Granulomatous mastitis | |
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Specialty | Gynecology |
Granulomatous mastitis can be divided into idiopathic granulomatous mastitis (also known as granular lobular mastitis [1] ) and granulomatous mastitis occurring as a rare secondary complication of a great variety of other conditions such as tuberculosis and other infections, sarcoidosis and granulomatosis with polyangiitis. Special forms of granulomatous mastitis occur as complication of diabetes. Some cases are due to silicone injection (Silicone-induced granulomatous inflammation) or other foreign body reactions. [2] [3]
Idiopathic granulomatous mastitis (IGM) is defined as granulomatous mastitis without any other attributable cause such as those above mentioned. It occurs on average two years and, almost exclusively, up to six years after pregnancy, usual age range is 17 to 42 years. Some cases have been reported that were related to drug induced hyperprolactinemia. [4] [5] It has been exceptionally rarely diagnosed during pregnancy and in men. [6] [7]
Primary presentation of any of these conditions as mastitis is very rare and in many cases probably predisposed by other breast or systemic conditions. Although granulomatous mastitis is easily confused with cancer it is a completely benign (non-cancerous) condition. Treatment is radically different for idiopathic granulomatous mastitis and other granulomatous lesions of the breast. The precise diagnosis is therefore very important.
Patients mostly present with a hard lump in one breast without any sign of a systemic disease. Other possible symptoms include nipple retraction, pain, inflammation of the overlying skin, nipple discharge, fistula, enlarged lymph nodes and, in rare cases, peau d'orange-like changes. Presentation is mostly unilateral although a significant share of cases is bilateral. In many cases contralateral or bilateral recurrences were documented. Several cases occurring together with fever, polyarthralgia and erythema nodosum, were documented.[ citation needed ]
Characteristic for idiopathic granulomatous mastitis are multinucleated giant cells and epithelioid histiocytes forming non-caseating granulomas around lobules. Often minor ductal and periductal inflammation is present. The lesion is in some cases very difficult to distinguish from breast cancer and other causes such as infections (tuberculosis, syphilis, corynebacterial infection, mycotic infection), autoimmune diseases (sarcoidosis, granulomatosis with polyangiitis), foreign body reaction and granulomatous. Reaction in a carcinoma must be excluded. [4] [8]
The condition is diagnosed very rarely. As the diagnosis is a lengthy differential diagnosis of exclusion, there is considerable uncertainty about incidence. It has been suspected that some cases diagnosed as IGM in developing countries may have other explanations. On the other hand, IGM is usually diagnosed only after complications and referral to a secondary breast care center so light cases may resolve spontaneously or after symptomatic treatment and thus never be diagnosed as IGM. As a completely pathogen free breast will be exceedingly rare even in a completely healthy population, there is also uncertainty when to consider pathogens as causative or as mere coincidental finding.[ citation needed ]
Causes are not known. The histology is suggestive of an autoimmune reaction. The high rate of relapses, as well as relatively high proportion of bilateral cases, is highly suggestive of a systemic predisposition. Presently most evidence points towards an important role of elevated prolactin levels or overt hyperprolactinemia with additional triggers such as local trauma or irritation. Alpha 1-antitrypsin deficiency was documented in one case and interferon-alpha therapy in another case. Similar cases of granulomatous mastitis were reported in IgG4-related disease though the exact relationship to IGM remains to be elucidated. Other contributing factors of IGM were investigated such as oral contraceptives usage. Many cases were reported after use of prolactin elevating medications such as antipsychotics. [4] [5] [9] [10] [11]
Elevated prolactin levels have the direct effects of increasing secretory activity of breast lobules, maintaining tight junctions of the ductal epithelium, preventing involution of the breast gland after weaning and are known to stimulate the immune system. It contributes to both physiological and pathological granulomatous lesions and non-caseating granulomas. [4] PRL is also secreted locally in the breast and local secretion by lymphocytes may be enhanced during inflammatory reactions. [12] Autoimmune reaction to extravasated fat and protein rich luminal fluid (denaturized milk) resulting from the secretory activity is assumed to be one of the triggers of IGM. [4] [13] Several other hormones can contribute to PRL signalling in the breast gland. High levels of insulin caused, for example, by peripheral insulin resistance, resulting from pregnancy, gestational diabetes or developing diabetes mellitus type 2, will enhance the galactogenic and antiapoptotic effects of PRL and growth hormone by acting synergistically with IGF-1.
