Definitions

phlegmonous mastitis

Mastitis

[ma-stahy-tis]
Mastitis is the inflammation of the parenchyma of the mammary gland (breast in primates, udder in other mammals). It is called puerperal mastitis when it occurs in lactating mothers and non-puerperal otherwise. Mastitis can occur in men, albeit rarely. Inflammatory breast cancer has symptoms very similar to mastitis and must be ruled out.

The popular misconception that mastitis in humans is an infection is highly misleading and in many cases plain wrong. Infections play only a minor role in the pathogenesis of both puerperal and nonpuerperal mastitis in humans and many cases of mastitis are completely aseptic under normal hygienic conditions. Infection as primary cause of mastitis is presumed to be more prevalent in veterinary mastitis and poor hygienic conditions.

The symptoms are similar for puerperal and nonpuerperal mastitis but predisposing factors and treatment can be very different.

Popular usage of the term mastitis varies by geographic region. Outside the US it is commonly used for puerperal and nonpuerperal cases, in the US the term nonpuerperal mastitis is rarely used and alternative names such as duct ectasia, subareolar abscess and plasma cell mastitis are more frequently used.

Chronic cystic mastitis is a different (older) name for fibrocystic disease.

American usage: mastitis usually refers to puerperal (occurring to breastfeeding mothers) mastitis with symptoms of systemic infection. Lighter cases of puerperal mastitis are often called breast engorgement.

Names for non-puerperal mastitis are not used very consistently and include Mastitis, Subareolar Abscess, Duct Ectasia, Periductal Inflammation, Zuska's Disease and others.

Breast cancer may coincide with or mimic symptoms of mastitis. Only full resolution of symptoms and careful examination are sufficient to exclude the diagnosis of breast cancer.

In this wikipedia article mastitis is used in the original sense of the definition as inflammation of the breast with additional qualifiers where appropriate.

Mastitis is also a very common condition in Veterinary medicine.

Puerperal mastitis

Puerperal mastitis is the inflammation of breast in connection with pregnancy, breastfeeding or weaning. It is caused by blocked milk ducts or milk excess. It is relatively common, estimates range depending on methodology between 5-33%. However only about 0.4-0.5% of breastfeeding mothers develop an abscess.

Some predisposing factors are known but their predictive value is minimal. It appears that proper breastfeeding technique, frequent breastfeeding and avoidance of stress are the most important factors that can be influenced.

Mastitis can be classified as milk stasis, non-infectious or infectious inflammation and abscess. It is impossible to correlate this classification with clinical symptoms, in particular milk stasis, non-infectious and infectious inflammation can be distinguished only by leukocyte count and bacteria culturing. Symptoms like fever, intensity of pain, erythema or rapid onset of symptoms can not be used to distinguish these.

Temperature and severity of symptoms at presentation do not predict outcome, women with sore or damaged nipples may need special attention (Kvist LJ et al 2007)

Light cases of mastitis are often called breast engorgement, the distinction is overlapping and possibly arbitrary or subject to regional variations.

Milk from the affected breast can be considerably saltier than normal, though this does not cause problems for the infant. However sudden changes in levels of salt supply must be avoided. When the infant adapts to the saltier milk and is suddenly weaned or fed exclusively from the other breast a hyponatremic shock can occur.

Early stages of mastitis can present with local pain, redness, swelling, and warmth, later stages also present with systemic symptoms like fever and flu-like symptoms and in rare cases an abscess can develop. However it is pretty common that symptoms develop very quickly without any warning.

Infectious pathogens commonly associated with mastitis are staphylococcus aureus, streptococcus spp., gram negative bacilli such as escherichia coli. Salmonella spp., mycobacteria, candida, and cryptococcus have been identified in rare instances.

Recent research suggests that infectious pathogens play a much smaller role in the pathogenesis than was commonly assumed only a few years ago. Most detected pathogens are very common species that are natural part of the breast fauna and simple detection of their presence is not sufficient to prove a causative role. Furthermore treatment with antibiotics appears to have minimal impact (Peters J. 2004, Barbosa-Cesnik et al 2003).

Except in severe cases it is not necessary to wean a nursling because of mastitis; in fact, nursing is the most effective way to remove the blockage and alleviate the symptoms. Sudden weaning can cause or exacerbate mastitis symptoms and cause hyponatremic shock in the infant.

Continued breastfeeding does not present any risk to the nursing infant and is very beneficial for the mother(Peters J. 2004, Barbosa-Cesnik et al 2003).

