The Nine-Year Survival of Patients Operated for Non-Small-Cell Lung Carcinoma in a Tertiary Centre: The Impact of the Tumour Stage and Other Patient-Related Parameters.

Background and Objectives: The mainstay treatment of non-small-cell lung carcinoma is still surgery, but its impact on survival beyond nine years has never been reported/analysed in Romania. Therefore, we studied the clinical characteristics and the short- and long-term survival of a population of 1369 patients diagnosed and treated in a single institution, with the variables included in the database being collected retrospectively. Materials and Methods: In this paper, we aimed to study a number of factors that might influence prognosis and survival in non-small bronchopulmonary carcinoma. Consequently, we analysed a series of parameters such as the age of patients, their sex, the histopathological type, the tumour stage, the presence of bronchial invasion, and the completeness of surgical resection. Results: All patients underwent major lung resection for curative purposes (pneumonectomy, lobectomy, or bilobectomy) between January 2015 and January 2023. The vital status of patients included in the study was obtained by checking the DGEP (General Directorate for Persons Record) database and verifying the reporting of "non-deceased" by the hospital administrative database, as well as by telephone interviews (with patients or their relatives). On univariate analysis, predictors of worse survival were the following: male sex (the hazard of death was 1.54 times higher in men); pT (compared to pT1 tumours, pT2 tumours have a 1.60 times higher hazard of death, pT3 tumours have a 2.16 times higher hazard, and pT4 tumours have a 2.97 times higher hazard); maximum tumour size (a 10 mm increase in tumour size is associated with a 10% increase in the hazard of death); the degree of differentiation (compared to patients with G1 tumours, those with G3 tumours have a 2.16 times higher hazard of death); resectability (compared to R0, R1 B+ has a 1.84 times higher hazard of death, R1 V+ has a 1.82 times higher hazard of death, and R1 B+&V+ has a 2.40 times higher hazard of death). Conclusions: As a result, long-term survival can be achieved after complete surgery for NSCLC, and factors that classically predict overall survival suggest that both the initial tumour aggressiveness and host characteristics act beyond the period usually considered in oncology.

Atypical Histopathological Aspects of Common Types of Lung Cancer-Our Experience and Literature Review.

Lung cancer is among the most common oncological diseases regarding incidence and mortality, with most of these having epithelial origins. Pathological reporting of these tumors is conducted according to the 5th edition of the World Health Organisation (WHO) classification of thoracic tumours. This study aims to draw the pathologist's attention to four rare, atypical microscopic aspects that some of the most common types of lung malignancies reveal upon standard evaluation (hematoxylin-eosin stain) that make histopathological diagnosis challenging: acantholytic, pseudoangiosarcomatous, signet ring cell, and clear cell features. Each of these aspects was exemplified by a case diagnosed in the pathology department of the "Marius Nasta" Institute. Furthermore, we analyzed the classification dynamics of different WHO editions and used PubMed to review articles written in English and published in the last eleven years on this subject. Pathologists should be familiar with these unusual aspects to avoid misdiagnoses and to ensure the correct classification of tumors, which is extremely important because these tumor phenotypes have been associated with specific molecular alterations and a worse clinical evolution. There is a need to clarify the histogenesis and associated genetic mutations, given the fact that the rarity of these tumor phenotypes makes their study difficult. Some authors consider these to be overlapping entities; however, we do not encourage this, as they may exhibit different prognoses and various molecular alterations with important therapeutic implications. The signet ring cell feature was associated with ALK rearrangement in lung adenocarcinoma; thus, these patients can benefit from tailored therapy with ALK-tyrosine kinase inhibitors (ALK-TKI). Recent studies associated clear cell morphology with FGFR3-TACC3 fusion, suggesting that patients with this diagnosis may be potentially eligible for FGFR inhibitors. We described, for the first time, the pseudoangiosarcomatous pattern in a case of lung adenocarcinoma; to our knowledge this aspect has only been described until now in the context of squamous cell carcinomas.

