THE PATIENT AND HIS ILLNESS

1. Anatomy and Physiology

The nipple and the areola are the darker part of the breast. The nipple is the central area through which the milk ducts open. The areola is the circular dark area around the nipple. The "bumps" on the areola and nipple are Montgomery's tubercles. These tubercles contain the opening of sebaceous and sweat glands (Montgomery glands) that secrete lubricating substances for the nipple. Frontal view of a breast

Lateral view with anatomical overlay

The lactiferous sinuses are located under the areola of the breast. The lactiferous sinuses drain out through the nipple. Lactiferous sinuses may open into Montgomery's tubercles or adjacent to them.

Milk is produced in the alveolus. The alveolus is made up of gland cells around a central duct. The milk is produced by the gland cells. Surrounding the gland cells are the myoepithelial cells which contract to cause milk ejection into the milk duct. The milk then travels down into the lactiferous ducts and into the lactiferous sinuses.

A cross-section view of the alveolus

Milk is stored in these ducts and sinuses in the period between breastfeedings. Mothers continue to make milk between feedings and they make more milk during feedings.

When an infant breastfeeds, the infant draws the nipple and the areola into their mouth. The mother's nipple elongates to about twice its normal length. The nipple height is compressed between the tongue and the palate. Milk is ejected about 0.03 seconds after

maximum nipple elongation

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Suckling infants compress the areola with their gums which stimulates oxytocin release. The oyxtocin release causes an increase in the diameter of the milk ducts and movement of milk in the ducts toward the nipple. Mothers may feel a sensation of pins and needles, pressure, or pain in the breast with milk ejection. This sensation may disappear as lactation continues over a several month period of time. Using ultrasound examination of the breast in women who had been breastfeeding for at least 1 month, Ramsay and others found that initial milk ejection as manifested by an increase in diameter of the milk duct and movement of the milk fat globules, occurred at an average of 50 seconds after suckling began. The number of milk ejections that a woman had during a breastfeeding varied from 1 milk ejection in 26% of the women to 2-9 milk ejections in the other women. The mean number of milk ejections was 2.5 ejections/breastfeed. Between milk ejections, the diameter of the milk duct returned to the pre-ejection diameter. This suggests that milk storage does not occur in the larger milk ducts, but in the smaller ductules. Mothers who noticed breast sensations with the first milk ejection reported no breast sensations with subsequent milk ejections

2. Pathophysiology

A. Book based (schematic diagram)

Non-Modifiable factor Modifiable factor Age Obesity Sex Diet Heredity Alcohol Hormones

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Time line of breast cancer suggesting probable heterogeneity. (1)Primary breast cancers begin as single (or more) cells which have lost normal regulation of differentiation and proliferation, (2) but remain confined within the basement membrane of the duct or lobule. (3) As these cells go through several doublings, at some point they invade through the basement membrane of the duct or lobule and (4) ultimately metastasize to distant organs.

A. Client based (schematic diagram)

Non-Modifiable factor Modifiable factor Age 47 y/o Stress Sex female Diet Alcohol

Time line of breast cancer suggesting probable heterogeneity. (1)Primary breast cancers begin as single (or more) cells which have lost normal regulation of differentiation and proliferation, (2) but remain confined within the basement membrane of the duct or lobule. (3) As these cells go through several doublings, at some point they invade through the basement membrane of the duct or lobule and (4) ultimately metastasize to distant organs.

b.1 Definition of the disease

Breast cancer is a cancer of the glandular breast tissue. Because the breast is composed of identical tissues in males and females, breast cancer also occurs in males, though it is less common.

There are numerous ways breast cancer is classified. Like most cancers, breast cancer can be divided into groups based on the tissue of origin, e.g. epithelial (carcinoma) versus stromal (sarcoma). The vast majority of breast cancers arise from epithelial tissue, i.e. they are carcinomas, which can divided further into subclassifications (e.g. DCIS versus LCIS versus papillary carcinoma).

Other pathologically based classifications:

Location of the tumour origin - breast duct (i.e. ductal) versus breast lobule (i.e. lobular).

Histology – the histologic types section. Grade of tumour - well-differentiated (looks almost like normal tissue) versus

poorly differentiated (does not look like any normal tissue/mass of proliferating cells) versus moderately differentiated (somewhere between poorly differentiated and well-differentiated).

