Early gastric cancer mimicking advanced gastric cancer.

The clinicopathological features of 37 early gastric cancers mimicking advanced gastric cancer were reviewed retrospectively, and were compared with 596 other early gastric cancers and 126 mp gastric cancers, defined as gastric cancer invading the muscularis propria of the stomach. A greater tumour size (P < 0.005), submucosal invasion (P < 0.005), lymph node and lymph vessel invasion (P < 0.005) and vascular invasion (P < 0.025) were found more frequently in early gastric cancers mimicking advanced gastric cancers than in other early gastric cancers. There were no significant differences in the clinicopathological findings between early gastric cancers mimicking advanced gastric cancers and mp gastric cancers. Patients with early gastric cancers mimicking advanced gastric cancers showed a lower survival rate than patients with other early gastric cancers, but a higher survival than those with mp gastric cancers. The macroscopic appearance of an advanced gastric cancer was an indicator of massive submucosal invasion and lymph node metastasis in early gastric cancer. As early gastric cancers mimicking advanced gastric cancers showed similar clinicopathological findings to mp gastric cancers, these cancers should be treated as mp gastric cancers.     

Distal colorectal cancers with microsatellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers

Promoter methylation of the mismatch repair gene plays a key role in sporadic microsatellite instability (MSI) colorectal cancers. However, promoter methylation often occurs in proximal colon cancers, and molecular phenotypes underlying MSI cancers in distal colon have not been fully clarified. Our goal was to clarify the difference between MSI and microsatellite stability (MSS) cancers and, furthermore, to determine distinct characteristics of proximal and distal MSI cancers. By DNA microarray analysis of 84 cancers (33 MSI and 51 MSS), we identified discriminating genes (177 probe sets), which predicted MSI status with a high accuracy rate (97.6%). These genes were related to phenotypic characteristics of MSI cancers. Next, we identified 24 probe sets that were differentially expressed in proximal and distal MSI cancers. These genes included promoter methylation-mediated genes, whose expression was significantly down-regulated in proximal MSI cancers. Among discriminating genes between MSI and MSS, nine methylation-mediated genes showed down-regulation in MSI cancers. Of these, 7 (77.8%) showed down-regulation in proximal MSI cancers. Furthermore, methylation-specific PCR confirmed that frequency of hMLH1 promoter methylation was significantly higher in proximal MSI cancers (P = 0.0317). These results suggested that there is a difference between proximal and distal MSI cancers in methylation-mediated influence on gene silencing. In conclusion, using DNA microarray, we could distinguish MSI and MSS cancers. We also showed distinct characteristics of proximal and distal MSI cancers. The inactivation form of hMLH, per se, differed between proximal and distal MSI cancers. These results suggested that distal MSI cancers constitute a distinct subgroup of sporadic MSI cancers.     

Mutations of the bak gene in human gastric and colorectal cancers

The Bcl-2 homologue Bak is a potent inducer of apoptosis. We performed PCR-based single-strand conformational polymorphism and sequencing analysis of the entire coding region of the bak gene (exons 2-6) in 24 primary gastric cancers (6 early-stage and 18 advanced-stage cancers) and 20 primary colorectal cancers (6 early-stage and 14 advanced-stage cancers). The data herein demonstrate, for the first time, the mutation of the bak gene in gastric and colorectal cancers. Missense bak gene mutations were observed in 3 of 24 (12.5%) gastric cancers and 2 of 20 (10.0%) colorectal cancers. Sequence alterations without amino acid alteration were observed 1 of 24 (4.2%) gastric cancers and 2 of 20 (10.0%) colorectal cancers. Mutations in the bak gene were observed only in advanced-stage gastrointestinal cancers but not in early-stage cancers. Our observations suggest that mutations in this gene predispose bearers to the development of gastrointestinal malignancies in at least a subset of the cases.     

