MIB-1 Staining Research Articles

Comparison of MIB-1-Specific Membrane Staining in Hyalinising Trabecular Tumor Using Mainstream Automated Immunohistochemical Staining Platforms.

MIB-1, a monoclonal antibody against Ki-67, exhibits specific membrane staining in the immunohistochemistry of hyalinising trabecular tumor (HTT). This specific staining pattern is crucial in diagnosing HTT. Although manual immunohistochemical staining remains the established method for MIB-1 staining, this process is complicated, inconsistent, and prone to false negatives. This study aimed to explore whether the classical reaction pattern can be replicated by utilizing the current mainstream automated immunohistochemical staining platforms. Furthermore, we examined the effect of different conditions on staining efficiency and their value in clinical diagnosis assistance. Specimens obtained from eight and six cases of HTT and non-HTT, respectively, from a single center were stained using the manual staining method and the Dako Autostainer Link 48 (AS48), Dako Omnis, Ventana BenchMark ULTRA, and Leica BOND-III automated immunohistochemical staining platforms. The Autostainer Link 48 was found to be the most stable staining platform, while the BenchMark ULTRA with primary antibody incubation at room temperature (RT) and the Omnis platform with antigen retrieval at pH 9.0 were able to reproduce membrane-positive staining for MIB-1 in the HTT specimens. Our results offer crucial reference value for clinical diagnostic assistance.

Optimal treatment strategy for low-grade spinal cord astrocytoma: a retrospective, multicenter analysis by the Neurospinal Society of Japan.

Primary spinal cord gliomas are rare, and among these astrocytomas (WHO grade II) are much rarer. The optimal treatment strategy thus remains unclear. The authors conducted a multicenter study led by the Neurospinal Society of Japan (NSJ) to analyze treatment policies and outcomes. The aim was to present optimal treatment methods for spinal cord astrocytoma and to identify predictors of better outcomes. Among 1033 consecutive cases of spinal cord intramedullary tumors treated surgically at 58 centers affiliated with the NSJ, 57 patients were diagnosed with diffuse astrocytoma (WHO grade II) and were enrolled in the present study. Among these 57 patients, treatment methods, outcomes, and tumor proliferation rate as evaluated by the MIB-1 staining index (SI) were analyzed, and the optimal treatment method for spinal cord astrocytomas (grade II) was determined. In addition, the authors searched for factors predicting better treatment outcomes. Treatment for spinal cord astrocytoma comprised three methods: surgery alone in 30 patients, adjuvant radiation therapy in 13 patients, and adjuvant chemoradiotherapy in 13 patients. One patient who did not undergo surgery was excluded from survival analysis. Treatment with surgery alone or surgery with radiotherapy was associated with significantly longer overall and progression-free survivals than that with adjuvant chemoradiotherapy. Patients treated with radiation therapy had a higher MIB-1 SI than those treated with surgery alone. The extent of tumor resection tended to correlate with longer survival. In contrast, postoperative neurological worsening showed the inverse order. Adjuvant chemoradiotherapy was associated with the shortest survival in both total cases and recurrent cases. The optimal cutoff value of MIB-1 SI for predicting longer survival by surgery alone was less than 4.0%. The optimal treatment for spinal cord astrocytoma is maximal tumor resection without neurological impairment. When some tumor remains in patients with an MIB-1 SI less than 4.0%, a wait-and-see approach is optimal. If the MIB-1 SI is higher than 4.0%, local radiation therapy is recommended. Adjuvant chemotherapy is not recommended for the treatment of grade II spinal cord astrocytoma.

Clinicopathologic Features in a TSH Secreting Pituitary Tumor : a Case Report

Thyrotropin-stimulating hormone-producing adenoma (TSHoma) is a rare cause of hyperthyroidism. Patients with this condition are often diagnosed when the tumor has already grown significantly, as the diagnosis of TSHoma is frequently delayed and confused with primary hyperthyroidism. Our case describes a 60-year-old woman with a goiter who was referred to our center from the otolaryngology department. Her thyroid panel in endocrinology showed elevated free hormone levels (fT3: 4.6 mg/ml and fT4: 1.93 mg/ml) and an unsuppressed TSH: 12.85 μ mIU/l, suggesting central hyperthyroidism. A thyroid gland sample obtained by a fine needle aspiration biopsy did not show malignant cells. An MRI scan of the pituitary gland revealed a macroadenoma with KNOSP grade 1. She underwent transsphenoidal surgery for the tumor. Histopathology revealed an acidophilic adenoma with the expression of TSH and prolactin by immunostaining. The proliferation rate, as indicated by MIB-1 staining, was only 0.6%. The decrease in thyroid hormones after the operation confirmed the effectiveness of the surgery. In conclusion, TSHoma, a rare tumor associated with hyperthyroidism, requires a careful diagnosis for effective management. Our article serves as reference material for understanding cases of pituitary-secreting tumors in Indonesia.

