Vol. 62 No. 4, October-December 2021

1. Uterine myxoid leiomyosarcoma - a rare malignant tumor: the role of complex morphopathological assay. Review and case presentation

Anca-Maria Istrate-Ofiteru, George Lucian Zorila, Dan Ruican, Ana-Maria Petrescu, Elena Iuliana Anamaria Berbecaru, Gabriela-Camelia Rosu, Razvan Grigoras Capitanescu, Rodica Daniela Nagy, Liliana Cercelaru, Antonie Edu, Dominic-Gabriel Iliescu, Roxana Cristina Dragusin

Malignant mixed mesodermal sarcomas (myxoid leiomyosarcomas - MLMS) are a rare form of uterine cancer developed from the smooth muscles of the uterus. It usually affects women in the postmenopausal period and has an aggressive character with an unfavorable evolution and prognosis. This paper presents a case where MLMS was postoperatively confirmed with the aid of the histopathological (HP) examination coupled with specific immunolabeling techniques. In addition, we reviewed modern literature to compare our results. Clinically, patients may present with a pelvic tumor, vaginal bleeding, or abdominal pressure. Imagistic investigations, such as pelvic ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)-CT may support the diagnosis. Nevertheless, solely the HP examination establishes it. Macroscopically, MLMS is soft and gelatinous, unlike the conventional rigid and spiral leiomyoma appearance. Furthermore, the infiltrative, irregular tumor margin is characteristic of MLMS. From a microscopic point of view, the following are present: tumor cell necrosis, nuclear pleomorphism, and variable mitotic activity. With classical Hematoxylin-Eosin (HE) staining, myometrium presents a leiomyomatous structure and multiple nodular formations with the aspect of malignant tumor proliferation, most likely mesenchymal. We used multiple special immunolabeling techniques. Thus, we observed the intense reactivity of the cells to the anti-vimentin antibody, which immunolabeled type III intermediate filament (IF) protein expressed in mesenchymal cells, thus demonstrating tumor mesenchymal affiliation. Smooth cell positivity for alpha-smooth muscle actin (alpha-SMA) demonstrates that the tumor is present in its whole myometrial structure. Tumor cells also underwent mutations involving the p53 tumor suppressor gene demonstrated by the number of tumoral cells in division immunolabeled with anti-Ki67 proliferation antibody. Tumor development was demonstrated by protein activation of cyclin-dependent kinase (CDK) and the presence of c-Kit-bound hematopoietic stem cells, immunolabeled with the anti-cluster of differentiation 117 (anti-CD117) antibodies. The anti-desmin antibody demonstrates, along with alpha-SMA, the involvement of myocytes in the tumoral process. The following microscopic characteristics laid the foundation for the diagnosis of MLMS: irregular myometrial invasion, rare mitosis on high-power fields (HPFs), cell pleomorphism, predominant myxoid component that gave a hypocellular appearance, the matrix rich in proteoglycans and glycosaminoglycans, especially hyaluronic acid.

Corresponding author: Dominic-Gabriel Iliescu, Associate Professor, MD, PhD; e-mail:; Dan Ruican, MD, PhD Student; e-mail:

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2. Novel concepts in psoriasis: histopathology and markers related to modern treatment approaches

Carina Mihu, Maria Adriana Neag, Ioana Corina Bocsan, Carmen Stanca Melincovici, Stefan Cristian Vesa, Calin Ionescu, Adrian Lucian Baican, Lorena-Alexandra Lisencu, Anca-Dana Buzoianu

Psoriasis is a chronic autoimmune disease affecting over 2% of the worldwide population. From an anatomopathological point of view, psoriasis is characterized by immune cells infiltration, epidermal hyperproliferation, and abnormal keratinocyte differentiation. Understanding the pathogenesis of psoriasis will allow clinicians to manage this complex disease. Under these conditions, the application of effective treatments requires a thorough knowledge of all the pathogenetic mechanisms that lead to psoriasis. Numerous immunopathological pathways play crucial roles in the development of new therapies, such as biological therapies, which have been a breakthrough in psoriasis s treatment. Pharmacogenetics is an essential factor in the patient s response to treatment. One important pathway targeted by modern treatments is the interleukin (IL)-23/T-helper (Th)17 axis. Like IL-17 inhibitors, IL-23 blockers are a very effective therapy for this autoimmune disease. It is considered that micro-ribonucleic acids (microRNAs) are the starting point for any autoimmune disease. Studying certain microRNA (miR) involved in the inflammatory pathway in psoriasis can find direct targets to future treatments that can even be more specific than actual biological therapies. As such, miR-210 has proven to be up-regulated in psoriasis, also leading to the up-regulation of the Th1/Th17 axis. On the other hand, miR-187 was found to be down-regulated, influencing the outcome of psoriasis by increasing the proliferation of IL-6 stimulated keratinocytes and consecutively generating epidermal thickening. In this review, we are aiming to do an up-to-date briefing of psoriasis histopathology and pharmacogenetic factors that are considered for the accurate evaluation of treatment response.