Double primary malignant tumors involving a lung cancer

Patients with multiple primary malignant tumors involving a primary lung cancer have been analyzed at our department in the Gunma University hospital. With reference to the lung cancer, three quarters of these patients were clinically in stages III or IV. The lung cancers were histologically classified into 26 epidermoid cancers, 14 adenocarcinomas, one large cell carcinoma, and one small cell carcinoma. Other primary cancers were 13 gastric cancers, 7 laryngeal cancers, 6 cervical cancers, 3 colon cancers, and other such cancers. Cases manifesting simultaneous cancers showing less than a one-year interval were 15 whereas 27 cases had double primary cancers with intervals of over one-year. Eleven patients had been given radiation therapy for their initial malignant tumor, but only two cases were considered to have incurred a radiation-induced lung cancer with a latent period of 5 and 12 years respectively.     

Expression Patterns of Thymosin β4 and Cancer Stem Cell Marker CD133 in Ovarian Cancers

Thymosin β4 (Tβ4), a small acidic actin binding peptide, is overexpressed in a side population of cancer stem cells and CD133-positive colorectal cancer stem cells. In order to understand the relationship between Tβ4 and CD133, we studied the expression patterns of Tβ4 and CD133 in ovarian cancers. The expression patterns of Tβ4 and CD133 were studied in normal ovaries, primary ovarian cancers, metastatic ovarian cancers, primary stomach cancers, and normal stomachs by Western blot and immunohistochemistry. Expression patterns and co-localization of Tβ4 and CD133 were examined by immunofluorescence and confocal laser-scanning microscopy. Tβ4 is overexpressed in primary ovarian cancers, but not in primary stomach cancers, when compared with normal controls. However, Tβ4 levels in metastatic stomach cancers to the ovary are significantly upregulated compared with levels in normal stomachs and primary stomach cancers. These results suggest that Tβ4 levels are related to tumorigenesis in ovarian cancers and metastasis in stomach cancers. The expression of Tβ4 in normal ovaries and normal stomachs was weak, but was co-localized with CD133 expression. Tβ4 expression was also co-localized with CD133 expression in primary ovarian carcinomas, metastatic ovarian cancers from stomach cancers and primary stomach cancers. These data suggest that Tβ4 expression is strongly related to CD133 expression and is a characteristic of stem cells or cancer stem cells.     

Prognostic significance of visible lesions on transrectal ultrasound in impalpable prostate cancers: implications for staging.

PURPOSE: The current tumor-node metastasis (TNM) staging system classifies impalpable prostate cancers identified by needle biopsy and invisible by imaging as T1c and those visible as T2. Palpable cancers are classified as at least T2. However, most urologists consider impalpable prostate cancers T1c tumors, irrespective of findings on transrectal ultrasound (TRUS). The aim of this article is to provide a differentiated view of the significance of TRUS findings for staging purposes in impalpable prostate cancers. PATIENTS AND METHODS: A consecutive series of 1670 patients with impalpable tumors and palpable T2 cancers after radical prostatectomy were evaluated. Tumor characteristics and 5-year biochemical cure rates of cancers invisible and visible on TRUS were compared, as well as the rates of impalpable but visible and palpable T2 cancers. RESULTS: Impalpable cancers invisible on TRUS presented significantly more favorable pathologic stages and lower cancer volumes than those visible on TRUS (P =.002, P =.010). In the latter, these clinical features were more favorable compared with T2 cancers (P <.001, P <.001). Progression-free probability of impalpable cancers invisible on TRUS was 86.8%; progression-free probability for impalpable cancers visible on TRUS was 85.4% (log-rank test P =.2060). The corresponding rate for T2 tumors was 73.9%, significantly lower when compared to those of visible and impalpable cancers (log-rank test P =.0001). CONCLUSION: Impalpable prostate cancers invisible on TRUS present more favorable cancer features than those that are visible on TRUS. However, these differences are not as pronounced as those between impalpable but visible cancers and palpable T2 tumors. Thus, based on our data, it seems inappropriate to classify impalpable prostate cancers visible on TRUS as T2 cancers.     

