Continuing Education Activity

Fibrocystic breast disease is the most common benign type of breast disease, diagnosed in millions of women worldwide. Certain hormonal factors underpin the function, evaluation, and treatment of this disease. Benign breast disease is an umbrella term for various non-malignant lesions, such as tumors, trauma, mastalgia, and nipple discharge. This activity reviews the indications, symptomology, management, and other key elements related to fibrocystic breast disease in the clinical setting related to the essential points needed by members of an interprofessional team managing the care of patients with the condition and sequelae.

Objectives:

• Summarize the pathophysiology of fibrocystic breast conditions.

• Outline the appropriate history, physical, and evaluation of a patient presenting with symptoms associated with benign breast disease.

• Review the treatment and management options available for fibrocystic breast disease.

• Describe some interprofessional team strategies for improving care coordination and communication to advance patient education regarding this disease and improve outcomes.

Introduction

Fibrocystic breast disease is the most common benign type of breast disease, diagnosed in millions of women worldwide. Certain hormonal factors underpin the function, evaluation, and treatment of this disease. Benign breast disease is an umbrella term for various non-malignant lesions, such as tumors, trauma, mastalgia, and nipple discharge.[1]

The above-mentioned benign lesions are not associated with an increased risk for malignancy; however, it associates with an up to 50% risk of developing breast cancer under certain histopathological and clinical circumstances.[2] A palpable mass upon clinical evaluation is evident in both benign and malignant breast conditions. The clinical findings include symptoms such as dimpling of the skin (peau d'orange), thickening, pain, and nipple discharge.[3]

The most common investigative tools to assess for these clinical findings are mammograms and ultrasound.[4]

The main components of the breast are prone to fibrocystic changes during hormonal fluctuations. These components include the stroma, ducts, and lobules of the breast. During the reproductive age, glandular breast tissue has a direct relation to cyclical surges of plasma levels of estradiol and progesterone.[1]

Etiology

The etiology of benign breast disease has demonstrated a strong clinical association with women receiving estrogen and anti-estrogen treatment. The prevalence of benign breast lesions in postmenopausal women receiving estrogens and progestins for over eight years is increased by 1.7 fold. During the Women’s Health Initiative study (WHI), the combined use of estrogen and progestin correlated with a 74% risk of benign breast disease. The use of anti-estrogens led to a 28% reduction in the prevalence of benign proliferative breast disease.[5]

Study selection criteria

The analysis used prospective cohort and nested case-control studies of at least 300 cases and meta-analyses.

See Table 1 

* Relative risks estimated from standardized incidence ratios. 

† Controls were women who had non-proliferative benign breast disease.[2] 

Polycystic ovary syndrome (PCOS) typically presents with factors such as anovulation and hyperandrogenaemia, which is evident in 5 to10% of women within reproductive age.[6]

Previous studies have concluded that hyperestrogenism and anovulation are associated with benign breast conditions, as the growth of glandular breast tissue is affected by the levels of estrogen and progesterone in pathological processes.[7]

Epidemiology

There is varied literature, ranging from 30 to 60% of all women. It is most common in women between the ages of 30 to 50 years.[8]

One of the most common forms of benign breast disease is fibroadenomas, characterized by localized proliferation of breast ducts and stroma. This subtype accounts for 70 to 95% of all tumor benign type of breast disease. The incidence is mostly seen in the 17 to 20 year age group, extending to 2 years premenarche at 35.[3]

Pathophysiology

Mammary gland development, maturation, and differentiation act upon the hormonal and growth factor changes affecting the stromal and epithelial cells.[4]

During the late proliferative phase, glandular tissue evolves to hyperplastic stages such as sclerosing adenosis or lobular hyperplasia. This state of hyperplasia, if associated with a 2% prevalence of Ki67 cells, has a twofold increased incidence for the development of breast cancer.[9]

Various types of benign breast disease exist, such as hyperplasia, cysts, fibroadenomas, sclerosing adenosis, and mastitis.

Histopathology

There is a limited pathological consensus regarding the histopathological appearance of benign breast disease.

The main features are an extracellular matrix of collagen, peri canalicular patterns of stromal cells with the presence of florid epithelial hyperplasia.

