CRYODESTRUCTION AND IMMUNOMODULATION IN THE TREATMENT OF BENIGN SUPERFICIAL NEOPLASMS ASSOCIATED WITH HUMAN PAPILLOMAVIRUS (HPV)

 Korsun V.V.

Proceedings of the St. Petersburg Cryotherapy Forum, ITMO University, 2025

The relevance of the topic of treatment of HPV-associated neoplasms.

According to WHO, 50-80% of the population is infected with HPV, but only 5-10% of infected individuals have clinical manifestations of the disease. The prevalence of HPV-associated neoplasms is steadily increasing. Over the past decade, the prevalence of papillomavirus infection of the anogenital region in the world has increased more than 10 times and is found in 13% of the population. The incidence of one of the manifestations of HPV infection, anogenital warts, is high, with 120.5 new cases per 100,000 population. Every year, 20 million people are diagnosed worldwide. new cancer cases (WHO data 2022), with 5% associated with HPV and the majority (75%) localized in the anogenital region. Frequent relapses of papillomavirus infection (PVI) necessitate comprehensive treatment. Previously, a sufficient number of studies have been conducted to determine the effectiveness of various types of surgical treatment in combination with immunomodulatory therapy, in particular with Allokin-Alpha, in the treatment of HPV-associated neoplasms, primarily such as genital warts of the anogenital region and cervical erosions. The previously obtained data convincingly showed that after the use of such treatment, PVI remission is registered in 90-96% of patients (according to various sources), human papillomavirus DNA was not detected in more than 80%. The best treatment results were obtained when cryosurgical treatment was combined with immunomodulatory therapy.

Cryosurgical treatment at the Edelweiss Center for Medicine and Dentistry has been carried out for 9 years.

Applied cryosurgical treatment methods at the Edelweiss Center for Medicine and Dentistry.

Justification of cryosurgical treatment in combination with immunomodulatory therapy in the treatment of HPV-associated neoplasms.

Cryosurgical treatment is effective and has a number of advantages over other types of surgical interventions, which is important in the treatment of HPV-associated neoplasms. The main advantage of cryodestruction is the phenomenon of organotypic regeneration, that is, healing without scarring, or healing with a mosaic regenerate, including areas of organotypic and scarring, which is one of the main cosmetic advantages of cryosurgery. During cryodestruction, nothing is immediately removed, the destroyed pathological tissue remains in place for a long time, acting as a wound dressing and providing another important advantage of cryosurgery. With prolonged enough contact of cryonecrosis with the whole organism, immunomodulatory reactions of the body are triggered. There is no denaturation of pathological proteins and nucleic acids during cryodestruction. However, these pathologically altered structures, which carry the main characteristics of the etiological factors of the pathological process, become antigens in the composition of non-viable, already alien tissue destroyed by cold. In response, specific antibodies are produced, phagocytosis is activated, directed against similar cryodestructible pathological elements throughout the body.

Different cells, tissues, and organisms have different intrinsic sensitivity to cold: melanocytes, basal cells, and bacteria die easily, while fibroblasts, collagen, nerve tissue, and blood vessels, as well as viruses, are less susceptible to cold injury. In this regard, especially in common or complicated forms of HPV-associated neoplasms, cryosurgical treatment should be performed simultaneously with the use of immunomodulatory drugs.

For cryodestruction of common or complicated forms of HPV-associated benign superficial neoplasms, we use drugs: Allokin-Alpha and Isoprinosine.

Applied schemes and results of cryosurgical treatment in combination with immunomodulatory therapy in the treatment of HPV-associated neoplasms.

Conclusions:

References:

Shafranov V.V., Borkhunova E.N., Taganov A.V., Torba A.I., Tsyganov D.I., Mazokhin V.N., Pisiskova A.V. "Theory and mechanism of damage to biological tissues during local freezing" Russian Bulletin of Pediatric Surgery, Anesthesiology and Intensive Care, Moscow, 2011 (1)

Borkhunova E.N. Features of reparative tissue regeneration after cryodestruction, microwave cryodestruction and microwave destruction: Dissertation of Doctor of Biological Sciences, Moscow 2004, 325 p.

