality were represented through Kaplan-Meier curves.&#x0D; Results: Eighty cases of myoinvasive endometrial endometrioid adenocarcinoma were reviewed. We found that infiltrating irregular gland pattern was the most frequent in all the age groups. Thirty-five (43.75%) cases showed this type of invasion, followed by broad front pattern 23 (28.75%), Microcystic Elongated and Fragmented (MELF) pattern 15 (18.75%) and adenomyotic pattern 6 (7.5%). One case showed a combination of the last two patterns, whereas adenoma malignum pattern was not seen. Follow-up of these patients showed 8 (10%) patients with relapse related mortality including 5 (62.5%) infiltrating irregular glands, 2 (25%) adenomyosis-like and 1 (12.5%) broad front pattern of myoinvasion. Seventy-two (90%) patients had recurrence free survival.&#x0D; Conclusion: Frequency of infiltrating irregular pattern of myoinvasion in endometrial endometrioid adenocarcinoma is high and associated with recurrence related mortality. Recognition....................

Strong expression of PD-L1 in invasive front of MELF pattern in endometrioid carcinoma

Endometrioid carcinoma (EC) is classified into 3 histological subtypes; Grade 1 (G1), Grade 2 (G2), and Grade 3 (G3). Although the prognosis is relatively good in G1, some G1 cases are more aggressive, which are called G1 with MELF (microcystic, elongated, and fragmented) pattern. Current therapy, such as radiotherapy and chemotherapy, is not effective in MELF, and more effective treatment is needed. The Cancer Genome Atlas (TCGA) performed an integrated genomic, transcriptomic, and proteomic analysis and classified EC into 4 groups: DNA polymerase epsilon (POLE) ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high, in which MELF was associated with microsatellite instability hypermutated. Microsatellite instability is detected in a wide variety of cancer, and PD-1 (programmed cell death 1) and PD-L1 (programmed cell death-ligand 1) are received a lot of attention as a therapeutic target. To date, no studies have been focused on PD-L1 expression in EC with MELF pattern. Then we performed immunohistochemical analysis of the distribution of PD-L1 expressing cells in G1 with MELF pattern. In cases of G1 with MELF pattern, tumor cells expressed PD-L1 significantly higher in invasive front area than in surface area. We often found lymphovascular invasion of PD-L1 expressing tumor cells. PD-L1 expressing tumor cells in MELF would be the cause of recurrence or lymph node metastasis. Moreover, in most G1 cases with MELF pattern, PD-L1 was expressed in inflammatory cells as well as tumor cells in invasive front area. PD-L1 expression in both tumor and immune cells contribute to immune suppression and both cells could be sensitive to therapeutic agents targeting the PD-L1/PD-1 axis. Therefore, significant therapeutic effect can be expected by applying PD-1/PD-L1 immunotherapy to the treatment of G1 with MELF.

Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma.

Grade 1 (G1) endometrioid carcinoma (EC) is relatively a good prognosis. However, in a minority of cases, G1 shows an aggressive histological pattern known as the microcystic, elongated, and fragmented (MELF) pattern. We previously reported that EC with high expression levels of S100A4 and serum deprivation‐response protein (SDPR) was related to MELF pattern invasion. However, the molecular features of the invasive front area of the MELF pattern have not been investigated. In this study, we searched for genes preferentially expressed in the invasive front area of EC with the MELF pattern using laser microdissection and RNA sequencing, and showed that nicotinamide N‐methyltransferase (NNMT) is related to MELF pattern invasiveness. Immunohistochemical analyses confirmed high NNMT expression in the invasive front area of the MELF pattern. Moreover, NNMT promoted migration, invasion, colony formation, epithelial–mesenchymal transition (EMT), and chemoresistance using EC cell lines. We speculate that depletion of NNMT promotes histone methylation and leads to tumor suppression because NNMT consumes S‐adenosyl methionine (SAM), which is an essential methylation cofactor. NNMT knockout cells showed enhanced expression of H3K9me2. RNA sequencing using NNMT knockout cell lines suggested that methylation of H3K9 leads to repression of the transcription of various oncogenic genes. Our findings demonstrate the possibility that NNMT inhibitors, which are expected to be used for the treatment of metabolic disorders, would be effective for the treatment of aggressive EC. This is the first report of gene analyses focusing on the morphological changes associated with MELF pattern invasion of EC.

