Acute and chronic cervicitis

At the onset of menarche, the production of estrogens by the ovary stimulates maturation of the cervical and vaginal squamous mucosa and formation of intracellular glycogen vacuoles in the squamous cells. As these cells are shed, the glycogen provides a substrate for endogenous vaginal aerobes and anaerobes, including streptococci, enterococci, Escherichia coli, and staphylococci; however, the normal vaginal and cervical flora is largely dominated by lactobacilli. Lactobacilli produce lactic acid that maintains the vaginal pH below 4.5, suppressing the growth of other saprophytic and pathogenic organisms. In addition, at low pH, lactobacilli produce bacteriotoxic hydrogen peroxide (H2O2).21 At higher, more alkaline pH caused by bleeding, sexual intercourse, vaginal douching as well as during antibiotic treatment, lactobacilli decrease H2O2 production, permitting the overgrowth of other microorganisms, which may result in clinically apparent cervicitis or vaginitis. Some degree of cervical inflammation may be found in virtually all women, and it is usually of little clinical consequence. However, infections by gonococci, chlamydiae, mycoplasmas, and herpes simplex virus may produce significant acute or chronic cervicitis and are important to identify due to their association with upper genital tract disease, complications during pregnancy, and sexual transmission. Marked cervical inflammation produces reparative and reactive changes of the epithelium and shedding of atypical-appearing squamous cells, and therefore may cause a nonspecific, abnormal Pap test result.

Endocervical Polyps

Endocervical polyps are benign exophytic growths that occur in 2% to 5% of adult women. Perhaps the major significance of polyps lies in their production of irregular vaginal "spotting" or bleeding that arouses suspicion of some more ominous lesion. Most polyps arise within the endocervical canal and vary from small and sessile to large, 5-cm masses that may protrude through the cervical os. All are soft, almost mucoid, lesions composed of a loose fibromyxomatous stroma harboring dilated, mucus-secreting endocervical glands, often accompanied by inflammation (Fig. 22-14). Simple curettage or surgical excision effects a cure.

Premalignant and Malignant Neoplasms

No form of cancer better documents the remarkable effects of screening, early diagnosis, and curative therapy on the mortality rate than does cancer of the cervix. Fifty years ago, carcinoma of the cervix was the leading cause of cancer deaths in women in the United States, but the death rate has declined by two thirds to its present rank as the eighth leading cause of cancer mortality. In sharp contrast to this reduced mortality, the detection frequency of early cancers and precancerous lesions is high. Much credit for these dramatic gains belongs to the effectiveness of the Pap test in detecting cervical precancers and to the accessibility of the cervix to colposcopy (visual examination of the cervix with a magnifying glass) and biopsy. While there are an estimated 11,000 new cases of invasive cervical cancer in the United States annually, there are nearly 1 million precancerous lesions of varying grade that are discovered yearly by cytologic examinations. Thus, it is evident that Pap smear screening not only has increased the detection of potentially curable, low-stage cancers but has also allowed the detection and eradication of preinvasive lesions, some of which would have progressed to cancer if not discovered and treated.

Pathogenesis

The pathogenesis of cervical carcinoma has been delineated by a series of epidemiologic, clinicopathologic, and molecular genetic studies. Epidemiologic data have long implicated a sexually transmitted agent, which is now established to be HPV. For his discovery of HPV as a cause of cervical cancer, Harald zur Hausen was awarded the Nobel Prize in 2008. HPVs are DNA viruses that are typed based on their DNA sequence and subgrouped into high and low oncogenic risk. High oncogenic risk HPVs are currently considered to be the single most important factor in cervical oncogenesis. High oncogenic risk HPVs have also been detected in vaginal squamous cell carcinomas and in a subset of vulvar, penile, anal, tonsillar, and other oropharyngeal carcinomas, as detailed in Chapter 7. As noted earlier, low oncogenic risk HPVs are the cause of the sexually transmitted vulvar, perineal, and perianal condyloma acuminatum. There are 15 high oncogenic risk HPVs that are currently identified. From the point of view of cervical pathology, HPV 16 and HPV 18 are the most important. HPV 16 alone accounts for almost 60% of cervical cancer cases, and HPV 18 accounts for another 10% of cases; other HPV types contribute to less than 5% of cases, individually.22 The risk factors for cervical cancer are related to both host and viral characteristics such as HPV exposure, viral oncogenicity, inefficiency of immune response, and presence of co-carcinogens.23 These include:

