Prognostic Value of Tumor-Infiltrating Lymphocyte Density Assessed Using a Standardized Method Based on Molecular Subtypes and Adjuvant Chemotherapy in Invasive Breast Cancer.

BACKGROUND: This study investigated the prognostic value of tumor-infiltrating lymphocyte (TIL) density as determined by molecular subtype and receipt of adjuvant chemotherapy in invasive breast cancer (IBC). METHODS: Stromal TIL densities were evaluated in 1489 IBC samples using recommendations proposed by the International TILs Working Group. Cases were allocated to high- and low-TIL density groups using a cutoff of 10%. RESULTS: Of the 1489 IBC patients, 427 (28.7%) were assigned to the high-TIL group and 1062 (71.3%) to the low-TIL group. High TIL density was found to be significantly associated with large tumor size (p = 0.001), high histologic grade (p < 0.001), and high Ki-67 labeling index (p < 0.001). Triple-negative and human epidermal growth factor receptor 2 (HER2)-positive subtypes had significantly higher TIL densities than luminal A or B (HER2-negative) subtypes (p < 0.001). High TIL density was significantly associated with prolonged disease-free survival (DFS) by univariate (p < 0.001) and multivariate (p < 0.001) analyses. In the low-TIL-density group, the patients who did not receive adjuvant chemotherapy showed better DFS (p < 0.001), but no such survival difference was observed in the high-TIL group (p = 0.222). For the patients who received adjuvant anthracycline, high-TIL density was found to be an independent prognostic factor of favorable DFS in the luminal B (HER2-negative; p = 0.003), HER2-positive (p = 0.019), and triple-negative (p = 0.017) subtypes. CONCLUSION: Measurements of TIL density in routine clinical practice could give useful prognostic information for the triple-negative, HER2-positive, and luminal B (HER2-negative) IBC subtypes, especially for patients administered adjuvant anthracycline.

ATRX protein is a potential prognostic marker in clear cell renal cell carcinoma.

Objective: Cancer cells activate either telomerase or alternative lengthening of telomeres (ALT) to maintain telomere length and achieve immortalization. Alpha thalassemia/mental retardation X-linked (ATRX) is involved in chromatin remodeling. Mutations in ATRX genes are associated with the loss of nuclear expression and correlated with the ALT phenotype. ATRX expression has been evaluated in various cancers, especially sarcoma and neuroendocrine tumors, and its clinical significance has been shown to be diverse, depending on the tumor types. The role and prognostic value of ATRX expression in clear cell renal cell carcinoma (CCRCC) have not been elucidated. Methods: We investigated the messenger RNA (mRNA) expression levels of ATRX using the gene expression profiling interactive analysis (GEPIA) database and evaluated the expression of ATRX using immunohistochemical (IHC) staining in 302 CCRCC cases. Results: Loss of ATRX expression was significantly associated with larger tumor size, higher nuclear grade (NG), lymphovascular invasion (LVI), pathologic T (pT) stage, recurrence/metastasis, and stage. Although ATRX was not an independent prognostic factor, patients with loss of ATRX expression showed poor survival. Conclusion: Our findings suggest that loss of ATRX expression could be a potential biomarker for predicting aggressive tumor behavior and poor clinical outcomes in CCRCC.

Aberrant Expression of E-cadherin, N-cadherin, and P-cadherin in Clear Cell Renal Cell Carcinoma: Association With Adverse Clinicopathologic Factors and Poor Prognosis.

OBJECTIVE: Aberrant expression of cadherins is known to be associated with tumor aggression. However, their role in clear cell renal cell carcinoma (CCRCC) is not well elucidated. This study investigated the expression of epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), and placental cadherin (P-cadherin) in CCRCC, and assessed their prognostic significance and clinicopathologic association. MATERIALS AND METHODS: We enrolled 254 patients with CCRCC who underwent radical or partial nephrectomy. E-cadherin, N-cadherin, and P-cadherin expression was evaluated by immunohistochemistry in a tissue microarray. RESULTS: Low E-cadherin expression was associated with larger tumor size, lymphovascular invasion, higher pT stage, lymph node and distant metastasis, and higher stage. High N-cadherin expression was significantly associated with larger tumor size, higher nuclear grade, and tumor necrosis. P-cadherin expression was found to be significantly associated with higher nuclear grade, distant metastasis, and higher stage. Univariate analysis revealed that aberrant expression of the 3 cadherins was significantly related to shorter overall survival (OS). Loss of E-cadherin, high P-cadherin expression, and higher stage were independent prognostic factors for OS. For recurrence-free survival, lymphovascular invasion, high P-cadherin expression, and higher stage were independent prognostic factors. Cadherin switch was significantly associated with aggressive clinicopathologic factors and poor outcomes. CONCLUSIONS: Aberrant expression of E-cadherin, N-cadherin, and P-cadherin was associated with adverse clinicopathologic factors and worse OS. Low E-cadherin and high P-cadherin expression were significantly associated with distant metastasis and independent prognostic factors. Therefore, cadherin expression may be used as a prognostic marker and therapeutic target, and cadherin switch plays an important role in CCRCC progression.

