Breast cancer (malignant breast neoplasm) is cancers originating from breast tissue, most * Histopathology.
Histopathology. Breast cancer is usually, but not always, primarily classified by its histological
commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk.
Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are
known as lobular carcinomas. There are many different types of breast cancer, with different
stages (spread), aggressiveness, and genetic makeup; survival varies greatly depending on those
factors.[1] Computerized models are available to predict survival.[2] With best treatment and
dependent on staging, 10-year disease-free survival varies from 98% to 10%. Treatment includes
surgery, drugs (hormonal therapy and chemotherapy), and radiation.
Worldwide, breast cancer comprises 10.4% of all cancer incidence among women, making it the
most common type of non-skin cancer in women and the fifth most common cause of cancer
death.[3] In 2004, breast cancer caused 519,000 deaths worldwide (7% of cancer deaths; almost
1% of all deaths).[4] Breast cancer is about 100 times more common in women than in men,
although males tend to have poorer outcomes due to delays in diagnosis.[5][6][7][8]
Some breast cancers require the hormones estrogen and progesterone to grow, and have
receptors for those hormones. After surgery those cancers are treated with drugs that interfere
with those hormones, usually tamoxifen, and with drugs that shut off the production of estrogen
in the ovaries or elsewhere; this may damage the ovaries and end fertility. After surgery, low-risk,
hormone-sensitive breast cancers may be treated with hormone therapy and radiation alone.
Breast cancers without hormone receptors, or which have spread to the lymph nodes in the
armpits, or which express certain genetic characteristics, are higher-risk, and are treated more
aggressively. One standard regimen, popular in the U.S., is cyclophosphamide plus doxorubicin
(Adriamycin), known as CA; these drugs damage DNA in the cancer, but also in fast-growing
normal cells where they cause serious side effects. Sometimes a taxane drug, such as docetaxel, is
added, and the regime is then known as CAT; taxane attacks the microtubules in cancer cells. An
equivalent treatment, popular in Europe, is cyclophosphamide, methotrexate, and fluorouracil
(CMF).[9] Monoclonal antibodies, such as trastuzumab (Herceptin), are used for cancer cells that
have the HER2 mutation. Radiation is usually added to the surgical bed to control cancer cells that
were missed by the surgery, which usually extends survival, although radiation exposure to the
heart may cause damage and heart failure in the following years.[10]
Classification
Main article: Breast cancer classification
Breast cancers can be classified by different schemata. Every aspect influences treatment response
and prognosis. Description of a breast cancer would optimally include multiple classification
aspects, as well as other findings, such as signs found on physical exam. Classification aspects
include stage (TNM), pathology, grade, receptor status, and the presence or absence of genes as
determined by DNA testing:
* Stage. The TNM classification for breast cancer is based on the size of the tumor (T), whether
or not the tumor has spread to the lymph nodes (N) in the armpits, and whether the tumor has
metastasized (M) (i.e. spread to a more distant part of the body). Larger size, nodal spread, and
metastasis have a larger stage number and a worse prognosis.
The main stages are:
Stage 0 is a pre-malignant disease or marker (sometimes called DCIS: Ductal Carcinoma in
Situ) .
Stages 1–3 are defined as 'early' cancer and potentially curable.
Stage 4 is defined as 'advanced' and/or 'metastatic' cancer and incurable.
appearance. Most breast cancers are' derived from the epithelium lining the ducts or lobules, and
are classified as mammary ductal carcinoma. Carcinoma in situ is proliferation of cancer cells
within the epithelial tissue without invasion of the surrounding tissue. In contrast, invasive
carcinoma invades the surrounding tissue.[11]
* Grade (Bloom-Richardson grade). When cells become differentiated, they take different
shapes and forms to function as part of an organ. Cancerous cells lose that differentiation. In
cancer grading, tumor cells are generally classified as well differentiated (low grade), moderately
differentiated (intermediate grade), and poorly differentiated (high grade). Poorly differentiated
cancers have a worse prognosis.
* Receptor status. Cells have receptors on their surface and in their cytoplasm and nucleus.
Chemical messengers such as hormones bind to receptors, and this causes changes in the cell.
