Correlation between matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 and white matter hyperintensities in patients with cerebral small vessel disease based on cranial magnetic resonance 3D imaging.

OBJECTIVE: The objective of this study was to investigate the correlation between serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels and their ratios with the severity of white matter hyperintensities (WMHs) in patients with cerebral small vessel disease (CSVD). METHODS: This cross-sectional study was done on a prospective cohort of patients with CSVD. Qualitative and quantitative analyses of WMHs were performed using Fazekas grading and lesion prediction algorithm (LPA) methods. Biomarkers MMP-2, MMP-9, and TIMP-1 were measured to explore their correlation with the severity of WMHs. RESULTS: The sample consisted of 144 patients with CSVD. There were 63 male and 81 female patients, with an average age of 67.604 ± 8.727 years. Among these, 58.33% presented with white matter hyperintensities at Fazekas grading level 1, with an average total template volume of WMHs of 4.305 mL. MMP-2 (P = 0.025), MMP-9 (P = 0.008), TIMP-1 (P = 0.026), and age (P = 0.007) were identified as independent correlates of WMHs based on Fazekas grading. Independent correlates of the total template volume of WMHs included MMP-2 (P = 0.023), TIMP-1 (P = 0.046), age (P = 0.047), systolic blood pressure (P = 0.047), and homocysteine (Hcy) (P = 0.014). In addition, age (P = 0.003; P < 0.001), interleukin-6 (IL-6) (P < 0.001; P = 0.044), Hcy (P < 0.001; P < 0.001), glycated hemoglobin (HbA1c) (P = 0.016; P = 0.043), and chronic kidney disease (P < 0.001; P < 0.001) were associated with both WMHs Fazekas grading and the total template volume of WMHs. CONCLUSION: Serum levels of MMP-9, MMP-2, and TIMP-1 were independently associated with the Fazekas grading, while serum TIMP-1 and MMP-2 levels were independently related to the total template volume of WMHs. The association of TIMP-1 and MMP-2 with the severity of CSVD-related WMHs suggests their potential role as disease-related biomarkers. However, further research is required to uncover the specific mechanisms underlying these interactions.

Bone metastasis in a novel breast cancer mouse model containing human breast and human bone.

In practice, investigations for bone metastasis of breast cancer rely heavily on models in vivo. Lacking of such ideal model makes it difficult to study the whole process or accurate mechanism of each step of this metastatic disease. Development of xenograft mouse models has made great contributions in this area. Currently, the best animal model of breast cancer metastasizing to bone is NOD/SCID-hu models containing human bone, which makes it possible to let the breast cancer cells and the bone target of osteotropic metastasis be both of human origin. We have developed a novel mouse model containing both human bone and breast, and proved it functional and reliable. In this study, a set of human breast cancer cell line including MDA-MB-231, MDA-MB-231BO, MCF-7, ZR-75-1 and SUM1315 were characterized their osteotropism in this model. A specific cell line SUM1315 made species-specific bone metastasis, certifying the osteotropism-identification utility of the novel mouse model. Furthermore, gene expression and microRNA expression profiling analysis were done to the two SUM1315 derived sub lines isolated and purified from the orthotopic and metastatic xenograft. In addition, to demonstrate the disparity between the "spontaneous" and "forced" bone metastasis in mouse model, MDA-MB-231 cells were inoculated into both the human implants in this model simultaneously, and then primary cultured and profiling analyzed. Supported by overall results of profiling analyses, this study suggested the novel model was a useful tool for understanding, preventing and treating bone metastasis of breast cancer, meanwhile it had provided significant information for further investigations.

Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with beta-catenin.