Kalmykova Z.V., Shafranov V.V. "The use of cryosurgery in a multidisciplinary clinic" - Plastic Surgery and Cosmetology journal, Moscow, 2013 (3)

CRYOSURGERY AND MODERN HIGH-TECH METHODS OF TREATMENT OF A NUMBER OF PATHOLOGICAL NEOPLASMS

Kalmykova Z.V., Korsun V.V.

The article is about the principles and fundamentals of cryotherapy, as well as the applied methods and experience of cryosurgical treatment of various neoplasms of the skin and mucous membranes on the basis of the cryogenic treatment room of the City Clinical Hospital №60.

In recent decades, so–called "new" types of energy have been introduced into medicine, particularly surgery - laser, ultrasound, magnetic devices, electromagnetic fields and low temperatures.

The number of malignant diseases is gradually and continuously increasing all over the world. The growth of the cancerous tumor itself and the development of distant malignant metastases means a fatal outcome for a sick person. Only a part of patients succeed after routine surgical operations. Most patients need a new radical and palliative approach to the treatment of malignant diseases, which leads to an improvement in the quality of life and an increase in life expectancy.

Cryosurgery is characterized by the local application of ultra-low temperatures, usually from -20 °C and much lower. As a result of the effects of the latter, their destruction occurs in the frozen biological tissue or organ, avital and irreversible physico-biochemical processes occur, the so-called local cryodestruction.

In medical scientific and clinical practice, LIQUID NITROGEN is most widely used for the use of local cryodestruction of biological tissue, especially in surgical oncology. This approach in the widespread use of liquid nitrogen is motivated by the most acceptable physical and technical characteristics of this cryoagent, as well as storage, transportation conditions, economic accessibility, etc. When using liquid nitrogen, temperatures from -25 °C to -50 ° C are reached in tissues or organs within about 30 seconds. Benign neoplasms usually require temperatures from -20 °C to -30 °C, and effective removal of malignant neoplasms often requires temperatures from -40 °C to -50 °C.

The theoretical basis of local freezing is the study of the "behavior" of water in biological systems when the temperature drops. Initially, the American biologist Peter Mazur proposed the theory of extracellular and intracellular crystallization of water (ice formation occurs in intracellular fluid and inside cells). Due to the crystallization of water, cellular structures are destroyed and tissues die. It should be said that this theory is certainly true, but only for cryopreservation processes.

This theory is not applicable for cryogenic tissue destruction, and that's why. The number of cells in 1 cubic cm of tissue reaches an average of 10 to 14 cells. This is an extremely dense package. The energy saturation of tissues is phenomenal: 1 gram of human body mass generates 1000 times more heat than 1 gram of the mass of the sun. For this reason, it is impossible to "freeze" a lot of tissues, and any local freezing process is limited in its capabilities. Studies have shown that the process of local cryodestruction with the help of simple devices lasts 3 minutes, and with the help of automatic systems it takes only 15 minutes. The area of thermodynamic equilibrium stops the growth zone of the ice ball. You can "freeze" the fabric for 1-2-10 hours or more, the thermodynamic equilibrium zone will not move anywhere and does not allow you to do more.

Thus, there are 2 stages in the mechanism of damaging effects:

• Primary tissue damage associated with direct cell destruction under the influence of low temperature
• Secondary damage caused by the death of pathological tissue as a result of hemodynamic disorders and during aseptic inflammation.

It is important to know that:

• The density of the tissue and the intensity of its metabolism determine a high level of heat production, which leads to thermodynamic equilibrium (self-limiting the size of the freezing zone).
• The volume of the freezing zone is 60% determined by the structure of the water contained in the tissue and the degree of development of the microcirculatory bed.

