High-grade Component Research Articles

Combination of grade and spread through air spaces (STAS) predicts recurrence in early stage lung adenocarcinoma: a retrospective cohort study.

Adenocarcinomas, a common subtype of lung cancer, exhibit diverse histological patterns. In 2020, The International Association for the Study of Lung Cancer (IASLC) introduced a grading system emphasizing high-grade components, which has shown prognostic value. Spread through air spaces (STAS) is recognized as a prognostic feature increasing the risk of recurrence in lung cancer. This study evaluates the combination of STAS status and the IASLC-grading system in surgically resected Stage I lung adenocarcinomas. This study is a retrospective analysis of 123 patients with Stage I lung adenocarcinoma who underwent lobectomy between 2011 and 2019. Histological patterns were assessed according to the IASLC criteria, and STAS status was documented. Patients were categorized based on their IASLC Grade and STAS status. Statistical analyses included Kaplan-Meier survival estimates, Cox proportional hazards models, and comparisons using Chi-square and t-tests. The cohort comprised 43 females and 80 males with a mean age of 61.8 ± 7.6years. STAS positivity was noted in 52.8% of patients. STAS positivity correlated significantly with Grade 3 tumors (p < 0.001). The 5-year recurrence-free survival was significantly lower in STAS-positive patients (70.7% vs. 88.7%, p = 0.026). Patients with Grade 3 and STAS positivity had significantly lower recurrence-free survival compared to other groups (p = 0.002). Grade 3 and STAS positivity were independent predictors of poor recurrence-free survival in multivariate analysis. IASLC Grade 3 tumors and STAS positivity are independent prognostic factors for poor recurrence-free survival in Stage I lung adenocarcinomas. Adjuvant treatment strategies should be considered for patients with these characteristics to improve outcomes.

The clinical relevance of cut-off percentage for high-grade urothelial carcinoma within low-grade urothelial carcinoma: A determining factor?

AimsThe aim of the study was to analyze the cut-off value for the percentage of the high-grade (HG) component that has clinical significance in urothelial carcinoma (UC). Material and MethodsThe study included a total of 362 patients, mixed-grade UC (MGUC) patients were classified as Combine Group (CG) 1 based on the presence of less than 5% HG areas. High-grade papillary UC (HGPUC) patients were grouped based on HG component proportions: CG2 (≥5%–<50% HG), CG3 (≥50%–<100% HG), and pure HGPUC (PHGPUC) for 100% HG components. ResultsThere was a statistically significant difference between low-grade papillary UC (LGPUC) and CG1, CG2, or CG3, as well as LGPUC and PHGPUC, in terms of cancer-specific survival (CSS) (hazard ratio (HR) = 19.85, 95% confidence interval (CI) = 2.30–171.10 P = 0.007, HR = 28.38, 95% CI = 3.50–229.97 P = 0.002, HR = 18.64, 95% CI = 2.26–153.64 P = 0.007, and HR = 35.41, 95% CI = 4.61–271.72 P < 0.001, respectively). There was no statistically significant difference between PHGPUC and CG1, CG2, or CG3 in terms of CSS. ConclusionsThese findings suggest that even the presence of less than 5% HGPUC within LGPUC significantly impacts CSS. Furthermore, the increase in the percentage of HGPUC beyond 5% does not substantially influence the CSS. Based on these findings, disclosing the percentage of the high-grade component may be crucial for future patient management and treatment.

Malignant Peripheral Nerve Sheath Tumor (MPNST) With Smooth Muscle Differentiation of the Uterus-A Case Report With Emphasis on Diagnostic Pitfalls and Value of DNA Methylation Analysis.

With no more than two dozen cases reported in the literature, malignant peripheral nerve sheath tumor (MPNST) is a rare primary mesenchymal neoplasm arising in the female genital tract. Most cases occurred in middle-aged adults with high grade histology, unfavorable clinical outcome, and no history of neurofibromatosis type 1. Its extreme rarity in this site no doubt poses a diagnostic challenge during routine clinical practice. In the following, we report an additional case of uterine MPNST occurring in a 49-year-old Chinese woman, which was initially misdiagnosed as a leiomyosarcoma. The primary tumor showed two distinctive components-a high-grade poorly differentiated component with markedly pleomorphic spindle cells arranged in a peritheliomatous pattern; and a leiomyosarcoma-like (LMS-like) component with tumor cells displaying obvious myoid differentiation. The patient suffered a recurrence less than 2 years later with the recurrent tumor demonstrating similar features to the high-grade component of the primary tumor. The patient eventually succumbed 46 months later after developing another recurrence despite receiving targeted therapy and chemotherapy. On retrospective molecular analysis, no clinically relevant fusion transcript was detected on RNA sequencing. Interestingly instead, DNA methylation analysis showed the tumor clustered with the "MPNST" group in the German Cancer Research Center (DKFZ) sarcoma classifier. The tumor was also found to have EED gene homozygous deletion, multiple copy number alterations and loss of H3K27me3 expression in both high-grade and LMS-like components. Combining histology with all the ancillary tests results, the diagnosis was most consistent with MPNST. Our case highlights the diagnostic pitfalls for MPNST arising in the female genital tract and the potential clinical utility of DNA methylation analysis.

