Studies show the association of the gut microbiome with gallbladder cancer.
\r\n\t
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The labia majora carry hair and contain sebaceous and sweat glands. Embryologically, they correspond to the male scrotum. The lymph nodes of vulva drain to the external iliac lymph nodes via inguinal lymph nodes. The area is extremely vascular [1, 2].
After taking a detailed personal medical history regarding to hygiene techniques focusing on the use of antibiotic ointments, antiseptics, topical analgesics, lubricants should the gynecologist establish, whether the examining woman suffers from general skin conditions including dermatitis, psoriasis, lichen sclerosus, allergic contact dermatitis, or suspicious vulva disorders. It is commonly agreed that the rate of allergic dermatitis is high in combination to vulvar symptoms [3]. During the examination, the clinician should carefully examine the vulva and pay attention to skin or mucosal color (erythema and intense red); texture can provide clues to correct diagnosis (e.g., slight hyperkeratosis and thickened skin) existence of any lesions, which seems unusual for such macules, papules, or ulcers [4, 5]. Ulcers of vulva are diagnostically challenging due to variation in clinical morphology [4, 5]. The primary morphology is clinically relevant for identifying because it can significantly narrow the differential diagnosis. Diagnosis of vulvar ulcers based solely on clinical findings is often inaccurate, in most cases depending on sexually transmitted infections, but the differential diagnosis can include also dermatoses, trauma, neoplasms, hormonal-induced ulcers, drug reactions, or ulcer of unknown etiology [6, 7].
Subsequent to the completion of detailed observation, the clinician can decide for the diagnosis, if additional tools are necessary like speculum examination, vulvoscopy, or dermoscopy. The benefit of vulvoscopy remains controversial [8]. The contribution of dermoscope is mainly for the evaluation of both pigmented and nonpigmented lesions, presence of scarring, and loss of architecture but required training to identified benign structures and suspicious, worrisome features. It is crucial to document the number, type, size, border characteristics, and depth of lesions, discharge if present, tenderness, and presence or absence of local lymphadenopathy, which could influence mode of treatment [9, 10]. Cultures should be taken if there is suspicion for an infection, and final genital biopsies were recommended without to be prerequisite for the completion of the definitive diagnosis. It is an all common finding for a clinician to be frustrated by pathology report because it is sometimes difficult for the gynecologist due to inherent challenges to approach the obtaining tissue from the genitalia.
In 1976, Freidich classified skin disorders of the vulva into three categories: (a) hyperplastic dystrophy, (b) lichen sclerosus, and (c) dystrophy with or without atypia. For example, the term of hyperplastic dystrophy was used to include completely different clinical features, such as psoriasis, chronic lichen planus, and Bowen’s disease [11].
Due to diagnostic problems resulting from this classification, in 1989, the International Society for the Study of Vulvar Diseases established a new terminology, which has been maintained to date [12]. Nonneoplastic epithelial lesions were delineated as follows: (a) lichen sclerosus and atrophicus, (b) squamous cell hyperplasia (former hyperplastic dystrophy without atypia), and (c) other diseases of vulva, a category in which various injuries occur, such as psoriasis, lichen planus, fungal infections, and condyloma acuminata. Since cytological atypia is found in this category, the damage is “changing” category and now belongs to the VIN classification [12].
“Dystrophy” of the vulva is an abnormality of the vulva epithelium. Epithelial growth may be hypoplastic, hyperplastic, or abnormal in some other way [13, 14].
Atrophic and hypertrophic disorders of the vulva come under the general term of dystrophies (formerly characterized as “precancerous” conditions). The skin, depending on the damage, may be appeared as white, dry, and thin or thickened, while hyperkeratosis and decreased vasculature are histologically present [15]. These alterations are mainly attributed to estrogen deficiency and, to this end, are often observed after menopause. The disorders may extend to the vaginal entrance, the perineum, etc. Usually there is intense pruritus, and the scratching it entails may result in an interception to the continuity of the skin. In addition to pruritus, there may be a burning sensation and dyspareunia, especially if the damage (usually atrophy) extends to the vaginal entrance [15]. For the treatment of pruritus, anti-inflammatory creams and topical corticosteroids are used (about two times a day). Antibiotic treatment is also administered in a transfection. In the absence of symptomatic treatment with conservative treatment and very intense annoyances of the patient, a simple vulvectomy can be chosen as “final” solution provided that the patient has been informed about the fact that in the half of the cases, the disease can relapse despite the surgical procedure [15].
Because of the fact that these disorders may coexist with malignancy, careful monitoring of the patient is required, and in doubt, multiple biopsies are required to exclude intraepithelial neoplasia (vulvar intraepithelial neoplasia/VIN) or cancer. Biopsies are often subjected to vulvovaginal screening after a 1–2% acetic acid solution is applied. However, the likelihood of developing invasive cancer in the soil of previous lesions is low. Given that these situations are well known, their descriptive “encyclopedic” terminology (in brackets, in italics) is not mentioned in the narrower “gynecological” or histological sense [16, 17, 18, 19, 20, 21].
These alterations include:
Lichen sclerosus
Scuamous cell hyperplasia
Condyloma acuminata
Psoriasis
Lichen planus
Mixed lichen sclerosus and atrophicus
The term dystrophic lesions of the vulva according to literature like writhing, leukoplakia, lichen sclerosus and atrophicus, it is preferable to not be used anymore [16, 20, 21].
“Lichen sclerosus” (LS) is a term used for a benign, chronic, progressive dermatological condition characterized by (intense) inflammation [22, 23, 24, 25]. The epithelium is getting thinner, and some characteristic dermatological changes appeared accompanied by itching and pain.
