Zhen Tian

Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma.

Neuroendocrine carcinoma (NEC) of the breast, a pathologic entity newly defined in the 2003 World Health Organization classification of tumors, is a rare type of tumor that is not well recognized or studied. The purpose of this first case‐controlled study is to reveal the clinicopathologic features, therapeutic response, and outcomes of patients with NEC of the breast.

Prognostic significance of tumor grading and staging in mammary carcinomas with neuroendocrine differentiation

Invasive mammary carcinoma with neuroendocrine differentiation has been controversial in terms of its definition and clinical outcome. In 2003, the World Health Organization histologic classification of tumors designated this entity as neuroendocrine carcinoma of the breast and defined mammary neuroendocrine carcinoma as expression of neuroendocrine markers in more than 50% of tumor cells. It is an uncommon neoplasm. Our recent study showed that it is a unique clinicopathologic entity and has a poor clinical outcome compared with invasive mammary carcinoma with similar pathologic stage. Other investigators have also demonstrated a different molecular profile in this type of tumor from that of invasive ductal carcinoma. It is unknown whether the current prognostic markers for invasive mammary carcinoma are also applicable for neuroendocrine carcinoma of the breast. In the current study, we reviewed the clinicopathologic features and outcome data in 74 cases of mammary neuroendocrine carcinoma from the surgical pathology files at The University of Texas, MD Anderson Cancer Center, to identify relevant prognostic markers for this tumor type. As shown previously by univariate analysis, large tumor size, high nuclear grade, and presence of regional lymph node metastasis are adverse prognostic factors for overall survival and distant recurrence-free survival. In the current study, multivariate analysis revealed that overall survival was predicted by tumor size, lymph node status, and proliferation rate as judged by Ki-67 immunohistochemistry. Only nodal status proved to be a significant independent prognostic factor for distant recurrence-free survival. Neither mitosis score nor histologic grade predicted survival in mammary neuroendocrine carcinoma. Our data suggest that routine evaluation of Ki-67 proliferation index in these unusual tumors may provide more valuable information than mitotic count alone.

Promoter Methylation as a Common Mechanism for Inactivating E-cadherin in Human Salivary Gland Adenoid Cystic Carcinoma

The role of promoter methylation in the inactivation of E‐cadherin (E‐cad) in salivary gland adenoid cystic carcinoma (ACC) is unknown. The objective of this study was to determine the role and potential clinical implications of promoter methylation of E‐cad in salivary gland ACC.

Invasive mammary carcinoma with neuroendocrine differentiation: histological features and diagnostic challenges

Tang F, Wei B, Tian Z, Gilcrease M Z, Huo L, Albarracin C T, Resetkova E, Zhang H, Sahin A, Chen J, Bu H, Abraham S & Wu Y
(2011) Histopathology59, 106–115

Adenoid cystic carcinoma of the head and neck: clinicopathologic analysis of 218 cases in a Chinese population.

OBJECTIVE The aim of this study was to analyze the clinicopathologic characteristics and prognostic factors of adenoid cystic carcinoma of the head and neck (ACCHN). STUDY DESIGN This was a retrospective study of 218 patients with ACCHN. RESULTS The cohort included 110 men and 108 women; the parotid and the palate were the most common site of involvement. Of 203 patients with follow-up information (range 2-132 months), 57 had died of the tumor. Distant metastasis (DM) and local recurrence (LR) were documented in 83 (40.9%) and 34 (16.7%) patients, respectively. Cox regression analysis indicated that a solid pattern was a marker for LR and that positive margins and older age were risk factors for DM. Histologic pattern, T stage, N stage, LR, DM, and patient age contributed to the prediction of disease-specific survival. CONCLUSIONS A solid pattern, metastasis, LR, and older age are the most important factors for predicting poor prognosis in Chinese patients with ACCHN.

High Expression of H3K9me3 Is a Strong Predictor of Poor Survival in Patients With Salivary Adenoid Cystic Carcinoma

CONTEXT Histone methylation and acetylation play important roles in the carcinogenesis and progression of cancer. OBJECTIVE To investigate whether histone modifications influence the prognosis of patients with salivary adenoid cystic carcinoma (ACC). DESIGN The expression of histone H3 lysine 9 trimethylation (H3K9me3) and histone H3 lysine 9 acetylation (H3K9Ac) was assessed by immunohistochemistry in 66 specimens of primary ACC. Tests were used to determine the presence of any correlation between H3K9me3 and H3K9Ac levels and clinicopathologic parameters. Log-rank test and Cox proportional hazards regression models were used to analyze the survival data. RESULTS H3K9me3 expression was positively correlated with solid pattern tumors (P = .002) and distant metastasis (P = .001). Solid pattern tumors had lower H3K9Ac expression levels than cribriform-tubular pattern tumors (P = .03). Patients whose tumors showed high H3K9me3 expression and a solid pattern had a significantly poorer overall survival (OS) (P < .001 and P < .001, respectively) and disease-free survival (P < .001 and P = .01, respectively). Low H3K9Ac expression was correlated with poor OS (P = .05). The multivariate analysis indicated that high levels of H3K9me3 expression and solid pattern tumors were independent prognostic factors that significantly influenced OS (P = .004 and P = .04, respectively). H3K9me3 expression was identified as the only independent predictor of disease-free survival (P = .006). CONCLUSIONS Our results suggest that high levels of H3K9me3 expression are predictive of rapid cell proliferation and distant metastasis in ACC. Compared with histologic patterns, H3K9me3 might be a better predictive biomarker for the prognosis of patients with salivary ACC.