The presence of cracks or sores on the nipples increases the likelihood of infection. Tight clothing or ill-fitting bras may also cause problems as they compress the breasts. There is a possibility that infants carrying infectious pathogens in their noses can infect their mothers; the clinical significance of this finding is still unknown.

Treatment

Frequent emptying of both breasts by breastfeeding is essential. Also essential is adequate fluid supply for the mother and baby. Use of pumps to empty the breast is now considered somewhat controversial.

In cases of light mastitis massage and application of heat prior to feeding can help as this may aid unblocking the ducts. However in more severe cases of mastitis heat or massage could make the symptoms worse and cold compresses are better suited to contain the inflammation.

Antibiotics are not needed in the overwhelming majority of cases and should be used only for bacterial infections (Peters J. 2004). If antibiotics are started a full course of up to 14 days should be used to avoid recurrence or antibiotics resistance.

In severe cases it may be required to restrict milk supply or stop lactation and use lactation inhibiting medication.

Puerperal breast abscess

Breast abscess develops only rarely, most sources cite about 0.4-0.5% of breastfeeding women. Known risk factors are age over 30, primiparous and late delivery. No correlation was found with smoking status however this may be in part because much fewer smoking women choose to breastfeed. Antibiotics were not shown effective in prevention of this kind of abscess but are useful to treat a secondary infection.

Keratinizing squamous metaplasia of lactiferous ducts may play a similar role like like in the pathogenesis of nonpuerperal subareolar abscess.

Aspiration or incision and drainage may be used to relieve the abscess. Breastfeeding from the affected breast should be continued where possible (Peters J. 2004).

Weaning and mastitis

Breast engorgement or mastitis occur frequently after weaning. The pregnancy/lactation related hormones usually return to normal levels shortly after weaning but for some women it can take several months and there is an increased risk of rebound lactation and mastitis before hormone levels settle. Avoiding stress is important because the same hormones are also stress hormones. Even after hormone levels settle it takes some time for the breast gland to rebuild to its nonlactating state and it may be particularly prone to mastitis during this time.

Most cases of post weaning mastitis or breast engorgement resolve with relatively little treatment. Recurrent post weaning mastitis on the other hand can be an indication of a developing hyperprolactinemia or thyroid disorders and endocrinological examination must be considered.

Cold compresses, lactation inhibiting herbs or medication can be used.

Salvia officinalis is commonly used for weaning (Veldhuizen-Staas C. 2007), but no peer reviewed literature is known on this subject. Chasteberry extract can improve prolactin levels which may reduce risk of recurrence but no data is available for use in mastitis.

Prolactin lowering medication has been frequently used for weaning in the past but is much less used since Parlodel (bromocriptine) approval for weaning has been withdrawn in the US over safety concerns. While the question of bromocriptin safety for weaning purposes was never completely resolved it became apparent that it was not very effective in the prescribed dose and did rarely justify the unpleasant side effects.

Other prolactin lowering medications (Cabergolin, Lisurid) are effective and appear safe but are not widely used for weaning.

Granulomatous (non-puerperal) mastitis is known to occur on average 2 years and almost exclusively up to 6 years after pregnancy. It is an extremely rare condition and believed to be in many cases related to an autoimmune reaction to milk proteins following incomplete inhibition of milk secretion and hyperprolactinemia.

Distinction between puerperal (but post-weaning) and nonpuerperal mastitis is somewhat arbitrary.

Nonpuerperal mastitis

The term nonpuerperal mastitis describes inflammatory lesions of the breast occurring unrelated to pregnancy and breastfeeding. This article includes description of mastitis as well as various kinds of mammary abscesses. Skin related conditions like dermatitis and foliculitis are a separate entity.

Acute mastitis, duct ectasia, Zuska's disease, subareolar abscess, retroareolar abscess, periductal mastitis, plasma cell mastitis, comedo mastitis, granulomatous mastitis and secretory disease are names used for nonpuerperal mastitis or special cases of it. The terminology is not entirely consistent and subject to regional variation. Duct ectasia has at least 4 different possible meanings.

Most patients are women of reproductive age but mastitis beyond the age of 60 is not uncommon. In postmenopausal cases it is usually linked to hormone replacement therapy or antipsychotic (prolactin raising) medication. Rarely occurs in newborn children (mastitis neonatorum) or prepubertal children.

