Endometriosis — insights into a multifaceted entity

   Firstly described at the end of nineteenth century, endometriosis remains an enigmatic disease, from etio­pathogenesis to specific markers of diagnosis and its ability to associate with malignancies. Our review has been designed from a historical perspective and steps up to an updated understanding of the disease, facilitated by relatively recent molecular and genetic progresses. Although the histopathological diagnosis is relatively simple, the therapy is difficult or ineffective. Experimental models have been extremely useful as they reproduce the human disease and allow the testing of different potential modulators or treatment options. Due to molecular resemblance to carcinogenesis, applications of anti-cancer agents are currently under scrutiny. The desired goal of an efficient therapy against symptomatic disease, along with associated infertility and malignancies, needs a deeper insight into the complex mechanisms involved in endometriosis initiation, development, and progres­sion. Current trends in genomic and proteomic approaches are useful for a more accurate classification and for the identification of new therapeutic targets

Periostin in ovarian carcinoma: from heterogeneity to prognostic value

Introduction. Periostin (POSTN), an extracellular matrix protein, is involved in tumor-associated extracellular matrix (ECM) remodeling. However, its potential value as a prognostic and/or predictive factor has not yet been confirmed. The present study aims to assess POSTN expression separately in tumor cells and stroma of different ovarian carcinoma (OC) histological types, and its relationship with clinicopathological features. Material and methods. 102 cases of different histological OC subtypes were immunohistochemically investigated, for POSTN expression assessment in both epithelial tumor cells and tumor stroma. Statistical analysis was performed to correlate POSTN profile with clinicopathological characteristics, therapeutic response, and survival. Results.  POSTN expression in epithelial tumor cells was significantly correlated with POSTN expression in tumor stroma. The expression of POSTN in tumor cells was associated with histological type, tumor type (type I and II), tumor recurrence, progression-free survival (PFS), and overall survival (OS), whereas stromal POSTN expression was significantly correlated with age, histological type, tumor type, grade, and stage, residual disease, tumor recurrence, response to chemotherapy, and OS. Survival analysis revealed significant differences of PFS and OS in patients with high POSTN expression in tumor cells and negative stromal POSTN expression compared to patients with low POSTN expression in tumor cells and positive stromal POSTN expression (PFS: hazard ratio (HR) = 2.11, 95% confidence interval (CI): 1.33–3.37, P = 0.002; OS: HR = 1.78, 95% CI: 1.09–2.89, P = 0.019). Conclusions. The comparative assessment of POSTN immunoexpression in two tumor compartments: in tumor cells and stroma, by use of different scoring systems revealed that higher stromal POSTN levels are evidently correlated with unfavorable clinical features and poorer prognosis, while POSTN expression in tumor cells seems to be associated with a better patient outcome

BMI-1 Expression Heterogeneity in Endometriosis-Related and Non-Endometriotic Ovarian Carcinoma

BMI-1 is a key component of stem cells, which are essential for normal organ development and cell phenotype maintenance. BMI-1 expression is deregulated in cancer, resulting in the alteration of chromatin and gene transcription repression. The cellular signaling pathway that governs BMI-1 action in the ovarian carcinogenesis sequences is incompletely deciphered. In this study, we set out to analyze the immunohistochemical (IHC) BMI-1 expression in two different groups: endometriosis-related ovarian carcinoma (EOC) and non-endometriotic ovarian carcinoma (NEOC), aiming to identify the differences in its tissue profile. Methods: BMI-1 IHC expression has been individually quantified in epithelial and in stromal components by using adapted scores systems. Statistical analysis was performed to analyze the relationship between BMI-1 epithelial and stromal profile in each group and between groups and its correlation with classical clinicopathological characteristics. Results: BMI-1 expression in epithelial tumor cells was mostly low or negative in the EOC group, and predominantly positive in the NEOC group. Moreover, the stromal BMI-1 expression was variable in the EOC group, whereas in the NEOC group, stromal BMI-1 expression was mainly strong. We noted statistically significant differences between the epithelial and stromal BMI-1 profiles in each group and between the two ovarian carcinoma (OC) groups. Conclusions: Our study provides solid evidence for a different BMI-1 expression in EOC and NEOC, corresponding to the differences in their etiopathogeny. The reported differences in the BMI-1 expression of EOC and NEOC need to be further validated in a larger and homogenous cohort of study