Multiparametric Classification of Non-Muscle Invasive Papillary Urothelial Neoplasms: Combining Morphological, Phenotypical, and Molecular Features for Improved Risk Stratification.

Diagnosis and grading of non-invasive papillary urothelial tumors according to the current WHO classification poses some challenges for pathologists. The diagnostic reproducibility of separating low-grade and high-grade lesions is low, which impacts their clinical management. Whereas papillary urothelial neoplasms with low malignant potential (PUN-LMP) and low-grade papillary non-invasive carcinoma (LG-PUC) are comparable and show frequent local recurrence but rarely metastasize, high-grade papillary non-invasive carcinoma (HG-PUC) has a poor prognosis. The main objective of this work is to develop a multiparametric classification to unambiguously distinguish low-grade and high-grade tumors, considering immunohistochemical stains for p53, FGFR3, CK20, MIB-1, p16, p21 and p-HH3, and pathogenic mutations in TP53, FGFR3, TP53, ERCC2, PIK3CA, PTEN and STAG2. We reviewed and analyzed the clinical and histological data of 45 patients with a consensus diagnosis of PUN-LMP (n = 8), non-invasive LG-PUC (n = 23), and HG-PUC (n = 14). The proliferation index and mitotic count assessed with MIB-1 and P-HH3 staining, respectively correlated with grading and clinical behavior. Targeted sequencing confirmed frequent FGFR3 mutations in non-invasive papillary tumors and identified mutations in TP53 as high-risk. Cluster analysis of the different immunohistochemical and molecular parameters allowed a clear separation in two different clusters: cluster 1 corresponding to PUN-LMP and LG-PUC (low MIB-1 and mitotic count/FGFR3 and STAG2 mutations) and cluster 2, HG-PUC (high MIB-1 and mitosis count/CK20 +++ expression, FGFR3 WT and TP53 mutation). Further analysis is required to validate and analyze the reproducibility of these clusters and their biological and clinical implication.

Hidradenocarcinoma Treated with Mohs Micrographic Surgery

Hidradenocarcinomas are very uncommon malignant tumors of sweat gland origin that exhibit a high potential for local recurrence, metastasis, and poor outcome. These neoplasms typically resemble benign appearing dermal nodules that lack distinguishable features. We present the case of hidradenocarcinoma in a 39-year-old male with a 5-year history of a slow growing nodule along his right eyebrow. Excisional biopsy of the lesion was taken with pathology showing nuclear pleomorphism, increased mitoses, and foci of necrosis. Immunohistochemical analysis revealed reactivity for Ki-67/MIB1 and strong diffuse staining for p63, CK5/6, and CK7. Mohs micrographic surgery was performed and clear margins were obtained after one stage. Compared to traditional treatment with wide local excision, Mohs micrographic surgery is a potentially advantageous alternative therapy as there have been no reported cases of tumor recurrence or metastasis to date.

Appendiceal Well-Differentiated Neuroendocrine Tumors: A Single-Center Experience and New Insights into the Effective Use of Immunohistochemistry.

Background. Appendiceal well-differentiated neuroendocrine tumor is the most common histological type of appendiceal tumor. The majority of tumors are found incidentally at the tip of the appendix, with few exceptions. Due to its primarily indolent nature, this entity presents unique pathological challenges, particularly in the appropriate use of immunohistochemistry which this study aims to clarify. Patients and methods. Patients diagnosed at University Health Network (Canada) between 2005-2019 were selected and reviewed. Results. We identified 70 patients and sex distribution was female 60%; median age 36.5 years. Among them, 63 patients underwent appendectomy, and seven had initial right hemicolectomy for non-appendix lesions. Mean tumor size was 5.0 mm. Tumor extent was submucosa (15%); muscularis propria (34%); subserosa or mesoappendix (42%); visceral peritoneum (8%). All were clinically non-functional and negative for nodal and distant metastasis. Ninety percent of tumors were WHO Grade 1; 10% were WHO Grade 2. Immunohistochemically, an average of six stains were performed per patient. Nearly all tumors were positive for chromogranin A, synaptophysin, CAM5.2, and CDX2. MIB-1 staining was < 3% in 58/63 tumors. Other immunohistochemical stainings performed were hormonal markers (serotonin, glucagon, pancreatic peptide, peptide YY). Subsequent right hemicolectomy was performed on five patients. All were followed up (median 4 years 8 months), and all were alive without recurrence except for one patient who died of another comorbidity. Conclusion. Tumors that are small, localized, and of low grade can be reasonably exempt from an extensive immunohistochemical panel in the absence of non-typical clinical and morphological features.

