Inflammatory breast diseases: clinical guidelines

List of Abbreviations

BD — breast disease

NLM — non-lactational mastitis

PDM — periductal mastitis

IGM – idiopathic granulomatous mastitis

Ultrasound — ultrasound examination

CDFI — color Doppler flow imaging

CE – contrast-enhanced ultrasound

MRI — magnetic resonance imaging

HR – heart rate

BP — blood pressure

Malignant neoplasm

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

MRI — magnetic resonance imaging

Terms and Definitions

Mastitis is an inflammatory disease of the breast of both infectious and non-infectious etiology [1], [2], [3].

Postpartum (lactational) mastitis is an inflammatory disease of the breast caused by bacteria, developing after childbirth and associated with the lactation process [8].

Hypergalactia is excessively abundant milk production in a nursing woman [8].

Non-lactational mastitis is an inflammatory disease of the breast unrelated to the postpartum period and lactation [1].

Idiopathic granulomatous mastitis is a rare benign inflammatory disease of the breast of unknown etiology [1], [4], [5].

Breast abscess is a localized inflammatory focus within the soft tissues of the breast, representing an encapsulated purulent cavity [1], [3].

Subareolar abscess is an encapsulated purulent cavity in the areolar region of the breast, a complication of periductal mastitis [1].

Periareolar fistula is a pathological tract between the inflammatory focus and the skin of the breast, a complication of mastitis [1].

Tuberculous mastitis is an extrapulmonary form of tuberculosis infection affecting the tissue of one or both breasts [1].

Areolitis is inflammation of the areolar region of the breast [6].

Thelitis is inflammation of the nipple of the breast [6].

Intraductal mastitis (galactophoritis) is intraductal inflammation of the breast [1].

Periductal mastitis is an inflammatory disease of the subareolar ducts of the breast [1].

Nipple fissures are defects or disruptions in the skin integrity of the nipples.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Mastitis is an inflammatory disease of the breast of both infectious and non-infectious etiology [1], [2], [3].

Postpartum (lactational) mastitis is an inflammatory disease of the breast caused by bacteria, developing after childbirth and associated with the lactation process [8].

Hypergalactia is excessively abundant milk production in a nursing woman [8].

Non-lactational mastitis is an inflammatory disease of the breast unrelated to the postpartum period and lactation [1].

Idiopathic granulomatous mastitis is a rare benign inflammatory disease of the breast of unknown etiology [1], [4], [5].

Breast abscess is a localized inflammatory focus within the soft tissues of the breast, representing an encapsulated purulent cavity [1], [3].

Subareolar abscess is an encapsulated purulent cavity in the areolar region of the breast, a complication of periductal mastitis [1].

Periareolar fistula is a pathological tract between the inflammatory focus and the skin of the breast, a complication of mastitis [1].

Tuberculous mastitis is an extrapulmonary form of tuberculosis infection affecting the tissue of one or both breasts [1].

Areolitis is inflammation of the areolar region of the breast [6].

Thelitis is inflammation of the nipple of the breast [6].

Intraductal mastitis (galactophoritis) is intraductal inflammation of the breast [1].

Periductal mastitis is an inflammatory disease of the subareolar ducts of the breast [1].

Nipple fissures are defects or disruptions in the skin integrity of the nipples.

Lactostasis is a dysfunctional state of the lactating breast based on a mismatch between milk production and milk ejection processes.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

There is no consensus regarding the etiology of lactational mastitis, which may be inflammatory, infectious, or multifactorial.

A large number of bacteria can colonize breast milk endogenously, for example, from the mother's intestine. Commensal organisms appear to be important for the developing infant gut microbiome. Etiology includes the addition of a bacterial infection, for example, through nipple fissures [93].

The bacterium Staphylococcus aureus (S. aureus) is considered the primary etiological factor of bacterial mastitis. In recent years, an increase in methicillin-resistant S. aureus (MRSA) breast infections has been observed in the USA. Mastitis is much less frequently caused by other microorganisms: Streptococcus groups A and B, Enterococcus, Escherichia coli, and Pseudomonas aeruginosa [94]. It should be noted that while Staphylococcus is the most widely isolated bacterial group (97.57%), Staphylococcus epidermidis is the dominant species (91.56%), with Staphylococcus aureus in second place (29.74%). Streptococcus and Corynebacterium constituted the second (70.20%) and third (16.60%) most dominant groups, respectively [95], [96].

Microorganisms penetrate the gland mainly via 2 pathways – through nipple fissures and via the galactogenic (intracanalicular) route. The hematogenous route of infection is extremely rare—metastasis from a generalized infection or from distant focal sources of infection. Through nipple fissures, infectious agents spread to the stroma located between the glandular lobules (interstitial mastitis develops). Via the galactogenic pathway, microbes penetrate deep into the breast during breastfeeding or milk expression through the milk ducts opening on the nipple, causing their inflammation followed by damage to the glandular tissue and the occurrence of parenchymal mastitis [97].

Infection of the breasts can occur from a focus of chronic infection or via external introduction of microorganisms (from patients with various manifestations of purulent-inflammatory infection or from Staphylococcus aureus carriers). The lobular structure, numerous natural cavities, abundance of adipose tissue, intensive blood supply, and extensive network of milk ducts and lymphatic vessels facilitate the rapid spread of inflammatory processes in the breast [94].

The primary initiating factor in the development of mastitis is lactostasis. Lactostasis leads to milk duct obstruction; a "white spot" appears on the nipple, representing an accumulation of oily material [98], [99].

Risk factors for lactostasis:

• Increased intervals between feedings;

• Limiting the duration of breastfeeding;

• Skipped feedings;

• Incorrect latch or ineffective suckling (congenital palate defects, tongue-tie);

• Hypergalactia;

• Rapid weaning;

• Bra pressure on the breast;

• Nipple fissure causing pain and delaying the next feeding;

• Nipple developmental anomalies (flat, inverted);

• Structural changes in the breasts (mastopathy, scarring from previous purulent mastitis);

• Immunosuppressive states;

• Poor hygiene and violation of breastfeeding rules [93], [100], [101].

Mastitis can have various etiologies, and disease progression is frequently observed, namely: milk stasis progresses to aseptic inflammation, which in turn can progress to septic inflammation, which later may develop into an abscess [94].

With delayed and ineffective treatment, the serous form of postpartum mastitis progresses within 1–3 days to the infiltrative form, which lasts from 5 to 10 days. If the infiltrate does not resolve, suppuration occurs. The predominant form of postpartum mastitis is infiltrative-purulent mastitis, which can present as diffuse and nodular forms.

The second most frequent form is the abscess-forming form of purulent postpartum mastitis: a furuncle and/or areolar abscess, and abscesses within and retromammarily. The most severe form is phlegmonous mastitis, in which generalization of the infection with progression to sepsis is possible [102], [98], [103], [104], [105].

Non-lactational mastitis is an inflammatory disease frequently caused by microbiota disruption against the background of increased secretory activity of the glandular epithelium of the breast [1], [2].