Nevertheless, in order to prolong the thermal (metabolic) barrier and structural resistance, i.e. to increase the volume of cryodestruction, in some cases a combination of the cryogenic method with preliminary exposure to a microwave electromagnetic field is required. The microwave field, interacting with additional structures, "tears out" up to 60-70% of the water, making it more "free". Subsequent freezing turns this water into tissue-destroying ice structures.

It should be noted the immunomodulatory effect that occurs after cryodestruction of pathological tumor or inflamed tissue, when the mechanism of stimulation of nonspecific immunity is triggered (humoral – production of bactericidal substances, primarily fibronectin, lysozyme, interfernes, complement system, etc.; cellular – phagocytosis and cytotactic effect) and specific (humoral – production of antibodies by B-lymphocytes and plasma cells by cells; cellular – with the participation of T-lymphocytes, or rather their populations of helpers, suppressors, killers, memory cells), antitumor, antiviral, antimicrobial, and antifungal immunity. There is no denaturation of pathological proteins and nucleic acids during cryodestruction. However, these pathologically altered structures (which carry the main characteristics of the etiological factors of the pathological process) are part of non-viable, already alien tissue destroyed by cold they become antigens. In response, specific antibodies are produced, phagocytosis is activated, directed against similar pathological elements subjected to cryodestruction, not only at the site of cryodestruction, but throughout the body.

The methods of cryogenic exposure used in our practice

It should be noted that for many years (since the opening of the cryosurgery and cryotherapy room at the City Clinical Hospital No. 60 in 1993), we have applied all cryogenic exposure techniques using all domestic cryomedical devices.

Cryodestruction by the application method is performed either by contact with a cryoapplicator and/or a portable filler cryoapplicator with a set of nozzles, or by using cryoapplicators. In any case, before exposure, it is necessary to select the size of the cryonic intestine corresponding to the size of the neoplasm.

The criterion for the cessation of exposure is the formation of a zone of thermodynamic equilibrium. Visually, the formation of a white stripe (frozen tissue) around the cryonic tip is noted. The moment when the increase in the width of the white stripe stops corresponds to the moment when the thermodynamic equilibrium zone is formed. The zone of thermodynamic equilibrium always extends beyond the boundaries of the tumor min. by 0.2 – 0.5 cm, which guarantees the devitalization of the tumor.

Cryospray destruction has proven to be a highly effective cryodestruction technique that can destroy any predicted amount of tissue. It is produced using portable or stationary spray-type devices.

In addition to destruction, cryospray can be used to irrigate the skin for cosmetic purposes using a cryoprotector, with the doctor holding the device at a distance of 30-50 cm from the patient. The diffused jet is directed to the skin of the face, neck and decollete area. The procedure is performed within 2-3 minutes. The effect is to activate microcirculation in the skin.

After thawing at the cryodestruction site, edema develops with the formation of a bladder with serous or serous-hemorrhagic contents, which can be opened for 3-5 days. After that, healing takes place under the scab.

Depending on the size of the neoplasm, one-, two- and three-fold freeze-thaw cycles can be used, and the number of cryodestruction sessions can range from 1 to several.

Post-destructive surface care consists of treatment with 70% alcohol and 5% potassium permanganate solution.

Microwave cryodestruction is implemented in 2 stages. At the 1st stage, irradiation with a microwave field (CMB range) is carried out for several minutes. Stage 2 - cryodestruction – is performed in the usual way. As a result, it is possible to obtain a cryodestruction zone 4-6 times larger than the "pure" cryodestruction zone.

Multifactorial quantum exposure after cryodestruction - usually several exposure sessions are performed. The use of multifactor sources of electromagnetic radiation makes it possible to enhance the processes of reparative regeneration of tissues and organs, as well as reduce inflammatory, edematous, painful and other possible manifestations of cryotherapy.

The results of our clinical achievements

It should be noted that our achievements presented in Russia, France, and Japan always arouse great interest. We are at the forefront of dealing with the problems of the theory of local cryogenic effects, which has gained recognition at the global level.

