[Correlation between tumor cell proliferation and prognosis of primary cutaneous malignant melanoma in 127 patients].

OBJECTIVE: To investigate the correlations among Ki-67 expression, mitosis and other clinicopathological parameters of primary cutaneous malignant melanoma, and search for prognostic factors of malignant melanoma. METHODS: Totally 127 cases of primary cutaneous malignant melanoma were collected from Beijing Cancer Hospital. Immunohistochemical study for Ki-67 was performed, and the mitosis was calculated referring to "hot spot" method recommended by the seventh edition of the American Joint Committee on Cancer (AJCC) melanoma staging system. The correlations of Ki-67 expression, mitosis and other clinicopathological parameters were analyzed, and the survival analysis of all these risk factors including TNM and Clark level was conducted based on follow up data. RESULTS: The expression level of Ki-67 was associated with necrosis and Breslow thickness (P < 0.05). Mitosis was correlated with Clark level and Ki-67 expression (P < 0.05). Univariate analysis indicated Ki-67 expression level (P = 0.043), mitosis (P = 0.030) and TNM stage (P < 0.001) might influence the survival of patients. However, multivariate analysis showed that the TNM staging was the only independent prognostic factor affecting survival. CONCLUSIONS: The prognosis of patients with primary cutaneous malignant melanoma was closely related to the TNM staging at the fist examination. Ki-67 expression and mitosis are two important clinicopathological parameters of primary cutaneous malignant melanoma.

[Expression and prognostic significance of galectin-1 and galectin-3 in benign nevi and melanomas].

OBJECTIVE: To study the expression and prognostic significance of galectin-1 and galectin-3 in different melanocytic lesions. METHODS: The expression of galectin-1 and galectin-3 in 39 cases of benign nevus, 58 cases of primary cutaneous melanoma, 24 cases of primary mucosal melanoma, 69 cases of melanoma with lymph node metastasis and 8 cases of melanoma with distant metastasis were studied by immunohistochemistry and tissue microarray. RESULTS: The expression of galectin-1 and galectin-3 was higher in benign nevi than in melanomas (P < 0.01). The nuclear expression of galectin-3 was higher in primary cutaneous melanomas than in primary mucosal melanomas or melanomas with metastases (P < 0.01, respectively). The expression correlated with age of patients (P < 0.05), necrosis (P < 0.05) and survival time (P < 0.01). Clark's level also correlated with survival time in patients with cutaneous melanomas (P = 0.037). TNM staging was the only independent prognostic factor for melanomas (P < 0.01). CONCLUSIONS: The expression of galectin-1 and galectin-3 is decreased in melanomas. The decrease in nuclear expression of galectin-3 may represent a poor prognostic factor for melanomas. TNM staging is an independent prognostic factor which influences the survival time.

Oncologic outcomes of primary and post-irradiated early stage rectal cancer: a retrospective cohort study.

AIM: To evaluate the oncologic outcomes of primary and post-irradiated early stage rectal cancer and the effectiveness of adjuvant chemotherapy for rectal cancer patients. METHODS: Eighty-four patients with stage I rectal cancer after radical surgery were studied retrospectively and divided into ypstage I group (n = 45) and pstage I group (n = 39), according to their preoperative radiation, and compared by univariate and multivariate analysis. RESULTS: The median follow-up time of patients was 70 mo. No significant difference was observed in disease progression between the two groups. The 5-year disease-free survival rate was 84.4% and 92.3%, respectively (P = 0.327) and the 5-year overall survival rate was 88.9% and 92.3%, respectively, for the two groups (P = 0.692). The disease progression was not significantly associated with the pretreatment clinical stage in ypstage I group. The 5-year disease progression rate was 10.5% and 19.2%, respectively, for the patients who received adjuvant chemotherapy and for those who rejected chemotherapy in the ypstage I group (P = 0.681). CONCLUSION: The oncologic outcomes of primary and post-irradiated early stage rectal cancer are similar. Patients with ypstage I rectal cancer may slightly benefit from adjuvant chemotherapy.

