Resistance to apoptosis should not be taken as a hallmark of cancer.

In the research community, resistance to apoptosis is often considered a hallmark of cancer. However, pathologists who diagnose cancer via microscope often see the opposite. Indeed, increased apoptosis and mitosis are usually observed simultaneously in cancerous lesions. Studies have shown that increased apoptosis is associated with cancer aggressiveness and poor clinical outcome. Furthermore, overexpression of Bcl-2, an antiapoptotic protein, is linked with better survival of cancer patients. Conversely, Bax, CD95, Caspase-3, and other apoptosis-inducing proteins have been found to promote carcinogenesis. This notion of the role of apoptosis in cancer is not new; cancer cells were found to be short-lived 88 years ago. Given these observations, resistance to apoptosis should not be considered a hallmark of cancer.

Overexpression of c-erbB-2 and loss of p16 have molecular diagnostic relevance but no prognostic value in lung cancer.

This study was designed to evaluate the expression of C-erbB-2 and p16 in lung cancers using tissue microarray technology and to determine their clinical and pathological significance. Immunohistochemical C-erbB-2 and p16 expressions and their associations with clinical and pathological features were analyzed in two tissue microarrays. The membranous and cytoplasmic expression rates of C-erbB-2 were 40.5 and 66.5% in non-small cell lung cancers (NSCLCs), and 0 and 9.5% in small cell lung cancers (SCLCs), respectively. The nuclear and cytoplasmic expression rates of p16 were 11.5 and 32.2% in NSCLs, and 45 and 80% in SCLCs, respectively. The cytoplasmic expression of both C-erbB-2 and p16 was more frequent than the membranous expression of C-erbB-2 and the nuclear expression of p16. The rates of overexpression of C-erbB-2 and loss of p16 expression were significantly higher in NSCLCs than in SCLCs (P < 0.05). Neither C-erbB-2 nor p16 expression was significantly associated with age, tumor grade or stage, presence of lymph node metastasis or survival duration. The abnormal expressions of p16 and C-erbB-2 may play a role in the progression of lung cancers. The variations in the expression patterns of C-erbB-2 and p16 between NSCLCs and SCLCs may aid the molecular classification of lung cancer. The abnormal expression of p16 may be involved in the development of NSCLCs, and the overexpression of C-erbB-2 in NSCLCs indicates that it can be a candidate target for gene therapy.

[Detection of micrometastases in sentinel lymph nodes of breast cancer].

OBJECTIVE: To investigate an optimal examination method to detect micrometastases in sentinel lymph nodes (SLNs) of breast cancer. METHODS: Firstly, the SLNs of breast cancer were found by 99mTc-DX isotope method. Secondly, all the SLNs which were negative by routine HE examination were serially sectioned at a 100 microm interval and stained by both HE and immunohistochemistry for detecting micrometastases. All tumor tissue paraffin blocks were also sectioned and stained with HE and immunohistochemistry as control. RESULTS: Totally, 121 SLNs and 44 tumors of 59 patients were examined. Micrometastasis was found to be positive in 17 SLNs (14.0%) of 14 patients (23.7%). When examined number of sections was increased from one to three, more positive micrometastatic SLNs were detected by HE staining only (3, 7, 10 for 1, 2, 3 sections, respectively). When HE staining was combined with immunohistochemical staining for AE1/3 or CK19 or muc1, much more positive micrometastatic SLNs were found (14, 12, 16 for 1, 2, 3 sections, respectively). The more sections were examined, the more micrometastases in SLNs were found. Furthermore, micrometastasis was also found to be positively correlated with the tumor size and the expression of c-erbB2, MMP-2, VEGF. The larger the tumor size was or the stronger expression of the above mentioned biomarkers, the more micrometastases in SLNs could be found. CONCLUSION: Serially sections at a 100 microm interval and staining with both HE and immunohistochemical technique using muc1 antibody may be the best way to detect micrometastases in sentinel lymph nodes in breast cancer patients.

[Intra-abdomen extragastrointestinal stromal tumors: a clinicopathologic study on 30 cases].