In general, lichen sclerosus appears in the skin of the genitalia. It was first described by Hallopeau and Darier at the end of the nineteenth century as a variety of lichen planus, which is not acceptable today. The term lichen sclerosus (and/or atrophicus) should no longer be used, as forms of lichen sclerosus are not all atrophic. When there is coexistence of squamous cell hyperplasia, it is characterized as “mixed squamous cell hyperplasia and lichen sclerosus” [26, 27, 28, 29, 30, 31, 32].
Lichen sclerosus is considered as the most common chronic lesion in vulva, referred to a chronic atrophy that usually observed after menopause. Clinically, vulva is glossy and dry, with no folds. The lesions are often symmetrical. Although the condition is observed over a wide range of ages, it has an increased incidence in women aged 50–59 years. Postmenopausal women and young girls are usually afflicted before menstruation. There is no clear justification. There is sufficient evidence of involvement of autoimmune mechanisms in the pathogenesis of lichen sclerosus. It is known that 21% of patients with lichen sclerosus also suffer from autoimmune disease more often than with thyroid disease. It is reported that 22% of patients with lichen sclerosus have an inherited history, and that 44% have one or more autoantibodies. Also, there is a correlation with HLA II antigens. There are studies associating inflammatory factors, e.g., Borrelia infection, with the development of lichen sclerosus. It is also reported that there is overexpression of wild-type P53 protein in lichen sclerosus, which occupies areas adjacent to squamous cell carcinoma (SCC) in which HPV is not detected.
Typically, the rash of lichen sclerosus begins as white polygonal papules, which flock to plaques. Typically, candlesticks and/or clearly cracked plugs appear on the surface of the plate, and they are similar to attached nozzles. Over time, plugs and craters may disappear by dropping a smooth, often porcelain plaque, and they rarely show up. Thus, the skin appears white and thin, although it may be present in SCH [26, 27, 28, 29, 30, 31, 32]. Originally, lichen sclerosus may have a bubbling consistency and is characterized by edema of the prepuce clitoris and telangiectasia of labia and purpura. Stretch marks appear mainly in the middle perineal line. Bullous lichen sclerosus is often accompanied by bleeding within the lesion, and the fillet can disappear. Later, labia minora and structures around clitoris disappeared too. The epithelium of the vagina and the cervix is not affected. However, there may be lesions in the forehead of the skin, which will lead to its constriction. Perianal lesions are described in 30% of cases [26, 27, 28, 29, 30, 31, 32].
Lichen sclerosus is a benign vulva condition associated to chronic and often progressive character with dermatologic location. Among the clinical findings are included marked inflammation, epithelial thinning, distinct dermal alterations like pruritus, and pain by varying degrees. The described lesions appear most frequently in the labia minora, but the early disease course affects not the vulvar architecture. During the disease progresses, the following pathological signs may be possible to occur: sexual dysfunction, fissuring in perineal region and around the clitoris, distinction between labia majora and minora, edema from inflammation, purpural lesions, and excoriations ecchymoses given fragility of the affected skin region [5, 33]. The main symptom is pruritus. Pain occurs if there are corrosions and stretch marks. Itching is intense during the night and may be so intense that it stops sleeping. Discomfort occurs when there is erosion, stretch marks, or narrowing of vaginal orifice [26, 27, 28, 29, 30, 31, 32]. Some women are asymptomatic, and LS is a random finding. Most of them had active childhood disease, which resulted in skin atrophy without symptomatology. Occasionally, hyperkeratosis and ecchymosis occur, which should be treated [26, 27, 28, 29, 30, 31, 32]. In childhood, the lesions are similar to adult lesions. But the ecchymosis may protrude and can be so intense that it leads us wrongly to the suspicion of sexual abuse. The diagnosis in most patients is indicated by the clinical picture, but its confirmation by histopathological examination is considered necessary. LS should be differentiated from lichen planus, vaginal pemphigoid, psoriasis, VIN, and SCC, and this is done by biopsy under colposcopic control. Ulcers, nodules, and granulomas should be controlled to exclude malignancy. The formation of hyperkeratotic plaques and erosions, which do not exist despite the applied treatment, suspects malignant transformation [26, 27, 28, 29, 30, 31, 32, 34].
Histologically, there is a decrease in subcutaneous fat, atrophy of all skin layers, and destruction of elastic tissue. The dermis is of some degree vitreous degeneration and round cell collections [35, 36, 37]. Typical histological findings are also including a thinned epidermis with areas hyperkeratosis, acanthosis, a broad band of homogenized collagen under the dermo-epidermal ligament, and lymphocyte infiltration under the homogenate area [33, 38, 39].
Few patients have thickening of the epidermis, and these are those who have not been responding to LS and who are at increased risk of developing SCC. Due to the frequent association of LS with autoimmune diseases, the appropriate control should be performed. In particular, the possibility of autoimmune thyroid disease should be investigated [26, 27, 28, 29, 30, 31, 32, 34].
