Cervical Cancer Case File

Cervical Cancer Case File

Eugene C. Toy, MD, Patti Jayne Ross, MD, Benton Baker III, MD, John C. Jennings, MD

CASE 58

A 50-year-old G5P5 woman complains of postcoital spotting over the past 6 months. Most recently, she complains of a malodorous vaginal discharge. She states that she has had syphilis in the past. Her deliveries were all vaginal and uncomplicated. She has smoked 1 pack per day for 20 years. On examination, her blood pressure is 100/80 mm Hg, temperature is 99°F (37.2°C), and heart rate is 80 beats per minute. Her heart and lung examinations are within normal limits. The abdomen reveals no masses, ascites, or tenderness. Her back examination shows right costovertebral angle tenderness (CVAT). The pelvic examination reveals normal external female genitalia. The speculum examination reveals a 3-cm exophytic lesion on the anterior lip of the cervix. No other masses are palpated. Her right leg is more swollen than her left leg.

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ANSWER TO CASE 58:

Cervical Cancer                                 

Summary: A 50-year-old G5P5 woman complains of a 6-month history of postcoital spotting and malodorous vaginal discharge. She has had a prior infection with syphilis, and is a smoker. The speculum examination reveals a 3-cm exophytic lesion on the anterior lip of the cervix. There is right CVAT and right leg swelling.

• Next step: Biopsy of the cervical lesion.
• Most likely diagnosis: Cervical cancer with metastases to the right pelvic sidewall.
• Best treatment: Radiotherapy with a chemosensitizer (such as a platinum agent).

ANALYSIS

Objectives

1. Understand that a cervical biopsy and not a Pap smear (which is a screening test) is the best diagnostic procedure when a cervical lesion is seen.
2. Know that postcoital spotting is a symptom of cervical cancer.
3. Know the risk factors for cervical cancer.
4. Know that radiotherapy is the best treatment for advanced cervical cancer.

Considerations

This 50-year-old woman presents with postcoital spotting. Abnormal vaginal bleeding is the most common presenting symptom of invasive cervical cancer, and in sexually active women, postcoital spotting is common. This patient’s age is close to the mean age of presentation of cervical cancer, 51 years. She also complains of a malodorous vaginal discharge that is because of the large, necrotic tumor. Notably, the woman has right flank tenderness, which is very suspicious for metastatic obstruction of the ureter, leading to hydronephrosis; her leg swelling is also consistent with involvement with the pelvic sidewall. A cervical biopsy and not Pap smear is the best diagnostic test to evaluate a cervical mass. A Pap smear is a screening test and appropriate for a woman with a normal-appearing cervix. Risk factors for cervical cancer in this woman include multiparity, cigarette smoking, and history of a sexually transmitted disease (syphilis). Other risk factors not mentioned would be early age of coitus, multiple sexual partners, and human immunodeficiency virus (HIV) infection (Table 58– 1).

APPROACH TO:

Cervical Cancer                                             

DEFINITIONS

CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN): Preinvasive lesions of the cervix with abnormal cellular maturation, nuclear enlargement, and atypia.

HUMAN PAPILLOMAVIRUS (HPV): Circular, double-stranded DNA virus that can become incorporated into cervical squamous epithelium, predisposing the cells for dysplasia and/ or cancer.

RADICAL HYSTERECTOMY: Removal of the uterus, cervix, and supportive ligaments such as the cardinal ligament, uterosacral ligament, and proximal vagina.

RADIATION BRACHYTHERAPY: Radioactive implants placed near the tumor bed.

RADIATION TELETHERAPY: External beam radiation where the target is at some distance from the radiation source.

HUMAN PAPILLOMAVIRUS VACCINE: Killed virus vaccine, FDA approved, for females and males aged 9 to 26. The quadrivalent vaccine contains antigens of HPV types 16 and 18 (which are associated with about 50% of cervical cancer and dysplasia in females) and 6 and 11 (which cause venereal warts in males and females).

CLINICAL APPROACH

Cervical Cancer

When a woman presents with postcoital spotting or has an abnormal Pap smear, cervical dysplasia or cancer should be suspected. An abnormal Pap smear is usually evaluated by colposcopy with biopsies, in which the cervix is soaked with 3% or 5% acetic acid solution. The colposcope is a binocular magnifying device that allows visual examination of the cervix. The majority of cervical dysplasia and cancers arise near the squamocolumnar junction of the cervix. Typically, cervical intraepithelial lesions will turn white with the addition of acetic acid, the so-called “acetowhite change.” Along with the change in color, dysplastic lesions will often have vascular changes, reflecting the more rapidly growing process; in fact, the vascular pattern usually characterizes the severity of the disease. An example of mild vascular pattern is punctuations (vessels seen end-on) versus atypical vessels (such as corkscrew and hairpin vessels). A biopsy of the worst-appearing area should be taken during colposcopy for histologic diagnosis. Hence, the next step to evaluate an abnormal Pap smear is colposcopic examinations with directed biopsies.