So called pre-pubertal mastitis (the name is apparently used only in the UK) can occur shortly before or during the first stages of puberty of both boys and girls with very mild symptoms and resolves without intervention.

Mastitis in truly prepubertal children on the other hand is very rare and appears to have a diverse spectrum causes. Hormonal and non hormonal causes as well as premature adrenarche have been suspected.

Mastitis in newborns may be due to a combination of infection and influence of maternal hormones.

Factors that were found to cause or predispose for nonpuerperal mastitis are hyperprolactinemia, thyroid problems, tobacco smoking, breast trauma, nipple piercings, diabetes and many prolactin raising medications.

Mastitis develops in tissue that is highly sensitive to systemic and local hormone and cytokine stimulation. Hormonal aspects are very important in aetiology and pathology. The inflammation or irritation resulting from abscess formation or surgical procedures does frequently cause marked temporary changes in hormones, mainly prolactin which may further aggravate the problem. Failure to consider the hormonal aspects in diagnosis and therapy can result in chronic disease.

Symptoms of nonpuerperal mastitis

Symptoms are in most cases local affecting only part of a breast, often close to the nipple and areola, more often the upper inner side of the breast. Rarely whole breast affected, mostly only one breast.

  • redness (about 80% cases)
  • diffuse swelling, tenderness (80%)
  • pain local to affected area (77%)
  • local overwarming, thermographically detectable hotspots (25%)
  • swollen lymph nodes on the affected side (65%), rarely both sides (11%)
  • abscess formation
  • inflammation intensity can be repeatedly flaring up and down
  • nipple discharge

In contrast to puerperal mastitis systemic fever and flu like symptoms are much less common, only part of the breast is affected and abscessation is frequent.

Depending on treatment and predisposing factors many cases develop an abscess. In one study 63% of the 54 patients treated exclusively with antibiotics developed an abscess as opposed to only 25% of the 48 patients treated with bromocriptin (Goepel & Pahnke 1991).

Abscesses are often recurring with repeated fistulation and draining. Recurrent abscesses and duct ectasia have been also observed to cause symptoms like nipple retraction and skin dimpling normally indicative of breast cancer.

Nipple discharge can be of several types. Clear to whitish fluid can be galactorrhea and a sign of hyperprolactinemia or thyroid problems. Pasty thick white to yellowish discharge is often associated with duct ectasia syndrome and subareolar abscess. Brown or dark nipple discharge is sometimes associated with progesterone excess or adrenal hyperplasia but requires further investigation to rule out malignancy.

Mammography and symptoms do not allow reliable exclusion of breast cancer. Mastitis can mimic several typical signs of malignancy on mammography and up to 70% mammographies present with suspicious results. Even after consideration of other symptoms 10–15% may require biopsy to rule out cancer. All symptoms that do not fully disappear after 5 weeks of treatment should prompt detailed investigation.

Aetiology and Pathogenesis

Most clinically significant cases present as inflammation of the ductal and lobular system (galactophoritis) and surrounding tissue.

The presumed pathogenesis is milk stasis which leads to periductal inflammation, leakage of glandular secretions and periductal plasmacell inflammation (Krause et al 1994, Lanyi 2003). Autoimmune reaction to the secretions also appear to be a factor, especially in idiopathic granulomatous mastitis.

The role of milk stasis may appear somewhat surprising in non-puerperal mastitis, however nonpuerperal secretory activity in the breast is well known. For example the incidence of galactorrhea is reported to be about 5-30% of healthy female population which is several orders of magnitude more than that of nonpuerperal mastitis. Sobrinho (2003) explains plausibly why weak lactation inhibition is advantageous for humans in evolutionary terms.

Most authors assume milk or milk-like extrapuerperal secretory activity (Peters F.& Schuth 1989, Goepel & Pahnke 1991, Krause et al 1994) and treatment success with dopamine agonists would appear to confirm that. Apocrine nonpuerperal secretory activity is also known (Vizoso et al 1994) but has received relatively little attention as possible cause of nonpuerperal mastitis.

Several factors are discussed in the literature that may cause or predispose nonpuerperal mastitis (Lanyi 2003, Peters F.& Schuth 1989, Goepel & Pahnke 1991, Krause et al 1994, Celis et al 2006):

  • secretory activity or galactorrhea
  • changes in permeability of lactiferous ducts (retention syndrome)
  • blockage of lactiferous ducts, for example duct plugging caused by squamous metaplasia of lactiferous ducts
  • hormonal/cytokine irritation caused by leaking breast cyst fluid
  • changes in luminal fluid consistence
  • autoimmune reaction to luminal fluid
  • trauma, injury
  • mechanical irritation caused by retention syndrome or fibrocystic condition
  • infection

It appears that several factors are usually involved, for example blockage of lactiferous ducts alone should not cause any problem unless there is considerable secretory activity and duct permeability (retention syndrome) is affected.

