Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva

In this updated systematic review and meta‐analysis, we estimate the pooled prevalence of human papillomavirus (HPV) DNA and HPV type distribution in squamous cell carcinoma of the vulva (vulvar cancer) and vulvar intraepithelial neoplasia (VIN). PubMed, Embase and Cochrane Library databases were used to identify studies published between 1990 and 2015 and using a PCR‐based or hybrid capture test to evaluate the presence of HPV DNA in vulvar cancer or VIN. Pooled estimates of the HPV prevalence with corresponding 95% confidence intervals (CI) were calculated based on a random effects model. The I² statistic was used to describe the amount of heterogeneity. In meta‐regression analyses, potential sources of heterogeneity were evaluated. We identified 92 eligible papers, comprising altogether 5,015 cases of vulvar cancer (64 papers) and 2,764 cases of VIN (48 papers). The pooled prevalence of HPV in vulvar cancer was 39.7% (95% CI: 35.1–44.4%). Overall, 76.3% (95% CI: 70.1–82.1%) of VIN lesions tested HPV‐positive, while the HPV prevalence in new subcategories of VIN, uVIN and dVIN, was 86.2% (95% CI: 73.5–95.5%) and 2.0% (95% CI: 0–10.0%), respectively. Substantial between‐study heterogeneity was observed (vulvar cancer: I² = 88.4%; VIN: I² = 90.7%) with the largest variation between geographical regions. Among HPV‐positive cases, the predominant high‐risk HPV type was HPV16, followed by HPV33 and HPV18. HPV6 was detected as a single infection in a small subset of VIN and vulvar cancer samples. Thus, HPV vaccination targeting these HPV types may prevent a substantial number of vulvar lesions.     

HPV status and favourable outcome in vulvar squamous cancer

It is universally accepted that high‐risk human papillomavirus (HR‐HPV) is the cause of cervical dysplasia and cancer. More recently, it has been shown that HPV is also a marker of clinical outcome in oropharyngeal cancer. However, contemporary information is lacking on both the prevalence of HPV infection in vulvar cancer (VSCC), its precursor lesion, vulvar intraepithelial neoplasia (VIN) and the influence of HPV‐status on the prognosis of this malignancy. We have conducted a detailed population‐based study to examine rates of progression of VIN to VSCC, type‐specific HPV prevalence in vulvar disease and the influence of HPV status on clinical outcome in VSCC. We observed that the age at which women are diagnosed with VSCC is falling and there is a significant time gap between first diagnosis of VIN and progression to invasive disease. HR‐HPV infection was detected in 87% (97/112) cases of VIN and 52% cases (32/62) of VSCC. The presence of HR‐HPV in squamous intraepithelial lesion was associated with lower rates of progression to invasive cancer (hazard ratio, 0.22, p = 0.001). In the adjusted analysis, HR‐HPV was associated with improved progression‐free survival of VSCC compared to those with HPV negative tumours (hazard ratio, 0.32, p = 0.02).     

Clinical validation of methylation biomarkers for optimal detection of high-grade vulvar intraepithelial neoplasia

The precursor lesions of vulvar squamous cell carcinoma (VSCC) include human papillomavirus (HPV)-associated and HPV-independent squamous neoplasia with a varying cancer risk. Our study aimed to validate the accuracy of previously identified DNA methylation markers for detection of such high-grade vulvar intraepithelial neoplasia (VIN). A large clinical series of 751 vulvar lesions, originally diagnosed as high-grade VIN, were reassessed and categorized into HPV-associated or HPV-independent vulvar disease categories. Together with 113 healthy vulvar controls, all samples were tested for 12 methylation markers with quantitative multiplex methylation-specific PCR (qMSP). Performance of individual markers and selection of an optimal marker panel for detection of high-grade VIN was determined by logistic regression analysis. SST was the best-performing individual marker (AUC 0.90), detecting 80% of high-grade VIN cases, with excellent detection of HPV-independent VIN (95%), known to have the highest cancer risk. Merely 2% of controls tested methylation positive for SST. Selection of a marker panel, including ZNF582, SST and miR124-2, resulted in a comparably high accuracy for detection of high-grade VIN (AUC 0.89). In conclusion, we clinically validated the accuracy of 12 DNA methylation markers for detection of high-grade VIN. SST, as a sole marker or in a panel, provides an optimal diagnostic tool to distinguish high-grade VIN in need of treatment, particularly HPV-independent VIN, from low-grade or reactive vulvar lesions. These findings warrant further prognostic validation of methylation biomarkers for cancer risk stratification of patients with VIN.     