OBJECTIVE: To investigate the clinicopathological characteristics and prognostic factors in patients with intra-abdomen extragastrointestinal stromal tumors (EGISTs). METHODS: The data of 47 patients of mesenchymal neoplasms that arose from the abdominal cavity and retroperitoneum, collected from July 1987 to June 2003 in our hospital with complete clinical and pathological data, were investigated retrospectively. EGISTs were diagnosed by reviewing the tumor slides stained with hematoxylin and eosin (H&E). Immunohistochemistry staining were performed on CD117, CD34, smooth muscle actin, Desmin and S-100 proteins. The relations of various clinicopathologic characteristics and outcomes were examined. RESULTS: Among the 47 cases, 30 tumors were confirmed to be EGISTs. Twelve cases arose from the mesentery, six from small omentum, eight from retroperitoneum and four from the abdominal cavity. The size of tumors ranged from 4 to 30 cm (median 12.5 cm) in diameter and the tumor cell components mainly included spindle cells (23 cases), epithelioid cells (4 cases), and mixed cells (3 cases). The follow-up rate was 90% and the median follow up time was 44 months. The patient survival rates at 1, 5 and 10 years were 79.7%, 59.5% and 45.4% respectively. Univariate analysis showed that tumor size >10 cm, tumor necrosis, mitoses > or =5/50HPF, obvious nuclear atypia, moderate and poor differentiated tumor cells were predictors of poor prognosis. CONCLUSIONS: EGISTs have specific clinical behaviors. The parameters used for predicting GISTs prognosis are not completely applicable for EGISTs. Tumor necrosis, obvious nuclear atypia and mitoses > or =5/50HPF help to predict aggressive behaviors in EGISTs.

Amplification and overexpression of CTTN (EMS1) contribute to the metastasis of esophageal squamous cell carcinoma by promoting cell migration and anoikis resistance.

Gain of chromosome 11q13 is a common event in esophageal squamous cell carcinoma (ESCC). The cortactin gene (CTTN, also EMS1), located at 11q13, plays a pivotal role in coupling membrane dynamics to cortical actin assembly. This gene has been implicated in the motility of several types of cells. In the present study, we found that the amplification and overexpression of the CTTN gene was associated with lymph node metastasis in ESCC. Functional analysis by small interfering RNA-mediated silencing of CTTN revealed that in addition to the effect on cell migration, CTTN influenced cell invasiveness by anoikis resistance. In vivo assay showed that inhibition of CTTN expression also decreased tumor growth and lung metastasis of ESCC cells. At the molecular level, we showed for the first time that the protective role of CTTN in anoikis resistance was correlated with the activation of the phosphatidylinositol 3-kinase/Akt pathway. Overall, the data suggest that CTTN is an oncogene in the 11q13 amplicon and exerts functions on tumor metastasis in ESCC.

Synchronous occurrence of carcinoid, signet-ring cell carcinoma and heterotopic pancreatic tissue in stomach: A case report and literature review.

We presented an unusual case with coexistence of carcinoid, signet-ring cell carcinoma (SRC) and heterotopic pancreatic tissue in stomach. Gastroscopic examination of this 63-year-old male patient showed multiple protrusions in gastric corpus near the greater curvature, identified by subsequent biopsy as carcinoid. Distal subtotal gastrectomy was performed. Histological and immunohistochemical examinations showed a carcinoid tumor in gastric corpus near the greater curvature, an intramucosal SRC at the lesser curvature of corpus and heterotopic pancreatic tissue in muscularis propria of the antrum at the lesser curvature with hyperplasia of peripheral endocrine cells producing multiple pancreatic hormones. We reviewed the literatures on clinicopathological characteristics and the differential diagnosis of the above three abnormalities, and concluded that the carcinoid in corpus near the greater curvature and SRC in the lesser curvature are independent lesions; the foci of endocrine cells in the muscularis propria and serosa are hyperplastic lesions from the heterotopic pancreatic tissue, rather than dissemination of carcinoid in corpus.

[Treatment option and outcome for patients with primary non-Hodgkin's lymphoma of the nasal cavity].

