Histological Criteria Research Articles

EPID-16. A MULTI-CENTER, PROGRESSION-FREE SURVIVAL ANALYSIS IN IDH-MUTANT GLIOMAS WITH CDKN2A DELETION: IMPLICATIONS FOR PROGNOSIS AND CLINICAL TRIAL DESIGN

Abstract Homozygous deletion of CDKN2A is an important predictor of poor prognosis in patients with IDH-mutant gliomas. The updated 2021 WHO classification now recognizes this alteration as sufficient for the designation of an astrocytoma, IDH-mutant, WHO Grade 4, which otherwise requires histological observation of necrosis or microvascular proliferation. While overall survival patterns associated with CDKN2A deletion have been well-described, we sought to characterize progression-free survival (PFS) in this patient population. Across three institutions (Massachusetts General Hospital, Boston; University Hospital Heidelberg, Heidelberg; TU Dresden, Dresden), we identified 48 patients with IDH-mutant gliomas in which CDKN2A deletion was detected at the time of diagnosis, followed for a median of 15.2 years. The average age of the cohort is 35 years, with 60% of the patients identified as male. Most patient received immediate treatment after surgery, with 81% of the cohort undergoing radiation therapy and 73% receiving chemotherapy. Based on RANO criteria, the median progression-free survival of this patient population is 2.8 years (95% CI 1.4 – 3.3 years) and median overall survival is 4.3 years (95% CI 2.1 – 6.6 years). A positive T2/FLAIR mismatch sign or lack of contrast enhancement on MRI at the time of diagnosis are both associated with improved PFS in univariate regression analysis. For comparison, we identified a control cohort of 51 patients with astrocytoma, IDH-mutant, grade 4 without CDKN2A deletion from MGH, achieving grade 4 by histologic criteria. Demographics were similar to the CDKN2A-deleted cohort, with median age (37 years) and percentage of male patients (60%). Notably, however, PFS for the grade 4, CDKN2A-intact, IDH-mutant glioma comparison group is estimated at 5.9 years (95% CI 3.3 – 7.9 years). Overall, these data reinforce the accelerated disease course associated with deletion of CDKN2A in IDH-mutant gliomas, providing an important reference for clinical trial design.

DISP-07. GLIOMAS IN HIV-POSITIVE PATIENTS CAN BE IDH-MUTANT OR -WILDTYPE

Abstract Recent review has emphasized that glioblastoma (GBM) in persons living with human immunodeficiency virus (HIV)(PLWH) is “severely underreported in the literature” (PMID 35857248), since only 24 cases could be identified. This 2022 study concluded that overall survival in this patient group is less than in persons who are HIV-negative. Given the predominantly single-case reports in the literature, it is not surprising that “data remains limited”. To this end, we report our 15-year experience with patients with HIV-positivity diagnosed at our institution. Text word search of Department of Pathology databases, 2008-2023, with review of histological sections and the medical record. 7 patients living with PLWH were identified, all males, ages at diagnosis 44-61 years, median 58 years. 3 had tumors that met histological criteria for GBM, IDH-wildtype, WHO grade 4, 1 had GBM by modern molecular criteria and 2 had astrocytoma, IDH-mutant, WHO grade 4. One of the latter had co-existent diffuse high grade B cell lymphoma intimately admixed within his glioma while the final patient had multifocal brain lesions of different neuroimaging appearances, with the bifrontal tumor consistent with GBM and posterior frontal lesions suspicious for progressive multifocal leukoencephalopathy. At the time of tumor diagnosis, 1 had HIV for 20+ years, a second was well controlled with normal CD4 count and a third had not yet been on anti-retroviral agents. Survival was poor, with 2 PLWH with IDH-mutant tumors succumbing at 2 and 4 months and 3 with GBMs at 7, 12 and 32 months; a 4th is alive at 6 months. PLWH can develop various glial tumor types including both IDH-mutant and IDH-wildtype tumors, strongly suggesting co-incident rather than causal relationship. Tumors may be first diagnosed at varying stages of their immunodeficiency disorder; survival is poor even for PLWH with IDH-mutant grade 4 tumor.