During the menopausal phase, fibroadenomas involute, which affects dense collagen stroma and atrophic glands.[10]

Cystic changes derive from the terminal duct lobular unit (TDLU). Due to the expansion of the efferent ductules of the TDLU, cysts form as a result of fluid accumulation in these structures. The lining appears flat with a myoepithelial layer present.[5]

Image 3

Microscopic histology section of fibroadenosis

History and Physical

Benign cysts are typically mobile within the glandular breast tissue, chest wall, and skin and are rubber-like in texture. Except for inflammatory type cysts, discomfort and tenderness experienced by a patient are either absent or mild. Most patients present with multiple cysts upon further clinical and diagnostic evaluation.[11]

Various subtypes of cysts are known, including hyperplastic fibrous cysts, adenosis, and papillomatosis. These types of cysts are usually found in the upper outer quadrants of the breast, as well as in the central margins. The texture upon evaluation ranges from a firm texture to multiple subcentimeter cysts.[12]

Fibroadenomas present in varied sizes with a common oval-shaped, well-defined margin. As with cysts, fibroadenomas are mobile upon evaluation and are often multiple, occurring either simultaneously or over a specified period.[13]

Nipple discharge is associated with ductal ectasia, intraductal papilloma, or in rare instances, carcinoma. 

The finding of an intraductal papilloma is associated with a single duct presenting a bloody, sudden discharge with a small palpable nodule in the retro areolar region. Multiple ducts presenting with nonspontaneous, green, yellow, clear discharges are a common feature with duct ectasia.[14]

Evaluation

Triple testing is a combination consisting of clinical examination, imaging, and excision biopsy. This is essential for all women with a clinical finding, such as a discrete palpable mass.

Nodularity in young women less than 30 years of age may have management with clinical surveillance and short-term follow-up examination in 2 to 3 months. An investigation may be necessary if the lump has changed on review or if, at the initial presentation, there is a new change in her breasts.[15] Nodularity or thickening that is asymmetric in women over the age of 30 years, further investigation utilizing mammography and ultrasound, is warranted. 

Short-term follow-up is an important part of the management of nodularity so that the progression in size of a mass of nodularity or other associated findings (e.g., skin or nipple changes) is detected. 

Mammography with ultrasound examination is required for all discrete palpable lesions in women over 35 to distinguish cysts from solid lesions. Complex cysts containing both fluid and solid matter require biopsy. For solid lesions, radiographically or ultrasonically directed core biopsy provides further information regarding the presence or absence of malignancy.

Core excision biopsy involves a cutting needle with a spring-loaded, automated biopsy instrument that allows sufficient specimen of tissue for histologic analysis.

FNA allows a cytopathologist to evaluate cellular material.[16] However, the amount of material retrieved during FNA procedures being sufficient for diagnosis is non-successful in 35 to 47% of non-palpable lesions. A core biopsy is then the recommendation.[17]

Cytology of nipple discharge has limited specificity and sensitivity to detect malignancy (35 to 47%). If the results of both clinical and diagnostic evaluations are benign, a 6 to 12-month clinical breast examination, ultrasound, and mammography are the suggested follow-up to confirm a stable appearance. 

A study of 156 patients in Japan who had a benign breast biopsy showed that 13 percent required a subsequent biopsy within two years of having routine FNA procedures performed. In a retrospective study, 150 patients with benign histology after ultrasound-guided vacuum-assisted biopsy for complex cystic breast lesions (BI-RADS 4) were assessed. 

This subset of patients underwent study in 6 monthly intervals. Of the 104 lesions, none led to the development of malignancy.[4]

Routine ultrasound screening in Japan was used with 10519 women to evaluate recall criteria. Researchers noted a cystic-type breast pattern in 6512 cases.

Only one of the patient cases reported malignancy the following year, related to a solid tumor with a cystic component, proven to be a micro-invasive cancer of less than 1 mm.

There was no cancer diagnosed in this subset of patients. Most of the study subjects were less than 40 years of age.[18]

Treatment / Management

Due to the role of estrogen and progesterone treatments, promoting fibrocystic changes in the breast, metformin has been suggested as a treatment method to reduce the excessive cell proliferation caused by associated hormones.[19]

For patients presenting with mastalgia, the first-line options are lifestyle changes. Other suggestions are the use of a supportive bra, as well as altering the dose of hormone replacement therapy regimen.

There is no evidence that reducing caffeine improves fibrocystic breast disease or mastalgia.[20][21]

Analgesics such as aspirin and ibuprofen are options.[22]

Researchers have proposed that a deficiency in prostaglandin E and its precursor gamma-linolenic acid (GLA) increase the sensitivity of breasts during the luteal phase of the menstrual cycle. GLA is subsequently also the active component of evening primrose oil.

Despite not having proven efficacy in previous studies, the use of evening primrose oil is warranted as supportive measures if pain persists despite treatment and advice. A 3 to 6 month period is the suggested timeframe to observe the desired effect[23]

If breast pain is severe for more than six months and disrupts daily activities, other therapies such as tamoxifen, bromocriptine, or danazol can be options. Due to the recurrent nature and long duration of these symptoms, several months of treatment is necessary.