Coincidence with galactorrhea has been observed but is relatively low - Peters F.& Schuth (1989) reported only approximately 9% despite approximately 55% of cases with transient or persistent elevation of serum prolactin levels. Rather it appears that galactorrhea and mastitis might be two alternative manifestations of the same underlying problem.

About 20–25% of patients may be hyperprolactinemic and significant coincidence with fibrocystic disease and thyroid anomalies (often subclinical) has been documented. Another 25% of patients present with temporary hyperprolactinemia possibly caused by the inflammation or treatment. Of the patients with normal basal prolactin levels most have abnormally high prolactin reserve.

Hyperprolactinemia or latent hyperprolactinemia is considered causative in many cases but may be also caused by the inflammation or treatment (Peters F.& Schuth 1989, Goepel & Pahnke 1991, Krause et al 1994).

While it appears that only 20-50% of cases are associated with increased serum levels of prolactin and overt hyperprolactinemia is probably even less frequent, the role of prolactin may be much larger than this numbers suggest. The results of Goepel and Pahnke (1991) suggest that bromocriptin may be curative in as much as 95% of cases practically irrespective of prolactin serum levels.

Several hypotheses have been put forward explaining the treatment effect of dopamine agonists despite relatively low prevalence of hyperprolactinemia.

While increased prolactin is required to initiate lactogenesis in humans, lactation can be maintained even with completely normal prolactin levels. Lowering prolactin bellow physiological levels does inhibit lactogenesis even in this cases. Because prolactin is also a stress hormone transient elevations of serum levels are very common (Goepel & Pahnke 1991, Sobrinho 2003).

Stauber & Weyerstahl (2005) assume hypersensitivity to prolactin, possibly caused by progesterone deficiency and steroid receptor crossregulation. Yet another possible explanation is that women with benign breast disease who have normal serum prolactin values usually have increased breast fluid concentration of prolactin (Vizoso et al 1994). Further possible explanations include: altered bioactivity of prolactin, other hormones affected by dopamine agonists (at least TSH, cortisol, growth hormone, insulin), other effects of dopamine agonists (histaminic, serotonergic or dopaminergic effects on target tissue) or prolactin lowering as a catch all treatment. In particular TSH, cortisol, insulin and growth hormones are lactogenic though not as potent as prolactin. The catch all effect of prolactin lowering may be similar to that in galactorrhea - while only about 50-75% of galactorrhea cases are caused by prolactin elevation or increased prolactin reserve, bromocriptin usually works even in the cases not detectably associated with prolactin.

Permeability the of the alveolar and ductal epithelia is a very important factor for in the regulation of secretory activity and resorption of ductal secretions, it is mostly controlled by tight junction regulation. The tight junctions are regulated by a multitude of systemic (prolactin, progesterone, glucocorticoids) and local (intramammary pressure, TGF-beta, osmotic balance) factors (Nguyen & Neville 1998).

Thyroid disorders have been implicated in the aetiology of nonpuerperal mastitis, however the underlying mechanisms are not well understood. Thyroid stimulating hormone is directly lactogenic and known to cause galactorrhea, furthermore thyroid problems are often accompanied by secondary hyperprolactinemia so that several plausible hypotheses for a possible pathogenesis exist. Closer examination of the issue by Goepel & Pahnke (1991) appears to confirm a significant role of thyroid disorders but also indicates that none of the obvious hypotheses offers a sufficient explanation of the underlying mechanism. Up to 50% of their examined patients had either nonspecific findings as thyroid enlargement or nodularity, relevant anamnesis or well controlled thyroid disease. However only a very small fraction of those had lab values out of range or secondary hyperprolactinemia. The authors note that prognosis for this patient group is not very good, maintenance of euthyroid state is clearly beneficial and patients were treated with bromocriptin and antibiotics.

Frequent coincidence of nonpuerperal mastitis with fibrocystic disease was observed and the conditions may be predisposed by the same factors, mainly (latent) hyperprolactinemia (Goepel & Pahnke 1991).

