Mammary hyperplasia is a common disease in breast surgery, accounting for more than 80% of the patients in breast specialist clinics and significantly affecting women’s health. Mastocytosis, also known as breast dysplasia, is mostly named cystic hyperplasia in foreign countries, while in Chinese women, among nearly 10,000 cases of mastocytosis, only 3% of them have cysts under the naked eye, only 20% have cysts under the microscope, and only 9% have cysts as the main manifestation of mastocytosis, therefore, some scholars suggest that the disease be officially named “mastocytosis The disease has been suggested to be officially named “mastocytosis”.
I. The pathogenesis of mastocytosis
The development and changes of the breast in normal women are regulated by sex hormones, and their glands and interstitium repeat the process of hyperplasia and rejuvenation with the sex hormone changes of the female cycle (menstrual cycle). During the follicular phase, estrogen action causes proliferation of terminal ductal and follicular epithelial cells in the mammary glands, increased DNA synthesis and mitosis, proliferation of interstitial cells, and water retention; during the luteal phase, estrogen and progesterone act together to promote the production of ductal and follicular structures in the normal mammary lobules, while progesterone regulates and antagonizes some of the effects of estrogen, inhibits cell mitosis, and attenuates the interstitial response by At the end of the luteal phase, the epithelial cells of the glandular follicles are highly differentiated, and under the action of basal levels of prolactin, the glandular lobules can produce and secrete small amounts of fluid; during the menstrual phase, due to the feedback inhibition of the hypothalamic-pituitary-ovarian axis, the secretion of sex hormones decreases, and along with the beginning of the menstrual cycle, the ductal-alveolar structures of the mammary glands are restored due to the loss of estrogen support The ductal-alveolar structures revert to the old due to the loss of estrogen support. This cycle is repeated to maintain the normal structure and function of the breast.
In women of reproductive age, various causes of ovarian dysfunction lead to estrogen dominance during the menstrual cycle and absolute or relative deficiency of progesterone, or a relatively shortened luteal phase, resulting in long-term estrogen dominance of the breast tissue, which leads to excessive hyperplasia and incomplete restoration, resulting in disruption of the normal structure of the breast. Patients may have significantly higher than normal plasma estradiol levels during the follicular phase, lower plasma progesterone concentrations during the luteal phase, normal or increased estrogen, and lower than normal progesterone concentrations during the luteal phase, which may be reduced to 1/3 of normal or have a shortened luteal phase. Some patients may have menstrual disturbances or previous ovarian or uterine disease. After menopause, hormone secretion by the ovaries decreases sharply and the lobular glandular structure of the breast shrinks and is replaced by fat and connective tissue, with only the larger ducts remaining. However, if estrogen replacement therapy is applied after menopause, the lack of coordinating effect of progesterone will easily lead to hyperplasia of breast duct epithelial cells.
The characteristics of the lesions in mastocytosis vary at different periods of the disease, resulting in a variety of patterns of pathological histological changes, the basic processes of which are
Initial stage: it first causes subepithelial stromal reaction, connective tissue edema, fibroblast proliferation, and in typical cases the parenchymal volume of the breast can increase by 15% at the end of the luteal phase, and the patient develops premenstrual breast swelling and pain. This is followed by hyperplasia of glandular epithelial cells in the lobules of the breast and may be secretory. If ovarian dysfunction is restored, the histological changes can be completely normalized.
Progressive stage: further development of lobular hyperplasia, enlargement and even fusion of lobules, resulting in irregularity and deformation of lobules. Some of the lobules are disorganized due to the proliferation of fibrous tissue, and the ducts in some areas are increased, dense and compressed, with fibrous tissue hyperplasia, showing adenoma-like changes, which are easily confused with breast tumors on clinical examination. Some of the ducts have fluid collection in the gland and appear as small diffuse cysts, also known as fibrocystic hyperplasia.
