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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 26736

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Special Issue Editors

Dr. Cinzia Giacometti

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Guest Editor

Pathology Unit, Department of Diagnostic Sciences, ULSS 6 Euganea, 35012 Camposampiero, Padua, Italy
Interests: feto-placental pathology; gynecologic pathology; breast pathology
Special Issues, Collections and Topics in MDPI journals

Dr. Kathrin Ludwig

E-Mail Website
Co-Guest Editor

Azienda Ospedaliera di Padova, Surgical Pathology Unit – Cytopathology Section, 35012 Padova, Italy
Interests: feto-placental pathology; cytology

Special Issue Information

Dear Colleagues,

When approaching diagnostic pathology in gynecologic diseases, many different scenarios can be encountered: benign lesions mimicking malignant ones, and vice versa; hormonal effects (either menstrual, pregnancy, or therapy-related) alter normal histology and create artifacts; systemic diseases (such as diabetes and connective tissue diseases) influence the hormonal status and affect placentation and gestation; genetic imbalance (BRCA, p53, mismatch repair protein deficiency) can cause breast, endometrial, and ovary cancer. This female “cosmos”, in which so much is interconnected and happens as the result of something else, is complex, and diagnostic challenges, tough differential diagnosis, and pitfalls are routinely encountered.

Based on this background, this Special Issue focuses on new, different, innovative approaches to the diagnosis, use, and application of alternative/ancillary techniques (immunohistochemistry, in situ hybridization, molecular biology) and methodological perspectives.

We warmly invite experts who contribute:

original research articles, also on animal models;
review articles/mini review;
short communication/expert point of view;
case reports on rare entities, with special regard to differential diagnosis and with literature reviews.

Dr. Cinzia Giacometti
Dr. Kathrin Ludwig
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

gynecologic pathology
breast pathology
placental pathology
diagnostic pitfalls
differential diagnosis
molecular biology
immunohistochemistry
in situ hybridization

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Related Special Issues

Pathology and Diagnosis of Gynecologic Diseases, 2nd Edition in Diagnostics (11 articles)
Pathology and Diagnosis of Gynecologic Diseases, 3rd Edition in Diagnostics

Published Papers (11 papers)

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Editorial

Jump to: Research, Review, Other

5 pages, 193 KiB

Open AccessEditorial

Editorial on the Special Issue Titled “Pathology and Diagnosis of Gynecologic Diseases”

by Cinzia Giacometti and Kathrin Ludwig

Diagnostics 2023, 13(22), 3480; https://doi.org/10.3390/diagnostics13223480 - 20 Nov 2023

Viewed by 829

Abstract

In the medical and diagnostic daily routine, gynecologic diseases present many different scenarios [...] Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

Research

Jump to: Editorial, Review, Other

12 pages, 1572 KiB

Open AccessArticle

Gestational Diabetes—Placental Expression of Human Equilibrative Nucleoside Transporter 1 (hENT1): Is Delayed Villous Maturation an Adaptive Pattern?

by Cinzia Giacometti, Kathrin Ludwig, Monica Guidi, Elvira Colantuono, Anna Coracina, Marcello Rigano, Mauro Cassaro and Alessandro Ambrosi

Diagnostics 2023, 13(12), 2034; https://doi.org/10.3390/diagnostics13122034 - 12 Jun 2023

Cited by 1 | Viewed by 1658

Abstract

Gestational diabetes mellitus (GDM) is a metabolic disease that can affect placental villous maturation and villous vascularity. The main effects of GDM on placental growth are a delay of villous maturation (DVM) and decreased formation of vasculo-syncytial membranes (VSM). Human equilibrative nucleoside transporter-1 (hENT1) is an adenosine transporter expressed in the human umbilical vein endothelial cells (HUVEC) and human placental microvascular endothelium cells (hPMEC). Its role is crucial in maintaining physiological fetal adenosine levels during pregnancy, and its reduction has been described in GDM. Twenty-four placentas from pregnancies with a confirmed diagnosis of GDMd and twenty-four matched non-GDM placentas (controls) were retrospectively analyzed to investigate the immunohistochemical expression of hENT1 in HUVEC and hPMEC. The study included the quantitative evaluation of VSM/mm² in placental tissue and the immunohistochemical quantitative evaluation of Ki-67, PHH3, and p57 in villous trophoblast. hENT1 expression was higher in all the vascular districts of the control cases compared to the GDMd placentas (p < 0.0001). The VSM/mm² were lower in the GDMd cases, while the Ki-67, PHH3, and p57 were higher when compared to the control cases. To our knowledge, this is the first report of hENT1 expression in the human placentas of GDM patients. The absence/low expression of hENT1 in all the GDMd patients may indicate a potential role in microvascular adaptative mechanisms. The trophoblasts’ proliferative/antiapoptotic pattern (high Ki-67, high PHH3, and high p57 count) may explain the statistically significant lower number of VSM/mm² found in the GDMd cases. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

