PD-L1 Assessment in Needle Core Biopsies of Non-Small Cell Lung Cancer: Interpathologist Agreement and Potential Associated Histopathological Features.

OBJECTIVE: Immune checkpoint inhibitors are used in the treatment of non-small cell lung cancer (NSCLC). Programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) assessed by pathologists is subject to interobserver variability. In advanced/metastatic disease and inoperable patients, PD-L1 assessment relies on biopsy specimens, commonly needle core biopsies (NCB). We aimed to determine the interobserver agreement for PD-L1 tumor proportion score (TPS) in NSCLC NCBs and identify histopathological features that may be related to interobserver variability. MATERIAL AND METHODS: Sixty NSCLC NCBs with PD-L1 IHC were evaluated independently by four pathologists from different institutions. PD-L1 TPS was evaluated in three categories: no/low expression ( < 1%), intermediate expression (1%49%), and high expression (≥50%). Histological tumor type, necrosis, tumor-infiltrating lymphocytes, tumor length/percentage in the biopsy, and crush/squeeze artifact was evaluated. RESULTS: The statistical analysis of the three PD-L1 TPS categories demonstrated moderate agreement (Fleiss Kappa 0.477) in the no/low category, fair agreement (Fleiss Kappa 0.390) in the intermediate category, and almost perfect agreement (Fleiss Kappa 0.952) in the high category. A significant correlation (p=0.003) was found between the crush/squeeze artifact in NCB and rate of discordant TPS categories. There was no significant correlation between pathologists' agreement in the TPS categories and histological tumor type, tumor length, tumor ratio, necrosis, and tumor-infiltrating lymphocytes. CONCLUSION: Our results demonstrated moderate agreement among pathologists for the PD-L1 TPS 1% cut-off in NSCLC NCB, which is lower than that reported in resection materials. The presence of crush/squeeze artifact in NCBs is significantly related to the rate of discordant TPS categories, suggesting that PD-L1 assessment of pulmonary NCBs requires an awareness of this artifact.

Expression of cytotoxic T lymphocyte-associated antigen 4, CD44, and E-cadherin in the microenvironment of breast carcinomas.

OBJECTIVE: The expression of cytotoxic T lymphocyte-associated antigen 4, E-cadherin, and CD44 in the area of tumor budding was investigated in breast carcinomas in our study. METHODS: Tumor budding was counted at the invasive margins in 179 breast carcinomas. To understand the microenvironment of tumor budding, we examined the expression status of the immune checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4, E-cadherin, and CD44. RESULTS: Tumors were separated into low (≤5) and high tumor budding groups (>5) based on the median budding number. Lymphovascular, perineural invasion, and the number of metastatic lymph nodes were significantly higher in high-grade budding tumors (p=0.001, p<0.001, and p=0.019, respectively). Tumor-infiltrating lymphocytes were significantly higher in tumors without tumor buddings (p<0.001). When the number of budding increases by one unit, overall survival decreases by 1.07 times (p=0.013). Also, it increases the risk of progression by 1.06 times (p=0.048). In high tumor budding groups, the cytotoxic T lymphocyte-associated antigen 4 staining percentage of lymphocytes was significantly higher (p=0.026). With each increase in the number of buds, an increase in the percentage of cytotoxic T lymphocyte-associated antigen 4 staining was seen in lymphocytes in the microenvironment of TB (p=0.034). CONCLUSION: Tumor budding could predict poor prognosis in breast carcinomas, and anti-cytotoxic T lymphocyte-associated antigen 4 immunotherapies may be beneficial in patients with high tumor budding tumors.

Expression of cytotoxic T lymphocyte-associated antigen 4, CD44, and E-cadherin in the microenvironment of breast carcinomas

SUMMARY OBJECTIVE: The expression of cytotoxic T lymphocyte-associated antigen 4, E-cadherin, and CD44 in the area of tumor budding was investigated in breast carcinomas in our study. METHODS: Tumor budding was counted at the invasive margins in 179 breast carcinomas. To understand the microenvironment of tumor budding, we examined the expression status of the immune checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4, E-cadherin, and CD44. RESULTS: Tumors were separated into low (≤5) and high tumor budding groups (>5) based on the median budding number. Lymphovascular, perineural invasion, and the number of metastatic lymph nodes were significantly higher in high-grade budding tumors (p=0.001, p<0.001, and p=0.019, respectively). Tumor-infiltrating lymphocytes were significantly higher in tumors without tumor buddings (p<0.001). When the number of budding increases by one unit, overall survival decreases by 1.07 times (p=0.013). Also, it increases the risk of progression by 1.06 times (p=0.048). In high tumor budding groups, the cytotoxic T lymphocyte-associated antigen 4 staining percentage of lymphocytes was significantly higher (p=0.026). With each increase in the number of buds, an increase in the percentage of cytotoxic T lymphocyte-associated antigen 4 staining was seen in lymphocytes in the microenvironment of TB (p=0.034). CONCLUSION: Tumor budding could predict poor prognosis in breast carcinomas, and anti-cytotoxic T lymphocyte-associated antigen 4 immunotherapies may be beneficial in patients with high tumor budding tumors.

