Nuclear Deformability of Breast Cells Analyzed from Patients with Malignant and Benign Breast Diseases.

Breast cancer is a heterogeneous and dynamic disease, in which cancer cells are highly responsive to alterations in the microenvironment. Today, conventional methods of detecting cancer give a rather static image of the condition of the disease, so dynamic properties such as invasiveness and metastasis are difficult to capture. In this study, conventional molecular-level evaluations of the patients with breast adenocarcinoma were combined with in vitro methods on micropatterned poly(methyl methacrylate) (PMMA) biomaterial surfaces that deform cells. A correlation between deformability of the nuclei and cancer stemness, invasiveness, and metastasis was sought. Clinical patient samples were from regions of the breast with different proximities to the tumor. Responses at the single-cell level toward the micropatterned surfaces were studied using CD44/24, epithelial cell adhesion marker (EpCAM), MUC1, and PCK. Results showed that molecular markers and shape descriptors can discriminate the cells from different proximities to the tumor center and from different patients. The cells with the most metastatic and invasive properties showed both the highest deformability and the highest level of metastatic markers. In conclusion, by using a combination of molecular markers together with nuclear deformation, it is possible to improve detection and separation of subpopulations in heterogenous breast cancer specimens at the single-cell level.

A Serous Peritoneal Cancer Revealing Itself With Double Breast Cancer Metastases in 2 Different Periods.

A 72-year-old woman presented with a mass on the right axilla. This was thought to be an occult breast cancer case, and the patient was treated with modified radical mastectomy, followed by hormonotherapy. Two years later she presented with incarcerated umbilical hernia. Pathology revealed Sister Mary Joseph's nodule inside the hernia sac. Further evaluation revealed that the primary tumor was papillary serous carcinoma of the peritoneal surface. The patient received adjuvant chemotherapy. Two years later the metastatic tumor was located on the other breast. The disease progressed gradually, and the patient eventually died from disseminated disease. This case is extraordinary in that it first presented with axillary metastasis without abdominal involvement and then later metastasized to the other breast after a long disease-free period.

Comparison of Clinicopathologic Parameters and Survivals Between Epstein-Barr Virus-positive and Her2-positive Gastric Cancers.

Gastric carcinomas are highly mortal neoplasms for which new therapeutic options are being searched. The molecular subtyping of gastric adenocarcinomas was proposed recently, and the relationship between etiopathogenetic types is still under investigation. Here we compared histopathologic, prognostic, and survival differences between Epstein-Barr virus (EBV)-positive and Her2-positive gastric adenocarcinomas. In a retrospective design, we searched the EBV status with Epstein Barr Virus encoded small RNA (EBER) in situ hybridization, and the Her2 status both by immunohistochemistry and by chromogenic in situ hybridization of 106 gastrectomized gastric carcinomas. Histologic and clinical prognostic parameters and survival information were determined, and retrieved from archival tissues and clinical notes. The Her2 positivity rate was 12.3% and the EBV positivity rate was 7.6%. Among EBER-positive cases, Her2 positivity was not detected. Her2 positivity was detected more in intestinal differentiated tumors, whereas EBER positivity was detected in undifferentiated tumors (P=0.003). There was no correlation of Her2 or EBER positivity with the tumor stage. Median survivals of EBER-positive, Her2-positive, and both negative cases were 11.5, 18, and 20.5 months, respectively. The tumor stage and distant metastasis were found to be significant for survival in the multivariate analysis. In our 106 gastrectomized gastric carcinoma cases, EBV-positive and Her2-positive groups were found to be unrelated as proposed in the upcoming classification of gastric carcinomas.

Thyroid FNAC containing hürthle cells and hürthle-like cells: A study of 128 cases.

AIM: It is a diagnostic challenge to differentiate benign and malignant cytology in the presence of Hürthle cells. In our previous study, it was determined that in fine needle aspirations (FNA), the malignancy outcome of the Hürthle cells containing group tend to be papillary thyroid carcinoma (PTC) in a higher percentage. The most common misinterpretation is caused by PTC cells with large cytoplasm-like Hürthle cells. The aim of this study is to predict histologic outcome of the nodules, which have Hürthle cells in FNA according to cytological, clinical features, and BRAFV600E mutation status. MATERIALS AND METHODS: Detailed cytological features of 128 cases were compared with histopathological diagnosis. The analysis of BRAFV600E mutation of the PTC cases were performed by real-time polymerase chain reaction. RESULTS: The neoplastic outcome was increased statistically significantly with younger age (P = 0.020), increase in cellular dyshesion (P = 0.016), presence of nuclear budding (P = 0.046), and granular chromatin (P = 0.003). Nuclear budding (P = 0.014), granular chromatin (P = 0.012), and hypoechoic nodules in ultrasonography (P = 0.011) were significant independent factors for the increase in the malignancy risk. Increased lymphocytes (P= 0.015) and colloid were related to non-neoplastic outcome. According to the surgical outcome, more than half of the malign cases were PTC (74%). BRAFV600E mutation was detected in 27.8% of the PTC cases. CONCLUSION: PTC cases containing Hürthle cell-like cells may lead to diagnostic errors. Nuclear budding and granular chromatin of Hürthle cells are significant, remarkable findings to predict the outcome of neoplasm and malignancy.

