A Novel Algorithm for Evaluating Bone Metastatic Potential of Breast Cancer through Morphometry and Computational Mathematics.

Bone metastases represent about 70% of breast cancer metastases and are associated with worse prognosis as the tumor cells acquire more aggressive features. The selection and investigation of patients with a high risk of developing bone metastasis would have a significant impact on patients' management and survival. The patients were selected from the database of Carol Davila Clinical Nephrology Hospital of Bucharest. Their tumor specimens were pathologically processed, and a representative area was selected. This area was scanned using an Olympus VS200 slide scanner and further analyzed using QuPath software v0.4.4. A representative group of approximately 60-100 tumor cells was selected from each section, for which the following parameters were analyzed: nuclear area, nuclear perimeter, long axis and cell surface. Starting from these measurements, the following were calculated: the mean nuclear area and mean nuclear volume, the nucleus to cytoplasm ratio, the length of the two axes, the long axis to short axis ratio, the acyclicity and anellipticity grade and the mean internuclear distance. The tumor cells belonging to patients known to have bone metastasis seemed to have a lower nuclear area (<55 µm2, p = 0.0035), smaller long axis (<9 µm, p = 0.0015), smaller values for the small axis (<7 µm, p = 0.0008), smaller mean nuclear volume (<200 µm3, p = 0.0146) and lower mean internuclear distance (<10.5 µm, p = 0.0007) but a higher nucleus to cytoplasm ratio (>1.1, p = 0.0418), higher axis ratio (>1.2, p = 0.088), higher acyclicity grade (>1.145, p = 0.0857) and higher anellipticity grade (>1.14, p = 0.1362). These parameters can be used for the evaluation of risk category of developing bone metastases. These results can be useful for the evaluation of bone metastatic potential of breast cancer and for the selection of high-risk patients whose molecular profiles would require further investigations and evaluation.

A consolidated working classification of gastric cancer for histopathologists (Review).

Gastric cancer (GC) remains a disease with poor prognosis despite increasing availability of more effective targeted treatment. This may be in part due to the difficulty in selecting patients for appropriate treatment. Conventional taxonomic classifications of GC are ill-suited to make full use of recent advances in personalised therapy. In the past decade a number of molecular classifications have been proposed to address this; however, to date, there has been little implementation in the diagnostic routine. The lack of harmonisation between these classifications, the complexity and unavailability of some of the tests required plus the demands on time and resources, all contribute to poor uptake in the diagnostic routine. In the present study, these classifications were reviewed and an inclusive working classification that includes their main points, focuses on prognosis and treatment options and can be delivered using four on-slide tests (in situ hybridization for Epstein-Barr encoding region and immunohistochemistry for mismatch repair, E-cadherin and p53) is proposed. These tests can be performed on paraffin-embedded tissue and could be available in the majority of histopathology laboratories. The proposed classification also includes reflex testing for specific biomarkers relevant to treatment selection.

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.

Implementing an On-Slide Molecular Classification of Gastric Cancer: A Tissue Microarray Study.

Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancers and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia and colleagues proposed an on-slide classification; however, this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein-Barr virus (GC EBV+), GC with mismatch-repair deficiency (GC dMMR), GC with epithelial-mesenchymal transformation (GC EMT), GC with chromosomal instability (GC CIN), CG that is genomically stable (GC GS) and GC not otherwise specified (GC NOS). This classification also has a provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here, we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC CIN cases were 23%, GC GS cases were 29%, and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted.

Relevance of Nerve Biopsy in the Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy-A Systematic Review.

Chronic Inflammatory Demyelinating Polyneuropathy is an immune-mediated pathology of the peripheral nerves and nerve roots that leads to weakness and sensory symptoms. Given its clinical heterogeneity, often times diagnosis is challenging. Even though nerve conduction studies and clinical features are the main criteria used for diagnosis, supplementary investigations, such as nerve biopsies, cerebral spinal fluid examination and magnetic resonance studies, may be used in order to confirm the diagnosis. Given the fact that the hallmark in CIDP physiopathology is the demyelination process, nerve biopsies are used to demonstrate and assess the magnitude of the phenomenon. The question and the main interest of this review is whether histopathological findings are relevant for the diagnosis and can be useful in disease assessment.