Squamous cell carcinoma (SCC) in women with LS is a common malignancy described. There are also reports of basal cell carcinoma and melanoma. The risk of developing SCC is about 5%. However, histopathologic examination in woman with lichen sclerosus during follow-up revealed squamous cell carcinoma. The role of HPV as a causative agent in malignant transformation is not entirely clear. There are studies suggesting the existence of two types of SCC: one type occurs in older patients with chronic LS disease and the other type is in younger women without LS but with proven infection by oncogenic HPV types. Although there is no evidence of the role of HPV as a causative agent in the development of SCC on LS, there is the theoretical risk of developing SCC from the topical use of corticosteroids, which may promote the development of HPV oncogenic strains, since it was found that in 20% of cases LS, there may be HPV infection [40, 41, 42, 43]. More recent reports support the strong relationship of vulvar invasive squamous cell carcinoma and LS, so that lichen sclerosus is considered as precancerous damage [33]. It is not uncommon for women with carcinoma of vulva from squamous cells to also have undiagnosed lichen sclerosis, which may also be asymptomatic [33, 38].
The role of midwives, especially those who have increased initiatives due to their position (e.g., the one who works in the Center of Health), is very important to properly direct these postmenopausal women. It is well known that empirical use of ointments in precancerous or cancerous lesions of the vulva delays proper treatment and requires a high degree of suspicion of the doctor and midwife for malignant malignancy [33, 38].
There is no universally accepted treatment for women with lichen sclerosus. The treatment includes education and support, change of behavior to ensure good pudding hygiene, medication, and, in a small proportion of cases, surgery or photochemotherapy. The medical treatment of the condition includes the topical use of corticosteroids, such as clobetasol [44, 45, 46, 47]. The major importance of LS treatment is proved by the fact that about 80% of invasive squamous cell carcinoma (SCC) of the vulva in elderly patients was associated with untreated, long-term conditions of lichen sclerosus (the final stage of the vicious cycle of itching-scratching-itching). Generally, the management should perform in twofold.
The first step aims to resolve LS symptoms, vulvar, and vaginal pain.
The second step’s goal is to reduce the disease signs like hyperkeratosis fissuring echymoses [44, 45, 46, 47].
The oldest term leukoplakia (“chronic inflammatory disease of the mucosa which results in keratinization of the epithelium and in the formation of white spots”) is still reported today. The disorder is characterized by white, tough, and overwhelmed, hyperkeratotic “plaques” of the vulvar epidermis, and a disorder of “hormonal homeostasis” in its etiology. Histologically, squamous cell hyperplasia is observed (Figures 1 and 2).
VIN lesions are usually characterized by a change in color on the skin of the vulva. They are usually white and/or gray.
VIN lesions: The rarities are lesions in red and brown. Their surface may be flat or abnormal.
This chronic and recurrent condition may occur at any age but is more common in older patients and usually manifests with pruritus. Less often, it occurs with dyspareunia or pain. It is an autoimmune condition and is associated with other autoimmune diseases such as malignant anemia, thyroid disease, diabetes mellitus, systemic lupus erythematosus, primary biliary cirrhosis, and bullous pemphigoid. Histologically, the skin appears thin with loss of the crevices found between the nipples. Surface skin is vitrified, and a set of chronic inflammatory cells is observed beneath it [48, 49, 50, 51, 52, 53].
Clinically, the skin appears white, thin, and corrugated but may be overlapped and keratinized, if there is coexistence of squamous cell hyperplasia. There may also be symphysis of the clitoris or the vulva. The diagnosis is made by biopsy. Lichen sclerosus is a nonneoplastic condition but can coexist with vulvar intraepithelial neoplasia, while there is correlation with invasive squamous cell carcinoma of the vulva in 2–5% of cases. This is describing the reason why possible long-term monitoring is required every 6–12 months [26, 27, 28, 29, 30, 31, 32].
Treatment is required, especially if the condition is symptomatic, and a strong local topical steroid cream (e.g., Dermovate per 12-hour period) is usually used, which is gradually replaced by a milder formulation (e.g., hydrocortisone per hour, 24 h or less) as the symptoms require. Fluorinated corticosteroids or testosterone ointment may also be helpful. Vulvectomy has no position in this case, as the recurrence rate after surgery is about 50% [26, 27, 28, 29, 30, 31, 32].
Psoriasis is manifested as dry, red, and papular rash, which is usually clearly circumscribed and extends to the thighs. Diagnosis occurs easily when bleeding is observed during the removal of classic silver-like scars. It may be difficult to differentiate psoriasis from candida infection or dermatitis because the vulva is very often fluid. Candida infection should be ruled out. The lesions can be treated locally with coal tar preparations, ultraviolet maize, steroid creams, or other suitable drugs [54, 55, 56].
It is a chronic papular rash with a bluish hue, which is located in the vulva and the bendable surfaces. It may be appeared in other areas like the mucous membrane of the oral cavity, and the diagnosis is enhanced by finding other lesions. Oral lesions precede genital lesions in one-third and simultaneously appear in half of women affected from the disease. After the vulva should be a vaginal examination, the walls of the vaginal may have following pathological abnormalities: erythema erosions and bleeding friable tissue. It is usually idiopathic but can also be related to medications. The treatment includes use of strong steroids locally or ultraviolet light, and the disease tends to subside within the next 2 years. Surgery removal should be avoided [57, 58, 59, 60, 61, 62].
The lesions of this disease can appear anywhere on the body with a predilection in the genital area. It can be confused with LS, associated to lack the classical signs of inflammation, possible coexistence with LS based on autoimmunogenity. In contrast to LS, which has predilection for hypoostrogenic states, vitiligo can be appeared at any age. No skin biopsies are necessary. Autoimmune thyroid disease is associated to vitiligo. Treatment includes administration of topical steroids and vitamins D, E, C, and B12. Surgery remains a viable option in unresponsive localized disease to conventional therapies [63, 64, 65, 66, 67, 68, 69, 70, 71].
