Extramammary Paget’s disease is a slowly progressive malignant neoplasia affecting the area of the external female genitals. It is characterized by the appearance of limited, slightly convex edematous or dense areas of predominantly red color in the area of the labia majora, remaining unchanged for a long time or slowly growing and accompanied by itching. Lesions are detected during gynecological examination, the diagnosis is verified by the results of laboratory studies of the biopsy, probable concomitant tumors are detected using instrumental methods. The main method of treatment is surgical, radiation, chemo and hormone therapy can also be used.
C51 Malignant neoplasm of the vulva
Extramammary Paget’s disease (Paget’s extramamillary cancer, Paget’s extramamillary dermatosis) is a malignant tumor originating from the glandular epithelial cells of the female external genitalia. The disease was named after the English surgeon and pathologist James Paget, who first described a morphologically similar neoplasm of the breast in 1874. Neoplasia is most often represented by a preinvasive cancer that lasts for years and develops into an invasive carcinoma in 10-20% of cases. Patients have an increased risk of extragenital cancers. In the structure of malignant neoplasms of the vulva, the proportion of Paget’s dermatosis is 2%. The disease mainly affects postmenopausal women (the average age of patients is 65 years) and is extremely rarely registered under the age of 40.
The etiology of extramammary Paget’s disease has not yet been studied. It is assumed that the malignancy of the source cells of this type of carcinoma may be associated with mechanical injuries, chemical and thermal burns, local chronic inflammatory process (for example, as a result of infection with certain types of herpes and papillomaviruses) and scarring of the epithelium. The role of exposure to ionizing radiation (including radiation therapy), dishormonal conditions as a result of obesity, disorders of the ovaries, thyroid and pancreas is considered.
It was noted that the lesion of the vulva with Paget’s dermatosis can be combined with other types of cancer: in 20-25% of cases with colorectal tumors, in 10-17% – with urogenital and less often – with hepatocellular, hepatobiliary carcinomas, neoplasia of the ovaries, mammary glands. According to the assumptions of some researchers, Paget’s cancer is secondary to the listed neoplasms and is a paraneoplastic disease (arising under the influence of biologically active substances and immune antigens synthesized by the tumor and the body in response to the tumor) or develops as a result of pagetoid (intraepithelial) screening of malignized cells. Others consider this combination to be a synchronous primary-multiple tumor process.
The exact histogenetic nature of the tumor has not been established. Precursors of basal epithelial cells (which are the source of Paget’s secondary cancer) and, according to modern theory, Toker cells (responsible for the primary tumor) can transform into Paget’s malignant cells. Back in the late XIX-early XX centuries, cases of detection of “mammary glands” in miniature in the vulva area were described. At the end of the last century, a histological difference was established and at the same time the similarity of these structures with breast tissue, and they were called “mammary glands” (MPH). Studies have shown that MPG is present normally in persons of both sexes, in women – mostly in the fold between the labia majora and labia minora and in less concentration in the anus and perineum.
Subsequently, the ability of MPG to express receptors for progesterone and estrogens, carcinoembryonic antigen and cytokeratins was discovered, as well as the presence of Toker cells in the epithelium of their ducts, which are morphologically similar to Paget’s cancer cells and presumably are the source of Paget’s primary mammary dermatosis. Toker cells and their malignant analogues, accumulating around the MPJ duct in epithelial tissue, can spread along it for considerable distances. This causes the screening of Paget cells from non-spread carcinomas of adjacent structures, as well as the multicentricity of Paget’s tumor and, as a result, its tendency to relapse and the presence in some cases of extensive lesions in non-invasive cancer.
For Paget’s extramarital lesions, the classification generally accepted in oncogynecology according to the international TNM system has not been developed at the present stage. According to the degree of spread, there are preinvasive (without germination of the basement membrane), microinvasive (with a spread into the stroma to a depth of less than 1 mm) and invasive (with a spread of more than 1 mm) carcinoma. According to the modern concept of Paget’s cancer associated with the discovery and research of MPJ, it is proposed to distinguish three forms that require a differentiated therapeutic approach:
- Primary. Paget’s disease is not associated with intraepithelial elimination from neighboring structures and develops from Toker cells.
- Secondary with a source in anogenital MPJ. Paget’s dermatosis occurs as a result of screening out of epithelial carcinomas of the MPJ: ductal, lobular, tubulobular, mucinous, adenocystic, papillary.
- Secondary, arising from other structures. The sources of this form of Paget’s cancer include carcinomas of the appendages of the skin, bartholinium gland, cervix, urethra, rectum.
Sometimes skin manifestations may be preceded by a feeling of dryness, gradually increasing itching in the genital area, in other cases, discomfort (itching and burning) are joined at the stage of visible changes and become a permanent symptom, although occasionally the pathological process proceeds painlessly. Most often, the tumor occurs in the area of the labia majora in the form of an erythematous spot or plaque. The size of the lesion can range from one millimeter to several centimeters and remain unchanged for a long time or spread to neighboring structures for several months (or years), eventually capturing the entire area of the vulva, as well as the perineum, anus, and in some cases, the skin of the inner thighs and lower abdomen.