The presence of Corynebacterium in granulomatous mastitis was first reported in 1996. [14] Since then multiple reports have confirmed the presence of this genus in granulomatous mastitis. [15] [16] [17] The most commonly isolated species is Corynebacterium kroppenstedtii. A selective medium for the isolation of this species has been described. [18] This organism, first isolated from human sputum in 1998, requires lipids for its growth which may help to explain its association with this condition.
Treatment protocols are not well established. Some sources report that approximately half of the patients will fully recover after a 2 – 24 month management. [19]
One review recommended complete resection or corticosteroid therapy, stating also that long-term follow-up was indicated due to a high rate of recurrence. [20] Treatment with steroids usually requires about 6 months. While some source report very good success with steroids, [21] most report a considerable risk of recurrence after a treatment with steroids alone. Steroids are known to cause elevation of prolactin levels and increase risk of several conditions such as diabetes and other endocrinopathies, which in turn increase the risk of IGM. For surgical treatment, recurrence rates of 5 - 50% have been reported. [4]
Treatment with a combination of glucocorticoids and prolactin lowering medications such as bromocriptine or cabergoline, was used with good success in Germany. [22] Prolactin-lowering medication has also been reported to reduce the risk of recurrence. [23] In cases of drug-induced hyperprolactinemia such as antipsychotics, prolactin-sparing medication can be tried. [4]
Methotrexate alone or in combination with steroids has been used with good success. Its principal mechanism of action is immunomodulating activity, with a side effect profile that is more favorable for treating IGM. [24]
Colchicine, azathioprine, and NSAIDs have also been used. [25] [26]
Hyperprolactinaemia is the presence of abnormally high levels of prolactin in the blood. Normal levels average to about 13 ng/mL in women, and 5 ng/mL in men, with an upper normal limit of serum prolactin levels being 15–25 ng/mL for both. When the fasting levels of prolactin in blood exceed this upper limit, hyperprolactinemia is indicated.
Mastitis is inflammation of the breast or udder, usually associated with breastfeeding. Symptoms typically include local pain and redness. There is often an associated fever and general soreness. Onset is typically fairly rapid and usually occurs within the first few months of delivery. Complications can include abscess formation.
Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.
Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis. It raises the level of prolactin in the human body and is used to induce and promote breast milk production off label. It may be taken by mouth or rectally.
Corynebacterium is a genus of Gram-positive bacteria and most are aerobic. They are bacilli (rod-shaped), and in some phases of life they are, more specifically, club-shaped, which inspired the genus name.
Witch's milk or neonatal milk is milk secreted from the breasts of some newborn human infants of either sex. Neonatal milk secretion is considered a normal physiological occurrence and no treatment or testing is necessary. It is thought to be caused by a combination of the effects of maternal hormones before birth, prolactin, and growth hormone passed through breastfeeding and the postnatal pituitary and thyroid hormone surge in the infant.
Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.
Invasive carcinoma of no special type, invasive breast carcinoma of no special type (IBC-NST), invasive ductal carcinoma (IDC), infiltrating ductal carcinoma (IDC) or invasive ductal carcinoma, not otherwise specified (NOS) is a disease. For international audiences this article will use "invasive carcinoma NST" because it is the preferred term of the World Health Organization (WHO).
Trichobacteriosis axillaris is a superficial bacterial colonization of the hair shafts in sweat gland–bearing areas, such as the armpits and the groin. It is a trivial disease of worldwide occurrence that is believed to be caused by the genus Corynebacteria.