BACKGROUNDS AND AIMS: Lgr5 is a member of the G protein receptor super-family and was shown recently to be a stem cell marker for cells with intestinal differentiation. Its over-expression has been demonstrated in hepatocellular, basal cell carcinoma, and ovarian cancers but the underlying mechanisms are poorly understood. The aim of this study was to investigate if Lgr5 over-expression was correlated with human colorectal carcinogenesis and its potential correlation with beta-catenin. METHODS: The study was carried out on a tissue microarray that consisted of 102 colorectal carcinomas (CRC; M:F = 55:47), 18 colon adenoma, and 12 colon normal mucosa cases. Immunostains were performed with the standard EnVision method with primary antibodies against Lgr5, beta-catenin, and p53 antigens. Immunoreactivity of neoplastic cells to each antibody was double-blindly semi-quantified by two pathologists and the data were analyzed with the Chi-square and Spearman rank correlation tests. Subsequently, expression of Lgr5 in tissue sections of tumor centre and invasive margins of 21 cases of CRC certified to be immunoreactive of Lgr5 in TMA were evaluated and possible differences of Lgr5 expression between them were analyzed. RESULTS: Lgr5 immunoreactivity was observed only in single cells in the base of normal colon mucosal crypts but high in 28% (five out of 18) adenomas, and significantly higher in 54% (55/102, p = 0.016) CRC cases. In normal mucosa, adenoma, and CRC, beta-catenin expression was seen in 25% (three out of 12), 27% (five out of 18), and 81% (83/102) cases, respectively, in contrast to 0, 0, and 40% (41/102) for p53 expression, respectively. In CRC, Lgr5 expression was more intense in women than men (p < 0.0001), and positively correlated with beta-catenin expression (p < 0.001), but not with patients' ages, tumor sizes, nodal status, TNM stages, and p53 expression. Different expression of Lgr5 between tumor centre and invasive margins was not found (p > 0.05). CONCLUSIONS: The results suggest that up-regulation of Lgr5 expression, especially in female patients, may play an important role in colorectal carcinogenesis, probably through the WNT/beta-catenin pathway, but not involve the progression of the CRC.

Superficial esophageal lymphoepithelioma-like carcinoma treated with endoscopic submucosal dissection: a case report.

Lymphoepithelioma-like carcinoma (LELC) of esophagus is an extremely rare tumor only a few cases were successfully treated with endoscopic submucosal dissection (ESD). We herein report one case of superficial esophageal LELC with adjacent squamous intraepithelial neoplasia successfully treated by ESD, and the status of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) were detected simultaneously. A 71-year-old woman presented with complaints of substernal discomfort. Under endoscopy, a dome-shaped bulge of 1.2 cm × 0.8 cm was located at the mucosal lamina propria in the left lateral wall of the middle esophagus, and the mucosa covering the bulge was smooth and normal-appearing. A brownish lesion was found adjacent to the bulge. Microscopically, the tumor was well demarcated, and nests of syncytial epithelioid cells were identified in the lamina propria of the mucosa, with a large number of inflammatory cells. The squamous epithelium covering the surface of the infiltrating tumor and the second brownish lesion demonstrated low grade squamous intraepithelial neoplasia. Tumor tissue showed CK5/6, p63, and p40 positive staining, was EBV negative, and had microsatellite stability. After treatment with ESD, this patient received no further treatment, and had no recurrence or metastasis at 25-month follow-up.

Molecular screening and clinicopathologic characteristics of Lynch-like syndrome in a Chinese colorectal cancer cohort.

Colorectal cancers (CRC) with microsatellite instability (MSI) or mismatch repair-deficiency (dMMR), but without detectable MMR germline mutations are termed Lynch-like syndrome (LLS). We assess the clinicopathologic and molecular characteristics of LLS tumors and the proportion in LLS, which remain poorly investigated in China. We enrolled 404 CRC patients with surgery in our institution from 2014 to 2018. LLS tumors were detected by a molecular stratification based on MMR protein expression, MLH1 methylation and MMR gene mutation. LLS tumors were profiled for germline mutations in 425 cancer-relevant genes. Among 42 MMR-deficient tumors, 7 (16.7%) were attributable to MLH1 methylation and 7 (16.7%) to germline mutations, leaving 28 LLS cases (66.6%). LLS tumors were diagnosed at a mean age of 60.7 years, had an almost equivalent ratio among rectum, left colon and right colon, and had high rates of lymph node metastases (50%, 4/28 N2). Most MMR gene mutations (88.2%, 15/17) in LLS tumors were variants of unknown significance (VUS). Two novel frameshift mutations were detected in ATM and ARID1A, which are emerging as candidate responsible genes for LLS. In this study, 28 (66.6%) MMRd tumors were classified as LLS, which were significantly higher than reports of western countries. LLS tumors were more likely to carry lymph node metastases. However, it's hard to differentiated LLS tumors from LS through family history, tumor location, histological type of tumors, immunohistochemistry (IHC) for MMR proteins and MSI analysis.

