Vol. 64 No. 1, January-March 2023

1. DNA damage response and potential biomarkers of radiosensitivity in head and neck cancers: clinical implications

Domnica Carpov, Rares Buiga, Viorica-Magdalena Nagy

Head and neck cancers include a wide variety of tumor sites that originate in the epithelium of the upper aerodigestive airways. The curative treatment of this group of pathologies most frequently involves multidisciplinary approach in which radiotherapy (RT) plays a central role. Treatment failures are mainly due to recurrences and local or regional evolution and rarely to distant metastases, which emphasizes the importance of ensuring local control. For patients with recurrences, the treatment options are significantly reduced, and prognosis is considerably attenuated. At the cellular level, the main irradiation target is the deoxyribonucleic acid (DNA), its lesions being largely responsible for radiation-induced cell death. However, not all DNA damage will have the same biological significance and a considerable part will be repaired through an intricate network of signaling proteins and repair pathways. Radiobiologically, compared to normal cells, tumor clonogens are defined by malfunction of DNA repair pathways. Tumors with an increased repair capacity, especially DNA double-strand breaks, the most lethal lesions induced by RT, will be radioresistant. The purpose of this review was to elucidate the mechanisms involved in avoiding radiation-induced apoptosis of head and neck cancers mediated by modulating the repair of DNA damage via p53, epidermal growth factor receptor (EGFR) and p16. The role of DNA damage-associated biomarkers in response to irradiation in clinical practice for the selection of personalized treatments and specifying the prognosis and, finally, the bases of immunotherapy association are presented.

Corresponding author: Domnica Carpov, MD, PhD Student; e-mail:

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2. Morphological aspects of basal cell carcinoma vascularization

Raluca-Maria Bungardean, Mirela-Anca Stoia, Bogdan Pop, Maria Crisan

Basal cell carcinoma (BCC) is a malignant skin cancer which commonly exhibits aberrant blood flow because of angiogenesis. Its invasiveness and lack of metastatic potential may be explained by the typical pattern of vascularization seen in BCCs, where blood vessels are absent in the tumor islands and prominent in the tumor s periphery. From clinical point of view, high-frequency ultrasound (HFUS) is a useful tool for the evaluation of the lateral and depth extension of these tumors; furthermore, by employing color Doppler, important data regarding the vascularization degree of BCCs is provided. Knowingly, the sonographic vascular pattern of cutaneous tumors can aid in improving diagnosis and treatment by differentiating between benign and malignant lesions, between various types of cutaneous malignancies and also between various types of BCC (e.g., low risk versus high risk). Our aim was to perform a review integrating all currently known vascular properties of BCC as a tumor entity.

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

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3. Immunohistochemical evaluation of biomarkers with predictive role in acromegaly: a literature review

Maximilian Cosma Gliga, Ligia Gabriela Tataranu, Mihaela Popescu, Laura Chinezu, Maria Ionela Pascanu

Acromegaly is a rare endocrine disorder, which despite the recent advances in diagnosis and management, remains a significant burden in terms of morbidity and mortality for patients because of the frequent aggressive evolution and lack of response to available first-line pharmacological therapy. A switch from the classical trial and error management to a personalized therapy approach has been proposed through early identification of biomarkers that could predict treatment response and biological behavior. Several such molecular markers have been extensively studied through immunohistochemistry (IHC), among them the somatostatin receptors type 2 (SSTR-2) and type 5 (SSTR-5), which are known to correlate with response to somatostatin analogues treatment, the SSTR-2 negative tumors usually being resistant to first-generation analogues, while SSTR-5 potentially being a predictive marker for the novel agent, Pasireotide. Based on cytokeratin (CK) immunostaining pattern, somatotropinomas have been classified into densely granulated adenomas (DGAs), which present a milder evolution and favorable outcomes after therapy, and sparsely granulated adenomas (SGAs), known to be more aggressive and frequently resistant to first-line treatment options. Other novel markers, such as the E-cadherin cell-adhesion protein, the aryl hydrocarbon receptor-interacting protein (AIP), the cytoskeleton molecule filamin A (FLNA) and the Ki-67 nuclear antigen have also been the highlight of IHC studies on growth hormone (GH)-producing tumors, with promising results regarding their predictive roles for the outcome of acromegalic patients. In this review, we aimed to summarize the current knowledge on the role of IHC for acromegaly, highlighting the most important biomarkers that could offer valuable information for predicting treatment response, biological behavior, and prognosis.