Lesser-Known Molecules in Ovarian Carcinogenesis

Currently, the deciphering of the signaling pathways brings about new advances in the understanding of the pathogenic mechanism of ovarian carcinogenesis, which is based on the interaction of several molecules with different biochemical structure that, consequently, intervene in cell metabolism, through their role as regulators in proliferation, differentiation, and cell death. Given that the ensemble of biomarkers in OC includes more than 50 molecules the interest of the researchers focuses on the possible validation of each one’s potential as prognosis markers and/or therapeutic targets. Within this framework, this review presents three protein molecules: ALCAM, c-FLIP, and caveolin, motivated by the perspectives provided through the current limited knowledge on their role in ovarian carcinogenesis and on their potential as prognosis factors. Their structural stability, once altered, triggers the initiation of the sequences characteristic for ovarian carcinogenesis, through their role as modulators for several signaling pathways, contributing to the disruption of cellular junctions, disturbance of pro-/antiapoptotic equilibrium, and alteration of transmission of the signals specific for the molecular pathways. For each molecule, the text is built as follows: (i) general remarks, (ii) structural details, and (iii) particularities in expression, from different tumors to landmarks in ovarian carcinoma

The Interplay between Tumour Microenvironment Components in Malignant Melanoma

Malignant melanoma has shown an increasing incidence during the last two decades, exhibiting a large spectrum of locations and clinicopathological characteristics. Although current histopathological, biochemical, immunohistochemical, and molecular methods provide a deep insight into its biological behaviour and outcome, melanoma is still an unpredictable disease, with poor outcome. This review of the literature is aimed at updating the knowledge regarding melanoma’s clinicopathological and molecular hallmarks, including its heterogeneity and plasticity, involving cancer stem cells population. A special focus is given on the interplay between different cellular components and their secretion products in melanoma, considering its contribution to tumour progression, invasion, metastasis, recurrences, and resistance to classical therapy. Furthermore, the influences of the specific tumour microenvironment or “inflammasome”, its association with adipose tissue products, including the release of “extracellular vesicles”, and distinct microbiota are currently studied, considering their influences on diagnosis and prognosis. An insight into melanoma’s particular features may reveal new molecular pathways which may be exploited in order to develop innovative therapeutic approaches or tailored therapy

IMMUNOHISTOCHEMICAL PROFILE OF ENDOMETRIOSIS-ASSOCIATED OVARIAN CARCINOMA

Objective: Endometriosis association with cancers is strongly supported by epidemiological criteria and shared protective factors, being identified as endometriosis-associated ovarian carcinoma (EOC). In this context, our study objective has been the evaluation of selected immunohistochemical markers expression (ER, PR, p53, and Ki-67) in both endometriosis and EOC as an attempt to identify common pattern of expression, in support of similar molecular pathway involved in their pathogenesis. Material and Methods: Our study comprised 19 cases of EOCs. The routine and immunohistochemical staining have been performed, followed by results statistical processing. Results: The following data have been assessed in EOCs: tumor size, histological type, ovarian capsule invasion, TNM and FIGO staging. The histological types have been: endometrioid (8 cases) and non-endometrioid (11 cases of clear cell, high-grade serous, and mixed types). FIGO stages have been: stage I (4 cases), stage II (6 cases), stage III (8 cases), and stage IV (1 case). Histological grades have been: G1 (1 case), G2 (6 cases), and G3 (12 cases). Conclusions: The comparison between immunohistochemical staining and different clinicopathological variables supported that the altered expression of steroid receptors in ovarian endometriotic tissue and EOC are involved in malignant transformation and progression. p53 is contributing to endometriosis pathogenesis and EOC progression. EOCs are associated with low Ki-67 index compared to more aggressive types of tumors. In conclusion, the immunohistochemical expression of ER, PR, and p53 corroborated with clinicopathological features support the mechanism of endometriosis transition to EOC, provide tools for prognosis evaluation, and open new perspectives of therap

Uncommon Metastasis of Ovarian Dysgerminoma: A Case Report and Review of the Literature

Ovarian malignant germ cell tumors (OMGCT) represent less than 10% of all ovarian tumors. Dysgerminoma is the most common malignant primitive germ cell tumor in young women, known for its curability and low propensity to invade and metastasize when diagnosed early. Herein, we report an unusual type of ovarian dysgerminoma (OD) metastasis with a brief review of the literature, lacking similar reported cases. To our knowledge, although there are several case reports of dysgerminoma metastases with variable anatomic location and presentation, vaginal metastasis has not been previously described. The local or systemic relapse together with local and distant metastasis is considered as an independent predictor of poor survival in patients with OD. In light of the absence of mutations status, our patient successfully responded to therapy. Currently, the patient remains in clinical remission. A specific follow-up plan is ongoing knowing that ovarian dysgerminomas tend to recur most often in the first 2–3 years after treatment

