Human leukocyte antigen class II DRB1*1302 allele protects against cervical cancer: At which step of multistage carcinogenesis?

We investigated the role of human leukocyte antigen (HLA) class II alleles in multistage cervical carcinogenesis. Cross-sectional analysis for HLA association with cervical cancer included 1253 Japanese women: normal cytology (NL, n = 341), cervical intraepithelial neoplasia grade 1 (CIN1, n = 505), CIN grade 2 or 3 (CIN2/3, n = 96), or invasive cervical cancer (ICC, n = 311). The HLA class II allele frequencies were compared by Fisher's exact test or the χ(2) -test. The Bonferroni adjustment corrected for multiple comparisons. Among the study subjects, 454 women with low-grade squamous intraepithelial lesion cytology were prospectively monitored by cytology and colposcopy every 3-4 months to analyze cumulative risk of CIN3 within the next 10 years in relation to HLA class II alleles. HLA class II DRB1*1302 allele frequency was similar between women with NL (11.7%) and CIN1 (11.9%), but significantly decreased to 5.2% for CIN2/3 and 5.8% for ICC (P = 0.0003). Correction for multiple testing did not change this finding. In women with low-grade squamous intraepithelial lesion cytology, the cumulative risk of CIN3 diagnosed within 10 years was significantly reduced among DRB1*1302-positive women (3.2% vs. 23.7%, P = 0.03). In conclusion, the two different types of analysis in this single study showed the protective effect of the DRB1*1302 allele against progression from CIN1 to CIN2/3.

Potential impact of combined high- and low-risk human papillomavirus infection on the progression of cervical intraepithelial neoplasia 2.

AIM: Few studies have examined the effect of combined low-risk human papillomavirus (LR-HPV) and high-risk human papillomavirus (HR-HPV) infection on the progression of cervical intraepithelial neoplasia (CIN)2 to CIN3. This multi-institutional prospective cohort study investigated the risk of progression of CIN2 with various combinations of HR-HPV and LR-HPV infection. METHODS: Between January 2007 and May 2008, 122 women with CIN2 (aged 20-50 years) from 24 hospitals throughout Japan were enrolled in the study. Ninety-three women were analyzed after a 2-year follow-up with cytology, colposcopy, HR-HPV testing and HPV genotyping. Colposcopy-directed biopsy was performed at entry and the end of this study, or when disease progression was suspected. RESULTS: Among 93 women with CIN2, 87 (93.5%) had HR-HPV infection. Among these 87 cases, 24 (27.6%) progressed to CIN3 and 49 (56.3%) regressed. None of the six women with CIN2 without HR-HPV infection progressed. The progression rate was significantly lower in women with combined HR-HPV and LR-HPV infection (3/28, 10.7%) than in those with HR-HPV infection only (21/59, 35.6%; P = 0.016). Multivariate analyses showed that CIN2 progression in women with HR-HPV infection was negatively associated with LR-HPV co-infection (hazard ratio = 0.152; 95% confidence interval [CI] = 0.042-0.553). CIN2 regression was positively associated with LR-HPV co-infection (odds ratio = 4.553; 95% CI = 1.378-15.039). CONCLUSION: The risk of CIN2 progression is low in women with combined infection of HR-HPV and LR-HPV. The finding may be useful for management of women diagnosed with CIN2.

Association between carotenoids and outcome of cervical intraepithelial neoplasia: a prospective cohort study.

BACKGROUND: It has been suggested that micronutrients such as alpha-tocopherol, retinol, lutein, cryptoxanthin, lycopene, and alpha- and beta-carotene may help in the prevention of cervical cancer. Our aim was to investigate whether serum concentrations and/or dietary intake of micronutrients influence the regression or progression of low-grade cervical abnormalities. METHODS: In a prospective cohort study of 391 patients with cervical intraepithelial neoplasia (CIN) grade 1-2 lesions, we measured serum micronutrient concentrations in addition to a self-administered questionnaire about dietary intake. We evaluated the hazard ratio (HR) adjusted for CIN grade, human papillomavirus genotype, total energy intake and smoking status. RESULTS: In non-smoking regression subjects, regression was significantly associated with serum levels of zeaxanthin/lutein (HR 1.25, 0.78-2.01, p = 0.024). This benefit was abolished in current smokers. Regression was inhibited by high serum levels of alpha-tocopherol in smokers (p = 0.042). In progression subjects, a significant protective effect against progression to CIN3 was observed in individuals with a medium level of serum beta-carotene [HR 0.28, 95 % confidence interval (CI) 0.11-0.71, p = 0.007), although any protective effect from a higher level of serum beta-carotene was weaker or abolished (HR 0.52, 95 % CI 0.24-1.13, p = 0.098). Increasing beta-carotene intake did not show a protective effect (HR 2.30, 95 % CI 0.97-5.42, p = 0.058). CONCLUSIONS: Measurements of serum levels of carotenoids suggest that regression is modulated by smoking status. Maintaining a medium serum level of beta-carotene has a protective effect for progression; however, carotene intake is not correlated with serum levels of carotenoids.