Corresponding author: Mihaela Popescu, Associate Professor, MD, PhD; e-mail:

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4. Apoptosis of pro-B lymphocytes induced by NR4A1 activation in the presence of gingival fibroblast exosomes and TNFalpha, caspase 8, STAT3, and Akt pathways modulators

Carmen Amititeloaie, Liliana Chelaru, Gabriela Luminita Geletu, Anca Sava, Alexandra Jitareanu, Andreea Mihaela Tibeica, Marcel Costuleanu

There is a lack of data in the mainstream literature regarding the interactions between gingival fibroblasts, as a component of the local niche, and tumor precursors of B-lymphocytes. Although it is known that the development of tumors and tumor precursors depends on the local environment s characteristics. In order to experimentally evaluate the apoptosis of pro-B type lymphocytes, induced as a result of the known activation of orphan nuclear receptor 4A1 (NR4A1), through Cytosporone B (Csn-B, 10 micro-M), in the presence or absence of exosomes derived from gingival fibroblasts, we administered as a treatment: 1 micro-M R-7050 [functional inhibitor of tumor necrosis factor alpha (TNFalpha)], 1 micro-M Z-IETD-FMK (functional inhibitor of caspase 8), 1 micro-M GSK690693 (functional inhibitor of Akt 1/2/3 pathways) and, last but not least, 1 micro-M scutellarin [functional inhibitor of receptor activator of nuclear factor-kappa B ligand (RANKL)] and therefore of the signal transducer and activator of transcription 3 (STAT3) pathway. Firstly, it is really clear that the presence of exosomes in the pro-B lymphocytes culture medium amplified the apoptotic effects of 10 micro-M Csn-B. The inhibition of tumoral precursors development, namely the pro-B type, might be highly dependent on the inhibition of Akt 1/2/3 pathways, the first and most important consequence being apoptosis induced by the activation of NR4A1 orphan nuclear receptors.

Corresponding author: Liliana Chelaru, Lecturer, MD, PhD; e-mail:; Gabriela Luminita Geletu, Lecturer, MD, PhD; e-mail:

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5. Assessment of tumoral and peritumoral inflammatory reaction in cutaneous malignant melanomas

Radu Florin Fruntelata, Assil Bakri, George Alin Stoica, Laurentiu Mogoanta, Nina Ionovici, George Popescu, Denisa Floriana Vasilica Pirscoveanu, Andrada Raicea, Marius Eugen Ciurea

Skin cancer is one of the most common types of cancer, with an increasing worldwide incidence in recent decades. The main risk factor for increasing the skin cancer incidence is ultraviolet (UV) radiation. Of the two major forms of skin cancer (melanomas and non-melanotic cancers), the cutaneous melanoma (CM) is the most aggressive form, causing about 80% of the deaths resulted from this type of tumor. Malignant melanoma develops through malignant transformation of melanocytes in the skin because of prolonged exposure to solar or artificial UV. The malignant transformation of the melanocytes in the skin is accompanied by the presence of a local inflammatory reaction that, in the initial stages of carcinogenesis, would oppose to tumor development. Chronic exposure to UV or other etiopathogenic factors induces chronic inflammation, which, by producing inflammatory molecules (cytokines, chemokines, prostaglandins), constitutes a tumoral microenvironment that favors carcinogenesis, tumor invasion, metastasis, and the presence of neoplastic mutant cells that avoid the protective action of the immune system. Using immunohistochemistry techniques, we assessed the intra- and peritumoral inflammatory infiltrate cells in CM. The chronic inflammatory infiltrate presented more intense in the peritumoral stroma compared to the intratumoral one, heterogenous, more intensely composed of lymphocytes, plasma cells, macrophages, and mast cells (MCs), the most numerous cells in the inflammatory infiltrate being T-lymphocytes, plasma cells and macrophages; B-lymphocytes and MCs were in a small number, especially intratumorally. Inflammatory cells had a direct contact with tumor cells, blood vessels, connective matrix, suggesting that the inflammatory microenvironment plays an important role in carcinogenesis, tumor invasion, local angiogenesis, and tumor metastasis.

