Etiology, pathogenesis and treatment of granulomatous mastitis

Yu-pei Chen, Shuo Zhang, Pu Zhang, Zhen-lin Chen＊

1. Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China

2. Beijing University of Chinese Medicine, Beijing 100029, China

Funding: General Project of the National Natural Science Foundation of China (No. 81974584)

Abstract Granulomatous mastitis is generally prevalent in the non-lactating period and belongs to the category of “Plasma Cell Mastitis” and “Mammary Fistula” in field of traditional Chinese medicine.The disease mainly affects the liver, spleen, kidney, thoroughfare and conception channels.The main causes and pathogenesis are the disharmony of qi and blood, stagnated heat of liver channel, spleen deficiency and phlegm coagulation. According to the patient’s symptoms and signs, the treatment principles include replenishing blood and activating qi, soothing the liver and clearing heat, invigorating the spleen and resolving phlegm. The prescriptions include Taohong Siwu Decoction, modified Chaihu Shugan Powder or modified Shenling Baizhu Powder. The prescription and drugs should be adapted to individual conditions and treat the same disease with different treatments. In addition to the internal treatment of the disease, the external treatment of Chinese medicine has also achieved good results in the treatment of early or purulent granulomatous mastitis.

Key words: Granulomatous mastitis; Replenishing blood and activating Qi; Soothing the liver and clearing heat; Invigorating the spleen and resolving phlegm

Introduction

Granulomatous mastitis (GM) is a relatively rare benign,chronic, and inflammatory breast disease limited to caseation-free necrosis of the breast lobules[1]. It is mainly manifested as a sudden enlargement of the breast mass,with or without pain, and without fever. Protracted course of this disease can form sinus ducts and sinus tracts. Some patients will also be accompanied by erythema nodosa and multiple joint pains. According to the theory of traditional Chinese medicine (TCM), its etiology and pathogenesis are believed to include the imbalance of qi and blood,stagnated heat of liver channel, spleen deficiency and phlegm coagulation or other factors. The treatment principles include replenishing blood and activating qi,soothing the liver and clearing heat, invigorating the spleen and resolving phlegm[2].

Etiology and Pathogenesis

TCM etiology and pathogenesis

Disharmony of qi and blood

As the “Plain Questions · Tiaojing Theory” says: “The owner of human is the composition of blood and qi”,women are based on blood and qi. The Chong meridian leads the blood pool. The Ren meridian takes charge of the uterus and pregnancy, and the two meridians regulate qi and the blood. The mutual interaction and fullness of qi and blood ensure the normal function of Chong and Ren channels. The “Complete Effective Preions for Women’s Diseases · Boji Recipe Theory” and “General Treatise on Causes and Manifestations of All Diseases”clearly point out that, most of the gynecopathy are caused by the excessive consumption of qi and blood and the insufficiency of Chong-Ren meridians[3]. Breast milk is transformed by qi and blood in the Chong-Ren meridians.The women’s menstruation, pregnancy, childbirth, and lactation are based on the blood, which is consumable. Qi is the commander of blood, blood is the mother of qi, qi can produce blood and carry blood, blood can nourish qi and carry qi, and qi and blood interact with each other.The deficiency of qi has the inability to promote blood circulation and leads blood stasis, which forms breast lumps in the breast collaterals, stagnated heat transforms to heat, heat exuberance and decayed flesh become pus;the stagnation of qi cannot activate blood, the interaction of blood and qi produces blood stasis, which causes the metaplasia of lactation and the impaired transfusion,leading to the formation of carbuncle. TCM theory believes that, Kidney-Menstruation-Chongren-Uterine constitutes the female reproductive axis[4], which regulates the functions of women’s menstruation, reproduction,lactation and other functions. The periodic changes of breast function are regulated by the female reproductive axis. The Menstruation transformed by the kidney essence nourishes the Chong and Ren meridians. If the kidney essence is deficient, the Menstruation is inadequate,Chong and Ren meridians are imbalanced, and the breast’s dysfunction will aggravate the condition.

