High grade tumor budding is associated with poor survival in pathologic stage I lung adenocarcinoma.

AIM: Tumor budding is a significant prognostic parameter that has been related to aggressive behavior in early-stage tumors of various origins. The aim of this study was to evaluate the clinicopathological significance of tumor budding in pathologic stage (pStage) I lung adenocarcinomas. METHODS: This study comprised 107 patients who underwent curative resection for pStage I lung adenocarcinomas at our hospital between December 2010 and January 2016. We examined tumor budding on routine hematoxylin and eosin (H&E) slides from resected specimens. Tumors were categorized into two groups based on the degree of tumor budding: low grade (grade 0-1) and high grade (grade 2-3). We evaluated the relationship between tumor budding and overall survival (OS), disease-free survival (DFS) and clinicopathological parameters. RESULTS: There is a significant difference (p = 0.002) between the 5-year DFS rates of the high-grade and the low-grade tumor budding group, which were 70 % and 90 %, respectively. High-grade tumor budding positive patients from the same pathological stage (p < 0.001; HR = 2.93 [1.51-5.68]) and clinical stage (p = 0.002) had poorer cumulative survival rates than low grade tumor budding positive patients. High grade tumor budding was positively associated with spread through air spaces (STAS) (p < 0 0.001), lymphovascular invasion (LVI) (p < 0.001), tumor necrosis (p < 0.001), high SUVmax value (SUVmax>3.0) (p < 0.001), and tumor size >20 mm (p = 0.024). High-grade tumor budding was significant prognostic factor of OS (p < 0.006) and DFS (p < 0.001) on univariate Cox regression hazard model analysis. However, it did not show significance in the multivariate analysis (p > 0.05). CONCLUSIONS: High-grade tumor budding is an independent prognostic factor and associated with adverse clinicopathological features and poor survival rates. We proposed that high-grade tumor budding should be recognized as a new prognostic parameter and will be beneficial in predicting the clinical course in pStage I lung adenocarcinomas.

Thymoquinone Inhibits Proliferation and Migration of MDA-MB-231 Triple Negative Breast Cancer Cells by Suppressing Autophagy, Beclin-1 and LC3.

BACKGROUND: Triple Negative Breast Cancer (TNBC) is an aggressive and highly heterogeneous subtype of breast cancer associated with poor prognosis. A better understanding of the biology of this complex cancer is needed to develop novel therapeutic strategies for the improvement of patient survival. We have previously demonstrated that Thymoquinone (TQ), the major phenolic compound found in Nigella sativa, induces anti-proliferative and anti-metastatic effects and inhibits in vivo tumor growth in orthotopic TNBC models in mice. Also, we have previously shown that Beclin-1 and LC3 autophagy genes contributes to TNBC cell proliferation, migration and invasion, suggesting that Beclin-1 and LC3 genes provide proto-oncogenic effects in TNBC. However, the role of Beclin-1 and LC3 in mediating TQ-induced anti-tumor effects in TNBC is not known. OBJECTIVE: To investigate the effects of TQ on the major autophagy mediators, Beclin-1 and LC3 expression, as well as autophagic activity in TNBC cells. METHODS: Cell proliferation, colony formation, migration and autophagy activity were evaluated using MTS cell viability, colony formation assay, wound healing and acridine orange staining assays, respectively. Western blotting and RT-PCR assays were used to investigate LC3 and Beclin-1 protein and gene expressions, respectively, in MDA-MB-231 TNBC cells in response to TQ treatments. RESULTS: TQ treatment significantly inhibited cell proliferation, colony formation, migration and autophagic activity of MDA-MB-231 cells and suppressed LC3 and Beclin-1 expressions. Furthermore, TQ treatment led to the inhibition of Integrin-ß1, VEGF, MMP-2 and MMP-9 in TNBC cells. CONCLUSION: TQ inhibits autophagic activity and expression of Beclin-1 and LC3 in TNBC cells and suppresses pathways related to cell migration/invasion and angiogenesis, including Integrin-ß1, VEGF, MMP-2 and MMP- 9, suggesting that TQ may be used to control autophagic activity and oncogenic signaling in TNBC.

