Clinical and morphological diagnosis and treatment of sexually transmitted infections - Yakymova T. P. 2007

Human Papillomavirus: Clinical and Morphological Diagnostics. Treatment of Human Papillomavirus Infection

According to some authors, the prevalence of human papillomavirus (HPV) infection ranges from 36% in women under 25 years of age to 2.8% in women aged 45 and older (Burk R.D. et al., 1996).

This suggests that the observed inverse correlation between the prevalence of human papillomavirus infection and age may be due to lifelong acquired Immunity against HPV (Sun Y. et al., 1996).

The high prevalence of HPV infection in the population may play a critical role in The Development of anal and cervical lesions in women. In such cases, HPV infection is almost invariably detected.

The causative agent belongs to the family Papovaviridae. Virions, measuring 40–50 nm in diameter, contain circular DNA. The virus replicates in human epithelial Cells, forming basophilic inclusions (Lützner bodies) visible under a Light Microscope (see color insert, Fig. 48). Electron Cell/15.html">Microscopy has revealed that these inclusions are aggregates of Viral Particles. These Viruses are highly resistant to disinfectants, but are destroyed by the high temperatures of autoclaving.

Human papillomavirus (HPV) is associated with the development of squamous Dysplasia and Cervical Cancer in up to 90% of cases. HPV was first identified in 1956, and over 100 strains of this virus are currently known, numbered in the order of their discovery. Approximately 30 types affect the genitalia in both sexes and are ranked according to their risk of causing cervical cancer. For instance, HPV types 6, 11, 30, 42, 43, and 44 are classified as low-risk types because they are typically associated with non-malignant cervical lesions. Conversely, HPV types 16 and 18, along with types 31, 33, 35, 39, 45, 52, 58, 59, and 68, are classified as high-risk types for cervical cancer—especially types 16 and 18, which are most frequently identified by the WHO International Agency for Research on Cancer. It has been established that the etiological role in the development of cervical cancer belongs to multiple HPV types, particularly 16, 18, 31, and 33, due to their high oncogenic potential to invade The Genome of stratified squamous epithelial cells, altering them, inducing Mutations, and disrupting regeneration and differentiation processes.

HPV types 16, 18, 31, and 33 are detected in 90–95% of cervical cancers and in 50–80% of precancerous conditions, such as grade II and III squamous dysplasia. Human papillomavirus is highly contagious; transmission occurs not only through sexual contact but also vertically from mother to foetus in utero. HPV infection in pregnant women can lead to miscarriages and stillbirths, while infection in late Pregnancy may result in children born with chickenpox, which can also be fatal for newborns.

The disease is most frequently diagnosed in individuals aged 22–24 and occurs with equal frequency in sexually active men and women. Infection can also occur at an advanced age. The incubation period for human papillomavirus infection ranges from 1 to 9 months, with an average of 3 months.

Since it is now established that cervical cancer frequently has a viral Etiology, women with multiple sexual partners and those infected with HPV are considered at high risk for developing cervical cancer. Promiscuity, a high rate of Sexually Transmitted Infections, early initiation of sexual activity, and early childbirth represent an incomplete list of challenges faced by physicians in treating and preventing Sexually Transmitted Diseases. Furthermore, this is not only a medical issue but a social one as well, as it concerns the young, future Generation of the country.

As a rule, the classic clinical manifestation of human papillomavirus infection is genital warts (condylomata acuminata)—ad oculus resembling cauliflower, primarily due to their papillary growth pattern. However, condylomas are not always pointed; they can also be flat, endophytic, giant condylomas, or take the form of bowenoid papulosis. Asymptomatic carriage is also known to occur.

Subjectively, patients report itching, tingling, Swelling, and burning, while severe edema may cause pain resulting from the compression of genital nerve endings by the swollen tissue.

As is known, the morphological equivalent of a viral infection in the cervical squamous epithelium is the koilocyte. These cells derive their name from the Greek word "koilos", meaning empty (see color insert, Figs. 49, 50).

Koilocytes frequently appear as large cells with clear Cytoplasm—either finely vacuolated or entirely colorless and seemingly empty. These cells are detected both in altered epithelial lesions of the cervix and in healthy zones (Koss L., 1987; Meisels A. et al., 1977; Selvaggi S.M., 1988). Koilocytes are modified squamous epithelial cells undergoing nuclear and cytoplasmic transformation. Similar to squamous cells in other pathologies, koilocytes in smears appear either scattered or in clusters. Cell sizes range from small to quite large, though they are predominantly large, exceeding the dimensions of corresponding healthy, unaltered cells. Koilocytes feature enlarged dimensions and large nuclei. The cells are typically round, less frequently elongated or oval, with distinct borders, originating from the deep layers of the functional superficial layer and deeper strata of the squamous epithelium (see color insert, Figs. 51–58).