Stagnated heat of liver channel

TCM theory believes that: “Women’s nipples belong to the liver, and breasts belong to the stomach.” In the“Miraculous · Meridian”, it is mentioned that “the liver channel of the foot-Jueyin runs through the upper diaphragm and goes around the breast nipple”. In the Qing Dynasty, Ye Tianshi proposed that “women are born with liver” in the “Guide to Clinical Practice with Medical Records”. The liver controls conveyance and dispersion,prefers free activity and dislikes depression. If the emotions are unsatisfactory, the depression stagnates, the rage impairs the liver, leading to liver dysfunction and the stagnation of liver qi, which stagnates in breasts and forms breast agglomerates[22]. The stagnated heat of liver channel injuries the fluid, refining liquid becomes phlegm, which blocks breast collaterals with uncirculated qi to form breast agglomerates, and the breast agglomerates are easy to transform into pus when the heat exuberance is present.Liver depression subjugates spleen, spleen will have dysfunction in transport, water dampness endogenously grows and gathers into phlegm. The phlegm-qi interlocks with the meridians to block the breast collaterals,leading to the formation of breast lumps; the stagnation of liver will cause qi and blood to flow abnormally,and the stagnation of qi, blood stasis, and phlegm will condense into lumps in breast venation, leading to further aggravation of breast lumps.

Spleen deficiency and phlegm coagulation

“Miraculous · Meridian” mentioned that “foot-Yangming stomach meridian runs through the breasts; foot-Taiyin spleen meridian gets to diaphragm and spreads out in the chest”. The spleen is located in the middle focal point and governs the transportation and transformation. It is the hub for the transportation and transformation of qi,blood and body fluid throughout the body. The spleen likes dryness and dislikes dampness. The spirit of thinking associates with spleen, women are more prone to anxiety,which burns out the spleen. If the spleen is weak, it will lose its normal function in transport and loss of control of body fluid. The damp turbidity accumulates into phlegm, which blocks the breast meridians and forms breast agglomeration[23]. Li Shizhen has pointed out in the “Lacustrine Pulse”: “Sputum causes all diseases”. Zhu Danxi puts forward the view that “all diseases are caused by phlegm.” The greasy and surfeit flavour is prone to form dampness pathogen, which obstructs spleen and aggravates spleen deficiency. The condensation of the phlegm dampness is easy to combine with heat, fire, wind and other pathogenic factors, causing further deterioration of masses, manifesting as redness, swelling, fever and pain,and then the heat exuberance and decayed flesh become pus, forming fistulas or sinus tracts and prolonging course of disease[5].

Other factors

In the Ming Dynasty, “Surgical Prescriptions · Mammary Carbuncle Theory” written by Zhou Wencai contains that: “Patients with breast pain are attacked by internal poisonous gas and external pathogenic wind, which are filled in the blood vessels and spread in breasts, gradually becoming swollen. Blood-coagulation and qi-stagnation or breast milk-staying cannot scatter and form carbuncle after a long time”. “Plain Questions · Qi and Heaven Theory” says, “Wind is the beginning of all diseases”, it often combines with fire, heat, cold, dampness and other exogenous pathogens to hurt people, causing qi, blood,phlegm, blood stasis to condense breast lumps; People with congenital nipple depression or breast deformity are more likely to suffer from this disease than those with normal breast development. Such patients often have blocked mammary ducts, which may cause breast milk to accumulate in the local galactophore[6]to form breast masses; trauma or incorrect breast massage can easily lead to obstruction of the milk ducts, because of blocked breast meridians, the obstruction of milk, blood stasis,and phlegm turbidity lead to the formation of local breast lumps in the breast collaterals.

Modern medical pathogenesis

The physiological and pathological activities of the breast are affected by sex hormones, and the secretion of sex hormones is regulated by the “hypothalamicpituitary-ovarian axis” (HPO axis)[7]. Granulomatous mastitis is mainly associated with pregnancy, lactation and contraceptive use; The incidence of granulomatous mastitis is mainly related to hyperprolactinaemia,autoimmune disease, breast trauma or deformity, infection and other high-risk factors[8]. The imbalance of hormone ratio or others causes result in the injury of mammary duct epithelium or abnormal development of mammary duct and lobules. The lipid and protein-like secretions spill into the connective tissue of the lobules, causing local hypersensitivity or inflammation of the connective tissue between the lobules[9], thus leading to the formation of breast granulomas.