Increased micronucleus count predicts malignant behavior in pleural effusion fluid

Background/aim: Micronucleus (MN) frequency is used as a biomarker of chromosomal damage, genome instability, and cancer risk. The aim of this study was to evaluate the diagnostic usefulness of MN frequency to differentiate between malignant and benign pleural effusion samples. Materials and methods: Retrospectively, 78 pleural fluid cytology samples (including 20 cases of benign reactive mesothelial cells, 22 cases of suspicious cytology, and 36 cases of malignant cytology) were examined. The number of micronucleated cells in 1000 well- preserved cells was counted. Statistical tests were performed to compare the study groups. Recover operating characteristics (ROC) curve analysis was performed to suggest a cut-off value for predicting malignant behavior. Results: We evaluated a total of 78 cases of pleural effusion cytology. The number of micronucleated cells was significantly higher in cases with malignant outcome compared to cases with benign outcome. We observed that malignant samples had more micronucleated cells than suspicious ones, and suspicious cases had more micronucleated cells than reactive ones. There was a significant difference among all study groups. In addition, the frequency of MN-containing cells in suspicious cases correlates well with their outcomes. Conclusion: The results of this study reveal that there is an absolute, consistent, and proportional relationship between MN counts and malignancy in cytological samples of pleural effusions. MN scoring may be a helpful diagnostic tool for distinguishing malignant effusions from benign ones, and may be used as an adjunct tool to predict malignant behavior in challenging cases.

Prognostic Value of Cancer Stem Cell Markers CD44 and ALDH1/2 in Gastric Cancer Cases

Purpose: To determine expression levels of CD44 and ALDH1/2, known cancer stem cell (CSC) markers, in stomach adenocarcinomas and assess relationships with clinicopathologic parameters and prognosis. Methods: Eighty patients diagnosed with gastric cancer between the years 2011-2015 were included in this study of clinicopathologic characteristics, postoperative prognostic indexes and stem cell marker CD44 and ALDH1/2 expression in paraffin-embedded tumour sections analyzed immunohistochemically. Clinicopathologic parameters were evaluated using the chi-square test and t-test. Survival analyses were conducted using Kaplan-Meier statistics. Results: We observed positive CD44 and ALDH1/2 staining in 45.0 % and 67.5% of tumour tissues, respectively, but not in normal gastric mucosa. Recurrence-free survival (RFS) was found to be shorter in cases with high levels of CD44 expression (p=0.004). Similarly, short RFS was observed in patients with high levels of CD44 and ALDH1/2 co-expression (p=0.004). Furthermore, tumour invasion depth was found to correlate with high CD44 and ALDH1/2 co-expression (p=0.028). Conclusion: The cancer stem cell markers CD44 and ALDH1/2 may indicate poor patient prognosis and play a role in tumour development and invasion.

Micronuclei and nuclear buds: Highlighting overlooked indicators of chromosomal damage in thyroid aspiration smears.

BACKGROUND: We aimed to examine the diagnostic utility of micronuclei (MN) and nuclear buds (NBs) in aspiration smears of the well-differentiated epithelial lesions of thyroid. METHODS: One hundred five cases composed of 34 follicular nodular disease (FND), 31 Hashimoto's thyroiditis (HT), and 40 papillary thyroid carcinoma (PTC) were compiled retrospectively. May- Grünwald Giemsa (MGG) stained smears of each case were selected to count cells with nuclear protrusions (NPs) per 1000 cells. The frequency of cells with NPs (MN&NBs) was compared by using Mann-Whitney U test and Kruskal-Wallis tests when appropriate. Post-Hoc Tukey test was used for pairwise comparison of different diagnostic categories. By running a ROC curve analysis, diagnostic usefulness of the frequency of cells with NPs (MN&NBs) and their cut-off values to predict malignant behavior were calculated. P < 0.05 was regarded as significant. RESULTS: NPs (MN&NBs) were significantly more frequent in malignant cases than benign ones. NBs were more frequent in conventional PTC compared to FV of PTC, but the frequency of MN did not significantly differ between these. ROC curve analysis revealed that evaluation of the frequency of cells with NPs (MN&NBs) was a highly specific, sensitive, and diagnostically useful method to identify malignant behavior. CONCLUSION: To the best of our knowledge, this is the first study in the literature to evaluate the frequency of cells with NPs (MN&NBs) in human thyroid aspiration smears. Our results show that evaluation of NPs (MN&NBs) may be a useful diagnostic tool to detect PTC in thyroid aspiration smears. Diagn. Cytopathol. 2017;45:673-680. © 2017 Wiley Periodicals, Inc.

