B. Verrucous carcinoma is a variant of squamous carcinoma that occurs in postmenopausal women. The tumors of verrucous carcinoma are large, fungating masses that may be mistakenly diagnosed as condyloma acuminata resistant to treatment. Because the histologic appearance of verrucous carcinoma so closely resembles that of normal squamous epithelium, a sufficiently deep biopsy must be obtained for diagnosis. It is helpful to include a good clinical history with the pathology specimen. Although lymph node metastasis is exceedingly rare, tumor recurrence is common. Treatment consists of radical local excision. Radiation is contraindicated because it may induce increased aggression in malignant activity.
C. Melanomas constitute the second most common primary malignancy of the vulva, with a peak frequency in the sixth to seventh decades of life. The lesions of melanomas are typically raised, with irregular pigmentation and irregular borders. The lesions are found with approximately equal frequency on the labia majora and on mucosal surfaces. Prognosis depends primarily on tumor thickness and on the presence or absence of lymph node involvement. Radical local excision is recommended for the primary lesion. The role of regional lymphadenectomy is not well defined.
D. Basal cell carcinomas, despite being the most common type of carcinoma of the skin, constitute only 2–3% of all vulvar carcinomas. They occur most commonly in postmenopausal white women. Most patients complain of pruritus. Grossly, these lesions appear as a whitish nodule or plaque. The prognosis is good, despite a roughly 20% risk of local recurrence. Metastases to the inguinal lymph nodes are rare; wide local excision is usually sufficient treatment.
E. Sarcomas of the vulva are rare but can arise in any connective tissue component of the vulva.
1. Leiomyosarcomas are the most common of the vulvar sarcomas. These lesions develop most frequently in the labium majus or in the region of
Bartholin's glands. Standard treatment includes radical local excision. An effective chemotherapeutic agent has not yet been developed for this disease.
2. Rhabdomyosarcoma is the most common soft tissue tumor of childhood. In 20% of cases, the pelvis or genitourinary system is involved. In such cases, the vagina is more frequently affected than the vulva. Combination chemotherapy generally is used as primary treatment, followed by conservative
surgery.
3. Malignant fibrous histiocytoma, although uncommon, is the second most common vulvar sarcoma in adults. The tumor involves deep soft tissue and skeletal muscle. The patient usually presents with a solitary mass that grows relatively rapidly. Although first-line therapy consists of radical local
excision, radiation therapy has been reported to decrease the rate of local recurrence.
4. Alveolar soft part sarcoma most frequently involves the soft tissue of extremities in young adults. Very rarely, alveolar soft part sarcoma can involve the vulva. Standard therapy consists of radical local excision.
5. Dermatofibrosarcoma protuberans is a low-grade sarcoma that can in rare cases occur in the vulva. This lesion may appear initially as an indurated plaque on which multiple firm reddish or bluish nodules may appear. Although the lesion may recur locally, systemic metastases are uncommon. Standard therapy consists of radical local excision.
F. Paget's disease of the vulva is rare. Most affected patients are in their seventh or eighth decade of life and experience local irritation and pruritus. The lesion has slightly raised edges and is red, with islands of white epithelium. The lesions are sharply demarcated and often have foci of excoriation and induration. Unlike in Paget's disease of the breast, in the majority of cases, no underlying adenocarcinoma is present. An adenocarcinoma of the underlying sweat glands is found in 15–20% of patients who have intraepithelial Paget's disease.
1. If the disease is limited to the epithelium, its clinical course may be both prolonged and indolent. Wide local excision is the mainstay of treatment.
Although grossly wide surgical margins are indicated, the use of frozen-section evaluation of margins at the time of operation is a subject of controversy.
Although recurrence is common when the surgical margins show positive findings, the histologic analysis on permanent section is more accurate than that possible on frozen section.
2. If an underlying adenocarcinoma is identified, the patient should undergo radical excision and inguinal lymphadenectomy. The prognosis in patients with lymph node involvement is poor.
II. Vaginal neoplasms are one of the least common types of malignancy of the female genital tract. The majority of vaginal neoplasms are squamous cell lesions, although other cell types can occur. It is thought that most vaginal squamous cell lesions are associated with HPV infection. Patients with malignant squamous lesions of the cervix and vulva are at increased risk of having vaginal lesions as well. Careful examination and colposcopy of the vagina should be performed on patients in whom a vulvar or cervical cancer is diagnosed. The spectrum of squamous lesions parallels that of squamous lesions in the cervix or vulva and ranges from vaginal intraepithelial lesions (VAINs, classified as VAIN 1, 2, or 3, depending on the thickness of the atypia) to invasive vaginal carcinoma. VAINs may be treated with local excision, laser ablation, or topical 5-fluorouracil cream. Early-stage vaginal cancer may be treated with local excision, brachytherapy, or both, whereas advanced-stage vaginal cancer is treated best with chemoradiation therapy.