A rare case of chondroblastoma of the acromion.

We present a 37-year-old patient with a chondroblastoma in his right acromion. The acromion is an unusual site for this type of tumor and the typical surgical treatment involves resection of the involved acromion bone. The patient was surgically treated with resection of the right acromion and autogenous iliac bone grafting. Twenty five months postoperatively, he demonstrated full shoulder function, without evidence of local recurrence or metastasis.

Primary mature cystic teratoma mimicking an adrenal mass in an adult male patient.

Teratomas are bizarre neoplasms derived from embryonic tissues that are typically found only in the gonadal and sacrococcygeal regions of adults. Primary retroperitoneal teratomas are rare and present challenging management options. We report a case of a unilateral primary retroperitoneal mature cystic teratoma mimicking an adrenal mass in a 54-year-old male patient. Complete resection of the adrenal mass was performed by the flank approach by using the 11th rib resection. Because of the risk of malignancy, follow-up radiographic studies were performed to ensure the oncologic efficacy of resection. The patient has been free of recurrence for longer than 12 months.

microRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers.

Triple Negative Breast Cancers (TNBC) is a heterogeneous disease at the molecular and clinical level with poor outcome. Molecular subclassification of TNBCs is essential for optimal use of current therapies and for development of new drugs. microRNAs (miRNA) are widely recognized as key players in cancer progression and drug resistance; investigation of their involvement in a TNBC cohort may reveal biomarkers for diagnosis and prognosis of TNBC. Here we stratified a large TNBC cohort into Core Basal (CB, EGFR and/or CK5, 6 positive) and five negative (5NP) if all markers are negative. We determined the complete miRNA expression profile and found a subset of miRNAs specifically deregulated in the two subclasses.We identified a 4-miRNA signature given by miR-155, miR-493, miR-30e and miR-27a expression levels, that allowed subdivision of TNBCs not only into CB and 5NP subgroups (sensitivity 0.75 and specificity 0.56; AUC=0.74) but also into high risk and low risk groups. We tested the diagnostic and prognostic performances of both the 5 IHC marker panel and the 4-miRNA expression signatures, which clearly identify worse outcome patients in the treated and untreated subcohorts. Both signatures have diagnostic and prognostic value, predicting outcomes of patient treatment with the two most commonly used chemotherapy regimens in TNBC: anthracycline or anthracycline plus taxanes. Further investigations of the patients' overall survival treated with these regimens show that regardless of IHC group subdivision, taxanes addition did not benefit patients, possibly due to miRNA driven taxanes resistance. TNBC subclassification based on the 5 IHC markers and on the miR-155, miR-493, miR-30e, miR-27a expression levels are powerful diagnostic tools. Treatment choice and new drug development should consider this new subtyping and miRNA expression signature in planning low toxicity, maximum efficacy therapies.

Androgen receptor status is a prognostic marker in non-basal triple negative breast cancers and determines novel therapeutic options.

Triple negative breast cancers are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapeutics. Androgen receptor has been associated with triple negative breast cancer pathogenesis, but its role in the different subtypes has not been clearly defined. We examined androgen receptor protein expression by immunohistochemical analysis in 678 breast cancers, including 396 triple negative cancers. Fifty matched lymph node metastases were also examined. Association of expression status with clinical (race, survival) and pathological (basal, non-basal subtype, stage, grade) features was also evaluated. In 160 triple negative breast cancers, mRNA microarray expression profiling was performed, and differences according to androgen receptor status were analyzed. In triple negative cancers the percentage of androgen receptor positive cases was lower (24.8% vs 81.6% of non-triple negative cases), especially in African American women (16.7% vs 25.5% of cancers of white women). No significant difference in androgen receptor expression was observed in primary tumors vs matched metastatic lesions. Positive androgen receptor immunoreactivity was inversely correlated with tumor grade (p<0.01) and associated with better overall patient survival (p = 0.032) in the non-basal triple negative cancer group. In the microarray study, expression of three genes (HER4, TNFSF10, CDK6) showed significant deregulation in association with androgen receptor status; eg CDK6, a novel therapeutic target in triple negative cancers, showed significantly higher expression level in androgen receptor negative cases (p<0.01). These findings confirm the prognostic impact of androgen receptor expression in non-basal triple negative breast cancers, and suggest targeting of new androgen receptor-related molecular pathways in patients with these cancers.