7824 Orbital Lymphoma masquerading as Thyroid Eye Disease

Abstract Disclosure: S. Ganawa: None. S. Joseph: None. C. Anshuman: None. D. Luciane L: None. A. Sajid: None. C. Anne: None. S. Dhage: None. Thyroid eye disease (TED) is the most common extrathyroidal manifestation in Graves’ disease (GD). In this case report, we present a case of a 64 years old lady, who was initially diagnosed with thyroid eye disease about 9 years ago. However, she was clinically and biochemically euthyroid. She was offered an orbital decompression surgery by local ophthalmology team. Patient wasn’t keen on the surgery at this stage.Recently she experienced increased swelling of her eyes, with conjunctival redness, oedema, and diplopia bilaterally, more evident on the left side. She was initiated on intravenous methylprednisolone (IVMP) weekly, by local ophthalmology team and was referred to our specialist thyroid eye clinic for further management.On presentation to us, her clinical activity score (CAS) was 5/7, but she was euthyroid clinically and biochemically. She was continued on weekly IVMP and oral mycophenolate mofetil (MMF) was added on as per the latest EUGOGO guidelines published in 2021. Her treatment was reviewed after the anti thyroperoxidase (TPO) and anti-Thyroid Stimulating Hormone receptor (TSH) antibodies were reported as negative and her eyes worsened despite the treatment with IVMP and MMF.Her repeat MR orbit at this stage showed possible orbital lymphoma. Her immunosuppressive medications were discontinued at this stage. After further discussions at regional thyroid eye MDT and radiology MDT, an orbital biopsy was arranged for, which confirmed Extra nodal Marginal Zone lymphoma, with no high-grade component. She has been referred to the oncology unit for further assessment and management.This case highlights the importance of considering alternative differential diagnosis in certain patients with atypical features or those who are non-responders to the first line immunosuppressive therapies for thyroid eye disease. Details of this case and relevant literature will be reviewed in this report. Presentation: 6/3/2024

8604 Ectopic Cushing’s Syndrome Associated with a Metastatic Pancreatic Mixed Neuroendocrine Non-neuroendocrine Neoplasm (MiNEN) with Amphicrine Features

Abstract Disclosure: A. DeMarsilis: None. C. Jiang: None. O. Lavrynenko: None. D. Motavalli: None. C. Musurakis: None. Z.H. Taxin: None. E.D. Rosen: Advisory Board Member; Self; Source Bio, Inc.. Consulting Fee; Self; Novartis Pharmaceuticals, Gensaic. M.S. Irwig: None. Background: Ectopic Cushing’s Syndrome (CS) makes up 9-18% of ACTH-dependent CS cases, of which fewer than 15% are attributed to pancreatic neuroendocrine tumors (1). Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are rare, aggressive carcinomas, often driven by high-grade neuroendocrine components, with a poor prognosis (2). Amphicrine neoplasms contain neuroendocrine and exocrine components in the same cell. Clinical Case: A 34 year-old woman with asthma, hypertension, and depression presented with new onset lower extremity edema, facial hirsutism, mood changes, polyuria and polydipsia. She had an elevated morning serum cortisol of 52 ug/dL (normal &amp;lt; 20) with plasma ACTH 42 pg/mL (normal &amp;lt; 50), 24-hour urine free cortisol of 1003 mcg (normal &amp;lt; 50), K+ of 2.6 mEq/L, and fasting glucose 164 mg/dL. CT showed multiple hepatic lesions, pulmonary nodules, a pancreatic tail lesion, and lymphadenopathy concerning for metastatic disease. Her adrenal glands were thickened bilaterally without nodules. A pituitary MRI was normal. These findings were concerning for ectopic CS. She was admitted due to rapidly developing symptoms. Potassium, insulin, sitagliptin, and prophylactic anticoagulation were started. Spironolactone and ketoconazole were initiated while awaiting biopsy results of liver and pancreas lesions. Osilodrostat was not available and a trial of metyrapone was poorly tolerated. The liver and pancreatic tail lesion biopsy revealed metastatic MiNEN with amphicrine features, of pancreatic origin, with Ki67 proliferation index of 70%. Section staining of pancreas and liver biopsies were negative for ACTH. A Ga-68 Dotatate scan showed minimal uptake, so octreotide was not prescribed. Palliative chemotherapy was planned. Although ketoconazole was titrated to 1600 mg/day, urine free cortisol levels and serum free cortisol levels did not reach target. Cushing disease was considered but not suspected, as ACTH levels remained modest despite a relative decrease in cortisol level. Given significant morbidity from uncontrolled hypercortisolism, and plans for urgent initiation of systemic chemotherapy, after multidisciplinary discussion the patient was treated with a surgical bilateral adrenalectomy. Post-operative morning serum cortisol measured 8.3 ug/dL. After one week, palliative chemotherapy with FOLFIRINOX (oxaliplatin, leucovorin, fluorouracil, and irinotecan) was initiated. She was discharged home on stress dose steroids with plan for taper. Conclusion: Ectopic ACTH secretion is a rare phenomenon, particularly when presenting with a rare case of metastatic pancreatic MiNEN with amphicrine features, associated with significant morbidity. To improve tolerance and survival of further treatment, early surgical bilateral adrenalectomy should be considered.