A. Clear cell carcinomas of the vagina are uncommon. However, in women exposed to diethylstilbestrol (DES) in utero, particularly before 18 weeks' gestation, careful surveillance of the vagina and cervix is prudent. DES was used until 1972 to treat pregnant women thought to be at risk for miscarriage. Although most patients with DES-related clear cell carcinoma of the vagina are diagnosed between the ages of 18 and 24 years, the oldest reported patient with a clear cell primary cancer of the vagina was 42 years old at the time of diagnosis.
1. Diagnosis. The most frequent location of clear cell adenocarcinoma is the upper one-third of the vagina. Many clear cell adenocarcinomas occur on the anterior surface and may present as a submucosal nodule. Therefore, it is necessary to rotate the speculum 90 degrees to visualize the anterior vaginal wall in addition to performing a careful bimanual examination. Many patients present with abnormal bleeding or vaginal discharge. The most important prognostic factor is stage at diagnosis.
2. Treatment. Small tumors limited to the vagina may be treated with partial vaginal excision and brachytherapy. Larger tumors or tumors close to the cervix may require partial vaginectomy, radical hysterectomy, and pelvic lymph node dissection. Patients with late-stage disease are treated with radiation.
B. Sarcoma botryoides occurs most often in children younger than 5 years. In this group, sarcoma botryoides is the most common vaginal neoplasm. As the age of the patient increases, the most frequent site of occurrence moves distally. The most common presenting symptom is vaginal bleeding. The lesion manifests as one or more polypoid excrescences that are pinkish red and translucent. Conservative surgery after neoadjuvant chemoradiation is the current standard of treatment.
42. CERVICAL INTRAEPITHELIAL NEOPLASIA
I. Epidemiology and risk factors. Each year, an estimated 500,000 cases of cervical cancer are newly diagnosed. Worldwide, it is the second leading cause of cancer death in women. In the United States, despite federally mandated screening programs, it remains the sixth most commonly diagnosed malignancy in women. Cervical cancer is thought to be caused by a sexually transmitted disease, human papillomavirus (HPV) infection of the cervix. HPV infection is common among women, and some studies suggest that more than 70% of women will have had an infection by the end of their sexual experience. Infection with a
high-risk type of HPV is a requisite for development of preinvasive and invasive squamous neoplasia of the cervix. Other risk factors include multiple sexual partners, intercourse at an early age, poor personal hygiene, immunocompromise, other sexually transmitted diseases (such as herpes simplex virus type 2), and cigarette smoking.
II. Pathophysiology. Nearly all cervical intraepithelial neoplasia (CIN) lesions arise in the transformation zone, which is the area of glandular epithelium that undergoes a process of squamous metaplasia. Maximal metaplasia occurs during fetal development, adolescence, and first pregnancy. Cells actively
undergoing metaplasia are vulnerable to carcinogens, which may explain the epidemiologic association between early age of first coitus and cervical cancer.
III. Terminology and definitions
A. The concept of cervical intraepithelial neoplasia stems from the hypothesis that cervical dysplasia represents a continuum of a single disease process.
The three grades of precursor lesions recognized are CIN I (mild dysplasia, involving the lower one-third of the epithelium), CIN II (moderate dysplasia, involving up to two-thirds of the epithelium), and CIN III (severe dysplasia, involving the upper third of the epithelium, or carcinoma in situ). The microscopic features of dysplasia include disordered maturation, nuclear hyperchromatism, increased nuclear to cytoplasmic ratio, pleomorphism, mitoses, and
dyskeratosis.
B. The Bethesda system divides cervical lesions into the following categories: atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and atypical glandular cells of undetermined significance (AGUS).
The category of LSIL consolidates HPV cellular changes with those of CIN I. HSIL includes CIN II and CIN III.
C. Specimen adequacy. A cytologic specimen reported as “unsatisfactory for evaluation” requires a repeat Pap smear. If a specimen is reported to be
“satisfactory but limited by . . . ,” the test may or may not be repeated, depending on the clinical situation. Specifically, an inadequate transformation zone component on Pap smear in a low-risk patient may require only routine follow-up smear. In a high-risk patient, the physician should consider repeating the endocervical portion of the Pap test.
IV. Molecular evidence. Infection with low-risk HPV can cause genital condyloma acuminatum and other manifestations of HPV infection that rarely progress to cervical carcinoma. Viral production occurs in low-grade lesions and is restricted to basal cells. Infection with high-risk HPV can lead to the development of cervical intraepithelial neoplasm and invasive carcinoma in approximately 1% of infected women. In most high-grade lesions, as well as in carcinomas, viral DNA is integrated into the host genome and no intact viral production is seen. The viral oncoproteins E6 and E7 inactivate the cell cycle regulators p53 and retinoblastoma (Rb), respectively, providing the initial events in progression to malignancy.