Predictors of progression in radiation-induced versus nonradiation-induced pediatric meningiomas: a large single-institution surgical experience.

The goal in this study was to outline unique differences between radiation-induced and nonradiation-induced pediatric meningiomas and to identify independent risk factors of tumor recurrence/progression. This is a retrospective cohort study of all pediatric meningiomas diagnosed and surgically treated at the authors' institution between 1993 and 2017. Multivariable Cox regression was applied to identify independent risk factors for tumor recurrence/progression. Thirty-five patients were identified. The primary etiology was nonradiation-induced (n = 24: n = 3 with neurofibromatosis type 2) or radiation-induced (n = 11: acute lymphoblastic leukemia [n = 5], medulloblastoma [n = 4], germ cell tumor [n = 1], and primitive neuroectodermal tumor [n = 1]) meningioma. The mean age at time of diagnosis was 10.7 ± 5.7 years for nonradiation-induced and 17.3 ± 3.5 years for radiation-induced meningiomas. Overall, 8/24 patients with nonradiation-induced meningioma experienced either recurrence or progression of the tumor. Of the 8 patients with tumor recurrence or progression, the pathological diagnosis was clear cell meningioma (n = 3: 2 recurrent and 1 progressive); grade I (n = 2 progressive); grade I with atypical features (n = 2: 1 recurrent and 1 progressive); or atypical meningioma (n = 1 recurrent). None of the patients with radiation-induced meningioma experienced recurrence or progression. Predictors of tumor recurrence/progression by univariate analysis included age at time of diagnosis ≤ 10 years (p = 0.002), histological subtype clear cell meningioma (p = 0.003), and primary etiology nonradiation-induced meningioma (p = 0.04), and there was a notable trend with elevated MIB-1 staining index (SI) (p = 0.09). There was no significant difference between nonradiation-induced and radiation-induced meningiomas (p = 0.258), although there was a trend between recurrent and nonrecurrent meningiomas (p = 0.09). Multivariate Cox regression, adjusted for length of follow-up, identified younger age at diagnosis (p = 0.004) and a higher MIB-1 SI (p = 0.044) as independent risk factors for recurrence. Elevated MIB-1 SI statistically correlated with atypia (p < 0.001). However, there was no significant statistical correlation between tumor recurrence/progression and atypia (p = 0.2). Younger patient age and higher MIB-1 SI are independent risk factors for recurrence. Atypia was not a predictor of recurrence.

Development of Delayed Paraneoplastic ACTH Syndrome in Small Cell Lung Carcinoma

Background: Paraneoplastic/ectopic ACTH syndrome (EAS) is a rare but well-recognized syndrome in small cell lung carcinoma (SCLC), occurring in 1-5% of cases (1) and most often at diagnosis. We present a patient with SCLC who developed paraneoplastic ACTH syndrome 9 months after initiation of treatment. Case: A 73 year old female with long history of smoking and COPD (on home O2) and SCLC seen during hospitalization with severe muscle cramps, generalized weakness, hypertension and hypokalemia. Eleven months prior, she was diagnosed with SCLC after presenting with left superior mediastinum, supraclavicular and neck lymphadenopathy. She received 4 cycles of chemotherapy and immune checkpoint inhibitor (ICI) therapy (atezolizumab) was also initiated and continued throughout. Good response to therapy occurred until nine months post initiation, when relapse in same regions was identified on repeat PETCT. Physical examination revealed new onset resistant hypertension up to 240/120mmHg, and extensive bilateral lower extremity edema. Labs showed hypokalemia of 2.3 mmol/l and metabolic alkalosis with serum bicarbonate 43 mmol/l. Further investigations showed a random cortisol of 97.1 ug/dl with repeat of 175.9 ug/dl the following AM. ACTH was 374.1pg/ml. TSH was 0.25 uU/ml with low normal T4 and T3. Pituitary MRI showed no evidence of hypophysitis or enlargement. Repeat biopsy of cervical lymph node was unchanged from initial biopsy with two notable differences: morphology showed a “more organized, trabecular pattern” and MIB-1 staining had declined from 70-80% to 20%, and tumor cells stained positive for ACTH. She did not respond to octreotide, but did respond to ketoconazole (hypokalemia, edema improved and cortisol levels decreased to 24.2 ug/dl). However, hepatotoxicity occurred and thus it was discontinued with rapid rise of cortisol. As she was not a candidate for bilateral adrenalectomy, we started metyrapone with lowering of cortisol levels within 4 doses. However, new cavitary lesions on chest CT developed with concern for disseminated fungal infection. Patient elected for hospice and passed away the following day. Conclusion: We present an unusual case of paraneoplastic ACTH syndrome that developed after immunotherapy in SCLC. In summary, the relapse of SCLC while on immune therapy was associated pathologically by differentiation into a neuroendocrine tumor type and biochemically by a considerable ACTH production. We conclude that ACTH production with subsequent severe hypercortisolism causing immunosuppression may be a novel mechanism by which SCLC can evade immunotherapy.Reference: (1) Nagy-Mignotte H, Shestaeva O, Moro-Sibilot D et al. Prognostic impact of paraneoplastic cushing’s syndrome in small-cell lung cancer. J Thorac Oncol. 2014 Apr,9.

