History of Present Illness

A 22-year-old woman presents to discuss management of her initial cervical cytology, which returned as low-grade squamous intraepithelial lesion (LSIL). She has no other complaints.

Her past medical and surgical histories are unremarkable. She is heterosexual, has had a total of two partners, and has been in a new relationship for the past four months. She is using combined oral contraceptive pills as her method of birth control and is happy with them. She is not taking any other medications. She has never received the human papilloma virus (HPV) vaccine. She denies smoking or illicit drug use.

Physical Examination

General appearance

Well-developed, well-nourished woman in no discomfort

Temperature

37.0°C

Pulse

60 beats/min

Blood pressure

110/72 mmHg

Respiratory rate

16 breaths/min

Height

65 inches

Weight

130 lb

BMI

21.6 kg/m²

Abdomen

Thin, soft, non-tender, non-distended, no guarding, no rebound

External genitalia

Unremarkable

Vagina

No blood or discharge

Cervix

Nulliparous, closed

Uterus

Anteverted, mobile, normal size, no tenderness on bimanual examination

Adnexa

No masses or tenderness bilaterally

Cervical cytology result

Low-grade squamous intraepithelial lesion

Gonorrhea and chla-mydia nucleic acid amplification tests

Negative

How Would You Manage This Patient?

The patient is a young woman with an LSIL cervical cytology result. After discussion with the patient, the patient was managed according to the American Society for Colposcopy and Cervical Pathology (ASCCP) 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Rather than immediate colposcopy, which would have been the preferred choice in older women, she was managed according to the algorithm for women ages 21–24 with either atypical squamous cells of undetermined significance (ASC-US) or LSIL, and was scheduled for repeat cytology alone in 12 months. She received the first dose of the HPV vaccine at this visit, with completion of the series at two and six months. Repeat cytology without HPV co-testing was performed in 12 months, which returned negative for intraepithelial lesion or malignancy. Repeat cytology was recommended in 12 months, with plan to return to routine screening if that test was also normal.

LSIL in Young Adults

Management

Based on these differences in the natural history of HPV infection and extremely low risk of cervical cancer in younger patients, LSIL and ASC-US found in patients between the ages of 21 and 24 years are managed differently than in older women (Boxes 38.1 and 38.2). The risk of histologic high-grade intraepithelial lesion (HSIL) (CIN 2 or 3) with LSIL cytology is low enough in young women that colposcopy is not necessary. Clinically significant abnormalities are usually associated with persistent disease. HSIL in this age group does not appear to progress rapidly as evidenced by the low cervical cancer rates in this younger group. This slow progression to cancer in younger women allows management by follow-up cytology, identifying those at risk for significant abnormalities by focusing further evaluation on patients with persistent disease.

Box 38.1 ASCCP guidelines for the management of women aged 21–24 years with LSIL [8]

For women with LSIL who are aged 21–24 years, follow-up with cytology at 12-month intervals is recommended. Colposcopy is not recommended. For women with ASC-H or HSIL+ at the 12-month follow-up, colposcopy is recommended. For women with ASC-US or worse at the 24-month follow-up, colposcopy is recommended. For women with two consecutive negative results, return to routine screening is recommended.

Box 38.2 ASCCP guidelines for the management of women aged 21–24 years with atypical squamous cells of undetermined significance [8]

Initial Management

For women aged 21–24 years with ASC-US, cytology alone at 12-month intervals is preferred, but reflex HPV testing is acceptable. If reflex HPV testing is performed with ASC-US and the HPV result is positive, repeat cytology in 12 months is recommended. Immediate colposcopy or repeat HPV testing is not recommended. If reflex HPV testing is performed and is negative, return for routine screening with cytology alone in three years is recommended.