NIMG-27. GLIOBLASTOMA IN THE MAKING? ADVANCED IMAGING TELLS "MOLECULAR GLIOBLASTOMA" APART FROM ASTROCYTOMA

Abstract The fifth WHO classification of tumors of the CNS allows the diagnosis of glioblastoma using specific molecular markers, even if the classical histological criteria (necrosis and neoangiogenesis) are not fulfilled. Since such cases also tend to lack blood-brain barrier disruption and necrosis on conventional imaging, these can be mistaken for low-grade astrocytomas. We investigated the potential of advanced imaging to capture tumor biology and thus reliably distinguish between those entities already preoperatively. Multimodal preoperative 3T-MRI scans were collected from 147 glioblastoma, 4 astrocytomas grade 4, 7 “Molecular glioblastoma” (molGBM) grade 4, 9 astrocytomas grade 2, and 12 astrocytomas grade 3. From AI-based multi-compartimental tumor segmentations, advanced imaging metrics from perfusion- and diffusion-imaging were automatically extracted. Two-sample t-test and one-way ANOVA analysis was performed to test for significant differences between apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV). Interestingly, rCBV (signifying neoangiogenesis) was significantly higher in molGBM as opposed to astrocytomas for the 5th percentile as well as for mean and median values (p < 0.05). ADC values were consequently lower (indicating higher cellularity) in molGBM than in astrocytomas grade 2 and 3 in the 95th percentile (p < 0.05). Although no molGBM showed contrast-enhancement initially, one untreated case showed a flaccid barrier disruption at 30d follow-up. Interestingly, the molecular imaging at the earlier timepoint showed significantly higher CBV values in the non-enhancing tumor than common glioblastoma and astrocytoma grade 4 (p = 0.013, ANOVA), which indicates highly active tumor portions. Perhaps it is precisely these areas that are on the verge of barrier disruption. Our results support the hypothesis that molGBM are truly early glioblastomas. Better understanding the molecular mechanisms involved in the transition to “classical” glioblastoma promises to provide important insight into tumor biology and potential therapeutic targets.

Prognostic Value of Histopathological Thrombus Age in Large Vessel Occlusion-Related Stroke

Introduction: Acute mechanical thrombectomy (MT) is the preferred treatment for large vessel occlusion-related stroke. Histopathological research on the obtained occlusive embolic thrombus may provide information regarding the aetiology and pathology of the lesion to predict prognosis and propose possible future acute ischaemic stroke therapy. Methods: A total of 75 consecutive patients who presented to the Amphia Hospital with acute large vessel occlusion-related stroke and underwent MT were included in the study. The obtained thrombus materials were subjected to standard histopathological examination. Based on histological criteria, they were considered fresh (<1 day old) or old (>1 day old). Patients were followed for 2 years for documentation of all-cause mortality. Results: Thrombi were classified as fresh in 40 patients (53%) and as older in 35 patients (47%). Univariate Cox regression analysis showed that thrombus age, National Institutes of Health Stroke Scale at hospital admission, and patient age were associated with long-term mortality (p < 0.1). Multivariable Cox hazards and Kaplan-Meier analysis demonstrated that after extensive adjustment for clinical and procedural variables, thrombus age persisted in being independently associated with higher long-term mortality (hazard ratio: 3.34; p = 0.038, log-rank p = 0.013). Conclusion: In this study, older thromboemboli are responsible for almost half of acute large ischaemic strokes. Moreover, the presence of an old thrombus is an independent predictor of mortality in acute large vessel occlusion-related stroke. More research is warranted regarding future therapies based on thrombus composition.

Prognostic Factors for Patients with Proliferative Hepatocellular Carcinoma After Liver Resection.

There is a scarcity of predictive models currently accessible for prognosticating proliferative hepatocellular carcinoma (HCC), an integrated class of subtype, characterized by a dismal prognosis. Consequently, this study aimed to develop and validate a novel prognostic model capable of accurately predicting the prognosis of proliferative HCC after curative resection. This retrospective multicenter study included patients with solitary HCC who underwent curative liver resection from August 2014 to December 2020 (n = 816). Patients were stratified into either the proliferative HCC cohort (n = 259) or the nonproliferative HCC cohort (n = 557) based on histological criteria. Disease-free survival (DFS) was compared between the two groups before and after one-to-one propensity score matching (PSM). Of all the proliferative HCC patients, 203 patients were assigned to training cohort, and 56 patients were assigned to validation cohort. Univariate and multivariate analyses were performed in training cohort to identify risk factors associated with worse DFS. Thereafter, a predictive model was constructed, subsequently validated in the validation cohort. The DFS of proliferative HCC was significantly worse than nonproliferative HCC before and after PSM. Meanwhile, multivariate regression analysis revealed that liver cirrhosis (P = 0.032) and larger tumor size (P = 0.000) were independent risk factors of worse DFS. Lastly, the discriminative abilities of the predictive model for 1, 3, 5-year DFS rates, as determined by receiver operating characteristic (ROC) curves, were 0.702, 0.720, and 0.809 in the training cohort and 0.752, 0.776, and 0.851 in the validation cohort, respectively. This study developed a predictive model with satisfactory accuracy to predict the worse DFS in proliferative HCCs after liver resection. Moreover, this predictive model may serve as a valuable tool for clinicians to predict postoperative HCC recurrence, thereby enabling them to implement early preventative strategies.