Predictive factors for residual disease in re-excision specimens after breast-conserving surgery.

Local recurrence is an issue of concern after breast-conserving therapy and removing the primary tumor with negative surgical margins is the most important determinant of local recurrence. However, some patients with positive margins after initial surgery will have no residual tumor in the re-excision specimen. To avoid unnecessary re-excisions, factors predicting residual disease in re-excision material should be determined. This study aimed to determine the predictive factors for residual disease in the re-excision material in a homogeneous group of patients with positive margins and only invasive ductal carcinoma. Breast cancer patients treated between 2005 and 2008 with breast-conserving surgery and subsequent re-excisions due to positive surgical margins after initial surgery were included in the study. Patients were divided into two groups as those with and without residual disease in the re-excision material. One hundred and four breast cancer patients were included in the study. Forty-seven patients (45.2%) had residual tumor in re-excision specimen. Patient characteristics such as age (p = 0.42) and physical findings (p = 1.0) and specimen volume (p = 0.24), tumor grade (p = 0.33), estrogen (p = 1.0), and progesterone (p = 0.37) receptor status, axillary lymph node metastases (p = 0.16), extensive intraductal component (p = 0.8), and lymphovascular invasion (p = 0.064) were found as insignificant factors for predicting residual tumor. Large tumor size (>3 cm) (p = 0.026), human epidermal growth factor receptor2 (HER2) positivity (p = 0.013), and tumor to specimen volume ratio of >70% (p = 0.002) significantly increased the probability of finding residual disease after re-excision. In multivariate analysis, HER2 positivity (p = 0.046) and tumor to specimen volume ratio of >70% (p = 0.006) independently predicted the presence of residual disease. As a result, in patients with HER2 positive tumors larger than 3 cm, larger volume of breast tissue around the tumor should be removed to decrease the number of re-excisions due to positive surgical margins.

The effects of tumor size, degree of differentiation, and depth of invasion on the risk of neck node metastasis in squamous cell carcinoma of the oral cavity.

Cervical lymph node metastasis is the most important prognostic factor in patients with head and neck carcinoma. We retrospectively analyzed the effects of three different variables-tumor size, degree of differentiation, and depth of invasion-on the risk of neck node metastasis in 50 adults who had been treated with surgery for primary squamous cell carcinoma of the oral cavity. Primary tumor depth and other pathologic features were determined by reviewing the pathology specimens. Preoperatively, 36 of the 50 patients were clinically N0; however, occult lymph node metastasis was found in 13 of these patients (36.1%). The prevalence of neck node metastasis in patients with T1/T2 and T3/T4 category tumors was 51.5 and 58.8%, respectively. The associations between the prevalence of neck node metastasis and both the degree of differentiation and the depth of invasion were statistically significant, but there was no significant association between neck node metastasis and tumor size. We conclude that the prevalence of neck lymph node metastasis in patients with squamous cell carcinoma of the oral cavity increases as the tumor depth increases and as the degree of tumor differentiation decreases from well to poor, as has been shown in previous studies. It is interesting that tumor size, which is the most important component of the TNM system, was not significantly associated with neck node involvement.

Stem cell-related markers in primary breast cancers and associated metastatic lesions.

It has been reported previously that: (1) normal-breast epithelial cells that are CD24-/44+ express higher levels of stem/progenitor cell-associated genes; (2) cancer cells that have undergone epithelial to mesenchymal transition display CD24-/44+ cell-surface expression, a marker for breast cancer stem cells; (3) loss of E-cadherin is a preliminary step in epithelial to mesenchymal transition; and (4) vimentin is a marker of mesenchymal phenotype. We hypothesized that stem cell subpopulations would be more frequent in metastatic than in primary tumors. Therefore we assessed by immunohistochemical analysis, tissue microarrays containing tissue from primary and associated metastatic breast cancers for expression of CD24, CD44, E-cadherin and vimentin to evaluate candidate cancer-initiating cell populations in breast cancer subtypes and metastatic lesions. The occurrence of CD24-/44+ and CD24+/44- cells did not differ in primary vs matched lymph node or distant and locoregional metastatic lesions; E-cadherin expression was decreased in primary vs lymph node metastases (P=0.018) but not decreased in distant and locoregional metastases relative to primary tumor, whereas vimentin, was more frequently expressed in lymph node and distant and locoregional metastases (P=0.013, P=0.004) than in matched primary cancers. Thus, the frequency of CD24-/44+ cells does not differ in metastases relative to the primary breast cancer but differs by tumor stage and subtype.