Prospective evaluation of the Amplicor HPV test for predicting progression of cervical intraepithelial neoplasia 2.

AIM: The aim of this study was to evaluate the clinical performance of the Amplicor HPV test, which detects 13 high-risk human papillomaviruses (HR-HPV), and to determine the association between consistent HR-HPV infection and progression of cervical intraepithelial neoplasia (CIN) 2 to CIN3. MATERIAL AND METHODS: This multi-institutional prospective study enrolled 122 women diagnosed with CIN2 by central pathological review. Subjects were tested at study entry and every 6 months over a 24-month period by cytology, Amplicor HPV test and colposcopy. Central pathological review was performed at the end of the study or if CIN progression was suspected. RESULTS: Ninety-three of the 122 participants completed all tests in the study and were included in the analysis. HR-HPV was detected in 87/93 (93.5%) participants at study entry. Twenty-four of the 87 HR-HPV-positive participants progressed to ≥CIN3, compared with none of the six participants who were HR-HPV-negative at study entry. The positive predictive value, negative predictive value, sensitivity and specificity of the Amplicor HPV test at study entry for predicting ≥CIN3 progression were 27.6%, 100%, 100% and 8.7%, respectively. Sixty-two participants were HR-HPV-positive from study entry through to study completion, 24 of whom progressed to ≥CIN3. None of 31 participants without continuous HR-HPV detection progressed to ≥CIN3. For continuous HR-HPV detection, the positive predictive value, negative predictive value, sensitivity and specificity of the Amplicor HPV test were 38.7%, 100%, 100% and 44.9%, respectively. CONCLUSIONS: All participants who progressed to ≥CIN3 were continuously HR-HPV-positive. The Amplicor HPV test thus demonstrated a good performance for predicting CIN3 progression.

Usefulness of intraoperative imprint cytology in ovarian germ cell tumors.

OBJECTIVE: This study retrospectively investigated the usefulness of intraoperative diagnosis based on imprint cytology and frozen sections for ovarian germ cell tumor. STUDY DESIGN: Intraoperative studies were reviewed for 23 cases with ovarian germ cell tumor treatment for which both frozen sections and imprint cytology were available. Final histopathologic diagnoses were compared with those based on intraoperative examinations. RESULTS: Underlying pathologies included dysgerminoma (n = 6), yolk sac tumor (n = 1), non-gestational choriocarcinoma (n = 1), mature cystic teratoma with malignant transformation (n = 1), immature teratoma (n = 11), and mixed germ cell tumor (n = 3). Discrepancies between intraoperative imprint cytology and definitive histologic diagnosis were seen in 6 of the 23 cases. Accuracy was 54.5% (6/11) for immature teratoma and 91.7% (11/12) for other tumors. Cytologic examination facilitated accurate diagnosis in both of our cases, and intraoperative diagnosis by frozen section proved inaccurate. CONCLUSION: These results demonstrate that intraoperative assessment based on imprint cytology for immature teratoma has a relatively lower sensitivity, but an acceptable sensitivity for other germ cell tumors. Diagnostic approaches combining frozen sections and imprint cytology are advisable to improve the yield for intraoperative diagnosis.

Prevalence of human papillomavirus in mobile tongue cancer with particular reference to young patients.