A Case Study of a High-Grade Serous Carcinoma of the Fallopian Tube Transformed into Carcinosarcoma at the Site of Peritoneal Dissemination With Immunohistological Evidence of an Epithelial-Mesenchymal Transition.

We report a patient in whom a primary high-grade serous carcinoma (HGSC) of the fallopian tube transformed into a carcinosarcoma at the site of peritoneal dissemination, and immunohistological analysis suggested the involvement of an epithelial-mesenchymal transition (EMT). The patient, a 70-year-old woman, had an abdominal mass palpated on admission, and a laparotomy was performed after a close examination. The resected right fallopian tube was cystically dilated, and a solid mass was observed in its lumen. The histological diagnosis was HGSC of the right fallopian tube with a papillary or complex tubular structure composed of tumor cells with marked nuclear irregularities. p53 was overexpressed, and no mesenchymal tumor component was observed. The resected left-sided abdominal mass of the omentum was a solid with a long diameter of 100 mm. Microscopically, the tumor exhibited a mixture of HGSC and high-grade sarcoma with nonspecific differentiation. Furthermore, a heterologous chondrosarcoma was subsequently observed from the high-grade sarcoma. The HGSC component was E-cadherin positive. The high-grade sarcoma component was positive for EMT-related proteins such as zinc finger E-box-binding homeobox 1 (ZEB1) and twist family bHLH transcription factor 1 (TWIST1). The chondrosarcoma component was ZEB1 positive and TWIST1 negative. p53 overexpression was found in all 3 components. The tumor of the omentum suggested that an EMT phenomenon was involved in the tumorigenesis. In this scenario, the primary HGSC of the fallopian tube with obvious invasion demonstrated that the conversion from carcinoma to sarcoma by EMT occurs only with peritoneal dissemination.

Elucidating the nature of acinic cell carcinoma of the breast with high-grade morphology: evidence from case report

BackgroundAcinic cell carcinoma (AciCC) of the breast is a rare subtype of breast cancer. It was considered a low-grade triple-negative breast cancer (TNBC) with the potential to progress or transform into a high-grade lesion because of the molecular similarities with conventional aggressive TNBC in several genetic studies. Microscopically, the coexistence of classical low-grade and high-grade triple-negative components in breast AciCC is not uncommon. However, there is a scarcity of research on the comparative histopathological and genetic aspects of both components.Case presentationA 34-year-old woman with a nontender mass in the upper outer quadrant of the left breast was initially diagnosed with a malignant small round cell tumor (undifferentiated or poorly differentiated carcinoma) based on a preoperative biopsy, which was later identified as breast AciCC with a high-grade solid component. Left breast-conserving surgery with sentinel lymph node biopsy was performed. Microscopically, the breast AciCC consisted of a classical acinic component and a high-grade component. The latter demonstrated a solid sheet-like pattern characterized by large, round, pleomorphic or vesicular nuclei, prominent nucleoli, and frequent mitotic activities. Classical acinic architectures focally merged together to form solid nests and transited into high-grade areas. Remarkably, in the high-grade lesion, conventional immunochemical markers for breast AciCC, such as α1-antitrypsin (AAT), Lysozyme (LYS), Epithelial membrane antigen (EMA), S100 protein (S100), and cytokeratin (CK) were negative, whereas cell cycle protein D1 (cyclin D1) and vimentin showed diffuse expression. Next‑generation sequencing (NGS) revealed that 43.5% of variants were identical in both components. Furthermore, PAK5 mutation; copy number (CN) loss of CDH1, CHEK1, and MLH1; and CN gains of CDK6, HGF, and FOXP1 were identified in the high-grade lesion. The patient was treated with eight cycles of adjuvant chemotherapy (epirubicin combined with cyclophosphamide) and radiotherapy after surgery, and she is currently alive for 43 months with no metastases or recurrences.ConclusionsThis case demonstrates a comparative analysis of the histopathological and genetic characteristics of classical low-grade and high-grade components of AciCC within the same breast. This information may serve as a morphological and molecular basis for further investigation into the molecular mechanisms underlying high-grade lesions in breast AciCC.