Breast hypertrophy is a rare medical condition of the breast connective tissues in which the breasts become excessively large. The condition is often divided based on the severity into two types, macromastia and gigantomastia. Hypertrophy of the breast tissues may be caused by increased histologic sensitivity to certain hormones such as female sex hormones, prolactin, and growth factors. Breast hypertrophy is a benign progressive enlargement, which can occur in both breasts (bilateral) or only in one breast (unilateral). It was first scientifically described in 1648.
Fibrocystic breast changes is a condition of the breasts where there may be pain, breast cysts, and breast masses. The breasts may be described as "lumpy" or "doughy". Symptoms may worsen during certain parts of the menstrual cycle due to hormonal stimulation. These are normal breast changes, not associated with cancer.
Lactation suppression refers to the act of suppressing lactation by medication or other non pharmaceutical means. The breasts may become painful when engorged with milk if breastfeeding is ceased abruptly, or if never started. This may occur if a woman never initiates breastfeeding, or if she is weaning from breastfeeding abruptly. Historically women who did not plan to breastfeed were given diethylstilbestrol and other medications after birth to suppress lactation. However, its use was discontinued, and there are no medications currently approved for lactation suppression in the US and the UK. Dopamine agonists are routinely prescribed to women following a stillbirth in the UK under the NHS.
The term nonpuerperal mastitis describes inflammatory lesions of the breast (mastitis) that occur unrelated to pregnancy and breastfeeding.
Also called Zuska's disease, subareolar abscess is a subcutaneous abscess of the breast tissue beneath the areola of the nipple. It is a frequently aseptic inflammation and has been associated with squamous metaplasia of lactiferous ducts.
Silicone granulomas are a skin condition that occur as a reaction to liquid silicones, and are characterized by the formation of nodules.
Generalized granuloma annulare is a skin condition of unknown cause, tending to affect women in the fifth and sixth decades, presenting as a diffuse but symmetrical, papular or annular eruption of more than ten skin lesions, and often hundreds.
Galactorrhea hyperprolactinemia is increased blood prolactin levels associated with galactorrhea. It may be caused by such things as certain medications, pituitary disorders and thyroid disorders. The condition can occur in males as well as females. Relatively common etiologies include prolactinoma, medication effect, kidney failure, granulomatous diseases of the pituitary gland, and disorders which interfere with the hypothalamic inhibition of prolactin release. Ectopic (non-pituitary) production of prolactin may also occur. Galactorrhea hyperprolactinemia is listed as a “rare disease” by the Office of Rare Diseases of the National Institutes of Health. This means that it affects less than 200,000 people in the United States population.
Gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Gynecomastia can cause significant psychological distress or unease.
Mammoplasia is the normal or spontaneous enlargement of human breasts. Mammoplasia occurs normally during puberty and pregnancy in women, as well as during certain periods of the menstrual cycle. When it occurs in males, it is called gynecomastia and is considered to be pathological. When it occurs in females and is extremely excessive, it is called macromastia and is similarly considered to be pathological. Mammoplasia may be due to breast engorgement, which is temporary enlargement of the breasts caused by the production and storage of breast milk in association with lactation and/or galactorrhea. Mastodynia frequently co-occurs with mammoplasia.
The side effects of cyproterone acetate (CPA), a steroidal antiandrogen and progestin, including its frequent and rare side effects, have been studied and characterized. It is generally well-tolerated and has a mild side-effect profile, regardless of dosage, when it used as a progestin or antiandrogen in combination with an estrogen such as ethinylestradiol or estradiol valerate in women. Side effects of CPA include hypogonadism and associated symptoms such as demasculinization, sexual dysfunction, infertility, and osteoporosis; breast changes such as breast tenderness, enlargement, and gynecomastia; emotional changes such as fatigue and depression; and other side effects such as vitamin B12 deficiency, weak glucocorticoid effects, and elevated liver enzymes. Weight gain can occur with CPA when it is used at high doses. Some of the side effects of CPA can be improved or fully prevented if it is combined with an estrogen to prevent estrogen deficiency. Few quantitative data are available on many of the potential side effects of CPA. Pooled tolerability data for CPA is not available in the literature.
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