Combined Positive Score for Programmed Death Ligand-1 Expression and Inflammatory Microenvironment in Gastrointestinal Stromal Tumors.

Background and Objectives: GISTs are the most frequent type of mesenchymal neoplasm of the digestive tract. The prognosis is mainly determined by tumor dimensions, mitotic rate and location, but other less well-documented factors can influence evolution and survival. The immune microenvironment and checkpoint molecule expression were proven to impact the prognosis in different types of cancer. The aim of this study was to determine PD-L1 expression in GISTs and to evaluate the level of intratumoral immune infiltration in relation to prognostic variables and survival. Materials and Methods: Sixty-five GISTs diagnosed in the same institution between 2015 and 2018 were immunohistochemically tested for PD-L1 and evaluated using CPS. Immune cells were emphasized, with CD3, CD4, CD8, CD20 and CD68 antibodies and quantified. All data were processed using statistical tools. Results: The median age was 61 years (range, 28-78) and 36 patients (55.4%) were males. The location of the tumors was predominantly gastric (46%), followed by the small bowel (17%) and colorectal (6%). In addition, 11% were EGISTs and 20% were secondary tumors (11% metastases and 9% local recurrences). PD-L1 had a variable expression in tumor and inflammatory cells, with a CPS ranging from 0 to 100. Moreover, 64.6% of cases were PD-L1 positive with no significant differences among categories of variables, such as the age and the sex of the patient, tumor location, the primary or secondary character of the tumor, dimensions, mitotic rate, the risk of disease progression and tumor cell type. Immune cells had a variable distribution throughout the tumors. CD3+ lymphocytes were the most frequent type. CD20+ cells were identified in a larger number in tumors ≤5 cm (p = 0.038). PD-L1-positive tumors had a higher number of immune cells, particularly CD3+, CD20+ and CD68+, in comparison to PD-L1-negative ones (p = 0.032, p = 0.051, p = 0.008). Epithelioid and mixed cell-type tumors had a higher number of CD68+ cells. Survival was not influenced by PD-L1 expression; instead, it was decreased in multifocal tumors (p = 0.0001) and in cases with Ki67 ≥ 50% (p = 0.008). Conclusions: PD-L1-positive expression and the presence of different immune cell types, in variable quantities, can contribute to a better understanding of the complex interactions between tumor cells and the microenvironment, with a possible therapeutic role in GISTs.

A Challenging Diagnosis: Placental Mesenchymal Dysplasia-Literature Review and Case Report.

We describe a 22-year-old woman (2-gravid) case who was referred to our clinic at 18 weeks of gestation for a placenta with vesicular lesions discovered on prenatal examination routine. An ultrasound exam at 31 weeks of gestation showed numerous vesicular lesions, which gradually augmented as the pregnancy advanced. A live normal-appearing fetus was confirmed by intrauterine growth restriction (IUGR). The maternal serum ß-human chorionic gonadotropin level remained in normal ranges. At some point, a multidisciplinary medical consensus considered the termination of the pregnancy, but the patient refused to comply. At 33 weeks of gestation, preterm premature rupture of membranes (pPROM) occurred, and she spontaneously delivered a 1600 g healthy female baby with a good long-term outcome. Placental mesenchymal dysplasia (PMD) was retrospectively diagnosed after confronting the data from ultrasound, chorionic villus sampling (CVS), amniocentesis, pathological examination, and immunohistochemical stain. The lack of sufficient reports of PMD determines doctors to be cautious and reserved, approaching these cases more radically than necessary. We reviewed this disease and searched for all cases of PMD associated with healthy, live newborns.

Current approach to branchial remnants in the neck.