They are vulva disorder associated to pain. Shallow ulcers most commonly occur on the oral mucosa and less commonly on the genital mucosa. The reasons are uncertain, and risk factors include stress, infections, hormonal factors, vitamin deficiency, and family history. The diagnosis result from exclusion of various genital ulcers causing in most cases in assumption of sexually transmitted infection. Aphthosis appears in simple and rare complex form, and the recurrence rate is about 20% of the general population. For the treatment, it is important to educate the patients to conform in skin and wound care and administration of topical corticosteroid propionate ointment in cases of complex aphthosis [63, 64, 65, 66, 67, 68, 69, 70, 71]. Apthae should differentiate from Behcet syndrome, a disorder that causes inflammation of the blood vessels throughout the body, and could affect the vuvla causing open sores in the vulva. Furthermore, vulva aphthous ulcers could appear in patients with HIV infection, Chrohn disease, and ulcerative colitis.
Intertrigo is a wet inflammatory dermatitis, which can occur on any fold of the body because of the irritation of the exposed skin surfaces from friction between them. This is more likely to occur in women who are overweight but also in those who wear tight clothing.
The skin is painful, often red and flaky, showing wetness and stretch marks. Weight loss, local hygiene, and local exposure to air, such as the use of socks and cotton lingerie instead of synthetic underwear, should be envisioned. Powders (e.g., talc), astringents (e.g., zinc), or blocking agents in the area may also help.
Candida usually complicates intertrigo and should be treated as described according to clinical practice guidelines for the management of candidiasis [56, 57]. In order to relief the inflammation, since there is no candida infection, steroid creams may be used.
The skin of the vulva, and especially the opening of vagina, is often affected by dermatitis. Dermatitis can be irritating (nonimmune) or actually allergic (immune-induced). Chemicals that cause skin hypersensitivity include, but are not limited to, cosmetics, perfumes, contraceptive lubricants, sprays, and vaginal washings. Detergents, dyes, softeners, bleaches, soaps, and bleach used to clean the underwear can also cause irritation. In severe cases, hypersensitivity may occur in topical application of anesthetic creams, as well as steroid preparations.
Women with contact dermatitis have an overgrowth inflamed vulva with eczema characters, and patch tests can reveal local irritants. Temporary relief can be achieved with lubricants of the vulva (e.g., Emulsiderm in a daily bath), softeners (e.g., local water creams), and topical corticosteroids (e.g., monthly treatment with Dermovate topical application). As before, nonresponsive lesions need biopsy to confirm the diagnosis [72, 73, 74, 75].
The term pruritus describes an intense feeling of itching. It is more common in women over the age of 40 years, and symptoms are getting worse by stress or depression. There are many causes of itching.
Biopsy may be necessary for diagnosis, as well as patch tests may be also helpful. If no cause is found, it may be worth considering the possibility of previous sexual abuse or psychosocial problems.
It is important to stop the vicious cycle of irritation/itching cycle that is using strong local steroids for a short time in order to reduce the local inflammation induced by scratching. Applying strong steroid ointment daily for 3 weeks followed by 1% hydrocortisone cream once a day is useful, as well as soap substitutes (e.g., Oilatum).
Irritants, cosmetics added to bath, and synthetic pantyhose, as well as soap substitutes, should be avoided, and comfortable cotton underwear should be used. The area should be gently dry (e.g., with a hairdryer). Antihistamines can also help. If depression coexists, it may require treatment [76, 77, 78, 79, 80, 81, 82, 83, 84].Reasons of vaginal pruritus
The term VIN was proposed to include dysplastic lesions and vulvar squamous in situ cancer and replace terms such as: (a) Bowen’s disease; (b) Bowen’s papilloma; and (c) dystrophy with atypia.
Depending on the degree of maturation of the neoplastic epithelium and the extent of atypia, three VIN classes, from I to III, are defined just like in CIN.
VIΝ I: mild dysplasia
VIΝ II: moderate dysplasia
VIN III: Toy Bowen’s disease, severe dysplasia
Squamous cell carcinoma in situ, erythroplasia of Queyrat
The lesion is characterized as VIN I when the cellular abnormalities, in comparison with absence of layout, are limited to the lower one-third of the vulvar squamous epithelium, VIN II when the abnormalities extend to the middle third of the epithelium, VIN III when they extend to the upper third of the epithelium, and CIS when lesions occupy all the epithelial layers. Approximately 40% of women present without accompanied symptoms and in the rest cases a background of inflammatory skin disease in the majority being lichen sclerosus exist.
The disease is not characterized as invasive carcinoma as long as the basal lamina remains intact [72, 73, 74, 75].
Common point: VIN is part of a total of epithelial changes in the woman\'s inferior genital system and may coexist (at least 15–20%). In particular, if there are acuminate warts in the vulva, the rate for CIN lesions is almost 50%.
Early onset of sexual activity
Switching (multiple) sexual partners
Immune system weakness
Cross-reaction or coexistence of high-risk HPV subtypes
Smoking, alcohol, and unbalanced diet
HPV infection
HSV-2 infection
Chronic irritation of the vulva
Warts
In most VIN cases, instead of CIN, the damage is high risk. It is also uncommon to diagnose just VIN I lesion.
VIN:
increased incidence in last two decades
average age of development 30 years
risk of progression to invasive cancer increased in women of the fifth decade (20%)
the recession is twice as likely as invasion.
VIN instead of CIN is not appeared during colposcopy with abnormal vasculation and mosaicism, but in the form of subtracted white or red plaques with clear borders.
Due to keratinization of the surface layer, in case of VIN, the cytological evaluation is more difficult.
