Review Reports - Characteristic of Endometrial Stromal Sarcoma by Algorithm of Potential Biomarkers for Uterine Mesenchymal Tumor

Round 1

Reviewer 1 Report

This is a case report of a 45-year-old woman diagnosed with ESS. The purpose of this manuscript is not clearly stated. The introduction section is too long. However, the authors do not provide a comparison between MRI and US in terms of diagnostic accuracy when diagnosing mesenchymal uterine tumours. In addition, carcinosarcomas are not classified as sarcomas any more, but rather as high-risk endometrial carcinomas. The immune markers characteristic for LG-ESS and HG-ESS have already been reported. It is not clear how many patients with myomas are treated in the authors’ institution each year and how many patients are diagnosed with sarcoma.

Author Response

Manuscript ID: cimb-2501848

Reviewer 1

This is a case report of a 45-year-old woman diagnosed with ESS. The purpose of this manuscript is not clearly stated.

Comment 1. The introduction section is too long.

Answer 1. We appreciate your comment. We referred to the word count of the introduction section of the following manuscripts and reports published by the journal.

The word count of the introduction section of our manuscript is 626.

Cymbopogon citratus Essential Oil: Extraction, GC-MS, Phytochemical Analysis, Antioxidant Activity, and In Silico Molecular Docking for Protein Targets Related to CNS.

Cortes-Torres AG, López-Castillo GN, Marín-Torres JL, Portillo-Reyes R, Luna F, Baca BE, Sandoval-Ramírez J, Carrasco-Carballo A. Curr Issues Mol Biol. 2023 Jun 16;45(6):5164-5179. doi: 10.3390/cimb45060328.

Introduction: 581 words

Potential Diagnostic Biomarker Detection for Prostate Cancer Using Untargeted and Targeted Metabolomic Profiling.

Nitusca D, et al. Curr Issues Mol Biol. 2023. PMID: 37367069

Introduction: 765 words

Synergistic Effects of New Curcumin Analog (PAC) and Cisplatin on Oral Cancer Therapy.

Semlali A, Beji S, Ajala I, Al-Zharani M, Rouabhia M. Curr Issues Mol Biol. 2023 Jun 8;45(6):5018-5035. doi: 10.3390/cimb45060319.

Introduction: 625 words

How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain?

Nicolini F, Todorovski T, Puig E, Díaz-Lobo M, Vilaseca M, García J, Andreu D, Giralt E. Curr Issues Mol Biol. 2023 Jun 7;45(6):4985-5004. doi: 10.3390/cimb45060317.

Introduction: 1043 words

Based on these previously published articles, we believe that the introduction section is not too long. Nevertheless, we rewrote the section to clarify the purpose of reporting a case of gynecological malignant tumor.

Comment 2. However, the authors do not provide a comparison between MRI and US in terms of diagnostic accuracy when diagnosing mesenchymal uterine tumours.

Answer 2. We agree with your comment. Based on the reviewer’s comments, we rewrote the following text and added it to the discussion section of the revised manuscript.

The annual incidence of uterine sarcoma is 1–2 per 100,000 women. Uterine sarcoma is relatively rare, accounting for approximately 0.5%–2.0% of all cases of uterine mesenchymal tumors [22]. Further, 50% of all uterine sarcoma cases recur within 2 years, even in patients with early-stage cancer (stage I). Furthermore, uterine sarcoma often exhibits distant metastasis, indicating its extremely poor prognosis. Approximately 90% of all patients with stage II or higher uterine sarcoma experience recurrence within 2 years [22]. Therefore, an accurate differential diagnosis of uterine leiomyoma and uterine sarcoma can greatly influence the treatment strategy. However, conventional diagnostic imaging methods (ultrasound tomography, CT, and MRI) do not provide sufficient accuracy for diagnosing uterine mesenchymal tumors. Among these methods, pelvic contrast-enhanced MRI has a relatively high diagnostic rate. When rapid tumor growth, hemorrhagic necrosis on MRI T1-weighted imaging, diffuse lobulated high-intensity mass on MRI T2-weighted imaging, tendency to infiltrate around the tumor, and vascular proliferation are observed, uterine sarcoma should be strongly suspected. However, MRI alone does not provide satisfactory results as a preoperative diagnostic method.

Murakami Y, Tsukata H, Ide M. Positron Emission Tomography (PET) Clinical Position Usefulness in Gynecology Prospects in Malignant Tumor Diagnosis Differentiating fibroids from sarcoma. Clinical Obstetrics and Gynecology 2005, 59(11) pp.1477-1481 https://doi.org/10.11477/mf.1409100432

Comment 3. In addition, carcinosarcomas are not classified as sarcomas any more, but rather as high-risk endometrial carcinomas.

Answer 3. We agree with your comment. Accordingly, we have rewritten the text as follows.

According to the WHO classification of tumors of the uterine corpus 2020, carcinosarcomas are classified as endometrial epithelial tumors and precursors.

