Proliferation Index Research Articles

SMARCA4-Deficient Undifferentiated Carcinoma of the Gastroesophageal Junction: A Case Report

Abstract Introduction/Objective To report a rare case of the newly characterized variant of gastric carcinoma; undifferentiated carcinoma with intact SMARCB1 (INI1) but lost SMARCA4/SMARCA2, and approach to diagnosis. Methods/Case Report A case of gastric mass extending to the gastroesophageal junction, microscopically, showing sheets of atypical, medium to large, discohesive, polygonal cells with large eccentric and pleomorphic nuclei, variably prominent nucleoli, and eosinophilic cytoplasm with brisk mitosis, in the background of marked necrosis and granulomatous inflammation. And having focally positive staining for cytokeratin and negative for melanoma, diffuse large B-cell lymphoma, high grade neuroendocrine tumor, sarcoma, rhabdoid/myoid-specific immunohistochemistry (IHC) markers. The case was further characterized with immunophenotypic, cytogenetic, and molecular findings. Results (if a Case Study enter NA) By immunohistochemistry (IHC), the large tumor cells were positive for vimentin, FLi-1 and patchy CD71. A subset of tumor cells showed CD34 positivity. The tumor cells were mainly negative (with rare focal positivity) for all cytokeratin including (CK AE1/AE3, EMA, and CK OSCAR). Tumor cells were negative for specific markers for melanoma, GIST, sarcomatous tumors, squamous cell carcinoma, hematolymphoid malignancies, and neuroendocrine tumors. EBER-ISH and HHV-8 were negative. The Ki67 showed a proliferative index of ~60%. The tumor cells demonstrated retention of INI1 (SMARCB1) with loss of both SMARCA2 and SMARCA4 by IHC. Molecular studies detected an inactivating mutation of the retinoblastoma-1 gene (RB1 I124Rfs*6) and TP53 with altered function compared to wild-type (TP53-G245S) with no mutations or deletion of SMARCB1 gene. The status of SMARCA4 gene came as indeterminate. No microsatellite Instability detected. Conclusion Our study demonstrates the challenge of diagnosing the SMARCA4/SMARCA1-deficient undifferentiating gastric carcinoma especially with negative cytokeratin stains, showing the immunohistochemistry profile of the tumor and its molecular findings in our case.

Calcifying Nested Stromal-Epithelial Tumor of the Liver: A Rare Find

Abstract Introduction/Objective Calcifying Nested Stromal-Epithelial Tumor (CNSET) is a rare tumor of the liver with less than 40 cases described in the literature. It is a low-grade tumor characterized by a distinctive nested architecture surrounded by a cellular myofibroblastic stroma and psammomatous calcifications. CTNNB1 gene deletions have been identified in several cases. CNSET typically arises in the right lobe and there is a female predominance with a predilection for children, adolescents, and young adults. Methods/Case Report We report an interesting case of CNSET in a 13-year-old male with no pertinent medical history who presented with a one-month history of fatigue, paleness, and liver mass on physical examination. MRI abdomen showed a 9.8 cm heterogenous mass with a central scar involving the right lobe of the liver, radiologically favored to be fibrolamellar hepatocellular carcinoma. AFP levels were normal. The patient underwent a partial hepatectomy. On gross examination, the specimen showed a yellow, circumscribed, firm mass. H&E slides showed scattered round to oval nests of bland spindle and epithelioid cells arranged in short fascicles at the periphery of nests. Collagenous stroma surrounding the nests showed spindle cells with tapered nuclei and pinpoint nucleolus. Areas with calcification and osseous metaplasia were also present. Immunohistochemistry performed showed the tumor cells to be positive for pan-cytokeratin (weak), WT-1, and vimentin, and negative for Hepar-1, arginase-1, synaptophysin, chromogranin, S100, NUT-1, myogenin, and desmin. Beta-catenin showed nuclear and cytoplasmic staining pattern. INI-1 was retained within the tumor cells and Ki-67 showed a proliferative index of approximately 10-20%. On MSK-Impact (next- generation sequencing), a mutation in CTNNB1 was detected. Archer FusionPlex was negative for gene fusions within the tumor. Results (if a Case Study enter NA) NA Conclusion It is crucial to become familiar with this rare entity and to avoid mistaking it for hepatoblastoma. CNSET exhibits a biphasic morphology characterized by a nested architecture featuring bland and uniform epithelioid and spindle cells, surrounded by a cellular myofibroblastic stroma. Confirming the diagnosis can be aided by nuclear β- catenin and the expression of WT1.