Role of Immunohistochemical Markers p53 and Ki-67 in Grading of Glial Tumours: A Prospective Study

Introduction: Gliomas are the tumours of neuroepithelial tissues and are named according to their cell of origin. Squash cytology and sterotactic biopsies with Haematoxylin and Eosin (H&amp;E) staining form the backbone of diagnosis, nevertheless recent advances in Immunohistochemistry (IHC) have revolutionised the way gliomas are diagnosed and graded. Aim: To evaluate expression and correlation of p53 and Ki-67/MIB 1 amongst a series of gliomas diagnosed morphologically according to World Health Organisation (WHO) classification of Central Nervous System (CNS) tumours 2007. Materials and Methods: The present study was a prospective study conducted over a period of 18 months from December 2016 to May 2018 at a tertiary care centre in Uttarakhand, India. The study group comprised all consecutive cases of glial tumours that were clinically diagnosed and histopathologically confirmed as Gliomas during this period. Histopathological sections were made from formalin fixed tissue and stained with H&amp;E and grading was done according to the WHO grading system 2007 for CNS neoplasms. Subsequently, IHC sections were taken on poly L-lysine coated slides and IHC staining of p53 and MIB1 (Ki-67) was performed. The IHC scores were calculated and correlated with histopathological grade. Statistical analysis was done using Statistical Package for the Social Sciences (SPSS) software version 17.0. Results: A total of 40 cases of glial tumours diagnosed on histopatholgy were included in the study. They showed M:F ratio of 1.22:1 with peak age incidence of 21-30 years. Astrocytoma, grade IV was the most frequent diagnosis followed by grade II on H&amp;E. On IHC, grade II diffuse astrocytomas, grade III Anaplastic Astrocytomas (AA), and Glioblastoma Multiforme (GBM) demonstrated a mean p53 positivity of 29.5, 50.83 and 47.66, respectively and a Ki-67 positivity of 32.5, 48.33 and 58.08, respectively. For ependymomas grade I, II and III the mean p53 positivity was 9, 5.26 and 12, respectively and the mean Ki-67 positivity was 2, 7.93 and 40, respectively. Amongst oligodendrogliomas grade II and III showed a p53 positivity of 6 and 8.25 and Ki-67 positivity of 12 and 30.5, respectively. A stronger correlation was found between an increase in histologic grade and proliferation markers. Conclusion: Histologic grade was the most important prognostic factor with respect to patient survival in glial neoplasms. The immunopositivity for p53 and Ki-67 correlated well with histological malignancy grade in all glioma subtypes, but a considerable overlap of proliferative index was observed between different subtypes.

PATH-37. IDENTIFYING HIGH-RISK PATIENTS FOR WHO GRADE I MENINGIOMA RECURRENCE USING HISTOPATHOLOGICAL FEATURES AND THE MIB-1 INDEX

Abstract BACKGROUND In this study, we identify clinical, radiographic, and histopathologic prognosticators of overall, early, and post-median recurrence in World Health Organization (WHO) grade I meningiomas. We also determine a clinically relevant cutoff for MIB-1 to identify patients at high risk for recurrence. METHODS A retrospective review of WHO grade I meningioma patients with available MIB-1 index data who underwent treatment at our institution from 2007-2017 was performed. Univariate and multivariate analyses, and recursive partitioning analysis (RPA), were used to identify risk factors for overall, early (within 24 months), and post-median (greater than 24 months post-treatment) recurrence. RESULTS A total of 239 patients were included. The mean age was 60.0 years, and 69.5% of patients were female. The average follow-up was 41.1 months. All patients received surgery and 2 patients each received either adjuvant radiotherapy or gamma knife treatment. The incidence of recurrence was 10.9%, with an average time to recurrence of 33.2 months (6-105 months). Posterior fossa tumor location (p=0.004), MIB-1 staining (p=0.008), nuclear atypia (p=0.003), and STR (p&amp;lt; 0.001) were independently associated with an increased risk of recurrence on cox-regression analysis. RPA for overall recurrence highlighted extent of resection, and after gross total resection (GTR), a MIB-1 index cutoff of 4.5% as key prognostic factors for recurrence. Patients with a GTR and MIB-1 &amp;gt;4.5% had a similar incidence of recurrence as those with STR (18.8vs.18.6%). Variables independently associated with early recurrence on binary logistic regression modeling included STR (p=0.002) and nuclear atypia (p=0.019). RPA confirmed STR as associated with early recurrence. MIB-1 index (p=0.010) was identified as an independent predictor of post-median recurrence using similar methods. CONCLUSIONS STR, posterior fossa location, nuclear atypia, and elevated MIB-1 index are prognostic factors for WHO grade I meningioma recurrence. Moreover, MIB-1 index &amp;gt;4.5% is prognostic for recurrence in patients with GTR.

