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Breast cancer

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Breast cancer
Classification & external resources
Histopathologic image from ductal cell carcinoma in situ (DCIS) of breast. Hematoxylin-eosin stain.
ICD-10 C50.
ICD-9 174-175
OMIM 114480
DiseasesDB 1598
MedlinePlus 000913
eMedicine med/2808 
MeSH D001943
Image:Breast cancer gross appearance.jpg
Typical macroscopic (gross) appearance of the cut surface of a mastectomy specimen containing a cancer (in this case, an invasive ductal carcinoma of the breast, pale area at the center).
Image:BreastCancer.jpg
Mastectomy specimen containing a very large cancer of the breast (in this case, an invasive ductal carcinoma).

Breast cancer is a cancer that starts in the cells of the breast.[1] Worldwide, breast cancer is the second most common type of cancer after lung cancer (10.4% of all cancer incidence, both sexes counted)[2] and the fifth most common cause of cancer death.[3] However, among women worldwide, breast cancer is by far the most common cause of cancer, both in incidence and death.[3] In 2005, breast cancer caused 502,000 deaths worldwide (7% of cancer deaths; almost 1% of all deaths).[3] The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly blamed on modern lifestyles in the Western world.[4][5]

Breast cancer incidence is much higher in the Western world, whether in Europe or North America, than in third world countries. North American women have the highest incidence of breast cancer in the world.[6] Among women in the U.S., breast cancer is the most common cancer and the second-most common cause of cancer death (after lung cancer).[6] Women in the U.S. have a 1 in 8 (12.5%) lifetime chance of developing invasive breast cancer and a 1 in 35 (3%) chance of breast cancer causing their death.[6] In 2007, breast cancer was expected to cause 40,910 deaths in the U.S. (7% of cancer deaths; almost 2% of all deaths).[7]

In the U.S., both incidence and death rates for breast cancer have been declining in the last few years.[8][7] Nevertheless, a U.S. study conducted in 2005 by the Society for Women's Health Research indicated that breast cancer remains the most feared disease,[9] even though heart disease is a much more common cause of death among women.[10]

Because the breast is composed of identical tissues in males and females, breast cancer also occurs in males.[11][12] Incidences of breast cancer in men are approximately 100 times less common than in women, but men with breast cancer are considered to have the same statistical survival rates as women.[13]

Contents

Classification

Image:BCtimeline.jpg
Time line of breast cancer suggesting probable heterogeneity. Primary breast cancers begin as single (or more) cells which have lost normal regulation of differentiation and proliferation but remain confined within the basement membrane of the duct or lobule. As these cells go through several doublings, at some point they invade through the basement membrane of the duct or lobule and ultimately metastasize to distant organs.[14]

Breast cancers are described along four different classification schemes, or groups, each based on different criteria and serving a different purpose :

  • Pathology - A pathologist will categorize each tumor based on its histological (microscopic anatomy) appearance and other criteria. The most common pathologic types of breast cancer are invasive ductal carcinoma, malignant cancer in the breast's ducts, and invasive lobular carcinoma, malignant cancer in the breast's lobules.
  • Grade of tumor - The histological grade of a tumor is determined by a pathologist under a microscope. A well-differentiated (low grade) tumor resembles normal tissue. A poorly differentiated (high grade) tumor is composed of disorganized cells and, therefore, does not look like normal tissue. Moderately differentiated (intermediate grade) tumors are somewhere in between.
  • Protein & gene expression status - Currently, all breast cancers should be tested for expression, or detectable effect, of the estrogen receptor (ER), progesterone receptor (PR) and HER2/neu proteins. These tests are usually done by immunohistochemistry and are presented in a pathologist's report. The profile of expression of a given tumor helps predict its prognosis, or outlook, and helps an oncologist choose the most appropriate treatment. More genes and/or proteins may be tested in the future.
  • Stage of a tumour - The currently accepted staging scheme for breast cancer is the TNM classification :
    • Tumor - There are five tumor classification values (Tis, T1, T2, T3 or T4) which depend on the presence or absence of invasive cancer, the dimensions of the invasive cancer, and the presence or absence of invasion outside of the breast (e.g. to the skin of the breast, to the muscle or to the rib cage underneath).
    • Lymph Node - There are four lymph node classification values (N0, N1, N2 or N3) which depend on the number, size and location of breast cancer cell deposits in lymph nodes.
    • Metastases - There are two metastatic classification values (M0 or M1) which depend on the presence or absence of breast cancer cells in locations other than the breast and lymph nodes (so-called distant metastases, e.g. to bone, brain, lung).