Treatment

Internal treatment of TCM

The treatment based on syndrome differentiation is the thinking and practice process, which analyzes and synthesizes all the information collected through the four methods of disease diagnosis to identify the cause, nature,location and development trend of the disease, summarizes and judges it as a certain type of syndrome, and then establishes the corresponding treatment principles and methods, and chooses appropriate treatment methods and measures to deal with the disease. The internal treatment methods of granulomatous mastitis also follow the principle of “treatment based on syndrome differentiation”.According to the etiology and pathogenesis of the disease,the principles are as follows:

Nourishing blood and activating qi-flowing

The therapeutic method is used to treat granulomatous mastitis caused by dissonance with qi and blood. The main clinical manifestations of this syndrome are breast lumps, pain, accompanied by irregular menstruation,dysmenorrhea, amenorrhea, hypogalactia, with wiry or unsmooth pulse, pale tongue, thin and white fur. The imbalance of Chong and Ren and the stagnation of Qi and blood stasis influence with each other and form a vicious circle, leading to the occurrence or aggravation of the disease. In clinical treatment, in addition to the use of drugs for nourishing blood and activating qi-flowing,products for promoting blood circulation and removing blood stasis can also be used[24]. The recipe chooses Taohong Siwu Decoction. The specific Chinese crude drugs are as follows: Chinese angelica, Szechwan lovage rhizome, peach seed, safflower, prepared rehmannia root, peony root, milkvetch root. In the prescription,Chinese angelica can not only nourish blood and promote blood circulation, but also alleviate swelling and relieve pain. Szechwan lovage rhizome activates qi-flowing and blood circulation, both of which are the sovereign drugs.Peach seed and safflower promote blood circulation and remove blood stasis, prepared rehmannia root nourishes blood and Yin. Peony root removes blood stasis and relieves pain. The above fours drugs are ministerial drugs to invigorate blood, promote qi, dredge channels and collaterals; milkvetch root has the effect of invigorating qi for strengthening superficies and expelling pus. When the pus is formed, these drugs can be added, including Dahurian angelica root, processed pinellia tuber, Spina gleditsiae, Thunberdg fritillary bulb, Honeysuckle bud and flower, dandelion; Others also can be added such as centipede and danshen root, which have the effect of resolving masses, dredging collaterals, activating blood,removing blood stasis, and relieving pain[20]. The two drugs are matched with Szechwan lovage rhizome to promote stagnation of qi in the blood as the character of messenger drugs. On the basis of nourishing deficiency and blood, it is supplemented by reducing swelling and ulceration.

Dispersing the depressed liver-energy and clearing away heat

The therapeutic method is used to treat granulomatous mastitis caused by the syndrome of liver depression and qi stagnation. The main clinical manifestations of this syndrome are breast lumps, pain or no pain, accompanied by fullness and pain in the chest and hypochondrium,blushing, red eyes, bitter taste, restlessness at night, red tongue, thin yellow fur, and wiry frequent pulse. The emotional disorder leads to stagnation of liver and qi,transforming fire for a long-term stagnation, which refines liquid into phlegm, then phlegm and blood stasis mutually block breast collaterals to form agglomerates. In clinical treatment, in addition to the drugs of dispersing stagnated liver qi for relieving qi stagnation, the drugs of clearing heat-toxicity, regulating qi-flowing and dissipating phlegm can be added, and the recipe of Chaihu Shugan Powder with modifications is chosen[10,11]. The specific Chinese crude drugs are as follows: Chinese thorowax root,pericarpium citri reticulatae viride, dried tangerine root,Szechwan lovage rhizome, nutgrass galingale rhizome,Chinese herbaceous peony, orange fruit, honeysuckle bud and flower, dandelion, seaweed, weeping forsythia capsule,spina gleditsiae, thunberbg fritillary bulb. In the recipe,Chinese thorowax root, pericarpium citri reticulatae viride and dried tangerine root dispel stagnated liver qi for relieving qi stagnation, and promote qi and resolve masses,and Chinese thorowax root enters the liver meridian,which can directly introduce various drugs to the disease;Szechwan lovage rhizome and nutgrass galingale rhizome promote qi and relieve pain; Chinese herbaceous peony astringes Yin, softens liver and relieves pain; honeysuckle bud and flower and seaweed forsythia capsule clear heatdetoxicity; seaweed, spina gleditsiae and thunberbg fritillary bulb are used for softening and relieving hard mass or dissipating phlegm to remove mass. The combined use of various drugs plays the role of dispersing stagnated liver qi for relieving qi stagnation, promoting qi and relieving pain, and clearing away heat and congestion.

