Investigation of the status of immune checkpoint molecules (PD-L1 and PD-1) in meningiomas by immunohistochemistry.

Background/aim: Meningiomas are the most common primary brain tumors of the central nervous system. Immunotherapy is a promising treatment method applied in many types of cancer. There is no standard and effective medical treatment to reduce recurrence and mortality in cases of incomplete resection of meningiomas and in high-grade cases. In order to investigate medical treatments in addition to surgery and radiotherapy, in this study, the status of immune checkpoint molecules (PD-L1/PD-1), which are the target of immunotherapy, in meningiomas was investigated. Materials and methods: Four hundred two cases of meningioma diagnosed between 2007 and 2020 at our institution were used. New blocks were prepared from the appropriate blocks of the cases using the tissue microarray method. Sections obtained from these blocks were immunohistochemically stained with PD-1 and PD-L1 antibodies. Obtained data were interpreted with statistical analysis. Results: Expression of PD-L1 was observed in 28.4% of meningiomas. Staining rates are higher in high-grade tumors. The staining rate of PD-L1 in the tumor increased significantly with pattern loss. PD-L1 expression in immune cells is 19.9%. Immune cell expression and the number of expressing immune cells correlate with spontaneous necrosis. Immune cell expression and the number of expressing immune cells are increased in high-grade meningiomas. PD-1 expression in immune cells is 9.0%, and this correlates with brain invasion. Conclusions: With these data, it was observed that the expression of immune checkpoint molecules PD-L1 and PD-1 increased especially in high-grade meningiomas. It may be the subject of research that these molecules may be targets of immunotherapy in the treatment of meningiomas.

Investigation of the relationship between immune checkpoints and mismatch repair deficiency in recurrent and nonrecurrent glioblastoma

Background/aim: Microsatellite instability tests and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) in the immune checkpoint pathway are the tests that determine who will benefit from immune checkpoint inhibitor therapy. We aimed to show the expression of DNA mismatch repair proteins and PD-1/PD-L1 molecules that inhibit immune checkpoints, to explain the relationship between them, and to demonstrate their predictive role in recurrent and nonrecurrent glioblastoma. Materials and methods: We analyzed 27 recurrent and 47 nonrecurrent cases at our archive. We performed immunohistochemical analysis to determine expressions of PD-1, PD-L1, and mismatch repair proteins in glioblastoma. We evaluated the relationship between these two group and compared the results with the clinicopathological features. Results: The mean age of diagnosis was significantly lower in recurrent glioblastoma patients. Median survival was longer in this group. We found that PD-L1 expression was reduced in recurrent cases. Additionally, recurrent cases had a significantly higher rate of microsatellite instability. Loss of PMS2 was high in both group but was substantially higher in recurrent cases. Conclusion: The presence of microsatellite instability and low PD-L1 levels, which are among the causes of treatment resistance in glioblastoma, were found to be compatible with the literature in our study, with higher rates in recurrent cases. In recurrent cases with higher mutations and where immunotherapy resistance is expected less, low PD-L1 levels thought that different combinations with other immune checkpoint inhibitors can be tried as predictive and prognostic marker in GBM patients.

Investigation of the Effectiveness of an Algorithm as an Auxiliary Method in Intraoperative Consultations of Central Nervous System Tumors.