Mammography screening interval and the frequency of interval cancers in a population-based screening.

In a population-based mammography screening, 129,731 examinations were carried out among 36,000 women aged 40-74 in the city of Turku, Finland, in the period 1987-94. Women older than 50 were screened at 2-year intervals, and those younger than 50 at either 1-year or 3-year intervals, depending on their year of birth. Screen-detected breast cancers numbered 385 and, during the same time period, 154 women were diagnosed with breast cancer outside screening in the same age group in the same city, and 100 interval cancers were detected. Two hundred and fifty (67%) of the screen-detected cancers were of post-surgical stage I compared with 45 (45%) of the interval cancers and 52 (34%) of the cancers found outside screening (P<0.0001). However, among women aged 40-49 the frequency of stage I cancers did not differ significantly among screen-detected cancers, interval cancers and cancers found outside screening (50%, 42% and 44% respectively; P=0.73). Invasive interval cancers were more frequent among women aged 40-49 if screening was done at either 1-year (27%) or 3-year intervals (39%) than in older women screened at 2-year intervals (18%; P=0.08 and P=0.0009 respectively). Even if adjusted for the primary tumour size, screen-detected cancers had smaller S-phase fractions than interval cancers or control cancers (P=0.01), but no difference in the S-phase fraction size was found between cancers of women younger than 50 and those older than this (P=0.13). We conclude that more interval cancers were found among women younger than 50 than among those older than 50 and that this could not be explained by the rate of cancer cell proliferation.     

Association of HNPCC and endometrial cancers

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.     

Interval cancers in a community-based programme of colorectal cancer screening with faecal occult blood test.

Interval cancers represent the major limitation of screening for colorectal cancer with the faecal occult blood test. The aim of this study was to describe the characteristics of interval cancers and the sensitivity of the screening programme in a well-defined French population. During five screening rounds, 398 cancers were diagnosed in those of the population having performed at least one screening test; 57.8% of them were interval cancers. The proportion of interval cancers was higher among cancers of the rectal ampulla (72.2%) than among cancers of other sites (52.9%) (P < 0.001). The proportion of TNM stage I and II were higher among screen-detected cancers (73.8%) than among interval cancers (57.4%). The overall sensitivity of the screening programme was 62.9% within 1 year, and 48.7% within 2 years. An improvement in the sensitivity of the faecal occult blood test for colorectal cancer screening is needed, without an unacceptable loss of specificity.     

Double and multiple primary cancers in an adult head and neck radiation therapy clinic

The records of 321 consecutive patients referred to the Radiation Oncology Center between January 1, 1980, and December 30, 1982, for head and neck cancers were reviewed to determine the incidence of other cancers. Two hundred sixty-two patients have had a single primary cancer in the head and neck region. Fifty-nine patients (18%) have had more than one cancer. These 59 patients have had 68 other cancers. While other head and neck cancers lead the list of second primaries, second cancers also occurred in the esophagus, lung, genitourinary system and elsewhere. Twenty cancers had occurred prior to the patient developing head and neck cancer. Thirty-two cancers were synchronous with the head and neck cancer; 16 have been metachronous. These numbers emphasize that patients with head and neck cancers are in a cancer-prone group that develops a variety of other cancers. These findings have important implications in work-up, radiation treatment planning, treatment goals and follow-up programs.     

The p53 mutational spectrum associated with BRCA1 mutant ovarian cancer.