The carcinogenetic role of human papillomavirus (HPV) in mobile tongue cancer remains unclear because of conflicting results reported in the literature. This disparity is likely to be due to variations in the samples and methods used. Furthermore, despite a tendency for increased prevalence of mobile tongue cancer in young adults, only a few reports specifically in young patients have been published. In the present study on 32 patients, including six in their 20s, we genotyped the prevalence of HPV using a highly sensitive detection tool in fresh-frozen samples from surgical specimens and a novel detection device with electrochemical DNA chip and loop-mediated isothermal amplification. In addition, we confirmed HPV prevalence by in situ hybridization and immunohistochemistry for the p16(INK4a) protein, regarded as a biomarker of HPV-associated cancers. The frequency of 13 genotypes of high-risk HPV was 0/32 (0%), which was further confirmed by in situ hybridization. Overexpression of p16(INK4a) protein was observed in six of the 32 patients (19%), with four (67%) also overexpressing p53. Because there is usually a lack of p53 overexpression in HPV-associated cancer, it is unlikely that p16(INK4a) protein overexpression is correlated with HPV infection. Consequently, it is unlikely that HPV infection plays an important role in mobile tongue carcinogenesis, in particular in young adults. In addition, our data suggest that the overexpression of p16(INK4a) protein is not an appropriate biomarker for HPV association in mobile tongue carcinogenesis.

Do neutralizing antibody responses generated by human papillomavirus infections favor a better outcome of low-grade cervical lesions?

To determine the role of neutralizing antibody generated by human papillomavirus (HPV) infections, baseline levels of serum neutralizing antibodies directed against HPV 16 and cervical HPV DNA were determined in 242 unvaccinated women with low-grade cervical abnormalities, who were then monitored by cytology and colposcopy every 4 months. In women infected with HPV 16 (n = 42), abnormal cytology persisted longer in those positive for HPV 16-specific neutralizing antibodies at baseline (median time to cytological regression: 23.8 vs. 7.2 months). Progression to cervical precancer (cervical intraepithelial neoplasia grade 3) within 5 years occurred only among women carrying HPV 16-specific neutralizing antibodies (P = 0.03, log-rank test). In women infected with types other than HPV 16 (n = 200), detection of HPV 16-specific neutralizing antibodies was not correlated with disease outcome. In conclusion, development of specific neutralizing antibodies following natural HPV 16 infection did not favor a better outcome of low-grade cervical lesions induced by HPV 16 or by other types; rather, detection of neutralizing antibodies generated by current infection may reflect viral persistence and thus help identify those who are at high risk of disease progression.

HLA class II DRB1*1302 allele protects against progression to cervical intraepithelial neoplasia grade 3: a multicenter prospective cohort study.

OBJECTIVE: Genetic variations in human leukocyte antigens (HLA) class II regions may influence the risk of cervical cancer by altering the efficiency of the immune responses to human papillomavirus antigens. This prospective study was designed to evaluate the effects of HLA class II alleles on the natural course of cervical precursor lesions. METHODS: We followed a total of 454 Japanese women with cytological low-grade squamous intraepithelial lesion (LSIL) and histological cervical intraepithelial neoplasia grades 1 to 2 (CIN1-CIN2). Patients were tested for HLA class II alleles and cervical human papillomavirus DNA at the time of entry and then monitored by cytology and colposcopy every 4 months for a mean follow-up of 39.0 months. We analyzed cumulative probabilities of cytological regression to at least 2 consecutive negative Papanicolaou tests and histological progression to biopsy-positive CIN3. RESULTS: During the follow-up period, 39 lesions progressed to CIN3, and 282 lesions regressed to normal cytology. Progression to CIN3 did not occur in DRB1*1302-positive women, and this protective effect of DRB1*1302 was statistically significant (P = 0.03). Low-grade squamous intraepithelial lesion regressed to normal cytology more quickly in DRB1*1302-positive women than in DRB1*1302-negative women (median time, 8.9 months vs 14.2 months), although the difference was not statistically significant (P = 0.16). The risk of LSIL persistence or progression to CIN3 within 5 years was not affected by any other HLA class II alleles. CONCLUSION: By using a prospective study design, we demonstrated the protective effect of the DRB1*1302 allele against progression to CIN3 among Japanese women with LSIL.

Subsequent risks for cervical precancer and cancer in women with low-grade squamous intraepithelial lesions unconfirmed by colposcopy-directed biopsy: results from a multicenter, prospective, cohort study.

