Simultaneous demonstration of gelatinolytic activity, morphology, and immunohistochemical reaction using zymography film

In situ zymography has been used to assess gelatinolytic activity, which is mainly due to matrix metalloproteinases (MMPs) in cancer tissues. MMPs play an important role in cancer invasion and metastasis. Film in situ zymography (FIZ) enables the in situ evaluation of gelatinolytic activity with high reproducibility. In this article, we report a study of FIZ, in a case of breast cancer with an invasive carcinoma component showing clear gelatinolytic activity, and in a non-invasive carcinoma component showing little gelatinolytic activity. Immunohistochemistry on FIZ was also performed. The simultaneous detection of gelatinolytic activity and immunohistochemical reaction was established in a single film. Immunohistochemistry on FIZ may have good potential for the investigation of cancer microenvironment.     

Distribution of type IV collagen immunoreactivity to assess questionable early stromal invasion.

AIMS: To determine if the immunocytochemical delineation of subepithelial basement membrane can be used in the assessment of questionable early invasive cervical carcinoma. METHODS: The distribution of immunoreactive type IV collagen was examined in 15 cervical biopsy specimens in which the reporting pathologist had specifically described difficulty in assessing or excluding early invasion of subepithelial stroma associated with cervical intraepithelial neoplasia (CIN). The results were compared with those from biopsy specimens showing CIN III (N = 8), carcinoma with definite early stromal infiltration (FIGO stage 1a1) (n = 6), and more advanced invasive squamous tumours (FIGO stages 1a2 to 3) (n = 8). In all cases the immunocytochemical findings were assessed in relation to serial sections stained with haematoxylin and eosin. RESULTS: Six of the 15 diagnostically problematic biopsy specimens were considered, on review, to show early infiltration of subepithelial tissue and putative invasive foci were consistently absent in basement membrane. A similar pattern was observed in the "definite" early invasive cases. Eight problematic biopsy specimens were considered to show only in situ neoplasia; five of these had intact though occasionally attenuated basement membrane, three showed focal type IV collagen defects. In the remaining case biopsy trauma precluded further assessment. Basement membrane defects were identified in five of eight cases of CIN III, while three of eight squamous carcinomas showed partial retention of type IV collagen immunoreactivity around invasive tumour cell nests. CONCLUSIONS: Defects in subepithelial basement membrane occur in in situ and invasive neoplasia in the uterine cervix. Immunocytochemical staining for type IV collagen is of limited diagnostic value in the assessment of biopsy specimens with questionable early stromal invasion.     

Maspin expression in CIN 3, microinvasive squamous cell carcinoma, and invasive squamous cell carcinoma of the uterine cervix.

Maspin is a serine protease inhibitor with tumor suppression activity. It is expressed in normal breast and prostate tissue but is downregulated or absent in breast and prostate tumors. Recent reports have shown that decreased expression is associated with a greater propensity for metastasis in oral squamous cell carcinomas. We know that some high-grade cervical intraepithelial neoplasia progress to invasive carcinomas while others either persist at the same degree of atypia or regress. The pattern of maspin expression in cervical intraepithelial neoplasia-grade 3, microinvasive squamous carcinomas and overtly invasive squamous cell carcinomas of the uterine cervix was studied to determine the relationship between the extent of maspin expression and the progression of cervical intraepithelial neoplasia to squamous cell carcinoma. In total, 36 cases were evaluated: 18 cases of cervical intraepithelial neoplasia-grade 3, seven cases of microinvasive squamous cell carcinoma and 11 cases of invasive squamous cell carcinoma. A monoclonal antibody was used on paraffin-embedded tissues. Immunoreactivity was scored semiquantitatively using a scale of 0-3. The sums of the scores of the different groups were compared using the Mann-Whitney U-test. A significant decrease in maspin scores was noted between cervical intraepithelial neoplasia-grade 3 vs invasive squamous cell carcinoma (P<0.005), microinvasive squamous cell carcinoma vs invasive squamous cell carcinoma (P<0.05), and cervical intraepithelial neoplasia-grade 3 vs tumor emboli (P<0.005). Although not statistically significant, scores of cervical intraepithelial neoplasia-grade 3 associated with invasive squamous cell carcinoma were lower compared to that cervical intraepithelial neoplasia-grade 3 without invasive squamous cell carcinoma. These findings suggest that maspin likely plays a role in disease progression from in situ to invasive carcinoma. Virtual absence of maspin immunopositivity in tumor emboli indicates that maspin may also play a role in metastasis.     