Patterns of Myometrial Invasion in Endometrial Adenocarcinoma with Emphasizing on Microcystic, Elongated and Fragmented (MELF) Glands Pattern: A Narrative Review of the Literature

Endometrioid endometrial adenocarcinoma (EEC) is the most common malignancy of the female genital tract. According to the 2009 FIGO staging system, the depth of myometrial invasion (MI), and tumor spread to adjacent organs or tissues are the staging criteria for endometrial carcinoma (EC). Therefore, assessment of the depth of MI is of great importance. There is a spectrum of morphological patterns of MI. Still, their number and features vary according to the scientific literature, with a certain overlap that creates difficulties and controversies in the precise assessment of MI depth. The purpose of this review is to present and discuss the most important and recent information about patterns of MI, focusing on the more aggressive and the elongated and fragmented glands (MELF) pattern in particular. Assessment of MI depth and correct staging of EC is possible only after the precise recognition of each MI pattern.

Prognostic significance of tumor budding, poorly differentiated cluster, and desmoplastic reaction in endometrioid endometrial carcinomas

The tumor budding (TB); poorly differentiated cluster (PDC); desmoplastic reaction (DR); and microcystic, elongated, and fragmented (MELF) patterns of invasion are pathological findings at the tumor invasion front associated with epithelial-to-mesenchymal transition. This study aimed to clarify the clinical significance of the TB, PDC, DR, and MELF patterns in endometrioid endometrial carcinomas (EEC). Two hundred and eight cases of histologically proven EEC retrieved from the archives of the Department of Pathology, Fukui Prefectural Hospital, and diagnosed between January 2000 and August 2020 were retrospectively analyzed. The TB, PDC, DR, and MELF patterns were identified in 29 (13.9%), 47 (22.6%), 45 (21.6%), and 23 (11.1%) cases, respectively. Kaplan-Meier curve analysis with log-rank test demonstrated that TB, PDC, and DR were associated with a lower progression-free survival (p=0.010, 0.002, and <0.0001, respectively), whereas the MELF pattern did not show any association (p=0.668). In multivariate analyses, only DR was significantly associated with lower progression-free survival (p=0.034). Moreover, only PDC was associated with lower overall survival in univariate analysis (p=0.018), but the association lost significance in multivariate analysis. The present study revealed that the histological confirmation of TB, PDC, and DR at the tumor invasive front predicts poor prognosis in EEC. However, the MELF pattern was not a predictor of poor prognosis in EEC.

Risk of recurrence in patients with MELF (microcystic, elongated and fragmented) pattern of invasion based on lymph node evaluation status

Objectives: Background. Myometrial invasion with an infiltrative gland pattern has been recently associated with higher stage, lymphovascular invasion, and recurrence. Additionally, a readily recognizable pattern of myometrial invasion characterized by microcystic elongated and fragmented (MELF) glands surrounded by myxoid and inflamed stroma has been associated with lymphovascular invasion (LVSI) and lymph node metastases. Although it is known that MELF increases the risk of a patient having lymph node metastases as well as MELF being associated with LVSI, we sought to understand whether MELF without lymph node metastases or lymphadenctomy portends a worse oncologic prognosis. Methods: We retrospectively reviewed all patients with endometrial cancer who underwent hysterectomy at a single institution between Jan 1, 2010 to Aug 1, 2020 with MELF pattern of invasion identified. Pathology was reviewed by a single reviewer (RM) with subspecialty training in gynecologic pathology. The electronic medical record was utilized to obtain preoperative, perioperative, and follow-up data. These patients were divided based on if they had not had a lymph node evaluation (Group A) or by the performance of lymph node evaluation (Group B). Results: Forty-one patients were identified as having MELF on their hysterectomy specimen. All patients had well-differentiated to moderately differentiated tumors. There was a similar proportion of patients how had LVSI in either group (Group A 80% vs Group B 92.3%). In this cohort, 63.4% underwent an evaluation of the retro-peritoneal lymph nodes, with 92.3% having a complete lymphadenectomy [Table 1]. As compared to Group B where only 7.7% had no adjuvant treatment, 53.3% in Group A were observed. No patients recurred in Group B, while 20% recurred in those without any lymph node evaluation. Looking specifically at the patients who had MELF without lymphadenectomy and recurred, all 3 patients had LVSI and were early stage, thus were at high risk for lymph node involvement. Download : Download high-res image (332KB) Download : Download full-size image Conclusions: In our study, patients with MELF pattern of invasion without lymph node evaluation at the time of hysterectomy were more likely to have no adjuvant therapy and recur than those who underwent lymphadenectomy. Additional multi-institution study should be done to further elucidate the nuances associated with MELF with and without LVSI in patients with early stage endometrial cancer who have undergone lymphadenectomy as this uterine characteristic is not factored in to any of our phase III randomized data.

Sentinel Nodal Metastasis Detection in Endometrial Carcinoma With Microcystic, Elongated, and Fragmented (MELF) Pattern by Cytokeratin Immunostaining.

