Inflammatory atypia. An apparent link with subsequent cervical intraepithelial neoplasia explained by cytologic underreading

A review of 5,752 cervical smears done on college students at a medium-sized midwestern university in a 24-month period showed 496 cytologic diagnoses of inflammatory atypia and 132 of dysplasia (cervical intraepithelial neoplasia: CIN). Further retrospective review of a nonselected cohort (178 cases) of the 496 patients with inflammatory atypia showed that their subsequent cytologic smears were more likely to show CIN than could be explained by chance alone. Only ten cases accounted for this difference, and a case-controlled blind review of the original cytologic smears of these ten patients resulted in the reclassification to CIN (mild dysplasia) of seven who had subsequently "progressed" from inflammatory atypia to dysplasia. Only one control smear was reclassified. In this population, underreading of a small number of cervical smears explained a strong statistical apparent correlation between inflammatory atypia and the subsequent development of CIN.     

Vaginal intraepithelial neoplasia and the Pap smear

OBJECTIVE: To assess the sensitivity of the vaginal smear cytologic examination in detecting vaginal intraepithelial neoplasia (VAIN) and to evaluate the cytologic findings of cases of VAIN. STUDY DESIGN: Cases with a histologic diagnosis of VAIN were identified from the Barnes-Jewish Hospital South and North Campus over a period of five and nine years, respectively. Only posthysterectomy patients with a tissue biopsy diagnosis of VAIN and with a vaginal smear obtained within three months of the biopsy were included in the study. Pertinent clinical information was obtained by reviewing the medical records. Two pathologists reviewed the pathologic samples. RESULTS: Thirty-five vaginal smears from 31 posthysterectomy patients were included in the study. The mean age was 57 years (range, 29-84). The cytologic diagnoses of smears from patients with VAIN included: high grade squamous intraepithelial lesion (19 cases), low grade squamous intraepithelial lesion (10 cases), atypical squamous cells of uncertain significance (5 cases) and negative for malignancy (1 case). CONCLUSION: The sensitivity of the vaginal smear cytologic examination in detecting VAIN is 83%. Obscuring inflammation contributed to false negative diagnoses in two cases.     

Cytologic predictors of cervical intraepithelial neoplasia in women with an ASCUS Pap smear

OBJECTIVE: To identify cytologic parameters on Pap smears of women with an atypical squamous cells of undetermined significance (ASCUS) diagnosis that could help cytologists to indicate whether a particular ASCUS case is most likely related to cervical intraepithelial neoplasia (CIN) grade 1 or 2/3. STUDY DESIGN: A total of 360 eligible women diagnosed with ASCUS and referred to the colposcopy clinic of Saint-Sacrement Hospital participated in the study. Eligible women were those aged 18-50 years, newly diagnosed with ASCUS, with no history of cervical biopsies or treatment, and not pregnant at the time of the visit. Colposcopically directed biopsies of lesions were obtained. All Pap smears were reviewed according to 36 different cytomorphologic criteria. The regression logistic model was used to estimate the odds ratios (ORs) for the associations between cytologic criteria observed in smears and the diagnosis of CIN made on biopsies. All cytologic criteria significantly (P < .05) associated with CIN were entered in the models, and a backward selection was done to determine independent cytologic predictors of CIN 1 and 2/3. RESULTS: Biopsies revealed that 22.2% of the study population had concurrent CIN. CIN I and 2/3 were identified in 61 (16.9%) and 19 women (5.3%), respectively. Clear perinuclear spaces (OR = 2.5, P = .002) and moderate nuclear atypia (OR = 4.4, P = .02) were two cytologic criteria independently associated with CIN 1. Four independent predictors of CIN 2/3 were identified: the presence of clear perinuclear spaces (OR = 5.9, P = .004), hyperchromasia (OR = 3.9, P = .04), moderate anisokaryosis (OR = 13.1, P = .01 and increased nuclear volume of metaplastic cells (OR = 5.1, P = .007). CONCLUSION: These observations may help cytologists to better categorize ASCUS lesions as intraepithelial ones and will also contribute to improving the Bethesda definition of ASCUS. Further studies are planned to validate these observations.     