    When a woman presents with a cervical mass, biopsy of the mass, not a Pap smear, is appropriate. Because the Pap smear is a screening test, used for asymptomatic women, it is not the best test for a visible lesion. The Papanicolaou smear test has a false-negative rate and may give false reassurance.

    When cervical cancer is diagnosed, the next step is staging the severity. Cervical cancer is staged clinically, meaning using physical examination, imaging tests, or nonsurgical procedures (Table 58– 2). Early cervical cancer (generally less than 4 cm in diameter and contained within the cervix) may be treated equally well with surgery (radical hysterectomy) or radiation therapy. However, advanced cervical cancer is best treated with radiotherapy, consisting of brachytherapy (implants) with teletherapy (whole pelvis radiation) along with chemotherapy, usually platinum-based (cis-platinum), to sensitize the tissue to the radiotherapy.

    Since HPV is the etiologic agent in the vast majority of cervical cancer, the advent of the HPV vaccine promises to prevent much of cervical dysplasia and cancer. At the time of this publication, the FDA has approved three HPV vaccines. The original quadrivalent vaccine Gardasil® (Merck) prevents infection of four strains of HPV (6, 11, 16, and 18) gained FDA approval in 2006 for use in males and females ages 9 to 26. In December 2014, the FDA approved Gardasil 9, which protects against the four strains in the previous Gardasil vaccine and also 31, 33, 45, 52, and 58. In 2009, GlaxoSmithKline’s bivalent vaccine, Cervarix® protects against HPV strains 16 and 18, was approved for females aged 10 to 25.

HPV subtypes 6 and 11 cause the majority of condyloma acuminata (venereal warts), and more importantly subtypes 16 and 18, which cause 50% to 70% of cervical cancer. Clinical research seems to indicate a protection against the acquisition of HPV infection from these subtypes; however, because other subtypes can still cause cervical dysplasia or cancer, regular Pap smears are still required even after vaccination. Ideally, the vaccine should be administered at an age prior to sexual activity. Cervical cancer often spreads through the cardinal ligaments toward the pelvic sidewalls. It can obstruct one or both ureters leading to hydronephrosis. In fact, bilateral ureteral obstruction leading to uremia is the most common cause of death due to this disease.

Pap Smear and Cervical Cancer Prevention

The purpose of cervical cytology is to detect premalignant conditions, and intervene before it becomes invasive cancer. In general, abnormal Pap smears as a screening test require colposcopy and biopsy to determine the full extent of the dysplasia. Recently, the strategy of cervical cytology has undergone substantial changes due to the availability of HPV testing, and recognition that adolescents often clear the HPV and dysplasia spontaneously.

    Cervical cytology is generally begun at age 21 years regardless of the age of onset of sexual intercourse (see Table 58–3). Pap smear every 2 years is then recommended up to age 30 years. For patients with three consecutive cervical cytology tests that are negative for intraepithelial lesions and malignancy at age 30, the interval of screening can be extended to every 3 years. Cotesting of HPV plus Pap smear is appropriate after age 30. If cervical cytology and HPV subtype testing are both negative, Pap smears do not need to be performed any sooner than every 3 years. Women with CIN risk factors, including HIV, immunosuppression, exposure to diethylstilbestrol (DES), and previous treatment for CIN 2, 3 or cancer may require more frequent screening. Screening can be stopped at age 65 to 70 after three negative cytology screening tests and no abnormal tests in the past 10 years. Finally, routine cervical cytology is not recommended in women who have had a total hysterectomy for benign indications, and no history of cervical dysplasia. However, if hysterectomy is performed for cervical dysplasia (ie, CIN III), then Pap smear of the vaginal cuff is still needed.

    HPV typing is helpful in triaging cytology showing atypical squamous cells of undetermined significance (ASCUS), but is generally not helpful with any higher dysplasia. Thus, cytology showing low-grade squamous intraepithelial lesion or high-grade squamous intraepithelial lesion (HSIL) generally requires colposcopic examination. Adolescents and pregnant women with ASCUS may be observed instead of immediate colposcopy or even HPV testing. Women younger than age 25 with biopsy proven CIN 1 or 2 may be observed with serial Pap smears since the resolution rate is high, and excisional procedures on the cervix may lead to cervical insufficiency and preterm delivery.