VIΝ: itching, burning sensation, pain, single, or multifocal lesions (40%)
CIN: there are usually no symptoms or findings, single, or multifocal lesions
VIN: lesions often situated in the inner lips of vagina and the perineum
CIN: lesions frequently cited in the transformation zone
Treatment of choice is the topical administration of clobetazole, which blocks mitosis and induces synthesis of proteins reducing inflammatory response. It is also believed that it affects Ki67 as well as promotes p53 expression.
For those cases that diagnosed for the first time, it is recommended to apply once daily for 4 weeks, then every second day for 4 more weeks and during the third month of treatment, twice a week (once a day is based on pharmacokinetic studies). If symptoms reappear, the minimal clobetazole dose in which disease was controlled is administered.
A 30 g tube should be used for 12 weeks, and then, the original is reconsidered. If treatment is effective, hyperkeratosis, bruising, erosions, and stretch marks will disappear, but atrophy and color change still remain.
Clobetazole is continued as needed. Most patients usually need 30–60 g per year. If therapy is complete, no further treatment is needed, but other patients will have relapses and should continue to receive treatment [72, 73, 74, 75].
An alternative option is triamcinolone ointments.
Nowadays, estrogens or testosterone creams have no place in the LS treatment. Also recent studies have shown that testosterone is less effective than clobetazole and has same effectiveness with petrolatum, the excipient used to make testosterone ointment.
It is referred to be extremely effective. It is prepared by mixing 400 mg progesterone oil with 4 oz Aqua-for. It is prescribed twice a day.
They are mainly used in the complicated LS on failure of corticoid treatment. It is considered that they reduce the degradation of the connective tissue.
Acitrecine (Nco-Tigason*) 25 or 50 mg/24 h per os in a single dose until symptom remission and continue 25–50 mg/24 hours go per os. The treatment stops when the lesions fall back.
Isotretinoin (Roaccutan*, Accurane*) synthetic 13 is isomer of tretinoin. It reduces sebaceous gland size and sebum production and inhibits abnormal keratinization. The dose is 0.5–1 mg/kg/24 hours, and the duration of treatment is 4–6 months.
Topical administration of retinoids is not recommended due to the local irritation they cause.
Close attention should be paid to per os administration of retinoids to adolescents due to the teratogenicity they cause and is recommended avoidance of pregnancy for 2 months (isotretinoin) and 3 years (acitretin) at the end of the treatment [72, 73, 74, 75].
Positive results from the administration of potassium para-aminobenzoate, as well as psoralen with UVA therapy, stanozolol, antimalarials, antihistamines (e.g. oxatomide), and various antibiotics (possible cause or infection by Borrelia), were also observed.
In uncomplicated forms of LS, there is no evidence of removal of vulvar tissue. Surgical treatment should be applied exclusively in case of malignant transformation and recurrent forms.
When there is a narrowing of the opening of vagina, perineoplasty is performed, which improves dyspareunia in 90% of cases and improves the quality of sexual life in 86% of cases.
Simple vulvectomy should not be preferred because the symptoms do not always disappear, the signs reappear, and the likelihood of malignant transformation persists. Also, the operation creates many psychosocial problems.
Positive results are reported with LASER ablation treatment, which is applied with LASER CO, 1–2 mm deep with complete healing 6 weeks after surgery and low relapse rates. It is considered a method of nonresponse to other forms of treatment.
Photodynamic therapy (topical application of the 5-aminolevulinic acid photosensitizer and exposure to argon laser light for 1–2 alphas in 1–3 sessions) is also used with very good results.
Patients with LS have thin skin, which is not considered a “satisfactory” barrier to the loss of moisture, and it would be a failure not to mention some general measures.
Excessive drying after bathing should be avoided.
Gentle moisturizing products such as, e.g., Vaseline should be used to improve the moisture of the affected skin.
Good hygiene, avoidance of irritants and allergens, use of cotton lingerie, and avoidance of tight and hot clothes.
A lesion that resides in the vulva or in the vaginal opening and continues after the skin lesion is absent is secondary to a sensory disorder. This pain does not correspond to topical administration of corticosteroids. A 5% xylocaine ointment is therapeutically administered; on failure, administration of amitriptyline is recommended [72, 73, 74, 75].
On unsuccessful treatment with corticosteroids, the following should be checked: patient compliance, misdiagnosis or coexistence of other disease entities, contact dermatitis, secondary candidiasis, VIN, SCC, psoriasis, or pemphigoid vulgaris.
If the symptoms persist after the medical repair of the damage, it is a secondary sensory disorder.
The risk of malignant transformation of LS is very small. Even if malignant transformation occurs, the progression of the disease is slow. However, patients should be screened at the end of the first trimester of treatment after 6 months and then yearly.
One-month follow-up requires patients with a poor response to corticosteroid therapy, and they are usually those in whom squamous cell hyperplasia coexists and are therefore susceptible to malignant transformation.
Vulva pathology is varied. Between all the described lesions, precancer conditions should be recognized early in order to stop the evolution. Strong dermocorticoids are the major local treatment on many vulvae chronic diseases. In specific conditions, local immune modulators or laser are necessary.
Many thanks to midwives (Mrs. Maria Strofali and Mrs. Stavroula Falaga) of family planning center, Democritus University of Thrace, Greece for their clinical support and examination of women, who visited our family planning examination center.
Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with an aggressive clinical course and short median survival [1]. While being a rarity in the western world, GBC is one of the major causes of cancer-related morbidity and mortality in South Asian and Southeast Asian countries [2]. Females are more commonly affected than males. According to the cancer statistics of 2020, GBC accounts for 0.6% of the total cancer cases and is associated with 0.9% of total cancer-related deaths [3]. Around 10% of the global GBC burden is contributed by India, with the Northern, Central, and North-eastern parts as the highest contributors [4]. Only 10% of cases present at an early stage which can be owed to the aggressive tumor biology of this cancer and the lack of effective screening techniques for its early detection [5]. Chronic inflammation of the gallbladder remains a major factor in the pathogenesis of GBC, although the causes are multifactorial. Gall stones, heavy metals, environmental toxins, and carcinogens have all been implicated in chronic irritation of the gallbladder mucosa, thereby leading to dysplasia and subsequent development of neoplasia.
The landscape of the microbiome populating our digestive tract has received a lot of scientific attention in recent years [5]. There is ample evidence linking the human microbiome and its metabolites to carcinogenesis. It is proven that balanced flora or microbial eubiosis is related to health while dysbiosis or unbalanced flora can lead to various diseases, including cancers [6, 7]. There can be multiple triggers causing dysbiosis, including fluctuations in the environment, inflammation, infection, medications, dietary changes, or genetic predisposition. The International Agency for Research on Cancer labeled ten microbial species as carcinogens [8]. Around 15–20% of cancers are linked to microbial pathogens, with
Detection of some bacteria does not indicate its causality in inflammation or cancer. However, recent amassing evidence indicates that microbiota dysbiosis and chronic inflammation contribute to carcinogenesis [16]. Several reports point towards strains of Salmonella and Helicobacter colonizing the gall bladder and are linked to an escalated risk of developing GBC [17, 18]. Premalignant lesions were found to be coexisting with chronic Salmonella infestation, despite the absence of gallstones [19]. Various experimental studies and epidemiologic data support the induction of carcinogenesis due to dysbiosis of the gallbladder microbiome. However, results indicating only cultivable species limit these claims. Also, despite the proximity of a large diverse microflora reservoir in the gut, little is known about its impact on the human bile microbiome. In this chapter, we aim to provide a comprehensive review of all the available literature on the gut and biliary microbiome and their association with GBC.
The term microbiome has been derived from two words, “micro” and “biome”, meaning, a specific microbial community with distinct physiological and chemical properties, residing in a well-defined habitat which is their “theatre of activity”. This definition was proposed by Whipps while working on mycoparasites [20]. The term “gut microbiome” or “human microbiome” was coined by Joshua Lederberg in 2001 and since then it has been a topic for debate among researchers [21]. The human microbiome can be defined as a specific community of commensal, symbiotic and pathogenic micro-organisms that reside within our body spaces [22]. These include gut bacteria, eukaryotes, archaea, and specific viruses [23, 24]. In a healthy individual, these bacteria are responsible for various synthetic and metabolic functions and detoxification of various xenobiotics [25]. They form an integral part of the “gut-brain axis” which is bidirectional communication between the gut and the cognitive and emotional centers of the brain. This link is responsible for satiety and appetite regulation, elevation of mood, cognitive development, and neuroprotection [26]. Studies have also found a link between the gut microbiome and immune homeostasis. The complex and bidirectional interaction between the gut microbiota and the host immune system is responsible for the development of both innate and adaptive immunity, thus preventing the body from pathogenic organisms [27, 28]. Moreover, the microbiota is also responsible for the maintenance of gut mucosal integrity and prevents the overgrowth of pathogenic organisms, thus maintaining the first line of defense against the pathogens [29]. Therefore, any imbalance in the gut microbiota may lead to the development of various autoimmune diseases. This concept of “dysbiosis” or “imbalance” in the gut microbiota may result in relative “blooms” of harmful bacteria, especially Enterobacteriaceae [30, 31]. Dysbiosis can be caused by a variety of factors, namely, dietary changes, inflammatory conditions, exposure to drugs, and toxins [32, 33] (Figure 1). The gut bacteria have been linked to a wide variety of cardiovascular diseases [34, 35], obesity [36, 37], inflammatory bowel disease [38], irritable bowel syndrome [39], and some neuropsychiatric diseases like depression [40]. But what has intrigued the researchers is the role of gut microbiota in the development of cancer.
Importance of gut bacterial microflora. The figure illustrates the role of enteric bacteria in the maintenance of homeostasis. The “eubiotic” bacteria display a complex interaction with the various synthetic and metabolic functions of our body as well as in the “gut-brain crosstalk”. Alteration or “dysbiosis” due to any factor (diet, chemicals, antibiotics, inflammatory conditions) may lead to “blooms” of harmful bacteria. The dysbiotic bacteria have now been linked to various cardiovascular, metabolic, neuropsychiatric diseases, including cancer.
To ascertain the role of gut microbiota in the development of cancer, we need to look at the mechanisms responsible for carcinogenesis. The normal cells get altered into cancerous cells, by changes at the cellular, genetic or epigenetic levels. This process is known as “cell transformation” [41]. TP53 is a tumor suppressor gene that encodes the protein P53. P53 acts as a tumor suppressor which causes a transient cell cycle arrest, allowing the cells to repair the damage caused to the DNA before the cell divides. The cells that are unable to repair the damage undergo apoptosis. This ensures that the potentially oncogenic mutations are not propagated [42]. Chronic inflammation causes alteration in the TP53 gene, leading to its inactivation. This results in an unregulated cell cycle and cell division, leading to the accumulation of mutations and uncontrolled cellular proliferation. TP53 alterations were seen in biliary epithelia of patients with gallstone disease with an increased frequency with the disease progression from metaplasia to carcinoma [43]. TP53 was the most commonly mutated gene, followed by PIK3CA, SMAD4, ARID1A, KRAS [44, 45, 46] and amplification of ERBB2 [47].