Congenital branchial fistulas and cysts are an interesting subject in cervical pathology. There are congenital malformations with late expression in young adults that require correct diagnosis and appropriate treatment. We review essential notions of cervical embryology to understand the mechanism of occurrence of these malformations and their clinical expression. The most common cases present vestiges from the second branchial arch, with the appearance of a cystic tumor or a fistulous orifice on the anterior edge of the sternocleidomastoid muscle, at the level of the hyoid bone. Performant imagery is mandatory for appropriate diagnosis, so we recommend a cervical computed tomography (CT) scan or cervical magnetic resonance imaging (MRI) to evaluate the relations with great vessels of the neck or other lesions. The treatment implies complete surgical excision because otherwise there is a high risk of recurrence of the lesion. The differential diagnosis includes cystic lymphangioma, dermoid cyst, tuberculous adenopathy, cystic hygroma, lateral cervical cystic metastases. Histological examination is mandatory for a definite diagnosis. Also, there is a small percentage of malignancy of these malformations, but it is very important to check that all the histological diagnostic criteria for a primary branchiogenic carcinoma are accomplished. Therefore, although it is a benign cystic cervical pathology, the diagnosis and treatment must be made very accurately for a complete cure, and this review aims to summarize the current approach to branchial remnants of the neck.

The role of the ultrasound examination in atypical placental site trophoblastic tumour differential diagnosis and management. A case report.

Placental site trophoblastic tumour (PSTT) is a very rare and unique form of gestational trophoblastic tumour, representing about 1-2% of all gestational trophoblastic tumours. Usually, the pattern is a slow growing nodule implicating the endometrium and myometrium, accompanied by abnormal uterine bleeding. Three ultrasound types of PSTT are described, but thereis no specific characteristic for diagnosis. We present the case of a patient with an atypical placental site trophoblastic tumour diagnosed two months after a caesarean scar pregnancy. In the presented case there are several particularities, such as the rapid growth and progression of the tumour, the limitation to the myometrium and the difficulty of the differential diagnosis and approach.

A novel histopathological grading system for ganglioglioma.

Gangliogliomas are central nervous system tumors located in the temporal lobe of young patients, frequently associated with epilepsy. In this paper, we propose a grading system based solely on histopathological criteria. We reevaluated all cases of ganglioglioma, atypical ganglioglioma, and anaplastic ganglioglioma diagnosed between 2011 and 2020 in the Pathology Department of the Emergency Clinical Hospital Bagdasar-Arseni, based on the type of glial mitoses, the number of neuronal and glial mitoses, presence of necrosis, microvascular proliferation, eosinophilic granular bodies, hypercellularity, presence and disposition of inflammatory infiltrate and atypical pleomorphism. Based on the proposed grading system, a score of 0-4 corresponded to a benign ganglioglioma, 5-9 to an atypical ganglioglioma, and 10-18 to an anaplastic ganglioglioma. The survival rates were 90% for benign ganglioglioma, 71.43% for atypical ganglioglioma, and 62.54% for anaplastic ganglioglioma. One case of benign ganglioglioma underwent a malignant transformation into anaplastic ganglioglioma, and recurrences were noticed in 28.57% of atypical ganglioglioma cases and 30.7% of all anaplastic gangliogliomas. The presence of rare glial mitoses and hypercellularity was correlated with mortality in cases of atypical ganglioglioma. We believe this histopathological scoring system could be used as a three-tier system to identify atypical ganglioglioma cases that are bound to have an aggressive course of evolution and require close follow-up. The other option would be to convert it to a two-tier grading system that can separate low-grade gangliogliomas from high-grade ones. The latter category can encompass both atypical and anaplastic ganglioglioma due to the high mortality of both entities.

Practical aspects regarding the histopathological grading and anaplastic transformation of gangliogliomas - a literature review.