Combined Pap smear, cervicography and HPV DNA testing in the detection of cervical intraepithelial neoplasia and cancer

OBJECTIVE: The sensitivity of the Pap smear (PAP) continues to be the subject of debate. During the past several years, cervicography (CER) and HPV DNA testing have been suggested as optional tools in the screening of cervical cancer precursors. STUDY DESIGN: The performance characteristics of PAP, CER and HPV DNA testing (hybrid capture test [HCT]) in all potential combinations were evaluated in a series of 1,030 women (aged 16-70, median, 33), subjected to colposcopy (COLPO) as the reference tool. RESULTS: Of the 992 evaluable cases, 402/992 (41%) had positive COLPO (i.e., an abnormal transformation zone). Of them, 298 women underwent directed punch biopsy, while of the COLPO negative patients, 18/93 positive by at least one of the three tests had endocervical curettage. Of the 402 COLPO positive women, 146 (36%) remained negative on all tests, whereas 256 (64%) had at least one positive test. There were 84 cervical intraepithelial neoplasia (CIN) 2 and 3 lesions and 6 invasive carcinomas. Of the former, 10 were detected by PAP alone, 4 by CER alone and 3 by HCT alone. Three of the 6 carcinomas were HCT negative. The predictive value (PPV) of a positive test was 45% for PAP, 51% for CER and 48% for HCT. The combinations of PAP with CER (for PAP negative cases) and PAP with HCT were more sensitive for CIN 2 and 3 (95% and 94%, respectively) as compared with PAP alone but were associated with a significant decrease in specificity (44% and 46% vs. 57%, respectively). However, both combinations retained a PPV (43%) similar to that of PAP alone (45%). CONCLUSION: The potential combinations of PAP with CER and with HCT were more sensitive in detecting CIN 2 and 3 as compared with PAP alone and retained a PPV similar to that of PAP.     

宫颈上皮内瘤变与宫颈微生物群落结构的相关性

目的分析宫颈上皮内瘤变与宫颈微生物群落结构的相关性。方法选取2017年1月至2018年10月于我院就诊的253例女性进行回顾性分析,根据是否患有宫颈上皮内瘤变分为CIN组(86例)及对照组(167例)。采集纳入对象的宫颈菌群并提取细菌基因组DNA,对细菌16S rRNA V3、V4区片段进行PCR扩增,并采用Illuminate Miseq测序平台对PCR产物进行测序,分析两组对象宫颈微生物群落结构,并分析患者宫颈微生物群落结构与宫颈上皮内瘤变的相关性。结果两组对象宫颈微生物群落的Simpson指数及Shannon指数比较差异无统计学意义(t=1.474、1.636,P0.05),而CIN组的Chao指数及ACE指数均高于对照组(t=9.213、10.420,P0.05)。16S rRNA分析显示放线菌是宫颈部位的主要菌群。CIN组女性宫颈微生物群落中放线菌、奇异菌属、放线菌门、阴道奇异菌及奇异变形菌占主要优势(LDA4log10),对照组中杆菌、厚壁菌门等占主要优势。Spearman相关分析示卷曲乳杆菌、惰性乳杆菌、格氏乳杆菌、詹氏乳杆菌与宫颈上皮内瘤变呈负相关,而加特纳菌、阴道奇异菌、普雷沃氏菌、粪球菌与宫颈上皮内瘤变呈正相关(均P0.05)。结论 CIN女性宫颈菌群与健康女性存在明显差异,其中卷曲乳杆菌、惰性乳杆菌、格氏乳杆菌、詹氏乳杆菌与宫颈上皮内瘤变呈负相关,而加特纳菌、阴道奇异菌、普雷沃氏菌、粪球菌与宫颈上皮内瘤变呈正相关。     

Mean nuclear volume in cervical intraepithelial neoplasia and carcinoma

OBJECTIVE: To correlate three-dimensional nuclear size (mean nuclear volume) estimated by the stereologic intercept methodfor objective classification of cervical intraepithelial neoplasia (CIN) and carcinoma. STUDY DESIGN: In this retrospective study a total number of 29 CIN cases (8 cases of CIN 1, 10 cases of CIN 2 and 11 cases of CIN 3) and 10 cervical squamous cell carcinoma cases were selected. Mean nuclear volume (MNV) of all cases was measured with an image cytometer (Leica, Cambridge, England) using Quantimet 600 software (Leica). Nuclear point resection method was adopted to measure nuclear volume. Mean intercepted diameter of at least 50 nuclei was measured randomly. MNV was correlated with the histologic grade and diagnosis. RESULTS: MNV of CIN 1, 2, 3 and carcinoma cases was 291.72, 403.33, 711.45 and 893 microm3, respectively. ANOVA test results showed that MNV of CIN 1 and 2 was significantly lower than that of CIN 3 and invasive carcinoma (P < .000). MNV of CIN 3 was also significantly lower than that of carcinoma cases (P <.05). CONCLUSION: The findings suggest that estimates of MNV on conventional histopathology slides provide objective and useful criteria for relatively subjective histopathologic grading.     