· Multiple sexual partners

· A male partner with multiple previous or current sexual partners

· Young age at first intercourse

· High parity

· Persistent infection with a high oncogenic risk HPV, e.g., HPV 16 or HPV18

· Immunosuppression

· Certain HLA subtypes

· Use of oral contraceptives

· Use of nicotine

Genital HPV infections are extremely common; most of them are asymptomatic, do not cause any tissue changes, and therefore are not detected on Pap test. Figure 22-15 shows age-dependent prevalence of HPVs in cervical smears in women with normal Pap test results. The high peak of HPV prevalence in 20-year-olds is related to sexual début, while the subsequent decrease in prevalence reflects acquisition of immunity and monogamous relationships. Most HPV infections are transient and are eliminated by the immune response in the course of months. On average, 50% of HPV infections are cleared within 8 months, and 90% of infections are cleared within 2 years. The duration of the infection is related to HPV type; on average, infections with high oncogenic risk HPVs last longer than infections with low oncogenic risk HPVs, 13 months versus 8 months, respectively.24 Persistent infection increases the risk of the development of cervical precancer and subsequent carcinoma.

HPVs infect immature basal cells of the squamous epithelium in areas of epithelial breaks, or immature metaplastic squamous cells present at the squamocolumnar junction (Fig. 22-16). HPVs cannot infect the mature superficial squamous cells that cover the ectocervix, vagina, or vulva. Establishing HPV infection in these sites requires damage to the surface epithelium, which gives the virus access to the immature cells in the basal layer of the epithelium. The cervix, with its relatively large areas of immature squamous metaplastic epithelium, is particularly vulnerable to HPV infection as compared, for example, with vulvar skin and mucosa that are covered by mature squamous cells. This difference in epithelial susceptibility to HPV infection accounts for the marked difference in incidence of HPV-related cancers arising in different sites, and explains the high frequency of cervical cancer in women or anal cancer in homosexual men and a relatively low frequency of vulvar and penile cancer.

Although the virus can infect only the immature squamous cells, replication of HPV occurs in the maturing squamous cells and results in a cytopathic effect, "koilocytic atypia," consisting of nuclear atypia and a cytoplasmic perinuclear halo. To replicate, HPV has to induce DNA synthesis in the host cells. Since HPV replicates in maturing, nonproliferating squamous cells, it must reactivate the mitotic cycle in such cells. Experimental studies have shown that HPV activates the cell cycle by interfering with the function of Rb and p53, two important tumor suppressor genes (Chapter 7).

Viral E6 and E7 proteins are critical for the oncogenic effects of HPV. They can promote cell cycle by binding to RB and up-regulation of cyclin E (E7); interrupt cell death pathways by binding to p53 (E6); induce centrosome duplication and genomic instability (E6, E7); and prevent replicative senescence by up-regulation of telomerase (E6) (Chapter 7). HPV E6 induces rapid degradation of p53 via ubiquitin-dependent proteolysis, reducing p53 levels by two- to three-fold. E7 complexes with the hypophosphorylated (active) form of RB, promoting its proteolysis via the proteosome pathway. Because hypophosphorylated RB normally inhibits S-phase entry via binding to the E2F transcription factor, the two viral oncogenes cooperate to promote DNA synthesis while interrupting p53-mediated growth arrest and apoptosis of genetically altered cells. Thus, the viral oncogenes are critical in extending the life span of epithelial cells-a necessary component of tumor development.

The physical state of the virus differs in different lesions, being integrated into the host DNA in cancers, and present as free (episomal) viral DNA in condylomata and most precancerous lesions. Certain chromosome abnormalities, including deletions at 3p and amplifications of 3q, have been associated with cancers containing specific (HPV-16) papillomaviruses.

Even though HPV has been firmly established as a causative factor for cancer of the cervix, the evidence does not implicate HPV as the only factor. A high percentage of young women are infected with one or more HPV types during their reproductive years, and only a few develop cancer. Other co-carcinogens, the immune status of the individual, and hormonal and other factors influence whether the HPV infection will regress or persist and eventually progress to cancer.23

In addition to infecting squamous cells, HPVs may also infect glandular cells or neuroendocrine cells present in the cervical mucosa and cause malignant transformation, resulting in adenocarcinomas, and adenosquamous and neuroendocrine carcinomas; these tumor subtypes, however, are less common since glandular and neuroendocrine cells do not support effective HPV replication.

Дата добавления: 2015-11-13