In the chronic phase, the ductal-alveolar system atrophies and hardens due to the compression of blood vessels by fibrous tissue and degenerative changes in the lobules of the breast, and the interstitial hyaline degeneration. Epithelial cell hyperplasia within the fibrous tissue encircling to the dilated ducts is common. Some manifest as isolated larger cysts.
It is important to note that the above processes are often not clearly separated and can be present in lesions with both progressive and degenerative changes, resulting in histologic manifestations of pleomorphic changes that are predominantly of one form or another.
Relationship between mammary gland hyperplasia and breast cancer
Available clinical, pathological and epidemiological studies have shown that carcinogenesis of benign breast disease is one of the important causes of breast cancer, the mechanism of which is still unclear. Mastocytosis is one of the most common benign breast diseases, and its relationship with breast cancer has always been emphasized. As early as the middle of the last century, many scholars have proposed that cystic hyperplasia of the breast is associated with breast cancer through the results of coexistence studies and clinical retrospective investigations of paraneoplastic lesions. The most important of these publications include Duppont and Page et al. 1985 in the New England Journal of Medicine, which published the results of over 10,000 cases with 17.5 years of follow-up. Their conclusions clearly suggest that: 1. the following lesions have little chance of cancer, such as cystic disease, ductal dilatation, sclerosing adenopathy, sclerosis and fibroadenomatosis; 2. biopsy findings of mild epithelial hyperplasia and sweat gland hyperplasia are not significant under 45 years of age; 3. the incidence of atypical hyperplastic carcinoma of the breast increases 4.7-fold compared to controls, and if there is a family history of breast cancer, the incidence of breast cancer increases nearly 10-fold. The relationship between mammary epithelial hyperplasia and atypical hyperplasia and breast cancer occurrence was confirmed. This was further followed by comparing women with different pathomorphological lesions clearly identified by biopsy with women of the same age without breast biopsy and using the rate of development of invasive breast cancer at 10-20 years of follow-up as the risk level. Classifying cystic hyperplasia of the breast by histologic type into cysts, sweat gland hyperplasia, adenopathy, sclerosing adenopathy, inflammation, calcification, intraductal papilloma and/or epithelial hyperplasia, non-proliferative lesions such as cysts, sweat gland hyperplasia, adenopathy, sclerosing adenopathy or inflammation were found to have no increased risk of breast cancer compared to the general population; those with ductal epithelial hyperplasia without atypical hyperplasia included Those with generalized, moderate hyperplasia had a mildly increased risk (1.5-2 times the risk of breast cancer in the control group); those with epithelial atypical hyperplasia, including ductal atypical hyperplasia and lobular atypical hyperplasia, had a toxic increased risk (4-5 times the risk of breast cancer in the control group); and those with carcinoma in situ, including lobular carcinoma in situ and ductal carcinoma in situ, had a highly increased risk of invasive carcinoma (4-5 times the risk of breast cancer in the control group). The risk of breast cancer was 8-10 times higher than that of the control group). The relationship between benign lesions carcinoma and atypical hyperplasia was clarified, and the development process was normal breast epithelial cells – general hyperplastic epithelial cells – atypical hyperplastic epithelial cells – carcinoma in situ – infiltrative carcinoma.
Clinical manifestations and diagnosis of mammary hyperplasia
Patients are mostly women of childbearing age, with a higher incidence in the age of 30-40. The main manifestations are breast pain, pressure pain, limited glandular thickening or formation of masses. The initial stage may be in one breast, mostly in the upper outer quadrant of the breast, and then gradually develop into multifocal, with bilateral breast onset. The course of the disease is often long, and the initial stage is often related to menstruation, showing increased pain before menstruation, gradually decreasing after menstruation, and gradually losing regularity of breast pain after a certain degree of development. Some patients may have nipple discharge, mostly from multiple breast ducts bilaterally, which can be watery, yellow plasma, milky or cloudy. 40%-60% of patients have irregular menstruation, early menstruation, dysmenorrhea, excessive menstruation or ovarian cysts. In addition, breast pain in most patients is often triggered and aggravated by intense psychological and emotional changes such as quarrels and anger. After menopause, the breast glands shrink and are gradually replaced by fatty tissue, and most patients’ symptoms and signs can be relieved.