OBJECTIVE: The optimal treatment for primary non-Hodgkin's lymphoma (NHL) of the nasal cavity remains controversial. This study was to analyze the initial response rate of radiotherapy and chemotherapy, and the influence of different treatment modalities on prognosis. METHODS: From January 1996 to December 2002, the clinical data of 129 patients with previously untreated nasal NHL were retrospectively reviewed with all lesions confirmed by pathology. 116 patients were morphologically diagnosed as having nasal NK/T cell lymphoma. The immunophenotype was available in 57 cases and 52 (91.2%) of them were confirmed as NK/T-cell lymphoma. According to the Ann Arbor Staging System, 102 patients had stage I(E), 22 stage II(E), and 5 stage IV(E) disease. Among the 124 patients with stage I(E) and II(E) diseases, 22 patients received radiotherapy alone, 7 chemotherapy alone, and 95 combined modality therapy (CMT). Of these 95 patients treated with CMT, 45 patients were treated with radiotherapy followed by chemotherapy, and 50 with chemotherapy followed by radiotherapy. The primary treatment for stage IV(E) patients was chemotherapy with or without radiotherapy to the primary tumor. RESULTS: The overall 5-year survival (OS) and disease free survival (DFS) for all patients was 68.0% and 55.8%, respectively. It was 71.7% and 60.9% for stage I(E), and 70.6% and 47.0% for stage II(E), respectively (P > 0.05). The OS and DFS at the 5th year were 83.1% and 68.0% for patients who achieved complete response (CR), and 18.0% and 15.5% for those who did not, respectively (P = 0.000). Of the 124 patients with stage I(E) and II(E) disease, 67 patients were treated with radiotherapy alone (22 patients) or radiotherapy followed by chemotherapy (45), whereas 57 were treated with chemotherapy followed by radiotherapy (50) or chemotherapy alone (7). The CR rate after radiotherapy was 74.7%, however, it was only 19.3% after chemotherapy (P = 0.000). Of the 46 patients with PR, SD or PD after chemotherapy, 42 still had locoreginally localized lesion and 31 of these patients achieved CR by following radiotherapy which revealed satisfactory results. For stage I(E) and II(E) disease, the 5-year OS and DFS were 76.0% and 65.0% for radiotherapy with or without chemotherapy, and 74.4% and 56.2% for chemotherapy followed by radiotherapy. The difference was statistically not significant. However, 7 stage I(E) and II(E) patients were treated with chemotherapy alone, and 4 of them died of disease progression, with 1-year survival of 26.7%. CONCLUSION: The majority of Chinese patients with primary nasal NHL are NK/T cell in origin. The complete response rate by radiotherapy is much higher than that by chemotherapy. The addition of chemotherapy to radiotherapy did not improve the survival of patients with early stage nasal lymphoma. Radiotherapy is suggested as the primary treatment for stage I(E) and II(E) nasal NK/T cell lymphoma.

[Differential diagnostic value of B72.3, Ber-EP4 and calretinin in serous effusions].

OBJECTIVE: To determine the diagnostic value of B72.3, BerEP4 and calretinin in differentiating metastatic carcinoma cells from reactive mesothelial cells (RMC) in serous effusions by using immunocytochemical method (ICC), and to investigate the feasibility of ThinPrep (TP) preparation for ICC. METHODS: One hundred fifty eight serous effusion specimens were examined by ICC on cell block (CB) sections (CB-ICC) using antibodies against of B72.3, BerEP4 and calretinin. Fourty-nine of the samples, ICC on ThinPrep slides (TP-ICC) and CB-ICC were performed concurrently. RESULTS: The sensitivities of B72.3 and Ber-EP4 for detecting carcimoma cells were 76.9% and 69.2% respectively, and when combined the sensitivity was increased to 89.7%. The sensitivity and specificity of Calretinin for detecting mesothelial cells were 90.9% and 87.2% respectively. The sensitivity of B72.3 in differentiating cancer cells from reactive mesothelial cells by CB-ICC and TP-ICC was 78.9% and 68.4%. It was 78.9% and 68.4% of BerEP4 respectively. No statistical significance was observed between CB-ICC and TP-ICC in differentiating metastatic carcinoma cells from reactive mesothelial cells. CONCLUSION: The combination of antibodies of B72.3, Ber-EP4 and calretinin is quite helpful as an auxiliary in differentiating metastatic carcinoma cells from reactive mesothelial cells. ThinPrep preparation slides may effectively replace the cell block sections for ICC in differential diagnosis of serous effusions.

[Analysis of prognostic factors in gastrointestinal stromal tumors of the small intestine].