Breast cancer cells may or may not have three important receptors: estrogen receptor (ER),
progesterone receptor (PR), and HER2/neu. Cells with none of these receptors are called basal-like
or triple negative. ER+ cancer cells depend on estrogen for their growth, so they can be treated
with drugs to block estrogen effects (e.g. tamoxifen), and generally have a better prognosis.
Generally, HER2+ had a worse prognosis,[12] however HER2+ cancer cells respond to drugs
such as the monoclonal antibody, trastuzumab, (in combination with conventional chemotherapy)
and this has improved the prognosis significantly.[13]
* DNA microarrays have compared normal cells to breast cancer cells and found differences in
hundreds of genes, but the significance of most of those differences is unknown.
[edit] Signs and symptoms
Breast cancer showing an inverted nipple, lump, skin dimpling
The first noticeable symptom of breast cancer is typically a lump that feels different from the rest
of the breast tissue. More than 80% of breast cancer cases are discovered when the woman feels a
lump.[14] By the time a breast lump is noticeable, it has probably been growing for years. The
earliest breast cancers are detected by a mammogram.[15] Lumps found in lymph nodes located
in the armpits[14] 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 ("mastodynia") is an
unreliable tool in determining the presence or absence of breast cancer, but may be indicative of
other breast health issues.[14][15][16]
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.[14]
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.[17]
In rare cases, what initially appears as a fibroadenoma (hard movable lump) could in fact be a
phyllodes tumor. Phyllodes tumors are formed within the stroma (connective tissue) of the breast
and contain glandular as well as stromal tissue. Phyllodes tumors are not staged in the usual sense;
they are classified on the basis of their appearance under the microscope as benign, borderline, or
malignant.[18]
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. Common sites of metastasis include bone, liver, lung and brain.[19] 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]
[edit] Risk factors
Main article: Risk factors of breast cancer
The primary risk factors that have been identified are sex,[22] age,[23] lack of childbearing or
breastfeeding,[24][25] and higher hormone levels[26][27].
In Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective, a 2007
report by American Institute for Cancer Research/ World Cancer Research Fund, it concluded
women can reduce their risk by maintaining a healthy weight, drinking less alcohol, being
physically active and breastfeeding their children.[28] This was based on an review of 873 separate
studies.
In 2009 World Cancer Research Fund announced the results of a further review review that took
into account a further 81 studies published subsequently. This did not change the conclusions of
the 2007 Report. In 2009, WCRF/ AICR published Policy and Action for Cancer Prevention, a Policy
Report that included a preventability study.[29] This estimated that 38% of breast cancer cases in
the US are preventable through reducing alcohol intake, increasing physical activity levels and
maintaining a healthy weight. It also estimated that 42% of breast cancer cases in the UK could be
prevented in this way, as well as 28% in Brazil and 20% in China.
In a study published in 1995, well-established risk factors accounted for 47% of cases while only
5% were attributable to hereditary syndromes.[30] Genetic factors usually increase the risk slightly
or moderately; the exception is women and men who are carriers of BRCA mutations. These
people have a very high lifetime risk for breast and ovarian cancer, depending on the portion of
the proteins where the mutation occurs. Instead of a 12 percent lifetime risk of breast cancer,
women with one of these genes has a risk of approximately 60 percent.[31] In more recent years,
research has indicated the impact of diet and other behaviors on breast cancer. These additional
risk factors include a high-fat diet,[32] alcohol intake,[33][34] obesity,[35] and environmental
factors such as tobacco use, radiation,[36] endocrine disruptors and shiftwork.[37] Although the
radiation from mammography is a low dose, the cumulative effect can cause cancer.[38] [39]
In addition to the risk factors specified above, demographic and medical risk factors include:
* Personal history of breast cancer: A woman who had breast cancer in one breast has an
increased risk of getting cancer in her other breast.
* Family history: A woman's risk of breast cancer is higher if her mother, sister, or daughter had
breast cancer. The risk is higher if her family member got breast cancer before age 40. Having
other relatives with breast cancer (in either her mother's or father's family) may also increase a
woman's risk.
* Certain breast changes: Some women have cells in the breast that look abnormal under a
microscope. Having certain types of abnormal cells (atypical hyperplasia and lobular carcinoma in
situ [LCIS]) increases the risk of breast cancer.