Comment 4. The immune markers characteristic for LG-ESS and HG-ESS have already been reported.

Answer 4. As indicated by the reviewer, the characteristic immune markers for LG-ESS and HG-ESS have already been reported.

The primary aim of our study is not to report a diagnosis using novel immunohistological markers for endometrial stromal sarcoma. We experienced the case of a woman suspected of developing uterine leiomyosarcoma based on contrast-enhanced MRI, who was eventually diagnosed with endometrial stromal sarcoma via surgical pathology. Therefore, our purpose is to inform the following objectives to healthcare professionals.

Owing to remarkable advancements in medical technology, T2-weighted MRI can detect small tumors. However, the usefulness of T2-weighted MRI in all gynecologic tumors remains uncertain. Therefore, this case report aimed to highlight the importance of histopathologic examinations based on surgical specimens.

Comment 5. It is not clear how many patients with myomas are treated in the authors’ institution each year and how many patients are diagnosed with sarcoma.

Answer 5. We appreciate your comment. The number of patients with uterine leiomyoma or uterine sarcoma at our medical institution is presented in the table below. We added the table as Supplemental Table 2 in the revised manuscript.

Supplemental Table 2

Uterine leiomyomas (uLMA)

Surgical procedures		Cases/year (2022)
Uterine leiomyoma enucleation	Laparotomy	4
Uterine leiomyoma enucleation	Laparoscopy	26
Simple hysterectomy	Laparotomy	12
Simple hysterectomy	Laparoscopy	50
Simple hysterectomy	Robot-assisted	18
Total		110

Uterine sarcoma (uterine leiomyosarcoma, uterine endometrial stromal sarcoma)

	Cases/year (2022)
Uterine leiomyosarcoma	6
Uterine endometrial stromal sarcoma	10
Total	16

Author Response File: Author Response.pdf

Reviewer 2 Report

This MS addresses some important issues of the diagnostic workup for clinicians.

A revision is suggested, including some points to consider.

For instance, the Abstract can be restructured, as follows:

Background/Aim: The benign tumor uterine leiomyoma (UL) derives from the smooth muscle tissue that constitutes the uterus. In contrast, the malignant tumor uterine sarcoma can derive from either smooth muscle or stroma and differs from both UL and endometrial cancer. Uterine sarcoma is broadly classified into three types: uterine leiomyosarcoma, endometrial stromal sarcoma (ESS), and carcinosarcoma. However, although uterine leiomyosarcoma and ESS are both classified as uterine sarcoma, they differ significantly in their sites of occurrence, symptoms, and treatment methods, among other factors. Uterine leiomyosarcoma arises from the muscle tissue constituting the wall of the uterus and accounts for approximately 70% of all uterine sarcoma cases. ESS arises from the stromal tissue beneath the endometrium and accounts for approximately 25% of all uterine sarcoma cases. ESS is classified as either low-grade (LG) or high-grade (HG).

This case report is aimed to highlight the importance of histopathologic exams based on surgical specimens. It illustrates a case of a 45-year-old woman suspected of having a submucosal leiomyoma of the uterus based on the results of imaging studies.

Materials and Methods: Transvaginal ultrasonography and endometrial biopsy or partial dilation and curettage were performed. Contrast-enhanced magnetic resonance imaging (MRI) revealed a 32 mm mass projecting from the posterior wall of the uterus into the uterine cavity. MRI T2-weighted imaging (T2WI) revealed a low signal within the mass, and so a submucosal UL was suspected.

Result: Histopathology examination of a surgical specimen from a patient who was thought to have submucosal UL after contrast-enhanced MRI found that the patient actually had ESS.

Conclusion: Despite the remarkable progress made in medical imaging technology, the accuracy of contrast-enhanced MRI for detecting uterine mesenchymal tumors is limited. Histopathologic diagnosis based on surgical specimens should therefore be performed when medical grounds for diagnosing a benign tumor on contrast-enhanced MRI are lacking.

Similarly, in the Introduction section (at the end), the goal of this case report presentation should be stated.

The Case description should include a detailed patient medical interview, family history, and physical exam.

In the Discussion section, the authors should provide some comments regarding the strengths and limitations of their study.

The authors could also provide a list of the abbreviations at the end of this MS.

Author Response

Manuscript ID: cimb-2501848

Reviewer 2.

This MS addresses some important issues of the diagnostic workup for clinicians.

A revision is suggested, including some points to consider.

Comment 1. For instance, the Abstract can be restructured, as follows:

Result: Histopathology examination of a surgical specimen from a patient who was thought to have submucosal UL after contrast-enhanced MRI found that the patient actually had ESS.

Answer 1. We appreciate your comment. However, we received the following comment from the Editor on July 5, 2023.

Please note "Background, Materials and Methods, Result and Conclusion" are not acceptable in abstract according to journal regulation. Please revise the abstract accordingly.

Dr. Maxine Mei
Assistant Editor

We have rewritten the abstract as follows according to the editor’s and reviewer’s comments.