    Once colposcopic-directed biopsies have delineated the extent of the dysplasia, appropriate therapy may be used. This may include observation in younger patients and/ or mild disease, cryotherapy (freezing of the cervix), or excisional procedures such as loop electrosurgical excision procedure for more significant dysplasia.

    Atypical glandular cells (AGCs) are more rarely found on Pap smears, and can indicate squamous pathology, or also endometrial or endocervical disease. For this reason, women with AGC Pap smears usually undergo colposcopy, endocervical curettage, and endometrial biopsy.

Emerging Concepts

Cervical cancer is typically treated with either radical hysterectomy if early (small tumor) invasive cancer is found or radiation therapy if advanced disease is found. However, in younger women who desire children, radical trachelectomy (removal of the cervix and upper vagina while leaving the uterus) can be performed. The surgeon places a purse-string suture at the uterine neck. This treatment attempts to remove the cervical cancer while allowing the patient to be able to achieve a pregnancy. Long-term results are pending for this rare procedure.

CASE CORRELATION See also Case 29 (Health Maintenance) for more details regarding cancer screening.

COMPREHENSION QUESTIONS

58.1 A 48-year-old woman who presents with postcoital vaginal bleeding is noted to have a cervical exophytic mass. A biopsy of the mass confirms squamous cell carcinoma. If molecular analysis of the cancer is performed, which of the following HPV subtypes is most likely to be found in the specimen?

A. 6 and 11

B. 16 and 18

C. 55 and 57

D. 89 and 92

58.2 A 39-year-old woman is diagnosed with advanced cervical cancer that appears to have spread to her right pelvic sidewall. She has right hydronephrosis as evidenced by the intravenous pyelogram (IVP). The biopsy specimen confirms that it is a poorly differentiated carcinoma. Which of the following statements regarding this patient’s condition is most accurate?

A. The best therapy for her is surgical excision.

B. Both brachytherapy and teletherapy are important in the treatment of this patient.

C. Radical hysterectomy is an option in the therapy of this patient.

D. The majority of cervical cancers are of adenomatous cell type.

58.3 A 45-year-old woman is diagnosed with an early cervical cancer, noted to be confined to the cervix and about 3 cm in diameter. Which of the following is a risk factor for cervical cancer?

A. Early age of coitus

B. Nulliparity

C. Obesity

D. Late menopause

E. Family history of cervical cancer

58.4 A 33-year-old woman has a Pap smear showing moderately severe cervical dysplasia (high-grade squamous intraepithelial neoplasia). She denies a smoking history and does not recall having any sexually transmitted infections. Which of the following is the best next step?

A. Repeat Pap smear in 3 months

B. Conization of the cervix

C. Colposcopy-directed biopsies

D. Radical hysterectomy

E. Computed tomography scan of the abdomen and pelvis

58.5 A 40-year-old woman is referred for a Pap smear showing high-grade squamous intraepithelial lesions. Which of the following statements is most accurate?

A. If HPV subtyping reveals no high-risk virus present, then routine cytology is recommended.

B. If colposcopy demonstrates the entire transformation zone, then no further analysis is needed.

C. If an endocervical curetting shows cervical dysplasia, then an excisional procedure of the cervix is appropriate.

D. Cervical cancer is highly unlikely due to the Pap smear revealing only HSIL.

58.6 A 47-year-old woman G4P4 has a Pap smear which shows HSIL. Colposcopy is performed which is adequate, and reveals CIN III. An endocervical curettage is negative. The patient also has menorrhagia caused by uterine fibroids. Thus, the patient undergoes a total abdominal hysterectomy, including removal of the cervix. The patient asks whether Pap smears need to be performed now that her cervix has been surgically removed. Which of the following is the most accurate statement?

A. The patient should continue to have annual Pap smears of the vaginal cuff.

B. The patient should have Pap smears every 2 to 3 years, which may be discontinued if negative after 10 years.

C. The patient does not need Pap smears any longer.

D. The patient should have the HPV vaccine.

ANSWERS

58.1 B. H PV subtypes 6 and 11 are associated with condylomata acuminata (venereal warts), whereas subtypes 16 and 18 are associated with cervical dysplasia and cancer. The other answer choices are uncommon subtypes and not associated with cervical cancer. Cervical dysplasia or cancer should be suspected when a woman presents with postcoital spotting or an abnormal Pap smear.