Differential diagnosis of small hepatocellular nodules incirrhosis: surrogate histological criteria of TERT promotermutations.

The differential diagnosis of small hepatocellular nodules in cirrhosis between dysplastic nodules and hepatocellular carcinoma (HCC) remains challenging on biopsy. As TERT promoter (pTERT) mutations may indicate the nodules already engaged in the malignant process, the aim of this study was to identify histological criteria associated with pTERT mutations by detecting these mutations by ddPCR in small formalin-fixed paraffin-embedded (FFPE) hepatocellular nodules arising in cirrhosis. We built a bicentric cohort data set of 339 hepatocellular nodules < 2 cm from cirrhotic samples, divided into a test cohort of 299 resected samples and a validation cohort of 40 biopsies. Pathological review, based on the evaluation of 14 histological criteria, classified all nodules. pTERT mutations were identified by ddPCR in FFPE samples. Among the 339 nodules, ddPCR revealed pTERT mutations in 105 cases (31%), including 90 and 15 cases in the test and validation cohorts, respectively. On multivariate analysis, three histological criteria were associated with pTERT mutations in the test cohort: increased cell density (P = 0.003), stromal invasion (P = 0.036) and plate-thickening anomalies (P < 0.001). With the combination of at least two of these major criteria, the AUC for predicting pTERT mutations was 0.84 in the test cohort (sensitivity: 86%, specificity: 83%) and 0.81 in the validation cohort (sensitivity: 87%, specificity: 76%). We identified three histological criteria as surrogate markers of pTERT mutations that may be used in routine biopsy to more clearly classify small hepatocellular nodules arising in cirrhosis.

The effect of platelet-to-lymphocyte ratıo (PLR) and glasgow prognostıc score (GPS) on recurrence, and survıval ın patıents undergoıng lobectomy for early-stage non-small cell lung cancer (NSCLC).

Tumor markers are indicators that can be used not only for cancer diagnosis but also for determining prognosis. Unfortunately, there is currently no tumor marker that reliably predicts the prognosis of lung cancer. In this study, we investigated the prognostic impact of the platelet-to-lymphocyte ratio (PLR) and Glasgow Prognostic Score (GPS), known as inflammation markers in peripheral blood, in patients who underwent resection for early-stage non-small cell lung cancer (NSCLC). We retrospectively analyzed the medical records of a total of 3300 patients who underwent surgery for NSCLC between 2010 and 2020. Among these patients, 250 met the inclusion criteria of lobectomy, pT1-T2N0 stage, and histology of adenocarcinoma or squamous cell carcinoma. Preoperative albumin, C-reactive protein (CRP), preoperative PLR, and postoperative 5th-day PLR values were determined from patient's peripheral blood data. The impact of these values on postoperative recurrence and survival was investigated. GPS was calculated based on preoperative CRP and albumin values, and patients were divided into 3 groups: 0 (mild), 1 (moderate), and 2 (severe). The relationship between preoperative GPS and survival was analysed. Among the included patients, 155 (62%) had adenocarcinoma and 95 (38%) had squamous cell carcinoma. A total of 185 (74%) patients had pT1 tumors, while 65 (26%) had pT2 tumors. During the postoperative follow-up period, local recurrence was observed in 28 (11.2%) patients and distant metastasis in 51 (20.4%) patients. The overall mortality rate was 19.6%. The 5-year survival rates for pT1 and pT2 tumors were 80.4% and 72.5%, respectively. Significant associations were found between preoperative PLR, postoperative PLR, and recurrence (p = 0.005 and p = 0.011). The expected overall survival (OS) was 103.4months in the mild GPS group, 91.8months in the moderate GPS group, and 50months in the severe GPS group. The relationship between GPS groups and OS was statistically significant (p = 0.005). Preoperative analysis of PLR and GPS may provide prognostic value in NSCLC patients who undergo surgical resection. Our study provides a rationale for further investigation of peripheral blood immune markers for prognostic purposes.

Anti-inflammatory, Antioxidant, and Wound-Healing Effects of Photobiomodulation on Type-2 Diabetic Rats.