Immunohistochemical expression profiles of BRAF (V600E/VE1) in serrated colon polyps in Turkish population.

BACKGROUND AND AIM: Colon carcinoma, as one of the most common cancers, has been investigated for genetic alterations. Besides well-known adenoma-carcinoma sequence, it is recently found that BRAF mutation had an important role particularly in early stages of adenocarcinomas with serrated features. There are no any studies concerning immunohistochemical expression status of BRAF V600E (VE1) antibody in serrated polyps in the Turkish population. The objective of this study is to observe the immunohistochemical staining of BRAF V600E (VE1) antibody in colon polyps in the Turkish population and investigate the frequency of presence of mutated BRAF proteins indicating malignant potential. MATERIALS AND METHODS: 59 cases of serrated polyps (27 cases of hyperplastic polyps, 18 cases of sessile serrated adenoma/polyps and 14 cases of traditional serrated adenomas) and 10 tubular adenomas, and 10 samples of normal colonic mucosa were immunohistochemically evaluated for the presence of BRAF V600E mutated proteins with the VE1 antibody. Results were statistically compared. RESULTS: All SSA/Ps; 92.8% of TSAs; 37% of HPs were stained positively. Of the 27 hyperplastic polyps, all GCHPs were negative but 10 of 12 MVHPs (83.3%) were weakly positive with the VE1 antibody. Cases in control groups and tubular adenomas didn't show any cytoplasmic staining. CONCLUSION: Serrated adenoma/polyps have been gaining much more importance because of their malignant potential. Their frequency is also relatively high in the Turkish population and they should be carefully handled. Detection of BRAF V600E status can be easily achieved immunohistochemically by VE1 antibody. It is easily applicable and reproducible method and it might be helpful in identifying serrated lesions of the colon in addition to morphological features.

A Rare Cause of Nasal Obstruction: Metastatic Renal Cell Carcinoma.

Introduction. Renal cell carcinoma can present with several interesting symptoms, paraneoplastic syndromes, and unusual metastatic sites. Head and neck region is one of the rare locations for renal cell carcinoma metastasis. Case Report. A 50-year-old man was admitted to the hospital with nasal congestion and snoring. Physical examination revealed nasal serous secretion. First taken biopsy was misinterpreted. The symptoms of the patient were not revealed and he was readmitted to the hospital. On radiologic examination, a vascular rich mass in maxillary sinus extending to the nasal cavity was observed. Biopsy was diagnosed as renal cell carcinoma metastasis. Herein, we present a patient with renal cell carcinoma presenting nasal obstruction and snoring as first and recurrent symptom.

Cytogenetic damage of radiotherapy in long-term head and neck cancer survivors.

PURPOSE: To evaluate cytogenetic damage of radiotherapy (RT) and chemoradiotherapy (CRT) in long-term head and neck cancer survivors. MATERIALS AND METHODS: This study included 20 patients treated with RT (10 patients) or CRT (10 patients) for head and neck cancer. Nine healthy volunteers were included as control subjects. Cytochalasin B-blocked micronucleus (CBMN) assay was used to evaluate cytogenetic damage. To evaluate micronucleus (MN) by CBMN, the venous blood samples were drawn median 68 months (range 60-239 months) after the completion of treatment (RT or CRT) for head and neck cancer. RESULTS: Nuclear division index (NDI) and number of MN in mononuclear and binuclear lymphocytes were significantly higher in patients with head and neck cancer than in control subjects [1.19 (1.08-1.47) vs. 1.07 (1.04-1.14), p < 0.001; 11.0 (2.0-22.0) vs. 1.0 (0-3.0), p < 0.001 and 15.0 (5.0-45.0) vs. 9.0 (2.0-15.0), p = 0.020, respectively]. NDI and number of MN in mononuclear lymphocytes were significantly lower in control subjects compared patients received CRT and those received only RT, but there was no significant difference between patients received CRT and those received only RT. Number of MN in binuclear lymphocytes was significantly lower in control subjects compared to patients received CRT, but there was no significant difference between control subjects and those received only RT. Also there was no significant difference between patients received CRT and those received only RT in terms of number of MN in binuclear lymphocytes. CONCLUSIONS: MN frequency of mononuclear and binuclear lymphocytes in medical follow-up of patients with head and neck cancer after RT could be important in evaluating cytogenetic damage of RT. However, further investigations are needed to provide quantitative correlations between MN yields and the clinical features in post-radiotherapy period.