OBJECTIVE: To explore the prognostic factors in patients with gastrointestinal stromal tumors of the small intestine. METHODS: Tumor slides stained with hematoxylin and eosin from these patients were reviewed. Two histomorphologically representative areas were identified and arrayed on a tissue microarray. Immunohistochemistry staining were performed using antibodies to detect the expression of c-kit protein (CD117), CD34, smooth muscle actin, desmin, S-100, Ki-67, P53 and bcl-2 protein. The relationship between clinicopathologic features and prognosis was analyzed by univariate analysis. RESULTS: The 1-, 3-, 5-year survival rate of 58 such patients were 98.3%, 69.7%, and 50.9% respectively. The prognosis was related with tumor size and gender by univariate analysis (P< 0.05). CONCLUSION: More attention should be paid to the male patients with small intestine stromal tumors,especially those with tumors size> 5 cm, because those tumors are more likely to metastasize than smaller tumors (< or = 5 cm).

[Mediastinal lymph nodes micro-metastases in patients with clinical stage I-II lung cancer].

OBJECTIVE: To investigate micro-metastasis in mediastinal lymph nodes (mLN) of patients with clinical stage I approximately II lung cancer and its clinical significance. METHODS: A total of 181 mLN from 32 lung cancer patients in clinical stage I approximately II were collected during operation and their frozen sections at two different levels were examined immunohistochemically (IHC) with an anti-epithelial cell monoclonal antibody Ber-Ep4. Routine HE staining was done for comparison. The results were processed by Chi-square tests in SPSS 10.0 soft ware. RESULTS: Fifteen of the 32 patients (46.9%) were found to have micro-metastasis in 21 of 181 mLN (11.6%) examined by immunohistochemical staining though routine histopathological examinations were negative. Of those 15 cases, micro-metastasis was detected in 9 only by IHC and in 6 both by IHC and HE stainings. The positive rate of micro-metastasis in N0, N1, and N2 stratified by routine pathology was 36.8% (7/19), 33.3% (2/6) and 85.7% (6/7), respectively (N0 vs N2, P < 0.05). When stratified according to clinical staging (cTNM), pathological staging (pTNM) and pathological staging on the basis of IHC (iTNM), the frequencies of N2 cases were 0, 18.8% and 46.9%, respectively (differences among the three groups: P < 0.01). Nine cases reported as N0(7) and N1(2) by routine histopathological examination were found to have micro-metastasis in mLN by IHC staining, therefore they were actually N2 cases. CONCLUSION: IHC staining with a monoclonal antibody specific for epithelial cells (Ber-Ep4) is more sensitive in the detection of mediastinal micro-metastais than routine HE staining. Underestimation of the extent of mLN metastasis by cTNM and/or pTNM stagings frequently exists in patients with clinically early lung cancer.

Tight association of hepatocellular carcinoma with HBV infection in North China.

BACKGROUND: Hepatocellular carcinoma (HCC) is the second most common cancer in China. Hepatitis B and C viruses (HBV and HCV) and aflatoxins are known risk factors for HCC, but the etiological status of these factors in HCC development is not clear. This study was undertaken to define the absolute importance of HBV in hepatocarcinogenesis of North China. METHODS: A consecutive series of 119 patients with pathologically proven HCC were collected from North China during January 1998 to December 2000 by the Cancer Hospital of the Chinese Academy of Medical Sciences, Beijing. Serum HBsAg, anti-HBc and anti-HCV were negative HBV sero-markers. The HBV X gene was analyzed for its expression by PCR, DNA sequencing, and immunohistochemistry. RESULTS: In the 119 HCC patients, 82.4% (98/119) were HBsAg seropositive. When a comprehensive set of HBV markers were detected, the HBV infection rate in these HCC patients was 99.2% (118/119). Of the patients, 11.8%(14/119) were found to be anti-HCV positive. But all the anti-HCV positive HCC patients were co-infected with HBV. CONCLUSIONS: HBV infection is virtually ubiquitous in HCC patients in North China. The tight association of HBV with HCC strongly suggests the dominant role of HBV infection in causing hepatocellular carcinoma. About 11.8% of HCC patients being HCV-related are co-infected with HBV.

[Multivariate analysis of prognosis in gastrointestinal stromal tumor].