The pathogenesis of the disease suggests a link between smoking and damage to subareolar ducts, tissue necrosis, and subsequent infection [1]. Toxic substances in cigarette smoke can directly damage the milk ducts or cause tissue hypoxia [1]. Excessive friction, trauma, and skin diseases (eczema, dermatitis, allergic reactions) can lead to nipple fissures, through which pathogenic flora invades, followed by the development of an inflammatory process [7]. Through nipple fissures in lactating women, infectious agents spread to the stroma located between the glandular lobules, leading to the development of interstitial mastitis [8]. Other factors increasing the risk of mastitis include nipple invagination, hyperprolactinemia, obesity, diabetes mellitus, and late menarche [9], [10], [11], [12], [13], [14]. Obstruction of the milk duct by desquamated epithelial cells and lipid secretion, as well as squamous metaplasia of the ductal epithelium under the influence of various etiological factors, provide a good substrate for bacterial growth [15]. Meanwhile, the main pathogens are Staphylococcus aureus, Bacteroides, and anaerobic streptococci [13].

Idiopathic granulomatous mastitis (idiopathic granulomatous lobular mastitis, IGM) is a rare benign inflammatory disease of the breast of unknown etiology (a nonspecific autoimmune inflammatory process) [1], [4], [5]. Currently, the etiology and pathogenesis of IGM are not fully understood. The risk of GLM is increased by alpha-1-antitrypsin deficiency, smoking, lactostasis, breast trauma, hyperprolactinemia, and autoimmune diseases [16], [17], [18], [19], [20], [21], [22]. Particular importance in the etiology of GLM is attributed to the bacterial factor Corynebacterium kroppenstedtii, belonging to the genus of gram-positive rod-shaped actinobacteria, which account for 1.1–58.9% of the breast abscess microflora in patients with IGM [23]. It is hypothesized that primary damage and dysfunction of ductal epithelial cells under the influence of various etiological factors causes ductal secretions to penetrate into the breast lobules. This transition triggers a local inflammatory reaction in the connective tissue with the migration of macrophages and lymphocytes, followed by a local granulomatous reaction around the glandular lobule [22].

Tuberculous mastitis is an extrapulmonary form of tuberculosis infection [1].

1.3 Epidemiology of the Disease or Condition

Nipple fissures occur in 29-76% of nursing women within the first week after delivery [106]. Postpartum mastitis develops predominantly in outpatient settings 2-4 weeks after delivery, with a frequency ranging from 0.5 to 6% [104].

The majority of cases are observed during the first 12 weeks of the postpartum period (74-95%). However, the disease may also occur in the second year of lactation [107].

Mastitis predominantly occurs in primiparas over 30 years of age. In 90% of patients, one breast is affected. The outer quadrant of the breast is most frequently involved; subsequently, the inflammation may remain localized or spread to other areas of the organ [104].

Non-lactational mastitis occurs in 5-9% of women, usually manifesting under the age of 30 or during menopause, although cases of mastitis are also registered in children and men [24], [25].

Idiopathic granulomatous mastitis is most commonly found in young women (within 5 years after pregnancy), but it can also occur in nulliparous women and men [1], [27], [28]. IGM accounts for 24% of all inflammatory diseases of the breast [29].

Tuberculous mastitis is rare, even in countries with a high burden of pulmonary tuberculosis. It predominantly affects women of reproductive age, including nursing mothers; cases in men are extremely rare [1], [30], [31].

A breast abscess as a complication may develop in 3-11% of patients with mastitis [6], [32].

1.4 Features of Coding the Disease or Condition

N61 – Inflammatory diseases of breast (non-puerperal mastitis and abscess).

N64.0 – Fissure and fistula of nipple.

P39.0 – Neonatal infectious mastitis

O91.0 – Infections of nipple associated with childbirth

O91.1 – Breast abscess associated with childbirth

O91.2 – Nonpurulent mastitis associated with childbirth

O92.1 – Nipple fissure associated with childbirth

1.5 Classification of the disease or condition

There is no universally accepted classification of mastitis.

In Russian clinical practice, the classification proposed by B.L. Gurtov (1975) is most widely used:

1. By the nature of the inflammatory process

   1. Serous (incipient) mastitis.

   2. Infiltrative mastitis.

   3. Purulent mastitis:

      • Infiltrative-purulent:

        • diffuse,

        • nodular.

      • Abscessing:

        • areolar furunculosis,

        • areolar abscess,

        • intramammary abscess,

        • retromammary (subfascial) abscess.

      • Phlegmonous:

        • purulent-necrotic.

      • Gangrenous.

2. Depending on the localization of the inflammation focus

   • subcutaneous, subareolar, intramammary, retromammary, and total, when all parts of the breast are affected [33].

3. By the presence of a pathogen

   • infectious mastitis

   • non-infectious mastitis

   • granulomatous mastitis (specific inflammation, productive inflammation – the body's reaction to bacteria, mycosis, or a foreign body)

1.6 Clinical presentation of the disease or condition

Clinical manifestations of mastitis include breast pain, hyperemia of the breast skin, nipple inversion, nipple discharge, presence of indurations, fistulas, and ulcers [1], [2], [3], [5], [6].

Postpartum mastitis typically has an acute onset and is characterized by [128]: elevated body temperature (38° C and above) with or without chills; deterioration of general condition (headache, weakness); onset of breast pain, particularly during feeding and expression; symptoms of milk stasis, enlargement of the breast; appearance of indurations in various areas of the breast: - in serous mastitis - without clear margins; in infiltrative mastitis - a dense infiltrate with clear margins; in purulent mastitis - a dense infiltrate with clear margins, areas of softening, and pronounced tissue edema over the inflammatory focus; skin discoloration of the breast in the affected area; enlargement of regional axillary lymph nodes; difficult breast emptying during milk expression [108], [98], [104].

Patients with nipple fissures complain of discomfort in the nipple-areola complex, itching, flaking, edema, hyperemia, and pain upon contact of the nipples with clothing (unilateral or bilateral), pain intensifying during feeding (in lactating women), bloody or purulent discharge from breast fissures, and crust formation (in candidal infection) [7], [26].

In adolescence, mastitis more frequently develops against the background of superficial breast cysts with a "pocket-like duct" opening onto the nipple or areola, which serves as a risk factor for infection amidst altered immune status during respiratory infections. Clinical manifestations include induration of the breast tissue in the areolar region, hyperemia of the breast skin, and sometimes low-grade fever [3].

In the neonatal period, the most probable causes of mastitis are attempts to express colostrum during physiological breast engorgement, trauma, and disruption of the skin integrity of the breast. Neonatal mastitis manifests as induration of the breast tissue under the nipple-areola complex and hyperemia of the skin [2].

