Ki-67 Proliferation Index Research Articles

AI-powered precision: breast carcinoma diagnosis through digital proliferation index (Ki-67) assessment in pathological anatomy

PurposeThe primary objective of the study is to enhance the accuracy and efficiency of assessing the proliferation index in cancer cells, specifically focusing on the role of Ki-67. The purpose is to address the limitations of traditional visual assessments conducted by pathologists by integrating AI technologies, particularly deep learning. By accurately computing the percentage of Ki-67-labeled cells, the research aims to streamline the diagnostic process, reduce subjectivity and contribute to the advancement of diagnostic precision in pathological anatomy.Design/methodology/approachThe research employs a methodological approach that integrates Ki-67, a non-histone nuclear protein, as a vital biomarker for assessing the proliferative status of cancer cells. Given the challenges associated with traditional visual assessments by pathologists, including inter- and intra-observer variability and time-consuming efforts, the study adopts a novel methodology leveraging artificial intelligence (AI) solutions. Deep learning is applied to precisely calculate the percentage of Ki-67-labeled cells. The process involves pathologists delineating the tumor area at x40 magnification, enabling the segmentation of various cell types (positive, negative and tumor-infiltrating lymphocytes). The subsequent percentage calculation enhances efficiency and minimizes subjectivity in the diagnostic process.FindingsDespite inherent errors, the research findings indicate that the model surpasses existing benchmarks, showcasing superior accuracy in terms of average error measurement. The comparison with diverse datasets and benchmarking against pathologists’ diagnoses contributes empirical evidence to support the effectiveness of the AI-based model in accurately computing the percentage of Ki-67-labeled cells. These findings signify a noteworthy advancement in diagnostic methodologies and reinforce the potential of AI technologies in improving the precision of cancer diagnostics within the realm of pathological anatomy.Originality/valueThe research contributes to the field by introducing an innovative approach that combines Ki-67 as a biomarker and AI technologies for improved diagnostic precision. The originality lies in the utilization of deep learning to calculate the percentage of labeled cells, mitigating the challenges associated with manual assessments. The validation of the model against diverse datasets and benchmarking against pathologists’ diagnoses demonstrates its superior accuracy, highlighting the value of integrating AI in pathological anatomy for enhanced diagnostic outcomes. The study represents a significant stride in original research, offering novel insights and methodologies in the pursuit of more precise cancer diagnostics.

Glucocorticoid Receptor Isoforms in Breast Cancer Raise Implications for Personalised Supportive Therapies

Glucocorticoid receptor (GR) activation may promote metastasis in oestrogen receptor-negative and triple-negative breast cancer (TNBC). However, the role of the GRβ isoform, which has opposing effects to the main isoform, has not been studied in clinical samples. We aimed to analyse the intracellular localisation of total GR and GRβ in vitro using plasmid constructs and fluorescent immunocytochemistry. Additionally, our goal was to perform immunostaining for total GR and GRβ on two cohorts: (i) on 194 clinical breast cancer samples to compare the expression in different molecular subtypes, and (ii) on 161 TNBC samples to analyse the association of GR with survival. We supplemented our analysis with RNA data from 1097 TNBC cases. We found that in the absence of the ligand, GR resided in the cytoplasm of breast cancer cells, while upon ligand activation, it translocated to the nucleus. A negative correlation was found between cytoplasmic GRtotal and Ki67 in luminal A tumours, while the opposite trend was observed in TNBC samples. Tumours with strong lymphoid infiltration showed higher cytoplasmic GRtotal staining compared to those with weaker infiltration. Patients with high nuclear GRtotal staining had shorter progression-free survival in univariate analysis. High cytoplasmic GRβ was a marker for better overall survival in multivariate analysis (10-year overall survival HR [95% CI]: 0.46 [0.22–0.95], p = 0.036). As a conclusions, this study is the first to investigate GRβ expression in breast tumours. Different expression and cellular localisation of GRtotal and GRβ were observed in the context of molecular subtypes, underscoring the complex role of GR in breast cancer. An inverse association between cytoplasmic GRtotal and the Ki67 proliferation index was observed in luminal A and TNBC. Regarding the impact of GR on outcomes in TNBC patients, while cytoplasmic GRβ was associated with a better prognosis, patients with nuclear GRtotal staining may be at a higher risk of disease progression, as it negatively affects survival. Caution should be exercised when using glucocorticoids in patients with nuclear GR staining, as it may negatively impact survival.