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11 pages, 913 KiB

Open AccessArticle

Endometrial Staining of CD56 (Uterine Natural Killer), BCL-6, and CD138 (Plasma Cells) Improve Diagnosis and Clinical Pregnancy Outcomes in Unexplained Infertility and Recurrent IVF Failures: Standardization of Diagnosis with Digital Pathology

by Suheyla Ekemen, Cem Comunoglu, Cavit Kerem Kayhan, Ebru Bilir, Ilkay Cavusoglu, Nilay Etiler, Selcuk Bilgi, Umit Ince, Cevayir Coban and Halit Firat Erden

Diagnostics 2023, 13(9), 1557; https://doi.org/10.3390/diagnostics13091557 - 26 Apr 2023

Cited by 1 | Viewed by 3240

Abstract

In women with unexplained infertility (UI) and recurrent in vitro fertilization (IVF) failures, the etiology is often unclear. Endometrial immune perturbations and the use of immune markers associated with these dysregulations are of great interest in the diagnosis and treatment of UI. However, reliable biomarkers and standardized quantification methods are lacking. Here, to address endometrial immune dysregulation in UI patients with recurrent IVF failures, we performed endometrial tissue sampling and immunostaining of CD56 (uNK), CD138, and BCL-6. Of these cases, 57.9% had positive CD56 in the endometrial stroma, while 46.1% had positive BCL-6 in the glandular epithelium, and 14.5% of the cases were found to be positive for CD138. Combined staining rates were 60.5%, 68.4%, and 71.05% for (CD56 or BCL-6), (CD56 or CD138), and (CD56, BCL-6, or CD138), respectively. There was a significant correlation between CD56 and BCL-6 positivity, while CD138 positivity was an independent parameter. After the recommended targeted therapy, pregnancy rates were found to increase from 58.5% to 61.6% and 73.8% in CD56-positive, (CD56- or BCL-6-positive), and (CD56-, BCL-6-, or CD138-positive) cases, respectively. Notably, a retrospective evaluation of digital pathology and light microscopy results showed a significant correlation. This study suggests that the examination of CD56, BCL-6, and CD138 in the same endometrial sample may be an effective method in determining the etiology of UI and reaching an early diagnosis and treatment options. Moreover, digital pathology can be used in the evaluation of CD56 and BCL-6 to provide objective, rapid, and reliable results. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

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10 pages, 1529 KiB

Open AccessArticle

Endometriosis-Related Ovarian Cancers: Evidence for a Dichotomy in the Histogenesis of the Two Associated Histotypes

by Alice Bergamini, Giorgia Mangili, Alessandro Ambrosi, Gianluca Taccagni, Emanuela Rabaiotti, Luca Bocciolone, Giorgio Candotti, Raffaella Cioffi, Francesca Pella, Giulia Sabetta, Costanza Saponaro and Massimo Candiani

Diagnostics 2023, 13(8), 1425; https://doi.org/10.3390/diagnostics13081425 - 15 Apr 2023

Cited by 8 | Viewed by 2353

Abstract

Evidence indicates that different pathways of malignant degeneration underlie the development of endometriosis-associated ovarian tumors of endometrioid and clear cell histotypes. The aim of this study was to compare data from patients affected by these two histotypes to investigate the hypothesis of a dichotomy in the histogenesis of these tumors. Clinical data and tumor characteristics of 48 patients who were diagnosed with either pure clear cell ovarian cancer and mixed endometrioid–clear cell ovarian cancer arising from endometriosis (ECC, n = 22) or endometriosis-associated endometrioid ovarian cancer (EAEOC, n = 26) were compared. A previous diagnosis of endometriosis was detected more frequently in the ECC group (32% vs. 4%, p = 0.01). The incidence of bilaterality was significantly higher in the EAOEC group (35% vs. 5%, p = 0.01) as well as a solid/cystic rate at gross pathology (57.7 ± 7.9% vs. 30.9 ± 7.5%, p = 0.02). Patients with ECC had a more advanced disease stage (41% vs. 15%; p = 0.04). A synchronous endometrial carcinoma was detected in 38% of EAEOC patients. A comparison of the International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis showed a significantly decreasing trend for ECC compared to EAEOC (p = 0.02). These findings support the hypothesis that the origin, clinical behavior and relationship with endometriosis might be different for these histotypes. ECC, unlike EAEOC, seems to develop within an endometriotic cyst, thus representing a window of possibility for ultrasound-based early diagnosis. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