Introduction: In the current study, the effects of photobiomodulation (PBM) treatments were examined based on biomechanical and histological criteria and mRNA levels of catalase (CAT), superoxide dismutase (SOD), and NADPH oxidase (NOX) 1 and 4 in a postponed, ischemic, and infected wound repair model (DIIWHM) in rats with type 2 diabetes (DM2) during the inflammation (day 4) and proliferation (day 8) stages. Methods: To study ischemic wound repair in a diabetic rat model (DIIWHM), 24 rats with type-2 diabetes were randomly divided into four groups and infected with methicillin-resistant Staphylococcus aureus (MRSA). The control groups consisted of CG4 (control group on day 4) and CG8 (control group on day 8), while the PBM groups comprised PBM4 (PBM treatment group on day 4) and PBM8 (PBM treatment group on day 8). These group assignments allowed for comparisons between the control groups and the PBM-treated groups at their respective time points during the study. Results: On days 4 and 8 of wound restoration, the PBM4 and PBM8 groups showed substantially modulated inflammatory responses and improved formation of fibroblast tissue compared with the CG groups (P<0.05). Concurrently, the effects of PBM8 were significantly superior to those of PBM4 (P<0.05). The antioxidant results on days 4 and 8 revealed substantial increases in CAT and SOD in the PBM groups compared with the CGs (P<0.05). Substantial decreases were observed in the antioxidant agents NOX1 and NOX4 of the PBM4 and PBM8 groups compared with both CGgroups (P<0.05). Conclusion: PBM treatments significantly sped up the inflammatory and proliferating processes in a DHIIWM in DM2 animals by modifying the inflammatory reaction and boosting fibroblast proliferation. Overall, the current findings indicated substantially better results in the PBM groups than in the CG groups.

Ultra high b-value diffusion weighted imaging enables better molecular grading stratification over histological grading in adult-type diffuse glioma

PurposeAccurate preoperative radiological staging of adult-type diffuse glioma is crucial for effective prognostic stratification and selection of appropriate therapeutic interventions. The purpose of this study was to compare the effectiveness of apparent diffusion coefficient (ADC) maps generated from ultrahigh b-value diffusion-weighted imaging (DWI) for molecular grading with that for histological grading of adult-type diffuse glioma, and to evaluate the correlation between these ADC maps and molecular and histological biomarkers. MethodsThis study retrospectively enrolled forty adult-type diffuse glioma patients, diagnosed using the 2021 WHO classification criteria. Preoperative imaging data, including multiple b-value DWI and conventional magnetic resonance imaging, were collected. Tumors were graded using both histological and molecular criteria. Histogram analysis was conducted to generate 14 parameters for each tumor. Receiver operating characteristic curves and the area under the curve (AUC) were used to evaluate tumor grading and molecular status differentiation. Analysis of histological biomarkers was performed by calculating the Pearson and Spearman correlation coefficients of continuous and hierarchical variables, respectively. ResultsThe intensity-related parameters for molecular grading were found to be superior to those for histological grading for the identification of WHO grade 4 (WHO4) adult-type diffuse glioma. The AUC of both grading systems increased with increasing b-values, with ADC8000-based histogram parameters showing the best results (molecular grading, square root: AUC = 0.897; histological grading, median: AUC = 0.737). The intensity-related parameters could also differentiate molecular WHO4 gliomas from histologically lower-grade gliomas (ADC8000-based square root: AUC = 0.919), and different ADC8000-based kurtosis was observed between molecular and histological WHO4 gliomas (AUC = 0.833). Significant correlations between the Ki-67 index and molecular status prediction for IDH, CDKN2A, and EGFR were also demonstrated. ConclusionThe histogram parameters derived from high b-value ADC maps were found to be more effective for differentiating molecular grades of WHO4 adult-type diffuse glioma than for differentiating histological grades.

SAT308 An Assessment Of Prognostic Markers To Predict Metastatic Pheochromocytoma/Paraganglioma

