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Spinal tap, if clinically indicated
Treatment depends on the specific etiology.
Therapeutic trials are a last resort and should be as specific as possible based on available clinical evidence. Avoid “shotgun” approaches as they obscure the clinical picture, have untoward effects, and do not provide a diagnostic solution (
First-line drugs depend on the diagnosis.
Evidence does not support isolated treatment of fever (
Antibiotic trial based on patient’s history and suspected culture negative endocarditis
Antituberculous therapy if there is a high risk for TB pending definitive culture results
Corticosteroid trial based on patient’s history (once occult malignancy is ruled out) if temporal arteritis is suspected
Reserved for the ill and debilitated
Consider if factitious fever has been ruled out or an invasive procedure is indicated.
The extended time required in establishing a diagnosis can be frustrating.
Depends on etiology and age
1-year survival rates (reflecting deaths due to all causes)
Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: a clinical approach. Am J Med. 2015;128(10):1138.e1–1138.e15.
Hayakawa K, Ramasamy B, Chandrasekar PH. Fever of unknown origin: an evidence-based review. Am J Med Sci. 2012;344(4):307–316. 
Mulders-Manders C, Simon A, Bleeker-Rovers C. Fever of unknown origin. Clin Med (Lond). 2015;15(3):280–284.
SEE ALSO
Arteritis, Temporal
CODES
Asequential approach to FUO based on a careful history, physical examination, with targeted testing and imaging typically yields an appropriate diagnosis and avoids excessive nontargeted testing.
Use empiric therapy only in carefully defined circumstances.
FUO cases that defy precise diagnosis after intensive investigation and prolonged observation generally have a favorable prognosis.
FUO in older persons may represent an atypical presentation of a common disease.
The most common causes of FUO in high-income countries are noninfectious inflammatory diseases and idiopathic causes.
Maria A. Pino, PhD
Fibrocystic changes (FCC) is not a disease but refers to a constellation of benign histologic findings. It is the most frequent female benign clinical breast finding.
FCC may also be described as aberrations of normal development and evolution.
The most common symptoms are cyclic pain, tenderness, swelling, and fullness.
The breast tissue may feel dense with areas of thicker tissue having an irregular, nodular, or ridge-like surface.
Women may experience sensitivity to touch with a burning sensation. For some, the pain is so severe that it limits exercise or the ability to lie prone. Usually affects both breasts, most often in the upper outer quadrant where most of the milk-producing glands are located.
Histologically, in addition to macrocysts and microcysts, FCC may contain solid elements including adenosis, sclerosis, apocrine metaplasia, stromal fibrosis, and epithelial metaplasia and hyperplasia.
System(s) affected: endocrine/metabolic, reproductive
Synonym(s): diffuse cystic mastopathy; fibrocystic disease; chronic cystic mastitis; or mammary dysplasia
With hormone replacement therapy, FCC may extend into menopause.
Less common in East Asian races
FCC originates from an exaggerated response of breast stroma and epithelium to a variety of circulating and locally produced hormones (mainly estrogen and progesterone) and growth factors.
Cysts may form due to dilatation of the lobular acini possibly due to imbalance of fluid secretion and resorption or due to obstruction of the duct leading to the lobule.
In many women, methylxanthine-containing substances (e.g., coffee, tea, cola, and chocolate) can potentiate symptoms of FCC, although a direct causality has not been established.
Diet high in saturated fats may increase risk of FCC.
Obtain personal history of breast biopsy and family history of breast disease (benign or malignant). It is important to ascertain if the patient has a known family history of BRCA1or BRCA2-related cancer.
Inquire regarding pertinent signs/symptoms, such as breast pain, engorgement, nipple discharge, palpable lumps, and tenderness.
The patient should be examined in the following positions while disrobed down to the waist:
Be certain to examine the creases under and between the breasts. If the patient has noted a lump, ask her to point it out; always palpate the opposite breast first.