Impact of the CPS-EG score as a new prognostic biomarker in triple-negative breast cancer patients who received neoadjuvant chemotherapy

BackgroundThis study aimed to establish risk groups on the basis of CPS-EG scores, independent of pCR status, in triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NACT) to identify the prognostic impact of the CPS-EG score.MethodsPatient characteristics included age, menopausal status, clinical stage, pathological stage, estrogen receptor (ER) expression, nuclear grade, Ki-67 proliferation index, residual cancer burden (RCB) score, HER2 status, and other tumor characteristics. The CPS-EG scoring system included clinical stage, pathological stage, ER status, and grade. Patients were divided into two groups on the basis of their CPS-EG scores ≤ 3 and > 3.ResultsA total of 148 patients who were diagnosed with TNBC and treated with NACT were included in the study. A total of 52.0% of the patients had a CPS-EG score of ≤ 3, whereas 48.0% had a score of > 3. The rate of patients who achieved pCR was 29.7% (n = 44). CPS-EG score (HR: 2.331; 95%CI; 1.179–4.608; p = 0.015), pCR (HR: 0.348; 95%CI; 0.144–0.844; p = 0.019), pre-treatment mKi-67 proliferation index (HR: 0.467; 95%CI; 0.251–0.871; p = 0.017), and RCB score (HR: 0.401; 95%CI; 0.174–0.923; p = 0.032) were identified as significant prognostic factors for 5-year DFS. For 5-year OS, significant prognostic factors were CPS-EG score (HR: 2.30; 95%CI; 1.036–4.799; p = 0.040) and pre-treatment mKi-67 proliferation index (HR: 0.484; 95%CI; 0.246–0.954; p = 0.036).ConclusionsThe CPS-EG score, pre-treatment mKi-67 level, and the pCR and RCB score were practical prognostic markers for long-term survival. Conversely, the prognostic significance of pCR status was diminished, particularly in predicting OS. These findings underscore the importance of not only post-treatment pathological staging but also the initial tumor stage and biological characteristics of the tumor in predicting ultimate survival outcomes following neoadjuvant chemotherapy in TNBC patients.

Investigation of IDO1 and TDO2 expression in breast tumors by immunohistochemistry and real-time polymerase chain reaction methods

Although diagnostic and therapeutic advances have been made in the treatment of breast cancer, the challenge of effectively controlling tumor progression persists. The objective of this study was to determine the relationship between IDO1 and TDO2 expression in breast cancer by immunohistochemistry and real-time polymerase chain reaction, hormone receptor status, Ki67 proliferation index, molecular classification, metastasis, and to investigate whether IDO1 and TDO2 expression can be used in combination with targeted therapy or as a marker to increase treatment efficacy in selected cases. The study included 74 cases of breast cancer and 14 cases of normal breast tissue as controls. All cases were analyzed for IDO1 and TDO2 by both immunohistochemistry and real-time polymerase chain reaction. The immunohistochemical analysis revealed that IDO1 immunoreactivity was significantly higher in tumor tissue compared to normal breast tissue. A statistically significant correlation was observed between IDO1 immunoreactivity and histologic subtypes. Furthermore, IDO1 gene expression was correlated with IDO1 immunoreactivity. TDO2 immune reactivity did not differ between tumor and non-tumor tissues and no correlation was found between histological subtypes. There was no correlation between TDO2 immunoreactivity and gene expression. The significant increase in IDO1 levels in tumor tissue and high positivity in age, HER2 positive and triple negative cases compared to other cases suggest that IDO1 inhibitors may be suitable for the target patient group in treatment selection.

A Rare Case of Signet Ring Cell Lymphoma and Review of the Literature

Signet ring cell lymphoma (SRCL) is a non-Hodgkin's lymphoma with a very rare variant. Although this morphology is frequently seen in follicular lymphoma, it can also be observed in the group of diffuse large B-cell lymphomas. A seventy-six year old woman with known diagnosis of gastric adenocarcinoma, tubular type, moderately differentiate presented with a lymphadenopathy with high FDG uptake (SUVmax: 21.3) in PET/CT during follow-up. A tru-cut biopsy was performed for histopathological diagnosis. Diffuse infiltrative singet ring neoplastic cells showed negativity for PanCK, CK7, CK20, S100, SMA, calretinin and vimentin. The panel was then expanded to include SRCL, a rare variant of lymphoma. Additional immunohistochemical evaluation revealed positivity for CD20, CD19, PAX-5 and Bcl-2. Ki-67 proliferation index was about 80%. CD3, CD30, Myc, Bcl-6, ALK, Cyclin-D1, CD23, CD10, CD21, and MUM-1 were negative. EBER was also negative by chromogen in situ hybridization (CISH). Based on these data, diffuse large B-cell lymphoma (DLBCL) was considered. We herein reported a case of signet ring cell lymphoma discussed its clinical and morphological features with regard to the literature.