自噬相关基因Beclin1在外阴鳞癌中的表达及临床意义

目的:探讨自噬相关基因Beclin1在外阴鳞癌中的表达及其与临床病理特征的关系.方法:采用免疫组织化学的方法检测Beclin1蛋白在50例外阴鳞癌、 30例外阴上皮内瘤变及10例正常外阴组织中的表达情况,RT-PCR的方法检测25例外阴鳞癌、13例外阴上皮内瘤变及10例正常外阴组织中Beclin1 mRNA的表达情况.结果:Beclin1蛋白在外阴癌、外阴上皮内瘤变、正常外阴组织中阳性率分别为52.0%、86.6%、90.0%,Beclin1蛋白在外阴癌组织中的表达明显低于外阴上皮内瘤变及正常外阴组织,具有统计学差异(P<0.05).Beclin1 mRNA在外阴癌中的相对表达量为(0.318±0.031),显著低于外阴上皮内瘤变(0.634±0.037)及正常外阴组织(0.702±0.042).Beclin1蛋白在外阴鳞癌中的表达与肿瘤临床分期、分化程度、有无淋巴结转移有关(P<0.05),与患者年龄无关(P>0.05).结论:Beclin1在外阴鳞癌组织中表达下调,提示自噬活性的改变可能对外阴鳞癌的发生、发展起一定的作用.     

Expression of Endogenous Hypoxia Markers in Vulvar Squamous Cell Carcinoma

Objective: To investigate the expression of endogenous hypoxia-related markers identified as beinginvolved in vulvar squamous cell carcinoma (VSCC). Methods: We performed immunohistochemical stainingof hypoxia-inducible factor-1α (HIF-1α), glucose transporter-1 (GLUT-1), carbonic anhydrase 9 (CA-9) andvascular endothelial growth factor (VEGF), on tissue sections of 25 VSCC patients, 10 vulvar intraepithelialneoplasia (VIN) patients and 12 healthy controls. Results: HIF-1α expression was found in all sections, with nosignificant difference between controls, VIN and VSCC sections (all P<0.05). Glut-1 expression was found in25% of control, 90% of VIN and 100% of VSCC sections. A significant difference between control and VIN orVSCC was observed (all P<0.05), while no difference was found between VIN and VSCC sections (P>0.05). CA-9expression was negative in control sections, but it was found in 30% of VIN sections and 52% of VSCC sectionswith strong staining. Similarly, CA-9 expression also showed obvious differences between controls and VIN orVSCC sections (all P<0.05). However, there was no significant difference between VIN and VSCC (P>0.05).There were only 25% of control sections with weak VEGF expression, while strong staining was found in about60% of VIN sections and 25% of VSCC sections (all P<0.05). In addition, a difference was also found betweenVIN and VSCC sections (P<0.05). Conclusion: Expression of endogenous hypoxia markers (HIF-1α, GLUT-1,CA-9 and VEGF) might be involved in the malignant progression of VSCC.     

Lichen sclerosus and risk of cancer

Malignant potential of lichen sclerosus (LS) has been suspected, but evidence is sparse. We used the population‐based Finnish Cancer Registry data to further study this connection. We identified all women with the diagnosis of LS (n = 7,616) listed in the Finnish Hospital Discharge Registry from 1970 to 2012. The cohort was followed through the Finnish Cancer Registry for subsequent cancer diagnoses until 2014. Standardized incidence ratios (SIRs) were calculated for different cancers by dividing the observed numbers of cancers by expected ones. The expected numbers were based on national cancer incidence rates. During the follow‐up period, we found 812 cancers among patients with LS (SIR: 1.13, 95% CI 1.05–1.21). LS was associated with an increased risk of vulvar (182 cases, SIR: 33.6, 95% CI 28.9–38.6) and vaginal cancer (4 cases, SIR: 3.69, 95% CI 1.01–9.44). The risk of cancers of the uterine cervix and lung was significantly decreased. LS is associated with an increased risk for vulvar and vaginal cancer. These data are important when designing the care of women diagnosed with LS.     