High-grade Anaplastic Transformation of Ovarian Serous Borderline Tumor: A Distinctive Morphology With Abundant Dense Eosinophilic Cytoplasm and Dismal Prognosis.

Ovarian serous borderline tumors (SBTs) have a generally favorable prognosis. Although the risk of progression to low-grade serous carcinoma is well documented, progression to high-grade carcinoma is rare. We report the clinicopathologic features of seven SBTs, each associated with the presence of a morphologically unique high-grade component with an extremely dismal prognosis. All of the SBTs exhibited typical hierarchical branching and scattered eosinophilic cells, whereas the high-grade component consisted of a profuse proliferation of epithelioid cells with abundant dense, eosinophilic cytoplasm, variable nuclear pleomorphism, and evident loss of WT1, estrogen receptor, and p16 positivity. In most cases, the SBT demonstrated an abrupt transition to the high-grade component, but one patient initially presented with the usual SBT and developed a recurrent disease that was composed entirely of the high-grade component. Targeted next-generation sequencing revealed identical driver mutations in both the SBT and high-grade components (BRAF in 3, KRAS in 1), confirming clonality. Three cases, in addition, harbored telomerase reverse transcriptase promoter mutations in both components. One case, despite insufficient material for sequencing, was BRAF V600E-positive by immunohistochemistry. Most patients with available follow-up data died within 9 months of diagnosis. This study confirms prior reports of ovarian SBT transformation to high-grade carcinoma and further characterizes a distinct subset with abundant dense eosinophilic cytoplasm and an extremely dismal prognosis. The presence of BRAF mutations in a major subset of these tumors questions the notion that BRAF is associated with senescent eosinophilic cells and improved outcomes in SBT. The role of the additional telomerase reverse transcriptase promoter mutations merits further investigation.

Mixed adenoma-neuroendocrine tumor of the stomach: analysis of nine cases with literature review.

Mixed adenoma-neuroendocrine tumor (MANET) comprises adenoma and well-differentiated neuroendocrine tumor (NET) components. Given the limited information on this due to its rarity, we aimed to clarify the clinicopathologic features and optimal management of gastric MANETs in a case series and literature review. Nine patients with gastric MANETs, including eight male and one female patient (mean age, 72years), were identified from the institutional pathology archive. Endoscopically, the tumors appeared as flat elevated lesions with sizes ranging from 0.8 to 4.4cm. One patient had familial adenomatous polyposis, and no patient had autoimmune gastritis. All MANETs developed in the gastric body mucosa exhibiting chronic metaplastic atrophic gastritis. The glandular components were intestinal-type low-grade adenoma, and focal high-grade dysplasia was also recognized in three cases. The NET component was in middle/deep lamina propria in six cases and confined to deep lamina propria in the remaining three cases. Minimal cytologic atypia was found in the NET component, with no recognizable mitosis and a Ki-67 labeling index of < 2%. The NET component mostly showed diffuse positivity for serotonin and CDX2, suggesting that it consists of enterochromaffin cells. Diffuse p53 immunostaining was observed only in the high-grade adenomatous component of one case. No recurrence was observed during the follow-up period of 2-94months. Correct distinction between the NET and poorly differentiated carcinoma components is crucial to prevent overtreatment of gastric MANETs. Considering its indolent nature, endoscopic resection is the primary recommendation for gastric MANETs as well as for pure adenomas.

Seromucinous borderline tumor-associated high-grade ovarian cancers

We present 6 high grade ovarian carcinomas that were associated with seromucinous borderline tumors. Patients ranged in age from 26 to 66 years. All cancers appeared as solid regions within otherwise paucicystic tumors that measured from 4.2 cm to 14.0 cm in greatest dimension. Five of the 6 tumors were bilateral, and endometriosis was seen in 4 of the tumors. Clinical data, with follow up periods ranging from 0 to 40 months, was available for all patients. Four patients died of their disease and two had recurrent disease at the time of this review. All tumors exhibited a low-grade carcinoma component, which is consistent with ovarian cancers developing in a progressive adenoma to carcinoma sequence (so-called type I ovarian cancers). Two of the associated low-grade/borderline tumors had focal serous characteristics with WT1+ epithelial cell clustering. High-grade tumors exhibited an array of cell types expressing endometrioid, undifferentiated, serous, clear cell, and mucinous features that were at times mixed within the same tumor. Five cancers were focally WT1+; two showed admixed lowgrade serous features and one showed a high-grade serous adenocarcinoma with transitional features. Two cancers had mucinous features (one with focal CK20 and CDX2 immunohistochemical staining and one only with focal CDX2 immunohistochemical staining). All the high-grade tumors showed a mutated-pattern of p53 nuclear staining with &gt;75% 2-3+ staining. We conclude that seromucinous borderline tumors need to be extensively sampled. Cyst wall membrane rolls are important to evaluate since they may reveal persisting endometriosis and solid regions most likely harbor a high-grade tumor. Identifying high-grade cancer within a seromucinous borderline tumor is important because, although seromucinous borderline tumors and their oftassociated low-grade endometrioid cancers have favorable outcomes, tumors harboring a high-grade component are aggressive and may eventuate in patient death.