Follow-Up

For women with ASC-US who are aged 21–24 years, follow-up with cytology at 12-month intervals is recommended. Colposcopy is not recommended. For women with ASC-H or HSIL+ (HSIL, atypical glandular cells [AGC], or cancer) at the 12-month follow-up, colposcopy is recommended. For women with ASC-US or worse at the 24-month follow-up, colposcopy is recommended. For women with two consecutive negative results, return to routine screening is recommended.

Unlike older women, an immediate colposcopy following ASC-US or LSIL is explicitly not recommended in younger women. Instead, cytology alone should be repeated in 12 months. If the 12-month follow-up cytology has a higher-grade abnormality (ASC-H, AGC, or HSIL), then colposcopy should be performed. Otherwise, if cytology is negative or again shows a low-grade abnormality (ASC-US or LSIL), cytology alone should be repeated again in 12 months. The patient can be returned to routine screening if both the 12-month and 24-month repeat cytology are negative. If any cytologic abnormalities are present 24 months after the initial abnormal cytology, colposcopy should be performed. Colposcopy is typically performed in patients with a negative 12-month cytology but an abnormal 24-month cytology [8] (Figure 38.1).

Figure 38.1 Management of LSIL in women 21–24 years old [6].

HPV testing is not recommended as a reflex test with LSIL because 77 percent of LSIL cytologic specimens are HPV positive [9]. As screening recommendations for women under age 30 do not include co-testing, HPV test results should not be inadvertently available as they sometimes are in older women with LSIL cytology. ASC-US management differs slightly from LSIL management. The preferred approach is similar to LSIL: testing with cytology alone and repeating in 12 months. Management without HPV testing is preferred. However, unlike LSIL, HPV reflex testing is acceptable following ASC-US. If the HPV test is positive, then the recommendation is to repeat cytology at 12 and 24 months. Immediate colposcopy is not recommended. If the HPV test is negative, then the patient can return to routine screening (repeat cytology in three years).

Management of a woman turning 25 during the surveillance period is not explicitly covered in the ASCCP guidelines. If the patient turns 25 years old during the surveillance period, it would be reasonable to complete the surveillance as planned. However, an abnormality detected should be managed per the management guidelines for women 25 and older [8].

In this case, the implications of LSIL cytology and management recommendations were reviewed with the patient. She was counseled that if her cytology at 12 months revealed a higher-grade abnormality, then a colposcopy should be performed at that time. HSIL cytology reveals HSIL histology on biopsy up to 70 percent of the time, which is significantly higher than found with LSIL cytology. Under Lower Anogenital Squamous Terminology nomenclature, cervical HSIL lesions include what were previously termed CIN 2 and CIN 3 [10]. HSIL histology is usually treated by excision or ablation in older women. However, because of high regression rates (Table 38.1) and potential pregnancy-related complications associated with treatment, a conservative approach is permissible for the management of cervical HSIL in patients like this one with fertility concerns. Cervical HSIL (CIN 2) can be followed with cytology and colposcopy at six-month intervals. In this case, her repeat cytology was negative, and she was scheduled to return for repeat cytology in 12 months [8, 11]. Use of HPV vaccine in a woman with abnormal cytology is discussed in detail in Case 44.

Table 38.1 Regression of CIN 2 over time in women ages 21–24 years [11]

Time interval (years)	Regression rate (%)
1	38
2	63
3	68

History of Present Illness

A 25-year-old woman presents for annual exam. She provides a letter from her aunt recommending that she undergo testing for Lynch Syndrome. Her mother was diagnosed with endometrial cancer at age 47, her maternal aunt was recently diagnosed with colon cancer at age 48 and tested positive for Lynch Syndrome, and her maternal grandmother had endometrial cancer diagnosed at age 53.

Her past medical and surgical histories are negative. Menarche was at age 12. Menses are normal and regular. She has no history of sexually transmitted infections, has had four lifetime sexual partners, and has been monogamous with a male partner for two years. She uses condoms for contraception. Pap test done three years ago was normal. She has never been pregnant and plans for pregnancy in about five years. She has never smoked, has less than one alcoholic drink per week, and denies substance use. She is an art history graduate student.