Stage of the tumour. Immunohistochemical marker status - (ER positive versus ER negative versus

HER2/neu positive versus HER2/neu negative), e.g. triple negative breast cancer which is ER negative, PR negative and HER2/neu negative.

TNM classification - o Tumour size/invasiveness - presence of invasion (poorer prognosis) versus

in situ (better prognosis).o Nodal status.o Presence/absence of metastases.

Histologic typesCarcinomas in situ

Ductal carcinoma (DCIS) 80% Lobular carcinoma (LCIS) 20%

Invasive Carcinoma NOS (not otherwise specified) Lobular carcinoma Tubular/cribriform carcinoma Mucinous (colloid) carcinoma Medullary carcinoma Papillary carcinoma Metaplastic carcinoma

Sarcomas Phyllodes tumour

Clinical categorizations

Breast cancer is occasionally classified clinically (on physical exam findings, (medical history). Inflammatory breast cancer (IBC) is an example of a clinically classified breast cancer and can be any histologic type. Symptoms

Early breast cancer can in some cases present as breast pain (mastodynia) or a painful lump. Since the advent of breast mammography, breast cancer is most frequently discovered as an asymptomatic nodule on a mammogram, before any symptoms are present. A lump under the arm or above the collarbone that does not go away may be present. When breast cancer associates with skin inflammation, this is known as inflammatory breast cancer. In inflammatory breast cancer, the breast tumor itself is

causing an inflammatory reaction of the skin, and this can cause pain, swelling, warmth, and redness throughout the breast.

Changes in the appearance or shape of the breast can raise suspicions of breast cancer.

Another reported symptom complex of breast cancer is Paget's disease of the breast. This syndrome presents as eczematoid skin changes at the nipple, and is a late manifestation of an underlying breast cancer.

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

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. Pleural effusions are not uncommon with metastatic breast cancer. Obviously, these symptoms are "non-specific," meaning they can also be manifestations of many other illnesses.

Epidemiologic risk factors and etiology

Epidemiological risk factors for a disease can provide important clues as to the etiology of a disease. The first work 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.

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

1. Lesions to DNA such as genetic mutations. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer. Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation.

2. Failure of immune surveillance, which usually removes malignancies at early phases of their natural history.

3. Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells, for example in the angiogenesis necessary to promote new blood vessel growth near new cancers.

4. Inherited defects in DNA repair genes, such as BRCA1, BRCA2 and p53.

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. Approximately 5% of new breast cancers are attributable to hereditary syndromes, while no etiology is known for the other 95% of cases.

Age

The risk of getting breast cancer increases with age. A woman who lives to age 90 has a lifetime risk of about 14.3%, or one in seven. The probability of breast cancer rises with age, but breast cancer tends to be more aggressive when it occurs in younger people. One type of breast cancer that is especially aggressive and that occurs disproportionately in younger people is inflammatory breast cancer. It is initially staged as Stage IIIb or Stage IV. It also is unique because it often does not present with a lump, so it is often undetected by mammography or ultrasound. It presents with the signs and symptoms of a breast infection like mastitis, and the treatment is usually a combination of surgery, radiation, and chemotherapy.Sex

Men have a lower risk of developing breast cancer (approximately 1.08 per 100,000 men per year), but this risk appears to be rising.

Heredity

In 5% of breast cancer cases, there is a strong inherited familial risk. Two autosomal dominant genes, BRCA1 and BRCA2, account for most of the cases of familial breast cancer. Family members who harbor mutations in these genes have a 60% to 80% risk of developing breast cancer in their lifetimes. Other associated malignancies include ovarian cancer and pancreatic cancer. If a mother or a sister was diagnosed breast cancer, the risk of a hereditary ‘’’BRCA1’’’ or ‘’’BRCA2’’’ gene mutation is about 2-fold higher than those women without a familial history. In addition to the BRCA genes associated with breast cancer, the presence of NBR2, near breast cancer gene 1, has been discovered, and research into its contribution to breast cancer pathogenesis is ongoing. Commercial testing for ‘’’BRCA1’’’ and ‘’’BRCA2’’’ gene mutations has been available since at least 2004. Genetic testing for BRCA gene mutations is conducted exclusively by Myriad Genetics, located in Salt Lake City.