Analysis of SLC genes alternative splicing identifies the SLC7A6 RI isoform as a therapeutic target for colorectal cancer.

Alternative splicing (AS), a crucial mechanism in post-transcriptional regulation, has been implicated in diverse cancer processes. Several splicing variants of solute carrier (SLC) transporters reportedly play pivotal roles in tumorigenesis and tumor development. However, an in-depth analysis of AS landscapes of SLCs in colon adenocarcinoma (COAD) is lacking. Herein, we analyzed data from The Cancer Genome Atlas and identified 1215 AS events across 243 SLC genes, including 109 differentially expressed AS (DEAS) events involving 62 SLC genes in COAD. Differentially spliced SLCs were enriched in biological processes, including transmembrane transporter activity, transporter activity, ferroptosis, and choline metabolism. In patients with COAD, tumor tissues exhibited higher expression of longer mitochondrial carrier SLC25A16 isoforms than adjacent normal tissues, consistent with bioinformatics analysis. Protein-coding sequences and transmembrane helices of survival-related DEAS were predicted, revealing that shifts in splicing sites altered the number and structure of their transmembrane proteins. We developed a prognostic risk model based on the screened 6-SLC-AS (SLC7A6_RI_37208 (SLC7A6-RI), SLC11A2_AP_21724, SLC2A8_ES_87631, SLC35B1_AA_42317, SLC39A11_AD_43204, and SLC7A8_AP_26712). Knockdown of the intronic region of SLC7A6-RI isoform enhanced colon cancer cell proliferation. Invivo, knockdown of the intronic region of SLC7A6-RI isoform enhanced tumor growth in colon cancer. Mechanistically, si-SLC7A6-RI isoform exerted oncogenic effects by activating the PI3K-Akt-mTOR signaling pathway and promoting cell proliferation, evidenced by increased expression of key regulators Phosphorylated Mammalian Target of Rapamycin (p-mTOR) and a cell proliferation marker Proliferating Cell Nuclear Antigen (PCNA) using western blotting. Our study elucidated SLC-AS in COAD, highlighting its potential as a prognostic and therapeutic target and emphasizing the suppressive influence of SLC7A6-RI in colon cancer progression.

The Utility of PRAME and Ki-67 as Prognostic Markers for Cutaneous Melanoma.

Cutaneous melanoma can lead to metastasis, and it is associated with high mortality. Currently, there are no widely accepted immunohistochemistry markers for melanoma prognosis in routine staging. Preferentially expressed antigen in melanoma (PRAME) is a possible biomarker for prognosis in several noncutaneous neoplasms. Ki-67 is a cell proliferation marker correlated with poor outcomes in many cancers. This study assessed PRAME and Ki-67 as potential prognostic markers for sentinel lymph node outcomes and survival among melanoma patients. This is a retrospective study analyzing cutaneous melanoma cases from a Brazilian cancer center (2005-2021). All cases were tested using immunohistochemistry to evaluate PRAME expression and Ki-67 index. Descriptive analysis, Spearman correlations, means comparison, Kaplan-Meier analysis, χ2, and Cox models were performed. In univariate analysis of 123 cutaneous melanoma cases, high extent (P = 0.0267) and elevated intensity (P = 0.043) of PRAME were associated with decreased overall survival. The Ki-67 index was associated with overall survival (P = 0.05) and sentinel lymph node status (P = 0.0403), with a positive correlation between the markers (P = 0.0004) and between Ki-67 and Breslow thickness (P = 0.0001). However, in multivariate analysis, only Breslow thickness significantly influenced overall survival (P = 0.0003). Then, the present results can suggest that elevated PRAME and Ki-67 expression are associated with poor overall survival in cutaneous melanoma; however, in multivariate analysis, only the Breslow thickness had a significant influence. These findings highlight the potential of PRAME and Ki-67 as prognostic markers, opening frontiers that could improve strategies for treating cutaneous melanoma.