PURPOSE: Cancer-specific p53 mutational spectra have been identified. Data from murine models and human BRCA1-related hereditary breast cancers suggest that both unique and specific BRCA1-associated p53 mutations may be found in BRCA1-related ovarian cancers. EXPERIMENTAL DESIGN: The p53 mutational spectrum from ovarian cancers containing either somatic or germ-line BRCA1 mutations was compared with that of sporadic ovarian cancers defined as those diagnosed with a negative family history for breast/ovarian cancer in a three-generation pedigree. Tumor DNA was screened over exons 2-11 of the p53 gene by the PCR and single-strand confirmation polymorphism analysis of the amplimers. Cycle-based DNA sequencing from separate reactions was used to confirm p53 mutations. RESULTS: p53 gene mutations were detected in 42 of 86 sporadic ovarian cancers, compared with 13 of 15 cancers with somatic BRCA1 mutations (P = 0.007) and 16 of 20 cancers with germ-line BRCA1 mutations (P = 0.01). p53 null mutations were found in 31.4% of BRCA1 mutant cancers, compared with only 9.3% of the sporadic cancers (P = 0.002). The p53 mutational spectrum of germ-line BRCA1-related cancers was shifted toward transversions, frameshifts, and non-CpG transitions relative to the spectrum of sporadic ovarian cancers. Thirty-three unique ovarian cancer p53 mutations were sequenced. However, the specific p53 mutations in the BRCA1 mutant cancers were no more unique to this cohort than the p53 mutations of the sporadic cancers. CONCLUSIONS: Ovarian cancers containing somatic or germ-line BRCA1 mutations are uniformly accompanied by p53 dysfunction. This finding offers additional support to observations regarding the importance of p53/BRCA1 interactions in ovarian carcinogenesis.     

Expression of pepsinogen II in gastric cancer. Its relationship to local invasion and lymph node metastases

We have determined the prevalence of pepsinogen II (PG II) immunoreactive cells in a large series of early and advanced gastric cancers and relationships among PG II-positivity, tumor histologic type, extent of gastric wall invasion, and presence of lymph node metastases. Of the 316 cancers evaluated, 150 (47%) expressed PG II. The prevalence by histologic type was 55% in 146 glandular tumors, 43% in 83 diffuse tumors, 16% in 25 mucoid tumors, and 51% in 59 mixed-type cancers. Two parietal cell cancers and one undifferentiated cancer were PG II-negative. In glandular and diffuse cancers, but not mucoid and mixed tumors, both the extent of gastric wall invasion and incidence of lymph node metastases were associated positively with PG II expression by the primary tumor. In particular, PG II-reactive cells were found significantly more often in advanced than in early diffuse cancers (P less than 0.05) and significantly more often in submucosal early cancers than in intramucosal early cancers (P less than 0.01). The prevalence of PG II expression also was higher significantly in metastatic cancers than in nonmetastatic cancers. This was true for advanced gastric cancers as a whole (P less than 0.01), advanced glandular-type cancer alone (P less than 0.01), advanced glandular- and diffuse- type cancers together (P less than 0.001), and early diffuse-type cancer (P less than 0.05). Only four (3%) of 145 cancers evaluated for pepsinogen I (PG I) were positive, and each also was positive for PG II. The results suggest that the expression of PG II by glandular and diffuse types of gastric cancer may be a marker of increased malignancy.     

Oncogenic nexus of cancerous inhibitor of protein phosphatase 2A (CIP2A): An oncoprotein with many hands

Oncoprotein CIP2A a Cancerous Inhibitor of PP2A forms an “oncogenic nexus” by virtue of its control on PP2A and MYC stabilization in cancer cells. The expression and prognostic function of CIP2A in different solid tumors including colorectal carcinoma, head & neck cancers, gastric cancers, lung carcinoma, cholangiocarcinoma, esophageal cancers, pancreatic carcinoma, brain cancers, breast carcinoma, bladder cancers, ovarian carcinoma, renal cell carcinomas, tongue cancers, cervical carcinoma, prostate cancers, and oral carcinoma as well as a number of hematological malignancies are just beginning to emerge. Herein, we reviewed the recent progress in our understanding of (1) how an “oncogenic nexus” of CIP2A participates in the tumorigenic transformation of cells and (2) how we can prospect/view the clinical relevance of CIP2A in the context of cancer therapy. The review will try to understand the role of CIP2A (a) as a biomarker in cancers and evaluate the prognostic value of CIP2A in different cancers (b) as a therapeutic target in cancers and (c) in drug response and developing chemo-resistance in cancers.     

Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry

The spectrum of cancers seen in a hospital based Lynch syndrome registry of mismatch repair gene mutation carriers was examined to determine the distribution of cancers and examine excess cancer risk. Overall there were 504 cancers recorded in 368 mutation carriers from 176 families. These included 236 (46.8?%) colorectal and 268 (53.2?%) extracolonic cancers. MLH1 mutation carriers had a higher frequency of colorectal cancers whereas MSH2, MSH6 and PMS2 mutation carriers had more extracolonic cancers although these differences were not statistically significant. Men had fewer extracolonic cancers than colorectal (45.3 vs. 54.7?%), whereas women had more extracolonic than colorectal cancers (59.0 vs. 41.0?%). The mean age at diagnosis overall for extracolonic cancers was older than for colorectal, 49.1 versus 44.8?years (P?≤?0.001). As expected, the index cancer was colorectal in 58.1?% of patients and among the extracolonic index cancers, endometrial was the most common (13.8?%). A significant number of non-Lynch syndrome index cancers were recorded including breast (n?=?5) prostate (n?=?3), thyroid (n?=?3), cervix (n?=?3), melanoma (n?=?3), and 1 case each of thymoma, sinus cavity, and adenocarcinoma of the lung. However, standardized incidence ratios calculated to assess excess cancer risk showed that only those cancers known to be associated with Lynch syndrome were significant in our sample. We found that Lynch syndrome patients can often present with cancers that are not considered part of Lynch syndrome. This has clinical relevance both for diagnosis of Lynch syndrome and surveillance for cancers of different sites during follow-up of these patients.     

Rare mutations of p53, Ki-ras, and beta-catenin genes and absence of K-sam and c-erbB-2 amplification in N-methyl-N'-nitro-N-nitrosoguanidine-induced rat stomach cancers.

Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) have been widely used as a model for human stomach cancers of the differentiated type. However, there has been little information regarding their molecular basis. In this study, we examined the genetic alterations reported in human stomach cancers in 10 rat stomach cancers that had been induced in male ACI/N rats by administering MNNG in the drinking water. One of the 10 cancers had a mutation of the p53 gene at the second position of codon 171 (Val --> Glu). However, none of the 10 cancers had mutations in codons 12, 13, or 61 of Ki-ras or in the N-terminal phosphorylation sites of the beta-catenin gene. Southern blot analysis showed no amplification of K-sam or c-erbB-2 in the seven cancers examined. Finally, we searched for microsatellite alterations in 12 loci in nine cancers, but no alterations were observed. As these genetic alterations are observed in only a minor fraction of human stomach cancers, further analysis of genetic and epigenetic alterations in MNNG-induced rat stomach cancers is needed to disclose the major mechanisms of stomach carcinogenesis.     

Human Papillomavirus Burden in Different Cancers in Iran: a Systematic Assessment

Certain types of human papillomaviruses (HPVs) are undoubtedly involved in genesis of human malignancies. HPV plays an etiological role in cervical cancer, but also in many vaginal, vulvar, anal and penile cancers, as well as head and neck cancers. In addition, a number of non-malignant diseases such as genital warts and recurrent respiratory papillomatosis are attributable to HPV. Moreover, HPV forms have detected in several other cancers including esophageal squamous cell carcinoma, lung, prostate, ovarian, breast, skin, colorectal and urinary tract cancers, but associations with etiology in these cases is controversial. The aim of this systematic assessment was to estimate the prevalence of HPV infection and HPV types in HPV-associated cancers, HPV-related non-malignant diseases and in cancers that may be associated with HPV in Iran. The present investiagtion covered 61 studies on a variety of cancers in Iranian populations. HPV prevalence was 77.5 % and 32.4% in cervical cancer andhead and neck cancers, respectively. HPV was detected in 23.1%, 22.2%, 10.4%, 30.9%, 14% and 25.2% of esophageal squamous cell, lung, prostate, urinary tract cancers, breast and skin cancers, respectively. HPV16 and 18 were the most frequent HPV types in all cancers. The findings of present study imply that current HPV vaccines for cervical cancer may decrease the burden of other cancers if they are really related to HPV.     