Diet

Dietary influences have been proposed and examined, and recent research suggests that low-fat diets may significantly decrease the risk of breast cancer as well as the recurrence of breast cancer. Another study showed no contribution of dietary fat intake on the incidence of breast cancer in over 300,000 women. A randomized controlled study of the consequences of a low-fat diet, the Women's Health Initiative, failed to show a statistically significant reduction in breast cancer incidence in the group assigned to a low-fat diet, although the authors did find evidence of a benefit in the subgoup of women who followed the low-fat diet in a strict manner. Another randomized trial, the Nurses' Health Study II, found increased breast cancer incidence in premenopausal women only, with higher intake of animal fat, but not vegetable fat. Taken as a whole, these results point to a possible association between dietary fat intake and breast cancer incidence, though these interactions are hard to measure in large groups of women.

In a study published in the Journal of the American Medical Association, biomedical investigators found that Brassica vegetable intake (broccoli, cauliflower, cabbage, kale and Brussels sprouts) was inversely related to breast cancer development. The relative risk among women in the highest decile of Brassica vegetable consumption (median, 1.5 servings per day) compared to the lowest decile (virtually no consumption) was 58%. That is, women who consumed the most Brassica vegetables were 58% less likely to develop breast cancer.

A significant environmental effect is likely responsible for the different rates of breast cancer incidence between countries with different dietary customs. Researchers have long measured that breast cancer rates in an immigrant population soon come to resemble the rates of the host country after a few generations. The reason for this is speculated to be immigrant uptake of the host country diet. The prototypical example of this phenomenon is the changing rate of breast cancer after the arrival of Japanese immigrants to America.

Alcohol

Alcohol appears to increase the risk of breast cancer, though meaningful increases are limited to higher alcohol intake levels. Breast cancer constitutes about 7.3% of all cancers. Among women, breast cancer comprises 60% of alcohol-attributable cancers. The UK's Review of Alcohol: Association with Breast Cancer concludes that "studies confirm previous observations that there appears to be an association between alcohol intake and increased risk of breast cancer in women. On balance, there was a weak association between the amount of alcohol consumed and the relative risk."

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) concludes that "Chronic alcohol consumption has been associated with a small (averaging 10 percent) increase in a woman's risk of breast cancer." According to these studies, the risk appears to increase as the quantity and duration of alcohol consumption increases. Other studies, however, have found no evidence of such a link.

The Committee on Carcinogenicity of Chemicals in Food, Consumer Products Non-Technical Summary concludes, "the new research estimates that a woman drinking an average of two units of alcohol per day has a lifetime risk of developing breast cancer 8% higher than a woman who drinks an average of one unit of alcohol per day. The risk of breast cancer further increases with each additional drink consumed per day. The research also concludes that approximately 6% (between 3.2% and 8.8%) of breast cancers reported in the UK each year could be prevented if drinking was reduced to a very low level (i.e. less than 1 unit/week)." A review article from JAMA also found that breast cancer incidence seems to increase with increasing alcohol consumption. It has been reported that "two drinks daily increase the risk of getting breast cancer by about 25 percent" (NCI), but the evidence is inconsistent. The Framingham study has carefully tracked individuals since the 1940s. Data from that research found that drinking alcohol moderately did not increase breast cancer risk (Wellness Facts). Similarly, research by the Danish National Institute for Public Health found that moderate drinking had virtually no effect on breast cancer riskOne study suggests that women who frequently drink red wine may have an increased risk of developing breast cancer

"Folate intake counteracts breast cancer risk associated with alcohol consumption" and "women who drink alcohol and have a high folate intake are not at increased risk of cancer." Those who have a high (200 micrograms or more per day) level of folate (folic acid or Vitamin B9) in their diet are not at increased risk of breast cancer compared to those who abstain from alcohol. 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.

Obesity

Gaining weight after menopause can increase a woman's risk. A recent study found that putting on 9.9kg (22lbs) after menopause increased the risk of developing breast cancer by 18%.

Staging

Breast cancer is staged according to the TNM system, updated in the AJCC Staging Manual, now on its sixth edition. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice.