Pediatric High-Grade Glioma Patterns of Failure by Molecular Subgroup

Pediatric high-grade gliomas (HGG), which include WHO Grades III and IV astrocytomas, are molecularly diverse as characterized by their mutations and histopathological features. There has been little progress over the last few decades in improving pediatric HGG outcomes, with published median survivals ranging from 9-15 months. We hypothesize that tumor molecular subgroup may be associated with survival outcomes and patterns of failure after definitive radiation therapy (RT). Medical records, pathology reports, RT plans and follow up brain MRIs for pediatric patients treated for HGG from 2006 to 2019 at a single institution were reviewed. Inclusion criteria were age 18 or younger, biopsy-proven WHO Grade III or IV astrocytoma, received at least 1 post-treatment MRI, and either already had molecular subgroup classification or had tissue available for further testing. Molecular testing is ongoing; genes in our molecular assay include, but are not limited to, Histone H3, PTEN, EGFR, BRAF and PDGFRA. Patients in this study were treated with fractionated volumetric modulated arc radiotherapy using a simultaneous integrated boost, 54 Gy to the T2/FLAIR signal abnormality plus margin, and 60 Gy to the T1 post-contrast abnormality, resection cavity, or any gross residual disease plus a margin, all in 30 fractions. Kaplan-Meier method was used to estimate overall survival (OS) and progression free survival (PFS). Univariate Cox proportional hazards models were fit for patient characteristics. Failure is characterized as local, marginal or distant. 39 patients with a median age at diagnosis of 11.2 years (range 3.7 – 18.3) met inclusion criteria, 29 with WHO Grade IV and 10 with WHO Grade III disease. Median survival was 10.4 months (95% CI 7.5, 17.2), with a 24-month survival of 25.4% (13.1%, 39.7%). Median PFS was 6.5 months (3.9, 10.1) with a 12-month PFS of 30.8% (17.3%, 45.4%). On univariate analysis, neither OS nor PFS were associated with any recorded patient characteristic including GTV size, age at diagnosis, type of surgery, receipt of chemotherapy or cumulative RT dose. 8 patients had distant failures; 6 had marginal failures. The remaining patients who had progressed prior to last analysis failed locally. Of the 8 patients with distant failure, 6 had leptomeningeal disease (LMD). Half of the patients with LMD had PTEN deletions. 5 of the 8 patients with distant failures had MIB-1 staining results, all with values below or equal to 50%. Additional molecular testing for patients in the entire cohort is ongoing and will be correlated with patterns of failure and survival. Pediatric high-grade gliomas are comprised of diverse mutational signatures, which may be associated with tumor aggressiveness and potential for treatment response. Molecular phenotyping of pediatric high-grade gliomas may provide valuable prognostic information that could inform treatment decision-making.

Myoepithelial Tumors of Salivary Gland: A Clinicopathologic and Immunohistochemical Study of 15 Patients with MIB-1 Correlation.

Myoepithelial neoplasms are rare tumors of the salivary glands with predominant myoepithelial differentiation and a broad histologic spectrum. Their histological features, immunohistochemical profile and biological behavior are not well characterized and pose a diagnostic challenge. A total of 15 myoepithelial tumors, diagnosed during 2012 and 2019 were subcategorized and correlated with MIB-1 labeling index (LI) and various histological parameters. Immunohistochemical stains for MIB-1 and other antibodies were performed. Statistical analysis was done by chi-square test, Fisher's exact test and Kaplan Meier curve. Nine patients were male and six were female with the median age of 44years (range 21-83years). Of the 15 patients, 6 cases were classified as myoepithelioma (ME) and 9 cases as myoepithelial carcinoma (MECA). Parotid gland was the most common site (46.7%) followed by the palate. MEs showed well circumscribed tumor borders whereas MECAs exhibited focal capsular to extensive invasion into adjacent tissues. Epithelioid cell morphology was most common followed by mixed cell morphology. MIB-1 LI was significantly associated with invasive tumor borders, necrosis and high mitosis. Increased frequency of recurrence was noted with high MIB-1 LI, though it was not statistically significant. MIB-1 LI was high in nearly all MECAs with focal capsular to extensive invasion while low in MEs. Myoepithelial tumor with multinodular growth pattern and focal capsular invasion may have an indolent behavior if mitotic activity and MIB-1 LI is low. Early diagnosis and treatment of MECAs significantly improves the patient's survival and prognosis.