Spontaneous Acroangiodermatitis.

Acroangiodermatitis is a rare self-limited angioproliferative lesion which can be associated with congenital vascular malformations or acquired venous insufficiency. Despite of its benign character, differential diagnosis of this lesion is very important because it closely resembles Kaposi sarcoma. Here we present a 26-year-old male patient with unilateral, purplish-red colored papules on his right ankle which diagnosed as acroangiodermatitis and discuss histopathological features, differential diagnosis and treatment of this unusual condition.

Emerin expression in well differentiated epithelial lesions of thyroid: implications in papillary thyroid carcinoma diagnosis and predicting malignant behavior.

Recently, it has been reported that identifying nuclear membrane irregularities with anti-emerin antibody is useful for papillary thyroid carcinoma diagnosis. However, literature regarding the significance of emerin immunohistochemistry in thyroid is limited. We evaluated the diagnostic accuracy of the well-established nuclear alterations, nuclear protrusions and recently described nuclear shapes (garlands and star-like shapes) with emerin immunohistochemistry and hematoxylin- eosin stain in thyroid lesions. We further evaluated the diagnostic accuracy measures of tissue microarrays evaluated with both stains, to detect whether emerin immunohistochemistry improves the diagnostic accuracy for papillary thyroid carcinoma. For papillary thyroid carcinoma, pseudo- inclusions were best performers with emerin (diagnostic accuracy: 0.91), whereas with hematoxylin- eosin diagnostic accuracy of grooves was the highest (0.92). For follicular variant of papillary thyroid carcinoma, with both stains, predominately oval nuclear shape had the best diagnostic performance (diagnostic accuracy: 0.95). Nuclear protrusions were poor identifiers for papillary thyroid carcinoma. However, with emerin immunohistochemistry, they could successfully identify malignancy in 83% of the cases. Using emerin immunohistochemistry, in addition to hematoxylin- eosin improved the diagnostic accuracy for papillary thyroid carcinoma when compared to hematoxylin- eosin evaluation only (sensitivity: 0.70 vs 0.86, negative predictive value: 0.81 vs. 0.94, diagnostic accuracy: 0.87 vs. 0.94). Consistent with the previous literature, our findings indicate that emerin immunohistochemistry may be used as an adjunct diagnostic method to identify papillary thyroid carcinoma. Additionally, we suggest that nuclear protrusions detected with emerin imunohistochemistry may be used as indicators of malignant behavior in small tissue samples of thyroid.

Phenytoin induced toxic epidermal necrolysis.

Toxic Epidermal Necrolysis (TEN) which is characterized by the detachment of the epidermis from the dermis is a rare (1.89/1.000.000 annually) and potentially life-threatening condition. The overall mortality is 20 - 30%. TEN is characterized by sudden apoptosis of keratinocytes leading to mucous membrane erosions and epidermal detachment; detachment of less than 10% of the total body surface area defines Stevens-Johnson Syndrome (SJS); when greater than 30%, it defines TEN, while intermediate cases are called SJS/TEN overlap. Many drugs, including prednisolone, cyclosporin, and intravenous immunoglobulin (IVIG), have been used in an attempt to halt the disease process. The use of phenytoin as a prophylactic anticonvulsant after brain surgery, particularly for brain tumors, is a common practice, regardless of whether the patient has a previous history of convulsions. This report described a case of haemorrhagic stroke where phenytoin use induced TEN.

The diagnostic importance of matrix metalloproteinase-7 and nestin in gastrointestinal stromal tumors.