HER2 low hormone positive breast cancer: Unveiling the driver.

e12561 Background: A new HER2 targeting drug, Trastuzumab deruxtecan, has shown effectiveness among a subgroup of breast cancer (BC) patients previously reported as HER2 negative, challenging the established classification. HER2 low (IHC 1+ or IHC +2/ISH negative) require further study to understand their clinicopathological features and prognosis to determine whether they are indeed distinctly different from the HER2 negative subgroup. Methods: This retrospective study of 1029 early BC patients diagnosed between 2014 and 2022 in Alexandria university hospitals. Tumors originally reported as HER2 negative were reclassified into HER2 0 and HER2 low and stratified based on hormone receptor (HR) status. Clinical and pathological features were compared. Disease free survival (DFS), overall survival (OS) and time to recurrence (TTR) were calculated. Results: Out of the 1029 patients, 779 (75.7%) were reported as HER2 negative, after reviewing their files, 441 (56%) of them were found to be IHC 0, and 338 (43%) were HER2 low. 192 (18.7%) HER2 positive patients and 58 (5.6%) patients with undetermined HER2 status were excluded. HER2-low tumors were found to be positively associated with HR positive status compared to HER2-0 (302 [89.3%] vs. 368 [83.4%]; P=0.019). The rate of HER2-low significantly increased as the level of ER expression increased, from 37 of 190 (19.5%) ER-negative to 40 of 143 (28%) ER-low, 94 of 264(35.6%) ER-moderate and 167 of 432(38.7%) ER strong, p=&lt;0.001. ER2-low were more likely to be ductal carcinoma (88.1% vs. 80.4%; p=0.004), and to have Ki67 level &lt;20 (55% vs. 33%; p=0.008). When stratified according to HR status, ductal histology was still significantly higher in the HER2 low HR positive subgroup compared to the HER2-0 HR positive (87.6% vs. 80.3%; p=0.011). No significant difference between HER2-0 and HER2-low regarding age at presentation, menopausal status, tumor size, lymph node status, lymphovascular invasion, high grade, multifocality or extensive intraductal component. Median follow-up duration was 55 months, no significant differences between HER2-0 and HER2 low groups regarding relapse rate (22.6% vs. 21.6%), 5-year DFS (76.4% vs. 78%) or 5-year OS (81.7% vs. 87.4%), however TTR was significantly longer in the HER2 low HR positive group compared to the HER2-0 HR positive group (41.6 months vs. 31.3 months; p= 0.031). Conclusions: A positive correlation was observed between HER2 low and estrogen receptor positivity, as well as its level of expression. No significant differences were found between HER2 low and HER2-0 to support classifying HER2 low as a distinct group.

Establishment of artificial intelligence model for precise histological subtyping of lung adenocarcinoma and its application to quantitative and spatial analysis.

The histological subtype of lung adenocarcinoma is a major prognostic factor. We developed a new artificial intelligence model to classify lung adenocarcinoma images into seven histological subtypes and adopted the model for whole-slide images to investigate the relationship between the distribution of histological subtypes and clinicopathological factors. Using histological subtype images, which are typical for pathologists, we trained and validated an artificial intelligence model. Then, the model was applied to whole-slide images of resected lung adenocarcinoma specimens from 147 cases. The model achieved an accuracy of 99.7% in training sets and 90.4% in validation sets consisting of typical tiles of histological subtyping for pathologists. When the model was applied to whole-slide images, the predominant subtype according to the artificial intelligence model classification matched that determined by pathologists in 75.5% of cases. The predominant subtype and tumor grade (using the WHO fourth and fifth classifications) determined by the artificial intelligence model resulted in similar recurrence-free survival curves to those determined by pathologists. Furthermore, we stratified the recurrence-free survival curves for patients with different proportions of high-grade components (solid, micropapillary and cribriform) according to the physical distribution of the high-grade component. The results suggested that tumors with centrally located high-grade components had a higher malignant potential (P<0.001 for 5-20% high-grade component). The new artificial intelligence model for histological subtyping of lung adenocarcinoma achieved high accuracy, and subtype quantification and subtype distribution analyses could be achieved. Artificial intelligence model therefore has potential for clinical application for both quantification and spatial analysis.

Outcome Analysis of a Series of Mixed-Grade, Non-muscle Invasive, Papillary Carcinomas of the Bladder.