Abstract Disclosure: M.D. Lundholm: None. E. Berber: None. P.P. Rao: None. Introduction: Pheochromocytoma/paraganglioma (PCC/PGL, or PPGL) are rare neuroendocrine tumors arising from chromaffin cells. Early identification of PPGL with metastatic potential is a diagnostic challenge. More data are needed on features and scoring markers used to predict PPGL metastasis. Methods: A single-center, retrospective observational study was performed of consecutive patients with pathology-confirmed PPGL from 2005 to 2022. Features associated with metastasis were identified and Pheochromocytoma of the Adrenal gland Scaled Score (PASS), Age, Size, Extra-adrenal location and Secretory type (ASES) score, and Size, Genetic, Age, and PASS (SGAP) score were calculated. Results: We identified 371 patients with PPGL (251 PCC, 120 PGL), age 52.2±15.4yrs, 60.6% female, 69.8% incidental. Metastatic disease was reported in 13.2% (N=49; 30 PCC, 19 PGL) associated with younger age (47.3 vs 53.0yrs, p=0.029), larger tumor size (6.3 vs 4.0cm, p&amp;lt;0.001), histologic findings of necrosis (26% vs 2.5%, p&amp;lt;0.001) and vascular invasion (42.1% vs 19.6% p=0.038), hyperadrenergic symptoms at diagnosis (38.8% vs 22.0%, p=0.038), norepinephrine-only secreting tumors (59.6% vs 30.1%, p&amp;lt;0.001), extra-adrenal location (51.0% vs 32.0%, p=0.009), presence of genetic mutations (72.4% vs 38.5%, p&amp;lt;0.001), particularly SDHx (31.0% vs 12.2%, p=0.020) and VHL mutations (24.1% vs 3.8%, p=0.001). There were no significant differences by gender, race, other histologic criteria from PASS, or other mutations such as RET or NF-1. ASES was positive (≥2) in 27.2% (N=100/371) with sensitivity (SN) 79.6%, specificity (SP) 81.1%, positive predictive value (PPV) 39.0%, and negative predictive value (NPV) 96.3% for predicting metastatic disease. PASS and SGAP could only be applied to patients with PCC: PASS was positive (≥4) in 29.7% (N=55/185) with SN 60.0%, SP 73.9%, PPV 21.8%, and NPV 93.8%. SGAP was positive (≥5) in 27.6% (N=32/116) with SN 56.3%, SP 77.0%, PPV 28.1%, and NPV 91.7%. Discussion: Metastatic PPGL is associated with age, tumor size and location, select histologic findings, symptomatic presentation, hormone-secreting pattern, and select genetic mutations. PPGL scoring markers ASES, PASS, and SGAP were all effective at identifying cases with low likelihood of metastasis, but had poor PPV. ASES outperformed PASS and SGAP in test metrics and practicality as the only clinically-derived marker which could be applied to all cases of PPGL. ASES can also be used pre-operatively. Most histologic features and genetic mutations included in PASS and SGAP were not strongly correlated with metastasis, though limited by lower prevalence in the study population. Conclusion: Our data supports the use of ASES alongside data on necrosis, vascular invasion, SDHx and VHL mutations where available to fine-tune our prediction of metastatic potential for PPGL. Presentation: Saturday, June 17, 2023

A multicentric case study of fibroblastic and myofibroblastic oral spindle cell lesions.

Spindle cell lesions comprise a vast plethora of benign and malignant lesions with similar clinical and radiographic features. Their overlapping histopathologic features ensure a diagnostic dilemma. The current multicentric study aims to delineate fibroblastic and myofibroblastic oral spindle cell lesions based on cytomorphology and comprehensive immunohistochemical analysis. The experimental study was conducted at MS Ramaiah University of Applied Sciences, Bangalore, and All India Institute of Applied Sciences, Delhi. A comprehensive histological scoring criteria and panel of immunohistochemical makers (STAT6, CD31, CD34, S100, SMA, vimentin, pan-CK, HHF-35, Ki67, ALK, desmin, HMB-45, SATB2, ERG, EMA and CD99) were employed concurrently for the first time for fibroblastic and myofibroblastic oral spindle cell lesions. The data obtained was tabulated and studied. NA. Results: Using cytological scoring criteria and panel of immunohistochemical makers, the cases analysed and characterized were desmoplastic fibroma, fibrosarcoma, leiomyosarcoma, nodular fasciitis, neurofibroma and epithelioid inflammatory myofibroblastic sarcoma (EIMS). The diagnostic strategies need to be upgraded for the diagnosis of spindle cell lesions. Emphasis must be placed on cytomorphology, an immunohistochemistry (IHC) panel of markers is imperative for the accurate diagnosis of fibroblastic and myofibroblastic oral spindle cell lesions.

Differential diagnosis between urticarial vasculitis and chronic spontaneous urticaria: An international Delphi survey.