Adeno-associated virus and development of cervical neoplasia.

Evidence from several sources has suggested that adeno-associated virus (AAV) infection might protect against cervical cancer, in part, by interfering with human papillomavirus (HPV)-induced tumorigenesis. Detection of AAV type 2 (AAV-2) DNA in cervical tissues has been reported. However, there have been few in vivo studies of women with cervical HPV infection or neoplasia, and these have reported inconsistent results. Therefore, we used polymerase chain reaction (PCR) assays targeted to the AAV-2 rep and cap genes to test tissue specimens from women in an epidemiological study of cervical neoplasia in Jamaica. We tested 105 women with low-grade cervical intraepithelial neoplasia (CIN-1), 92 women with CIN-3/carcinoma in situ or invasive cancer (CIN-3/CA), and 94 normal subjects. PCR amplification of human beta-globin DNA was found in almost all cervical specimens, indicating that these materials were adequate for PCR testing. The prevalence of HPV DNA, determined by HPV L1 consensus primer PCR was, as expected, strongly associated with presence and grade of neoplasia. Each of the AAV PCR assays detected as few as 10 copies of the virus genome. However, none of the 291 cervical specimens from Jamaican subjects tested positive for AAV DNA. Negative AAV PCR results were also obtained in tests of cervical samples from 79 university students in the United States. Exposure to AAV was assessed further by serology. Using a whole virus AAV-2 sandwich enzyme-linked immunosorbent assay, we found no relationship between AAV antibodies and presence or grade of neoplasia in either the Jamaican study subjects or women enrolled in a U.S. cervical cancer case (n = 74) -control (n = 77) study. Overall, the data provide no evidence that AAV infection plays a role in cervical tumorigenesis or that AAV commonly infects cervical epithelial cells.     

Detection of human papillomavirus DNA sequences by in situ DNA-DNA hybridisation in cervical intraepithelial neoplasia and invasive carcinoma: a retrospective study.

Human papillomavirus (HPV) infection of cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma was investigated using in situ DNA-DNA hybridisation on histological sections of formalin fixed, paraffin embedded tissue to assess the technique's sensitivity and to assess retrospectively the association between HPV16 and invasive cervical carcinoma. HPV DNA was detected in 16 of 33 biopsy specimens of CIN. Cells containing viral DNA were more numerous than those positive for viral structural proteins. HPV DNA was also present in less differentiated cells deeper in the epithelium. The detection rate in CIN was lower than that reported for other hybridisation techniques such as Southern blotting. In a retrospective study of biopsy specimens of invasive squamous carcinoma of the cervix HPV16 DNA, the virus most commonly associated with cervical malignant disease, was found in 20 of 25 cases, including those dating from as far back as 1932. The level of sensitivity was similar to that reported for other hybridisation techniques. DNA positive cells were focally distributed in the invasive tumours, and most tumour cells were negative for viral DNA, a result consistent with the low copy number found in malignant cells. It is concluded that HPV16 is not a new virus but that its prevalence is a result of changes in sexual behaviour and that in situ hybridisation is useful in the localisation of HPV DNA replication in CIN and invasive carcinoma.     

人宫颈上皮内瘤变和浸润癌组织中树突状细胞及T细胞的免疫组织化学定量分析

目的 研究人宫颈上皮内瘤变和浸润癌组织中树突状细胞和T细胞的数量、分布变化,为人宫颈癌的诊断和生物治疗提供实验依据.方法 采用免疫组织化学和图像分析技术,测定人宫颈上皮内瘤变、宫颈浸润癌和正常宫颈组织中树突状细胞表型抗原CD1a、S-100及T细胞表面分化抗原CD3、CD8阳性细胞的数量、分布和表达强度.结果 与人正常宫颈组织比较,宫颈上皮内瘤变中CD1a 、S-100 、CD3 、CD8 细胞数量增多(P＜0.05),与组织分级呈正相关(P＜0.05),抗体表达强度增高;宫颈浸润癌中4种抗体阳性细胞数量减少,与临床分期呈负相关(P＜0.05),强度略有下降.结论 人宫颈上皮癌前病变至浸润癌变过程中树突状细胞和T细胞数量及抗体表达强度发生变化,提示宫颈病变局部的免疫功能发生了改变.     