Distributed parameter model of dynamic contrast-enhanced MRI in the identification of IDH mutation, 1p19q codeletion, and tumor cell proliferation in glioma patients

ObjectivesTo investigate the clinical value of hemodynamic parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) in predicting glioma genotypes including isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion status and the tumor proliferation index (Ki-67) noninvasively. And to compare the diagnostic performance of parameters of distributed parameter (DP)model and extended Tofts (Ex-Tofts) model.Materials and methodsDynamic contrast-enhanced MRI (DCE-MRI) data of patients with glioma were prospectively enrolled from April 2021 to May 2023. The imaging data were analyzed using DP and Ex-Tofts model for evaluating the perfusion and permeability characteristics of glioma. Comparisons were performed according to IDH genotype in all glioma patients and 1p/19q codeletion in IDH mutation glioma patients. Receiver operating characteristic (ROC) curves were generated for DCE-MRI parameters. The Spearman rank correlation coefficients were calculated between DCE MRI parameters and Ki-67 index.ResultsIn IDH-mutation gliomas, a higher blood flow (F) was found in 1p/19q codeletion gliomas than in 1p/19q intact gliomas. No parameter derived from Ex-Tofts model showed significant differences in predicting 1p/19q status. Fractional volume of interstitial space (Ve) derived from both the DP and Ex-Tofts models exhibited optimal performance in predicting IDH genotype (AUC = 0.818, 0.828, respectively). Ve also showed the highest correlations with Ki-67 LI within their respective models in all gliomas (ρ = 0.62, 0.61), indicating comparable moderate positive associations. Ki-67ConclusionDP model showed a clear advantage in predicting 1p/19q status compared to Ex-Tofts model. The DP and Ex-Tofts models performed similarly in predicting IDH mutation and Ki-67 index.

Associations between Dynamic-Contrast enhanced MRI with histopathological features in cholangiocarcinoma.

The associations between histopathology and imaging remain elusive and investigating underlying reasons of tumor microstructure resulting in an imaging phenotype is of clinical importance. The present study used cross-sectional guided biopsy specimen to employ the exact spatial biopsy localization to correlate the prebioptic magnetic resonance imaging (MRI) with immunohistochemical stainings of the histopathological specimen. Twenty-seven patients with mass-forming cholangiocarcinoma (CCA) were included in the present analysis. All patients were imaged by a 1.5 T clinical scanner at last one month before the biopsy. The contrast enhanced dynamic sequences were analyzed with quantified signal intensities. The bioptic specimen were obtained by cross-sectional guided biopsy and was further analyzed with cell density, proliferation index (Ki67), tumor-infiltrating lymphocytes, tumor-stroma ratio as well as Collagen. There were no statistically significant correlations between the signal intensities of the MRI with cell count, tumor-stroma ratio, Ki67 index and CD45 count. Only a moderate correlation was identified between relative signal intensities of the venous phase with the Collagen-stained area (r=0.40, p=0.04). DCE MRI is not associated with histopathology features in CCA. The complex interactions of the tumor and the tumor micromilieu are not reflected by the MRI phenotype.

Sclerosing Extramedullary Hematopoietic Tumor of the Breast

Abstract Introduction/Objective Sclerosing extramedullary hematopoietic tumor (SEMHT) is a rare tumor that occurs in patients with chronic myeloproliferative conditions. SEMHT can be seen in abdominal organs, retroperitoneum and mesentery. It can also be regarded as an advanced manifestation of myelofibrosis. SEMHT can occur singly or as multiple masses and manifests later in the disease course of CMPD. The differential diagnosis includes breast cancer, soft tissue tumor, and extramedullary hematopoiesis. Here we present a case of SEMHT in the breast. Methods/Case Report This is a 80-year-old female, who has a history of left breast ductal carcinoma in situ who underwent lumpectomy and received radiation in 2020. The patient also has Polycythemia Vera and MF. Bone marrow aspiration, Trephine biopsy imprints and Trephine and clot biopsies showed persistent myelofibrotic myeloid neoplasm involving a cellular bone marrow with marked fibrosis (MF Grade 3), megakaryoblastic hyperplasia, atypical megakaryocytes. In 3/2023, there were two small masses found in upper outer right breast by ultrasound measuring 4 mm and 3 mm in diameter. Breast biopsy sections showed scattered rare atypical cells within fibrotic stroma. They were only positive for Vimentin and Androgen Receptor (rare) within the performed immunohostochemistry panel. Ki67 proliferation index was 20%. The biopsy report was signed out as aytpical mesenchymal tumor. Resection was recommended. The resection showed same atypical cells within large sclerotic stroma. These atypical cells were scattered in the breast tissue along with sinusoidal capillarization. The atypical cells were atypical megakaryocytes highlighted with CD61. Erythrocyte precursors are highlighted with glycophorin a. Based on the clinical history and histologic features, SEMHT diagnosis was made. Results (if a Case Study enter NA) NA due to being a case study. Conclusion SEMHT is a rare tumor, that can occur in patients with CMPD. It can occur within different locations in the body, including breast. SEHMT should be kept in mind for an accurate diagnosis of the tumor and correct management of the patients.