A clinical feature of PDM is the localization of the lesion in the subareolar region, with the formation of a periareolar abscess or fistula. The clinical picture is variable. The acute stage resembles acute purulent mastitis with bright skin hyperemia, marked edema, severe breast pain, fever, and deterioration of the general condition (headache, weakness). In some cases, a periareolar abscess may form. In the subacute stage, general symptoms are absent, but induration in the breast and dark red skin color persist. In the chronic stage, induration persists in the breast, primarily in the areolar region [34]. The disease has a protracted, recurrent course with the formation of fistulas that are refractory to treatment [11], [13], [35].

IGM typically affects one breast, and the disease may manifest in any quadrant except the subareolar region. Approximately 1/3 of patients (28%) exhibit enlargement of axillary lymph nodes, especially in chronic cases [36]. Manifestation of the disease as an aseptic abscess with or without a skin sinus tract has been described, which can be either a manifestation of the primary process or a complication of core-needle biopsy [35], [36], [37], [38], [39], [30]. In some cases, edematous skin acquires a peau d'orange appearance, complicating differential diagnosis with malignant tumors [41]. Approximately 34% of patients with IGM present with extramammary manifestations, which typically include joint edema and pain, as well as erythema nodosum of the lower extremities [40], [42], [43].

The most common finding in tuberculous mastitis is a single, painful, poorly demarcated, irregularly shaped breast mass, sometimes with a firm consistency [1], [30], [31]. Both breasts are affected in 3% of patients; involvement of the nipple and areola is extremely rare. Characteristic signs of tuberculous mastitis include multiple cavities, sinus tracts, and enlarged axillary lymph nodes. Bacterial culture of purulent exudate shows no microbial growth. Cytological examination of breast discharge may reveal Langhans giant cells. Although the disease frequently involves the skin, the breasts generally remain mobile on the chest wall unless the process involves the underlying ribs. The skin of the breast in tuberculous mastitis may be thickened, with ulceration or cavity formation discharging pus from the ulcer or nipple. In later stages, sclerosis may lead to a reduction in breast size. In the majority of patients, symptom duration can reach several years [1], [30], [31].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of mastitis is established based on patient complaints, anamnesis, physical examination, and instrumental and laboratory methods.

2.1 Complaints and Anamnesis

Comment: When taking the medical history, it is necessary to ascertain the presence of respiratory symptoms, episodes of hypothermia, and breast tissue trauma. It is important to determine age, presence of bad habits (smoking), history of lactation, history of mastitis and its clinical form in previous deliveries, scarring from previous purulent mastitis or breast surgeries for neoplasms, plastic or cosmetic surgeries; structural breast changes (mastopathy, gigantomastia); specific features of the recent delivery and postpartum period (breastfeeding, nipple fissures, milk stasis, level of lactation). A family history of breast cancer in first-degree relatives is important. Inquiries must be made regarding allergic reactions and medications being taken. Attention should be paid to the general condition, skin discoloration of the breast, localization, duration, and dynamics of pain, presence of nipple fissures, indurations, abnormal nipple discharge, and its color [1], [2], [3], [33], [97].

2.2 Physical Examination

Comments: Inflammatory breast disease is characterized by tenderness and skin hyperemia over the area of breast induration, accompanied by hyperthermia and, rarely, symptoms of intoxication [1], [2], [3].

The examination should be performed in a standing position, first with arms lowered and then raised behind the head. The symmetry and shape of the mammary gland, as well as the condition of the nipples and skin, are evaluated. Palpation is performed in the patient's vertical position; for additional information, it is also advisable to perform it in a horizontal position on a couch on the back and side. Palpation determines the localization, size, contours of indurations, their surface and consistency, as well as compressibility and relationship with surrounding tissues. The entire mammary gland is examined by palpation - around the nipple and sequentially by quadrants down to the inframammary fold. The presence of nipple discharge is checked, and palpation of the axillary lymph nodes is performed (in an inflammatory process, lymph node palpation is painful).

Medical documentation must indicate the location, size, and consistency of detected neoplasms and indurations, their connection with the skin and surrounding tissues, the distance from the edge of the areola, the presence of ulcerations, fistulas, as well as the color, consistency, and amount of nipple discharge.

2.3 Laboratory Diagnostics

Comments: The dynamics of hematological parameters during the course of therapy has significant prognostic value [97]. However, there is no data on the correlation between complete blood count parameters and the need to prescribe antibacterial therapy.

Comment: During the cytological examination of an impression smear from the nipple, applied to a coverslip during therapeutic and diagnostic puncture and core-needle biopsy, the material is examined for cellular composition, inflammatory elements (neutrophils) are identified, and histological verification of the diagnosis is performed.

Comments: Bacteriological examination of milk with determination of pathogen susceptibility to antibiotics should preferably be performed before initiating antibacterial therapy. Milk for testing is collected from both the affected and healthy mammary glands. The test results can be used to adjust antibacterial therapy [107], [102], [109], [104], [128].

Comment: Considering the predominance of Staphylococcus aureus as the main pathogenic flora in breast inflammation, bacterial examination may not be performed in a newly diagnosed inflammatory process. Lack of response to broad-spectrum antibacterial therapy is an indication for Gram-stained microscopy and microbiological examination of breast discharge with determination of susceptibility to antibacterial drugs in order to adjust treatment [1], [2], [3]. Microbiological examination detects pathogenic or potentially pathogenic microorganisms in 62-85% of cases [1], [44]. The most common microorganisms are staphylococci, enterococci, anaerobic streptococci, bacteroides, and Proteus [1], [2], [3].

Comment: During dynamic follow-up, in the absence of a positive effect from anti-inflammatory therapy within 7–10 days, ruling out a neoplastic process (core-needle biopsy) is indicated, as well as bacterial examination of breast milk/secretion to determine antimicrobial susceptibility and rule out specific processes. The microbiological laboratory must be informed about the possible connection of the clinical manifestations of IGM with Corynebacterium. Based on the study results, tuberculosis, sarcoidosis, fungal diseases, histoplasmosis, granulomatosis with polyangiitis, breast cancer, and foreign bodies, which can cause granulomatous mastitis, should be ruled out [1]. Purulent contents or drainage discharge are insufficient for detecting tuberculosis because mycobacteria in these samples are difficult to cultivate. Histological detection of a granulomatous lesion with Langhans giant cells indicates tuberculosis, but does not confirm the diagnosis. To confirm the tuberculous etiology of mastitis, one or two tissue samples from the breast and/or axilla should be sent for acid-fast bacteria testing and microbiological examination.

2.4 Instrumental Diagnostics

Comments: Ultrasound examination is not mandatory for establishing a diagnosis of mastitis, but is indicated for differential diagnosis between mastitis, breast abscess, and the consequences of breast trauma [1], [2]. Breast ultrasound can detect residual, recurrent, or new abscesses, especially if breast tissue induration makes it difficult to assess fluctuation [2], [3]. Ultrasonography allows differential diagnosis between mastitis and mammary duct ectasia mimicking mastitis in older children and adolescents [3]. Ultrasound is the preferred initial imaging modality in IGM, with diagnostic criteria being the presence of an area of induration with one or more abscesses [1]. In postpartum mastitis, ultrasound is usually performed to rule out an abscess, presence of a neoplasm, or performed if signs of infection do not resolve within a few days of treatment [1]. In tuberculous mastitis, ultrasound is indicated to assess regional lymph nodes and perform biopsy [1]. Ultrasound examination is also indicated when performing diagnostic and therapeutic fine-needle aspiration biopsy [2], [3].