[Clinicopathological observation of gastric cancer with pathological complete response following neoadjuvant chemotherapy].

OBJECTIVE: To observe the clinicopathological characteristics of gastric cancer with pathological complete response(pCR) following neoadjuvant chemotherapy. METHODS: Data of gastric cancer patients who received neoadjuvant chemotherapy from 2002 to 2008 in the Beijing Cancer Hospital were reviewed. Five cases were found to have pCR. The slides were reviewed by two experienced pathologists independently. Histological structure, morphology of tumor cells, morphology and quantity of stromal cells were evaluated. RESULTS: Structure of the gastric wall was distinguishable in all the 5 cases, while distortion and rupture of muscular layer were found in 2 cases. Exudative inflammatory reaction was present in the whole gastric wall including the serosa layer. Three patients had ulcerative lesions with epithelial layer shedding, and atypical hyperplasia was found around the border of the ulcer, and vascular endothelial cells were swollen. Residual distorted necrotic tumor cells resided in 1 case only and no residual tumor cells was present in the other 4 patients. Significant hyperplasia of fibroblasts was present in 4 cases, large amount of lymphocytes infiltration in 3 cases including concurrent plasma cell infiltration in 1 case, multinucleated giant cell reaction in the muscular layer of 1 case, and foam cells aggregation in 1 case with mucinous adenocarcinoma. In addition, there were 2 cases with pCR had lymph node metastasis. CONCLUSIONS: For cases with pCR following neoadjuvant chemotherapy, heterogeneity of stromal cells reaction is found in previous tumor site. Furthermore, the response of primary tumor does not necessarily parallel to that of lymph nodes.

Endometrial stromal sarcoma of uterus.

Endometrial stromal sarcomas are the second most common uterine sarcomas. Currently, they are classified into low-grade endometrial stromal sarcomas and undifferentiated endometrial sarcoma. Low-grade endometrial stromal sarcomas are biologically low-grade uterine sarcomas, and typically composed of uniform cells intimately associated with prominent arterioles, resembling the endometrial stroma in proliferative phase. There is usually little cytological atypia or pleomorphism, and mitoses are scanty. In contrast, undifferentiated endometrial sarcomas are frankly malignant, lack specific differentiation and any features of normal endometrial stroma. It is a highly aggressive neoplasm, often exhibiting myometrial invasion, haemorrhage and necrosis, as well as marked nuclear pleomorphism and high mitotic activity. The diagnosis of undifferentiated endometrial sarcoma is reached after excluding other uterine tumours with a sarcomatous component, such as adenosarcoma and malignant mixed Müllerian tumour. Histological variants of endometrial stromal sarcomas, including the so called 'high-grade endometrial stroma sarcomas' are addressed. The problems with histologic diagnosis and application of immunohistochemical studies and molecular pathology are highlighted.

Correlation of diffusion-weighted imaging data with apoptotic and proliferation indexes in CT26 colorectal tumor homografts in balb/c mouse.

PURPOSE: To investigate whether the percentage of apparent diffusion coefficient (ADC) changes could be used as an imaging marker related to tumor cell apoptotic and Ki-67 proliferation index of tumors. MATERIALS AND METHODS: Mice bearing CT26 colorectal carcinoma tumors were scanned before radiotherapy, then divided into radiotherapy (n = 24) and control groups (n = 24). Diffusion-weighted imaging (DWI) and anatomic T2WI were performed on six randomly chosen mice in total from two groups at different timepoints after radiotherapy (4, 8, 12 hours, 1, 2, 3, 5, 7 days). After imaging, six animals were sacrificed at each timepoint and histological analyses were undertaken. ADC maps were calculated on a pixel-by-pixel basis using built-in software (Functool, GE). Regions of interest were manually circumscribed for all high-signal areas on lesions observed during DWI. The percentage of ADC changes were calculated at predefined timepoints and compared with the apoptotic and proliferation index from the histological analyses by using the Pearson correlation test. RESULTS: A significant positive correlation was found between the percentage of ADC changes of the viable tissue and apoptotic index. A significant negative correlation was found between the percentage of ADC changes of the viable tissue and Ki-67 proliferation index. CONCLUSION: Our results suggest that the percentage of ADC changes can be used as a measurement of cell apoptotic and proliferation index in colorectal carcinoma.