Corresponding author: Laurentiu Mogoanta, Professor, MD, PhD; e-mail:; Denisa Floriana Vasilica Pirscoveanu, Lecturer, MD, PhD; e-mail:

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6. Osseointegration evaluation of an experimental bone graft material based on hydroxyapatite, reinforced with titanium-based particles

Maria Alexandra Draghici, Ioana Mitrut, Alex Ioan Salan, Petre Costin Marasescu, Ruxandra Elena Caracas, Adrian Camen, Lucian Toma Ciocan, Oana Gingu, Horia Octavian Manolea

Bone graft materials are more and more frequently used in dentistry for improving the periodontal support and for creating a bone support favorable for the insertion of dental implants. The experimental study carried out on laboratory animals aimed to evaluate the biocompatibility and the manner of integration of an experimental bone augmentation material, based on hydroxyapatite (HAp), reinforced with titanium-based particles by comparison with a commercial synthetic graft material already existing on the profile market, also based on HAp. We noticed a common pattern of evolution, although there were differences related to the speed of new bone tissue formation and implicitly the morphological elements captured at the two moments of time. In the presence of both synthetic materials, ossification also begins from the center of the cavity at distance from the margins of the bone defect, with a common pattern with an appearance with the presence of osteon-like structures. The experimental material generally determined a more intense initial inflammatory reaction, followed by the generation of a repair bone tissue with a denser appearance but with a less uniform structure and a greater number of residual particles.

Corresponding author: Lucian Toma Ciocan, Associate Professor, DMD, PhD; e-mail:; Adrian Camen, Associate Professor, DMD, PhD; e-mail:

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7. Investigation of distribution of GSK-3beta signal pathway by age groups in cases of ulcerative colitis

Caner Ozbey, Isil Aydemir

Ulcerative colitis (UC), one of the inflammatory bowel diseases, has been reported to increase in recent years. Although the exact cause is unknown, disruptions in the molecular pathways are thought to trigger UC. We aimed to examine the distributions of glycogen synthase kinase-3beta (GSK-3beta), nuclear factor-kappa B (NF-kappaB) and wingless/int-1 (Wnt-1) in different age groups diagnosed with UC. Patients diagnosed with UC were divided into four groups according to their ages: Group 1, aged 18-30 (n=20); Group 2, aged 31-45 (n=20); Group 3, aged 46-60 (n=20); Group 4, aged 61-75 (n=20). Tissue sections were histochemically stained to examine the parameters of epithelial cell height, length of crypt, thickness of muscularis mucosa and extent of submucosal fibrosis. The immunohistochemistry assay was performed using cell survival and for GSK-3beta, NF-kappaB and Wnt-1 cell growth markers. Immunoreactivities were evaluated using H-score and analyzed using the one-way analysis of variance (ANOVA) test for statistics. It was detected a decrease in the histopathological parameters whereas the immunoreactivities of GSK-3beta, NF-kappaB and Wnt-1 were increased with increasing age. The levels of GSK-3beta immunoreactivity were similar in both epithelium and submucosa in all groups. NF-kappaB immunoreactivity was higher in submucosa of Groups 1, 2 and 3, while Wnt-1 was enhanced in Groups 1 and 3. The results of histopathology showed that the integrity of the epithelial tissue in the colon deteriorated with increasing age. The expressions of GSK-3beta, NF-kappaB and Wnt-1 were detected in all age groups. We thought that there was a synergistic activation between these three markers. Nevertheless, studies are needed to investigate this molecular pathway.

Corresponding author: Isil Aydemir, Associate Professor, MD, PhD; e-mail:

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8. Molecular prognostic factors in colorectal cancer: 5-year follow-up

Alina Elena Ciobanu, Daniel-Cristian Pirvu, Cristina Maria Marginean, Anda Lorena Dijmarescu, Adriana-Estefa Munoz-Groza, Cristian Mesina, Tudor-Adrian Balseanu, Vlad Dumitru Baleanu, Tiberiu Stefanita Tenea-Cojan, Daniela Ciobanu

Colorectal cancer (CRC) is a frequently diagnosed and lethal disease. The risk of developing CRC is determined by environmental and genetic factors. Surgical treatment is the main curative modality for patients with CRC up to stage III. In recent years, a special place has been given to biological agents used as targeted therapy following the genetic analysis of the tumor: Bevacizumab (Avastin), Cetuximab (Erbitux), Ziv-aflibercept (Zaltrap). We present a study based on 46 colorectal tumor resection specimens from patients operated for CRC in the Surgery Departments of the Emergency County Clinical Hospital of Craiova, Romania. Histopathological examination and immunohistochemistry staining of tissue sections were performed to determine the degree of aggressiveness. Using the Kaplan-Meier test, we calculated the correlation coefficient between survival time and immunohistochemical prognostic factors. The patients were followed for 60 months postoperatively.