Significance of the Galectin-8 Immunohistochemical Profile in Ovarian Cancer

Ovarian cancer (OC) still registers a high prevalence in female gynecological pathology. Given the aggressiveness of the tumor and the lack of response to conventional therapies, a current research interest is the identification of new prognostic markers. Gal-8, a member of the galectin family of molecules, involved in tumorigenesis, disease progression, and metastasis, has been assigned as a valuable tumor prognostic factor, and its inhibition may open new perspectives in cancer therapeutic management. Few studies have been carried out so far to evaluate OCs’ galectin profiles. Our study aimed to characterize the Gal-8 profile in different types of ovarian neoplasia and to demonstrate its prognostic value. Our study group comprised 46 cases of OCs that were histologically and immunohistochemically investigated, introduced to Gal-8 immunoreactivity, qualitatively and semi-quantitatively evaluated, and correlated with clinicopathological characteristics. Gal-8 immunoexpression was identified in tumor epithelial cells, showing a dominant nuclear labeling, followed by cytoplasmic and mixed, nuclear, and cytoplasmic labeling. Significant differences between tumor histotypes were found in the statistical analysis between low and high Gal-8 immunoscore levels and clinicopathological features: HGSC (eng.= high-grade serous carcinoma) vs. LGSC (eng. = low-grade serous carcinoma), pathogenic types (type I vs. type II), and tumor grades. Our results reflect Gal-8 expression variability depending on the histological type and subtype, the progression stages, and the degree of differentiation of ovarian tumors, supporting its value as a prognostic factor. Our findings open perspectives for larger studies to validate our results, along with a potential Gal-8 transformation into a future therapeutic target

Struma Ovarii: Clinico-Morphological Features and Therapeutic Experience of a Romanian Institution over 20 Years

Struma ovarii is a rare condition with scarce published data regarding clinical, morphological, and therapeutic approaches. This study reports the experience of 25 patients with struma ovarii who received surgical treatment in a gynecology department in Romania. The study was conducted from January 1999 to September 2021 and included patients with confirmed struma ovarii whose medical records were retrospectively reviewed and evaluated. Struma ovarii represented 2.8% of the total number of benign ovarian tumors treated by surgery. The age of the patients was between 24 and 71 years. The tumor was unilateral in 24 cases, 13 cases on the left ovary, 11 on the right side, and bilateral in 1 case. Tumor dimensions ranged between 1 cm and 20 cm. In two cases, the patients had symptoms of hyperthyroidism. The procedure was performed on four women for diagnoses other than an ovarian tumor. In another five situations, there was suspicion of ovarian malignancy. In addition, struma ovarii was associated with other clinical conditions in 22 cases. These lesions represent a diagnostic challenge with heterogeneous clinical and imaging manifestations. Complete information of clinical, morphologic, and surgical findings may improve the diagnostic algorithm and better predict patient outcomes

THE GASTROINTESTINAL NEUROENDOCRIN TUMORS

Objectives. The gastrointestinal neuroendocrin tumors are rare events with clinical presentation widely variable and surgical management that is often challenging. Material and methods. We performed a retrospective study in the First Surgical Clinic, St Spiridon University Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, Romania, in the 2005-2019 period, which included all the patients diagnosed with gastrointestinal neuroendocrin tumors by immunehistochemistry. Results. There were 37 cases diagnosed with gastrointestinal neuroendocrin tumors. The ratio male/female was 15/22 and mean age was de 42±4.365 years old (range 27-79 years). The gastrointestinal neuroendocrin tumors were: 13 – gastric, one – duodenal, 10 cases – small intestine, 10 cases – appendicular, 7 cases – large intestine and hepatic metastases – 4 cases. The carcinoid syndrome was present in 7 cases. The biological diagnosis included biological markers (e.g. serotonine, 5-HIAA). Diagnosis of the tumor site and dimension was done by ultrasound exam, Computed Tomography scan, Positron Emission Tomography scan, Octreoscan and intraoperative ultrasonography. Surgical procedures for gastric neuroendocrin tumors were: wedge tumor resection – one case; subtotal gastrectomy – one case, total gastrectomies – 3 cases. For neuroendocrin tumors of small bowel we performed 6 enterectomies and 4 ileocolectomies with lymphadenectomy. We also performed 7 appendectomies and 3 right colectomies for appendicular carcinoids. We performed 4 right colectomies, 2 left colectomies and one low anterior resection of the rectum for colorectal neuroendocrin tumors. For neuroendocrin tumors with hepatic metastases disease we performed one hepatectomy and 3 termoablations. Conclusions. The gastrointestinal neuroendocrin tumors are rare tumors, and their management is always challenging. Immunohistochemistry is mandatory for confirmation, appreciation of the proliferation and biological behavior, and permissible to use specific therapy. Aggressive surgical treatment is indicated, even in advanced stages. The treatment in patients with advanced gastrointestinal neuroendocrin tumors with metastatic disease include chemotherapy, biological therapies, and peptide receptor radionuclide therapy