* Race: Breast cancer is diagnosed more often in women of European ancestry than those of
African or Asian ancestry.
A National Cancer Institute (NCI) study of 72,000 women found that those who had a normal body
mass index at age 20 and gained weight as they aged had nearly double the risk of developing
breast cancer after menopause in comparison to women maintained their weight. The average 60
year-old woman's risk of developing breast cancer by age 65 is about 2 percent; her lifetime risk is
13 percent.[40]
Abortion has not been found to be a risk factor for breast cancer. The breast cancer abortion
hypothesis, however, continues to be promoted by some pro-life groups.[41][42][43]
The United Kingdom is the member of International Cancer Genome Consortium that is leading
efforts to map breast cancer's complete genome.
Pathophysiology
Breast cancer, like other cancers, occurs because of an interaction between the environment and a
defective gene. Normal cells divide as many times as needed and stop. They attach to other cells
and stay in place in tissues. Cells become cancerous when mutations destroy their ability to stop
dividing, to attach to other cells and to stay where they belong. When cells divide, their DNA is
normally copied with many mistakes. Error-correcting proteins fix those mistakes. The mutations
known to cause cancer, such as p53, BRCA1 and BRCA2, occur in the error-correcting mechanisms.
These mutations are either inherited or acquired after birth. Presumably, they allow the other
mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant organs.
[36][44] Normal cells will commit cell suicide (apoptosis) when they are no longer needed. Until
then, they are protected from cell suicide by several protein clusters and pathways. One of the
protective pathways is the PI3K/AKT pathway; another is the RAS/MEK/ERK pathway. Sometimes
the genes along these protective pathways are mutated in a way that turns them permanently
"on", rendering the cell incapable of committing suicide when it is no longer needed. This is one of
the steps that causes cancer in combination with other mutations. Normally, the PTEN protein
turns off the PI3K/AKT pathway when the cell is ready for cell suicide. In some breast cancers, the
gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the "on" position, and
the cancer cell does not commit suicide.[45]
Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.
[46]
Failure of immune surveillance, the removal of malignant cells throughout one's life by the
immune system.[47]
Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can
facilitate malignant cell growth.[48][49]
People in less-developed countries report lower incidence rates than in developed countries.
[citation needed]
In the United States, 10 to 20 percent of patients with breast cancer and patients with ovarian
cancer have a first- or second-degree relative with one of these diseases. Mutations in either of
two major susceptibility genes, breast cancer susceptibility gene 1 (BRCA1) and breast cancer
susceptibility gene 2 (BRCA2), confer a lifetime risk of breast cancer of between 60 and 85 percent
and a lifetime risk of ovarian cancer of between 15 and 40 percent. However, mutations in these
genes account for only 2 to 3 percent of all breast cancers.[50]
[edit] Diagnosis
This section does not cite any references or sources.
Please help improve this article by adding citations to reliable sources. Unsourced material may be
challenged and removed. (October 2007)
While screening techniques (which are further discussed below) are useful in determining the
possibility of cancer, a further testing is necessary to confirm whether a lump detected on
screening is cancer, as opposed to a benign alternative such as a simple cyst.
In a clinical setting, breast cancer is commonly diagnosed using a "triple test" of clinical breast
examination (breast examination by a trained medical practitioner), mammography, and fine
needle aspiration cytology. Both mammography and clinical breast exam, also used for screening,
can indicate an approximate likelihood that a lump is cancer, and may also identify any other
lesions. Fine Needle Aspiration and Cytology (FNAC), which may be done in a GP's office using local
anaesthetic if required, involves attempting to extract a small portion of fluid from the lump. Clear
fluid makes the lump highly unlikely to be cancerous, but bloody fluid may be sent off for
inspection under a microscope for cancerous cells. Together, these three tools can be used to
diagnose breast cancer with a good degree of accuracy.
Other options for biopsy include core biopsy, where a section of the breast lump is removed, and
an excisional biopsy, where the entire lump is removed.