Summary of stages: Stage 0 - Carcinoma in situ Stage I - Tumor (T) does not exceed 2 cm, no axillary lymph nodes (N) involved. Stage IIA – T 2-5 cm, N negative, or T <2 cm and N positive. Stage IIB – T > 5 cm, N negative, or T 2-5 cm and N positive (< 4 axillary nodes). Stage IIIA – T > 5 cm, N positive, or T 2-5 cm with 4 or more axillary nodes Stage IIIB – T has penetrated chest wall or skin, and may have spread to < 10

axillary N Stage IIIC – T has > 10 axillary N, 1 or more supraclavicular or infraclavicular N,

or internal mammary N. Stage IV – Distant metastasis (M)

Breast lesions are examined for certain markers, notably sex steroid hormone receptors. About two thirds of postmenopausal breast cancers are estrogen receptor positive (ER+) and progesterone receptor positive (PR+). Receptor status modifies the treatment as, for instance, only ER-positive tumors, not ER-negative tumors, are sensitive to hormonal therapy.

The breast cancer is also usually tested for the presence of human epidermal growth factor receptor 2, a protein also known as HER2, neu or erbB2. HER2 is a cell-surface protein involved in cell development. In normal cells, HER2 controls aspects of cell growth and division. When activated in cancer cells, HER2 accelerates tumor formation. About 20-30% of breast cancers overexpress HER2. Those patients may be candidates for the drug trastuzumab, both in the postsurgical setting (so-called "adjuvant" therapy), and in the metastatic setting.

Treatment

The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor), chemotherapy, and/or radiotherapy. At present, the treatment recommendations after surgery (adjuvant therapy) follow a pattern. This pattern is subject to change, as every two years, a worldwide conference takes place in St. Gallen, Switzerland, to discuss the actual results of worldwide multi-center studies. Depending on clinical criteria (age, type of cancer, size, metastasis) patients are roughly divided to high risk and low risk cases, with each risk category following different rules for therapy. Treatment possibilities include radiation therapy, chemotherapy, hormone therapy, and immune therapy.

In planning treatment, doctors can also use PCR tests like Oncotype DX or microarray tests like MammaPrint that predict breast cancer recurrence risk based on gene expression. In February 2007, the MammaPrint test became the first breast cancer predictor to win formal approval from the Food and Drug Administration. This is a new gene test to help predict whether women with early-stage breast cancer will relapse in 5 or 10 years, this could help influence how aggressively the initial tumor is treated.

Surgery

Depending on the staging and type of the tumor, just a lumpectomy (removal of the lump only) may be all that is necessary, or removal of larger amounts of breast tissue may be necessary. Surgical removal of the entire breast is called mastectomy.

Lumpectomy techniques are increasingly utilized for breast-conservation cancer surgery. However, mastectomy may be the preferred treatment in certain instances:

Two or more tumors exist in different areas of the breast (a "multifocal" cancer). The breast has previously received radiation (XRT) treatment. The tumor is large relative to the size of the breast. The patient has had scleroderma or another disease of the connective tissue,

which can complicate XRT treatment. The patient lives in an area where XRT is inaccessible. The patient is apprehensive about the risk of local recurrence after lumpectomy.

Standard practice requires the surgeon to establish that the tissue removed in the operation has margins clear of cancer, indicating that the cancer has been completely excised. If the removed tissue does not have clear margins, further operations to remove more tissue may be necessary. This may sometimes require removal of part of the pectoralis major muscle, which is the main muscle of the anterior chest wall.

During the operation, the lymph nodes in the axilla are also considered for removal. In the past, large axillary operations took out 10 to 40 nodes to establish whether cancer had spread. This had the unfortunate side effect of frequently causing lymphedema of the arm on the same side, as the removal of this many lymph nodes affected lymphatic drainage. More recently, the technique of sentinel lymph node (SLN)

dissection has become popular, as it requires the removal of far fewer lymph nodes, resulting in fewer side effects.

The sentinel lymph node is the first node that drains the tumor, and subsequent SLN mapping can save 65-70% of patients with breast cancer from having a complete lymph node dissection for what could turn out to be a negative nodal basin. Advances in Sentinel Lymph Node mapping over the past decade have increased the accuracy of detecting Sentinel Lymph Node from 80% using blue dye alone to between 92% and 98% using combined modalities. SLN biopsy is indicated for patients with T1 and T2 lesions (<5cm) and carries a number of recommendations for use on patient subgroups.

Chemotherapy

Chemotherapy (drug treatment for cancer) may used before surgery, after surgery, or instead of surgery in those patients who are unsuitable for surgery.