Urticarial vasculitis (UV) should be differentiated from chronic spontaneous urticaria (CSU) in patients initially presenting with recurrent wheals, although criteria for differential diagnosis remain ill-defined. To set the goals, define criteria and unmet needs in UV diagnosis and differential diagnosis with CSU, and explore the possibility of coexistence of both diseases. Thirteen experts experienced in UV research participated in a Delphi survey of European Academy of Allergy and Clinical Immunology taskforce. This Delphi survey involved three rounds of anonymous responses to n=32 questions with the aim to aggregate the experts' opinions and to achieve consensus. Urticaria specialists (n=130, most from Urticaria Centers of Reference and Excellence) evaluated the consensus statements and recommendations in the fourth and final round. The panel agreed that essential criteria to guide a skin biopsy in patients with recurrent wheals should include at least one of the following features: wheal duration >24h, bruising/postinflammatory hyperpigmentation, and systemic symptoms. Leukocytoclasia and fibrin deposits were identified as a minimum set of UV histological criteria. As agreed by the panel members, CSU and normocomplementemic UV (NUV) may coexist in some patients. The use of established criteria for the diagnosis and differential diagnosis of UV in patients with recurrent wheals can help guide the diagnostic approach and prompt earlier treatment. Further studies should investigate whether CSU and NUV are different entities or part of a disease spectrum.

Therapeutic effect of a new immunotropic composition tested in the model of periodontitis in experimental animals

The article deals with usage of a novel immunotropic drug composition in experimental model of periodontitis. The composition contains silicoorganic glycerogel, exhibits broad spectrum of action upon the etiological pathogen. A good therapeutic effect was revealed by clinical, laboratory and histological criteria. Histology showed absence of osteoclasts, reduced lacunas, higher density and normalization of tissue structures, recovery of microcirculation, angiogenesis and formation of granulation tissues. However, the phosphorus-to-calcium ratio in the group supplied with peroral vitamin D treatment, was characterized by significant decrease in alkaline phosphatase and inorganic phosphorus thus confirming efficiency of complex topical effect of the given composition and vitamin D.

Spiradenoma With Adenoid Cystic Carcinoma-like Changes: A Case Series of This Rare Variant With a Potential Diagnostic Pitfall.

Spiradenomas are benign cutaneous adnexal neoplasms with sweat gland differentiation that can manifest a broad spectrum of histomorphologic appearances. While they show a characteristic histopathologic phenotype and clinical management involves surgical excision with a low risk of recurrence, there have been unusual histopathologic variants of spiradenoma reported, including cases with adenoid cystic carcinoma (ACC)-like changes. Primary cutaneous ACC is a low-grade malignancy presenting as a subcutaneous mass with the potential for local invasion, perineural invasion, and high rates of local recurrence after excision. The diagnosis of spiradenomas with ACC-like features can be challenging, especially when only the ACC-like component is present for evaluation. A retrospective analysis of 21 cases of spiradenoma with ACC-like changes were obtained from large academic institutions, was performed, and summarized below. All cases showed background of conventional spiradenoma, and the ACC-like areas represented a component in all lesions. The percentage of ACC-like component ranged from 5% to 40% in all cases. The ACC-like component was multifocal and without pleomorphism, perineural and/or vascular invasion, necrosis, or increased mitotic activity. MYB translocation and protein expression was studied in 16 cases by fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemistry. All studied cases were negative for MYB / NFIB , MYB L1, and MYB F by fluorescence in situ hybridization and polymerase chain reaction and 3 cases were positive for MYB expression by immunohistochemistry. Our study expands on spiradenomas with ACC-like features that ought to be considered in the differential diagnosis of cutaneous neoplasms such as primary cutaneous ACC. Our results indicate that a thorough histopathologic inspection and strict application of well-defined histologic criteria are necessary to support the diagnosis of this unusual histopathologic variant. These tumors can be difficult to diagnose, and awareness of their histomorphologic spectrum will facilitate definitive diagnosis and avoid misdiagnosis with other conditions.

Maturation of metastases in peripheral neuroblastic tumors (neuroblastoma) of children.

Peripheral neuroblastic tumors of childhood exhibit 3 principal neural crest lineages: primitive neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. They are unique in undergoing maturation of neurons (ganglion cells) and Schwann cells, thereby recapitulating normal fetal neuronal development in the brain. Precision in estimating neurogenesis is enhanced by immunoreactivities of markers of neuronal maturation. Whether organ tissue factors in different sites of metastases influence rates of maturation and whether metastases are similar to their primary neuroblastic tumor are incompletely documented. Four young children, 1 with a mixed primary adrenal tumor and 3 with metastases were studied at surgery or autopsy. Immunocytochemical reactivities included microtubule-associated protein-2, synaptophysin, chromogranin-A, somatostatin, keratan sulfate, vimentin, S-100β protein, and PHOX2B. Primary tumors were non-uniform with regions of either poor or enhanced maturation. Both neuronal and Schwannian lineages were represented in each tumor type but differed in proportions. Bi- or multi-nucleated ganglion cells matured equal to mononuclear forms. Ganglion cell maturation was similar in metastases regardless of the target organ. Metastases resembled primary tumors. Immunocytochemical markers of neuronal and of Schwann cell maturation provide greater diagnostic precision to supplement histological criteria. Interval between diagnosis of primary tumor and metastases, metastatic target tissues, and chemotherapy over an interval of time do not appear to influence neuroblastic or Schwann cell differentiation.