Corresponding author: Maria Adriana Neag, Lecturer, MD, PhD; e-mail:

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3. Clinical and immunohistopathological study of conjunctival melanocytic lesions in pediatric and adolescent patients. A case series

Camelia Margareta Bogdanici, Claudia Florida Costea, Gabriela Florenta Dumitrescu, Anca Sava, Delia Gabriela Ciobanu Apostol, Dragos Viorel Scripcariu, Simona Delia Nicoara, Daniela Maria Tanase, Elena Corina Andriescu, Alexandru Carauleanu, Mihai Danciu, Silvia Cristina Salavastru, Speranta Schmitzer, Andrei Ionut Cucu, Irina Andreea Niagu

Background: Conjunctival pigmented neoplasia can be benign, premalignant or malignant tumors. Our study aims to establish the epidemiological, gross morphological and immunohistopathological features of the conjunctival pigmented lesions in pediatric and adolescent patients (<18 years), to establish an accurate diagnosis. Patients, Material and Methods: This is a retrospective case series study conducted within two Ophthalmology Clinics from Iasi, Romania, on seven pediatric and adolescent patients. Using the Clinical Observation Chart and the Pathology Registers over a six-years period (January 2015-December 2021), we noted the patients demographic data, clinical data, and ophthalmological investigations of the lesion, as well as the type of their treatment. All histological sections stained with Hematoxylin-Eosin (HE) and with five antibodies [pan-cytokeratin (pan-CK) AE1/AE3, S100 protein, Melan A, human melanoma black 45 (HMB45), and Ki67] were re-examined by four pathologists for each case, to identify the type of the conjunctival lesion and its histological and immunohistochemical features. Results: The mean age of all patients was 10.28 years, and the female/male ratio was 1.3. Right eye was more often affected (71.42%). 71.42% of cases presented an elevated lesion, 57.14% of cases showed a lightly pigmented lesion, but 14.28% of cases exhibited a pink lesion and this feature described the inflamed juvenile conjunctival nevus. In all cases (100%) the conjunctival pigmented tumor was removed with safety margins. The microscopic examination revealed a compound melanocytic nevus in 57.14% cases, a junctional conjunctival nevus in 14.28% cases, an inflamed juvenile nevus in 14.28% cases, and a conjunctival melanoma arising from a pre-existing nevus in 14.28% cases. In all cases of nevi, the nevoid melanocytes showed strong immunopositivity for Melan A and S100 protein, variable and weak immunopositivity for HMB45, and a mean Ki67 labeling index of 1.71%. Conjunctival melanoma revealed strong immunopositivity of tumor cells for HMB45, Melan A and S100 protein, and a Ki67 labeling index of 20%. In all cases, the conjunctival epithelium showed strong immunopositivity for pan-CK AE1/AE3. All our cases (100%) had a favorable outcome after the surgical removal of the tumor. Conclusions: Any excision of a conjunctival pigmented lesion must be subject to a systematic immunohistopathological examination, and there is a set of antibodies (anti-HMB45 and anti-Ki67) that are useful for differential diagnosis between a conjunctival nevus and a conjunctival melanoma.

Corresponding author: Claudia Florida Costea, Associate Professor, MD, PhD; e-mail:; Anca Sava, Professor, MD, PhD; e-mail:

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4. Factors predicting occurrence and therapeutic choice in malignant colorectal polyps: a study of 13 years of colonoscopic polypectomy

Sergiu Marian Cazacu, Adrian Saftoiu, Sevastita Iordache, Mirela-Corina Ghilusi, Claudia Valentina Georgescu, Vlad Florin Iovanescu, Carmen Daniela Neagoe, Liliana Streba, Mihaela Calita, Elena Daniela Burtea, Dan Cartu, Polliana Mihaela Leru

Colorectal carcinoma represents a major cause of mortality and 0.2-12% of resected colonic polyps have malignant cells inside. We performed a retrospective study of patients with resected polyps during a period of 13 years. A total of 905 patients had 2033 polyps removed; 122 polyps (109 patients) had malignant cells. Prevalence of malignant polyps with submucosal invasion was 1.23% and for all polyps with malignant cells was 6%; malignant polyps had a larger size (23.44 mm mean diameter) vs benign polyps (9.63 mm); the risk of malignancy was increased in polyps larger than 10 mm, in lateral spreading lesions and in Paris types 0-Ip, 0-Isp, in sigmoid, descending colon and rectum, in sessile serrated adenoma and traditional serrate adenoma subtypes of serrated lesions and in tubulovillous and villous adenoma. In 18 cases surgery was performed, in 62 patients only colonoscopic follow-up was made and in 35 patients no colonoscopic follow-up was recorded. From initially endoscopic resected polyps, recurrence was noted in seven (11.3%) cases; there was a trend toward association with depth of invasion, piecemeal resection, right and rectum location, sessile and lateral spreading type and pathological subtype. In surgical group, post-therapeutic staging was available in 11 cases; nodal involvement was noted in three (27.27%) cases; none had lymphatic or vascular invasion in endoscopically resected polyps. Four patients with no macroscopic local recurrence underwent surgery with no residual tumor. The rate of metastasis was 16.67% in surgical group and 1.61% in endoscopic group. Evaluation of lymph node (LN) invasion was available for 11 operated patients, with LN invasion (N1) in three patients, local residual tumoral tissue in one patient with incomplete resection and no residual tumor (R0 resection) in four patients with endoscopic resection before surgery.