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14 pages, 4154 KiB

Open AccessArticle

Identifying ITGB2 as a Potential Prognostic Biomarker in Ovarian Cancer

by Chanyuan Li, Ting Deng, Junya Cao, Yun Zhou, Xiaolin Luo, Yanling Feng, He Huang and Jihong Liu

Diagnostics 2023, 13(6), 1169; https://doi.org/10.3390/diagnostics13061169 - 18 Mar 2023

Cited by 8 | Viewed by 2477

Abstract

Epithelial ovarian cancer is by far the most lethal gynecological malignancy. The exploration of promising immunomarkers to predict prognosis in ovarian cancer patients remains challenging. In our research, we carried out an integrated bioinformatic analysis of genome expressions and their immune characteristics in the ovarian cancer microenvironment with validation in different experiments. We filtrated 332 differentially expressed genes with 10 upregulated hub genes from the Gene Expression Omnibus database. These genes were closely related to ovarian tumorigenesis. Subsequently, the survival and immune infiltration analysis demonstrated that the upregulation of five candidate genes, ITGB2, VEGFA, CLDN4, OCLN, and SPP1, were correlated with an unfavorable clinical outcome and increased immune cell infiltration in ovarian cancer. Of these genes, ITGB2 tended to be the gene most correlated with various immune cell infiltrations and had a strong correlation with significant M2 macrophages infiltration (r = 0.707, p = 4.71 × 10⁻³⁹), while it had a moderate correlation with CD4+/CD8+ T cells and B cells. This characteristic explains why the high expression of ITGB2 was accompanied by immune activation but did not reverse carcinogenesis. Additionally, we confirmed that ITGB2 was over-expressed in ovarian cancer tissues and was mainly located in cytoplasm, detected by Western blotting and the immunohistochemical method. In summary, ITGB2 may serve as a prognostic immunomarker for ovarian cancer patients. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

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12 pages, 3490 KiB

Open AccessArticle

HPV-Induced Anal and Peri-Anal Neoplasia, a Surgeon’s Experience: 5-Year Case Series

by Christoforos Kosmidis, Christina Sevva, Vasiliki Magra, Nikolaos Varsamis, Charilaos Koulouris, Ioannis Charalampous, Konstantinos Papadopoulos, Panagiota Roulia, Marios Dagher, Vasiliki Theodorou, Chrysi Maria Mystakidou and Isaak Kesisoglou

Diagnostics 2023, 13(4), 702; https://doi.org/10.3390/diagnostics13040702 - 13 Feb 2023

Cited by 1 | Viewed by 4253

Abstract

Purpose: One of the most known sexually transmitted diseases is Condylomata acuminata (CA), a skin lesion occurring due to infection from Human Papilloma Virus (HPV). CA has a typical appearance of raised, skin-colored papules ranging in size from 1 mm to 5 mm. These lesions often form cauliflower-like plaques. Depending on the involved HPV-subtype (either high-risk or low-risk) and its malignant potential, these lesions are likely to lead to malignant transformation when specific HPV subtypes and other risk factors are present. Therefore, high clinical suspicion is required when examining the anal and perianal area. Methods: In this article, the authors aim to present the results of a five-year case series (2016–2021) of anal and perianal cases of CA. Results: A total of 35 patients were included in this study. Patients were categorized based on specific criteria, which included gender, sex preferences, and human immunodeficiency virus infection. All patients underwent proctoscopy and excision biopsies were obtained. Based on dysplasia grade patients were further categorized. The group of patients where high-dysplasia squamous cell carcinoma was present was initially treated with chemoradiotherapy. Abdominoperineal resection was necessary in five cases after local recurrence. Conclusions: CA remains a serious condition where several treatment options are available if detected early. Delay in diagnosis can lead to malignant transformation, often leaving abdominoperineal resection as the only option. Vaccination against HPV poses a key role in eliminating the transmission of the virus, and thus the prevalence of CA. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