I. Malignant tumors

• Basal cell carcinoma - 3181
• Squamous cell carcinoma - 1510
• Spindle cell carcinoma - 18
• Melanomas - 7
• Myxosarcoma - 3
• Pseudocarcinomatous hyperplasia - 3
• Giant cell tumor of soft tissues - 3
• Cancer of the rectum in the anal area - 1
• Total - 4,726

II. Benign tumors

• Papilloma - 3690
• Keratopapilloma - 1744
• Clear cell papilloma - 22
• Basal cell papilloma - 25
• Squamous cell papilloma - 20
• The wart - 3020
• Condyloma (genital organs and anus) - 103
• Keratoma - 330
• Senile keratoma - 445
• Senile acanthoma - 330
• Seborrheic keratosis - 761
• Intradermal pigmented nevus - 450
• Intradermal nevus with basal cell papilloma - 10
• Fibropapilloma - 500
• Dermatofibroma - 230
• Keloid scar - 44
• Epidermal cyst - 16
• Cystic epithelioma - 16
• Atheroma - 60
• Granulomatous epulis - 8
• Trichoepithelioma - 26
• Fibroma - 350
• Angiofibroma - 150
• Acanthoma - 32
• Keratoacanthoma - 114
• Eccrine spiradenoma - 1
• Cylinder - 2
• Osteoma - 2
• Chondroma - 2
• Total - 12 503

III. Suppurative processes

• Boils, carbuncles, and hydradenites - 641
• Phlegmon - 5
• Trophic ulcer - 326
• Suppurated atheroma - 10
• Infected facial wound - 22
• Fistulas (vaginas, feet, shins) - 32
• Total – 1 036

IV. Otorhinolaryngic diseases

• Polypous ethmoiditis - 341
• Chronic tonsillitis - 109
• Granulosa pharyngitis - 253
• Atrophic pharyngitis - 253
• Vasomotor rhinitis - 198
• Hypertrophic rhinitis - 319
• Nosebleeds (including Randu-Osler's disease) - 182 (60 )
• Total - 1,655

V. Other diseases

• Leukoplakia of the cervix - 12
• Bladder cancer - 1
• Allergic contact dermatitis - 7
• Tick bite - 3
• Ingrown toenail - 4
• Corn - 6
• Total - 33

Total patients treated - 19 953

The results of treatment of patients with the presented nosologies were as follows:

Group 1 – patients with malignant skin tumors. In most cases, basal cell and squamous cell carcinoma with a predominant localization on the face and locally destructive growth leading to disfiguring destruction of the nose, jaw, orbit and auricles were registered in this group. Patients in this group underwent cryodestruction (cryodestruction with a filler-type device, cryoapplicator or cryospray) and microwave cryodestruction. After the treatment, a positive result was noted, which consisted in eliminating the tumor and replacing it with thin scar tissue. The formation of coarse scars or long-term non-healing wound surfaces was not observed in any case.

Group 2 – patients with benign skin tumors. Patients in this group underwent 2-3 sessions of cryotherapy (cryodestruction with a filler-type device, cryoapplicator or cryospray) and microwave cryodestruction. In all cases, positive surgical and cosmetic results were noted, which was manifested by the formation of an atrophic scar or regenerate at the site of cryotherapy, which looks similar to the surrounding skin.

Group 3 – patients with purulent diseases of soft tissues and trophic ulcers. Cryodestruction - cryospray destruction and microwave cryodestruction were used in this group of patients with carbuncles, boils, abscesses, and hydradenitis. In all patients, after the treatment, necrosis of the capsule of the purulent focus was observed, its separation along with its contents from the surrounding tissues, peeling, filling the defect with granulation tissue and the formation of an atrophic scar at the site of the defect. Cryodestruction and cryospray irrigation were used in patients with long-term non-healing trophic ulcers as a stage of preparation of the wound surface for skin grafting. After the treatment, the elimination of excessive pathological granulations and epithelialization of the ulcerative surface were noted, and graft engraftment was noted in patients who later underwent flap transplantation.