Fluid from cysts aspirated for symptomatic relief does not require cytological assessment. This evaluation is reserved for clinically evident lumps that resolve following the FNA procedure or where the cyst fluid appears macroscopically bloodstained.

Fluid from atypical cysts should have a cytological assessment.[24]

Surgery is indicated for cysts that repetitively, despite frequent FNA, which have an intra-cystic solid appearance on ultrasound or have atypical cells present upon cytopathological evaluation.[25]

Differential Diagnosis

• Breast lump
• Breast abscess
• Fibrocystic changes
• Fibroadenomas
• Infections[26] 
• Trauma
• Fat necrosis
• Papilloma
• Phyllodes tumor
• Breast ectasia[27] 

Pertinent Studies and Ongoing Trials

1. Thirty patients with fibrocystic breast disease received a clinical trial of danazol. Twenty-three patients had a 5 to 6-month treatment regime.
   • Partial or complete relief of breast pain and nodularity for all patients included in the clinical trial.
   • The researchers found malignancy in one patient following three months of therapy. There were limited reported side effects.
   • Recurrence of symptoms occurred after discontinuation of the drug.[28]
2. A study currently being performed in Japan will assess the efficacy and safety of the Xiaoru Sanjie capsule in the treatment of cyclo-mastopathy. The study will be a multicenter, randomized, open controlled clinical study.

Staging

There are not specific characterized stages of benign breast disease used as a standard method of diagnosis; however, fibrocystic type breast disease can be proliferative or non-proliferative types.

Non-proliferative types are not associated with unexpected cell growth. Common non-proliferative lesions would include:-

• Periductal fibrosis
• Nonsclerosing adenosis
• Cysts
• Epithelial-related calcifications
• Mild epithelial hyperplasia
• Papillary apocrine changes.

Non-proliferative lesions are the most common finding in breast cancer screening biopsies, seen in 70% of all cases.

Proliferative changes include factors such as Intraductal hyperplasia, sclerosing adenosis, radial scars, and papillomas.

Prognosis

Proliferative type lesions have a 1.3 to 1.9 times increased risk of malignancy for both breasts.

Any increase in pleomorphic calcifications on mammograms should qualify for a 6-month interval follow-up regime.

Complications

A random sampling of fibrocystic breast disease will often reveal fibrosis if fibrosis is detected using MR-guided sampling. Discordant results should be considered, with further evaluation warranted.[29]

Deterrence and Patient Education

Advice to be provided to patients for preventing and treating fibrocystic breast disease includes:

• Use over-the-counter pain relievers such as acetaminophen or ibuprofen.
• Apply warm or cool compresses to breasts when most painful.
• Wear a comfortable, supportive bra.
• Avoid large amounts of salt or fat in the diet, which some women find can worsen symptoms.
• Consider an oral contraceptive.

Check thyroid levels and suggest the use of iodine.

Consider vitamin E, evening primrose oil, and B vitamins.

Pearls and Other Issues

• A true lateral mammogram can be useful to distinguish benign calcifications from malignant calcifications, such as milk of calcium deposits.[30]
• Diffuse, scattered, similar bilateral findings favor a benign result.
• Focal pain is not a sign of malignancy though ultrasound can serve as a reassurance tool for patients.
• Thermoablation is currently under assessment as a treatment option for benign and malignant lesions.
• The American Society of Breast Surgeons has raised a warning in the assessment and has released a statement for the use of ablative treatment.
• The statement concludes that ablative techniques are currently investigational and should not be performed in the United States unless part of a clinical research trial.[31]

Enhancing Healthcare Team Outcomes

Communicating information about the diagnosis, treatment, and prognosis to patients with breast disease is important for all reported cases in a breast clinic. The best means to accomplish this is an interprofessional team consisting of primary care providers, general surgeons, radiologists, pharmacists, and specialty-trained breast care nurses.

Concerns of patients included the language of physicians, lack of consideration for patient autonomy, and promotion of decision-making power to patients.[32]

Pharmacists become involved when using medications to treat this condition. They counsel patients, review side effects, check for drug interactions, and stress the importance of compliance. Breast care nurses educate patients about the good prognosis and the importance of close follow-up initially. They can also chart progress in treatment, or lack thereof, and inform the lead clinician of any concerns that may arise. These examples of interprofessional collaboration show how the team approach can improve patient outcomes and minimize adverse events. [Level 5] 

Image 4 and 5: Interprofessional care factors to consider during clinical evaluation of breast disease, both benign and malignant findings.

Psychosocial, home, and work environments require a stable structure to ensure both physical and mental wellbeing. Patients diagnosed with fibrocystic breast disease are also associated with fear and uncertainty due to a lack of education regarding their diagnoses. 

Proper medical interaction and interprofessional coordination and communication are necessary to ensure a holistic patient output.