Investigation of the Presence of Integrin Alpha-3 and Beta-1 Receptors on Tumor Tissue, Metastatic Lymph Node and Normal Tissue in Thyroid Cancer.

Objectives: The important roles of integrins in tumor invasion, migration and proliferation are well known. In this study, we investigated the presence of integrin α3 and ß1 receptors in tumor tissue, metastatic lymph node (LN) and normal thyroid tissue of patients diagnosed with thyroid cancer (TCa) and showed the prognostic and diagnostic value of these molecules as well as peptide-receptor. Methods: Sixty-one patients with TCa were included in this study. The presence of integrin α3 and ß1 expression was investigated by immunohistochemical methods from tumor tissue after total thyroidectomy. TNM system was used in tumor staging. The relationship between prognostic properties such as tumor size, LN metastasis, capsular invasion and the presence of integrin α3 and ß1 expression was investigated. Results: Classical type papillary TCa was the most common subtype in our study group with 31.1%. Integrin ß1 was expressed in 4.9% (n=3) of normal tissue, 57.4% (n=35) of tumor tissue and 16.4% (n=10) of metastatic LN; integrin α3 was expressed in 50.8% (n=31) of normal tissue, 67.2% (n=41) of tumor tissue and 9.8% (n=6) metastatic LN. Integrin ß1 expression was observed 21.3% (n=13), integrin α3 in 14.8% (n=9) and integrin α3 and ß1 expression in 36.1% (n=22). Integrin ß1 expression increased statistically significantly in the presence of LN metastasis and capsular invasion (p=0.022, 0.014, respectively). Furthermore, the expression of integrin α3 was found to be statistically significant in primary tumors of patients with LN metastasis (p=0.045). Conclusion: Our study showed a significant increase in integrin α3 and ß1 expression in LN metastasis or thyroid capsule invasion in tumor. Thus, it appears that the demonstration of the presence of integrin α3 and ß1 expression in TCa is not only a prognostic biomarker but also has value as a potential theranostic target with peptide-bound radioactive agents.

Alternative volumetric PET pjmirometers for evaluation of breast cancer cases with 18F-FDG PET/CT imaging: Metabolic tumour volume and total lesion glycolysis.

INTRODUCTION: We aimed to investigate the prognostic and clinical values of two volumetric PET pjmirometers used in conjunction with SUVmax at different thresholds in invasive ductal carcinoma (IDC). METHODS: A total of 139 metastatic IDC BC who underwent 18F-FDG PET/CT imaging were included to study. MTV and TLG (40%, 50%, 60% and 70%) used in conjunction with primary tumour SUVmax . Nodal involvement, distant metastasis, ER, PR, Ki-67 expression and survival data evaluated by comparing FDG PET pjmirometers. RESULTS: Mean ± SD SUVmax of lesions (n = 139) was 13.97 ± 9.21. Primary tumour 18F-FDG uptake associated increased tumour diameter (>2 cm), high Ki-67 (>15%) and distant organ metastasis (DOM) (P = 0.015, 0.005 and 0.016, respectively). There was significant association between molecular subtypes and SUVmax (P = 0.002). High MTV associated with tumour diameter (MTV 40-70%), axillary lymph node (ALN) diameter (MTV 40-70%), and distant nodal metastasis (DNM) (MTV 50-70%). High TLG associated with tumour diameter (TLG 40-70%), high Ki-67 (TLG 40-70%), ALN metastasis (TLG 40%), ALN diameter (TLG 40-70%) and DNM (TLG 40-70%). Median survival found shorter in DOM patients (P = 0.030, Log Rank = 0.110). CONCLUSION: We think evaluation of MTV and TLG at different thresholds in addition to SUVmax would enhance diagnostic and prognostic value of 18F-FDG PET/CT, and thus contribute to disease management.