Corresponding author: Daniel-Cristian Pirvu, MD; e-mail:; Cristina Maria Marginean, MD; e-mail:

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9. Primary de novo malignant peripheral nerve sheath tumor of the breast mimicking mastitis. Report of a case and review of the literature

Jose-Fernando Val-Bernal, Sandra Hermana, Fernando Hernanz, German Moreno

Malignant peripheral nerve sheath tumor (MPNST) is a rare tumor representing <0.1% of malignant breast tumors. Here, we report a case of sporadic MPNST of the breast in a 45-year-old woman with a fast-evolving painful mass in the right breast associated with edema, redness, and increased local temperature, simulating mastitis. This presentation has not been reported. A review of the literature since 1992 has revealed 15 MPNST cases, including the present one with sufficient data for analysis. All the cases were women. The ages ranged from 16-60 years (mean 40.5 years). Duration of symptoms varied from four days to 15 years (mean 2.7 years). Tumor size ranged from 2.5-30 cm (mean 10.9 cm). 64.3% of tumors were well-circumscribed. Tumors were graded as grade 1 (7.7%), grade 2 (38.5%), and grade 3 (53.8%). Three (20%) cases showed histopathological peculiarities. Simple mastectomy was performed in four (26.7%) cases, radical mastectomy in six (40%) cases, and simple excision in five (33.3%) cases. There were no metastases in the six cases where axillary dissection was performed. Seven (53.8%) patients received adjuvant therapy, including chemotherapy and/or radiotherapy. Local recurrence was observed in two (16.7%) patients. Distant metastasis was detected in one patient (7.7%) affecting the lung 11 months after radical mastectomy. The follow-up was available for 10 patients (mean 2.2 years, median 1 year). One patient (10%) died of the disease. At the last follow-up, 80% of patients were still alive. The main differential diagnosis includes nonpleomorphic spindle cell tumors.

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

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10. Uterine embryonal rhabdomyosarcoma in adult women: a case report on the challenging diagnosis and treatment

Catalin Florin Pop, Claudia Maria Stanciu-Pop, Christiane Jungels, Marie Chintinne, Carlos Artigas Guix, Florin Grosu, Ciprian Juravle, Isabelle Veys

Background: Uterine embryonal rhabdomyosarcoma (uERMS) in adult women is a very rare malignant entity. The study aim was to report a case of adult uERMS and to discuss the implications of histopathological diagnosis on the treatment and prognosis. Case presentation: We present here the clinicopathological features of a uERMS case in an adult woman. The study has been approved by the institutional Ethics Committee and an informed consent has been obtained (IJB/CE3005). A 45-year-old woman presented to her gynecologist with intermenstrual bleedings and polypoid cervical mass (initially interpreted as benign polyp). A second biopsy was sent to our Department of Pathology at the Jules Bordet Institute, Brussels, Belgium for revision and was reinterpreted as botryoid-type uERMS. The patient underwent a total hysterectomy. The final pathology confirms a 3 cm cervical ERMS, and a simple surveillance was decided by our multidisciplinary team. Six months later, pelvic magnetic resonance imaging control showed a recurrence in the right pelvic lymph nodes. Multi-drug chemotherapy and radiotherapy were done before surgical resection. Pathological examination of the resected pelvic mass confirmed uERMS recurrence of 60 mm, with large zones of necrosis and the presence of cartilaginous structures. The patient is free of disease 60 months after diagnosis. Conclusions: Adult uERMS is rare and the pathological examination is the main element for diagnosis and treatment. It is often confused with other benign entities, at least at the time of diagnosis. ERMS should be included in the differential diagnosis of cervical and uterine polyp of adult women. Long-term survival is possible with a multimodal therapy approach.