Severe fibrocystic disease can directly cause mastitis. The fluid filled cysts in fibrocystic disease usually contain high concentrations of cytokines, hormones and growth factors which when leaked into surrounding tissue can cause inflammation (Celis et al 2006).

Hormone replacement therapy can cause mastitis in postmenopausal patients. Hypothesized mechanism is increased sensitivity to prolactin caused by increased estrogen to progesterone ratio (Goepel & Pahnke 1991). A similar role for birth control pills in premenopausal patients was suspected by some authors but available statistics do not support this hypothesis. This may be in part because most patients have strong counterindication for birth control pills (age over 30 and smoking). Anecdotal evidence also shows that some patients do not tolerate birth control pills.

Tobacco smoking appears to be an important factor in the aetiology of squamous metaplasia of lactiferous ducts, around 90% of patients with this condition are smokers. Current smokers have the worst prognosis and highest rate of recurrent abscesses.

Acromegaly may present with symptoms of nonpuerperal mastitis, this may be due to direct effects of growth hormone and IGF1 or because prolactin is frequently also increased in acromegaly.

Diabetes and many conditions with suppressed immune system can cause various infections of the breast and mastitis. Such conditions often present with inflammation of peripheral tissue and exotic infections. Insulin resistance and high levels of insulin may also be a factor in the pathogenesis of mastitis.

Nipple piercings pose a risk due to bacterial infection following the injury and hormonal stimulation by the piercing (Jacobs et al 2003, Modest & Fangman 2002, Demirtas et al 2003).

Duct Ectasia

Duct ectasia - literally (lactiferous) duct widening is a very common and thus rather unspecific finding, increasing with age.

Duct ectasia syndrome is a synonym for nonpuerperal mastitis but the term has also been occasionally used to describe special cases of fibrocystic diseases, mastalgia or as a wastebasket definition of benign breast disease.

Correlation of duct widening with the "classical" symptoms of duct ectasia syndrome is not at all clear. However duct widening was recently very strongly correlated with noncyclic breast pain (Browning et al 1986, Peters et al 2003)

Duct diameter is naturally variable, subject to hormonal interactions. Duct ectasia syndrome in the classical meaning is associated with additional histological changes.

Disambiguation

The term has several meanings on histological and symptomatic levels and on both levels usage overlaps with mastalgia, fibrocystic disease and specific sub- or superclasses of nonpuerperal mastitis. While this is not ideal for a definition it results from actual usage in international literature. Because research literature regarding duct ectasia is anything but abundant it is probably easiest to determine the exact meaning(s) intended by the respective authors on a case by case basis and this section can offer only a few hints.

Typical usage in north America is a synonym of nonpuerperal mastitis, including the special cases of granulomatous mastitis, comedo mastitis, subareolar abscess with or without squamous metaplasia of lactiferous ducts and fistulation. See for example the Stanford University criteria

Simple duct widening should be carefully distinguished from more complex histological changes.

Noninvasive methods to determine duct diameter in live patients are available only recently and it is not clear how the results should be compared with older results from biopsies.

Duct widening with associated periductal fibrosis is frequently included in the wastebasket definition of fibrocystic disease.

The term duct ectasia syndrome has been used to describe symptoms of nonpuerperal mastitis, possibly associated with nipple inversion and nipple discharge. Abscessation is not very frequent but by some definitions recurrent subareolar abscess is merely a variant of duct ectasia syndrome - abscessation would be obviously more frequent with this definition.

Duct ectasia syndrome has been associated with histopathological findings that are distinct from a simple duct widening. In addition to nonspecific duct widening the myoepithelial cell layer is atrophic, missing or replaced by fibrous tissue. The original cuboidal epithelial layer may be also severely impaired or missing. Characteristic calcifications are often visible on mammographic images.

The term duct ectasia has been also used to describe symptoms of cyclical and noncyclical mastalgia and fibrocystic disease.

The term duct ectasia syndrome was in some contexts used to describe a particular form of nonpuerperal mastitis coincident with fibrocystic disease, frequently involving pasty (coloured) nipple discharge, nipple retraction, retroareolar abscess and blue dome cysts.

Periductal mastitis, comedo mastitis, secretory disease of the breast, plasma cell mastitis and mastitis obliterans are sometimes considered special cases or synonyms of duct ectasia syndrome.

Pathogenesis

This section should be seen in the context of the main aetiology and pathogenesis section of nonpuerperal mastitis.