Cutaneous Melanoma: A Review of Multifactorial Pathogenesis, Immunohistochemistry, and Emerging Biomarkers for Early Detection and Management.

Cutaneous melanoma (CM) is an increasingly significant public health concern. Due to alarming mortality rates and escalating incidence, it is crucial to understand its etiology and identify emerging biomarkers for improved diagnosis and treatment strategies. This review aims to provide a comprehensive overview of the multifactorial etiology of CM, underscore the importance of early detection, discuss the molecular mechanisms behind melanoma development and progression, and shed light on the role of the potential biomarkers in diagnosis and treatment. The pathogenesis of CM involves a complex interplay of genetic predispositions and environmental exposures, ultraviolet radiation exposure being the predominant environmental risk factor. The emergence of new biomarkers, such as novel immunohistochemical markers, gene mutation analysis, microRNA, and exosome protein expressions, holds promise for improved early detection, and prognostic and personalized therapeutic strategies.

The Impact of Clinical and Histopathological Factors on Disease Progression and Survival in Thick Cutaneous Melanomas.

Thick cutaneous melanomas (Breslow depth > 4 mm) are locally advanced tumors, generally associated with poor prognosis. Nevertheless, these tumors sometimes display unpredictable behavior. This study aims to analyze clinical and histopathological features that can influence the prognosis of thick melanomas. This is a retrospective study on 94 thick primary cutaneous melanomas diagnosed between 2012 and 2018 that were followed-up for at least five years to assess disease progression and survival. We evaluated the age, gender, tumor location, histological subtype, Breslow depth, Clark level, resection margins, mitotic index, the presence/absence of ulceration, necrosis, regression, microsatellites, neurotropism, lymphovascular invasion, and the pattern of tumor-infiltrating lymphocytes, and their association with disease progression and survival. By conducting univariate analysis, we found that progression-free survival (PFS) was significantly associated with female gender, the superficial spreading melanoma (SSM) subtype, mitotic index, necrosis, microsatellites, and perineural invasion. Overall survival (OS) was significantly associated with female gender, Breslow depth, SSM subtype, necrosis, microsatellites, and perineural invasion. Through multivariate Cox proportional hazards regression, we found that the only factors associated with PFS were Breslow depth, necrosis, microsatellites, and perineural invasion, while the factors associated with OS were Breslow depth, necrosis, microsatellites, and perineural invasion. Certain histopathological features such as Breslow depth, necrosis, microsatellites, and perineural invasion could explain differences in disease evolution. This is one of the first studies to demonstrate an association between necrosis and perineural invasion and outcomes in patients with thick melanomas. By identifying high-risk patients, personalized therapy can be provided for improved prognosis.

Gallbladder Pancreatic Heterotopia-The Importance of Diagnostic Imaging in Managing Intraoperative Findings.

Pancreatic heterotopy is a rare entity defined as the presence of abnormally located pancreatic tissue without any anatomical or vascular connection to the normal pancreas. Heterotopic pancreatic tissue can be found in various regions of the digestive system, such as the stomach, duodenum, and upper jejunum, with the less commonly reported location being the gallbladder. Gallbladder pancreatic heterotopia can be either an incidental finding or diagnosed in association with cholecystitis. Pancreatitis of the ectopic tissue has also been described. In this context, we report three cases of heterotopic pancreatic tissue in the gallbladder with different types of pancreatic tissue according to the Heinrich classification. One patient was a 24-year-old male who presented with acute pancreatitis symptoms and an ultrasonographical detected mass in the gallbladder, which proved to be heterotopic pancreatic tissue. The other two cases were female patients aged 24 and 32, respectively, incidentally diagnosed on histopathological examination after cholecystectomy for symptomatic cholelithiasis. Both cases displayed chronic cholecystitis lesions; one of them was also associated with low grade dysplasia of the gallbladder. Although a rare occurrence in general, pancreatic heterotopia should be acknowledged as a possible incidental finding in asymptomatic patients as well as a cause for acute cholecystitis or pancreatitis.

Primary Undifferentiated/Dedifferentiated Cutaneous Melanomas-A Review on Histological, Immunohistochemical, and Molecular Features with Emphasis on Prognosis and Treatment.