Corresponding author: Vlad Florin Iovanescu, Teaching Assistant, MD; e-mail:; Carmen Daniela Neagoe, Associate Professor, MD, PhD; e-mail:

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5. Oral squamous cell carcinomas: a histopathological review of multiple cases from Western Romania

Ioana Cristina Niculescu Talpos, Ramona-Camelia Rumel, Alexandra Denisa Scurtu, Stefania Dinu, Mariana Ioana Miron, Antoaneta Denisa Predut, Raluca-Mioara Cosoroaba, Ramona Amina Popovici, Marius Raica

Malignant tumors of the oral cavity have a growing incidence, most being squamous cell carcinomas, generally called oral cancers (OCs), clinically detected at various stages of natural evolution. The increased incidence in Romania in recent years and the lack of conclusive data have led to the development of this study. The main purpose of this study was to assess the molecular profile of tumors, the types of blood vessels associated with the tumor, and expression of tumor immunomarkers. Regarding morphological findings, focal epithelial hyperplasia, dysplastic lesions, typical mitoses, perineural invasion, parakeratosis and keratosis beads, intracytoplasmic keratinization were observed. Microvascular density was higher in the tumor area compared to the peritumoral area. Lymphovascular invasion was identified in 13% of cases, which also presented regional lymph node metastases. Podoplanin expression was identified in 79% of cases which were tested positive for the D2-40 immunomarker. All p53-positive cases co-expressed epidermal growth factor receptor (EGFR), half of the EGFR-positive cases co-expressed p53, and co-expression of CD117 and p63 was identified in 80% of EGFR-positive/cytokeratin 5 (CK5)-positive cases being proposed the basal-like subtype of OCs, defined as EGFR-positive/CK5-positive, CD117-positive and p63-positive. Results support the need for molecular classification of OCs based on of tumor immunomarker expression and gene analysis.

Corresponding author: Stefania Dinu, DMD, PhD; e-mail:; Mariana Ioana Miron, DMD, PhD; e-mail:

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6. Prediction of histopathological local staging by radiological findings and differential diagnosis overview in children with nephroblastoma

Radu Ninel Balanescu, Laura Balanescu, Tudor Stejarel Strimbu, Ancuta Mihaela Cardoneanu, Andreea Alecsandra Moga

Background: Nephroblastoma is the most common renal malignancy in children kidney. They are highly heterogeneous tumors with challenging imagistic and histopathological (HP) differential diagnosis. Imaging is critical for understanding local anatomy, staging and for planning surgical approach. Purpose: To determine whether HP staging can be successfully predicted by the imagistic staging using computed tomography. Also, we find it important to make a brief review of the imagistic, HP and immunohistochemical differential diagnosis of nephroblastoma, considering that a correct diagnosis is essential for an appropriate therapeutic strategy in all stages. Patients, Materials and Methods: We present a retrospective study of the medical dossiers of 22 patients that underwent surgery at our Center between 2014 and 2020. We provided descriptive data and compared imagistic and HP staging using a Mann-Whitney U-test. An up-to-date literature review was also done. Results: We found that imagistic staging tends to under- or over-stage at similar rates and that the difference between the two staging systems is statistically significant. Immunohistochemistry is necessary for establishing the correct diagnosis, especially in cases with one predominant HP pattern. Conclusions: HP and imagistic staging are not yet sufficiently similar for successfully predict the former via imagistic means.

Corresponding author: Laura Balanescu, MD, PhD; e-mail:

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7. Clinical and pathological considerations in lumbar herniated disc associated with inflammatory lesions

George Sorinel Diaconu, Constantin George Mihalache, George Popescu, George Mihail Man, Razvan Gheorghe Rusu, Corneliu Toader, Constantin Ciucurel, Cristina Mariana Stocheci, George Mitroi, Luminita Ionela Georgescu

Lumbar herniated disc is the most frequent cause for lumbar pain. It is caused by degenerative, macroscopic and microscopic changes of the intervertebral discs. It is a chronic disease, with periods of exacerbation and remission under drug and physiotherapeutic treatment. When the disc lesions are large, with intense symptoms, reduced or impossible movements, with pain radiating to the sciatic nerve trajectory, a surgical treatment is required, to remove the herniated nucleus pulposus and decompress the nerve roots. Patients who present high inflammatory signs, high inflammatory serous markers, may have a longer postoperative recovery period, while the motor recovery may be late and incomplete. We analyzed a group of 24 patients with lumbar herniated disc that required discectomy, with clear inflammatory signs, together with histopathological and immunohistochemical changes present in the herniated disc.