Squamoid eccrine ductal carcinoma of the vulva: A case report

Abstract Introduction/Objective A 53-year-old female sought medical attention for left vulvar pain and a vulvar lesion. Methods/Case Report Physical examination revealed a 1.0 x 1.0 cm lesion within a background of lichen sclerosus. Biopsy demonstrated a carcinoma with tubular and glandular architecture, areas of squamoid differentiation and widespread perineural invasion. Ancillary immunohistochemistry testing with keratin 7 highlighted foci of ductal differentiation. Tumor cells were also positive for p53, p63, pankeratin, and keratin 5/6. The Ki-67 proliferation index was approximately 15%. Tumor cells were negative for Keratin 20, PAX 8, p16, and CD 34. We diagnosed the lesion as a vulvar sweat gland adenocarcinoma of the squamoid eccrine ductal subtype. Results (if a Case Study enter NA) N/A Conclusion Carcinomas of vulvar sweat gland origin are extremely rare, comprising less than 1% of all vulvar cancers. To the best of our knowledge, this is the first case report of squamoid eccrine ductal carcinoma afflicting the vulva.

Diagnostic workup of triple hit lymphoma by fine needle aspiration

Abstract Introduction/Objective Triple-hit lymphomas (THL) represent a rare and aggressive subset of high-grade B-cell lymphomas characterized by a triad of translocations involving MYC, BCL2, and BCL6. Patients with THL face poor outcomes when treated with the standard diffuse large B-cell lymphoma protocol. Thus, intensified regimens have emerged as a frontline strategy for managing these patients. Therefore, accurate diagnosis and molecular subclassification of these lymphomas are essential for guiding therapeutic decisions for these patients. Here, we report a case study detailing the diagnostic assessment of THL utilizing limited diagnostic material obtained through palpation-guided fine-needle aspiration (FNA). Methods/Case Report A 58-year-old male presented with a rapidly enlarging neck mass, accompanied by worsening dysphagia, pain, and fatigue over the course of two months. Laboratory testing showed leukocytosis and imaging studies revealed a partially necrotic, 7.8 x 9.1 x 9.4 cm right jugular nodal mass. The patient was referred to otolaryngology for further evaluation, where FNA of the mass was performed by the cytopathology team. The aspirate was sent for cytology with cell block and flow cytometry. The Romanowsky stain revealed abundant, large, discohesive cells with prominent nucleoli and scant cytoplasm with an abundance of lymphoglandular bodies in the background. Immunohistochemistry (IHC) on the cell block demonstrated BCL-2, BCL-6, and MYC expression, and a Ki-67 proliferation index >95%. Concurrent flow cytometric analyses showed an aberrant B-cell population expressing CD19, CD20, CD22, CD23 and surface lambda light chain. Further fluorescence in situ hybridization (FISH) analysis performed on the cell block confirmed gene rearrangements in BCL2, BCL6 and MYC, thereby classifying this patient’s disease as THL. Results (if a Case Study enter NA) NA Conclusion Diagnosing THL typically demands sufficient tissue for histology, cytology, flow cytometry, IHC, and molecular testing. Herein, we showcase a notable example where the diagnostic evaluation of THL was accomplished using limited material obtained from FNA. This case highlights the efficacy of conducting comprehensive diagnostic studies even when tissue availability is constrained. Utilizing cytologic samples not only streamlines the diagnostic process but also minimizes the need for patients to undergo additional invasive procedures, thus potentially reducing delays in diagnosis and therapeutic intervention.

A Frozen Tale of Two Tumors in the Pancreas: An Intraoperative Diagnostic Challenge of Clear Cell Pancreatic Neuroendocrine Tumor Mimicking Metastatic Clear Cell Renal Cell Carcinoma

Abstract Introduction/Objective Clear cell pancreatic neuroendocrine tumor (PanNET) is rare, with very few cases reported in the literature, and is often found in patients with von Hippel-Lindau (VHL) disease. The differential for this entity includes ectopic adrenal tissue and metastatic clear cell neoplasms. These challenges during intraoperative consultation add to the complexity of diagnosing this condition. Distinguishing it from other pancreatic lesions requires careful examination and further ancillary testing. Methods/Case Report We report a case of clear cell PanNET mimicking metastatic clear cell renal cell carcinoma (RCC) in a 56-year-old woman with recently diagnosed VHL. She presented with renal masses and a pancreatic lesion with previous biopsy showing conventional NET. Intraoperative consultation during her pancreaticoduodenectomy identified a 1.3 cm well-circumscribed, golden-yellow solid mass. Further characterization was deferred to permanent sections given the diagnostic challenge of distinguishing between a PanNET and metastatic clear cell RCC. Permanent sections showed nests of clear cells with prominent nucleoli. The neoplastic cells were immunohistochemically positive for neuroendocrine markers synaptophysin, chromogranin and insulinoma- associated protein 1(INSM1), as well as pankeratin and PAX8, with a Ki-67% proliferation index <1%, consistent with low-grade clear cell PanNET. Clear cell RCC marker, CA-IX, as well as adrenocortical marker SF1, were negative. The combination of immunohistochemical stains is key for making the diagnosis. The previously biopsied conventional PanNET was also identified, which was positive for neuroendocrine markers and had a Ki-67 proliferation index <1%. Results (if a Case Study enter NA) NA Conclusion Given the rarity of this entity and its strong association with VHL, clear cell PanNET should be considered in the intraoperative consultation to inform clinical management. Furthermore, literature review indicates that metastatic RCC in the pancreas is exceptionally rare in VHL patients and typically of low nuclear grade, suggesting low metastatic potential. Thus, this case emphasizes the diagnostic challenges and the necessity of deferring to permanent sections with immunohistochemical work-up during intraoperative consultation or when assessing small biopsies.