Gelatinolytic activity of matrix metalloproteinase in tumor tissues correlates with the invasiveness of oral cancer

We examined whether or not the gelatinolytic activity in tumor tissue was associated with the invasion and metastasis of oral squamous cell carcinoma (OSCC). Tissue homogenates were prepared from 57 biopsy specimens of OSCC. The gelatinolytic activities in the homogenates were measured by gelatin zymography and its densitometric analysis. The Immunoblot findings revealed the major gelatinolytic activities to be due to matrix metalloproteinase (MMP)-2 and -9. The zymography-detected gelatinolytic activities of MMP-2 and MMP-9 in the tissue specimens significantly correlated with the degree of immunohistochemical staining detected in frozen sections of the same biopsy specimens. According to a histopathological analysis of the mode of invasion, highly invasive cases showed the increased gelatinolytic activities of MMP-2 as well as MMP-9 in the tissue specimens. Although no significant differences were observed in the gelatinase activities between the metastatic cases and the non-metastatic cases, the levels of tissue inhibitor of MMP (TIMP)-1 in the tumor tissue specimens were higher in the non-metastatic cases than in the metastatic cases. The cases with the high levels of MMPs and low levels of TIMP-1 thus seemed to have a high potential to metastasize. As a result, the zymographic measurement of the gelatinolytic activity in biopsy tissue specimens may therefore be useful in predicting the behavior and prognosis of OSCC.     

Comparison of peroxidase-labeled DNA probes with radioactive RNA probes for detection of human papillomaviruses by in situ hybridization in paraffin sections.

A study comparing in situ hybridization using nonradioactive DNA probes directly conjugated with horseradish peroxidase (HRP), and 35S-labeled antisense RNA probes for human papillomavirus (HPV) types 6/11, 16, and 18 was performed on formalin-fixed, paraffin-embedded tissue from 34 lesions of the cervix and vulva. These lesions included exophytic condylomas and intraepithelial and invasive neoplasms. HPV 6/11 was detected in two of four condylomata acuminata by both in situ techniques. HPV 16 was detected in 13 of 30 cases of intraepithelial and invasive neoplasms by both methods. Discordance between the two methods occurred in two instances. The radiolabeled probe but not the HRP probe detected HPV 16 in one case of cervical intraepithelial neoplasia (CIN 3), whereas the converse occurred in one case of vulvar intraepithelial neoplasia (VIN 3). HPV 18 was not detected in any of the specimens by either method. This study demonstrates that nonradioactive HRP-labeled probes for the detection of specific HPV types are as sensitive as the more laborious and potentially hazardous radioactive probes.     

Human papillomavirus genotyping by oligonucleotide microarray and p16 expression in uterine cervical intraepithelial neoplasm and in invasive carcinoma in Korean women

For evaluating the diagnostic significance of p16(INK4A) over-expression in the uterine cervical intraepithelial neoplasm and in invasive carcinoma, human papillomavirus (HPV) was detected and genotyped by oligonucleotide microarray in archival tissues of 117 cervical specimens, including 47 invasive squamous cell carcinomas (SCC), 30 cases of cervical intraepithelial neoplasia (CIN), 20 adenocarcinomas, and 20 cases of non-neoplastic cervix. The expression of p16(INK4A) protein was immunohistochemically studied in these cases and in five HPV-positive and one HPV-negative cervical cancer cell lines. HPV was detected in 50% of CIN, 61.7% of SCC, and 45.5% of adenocarcinomas. p16(INK4A) expression was seen in all 20 cases of adenocarcinoma, 78.7% (37/47) of SCC, and 96.7% (29/30) of CIN, but not in any cases of the non-neoplastic cervix. There was no difference in p16(INK4A) expression between the HPV-positive and HPV-negative cervical lesions. All HPV-positive and -negative cervical cancer cell lines expressed p16(INK4A) protein. In conclusion, the presence of p16(INK4A) expression in cervical squamous and glandular epithelium indicates the existence of dysplasia or malignancy in the uterine cervix, regardless of HPV infection.     

CD34(+) fibrocytes in normal cervical stroma,cervical intraepithelial neoplasia III,and invasive squamous cell carcinoma of the cervix uteri