Effect of multidisciplinary team treatment on outcomes of patients with gastrointestinal malignancy.

AIM: To evaluate the effect of multidisciplinary team (MDT) treatment modality on outcomes of patients with gastrointestinal malignancy in China. METHODS: Data about patients with gastric and colorectal cancer treated in our center during the past 10 years were collected and divided into two parts. Part 1 consisted of the data collected from 516 consecutive complicated cases discussed at MDT meetings in Peking University School of Oncology (PKUSO) from December 2005 to July 2009. Part 2 consisted of the data collected from 263 consecutive cases of resectable locally advanced rectal cancer from January 2001 to January 2005. These 263 patients were divided into neoadjuvant therapy (NT) group and control group. Patients in NT group received MDT treatment, namely neoadjuvant therapy + surgery + postoperative adjuvant therapy. Patients in control group underwent direct surgery + postoperative adjuvant therapy. The outcomes in two groups were compared. RESULTS: The treatment strategy was altered after discussed at MDT meeting in 76.81% of gastric cancer patients and in 58.33% of colorectal cancer patients before operation. The sphincter-preservation and local control of tumor were better in NT group than in control group. The 5-year overall survival rate was also higher in NT group than in control group (77.23% vs 69.75%, P = 0.049). CONCLUSION: MDT treatment modality can significantly improve the outcomes of patients with gastrointestinal malignancy in China.

[Epidermal growth factor receptor gene mutations and clinicopathologic correlation in 309 patients with non-small cell lung cancer].

OBJECTIVE: To investigate the epidermal growth factor receptor (EGFR) gene mutation profile and related clinicopathological features in Chinese patients with non-small cell lung carcinoma (NSCLC). METHODS: Optimized oligonucleotide probe method was applied to detect EGFR mutations involving exons 18 - 21 using formalin fixed paraffin embedded tissue specimens of 309 NSCLC patients. The relationship between EGFR mutations and clinicopathological features were analyzed. RESULTS: The overall EGFR mutation rate was 34% (105/309) in this study cohort. Mutation rates in male and female were 30.4% (56/184) and 39.2% (49/125), respectively. The mutation rate was higher in patients less than 60 years of age, non-smokers and adenocarcinoma subtype than in their counterparts (P<0.05), with the percentage of 40.5% (87/215), 40.2% (51/127), 38.8% (78/201), respectively. The EGFR mutation types included exon 18 G719X mutation (5.7%, 6/105), exon 19 deletion (39.0%, 41/105) and exon 21 L858R mutation (55.2%, 58/105). In large cell undifferentiated carcinomas and squamous cell carcinomas, EGFR mutation rates were 22.2% (58/105) and 3/14, respectively. The overall mutation rate of exon 18 was low, but the proportion of its mutation was higher in squamous and adenosquamous carcinomas than in adenocarcinomas. CONCLUSIONS: There is a higher EGFR mutation rate in female, age of less than 60 years, non-smoker and adenocarcinoma among Chinese patients with NSCLC. Optimized oligonucleotide probe method is a sensitive and convenient method for the detection of EGFR mutations.

[Comparison of pathologic and clinical characteristics of young and old patients with advanced rectal cancer after neoadjuvant radiotherapy].