WHO Grade I Meningioma Recurrence: Identifying High Risk Patients Using Histopathological Features and the MIB-1 Index.

Objective: In this study, we identify clinical, radiographic, and histopathologic prognosticators of overall, early, and post-median recurrence in World Health Organization (WHO) grade I meningiomas. We also determine a clinically relevant cutoff for MIB-1 to identify patients at high risk for recurrence.Method: A retrospective review of WHO grade I meningioma patients with available MIB-1 index data who underwent treatment at our institution from 2007 to 2017 was performed. Univariate and multivariate analyses, and recursive partitioning analysis (RPA), were used to identify risk factors for overall, early (within 24 months), and post-median (>24 months post-treatment) recurrence.Result: A total of 239 patients were included. The mean age was 60.0 years, and 69.5% of patients were female. The average follow-up was 41.1 months. All patients received surgery and 2 patients each received either adjuvant radiotherapy (2/239) or gamma knife treatment (2/239). The incidence of recurrence was 10.9% (26/239 patients), with an average time to recurrence of 33.2 months (6–105 months). Posterior fossa tumor location (p = 0.004), MIB-1 staining (p = 0.008), nuclear atypia (p = 0.003), and STR (p < 0.001) were independently associated with an increased risk of recurrence on cox-regression analysis. RPA for overall recurrence highlighted extent of resection, and after gross total resection (GTR), a MIB-1 index cutoff of 4.5% as key prognostic factors for recurrence. Patients with a GTR and MIB-1 >4.5% had a similar incidence of recurrence as those with STR (18.8 vs. 18.6%). Variables independently associated with early recurrence on binary logistic regression modeling included STR (p = 0.002) and nuclear atypia (p = 0.019). RPA confirmed STR as associated with early recurrence.Conclusion: STR, posterior fossa location, nuclear atypia, and elevated MIB-1 index are prognostic factors for WHO grade I meningioma recurrence. Moreover, MIB-1 index >4.5% is prognostic for recurrence in patients with GTR. Verification of our findings in larger, multi-institutional studies could enable risk stratification and recommendations for adjuvant radiotherapy following resection of WHO grade I meningiomas.

Prediction of relapse in stage I testicular germ cell tumor patients on surveillance: investigation of biomarkers

BackgroundBetter biomarkers for assessing risk of relapse in stage I testicular germ cell tumor patients are needed, to complement classical histopathological variables. We aimed to assess the prognostic value of previously suggested biomarkers, related to proliferation (MIB-1 and TEX19) and to immune microenvironment (CXCL12, CXCR4, beta-catenin and MECA-79) in a surveillance cohort of stage I testicular germ cell tumor patients.MethodsA total of 70 patients were included. Survival analyses were performed, including Cox regression models.ResultsPatients with vascular invasion and elevated human chorionic gonadotropin levels showed significantly poorer relapse-free survival in multivariable analysis (hazard ratio = 2.820, 95% confidence interval 1.257–6.328; hazard ratio = 3.025, 95% confidence interval 1.345–6.808). Patients with no vascular invasion but with MIB-1 staining in > 50% tumor cells showed significantly shorter relapse-free survival (p = 0.042). TEX19 nuclear immunoexpression was confirmed in spermatogonial cells, and weak cytoplasmic immunoexpression was depicted in 15/70 tumors, not significantly impacting survival. CXCL12 immunoexpression in tumor cells did not associate with relapse, but non-seminoma patients exhibiting vascular invasion and CXCL12-positive stromal/inflammatory cells showed significantly improved relapse-free survival (p = 0.015). Exclusively nuclear immunoexpression of CXCR4 associated with better relapse-free survival (p = 0.032), but not after adjusting for vascular invasion. Patients with higher beta-catenin scores showed a tendency for poorer relapse-free survival (p = 0.056). MECA-79 immunoexpression was absent.ConclusionsThe informative protein biomarkers (i.e., MIB-1, CXCL12, beta-catenin, and possibly CXCR4) may prove useful for risk-stratifying patients if validated in larger, multicentric and well-defined studies. Currently, classical histopathological features of testicular germ cell tumors remain key for relapse prediction.

Long and Very-Long-Chain Ceramides Correlate with A More Aggressive Behavior in Skull Base Chordoma Patients.