This characteristic is highly significant, as other cells do not always possess distinct borders. Like cells in Other forms of genital pathology, koilocytes may exhibit degenerative nuclear changes (such as karyorrhexis) and cytoplasmic changes (such as vacuolar and fatty dystrophy). Koilocytes are not only enlarged but also pleomorphic and heterochromatic, occasionally featuring clear, seemingly empty cytoplasm, yet they may also display a basophilic tint, particularly along the cytoplasmic margin.

Nuclear Chromatin is homogeneous, and nuclear staining is hazy and blurred, which, combined with a distinct karyolemma border, gives The Nucleus a "ground-Glass" appearance. The karyolemma is usually irregular and folded, though it may have sharply defined boundaries. Typically, koilocytes are mononucleated, but binucleated cells may also be observed.

The cytoplasm of koilocytes exhibits distinct differences compared to normal cells and those affected by other pathologies. Koilocytic cytoplasm is abundant, containing numerous clear, empty cavities of varying sizes located in the perinuclear zone (see color insert, Figs. 59, 60).

These perinuclear halo zones are sharply demarcated from the peripheral Regions of the cytoplasm, resulting in koilocytes possessing two distinct cytoplasmic zones: a light perinuclear zone and a dark peripheral zone.

The presence of a clear cellular boundary and a two-component cytoplasm distinguishes koilocytes from other squamous epithelial cells and makes them easily distinguishable under low magnification, simplifying their search and verification. The perinuclear halo in koilocytes is caused by necrotic Changes in the cytoplasm that initially develop perinuclearly and then spread toward the periphery of The Cell. Condensation of the cell's fibrillar structures occurs at the periphery of the necrosis zone, ensuring a sharp demarcation of the perinuclear necrosis zone (see color insert, Figs. 61–63).

Unlike degeneratively altered squamous cells associated with other pathologies, koilocytes stand out due to their unusual planar orientation. While cells are typically viewed in a planar image, koilocytes are more convex cells, a feature observable under the microscope. Scanning electron microscopy has established that, unlike normal squamous epithelial cells, koilocytes lose their ability to flatten and form three-dimensional structures. Consequently, we observe a certain sphericity of these clear cells with a two-layer cytoplasm in smears, which sets them apart from cells in Other types of pathology.

Transmission electron microscopy has revealed the crystalline Structure of viral particles, though non-crystalline viral aggregates may also occur, localized as inclusions within the nucleoplasm or concentrated around nuclear chromatin. Viral particles are typically located within the nucleus, but may also be present in the perinuclear halo. It should be noted that in benign Background processes of the cervix and precancerous lesions, HPV is localized episomally, whereas in cancer, the virus is integrated into the cell genome (Sato S. et al., 1988). Viral integration into the genome leads to pronounced dysplasia and the development of cervical cancer (see color insert, Fig. 64).

Pronounced dysplasia, suspected of progressing to cancer, is accompanied by atypia, enlargement of both cell and nuclear size with a disruption of the nuclear-cytoplasmic ratio in favor of the nucleus, and the appearance of nucleoli. Malignant cells in highly differentiated Squamous Cell Carcinoma vary in keratinization degree and size. Fig. 55 (see color insert) presents a Cervical smear containing a koilocyte, a keratinized cancer cell, and an anuclear cornified squama.

The detection of koilocytes is of great importance for the subsequent evaluation of patients using enzyme immunoassay, immunofluorescence, and PCR Methods. Because it leads to carcinogenic effects, women with human papillomavirus infection are at risk not only for cervical cancer but also for synchronous and metachronous malignancies and other metaplastic processes, thus requiring prompt Treatment and long-term follow-up. Women of reproductive age planning a family should first be cleared of viral infection, verified by repeated testing (at least 3 times) confirming a complete cure, to prevent in utero foetal INFECTION AND ITS adverse consequences.

TREATMENT

Numerous methods have been developed for treating patients suffering from human papillomavirus infection, including X-ray therapy, but no specific curative method exists.

Given the viral origin of condylomas, domestic antiviral agents such as bonafton and riodoxol are used in the treatment of patients suffering from this condition.

Riodoxol (triiodoresorcinol) is applied topically as 0.25% and 0.5% ointments applied to affected areas daily every 3 hours for 12–18 days.

Bonaphton is prescribed as a 0.5%, 1%, or 2% ointment, which is applied to the affected areas 5 to 6 times a day for 2–3 weeks.

In severe or advanced cases where local ointment therapy proves insufficiently effective, Bonaphton is administered orally as 0.2 g tablets 3 times a day for 10 days.

Good results have been achieved in treating warts using leukocyte interferon injected directly into the Base of the wart. These positive outcomes are explained by the fact that interferon introduced into the tissue triggers The production of an antiviral protein that blocks viral Replication. As a result, surrounding cells become resistant to the virus (the pathogen), thereby preventing the further development of warts.

To maintain cellular resistance to the virus, interferon must be delivered in a sufficient concentration, which necessitates repeated Applications.