Marked thickening of muscularis mucosae and submucosa in the gastric cardia: A histopathological study of 110 surgical resection cases.

OBJECTIVE: To investigate histopathologic changes of muscularis mucosae (MM) and submucosa in the gastric cardia. METHODS: We performed a histopathology study of 50 distal esophagectomies with proximal gastrectomies for esophageal squamous cell carcinoma as the study (non-cancerous cardiac) group and 60 gastrectomies for early gastric cardiac carcinoma as the cancer group. The gastroesophageal junction was defined as the distal end of squamous epithelium, multilayered epithelium, or deep esophageal glands or ducts. Gastric cardia (n = 110) was defined as the presence of cardiac and cardio-oxyntic mucosae distal to the gastroesophageal junction. RESULTS: The average thickness of MM and submucosa in the cardia was 1.04 and 1.41 mm, respectively, which was significantly thicker than that in distal stomach (n = 34) (0.22 and 0.99 mm) or distal esophagus (n = 92) (0.60 and 1.15 mm). In the cardia, thickened MM displayed frayed muscle fibers (93.3%) with a significantly higher prevalence of entrapped glands, cysts, and lymphoid follicles than in the distal stomach or distal esophagus. In the submucosa fatty changes, cysts, and abnormal arteries were significantly more common in the cardia than in the distal stomach or distal esophagus. Compared with the study group, the cardia in the cancer group showed significantly thicker MM (average 1.31 vs 0.72 mm) and submucosa (average 1.61 vs 1.16 mm), more frequent frayed MM (93.3% vs 60.0%), prolapse-like changes (50.0% vs 2.0%), and cysts (26.7% vs 4.0%). CONCLUSION: MM and submucosa of the cardia were significantly thickened, especially in early gastric cardiac carcinomas.

[Factors influencing the progression-free survival time of prostate cancer patients after endocrine therapy].

OBJECTIVE: The progression of prostate cancer (PCa) after endocrine therapy varies widely in different PCa patients. This study aims to analyze the factors that influence the progression-free survival time of PCa patients after endocrine therapy in an attempt to improve the prognosis of the disease. METHODS: We reviewed the clinicopathological data of 116 cases of prostate cancer treated by endocrine therapy, analyzed the clinicopathological factors that influence the progression-free survival time of PCa patients using univariate (log-rank test) and multivariate Cox proportional hazard models, and investigated the correlation among these factors by Spearman rank correlation analysis. RESULTS: In the stepwise Cox proportional hazard model, the independent prognostic factors for PCa progression after endocrine therapy were found to be Gleason score (P < 0.01) and clinical stages (P < 0.01). The hazard of PCa progression after endocrine therapy increased 2.126 times that of the baseline for each unit of increase in Gleason score, and 6.625 times for each unit of increase in the clinical stage. The pretreatment PSA level was correlated with both clinical stages (P < 0.01) and Gleason score (P < 0.01). CONCLUSION: Clinical stages and Gleason score were important factors that influenced the progression-free survival time after endocrine therapy in this cohort of PCa patients.

Alveolar soft-part sarcoma of the prostate: a case report and review of the literature.