CD34(+) fibrocytes are widely distributed in normal connective tissues but have been reported to be absent within the stroma associated with invasive carcinomas. In the present study we investigated the presence and distribution of CD34(+) fibrocytes and alpha-smooth muscle actin (alpha-SMA) positive myofibroblasts in cervical intraepithelial neoplasia III (CIN III; n=8), invasive carcinoma of the cervix ( n=18) and adjacent normal cervical stroma. Normal cervical stroma and the stroma adjacent to CIN III disclosed a dense network of CD34(+) fibrocytes, whereas the stroma of invasive carcinoma was virtually free of this cell population. Early stromal invasion by squamous carcinoma was characterized by a focal loss of CD34(+) fibrocytes. alpha-SMA-positive myofibroblasts were not seen in the normal cervical stroma but occurred in six of eight cases of CIN III adjacent to the atypical epithelium. The stroma of invasive carcinoma was made up of large amounts of haphazardly arranged alpha-SMA-positive myofibroblasts. In the setting of the present study, a loss of CD34(+) fibrocytes was specific for stromal alterations associated with invasive carcinoma and proved to be a sensitive tool in detecting small foci of stromal invasion. Therefore, detection of a loss of CD34(+) fibrocytes may constitute an adjunctive tool in detecting (1) early stromal invasion and (2) invasive carcinoma in small biopsy specimens. Moreover, the present study shows that CD34(+) fibrocytes and myofibroblasts play an important role in stromal remodeling associated with invasive squamous cell carcinoma of the cervix.     

Distribution of HPV genotypes in uterine cervical lesions in Yanbian, northern China

The aim of the present study was to investigate the distribution of HPV genotypes in uterine cervical lesions in Yanbian, northern China. HPV-DNA chip (oligonucleotide microarray) and cervical biopsy were used for 322 women in 1998-2005. All the normal cervical epithelia were negative for HPV. The positive rate of high-risk HPV was 33.9% in cervical intra-epithelial neoplasia (CIN)-1, 51.6% in CIN-2, 57.7% in CIN-3, 66.7% in cervical glandular intra-epithelial neoplasia (CGIN), 91.7% in squamous cell carcinoma (SCC), and 78.6% in adenocarcinoma. HPV-16 was the major type in all CIN and SCC cervical lesions, but in cervical adenocarcinoma HPV-18 was the most common type, and HPV-16 was the second most common type. Several cases of CIN-3, SCC and adenocarcinoma had multiple types of HPV, but there was none in CIN-1/2. In summary, HPV-16 is the type most frequently involved in the development of SCC of the cervix, and this may be helpful for the prediction of the development and progress of CIN-2/3, whereas both HPV-18 and -16 play a prominent role in the development of adenocarcinoma and CGIN of the cervix in Yanbian, northern China.     

RANTES在HPV感染的子宫颈鳞癌及癌前病变中的表达

目的 探讨趋化因子RANTES在人乳头瘤病毒(HPV)感染的子宫颈鳞癌及癌前病变中的表达.方法 用免疫组化方法 对133例HPV阳性病例子宫颈组织中趋化因子RANTES进行检测.其中正常子宫颈组织10例,子宫颈上皮内瘤变Ⅰ、Ⅱ、Ⅲ级各30例,子宫颈鳞癌33例.结果 RANTES在子宫颈鳞癌组的阳性表达率较CIN组和正常对照组显著增高(P<0.01),其阳性表达强度亦较CIN组和正常对照组显著增高(P<0.01).CIN组内的阳性表达率和阳性表达强度随分级升高而增高,且各组之间比较差异均具有统计学意义(P<0.05);CINⅢ组的阳性表达率和阳性表达强度较正常对照显著增高(P<0.05);CINⅠ、Ⅱ与正常组比较其阳性表达率和阳性表达强度均无统计学意义(P>0.05).结论 RANTES与HPV感染的子宫颈鳞癌及癌前病变密切相关.     

p16INK4A and p14ARF expression pattern by immunohistochemistry in human papillomavirus-related cervical neoplasia.

Human papillomavirus is known to play an important etiological role in the genesis of cervical cancer, but only a very small proportion of infected women develop invasive cervical cancer. The purpose of cervical cancer prevention is early diagnosis of its precursors. The molecular detection of human papillomavirus DNA as a diagnostic test to cervical carcinogenesis gave a low positive predictive value as compared to the use of biomarkers. p16INK4A and possibly p14ARF have been proposed as putative surrogate biomarkers that would allow identification of dysplastic cervical epithelia. Serial consecutive biopsies representing normal cervical epithelium to cervical intraepithelial neoplasia and/or invasive cervical cancer were stained with immunohistochemistry for p16INK4A, p14ARF and proliferating cell nuclear antigen. The positive rates of these markers were significantly higher in cervical intraepithelial neoplasia and in squamous cell carcinoma than in normal cervix (P<0.01). No significant difference was noted between lesions progressing from cervical intraepithelial neoplasia to squamous cell carcinoma for both p16INK4A and p14ARF expression (P>0.05). For both biomarkers, nuclear staining was predominantly seen. However, the cytoplasmic stain of p16INK4A increased with disease progression and the pattern of expression varied between different tumors and its location within the lesion. Both nuclear and cytoplasmic staining with p16INK4A and p14ARF of affected epithelial cells were considered positive. In the adjacent normal tissue to cervical neoplasia, the positive rates of p16INK4A, p14ARF and proliferating cell nuclear antigen expression were higher than those found distant to these lesions but the findings did not reach statistical significance. No correlation was seen between the human papillomavirus types detected and the expression of p16INK4a and p14ARF. In conclusion, overexpression of p16INK4A and p14ARF act as potential biomarkers for cervical cancer progression from premalignant lesions.     