Ultrasound signs of acute mastitis:

• increased skin thickness (usually exceeds the skin thickness of other areas of the examined breast and the symmetrical area of the contralateral breast);

• increased echogenicity of subcutaneous adipose tissue (if the inflammatory focus is located close to the skin);

• hyperechoic changes in the inflammation zone or around the inflammatory focus (due to lymphoid tissue infiltration);

• presence of areas of decreased echogenicity (hypoechoic and anechoic) indicating structural disorders of the breast parenchyma, single or multiple, well-circumscribed or ill-defined;

• heterogeneous cyst contents in the presence of inflammation of a cystic lesion;

• dilatation of the milk ducts in the inflammation zone;

• increased blood flow in the edema zone on color Doppler mapping (CDFI);

• enlargement of axillary lymph nodes.

Ultrasonic signs of breast abscess:

• hypoechoic lesion;

• round or irregular shape;

• well-defined, smooth margins;

• heterogeneous structure;

• avascular on color Doppler and power Doppler modes;

• painful upon probe compression;

• areas of infiltration, decreased differentiation of parenchymal structures, increased vessel number and diameter may be detected around the abscess;

• enlargement of regional lymph nodes [45].

According to ultrasound results lesions in GDM and IGM have an irregular shape [31]. In GDM, typical duct ectasia may be observed, with duct diameters potentially exceeding 3 mm, and in some cases, hyper- or hyperechogenic inclusions are diagnosed within them [46]. In IGM, hyperechogenic (more often multiple) breast masses are usually visualized against the background of parenchymal edema and duct ectasia; in some cases, axillary lymphadenopathy may be diagnosed [47], [48], [49], [50], [51].

Tuberculous mastitis manifests as single or multiple slowly enlarging masses with clear borders, mimicking a fibroadenoma in the early stages and a carcinoma in the late stages of the disease [30], [31], [52].

During dynamic monitoring of patients with acute mastitis receiving anti-inflammatory and antibacterial therapy, the following ultrasound symptoms can be used as criteria for positive dynamics:

• normalization of skin thickness;

• normalization of breast tissue architectonics (decrease in the number of hypoechoic and anechoic structures);

• normalization of the definition of breast structure differentiation;

• decrease in the number of visualized vessels in the inflammation zone;

• disappearance of previously enlarged lymph nodes [45].

Comments: Mammography is not the primary diagnostic method for inflammatory breast diseases, but it allows for clarifying the architectonics and tissue composition of a breast mass when necessary [1]. Simple mammography is usually not required to diagnose mastitis due to the prominent clinical manifestations of the disease. Performing mammography in young patients with mastitis is extremely painful; moreover, the informative value of this method is reduced due to increased mammographic density in young women [1]. However, dual-energy contrast-enhanced spectral mammography (CESM) makes it possible to visualize increased blood flow in a sector or along the contour of an inflamed breast cyst. On mammograms, IGM most commonly manifests as focal asymmetry, skin thickening, and axillary lymphadenopathy, which complicates differential diagnosis with malignant neoplasms [5], [46], [47], [48], [49], [51].

Comment: Nonspecific infectious mastitis is most often characterized by a regional and diffuse contrast enhancement pattern. MRI may visualize coalescing microabscesses, which are characterized by high signal intensity on T2-weighted images with peripheral contrast enhancement [55]. The most common manifestation of IGM is a heterogeneous or ring-like pattern of paramagnetic agent enhancement by the mass, which may be combined with non-mass-like enhancement (segmental or regional). In 30–80% of cases, only a non-mass paramagnetic enhancement pattern is encountered − most commonly of the segmental type, less frequently regional, and extremely rarely diffuse [56], [57], [58]. Additional symptoms of a malignant neoplasm are lymph node enlargement, nipple and skin thickening [57]. The MRI picture in the postpartum and lactation periods has a number of specific features: increased volume of glandular tissue, diffusely enhanced background parenchymal enhancement, increased signal intensity on T2-weighted images, and increased vascularity. If contrast-enhanced MRI is necessary, it should be kept in mind that gadolinium-based contrast agents contain gadolinium and are capable of crossing the blood-placental barrier; the amount of gadolinium excreted in milk is small, and breastfeeding after intravenous administration of gadolinium contrast agents is safe and can be resumed 24 hours after the injection [110], [111], [112], [113].

Comment: The diagnosis of mastitis is established based on clinical examination results, ultrasound data, and fine-needle biopsy followed by cytological examination in patients with a fluid-filled breast lesion [1], [2], [3]. To diagnose tuberculous mastitis, a needle biopsy of both the primary lesion in the breast and abnormal axillary lymph nodes is required [1]. The puncture site for fine-needle biopsy is the skin over the lesion or area of induration. Puncturing through the areola or nipple is not performed.

Comment: The histological picture of PDM is characterized by dilatation of large ducts of irregular shape with periductal fibrosis and varying degrees of periductal lymphoid-plasmacytic infiltration, the presence of foamy macrophages in the lumen of dilated ducts and within the lining ductal epithelium, the presence of neutrophilic infiltration during exacerbations of the inflammatory process, duct obliteration, and replacement by sclerotic tissue (“mastitis obliterans”) [59], [60].

The histological features of IGM are necrotizing chronic granulomatous lobulitis and abscess formation [61], [62]. Characteristic histopathological features include: fibrosclerosis of the breast stroma with replacement of adipose tissue and pronounced perivascular, intra-, and perilobular infiltration by lymphocytes, lobular hypotrophy, and epithelioid granulomas without caseous necrosis. Vascular calcinosis and fat necrosis are also possible [41]. A characteristic morphological feature of IGM is the proliferation of epithelioid fibroblasts.

2.5 Other Procedures

Comment: The nipple of the breast can be involved in the pathological process in both benign and malignant pathology. Paget's disease, atopic dermatitis, and nipple candidiasis can cause eczematous changes in the nipple-areolar complex and lead to nipple fissures. In case of diagnostic uncertainty, tissue sampling followed by histological and immunohistochemical examination may be indicated [63], [64].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Non-drug treatment

Comments: in lactostasis, the most important step in treatment is frequent and effective milk removal. Mothers should be encouraged to breastfeed more frequently, starting with the affected breast. After feeding, manual expression or expression with an electric breast pump can help achieve good breast emptying; massaging the painful area toward the nipple helps drain the breast properly. Immediately before feeding, the nipple should be slightly compressed to make it easier for the infant to latch. It is necessary for lactation consultants to teach mothers this technique. Painful massage and all forms of heavy pressure should be avoided as they increase the risk of tissue damage with the subsequent development of mastitis [114], [115], [98], [94], [116].