Ganglioglioma represents a benign central nervous tumor, occurring predominantly in the pediatric population and affecting the temporal lobe. It is also renowned for its epileptogenic potential. However, to date, there are numerous uncertain features about this tumor, especially about its grading system. In the former World Health Organization (WHO) Classification of central nervous tumors system, gangliogliomas could have been attributed one out of three grades: grade I (benign), grade II (atypical), and grade III (anaplastic). The new classification systems have renounced to atypical ganglioglioma nomenclature, due to the lack of histopathological criteria for this entity. Another controversial aspect of grade I ganglioglioma is its potential to transform into a malignant tumor, namely, most frequently an anaplastic ganglioglioma. Based on our knowledge, there are no literature reviews to date focusing on anaplastic transformation potential. The present paper encompasses all anaplastic transformation of gangliogliomas and has analyzed the time frame between the two events, the age of the patients and its relationship to the complete or subtotal resection and administration of radiotherapy. Thirty-three cases of malignant transformation of ganglioglioma have been reported so far in the literature, with 54.54% of them undergoing progression to anaplastic ganglioglioma and 21.21% to anaplastic ganglioglioma. Median age was 26 years, and the cases were evenly distributed between the two genres. Only 27.27% of all evaluated cases had been administrated adjuvant radiotherapy, and only 44% of the latter have had an incomplete tumoral resection.

Lung cancer mimickers - a case series of seven patients and review of the literature.

BACKGROUND: Lung is the third most frequent identified site of malignancy and lung cancer is the most lethal type of cancer in the world. Several benign lung diseases or proliferations may mimic lung carcinoma in its clinical, pathological, and radiological presentation, which makes the differential diagnosis life changing. This case series was designed to describe the main diagnosis encountered in a multidisciplinary emergency hospital during the last years in Romania. RESULTS: The most challenging cases encountered during the recent years were those of lung hamartoma associated with eosinophilic pneumonia because of the multicentricity of the disease and the suspicion for metastasis in the clinical setting, pulmonary aspergillosis that presented as a cystic lesion with a 9 mm mural nodule, actinomycosis discovered as firm nodule showing aspects of false pleural invasion, cryptococcosis - a hilar mass for which a pneumectomy was prepared, pulmonary parasitosis that presented as a nodule with irregular borders, causing pleural retraction, one case of inflammatory myofibroblastic tumor of the lung, one case of tumorlet type neuroendocrine lesion in a patient with history of melanoma and renal oncocytoma, admitted under the suspicion of lung metastasis. CONCLUSIONS: These are some of the main mimickers of primary or secondary lung cancers and one must be aware of these similitudes to avoid higher cost procedures, psychological stress for the patient and higher mortality.

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.

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

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.

A Morphological and Immunohistochemical Study of the Tumoral and Inflammatory Cells in Pancreatic Ductal Adenocarcinoma.

This study is aimed at investigating tumoral and inflammatory cells and the significance of the prognostic factors of pancreatic ductal adenocarcinoma (PDAC); it is also aimed at determining the role of immunohistochemistry in the diagnosis and prognosis of this neoplasm. Materials and Methods. 230 cases of pancreatic ductal adenocarcinoma were included in the study group; these cases were selected from the archives of the Department of Pathology of the Fundeni Clinical Institute over a ten-year period. Immunohistochemistry was performed using the following antibodies: MUC 1, CD 34, Factor VIII, CD 68, MMP-7, CEA, p21, p53, and Ki 67. Results. There were 133 male (57.8%) and 97 female (42.2%) patients included in this study, with ages between 20 and 81 years old (mean age: 58.2 years) and with tumors located in the pancreatic head (n = 196; 85.2%), pancreatic body (n = 12; 5.2%), and pancreatic tail (n = 20, 8.7%), as well as panpancreatic tumors (n = 2; 0.9%). Patients presented with early stages (IA and IB), with low pathologic grade (G1), with small size tumors (less than 1-1.5 cm), with tumors located in the head of the pancreas, (p53: negative; p21: positive; and CD 68: positive in peritumoral tissue), with low nuclear index (Ki 67 < 10%), without metastases at the time of surgery (had a better prognosis), and with a survival rate of about 7 months. Conclusions. Immunohistochemistry is useful for an accurate diagnosis, differential diagnosis, and establishment of additional factors that might have a prognostic importance. It is recommended to study peritumoral tissue from the quantitative and qualitative points of view to increase the number of prognostic factors. This study represents a multidisciplinary approach, and it is a result of teamwork; it presents histopathological methods of examination of this severe illness and describes only a part of the scientific effort to determine the main pathological mechanisms of this neoplasm.