A Rare Case of Diffuse Large B Cell Lymphoma Co-occurring with Small Lymphocytic Leukemia: De Novo Process or Richter’s Syndrome?

Abstract Introduction/Objective Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of lymphoma and can arise either de novo or through transformation from indolent lymphomas, such as Chronic Lymphocytic Leukemia (CLL), known as Richter syndrome (RS). DLBCL derived from RS tends to exhibit more aggressive behavior compared to de novo DLBCL. Methods/Case Report We present a case of a 57-year-old female with no significant medical history, who initially presented with antibiotic and prednisone-resistant sinusitis, progressing to bilateral neck pain and eye congestion. Computed tomography (CT) imaging revealed a 3 cm mass in the right nasal cavity extending to the right maxillary sinus and medial right orbit. Histopathological examination showed diffuse sheets of intermediate to large cells with irregular nuclear contours, dispersed chromatin, variably conspicuous nucleoli, and moderate cytoplasm. Additionally, scattered foci of monotonous, atypical lymphoid cells with lower grade morphology, including small size and condensed chromatin, were also present. Immunohistochemical analysis revealed differential staining patterns between the two cell populations. The larger atypical cells expressed CD20, PAX5, CD10, BCL-6, MUM1, BCL-2, MYC, CD19 (dim), and exhibited a high Ki-67 proliferation index (>80%). In contrast, the smaller atypical cells were positive for CD5, CD19, CD20, PAX5, BCL-2, and CD23 (subset), with a lower Ki-67 proliferation index (<5%). Flow cytometry analysis of tissue samples revealed two distinct clones: Surface Kappa-restricted CD19 dim B cells (38.9%) with CD5- CD10 dim CD20+ and surface Lambda-restricted CD19+ B cells (58.7%) with CD5+ CD10- CD20+. FISH analysis revealed no gene rearrangements. The final diagnosis was Diffuse large B-cell lymphoma, germinal center B- cell phenotype, with aggressive features and focal involvement by small lymphocytic lymphoma/chronic lymphocytic leukemia. Results (if a Case Study enter NA) NA Conclusion The relationship between the large B-cell lymphoma and SLL/CLL remains uncertain; however, given the different immunophenotype and light chain expression observed by flow cytometry, they are likely to represent separate processes.

Cardiac Angiosarcoma with Unusual Cytologic Features Causing Cardiac Tamponade in a Young Adult Patient

Abstract Introduction/Objective Cardiac angiosarcoma is a rare endothelial malignancy with poor prognosis, frequent metastasis, and short median survival of only a few months. The disease has a wide age spectrum and can occur in young adult patients. The cytological diagnosis of cardiac angiosarcomas is challenging as cases are rare and its cytology is not extensively described or reported in literature. Here, we describe a rare case of cardiac angiosarcoma with unusual cytologic features. Methods/Case Report Our patient is a 30 year old male presenting with three days of worsening dyspnea and palpitations and was discovered on ultrasound to have large pericardial effusion compressing the right ventricle and causing cardiac tamponade. CT/MRI imaging revealed a 4.5 x 4.3 x 2.6 cm mass inside the right ventricle with extra- cardiac invasion through the pericardium and into the anterior mediastinum. Pericardiocentesis yielded 1.5 liters of hemorrhagic, brown, pericardial fluid with elevated LDH and protein levels. Cytology of the pericardial fluid revealed numerous tumor cells occurring singly or in monolayered, acinar clusters or cohesive spheres containing amorphous, eosinophilic cores made of collagen as evidenced on trichrome stain. The tumor cells possessed hyperchromatic, irregular, variably sized nuclei, prominent nucleoli, and cytoplasmic vacuoles. The tumor cells were positive for vimentin, CD31, and CD34, and showed high Ki67 proliferation index > 50%. A catheter-mediated biopsy of the right ventricular mass revealed spindled and epithelioid tumor cells strongly positive for CD31, CD34, and vimentin, focally positive for Factor VIII and AE1/AE3, and showing high Ki67 proliferation index of roughly 50%. The cytological, histological, and immunohistochemical findings were most consistent with cardiac angiosarcoma as the diagnosis. The patient eventually developed worsening chronic left chest pain and expired from cardiac arrest six months after his diagnosis. Results (if a Case Study enter NA) NA Conclusion We report a rare case of cardiac angiosarcoma with unusual cytologic features, manifesting as acinar clusters and cohesive spheres with collagenous cores that are not typical of malignant endothelial neoplasms. Currently there are no effective, standardized therapies that can significantly prolong survival for this malignancy, and treatment is often palliative. The cytological diagnosis of cardiac angiosarcoma is challenging given the rarity of this disease and the paucity of literature describing its cytology.