Comment: performing breast massage in the treatment of mastitis, regardless of the breast massage technique used, reduces the severity of pain [114], [117].

Comments: significant pain reduction and rapid healing of nipples in nursing women after laser therapy following several sessions. The analgesic effect is associated with a decrease in the inflammatory reaction, including reduced edema. The use of phototherapy also reduces pain and inflammation, which promotes the healing of nipple fissures [119], [118].

Comments: according to domestic authors, lactation suppression is advisable in purulent mastitis, but currently this practice should be avoided. For mothers with mastitis caring for full-term infants, the decision whether to interrupt breastfeeding for a short period while continuing to express breast milk regularly or to stop breastfeeding is an individual choice [107], [98], [121], [122].

3.2 Pharmacotherapy

Comment: Treatment should be selected taking into account the extent of the inflammatory process, disease duration, patient age, and the results of microbiological examination of breast discharge (if available). In the neonatal period, topical antibacterial therapy is recommended, and in case of ineffectiveness, systemic antibacterial therapy. In adolescents with inflammation associated with a breast cyst, treatment includes sanitation of the infection focus, topical antibacterial therapy, and NSAIDs (non-steroidal anti-inflammatory and antirheumatic drugs), with systemic antibacterial therapy if ineffective. In reproductive age, treatment includes sanitation of the infection focus with washing of the cavity using antiseptic solutions (antiseptics and disinfectants) (chlorhexidine** 0.5% aqueous solution + sodium chloride** 0.9% solution in a 1:10 ratio), topical and systemic antibacterial therapy, and NSAIDs (non-steroidal anti-inflammatory and antirheumatic drugs). If thick purulent discharge is present, a proteolytic enzyme (#chymotrypsin) can be injected into the cavity of the purulent focus with repeated puncture in 24-48 hours. If treatment is ineffective after 7 days, additional diagnostics are performed to exclude an oncological process (contrast-enhanced mammography and core-needle biopsy), and discharge is sent for microbiological examination to adjust antibacterial therapy.

Empirical antibacterial therapy for mastitis: Amoxicillin + [Clavulanic acid] for patients aged over 12 years and weighing more than 40 kg 875+125 mg orally every 12 hours; aged 3 months to 12 years 90+6.4 mg daily divided into 2 doses every 12 hours; aged under 3 months 30 mg (calculated as amoxicillin) daily divided into 2 doses every 12 hours [1]. In lactational mastitis, first- and second-generation cephalosporins are also approved as first-line therapy [95, 94, 96]. Alternative treatment regimen for non-lactational mastitis: for adults and children weighing over 40 kg, amoxicillin** 500 mg orally every 6 hours + #metronidazole** 500 mg orally every 8 hours; for children weighing under 40 kg, amoxicillin** 20-90 mg per kg of body weight daily divided into 2 or 3 oral doses + #metronidazole** 500 mg every 12 hours orally (if anaerobic infection is suspected) [1]. If there is a high risk of infection caused by methicillin-resistant Staphylococcus aureus (MRSA), doxycycline** 100 mg orally every 12 hours is recommended. In case of an allergic reaction to beta-lactam antibacterial drugs (penicillins), clindamycin** 300 mg orally every 8 hours is an alternative drug for adults and children over 12 years of age [1]. Taking into account the sensitivity of the etiological agent based on microbiological test results, drugs from the following groups may be prescribed: beta-lactam antibacterial drugs: penicillins, cephalosporins (1st and 2nd generations for oral administration, 3rd generation for parenteral administration), macrolides, lincosamides and streptogramins, fluoroquinolones, antiprotozoal drugs, antimicrobial drugs [1], [2], [3].

Comments: Nipple infection is associated with a high risk of developing mastitis and requires treatment with antibacterial drugs. Topical antibacterial agents are preferred.

Comment: Clinical trial results have shown that the use of glycerol-based ointments does not reduce nipple pain. However, emollient ointments and oils (ATC code: D02 – Emollients and protectives) are used for the prevention of nipple fissures [65].

Comments: One of the possible consequences of antibacterial therapy for mastitis can be pathological overgrowth of Candida on the nipple. Clotrimazole or miconazole should be applied to the nipples after each feeding, or every 3–4 hours, for a week (for the treatment of dermatomycosis). A combination steroid ointment may be considered in case of pain and a prominent inflammatory component. Excess cream can be gently wiped off before the next feeding. Both mother and infant should be treated for a week or longer. In cases of open nipple fissures, antifungal treatment can be combined with an antibiotic ointment (D06AX Other topical antibiotics) such as mupirocin (2% ointment up to 3 times a day for 10 days). [102], [123], [94].

Comment: The use of probiotics (ATC: Lactobacilli) compared to placebo reduces the risk of mastitis. In the probiotic study group, the bacterial count in breast milk cultures was significantly lower than in the placebo group [124], [115].

Comment: Treatment with antibacterial drugs and abscess drainage leads to resolution of complications. The choice of antibacterial drug is made in accordance with the microbiological examination data of the abscess contents / breast discharge [1]. When Corynebacterium is identified as a monoculture as the etiological factor of IGM, the optimal treatment approach remains uncertain to date due to the numerous species of Corynebacterium and the lack of predictable susceptibility models. In such cases, the recommended regimen is: doxycycline** 100 mg orally every 12 hours; if ineffective, linezolid** 600 mg orally every 12 hours, clarithromycin** 250-1000 mg orally every 12 hours, rifampicin** 300 mg orally twice daily for 6-9 months [1], [27], [67], [68].

Comment: The treatment regimen is selected individually depending on clinical manifestations. Prednisolone** is prescribed at 0.5-1 mg/kg/day [4], [28], [69], [71], [73], [74]. The dose of prednisolone** is tapered gradually over 8-12 days after the resolution of erythema and pain (usually after 4 weeks). If an exacerbation occurs in patients receiving systemic corticosteroids, #methotrexate** 10-15 mg/week is added to the treatment. Topical #prednisolone** ointment may be used 5 days a week for 2–10 months [1]. In case of exacerbation in patients receiving #prednisolone** and #methotrexate**, the dose of #methotrexate** is increased by 2.5-5 mg every few weeks. After achieving remission, the #methotrexate** dose is tapered monthly for 12 months [75].

Comment: Non-steroidal anti-inflammatory drugs (NSAIDs - non-steroidal anti-inflammatory and antirheumatic products) can reduce edema and inflammation and provide symptomatic relief [1].

Comments: Treatment for a patient with tuberculous mastitis is carried out under the supervision of a phthisiatrician in accordance with clinical guidelines for the treatment of tuberculosis [1].