Progressive vacuolar myelopathy and leukoencephalopathy in childhood acute lymphoblastic leukemia and transient improvement with vitamin B12.

Vacuolar myelopathy (VM) in leukemia is rare. We report a boy with leukemia who developed isolated central nervous system (CNS) relapse during reinduction therapy. 5 months after cranial radiotherapy, he gradually developed quadriparesis. Magnetic resonance imaging revealed an intramedullary lesion which extended through the cervical spine. Serum vitamin B12, folic acid, cerebrospinal fluid methyl malonic acid were normal. Viral screening by ELISA was negative. He had lymphopenia, and reduced immunoglobulins, from a cardiac arrest. Biopsy revealed VM. He responded to weekly vitamin B12 treatment but on the 6th week of the therapy he died after developing periventricular, gliotic, hyperintense lesions in the brain.

Multidrug resistance in locally advanced breast cancer.

BACKGROUND: Advanced breast cancer cases can still be encountered resulting in poor prognosis. The primary treatment for these patients is chemotherapy, and multidrug resistance (MDR) is a serious obstacle in the treatment. Detecting drug resistance before first-line chemotherapy may increase the patient's survival. In this study, the role of MDR is evaluated in locally advanced breast cancer patients. METHODS: Reverse transcriptase polymerase chain reaction was used for the detection of MDR genes, ABCB1 and ABCC1. Immunohistochemistry was used for the detection of MDR proteins, P-glycoprotein (Pgp) and MDR-associated protein 1. RESULTS: Breast tissues from 25 patients both before and after chemotherapy were examined. Five patients were unresponsive to chemotherapy. Four had ABCB1 gene expression induced by chemotherapy, and Pgp positivity was detected in 9 patients after chemotherapy. Both the induction of ABCB1 gene expression (p < 0.001) and Pgp positivity (p < 0.001) during chemotherapy were significantly related with clinical response. Although 80% of the clinically unresponsive patients had ABCC1 gene expression, the relation between ABCC1 expression and clinical drug response was not significant. CONCLUSION: In locally advanced breast cancer, ABCB1 gene expression during chemotherapy contributes to clinical unresponsiveness. However, ABCC1 gene expression did not correlate strongly with the clinical response.

Splenogonadal fusion: report of a case.

A 15-year-old male patient was admitted to our hospital with a left undescended testis. He also suffered from congenital limb defects. Ultrasonography revealed atrophic testicular tissue in the left groin, approximately 2-cm in size. Upon left inguinal exploration, atrophic testicular tissue was found and an orchidectomy was performed. Histopathological examination revealed splenogonadal fusion, which has a known association with congenital limb defects.

Is Nothingham Prognostic Index correlated with apoptosis and p53 expression in infiltrating ductal carcinoma of the breast?

The role of p53 as a prognostic factor is not clear. P53 named as "guardian of the genome" plays an important role in many intracellular regulatory systems, one of which is apoptosis, having an impact on tumor kinetics. A retrospective study was undertaken to assess the relationship of the Nothingham Prognostic Index (NPI) to p53 expression and apoptotic cell counts. To conduct the study, 160 successive cases of infiltrating ductal carcinoma of the breast were included. P53 was assessed on AP-AAP stained sections. Apoptotic cell counting (ACC) was done on the HE stained routine sections in 10 HPFs. Clinical data were derived from the hospital files. Apoptotic cell counts were higher in the p53 positive group but the difference was not significant (p=0.079). P53 positivity was found to be related to the disease-free survival (DFS) (p=0.008). NPI was significantly higher in apoptotic cell containing group (p=0.006). There was a positive linear correlation between ACC and NPI scores (p=0.004). This correlation was not present between apoptosis and disease free survival. P53 expression was found to be related with DFS but not with the NPI which is a score composed of the best prognostic indicators known today. In contrast to this, ACC was found to be closely and linearly associated to the known prognostic factors. This may suggest that the apoptotic cell counts done on routine sections may be used as a part of prognosis assessment in infiltrating ductal carcinoma.