Conservative management of intraepithelial cervical neoplasia.

In a prospective trial cryotherapy was performed in 164 patients with preinvasive cervical neoplasia, most of whom desired future childbearing. Their disease had been evaluated by repeat cytology, colposcopy and colposcopically directed punch biopsies, with endocervical curettage when necessary. This conservative treatment eradicated the disease in 147 (89.6%) of the patients. The remaining 17 underwent complete reinvestigation. The focal residual disease in 12 was successfully treated by conservative means--repeat cryotherapy, focal electrocautery or punch biopsy. The other five required either cone biopsy or hysterectomy because of more extensive lesions.     

DNA changes in progressive cervical intraepithelial neoplasia.

Cervical intra-epithelial neoplasm (CIN) is treated as a progressive lesion, even though most CIN will not progress to invasive cancer if left untreated. This study focussed on DNA-cytometric analysis of cytologic smears of patients who had developed invasive cancer after initial smears showing CIN. The first part of the study aimed at describing the DNA-cytometric changes in these progressive ('malignant') CIN lesions. In the second part a cluster analysis was performed on 'malignant' CIN III lesions and CIN III lesions, with 'unknown' malignant potential. The results indicated that 'malignant' CIN lesions developed high DNA-index (DI) values during malignant transformation, as demonstrated by increasing mean DI values, a high percentage of DNA-aneuploidy and 2.5c Exceeding Rates. Furthermore, a trend-like pattern of texture feature values occurred in 'malignant' CIN lesions with increasing severity. These findings provide objective quantitative confirmation of the evolution of nuclear changes during malignant transformation. Cluster analysis showed that it was possible, using a set of four cytometric features, to subdivide the 'unknown' CIN III lesions into a cluster of lesions with feature values similar to the vast majority of the 'malignant' CIN III lesions, and a second cluster of lesions with feature values dissimilar to 'malignant' CIN III. It is argued that the profile of 'malignant' CIN has become clearer and that the results of this study may serve as a basis for a more objective cytopathologic subdivision of premalignant CIN. It may be justified to follow up patients whose lesions do not yet fit this 'malignant' profile. Not treating the non-progressive lesion group will avoid putting these patients at risk.     

Immunocytochemical staining of cervical smears for the diagnosis of cervical intraepithelial neoplasia

A total of 233 cervical smears were stained by immunocytochemical methods for epithelial membrane antigen (EMA); the findings were compared with those from Papanicolaou-stained smears from the same women. Squamous epithelial cells from normal cervices did not stain, but cells shed from cervices with cervical intraepithelial neoplasia (CIN) did express the EMA marker. Metaplastic cells from normal and abnormal cervices also frequently stained. The results confirm that this marker detects cervical intraepithelial neoplasia in vitro, but its potential use in an automated screening program may be limited by the staining of the metaplastic cells.     

Plasma proteome analysis of cervical intraepithelial neoplasia and cervical squamous cell carcinoma

Although cervical cancer is preventable with early detection, it remains the second most common malignancy among women. An understanding of how proteins change in their expression during a particular diseased state such as cervical cancer will contribute to an understanding of how the disease develops and progresses. Potentially, it may also lead to the ability to predict the occurrence of the disease. With this in mind, we aimed to identify differentially expressed proteins in the plasma of cervical cancer patients. Plasma from control, cervical intraepithelial neoplasia (CIN) grade 3 and squamous cell carcinoma (SCC) stage IV subjects was resolved by two-dimensional gel electrophoresis and the resulting proteome profiles compared. Differentially expressed protein spots were then identified by mass spectrometry. Eighteen proteins were found to be differentially expressed in the plasma of CIN 3 and SCC stage IV samples when compared with that of controls. Competitive ELISA further validated the expression of cytokeratin 19 and tetranectin. Functional analyses of these differentially expressed proteins will provide further insight into their potential role(s) in cervical cancer-specific monitoring and therapeutics.     