Pathologic types

The latest (2003) World Health Organization (WHO) classification of tumors of the breast[15] recommends the following pathological types:

Invasive breast carcinomas

  • Invasive ductal carcinoma
    • Most are "not otherwise specified"
    • The remainder are given subtypes:
      • Mixed type carcinoma
      • Pleomorphic carcinoma
      • Carcinoma with osteoclastic giant cells
      • Carcinoma with choriocarcinomatous features
      • Carcinoma with melanotic features
  • Invasive lobular carcinoma
  • Tubular carcinoma
  • Invasive cribriform carcinoma
  • Medullary carcinoma
  • Mucinous carcinoma and other tumours with abundant mucin
  • Neuroendocrine tumours
    • Solid neuroendocrine carcinoma (carcinoid of the breast)
    • Atypical carcinoid tumour
    • Small cell / oat cell carcinoma
    • Large cell neuroendocrine carcioma
  • Invasive papillary carcinoma
  • Invasive micropapillary carcinoma
  • Apocrine carcinoma
  • Metaplastic carcinomas
  • Lipid-rich carcinoma
  • Secretory carcinoma
  • Oncocytic carcinoma
  • Adenoid cystic carcinoma
  • Acinic cell carcinoma
  • Glycogen-rich clear cell carcinoma
  • Sebaceous carcinoma
  • Inflammatory carcinoma
  • Bilateral breast carcinoma

Mesenchymal tumors (including sarcoma)

  • Haemangioma
  • Angiomatosis
  • Haemangiopericytoma
  • Pseudoangiomatous stromal hyperplasia
  • Myofibroblastoma
  • Fibromatosis (aggressive)
  • Inflammatory myofibroblastic tumour
  • Lipoma
    • Angiolipoma
  • Granular cell tumour
  • Neurofibroma
  • Schwannoma
  • Angiosarcoma
  • Liposarcoma
  • Rhabdomyosarcoma
  • Osteosarcoma
  • Leiomyoma
  • Leiomysarcoma

Precursor lesions

  • Lobular neoplasia
    • lobular carcinoma in situ
  • Intraductal proliferative lesions
  • Microinvasive carcinoma
  • Intraductal papillary neoplasms
    • Central papilloma
    • Peripheral papilloma
    • Atypical papilloma
    • Intraductal papillary carcinoma
    • Intracystic papillary carcinoma

Benign epithelial lesions

  • Adenosis, includin variants
    • Sclerosing adenosis
    • Apocrine adenosis
    • Blunt duct adenosis
    • Microglandular adenosis
    • Adenomyoepithelial adenosis
  • Radial scar / complex sclerosing lesion
  • Adenomas

Myoepithelial lesions

  • Myoepitheliosis
  • Adenomyoepithelial adenosis
  • Adenomyoepithelioma
  • Malignant myoepithelioma

Fibroepithelial tumours

Tumours of the nipple

Malignant lymphoma

Metastatic tumours

Tumours of the male breast

The classifications above show that breast cancer is usually, but not always, classified by its histological appearance. Rare variants are defined on the basis of physical exam findings. For example, Inflammatory breast cancer (IBC), a form of ductal carcinoma or malignant cancer in the ducts, is distinguished from other carcinomas by the inflamed appearance of the affected breast.[16] In the future, some pathologic classifications may be changed. For example, a subset of ductal carcinomas may be re-named basal-like carcinoma (part of the "triple-negative" tumors).[citation needed]

Signs and symptoms

The first symptom, or subjective sign, of breast cancer is typically a lump that feels different than the surrounding breast tissue. According to the Merck Manual, greater than 80% of breast cancer cases are discovered as a lump by the woman herself.[17] According to the American Cancer Society (ACS), the first medical sign, or objective indication of breast cancer as detected by a physician, is discovered by mammogram.[7] Lumps found in lymph nodes located in the armpits[17] and/or collarbone[citation needed] can also indicate breast cancer.