Introduction. Papillary urothelial carcinomas are currently graded as either low- or high-grade tumors based on World Health Organization (WHO) 2022 guidelines for genitourinary tumors. However, a minority of tumors are mixed-grade tumors, composed predominantly of low-grade cancer with a minor high-grade component. In the 2022 WHO these cancers are recognized as having outcomes comparable to low-grade cancers, although data to date has been limited. Methods. The pathology records of a large academic institution were searched for mixed-grade, non-muscle invasive papillary carcinomas of the bladder and ureter in order to characterize prognosis of these cancers. Results. Of 136 cancers, the majority (n = 104, 76.5%) were solitary, mixed-grade tumors, while 21 (15.4%) had a concurrent low-grade cancer and 11 (8.1%) had multiple mixed-grade tumors at the time of diagnosis. At follow-up (median 48.3 months, range = 1.3 months-18.1 years), 71 cancers recurred (52.2%): 52 (38.2%) as low- or mixed-grade cancers and 18 (13.2%) as high-grade cancers. There were no instances of stage-progression to >pT2. Conclusions. The clinical outcome of mixed-grade carcinomas was similar to what has been reported for low-grade carcinomas. Based on our results, and prior congruent studies of mixed-grade lesions, these lesions may be regarded as a distinct sub-category with a better prognosis than high-grade tumors.

Parts repairing and microstructural refinement of high-pressure die cast aluminum alloys through friction stir processing for bulk production

A key challenge in the production of high-grade automotive aluminum components through the High-Pressure Die Casting (HPDC) process is the imperative to minimize imperfection. In addressing this concern, this study utilizes friction stir processing (FSP), a widely recognized intense plastic deformation technique. FSP is applied to systematically alter the microstructure of HPDC Al-4Mg-2Fe, a prominent alloy extensively used in the die-casting sector. By using the pass strategy to incorporate both one-pass and two-pass approaches, the microstructure is selectively altered to establish a defect-free processed zone. The utilization of FSP demonstrates its efficacy in breaking aluminum dendrites and acicular silicon particles, leading to a uniformly dispersed arrangement of equiaxed silicon particles within the aluminum-based matrix. In addition, FSP eradicates porosity and disintegrates needle-like Fe particles, resulting in a more refined and homogeneously distributed structure. Subsequently, the material's mechanical properties processed by FSP were assessed in the longitudinal direction concerning the processing axis and then compared with those of the original base material.The microstructural refinement and reduction in porosity induced by FSP result in a notable enhancement in hardness, with an increase of 23 % after one pass and 37 % after two passes. The substantial improvement in mechanical properties during the FSP process is predominantly attributed to modifications in the morphology, refinement, and dispersion of intermetallic particles within the matrix. This improvement is further complemented by the ultrafine dispersion of casting defects.This study underscores the efficacy of FSP as a valuable tool for modifying microstructures and improving mechanical properties in HPDC Al-4Mg-2Fe alloys. Such advancements align with the lightweighting objectives pursued by the automotive industry.

P53 Overexpression May Represent an Early Marker of Clinicopathologic Progression in Vasculogenic Mesenchymal Lesions of Germ Cell Tumor Origin.

Vasculogenic mesenchymal lesions (VMLs) of germ cell tumor origin are thought to originate in postpubertal-type yolk sac tumor componentsand include a spectrum of lesions from teratoma with vasculogenic stroma (TVS), to low and high-grade vasculogenic mesenchymal tumors (VMTs). VMLs exhibit rudimentary to well-developed neoplastic vessels within primitive mesenchyme, being considered a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac. They occur in patients with primary mediastinal germ cell tumors after chemotherapy, and a subset progresses to "somatic-type" sarcomas [including angiosarcoma (AS)], with high-grade VMTs likely portending a higher risk. Recently, we encountered a low-grade VMT that progressed to metastatic AS during follow-up. In this case, both the low-grade VMT and the subsequent AS demonstrated p53 overexpression, suggesting that p53 alterations may precede histopathologic transformation. To test this hypothesis, we evaluated neoplasms representing the entire spectrum of VMLs using p53 immunohistochemistry (IHC; clone DO-7, Dako). Overexpression was defined as nuclear positivity in > 80% of neoplastic cells. Because the distinction between high-grade VMT and AS can be subjective in some cases, they were grouped together in a single category. Thirty-nine VMLs were assessed: 16 high-grade VMT/AS, 19 low-grade VMT, and 4 TVS. Patient age ranged from 19 to 46 years (mean, 30 years; male = 97%). Four high-grade VMT/AS and one low-grade VMT showed p53 overexpression (5/39 VMLs, 13%; 4/16 high-grade VMT/AS, 25%). These tumors included 1 unequivocal AS and 1 high-grade VMT/AS with progression to rhabdomyosarcoma. The only low-grade VMT with p53 overexpression demonstrated progression to AS. Another high-grade VMT that progressed to sarcoma demonstrated p53 overexpression in the sarcoma component, but it was excluded because the VMT was not represented in the material availableat the time of the study. Lesions with intratumoral grade heterogeneity (classified based the highest grade), demonstrated more pronounced p53 overexpression in the high-grade components. P53 overexpression is associated with disease progression in a subset of VMTs and may precede morphologic transformation to sarcoma. Routine evaluation of VMTs with p53 IHC seems justified, with overexpressors likely requiring an close clinical surveillance.