To the touch, the affected areas are superficial, thickened, have an unevenly dense structure, and may be accompanied by edema. Visually, the borders of the spot are clear, uneven. The palpable node under the altered epithelium indicates a combined adenocarcinoma. Red, hyperemic areas of the skin eventually become covered with a white coating (a specific sign of Paget’s vulvar dermatosis), puffiness increases, peeling, erosion and bloody crusts are observed in places due to scratching due to permanent itching. Damage to the crusts is accompanied by bloody-serous discharge.
Invasion of Paget vulvar cancer in 50% of patients is accompanied by metastasis to the inguinal and femoral lymph nodes, which leads to their ulceration and suppuration in case of infection. Further spread of metastases into the walls of large vessels, lungs, liver, as a rule, entails a fatal outcome. The local spread of the tumor can lead to partial overlap of the urethra and difficulty urinating, which adversely affects the condition of the bladder and kidneys. In addition, extensive tumors exclude the possibility of surgery, and radiotherapy in such cases carries an increased risk of post-radiation complications.
Due to the superficial location of neoplasia, its detection is not difficult. The difficulties are caused by the complexity of differential diagnosis due to the many visually similar nosological forms of vulvar pathology. A tumor lesion is detected during a gynecological examination, then the following types of research are prescribed:
- Laboratory verification. It is performed to determine the histotype and the nature of the neoplasm. Histological examination reveals the microscopic structure characteristic of Paget’s cancer and determines the degree of invasion. Immunohistochemical analysis confirms the diagnosis, allows you to assess the hormone sensitivity of tumor cells and determine their source (from which organ the secondary neoplasia originates).
- Instrumental research. They are carried out to identify combined carcinomas. Ultrasound of the bladder, urethroscopy, rectoromanoscopy help to detect neoplasia of the bladder, urethra and rectum. Ultrasound of the vulva, pelvis, abdominal cavity and mammary glands make it possible to suspect malignant tumors of these organs, and colposcopy – a tumor of the cervix.
Extramammary Paget’s disease is differentiated with Bowen’s disease, psoriasis, eczema, seborrheic dermatitis, fungal infection, primary syphilis, vulvar granuloma, squamous cell carcinoma, vulvar sarcoma, bartholinium gland cancer, melanoma and a number of other inflammatory and tumor diseases of the vulva. Oncogynecologist, dermatovenerologist, oncoproctologist, oncourologist, abdominal surgeon, if necessary, participate in the diagnosis.
Treatment of extramammary Paget’s disease is carried out by specialists in the field of oncology, in the case of invasive and secondary forms, radiologists and chemotherapists can be involved. The treatment program depends on the local prevalence of the process, the combination of Paget’s disease with other malignant neoplasms, the immunohistochemical characteristics of the tumor, the general condition of the patient. In relation to Paget ‘s disease of the vulva , it is applied:
- Surgical operation. It is the main method of treatment. In primary pre- and microinvasive forms, combinations with other types of treatment are usually not required. Depending on the prevalence of the tumor process, the operation can be performed in the volume of a wide excision or vulvectomy. The likelihood of recurrence is significantly reduced by the use of microscopically controlled removal (Mohs micrographic surgery).
- Radiotherapy. Radiation therapy can be used as a treatment according to a radical program (for example, with the prevalence of the process that does not allow radical surgery to be performed) or as an additional method – after and (or) before surgery. In combination with surgical intervention, it is prescribed in case of secondary or invasive Paget cancer, “positivity” of the resection edge.
- Cytostatic therapy. Chemotherapy is an additional method and can be prescribed before or after surgery, for invasive, extensive or secondary lesions. Pyrimidines and platinum derivatives are used.
- Hormone therapy. An additional method is used to prevent relapses. Hormone antagonists are prescribed in combination with surgical and radiation treatment with immunohistochemically proven hormonal sensitivity of tumor cells.
Prognosis and prevention
The prognosis for primary intraepithelial cancer is favorable (five-year survival is 100%), in the case of invasion and (or) combination with other adenocarcinomas, it deteriorates sharply and depends on the prevalence of the primary and primary multiple process. The fatal outcome, as a rule, is due to the generalization of the combined tumor. After surgical treatment, relapses occur in 9% of patients with a non-invasive form of Paget’s dermatosis for eight years and in 67% with an invasive form for one and a half years. After radiation treatment (when surgery is impossible for some reason), this figure averages up to 50% for four years.
Primary prevention includes the prevention of infections (including sexually transmitted infections), correction of endocrine and metabolic disorders. Secondary prevention is aimed at early detection of the tumor and its relapses, involves annual gynecological examinations of elderly and senile women and lifelong follow-up of patients treated for extramammary Paget’s disease.