Indications of breast cancer other than a lump may include changes in breast size or shape, skin dimpling, nipple inversion, or spontaneous single-nipple discharge. Pain is an unreliable tool in determining the presence of breast cancer, but may be indicative of other breast-related health issues such as mastodynia.[7][17][18]

When breast cancer cells invade the dermal lymphatics, small lymph vessels in the skin of the breast, its presentation can resemble skin inflammation and thus is known as inflammatory breast cancer (IBC). Symptoms of inflammatory breast cancer include pain, swelling, warmth and redness throughout the breast, as well as an orange peel texture to the skin referred to as peau d'orange.[17]

Another reported symptom complex of breast cancer is Paget's disease of the breast. This syndrome presents as eczematoid skin changes such as redness and mild flaking of the nipple skin. As Paget's advances, symptoms may include tingling, itching, increased sensitivity, burning, and pain. There may also be discharge from the nipple. Approximately half of women diagnosed with Paget's also have a lump in the breast.[19]

Occasionally, breast cancer presents as metastatic disease, that is, cancer that has spread beyond the original organ. Metastatic breast cancer will cause symptoms that depend on the location of metastasis. More common sites of metastasis include bone, liver, lung and brain. Unexplained weight loss can occasionally herald an occult breast cancer, as can symptoms of fevers or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological symptoms. These symptoms are "non-specific," meaning they can also be manifestations of many other illnesses.[20]

Most symptoms of breast disorder do not turn out to represent underlying breast cancer. Benign breast diseases such as mastitis and fibroadenoma of the breast are more common causes of breast disorder symptoms. The appearance of a new symptom should be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancer at almost any age.[21]

Epidemiology and etiology

Epidemiological risk factors for a disease can provide important clues as to the etiology, or cause, of a disease. The first case-controlled study on breast cancer epidemiology was done by Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health.[22][verification needed][23]

Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors. Some of these factors include:

  1. Lesions to DNA such as genetic mutations. Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.[24] Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation in causing genetic mutations.[citation needed]
    1. Failure of immune surveillance, a theory in which the immune system removes malignant cells throughout ones life.[25]
      1. Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth. For example, tumors can induce blood vessel growth (angiogenesis) by secreting various growth factors further facilitating cancer growth.[citation needed]
      2. Inherited defects in DNA repair genes, such as BRCA1, BRCA2[26] and p53.[citation needed]

        Although many epidemiological risk factors have been identified, the cause of any individual breast cancer is often unknowable. In other words, epidemiological research informs the patterns of breast cancer incidence across certain populations, but not in a given individual. The primary risk factors that have been identified are sex,[27] age,[28] childbearing, hormones,[29] a high-fat diet,[30] alcohol intake,[31] obesity,[32] and environmental factors such as tobacco use and radiation.[26]

        No etiology is known for 95% of breast cancer cases, while approximately 5% of new breast cancers are attributable to hereditary syndromes.[33] In particular, carriers of the breast cancer susceptibility genes, BRCA1 and BRCA2, are at a 30-40% increased risk for breast and ovarian cancer, depending on in which portion of the protein the mutation occurs.[34]

        Prevention

        Phytoestrogens and soy

        Phytoestrogens such as found in soybeans have been extensively studied in animal and human in-vitro and epidemiological studies. The literature support the following conclusions:

        1. Plant estrogen intake, such as from soy products, in early adolescence may protect against breast cancer later in life.[35]
          1. Plant estrogen intake later in life is not likely to influence breast cancer incidence either positively or negatively.[36]

            Folic acid (folate)

            Studies have found that "folate intake counteracts breast cancer risk associated with alcohol consumption"[37] and "women who drink alcohol and have a high folate intake are not at increased risk of cancer."[38][39][40] A prospective study of over 17,000 women found that those who consume 40 grams of alcohol (about 3-4 drinks) per day have a higher risk of breast cancer. However, in women who take 200 micrograms of folate (folic acid or Vitamin B9) every day, the risk of breast cancer drops below that of alcohol abstainers.[41]