In addition vacuum-assisted breast biopsy (VAB) may help diagnose breast cancer among patients
with a mammographically detected breast in women according to a systematic review .[51] In this
study, summary estimates for vacuum assisted breast biopsy in diagnosis of breast cancer were as
follows sensitivity was 98.1% with 95% CI = 0.972-0.987 and specificity was 100% with 95% CI =
0.997-0.999. However underestimate rates of atypical ductal hyperplasia (ADH) and ductal
carcinoma in situ (DCIS) were 20.9% with 95% CI =0.177-0.245 and 11.2% with 95% CI = 0.098-
0.128 respectively.
Excised human breast tissue, showing an irregular, dense, white stellate area of cancer 2 cm in
diameter, within yellow fatty tissue.
Micrograph showing a lymph node invaded by ductal breast carcinoma and with extranodal
extension of tumour.
Neuropilin-2 expression in normal breast and breast carcinoma tissue.
Lymph nodes which drain the breast
Screening
Breast cancer screening refers to testing otherwise-healthy women for breast cancer in an attempt
to achieve an earlier diagnosis. The assumption is that early detection will improve outcomes. A
number of screening test have been employed including: clinical and self breast exams,
mammography, genetic screening, ultrasound, and magnetic resonance imaging.
A clinical or self breast exam involves feeling the breast for lumps or other abnormalities. Research
evidence does not support the effectiveness of either type of breast exam, because by the time a
lump is large enough to be found it is likely to have been growing for several years and will soon be
large enough to be found without an exam.[52] Mammographic screening for breast cancer uses x-
rays to examine the breast for any uncharacteristic masses or lumps. The Cochrane collaboration
in 2009 concluded that mammograms reduce mortality from breast cancer by 15 percent but also
result in unnecessary surgery and anxiety, resulting in their view that mammography screening
may do more harm than good.[53] Many national organizations recommend regular
mammography, nevertheless. For the average woman, the U.S. Preventive Services Task Force
recommends mammography every two years in women between the ages of 50 and 74.[54] The
Task Force points out that in addition to unnecessary surgery and anxiety, the risks of more
frequent mammograms include a small but significant increase in breast cancer induced by
radiation.[55]
In women at high risk, such as those with a strong family history of cancer, mammography
screening is recommended at an earlier age and additional testing may include genetic screening
that tests for the BRCA genes and / or magnetic resonance imaging.
Treatment
Breast cancer is usually treated first with surgery and then with chemotherapy or radiation, or
both. Treatments are given with increasing aggressiveness according to the prognosis and risk of
recurrence.
Stage 1 cancers (and DCIS) have an excellent prognosis and are generally treated with lumpectomy
and radiation.[56] The aggressive HER2+ cancers should be treated with the trastuzumab
(Herceptin) regime[57] but chemotherapy is otherwise uncommon.
Stage 2 and 3 cancers with a progressively poorer prognosis and greater risk of recurrence are
generally treated with surgery (lumpectomy or mastectomy with or without lymph node removal),
chemotherapy (plus trastuzumab for HER2+ cancers) and sometimes radiation (particularly
following large cancers, multiple positive nodes or lumpectomy).
Stage 4, metastatic cancer, (i.e. spread to distant sites) is not curable and is managed by various
combinations of all treatments from surgery, radiation, chemotherapy and targeted therapies.
However, stage 4 breast cancer management has been very disappointing, with only a 6 month
increase in median survival following these treatments.[58]
[edit] Medications
Drugs used after and in addition to surgery are called adjuvant therapy. Chemotherapy prior to
surgery is called neo-adjuvant therapy. There are currently 3 main groups of medications used for
adjuvant breast cancer treatment:
* Hormone Blocking Therapy
* Chemotherapy
* Monoclonal Antibodies

One or all of these groups can be used.
Hormone Blocking Therapy: Some breast cancers require estrogen to continue growing. They can
be identified by the presence of estrogen receptors (ER+) and progesterone receptors (PR+) on
their surface (sometimes referred to together as hormone receptors, HR+). These ER+ cancers can
be treated with drugs that either block the receptors, eg tamoxifen, or alternatively block the
production of estrogen with an aromatase inhibitor, eg anastrozole (Arimidex) or letrozole
(Femara). Aromatase inhibitors, however, are only suitable for post-menopausal patients.