Human papillomavirus and nonhuman papillomavirus pathways to vulvar squamous cell carcinoma: A review

Vulvar squamous cell carcinoma (VSCC) is a rare tumor of the female genital tract. While previously considered a disease of older women, the epidemiologic landscape is changing with more young women diagnosed with VSCC and its precursor lesions. This may be secondary to the global increase in human papillomavirus (HPV) infection of the lower genital tract. While VSCC precursor lesions have been described for many years, the terminology, and thus the understanding and reproducibility of these lesions have been debated. In the most recent publication from the International Society of the Study of Vulvovaginal Disease (ISSVD), there is a distinction between high-risk vulvar lesions associated with HPV infection (vulvar HSIL) and high-risk vulvar lesions that are not thought to be associated with HPV infection (differentiated VIN or dVIN). These precursors have different risk factors and thus affect different populations, leading to two separate pathways for developing VSCC. The HPV-related VSCC is likely to have a better prognosis than the non–HPV-related VSCC, as seen in other disease sites. Early-stage VSCC may be surgically treated with margin and node status affecting whether adjuvant radiation is recommended. Advanced stage VSCC may be unresectable, requiring neoadjuvant chemoradiation. Although VSCC is a rare disease, ongoing studies investigating the different pathways leading to carcinogenesis may increase the understanding of VSCC and improve therapeutic options for patients.     

EZH2与VEGF在外阴鳞癌组织中的表达及临床意义

目的:探讨EZH2与VEGF在外阴鳞癌中的表达情况及两者与外阴鳞癌临床病理特征的关系。方法:采用免疫组化法对43例外阴鳞癌患者组织,30例外阴上皮内瘤变（VIN II-III）和10例外阴癌病灶外正常组织中的EZH2与VEGF蛋白表达进行测定。结果:外阴鳞癌组织中EZH2与VEGF的阳性率均高于VIN II-III组织及癌旁正常组织,三者间差异有统计学意义（P＜0.05）。EZH2与VEGF在外阴鳞癌中的表达与临床分期、病理分级、有无淋巴结转移有关（P均<0.05)。相关性分析显示,EZH2与VEGF在外阴鳞癌中的表达呈正相关（P＜0.05）。结论:EZH2与VEGF异常表达与外阴鳞癌发生和进展密切相关,其机制可能与二者协同促进肿瘤血管生成有关。     

中性粒细胞/淋巴细胞比值在外阴鳞癌和外阴上皮内瘤变筛查中的预测价值

目的 本研究旨在探讨中性粒细胞/淋巴细胞比值(NLR)与外阴病变活检病理的关系,并探讨NLR能否作为鉴别外阴鳞癌与其癌前病变外阴上皮内瘤变的炎症标志物的可行性.方法 回顾分析2012年12月—2020年6月386例因外阴病变进行活检的患者,评估术前NLR与外阴病变的病理结果的相关性.结果 外阴鳞癌组的平均NLR明显高于...     

Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age

ObjectiveThe purpose of the present study is to investigate the trends in incidence of both usual (u) and differentiated (d) vulvar intraepithelial neoplasia (VIN) separately, their malignant potential and the relation with other HPV related anogenital lesions in the Netherlands during a 14-year-period.MethodsThe incidences of both types of VIN and vulvar SCC were retrieved from the Nationwide Netherlands Database of Histo- and Cytopathology. Population data were retrieved from the Database of Statistics Netherlands.ResultsIn the study period, the incidence of uVIN and dVIN increased, while the incidence of vulvar SCC remained stable. The overall percentage of uVIN patients that were later diagnosed with vulvar SCC was 5.7%, which was significantly lower than the percentage for dVIN patients (32.8%). In addition to this 5.6-fold increased conversion rate, the time of progression from dVIN to SCC development was significantly shorter than that of uVIN (p = 0.005). Percentage of uVIN patients that were later diagnosed with SCC significantly increased with age (p = 0.005), whereas the time to SCC significantly shortened with age (p = 0.05). Forty-one percent of uVIN patients had a past, concomitant or future HPV-associated lesion of the lower genital tract, which is in contrast to the 3% for dVIN patients.ConclusionsAn increase in diagnoses of both uVIN and dVIN has not led to an increase in vulvar SCC incidence. The malignant potential of dVIN is higher than that for uVIN. For uVIN the malignant potential increases with age.     