            Folate is involved in the synthesis, repair, and functioning of DNA, the body’s genetic map, and a deficiency of folate may result in damage to DNA that may lead to cancer.[42] In addition to breast cancer, studies have also associated diets low in folate with increased risk of pancreatic, and colon cancer.[43][44]

            Foods rich in folate include citrus fruits, citrus juices, dark green leafy vegetables (such as spinach), dried beans, and peas. Vitamin B9 can also be taken in a multivitamin pill.

            Avoiding exposure to secondhand tobacco smoke

            Breathing secondhand smoke increases breast cancer risk by 70% in younger, primarily premenopausal women. The California Environmental Protection Agency has concluded that passive smoking causes breast cancer[45] and the US Surgeon General[46] has concluded that the evidence is "suggestive," one step below causal. There is some evidence that exposure to tobacco smoke is most problemmatic between puberty and first childbirth. The reason that breast tissue appears most sensitive to chemical carcinogens in this phase is that breast cells are not fully differentiated until lactation.[47]

            Oophorectomy and mastectomy

            Prophylactic oophorectomy (removal of ovaries), in high-risk individuals, when child-bearing is complete, reduces the risk of developing breast cancer by 60%, as well as reducing the risk of developing ovarian cancer by 96%.[48]

            Medications

            Hormonal therapy has been used for chemoprevention in individuals at high risk for breast cancer. In 2002, a clinical practice guideline by the US Preventive Services Task Force (USPSTF) recommended that "clinicians discuss chemoprevention with women at high risk for breast cancer and at low risk for adverse effects of chemoprevention" with a grade B recommendation.[49][verification needed][50][51]

            Selective estrogen receptor modulators (SERMs)

            The guidelines[clarify] were based on studies of SERMs from the MORE, BCPT P-1, and Italian trials. In the MORE trial, the relative risk reduction for raloxifene was 76%.[52] The P-1 preventative study demonstrated that tamoxifen can prevent breast cancer in high-risk individuals. The relative risk reduction was up to 50% of new breast cancers, though the cancers prevented were more likely estrogen-receptor positive (this is analogous to the effect of finasteride on the prevention of prostate cancer, in which only low-grade prostate cancers were prevented).[53][54] The Italian trial showed benefit from tamoxifen.[55]

            Additional randomized controlled trials have been published since the guidelines. The IBIS trial found benefit from tamoxifen.[56] In 2006, the NSABP STAR trial demonstrated that raloxifene had equal efficacy in preventing breast cancer compared with tamoxifen, but that there were fewer side effects with raloxifene.[57] The RUTH Trial concluded that "benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke".[58] On September 14, 2007, the US Food and Drug Administration approved raloxifene (Evista) to prevent invasive breast cancer in postmenopausal women.[59]

            Screening

            Breast cancer screening is an attempt to find unsuspected cancers. The most common screening methods are self and clinical breast exams, x-ray mammography, and breast Magnetic resonance imaging (MRI)

            X-ray mammography

            Mammography is still the modality of choice for screening of early breast cancer, since it is relatively fast, reasonably accurate, and widely available in developed countries.

            Due to the high incidence of breast cancer among older women, screening is now recommended in many countries. Recommended screening methods include breast self-examination and mammography. Mammography has been estimated to reduce breast cancer-related mortality by 20-30%.[60] Routine (annual) mammography of women older than age 40 or 50 is recommended by numerous organizations as a screening method to diagnose early breast cancer and has demonstrated a protective effect in multiple clinical trials.[61] The evidence in favor of mammographic screening comes from eight randomized clinical trials from the 1960s through 1980s. Many of these trials have been criticised for methodological errors, and the results were summarized in a review article published in 1993.[62]

            Improvements in mortality due to screening are hard to measure; similar difficulty exists in measuring the impact of Pap smear testing on cervical cancer, though worldwide, the impact of that test is likely enormous. Nationwide mortality due to cancer before and after the institution of a screening test is a surrogate indicator about the effectiveness of screening, and results of mammography are favorable.