Corresponding author: George Mitroi, Associate Professor, MD, PhD; e-mail:; Corneliu Toader, Associate Professor, MD, PhD; e-mail:

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8. The perioperative effect of anesthetic drugs on the immune response in total intravenous anesthesia in patients undergoing minimally invasive gynecological surgery

Marius Bogdan Novac, Lidia Boldeanu, Luciana Teodora Rotaru, Anda Lorena Dijmarescu, Mircea-Sebastian Serbanescu, Lucretiu Radu, Simona Daniela Neamtu, Alina Maria Vilcea, Mihaela Niculescu, Cecil Sorin Mirea, Mihail Virgil Boldeanu, Maria Magdalena Manolea

Background: The specific mechanism of action of each anesthetic drug on the immune system is still incompletely known. It is important to know how the various anesthetics used in minimally invasive surgery (MIS) act on the inflammatory response because the choice of the anesthetic agent can influence the patient s immune system. Aim: Evaluation of the effect of anesthetic drugs used for total intravenous anesthesia (Propofol and Midazolam) on the inflammatory response after minimally invasive gynecological surgery. Patients, Materials and Methods: The inflammatory response in 20 female patients who underwent minimally invasive gynecological surgery under which intravenous anesthesia was performed. Depending on the combination of anesthetics used, we subdivided the study group into two groups, Group 1 consisting of the patients (n=10) who were given for total intravenous anesthesia, the combination with Midazolam+Fentanyl, and Group 2 (n=10) the patients who received the combination of Propofol+Fentanyl, respectively. Surgical interventional procedures included day surgery: diagnostic and operative hysteroscopy, endometrial ablation, surgical treatment of vulvar disorders. Serological profiling of patients was performed by dosing the serum concentration of nucleotide-binding domain (NOD) and leucine-rich repeat protein 3 (NLRP3) inflammasomes, interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), IL-10 before and two hours after the surgical procedure. Results: In our study, we found that in both groups of patients (Midazolam+Fentanyl - Group 1, Propofol+Fentanyl - Group 2), NLRP3 and cytokines concentrations in the serum were higher after MIS than those before MIS. Conclusions: It appears that both Midazolam and Fentanyl and Propofol and Fentanyl have an immunomodulatory action due to the anti-inflammatory effect of both anesthetics. Therefore, anesthesiologists must choose an anesthetic method that uses individualized anesthetic agents, depending on the patient s immune status and disease.

Corresponding author: Mihail Virgil Boldeanu, Associate Professor, MD, PhD; e-mail:,; Mircea-Sebastian Serbanescu, Associate Professor, MD, PhD; e-mail:

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9. MLH1, BRAF and p53 - searching for significant markers to predict evolution towards adenocarcinoma in colonic sessile serrated lesions

Diana Raduta, Octavian Marius Dinca, Gianina Viorica Micu, Luciana Nichita, Mirela Daniela Cioplea, Radu Mihai Busca, Raluca Ardeleanu, Radu Bogdan Mateescu, Andreea Bengus, Sabina Andrada Zurac, Cristiana Gabriela Popp, George Cristian Vladan

Background and Aim: Colonic serrated lesions are premalignant lesions, using an alternative malignization pathway, including multiple genetic and epigenetic alterations, as: mismatch repair deficiency due to MutL homolog 1 (MLH1) promoter methylation, tumor protein p53 (TP53) mutations, activating mutations of v-Raf murine sarcoma viral oncogene homolog B (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS). Our study aims to evaluate MLH1, BRAF and p53 immunohistochemical (IHC) status in sessile serrated lesions (SSLs), with and without dysplasia. Materials and Methods: This is a retrospective case-control study including 20 SSLs with dysplasia and 20 SSLs without dysplasia (matching sex and age). IHC expression of MLH1, BRAF and p53 was evaluated as the percent of nuclear loss of MLH1, cytoplasmic positivity of BRAF and nuclear positivity of p53. Data concerning age, sex, localization of the lesion, dysplasia and IHC results were statistically processed using Microsoft Excel. Results: We had very polymorphous patterns of IHC expression for BRAF, MLH1 and p53, especially in the dysplastic group. Thus, two patients were BRAF+/MLH1-/p53+, three were BRAF+/MLH1-/p53-, one was BRAF+/MLH1+/p53- and six were BRAF+/MLH1+/p53+. Dysplastic lesions without BRAF mutation exhibited the following phenotype: one case BRAF-/MLH1-/p53+, four BRAF-/MLH1-/p53- and three BRAF-/MLH1+/p53+. In the control group (SSLs without dysplasia), there was a more homogenous distribution of cases: eight cases BRAF+/MLH1+/p53-, seven BRAF-/MLH1+/p53-, one BRAF-/MLH1-/p53+, two BRAF-/MLH1-/p53- and two BRAF-/MLH1+/p53+. Conclusions: There are more routes on the serrated pathway, with different mutations and time of acquisition of each genetic or epigenetic lesion with the same morphological result. These lesions should be stratified according to their risk to poor outcome and their need to further surveillance.