Diagnosing cutaneous melanoma is usually straightforward based on these malignancies' histopathological and immunohistochemical features. Nevertheless, melanomas can imitate various other neoplasms, sometimes lacking the expression of conventional melanocytic markers and expressing non-melanocytic ones. Furthermore, divergent differentiation is more often encountered in metastatic melanomas and is still poorly described in primary cutaneous melanomas, and little is known about these patients' prognosis and therapeutic approach. Therefore, we reviewed the literature on undifferentiated/dedifferentiated cutaneous melanomas, and we discuss the histological, immunohistochemical, and molecular profiles of undifferentiated/dedifferentiated cutaneous melanomas to understand these peculiar lesions better and improve their diagnostic algorithm. In addition to this, we also discuss how different genetic mutations may influence prognosis and become potential therapeutic targets.

The Conundrum of Dedifferentiation in a Liposarcoma at a Peculiar Location: A Case Report and Literature Review.

Dedifferentiated liposarcoma of the deep soft tissue of the lower extremities is an infrequent finding. Myxoid liposarcoma is considered the most common soft tissue neoplasia arising in this anatomic region. Divergent differentiation usually occurs within well-differentiated liposarcoma and is exceedingly rare in a myxoid liposarcoma. We report a 32-year-old man who developed a dedifferentiated liposarcoma of the thigh on the background of a pre-existing myxoid liposarcoma. The gross examination of the surgical specimen showed a 11/7/2 cm tumour mass with solid tan-grey areas and focal myxoid degeneration. The microscopic examination revealed a malignant lipogenic proliferation, containing round cells with hyperchromatic nuclei and atypical lipoblasts, confined to the basophilic stroma with a myxoid aspect. Abrupt transition towards a hypercellular, non-lipogenic area consisting of highly pleomorphic spindle cells with atypical mitotic figures was also noted. Immunohistochemical staining was performed. Tumour cells in the lipogenic area were intensely positive for S100 and p16, and CD34 staining highlighted an arborizing capillary network. The dedifferentiated tumour areas showed positive MDM2 and CDK4 staining within neoplastic cells, with the Ki 67 proliferation marker expressed in approximately 10% of the cells. Wild-type TP53 protein expression pattern was documented. Thus, the diagnosis of a dedifferentiated liposarcoma was established. This paper aims to provide further knowledge about liposarcomas with divergent differentiation at peculiar locations, emphasizing the importance of histopathologic examination and immunohistochemical analysis for establishing the diagnosis and assessing the therapeutic response and prognosis of this condition.

Comparative Expression Profiling Reveals Molecular Markers Involved in the Progression of Cutaneous Melanoma towards Metastasis.

Cutaneous melanoma is one of the most aggressive types of cancer and often proves fatal in metastatic stages. Few treatment options are available, and its global incidence is quickly increasing. In order to gain an improved understanding of the molecular features regarding melanoma progression, we have compared gene and small non-coding RNA expression profiles from cell lines derived from primary melanoma (MelJuSo), lymph node metastasis (MNT-1) and brain metastasis (VMM1), representing distinct stages of malignant progression. Our preliminary results highlighted the aberrant regulation of molecular markers involved in several processes that aid melanoma progression and metastasis development, including extracellular matrix remodeling, migratory potential and angiogenesis. Moreover, bioinformatic analysis revealed potential targets of the microRNAs of interest. Confocal microscopy and immunohistochemistry analysis were used for validation at the protein level. Exploring the molecular landscape of melanoma may contribute to the achievement of future efficient targeted therapy, as well as better prevention, diagnosis and clinical management.

A Disguising Fast-Growing Metachronous Melanoma and COVID-19.

An unusual case of a 52-year-old female with two metachronous melanomas is presented. An atypical fast-growing nodular melanoma appeared 18 months after the complete excision of an in situ melanoma and one month afterward a SARS-CoV-2 infection. Intra-nodal melanocytic proliferations were identified during lymph node assessment, raising important diagnostic and prognostic concerns. No melanoma susceptibility genes were found. This case report raises the question about the COVID-19 immunosuppression effect on the tumor microenvironment and the oncogenic potential of SARS-CoV-2. It also highlights the importance of clinical follow-up in melanoma patients, which was significantly delayed during the COVID-19 pandemic.