            Normal (left) versus cancerous (right) mammography image.
            Normal (left) versus cancerous (right) mammography image.

            The U.S. National Cancer Institute recommends screening mammography every one to two years beginning at age 40.[63] In the UK, women are invited for screening once every three years beginning at age 50. Women with one or more first-degree relatives (mother, sister, daughter) with premenopausal breast cancer should begin screening at an earlier age. It is usually suggested to start screening at an age that is 10 years less than the age at which the relative was diagnosed with breast cancer.

            A clinical practice guideline by the US Preventive Services Task Force recommended "screening mammography, with or without clinical breast examination (CBE), every 1 to 2 years for women aged 40 and older."[64] The Task Force gave a grade B recommendation.[49][verification needed]

            In 2005, 67.9% of all U.S. women age 40–64 had a mammogram in the past two years (74.5% of women with private health insurance, 56.1% of women with Medicaid insurance, 38.1% of currently uninsured women, and 32.9% of women uninsured for > 12 months).[65]

            Criticisms of screening mammography

            Several scientific groups however have expressed concern about the public's perceptions of the benefits of breast screening.[66] In 2001, a controversial review published in The Lancet claimed that "there is no reliable evidence that screening for breast cancer reduces mortality".[67][68]The Cochrane Collaboration concluded, "for every 2000 women invited for screening throughout 10 years, one will have her life prolonged. In addition, 10 healthy women, who would not have been diagnosed if there had not been screening, will be diagnosed as breast cancer patients and will be treated unnecessarily. It is thus not clear whether screening does more good than harm."[69]

            False positives are a major problem of mammographic breast cancer screening. Data reported in the UK Million Woman Study indicates that if 134 mammograms are performed, 20 women will be called back for suspicious findings, and four biopsies will be necessary, to diagnose one cancer. Recall rates are higher in the U.S. than in the UK.[70] The contribution of mammography to the early diagnosis of cancer is controversial, and for those found with benign lesions, mammography can create a high psychological and financial cost.

            Mammography in women less than 50 years old

            Part of the difficulty in interpreting mammograms in younger women stems from the problem of breast density. Radiographically, a dense breast has a preponderance of glandular tissue, and younger age or estrogen hormone replacement therapy contribute to mammographic breast density. After menopause, the breast glandular tissue gradually is replaced by fatty tissue, making mammographic interpretation much more accurate. Some authors speculate that part of the contribution of estrogen hormone replacement therapy to breast cancer mortality arises from the issue of increased mammographic breast density. Breast density is an independent adverse prognostic factor on breast cancer prognosis.

            A systematic review by the American College of Physicians concluded "Although few women 50 years of age or older have risks from mammography that outweigh the benefits, the evidence suggests that more women 40 to 49 years of age have such risks".[71].

            A report released November 27, 2007 by the Journal of the National Cancer Institute showed that the formula doctors use to calculate a woman's risk of breast cancer underestimates the danger for black women most of the time and especially for those age 50 and older — the age when they are most likely to benefit from screening tests and protective drugs, according to the first major reassessment of the widely used tool.[72]

            Enhancements to mammography

            CAD is especially established in US and the Netherlands. It is used in addition to the human evaluation of the diagnostician.

            Breast MRI

            Magnetic resonance imaging (MRI) has been shown to detect cancers not visible on mammograms, but has long been regarded to have disadvantages. For example, although it is 27-36% more sensitive, it is less specific than mammography.[73] As a result, MRI studies will have more false positives (up to 5%), which may have undesirable financial and psychological costs. It is also a relatively expensive procedure, and one which requires the intravenous injection of a chemical agent to be effective. Proposed indications for using MRI for screening include:[74]

            • Strong family history of breast cancer
            • Patients with BRCA-1 or BRCA-2 tumour suppressor gene mutations
            • Evaluation of women with breast implants
            • History of previous lumpectomy or breast biopsy surgeries
            • Axillary metastasis with an unknown primary tumor
            • Very dense or scarred breast tissue

            However, two studies published in 2007 demonstrated the strengths of MRI-based screening:

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