The study of these genetic alterations and mechanisms of carcinogenesis has been made possible with the development of various ex vivo and in vivo animal models. These models have been used extensively to decipher the etiopathogenesis of GBC and to develop and test the treatment protocols [48]. Ex vivo models use cell lines to study the tumor characteristics and cellular and genetic abnormalities. But it was seen that different cell lines yielded different tumor characteristics for the same type of tumor, thus complicating the interpretation [49]. In vivo models were superior to the cell lines as they used genetically engineered animals that could retain the genetic mutations and could undergo cellular differentiation. The tumor cells with mutated or amplified genes were inoculated in them and studied for the development of cancer [49, 50, 51]. The drawback of these models was the lack of innate immunity which led to altered results as the cancer was not strictly recapitulated [51].
Although these models indicate a causal relationship between the risk factors and carcinogenesis, the human body reacts quite differently as compared to an animal model, thus necessitating the need for the development of an ideal human model.
There has been an ongoing debate among researchers on the role of gut microbiota in the causation of cancer as cancer is neither a contagious nor an infectious disease [16]. The first proposition of the possible role of gut microbiota in cancer causation was given by Russel in 1890, which was supported by positive results over the subsequent years [52, 53, 54]. However, in 1963, a group of scientists from NCI, USA claimed that the bacteria found in the cancer tissues were probably contaminants [16]. This subject remained controversial until Marshall, in his study, proved the association between
Microbiota may act as a carcinogen in two ways, either by inducing a chronic inflammatory state or direct injury by material toxins and metabolites [16, 60, 61, 62]. Release of pro-inflammatory mediators like TNF-α and IL-1 and generation of reactive oxygen species (ROS) stimulates lymphoepithelial proliferation and cell division. This leads to immune dysregulation, thereby leading to tumorigenesis [27]. It causes alteration in the cell cycle leading to immunosuppression [63]. It also results in genetic and cellular damage and genomic instability which preclude carcinogenesis [64]. The bacterial toxins are genotoxins that cause DNA damage and may lead to the development of cancer [65, 66]. Thus, chronic bacterial infections demonstrate a dual role in carcinogenesis by both stimulating and inhibiting the immune system.
According to traditional thinking, the biliary tract has always been considered sterile. This is because of the anti-microbial properties possessed by bile which affects the bacterial membrane and DNA [67]. However, inflammatory conditions of the biliary tract, like acute cholecystitis and cholangitis have frequently cultured bacterial colonies commonly found in the human gut; the common organisms being,
Dysbiosis of the gut bacteria has been implicated in the development and progression of various cancers, including gastric [73, 74], colorectal [75], and oral cancers [76, 77], however, their association with causation or progression of the hepatobiliary cancers is still in question. The natural synergy that exists between the bile acid metabolism and the biliary microbiome reaffirms the proposition that biliary microbial dysbiosis may lead to various biliary tract diseases including gallstone formation and the development of cancer.
Cholangiocytes are considered the potential cells of origin for biliary tract cancers, including gallbladder cancer [78]. Any insult to the cholangiocytes leads to the release of pro-inflammatory mediators like IL-6 and IL-1β which results in the differentiation of T helper cells (Th-17 cells). The cholangiocytes interact with Th-17 cells leading to their activation and proliferation, in order to compensate for the cell loss [79]. Moreover, the bacteria and their products are recognized by the cholangiocytes through the Pathogen Associated Molecular Patterns (PAMPs) present in the bile, which interacts with the pattern recognition receptors, that are, the Toll-like receptors (TLRs) and the NOD-like receptors (NLRs), leading to their activation [80]. This results in collagen deposition and fibrosis. The resultant cholangiopathy may lead to ductopenia, dysplasia, and malignant transformation [81]. Chronic inflammation leads to the release of mediators like IL-17, TNF-α, and TGF-β which cause genetic alterations in the tumor suppressor genes and the proto-oncogenes resulting in cell transformation [82]. These mediators are among the few which have been implicated in the causation of carcinogenesis [83, 84, 85].