Gastric Epithelial Neoplasm of Fundic-Gland Mucosa Lineage: Showed the Same Genetic Lineage and Ki67 May Help in Their Identification

Abstract Introduction/Objective Gastric epithelial neoplasm of the fundic-gland mucosa lineages (GEN-FGMLs) are rare form of gastric tumors that encompasses oxyntic gland adenoma (OGA), gastric adenocarcinoma of the fundic-gland type (GA-FG), and gastric adenocarcinoma of the fundic-gland mucosa type (GA-FGM). There is no consensus on the clinicopathologica and molecular characteristics of GEN-FGMLs, and misdiagnosis is common because of similarities in symptoms. Methods/Case Report The NGS and immunohistochemical staining were performed on 37 cases diagnosed with GEN-FGMLs with a thorough histological evaluation. Gene alternations were analysed and compared across histological subtypes. we used an artificial intelligence approach for the recognition of the Ki67 immunohistochemistry stained. Results (if a Case Study enter NA) The patient’s ages ranged from 42 to 79 years, with a median age of 60. 17 were male and 20 were female. Morphologically, 19 OGAs, 16 GA-FGs, and two GA-FGMs were identified. Histopathological similarities exist between GEN-FGMLs. The tumors demonstrated well-formed glands, expanding with dense growth patterns comprising pale, blue-grey columnar cells with mild nuclear atypia. The normal gastric pit epithelium covered the entire surface of the OGA and GA-FG, but the dysplasia pit epithelium covered the GA-FGM. Compared with OGA, GA-FG and GA-FGM were more prominent in the macroscopic view (p<0.05) and had larger sizes (p<0.0001). Additionally, GA-FG and GA-FGM exhibited higher Ki67 indices than OGA (p<0.0001). The heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across histological subtypes. The top five mutational signatures in OGA were ROS1, CTNNA1, GNAS, BRCA2, and ZFHX3. The top five mutational signatures in GA-FG and GA-FGM were GNAS, MLL3, BRAF, MSH3, and EGFR. GNAS were both found in OGA, GA-FG and GA-FGM. Compared with well-differencent gastric adenocarcinoma, The top five mutational signatures in GEN-FGMLs were GNAS, BRAF, ROS1, MLL3, and MSH3. Recurrently mutated key signaling pathways across tumor types in GEN-FGML were Wnt signaling pathways. Conclusion GEN-FGMLs are a group of well-differentiated gastric tumors with favourable biological behaviours. Compared with OGA, GA-FG and GA-FGM have larger sizes and higher Ki67 proliferation indices, indicating that they play a critical role in the identification of GEN-FGML. GEN-FGMLs showed the same genetic lineage, the Wnt signalling pathway plays a role in the development and progression of GEN-FGMLs.

Primary Cutaneous Acral-type CD8-positive T-cell Lymphoproliferations: Widely Divergent Clinical Outcomes Despite Nearly Identical Histomorphology

Abstract Introduction/Objective Non-epidermotropic and acral CD8(+) T-cell proliferations have recently been reclassified as lymphoproliferative disorders (LPDs) due to their indolent course clinical. Here, we describe two cases with similar histomorphology but disparate clinical outcomes, highlighting the diagnostic challenges. Methods/Case Report Case 1: An 89-year-old male developed a 2 cm erythematous papule on the forehead. Biopsy showed a non-epidermotropic pan-dermal lymphocytic infiltrate, a distinct grenz zone, and areas of necrosis. Case 2: A 53-year-old male presented with a rapidly growing, ulcerating 8.9 cm scalp lesion. Biopsy showed a deep dermal lymphoid infiltrate with complete epidermal sparing. In both cases neoplastic cells were positive by immunohistochemistry for CD2, CD3, CD5, CD7 (partial), CD8, granzyme B, TIA-1, and CD68 (perinuclear dot-like pattern). The Ki-67 proliferation index varied modestly between cases (50% in case 1 and 70% in case 2, respectively). Despite treatment, within the span of a few months, case 2 developed adjacent, widely distributed scalp nodules with extensive local tissue destruction. Pathology was consistent with recurrent disease (flow cytometry demonstrating T-cells, co-expressing CD8, CD2, CD3, CD5, CD7 and monotypic TRBC1). Results (if a Case Study enter NA) NA Conclusion CD8+ T-cell lymphoproliferative disorders, specifically primary cutaneous acral CD8+ T-cell lymphoproliferative disorder, is a rare cutaneous T-cell disorder that was re-classified, owing to its indolent clinical course, low risk of systemic dissemination, and favorable prognosis. We report two cases of nearly identical isolated cutaneous lesions that demonstrated a CD8(+)-cytotoxic phenotype with CD68-dot-like positivity. Although all morphologic findings were supportive of the diagnosis, the aggressive clinical progression in case 2 highlights the potential for the disease to defy the classically described indolent behavior. Given that few cases with aggressive clinical courses have been published, we present these cases to underscore their complexity and propose that the classification incorporate clinicopathological correlation to guide management.