Invigorating the spleen and removing phlegm

The therapeutic method is used for the treatment of granulomatous mastitis caused by spleen deficiency and phlegm condensation. The main clinical manifestations of this syndrome are breast lumps, pain or no pain, obesity,depressed, fullness sensation in chest and hypochondrium,sticky and tasteless mouth, tiredness and fatigue, slippery and greasy fur, and slow and weak pulse. The deficiency of the spleen produces dampness and phlegm. The greasy and surfeit flavour can easily dissolve dampness and produce phlegm, which forms lumps in the breast meridians.The main treatment is to invigorate spleen and resolve phlegm, and accompanied by the heat-clearing and dampdrying drugs. The recipe of Shenlingbaizhu Powder with modifications is chosen. The specific Chinese crude drugs are as follows: Tangshen, largehead atractylodes rhizome,indian bread, common yam rhizome, semen dolichoris,coix seed, villous amomum fruit, common ancklandia root, golden thread and baical skullcap root. In the prescription, Tangshen, largehead atractylodes rhizome and indian bread are sovereign drugs for benefiting qi,invigorating spleen and eliminating dampness; common yam rhizome, semen dolichoris and common ancklandia root are ministerial drugs to nourish spleen and benefit qi;semen dolichoris and coix seed are adjuvants to invigorate spleen and eliminate dampness. Golden thread and baical skullcap root clear heat-dampness, and remove spleenstomach dampness-heat[21]. When the pus is not formed,honeysuckle bud and flower, Fritillaria Thunbergii and Trichosanthes can be added to clear away heat; when the pus is formed, in addition to the products that promote qi and blood circulation, Spina gleditsiae and platycodon root can be added to resolve carbuncle and expel pus.

External treatment of TCM

TCM external treatment method has also achieved certain results in the treatment of granulomatous mastitis.Professor Lin Yi created the original “pus-removing method” to treat the disease according to the theory of “removing decay and generating muscle” in Chinese medicine surgery[12]. On the basis of this method, the original fire-needle cautery technique was also used to treat granulomatous mastitis and achieved clinical effects[13]; Professor Liu Sheng advocated the use of stickers in the early stage of onset or when the skin is not red or slightly red at the beginning of the tumor. The golden cream or compound phellodendron solution were commonly used for external application[14], both of two drugs can clear away heat and detoxify, reduce swelling and dispel lumps; Ma Qiao-ling used Qingfu ointment to treat granulomatous mastitis, in combination with abscess incision and counterpart drainage, if the sinus is formed,doctors can use curette to scrape sinus, cotton twist and twist thread and other traditional Chinese medicine external treatment methods to treat the disease, and if necessary, traditional Chinese drugs can be taken orally for adjuvant treatment[10]; Zhao Hai-jun et al found that,the orally and externally application of Kangfuxin Liquid can promote the hyperplasia of granulation tissue and the healing of ulcers[15].