Corresponding author: Cristiana Gabriela Popp, MD; e-mail:

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10. The potential value of diagnostic and predictive serum biomarkers for preeclampsia

Anda Lorena Dijmarescu, Lidia Boldeanu, Mirela Radu, Ionela Rotaru, Mirela Anisoara Siminel, Maria Magdalena Manolea, Sidonia Catalina Vrabie, Marius Bogdan Novac, Mihail Virgil Boldeanu, Florentina Tanase

Background: Preeclampsia (PE), one of the classes of hypertensive pregnancy disorders, is one of the three causes of maternal morbidity and mortality worldwide. The angiogenic and anti-angiogenic factors are useful markers in predicting and diagnosing PE. Aim: This study aims to detect and measure the serum level of some biomarkers [hypoxia-inducible factor-1 subunit alpha (HIF-1A), vascular endothelial growth factor (VEGF), interferon-gamma-inducible protein of 10 kDa (IP-10), matrix metalloproteinase-13 (MMP-13)] in patients with PE and their correlation with the severity of the disease, to find a good predictor for PE. Patients, Materials and Methods: This prospective study aims to monitor 48 pregnant women who address obstetric consultation and who present risk factors for PE, and a control group with characteristics similar to the study group. Patients were divided into three groups: Group I (n=15) including normal pregnant (NP) women with blood pressure <140/90 mmHg, without proteinuria, Group II (n=18) including patients with mild PE (MildPE), Group III (n=15) including patients with severe PE (SeverePE). The analysis of serum biomarkers was based on a quantitative sandwich enzyme-linked immunosorbent assay (ELISA), according to the manufacturer s instructions. Results: In our study, we found that all biomarkers investigated have higher concentrations in the serum of patients with SeverePE and MildPE than those in the control subjects (Group I, NP), the concentrations were increasing along with the disease activity. The means concentrations of HIF-1A, VEGF, IP-10, MMP-13, better correlated with indices in SeverePE group than in MildPE group. We found that VEGF was the biomarker that best correlates with indices that assess the severity of PE. The best separation of patients with SeverePE from those with MildPE can be done with the help of MMP-13 (82% accuracy), followed by VEGF (80.40% accuracy) and the least good detection being done by dosing IP-10. Conclusions: We can say that, due to high specificity diagnostic accuracy, determination of serum concentrations of MMP-13 and VEGF, could be useful in the diagnosis and distinguishing of patients with SeverePE and may prove useful in the monitoring of the disease course.

Corresponding author: Mihail Virgil Boldeanu, Associate Professor, MD, PhD; e-mail:,; Marius Bogdan Novac, Lecturer, MD, PhD; e-mail:

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11. Postoperative retinal microstructure and functional outcome after inverted-flap technique associated with silicone oil tamponade in macular hole surgery

Christiana Diana Maria Dragosloveanu, Nicoleta Zamfiroiu-Avidis, Serban Dragosloveanu, Mihai Adrian Pasarica, Catalina Ioana Tataru, Paul Filip Curca

Purpose: Our retrospective study on 27 patients with a large mean macular hole diameter (MH-D) of 480.08+/-78.62 micro-m evaluates the usefulness of combining the current internal limiting membrane (ILM) inverted-flap surgical technique with silicone oil tamponade, which has been associated with the classical technique of ILM peeling. Results: Functional results: mean visual acuity (VA) improved to 0.89+/-0.11 logMar (logarithm of the minimum angle of resolution, at one month), 0.67+/-0.03 logMar (at three months), 0.52+/-0.04 logMar (at six months), 0.42+/-0.15 logMar (at one year) postoperative (final VA), with statistical linkage between preoperative VA and final VA (two-sample t-test, p=0.007), mean MH-D and final VA (regression analysis, p=0.003). We compared the results by MH size (Group A <=400 micro-m - eight eyes and Group B >400 micro-m - 19 eyes), finding statistical variance (Bonett and Levene methods). Group A presented a final VA of 0.21+/-0.12 logMar, while Group B had 0.51+/-0.17 logMar. Successful closure was noted in 25 (92.59%) cases, with Group A having complete closure and external limiting membrane (ELM) restoration with ellipsoid zone (EZ) regeneration in six cases. Group B had successful closure in 17 (89.47%) cases with ELM restoration in 16 cases and EZ regeneration in seven (38.88%) cases, with reintervention in two cases. Restoration of the ELM was correlated [Pearson s correlation coefficient (PCC) of 0.999, p=0.022] with successful closure, with overall restoration obtained in 24 (88.88%) cases and EZ regeneration in 13 (48.14%) cases. Conclusions: ILM inverted-flap technique with silicone oil tamponade had favorable functional and anatomical outcomes. ELM restoration was associated with successful MH closure.

Corresponding author: Catalina Ioana Tataru, MD, PhD; e-mail:

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12. Expression of M3 muscarinic acetylcholine receptors in gastric cancer

Alina Maria Mehedinteanu, Cecil Sorin Mirea, Puiu Olivian Stovicek, Michael Schenker, Marius Ionut Stancu, Ana-Maria Ciurea, Liliana Streba, Anca-Maria Istrate-Ofiteru, Teodor-Nicusor Sas, Cristin Constantin Vere

Introduction: Gastric cancer represents a real public health problem as far as incidence, aggressiveness and unfavorable prognosis are concerned. The autonomous nervous system might be one of the major factors involved in the onset, progression, and metastasis, both sympathetically and parasympathetically. The increased activation of the M3 muscarinic acetylcholine receptors (mAChRs) triggers pro-oncogenic mechanisms, especially at a gastric level, through the activation of the Hippo signaling pathway and the increase of the nerve growth factor. Patients, Materials and Methods: In this study, biopsy or postoperative gastric resection pieces have been evaluated by histopathological (HP) and immunohistochemical (IHC) examination in a group of 77 gastric patients and 23 patients without an oncological diagnosis. To quantify the IHC signal, also considering the HP aspect, light microscopy images were obtained. Results: The M3 mAChR expression analysis has been correlated with the different gastric adenocarcinoma differentiation degrees (G1-G3). M3 mAChR presence has been observed also in the non-malignant gastric tissue, but it was significantly increased in the tumor tissue. The highest receptor expression was recorded in patients with a poorly-differentiated (G3) adenocarcinoma, these expressions decreasing with the increase of the differentiation degree towards moderately-differentiated (G2) and well-differentiated (G1). Conclusions: Surgical or pharmacological parasympathetic activity inhibition could decrease the development and progression of gastric tumors and could improve the gastric cancer patient s prognosis.