Trends in incidence and survival of Dutch women with vulvar squamous cell carcinoma

AimPrevious studies showed an increase in incidence of vulvar intraepithelial neoplasia (VIN), the premalignant lesion of Vulvar Squamous Cell Carcinoma (VSCC). Furthermore, during the last decades treatment of VSCC became less radical. Considering these changes the aim of this study was to describe trends of incidence and survival of patients with VSCC in the Netherlands.MethodsAll patients with VSCC diagnosed between 1989 and 2010 (n = 4614) were selected from the Netherlands Cancer Registry. Trends in age-adjusted incidence rates were evaluated by calculating the estimated annual percentage change (EAPC). Joinpoint regression analysis was used to detect changes in trends. Five-year relative survival rates were calculated for four time periods.ResultsThe incidence of VSCC has increased since 2002 (EAPC 5.0; 95% confidence interval (CI): 2.7–7.7%). In women aged <60 years incidence rates increased significantly during the whole study period (EAPC 3.5%; 95% CI: 2.0–4.9), while in women aged ?60 years only an increase has observed from 2004 onwards (EAPC 5.0; 95% CI: 1.5–8.6). Survival rates did not change over time.ConclusionThe incidence rate of VSCC has increased from 2002 onwards in all women. Over the whole study period the increase was strongest in women aged <60 years. The introduction of less radical surgery did not affect survival.     

Patients with usual vulvar intraepithelial neoplasia-related vulvar cancer have an increased risk of cervical abnormalities

Background:

Vulvar squamous cell carcinoma (SCC) originates the following two pathways, related to differentiated (d) vulvar intraepithelial neoplasia (VIN) or to human papillomavirus (HPV)-related usual (u) VIN. Multicentric HPV infections (cervix, vagina and vulva) are common. We hypothesise that patients with a uVIN-related vulvar SCC more often have cervical high-grade squamous intraepithelial lesions (HSILs) compared with women with dVIN-related vulvar SCC.

Methods:

All vulvar SCCs (201) were classified to be dVIN- (n=164) or uVIN related (n=37). Data with regard to the smear history and cervical histology were retrieved from PALGA, the nationwide Netherlands database of histo- and cytopathology. For HSIL cervical smears of which histology was taken, HPV DNA analysis on both the vulvar and cervical specimens was performed.

Results:

At least one smear was available in 145 (72%) of the 201 patients. Patients with a uVIN-related vulvar SCC more often had an HSIL compared with patients with a dVIN-related SCC (35 vs 2%, P<0.001). A total of 10 of the 13 HSILs were histologically assessed and identical HPV types were found in the vulva and cervix.

Conclusion:

These data emphasise the necessity to differentiate between dVIN- and uVIN-related vulvar tumours and to examine the entire lower female ano-genital tract once an uVIN-related lesion is found.     

A cluster of vulvar cancer and vulvar intraepithelial neoplasia in young Australian Indigenous women

Objective  To describe the epidemiological features of a possible disease cluster of vulvar cancer and pre-cancers in Australian Indigenous women living in the Northern Territory (NT) of Australia. Methods  We identified NT-resident women with a confirmed histological diagnosis of vulvar cancer or high-grade vulvar intraepithelial neoplasia (VIN) between 1 January 1996 and 31 December 2005. Results  Seventy-one women were identified; 32 diagnosed with vulvar cancer and 39 with high-grade VIN. Most women diagnosed were Indigenous, aged less than 50 years and living in remote communities in the East Arnhem (EA) district, on the north-east coast of the NT. The age-adjusted incidence rate of vulvar cancer in EA Indigenous women aged 0–49 years was 31.1 per 100,000 (95% CI 13.1–49.1), over 50 times higher than the national Australian rate (0.4 per 100,000, 95% CI 0.4–0.5) for the same age-group. In the age-group of 0–49 years, the age-adjusted incidence rate of VIN for EA Indigenous women was 34.7 per 100,000 (95% CI 15.2–54.3), compared with 6.7 per 100,000 (95% CI 2.0–11.4) for Indigenous women living elsewhere in the Top End of the NT. Conclusion  These data provide evidence of a geographic cluster of vulvar cancer in remote Indigenous communities in northern Australia.     