The duct widening is commonly believed to be a result of secretory stasis which also causes periductal inflammation and fibrosis. However because nonspecific duct widening is common it might be also coincidental finding in many processes.

Smokers seem more often affected by duct ectasia syndrome although the reported results are not entirely consistent. The correlation with smoking status appears weaker than for subareolar abscess. Correlation with the actual duct widening is not known.

Both duct widening and duct ectasia syndrome are frequently bilateral, hence systemic causes are likely involved.

Duct ectasia syndrome (in the sense of nonpuerperal mastitis and cylcical mastalgia) appears to be highly correlated with increased prolactin serum levels (Peters F & Schuth 1989). This authors also reported that treatment with bromocriptin can reduce recurrence rate of duct ectasia syndrome related mastitis.

Duct ectasia syndrome in the sense of noncyclical mastalgia does not appear to be correlated with high prolactin levels (Peters F. et al 2003).

Local prolactin overexpression does cause histological abnormalities strikingly similar to duct ectasia and duct ectasia syndrome in transgenic mouse models, including atrophy of the myoepithelial layer and ducts filled with dense eosinophilic secretions (Manhès et al 2006).

Subareolar abscess

Also called Zuska's disease (only nonpuerperal case), is a frequently aseptic inflammation and has been associated with squamous metaplasia of lactiferous ducts.

Subareolar abscess can develop both during lactation or extrapuerperal, the abscess is often flaring up and down with repeated fistulation.

90% of cases are smokers, however only a very small fraction of smokers appear to develop this lesion. It has been speculated that either the direct toxic effect or hormonal changes related to smoking could cause squamous metaplasia of lactiferous ducts. It is not well established whether the lesion regresses after smoking cessation.

Extrapuerperal cases are often associated with hyperprolactinemia or thyroid problems.

Treatment is problematical unless an underlying endocrine disorder can be successfully diagnosed and treated.

The inflammation should be controlled by bromocriptine even in absence of hyperprolactinemia (Goepel & Pahnke 1991, Krause et al 1994). As much as 30% of cases may develop repeatedly recurring abscesses and require long term or indefinite treatment with a low dose of bromocriptin (Goerke et al 2003)

Duct resection has been traditionally used to treat the condition, the original Hadfield procedure has been improved many times but long term success rate remains poor even for radical surgery (Hanavadi et al, 2005). Petersen (2003) even suggests that damage caused by previous surgery is a frequent cause of subareolar abscesses. Goepel and Pahnke (1991) and other authors recommend performing surgeries only with concomitant bromocriptine treatment.

Squamous metaplasia of lactiferous ducts

Squamous metaplasia of lactiferous ducts - abbreviated SMOLD is a change where the normal double layer cuboid epithelium of the lactiferous ducts is replaced by squamous keratinizing cell layers. The resulting epithelium is very similar to normal skin, hence some authors speak of epidermalization. SMOLD is rare in premenopausal women (possibly 0.1-3%) but more frequent (possibly up to 25%) in postmenopausal women where it does not cause any problems at all.

SMOLD appears to be a completely benign lesion and may exist without causing any symptoms. In principle it ought to be completely reversible as the classification as metaplasia would suggest. Because of difficulties in observing the actual changes and rare incidence of the lesion this does not appear to be documented.

The last section of the lactiferous ducts is always lined with squamous keratinizing epithelium which appears to have important physiological functions. For example the keratin forms plugs sealing the duct entry and has bacteriostatic properties. In SMOLD the keratinizing lining which is supposed to form only the ends of the lactiferous ducts extends deep into the ducts.

SMOLD is distinct from squamous metaplasia that may occur in papilomatous hyperplasia. It is believed to be unrelated to squamous cell carcinoma of the breast which probably arises from different cell types.

The keratin plugs (debris) produced by SMOLD have been proposed as the cause for recurrent subareolar abscesses by causing secretory stasis. The epidermalized lining has also different permeability than the normal lining, hindering resorption of glandular secretions. The resorption is necessary to dispose of stalled secretions inside the duct - and at least equally important it affects osmotic balance which in turn is an important mechanism in the control of lactogenesis (this is relevant both in puerperal and nonpuerperal mastitis).

While in lactating women this would appear to be a very plausible pathogenesis, there is some uncertainty about the pathogenesis in non-lactating women where breast secretions should be apriori minimal. It appears pathologic stimulation of lactogenesis must be present as well to cause subareolar abscess and treatment success with bromocriptin appears to confirm this (Goepel & Pahnke 1991) as compared to poor success rate of the usual antibiotic and surgical treatments documented by Hanavadi et al (2005).