Physical Examination

General appearance

Well developed, well nourished

Temperature

37.0°C

Pulse

76 beats/min

Blood pressure

110/68 mmHg

Respiratory rate

16 breaths/min

Height

63 inches

Weight

142 lb

BMI

25 kg/m²

Breasts

Symmetric, no skin changes, no palpable masses or axillary lymphadenopathy, no nipple discharge

Abdomen

Thin, soft, non-tender, no masses

External genitalia

Normal female

Vagina

Scant physiologic discharge

Cervix

Nulliparous without lesions

Uterus

Anteverted, mobile, normal size, non-tender

Adnexa

No palpable masses, non-tender

Depression screen

Negative

Laboratory Studies

Pap test negative for intraepithelial lesion, gonorrhea and chlamydia tests negative

How Would You Manage This Patient?

The patient’s family history is notable for three relatives with Lynch associated cancers diagnosed at young ages. Her maternal aunt has a Lynch syndrome mutation. Cascade testing (genetic testing for an at-risk individual who has a family member with a known mutation) is indicated. The patient was referred to a cancer genetics specialist, underwent counseling, and chose to be tested. Presence of the MSH2 gene mutation was confirmed. She initiated a combination oral contraceptive pill to reduce her risk for endometrial and ovarian cancers and aspirin 600 mg daily to reduce colorectal cancer risk. Screening colonoscopy was normal, and repeat screening was planned every 1–2 years. Additional screening recommendations included annual clinical breast and pelvic examinations, and starting at age 30–35, endometrial biopsy every 1–2 years. She plans hysterectomy with bilateral salpingoophorectomy by age 40.

Lynch Syndrome and Cascade Testing

Risk Assessment and Testing

Genomic instability in Lynch syndrome is due to a defect in DNA mismatch repair affecting the entire genome, including noncoding single nucleotide and dinucleotide repeats scattered throughout the DNA. Microsatellites are noncoding single nucleotide and dinucleotide repeats. Microsatellite instability is the insertion or deletion of additional nucleotides into or from the microsatellites. Almost all Lynch syndrome tumors exhibit microsatellite instability. Nonhereditary tumors can arise from microsatellite instability, but the mechanism differs, and is due to methylation of the MLH1 promoter.

Testing for Lynch syndrome can be complex, and referral to a cancer genetics specialist is advised. Family history alone can suggest risk for Lynch syndrome. Women with a first-degree relative with endometrial or colorectal cancer diagnosed before age 60 or a pattern of repeated generations affected by Lynch-associated cancers should be referred for genetic counseling [1]. Referral should also be considered if the relative with cancer is a distant relative if few family members reached advanced age, if she has few female relatives, or female family members had hysterectomy or oophorectomy at young ages [1]. Guidelines can help identify at-risk individuals (Table 39.2). The Amsterdam II criteria have sensitivity and specificity for diagnosing Lynch syndrome of 22 percent and 98 percent respectively [5]. If each of the criteria is met, Lynch syndrome should be suspected. The Revised Bethesda Guidelines aim to identify individuals with colorectal cancer who should undergo tumor testing. The sensitivity and specificity of any one of these guidelines are 82 percent and 77 percent respectively [6].

When possible, Lynch syndrome testing should start with tumor tissue from an affected relative. Immunohistochemistry can detect Lynch syndrome mismatch repair genes. Presence or absence of these genes further guides germline testing. Lynch syndrome is excluded if all four mismatch repair proteins are present. However, when family history is suspicious, microsatellite instability testing can be done. If microsatellite instability is absent, Lynch syndrome is excluded. When immunohistochemistry reveals MLH1 protein absence, promoter methylation testing is done. If there is promoter methylation, Lynch syndrome is excluded. If promoter methylation is absent, then unaffected relatives require germline DNA testing. If tumor testing reveals absent MSH2, MSH6, or PMS2, then targeted germline testing can be done for at-risk relatives. If a tumor from an affected relative is not available, relatives should first be counseled by a cancer genetics specialist, and then undergo testing as appropriate.