Development of Prostatic Carcinoma: Morphometric and pathologic features of early stages

The natural history of prostatic adenocarcinoma has been studied in a series of 261 radical prostatectomy specimens from Stanford. Total tumor histologic grade, cancer volume, zonal distribution of the tumor and correlation with its direction of spread, capsular penetration, seminal vesicle invasion and peripro-static extension were quantitated for each case. We identified specific morphologic and histologic features for cancers which arise in the anteromedial transition zone which contains BPH nodules, and for cancers which arise in the posterolateral peripheral zone. Stage A cancers are almost equivalent to transition cancers and stage B cancers to peripheral zone cancers. Prognosis as measured by lymph node metastasis was not different between these two groups of cancers but only related to their volume of poorly differentiated areas.     

Cancers rares : des entités différentes, des problématiques communes

Rare cancers are better defined by their incidence (< 3/100 000 per year) than by their prevalence. Rare cancers include various types of cancer: intrinsically rare cancers (sarcomas, primary CNS tumours, cancers of the endocrine system, and cancers of the biliary tract); sub-entities of frequent cancers (male breast cancer, non epithelial ovarian cancers, apocrine carcinomas, MALT lymphomas); genetically determined cancers; and cancers occurring during pregnancy or in organ transplant recipients. Although widely different, these cancers raise common questions and problems: 1) the limitation of preclinical studies in relation with insufficient preserved tumour samples, the rarity of preclinical models, and the poor interest for preclinical pharmacology; 2) the limited number of comprehensive “expert” centres (less than 10–15 in Europe), emphasizing the role of networks; 3) the difficulties in conducting clinical and therapeutic studies due to the small number of concerned patients and methods available to run studies in rare populations. Effective support appears necessary to improve both research on these rare cancers and their management (constitution and maintenance of databases on this topic, constitution of virtual tumour banks, harmonization of the diagnostic procedures, especially regarding pathology and imaging, and “academic” support for clinical studies. Paris University Hospitals include more than 20 comprehensive centres dedicated to almost all rare cancers; these centres are useful for the implementation and evaluation of such methodological and logistic support.     

A comparison of axillary node status between cancers detected at the prevalence and first incidence breast screening rounds.

Screen-detected breast cancers are smaller than those detected in symptomatic populations and, for any given size, they are associated with fewer lymph node metastases. The management of axillary lymph nodes in patients with screen-detected breast cancer remains controversial. We have previously reported that prevalence (initial screen)-detected cancers are associated with nodal metastases in 17.4% of cases overall. Cancers < or = 10 mm, of any grade, are associated with metastases in only 5% of cases, and grade I cancers <30 mm are not associated with metastases. This led to our recommendation that axillary surgery is unnecessary for these groups of women. The present study compared the nodal status of cancers detected at the prevalence and first incidence (second) screens in order to determine whether our recommendation is appropriate for cancers detected at the first incidence screen. Overall, 30.1% of cancers detected in the first incidence screen presented axillary nodal metastases. At all size ranges, cancers detected at the first incidence screen were associated with significantly more lymph node metastases than prevalence-detected cancers. In particular, cancers < or = 10 mm were associated with metastases in 14.3% of cases. With the possible exception of grade I cancers, we believe that surgical staging of the axilla is essential for cancers detected at the first incidence screen, irrespective of size.