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13 pages, 1509 KiB

Open AccessArticle

Gross Cystic Disease Fluid Protein-15 (GCDFP-15) Expression Characterizes Breast Mucinous Carcinomas in Older Women

by Mayumi Kinoshita, Motoji Sawabe, Yurie Soejima, Makiko Naka Mieno, Tomio Arai and Naoko Honma

Diagnostics 2022, 12(12), 3129; https://doi.org/10.3390/diagnostics12123129 - 12 Dec 2022

Cited by 2 | Viewed by 1921

Abstract

The predominant histological subtype of breast mucinous carcinoma in older women is type B (hypercellular type), and, in younger women, it is type A (hypocellular type). The characteristics of mucinous carcinomas of the same histological subtype may differ between older and younger women. This study aims to systematically clarify the pathological/immunohistochemical features of mucinous carcinomas. A total of 21 surgical cases of mucinous carcinoma (type A/B: 9/12 cases) in the older group (≥65 years) and 16 cases (type A/B: 14/2 cases) in the younger group (≤55 years) (n = 37) were included. Gross cystic disease fluid protein-15 (GCDFP-15) and eight other markers were used for immunostaining. The GCDFP-15-positive rate in the older group was high regardless of the histological subtype (type A, 77.8%; type B, 91.7%). The GCDFP-15 positivity in the older group was significantly higher than that in the younger group (p < 0.001 for Allred score). Among type A, GCDFP-15 positivity was significantly higher in the older group than in the younger group (p = 0.042 for the Allred score and p = 0.007 for the positivity rate). The present results suggest that GCDFP-15 expression characterizes mucinous carcinomas in older women. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

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19 pages, 7703 KiB

Open AccessArticle

Endometrioid Carcinomas of the Ovaries and Endometrium Involving Endocervical Polyps: Comprehensive Clinicopathological Analyses

by Jihee Sohn, Yurimi Lee and Hyun-Soo Kim

Diagnostics 2022, 12(10), 2339; https://doi.org/10.3390/diagnostics12102339 - 27 Sep 2022

Cited by 8 | Viewed by 2496

Abstract

While synchronous ovarian and endometrial endometrioid carcinomas (ECs) have long been described in the literature, ovarian or endometrial EC involving concomitant endocervical polyp (ECP) has not yet been reported. This study aimed to investigate the histological types and prevalence of gynecological tumors co-existing with ECP and to comprehensively analyze the clinicopathological characteristics of ovarian and endometrial ECs involving ECPs. We searched for ECP cases associated with premalignant lesions or malignancies of the female genital tract occurring between March 2019 and February 2022. We then investigated the histological types and prevalence of gynecological tumors co-existing with ECP. In addition, we reviewed electronic medical records and pathology slides to collect the clinicopathological features of four patients with ovarian or endometrial EC involving ECP. We found 429 ECPs over the three-year study period. Of these, 68 (15.9%) were associated with premalignant or malignant lesions occurring in the uterine cervix, endometrium, and ovaries. Four of these cases, including two (0.5%) ovarian grade 3 ECs and two (0.5%) endometrial grade 1 ECs, involved ECPs. In the former cases (cases 1 and 2), ECs involving ECPs exhibited similar morphology and immunohistochemical staining results to those of advanced-stage ovarian EC. In the latter cases (cases 3 and 4), the histological and immunophenotypical features of EC involving ECP were identical to those of primary endometrial EC, despite the lack of tumor involvement in the myometrium, lower uterine segment, and cervical stroma as well as the absence of lymphovascular invasion and lymph node metastasis. In all cases, no evidence of benign endometriosis, endometrial hyperplasia without atypia, or atypical hyperplasia/endometrial intraepithelial neoplasm within ECP or the adjacent endocervical tissue was noted. Considering our results, the involvement of ECP by EC may have been caused by an implantation metastasis from the ovarian (cases 1 and 2) or endometrial (cases 3 and 4) EC. To the best of our knowledge, this is the first exploration of the synchronous occurrence of endometrial or ovarian EC and ECP involvement. Implantation metastasis via transtubal and trans-endometrial cavity migration may have been the pathogenic mechanism of ECP involvement. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

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Review

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14 pages, 333 KiB

Open AccessReview

The Female Reproductive Tract Microbiome and Cancerogenesis: A Review Story of Bacteria, Hormones, and Disease

by Oana Gabriela Trifanescu, Raluca Alexandra Trifanescu, Radu Iulian Mitrica, Diana Maria Bran, Georgia Luiza Serbanescu, Laurentiu Valcauan, Serban Andrei Marinescu, Laurentia Nicoleta Gales, Bogdan Cosmin Tanase and Rodica Maricela Anghel