Corresponding author: Puiu Olivian Stovicek, Lecturer, MD, PhD; e-mail:; Teodor-Nicusor Sas, Lecturer, MD, PhD; e-mail:

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13. Morphological and immunohistochemical diagnostic of extragastrointestinal stromal tumors - a 51 case series analysis

Valentin Tiberiu Moldovan, Oana Maria Patrascu, Leila Ali, Mariana Costache, Maria Sajin

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract, originating from structures differentiating towards Cajal cells. Due to their morphology and localization, the extragastrointestinal stromal tumors (EGISTs) can be a diagnostic challenge. We investigated a series of 51 EGISTs diagnosed in our institutions, aiming to explore the immunophenotypes and to analyze the process and the utility of the antibodies required for a positive diagnosis. Immunohistochemical examinations were done for pan-cytokeratin (pan-CK), Ki67, discovered on GIST1 (DOG1) protein and platelet-derived growth factor receptor alpha (PDGFRA), as necessary. The main tumor site was abdominal wall in 43 (84%) cases, most of the tumors showed spindle cell cellularity, followed by mixed and epithelioid type. Twenty-six cases revealed a full conventional immunohistochemical profile with DOG1 positivity. In 10 cases, c-KIT expression was absent but with the preservation of cluster of differentiation (CD)34 positivity, and eight cases were positive for PDGFRA. In our study, we found a subgroup of eight cases presenting in extra-abdominal settings (including one in lung and two in the head-and-neck area). We concluded EGISTs represent a histopathological and immunohistochemically challenging subgroup testing more often negative for c-KIT mutations and positive for PDGFRA compared to GIST. DOG1 remains the marker of choice regardless of tumor site, while CD34 and CD117 should be considered as adjuvants.

Corresponding author: Leila Ali, MD; e-mail:; Oana Maria Patrascu, MD; e-mail:

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14. Deep learning with transfer learning in pathology. Case study: classification of basal cell carcinoma

Raluca Maria Bungardean, Mircea-Sebastian Serbanescu, Costin Teodor Streba, Maria Crisan

Establishing basal cell carcinoma (BCC) subtype is sometimes challenging for pathologists. Deep-learning (DL) algorithms are an emerging approach in image classification due to their performance, accompanied by a new concept - transfer learning, which implies replacing the final layers of a trained network and retraining it for a new task, while keeping the weights from the imported layers. A DL convolution-based software, capable of classifying 10 subtypes of BCC, was designed. Transfer learning from three general-purpose image classification networks (AlexNet, GoogLeNet, and ResNet-18) was used. Three pathologists independently labeled 2249 patches. Ninety percent of data was used for training and 10% for testing on 100 independent training sequences. Each of the resulted networks independently labeled the whole dataset. Mean and standard deviation (SD) accuracy (ACC) [%]/sensitivity (SN) [%]/specificity (SP) [%]/area under the curve (AUC) for all the networks was 82.53+/-2.63/72.52+/-3.63/97.94+/-0.3/0.99. The software was validated on another 50-image dataset, and its results are comparable with the result of three pathologists in terms of agreement. All networks had similar classification accuracies, which demonstrated that they reached a maximum classification rate on the dataset. The software shows promising results, and with further development can be successfully used on histological images, assisting pathologists diagnosis and teaching.

Corresponding author: Mircea-Sebastian Serbanescu, Associate Professor, MD, PhD; e-mail:

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15. Role of ProEx C immunocytochemistry in cervical high-grade squamous intraepithelial lesions detection

Carmen Ungureanu, Demetra Gabriela Socolov, Gabriela Anton, Eugenia Morosan, Laura Mihaela Trandafir, Ludmila Lozneanu, Mioara Florentina Trandafirescu, Elena Cojocaru

Background: Screening programs using Papanicolaou smear along with human papillomavirus (HPV) testing led to a significantly decrease of cervical cancer rates. Nevertheless, both assessments have limited specificity for revealing cervical high-grade lesions. The main problem is how to identify the real precursor of cervical squamous cell carcinomas (SCC), namely high-grade squamous intraepithelial lesions (HSIL). Aim: The aim of our study was to conclude if ProEx C might be used as a marker for high-grade cervical intraepithelial neoplasia (CIN). Materials and Methods: In this study, we detected the immunochemical expression of anti-ProEx C antibody in liquid-based cytology (LBC) samples. We analyzed a total number of 125 cervical cytology specimens. Results: In 48% of all cases, ProEx C was found to be positive. The percentage increased from 0% in negative for intraepithelial lesion or malignancy (NILM) cases to 100% in SCC cases. Conclusions: ProEx C may be utilized to improve the accuracy of cytological diagnosis on cervical smears, according to the findings of this study. This marker is also useful in detecting unrevealed high-grade lesions on atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesions (LSIL) smears, being very useful in establishing the conduct of these cases.