BACKGROUND: The importance of the matrix metalloproteinase-7 (MMP-7) and nestin immunomarkers, C-kit proto-oncogene (CD117), and the efficiency of the Ki-67 proliferation index for gastrointestinal stromal tumors were evaluated. MATERIAL AND METHODS: This study was conducted by examining the microscope slides of 72 patients with gastrointestinal stromal tumors that were sent to the pathology laboratory between 2007 and 2012. Immunohistochemical staining for CD117, MMP-7, nestin, and marker of proliferation Ki-67 was performed. The correlations between the positive results for Ki-67, CD117, MMP-7, and nestin were evaluated relative to the tumor characteristics of size, localization, grade, cellular type, cellularity, cytology type, growth pattern, ulceration, necrosis, hemorrhage, invasion depth, and lymph node metastasis. RESULTS: The tumor was localized in the stomach in 42 of the patients, the intestines in 19, the colon in 7, and the rectum in 4. Comparisons among the groups showed that MMP-7 was correlated with the tumor grade (p<0.001), cellularity (p<0.009), cytologic atypia (p<0.001), ulceration (p=0.002), necrosis (p<0.001), and tumor size (p=0.001). Nestin was correlated with the tumor grade (p=0.013), and tumor size (p=0.024). Correlations among CD117, MMP-7, nestin, and Ki-67 were examined. Nestin and Ki-67 were both significantly correlated with CD117 and MMP-7 [(r=0.279, p=0.018), (r=0.322, p=0.006), (r=0.386, p=0.001), (r=0.386, p=0.002)], respectively. CONCLUSIONS: MMP-7 and nestin may be beneficial as markers, given their sensitivity to gastrointestinal stromal tumors.

Interobserver agreement in salivary gland neoplasms by telepathology: An analysis of 47 cases.

OBJECTIVE: To assess the discrepancies that prevailed among the members of the Head and Neck Pathology Working Group in Turkey in diagnosing salivary gland tumors, classified primarily according to myoepithelial origin, by utilizing telepathology. STUDY DESIGN: At least 4 representative images were obtained from each case of a total of 47 salivary gland tumors, and these were studied by 14 participants. The tumors examined were classified into 2 categories under behavior as malignant or benign, and also grouped into 2 categories under differentiation: those showing and those not showing myoepithelial differentiation. Representative areas from hematoxylin and eosin-stained slides were imaged by experienced pathologists. Images from the cases were recorded and distributed via compact disc. RESULTS: The participants in this study had a mean of 12.8 years' experience in pathology. The agreement ratios on tumors showing myoepithelial differentiation and malignancy were 86% and 81%, respectively. Basal cell adenocarcinoma gathered the lowest agreement of the myoepithelial differentiation among the tumors by 64%. The highest agreement (100%) was for 17 myoepitheliomas. While adenoid cystic carcinoma attained the highest ratio (95%), myoepithelial carcinoma had the lowest ratio (47%) of agreement on malignancy among the 19 observers. Accordingly, regarding benign tumors the ratio of agreement on the benignancy was 70%, with the highest percentage being 91% for basal cell adenoma. CONCLUSION: Electronic media acting as a usable technological tool for the distribution of pathology expertise may be used to obtain a second opinion about salivary gland tumors.

Incidence, hormonal distribution and postoperative follow up of atypical pituitary adenomas.

AIM: To assess the incidence, hormonal activity and postoperative follow up of the cases that are histopathologically diagnosed as atypical pituitary adenoma (APA) in our series. MATERIAL AND METHODS: In this study, 13 atypical pituitary adenoma cases, by the WHO 2004 criteria, among the 146 pituitary adenoma patients operated on in our clinic between January 2009 and May 2012 by endoscopic endonasal transsphenoidal approach were included. RESULTS: In histological studies, 133 cases were diagnosed as typical pituitary adenoma (91.1%) and 13 cases were APAs (8.9%) of which 10 were male (76.9%) and 3 were female (23.1%), ranged between 27 and 80 (mean 52.7) ages. Histopathological distribution of APAs was 9 nonsecretory adenomas (69.3%), 3 prolactinomas (23.1%) and 1 somatostatinoma (7.6%). Asymptomatic pituitary apoplexy was diagnosed in 4 cases (30.7%). Eleven cases of typical pituitary adenomas (8.2%) and 5 cases of the atypical pituitary adenomas (38.4%) were re-operated due to tumor recurrences. CONCLUSION: Accurate histopathological examination shows that atypical pituitary adenoma is not a rare disease. Although it is not the only determinant, APAs are more prone to recurrence than typical adenomas. In our opinion, if total resection is not possible for the patients with APA, close postoperative follow up and additional curative therapy modalities are needed.