Gallbladder cancer is the most common biliary tract cancer and the etiopathogenesis is multifactorial [86]. However, chronic inflammation [87] and gallstone disease represent the most important aetiologies in the development of GBC and are supported by Level II evidence [88]. The recent development of culture and culture-independent techniques have identified various organisms which are associated with the formation of both pigmented as well as cholesterol gallstones [89, 90]. These dysbiotic organisms are mainly enteric bacteria that have the ability to form a biofilm, thereby resisting cellular and DNA damage caused by bile. They are namely,
Although various bacteria have now been identified and linked with the development of gallstones and their theoretical association with GBC,
The
Since the first evidence of
There have been several meta-analyses suggesting an association between Helicobacter infection and cancer of the biliary tract with conflicting results [121, 122]. However, a recent meta-analysis has suggested a significant association between
Typhoid fever and GBC are endemic in the Gangetic belt and the northern states of India which provides strong evidence to suggest an association between
Gene fragments of
Study/year | Sample | Bacterial strain | Isolation technique | Inference |
---|---|---|---|---|
Welton et al. [125] | Deceased typhoid carriers | S. typhi | Record registers | Chronic typhoid carriers are 6 times more likely to die of hepatobiliary cancer than controls (P < 0.001) |
Caygill et al. [124] | Chronic typhoid carriers | S. typhi | Record registers | 167-fold higher risk of GBC in chronic typhoid carriers Chronic, and not acute infection is a risk factor for GBC |
Csendes et al. [137] | Tissue, bile | E. coli, E. faecalis, Klebsiella Enterobacter | Culture | Both aerobic and anaerobic gram-negative bacteria were found and may have a role in GBC |
Shukla et al. [130] | Serum | S. typhi | IHA Vi antigen | Significantly high Vi positivity in patients with gallbladder carcinoma compared to controls Risk of developing GBC is 8.47 times more in culture-positive typhoid carriers than the noncarriers |
Dutta et al. [131] | Serum | S. typhi | ELISA Vi antigen | Chronic typhoid carrier state is a risk factor for GBC |
Dewhirst et al. [117] | Multiple sources: animal and human tissue, blood, stool, fetus | H. bilis, Flexisipira rappini, H. pullorum | PCR (16S rRNA) | Correlation of Helicobacter species with GBC and other biliary tract diseases Identified 5 strains of H. bilis, 2 strains of Flexisipira rappini, and one strain of H. pullorum |
Matsukura et al. [118] | Bile | H. bilis | PCR (16S rRNA) | H. bilis infection in bile was associated with gallbladder cancer in Japanese and Thai patients |
Fukuda et al. [112] | Bile, tissue | Helicobacter | PCR, Histology, IHC | Significantly high positivity of Helicobacter DNAs in 52.6% of patients with hepatobiliary cancer than that in the benign cases (P = 0.03) |
Lu et al. [134] | Tissue | Colibacillus B. fragilis, Klebsiella C. perfringens Clostridium | PCR 16S rRNA | Possible association of both aerobic and anaerobic bacteria with GBC |
Murata et al. [119] | Tissue | H. bilis | Nested PCR (16S rRNA) | 4 out of 14 cases with biliary tract cancer were positive for H. bilis which may indicate their role in GBC |
Kobayashi et al. [120] | Bile | H. pylori H. hepaticus H. bilis | PCR | Helicobacter DNA was detected in bile of 86% of malignant biliary diseases DNA fragments of Helicobacter species other than H. pylori, H. hepaticus, and H. bilis were commonly detectable |
Bohr et al. [115] | Tissue | Helicobacter spp. | Culture, IHC, PCR (16S rRNA) | Helicobacter species do not play a predominant role in the pathogenesis of GSD and GBC in the German population |
Shimoyama et al. [113] | Blood | H. hepaticus | ELISA | H. hepaticus-specific antigen was significantly higher in patients with biliary tract cancer (P < 0.05) |
Iyer et al. [132] | Tissue | 143 HPV S. typhi Ty2 S. typhi CT18 S. typhimurium-LT2 S. choleraesuis-SCB67 S. paratyphi-TCC S. paratyphi SPB7 | PCR analysis | Association of non-typhoidal Salmonella species with GBC along with typhoidal strains Chronic carrier state is a risk factor for GBC |
Tsuchiya et al. [114] | Blood | H. pylori | ELISA | No significant differences in antibody titers or H. pylori infection positivity rates between cases and controls |
Song et al. [135] | Tissue | Peptostreptococcus stomatis Enterococcus faecium | DNA extraction and metagenomic sequencing | Existence of an altered microbiota in GBC |
Studies show the association of the gut microbiome with gallbladder cancer.
There is a complex interplay between the human body and its microbiome. While a normal gut flora is essential for homeostasis, dysbiosis may lead to a multitude of diseases. Several mechanisms associated with carcinogenesis are now being utilized in its prevention. GBC has been associated with chronic inflammation and chronic typhoid carrier state; thus, many animal models have been developed to study the role of antibiotics in the eradication of Salmonella, thereby reducing the chances of development of GBC. But the results have been conflicting [128] and Cholecystectomy remains the only definitive treatment for eradication of the carrier state of Salmonella [128]. There was a rise in the number of prophylactic cholecystectomies owing to this but it also saw an increase in the number of colorectal malignancies due to gut bacterial dysbiosis, thereby emphasizing their role in the development of cancer [141].
The role of the gut microbiome in the maintenance of homeostasis encouraged the researchers to utilize their potential in the therapeutic management of the disease. Microbiome therapeutics consist of additive therapy, subtractive therapy, and modulatory therapy. Additive therapy with genetically engineered or natural probiotic agents has shown some benefit in colorectal cancer and is now being utilized in GBC. There is emerging evidence regarding the association of probiotics and dietary changes with a decreased incidence of gallstone disease, thereby reducing the chances of GBC, thus additive therapy with natural or genetically engineered probiotic organisms may prove beneficial. However, there is still a dearth of evidence in this aspect [142, 143]. Subtractive therapy is being utilized by genetically engineered
The gut microbiome forms an integral part of the human body and is often referred to as the “forgotten organ”. Its role in health and disease has been studied extensively over the past two decades but the possibility of its role in cancer causation has caught the eye of researchers. The association between the gut microbiome and cancer has provided new insight into understanding the pathophysiology of cancer and planning the management strategies. There is a strong correlation between gut microbial dysbiosis and the development of colorectal and gastric adenocarcinomas, however, their role in hepatobiliary cancers, especially GBC remains poorly understood. This can be owed to the short survival of GBC resulting in vast unexplored domains of this disease and the difficulty to isolate the bacteria involved via routine culture methods. Moreover, the lack of an ideal animal or a human model has greatly limited the research. The advent of the next-generation sequencing methods has seen emerging evidence linking various bacteria to the etiopathogenesis of GBC, but causality is far from proven. A higher level of evidence either in the form of larger meta-analyses or larger epidemiological studies is needed to establish a consensus.
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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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