OBJECTIVE: To identify prognostic factors in patients with gastrointestinal stromal tumors (GIST). METHODS: Hematoxylin and eosin (H&E) stained histopathological slides of tumors from patients with mesenchymal neoplasms growing in the gastrointestinal tract and abdomen were reviewed. Two histologically representative areas were identified and chosen for tissue microarray. Immunohistochemical staining was performed to demonstrate c-kit protein (CD117), CD34, smooth muscle actin, desmin and S-100 protein. The relations of various clinicopathologic features to outcome were analyzed. RESULTS: The overall disease-specific survival of 194 patients was 93.5% at 1 year, 72.1% at 3 years and 63.2% at 5 years. Univariate analysis indicated that the tumor size, mitotic count, primary location, necrosis, high cellularity, mucosal invasion, mixed cell type, hemorrhage, direct tumor invasion of surrounding tissue, male sex, incompleteness of resection, cytologic atypia were significant predictors of survival. Multivariate analysis showed that tumor size, mitotic count, necrosis, direct tumor invasion of surrounding tissue and male sex were poor prognostic signs. CONCLUSION: Tumor size and mitotic count are important prognostic factors. However, to evaluate the prognosis of these tumors, a surgical pathologist should incorporate multiple parameters into their histologic evaluation in attempt to reach an appropriate opinion on the aggressiveness of GIST.

[Relationship between overexpression of the RIalpha subunit of the cAMP-dependent protein kinase and clinicopathological features of lung cancer].

OBJECTIVE: To explore the relationship between the overexpression of PKA RIalpha mRNA and cliniopathological parameters in lung cancer. METHODS: RT-PCR was used to detect the expression of PKA RIalpha mRNA in 54 cases with human lung cancer and matched normal tissues. RESULTS: (1) The expression of PKA RIalpha mRNA was significantly higher in cancer tissue (66.7%) than in normal tissues (20.4%) (P < 0.01). (2) The expression was significantly correlated with TNM stage (P < 0.01), being increased with TNM stage. (3) The expression was significantly higher in patients with positive lymph nodes than in those with negative lymph nodes (P < 0.01). (4) There were no significant associations of PKA RIalpha mRNA expression with histological type, differentiation grade or size of the tumor. CONCLUSION: This study indicates that the overexpression of PKA RIalpha mRNA may play an important role in the progression, metastasis and prognosis of lung cancer.

[A comparison of Thinprep and conventional smears].

OBJECTIVE: To analyze ThinPrep (TP) application by comparing TP slides with conventional smear (CS) slides in fine needle aspiration cytology. METHODS: A total of 522 samples from the breast, metastatic cancer, lymph node, thyroid and salivary gland were used in parallel preparations of one TP slide and one CS slide. The paired slides were compared according to cell quality, overall cellularity, cell preservation, nuclear architecture and background. RESULTS: Cell quality of TP was superior to CS in the breast group (36.2%, 28.0%, P > 0.05) and metastatic cancer group (51.0%, 14.9%, P < 0.05), but inferior to CS in lymph node group (16.5%, 58.2%, P > 0.05). Cellularities of TP and CS were similar in breast groups (25.1%), while TP had greater cellularity than CS in metastatic cancer group (32.2%, 21.8%, P > 0.05). Cell preservation and abnormal architecture of TP were superior to CS in breast group (36.7%, 12.1%, P < 0.05) and metastasis cancer group (60.9%, 9.4%, P < 0.05). Cell quality of TP slide was inferior to CS in lymph node group (16.5%, 58.2%, P < 0.05) with 27 of the 46 cases showing tuberculosis. Cell quality of TP and CS slide was similar in the thyroid and salivary gland group (35.3%). Myoepithelial cells of fibroadenoma on the TP slide were decreased in number and, due to the increased papillary and flattened cells, it was easy to diagnose benign lesion. CONCLUSION: In the breast group and metastatic cancer group, cell quality of the TP slides is superior to CS, but they are similar in thyroid and salivary gland group. The difference of diagnosis criteria between TP and CS slides exists only in tuberculosis, partly the reactive hyperplasia cases.

[Expression of annexin II in human esophageal squamous cell carcinoma].

OBJECTIVE: To evaluate the expression of annexin II in human esophageal squamous cell carcinoma (ESCC) and its relation with clinicopathological data. METHODS: The expression of annexin II mRNA and protein in paired cancer tissues and their adjacent quasi-normal tissues were detected by RT-PCR, immunohistochemical method and densitometric scanning. The relation between annexin II expression and the status of tumor differentiation was analyzed. RESULTS: The expression of annexin II was significantly lower in the tumor tissue than that in its paired normal counterpart both in mRNA and protein level (P < 0.05, P < 0.01). The protein expression of annexin II was significantly lower in moderately and poorly differentiated tumors than those in well differentiated ones (P < 0.05). CONCLUSION: Down-regulation of annexin II in esophageal carcinogenesis may play an important role in squamous cell differentiation.