Local expression of interferon-alpha and interferon receptors in cervical intraepithelial neoplasia

Purpose  

The present study evaluated mRNA expression of interferon-alpha (IFN-α), IFN-α receptor subunits (IFNAR-1 and IFNAR-2) and an IFN-stimulated gene encoding the enzyme 2′,5′-oligoadenylate synthetase (2′5′OAS) in biopsies on patients with varying grades of cervical intraepithelial neoplasia (CIN I, II and III).     

Diagnosis and treatment of cervical intraepithelial neoplasia in general practice.

OBJECTIVE--To audit the first five years of a colposcopy and treatment service for cervical dysplasia established within a general practice. DESIGN--A cervical smear register was established to determine which women were "at risk" of dysplasia. The results of colposcopy and treatment of dysplasia were analysed. SETTING--A large rural general practice with community hospital facilities in mid-Wales. PATIENTS--4437 Women at risk in a total practice population of 14,100. INTERVENTIONS--Colposcopy of women with dyskaryotic smear results, persistent inflammatory smear results, or vulval warts. Treatment of women with proved dysplasia by electrodiathermy of the cervix or cone biopsy. RESULTS--138 Women with dysplasia were diagnosed over five years: 36 mild, 97 moderate or severe, and five with microinvasion. Despite a 78% smear rate of at risk women over five years, nine invasive cancers still occurred. CONCLUSIONS--The results of treatment are acceptable. Cervical dysplasia has become very common, the risk of a dysplasia in women aged 20-39 who had smear tests being one in 14 over five years.     

Clinical and pathological heterogeneity of cervical intraepithelial neoplasia grade 3

Objective

Cervical intraepithelial neoplasia grade 3 (CIN3), the immediate cervical cancer precursor, is a target of cervical cancer prevention. However, less than half of CIN3s will progress to cancer. Routine treatment of all CIN3s and the majority of CIN2s may lead to overtreatment of many lesions that would not progress. To improve our understanding of CIN3 natural history, we performed a detailed characterization of CIN3 heterogeneity in a large referral population in the US.

Methods

We examined 309 CIN3 cases in the SUCCEED, a large population-based study of women with abnormal cervical cancer screening results. Histology information for 12 individual loop electrosurgical excision procedure (LEEP) segments was evaluated for each woman. We performed case-case comparisons of CIN3s to analyze determinants of heterogeneity and screening test performance.

Results

CIN3 cases varied substantially by size (1–10 LEEP segments) and by presentation with concomitant CIN2 and CIN1. All grades of CINs were equally distributed over the cervical surface. In half of the women, CIN3 lesions were found as multiple distinct lesions on the cervix. Women with large and solitary CIN3 lesions were more likely to be older, have longer sexual activity span, and have fewer multiple high risk HPV infections. Screening frequency, but not HPV16 positivity, was an important predictor of CIN3 size. Large CIN3 lesions were also characterized by high-grade clinical test results.

Conclusions

We demonstrate substantial heterogeneity in clinical and pathological presentation of CIN3 in a US population. Time since sexual debut and participation in screening were predictors of CIN3 size. We did not observe a preferential site of CIN3 on the cervical surface that could serve as a target for cervical biopsy. Cervical cancer screening procedures were more likely to detect larger CIN3s, suggesting that CIN3s detected by multiple independent diagnostic tests may represent cases with increased risk of invasion.     

In situ immunopathological events in human cervical intraepithelial neoplasia and cervical cancer: Review

Neoplasia of the cervix represents one of the most common cancers in women. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. The in-situ expression of several cytokines by uterine epithelial cells and by infiltrating leukocytes occurs during the cervical intraepithelial neoplasia and cervical cancer. Some of these cytokines can prevent and others can induce the progression of the neoplasm. The infiltrating leukocytes also produce cytokines and growth factors relate to angiogenesis, chemotaxis, and apoptosis capable of modulating the dysplasia progression. In this review we analyzed several interleukins with an inductive effect or blocking effect on the neoplastic progression. We also analyze the genetic polymorphism of some cytokines and their relationship with the risk of developing cervical neoplasia. In addition, we describe the leukocyte cells that infiltrate the cervical uterine tissue during the neoplasia and their effects on neoplasia progression.