Correlation between human papillomavirus infection and histopathological diagnosis of women in Northeast Brazil

Cervical carcinoma is the fourth leading cause of death among women worldwide. Epidemiological studies claim that human papillomavirus (HPV) infection is a necessary condition for cervical cancer development. Knowledge of the geographic distribution of HPV is important in guiding the introduction of prophylactic vaccines. This study analyzed the prevalence of HPV infection in cervical samples obtained from women with abnormal cervical histopathological diagnosis in Northeast Brazil. The study included an analysis of 211 women whose diagnosis was confirmed for cervical intraepithelial neoplasia type 1 (CIN-1), cervical intraepithelial neoplasia type 2 (CIN-2), cervical intraepithelial neoplasia type 3 (CIN-3), and cancer. The identification of the HPV genotypes was based on the polymerase chain reaction–restriction fragment length polymorphism technique. A total of 42.7% of the samples showed a single HPV infection, while 57.3% showed multiple infections. The most common genotypes detected were HPV-16, HPV-18, and HPV-31. HPV-16, HPV-31, HPV-35, and HPV-18 were the most common types in CIN-1 with a single infection. HPV-16 and HPV-18 were the most often found in CIN-2 with a single infection. HPV-16, HPV-18, and HPV-31 were the most detected in CIN-3 with a single infection. HPV-16 and HPV-31 were the most frequent in cancer with a single infection. Multiple infection with HPV-16 shows a 2.7 times greater risk of CIN-3 (P = .04). Multiple infections for HPV with HPV-16 and excluding the HPV18/31 types, were associated with CIN-3 (P = .01). The results allowed the detection and genotyping of HPV types circulating in the population studied. These findings must be taken into account when devising vaccination strategies against HPV.     

Adenoid basal carcinoma combined with invasive squamous cell carcinoma of uterine cervix: A case report of a 37‐year‐old woman and literature review

Adenoid basal carcinoma (ABC) is uncommon malignancy of the uterine cervix and it can be pure or combined with cervical intraepithelial lesions. There were less than 20 cases of ABC combined with invasive squamous carcinoma (mixed type) in English literature. These cases had similar properties as seen at postmenopausal women and diagnosed with abnormal cervical smear findings. Here we present a case of 37‐year‐old woman who suffered from spotting and received endocervical curettage. The pathological report revealed squamous cell carcinoma (SCC) of the cervix. The patient underwent type 3 radical hysterectomy and bilateral pelvic and para‐aortic lymph node dissection. The final pathological report revealed SCC coexisting with ABC. Human papillomavirus (HPV) 16,18 and others (11 types) were negative in both components of the mixed tumor by in situ hybridization detection. Our case was cytokeratin 7 negative, cytokeratin 8 positive and p63 positive which supports the hypothesis that mixed type cervical carcinoma originates from endocervical reserve cells.     

Human papillomavirus and the three group metaphase figure as markers of an increased risk for the development of cervical carcinoma.

In this study, the presence of atypical mitotic figures and human papilloma virus (HPV) genomes was related to the degree of cervical intraepithelial neoplasia (CIN) or microinvasive carcinoma (MIC) as found in 94 paraffin-embedded biopsies from cervical lesions. The results showed that the frequency of three group metaphase (TGM) figures, a special kind of atypical mitotic figure, as well as the presence of HPV 16 and 18 genomes increased with the degree of cervical intraepithelial neoplasia. TGM figures were observed in 24% of CIN2, up to 61% in CIN3 lesions, and in 83% of the microinvasive cervical carcinomas. HPV genomes were detected in 15% of CIN1, up to 75% in CIN3 lesions, and in 92% of the invasive carcinomas of the cervix. The combination of these two markers showed even a better association with a higher degree of cervical intraepithelial neoplasia. The results of these studies suggest that detection of particular HPV types, mainly HPV 16 and 18, and the presence of TGM figures can be considered as markers that indicate an increased risk for progression of cervical intraepithelial neoplasia to invasive carcinoma.     