OBJECTIVE: To investigate the natural course of low-grade squamous intraepithelial lesions (LSILs) that cannot be histologically confirmed by colposcopy-directed biopsy. METHODS: In a multicenter, prospective, cohort study of Japanese women with LSILs, we analyzed the follow-up data from 64 women who had a negative biopsy result at the initial colposcopy (biopsy-negative LSIL) in comparison with those from 479 women who had a histologic diagnosis of cervical intraepithelial neoplasia grade 1 (LSIL/CIN1). Patients were monitored by cytology and colposcopy every 4 months for a mean follow-up period of 39.0 months, with cytologic regression defined as two consecutive negative smears and normal colposcopy. RESULTS: In women with biopsy-negative LSILs, there were no cases of CIN3 or worse (CIN3+) diagnosed within 2 years; the difference in the 2-year risk of CIN3+ between the two groups was marginally significant (0 vs. 5.5%; P = 0.07). The cumulative probability of cytologic regression within 12 months was much higher in the biopsy-negative LSIL group (71.2 vs. 48.6%; P = 0.0001). The percentage of women positive for high-risk human papillomaviruses (hrHPVs) was significantly lower in the biopsy-negative LSIL group than in the LSIL/CIN1 group (62.1 vs. 78.4%; P = 0.01); however, the 12-month regression rate of biopsy-negative LSIL was similar between hrHPV-positive and -negative women (67.3 vs. 74.4%, P = 0.73). CONCLUSION: In women with biopsy-negative LSILs, the risk of CIN3+ diagnosed within 2 years was low; furthermore, approximately 70% underwent cytologic regression within 12 months, regardless of HPV testing results. Biopsy-negative LSILs may represent regressing lesions rather than lesions missed by colposcopy.

Predicting the progression of cervical precursor lesions by human papillomavirus genotyping: a prospective cohort study.

Only a subset of cervical precursor lesions progress to cervical cancer and because of the lack of the predictive markers, it cannot be ascertained which lesions will progress or not. To estimate the risk of disease progression associated with human papillomavirus (HPV) genotypes, we followed 570 Japanese women with cytological LSIL (low-grade squamous intraepithelial lesion) and histological CIN (cervical intraepithelial neoplasia) grade 1-2 lesions (479 CIN 1; 91 CIN 2) at 3 to 4 month intervals for a mean follow-up period of 39.1 months. At entry, we detected HPV DNA in cervical samples by polymerase chain reaction-based methodology. Over the period of follow-up period, 46 lesions progressed to CIN 3 while 362 regressed to normal cytology. Women with multiple HPV infections were more likely to have persistent lesions (hazard ratio [HR] for regression, 0.65; 95% confidence interval [CI], 0.42-1.02; p = 0.07); however, multiple infections did not increase the risk of progression (HR for progression, 1.04; 95% CI, 0.37-2.94; p = 0.94). After adjusting for CIN grade and women's age, HRs for progression to CIN 3 (vs. women with low-risk types or negative for HPV DNA) varied markedly by HPV genotype: type 16 (11.1, 95% CI: 1.39-88.3); 18 (14.1, 0.65-306); 31 (24.7, 2.51-243); 33 (20.3, 1.78-231); 35 (13.7, 0.75-251); 52 (11.6, 1.45-93.3); 58 (8.85, 1.01-77.6); other high-risk types (4.04, 0.47-34.7). HPV 45 was not detected in our study subjects. The cumulative probability of CIN 3 within 5 years was 20.5% for HPV 16, 18, 31, 33, 35, 52 and 58; 6.0% for other high-risk types; 1.7% for low-risk types (p = 0.0001). In conclusion, type-specific HPV testing for women with LSIL/CIN 1-2 lesions is useful for identifying populations at increased or decreased risk of disease progression.

Mixed squamous cell and glandular papilloma of the lung: a case study and literature review.