Aberrant protein expression and promoter methylation of p16 gene are correlated with malignant transformation of salivary pleomorphic adenoma.

CONTEXT The significance of promoter methylation of the p16 gene and intracellular localization of p16 protein in the carcinogenesis of salivary carcinoma ex pleomorphic adenoma (Ca-ex-PA) is not clear. The correlation of the promoter methylation of the p16 gene and the expression and localization of p16 protein in Ca-ex-PA need to be further clarified. OBJECTIVE To investigate the p16 protein expression and promoter methylation of p16 gene in Ca-ex-PA and their roles in the malignant transformation of pleomorphic adenoma to Ca-ex-PA. DESIGN The p16 protein expression and promoter methylation of the p16 gene were determined in both benign and malignant components of 50 primary salivary Ca-ex-PA tissues by immunohistochemistry and methylation-specific polymerase chain reaction. Expression of p16 protein and promoter methylation of the p16 gene between the benign and the malignant components was compared statistically. RESULTS The tumor cells in the malignant components showed significantly higher p16 protein expression in the cytoplasm and lower expression in the nuclei than those in the benign components. Promoter methylation frequency of the p16 gene in the malignant components (36%) was significantly higher than that in the benign components (16%). There were no correlations between p16 protein expression and promoter methylation of the p16 gene in either benign or malignant components. CONCLUSIONS Overexpression of p16 protein in the cytoplasm and decreased expression of p16 protein in the nucleus may play important roles in the evolution of pleomorphic adenoma to Ca-ex-PA. Promoter methylation of the p16 gene may be correlated with the malignant transformation of pleomorphic adenoma.

RASSF1A Promoter Hypermethylation Is a Strong Biomarker of Poor Survival in Patients with Salivary Adenoid Cystic Carcinoma in a Chinese Population

In addition to the clinicopathological parameters, molecular biomarkers are becoming increasingly important in the prognostic evaluation of cancer patients. This study aimed to determine the molecular alterations in the RAS association domain family protein1A gene (RASSF1A) in salivary adenoid cystic carcinoma (ACC) and to evaluate the potential of such alterations as prognostic markers. One hundred and sixty-seven ACC tumor tissues and 50 samples of matched normal salivary gland tissues from the same patients were analyzed for RASSF1A promoter methylation status by bisulfite sequencing PCR (BSP) and/or methylation-specific PCR (MSP). Fifty ACC tumor tissues and matched normal salivary gland tissues were analyzed for loss of heterozygosity (LOH) by examining two microsatellite markers (D3S1478, D3S1621) at 3p21. RASSF1A gene mutations were detected by direct sequencing of all six exons in 50 tumor and normal tissue specimens. Over-all, RASSF1A promoter hypermethylation was detected in 35.3% (59/167) of ACC tissues and was associated with histologically solid tumor pattern (P = 0.002) and advanced TNM stage (P = 0.014). RASSF1A LOH was observed in 18.0% (9/50) of cases, and no somatic mutation of RASSF1A was detected in any cases. RASSF1A promoter methylation was associated with the poor over-all survival (Log-rank test, P <0.001) and disease-free survival (Log-rank test, P <0.001) and identified as an independent predicator of over-all patient survival (P = 0.009) and disease-free survival (P <0.001). It was concluded that RASSF1A methylation is involved in the development, differentiation and progression of ACC and is a strong independent biomarker of poor survival in ACC patients in a Chinese population.

An unusual cribriform variant of salivary basal cell tumours: a clinicopathological study of 22 cases

Tian Z, Hu Y, Wang L, Li L, Zhang C & Li J 
(2012) Histopathology 61, 921–929

Predictive value of pAKT/PTEN expression in oral squamous cell carcinoma treated with cetuximab-based chemotherapy.

OBJECTIVE Molecular alterations in downstream effectors of epidermal growth factor receptor may confer resistance to epidermal growth factor receptor inhibitors. Our aim is to investigate whether PTEN/pAKT expression predicts response to cetuximab-based chemotherapy in oral squamous cell carcinoma. STUDY DESIGN We analyzed a cohort of 50 patients with oral squamous cell carcinoma treated with cetuximab-based induction chemotherapy. PTEN expression and pAKT expression were assessed by immunohistochemistry and their correlation with treatment outcome was analyzed. RESULTS Of the study patients, 18.4% had low PTEN expression, and 38.8% had high pAKT expression. Lower pAKT expression were associated with pathologic remission (P = .034) and better disease-free survival (P = .031). CONCLUSION Our study demonstrates that pAKT expression is a predictive biomarker of cetuximab-based induction chemotherapy in OSCC.