Abnormal Pap smear

Summary

Cervical cancer screening has been hailed as one of the most successful preventative medical strategies. It has been associated with a 70% reduction in cervical cancer mortality in developed countries since the introduction of the Papanicolaou (Pap) test in 1941. [1] View image

[American College of Obstetricians and Gynecologists: the Pap test]

[National Cancer Institute: Pap test]

Cervical sampling techniques

George Papanicolaou developed the Pap smear technique and reported the serendipitous discovery of cervical cancer. [2] The Pap smear samples cells from the junction of the ectocervix and endocervix (the transformation zone or squamocolumnar junction, where 90% of cervical neoplasias originate) to identify pre-malignant or malignant lesions. [3] It should be done when a woman is not menstruating.

Epidemiological, not randomised, data support the impact of Pap smears. The sequential introduction of screening in Canada, matched neighbourhood controlled studies, and the introduction of screening to Finland, Sweden, and Iceland in the 1960s were associated with a fall in the incidence of cervical cancer. [4] [5] [6] More than half of cervical cancers diagnosed in the US occur in women who fail to attend screening. [7]

Conventional cytology using fixed cells on a slide sampled by spatula has a reported sensitivity of 30% to 87% for dysplasia. A meta-analysis suggested a sensitivity of 58% when used for population screening. [8] [9] Since the mid-1990s, newer techniques have used a liquid transport medium (liquid-based cytology) based on ethanol to preserve cells. Several commercial products are available. The liquid sample has the advantage of allowing other diagnostic assessments for sexually transmitted diseases such as gonorrhoea, chlamydia, and HPV to triage risk. Additionally, the proportion of unsatisfactory specimens has been reduced from 4.1% to 2.6%. [10] Standard slide cytology and liquid-based cytology have similar diagnostic accuracy, with reported sensitivity of liquid-based cytology ranging from 61% to 66% with a specificity of 80% to 91%. [11] [12]

Histology of cervical intra-epithelial neoplasiaFrom the collection of Dr Richard Penson, Massachusetts General Hospital, Boston; used with permission

Pap report

Classification of Pap test results, based on the Bethesda System for reporting cervical cytology, was first introduced in 1988 and revised in 2001 to define satisfactory samples and to standardise reporting. [13] Inadequate samples for evaluation include those tests that lack patient-identifying information, broken slides, inadequate squamous component (defined as <5000 squamous cells on liquid-based medium or <8000 to 12,000 cells on conventional medium), or obscuring elements on over 75% of squamous cells (typically due to lubricant, inflammation, or blood).

The Bethesda System terminology for cytological reporting classifies epithelial abnormalities as follows. [13]

• Squamous cell abnormalities

  • Atypical squamous cells (ASC)

  • Atypical squamous cells of undetermined significance (ASC-US)

  • Atypical squamous cells, cannot exclude high-grade squamous intra-epithelial lesion (ASC-H)

  • Low-grade squamous intra-epithelial lesion (LSIL), encompasses those previously classified as koilocytic atypia (HPV changes) or cervical intra-epithelial neoplasia (CIN) 1

  • High-grade squamous intra-epithelial lesion (HSIL), encompasses those formerly called CIN 2 or CIN 3

  • Squamous cell carcinoma.

• Glandular cell abnormalities

  • Atypical glandular cells (AGC)

  • Atypical glandular cells, favour neoplastic

  • Endocervical adenocarcinoma in situ (AIS)

  • Adenocarcinoma.

The Bethesda System classifies LSIL and HSIL as squamous cervical precursor lesions.

Although originally used as cytological diagnoses, the squamous intra-epithelial lesion terminology can be used for histological classification as well. Generally, CIN grades 1 to 3 are used to classify histological diagnoses. More than two-thirds of smears showing cellular atypia do not meet diagnostic criteria for dysplasia and are classified as ASC-US or as ASC-H. Studies have shown that up to 90% of lower-grade Pap tests (LSIL) will spontaneously regress. [14] [15] However, some estimates suggest that LSIL may carry up to a 33% risk of harbouring a higher-grade lesion (CIN 2 or 3). HSIL carries a risk of >70%. [16] [17]