Alveolar soft-part sarcoma (ASPS) is a rare malignant soft tissue tumor of uncertain cellular origin. We reported the case of a 21-year-old man with ASPS presenting itself as a markedly vascular tumor of the prostate. Immunohistochemistry showed positive nuclear staining for TFE3, positive cytoplasm staining for MyoD1 and neuron-specific enolase, and negative for S100, CK, synaptophysin, chromogranin A, myogenin and PSA. A dual-color, break-apart fluorescence in situ hybridization (FISH) assay identified the presence of a TFE3 gene fusion in the tumor cells. RT-PCR was performed to confirm the ASPSCR1 (ASPL)/TFE3 fusion transcript product in the tumor tissue. The patient suffered bone metastases 8 months after surgery and died of cachexia 14 months later. ASPS of the prostate should be discussed in terms of differential diagnosis from clinicopathological characteristics, immunophenotypes, and molecular genetic features.

Risk factors of lymph node metastasis in 1620 early gastric carcinoma radical resections in Jiangsu Province in China: A multicenter clinicopathological study.

OBJECTIVE: To investigate risk factors of lymph node metastasis (LNM) in early gastric carcinoma (EGC) in four tertiary medical centers in Jiangsu Province, China. METHODS: Among 10 097 consecutive combined gastric cancer radical resections, 1903 EGC were identified and reviewed, 283 excluded and 1620 included in the study. All pathological and some endoscopic reports were reviewed for patients' characteristics, tumor location, gross features, and the number of lymph nodes retrieved and involved. Two pathologists independently investigated the pathological features of tumor type, differentiation, invasion depth, lymphovascular invasion (LVI), and perineural invasion. The data were statistically analyzed to identify risk factors for LNM. RESULTS: The average number of lymph nodes retrieved was 17.5 per patient. LNM was diagnosed in 15.5%. By univariate analysis, significant risk factors for LNM included age ≥ 41 years, female sex, size over 1 cm, submucosal invasion, poor differentiation, poorly cohesive carcinoma, micropapillary adenocarcinoma, adenocarcinoma mixed with signet-ring cell carcinoma, LVI, perineural invasion, and distal gastric location. By multivariate analysis, independent risk factors for LNM were size ≥ 3 cm (odds ratio [OR] 1.9), poor differentiation (OR 2.5), adenocarcinoma mixed with signet-ring cell carcinoma (OR 1.7), LVI (OR 5.8) and submucosal invasion (OR 2.9). In contrast, size < 3 cm and ulcer were not significant risk factors. Early cardiac carcinoma (OR 0.4) had significantly lower risk. CONCLUSIONS: Independent risk factors for LNM in EGC in Chinese patients included tumor size ≥ 3 cm, poor differentiation, submucosal invasion, adenocarcinoma mixed with signet-ring cell carcinoma and LVI. Early cardiac carcinoma had a significantly lower risk for LNM.

Solitary endobronchial papillomas with false impression of malignant transformation: report of two cases and review of the literature.

Solitary endobronchial papillomas (SEPs) are rare benign tumors of the lung, seldom transform to malignancy. This tumor had been reported occasionally manifest like carcinomas histologically. Herein we report 2 cases of SEPs; one is a squamous cell papilloma providing a false impression of interstitial micro-invasion. The other is a mixed squamous cell and glandular papilloma with massive lipid pneumonia gross appearance, and focally resembles adenocarcinoma with lepidic-like pattern on histological examination. A review of associated literatures was provided.

Diagnostic problems related to acute fibrinous and organizing pneumonia: misdiagnosis in 2 cases of lung consolidation and occupying lesions.

Acute fibrinous and organizing pneumonia (AFOP) is a histological pattern characterized by intra-alveolus fibrinous deposition accompanied with a spectrum of clinical condition. It also presents in other types of lung lesions, thus renders risks to its diagnosis with small biopsies. Here we present 2 cases of lung consolidation and occupying lesions with typical histological presentation of AFOP. One case is tuberculosis presented as massive lung consolidation, initially treated as AFOP, and eventually progressed to bilateral military tuberculosis. The other case presented an occupying mass in the lung which was initially suspected to be an inflammatory mass with AFOP. Lobectomy revealed a poorly-differentiated adenocarcinoma, with AFOP pattern present in the peripheral tissues of the neoplastic mass. In conclusion, we suggest that it is not preferable to diagnose idiopathic AFOP in lung consolidation and occupying lesions before excluding other types of lesions. The diagnostic significance of AFOP should be deliberated.