Corresponding author: Ludmila Lozneanu, Lecturer, MD, PhD; e-mail:; Mioara Florentina Trandafirescu, Lecturer, MD, PhD; e-mail:

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16. Diagnostic difficulties in giant benign phyllodes tumor

Ramona-Andreea Matei, Mihai Mehedintu-Ionescu, Stefan Paitici, Eugen Florin Georgescu, Andreas Donoiu, Adina Mariana Ghemigian, Mihaela Popescu, Bogdan Dan Totolici, Carmen Neamtu, Stelian Stefanita Mogoanta

Phyllodes tumors (PTs) are rare tumors of the breast, which encompass both stromal and epithelial components. The maximum incidence is in the fourth decade of life. Most of these tumors are benign, but about one third can be malignant acting as sarcomas. Due to their rarity and atypical clinical behavior (especially for the giant ones), the management of these tumors is usually difficult. We report a case of a 24-year-old woman who presented in the Department of Oncology for rapid increase in volume of the left breast. She had no personal pathological or family history. Initial clinical exam showed a large irregular mass in the left breast of approximately 30 cm and palpable lymph nodes in the ipsilateral axilla. A core needle biopsy for the tumor was performed with histopathological (HP) result that revealed an aspect suggesting fibroadenoma/PT. Contrast-enhanced computed tomography (CT) scan identified lymph node enlargement in the left axilla and a peripheral nodule in the lung about 5.5/3.4 mm with no specific features. The patient was then transferred to the Department of Surgery, where left mastectomy and axillary lymph node sampling were performed. HP result of the surgical specimens confirmed the presence of both fibroadenoma and PT, with clear margins above 1 cm, but recommended immunohistochemistry (IHC) to clearly specify benign versus borderline type. Five lymph nodes out of six resected presented microscopic reactive changes. We performed a search of literature using the keywords giant, benign and phyllodes. The results were used to summarize and discuss some of the main features of this type of tumors as well as diagnostic and therapeutic difficulties.

Corresponding author: Stelian Stefanita Mogoanta, Professor, MD, PhD; e-mail:; Stefan Paitici, Assistant, MD; e-mail:

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17. Unilateral agenesis of permanent superior canine in familial peg-shaped lateral incisors: rare case report and literature review

Oana-Cella Andrei, Catalina Farcasiu, Adriana Bisoc, Daniela Ioana Tarlungeanu, Livia Alice Tanasescu, Magdalena Natalia Dina, Mihai Burlibasa, Ruxandra Margarit

Agenesis of permanent maxillary and mandibular canines is very rare; one to all four can be missing, isolated or in association with other missing teeth or with dental morphology abnormalities. Such cases can present functional, esthetic, and psychological problems, since the canine s role in functional occlusion and in obtaining an aesthetic smile is crucial. Frequently, the canine s absence from the arch is caused by impaction; its congenital absence is extremely rare in patients with no associated syndrome. The aim of this paper was to present a very rare case of a non-syndromic Romanian adult female patient with a unilateral permanent maxillary missing canine, in association with peg-shaped maxillary lateral permanent incisors, which can have a genetic cause, since the same morphological abnormality was present in her father and her younger sister, who also presented a rare situation of bilateral upper transposition between the canines and lateral incisors. The association of a permanent maxillary canine hypodontia with bilateral peg laterals and transposition between the maxillary canine and the peg-shaped lateral incisors is also rare as a family character in healthy patients. Future statistical studies are necessary to establish the incidence of permanent maxillary canine agenesis in Romanian population. Also, the article includes a detailed literature review of reported cases of agenesis of permanent maxillary canines.

Corresponding author: Livia Alice Tanasescu, Assistant, DMD, PhD; e-mail:; Magdalena Natalia Dina, Assistant, DMD, PhD; e-mail:

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18. Esophageal spindle cell lipoma

Jose-Fernando Val-Bernal, Marta Maria Mayorga, Natalia Fontanil, Alvaro Teran

Symptomatic ordinary esophageal lipomas are rare tumors. Spindle cell lipomas (SCLs) of this location are even more infrequent. To our knowledge, only a previous esophageal SCL case has been reported. We describe herein the case of a 62-year-old woman with a long history of heartburn and feeling of abdominal distension. Preoperative investigations, including a Barium meal, gastroscopy, and echoendoscopy revealed a lipomatous polypoid mass attached to the middle esophageal segment. The lesion (3.5x2x1 cm) was excised endoscopically under deep sedation. The final histopathology diagnosis was pedunculated SCL. An accurate diagnosis of esophageal SCL is crucial to rule out malignant lesions, relieve symptoms, and undertake suitable treatment. The main differential diagnosis includes well-differentiated sclerosing liposarcoma, atypical spindle cell/pleomorphic lipomatous tumor, giant fibrovascular polyp, and fat-forming solitary fibrous tumor. Although rare, SCL should be added to the list of lipomatous tumors that can affect the esophagus. Complete excision is the appropriate treatment.