Stromal expression of CD34, α-smooth muscle actin and CD26/DPPIV in squamous cell carcinoma of the skin: a comparative immunohistochemical study.

Invasion pathogenesis is one of the most complicated issues in the literature. There are numerous studies concerning the tumor markers implicated in the preinvasive-invasive tumor sequence. Despite ample studies on the invasion pathogenesis of cutaneous melanomas, there is limited and dispersed work presently available on non-melanoma skin cancer. The vast knowledge in the literature concerning this issue in squamous cell carcinoma comes mostly from the studies of the oral cavity, esophagus, larynx, and cervix. In this study, we investigated tumor-free neighboring stroma and tumor stroma in squamous cell carcinomas (SCCs) of the skin as well as keratoacanthomas (KAs) with respect to the presence of stromal CD34-positive (CD34+) fibrocytes and α-smooth muscle actin-positive (α-SMA+) myofibroblasts using seborrheic keratosis (SKs) and non-tumoral skin samples as controls. We also evaluated the stromal expression pattern of CD26/DPPIV (CD26), a tumor suppressor gene product that also has immunoregulatory properties. Immunohistochemistry was performed on samples of 31 SCC, 8 KA, 15 SK and 10 non-tumoral skin samples. Peri-tumoral stroma from resection margins was also evaluated. We found that CD34 and α-SMA demonstrated significantly different staining between benign and malignant squamous skin lesions consisting of a loss of CD34+ fibrocytes paralleled by a gain of α-SMA+ myofibroblasts in malignant tumor stroma. Additionally, it was shown that CD26 expression was lower in tumor stroma when compared to that of tumor neighboring stroma. However, we concluded that this finding may be attributable to the solar elastosis areas in the peritumoral tissue, which shows diffuse strong positivity for this marker.

Spindle cell carcinoma of the tongue: a rare tumor in an unusual location.

Spindle cell carcinoma is a rare biphasic tumor consisting of epithelial and mesenchymal components. Presence of this tumor type in the tongue has rarely been reported. Herein, a case of 55-year-old woman who presented with a polypoid lesion at her tongue has been reported. Surgery was performed and pathologic examination revealed a spindle cell carcinoma. We present this rare tumor with an unusual location to contribute in part to the better understanding and awareness of this rare malignancy.

Cerebral leukoencephalopathy with calcifications and cysts operated for signs of increased intracranial pressure: case report.

BACKGROUND: Association of leukoencephalopathy with calcifications and cysts is extremely rare. It should be differentiated from FD or bilateral striopallidodentate calcinosis and astrocytoma. Yet, there are many other clinical syndromes featuring bilateral symmetric cerebral calcifications. Neuroradiologic and histopathologic findings are more helpful than clinical picture in differentiating these 3 entities from each other. CASE DESCRIPTION: We report a sporadic case operated for signs of increased ICP and cerebellar cystic mass. The patient had symmetric bilateral cerebral and cerebellar calcifications, white matter edema, and a secondary thalamic cyst as well. After resection of the cerebellar mass, clinical picture returned to normal and edematous findings on MRI resolved in addition to a decrease in size of the thalamic lesion on follow-up. CONCLUSION: Patients with findings of cystic cerebral calcifications on CT scans should be followed cautiously for acute deterioration because surgery is indicated in cases having signs of increased intracranial pressure.

Atypical lipomatous tumor in the submental region.

A 54-year-old male patient presented to our outpatient clinic complaining of a mass under his chin, which appeared nearly 1 year earlier. Pathologic diagnosis was atypical lipomatous tumor. To the best of our knowledge, this is the first reported case to localize subcutaneously in the head and neck region. Atypical lipomatous tumors/well-differentiated liposarcomas are rarely reported in the head and neck. We review the clinical and management features of atypical lipomatous tumors.