A. The HPV screening methods available include DNA dot blot hybridization systems and the more sensitive polymerase chain reaction testing. A great majority of patients diagnosed with LSIL have positive test results for HPV DNA. In the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study Group (ALTS trial), HPV DNA was detected by Hybrid Capture II assay in over 80% of women with LSIL.
Hence, the high percentage of HPV DNA positivity in LSIL cases may limit the usefulness of HPV DNA testing for triage of LSIL. Others, however, have reported that testing may be useful for triage of women with Pap smears showing ASCUS.
B. HPV typing. The high-risk HPV subtypes 16, 18, 31, 33, and 51 have been recovered from more than 95% of cervical cancers. HPV-16, alone, is found in over 70% of high-grade lesions. The finding of high-risk HPV and a positive Pap smear result more likely indicates a squamous intraepithelial lesion (SIL) rather than a benign process. The finding of a low-risk HPV type, which rarely is found in cancers in nonimmunosuppressed women, suggests that the lesion is not likely to progress. The future contribution of HPV testing to the management of cervical dysplasia is uncertain; however, it may help identify high-risk HPV in cytologic reports describing the findings as ASCUS.
C. HPV viral load. The risk of carcinoma in situ has been shown to increase with consistently high viral loads of HPV-16. The amount of HPV DNA may predict the risk of developing cervical cancer before any cytologic alterations are visible and long before the appearance of tumors. Some authors suggest that HPV quantitative testing, particularly for HPV-16, might help distinguish between infections that have a high or low risk of progressing into cervical cancer.
D. HPV vaccines. In animal papillomavirus models, vaccination against viral capsid proteins provides protection against infection. This involves virus type–specific neutralizing antibodies. Prophylactic vaccines produced using recombinant DNA technology are in phase I/II clinical trials for HPV-6 and HPV-11, and for HPV-16. Therapeutic vaccines targeted at the HPV-16 E7 antigen are currently being evaluated in phase I/II clinical trials.
V. Progression of cervical intraepithelial neoplasia. CIN I and CIN II/III are thought to represent distinct processes, with CIN I being the morphologic
manifestation of a self-limited sexually transmitted HPV infection and CIN II/III being a cervical cancer precursor. Approximately 60% of CIN I lesions regress spontaneously. Ten percent of CIN I lesions progress to CIN III, and 1% may ultimately progress to invasive cancer. Persistent positive test results for oncogenic HPV types may indicate a significant risk for the development of HSIL and cancer.
VI. The Pap smear test and other diagnostic tools A. Cytologic analysis
1. Screening for cervical cancer. Women who are sexually active or have reached the age of 18 should undergo an annual Pap smear and pelvic
examination. After three or more consecutive satisfactory smear findings, the test may be performed less frequently, at the discretion of the physician.
The false-negative rate ranges between 15% and 30% and usually results from inadequate sampling, poor processing, or laboratory error.
2. Technique. To sample the ectocervix, a wooden spatula is placed against the external os and rotated 360 degrees. To sample the endocervix, a cytobrush is inserted into the external os and rotated. The sample obtained by the spatula and cytobrush is spread on a glass slide and immediately placed in a fixative, usually 95% ethanol. Another method is the use of a liquid-based Pap smear (thin preparation), which was developed to improve the preservation and presentation of cells for cervical cytologic analysis. This method may be more sensitive in detecting SILs than the conventional
technique. The specificity of both methods, however, may be equivalent. In addition, the residual fluid that remains after processing a liquid specimen may be used for HPV DNA testing.
3. Atypical findings. Infection, inflammatory or reparative changes, and the effects of irradiation can result in atypical smear results suggestive, but not diagnostic, of CIN. In these cases, smears should be repeated in 3–6 months. If there is evidence of a specific infectious agent causing atypical
inflammation, antibiotic or antifungal therapy may be appropriate.
4. Positive findings. Patients with Pap smear findings suggesting HSIL require colposcopy.
B. Colposcopy allows examination of the cervix at magnifications ranging from 6- to 40-fold. Use of a green filter better defines vascular architecture by absorbing red light and making blood vessels appear black and more prominent. Colposcopy does not evaluate disease in the endocervical canal.
1. Technique. Acetic acid (3.0% or 5.0%) is applied to the cervix. This removes mucus and dehydrates cells. The more protein in the cell, the whiter it becomes. Dysplastic cells contain large nuclei with abnormally large amounts of chromatin (protein). The application of acetic acid coagulates these intracellular proteins and makes them opaque and white. Hence, cells with an increased nucleus to cytoplasm ratio appear opaque on colposcopic examination.