Corresponding author: Jose-Fernando Val-Bernal, Professor, MD, PhD; e-mail:

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19. The diagnostic challenges in a child with intestinal tuberculosis

Raluca Maria Vlad, Elena Roxana Smadeanu, Gabriel Becheanu, Ruxandra Darie, Daniela Pacurar

Introduction: Romania is one of the European countries with a significant burden of tuberculosis (TB). Although pulmonary TB is still highly prevalent, intestinal TB is very rare and remains a diagnosis of exclusion, especially in children. The authors aimed to raise the awareness on this pathology by discussing the challenges faced in the management of one difficult case. Case presentation: A 3-year-old boy was hospitalized in the Pediatrics Department of Grigore Alexandrescu Emergency Children s Hospital, Bucharest, Romania, for abdominal pain and melena. On clinical examination, he was malnourished, with generalized edema and marked abdominal distension. Laboratory tests revealed iron-deficiency anemia, low plasma proteins, inflammatory syndrome and high fecal calprotectin. The abdominal ultrasound showed bowel wall thickening and diffuse edematous mesentery; the colonoscopy described multiple ulcers with edematous margins. Parenteral nutrition and complex antibiotic treatment were initiated with no effect. During the hospital stay, the medical staff observed how the mother chewed the patient s food. The child s pulmonary X-ray was normal, but the mother s was suggestive for pulmonary TB. The QuantiFERON test was positive. Biopsy of the bowel mucosa revealed numerous granulomas; the Auramine O/Rhodamine B staining of the specimen was positive. Specific TB treatment was started with good results: the patient resumed growth, abdominal pain and distention disappeared. Conclusions: Intestinal TB poses a diagnostic challenge, especially in the absence of pulmonary disease. It may mimic many other intestinal pathologies. Since correct treatment depends on making the correct diagnosis, a high index of suspicion must be kept when facing atypical abdominal symptoms.

Corresponding author: Raluca Maria Vlad, Assistant Professor, MD, PhD; e-mail:

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20. Health data protection and confidentiality in EU BTC legislation: ethical and safety standards

Anca Parmena Olimid, Daniel-Alin Olimid

Purpose: The current paper focuses on the ethical approaches to data protection and confidentiality (DP and C) and the quality and safety (Q and S) requirements in the European Union (EU) blood, tissues and cells (BTC) legislation, namely: Directive 2002/98/EC, Directive 2004/23/EC, Directive 2005/61/EC, Directive 2005/62/EC, Directive 2006/86/EC, Commission Directive (EU) 2015/565, SWD(2019) 376 final and the external evaluation SANTE/2017/B4/010. Background: In the EU, the ethical requirements for the BTC legal framework focus also on the quality, eligibility, safety, and protection standards. In addition, the SWD(2019) 376 final on the evaluation of the EU BTC legislation released in October 2019 draws attention to the challenges of technology, consent and donation, testing procedures and management of the BTC services. Content: The paper highlights the EU BTC setting standards by examining the particular provisions for the: hemovigilance, eligibility of donors, blood and blood components (BBC), consent, decisions required at the Member States (MS) level, healthcare standards, measures for the blood establishments (BE) and tissue establishments (TE) and particular issues concerning the donation of tissues and/or cells (T and C). Conclusions: Nevertheless, the intended function of the analysis is to focus on the EU BTC legislation and to enable research responsive to the latest initiatives launched by the European Blood Alliance (EBA) and Nuffield Council on Bioethics (NCB) in the field of the definitions and ethical processes.

Corresponding author: Anca Parmena Olimid, Associate Professor, PhD; e-mail:

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21. The efficiency of public policies and programs for breast cancer prevention. Socio-medical perspectives within a Romania-France comparison

Gabriela Motoi, Andreea Mihaela Nita

The World Health Organization (WHO) estimates that one of five persons develops a cancer form during their lives. Out of the total of malignant cancer forms known up to the present, the statistics currently place breast cancer on the first rank at European level, as a type of neoplasm registered and treated with a standard protocol through the medical programs approved within public policies. The cost for the treatment of this type of oncological disease is enormous; for this reason, the state should manifest a direct interest for the prevention, early diagnose and investments in the research of mammary neoplasm. The coherence of national and European policies is achieved on a regular basis, subject to changes in Community legislation and the approval of European Commission (EC) documents that design unified approaches. This year, the emergence of the Europe s Beating Cancer Plan, launched in 2021, has taken on the objective of investing in research and innovation, with a focus on the development of digital technologies that will increase expertise in genomics, onco-radiology, and digital health. The article analyzes the secondary data and empirical research collected at national and European level with the aim of highlighting the significant differences between public policies in Romania and France and identifying the pillars on which a national strategy similar to a functional European model can be built.

Corresponding author: Gabriela Motoi, Senior Lecturer, PhD; e-mail:; Andreea Mihaela Nita, Associate Professor, PhD; e-mail:

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22. Letter to the Editor: Esophageal pulmonary fistula and malignancy

Vitorino Modesto Dos Santos, Lister Arruda Modesto Dos Santos


Corresponding author: Vitorino Modesto dos Santos, Professor, MD, PhD; e-mail:

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