Squamous metaplasia within a sigmoid adenoma. A rare feature.

Squamous metaplasia occurring within a colorectal polyp is a rare finding, having a reported incidence of approximately 0.44%. The origin of the squamous cells in this type of setting is uncertain (mechanical irritation and chronic inflammation are potential predisposing factors). It has been implied that the significance of squamous metaplasia in colorectal adenomas is that of a preneoplastic lesion for squamous cell and adenosquamous carcinoma, however the evidence to support this statement is scarce. We present a case of a large tubulovillous adenoma located in the sigmoid, with low-grade dysplasia and multiple foci of p16-positive immunoexpression squamous metaplasia in a 54-year-old Caucasian male, presenting with rectal bleeding.

Giant pleomorphic sarcoma of the tongue base - a cured clinical case report and literature review.

Pleomorphic sarcoma of the tongue base is an extremely rare pathology finding. Our review of current databases returned fewer than 10 articles available free full text on this subject. We review the current state of art management guidelines for this type of tumor. Our case presented surprisingly a favorable evolution despite the huge dimensions, the tumor type, and associated pathology. The patient received radiation therapy and oncological treatment followed by revision surgery consisting of partial glossectomy for the residual tumor. Histological examination of the operatory specimen showed a residual tumor of pleomorphic sarcoma type, with clear margins. The evolution was without relapse after 18 months.

Colon cancer in pregnancy: a diagnostic and therapeutic challenge.

Metastatic colorectal cancer during pregnancy and postpartum is rather rare, but it represents major diagnostic and therapeutic challenges for obstetricians and surgeons. Cancer itself rarely affects the placenta or growing baby directly. However, metastatic disease is much more common than in nonpregnant patients and detecting cancer while pregnant can be complicated for both the mother and the health care team. In this article, we report a case of moderately differentiated colon adenocarcinoma in pregnancy that was diagnosed in an advanced stage, implying a complex diagnostic and therapeutic approach. The classic histological and immunohistochemical (IHC) study on this case reveals that tumorous areas have lost goblet cells and, implicitly, mucus; also, there are absent estrogen and progesterone receptors, possible causes of neoplasm in pregnancy, the rate of tumor proliferation is increased, the IHC reaction that highlights the protein responsible for cytoplasmatic anchoring of cadherins is intense positive, and the enzyme responsible for inflammation and pain is increased in these areas.

Quantitative second harmonic generation microscopy for the structural characterization of capsular collagen in thyroid neoplasms.

Quantitative second harmonic generation microscopy was used to investigate collagen organization in the fibrillar capsules of human benign and malignant thyroid nodules. We demonstrate that the combination of texture analysis and second harmonic generation images of collagen can be used to differentiate between capsules surrounding the thyroid follicular adenoma and papillary carcinoma nodules. Our findings indicate that second harmonic generation microscopy can provide quantitative information about the collagenous capsule surrounding both the thyroid and thyroid nodules, which may complement traditional histopathological examination.

Cystic lymphangioma of nasopharynx in a 54-year-old man - case report. A new histogenetic hypothesis.

Lymphangiomas are enough rare benign congenital tumors of the lymphatic vessels, frequently encountered during childhood. They are found in the head and neck region, the isolated localization in the nasopharynx is very rare. We present the case of 54-year-old man admitted in the Department of Ear, Nose and Throat (ENT), Emergency University Hospital of Bucharest, Romania, with a nasopharynx tumor certificated by computed tomography (CT) scan with significant bleeding to a previous incisional biopsy temptation rising angiofibroma suspicion. We performed the radical surgical excision of mass by transoral approach. Postoperative bleeding imposed angiography with right internal maxillary artery embolization. Histopathological evaluation showed the diagnosis of lymphangioma. After three years, the patient is without recurrence.