Further uncertainty in the relation of SMOLD and the subareolar abscess is that squamous metaplasia is very often caused by inflammatory processes. SMOLD could be the cause of the inflammation - or the result of a previous or longstanding inflammation.

SMOLD usually affects multiple ducts and frequently (relative to extremely low absolute prevalence) both breasts hence it is very likely that systemic changes such as hormonal interactions are involved.

At least the following factors have been considered in the aetiology of SMOLD: reactive change to chronic inflammation, systemic hormonal changes, smoking, dysregulation in beta-catenin expression, changes in retinoic acid and vitamin D metabolism or expression.

Prolactin has been implicated in squamous metaplasia of lactiferous ducts (Manhès et al 2006). Prolactin also has direct and indirect effects on IGF1 and IGF-BP5 in the mammary gland.

Vitamin A deficiency has been observed to cause squamous metaplasia in many types of epithelia. However supplementation with Vitamin A would be beneficial only in exceptional cases because normally the local catabolism of vitamin A will be the regulating factor.

Squamous metaplasia of breast epithelia is known to be more prevalent in postmenopausal women (where it does not cause any problems at all). Staurosporine, a nonspecific protein kinase C inhibitor can induce squamous metaplasia in breast tissue while other known PKC inhibitors did not show this effect. cAMP stimulation can also induce squamous metaplasia (Heffelfinger et all 1998)

Granulomatous mastitis

Characteristic for granulomatous mastitis are multinucleated giant cells and epithelioid histiocytes around lobules. Often minor ductal and periductal inflammation is present. The lesion is in some cases very difficult to distinguish from breast cancer.

Patients usually present with a distinct firm mass mostly in the subareolar region. It occurs on average 2 years and almost exclusively up to 6 years after pregnancy, usual age range is 17 to 42 years. Use of hormonal contraceptives, prolactin raising medications and hyperprolactinemia have been implicated in the pathogenesis or as predisposing factors.

Granulomatous mastitis is most often completely aseptic but infectious causes must be considered as well.

Idiopathic granulomatous mastitis is thought to be an autoimmune reaction to extravasated fat and protein rich luminal fluid (denaturized milk)(Krause et al 1994, Bässler 1997). This form is often associated with increased prolactin levels while some infectious forms are often associated with diabetes.

Comedo mastitis

Comedo mastitis is a very rare form similar to granulomatous mastitis but with tissue necrosis. Because it is so rare it may be sometimes confused with comedo carcinoma of the breast although the conditions appear to be completely unrelated.

Treatment

Diagnosis and treatment of underlying endocrine problems is of paramount importance in nonpuerperal mastitis, however only a small minority of patients does have overt endocrine disorders.

Prolactin lowering medication has been shown to be significantly more effective than antibiotics and reduce risk of recurrence even in absence of increased prolactin levels (Goepel & Pahnke 1991, Krause et al 1994, Stauber & Weyerstrahl 2005, Petersen 2003, Goerke et al 2003). The suggested dose of 5-7.5mg/day BCS or equivalent makes it appear unlikely that any prolactin lowering herbal medication could be used for this purpose.

Antibiotics should be given in addition to prolactin inhibiting medication if there are clear signs of infection, preferably after determination of the involved pathogens (Petersen 2003).

Granulomatous mastitis has been treated with some success by a combination of steroids and prolactin inhibiting medication (Krause et al 1994).

More exotic treatments for nonpuerperal mastitis that have been mentioned to show at least some efficiacy include local and systemic progestins or progesteron (Goepel & Pahnke 1991), antidiuretics, danazol and Vitex Agnus Castus extract. Progestins probably increase lactiferous duct permeability and reduce prolactin sensitivity.

NSAIDs may be used to relieve symptoms of the inflammation, however it must be considered that these medications also affect pituitary function and may increase prolactin and growth hormone levels (Caviezel et al 1983).

Many variants of surgical procedures such as duct resection have been tried to reduce the risk of recurrent subareolar abscesses. So far the success rates are limited and conservative treatment seems preferable whenever possible (Petersen 2003).

Up to 30% of cases may develop recurring mastitis requiring long term or indefinite treatment with prolactin inhibiting medication (Goerke et al 2003). Vitex Agnus Castus extract has been used for this purpose but so far no peer reviewed publication is known to recommend it.