Glutathione S-transferase detoxication enzymes in cervical neoplasia

Altered expression of the glutathione S-transferases (GSTs) has been implicated in the progression to tumour after exposure to carcinogens, and GST Pi has been suggested as a possible marker of preneoplasia in the cervix. We have studied expression of the GST isoenzymes in normal cervix, non-dysplastic cervical condylomata, cervical intraepithelial neoplasia (CIN), and invasive squamous carcinoma of the cervix using immunocytochemistry. An increase in GST Pi in CIN as compared with normal cervix was paralleled by a reduction in the expression of microsomal GST. Similar changes were seen in cervical condylomata and immature squamous metaplasia, and thus neither isoenzyme is a marker of dysplasia. Microsomal GST was expressed in only 66 per cent of cases and in 22 per cent showed strong expression in vascular endothelium. These findings are of particular interest in view of the association between cervical carcinoma and cigarette smoking. Differences between individuals in the ability to detoxify environmental carcinogens may influence the likelihood of progression from benign proliferation to invasive malignancy.     

Exfoliative immunocytology of cervical carcinoma.

Fluorescent antibody tracing was applied to exfoliative specimens from 456 women, who were also screened by cytology and partly by histopathology for carcinoma of the cervix. Fixed cervicovaginal smears were treated with autologous serum; the smears then were added labeled antihuman globulin antibody and observed for reactivity. A pattern of cytoplasmic fluorescence was observed in cases that were cytologically diagnosed as severe dysplasia, carcinoma in situ of the cervix, or in cases with positive reactions for malignant cells. Negative Papanicolaou smears appeared nonreactive. A probe into the immunoglobulin class of the antibody that reacted with dyskaryotic and abnormal cells revealed that IgA and IgG but not IgM were involved. The results indicate that a humoral immune response occurs and may be used diagnostically for a demonstration of cellular abnormality in premalignant and invasive cases of cervical carcinoma.     

Divergent expression of L-type amino acid transporter 1 during uterine cervical carcinogenesis

L-type amino acid transporter 1 (LAT1) is a Na?-independent neutral amino acid transporter that has an essential role in cell proliferation. Although LAT1 expression is observed in various tumor cell lines and immunohistochemical expression of LAT1 has been investigated in carcinomas of various organs, LAT1 expression in uterine cervical neoplasm has not been reported. Therefore, in the present study, we immunohistochemically analyzed LAT1 expression along with the well-known markers of cervical carcinogenesis Ki-67 and p16 in normal uterine cervical mucosa (49 specimens) as well as cervical intraepithelial neoplasia (17 mild or moderate dysplasias and 19 severe dysplasias or carcinomas in situ) and invasive carcinomas (17 squamous cell carcinomas and 9 adenocarcinomas). LAT1 expression was limited to the basal layer of normal squamous epithelium, and it was significantly decreased in cervical intraepithelial neoplasia (P < .001), generally paralleled by increased expression of Ki-67 and p16. Interestingly, in invasive squamous cell carcinoma, LAT1 expression again increased especially at the invasive fronts (P < .001), whereas Ki-67 and p16 expressions were almost unchanged relative to noninvasive neoplasia. Although virtually no LAT1 expression was demonstrated in normal uterine cervical glands, LAT1 expression was observed in some adenocarcinomas (P < .001). The present study suggests that LAT1 expression decreases because of human papillomavirus infection as reflected by p16 overexpression in cervical intraepithelial neoplasia, whereas LAT1 expression in invasive carcinoma is associated with acquired malignant potential.     

Human papillomavirus variants and squamous neoplasia of the cervix

Human papillomaviruses (HPVs) play a central role in the aetiology of cervical neoplasia. However, only a small proportion of cervical intraepithelial lesions infected with high-risk HPVs will progress to invasive cervical carcinoma, which indicates the involvement of additional factors. An important emerging viral factor is naturally occurring intratypic sequence variation. Such variation has been used to study the geographical spread of HPVs, but there is increasing evidence that it may be important in determining the risk of development of neoplastic disease. The collected data indicate that different HPV variants have altered biochemical and biological properties and represent an additional risk factor in the development of squamous intraepithelial lesions and invasive carcinoma of the cervix. This may be relevant not only to the biology of HPV infection and its association with squamous neoplasia, but also to the use of HPV typing in clinical practice.