Modern medical treatment methods

The main methods of modern medical treatment of granulomatous mastitis include drug treatment and surgical treatment. Most doctors choose to perform surgical treatment during the prolonged period or interval of the disease. The surgical methods include largescale resection of the lesion + plastic surgery or smallscale lesion removal + debridement and drainage[16].Drug therapy includes hormone, immunosuppressant or antibiotic therapy. Hormone therapy is suitable for the early stage of tumors less than 4 cm in diameter, or the treatment of certain special causes. For example,patients with hyperprolactinemia can be treated with bromocriptine orally and receive the pituitary gland MRI examination, oral contraceptives should be discontinued immediately for acute onset of oral contraceptives. The literature points out that surgery after corticosteroid therapy can reduce the recurrence rate of the disease; for granulomatous mastitis related to immunosuppression,patients can be treated with methotrexate, interferon and thymosin. Other methods applied to treat granulomatous mastitis have also achieved certain clinical effects, such as autohemotherapy combined with methylprednisolone,minimally invasive atherectomy for the treatment of pyogenic granulomatous mastitis[17-19].

Typical Case

Patient Wei, female, 37 years old, was first diagnosed on September 15, 2010. Main complaint: A lump on the right breast was found for 7 days, and local redness, swelling,heat and pain for 3 days. The patient reported that she found a right breast lump 7 days ago without obvious redness, swelling, heat and pain. The lump gradually increased 3 days ago, the lump was painful, so she came to our outpatient clinic. The attending physician perfected the relevant examinations. The B-ultrasound examination of the bilateral breast and axilla showed: abnormal echo of the right breast, suggesting inflammatory changes;edema of the fat layer in the upper outer quadrant of the right breast; swelling of the right axillary lymph nodes.Pathological biopsy results reported: granulomatous lobular mastitis. The immediate symptoms: there is a lump on the right breast, the pain is obvious, with occasional cough, no sputum, no chest tightness, shortness of breath,no fever, poor appetite and night rest, normal urine and stools. Physical examination: bilateral breast asymmetry,swelling of the right breast, palpable mass in the upper and lower outer quadrants of the right breast, about 13 cm *11 cm in size, with clear border, smooth surface, medium texture, tenderness (+), high skin temperature, with sunken nipples, no obvious nipple discharge, hemorrhage and other secretions, no orange peel-like lesions in breasts.Red tongue, yellow greasy fur, slippery frequent pulse.In the past, the physique was average, and the menstrual cycle was disordered, sometimes advanced and sometimes delayed. Western medicine diagnosis: granulomatous mastitis; Chinese medicine diagnosis: acne mastoid carbuncle (liver stagnation and phlegm coagulation syndrome); treatment method: relieving phlegm, softening the masses, soothing the liver and regulating qi. The recipe of Chaihu Shugan Powder and Xiaoyao Loubei Powder with modifications are used, prescription composition:Chinese thorowax root 12 g, nutgrass galingale rhizome 12 g, Corydalis Yanhusuo 12 g, Szechwan lovage rhizome 12 g, prepared rehmannia root 12 g, Chinese angelica 12 g,peony root 12 g, processed pinellia tuber 12 g, snakegourd fruit 30 g, seaweed 12 g, tangle 12 g, thunberbg fritillary bulb 12 g, common buried rubber 12 g, zedoray rhizome 12 g, oyster shell 30 g, platycodon root 6 g, tuber fleeceflower stem 12 g, Bupleurum 12 g, Cyperus rotundus 12 g,Corydalis 12 g, Chuanxiong 12 g, Rehmannia 12 g. Seven doses of the above drugs are decocted in water, 1 dose a day, taken in morning and evening. 500 g of crystallized sodium sulfate is divided into 14 aliquots, twice a day, 1 aliquot/each, for external application.

Patient’s second visit was on the 22nd. The tumor was smaller than before (about 3/4 of the original size), the texture was softer than before, the swelling and pain was relieved, and the skin color was lighter than before.Occasionally cough, average food intake, bad night rest.Red tongue, yellow greasy fur, slippery frequent pulse.The treatment is the same as before, with the addition and subtraction as follows: reducing the platycodon root to 3 g. Seven doses of the drugs are decocted in water, 1 dose a day, taken in morning and evening.