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.

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.

Composite Lymphoma Comprising of BCL2 Rearrangement Negative, CD23 Positive Follicle Center Cell Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Case Report

Abstract Introduction/Objective BCL2 rearrangement negative, CD23-positive follicle center cell lymphoma (BCL2 neg CD23 pos FCL) is a rare, recently described provisional entity in International Consensus Classification (2022). It has a predominantly diffuse growth pattern and often involves inguinal region. The molecular profile includes a high frequency of STAT6 and CREBBP co-mutation as well as 1q gain and a recurrent 1p36 loss/TNFRS14 abnormalities. We describe a composite tumor comprising of a rare entity BCL2 neg CD23 pos FCL and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). To the best of our knowledge this is the first reported case description of this co-occurrence. Methods/Case Report A 59 y/o woman presented with right cervical and axillary lymphadenopathy (upto 1.6 cm). Sections showed partial effacement of nodal architecture by interfollicular and diffuse proliferation of atypical lymphoid cells. The interfollicular areas were comprised of a monotonous population of small lymphocytes. Immunohistochemical stains performed showed that the interfollicular CD20+ PAX5+ atypical lymphoid cells coexpressed CD5, CD23, BCL2 and LEF1 and were negative for CD10, BCL6, CD3, and SOX11, with MIB1 of 5-10%. Based on these, a diagnosis of CLL/SLL was made. Admixed with the CLL/SLL, a second neoplastic B-cell component that distorted nodal architecture was also identified. It composed of a diffuse proliferation of intermediate sized lymphoid cells with a centrocytic/centroblastic morphology. This smaller population of small to intermediate sized B cells expressed CD10, BCL6, and CD23 with a MIB1 proliferation index of ~30%. This population was CD5 and BCL2 negative. CD21 showed residual follicular dendritic cell meshworks. SOX11 and BCL1 were negative. Therefore, a diagnosis of BCL2 neg CD23 pos FCL was made. Flow cytometry showed two distinct populations of monotypic B-cells, one CD5-positive and the other CD10-positive. FISH studies were negative for BCL2 and BCL6 rearrangements as well as del1p36. Cytogenetics was positive for trisomy 12, supporting CLL/SLL. Next Generation Sequencing showed Tier 1 / 2 mutations in STAT6, TNFRSF14, CREBBP, and FOXO1, supporting BCL2 neg CD23 pos FCL. Hence, this represents a unique case of composite CLL/SLL and BCL2 neg CD23 pos FCL. B cell gene rearrangement showed 2 distinct clones confirming 2 separate B cell lymphomas. Results (if a Case Study enter NA) NA Conclusion Here, we describe a composite CLL/SLL and BCL2 rearrangement negative, CD23 positive, FCL never previously described in literature.