Chemotherapy: Predominately used for stage 2-4 disease, being particularly beneficial in estrogen
receptor-negative (ER-) disease. They are given in combinations, usually for 3–6 months. One of
the most common treatments is cyclophosphamide plus doxorubicin (Adriamycin), known as AC;
these drugs damage DNA in the cancer, but also in fast-growing normal cells where they cause
serious side effects. Damage to the heart muscle is the most dangerous complication of
doxorubicin. Sometimes a taxane drug, such as docetaxel, is added, and the regime is then known
as CAT; taxane attacks the microtubules in cancer cells. Another common treatment, which
produces equivalent results, is cyclophosphamide, methotrexate, and fluorouracil (CMF).
(Chemotherapy can literally refer to any drug, but it is usually used to refer to traditional non-
hormone treatments for cancer.)
Monoclonal antibodies: A relatively recent development in HER2+ breast cancer treatment.
Approximately 15-20 percent of breast cancers have an amplification of the HER2/neu gene or
overexpression of its protein product.[59] This receptor is normally stimulated by a growth factor
which causes the cell to divide, however in the absence of the growth factor, the cell will normally
stop growing. Overexpression of this receptor in breast cancer is associated with increased disease
recurrence and worse prognosis. Trastuzumab (Herceptin), a monoclonal antibody to HER2, has
improved the 5 year disease free survival of stage 1–3 HER2+ breast cancers to about 87% (overall
survival 95%).[60] Trastuzumab, however, is expensive, and approx 2% of patients suffer
significant heart damage; it is otherwise well tolerated with far milder side effects than
conventional chemotherapy.[61] Other monoclonal antibodies are also being trialled.
Finally, a recent article has claimed that Aspirin may reduce mortality from breast cancer.[62]
[edit] Radiation
Radiotherapy is given after surgery to the region of the tumor bed, to destroy microscopic tumors
that may have escaped surgery. It may also have a beneficial effect on tumour
microenvironment[63][64]. Radiation therapy can be delivered as external beam radiotherapy or
as brachytherapy (internal radiotherapy). Conventionally radiotherapy is given after the operation
for breast cancer. Radiation can also be given, arguably more efficiently, at the time of operation
on the breast cancer- intraoperatively. The largest randomised trial to test this approach was the
TARGIT-A Trial[65] which found that targeted intraoperative radiotherapy was equally effective at
4-years as the usual several weeks' of whole breast external beam radiotherapy[66]. Radiation can
reduce the risk of recurrence by 50-66% (1/2 - 2/3rds reduction of risk) when delivered in the
correct dose[67] and is considered essential when breast cancer is treated by removing only the
lump (Lumpectomy or Wide local excision)
[edit] Prognosis
A prognosis is a prediction of outcome and the probability of progression-free survival (PFS) or
disease-free survival (DFS). These predictions are based on experience with breast cancer patients
with similar classification. A prognosis is an estimate, as patients with the same classification will
survive a different amount of time, and classifications are not always precise. Survival is usually
calculated as an average number of months (or years) that 50% of patients survive, or the
percentage of patients that are alive after 1, 5, 15 and 20 years. Prognosis is important for
treatment decisions because patients with a good prognosis are usually offered less invasive
treatments, such as lumpectomy and radiation or hormone therapy, while patients with poor
prognosis are usually offered more aggressive treatment, such as more extensive mastectomy and
one or more chemotherapy drugs.
Prognostic factors include staging, (i.e., tumor size, location, grade, whether disease has traveled
to other parts of the body), recurrence of the disease, and age of patient.
Stage is the most important, as it takes into consideration size, local involvement, lymph node
status and whether metastatic disease is present. The higher the stage at diagnosis, the worse the
prognosis. The stage is raised by the invasiveness of disease to lymph nodes, chest wall, skin or
beyond, and the aggressiveness of the cancer cells. The stage is lowered by the presence of
cancer-free zones and close-to-normal cell behaviour (grading). Size is not a factor in staging
unless the cancer is invasive. For example, Ductal Carcinoma In Situ (DCIS) involving the entire
breast will still be stage zero and consequently an excellent prognosis with a 10yr disease free
survival of about 98%.[68]
Grading is based on how biopsied, cultured cells behave. The closer to normal cancer cells are, the
slower their growth and the better the prognosis. If cells are not well differentiated, they will
appear immature, will divide more rapidly, and will tend to spread. Well differentiated is given a
grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4
(depending upon the scale used).