Group 4 – patients with otorhinolaryngic diseases. Patients in this group underwent cryosurgical treatment, after which complete regeneration of the mucous membrane of the organs was observed. The effectiveness of cryotherapy has also been noted in the treatment of patients with Randu-Osler disease. So, during repeated examinations after 3-5 years, the elimination of telangiectasia was noted, which led to the absence of nosebleeds characteristic of this pathology.

Group 5 – patients with other diseases – in this group, positive treatment results were obtained using these methods.

The use of cryospray for skin biorevitalization seems to us to be an effective method that deserves attention for dermatocosmetological practice. When using it, moderate skin hyperemia is observed due to the activation of microcirculation processes, which leads to an improvement in appearance, as well as to the optimization of metabolic processes in the skin.

The use of multifactorial quantum effects after cryodestruction makes it possible to somewhat reduce the healing time of cryogenic wounds by improving trophic and tissue regeneration in the field of cryodestruction.

Based on many years of experience and analysis of the treatment results of a large group of patients, the following conclusions can be drawn:

1. The cryosurgical method is one of the competitive methods in the treatment of oncological diseases, since low-temperature exposure is highly effective, ablastic, painless, bloodless, well tolerated by patients, has an immunomodulatory effect with good long-term results.

2. Cryodestruction using our methods (using cryoapplicators, filler-type devices, cryospray and tubes that localize the refrigerant jet), as well as microwave cryodestruction, makes it possible to achieve the destruction of a neoplasm with the capture of the perifocal zone and devitalization of the entire volume of tumor tissue. Healing is completed by the formation of an atrophic scar or regenerate, superficially similar to the surrounding skin. The high efficiency of the technique is confirmed by the absence of relapses in patients of the studied group.

3. Cryosurgical methods are effective in a wide range of diseases: inflammatory processes, tumors, precancerous conditions, viral dermatoses, scars, and long-term non-healing wounds. It is important to emphasize the effectiveness of these techniques in the treatment of trophic ulcers in patients with diabetes mellitus in the decompensation stage.

4. Cryosurgery does not require anesthesia and does not cause pronounced general reactions from the cardiovascular system. This expands the possibility of providing surgical care to patients who are contraindicated in the traditional surgical method of treatment.

5. In some cases, it is necessary to perform local anesthesia in patients who react emotionally to cryosurgery or in people with a reduced pain threshold. Prior exposure to lidocaine aerosol on the surface of the skin or mucous membrane makes the operation painless.

6. The cryogenic treatment method in the presented variants does not cause general intoxication and is accompanied by minimal operational risk. Postoperative complications are extremely rare and are usually associated with careless or improper care of the post-destructive surface.

7. The simplicity of the cryosurgical treatment method allows it to be widely used in daily practice in both the office and the operating room.

References:

Kalmykova Z.V. "Clinical geriatrics in a multidisciplinary hospital" Proceedings of the scientific and practical conference GKBNo. 60, Moscow, 2010.

Kalmykova Z.V., Shafranov V.V. "Application of cryosurgery in a multidisciplinary clinic" Journal of Plastic Surgery and Cosmetology, Moscow, 2013 (3)

Shafranov V.V., Reznitsky V.G., Shestiperov V.A. "Combined effect of microwave electromagnetic field and local freezing on biological tissue" Bulletin of Experimental Biology and Medicine, 1982 No. 4, pp. 95-98.

Borkhinova E.N. "Features of reparative tissue regeneration after cryodestruction, microwave cryodestruction and microwave destruction" Dissertation of Doctor of Biological Sciences, Moscow 2004, 325 p.

Gatkin E.Ya. "Application of laser photostimulation in pediatric surgery" Dissertation of Doctor of Medical Sciences, Moscow, 2009, 298 p.

Gatkin E.Ya., Shafranov V.V., Petlakh V.I., Sukhorukov V.S. "Method of treatment of cryogenic wounds" Patent for invention No. 2366472, FSU FIPS 09.10.2009.