High MCM6 Expression as a Potential Prognostic Marker in Clear-cell Renal Cell Carcinoma.

AIM: Minichromosome maintenance (MCM) proteins are involved in initiation of DNA replication and cell-cycle progression. Loss of MCM function results in genomic instability and causes carcinogenesis. Among MCM genes, the role and prognostic value of MCM6 expression in clear-cell renal cell carcinoma (ccRCC) has not been elucidated. MATERIALS AND METHODS: We assessed the mRNA expression level of MCM6 using the Gene Expression Profiling Interactive Analysis database and investigated MCM6 protein expression by immunohistochemistry in 238 ccRCC cases. RESULTS: High MCM6 expression was significantly associated with increasing tumor size, pT, stage, tumor necrosis, and metastasis. Furthermore, high MCM6 expression was significantly associated with shorter overall and disease-free survival, and was an independent unfavorable prognostic marker. Regarding patients with metastasis, high MCM6-expressing ccRCC conferred significantly shorter survival than for those with low expression. CONCLUSION: A high MCM6 expression level may be a promising biomarker to predict tumor progression, metastasis, and survival in patients with ccRCC.

CD9 Expression in Tumor Cells Is Associated with Poor Prognosis in Patients with Invasive Lobular Carcinoma.

PURPOSE: We investigated the prognostic significance of CD9 expression in tumor cells of patients with invasive lobular carcinoma (ILC). METHODS: CD9 expression was evaluated by immunohistochemistry in 113 ILC tissue samples. Correlation of CD9 expression with the patients' clinicopathological parameters and overall survival was assessed. RESULTS: CD9 expression was detected in 48 (42.5%) ILC patients. However, no significant relation could be determined between CD9 expression and the clinicopathological parameters of the patient including tumor size, lymph node metastasis, lymphovascular invasion, histologic grade, expression of hormone receptors, human epidermal growth factor receptor 2 status, and Ki-67 labeling index. Patients with CD9 expression had worse overall survival (p = 0.051) and disease-free survival (DFS, p = 0.014) compared to patients without CD9 expression. Multivariate analysis revealed that CD9 expression was an independent prognostic factor for DFS (p = 0.049). CONCLUSION: CD9 expression in tumor cells could be a significant prognostic marker in patients with ILC.

Validation of the pathological prognostic staging system proposed in the revised eighth edition of the AJCC staging manual in different molecular subtypes of breast cancer.

The authors investigated the clinical utility of the revised prognostic staging system proposed in the eighth edition of the American Joint Committee on Cancer (AJCC) staging manual in breast cancer (BC) patients. We retrospectively reviewed the data of 714 BC patients that received surgical treatment and standard adjuvant therapy from January 2005 to December 2007. All patients were restaged for anatomic TNM stage and pathological prognostic (PP) stage as defined in the revised eighth edition of the AJCC manual. Compared with anatomic stage, PP stage was different from anatomic stage in 325 (45.5%) patients, 254 were down-staged and 71 were upstaged. There were significant differences in overall survival (OS) and disease-free survival (DFS) according to different anatomic stages or PP stages (all, p < 0.001). In anatomic stage I patients, OS was significantly different between PP stages IA and IB (p < 0.001), but no significant difference was observed between anatomic stages IA and IB (p = 0.413). PP stages exhibited significant OS differences in anatomic stage IIB (p = 0.011), but survival differences according to PP stages were not observed in anatomic stage IIA, IIIA, or IIIC. PP stages were found to have prognostic value with respect to OS and DFS for luminal (p < 0.001 and p < 0.001), HER2-positive (p = 0.001 and p = 0.013), and triple-negative (p = 0.008 and p = 0.03) subtypes. The prognostic staging system proposed in the eighth edition of the AJCC more accurately predicts the clinical outcomes of BC patients than the traditional anatomic staging system.

Mammary Paget's disease without underlying malignancy of the breast.

Mammary Paget's disease (MPD) is usually accompanied by underlying breast malignancy; however, a few cases have been reported as only skin lesions without any evidence of malignancy of the breast on imaging tests and microscopic examination of surgical specimen. Here, we describe a 47-year-old woman who visited our hospital who had an eczematous lesion on right nipple and areola for over 10 years. The lesion was diagnosed as Paget's disease by punch biopsy; however, imaging studies demonstrated no breast malignancy or lymph node metastasis. The patient underwent surgery of on the nipple and areola including underlying breast tissue. No underlying malignancy was found upon microscopic examination, except for Paget's disease. Immunohistochemical stains revealed that the tumor cells were positive for cytokeratin 7, and negativity for p63, cytokeratin 5/6, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. We report a case of MPD without underlying malignancy. To the best of our knowledge, this is the third case reported in Korea.