Patient’s third visit was on the 29th. Physical examination:the mass is smaller than before (about 1/3 of the original size), soft texture, occasional pain, no swelling, and the skin color is as usual. No cough, no food, normal night rest. Red tongue, white greasy fur, slippery frequent pulse. The treatment method is the same as before, with the addition and subtraction as follows: reducing the Corydalis Yanhusuo to 10 g, the snakegourd fruit to 20 g, and Chinese angelica, peony root, processed pinellia tuber to 10 g; removing platycodon root. Seven doses of the drugs are decocted in water, 1 dose a day, taken in morning and evening.

Patient’s fourth visit was on October 6. The tumor was smaller than before (about 1/5 of the original size), soft in texture, painless, normal appetite and night sleep. Red tongue, thin white fur, frequent pulse. The treatment method is the same as before, with the addition and subtraction as follows: removing tuber fleeceflower stem,snakegourd fruit, common buried rubber and zedoray rhizome. Seven doses of the drugs are decocted in water, 1 dose a day, taken in morning and evening.

Patient’s fifth visit was on November 1. Re-examination of B-ultrasound: no obvious abnormalities in bilateral breasts. The imaging results reported that the patient’s right breast mass had completely disappeared, and there was no obvious abnormality on palpation.

Discussion

The patient in this case usually has a menstrual cycle disorder, and the “kidney-menstruation-Chongren-uterus”female sexual reproductive axis is unbalanced, causing imbalance of qi and blood, generating endogenous blood stasis in the breast, blocking the breast collaterals and forming breast masses. The liver governs dredging, and patients usually have emotional discomfort and stagnation of liver qi, which leads to the dysfunction of the liver governing dredging. Liver stagnation transforms fire,refining liquid to phlegm, which is easy to form stagnation of qi, phlegm coagulation and blood stasis. They obstruct breast collaterals and cause breast agglomeration. Liver depression involves spleen, spleen likes dryness and disgusts dampness, dampness traps in the spleen, spleen deficiency causes the loss of its function and is easy to produce internal dampness, accumulate dampness into phlegm. Phlegm-dampness blocks breast collaterals and forms breast lumps. Therefore, the prescription of Chinese thorowax root soothes the liver, regulates qi and relieves depression, nutgrass galingale rhizome, Corydalis Yanhusuo and Szechwan lovage rhizome activate bloodcirculation and promote qi-flowing, processed pinellia tuber, snakegourd fruit, seaweed, tangle and thunberbg fritillary bulb relieve phlegm and dissipate congestion,common buried rubber and zedoray rhizome break blood and promote qi-accumulation, oyster shell softens and resolves hard mass. Prepared rehmannia root nourishes blood and yin, tonify the yin fluid to produce blood,Chinese angelica and peony root nourish blood and activate blood, tuber fleeceflower stem nourishes blood and soothes the nerves, platycodon root promotes lungs and discharges pus. All drugs are used together to promote qi and blood circulation, reduce phlegm and soften mass.In addition, the application of crystallized sodium sulfate has the effect of reducing swelling and relieving masses.

Conclusion

The process of treatment based on syndrome differentiation is generally divided into three steps:formulating the law based on symptoms, selecting prescriptions according to the law, and applying the law based on the prescription. In the field of TCM, it is believed that the etiology and pathogenesis of the disease mainly include the imbalance of qi and blood,liver meridian stagnation and heat, spleen deficiency and phlegm coagulation, or other factors. According to the etiology and pathogenesis of syndrome differentiation and treatment, the method of enriching blood and promoting qi, soothing liver and clearing heat or invigorating spleen to reduce phlegm is used to treat this disease; the prescription of Taohong Siwu Decoction,Chaihu Shugan Powder or Shenlingbaizhu Powder with some modifications is chosen. Due to the different physiques, time of onset, accompanying symptoms,and developmental stages of the disease, the symptoms reflected are different, and the treatment is also different,which is in line with the theory of the same disease with different treatment in TCM syndrome differentiation. The incidence of granulomatous mastitis has been increasing year by year. The preventive treatment of the disease in the theory of TCM can be used to guide the prevention of diseases. Modern research has found that abnormal breastfeeding, milk stasis caused by various reasons,impaired autoimmune function, hyperemia and nipple deformity or other factors are important causes of the disease. Therefore, avoiding the occurrence of the abovementioned causes in daily life can reduce the incidence of the disease.