Mixed squamous cell and glandular papilloma (mixed papilloma) of the lung is an extremely rare neoplasm, with only 10 cases reported so far in the English literature. We present a case study of endobronchial mixed papilloma with immunohistochemical and etiological investigations. A 49-year-old male with a smoking history complained of hemoptysis, presented with a lung mass closely adjacent to large vessels in the computed tomography findings, and underwent lobectomy. The 3.0-cm sized polypoid tumor was histologically diagnosed as endobronchial mixed papilloma. Immunohistochemically, intracellular mucin was positive for MUC5AC, which is expressed in tracheobronchial goblet cells. CAM5.2 and CK19 were diffusely positive, indicating that the tumor originated from the columnar epithelium by squamous metaplasia. CEA and CA19-9 were focally positive. A human papillomavirus (HPV) investigation with in situ hybridization using a wide spectrum probe and a newly-developed PCR system did not detect any HPV infection. Including this case with a detailed HPV investigation, all of the reported cases of mixed papilloma were HPV-negative, and a literature review including newly-reported cases indicated a high frequency of smoking in such cases. Endobronchial mixed papillomas might have a smoking-related etiology.

Stage IA ovarian cancers: comparison of sonographic findings and histopathologic types between patients with normal and elevated serum cancer antigen 125 levels.

OBJECTIVES: The purpose of this study was to compare sonographic findings and histopathologic types of stage IA ovarian cancers between groups with normal and elevated cancer antigen 125 (CA-125) levels. METHODS: Between 2000 and 2009, 146 stage IA ovarian cancers were treated surgically (85 invasive and 61 borderline, 73 self-referred with tumor-related symptoms, 20 self-referred with nonspecific symptoms, 52 identified through screening, and 1 other). Of these, 87 cases (60%) had normal serum CA-125 levels (<35 U/mL). Their pre-operative sonographic findings and histopathologic types were compared to those of cases with elevated CA-125 levels. RESULTS: Statistically significant differences were found between the proportions of patients with elevated CA-125 levels in groups having tumors with maximal diameters of less than 20 cm and at least 20 cm (P = .03) and groups having tumors with less than 50% and 50% to 80% solid components (P = .02). In the group with normal CA-125 levels, we found predominantly mucinous adenocarcinoma in multilocular cysts with less than 50% solid components (25 cases), and clear cell adenocarcinoma in unilocular cysts with less than 50% solid components (12 cases), whereas in the group with elevated CA-125 levels, mucinous adenocarcinoma in multilocular cysts with less than 50% solid components (19 cases) and endometrioid adenocarcinoma in solid tumors (≥80% solid components) were predominant (5 cases). CONCLUSIONS: Stage IA ovarian cancers with normal CA-125 levels tend to be smaller, have less solid components, and have a slightly different distribution of histopathologic types than cancers with elevated CA-125 levels.

Tobacco smoking and regression of low-grade cervical abnormalities.

The role of tobacco smoking in the multistage carcinogenesis at the cervix is not fully understood because of a paucity of prospective data. To assess the relationship between smoking and spontaneous regression of cervical precursor lesions, a total of 516 women with low-grade squamous intraepithelial lesion (LSIL) were monitored by cytology and colposcopy every 4 months. Probability of LSIL regression within 2 years was analyzed in relation to smoking behaviors, with regression defined as at least two consecutive negative Pap smears and normal colposcopy. Women's age, initial biopsy results, and human papillomavirus (HPV) genotypes were included in the multivariate models for adjustments. Our study subjects included 258 never-smokers and 258 smokers (179 current and 79 former smokers). During a mean follow-up time of 39.8 months, 320 lesions regressed to normal cytology. Probability of regression within 2 years was significantly lower in smokers than in never-smokers (55.0%vs 68.8%, P = 0.004). The risk of LSIL persistence increased with smoking intensity and duration and with younger age at starting smoking (P = 0.003, P < 0.001, and P = 0.03, respectively). Smokers had twice as high a risk of persistent HPV infection compared to never-smokers (odds ratio, 2.50; 95% confidence interval, 1.30-4.81; P = 0.006). In young women, passive smoking since childhood reduced probability of regression within 2 years (56.7%vs 85.9%, P < 0.001). Further adjustments for a wide range of cervical cancer risk factors did not change the findings. In conclusion, tobacco smoking may interfere with regression of cervical precursor lesions. Childhood exposure to second-hand smoke may increase a risk of persistent cervical abnormalities among young women.

Cytological Findings of Gastrointestinal Stromal Tumor-Derived Bone Metastasis.