58.2 B. For patients with advanced cervical cancer (such as this patient with extension to the pelvic side walls), radiotherapy is superior to surgical therapy. Major advantages of radical hysterectomy over radiotherapy are preservation of sexual function (owing to vaginal agglutination caused by the radioactive implants—essentially closes the vagina) and preservation of ovarian function. Radiotherapy can be performed on women who are poor operative candidates and is the best therapy for advanced disease, consisting of brachytherapy and teletherapy. Advanced disease involves spread to the pelvic sidewalls or hydronephrosis. Early-stage cervical cancer can be treated equally well with surgery or radiation therapy. The majority of cervical dysplasia and cancers arise near the squamocolumnar junction of the cervix and are of the squamous, not adenomatous, type.

58.3 A. Early age of coitus, a history of STDs, early childbearing, low socioeconomic status, HPV, HIV, cigarette smoking, and multiple sex partners are all risk factors for developing cervical cancer. HPV is the main risk factor, and is usually acquired from sexual exposure. Late menopause, obesity, and nulliparity are risk factors for endometrial cancer, not cervical cancer. Family history is not shown to be a risk factor for cervical cancer.

58.4 C. Colposcopic examination with directed biopsies is the next step to evaluate abnormal cytology on Pap smear.

58.5 C. When high-grade SIL is present, colposcopic examination is important. HPV typing has a role in triaging atypical cells of undetermined significance, but not H SIL. Demonstration of the entire transformation zone during colposcopy allows biopsy of the worst area. A cervical excisional procedure (loop electrosurgical excisional procedure) or cone biopsy is indicated when there is the possibility of endocervical disease.

58.6 A. When the patient has a history of cervical dysplasia, even after total hysterectomy (removal of uterine corpus and cervix), annual Pap smears should be performed of the vaginal cuff. This is because vaginal cancer may arise. In contrast, when total hysterectomy is performed for benign reasons, and no history of cervical dysplasia, then no further Pap smears need to be performed.

    CLINICAL PEARLS    

» The main risk factors for cervical cancer are sexually related, especially exposure to human papillomavirus. » Human papillomavirus 16 and 18 are the most commonly isolated subtypes in cervical dysplasia and cancer. » Flank tenderness or leg swelling indicate advanced cervical cancer, which is best treated by radiotherapy with a chemotherapeutic radiosensitizer. » A visible lesion of the cervix should be evaluated by biopsy and not Pap smear. » An abnormal Pap smear is usually evaluated with colposcopy-directed biopsies. » The HPV vaccine is approved for females and males aged 9 to 26 to reduce the likelihood of cervical dysplasia or cancer in females, and venereal warts in males and females. » Cervical cytology no longer needs to be performed after age 65 to 70 years, and after total hysterectomy for benign reasons and when there is no history of cervical dysplasia.

REFERENCES

American College of Obstetricians and Gynecologists. Cervical Cancer Screening and Prevention. ACOG Practice Bulletin 157. Washington, DC; 2016. 

American College of Obstetricians and Gynecologists. Evaluation and management of abnormal cervical cytology and histology in the adolescent. ACOG Committee Opinion 330. Washington, DC; 2006. 

American College of Obstetricians and Gynecologists. Human papillomavirus vaccination. ACOG Committee Opinion 641. Washington, DC; 2015. 

American College of Obstetricians and Gynecologists. Management of abnormal cervical cancer screening test results and cervical cancer precursors. ACOG Practice Bulletin 140. Washington, DC; 2013. 

Hacker NF. Cervical cancer. In: Berek JS, Hacker NF, eds. Practical Gynecologic Oncology. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2014:345-406. 

Hacker NF. Cervical dysplasia and cancer. In: Hacker NF, Gambone JC, Hobel CJ, eds. Essentials of Obstetrics and Gynecology. 6th ed. Philadelphia, PA: Saunders; 2015:402-411. 

Jhingran A, Levenback C. Malignant diseases of the cervix. In: Katz VL, Lentz GM, Lobo RA, Gersenson DM, eds. Comprehensive Gynecology. 6th ed. St. Louis, MO: Mosby-Year Book; 2012:759-780. 

Massad SL, Einstein MH, Huh WK et al for the 2012 ASCCP Consensus Guidelines Conference. 2012 Updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precurors. Obset Gynecol 2013;121(4):829-46. 

Noller KL. Intraepithelial neoplasia of the lower genital tract (cervix, vulva). In: Katz VL, Lentz GM, Lobo RA, Gersenson DM, eds. Comprehensive Gynecology. 6th ed. St. Louis, MO: Mosby-Year Book; 2012:743-754.

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