Synchronous Endometrial and Ovarian Carcinomas: Pathologic and Molecular Analysis Highlights the Monoclonal Origin of the Lesions.

The diagnosis of synchronous carcinomas, involving both the endometrium and ovaries, is not a rare finding in gynecologic pathology and represents a challenge with implications on tumor staging and therapeutic decision-making. A mono-institutional series of 11 metastatic and 6 paired synchronous endometrial and ovarian carcinomas were reviewed by 2 expert pathologists based on previously published histopathologic criteria. The series was investigated for DNA mismatch repair proteins, p53, and POLE status and was subject to DNA-based next-generation sequencing targeting 67 cancer-related genes. Out of 17 pairs, 16 featured the same histotype (10 endometrioid, 4 serous high-grade, and 2 clear cells). By using WHO 2020 criteria, 11 couples of tumors were confirmed as metastatic and 6 couples were confirmed as independent. Based on next-generation sequencing analysis, 16 of 17 cases (11 metastatic and 5 independent) of our series showed evidence of a clonal relationship between endometrial and ovarian carcinomas. In metastatic cases, the adverse outcome was associated with nonendometrioid/high-grade endometrioid histotype and with the p53-abnormal molecular subtype. Four cases originally fulfilling clinicopathological criteria of independent endometrial and ovarian carcinomas were clonally related, low-grade endometrioid histotype and POLE -mut, mismatch repair deficient, and no specific molecular profile molecular subtypes; no adverse event was recorded in this group. In summary, the molecular characterization of synchronous gynecologic carcinomas confirms their clonal origin in most cases. However, the results of our study point out that the clinical behavior of these tumors seems to be determined by the presence of high-risk WHO 2020 histologic criteria and molecular features (i.e. p53-abnormal), rather than the monoclonal origin.

Presence of Gastrointestinal Paraneoplastic Syndrome at Diagnosis in Dogs With Cutaneous Mast Cell Tumors and Its Influence on Disease-Free Interval and Survival

Paraneoplastic syndrome (PNS) is a combination of signs unrelated to the physical presence of a tumor and/or its metastases. Its presence may result in poorer clinical outcomes and prognosis. Gastrointestinal ulceration is a well-known PNS in animals with cutaneous MCT. This retrospective study analyzed the occurrence of gastrointestinal (GI) PNS at the time of diagnosis. Using medical records, we attempted to correlate the occurrence of these GI signs with clinical and histologic criteria, as well as to evaluate their influence on the disease-free interval (DFI) and survival (ST) over a 6-year follow-up period (2013-2020). The medical records of 41 dogs with a confirmed diagnosis of cutaneous MCT treated between 2013 and 2014 were included. All dogs underwent surgical biopsy or tumor excision, endoscopic and histologic examination to evaluate possible GI lesions. The presence and severity of GI signs were recorded. Clinical data such as the history of recurrence, number of tumors, tumor size, presence of ulceration, local pruritus, edema and erythema, histopathological classification, and mitotic index were extracted from medical records. Clinical signs relating to the GI system were observed in 41.5% of the dogs and were classified as mild in 94.1% at the time of diagnosis. Endoscopic examination of the upper digestive tract showed evidence of inflammation, but histologic examination of the mucosa showed no serious lesions in any case. There was no significant association between the occurrence of clinical GI signs and any of the variables studied. Follow-up issues meant that only 38 dogs were included for evaluation of the ST and 32 for DFI analysis. DFI was 25.1 months for dogs with GI signs and 14.8 months for dogs without GI signs. At the end of the study, 71.1% of patients had died. Survival time for dogs with GI signs was 54.9 months and 48 months for dogs without GI signs. Over the 6 years of the study, no differences were observed between the ST and the DFI, and the presence or absence of GI PNS at the time of diagnosis.

Debating Deposits, Redux: Substantial Interobserver Agreement Exists in Distinguishing Tumor Deposits From Nodal Metastases in Small Bowel Neuroendocrine Tumors.