An unusual case of a de novo high-grade B cell neoplasm with MYC and BCL2 rearrangements, strong TdT expression, and BRAF V600E mutation

Abstract Introduction/Objective Aggressive de novo B cell neoplasms can rarely exhibit overlapping features of B- lymphoblastic leukemia/lymphoma (B-ALL) and high-grade B cell lymphoma (HGBL) making their definitive classification challenging. The distinction between mature and immature B cell neoplasms is critical as treatment approaches differ. We report a unique case of an aggressive B cell neoplasm that not only posed diagnostic difficulties but was also found to harbor a BRAF V600E mutation, an unusual finding in such cases. Methods/Case Report A 33-year-old man without any significant past medical history presented for evaluation of a large tonsil mass and diffuse lymphadenopathy. The tonsil was excised, and histologic examination showed a diffuse atypical infiltrate composed of medium to large monomorphic lymphoid cells with high-grade cytology. By immunohistochemistry, the atypical cells were positive for CD19, CD79a, CD22, PAX5, CD10 (strong), CD45 (strong), BCL2, MYC, and TdT (strong). Ki67 showed a high proliferation index (80%). The atypical cells were negative for CD20, CD34, CD1a, CD30, Cyclin D1, T cell markers, myeloid markers, HHV8, and EBER. Flow cytometry detected a CD10 positive B cell population that was negative for CD20, CD34, and surface light chain expression. Fluorescence in-situ hybridization (FISH) detected BCL2 and MYC rearrangements. Staging marrow showed diffuse involvement by a neoplastic infiltrate with similar features to those observed in the tonsil. Chromosome analysis showed a complex karyotype. The patient was treated with two cycles of da-EPOCH-R. A neck lymph node biopsy two months later showed persistent disease. Next-generation sequencing (NGS) on this sample demonstrated a BRAF V600E mutation at 31% allele frequency. A mutation-specific BRAF-VE1 immunostain was diffusely positive. Results (if a Case Study enter NA) NA Conclusion This was a diagnostically challenging case of a de novo B-cell lineage neoplasm with high-grade features, MYC and BCL2 rearrangements, and strong diffuse TdT expression. There is limited literature on mutational profiles and prognostic data for such cases, and whether they are best classified (and treated) as HGBL or B-ALL remains challenging and controversial. In our case, we also discovered an unexpected finding of a BRAF V600E mutation, which has not been reported in similar cases in the existing literature and could serve as a potential therapeutic target. Additional reporting and genetic profiling of such cases may help further elucidate their biology and guide treatment protocols.

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.

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.

Comparison of the Mitotic Count With Various Proliferative Markers for the Effective Differentiation of Benign, Borderline, and Malignant Phyllodes Tumors

Comparison of the Mitotic Count With Various Proliferative Markers for the Effective Differentiation of Benign, Borderline, and Malignant Phyllodes Tumors

PARP1 acetylation at K119 is essential in regulating the progression and proliferation of cervical cancer cells.

Cervical cancer, CC, is one of the malignant cancers in women worldwide. Many studies about the genesis and progression of CC have been done at genomic, transcriptional, translational, and epigenetic levels. However, much less is done at post-translational modification (PTM) level. We first used pan-PTM antibodies to compare the pan PTM levels between clinical normal cervical tissues and CC tissues; we then sent the selected samples for label-free identification of acetylation sites. Next, we employed WT or K119A mutant PARP1-EGFP-STREPII plasmid transfection in Hela cells and examined various indexes including colony formation, wound healing, ROS generation, early apoptosis, and immunofluorescence and quantification of proliferation markers (Ki67, PCNA, and p-P53). Last, we examined the levels of multiple important kinases regulating cervical cancer progression. We found that pan-acetylation was the most downregulated in clinical CC samples, whereas the acetylation of PARP1, Poly(ADP-ribose) polymerase-1, was upregulated at K119. Next, we showed that PARP1-WT overexpression significantly suppressed the proliferation and progression in CC cell line Hela, while K119A overexpression didn't show any impact. Finally, PARP1-WT overexpression significantly decreased p-ERK1/2 while didn't affect the phosphorylation levels of other important kinases such as AKT, MTOR, and RPS6. This study discovered a new type of PTM of PARP1 in CC, and showed that PARP1 acetylation at K119 is essential in regulating the proliferation and progression of CC through ERK1/2. Further studies are required to investigate how PARP1 acetylation impact its function.

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.