Abstract

Benign tumor uterine leiomyoma (UL) develops from the smooth muscle tissue that constitutes the uterus, whereas malignant tumor uterine sarcoma develops from either the smooth muscle tissue or stroma and is different from UL and endometrial cancer. Uterine sarcoma is broadly classified into three types: uterine leiomyosarcoma, endometrial stromal sarcoma (ESS), and carcinosarcoma. Although uterine leiomyosarcoma and ESS are both classified as uterine sarcoma, they significantly differ in terms of their sites of occurrence, symptoms, and treatment methods. Uterine leiomyosarcoma develops from the muscle tissue constituting the wall of the uterus and accounts for approximately 70% of all uterine sarcoma cases. In contrast, ESS develops from the stromal tissue beneath the endometrium and accounts for approximately 25% of all uterine sarcoma cases. ESS is classified as either low grade (LG) or high grade (HG). This case report aimed to highlight the importance of histopathologic examinations based on surgical specimens. Herein, we reported the case of a 45-year-old woman suspected of having submucosal leiomyoma of the uterus based on imaging results. Transvaginal ultrasonography and endometrial biopsy or partial dilation and curettage were performed. Contrast-enhanced magnetic resonance imaging (MRI) revealed a 32-mm mass projecting from the posterior wall of the uterus into the uterine cavity. T2-weighted imaging revealed a low signal within the mass; thus, submucosal UL was suspected. Histopathologic examination of surgical specimens obtained from a patient suspected of having submucosal UL after contrast-enhanced MRI indicated that the patient had ESS. Despite the remarkable advancements in medical imaging technology, the accuracy of contrast-enhanced MRI for detecting uterine mesenchymal tumors is limited. Therefore, histopathologic diagnosis based on surgical specimens should be performed when medical grounds for diagnosing a benign tumor on contrast-enhanced MRI are lacking.

Comment 2. Similarly, in the Introduction section (at the end), the goal of this case report presentation should be stated.

Answer 2. We appreciate your comment. Accordingly, we have added the following text at the end of the Introduction section in the revised manuscript.

This case report aimed to highlight the importance of histopathologic examinations based on surgical specimens. Herein, we reported the case of a 45-year-old woman suspected of having submucosal leiomyoma of the uterus based on imaging results.

Comment 3. The Case description should include a detailed patient medical interview, family history, and physical exam.

Answer 3. We appreciate your comment. When medical researchers prepare manuscripts for clinical trials, clinical studies, and case reports, they must adhere to the following disciplines.

Please note that editors of the medical journals require that there should be less than three indirect identifiers remaining in your manuscript and supplemental information (if present) for the study to be approved for posting in medical journals.

Examples of indirect identifiers are as follows:

- Age range (patient age, 45 years)

- Exact dates of patient-related events

- Ethnicity–religion

- Details about family and family history

- Occupation

- Geographical area (The patient lives in Kyoto City, Kyoto Prefecture.)

- Potentially identifying medical conditions (The patient was diagnosed with endometrial stromal sarcoma.)

Your manuscript will not be approved for posting in medical journals if you do not include the abovementioned information about ethical oversight of your study in your ethics declaration.

Three indirect identifiers (age range, geographical area, and potentially identifying medical conditions) have been described in the revised manuscript. Therefore, based on the abovementioned guidelines, we did not include detailed patient medical interview, family history, and physical exam in the manuscript.

Comment 4. In the Discussion section, the authors should provide some comments regarding the strengths and limitations of their study.

Answer 4. We appreciate your comment. We added the following text in the revised manuscript accordingly.

Comment 5. The authors could also provide a list of the abbreviations at the end of this MS.

Answer 5. We appreciate your comment. Accordingly, we have added a list of abbreviations in the revised manuscript as follows:

Abbreviations: Abbreviations: α-SMA; α-smooth muscle actin, CA19-9; carcinoma antigen 19-9, ATRX; ATRX chromatin remodeler, CA; caveolin, CNNB; cyclin B, CCNE 1; cyclin E, DAB; 3,39′-diaminobenzidine tetrahydrochloride hydrate, Ep2d; echo-planar two-dimensional sequence, ESS; endometrial stromal sarcoma, HHF-35; hyperinsulinemic hypoglycema familial-35, HG; high-grade, HG-ESS; high-grade endometrial stromal sarcoma, IHC; immunohistochemistry, LMP2; large multifunctional protease 2; LG; ow-grade, LG-ESS; low-grade endometrial stromal sarcoma , LMS; leiomyosarcoma, MDM2; mouse double ninute 2 Homolog, MRI; magnetic resonance imaging, mem, MED12; mediator complex subunit 12, T2WI; T2-weighted imaging , UL; uterine leiomyoma, TMB; tumor mutation burden, TP53; tumor protein 53, WHO; World Health Organization.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

thank you for your efforts - the manuscript has been sufficiently improved to warrant publication