Diagnostics 2023, 13(5), 877; https://doi.org/10.3390/diagnostics13050877 - 24 Feb 2023

Cited by 7 | Viewed by 2349

Abstract

The microbiota is the complex community of microorganisms that populate a particular environment in the human body, whereas the microbiome is defined by the entire habitat—microorganisms and their environment. The most abundant and, therefore, the most studied microbiome is that of the gastrointestinal tract. However, the microbiome of the female reproductive tract is an interesting research avenue, and this article explores its role in disease development. The vagina is the reproductive organ that hosts the largest number of bacteria, with a healthy profile represented mainly by Lactobacillus spp. On the other hand, the female upper reproductive tract (uterus, Fallopian tubes, ovaries) contains only a very small number of bacteria. Previously considered sterile, recent studies have shown the presence of a small microbiota here, but there are still debates on whether this is a physiologic or pathologic occurrence. Of particular note is that estrogen levels significantly influence the composition of the microbiota of the female reproductive tract. More and more studies show a link between the microbiome of the female reproductive tract and the development of gynecological cancers. This article reviews some of these findings. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

Other

Jump to: Editorial, Research, Review

9 pages, 1545 KiB

Open AccessCase Report

Complete Hydatidiform Mole with Lung Metastasis and Coexisting Live Fetus: Unexpected Twin Pregnancy Mimicking Placenta Accreta

by Hera Jung

Diagnostics 2023, 13(13), 2249; https://doi.org/10.3390/diagnostics13132249 - 3 Jul 2023

Cited by 1 | Viewed by 1855

Abstract

Twin pregnancy with a complete hydatidiform mole and coexisting fetus (CHMCF) is an exceedingly rare condition with an incidence of about 1 in 20,000–100,000 pregnancies. It can be detected by prenatal ultrasonography and an elevated maternal serum beta-human chorionic gonadotropin (BhCG) level. Herein, the author reports a case of CHMCF which was incidentally diagnosed through pathologic examination without preoperative knowledge. The 41-year-old woman, transferred due to preterm labor, delivered a female baby by cesarean section at 28 + 5 weeks of gestation. Clinically, the surgeon suspected placenta accreta on the surgical field, and the placental specimen was sent to the pathology department. On gross examination, focal vesicular and cystic lesions were identified separately from the normal-looking placental tissue. The pathologic diagnosis was CHMCF and considering the fact that placenta accreta was originally suspected, invasive hydatidiform mole was not ruled out. After radiologic work-up, metastatic lung lesions were detected, and methotrexate was administered in six cycles at intervals of every two weeks. The author presents the clinicopathological features of this unexpected CHMCF case accompanied by pulmonary metastasis, compares to literature review findings, and emphasizes the meticulous pathologic examination. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

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8 pages, 3797 KiB

Open AccessInteresting Images

Clear-Cell Mesothelioma of Uterine Corpus: Diagnostic Challenges in Intraoperative Frozen Sections

by Tip Pongsuvareeyakul, Kanokkan Saipattranusorn, Kornkanok Sukpan, Prapaporn Suprasert and Surapan Khunamornpong

Diagnostics 2023, 13(6), 1119; https://doi.org/10.3390/diagnostics13061119 - 15 Mar 2023

Cited by 2 | Viewed by 1787

Abstract

The clear-cell variant of epithelioid mesothelioma is an extremely rare neoplasm of the peritoneum. It shares histomorphologic features overlapping with a wide variety of tumors including carcinomas and other non-epithelial neoplasms. The diagnosis of peritoneal clear-cell mesothelioma is not always straightforward, despite known immunohistochemistry (IHC) markers. Due to its rarity, this entity may be diagnostically confused with other clear-cell neoplasms, particularly in intraoperative frozen sections. Here, we present a case of clear-cell mesothelioma originating in the uterine serosa that was initially misdiagnosed as clear-cell adenocarcinoma in the intraoperative frozen section. Microscopically, the tumor showed diffuse tubulocystic spaces of variable size lined by clear cells with moderate nuclear atypia. Immunohistochemical staining confirmed the diagnosis of clear-cell mesothelioma. Recognition of this entity, albeit rare, is important as the diagnosis may significantly affect the management considerations. The judicious use of an IHC panel helps to distinguish this tumor from other mimickers. Full article

(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases)

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