OBJECTIVE: One of the most difficult areas in a surgical pathology practice is intraoperative consultation. In a previous study, we proposed an algorithm that provides a systematic approach to intraoperative consultation for central nervous system tumors. Our aim was to demonstrate the effectiveness of this algorithm. MATERIAL AND METHODS: 102 cases were selected from intraoperative consultation procedures performed at our institution between 2012 and 2020. The algorithm was tested by five observers. The observers examined the smears and frozen sections without the algorithm, and then with the algorithm. RESULTS: The percentage change in the rate of correct diagnoses made by the four observers (O) increased after using the algorithm (O2: 8%, O3: 5%, O4: 8% and O5: 13%), but decreased for only one observer (O1) (5%). The most common error made by the four observers was `grading of glial tumors` (O1: 40%; O2: 23%; O4: 40% and O5: 27.5%), and this group of errors was mostly corrected by using the algorithm (O1: 33%; O2: 3.8%; O4: 23% and O5: 10%). For two observers (O2 and O5), a statistically significant change in diagnostic levels was observed after using the algorithm (p=0.024 and p=0.040; respectively). In addition, thanks to the use of the algorithm, a high degree of agreement was found between the observers` diagnoses (77.7%, p < 0.001). CONCLUSION: In the intraoperative consultation of central nervous system lesions, algorithms can help to increase the accuracy of the diagnosis and reduce interobserver variability. This study demonstrates that an algorithmic approach is an effective method for pathologists in intraoperative consultation procedures.

Investigation of the Status of Immune Checkpoint Molecules in Meningiomas by Immunohistochemistry.

AIM: To investigate the status of immune checkpoint molecules (CTLA-4 and TIM-3) in meningiomas and thus contribute to the development of new personalized treatment strategies. MATERIAL AND METHODS: We utilized 402 cases of meningioma for this study. New blocks were prepared using the tissue microarray method, and sections obtained from these blocks were immunohistochemically stained with CTLA-4 and TIM-3 antibodies. Subsequently, statistical analysis were performed. RESULTS: Our findings revealed that CTLA-4 expression were observed in 25.1% of meningiomas. CTLA-4 expression and the number of expressing lymphocytes were found to be significantly higher in high-grade tumors and in those with brain invasion. Meningiomas with staining of immune cells with TIM-3 are 3.5%, and the tumor grade was correlated with the number of immune cells expressing TIM-3. CONCLUSION: Immune checkpoint molecules (CTLA-4 and TIM-3) with varying levels of expression can serve as prognostic and predictive biomarkers, as well as important targets for therapy. Drugs developed for CTLA-4 and TIM-3 molecules may prove to be more effective in treating meningiomas with high-grade, brain-invading, spontaneous necrosis, and macronucleolus.

Erdheim-Chester disease misdiagnosed as meningioma of the pontocerebellar angle: A case report and review of literature.

Erdheim-Chester Disease (ECD) is a rare non-Langerhans form of systemic histiocytosis of unknown etiology with multiple organ involvement. It most commonly affects the long bones, lungs, heart, retroperitoneum, eyes, and kidneys and less commonly the brain and spinal cord. Although there are very few cases of supratentorial ECD mimicking intracranial meningioma reported in literature, to the best of our knowledge, there are no reports on ECD mimicking infratentorial pontocerebellar angle meningioma. The present study reports a case of ECD mimicking pontocerebellar angle meningioma. This study aimed to emphasize the importance of systemic evaluation using a multidisciplinary approach as well as the need for considering ECD as a differential diagnosis of xanthomatous meningioma.

The status of HER2 in colorectal carcinoma and the relation of HER2 with prognostic parameters and MSI.

Background: Colorectal cancer (CRC) is the third most commonly occurring cancer in men and the second most common cancer in women. Despite advances in surgical techniques and chemotherapeutic regimens, CRC continues to be one of the main causes of cancer-related deaths in the world. Aims: The aim of the study was to evaluate the immunohistochemical expression of human epidermal growth factor receptor 2 (HER2) and the relationship between HER2, clinicopathological parameters, and microsatellite instability (MSI). Materials and Methods: Two hundred and forty resected CRCs at our institution between 2016 and 2019 were included in the study. Tumors were re-evaluated and classified according to the World Health Organization. Tissue macroarray techniques were used to generate tissue samples. HER2 antibody was performed using the automated system. Results: HER2 antibody was score 3 positive in only 5 cases. Score 2 was observed in 13 cases, score 1 in 27, score 0 in 195. All of the HER2-positive cases were metastatic. All of them were tubular adenocarcinoma. HER2 positive cases were well and moderately differentiated. Four of the HER2 positive cases were T3 stage, and one was T4. Conclusion: A total of 2.1% of CRCs were positive for HER2 antibody. There was a positive correlation between HER2 and distant metastasis. There was no significant relationship between MSI, other prognostic parameters, and HER2.