OBJECTIVES: To address the difference of pathologic and clinical characteristics of the young and the middle-aged and elderly patients with advanced rectal cancer after neoadjuvant radiotherapy. METHODS: A total of 252 patients undergoing radical surgery from January 2000 to January 2005 were included in this study. The patients were divided into two groups according to the age at diagnosis:young-patient group (< 40 years) and old-patient group (≥ 40 years). The pathologic and clinical materials were collected and the oncologic outcome was compared between the two arms. RESULTS: A total of 252 patients were included in this study, included 54 patients in young-patient group and 198 patients in old-patient group, respectively. There was no significant difference in gender, clinical stage and pretreatment serum carcinoembryonic antigen (CEA) between the two groups. However, the proportion of mucinous and signet-ring cell cancer was significantly higher in young-patient group (20.4% vs. 4.0%, P < 0.05), and furthermore, the proportion of pathologic stage later than IIIA was also significantly higher in the young-patient group (61.1% vs. 42.9%, P < 0.05). There was no significant difference in local recurrence rate between the patients who received neoadjuvant radiotherapy and those who did not in the young-patient group, whereas the difference was observed significant in the old-patient group (3.3% vs. 11.2%, P < 0.05). There was no significant difference in both the disease free survival and overall survival between the two arms (5y-DFS: 63.3% vs. 68.5%, P > 0.05; 5y-OS: 73.5% vs. 72.9%, P > 0.05). CONCLUSIONS: Rectal cancer in young patients has poorer histologic differentiation and more advanced pathologic stage, but the long-term survival is similar to that in middle-aged and elderly patients. The local control effect of neoadjuvant radiotherapy on rectal cancer in young patients still need to be further investigated.

Lymphovascular invasion in rectal cancer following neoadjuvant radiotherapy: a retrospective cohort study.

AIM: To investigate the meaning of lymphovascular invasion (LVI) in rectal cancer after neoadjuvant radiotherapy. METHODS: A total of 325 patients who underwent radical resection using total mesorectal excision (TME) from January 2000 to January 2005 in Beijing cancer hospital were included retrospectively, divided into a preoperative radiotherapy (PRT) group and a control group, according to whether or not they underwent preoperative radiation. Histological assessments of tumor specimens were made and the correlation of LVI and prognosis were evaluated by univariate and multivariate analysis. RESULTS: The occurrence of LVI in the PRT and control groups was 21.4% and 26.1% respectively. In the control group, LVI was significantly associated with histological differentiation and pathologic TNM stage, whereas these associations were not observed in the PRT group. LVI was closely correlated to disease progression and 5-year overall survival (OS) in both groups. Among the patients with disease progression, LVI positive patients in the PRT group had a significantly longer median disease-free period (22.5 mo vs 11.5 mo, P = 0.023) and overall survival time (42.5 mo vs 26.5 mo, P = 0.035) compared to those in the control group, despite the fact that no significant difference in 5-year OS rate was observed (54.4% vs 48.3%, P = 0.137). Multivariate analysis showed the distance of tumor from the anal verge, pretreatment serum carcinoembryonic antigen level, pathologic TNM stage and LVI were the major factors affecting OS. CONCLUSION: Neoadjuvant radiotherapy does not reduce LVI significantly; however, the prognostic meaning of LVI has changed. Patients with LVI may benefit from neoadjuvant radiotherapy.

[Clinical analysis of rectal neuroendocrine carcinoma:a report of 16 cases].

OBJECTIVE: To study the clinical data and surgical treatment strategy of rectal neuroendocrine carcinoma (NEC). METHODS: Sixteen cases of rectal NEC and 222 cases of rectal carcinomas receiving surgical treatment in Beijing Cancer Hospital from 2003 to 2007, were analyzed retrospectively. RESULTS: Among the 16 rectal NEC patients, 4(25%) received Miles surgery, 7(43.8%) Dixon surgery, 2 combined multiple organ resection and 3 local resection. Lymph note metastases occurred in 11 cases(68.8%) and distant metastases in 7 cases (43.8%). Among the 222 rectal carcinoma patients, 43(19.4%) received Miles surgery, 152(68.5%) Dixon surgery, 12 palliative operation, 6 colostomy and 9 just received laparotomy. Lymph note metastases occurred in 125 cases (56.3%). In rectal NEC group, postoperative 1-, 2- and 3-year survival rates were 62.5%, 25.0% and 0.63% respectively, which were significantly lower than 83.1%, 61.7% and 46.1% in rectal carcinoma group(all P<0.01). CONCLUSIONS: Rectal NEC is a rare disease. More vascular invasion, lymph node and distant organ metastases are found in rectal NEC than rectal carcinoma, and the prognosis of rectal NEC is worse than rectal cancer.