Low-grade central osteosarcoma with extraosseous dedifferentiation: a rare case.

Low-grade central osteosarcoma (LGCOS), which arises from the intramedullary cavity of the metaphysis of long bones, occasionally exhibits extraosseous spread. Approximately 10-30% of patients with LGCOS exhibit dedifferentiation, but it is rare to experience a primary tumor with a dedifferentiated component. A 38-year-old female patient presented with right knee pain for two months. Imaging studies revealed a bone mass with extraosseous involvement. Wide resection was performed, and pathologic examination led to the diagnosis of LGCOS with a dedifferentiated extraosseous lesion. A single defect in the bone cortex constituted the boundary between the low- and high-grade components. The extraosseous high-grade component included more tumor cells with p53 overexpression and more murine double minute 2 (MDM2) copies compared with the low-grade component. These genetic mutations and copy number alterations can be associated with malignant transformation of LGCOS.

Mixed-Grade Urothelial Carcinoma: Insights Into Clinical Behavior and Prognostic Implications Compared to Pure Low-Grade and High-Grade Urothelial Carcinomas.

Low-grade urothelial carcinoma (LGUC) and high-grade urothelial carcinoma (HGUC) are distinguished based on architectural and cytological features, with the anticipation that HGUC exhibits more aggressive behavior and a worse prognosis compared to LGUC. The current World Health Organization classification recognizes mixed-grade urothelial carcinoma (MGUC, for the purposes of this study) as a separate category that behaves like LGUC if the high-grade component is <5% and states that any tumor with ≥5% high-grade component should be graded as HGUC. To evaluate the risk of tumor recurrence, grade, and stage progression of MGUC compared to LGUC and HGUC. A total of 150 de novo noninvasive polypoid urothelial carcinomas (41 cases of MGUC, 59 of LGUC, and 50 of HGUC) were included. Tumor recurrence, grade, and stage progression were compared among the MGUC, LGUC, and HGUC cases. Tumor recurrence was observed in 14 of 41 (34.2%) of MGUC, 33 of 59 (55.9%) of LGUC, and 28 of 50 (56%) of HGUC. Grade progression occurred in 5 of 41 (12.2%) of MGUC cases and 5 of 59 (8.5%) of LGUC cases. No stage progression was observed in LGUC or MGUC cases, while 7 of 50 (14%) of HGUC cases showed stage progression. MGUC was associated with lower odds and hazard of recurrence compared to LGUC. The rate of grade progression was higher in MGUC and occurred after a shorter interval compared to LGUC. MGUC showed a prognosis closer to LGUC. Our study supports the current recommendation to classify tumors with <5% high-grade component as MGUC, as these tumors display clinical characteristics and outcomes close to that of pure LGUC.

Premature Classification of Early-stage Endometrioid Ovarian Carcinoma With Mesonephric-like Differentiation as Mesonephric-like Adenocarcinoma.

Ovarian mesonephric-like adenocarcinoma (MLA) is a rare tumor with potential origins in endometriosis and Müllerian-type epithelial tumors. The morphologic patterns of MLA overlap with those of endometrioid ovarian carcinoma (EnOC). We speculated that a subset of MLAs would be classified as EnOCs. In this study, we attempted to identify MLAs from malignant endometrioid tumors. Given that the study patients with MLAs had both endometrioid-like and mesonephric-like morphologies, we defined mesonephric-like differentiation (MLD) as an endometrioid tumor with focal or diffuse MLA morphology and immunophenotype. Twelve patients exhibited mesonephric-like morphologic patterns. Immunohistochemistry analysis for CD10, TTF-1, estrogen receptor (ER), GATA3, calretinin, and PAX8 expression was done using whole-section slides. Two patients without the MLA immunophenotype were excluded. Ten patients with EnOCs with MLD (8.3%) were identified from a cohort of 121 patients with malignant endometrioid tumors. All 10 patients were positive for TTF-1 and/or GATA3. Most patients were ER-negative. Morphologically, MLD was associated with papillary thyroid carcinoma-like nuclei, flattened cells, tubular, nested, reticular, or glomeruloid architecture, and infiltrative growth. All 10 patients had pre-existing endometriosis and/or adenofibromas. Among the EnOCs with MLD, 5 had coexisting components such as EnOC grade 1 [(G1), cases 4, 7, and 9], mucinous borderline tumor (case 1), and dedifferentiated carcinoma (case 10), with distinct borders between EnOC with MLD and the other components. Nine of the 10 MLA patients (90%) harbored KRAS hotspot mutations. In addition, 4 patients harboring other components shared common KRAS hotspot mutations. No significant prognostic differences were observed between patients with and without MLD. Based on our findings, we suggest that EnOC with MLD, especially in the early stages and without high-grade components, should be considered a subtype of EnOC. Overtreatment should be avoided in such patients, particularly in the early stages. In this study, as the characteristics between EnOC with MLD and MLA were not distinguishable, we considered both conditions to be on the same spectrum. EnOCs with MLD exhibit the MLA phenotype during disease progression and are prematurely classified as MLA. Nevertheless, more patients with EnOC who have MLD/MLA are required for a more robust comparison between conventional EnOC according to staging and grading.