Histopathological and Clinical Differences Between Primary Breast Carcinomas With Neuroendocrine Features and Primary Breast Carcinomas Mimicking Neuroendocrine Features.

We aimed to determine the histopathological differences between primary breast carcinomas with neuroendocrine features (NEBC) and carcinomas mimicking neuroendocrine features (NEBC-like). Twenty-three cases with NEBC, all showing positive staining for synaptophysin and/or chromogranin-A in ≥50% of tumor cells and 36 cases with NEBC-like (no staining for neuroendocrine [NE] markers but suspicious for NE morphology in terms of solid/trabecular growth patterns) were included in the study. Significant differences were found between the groups in terms of the patients' ages, histologic/nuclear grade of tumor, lymphovascular invasion, comedo-type ductal carcinoma in situ (DCIS), microcalcification, Ki-67 proliferation index, nuclear shape, and level of peritumoral lymphocytic infiltration. The presence of large-size solid cohesive groups of tumor cells; plasmocytoid, spindle, and/or columnar shapes of tumor cells; and eosinophilic-granular appearance of cytoplasm were mostly noted in the NEBC group. The presence of small- to medium-sized solid cohesive groups of tumor cells; high-grade histologic and nuclear features; clear cytoplasm; and round to ovoid nucleus were mostly noted in the NEBC-like group. No significant differences were found in terms of tumor size, ER/PR/HER2 status, as well as the presence of DCIS, elastosis, extracellular/intracellular mucin, signet ring cells, apocrine features, and accompanying papilloma or ductal ectasia. In conclusion, small- to medium-sized solid cohesive groups of tumor cells, high-grade features, clear cytoplasm, round to ovoid shape of nucleus, lymphovascular invasion, comedo-type DCIS, microcalcification, high level of Ki-67 proliferation index (≥20%), and moderate/strong level of peritumoral lymphocytic infiltration might support non-NE features in breast carcinomas.

A new immunohistochemical marker, insulinoma-associated protein 1 (INSM1), for Merkel cell carcinoma: Evaluation of 24 cases.

Merkel cell carcinoma (MCC) is an uncommon primary neuroendocrine carcinoma of the skin. Nowadays, pathologists are required to perform immunohistochemistry to demonstrate neuroendocrine and epithelial differentiation for diagnosis of MCC. Insulinoma-associated protein 1 (INSM1) is a zinc-finger transcription factor expressed in tissues undergoing terminal neuroendocrine differentiation, and INSM1 immunohistochemistry is a well-validated nuclear marker of neuroendocrine differentiation. We evaluated 24 cases of MCC for the expression of INSM1 and compared it with frequently used neuroendocrine markers, Chromogranin A, Synaptophysin, and CD56. INSM1 was positive in all cases, and its expression was stronger, more extensive, clean and homogeneous compared to other markers. As a consequence, INSM1 can be used to serve as a solitary marker for neuroendocrine differentiation due to high sensitivity and specificity in MCC cases.

Palisaded Encapsulated (Solitary Circumscribed) Neuroma: A Review of 30 Cases.

Background. Solitary circumscribed neuroma (SCN), also known as palisaded encapsulated neuroma (PEN), is a benign neural tumor. It may be mistaken as either schwannoma or neurofibroma in pathology practice. In this study, we aimed to define clinicopathologic and immunohistochemical features and discuss its differential diagnosis. Materials and Methods. The histopathological features of 30 cases of SCN/PEN were reviewed. The presence of intralesional axons, Schwann, and perineural cell distributions were investigated by performing neuronal immunomarkers. Results. Twelve cases were females, and 18 cases were males. The mean age was 48 years. Lesions were mostly located on the face (27/30). Histologically, 18 had a lobular pattern, 9 were plexiform, 2 fungating, and 1 multilobular. Although the majority of cases were well circumscribed, capsular integrity was at least focally disrupted (73%). Verocay body was noted only in 6 cases (20%). One case showed excessive hyperkeratosis, forming a keratin horn. Adipocytic change was detected in another case. The lesions consisted of S100-positive Schwann cell proliferation and were partially surrounded by perineural cells highlighted by EMA or Claudin-1. The amount of intralesional axons revealed by neurofilament immunostaining was variable. Conclusion. SCN/PEN is a relatively common lesion, and usually seen as an asymptomatic papule on the face of elderly patients. A circumscribed lesion composed of bundles of bland-looking spindle cells thought to be of neural origin is seen in the dermis. Pathologists should be aware of the existence of plexiform and multilobular PEN/SCN variants, to avoid misdiagnosis of plexiform neurofibroma or schwannoma.