Clinicopathological features of pulmonary cryptococcosis with cryptococcal titan cells: a comparative analysis of 27 cases.

In addition to the typical size, Cryptococcus neoformans can enlarge its size to form titan cells during infection, and its diameter can reach up to 100 µm. Clinical reports about cryptococcal titan cells are rare. Most studies focus on aspects of animal models of infection with titan cells. Herein, we report the clinical and imaging characteristics and histopathologic features of 3 patients with titan cells and 27 patients with pathogens of typical size, and describe the morphological characteristics of titan cells in details. Histologically, 3 patients with titan cells show necrosis, fibrosis and macrophage accumulation. The titan cells appear in necrotic tissue and between macrophages, and have thick wall with unstained halo around them and diameters range from 20 to 80 µm with characteristic of narrow-necked single budding. There are also organisms with typical size. All 27 patients with normal pathogens show epithelioid granulomatous lesions. There is no significantly difference in clinical and imaging feature between the two groups. Cryptococcus neoformans exhibits a striking morphological change for the formation of titan cells during pulmonary infection, which will result in misdiagnosis and under diagnosis. The histopathological changes may be new manifestation, which need to be further confirmed by the study with animal models of infection and the observation of more clinical cases. Careful observation of the tissue sections is necessary.

Changing trends in the proportions of small (≤ 2 cm) proximal and non-proximal gastric carcinomas treated at a high-volume tertiary medical center in China.

OBJECTIVE: Guided by the recently established histological criteria of the gastroesophageal junction (GEJ), we aimed to investigate and compare trends in the proportions of small (≤ 2 cm) proximal gastric carcinoma (PGC) vs non-PGC (NPGC) in Chinese patients over an 8-year period. METHODS: The study was conducted with consecutive surgical resected specimens of small PGC that was located within 3 cm below the GEJ and NPGC (located at all other gastric regions) treated at a single medical center in China. Differences in proportions between the two groups were compared. RESULTS: Among all 313 cases, 111 (35.5%) were classified as PGC and the remaining 202 (64.5%) as NPGC. Patients with PGC were significantly elder than those with NPGC, and none aged younger than 40 years. The proportions of PGC significantly and progressively increased from 16% in 2004 to 45% in 2011, in contrast to a steady decreasing trend for NPGC from 84% to 55% over the same period. The difference in trends between the two groups approached, but was not at a statistically significant level (P = 0.08). Proportions of small cancers in the gastric corpus and in female patients remained low and stable, in contrast to a significantly higher proportion in male patients (P < 0.05). CONCLUSIONS: Our data showed a significantly upward-shifting trend in the proportions of small PGC, primarily in elderly male patients, in contrast to a downward shifting trend in NPGC over the most recent 8-year period in Chinese patients.

SOX2 overexpression correlates with poor prognosis in laryngeal squamous cell carcinoma.

OBJECTIVE: The aim of present study was to investigate the expression of SOX2, a key transcription factor, in LSCC and to assess its prognostic significance. METHODS: SOX2 expression of 161 LSCC tissues was detected by immunohistochemistry using a tissue microarray and statistically analyzed for its correlation with clinicopathological charateristics and patient outcome. In addition, SOX2 expression was also observed in 20 self-paired fresh LSCC tissues by western blot. RESULTS: SOX2 was overexpressed in LSCC tissues as compared to the corresponding adjacent normal tissues. SOX2 expression was significantly associated with tumour T classification (p<0.001), clinical stage (p<0.001), lymph node metastasis (p=0.007) and recurrence (p=0.001). Univariate analysis revealed that patients with high SOX2 expression were significantly related to overall survival (p<0.001). Multivariate survival analysis further demonstrated that SOX2 expression was an independent prognostic factor for LSCC patients. CONCLUSION: SOX2 may contribute to the malignant progression of laryngeal squamous cell carcinoma (LSCC), and present as a useful prognostic marker and a potential therapeutic target for LSCC patients.