[Clinicopathologic analysis and expression of cyclin D1 and p53 of ovarian borderline tumors and carcinomas].

OBJECTIVE: To study the clinicopathological features and expression of cyclin D1 and p53 in epithelial ovarian tumors, and to investigate the correlation between pathogenesis of ovarian cancer and epithelial borderline tumors. METHODS: Fifty four cases of ovarian borderline tumors and 45 cases of ovarian carcinomas from the People's Hospital, Peking University were reviewed retrospectively. The clinical data and pathological findings were analyzed. Immunohistochemical study of cyclin D1 and p53 was performed in all 99 cases. RESULTS: (1) In borderline tumors, the age of patients ranged from 14 - 82 (mean age = 42.5) years. International Federation of Gynecology and Obstetrics (FIGO) stage of borderline tumors was stage I in 48 cases, stage II in 3 cases, and stage III in 3 cases. In ovarian carcinomas, the age of patients ranged from 26 - 80 (mean age = 53.5) years. FIGO stage of carcinoma was stage I in 6 cases, stage II in 8 cases, stage III in 26 cases, and stage IV in 5 cases. In follow-up of 54 cases with borderline tumors the 5-year survival rate was 98% and of 45 cases with carcinomas a 5-year survival rate of 51% was noted. (2) In 54 cases of borderline tumors, mucinous types accounted for 56% (30/54) and serous types accounted for 30% (16/54). There were 5 cases with micropapillary pattern, 3 cases with peritoneal implants, 3 cases with lymph node involvement, 6 cases with microinvasion, one case with intraepithelial carcinoma, and one case with mural nodules. In 45 cases of carcinomas, serous carcinoma was the most (49%, 22/45). The remainder included 3 cases of mucinous types, 8 cases of endometrioid types, 6 cases of transitional cell types, 3 cases of mixed phenotype and 3 cases of undifferentiated types. (3) Overexpression of cyclin D1 and p53 was observed in 31% (14/45) and 56% (25/45) of ovarian carcinomas, respectively. There was a significant association between p53 overexpression and tumor grade. In the borderline tumor group, 69% (37/54) had overexpression of cyclin D1 and 6% (3/54) had overexpression of p53. There were significant differences in expression of cyclin D1 and p53 between conventional serous borderline tumors and high-grade serous carcinomas (cyclin D1: 91% vs 26%; p53: 0 vs 58%). However, micropapillary serous borderline tumors and low-grade serous carcinomas showed remarkably similar expression of cyclin D1 and p53. CONCLUSIONS: Epithelial ovarian borderline tumors are distinct from ovarian cancer in clinical progress and prognosis, and histological types. Overexpression of cyclin D1 is common in ovarian borderline tumors and low grade carcinomas. And overexpression of p53 is more common in high grade ovarian carcinomas. Conventional serous borderline tumors are distinct from high-grade serous carcinomas in pathogenesis. Micropapillary serous borderline ovarian tumors may be closely related to low grade serous carcinomas.

Detection of mosaic pattern of mitochondrial DNA alterations in different populations of cells from the same endometrial tumor.