3.3 Surgical Treatment

For adults: Level of recommendation A (evidence level – 1)

For children: Level of recommendation B (evidence level – 3)

Comments: Abscess treatment is possible via debridement using ultrasound-guided fine-needle aspiration, which preserves breast tissue architectonics and natural anatomical barriers, does not deform the breast shape, and maintains the functional capacity of the breast during subsequent lactation [2], [3]. Breast abscess puncture with evacuation of contents combined with antibacterial therapy leads to recovery in the vast majority (81%) of patients [76]. If drainage is necessary, short-term placement of a drain (no more than 2 days) is recommended. In the absence of an effect from minimally invasive treatments or in case of disease recurrence, surgical intervention is indicated: opening and debridement of the abscess (in lactational mastitis) and breast resection (in non-lactational mastitis). In non-lactational mastitis, surgery should be performed after acute inflammatory symptoms have subsided. The principle of the operation is the thorough removal of all macroscopically visible affected tissues and achieving the widest possible "clean" margins to minimize the likelihood of disease recurrence [7], [10], [11], [59].

In case of recurrence of the inflammatory process in patients with breast cysts or fistulous tracts when conservative treatment fails, surgical techniques include opening the fistula or excision of the fistulous tract, usually combined with complete duct excision [1]. When multiple ducts are affected with multiple fistulas, all affected ducts should be removed to achieve a cure [1].

Comments: Surgical removal of lesions in idiopathic granulomatous mastitis is accompanied by slow wound healing. The recurrence rate of idiopathic granulomatous mastitis is comparable in patients with and without surgical treatment. Diagnostic and therapeutic puncture is indicated for the treatment of complications (secondary infection, abscess) of idiopathic granulomatous mastitis [1].

Comments: Extensive breast resection with maximal removal of affected tissues and achieving clean margins significantly reduces the risk of the disease [72], [77]. The combination of surgical treatment with systemic corticosteroids significantly reduces the risk of disease recurrence [78]

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

Comments: Maternal anatomical features (flat or inverted nipples) or infant features (incorrect tongue positioning, too short lingual or labial frenulum, jaw asymmetry, palate anomalies) can affect latch, positioning, and suckling. In such cases, special attention should be paid to achieving a correct latch. When using auxiliary devices (breast pump, nipple shields), it is important to ensure they are used correctly. Different maternal positions during breastfeeding and measures to stimulate the relaxation reflex (relaxation, massage, moist heat) can help manage breast soreness. Breastfeeding implies physical and emotional intimacy. In addition, general hygiene rules must be observed. In addition to standard hand hygiene measures, nipples should be thoroughly cleansed (using sterile saline, neutral pH liquid soap, or an antiseptic) [98], [125], [8].

Comment: active milk removal from the breast can prevent the development of mastitis in most cases [107], [109], [122].

Comment: breast massage reduces the risk of mastitis [115].

Comment: It is advisable to use a shower or hot compress immediately before feeding, which can help induce relaxation and improve milk flow. After feeding or after expressing milk from the breast, cold compresses can be applied to the breast to reduce pain and edema [114], [120].

• To prevent periductal mastitis, smoking cessation is recommended for all patients [1], [79].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• To prevent the occurrence of nipple fissures in non-lactating patients of all age groups, it is recommended to avoid excessive friction in the nipple-areolar area; for patients with skin conditions (eczema, dermatitis), dispensary follow-up by a dermatologist is recommended [63], [64].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

6. Organization of Medical Care

• Indications for planned hospitalization: none.

• Outpatient treatment is possible.

• Indications for emergency hospitalization:

  • lack of positive dynamics within 24 hours of outpatient treatment;

  • purulent forms of mastitis.

• Indications for patient discharge from the hospital:

  • regression of clinical symptoms;

  • regression of ultrasound findings;

  • absence of complications.

7. Additional Information

Non-lactating mastitis in children under 2 months of age.

During the first year of life, mastitis is more common in infants under 2 months of age [2, 82]. During the first 2 weeks of life, mastitis occurs with equal frequency in girls and boys, and thereafter the ratio is 2:1 [2]. Most cases of mastitis and breast abscess in infants are caused by Staphylococcus aureus [2], [81], [82]. Less common causes include gram-negative enteric microorganisms (Escherichia coli, Salmonella), anaerobes, and group B streptococci (Streptococcus agalactiae) [2], [83].

The pathogenesis of neonatal mastitis involves the spread of pathogenic bacteria from the skin and/or mucous membranes into the mammary gland parenchyma via the nipple [2]. In infants with systemic infection (usually Gram-negative), bacteria can also enter the mammary glands hematogenously. Predisposing factors include mammary gland stimulation by placental and maternal hormones (estrogens), which lead to physiological mammary gland hypertrophy in term infants, as well as maternal skin or soft tissue infections in the postpartum period [2]. It is believed that the risk of mastitis may increase with chest and mammary gland massage [85]. It has been suggested that preterm infants have insufficiently developed mammary glands and are therefore less susceptible to developing infections [2].

Mastitis in infants is usually unilateral and remains localized [2], [83]. Characteristic signs of mastitis in infants include erythema, tenderness, and induration of the affected mammary gland [2]. Sometimes concomitant skin lesions (pustules, bullae) occur, and the axillary lymph nodes enlarge and become tender [2], [85], [86]. Purulent nipple discharge occurs in 20% of infants, and more than half of infants with mastitis develop abscesses, which may be indicated by fluctuation [2], [83], [86]. Usually, mastitis in children under 2 months runs an uncomplicated course, but literature describes cases of mastitis complicated by extensive cellulitis, necrotizing fasciitis, and osteomyelitis [2], [87]. Mammary gland ultrasound is not mandatory for diagnosis, but can confirm the diagnosis of mastitis or a mammary gland abscess if further diagnostic clarification is needed [88], [89].

Differential diagnosis of mastitis in infants is carried out with physiological breast engorgement (physiological hypertrophy) of the mammary glands, in which mammary gland hypertrophy is usually bilateral and symmetrical, with no erythema, breast pain, or nipple discharge (if present) of a milk color (rather than purulent as in mastitis) containing no polymorphonuclear leukocytes or bacteria on Gram stain [2]. A rare pathology that resembles mastitis and mammary gland abscesses is infantile hemangiomas and lymphangiomas, which require consultation with a vascular surgeon.

Comments: In infants with mastitis and clinical and laboratory data of an acute inflammatory process, daily monitoring of the general condition and, if necessary, an expanded clinical and laboratory examination are indicated [2].

Comments: Initial therapy for mastitis in infants consists of prescribing topical forms of antibacterial drugs; if treatment is ineffective, systemic antibacterial drugs are prescribed. Microscopic examination with Gram stain and microbiological culture of mammary gland discharge or a mammary gland abscess fluid sample with determination of antimicrobial susceptibility is performed in the absence of a positive treatment response.

If a cavity larger than 1 cm in diameter is present, fine-needle aspiration is performed to drain the purulent content; with a smaller cavity size, watchful waiting against the background of anti-inflammatory treatment is possible. [2], [87], [94].