Prognostic Factors in Gastrointestinal Stromal Tumors (GIST): Could Prognostic Nutritional Index (PNI) be a New Prognostic Factor?

OBJECTIVE: To investigate factors that may affect prognosis in gastrointestinal stromal tumors (GISTs). STUDY DESIGN: A descriptive study. PLACE AND DURATION OF STUDY: Karadeniz Technical University Hospital, Trabzon, Turkey from 2000 to 2019. METHODOLOGY: All the patients diagnosed with GIST and followed-up in this centre were included. Those who were not followed-up in this centre were excluded. The Chi-square test for differences between variables in independent groups; and the Kaplan-Meier method for survival rates were used. RESULTS: Median tumor size was larger in patients with recurrence, compared to those without (8cm vs. 5 cm, p <0.001). Recurrence rates were higher with mitosis ≥5 in 50 high-power-fields than with low mitosis (52.6% vs. 23.4%, p = 0.021). Median Ki-67 percentages were higher in patients with recurrence than without (5 vs. 2, p = 0.031). Recurrence rates were higher with necrosis and bleeding than without (57.7% vs. 14.3%, p = <0.001; 50% vs. 13.8%, p = 0.003). Median overall-survival (OS) was shorter in with mitotic counts ≥5 compared to <5 (52.0 vs. 110.0 months, p = 0.051) and with ulceration than without (36.0 vs. 110.0 months, p = 0.017). The groups below (<43.5) and above (>43.5) the median prognostic-nutritional-index (PNI) value were similar in terms of OS and disease-free survival (DFS) (52 vs. 70 months, p = 0.174; 82 vs. 100 months, p = 0.411). Median DFS was shorter with ulceration than without (27 vs. 100 months, p = 0.048). CONCLUSION: While necrosis, bleeding, ulceration, mitosis, size, and Ki-67 significantly affect the prognosis in GIST, PNI has no significant effect. Key Words: Gastrointestinal stromal tumors (GIST), Survival, Prognosis, Recurrence, Prognostic Nutrition Index (PNI).

PD-L1 expression in invasive solid papillary breast carcinomas.

Background: Invasive solid papillary carcinomas (ISPC) are rare malignant neoplasms in the classification of WHO 2019 breast tumors. Aims: We aimed to investigate the correlations between programmed cell death ligand-1 (PD-L1) expression status of tumor and immune cells and clinicopathological parameters by molecular classification of this rare morphological subtype. This study will contribute to the literature about the PD-L1 expression state of ISPCs for the first time. Material and Methods: The study included 19 invasive solid papillary carcinoma cases diagnosed between 2009 and 2019 in Pathology Department. Molecular subtyping was performed in 19 cases by immunohistochemical studies (ER/PR, Her-2/neu, Ki-67), and PD-L1 expression was evaluated in neoplastic and immune cells. Results: PD-L1 expression was detected in 4 (21%) cases, 3 (75%) of them were in luminal B and 1 (25%) were in the luminal A group. The correlation between molecular subtypes and PD-L1 expression was statistically significant (P = 0.016). Patients with PD-L1 expression had a higher Ki-67 index than patients without PD-L1 expression (P = 0.037). In addition, there was a statistically significant correlation between PD-L1 expressions of intratumoral lymphocytes and PD-L1 expressions of neoplastic cells (P = 0.004). Conclusions: While predicting the group that will benefit more from immunotherapy in solid papillary carcinoma cases, not only PD-L1 expression of tumor cells but also PD-L1 expression in tumor infiltrating lymphocyte (TIL) can help. In addition, PD-L1 staining rates of tumor cells as well as clinicopathological parameters (molecular subtype, high Ki-67 index, presence of TIL) can be predictive about immunotherapy.

Angiokeratoma of the clitoris with evident vulvar varicosity.