Background: Skull base chordomas are rare tumors arising from notochord. Sphingolipids analysis is a promising approach in molecular oncology, and it has never been applied in chordomas. Our aim is to investigate chordoma behavior and the role of ceramides. Methods: Ceramides were extracted and evaluated by liquid chromatography and mass spectrometry in a cohort of patients with a skull base chordoma. Clinical data were also collected and correlated with ceramide levels. Linear regression and correlation analyses were conducted. Results: Analyzing the association between ceramides level and MIB-1, total ceramides and dihydroceramides showed a strong association (r = 0.7257 and r = 0.6733, respectively) with MIB-1 staining (p = 0.0033 and p = 0.0083, respectively). Among the single ceramide species, Cer C24:1 (r = 0.8814, p ≤ 0.0001), DHCer C24:1 (r = 0.8429, p = 0.0002) and DHCer C18:0 (r = 0.9426, p ≤ 0.0001) showed a significant correlation with MIB-1. Conclusion: Our lipid analysis showed ceramides to be promising tumoral biomarkers in skull base chordomas. Long- and very-long-chain ceramides, such as Cer C24:1 and DHCer C24:1, may be related to a prolonged tumor survival and aggressiveness, and the understanding of their effective biological role will hopefully shed light on the mechanisms of chordoma radio-resistance, tendency to recur, and use of agents targeting ceramide metabolism.

Classic Vulvar Intraepithelial Neoplasia With Superimposed Lichen Simplex Chronicus: A Unique Variant Mimicking Differentiated Vulvar Intraepithelial Neoplasia.

High-grade vulvar intraepithelial neoplasia, a precursor lesion to vulvar squamous cell carcinoma, is subdivided into 2 types, classic or usual vulvar intraepithelial neoplasia (CVIN) and differentiated vulvar intraepithelial neoplasia (DVIN). CVIN, which is a human papilloma virus (HPV)-dependent lesion, is typically distinguished from DVIN, a p53 mutation-dependent process, by its distinct histomorphologic and immunohistochemical characteristics. However, distinguishing between the 2 entities becomes challenging in cases of CVIN with superimposed inflammatory changes, especially lichen simplex chronicus (LSC). Twelve cases of DVIN, 9 cases of LSC, and 9 cases of CVIN with superimposed LSC were assessed for a number of morphologic features, including hyperkeratosis, hypergranulosis, acanthosis, hypercellularity, abnormal maturation (i.e. abnormal keratinization close to the base and/or dyskeratosis), hyperchromasia, and basal atypia. Immunohistochemistry for p53, p16, and MIB-1 was performed for all cases. When sufficient tissue was available, HPV genotyping was performed for cases of CVIN with superimposed LSC. DVIN uniformly demonstrated abnormal maturation, and atypia involving the basal cell layer; they were all p16 negative and demonstrated p53 positivity of moderate to strong intensity in a basal and parabasal distribution. CVIN with superimposed LSC frequently displayed hyperchromasia involving the basal 3 to 4 cell layers, basal to full-thickness atypia, and apoptosis. CVIN with superimposed LSC demonstrated intense p16 positivity extending from the basal cells to the mid-epithelium and a reduction or loss of staining in maturing keratinocytes. P53 staining revealed a unique pattern of parabasal and mid-epithelial weak to moderate staining with sparing of the basal layer. Cases of LSC demonstrated heterogenous p53 positivity and were negative for p16. MIB-1 staining showed a similar range of positivity for all diagnoses. HPV genotyping revealed HPV 16 in all 5 cases of CVIN with LSC that underwent testing. We conclude that, although CVIN with superimposed LSC can closely resemble DVIN, morphologic features such as nuclear hyperchromasia uniformly involving the basal 3 to 4 cell layers, apoptosis, and absent or less pronounced cytoplasmic maturation are more suggestive of CVIN with superimposed LSC. In cases where the morphology remains ambiguous, immunohistochemistry for both p16 and p53 can be helpful. In particular, p53 parabasal and mid-epithelial staining without involvement of the basal layer appears to be a characteristic finding in CVIN with superimposed LSC. MIB-1 staining is of little utility in distinguishing between these entities and should not be routinely performed.

Expression of GLUT1 in Pseudopalisaded and Perivascular Tumor Cells Is an Independent Prognostic Factor for Patients With Glioblastomas.

Glioblastomas are highly aggressive brain tumors with a particularly poor prognosis. Glucose transporter-1 (GLUT1/SLC2A1), a uniporter that is expressed by various carcinomas and may be involved in malignant neoplasm glycometabolism, may also be related to prognosis in glioblastomas. GLUT1 is essential to central nervous system glycometabolism. To clarify the exact role of GLUT1 in glioblastoma, we assessed the expression and localization of GLUT1 in patient samples by immunohistochemistry and in situ RNA hybridization. This revealed that GLUT1 was mainly expressed on perivascular and pseudopalisaded tumor cell membranes. All samples expressed GLUT1 to some degree, with 30.8% showing stronger staining. On the basis of these data, samples were divided into high and low expression groups, although SLC2A1 mRNA expression was also higher in the high GLUT1 expression group. Kaplan-Meier survival curves revealed that high GLUT1 expression associated with lower overall survival (log-rank test, p = 0.001) and worse patient prognoses (p = 0.001). Finally, MIB-1 staining was stronger in high GLUT1 expression samples (p = 0.0004), suggesting a link with proliferation. We therefore hypothesize that GLUT1 expression in glioblastomas may enhance glycolysis, affecting patient prognosis. Examination of GLUT1 in patients with glioblastomas may provide a new prognostic tool to improve outcome.