Corresponding author: Ciprian Juravle, MD; e-mail:; Catalin Florin Pop, MD; e-mail:

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11. Metastasis to the penis from a bladder carcinoma invading only the lamina propria: case report and description of the morphological aspects

Marius Stanimir, Francis Lorge, Lionel D Hondt, Marie-Cecile Nollevaux, Marcelo Di Gregorio

Introduction: Data shows that bladder cancer (BC) takes the seventh place as the most commonly diagnosed when it comes to the male population. Whereas when both genders considered, it moves down the tenth place. Although 75% of patients with BC present with the disease confined to the mucosa or submucosa, rarely secondary metastasis to the penis occurs. Case presentation: A 73-year-old male was referred for gross hematuria in May 2018. A cystoscopy was performed detecting a bladder tumor. The resection of the tumor revealed an invasive high-grade (HG) papillary transitional carcinoma of the bladder with nest variants and lamina propria invasion. The histological examination of the second-look resection disclosed the same tumor characteristics. The patient was scheduled for bacillus Calmette-Guerin (BCG) instillations. Meanwhile, he was diagnosed and treated for a primitive lung acinar adenocarcinoma. Seven months after the first diagnosis, the patient progressed to cT4 at the level of the bladder. He underwent four cycles of Methotrexate, Vinblastine, Doxorubicin (Adriamycin) and Cisplatin (MVAC) chemotherapy followed by a cystoprostatectomy. The histological result was fibrosis and ypT0pN0 classification. Due to pain and solid mass in the penis, a total penectomy was performed and the histological result showed a transitional carcinoma suggesting a metastasis of the urothelial carcinoma of the bladder. Three months following the penectomy, a positron emission tomography/computed tomography (PET/CT) scan results showed multiple metastases and positive lymph nodes. Hence, Pembrolizumab treatment was started, providing very good clinical and radiological evolution. At the time of publishing, the patient is alive, and the radiological exams show stability of the disease. Conclusions: The detailed descriptions of all histological variants of carcinoma of the bladder in the specimen has great importance and significant impact on the management of the disease.

Corresponding author: Marius Stanimir, MD; e-mail:

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12. Carl Weigert s pioneer definition of heart infarction as myocardial, coagulative necrosis due to obstruction of atherosclerotic coronary arteries in 1880, overshadowed by subsequent, secondary publications in the field

Andrzej Wincewicz, Piotr Woltanowski

In 1880, a German Jewish Professor of Pathology, Carl Weigert (1845-1904) first defined heart infarction as myocardial, coagulative necrosis (Coagulationsnekrose) due to obliteration of atherosclerotic coronary arteries thanks, at least, partially to his great diligence in vascular staining methods. Histochemical techniques made his name eponymic as Weigert s Hematoxylin or Weigert s and Van Gieson s elastic stains are still used in routine practice to visualize, e.g., the framework of vessels. However, his discovery has been overshadowed by far more frequently cited in recent decades, subsequent but secondary, 214-page-long book dated on 1896 and titled L infarctus du myocarde et ses consequences - ruptures, plaques fibreuses, anevrismes du coeur, in which Rene Marie repeated Carl Weigert s words that dead cardiomyocytes lost their cellular nuclei. Weigert introduced the term die Infarcte des Herzmuskels, in 1880, in his paper titled Uber die pathologischen Gerinnungsvorgange, in Virchows Archiv. According to Weigert, occlusions were caused by white thrombi (weissen Thromben) on the ground of atheromatous changes of the coronary arteries. In following manner, he gave macroscopic description of heart infarction: If a blood supply is very roughly (German: brusk), completely cut off in individual parts of the heart muscle, yellowish dry masses are formed that resemble coagulated fibrin. If examined microscopically, one usually does not find any fibrinous material exudate, but often a delusively normal tissue (sometimes you can even see cross striation of the muscle fibers): but all muscle fibers (…) are anucleate. Paradoxically, coronary thrombosis was also a cause of Carl Weigert s death.

Corresponding author: Andrzej Wincewicz, Associate Professor, MD, PhD; e-mail:,

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13. Letter to the Editor: Variable response to Idebenone in LHON is multifactorial

Josef Finsterer, Sounira Mehri


Corresponding author: Josef Finsterer, MD, PhD; e-mail:

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