Paraneoplastic Pemphigus Mimicking Pemphigus Vulgaris Associated With Castleman Disease.

Paraneoplastic pemphigus (PNP) is a rare bullous disease with a polymorphic presentation. Diagnosis can be difficult because it can mimic other bullous diseases, while the underlying neoplasm may be completely asymptomatic. We present the case of a 19-year-old female with a four-year history of exclusively oral bullous lesions, mimicking pemphigus vulgaris, before the diagnosis of a retroperitoneal Castleman disease. While PNP is a severe and sometimes deadly condition, our patient had a mild and long evolution on minimal treatment, with complete resolution after tumor excision. Practitioners should be aware of PNP in young patients presenting with bullous disease and should conduct prompt systemic investigations in refractory or long-evolving cases, even when PNP diagnostic criteria are not fully met.

Oral leukoplakia: A clinicopathological study and malignant transformation.

OBJECTIVES: To assess the clinicopathological characteristics of a cohort of patients with oral leukoplakia (OL) managed in a Romanian dental hospital and to evaluate the risk of malignant transformation (MT). MATERIALS AND METHODS: We conducted a hospital-based retrospective study using the clinical charts of patients diagnosed with OL that had complete clinical and histopathological evaluation followed up for 1-16 years. RESULTS: From 120 included patients, 68 (56.7%) were females, and 71 (59.2%) were current smokers. The homogeneous form was present in 60% of cases; the buccal mucosa was the most frequently involved site. MT was observed in 9 cases, which was more common in females and in those with dysplastic leukoplakia. A significant statistical association was found between MT and dysplasia grade (χ2 test: p = 0.007). MT occurred during a mean interval of time 75 months in both treated and non-treated patients. CONCLUSIONS: In this leukoplakia cohort, most of the lesions encountered were in smokers, clinically homogeneous and 62.5% proved histologically benign. But despite the clinically benign appearance of leukoplakia, tissue diagnosis of some cases was carcinoma. The results of the current study advocate the necessity for biopsy even in apparently homogeneous, clinically benign lesions. The malignization rate was 7.5%; two-thirds were nonhomogeneous lesions.

Super-resolution re-scan second harmonic generation microscopy.

Second harmonic generation microscopy (SHG) is generally acknowledged as a powerful tool for the label-free three-dimensional visualization of tissues and advanced materials, with one of its most popular applications being collagen imaging. Despite the great need, progress in super-resolved SHG imaging lags behind the developments reported over the past years in fluorescence-based optical nanoscopy. In this work, we demonstrate super-resolved re-scan SHG, qualitatively and quantitatively showing on collagenous tissues the available resolution advantage over the diffraction limit. We introduce as well super-resolved re-scan two-photon excited fluorescence microscopy, an imaging modality not explored to date.

Hypocomplementemic Urticarial Vasculitis Associated With Hashimoto's Thyroiditis and Hepatitis B Virus Infection: A Case Report.

Urticarial vasculitis (UV) is an uncommon condition characterized by recurrent episodes of urticarial lesions and angioedema and the pathological features of leukocytoclastic vasculitis. UV divides into two subgroups based on the level of serum complement. Usually, patients with hypocomplementemia experience internal organ involvement and an unfavorable prognosis. We report the case of a 33-year-old woman with a history of hepatitis B infection and autoimmune thyroiditis who developed hypocomplementemic urticarial vasculitis with recurrent angioedema and arthralgia. Complete remission was achieved using dapsone in monotherapy. We suggest dapsone as a potential treatment of choice for hypocomplementemic urticarial vasculitis. This clinical case emphasizes the need for urticarial vasculitis treatment guidelines.

Clinical, Dermoscopic and Microscopic Features of a "Collision Tumour" Ultimately Confirmed as a Regressing Melanoma - Lessons Learnt from a Chance Diagnosis.