2. Abnormal or unsatisfactory results. Abnormal features that may represent CIN include epithelium that whitens with the application of acetic acid (acetowhitening), mosaicism, and punctation. Several processes, including inflammation, can cause acetowhite changes. Typically, intraepithelial lesions are characterized by discrete, sharp margins. Classification of examination results as “unsatisfactory” indicates that the transformation zone was not completely visualized or the full extent of the lesion was not visualized. Biopsy should be performed on abnormal areas.
3. Endocervical curettage (ECC) helps evaluate the endocervical canal for the presence of dysplasia.
VII. Low-grade squamous intraepithelial lesions
A. Principles for evaluation. Most Pap smear findings suggestive of LSIL represent lesions that regress spontaneously. A few women with results in this category, however, have a lesion that progresses. Between 20% and 30% of women with smear results indicating mild dysplasia actually have a high-grade lesion present. Such women usually are identified by continued cytologic surveillance. The clinical challenge is to distinguish the patients who have LSIL that will persist unchanged or regress spontaneously.
B. Strategies for evaluation and management. In more than 75% of immunocompetent women with a diagnosis of LSIL, the condition resolves without intervention in 9 months. Thus, LSILs may be followed conservatively, depending on the degree of patient compliance.
1. Reliable or low-risk patients. Observation with repeat Pap smear every 4–6 months for 1 year is recommended for reliable or low-risk patients. After three consecutive negative findings on Pap smears that are satisfactory for evaluation, routine screening protocol is resumed. If LSIL persists,
colposcopy, ECC, directed biopsy, or some combination of these, is recommended.
2. Unreliable or high-risk patients. Colposcopy is recommended to identify the 20–30% of high-risk patients who may have an underlying HSIL. If directed biopsy confirms HSIL, these patients require the appropriate treatment (refer to sec. X on HSIL management). If colposcopy confirms LSIL, these patients may be followed every 6–9 months with repeat cytologic examination. If LSIL persists, they may require repeat colposcopy and appropriate treatment.
Excision or ablation should be considered for patients who are not likely to return for follow-up. Carbon dioxide laser or cryotherapy is used for ablation.
The loop electrosurgical excision procedure is both diagnostic and therapeutic, and is the preferred method of treatment, with a cure rate of approximately 96%. Before an ablative procedure is performed, biopsy samples should be obtained to evaluate the extent of the lesion and rule out higher-grade
disease. Ablative or destructive procedures are not always curative. In addition, the healing process may draw the transformation zone proximally into the endocervical canal, which makes subsequent surveillance and diagnosis more difficult.
VIII. Atypical squamous cells of undetermined significance. The term atypia is reserved for abnormalities that do not qualify as a SIL or reactive change.
A. Incidence. Variation exists in the criteria used by different laboratories to designate ASCUS. This cytologic diagnosis is expected in no more than 5% of routine Pap smears. In high-risk populations with a higher prevalence of SILs, a correspondingly higher prevalence of ASCUS is to be expected. It has been useful to qualify ASCUS by adding the statement “favor reactive” or “favor dysplasia.” Less than 5% of women with ASCUS classified as “favor reactive” are eventually confirmed histologically to have HSIL; however, women with ASCUS designated “favor dysplasia” have biopsy-confirmed HSIL or invasive cancer in 8–10% of cases.
B. Management
1. Unqualified results. Pap smear results may be followed without colposcopy in reliable patients. A smear should be repeated every 4–6 months for 2 years until there have been three consecutive (and adequate) smears with negative findings, at which point the patient can be monitored routinely. If a second ASCUS result is obtained during the 2-year period, colposcopy should be considered. The diagnosis of unqualified ASCUS with severe
inflammation should be reevaluated after 2–3 months.
2. ASCUS in high-risk patients requires colposcopy and directed biopsy as indicated.
3. Infections. If chlamydiosis, gonorrhea, or vaginitis (due to Candida or Trichomonas) is identified, antibiotic or antifungal treatment is appropriate.
4. Postmenopausal patients not on hormone replacement therapy have atrophic cells that may resemble parabasal cells with a high nucleus to cytoplasm ratio, suggestive of dysplasia. Use of topical estrogen may be helpful in resolving the cellular atypia. If ASCUS remains, colposcopy is recommended.
4. Postmenopausal patients not on hormone replacement therapy have atrophic cells that may resemble parabasal cells with a high nucleus to cytoplasm ratio, suggestive of dysplasia. Use of topical estrogen may be helpful in resolving the cellular atypia. If ASCUS remains, colposcopy is recommended.