OBJECTIVE: Procedures for diagnosing bone tumors should be rapid and minimally invasive. Thus, cytological examinations are more useful for such purposes than histological examinations. In order to identify cytomorphological findings that could be used to diagnose bone metastasis from gastrointestinal stromal tumors (GIST), previous cases were reviewed. STUDY DESIGN: Cytological samples of 7 lesions from 4 patients with GIST-derived bone metastasis, which were obtained from 2001 to 2017 at the JFCR Cancer Institute Hospital, were reviewed. RESULTS: The metastasis of GIST to the bone was clinically suspected before the cytological and histological examinations in all cases since they all involved other metastatic lesion(s), and characteristic osteolytic lesions were detected on radiological images. Although various cell shapes were encountered, spindle cell proliferation was seen in all cytological samples. No pleomorphism was apparent. Characteristic nuclear findings were observed. All of the cases could be diagnosed as GIST-derived bone metastasis. CONCLUSION: GIST-derived bone metastasis can be diagnosed by examining cytological samples.

A unique fibrous tumor of the ovary: fibrosarcoma or mitotically active cellular fibroma?

A unique fibrous tumor of the ovary is reported. A 32-year-old nulliparous woman was diagnosed with a left ovarian tumor and underwent left salpingo-oophorectomy. Macroscopically, the cut surface of the tumor showed yellowish multilobular areas. There was no sign of necrosis or hemorrhage within the tumor. Microscopically, the tumor consisted of two well-circumscribed components. One corresponded to the yellowish lobular areas; there were more than 10 mitotic figures per 10 high-power fields and strong staining for Ki-67, suggesting fibrosarcoma, but nuclear atypia was not severe. In the other component, there were few if any mitotic figures; there was no nuclear atypia and marked cellularity. Pathologically, the tumor was considered a variant fibrosarcoma or a mitotically active cellular fibroma. In light of these pathological findings along with the patient's age and obstetrical history, no further treatment was performed. There has been no evidence of recurrence after 1-year follow-up.

Touch cytology smear of an inflammatory hepatocellular adenoma displaying an unusual pattern: A case report.

The cytological diagnosis of hepatocellular adenoma (HCA) is difficult since it is a very rare tumor and lacks characteristic cytological features. We have just reported a case of inflammatory HCA that displayed an unusual histological pattern (Clin J Gastroenterol 8:426-434, 2015). A touch cytology smear sample was obtained from the surgical specimen, and it also exhibited very unique features. A 56-year-old male underwent partial hepatectomy for an inflammatory HCA (diameter: 1.4 cm) in the right posterior lobe of the liver. The cytological sample displayed a characteristic two-cell pattern. One type of cells contained thick cytoplasm, a high nucleus/cytoplasmic (N/C) ratio, and well-defined cytoplasmic borders. The other type demonstrated small pyknotic nuclei and a lower N/C ratio. The immunohistochemical staining pattern of the histological specimen suggested that the latter cells might have been undergoing apoptosis. We report a case of inflammatory HCA with characteristic features. To diagnose this type of variant, it is important to recognize the unique pattern described in this study. Diagn. Cytopathol. 2016;44:1074-1077. © 2016 Wiley Periodicals, Inc.

A case of inflammatory hepatocellular adenoma displaying an unusual histological pattern.

Hepatocellular adenoma (HCA) is a rare type of liver tumor. Here, we report a variant case of HCA in a 56-year-old Japanese man which displayed unusual histological features. The patient had undergone surgery for esophageal and gastric cancer 2 years prior. A computed tomography scan performed in the follow-up period detected a single lesion (diameter 1.4 cm) in the right posterior lobe of the liver, leading to a partial hepatectomy. Histologically, the lesion was composed of two different types of cells. The larger cells, which accounted for most of the cells in the tumor, exhibited granular and eosinophilic cytoplasm, large nuclei and apparent nucleoli. These cells, which were designated the common cells, were typical of the HCA. The other cells, which were designated the pyknotic cells, were smaller, possessed an eosinophilic, homogeneous cytoplasm and pyknotic small nuclei, but did not contain nucleoli. Immunohistochemically, the common cells reacted strongly positive for C-reactive protein and serum amyloid A, which is compatible with a diagnosis of inflammatory HCA; in contrast, the pyknotic cells tested negative for these molecules. Since the pyknotic cells tested positive for several markers of apoptosis, they were considered to be apoptotic. In addition, as the common cells demonstrated a higher ki-67 labeling index, the lesion was considered to display upregulated cell kinetics, i.e. increases in both cell growth and death. Although HCA is a rare type of tumor, there have been several reports on HCA variants. The case reported here is that of a new type of HCA variant that demonstrated an unusual histological pattern and upregulated cell kinetics.