When treating genital warts in men with a 25% podophyllin solution and Solcoderm applied locally to the lesions 1–2 times a week, combined with intramuscular injections of Leukinferon (1 million IU every other day for a total of 10 injections, followed by twice weekly for a month), a therapeutic effect is observed; however, recurrences occur in some treated patients (about 17%) within 6 months.

Anogenital warts are frequently caused by HPV-6 or HPV-11. These infections remain in a latent or inapparent stage.

For the treatment of condylomata acuminata, a preparation called Condyline (Netherlands) is recommended. It is a purified and standardized alkaloid—a 0.5% solution of podophyllotoxin in alcohol—which is applied to the affected areas using an applicator twice daily for 3 days, taking care to avoid contact with healthy Skin. It does not need to be washed off after application. Alternative treatment modalities include destructive methods (cryodestruction, laser therapy, diathermocoagulation, trichloroacetic acid, Fереzol, Solcoderm), Interferon Therapy (alpha, beta, and gamma interferons), cytotoxic agents (podophyllin, podophyllotoxin, 5-fluorouracil), or combinations thereof.

Cytotoxic medications can be self-administered by patients at home. For this purpose, genital warts should be dabbed with a 0.5% podophyllotoxin solution using a swab twice daily for 3 days, followed by a 4-day break. If necessary, the treatment cycle can be repeated. Local applications of podophyllin, most commonly recommended for treating anogenital warts, result in a cure in 38.8% of patients within three weeks.

Cryotherapy is considered more successful, achieving cure rates of up to 85%.

Podophyllin is used as a 10–25% solution combined with benzoin tincture, applied 1–2 times a week. If the warts do not disappear after six applications, another treatment method should be adopted, such as daily applications of a 5% 5-fluorouracil ointment to the affected areas for 7–8 weeks. If this ointment proves ineffective, laser therapy should be considered.

It is also recommended to use Solcoderm and an 80–90% trichloroacetic acid solution, which are applied to the warts daily for 6 weeks; if the warts do not disappear completely by the end of this period, switching to an alternative treatment method is warranted.

Chemical cauterization of condylomata acuminata using Fереzol, hydrogen peroxide, or liquid nitrogen can cause significant local complications and is associated with severe pain.

Interferon can be considered an effective agent in treating recurrent genital papillomavirus infection. When clinical improvement is achieved through interferon therapy, patients show a decreased viral DNA copy number as confirmed by PCR.

For vaginal condylomata acuminata, 5% fluorouracil ointment is appropriately applied for 7–8 weeks, though in rare and severe cases unresponsive to standard care, intravenous injections of this drug may be utilized.

Cervical warts should not be treated until Pap smear results are available. Fluorouracil should be avoided during pregnancy.

Lycopid is an antiviral medication with potent immune-stimulating properties. It is used as an adjunct to primary therapy to help reduce the dosage of Antibiotics and antivirals, thereby promoting more complete clearance of the infection focus and reducing recurrences. For treatment, it is administered sublingually at a dose of 2 mg 2–3 times a day for 10 days. For prophylactic purposes, 1 mg is taken sublingually once a day for 10 days.

Currently, the immunomodulator imiquimod is used to stimulate the production of interferon-alpha and other endogenous cytokines. It is available as a 1% and 5% cream for the treatment of anogenital warts.

Imiquimod can be used to stimulate local cytokine production and cellular immune responses in patients with papillomavirus infection. Stimulation of local cytokine synthesis leads to the suppression of viral replication, the clearance of anogenital warts, and the healing of lesions without scarring.

Condyline is also an excellent remedy for treating external condylomata acuminata, leading to either complete clearance or significant improvement in most patients within a few weeks. Condyline is safe, more effective than previously used therapies, and, importantly, can be applied by the patients themselves. Patients with penile warts can safely use these preparations for self-treatment.

Warts located on moist surfaces or in skin folds respond better to topical treatment with trichloroacetic acid (or podophyllin, podofilox, and imiquimod) than warts situated on dry skin surfaces.

If there is no improvement after three courses of treatment, or if the warts show no change after six courses, the treatment approach must be revised.

Surgical removal of warts offers advantages over other modalities by providing rapid clearance, typically in a single visit.

Genital warts can be ablated using electrosurgical techniques. Surgical management is most appropriate for patients with a high burden or a large surface area of genital warts. CO₂ lasers and surgery can be employed in patients with multiple or intraurethral warts, especially when other therapeutic approaches have failed.

For the treatment of condylomata acuminata, a gel containing 5-fluorouracil and epinephrine has also been successfully used via lesional injections once a week for 6 weeks.

Thus, the modern management protocol for papillomavirus infection incorporates cryotherapy, podophyllum resin, podofilox, trichloroacetic acid, laser therapy, electrosurgical excision, fluorouracil, and alpha-interferon, among others. Wart treatment can be enhanced if the lesion area is initially primed with a 5% acetic acid solution to more clearly delineate the margins of the infection.

The problem of recurrence is independent of the chosen treatment method.

None of the methods is a panacea, as fairly frequent recurrences are observed with any treatment approach.