Younger women tend to have a poorer prognosis than post-menopausal women due to several
factors. Their breasts are active with their cycles, they may be nursing infants, and may be
unaware of changes in their breasts. Therefore, younger women are usually at a more advanced
stage when diagnosed. There may also be biologic factors contributing to a higher risk of disease
recurrence for younger women with breast cancer.[69]
The presence of estrogen and progesterone receptors in the cancer cell is important in guiding
treatment. Those who do not test positive for these specific receptors will not be able to respond
to hormone therapy, and this can affect their chance of survival depending upon what treatment
options remain, the exact type of the cancer, and how advanced the disease is.
In addition to hormone receptors, there are other cell surface proteins that may affect prognosis
and treatment. HER2 status directs the course of treatment. Patients whose cancer cells are
positive for HER2 have more aggressive disease and may be treated with the 'targeted therapy',
trastuzumab (Herceptin), a monoclonal antibody that targets this protein and improves the
prognosis significantly. Tumors overexpressing the Wnt signaling pathway co-receptor low-density
lipoprotein receptor-related protein 6 (LRP6) may represent a distinct subtype of breast cancer
and a potential treatment target.[70]
Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss in renal
function over a period of months or years. The symptoms of worsening kidney function are
unspecific, and might include feeling generally unwell and experiencing a reduced appetite. Often,
chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney
problems, such as those with high blood pressure or diabetes and those with a blood relative with
chronic kidney disease. Chronic kidney disease may also be identified when it leads to one of its
recognized complications, such as cardiovascular disease, anemia or pericarditis.[1]
Chronic kidney disease is identified by a blood test for creatinine. Higher levels of creatinine
indicate a falling glomerular filtration rate and as a result a decreased capability of the kidneys to
excrete waste products. Creatinine levels may be normal in the early stages of CKD, and the
condition is discovered if urinalysis (testing of a urine sample) shows that the kidney is allowing
the loss of protein or red blood cells into the urine. To fully investigate the underlying cause of
kidney damage, various forms of medical imaging, blood tests and often renal biopsy (removing a
small sample of kidney tissue) are employed to find out if there is a reversible cause for the kidney
malfunction.[1] Recent professional guidelines classify the severity of chronic kidney disease in five
stages, with stage 1 being the mildest and usually causing few symptoms and stage 5 being a
severe illness with poor life expectancy if untreated. Stage 5 CKD is also called established chronic
kidney disease and is synonymous with the now outdated terms end-stage renal disease (ESRD),
chronic kidney failure (CKF) or chronic renal failure (CRF).[1]
There is no specific treatment unequivocally shown to slow the worsening of chronic kidney
disease. If there is an underlying cause to CKD, such as vasculitis, this may be treated directly with
treatments aimed to slow the damage. In more advanced stages, treatments may be required for
anemia and bone disease. Severe CKD requires one of the forms of renal replacement therapy; this
may be a form of dialysis, but ideally constitutes a kidney transplant.[1]
Signs and symptoms
CKD is initially without specific symptoms and can only be detected as an increase in serum
creatinine or protein in the urine. As the kidney function decreases:
* blood pressure is increased due to fluid overload and production of vasoactive hormones,
increasing one's risk of developing hypertension and/or suffering from congestive heart failure
* Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from
lethargy to pericarditis and encephalopathy). Urea is excreted by sweating and crystallizes on skin
("uremic frost").
* Potassium accumulates in the blood (known as hyperkalemia with a range of symptoms
including malaise and potentially fatal cardiac arrhythmias)
* Erythropoietin synthesis is decreased (potentially leading to anemia, which causes fatigue)
* Fluid volume overload - symptoms may range from mild edema to life-threatening pulmonary
edema
* Hyperphosphatemia - due to reduced phosphate excretion, associated with hypocalcemia (due
to vitamin D3 deficiency). The major sign of hypocalcemia is tetany.
o Later this progresses to tertiary hyperparathyroidism, with hypercalcaemia, renal
osteodystrophy and vascular calcification that further impairs cardiac function.