Differences in HER2 over-expression between proximal and distal gastric cancers in the Chinese population.

AIM: To investigate HER2 expression and its correlation with clinicopathological variables between proximal and distal gastric cancers (GC) in the Chinese population. METHODS: Immunostaining of HER2 was performed and scored on a scale of 0-3 in 957 consecutive GC cases, according to the revised scoring criteria of HercepTest(TM) as used in the ToGA trial. Correlations between HER2 expression and clinicopathologic variables of proximal (n = 513) and distal (n = 444) GC were investigated. RESULTS: Our results showed that HER2 expression was significantly higher in the proximal than in distal GC (P < 0.05). Overall, HER2 expression was significantly higher in male patients (P < 0.01), the Lauren intestinal type (P < 0.001), low-grade (P < 0.001) and pM1 (P < 0.01) diseases, respectively. There was a significant difference in HER2 expression among some pTNM stages (P < 0.05). In contrast, HER2 expression in the distal GC was significantly higher in male patients (P < 0.001), low-grade histology (P < 0.001), the Lauren intestinal type (P < 0.001), and pM1 (P < 0.001). In the proximal GC, however, higher HER2 expression scores were observed only in tumors with low-grade histology (P < 0.001) and the Lauren intestinal type (P < 0.001). CONCLUSION: HER2 over-expression in GC of Chinese patients was significantly more common in proximal than in distal GC, and significantly correlated with the Lauren intestinal type and low-grade histology in both proximal and distal GC, and with pM1 disease and male gender in distal GC.

Factors predicting survival in patients with proximal gastric carcinoma involving the esophagus.

AIM: To investigate the clinicopathologic features which predict surgical overall survival in patients with proximal gastric carcinoma involving the esophagus (PGCE). METHODS: Electronic pathology database established in the Department of Pathology of the Nanjing Drum Tower Hospital was searched for consecutive resection cases of proximal gastric carcinoma over the period from May 2004 through July 2009. Each retrieved pathology report was reviewed and the cases with tumors crossing the gastroesophageal junction line were selected as PGCE. Each tumor was re-staged, following the guidelines on esophageal adenocarcinoma, according to the 7th edition of the American Joint Commission on Cancer Staging Manual. All histology slides were studied along with the pathology report for a retrospective analysis of 13 clinicopathologic features, i.e., age, gender, Helicobacter pylori (H. pylori) infection, surgical modality, Siewert type, tumor Bormann's type, size, differentiation, histology type, surgical margin, lymphovascular and perineural invasion, and pathologic stage in relation to survival after surgical resection. Prognostic factors for overall survival were assessed with uni- and multi-variate analyses. RESULTS: Patients' mean age was 65 years (range: 47-90 years). The male: female ratio was 3.3. The 1-, 3- and 5-year overall survival rates were 87%, 61% and 32%, respectively. By univariate analysis, age, male gender, H. pylori, tumor Bormann's type, size, histology type, surgical modality, positive surgical margin, lymphovascular invasion, and pT stage were not predictive for overall survival; in contrast, perineural invasion (P = 0.003), poor differentiation (P = 0.0003), > 15 total lymph nodes retrieved (P = 0.008), positive lymph nodes (P = 0.001), and distant metastasis (P = 0.005) predicted poor post-operative overall survival. Celiac axis nodal metastasis was associated with significantly worse overall survival (P = 0.007). By multivariate analysis, ≥ 16 positive nodes (P = 0.018), lymph node ratio > 0.2 (P = 0.003), and overall pathologic stage (P = 0.002) were independent predictors for poor overall survival after resection. CONCLUSION: Patients with PGCE showed worse overall survival in elderly, high nodal burden and advanced pathologic stage. This cancer may be more accurately staged as gastric, than esophageal, cancer.