Loss of heterozygosity and the smoking index increase with decrease in differentiation of lung adenocarcinomas: etiologic implications.

To better understand causative relations of smoking to lung adenocarcinomas, the frequency of loss of heterozygosity (LOH) of all autosomal chromosomes was compared among the three grades of histological differentiation with 119 pulmonary adenocarcinomas (AC) and 41 squamous cell carcinomas (SCC), using Southern blotting. The fractional allelic loss (FAL) values, defined as (number of chromosome arms with LOH)/(number of informative arms), and smoking index (a product of number of cigarettes per day and duration in years) for all ACs were 0.19 and 520 whereas those for SCCs were 0.34 and 1,160, respectively. Those for well- (n=33), moderately (n=63) and poorly (n=23) differentiated ACs were 0.100, 0.197, 0.295 and 310, 480, 1,010, respectively. These results showed that less differentiated ACs are more similar to SCC in terms of LOH frequency and smoking.

Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix.

We established 2 novel human cell lines (GCCOT-1, GCCRK) from glassy cell carcinoma. Both cell lines showed dual tendencies of glandular and squamous differentiation, and thus possess the characteristics resembling reserve cells, the putative origin of most carcinomas arising from the uterine cervix. HPV type 18 DNA including E6-E7, which is commonly found in cell types other than squamous cell carcinoma of uterine cervix, was detected in both cell lines. We analyzed gene copy number alterations of the 2 cell lines using conventional comparative genomic hybridization (CGH) coupled with array-based CGH. Among the putative oncogenes demonstrating copy number gain in both cell lines, FGR(SRC2) at 1p36.2-1 and LAMC2 at 1q25-31 have not been reported to show amplification in previous analyses of conventional cervical cell lines. These oncogenes are thus speculated to be directly associated with oncogenesis of glassy cell carcinoma. On the other hand, among the putative suppressor genes demonstrating copy number loss in both cell lines, the 9q region, ATM at 11q22.3, and CYLD at 16q12-13 have not been reported to show loss in conventional cervical cancer cell lines. These sites are speculated to be important as tumor suppressors directly associated with oncogenesis of glassy cell carcinoma. This study suggests for the first time that together with the presence of HPV type 18, alterations at the above sites are closely associated with oncogenesis of glassy cell carcinoma, a special type of carcinoma in the uterine cervix.

Villin1, a novel diagnostic marker for cervical adenocarcinoma.

The number of new cervical adenocarcinoma (AD) cases has risen slowly, however, its histological similarity to other tumor types and the difficulty of identifying the site of the original tumor makes the diagnosis of cervical AD particularly challenging. We investigated a novel molecular biomarker for cervical AD through the integration of multiple methods of genomic analysis. Tumor samples in discovery set were obtained from 87 patients who underwent radiotherapy, including 31 cervical AD. Microarray analysis and quantitative polymerase chain reaction analysis were performed to screen a candidate diagnostic molecule for cervical AD, and its clinical significance was investigated by immunohistochemical analysis (IHC). We found a difference between biopsy samples of AD and squamous cell carcinoma (SCC) in the expression and genomic copy number of Villin1 (VIL1), which maps to 2q35. IHC revealed 14 VIL1-positive tumors; 13 cervical AD and one small cell carcinoma of cervix, while none of SCC or endometrial AD was VIL1-positive. Kaplan-Meier survival curves revealed worse disease-free survival in VIL1-positive tumors. The marker was validated by newly enrolled 65 patients, and VIL1 positive staining showed 52% of sensitivity and 100% of selectivity for cervical AD. In conclusion, we have identified VIL1 as a novel biomarker of cervical AD. VIL1, a major structural component of the brush border cytoskeleton, which was recently found to be an epithelial cell-specific anti-apoptotic protein. Our study suggests the existence of a subtype of cervical tumors which are VIL1 positive with poor radioresponse.