Angiokeratomas of the vulva are uncommon, benign vascular lesions that are generally located on the labia. However, the clitoris is an extremely rare location, with only three published cases. We report a case of clitoral angiokeratoma in a 22-year-old nulligravida with a history of surgery to remove a clitoral mass at 6 years of age. The case described herein is distinguished from the other case reports by an accompanying varicose structure involving the vulva.

A comparison between unifocal papillary thyroid microcarcinoma with noninvasive follicular thyroid neoplasm with papillary-like nuclear features and other patterns: A retrospective clinicopathological study.

BACKGROUND: Papillary thyroid microcarcinoma (mPTC) is defined as a tumor with low malignancy potential. Different treatment protocols have been used at different centers for analyzing this tumor which has common recurrence and metastasis rates. Consequently, in 2016, the definition of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was accepted which included the lesions > cm. It is important to explain the clinical course and appropriate treatment options for mPTC and its subtypes. AIMS: In this study, we aimed to describe the clinical course of mPTC with and without NIFTP and to determine different risk groups among these subtypes. MATERIAL AND METHODS: We performed microscopic reexamination of about 280 unifocal mPTCs retrieved from our archives between 2007-2018 and analyzed the results of morphological and clinical comparison among these cases that had 0-11-years of clinical follow-up. RESULTS: Among 280 unifocal mPTCs, 127 cases (45.4%) had classical morphology, 58 (20.7%) had NIFTP, 53 (18.9%) had infiltrative pattern, 27 (9.6%) had oncocytic pattern, 12 (4.3%) showed capsular invasion, and 3 (1.1%) showed other morphologies. Seven patients were detected with lymph node metastasis and one with distant metastasis at diagnosis. Lymph node metastasis (recurrence) was postoperatively detected in five patients. All patients with recurrence were women. Moreover, three of these patients were in their 30s and two in 70s. The median diameter of the tumor was 3 mm. Both invasive and noninvasive cases have recurred. CONCLUSION: Contrary to the results of the previous studies, the results of our study did not confirm the indolent course of mPTC with NIFTP. However, metastasis was detected both at the time of diagnosis and during the postoperative period. The malignancy potential of these tumors may not be low. Therefore, more clinicopathological and molecular studies are needed to determine the biological behavior of mPTC cases with different histology.

Investigation of Relationship Between Hypoxic Process and Cancer Stem Cells in Meningioma.

AIM: To investigate the relationship between cancer stem cells (CD133 and CD44) and HIF1? expression in meningioma. MATERIAL AND METHODS: In an immunohistochemistry experiment, three expert pathologists examined 100 meningioma slides stained for HIF1?, CD133, and CD44 antibodies. Statistical analyses were performed using the SPSS 23 Statistics packet program. P values < 0.05 were statistically significant. RESULTS: HIF1? staining was correlated with high grade (Grade 2) meningioma. Cytoplasmic staining was negatively correlated with meningioma grade. High grade meningioma was positive for nuclear HIF1? and showed increased cytoplasmic expression of CD44 and CD133. CONCLUSION: In accordance with previous studies, the level of hypoxia and HIF1? were correlated with meningioma grade. Furthermore, expression of HIF1? was correlated with expression of CD133 and CD44, which are cancer stem cell surface markers, as well as with meningioma grade. In light of these data, new treatment modalities related to CD44 and CD133 stem cell markers and to HIF1? may be developed.

Choroid plexus papilloma in extragonadal teratoma with predominantly neurogenic elements: a case report and review of the literature.

BACKGROUND: Teratoma is a germ cell tumor that develops gonadal or extragonadal. Benign or malign somatic tumors can develop in teratoma. Choroid plexus papilloma is a benign, grade I intraventricular neoplasm that occur mostly in children. Choroid plexus papilloma in a teratoma is not often seen. CASE: We present the fifth case of a choroid plexus papilloma in a teratoma in the English literature. It was extragonadal and localized on the right side of the neck. It included only neuroglial tissue. CONCLUSION: It is important to separate a teratoma with normal choroid plexus from a teratoma with choroid plexus tumor. Pathologists need to be aware of this entity in the distinction from other papillary neoplasms that may be primary or metastatic.