Breast cancer and mastitis

Lifetime risk for breast cancer is significantly reduced for women who were pregnant and breastfeeding. Mastitis episodes do not appear to influence lifetime risk of breast cancer.

Mastitis does however cause great difficulties in diagnosis of breast cancer and delayed diagnosis and treatment can result in worse outcome.

Breast cancer may coincide with mastitis or develop shortly afterwards. All suspicious symptoms that do not completely disappear within 5 weeks must be investigated.

Breast cancer incidence during pregnancy and lactation is assumed to be the same like in controls. Course and prognosis are also very similar to age matched controls (Middleton et al 2003, Shousha 2000). However diagnosis during lactation is particularly problematic, often leading to delayed diagnosis and treatment.

Some data suggests that noninflammatory breast cancer incidence is increased within a year following episodes of nonpuerperal mastitis and special care is required for followup cancer prevention screening (Peters et al 2002). So far only data from short term observation is available and total risk increase can not be judged. Because of the very short time between presentation of mastitis and breast cancer in this study it is considered very unlikely that the inflammation had any substantial role in carcinogenesis, rather it would appear that some precancerous lesions may increase the risk of inflammation (hyperplasia causing duct obstruction, hypersensitivity to cytokines or hormones) or the lesions may have common predisposing factors.

A very serious type of breast cancer called inflammatory breast cancer presents with similar symptoms as mastitis (both puerperal and nonpuerperal). It is the most aggressive type of breast cancer with the highest mortality rate. The inflammatory phenotype of IBC is thought to be mostly caused by invasion and blocking of dermal lymphatics, however it was recently shown that NF kappaB target genes activation may significantly contribute to the inflammatory phenotype. Case reports show that inflammatory breast cancer symptoms can flare up following injury or inflammation making it even more likely to be mistaken for mastitis. Symptoms are also known to partially respond to progesterone and antibiotics, reaction to other common medications can not be ruled out at this point. (Kusama et al 1994, Yamada et al 1992, Van Laere et al 2006, Van Laere et al 2007, Van der Burg & Van der Saag 1996, Srivastava et al 2003, Takada et al 2004, Boutet et al 2007).

Terminology

Depending on appearance, symptoms, aetiological assumptions and histological findings a variety of terms has been used to describe mastitis and various related aspects.

  • galactopoiesis: milk production
  • secretory disease: aberrant secretory activity in the lobular and lactiferous duct system, believed to be the most frequent factor causing galactophoritis. The secretions may be milk like or apocrine luminal fluid.
  • retention syndrome (aka retention mastitis): accumulation of secretions in the ducts with mainly intraductal inflammation.
  • galactostasis: accumulation of milky secretions in the ducts
  • galactophoritis: inflammation of the lobular and lactiferous duct system, mainly resulting from secretory disease and retention syndrome.
  • plasma cell mastitis: plasma cells from the intraductal inflammation infiltrate surrounding tissue.
  • duct ectasia: literally widening of lactiferous ducts - relatively common finding in breast exams, increase with age. Strongly correlated with cyclic and noncyclic breast pain. Correlation with mastitis is of anecdotal quality.
  • duct ectasia syndrome: in older literature this was used as synonym for nonpuerperal mastitis with recurring breast abscess, nipple discharge and possibly associated fibrocystic condition with blue dome cysts. Recent research shows that duct ectasia is only weakly correlated with mastitis symptoms (inflammation, breast abscess). The use of the terms Duct Ectasia and Duct Ectasia Syndrome is inconsistent throughout the literature.
  • squamous metaplasia of lactiferous ducts: cuboid cells in the epithelial lining of the lactiferous ducts transform (squamous metaplasia) to squamous epithelial cells. Present in many cases of subareolar abscesses.
  • subareolar abscess: abscess bellow or in close vicinity of the areola. Mostly galactophoritis resulting from secretory disease, duct blockage and duct permeability changes
  • retroareolar abscess: deeper (closer to chest) than a subareolar abscess.
  • periductal inflammation (aka periductal mastitis): inflammation infiltrated tissue surrounding lactiferous ducts. Almost synonym for subareolar abscess. May be just a different name for plasma cell mastitis.
  • fistula: fine channel draining an abscess cavity
  • Zuska's disease: subareolar abscess associated with squamous metaplasia of lactiferous ducts. Some authors also associate this with nipple discharge.

See also

References

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  • Mastitis Nonpuerperalis

Notes

External links

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