转录因子KLF5在外阴鳞癌中的表达及其临床意义

目的:探讨转录因子KLF5在外阴鳞癌中的表达及其临床意义。方法:采用免疫组织化学法分别检测四川大学华西第二医院2017年1月至2019年6月行手术治疗的60例外阴病变石蜡标本的KLF5表达水平,包括19例外阴正常组织、15例外阴上皮内瘤变、26例外阴鳞癌,分析KLF5表达与外阴鳞癌患者临床病理特征的关系。结果:由外阴正常组织向上皮内瘤变的进展过程中,KLF5的表达量是逐步增加的。KLF5在外阴上皮内瘤变、外阴鳞癌组织中的表达均显著高于外阴正常组织,不同分化程度的外阴鳞癌组织中KLF5表达量不同(P＜0.05)。KLF5在外阴鳞癌中的表达与是否淋巴结转移、临床分期无明显差别(P＞0.05)。结论:转录因子KLF5在外阴上皮内瘤变、外阴鳞癌组织中表达上调,且与外阴鳞癌的分化程度有关,提示KLF5可能与外阴鳞癌的发生、发展有关。     

AKT和p62在外阴鳞状细胞癌变中的表达及意义

目的:研究自噬相关基因AKT和p62在外阴鳞癌中的表达,明确二者与外阴鳞癌临床病理特征的关系。方法:选取2008年1月至2014年12月盛京医院外阴鳞癌（VSCC）40例石蜡包埋组织作为实验组;外阴上皮内瘤变（VIN）30例、正常外阴皮肤10例石蜡包埋组织作为对照组。采用免疫组化SP法检测AKT和p62蛋白在外阴鳞癌、VIN和外阴正常皮肤中的表达水平。分析AKT、p62与VSCC 临床病理特征相关性。结果:与正常外阴皮肤相比,AKT和p62蛋白在VIN中的表达显著增加,在VSCC 组织中的表达量增加更为显著,与VSCC的病理分级呈正相关（P＜0.05）。AKT和p62蛋白呈正相关（P＜0.05）。结论:自噬相关蛋白AKT和p62在VSCC中表达增加,与VSCC的病理分级呈正相关,二者的表达改变与VSCC的发生和进展相关。     

High frequency of loss of heterozygosity in vulval intraepithelial neoplasia (VIN) is associated with invasive vulval squamous cell carcinoma (VSCC).

Vulval intraepithelial neoplasia (VIN) is thought to be the premalignant phase of human papillomavirus (HPV)-associated vulval squamous cell carcinoma (VSCC). Various molecular events have been suggested as markers for progression from VIN to VSCC, but loss of heterozygosity (LOH) in vulval neoplasia has rarely been studied in this context. We performed LOH analysis by polymerase chain reaction (PCR) amplification of polymorphic microsatellite markers at 6 chromosomal loci (17p13-p53, 9p21-p16, 3p25, 4q21, 5p14 and 11p15). The presence of HPV was assessed using consensus PCR primers and DNA sequencing. To examine any association between LOH and the presence of invasive disease, we analyzed 43 cases of lone VIN III, 42 cases of lone VSCC and 21 cases of VIN with concurrent VSCC. HPV DNA was detected in 95% of lone VIN III samples and 71% of lone VSCC samples. Fractional regional allelic loss (FRL) in VIN associated with VSCC was higher than in lone VIN (mean FRL 0.43 vs. 0.21, p < 0.005). LOH at 3p25 occurred significantly more frequently in HPV-negative VSCC than in HPV-positive VSCC (58% vs. 22%, p < 0.04). These data suggest that genetic instability in VIN, reflected by LOH, may increase the risk of invasion. In addition, molecular events differ in HPV-positive and -negative VSCC and 3p25 may be the site of a tumor suppressor gene involved in HPV-independent vulval carcinogenesis.     