Interobserver Variability in Mitotic Count for Meningioma Grading: How Can We Reduce It?

AIM: To evaluate the interobserver variability in determining the number of mitoses in 10 high-power field (HPF) and thus the tumor grade, and to investigate how to reduce grade discordance between the observers and the most useful method to identify the patients who would receive an additional treatment. MATERIAL AND METHODS: Two hundred and seventy cases with meningioma were re-evaluated by three experienced pathologists and five senior residents. They determined the number of mitotic figures in 10 HPF in each slide. Re-evaluation of the cases, which were found of different grades from the reference observers was requested by full scan method. Statistical analysis was performed by using SPSS V23.0. RESULTS: A moderate agreement was found between the observers and the reference observer. After the evaluation of mitotic activity with the full scan method, the mean numbers of mitoses found by the observers in 10 HPF were increased. In the first evaluation, 4?6 cases were defined as Grade II by the observers. Whereas, 23?27 cases were defined as Grade II after the full scan method. CONCLUSION: If there are less than 16 mitotic figures throughout the slide, it is more difficult to find the 10 HPF including 4 or more mitosis. Interobserver variability in mitotic figure counting can be reduced by full scan method, and examining the hematoxylin and eosin stained slides by the full scan method helps us to determine the true histologic grade of meningiomas in most cases, who would receive an additional treatment.

WITHDRAWN:Interobserver Variability in Mitotic Count for Meningioma Grading: How Can We Reduce It?

Ahead of Print article withdrawn by publisher.

Incidental retroperitoneal oncocytoma (Ectopic oncocytic adrenocortical adenoma): Case report and review of the literature.

Ectopic adrenocortical tissue may be present in many anatomical localizations. Hyperplasia, adenoma or carcinoma can occasionally develop from the ectopic adrenal tissue. Therefore, it should be surgically excised when it is detected. Adrenocortical tumors are the most common type of adrenal neoplasms. Ectopic adrenocortical adenomas are rarely seen. A total of 34 cases of ectopic adrenocortical adenoma (14 of which are oncocytomas) have been reported at different localizations in English literature. Most of them are non-functional. Differential diagnosis is required with other benign or malign oncocytic neoplasms. We report a 56-year-old male patient, who presented with a retroperitoneal mass. Our case is the seventh case of ectopic retroperitoneal adrenal adenoma with oncocytic cells.

Intraoperative Consultations of Central Nervous System Tumors: A Review for Practicing Pathologists and Testing of an Algorithmic Approach.

Intraoperative consultations or frozen sections for central nervous system (CNS) tumors present a significant challenge for surgical pathologists because of their relative rarity and diversity. Yet, such lesions are encountered by every surgical pathologist, and a basic understanding of clinical, radiological and genetic information is critical to successfully evaluate CNS frozen sections. It is often beneficial to have a systematic approach or an algorithm, and to be aware of the common pitfalls and mimickers when dealing with these lesions. We propose such an algorithm in an effort to construct a sensible approach to CNS frozen sections that considers recent developments in the WHO CNS tumor classification. The algorithm was developed for surgical pathologists who are occasionally faced with making diagnosis of CNS tumors on frozen sections. To test the algorithm and its practicability, we selected a group of tumors among a total of 3288 consecutive intraoperative consultations performed at UCSF between 2013 and 2017. The selected cases represented lesions that may be encountered in everyday surgical pathology and constituted a fair reflection of the main group. The algorithm was used by three of the authors who did not have formal neuropathology training and had been in surgical pathology practice for at least 3 years. There was a very high level of concordance among the authors' diagnosis (interobserver concordance: 0.83-0.97-kappa value) using the algorithm with high intraobserver reliability (concordance 93%, p < 0.001). We suggest that an algorithmic approach is an effective means for the surgical pathologists, and may help reach diagnosis during frozen sections.