Comments: In the treatment of mastitis in children under 2 months of age, topical use of antibiotics (systemic antibacterial drugs (J01)) and topical antimicrobials is indicated, avoiding expression of fluid from the nipple. For a mammary gland abscess, aspiration of the lesion contents is performed [2], [90]. Any surgical manipulations on the mammary glands in children and adolescents are performed only in cases of acute necessity after conservative and minimally invasive surgical techniques, due to the potential threat of mammary gland hypoplasia during puberty or the formation of disfiguring scars [2].

In children under 2 months of age with mastitis, antibacterial therapy is carried out using topical forms of drugs, and if treatment is ineffective, a systemic antibacterial drug is selected in accordance with the culture results.

In the presence of septic manifestations, treatment should cover methicillin-resistant (MRSA) and methicillin-susceptible Staphylococcus aureus, and Gram-negative microorganisms: vancomycin** / #clindamycin** + oxacillin** + gentamicin** / cefotaxime** / ceftazidime** / ceftriaxone** are used. If Gram-negative microorganisms are identified, empirical therapy should include aminoglycosides (gentamicin**, amikacin**) or 3rd-generation cephalosporins (ceftriaxone**, ceftazidime**, cefotaxime**) [2].

Non-lactational mastitis in children over 2 months of age and adolescents.

Non-lactational mastitis in children after 2 months of life most commonly occurs in the pre- and pubertal period (after 8 years) [3]. In children and adolescents, mastitis is most often caused by Staphylococcus aureus, but can also be caused by Enterococcus, Streptococcus pyogenes (group A Streptococcus), anaerobic streptococci, Pseudomonas aeruginosa, Streptococcus agalactiae (group B Streptococcus), and Bacteroides species [3]. In female patients with nipple piercings, actinomycosis may be detected [91].

Mastitis in children over 2 years of age and adolescents results from bacteria entering the duct system, which is more likely during puberty or within a few months after menarche, when breast changes and growth reach their peak [3], [92]. Factors predisposing to mammary gland infection in children and adolescents outside of lactation include superficial chest and mammary gland injuries (e.g., due to breast manipulation during sexual activity, shaving or plucking periareolar hair, squeezing chest acne, nipple piercings, insect bites), obesity, mammary duct ectasia, hidradenitis suppurativa, local skin infection, and epidermoid cysts [3], [90]. Peripheral mastitis may be associated with diabetes mellitus, rheumatoid arthritis, systemic corticosteroid therapy, granulomatous disease, and blunt trauma [3].

Clinically, mastitis in children and adolescents presents with erythema, edema, warmth, tenderness, and induration in the central and peripheral parts of the mammary gland [3], [90]. A mammary gland abscess is indicated by fluctuation and purulent nipple discharge.

Comments: A complete blood count with differential leukocyte count is indicated in patients with fever, systemic symptoms of inflammation, presence or suspected presence of a mammary gland abscess, or with recurrent mastitis. Leukocytosis confirms the diagnosis, and serial monitoring of complete blood count parameters allows for assessing treatment efficacy [3].

Comments: Nipple discharge or mammary gland abscess contents are submitted for cytological examination. Cytological examination predominantly reveals neutrophils. Evaluation of the Gram-stained smear and culture of the mammary gland discharge helps identify the pathogen and determine antimicrobial susceptibility, but this study is indicated only if prescribed treatment is ineffective [3].

Comments: Ultrasound is the primary method for confirming the inflammatory process and is essential for diagnosing breast abscess. Ultrasound findings of a breast abscess include anechoic structures with a thickened capsule and signs of surrounding tissue edema [90].

Differential diagnosis of mastitis in children and adolescents is carried out with juvenile cysts, adolescent papillomatosis, and isolated premature thelarche or simply thelarche (the natural and timely onset of breast development) [3], [90].

Antimicrobial therapy is carried out with systemic antibacterial drugs. In children and adolescents with mastitis and abscess, following diagnostic and therapeutic puncture, topical antibacterial drugs alone may be prescribed. The treatment course is 5–10 days. The response to therapy is clinical improvement within 24–48 hours after starting antibacterial therapy. Lack of response to treatment may indicate a resistant pathogen, inadequate concentration of the antibacterial drug, an abscess (residual, recurrent, or new), or an incorrect prognosis. Most patients with mastitis or abscess recover without complications [3].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Leyla V. Adamyan — Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Honored Scientist of Russia, Head of the Department of Reproductive Medicine and Surgery at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Chief Gynecologist of the Russian Ministry of Health, President of the Society for Reproductive Medicine and Surgery, the Russian Association of Gynecological Endoscopists, and the Russian Association for Endometriosis, and a member of the Russian Society of Obstetricians and Gynecologists. No conflict of interest.

Natalia E. Kan — Doctor of Medical Sciences, Professor, Director of the Institute of Obstetrics at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

Uvarova Elena Vitalievna – Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Head of the 2nd Gynecological Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation, Honored Scientist of the Russian Federation, Professor at the Department of Obstetrics, Gynecology, Perinatology and Reproductology of the Institute of Professional Education at the First Moscow State Medical University named after I.M. Sechenov (Sechenov University), President of the Association of Pediatric and Adolescent Gynecologists. No conflict of interest.

Rodionov Valery Vitalievich – Head of the Breast Pathology Department at the Institute of Oncogynecology and Mammology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation, Doctor of Medical Sciences, member of the Russian Association of Oncomammologists (ROOM), Russian Society of Oncosurgeons (ROSORS). No conflict of interest.

Travina Marina Lvovna – Candidate of Medical Sciences, Head of the Mammology Department at the National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation. No conflict of interest.

Salnikova Irina Alexandrovna – Candidate of Medical Sciences, Researcher at the 2nd Gynecological Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation. No conflict of interest.

Alla A. Ignatyeva – PhD, Head of the 2nd Obstetric Physiological Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). There is no conflict of interest.

Korotkova Svetlana Anatolyevna – Head of the Gynecological Department at the Morozov Children's City Clinical Hospital of the Moscow City Health Department. No conflict of interest.

Tonoyan Narine Marzpetunovna – Candidate of Medical Sciences, Obstetrician-Gynecologist at the Department of Operative Gynecology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation. No conflict of interest.

Sencha Alexander Nikolaevich – Head of the Medical Imaging Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation, Doctor of Medical Sciences, member of the Russian Society of Roentgenologists and Radiologists (RORR). No conflict of interest.

Priputnevich Tatyana Valeryevna – Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Associate Professor, Director of the Institute of Microbiology, Antimicrobial Therapy and Epidemiology at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health. No conflict of interest.

Shabanova Natalia Evgenyevna – Candidate of Medical Sciences, Associate Professor, Head of the Department of Clinical Pharmacology of Antimicrobial and Immunobiological Agents at the Institute of Microbiology, Antimicrobial Therapy and Epidemiology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation. No conflict of interest.

Mikhailova Olga Igorevna – Candidate of Medical Sciences, Obstetrician-Gynecologist at the 2nd Physiological Obstetric Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

Balushkina Anna Andreevna – Candidate of Medical Sciences, Obstetrician-Gynecologist at the 1st Physiological Obstetric Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Obstetrician-gynecologist.