外阴鳞癌动物模型的建立及MDM2表达的研究

目的:探讨外阴鳞癌动物模型建立的方法,研究在鼠外阴癌变发生、演进过程中MDM2的表达变化。方法:采用苯甲酸雌二醇注入32只129/J型鼠腹部皮下,8只为对照组,观测肿瘤的体积,取材做病理诊断。采用RT-PCR技术检测MDM2基因的mRNA表达。结果:外阴上皮内瘤变(VIN)发生率为65.5%(19/29),其中VIN1、VIN2各5例,VIN39例;外阴鳞状细胞癌(VSCC)发生率为34.5%。VIN1～2、VIN3、VSCC和对照组中,MDM2基因的mRNA的相对表达量分别为0.34±0.11、0.42±0.20、1.84±0.32和0.30±0.01;VSCC分别与VIN1～2、VIN3和对照组相比,差异均有统计学意义(P<0.05)。结论:129/J型鼠可为外阴病变(VINs/VSCC)的研究提供动物模型。MDM2在鼠外阴鳞癌中的变化与人组织相同,MDM2可作为外阴癌变的生物学指标。     

Prior human papillomavirus‐16/18 AS04‐adjuvanted vaccination prevents recurrent high grade cervical intraepithelial neoplasia after definitive surgical therapy: Post‐hoc analysis from a randomized controlled trial

We evaluated the efficacy of the human papillomavirus (HPV)?16/18 AS04‐adjuvanted vaccine in preventing HPV‐related disease after surgery for cervical lesions in a post‐hoc analysis of the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681). Healthy women aged 15–25 years were randomized (1:1) to receive vaccine or control at months 0, 1 and 6 and followed for 4 years. Women were enrolled regardless of their baseline HPV DNA status, HPV‐16/18 serostatus, or cytology, but excluded if they had previous or planned colposcopy. The primary and secondary endpoints of PATRICIA have been reported previously; the present post‐hoc analysis evaluated efficacy in a subset of women who underwent an excisional procedure for cervical lesions after vaccination. The main outcome was the incidence of subsequent HPV‐related cervical intraepithelial neoplasia grade 2 or greater (CIN2+) 60 days or more post‐surgery. Other outcomes included the incidence of HPV‐related CIN1+, and vulvar or vaginal intraepithelial neoplasia (VIN/VaIN) 60 days or more post‐surgery. Of the total vaccinated cohort of 18,644 women (vaccine = 9,319; control = 9,325), 454 (vaccine = 190, control = 264) underwent an excisional procedure during the trial. Efficacy 60 days or more post‐surgery for a first lesion, irrespective of HPV DNA results, was 88.2% (95% CI: 14.8, 99.7) against CIN2+ and 42.6% (?21.1, 74.1) against CIN1+. No VIN was reported and one woman in each group had VaIN2+ 60 days or more post‐surgery. Women who undergo surgical therapy for cervical lesions after vaccination with the HPV‐16/18 vaccine may continue to benefit from vaccination, with a reduced risk of developing subsequent CIN2+.     

Should LSIL‐H be a distinct cytology category?

BACKGROUND:

The 2001 Bethesda System for gynecologic cervical cytology reporting classifies squamous intraepithelial lesions into low‐grade (LSIL) and high‐grade (HSIL) lesions. An intermediate term, “low‐grade squamous intraepithelial lesion, cannot exclude high‐grade squamous intraepithelial lesion (LSIL‐H),” has been used in a small percentage of LSIL cases. To the authors' knowledge, little is known regarding the human papillomavirus (HPV) status in patients with LSIL‐H.

METHODS:

A total of 808 SurePath specimens obtained between December 2009 and April 2011 were tested for 40 HPV genotypes using DNA microarray, followed by a confirmatory DNA sequencing assay.

RESULTS:

The infection rate for high‐risk HPV in women with LSIL‐H (92%) was strikingly close to that for women with HSIL (91%), which was higher than that for those with LSIL (74%); atypical squamous cells, cannot rule out high‐grade lesion (ASC‐H) (78%); or LSIL and ASC‐H combined (74%). HPV type 16, the most common carcinogenic HPV genotype, was detected in 36% of women with LSIL‐H, which was significantly higher than that in women with LSIL and ASC‐H combined (13.8%), but less than that in women with HSIL (44.6%). Patients with LSIL‐H and HSIL had similar infection rates for low‐risk/intermediate‐risk HPV genotypes, which were lower than those in LSIL or LSIL and ASC‐H combined.

CONCLUSIONS:

Women found to have LSIL‐H on a Papanicolaou test appear to have a unique HPV distribution pattern that clearly differs from LSIL and is comparable to that for HSIL, suggesting an increased risk of high‐grade lesions over that of women with LSIL. Recognizing LSIL‐H as an independent diagnostic category may help in the early identification of the high‐risk subgroup that may require a management algorithm comparable to that for patients with HSIL. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.