Bihemispheric IDH-Wildtype Glioblastoma with Unilateral FGFR3-TACC3 Fusion in Patient with Breast Cancer History: A Case Report and Literature Review

Abstract Introduction/Objective Adult IDH-wild type glioblastomas comprise a heterogeneous spectrum of neoplasms, characterized by poor prognosis and resistance to the chemoradiotherapy. For WHO integrated diagnosis classification and to establish treatment options, molecular analysis is necessary. Herein, we present a case of a glioblastoma, IDH-wildtype with involvement of both cerebral hemispheres and an uncharacteristic in-frame fusion limited to one hemisphere. Methods/Case Report The patient is a 52-year-old woman with past medical history of metastatic breast cancer who presented with headache and worsening facial pain. Brain magnetic resonance imaging brain demonstrated a right frontal lobe lesion with vasogenic edema. The patient was treated with Gamma Knife radiosurgery. Scans revealed enlargement and a new left frontal lobe lesion. Bihemispheric tumor resection and GammaTile placement was undertaken. Results (if a Case Study enter NA) Histologically, the tumor was composed of hypercellular astrocytes, microvascular proliferation, and necrosis with no evidence of metastatic disease. Immunohistochemistically, neoplastic cells showed glial fibrillary acidic protein expression and elevated Ki-67 proliferation index. Molecular examination revealed in the right hemisphere lesion post-radiation (1) FGFR3::TACC3 (exon 17::exon 11) fusion and (2) TERT promoter, while the left hemisphere lesion which did not receive radiation showed clinically relevant variants in (1) TERT promoter, (2) TP53, (3) NF1, and (3) PIK3CA without identification of a fusion. An integrated diagnosis of glioblastoma, IDH- wildtype, CNS WHO grade 4 was established bilaterally. Conclusion The fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil 3 (TACC3) fusion is identified as a rare molecular feature in glioblastomas with an estimated prevalence of 4%. Clinical trials suggest that F3T3-positive tumors have a better prognosis than those without the translocation. The identification of the oncogenic FGFR3-TACC3 fusion highlights the possibility of identifying patients potentially responsive to targeted therapy with FGFR kinase inhibitors. The significance of the molecular differences in the right and left hemisphere lesions is uncertain; glioblastomas are heterogeneous tumors with intra-and intertumoral heterogeneity but it may suggest independent origins.

Leiomyoma with bizarre nuclei occurring post hysterectomy mimicking malignancy: a rare case report

Abstract Introduction/Objective Leiomyoma with bizarre nuclei (LBN), also known as symplastic leiomyoma, represents a rare subtype of benign uterine smooth muscle neoplasm. Histologically, it is characterized by significant cytological atypia in a typical leiomyoma background with rare mitoses and without tumor necrosis. Methods/Case Report We report a case of a 48-year-old woman, status post hysterectomy for symptomatic fibroids, with imaging showing multiple contiguous pelvic masses extending from the pelvis to the upper abdomen and displacing the colon laterally and small bowel posteriorly. The findings were highly suspicious for ovarian malignancy. A bilateral salpingo-oophorectomy and a partial colectomy were performed with tumor debulking and omentectomy. Grossly, multiple well-circumscribed soft masses ranging in size from 1.5-16 cm, in contiguity with pericolonic mesentery with a smooth fleshy cut surface and cystic changes were found. Bilateral ovaries were unremarkable. Microscopically the larger masses were composed of spindle cells with bizarre nuclei throughout, while smaller masses showed foci of bizarrely shaped-spindle cells with bizarre nuclei in a background of a typical leiomyoma. Mono- and multinucleated cells with smudged chromatin were also seen. The mitotic index was low confirmed with a low Ki-67 proliferation index (< 5%). Immunohistochemical stainings showed that the neoplastic cells were positive for desmin, SMA, and caldesmon; and negative for CD10, with a wild type p53 expression. Fumarate hydratase immunostain was retained. MDM2 amplification was not detected by FISH. The morphology and immunohistochemical findings were compatible with LBN. Results (if a Case Study enter NA) NA Conclusion In summary, this is a rare and challenging case of multiple LBN developed years post hysterectomy and clinically mimicking a malignancy.