HPV testing

HPV infection has been implicated in over 90% of high-grade cervical dyplasia and nearly 100% of cervical cancers. [18] [19] Oncogenic or high-risk subtypes of HPV are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. [20] Failure to clear HPV is likely to be a primary factor in the subsequent development of dysplasia and can be used to triage patients with equivocal or low-grade Pap test risk. Multiple studies, including the ASCUS-LSIL Triage Study (ALTS), have demonstrated that HPV testing after ASCUS test results are obtained can improve detection of higher-grade lesions. [16] [21] [22] [23] Commercially available HPV tests screen for multiple strains of high-risk HPV (e.g., Cervista™ detects 13 high-risk subtypes and has less cross-reactivity with low-risk types compared with other assays). Investigations have shown that HPV-16 and -18 are associated with significantly more high-grade (at least CIN 2) lesions than other high-risk subtypes. [23] At 10-year follow-up, 1 study reported finding CIN 3 in 21% and cervical cancer in 18% of women who were initially cytology-negative but HPV-16- or HPV-18-positive. High-grade lesions (CIN 3 and cervical cancer) were identified in only 1.5% of all other cytology-negative, high-risk HPV-positive women at 10-year follow-up. [23] HPV testing may have a role in the rural setting of developing countries. One Indian study reported a reduction in advanced cervical cancer in women aged more than 30 years compared with those screened by Pap smear. [24] Due to the high prevalence of HPV infection in women younger than 30 years and the fact that many infections are fleeting, HPV testing is not routinely recommended. HPV testing is more useful in the older age groups, because those women are more likely to have established infection.

Vaccines against HPV-16 and HPV-18 may prevent more than 70% of cervical cancers. [19] In HPV-naive patients, the vaccine has 100% efficacy in preventing HPV-6, HPV-11, HPV-16, and HPV-18-related cervical, vaginal, and vulvar dysplasia and condyloma. The immunogenicity data suggests high levels of persistent antibody titres 5 years after immunisation. The recommended age for vaccination is 11 to 12 years; however, data support immunising as young as 9 years or up to 26 years of age. [25] [26] The vaccines are considered to be very safe, with typical side effects including pain, itching, irritation, erythema, and low-grade fever.

Colposcopy

Colposcopy provides a magnified view of the cervix and vaginal tissue, which enables normal-appearing tissue to be distinguished from abnormal-appearing tissue. Additionally, it allows directed biopsies for pathological examination. Reported sensitivity of colposcopy can be as low as 58%, although this may increase with analysis of 2 or more directed biopsies. Cytological diagnosis and histological diagnosis are directly correlated in 50% of patients. In a study of patients with LSIL, 45% of patients had CIN 1 on biopsy, 16% had CIN 2 or 3, and 33% had normal histology. [27] Findings were similar for HSIL. All visible lesions should be biopsied, with repeated colposcopic examinations to follow persistently abnormal cytology. Treatment is determined by findings on colposcopy and biopsy.

[American Society for Colposcopy and Cervical Pathology: consensus guidelines]

Screening

Screening guidelines are available from:

• European Guidelines for Quality Assurance in Cervical Cancer Screening [European guidelines for quality assurance in cervical cancer screening: recommendations for collecting samples for conventional and liquid-based cytology] [28] [29]

• American College of Obstetricians and Gynecologists (ACOG) [American College of Obstetricians and Gynecologists: cervical cytology screening]

• US Preventive Services Task Force [US Preventive Services Taskforce: screening for cervical cancer]

• American Society for Colposcopy and Cervical Pathology (ASCCP) [American Society for Colposcopy and Cervical Pathology: consensus guidelines]

• American Cancer Society (ACS) [American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology: screening guidelines for the prevention and early detection of cervical cancer] [30]

The USPSTF and the ASCCP now recommend screening in women from age 21 to 65 years. If cytology alone is used, screening in this patient population should be every 3 years. For women age 30 to 65 years, screening interval can be lengthened to every 5 years if both cytology and HPV testing are utilised. Unsatisfactory Pap tests should be repeated in 2 to 4 months. If initial cytology is normal and HPV testing is positive, guidelines recommend retesting in 1 year. [31]

Women with a negative Pap smear and a positive HPV test should have both tests repeated at 12 months. If both tests are negative at that time, they can be returned to routine screening. If the HPV test remains positive, women should be referred for colposcopy. For women with an abnormal Pap smear, irrespective of HPV testing status, appropriate evaluation should be undertaken. It is important to note that women should continue to have cytological screening even if they have been immunised for HPV. [31]