Risk Reduction

Women with Lynch syndrome can reduce cancer risk through screening, chemoprevention, and surgery. There are no current proven cost-effective endometrial or ovarian cancer screening strategies for women with Lynch syndrome. National Comprehensive Cancer Network guidelines recommend endometrial sampling every 1–2 years starting at age 30–35 [7, 8]. Transvaginal ultrasound and CA 125 measurements are not useful in screening for Lynch-associated ovarian cancer likely because these tumors are different than BRCA-associated tumors [3]. Screening colonoscopy significantly reduces risk for colorectal carcinoma in Lynch syndrome patients, and is recommended every 1–2 years starting at age 20–25, or 2–5 years before the earliest relative’s cancer diagnosis, whichever is earlier [7, 8]. While some breast cancers are included in Lynch syndrome, routine screening is recommended [1].

Chemoprevention for women with Lynch Syndrome further reduces cancer risk. Aspirin 600 mg daily can reduce colorectal cancer risk by up to 63 percent [7]. Participants in the CAPP2 trial taking aspirin also noted reduction in all Lynch-associated cancers [9]. Given the 50 percent reduction in endometrial and ovarian cancers in the general population on combination hormonal contraceptives, it is thought that women with Lynch syndrome will also benefit, although studies of affected families are limited [3]. Progestin only medications may also reduce risk for endometrial cancer.

Risk-reducing hysterectomy with bilateral salpingoophorectomy should be offered once childbearing is complete [8, 10]. Surgical approach should be individualized, and colorectal screening should be up to date preoperatively. Gynecologic surgery can be done concurrently for women with Lynch syndrome undergoing surgery for colorectal cancer.

Cascade Testing

Cascade testing is active, targeted genetic testing of at-risk individuals who have a family member with a known mutation. When the exact mutation and its location are known, testing is efficient and less costly. Cascade testing systematically reaches all potentially affected family members to allow identification and cancer prevention while minimizing screening and testing costs. Mutation carriers can benefit from increased surveillance, chemoprevention, and risk-reducing surgery, and those who test negative can follow routine cancer screening guidelines. The estimated cost of testing an individual for all Lynch mutations is $1500–4000 versus $200–500 when the specific mutation is known [11]. When a family member tests positive for Lynch syndrome, all first-degree relatives have a 50 percent chance of having the mutation. Therefore, genetic testing should be offered and begin with all first-degree relatives of the tested patient, and then branch outward [11]. For our patient, her mother and uncle should be offered testing first (Figure 39.1). If her mother tests positive, then our patient should be offered testing. If her uncle tests negative, his children do not need testing. Cascade testing is similarly effective for other autosomal dominant adult onset diseases such as familial hypercholesterolemia and hereditary breast and ovarian cancer.

Figure 39.1 Pedigree for our patient’s family to illustrate cascade testing. First-degree relatives of maternal aunt (patient’s mother and uncle) should be offered testing first.

When discussing Lynch syndrome testing results with an affected patient, The American Medical Association and other authors support protecting patient confidentiality [12]. Patients who test positive for Lynch syndrome should be informed of the risks to their family members, as well as the benefits for family members who undergo testing. The affected family member should be encouraged to disclose this information to all relatives. Physicians should offer to assist with disclosure to other family members, including enlisting the help of a cancer genetics specialist [12]. A multicenter study of 174 affected individuals who underwent Lynch syndrome testing showed that 98 percent disclosed test results to their relatives. As a result, up to three first-degree relatives were tested for Lynch syndrome for each affected individual [13].