Atypical Spindle Cell/Pleomorphic Lipomatous Tumor With Sarcomatous Transformation: Clinicopathologic and Molecular Analysis of 4 Cases

Atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) is a recently described adipocytic tumor predominantly affecting the subcutaneous soft tissues of adults. Previous studies have shown that ASPLT follows a benign clinical course with a 4% to 12% local recurrence rate and no risk of dedifferentiation. Herein, we describe the clinicopathologic and molecular findings of 4 cases of ASPLT showing unequivocal sarcomatous transformation. Three patients were male and one was female, aged 65, 70, 74, and 78 years. Two cases presented as mass-forming lesions, while 1 case was incidentally discovered. The tumors measured 30, 55, 80, and 110 mm and occurred in the chest wall (n = 2) or arm (n = 2); all were subcutaneous. Microscopically, they showed a biphasic appearance comprising a low-grade ASPLT component and a high-grade sarcomatous component. The low-grade components showed features in the spectrum of either atypical pleomorphic lipomatous tumor (n = 2) or atypical spindle cell lipomatous tumor (n = 2). The high-grade components displayed leiomyosarcoma-like (n = 2), pleomorphic liposarcoma-like (n = 1) or undifferentiated sarcoma-like (n = 1) morphology. On immunohistochemistry, tumors were negative for MDM2 and showed loss of RB1 expression. In addition, the leiomyosarcoma-like areas seen in 2 cases were positive for smooth muscle actin and H-caldesmon. Single-nucleotide polymorphism array, performed in 3 cases, showed deletions of TP53, RB1, and flanking genes in both components. In contrast, the sarcomatous components showed more complex genomic profiles with rare segmental gains and recurrent loss of PTEN (n = 3), ATM (n = 2), and CDKN2A/B (n = 2) among other genes. Whole exome sequencing identified a TP53 variant in one case and an ATRX variant in another, each occurring in both tumor components. Limited clinical follow-up showed no recurrence or metastasis after 1 to 13 months (median, 7.5 months) postsurgical excision. Altogether, our data support that ASPLT can rarely develop sarcomatous transformation and offer insights into the molecular mechanisms underlying this event.

Predictive value of systemic immune-inflammation index in the high-grade subtypes components of small-sized lung adenocarcinoma

BackgroundIdentification of micropapillary and solid subtypes components in small-sized (≤ 2 cm) lung adenocarcinoma plays a crucial role in determining optimal surgical procedures. This study aims to propose a straightforward prediction method utilizing preoperative available indicators.MethodsFrom January 2019 to July 2022, 341 consecutive patients with small-sized lung adenocarcinoma who underwent curative resection in thoracic surgery department of Xuanwu Hospital, Capital Medical University were retrospectively analyzed. The patients were divided into two groups based on whether solid or micropapillary components ≥ 5% or not (S/MP5+ and S/MP5-). Univariate analysis and multivariate logistic regression analysis were utilized to identify independent predictors of S/MP5+. Then a nomogram was constructed to intuitively show the results. Finally, the calibration curve with a 1000 bootstrap resampling and the receiver operating characteristic (ROC) curve were depicted to evaluate its performance.ResultsAccording to postoperative pathological results, 79 (23.2%) patients were confirmed as S/MP5+ while 262 (76.8%) patients were S/MP5-. Based on multivariate analysis, maximum diameter (p = 0.010), consolidation tumor ratio (CTR) (p < 0.001) and systemic immune-inflammation index (SII) (p < 0.001) were identified as three independent risk factors and incorporated into the nomogram. The calibration curve showed good concordance between the predicted and actual probability of S/MP5+. Besides, the model showed certain discrimination, with an area under ROC curve of 0.893.ConclusionsThe model constructed based on SII is a practical tool to predict high-grade subtypes components of small-sized lung adenocarcinoma preoperatively and contribute to determine the optimal surgical approach.