Recent data suggest mesenteric tumor deposits (MTDs) indicate poor prognosis in small bowel well-differentiated neuroendocrine tumors (SB-NETs), including compared to positive lymph nodes, making their distinction crucial. To study interobserver agreement in distinguishing SB-NET MTDs from positive nodes. Virtual slides from 36 locally metastatic SB-NET foci were shared among 7 gastrointestinal pathologists, who interpreted each as an MTD or a positive node. Observers ranked their 5 preferred choices among a supplied list of potentially useful histologic features, for both options. Diagnostic opinions were compared using Fleiss multirater and Cohen weighted κ analyses. Preferred criteria for MTD included irregular shape (n = 7, top choice for 5), perineural invasion/nerve entrapment (n = 7, top choice for 2), encased thick-walled vessels (n = 7), and prominent fibrosis (n = 6). Preferred criteria for positive nodes included peripheral lymphoid follicles (n = 6, top choice for 4), round shape (n = 7, top choice for 2), peripheral lymphocyte rim (n = 7, top choice for 1), subcapsular sinuses (n = 7), and a capsule (n = 6). Among 36 foci, 10 (28%) each were unanimously diagnosed as MTD or positive node. For 13 foci (36%), there was a diagnosis favored by most observers (5 or 6 of 7): positive node in 8, MTD in 5. Only 3 cases (8%) had a near-even (4:3) split. Overall agreement was substantial (κ = .64, P < .001). Substantial interobserver agreement exists for distinguishing SB-NET MTDs from lymph node metastases. Favored histologic criteria in making the distinction include irregular shape and nerve/vessel entrapment for MTD, and peripheral lymphocytes/lymphoid follicles and round shape for positive nodes.

Intracranial meningiomas: an update of the 2021 World Health Organization classifications and review of management with a focus on radiation therapy.

Meningiomas account for approximately one third of all primary intracranial tumors. Arising from the cells of the arachnoid mater, these neoplasms are found along meningeal surfaces within the calvarium and spinal canal. Many are discovered incidentally, and most are idiopathic, although risk factors associated with meningioma development include age, sex, prior radiation exposure, and familial genetic diseases. The World Health Organization grading system is based on histologic criteria, and are as follows: grade 1 meningiomas, a benign subtype; grade 2 meningiomas, which are of intermediately aggressive behavior and usually manifest histologic atypia; and grade 3, which demonstrate aggressive malignant behavior. Management is heavily dependent on tumor location, grade, and symptomatology. While many imaging-defined low grade appearing meningiomas are suitable for observation with serial imaging, others require aggressive management with surgery and adjuvant radiotherapy. For patients needing intervention, surgery is the optimal definitive approach with adjuvant radiation therapy guided by extent of resection, tumor grade, and location in addition to patient specific factors such as life expectancy. For grade 1 lesions, radiation can also be used as a monotherapy in the form of stereotactic radiosurgery or standard fractionated radiation therapy depending on tumor size, anatomic location, and proximity to dose-limiting organs at risk. Optimal management is paramount because of the generally long life-expectancy of patients with meningioma and the morbidity that can arise from tumor growth and recurrence as well as therapy itself.

Esophageal Mucosal Resistance in Reflux Esophagitis: What We Have Learned So Far and What Remains to Be Learned.

Gastroesophageal reflux disease (GERD) has the highest prevalence among diseases of the digestive system and is characterized by a significant decrease in patients' quality of life, comparable to arterial hypertension and coronary heart disease. One in every ten cases of reflux esophagitis leads to the formation of Barrett's esophagus, which is associated with a high risk of esophagus adenocarcinoma. The key factors determining the progression of the disease are the frequency and duration of the reflux of the stomach's contents. As a result, refluxate, which includes hydrochloric acid, pepsin, and, in the case of concomitant duodeno-gastric reflux, bile acids and lysolecithin, is thrown into the overlying sections of the digestive tract. At the same time, in addition to aggression factors, it is necessary to take into account the state of resistance in the esophageal mucosa to the effects of aggressive refluxate molecules. This review was prepared using systematized data on the protective properties of the esophageal mucosa and modern methods to assess the mucosal barrier in reflux esophagitis. Lesions of the epithelial barrier structure in the esophagus are recognized as the main pathogenetic factor in the development of reflux esophagitis and are a potentially significant therapeutic target in the treatment of GERD and Barrett's esophagus. This article presents the characteristics of the esophageal mucosal barrier and the protective mechanisms of the esophagus's mucous membrane in conditions of gastroesophageal reflux. Diagnostic approaches for assessing the course of reflux esophagitis are described for both histological criteria and the possibility of a comprehensive assessment of the state of mucins, tight-junction proteins, and the proliferative activity of the mucosa, including under the conditions of ongoing therapy.