Cascade testing confers cost savings and significant public health benefit; however, communication and organizational barriers exist in implementation. Physicians and patients may not understand test results and genetic testing options. Patients may express privacy concerns, fear blame, or may not be in contact with relatives. Other countries employ national cancer registries and public health coordinators to track results, arrange genetic testing, contact relatives, and schedule surveillance exams. Studies and experience gleaned from other countries shows that direct contact of family members by genetic counselors improves testing uptake [11]. Efforts are underway to improve US systems, including the Electronic Medical Records and Genomics (eMERGE) network, part of the National Human Genome Research Institute of the NIH. A secure website developed by genetic counselors at the University of California San Francisco, Kintalk.org, provides Lynch syndrome patients a forum to share results, connect with others, and be updated regarding new research. The site also includes educational videos on genetic counseling and testing for Lynch syndrome. These and other broad-based public health outreach strategies will be necessary to improve the rate of cascade testing for relatives of individuals affected with Lynch syndrome as well as those affected by other autosomal dominant adult onset diseases.

Key Teaching Points

• 
  

  Women with personal or family history suggestive of Lynch syndrome should be referred to a cancer genetics specialist.

  
  
• 
  

  When possible, Lynch syndrome testing should begin with tumor tissue to yield the most informative results for affected and unaffected relatives.

  
  
• 
  

  Screening for women identified with Lynch syndrome should include endometrial biopsy every 1–2 years starting between age 30–35 and colonoscopy every 1–2 years. starting between age 20–25, or 2–5 years before the earliest cancer diagnosis in the family, whichever is earlier.

  
  
• 
  

  Aspirin 600 mg daily can reduce colorectal cancer risk. Progestin-only treatment or combination oral contraceptives may reduce risk for endometrial and ovarian cancers.

  
  
• 
  

  Cascade testing includes genetic counseling and targeted testing of family members who have a relative diagnosed with diseases caused by autosomal dominant mutations.

  
  
• 
  

  Cascade testing reduces screening and testing costs, and facilitates early identification and disease treatment.

  
  
• 
  

  Cascade testing for Lynch syndrome allows early initiation of measures to reduce cancer risk in affected family members.

History of Present Illness

A 30-year-old gravida 1, para 1 woman presents for follow-up after a Loop Electrosurgical Excision Procedure (LEEP) three weeks ago. Her referral Pap showed a high-grade squamous intraepithelial lesion (HSIL) and was human papillomavirus (HPV) positive. Colposcopy performed three weeks prior to the LEEP revealed a small punctate lesion with an area of mosaicism at 6 o’clock. The pathology of the colposcopy directed biopsies showed cervical HSIL. The pathologist commented “cervical intraepithelial neoplasia (CIN) III in the background of CIN II noted at the squamocolumnar junction at 6 o’clock” on her ectocervical biopsy. An endocervical curettage (ECC) performed at the time was read as CIN II. The patient’s LEEP procedure was uncomplicated. During the consent discussion before the LEEP, the patient expressed significant concerns regarding impact of the procedure on future child bearing.

She has a history of smoking, but discontinued use following her abnormal colposcopy. She reports first intercourse at age 14. She is currently in a monogamous relationship. She has had regular cervical screening, and all prior tests were normal. She has no significant medical, surgical, or family history. She had chlamydia when she was an adolescent.

Physical Examination

General appearance

Well-appearing obese female in no apparent discomfort. Alert and oriented.

Temperature

37.2°C

Pulse

88 beats/min

Blood pressure

112/68 mmHg

Respiratory rate

16 breaths/min

Oxygen saturation

99 percent on room air

Abdomen

Soft, nontender, nondistended, no rebound or guarding

External genitalia

Unremarkable, no lymphadenopathy

Vagina

Normal vaginal mucosa

Cervix

Parous cervix with no visible lesions. No friability or bleeding. Site of LEEP procedure healing appropriately.

Uterus

Anteverted, mobile, normal size with no tenderness on bimanual exam.

Adnexa

No abnormalities appreciated on palpation.

Extremities

No tenderness or edema.

Pathology report of LEEP specimen

Foci of HSIL (CIN II/III) as well as extensive background of CIN II extending past ectocervical surgical margin. (Figure)