Spontaneous regression of malignant melanoma was first reported over a century ago. Clinically, areas of blue or grey colouration in lesions may be indicative of regression. Dermoscopy is a very useful tool for diagnosing regression. An important criterion is the blue-white scar. About 10-35% of excised melanomas show features of regression histopathologically. We present a case of regressing melanoma, with clinical and dermoscopic features suggesting a collision tumour, diagnosed histopathologically. This case might improve our knowledge of the potential clinical manifestations, and the biology, of regressing melanoma.

PSHG-TISS: A collection of polarization-resolved second harmonic generation microscopy images of fixed tissues.

Second harmonic generation (SHG) microscopy is acknowledged as an established imaging technique capable to provide information on the collagen architecture in tissues that is highly valuable for the diagnostics of various pathologies. The polarization-resolved extension of SHG (PSHG) microscopy, together with associated image processing methods, retrieves extensive image sets under different input polarization settings, which are not fully exploited in clinical settings. To facilitate this, we introduce PSHG-TISS, a collection of PSHG images, accompanied by additional computationally generated images which can be used to complement the subjective qualitative analysis of SHG images. These latter have been calculated using the single-axis molecule model for collagen and provide 2D representations of different specific PSHG parameters known to account for the collagen structure and distribution. PSHG-TISS can aid refining existing PSHG image analysis methods, while also supporting the development of novel image processing and analysis methods capable to extract meaningful quantitative data from the raw PSHG image sets. PSHG-TISS can facilitate the breadth and widespread of PSHG applications in tissue analysis and diagnostics.

Influence of the microenvironment dynamics on extracellular matrix evolution under hypoxic ischemic conditions in the myocardium.

The extracellular matrix (ECM) consists of fibrillary and non-fibrillary components in the extracellular zone, and fulfills structural and signaling roles. Cardiac insult can lead to cardiomyocyte death, which subsequently determines dynamic changes of ECM composition and regulates cellular responses, ultimately contributing to cardiac repair. The present retrospective study on a small batch selected from the database of the Pathology Department of 'Sf. Pantelimon' Hospital aimed to determine which molecules may have a role in the dynamics of ECM using histopathology and immunohistochemistry methods. The study batch was composed of cases with cardiac ischemic conditions who died at various ages of myocardial infarcts. Tissue samples were taken from the myocardium of the left ventricle (anterior and lateral walls), and multiple series of histological sections were produced and analyzed using immunohistochemistry for collagen type I (Col-1), tenascin C (Tn-C), matrix metalloproteinase 9, CD34, and CD68. Col-1 and Tn-C showed variable patterns of fibrillar plexiform network, associated with a high micro-vascular density of newly formed capillaries revealed by CD34, and an interstitial infiltrate with histiocytes demonstrated by CD68 presence. The ECM represents therefore a polymorphic microenvironment with its own dynamics that is in continuous change, involving a large spectrum of heterogenous molecules, which play different roles in myocardium remodeling under hypoxic ischemic conditions.

Influence of hematoxylin and eosin staining on the quantitative analysis of second harmonic generation imaging of fixed tissue sections.

Second harmonic generation (SHG) microscopy has emerged over the past two decades as a powerful tool for tissue characterization and diagnostics. Its main applications in medicine are related to mapping the collagen architecture of in-vivo, ex-vivo and fixed tissues based on endogenous contrast. In this work we present how H&E staining of excised and fixed tissues influences the extraction and use of image parameters specific to polarization-resolved SHG (PSHG) microscopy, which are known to provide quantitative information on the collagen structure and organization. We employ a theoretical collagen model for fitting the experimental PSHG datasets to obtain the second order susceptibility tensor elements ratios and the fitting efficiency. Furthermore, the second harmonic intensity acquired under circular polarization is investigated. The evolution of these parameters in both forward- and backward-collected SHG are computed for both H&E-stained and unstained tissue sections. Consistent modifications are observed between the two cases in terms of the fitting efficiency and the second harmonic intensity. This suggests that similar quantitative analysis workflows applied to PSHG images collected on stained and unstained tissues could yield different results, and hence affect the diagnostic accuracy.