Somatic mitochondrial DNA (mtDNA) alterations including point mutations and microsatellite instability (MSI) have been frequently detected in human cancers. To further explore the extensiveness of mtDNA alterations, we have analyzed the occurrence of somatic mtDNA mutations in different populations of endometrial cancer cells from the same tumor tissues as compared with adjacent non-tumor cells. Laser-captured micro-dissection was used to harvest endometrial cancer cells from separated areas of the same tumor and adjacent normal cells. Total DNA isolated from micro-dissected cells was PCR amplified and analyzed for mtDNA alterations by polyacrylamide gel electrophoresis and DNA sequencing. Multiple mtDNA alterations were detected in different portions of the same tumor. Different populations of endometrial cancer cells carried different patterns of mtDNA mutations. Interestingly, unlike previous reports, most mutations were found to be heteroplasmic. We have demonstrated the occurrence of hyper-variability of mtDNA alterations in a single piece of tumor tissue. Our observations support the hypothesis that the accumulation of mtDNA alterations is random and expands independently. The data presented here showed the heterogeneity of cancer cells in terms of mtDNA alterations in endometrial cancer.

Differential expression of insulin-like growth factor binding protein 1 and ferritin light polypeptide in gestational trophoblastic neoplasia: combined cDNA suppression subtractive hybridization and microarray study.

BACKGROUND: Hydatidiform mole (HM), the most common type of gestational trophoblastic diseases, can be considered as placenta with abnormal chromosome composition with potential of malignant transformation. Few biologic markers can predict subsequent development of persistent gestational trophoblastic neoplasia (GTN) requiring chemotherapy. METHODS: Suppression subtractive hybridization (SSH) combined with cDNA microarray was used to compare the differential expression pattern of HM that spontaneously regressed and that subsequently developed metastatic GTN. Tissue-specific chips were constructed from the subtracted cDNA libraries, followed by cDNA microarray analysis. Verification by quantitative RNA analysis by real-time polymerase chain reaction (PCR) and immunohistochemical analysis was performed in 23 genotyped complete HM. RESULTS: Sixteen differentially expressed transcripts were identified. Quantitative RNA analysis confirmed down-regulation of ferritin light polypeptide (FTL) (P = 0.037) and insulin-like growth factor binding protein 1 (IGFBP1) (P = 0.037) in HM that subsequently developed GTN when compared with those HM that regressed. Immunohistochemical analysis further confirmed reduced IGFBP1 protein (P = 0.03) expression in HM that developed GTN. CONCLUSIONS: Findings showed that reduced expression of genes related to cell invasion and immunosuppression, especially FTL and IGFBP1, were associated with development of GTN, and this finding may provide a better understanding of the pathogenesis of GTN. The potential application of FTL and IGFBP1 in management of patients with HM should be explored.

The increase of mitochondrial DNA content in endometrial adenocarcinoma cells: a quantitative study using laser-captured microdissected tissues.

OBJECTIVE: Microsatellite instability (MSI) is a frequent genetic event in the D-loop region (which controls mitochondrial DNA (mtDNA) replication) of mitochondrial genome of endometrial cancer. We therefore investigated the relationship between mtMSI and mtDNA content in endometrial cancer. METHODS: Tumor tissues from 65 cancer patients and normal tissues from 41 non-cancer patients were used in this study. Pure endometrial adenocarcinoma cells and normal endometrial glandular epithelial cells were collected by laser capture microdissection, and analyzed for levels of mtDNA copy number by real-time quantitative PCR. RESULTS: Our data show that mtDNA copy number was not related with age in both endometrial cancer and normal endometrium cells. Great inter-individual variations in mtDNA copy number in endometrial cancer group were found; and mtDNA content was significantly larger than that in normal endometrium group. About 2-fold increase of mtDNA copy number was found in endometrial adenocarcinoma compared with normal endometrial glandular epithelium (P = 0.001). In particular, the analysis also shows that the copy number of mtDNA in the cases that carried the mtMSI at nucleotide position 303 was significantly higher than that of the negative cases (P = 0.048). CONCLUSIONS: Our data indicate that mtDNA copy number increased during endometrial cancer development. There is also a correlation between the mtDNA instability and mtDNA content in endometrial cancer cells. Role of mitochondrial genome changes in carcinogenesis warrants further investigation.