The microcystic, elongated, and fragmented (MELF) pattern of myoinvasion in endometrial carcinoma (EC) is associated with an increased risk of lymph node metastasis. Our aim is to assess the role of cytokeratin immunohistochemical (IHC) stains in detecting sentinel nodal metastasis in MELF pattern tumors. We recovered 19 MELF pattern EC hysterectomies with lymphadenectomy from our files. Negative nodes were subjected to cytokeratin AE1/AE3 IHC. Ten additional cases with sentinel lymph node (SLN) biopsies primarily assessed by IHC were also analyzed. Of the 19 cases of EC, 6 had positive lymph nodes based on H&E-stained sections at the time of their initial diagnosis. With the addition of IHC stains, 8 previously negative cases were found to have node metastases, and 3 of these were SLNs. Among the 10 cases primarily assessed by IHC, 5 had malignant cells in their SLNs. Cytokeratin IHC staining detected malignant cells in 9 of 16 cases with SLNs in our sample of women with MELF pattern of myoinvasion. Immunohistochemical stains should be routinely performed on SLNs from all MELF-positive cases to detect occult lymph node metastases and isolated tumor cells.

Grossly unremarkable cervix in endometrial carcinomas: lymphovascular space invasion and microcystic elongated and fragmented pattern may be associated with high incidence of cervical stromal involvement

Accurate staging of endometrial carcinoma is crucial to optimize patients' care. A pivotal parameter that pathologists evaluate to guide staging is the presence of cervical stromal involvement. However, the standard protocol for adequate sampling of the cervix is lacking. A total of 71 grossly unremarkable cervices in hysterectomy specimens with endometrial carcinomas have been studied. Sixty-three (89.7%), five (7.0%), and three (4.2%) were FIGO stage I, II, and III, respectively. Of 71 (8.5%) cases, 6 cases had cervical stromal involvement, among which, 4 (67%) showed endometrioid carcinoma (EC), 1 case of serous carcinoma, and 1 carcinosarcoma. Microcystic elongated and fragmented (MELF) pattern was identified in 12 (16.9%) cases, among which 11 were EC. The presence of MELF pattern was associated with advanced age, deeper myometrial invasion, and advanced FIGO stage. Tumors with lower uterine segment involvement (5/6; 80%), lymphovascular space invasion (4/6; 67%), and MELF pattern (3/6; 50.0%) tended to have cervical stromal involvement. Thus, we provide evidence that the presence of these features in hysterectomy specimens from patients with endometrial carcinoma may warrant extended sampling of the cervix while submitting four representative sections (one section from each quadrant) seems adequate to evaluate for occult cervical stromal involvement in grossly unremarkable cervices in the absence of these features.

Prognostic impact of tumor budding in endometrial carcinoma within distinct molecular subgroups

Tumor budding is a robust prognostic parameter in several tumor entities but is rarely investigated in endometrial carcinoma. We applied the recently standardized counting method from the International Tumor Budding Consensus Conference for colorectal cancer (ITBCC) on a cohort of 255 endometrial carcinomas with known molecular profiles according to The Cancer Genome Atlas (TCGA) subgroups. Our investigation aims to clarify the potential prognostic role of tumor budding in endometrial carcinoma in contrast to other known prognostic factors, including molecular factors. In addition, the microcystic elongated and fragmented (MELF) pattern and tumor budding were compared with respect to their potential as markers for epithelial–mesenchymal transition (EMT). Tumor budding was found in n = 67 (26.3%) tumors, with a very low mean of 0.7 buds per ×20 HE field. Tumor budding was significantly associated with depth of invasion, nodal status, lymphatic invasion (each p < 0.001), grading (p = 0.004), and vascular invasion (p = 0.01). Tumor budding showed moderate inter-observer-variability with prognostic stratification irrespective of the observer (κ-value = 0.448). In multivariate analysis, tumor budding served as a significant independent prognosticator for worse outcomes in overall and recurrence-free survival (HR 2.376 and 2.736, p < 0.001), but not when the TCGA subgroups entered into the analysis. In consequence, dependency had to be clarified in the subgroup analysis for Polymerase E mutated (POLEmut), mismatch repair deficient (MMRdef), nonspecific mutation profile (NSMP), and P53 aberrant (P53abn) endometrial carcinomas. A particular impact was identified in the intermediate prognostic groups of NSMP and MMRdef carcinomas. Tumor budding outperformed the MELF pattern in single and combined prognostic information. In conclusion, the presence of tumor budding alone is a promising, robust, and easy-to-apply prognostic parameter in endometrial carcinoma. In a morpho-molecular approach, it exerts its prognostic potential in the most clinically relevant subgroups of endometrial carcinoma and serves as a good biomarker for EMT.