2. Surgeon.

3. Ultrasound Diagnostics Physician

4. Oncologist.

5. General practitioner.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) rating scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Appendix A3. Reference Materials

1. Order of the Ministry of Health of the Russian Federation No. 1130n dated October 20, 2020, "On Approval of the Procedure for Providing Medical Care in the Profile of 'Obstetrics and Gynecology (Excluding Assisted Reproductive Technologies)'" (as amended and supplemented).

2. Federal Law No. 323-FZ of November 21, 2011, «On the Fundamentals of Protecting Citizens' Health in the Russian Federation».

3. Collection of the Federal Research Institute for Health Organization and Informatics of the Russian Ministry of Health, "Main indicators of maternal and child health, the activities of the child and maternity welfare services in the Russian Federation", Moscow, 2019.

4. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care"

5. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on April 16, 2019) "On approval of the nomenclature of medical services".

Appendix B. Physician Action Algorithms

Management algorithm for patients with non-lactational mastitis.

Management algorithm for patients with non-lactational mastitis.

Management algorithm for patients with idiopathic granulomatous mastitis.

Appendix C. Patient Information

What is mastitis?

Mastitis is an inflammatory disease of the breast that can be of both infectious and non-infectious origin. Most commonly, mastitis occurs in the postpartum period during lactation (breastfeeding), a condition known as lactational mastitis. However, mastitis can also occur in non-pregnant women, men, and children (non-lactational mastitis). Symptoms of mastitis include pain in one (more frequently) or both breasts, and there may be an area of skin redness overlying a palpable area of induration in the breast tissue.

Why does mastitis develop?

The most frequent causes of lactational mastitis include: infrequent feedings or feeding on demand, incorrect latch and positioning, milk oversupply, partial milk duct obstruction; impaired drainage leads to milk stasis, pressure on the breast area (e.g., tight bra or seatbelt), maternal stress or excessive fatigue, rapid weaning, maternal or infant illness, maternal nutritional deficiency, use of a pacifier or feeding bottle, history of mastitis, blocked duct, nipple fissures, use of a breast pump, use of nipple shields (reducing suckling and emptying efficiency), accessory breast tissue, breast augmentation or other breast surgeries, infant tongue-tie (ankyloglossia).

The exact causes of non-lactational mastitis are not fully established. The most common cause is the presence of secretion in the breast and a disturbed microbiome in these areas, followed by the development of an inflammatory process. In chronic or acute inflammatory diseases, bacteria (infectious agents) can enter the breast through skin wounds, via lymphatic pathways, or through the bloodstream. A significant role in the onset of mastitis is played by quantitative and qualitative alterations in the breast microflora.

What warning signs should prompt a visit to a doctor?

• painful indurated area in the breast

• redness and swelling of the breast skin

• elevated skin temperature over the indurated area of the breast

• body temperature >38.4 °C (measured in the armpit)

• sometimes flu-like symptoms (chills, headache, muscle pain) may indicate worsening of the disease

The presence of 2 or more signs indicates mastitis and requires medical evaluation.

What are the consequences and why is it necessary to treat mastitis?

If mastitis is not treated in a timely manner, body temperature rises, general well-being deteriorates, and painful lumps appear in the breasts. Subsequently, without treatment, a breast abscess (a localized inflammatory lesion with a pus-filled cavity) develops, body temperature rises to 38–40 °C, and marked general weakness and sweating occur. With further lack of treatment, recurrent fever spikes and chills occur, general condition worsens, and a systemic inflammatory response throughout the entire body (sepsis) may develop.

What is the management strategy for lactational mastitis?

Active conservative management with continued breastfeeding, starting on the affected side. If direct feeding is not possible, expression and complete breast emptying are necessary. Lactational mastitis arises from breastfeeding problems that lead to impaired milk evacuation and poor drainage.

Mastitis, including purulent mastitis, should not be a reason to introduce infant formula.

What are the treatment methods for mastitis?

For lactational mastitis, the first-stage treatment is symptomatic to reduce pain and swelling: a warm compress before feeding/expression and a cold compress immediately after, complete emptying of the breast, lymphatic drainage massage of the breast from the areola toward the axillary lymph nodes using circular movements along the upper and lower hemispheres of the gland, adequate rest, sufficient fluid intake (without volume restriction), and a rational diet. If symptoms persist for 24 hours after initiating the above measures, antibacterial therapy is additionally prescribed.

In case of a moderate fever, disease duration of less than 3 days, and relatively favorable general condition, mastitis can be treated without hospitalization. The doctor will decide on prescribing anti-inflammatory and/or antibacterial drugs (systemic antimicrobial agents and/or nonsteroidal anti-inflammatory and antirheumatic drugs).

In the presence of purulent forms of the disease or worsening of general well-being, a medical consultation is indicated, along with the prescription of anti-inflammatory therapy with the possible use of minimally invasive surgical treatment methods. Hospitalization in a specialized surgical hospital for treatment is carried out according to indications determined by a surgeon. Timely and adequate treatment of the purulent focus prevents the spread of the process and helps achieve a complete recovery.

How to prevent the development of mastitis?

The risk of inflammatory processes in the mammary gland is reduced with proper breast care and adherence to breastfeeding guidelines, timely treatment of dyshormonal states (dysplasia) of the mammary gland, management of symptoms of functional hyperprolactinemia, and the detection and treatment of endocrine diseases such as diabetes mellitus, obesity, and hypothyroidism. Bad habits (smoking) contribute to the development of inflammatory processes in the mammary gland.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Russian title: Visual Analog Scale for Pain (VAS)

Source (official developer website, publication with

validation): Halaska M., Beles P., Gorkow C., Sieder C. Treatment of cyclical mastalgia with a solution containing the extract of Vitex agnus castus: Recent results of a placebo-controlled doubled-blind study. Breast. 1999;8:175–81; Kaviani A, Vasigh M, Omranipour R, et al. Idiopathic granulomatous mastitis: Looking for the most effective therapy with the least side effects according to the severity of the disease in 374 patients in Iran. Breast J 2019;25:672-7..

Type (underline):

• rating scale

• index

• questionnaire

• other

Prescription:

Content (template): The VAS is a straight line segment 10 cm long. Its beginning corresponds to the absence of pain sensation — "no pain", and the end point reflects agonizing, unbearable pain — "unbearable pain". The line can be either horizontal or vertical. The patient is asked to make a mark on it corresponding to the intensity of the pain they are experiencing at the moment. The distance between the beginning of the segment ("no pain") and the made mark is measured in centimeters and rounded to the nearest whole number. Each centimeter on the line corresponds to 1 point.

Key (interpretation): With a mark up to 2 cm, pain is classified as mild, from 2 to 4 cm as moderate, from 4 to 6 cm as severe, from 6 to 8 cm as very severe, and up to 10 cm as unbearable.