The clinical diagnostic criteria for mastocytosis are not uniform, but currently women with significant breast pain, lump-like thickening of the breast or with multiple ductal nipple overflow are generally diagnosed as mastocytosis. Auxiliary examinations are the means to further clarify the diagnosis, mainly including color ultrasonography, mammography and selective mammography ductography, and optional fiberoptic ductoscopy for those with nipple overflow. Pathological puncture biopsy is performed on suspicious lesions to exclude breast cancer. The pathomorphologic diagnosis of mastocytosis remains the gold standard for clinical diagnosis. It should be noted that for female patients over 40 years of age, especially those with limited breast thickening or lump-like changes, the diagnosis of mastocytosis cannot be made easily and requires the above-mentioned tests to exclude breast cancer before the diagnosis of mastocytosis can be made.
Treatment of mastocytosis
The treatment of mastocytosis mainly includes the following four aspects: 1) psychotherapy; 2) medication; 3) surgery; 4) follow-up observation.
1.Psychotherapy Traditionally, women with breast pain are often accompanied by neurotic manifestations. For some patients with breast enlargement who have mild breast pain and no obvious signs but show great nervousness, they can be given psychological pacification treatment. These patients often attach great importance to breast diseases and often doubt whether they are suffering from breast cancer, so they can be given the corresponding auxiliary examinations to relieve their worries and explain the knowledge related to breast enlargement to dispel their fear of cancer, which is often very effective. These patients should be advised to restrain their emotions, participate in more outdoor activities and social activities, maintain a calm psychology, learn self-psychological regulation and, if necessary, be given medication to regulate the function of plant nerves.
2.Drug treatment Clinically, patients with mastocytosis are given targeted and active treatment for different conditions, and are closely monitored and followed up to prevent and detect breast cancer at an early stage. Commonly used drugs include the following categories.
(1) Chinese herbal medicine: Chinese medical analysis of mastocytosis mainly includes liver-depression and qi-stagnation type, phlegm-stasis type, liver-kidney deficiency type, and punch-disorder type. The Chinese herbal medicines and proprietary medicines for the treatment of this disease include those that regulate the flushing and the stagnation of the liver, relieve depression, invigorate blood circulation and remove blood stasis, soften and disperse knots, soothe tendons and channels, disperse knots and relieve pain, etc., which are often effective according to the specific conditions of the patients.
(2) Vitamin drugs: Vitamins A, B, C and E can protect the liver and improve liver function, thus improving the metabolism of estrogen. Retinoic acid is an inducer of epithelial cell growth and differentiation, which has a certain role in preventing the occurrence of breast cancer. Vitamin E prevents peroxidation of important cellular components and plays an important role in maintaining the normal function of epithelial cells. At present, vitamins are often used as adjuvant drugs in the treatment of breast hyperplasia, but there are also data showing that their efficacy is not higher than that of placebo.
(3) Hormonal drugs: 1) Triamcinolone has estrogen-like activity and acts as a competitive agent for estradiol to compete for estrogen receptors in target cells and make estrogen lose its effect on target cells without affecting plasma estrogen levels. It has an inhibitory effect on the growth of atypical hyperplasia cells in the breast, and is effective in mastocytosis. However, it can cause menstrual disorders and increased vaginal discharge, and should be used under the guidance and observation of a doctor. 2) Bromocriptine is a semi-synthetic ergot alkaloid derivative with dopamine activity. It can inhibit the synthesis and release of prolactin, and can act directly with the anterior pituitary gland to release the action of prolactin on gonadotropin and promote the cyclic release of luteinizing hormone, etc. It is effective in the treatment of mastocytosis. This drug often causes nausea, vomiting, and postural hypotension in severe cases, and needs to be used under the guidance of a specialist. 3) Methyltestosterone and Danazol are androgenic drugs that can counteract estrogen and inhibit ovarian function, and play a role in the treatment of mastocytosis.