Correction to: The proliferation marker pKi-67 becomes masked to MIB-1 staining after expression of its tandem repeats.

In the PubMed citation records, the author's name shows.

Pyloric Gland Adenoma (PGA) of the Gallbladder: A Unique and Distinct Tumor from PGAs of the Stomach, Duodenum, and Pancreas.

Twenty-four surgically resected, gallbladder pyloric gland adenomas (GB-PGAs) were examined and their features were compared with the reported features of stomach, duodenum, and pancreatic PGAs to better understand GB-PGAs. Clinical information on background gallbladder lesions and histologic data, including tumor grade, existence of squamoid morules, intratumoral cholesterosis, and intracytoplasmic mucins were collected. Immunohistochemical staining for MUC2, MUC5AC, MUC6, CDX2, pepsinogen I, p53, and MIB-1/nuclear β-catenin were evaluated. Targeted mutational analyses of KRAS exon2, GNAS exon 7, and CTNNB1 exon 3 were conducted. We found that 29.2% of the GB-PGAs were histologically high-grade dysplasias/carcinomas; 70.8% were low grade; and 20.8% and 33.3% contained squamoid morules and intratumoral cholesterosis, respectively. In addition, 45.8% and 54.2% of GB-PGAs were mucin-rich and mucin-poor types, respectively. Immunohistochemically, MUC6 was diffusely positive in all GB-PGAs; MUC2, MUC5AC, and CDX2 were only focally positive, and no pepsinogen-I positive cells were observed. Nuclear β-catenin accumulation was observed in all cases; however, the ratio varied among cases. Mucin-poor types were significantly associated with high histologic grade dysplasias/carcinomas and high nuclear β-catenin labeling indices. Mutational analyses identified CTNNB1 mutations in 100% of GB-PGAs (21/21), KRAS in 4.2% (1/23), and GNAS in 0% (0/22). The present study clarified the unique histologic features, phenotypic differentiation, and molecular statuses frequently associated with GB-PGAs. Altogether, our data suggest that tumorigenesis of GB-PGA is distinct from that of stomach, duodenum, and pancreatic PGAs.

Associations Between [18F]FDG-PET and Complex Histopathological Parameters Including Tumor Cell Count and Expression of KI 67, EGFR, VEGF, HIF-1α, and p53 in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of common cancers worldwide. Positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is increasingly used for diagnosing and staging, as well as for monitoring of treatment of HNSCC. PET parameters like maximum and mean standard uptake values (SUVmax, SUVmean) can predict the behavior of HNSCC. The purpose of this study was to analyze possible associations between these PET parameters and clinically relevant histopathological features in patients with HNSCC. Overall, 22 patients, mean age, 55.2 ± 11.0years, with different HNSCC were acquired. Low grade (G1/2) tumors were diagnosed in 10 cases (45%) and high grade (G3) tumor in 12 (55%) patients. In all cases,whole body PET was performed. For this study, the following specimen stainings were performed: MIB-1 staining (KI 67 expression), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, hypoxia-inducible factor (HIF)-1α, and human papilloma virus (p16 expression). All stained specimens were digitalized and analyzed by using the ImageJ software 1.48v. Spearman's correlation coefficient (ρ) was used to analyze associations between investigated parameters. P values <0.05 were taken to indicate statistical significance. P16-negative tumors showed statistically significant higher SUVmax (ρ = 0.006) and SUVmean values (ρ = 0.002) in comparison to p16-positive carcinomas. No significant differences were identified in the analyzed parameters between poorly and moderately/well-differentiated tumors. In overall sample, there were no statistically significant correlations between the [18F]FDG-PET and histopathological parameters. Also, in G1/2 tumors, no significant correlations were identified. In G3 carcinomas, cell count correlated statistical significant with SUVmax (p = 0.580, P = 0.048) and SUVmean (ρ = 0.587, P = 0.045). Associations between [18F]FDG-PET parameters and different histopathological features in HNSCC depend significantly on tumor grading. In G1/2 carcinomas, there were no significant correlations between [18F]FDG-PET parameters and histopathology. In G3 lesions, SUVmax and SUVmean reflect tumor cellularity.