Fibroblast involvement in cardiac remodeling and repair under ischemic conditions.

Cardiac fibroblasts play a main role in the physiological turnover of the extracellular matrix, as well as its pathological remodeling. A study was performed on a batch of 23 cases who died of various cardiac complications secondary to scarring myocardial infarctions. The aim of the study was to assess the fibroblast involvement in cardiac repair under ischemic conditions after myocardial infarction. Tissue myocardial samples from the left ventricle were taken from these cases for microscopy examination, in order to investigate the type and degree of fibrosis as well as the presence of cardiac interstitial fibroblasts. Multiple series of histological sections were also performed and examined, along with immunohistochemical analysis. The fibroblasts were diffusely distributed in the interstitium among the residual cardiomyocytes, showing variable expression of vimentin and smooth muscle actin. During cardiac remodeling, there was a successive interstitial deposition, first of reticulin fibers and then of collagen fibers, leading to interstitial fibrosis and myocardial replacement. There was a correlation between vimentin and smooth muscle actin expression and collagen deposition. Fibrosis with cardiac remodeling is based on maintaining proliferation capacity of the fibroblast and its capacity of protein synthesis in the extracellular matrix. Under hypoxic ischemic conditions, followed by myocardial infarction, the fibroblast switches phenotype and transdifferentiate into myofibroblast, contributing to the healing by secreting extracellular matrix proteins and collagen deposition, with subsequent cardiac remodeling and regulation of the micro-environment metabolism.

Therapy Delayed is Therapy Denied: A Case Report of Melanoma Misdiagnosed as Diabetic Foot Ulcer.

Malignant melanoma is a deadly form of skin cancer, and prompt diagnosis is a key factor in providing adequate, life-saving therapy. A 75-year-old man, with long-standing type 2 diabetes mellitus, presented with a 2- to 3-year history of right heel ulcer. He had received various therapies for a diagnosis of diabetic foot ulcer, to no avail. Physical examination showed a black, fungating ulcerated lesion on his right heel, with minimal bleeding. No inguinal lymphadenopathy was palpated. A biopsy was done, which revealed BRAF-negative malignant melanoma, with a vertical growth phase, Breslow 3.1 mm, ulceration, 11 mitoses/mm2, Clark level IV, no lymphatic or vascular invasion observed. Right inguinal lymph node sampling suggested no involvement, but PET-CT suggested pulmonary, right inguinal lymph node and bone involvement. The patient was referred to the oncologists. Written informed consent for publication was given by the patient. Diabetic foot ulcers are a frequently encountered, but serious complication of diabetes mellitus. Delayed healing is often seen, despite adequate therapy. The differential diagnosis of diabetic foot ulcers is vast and includes neoplasia. When a foot ulcer fails to heal, other differential diagnoses must be considered, in order for the patient to receive adequate therapy. Here specialist consultations, including dermatology consultations, could improve chances of delivering the right therapy promptly. This is a factor underlying the emphasis on a multidisciplinary approach to foot ulcer therapy. Our presentation - reported according to the CARE guidelines - also illustrates the fact that failure to reach a timely diagnosis may deny the patient the opportunity to receive adequate treatment. In such cases, "delayed therapy becomes denied (or failed) therapy", paraphrasing the old adage "Justice delayed is justice denied".

A rare case of placental mesenchymal dysplasia - case report and literature review.

Described as a rare anomaly of the placenta, with a reported incidence of 0.02%, mesenchymal dysplasia is a benign condition characterized by placentomegaly, grape-like vesicles and by microscopic features resembling those of a molar pregnancy, such as hydropic villi, cistern formation and dysplastic blood vessels. We report a rare case of placental mesenchymal dysplasia diagnosed in a pregnancy with early symmetric fetal intrauterine growth restriction and a normal karyotype. Based on this case report, we discuss the particularities of this condition, emphasizing the ultrasonography and histopathological findings.