Atypical Gastric Glomus Tumor of Uncertain Malignant Potential in A 16-Year-Old Female; A Rare Entity with Unique Findings

Abstract Introduction/Objective Gastric glomus tumor (GGT) is a rare mesenchymal tumor that is challenging to diagnose, especially when the immunoprofile overlaps with other more common gastric mesenchymal tumors. The majority of GGT are benign, however, rarely it can be atypical or even malignant. Herein, we present a case of a young female with atypical gastric glomus tumor of uncertain malignant potential. Methods/Case Report A 16-year-old female presented to the emergency with abdominal pain, coffee ground emesis, and melena. Imaging showed a 3.2 cm well-defined gastric mass arising from the muscularis propria. Results (if a Case Study enter NA) The FNA biopsy revealed clusters of tumor cells with uniform characteristics, exhibiting distinct cell membranes and eosinophilic to clear cytoplasm, surrounding prominent vasculature. Immunohistochemical analysis showed that the tumor cells were positive for SMA, synaptophysin, vimentin, calponin, and caldesmon, with weak, patchy positivity for DOG1. CD34 highlighted the vessels separating the tumor cellular clusters into lobules. CD117 and Desmin were negative. The Ki67 proliferation index varied with hotspot foci 25-30%. Morphology and immunoprofile suggest glomus tumor, however, neuroendocrine tumor and epithelioid GIST needed to be excluded. Subsequent resection specimen showed that the tumor was located within the muscularis propria with extension into the serosal vessels, suggesting vascular invasion, along with foci of cellular spindling and nuclear irregularity are identified. No necrosis noted. Tumor cells were positive for cyclin D1 while negative for myogenin, chromogranin, and DOG1. Overall, findings were consistent with GGT of uncertain malignant potential. Conclusion Although GGT are rare, they should be considered in the differential diagnosis of gastric mesenchymal tumors. The presence of diffuse SMA staining can help distinguishing them from GIST. It is crucial to scrutinize for signs of cellular and nuclear atypia, particularly in deeply seated glomus tumors.

Adenoma, Hamartoma, or Something Else? Unique Diagnostic Challenges in Mixed Epithelial-Mesenchymal Lesions of the Gastrointestinal Tract

Abstract Introduction/Objective Mixed epithelial-mesenchymal lesions (MEMLs) are well-known in the gynecologic tract and, to a lesser extent, in the lungs and kidneys. However, the literature is mostly lacking in the GI tract. These cases pose significant diagnostic challenge when encountered upon, as there are many pitfalls and gray areas exist in characterization. Amongst other entities, hamartomas can account for a portion of these cases. Herein, we present a unique case of MEML identified in duodenum, which was reported as a hamartoma. Methods/Case Report A 59-year-old male presented with persistent upper GI bleeding requiring multiple transfusions. Initial upper GI endoscopy revealed an oozing ulcer as part of a 30 mm polyp in the second portion of duodenum opposite to ampulla. Epinephrine was injected for homeostasis. After repeat endoscopy failed to completely resect the lesion, the patient underwent exploratory laparotomy with resection of the 2nd portion of duodenum. The sections showed a submucosal proliferation of epithelial and mesenchymal elements. The epithelial component consisted of bland-appearing foveolar type mucinous glands, partly showing cystic dilation, while the mesenchymal component consisted of lymphovascular and neural structures as well as a population of small round cells that showed patchy SMA immunolabeling and low Ki67 proliferation index. The case was reported as hamartoma, however, a Brunner’s gland cyst and pericytic tumors (i.e. glomus tumor) were also considered. While the histologic features did not suggest malignancy, the patient had been followed-up closely for 6 months. Recurrence or malignant transformation was not reported. Results (if a Case Study enter NA) NA Conclusion MEMLs in the GI tract are always challenging to diagnose due to their rarity, unknown etiology and natural history, and lack of established risk factors. Furthermore, mesenchymal component is often difficult to characterize due to multiple differentiations and patchy/unrevealing immunohistochemistry. We report this unique case to enhance the awareness and recognition of MEMLS in the GI tract.

Pesticide exposure and oxidative stress generation are linked to poor prognosis outcomes in breast cancer women carrying the allelic variant rs7438135 in the UGT2B7 gene.

Pesticide exposure is a risk factor for the development of several diseases, including breast cancer (BC). The enzyme UGT2B7 participate in detoxification of pesticides and the presence rs7438135 (G > A) variant in your gene increases its glucuronidation potential, contributing to oxidative stress metabolites neutralization. Here we investigated the impact of occupational pesticide exposure on the systemic oxidative stress generation from 228 women with BC depending on their UGT2B7 rs7438135 (G > A) status. q-PCR investigated the presence of the rs7438135 variant, and oxidative stress markers (lipid peroxidation levels, total antioxidant capacity-TRAP, and nitric oxide metabolites-NOx) were measured in plasma. Pesticide exposure induced significant augment in the systemic lipid peroxidation in the presence of the variant for several clinicopathological conditions, including tumors with high proliferation index (ki67) and with high aggressiveness. NOx was augmented in high ki67, positive progesterone receptors, high-grade and triple-negative/Luminal B tumors, and low-risk stratified patients. TRAP was depleted in young patients at menopause and those with triple-negative/Luminal B tumors, as well as those stratified as at low risk for death and recurrence. These findings showed that the presence of the variant was not able to protect from pesticide-induced oxidative stress generation in BC patients.