Patients with FCC have clinical breast findings that range from mild alterations in texture to dense, firm breast tissue with palpable masses.
Pain
Evaluation should focus on excluding breast cancer.
Testing may be conducted based on a level of clinical suspicion.
FCC can be evaluated with mammogram, although dense breast tissue may appear normal in women <35 years of age.
Ultrasound (US) is the most important method in assessing a cyst.
On mammogram, FCC appears as nodular densities of breast tissue; solitary cysts can appear as round or ovoid or well-circumscribed masses, usually with low to intermediate density. FCC may also contain calcifications.
On US, if a simple cyst is demonstrated as an anechoic structure with imperceptible wall and posterior acoustic enhancement, benign diagnosis is confirmed and no further imaging or intervention is indicated. However, if the cyst appears to be thick-walled and/or contains internal echoes, differential diagnosis should include a complicated cyst, an abscess, a galactocele, or a focal duct ectasia in the appropriate clinical contexts.
MRI is indicated in patients with BRCA1 or BRCA2 mutation or in any woman with ≥25% lifetime risk for breast cancer.
On MRI, cystic changes are well-circumscribed lesions of high-signal intensity on T2-weighted sequences and of low-signal intensity on T1weighted images (
Fine-needle aspiration (FNA) biopsy:
If mass disappears, no further evaluation is necessary (including cytologic evaluation of aspirated fluid).
On the basis of the presence and degree of epithelial hyperplasia, FCC is comprised of nonproliferative (approximately 65% of the total), proliferative without atypia (approximately 30% of the total), and proliferative with atypia (approximately 5–8% of the total) (
Nonproliferative changes: relative risk of 1.2 to 1.4
Proliferative disease (PD) without atypia: relative risk of 1.7 to 2.1 
PD with atypia: relative risk ≥4 (
After ruling out malignancy by means of examination and/or imaging and diagnostic procedures, FCC may not require treatment and often resolves with time.
Cool compresses, avoiding trauma, and around-the-clock wearing of a wellfitting, supportive brassiere may be useful for symptom relief.
Reduction in caffeine, additional supplementation with vitamin E, and/or evening primrose oil have been advocated. Recent trials have not proven benefit (
Acetaminophen: 1,000 mg every 6 hours; maximum daily dose of 3,000 mg
unless directed by health care provider
Ibuprofen: 400 mg every 4 to 6 hours as needed
Naproxen:500 mg every 12 hours as needed
Second Line
Oral contraceptives (OCPs) may be useful in modulating symptoms or in preventing the development of new changes in females with cyclic symptoms. 
For severe pain, consider the following (4,5)[B]:
–Danazol is effective for reducing breast pain and tenderness, but has androgenic effects and is associated with hepatotoxicity and teratogenicity, which limits its use. This drug is administered orally at a dosage of 100 to 400 mg/day in 2 divided doses.
–Tamoxifen 10 mg/day for 3 to 6 months. Along with teratogenicity, this selective estrogen receptor modulator (SERM) can increase the risk of thromboembolism and endometrial carcinoma in treated females.
–Several other medications, such as bromocriptine and GnRH agonists have been studied, but are associated with toxicities.
ISSUES FOR REFERRAL
If discrete palpable lesion in a woman <35 years: US, then refer to a surgeon
If discrete palpable lesion in a woman >35 years: diagnostic mammography ± US, then refer to surgeon
SURGERY/OTHER PROCEDURES
Breast cyst aspiration can be both diagnostic and therapeutic.
Core-needle biopsies performed under stereotactic guidance with vacuum assistance has similar accuracy in distinguishing between malignant and benign lesions compared to open surgical biopsy (6)[A].
COMPLEMENTARY& ALTERNATIVE MEDICINE
The use of vitamin E has shown effectiveness in treating breast pain due to FCC (3)[B].
Little evidence supports the use of evening primrose oil for FCC.
ONGOING CARE
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