(4) Other drugs: 1) Asparagine tablets, originally extracted from fresh asparagus, later synthesized, the active ingredient is asparagine, clinically proven to have a therapeutic effect on some mastocytosis. 2) Iodine preparations, the role of which is to stimulate the anterior pituitary gland, the production of luteinizing hormone to promote ovarian follicular sac luteinizing, regulate and reduce estrogen levels, thereby treating mastocytosis. 3) Evening primrose oil, which contains the active ingredient gamma linolenic acid (GLA), an essential fatty acid (EFA), is effective in relieving breast pain, but its action is very slow, taking effect after two months of treatment, but noticeable effects are not visible until four months after the use of the drug. It is more commonly used in women with moderate pain and who wish to continue taking oral contraceptives.
(5) Medication methods and precautions: The treatment of mastocytosis is generally preferred to a combination of herbal or proprietary Chinese medicine, supplemented by vitamin-based drugs. Generally speaking, the selected drugs should not only relieve symptoms but also achieve the purpose of adjusting the body’s cyclic hormone balance and preventing the development of hyperplastic lesions. Therefore, the duration of medication should generally be 2-3 months as a course of treatment, and continuous medication can be discontinued after the symptoms are completely relieved, the main signs of breast hyperplasia disappear, and the auxiliary examination indicates that the lesions improve or subside. For patients over 40 years old, with family history of breast cancer and other high-risk factors, and biopsy confirmed atypical hyperplasia of breast epithelium, triamcinolone should be preferred.
3.Surgical treatment For those who are not well treated by medication, have high risk factors for breast cancer and cannot exclude cancerous lesions, surgery can be considered for examination and treatment.
(1) Hollow needle biopsy: For those with limited thickening of breast enlargement, pain without regularity, poor effect of drug treatment, symptoms of breast enlargement over 40 years old, and those with family history of breast cancer or suspicious lesions found in adjuvant examination, hollow needle aspiration biopsy should be actively performed, if necessary, under B-ultrasound or X-ray positioning to improve the diagnostic accuracy of microscopic lesions. This method has the advantages of minimally invasive and no (or minimal) scars compared to other surgeries.
(2) Mass excision: For those who have breast hyperplasia that does not work with general drug therapy, or whose other hyperplastic lesions improve after treatment but the isolated breast mass does not disappear, or who have a single breast duct overflow combined with ultrasound or X-ray suggesting a tumor-like lesion, mass excision should be actively performed, and preparations for radical breast cancer surgery should be made before surgery.
(3) Mastectomy: Mastectomy should be performed for patients with biopsy confirmed multifocal grade II or above atypical hyperplasia, with intraductal papillary tumors, or with mutation of breast cancer susceptibility gene (BRCA1/2) at the same time, and such patients can choose lumpectomy with one-stage prosthesis implantation, which can restore the perfect shape of female breast while removing lesions.
4. Follow-up observation For patients with high-risk factors of breast enlargement, a reasonable follow-up observation plan should be formulated along with active treatment. Patients should be taught to do self-examination during the initial consultation.
V. Prevention of breast hyperplasia
With the improvement of people’s living standard and the accelerated pace of life, the incidence of mastocytosis is gradually increasing, therefore, it is very important to take active prevention and treatment measures. Combined with the pathogenesis of mastocytosis, we believe that prevention should be carried out in the following aspects: 1, choose the appropriate age to get married and have children; 2, breastfeeding as much as possible after childbirth; 3, usually pay attention to take effective contraceptive measures; 4, pay attention to maintain a regular and quality sex life; 5, good at adjusting their emotions in life, maintain a cheerful and peaceful state of mind; 6, multi-faceted to adopt a scientific lifestyle, living with Regularity, less late night, quit smoking and alcohol, low-fat diet, less drinks containing caffeine, theophylline, theobromine and other ingredients, careful use of breast enlargement products, use the right type of support bra, etc.; 7, actively prevent and treat various gynecological diseases; 8, once a year for breast examination.