* Metabolic acidosis, due to accumulation of sulfates, phosphates, uric acid etc. This may cause
altered enzyme activity by excess acid acting on enzymes and also increased excitability of cardiac
and neuronal membranes by the promotion of hyperkalemia due to excess acid (acidemia)[2]
People with chronic kidney disease suffer from accelerated atherosclerosis and are more likely to
develop cardiovascular disease than the general population. Patients afflicted with chronic kidney
disease and cardiovascular disease tend to have significantly worse prognoses than those suffering
only from the latter.
[edit] Causes
The most common causes of CKD are diabetic nephropathy, hypertension, and glomerulonephritis.
[3] Together, these cause approximately 75% of all adult cases. Certain geographic areas have a
high incidence of HIV nephropathy.
Historically, kidney disease has been classified according to the part of the renal anatomy that is
involved, as:[citation needed]
* Vascular, includes large vessel disease such as bilateral renal artery stenosis and small vessel
disease such as ischemic nephropathy, hemolytic-uremic syndrome and vasculitis
* Glomerular, comprising a diverse group and subclassified into
o Primary Glomerular disease such as focal segmental glomerulosclerosis and IgA nephritis
o Secondary Glomerular disease such as diabetic nephropathy and lupus nephritis
* Tubulointerstitial including polycystic kidney disease, drug and toxin-induced chronic
tubulointerstitial nephritis and reflux nephropathy
* Obstructive such as with bilateral kidney stones and diseases of the prostate
* On rare cases, pin worms infecting the kidney can also cause idiopathic nephropathy.
Diagnosis
In many CKD patients, previous renal disease or other underlying diseases are already known. A
small number presents with CKD of unknown cause. In these patients, a cause is occasionally
identified retrospectively.[citation needed]
It is important to differentiate CKD from acute renal failure (ARF) because ARF can be reversible.
Abdominal ultrasound is commonly performed, in which the size of the kidneys are measured.
Kidneys with CKD are usually smaller (< 9 cm) than normal kidneys with notable exceptions such as
in diabetic nephropathy and polycystic kidney disease. Another diagnostic clue that helps
differentiate CKD and ARF is a gradual rise in serum creatinine (over several months or years) as
opposed to a sudden increase in the serum creatinine (several days to weeks). If these levels are
unavailable (because the patient has been well and has had no blood tests) it is occasionally
necessary to treat a patient briefly as having ARF until it has been established that the renal
impairment is irreversible.[citation needed]
Additional tests may include nuclear medicine MAG3 scan to confirm blood flows and establish the
differential function between the two kidneys. DMSA scans are also used in renal imaging; with
both MAG3 and DMSA being used chelated with the radioactive element Technetium-99.[citation
needed]
In chronic renal failure treated with standard dialysis, numerous uremic toxins accumulate. These
toxins show various cytotoxic activities in the serum, have different molecular weights and some of
them are bound to other proteins, primarily to albumin. Such toxic protein bound substances are
receiving the attention of scientists who are interested in improving the standard chronic dialysis
procedures used today.[citation needed]
[edit] Stages
All individuals with a Glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for 3 months are
classified as having chronic kidney disease, irrespective of the presence or absence of kidney
damage. The rationale for including these individuals is that reduction in kidney function to this
level or lower represents loss of half or more of the adult level of normal kidney function, which
may be associated with a number of complications.[1]
All individuals with kidney damage are classified as having chronic kidney disease, irrespective of
the level of GFR. The rationale for including individuals with GFR 60 mL/min/1.73 m2 is that GFR
may be sustained at normal or increased levels despite substantial kidney damage and that
patients with kidney damage are at increased risk of the two major outcomes of chronic kidney
disease: loss of kidney function and development of cardiovascular disease.[1]
The loss of protein in the urine is regarded as an independent marker for worsening of renal
function and cardiovascular disease. Hence, British guidelines append the letter "P" to the stage of
chronic kidney disease if there is significant protein loss.[4]
Stage 1
Slightly diminished function; Kidney damage with normal or relatively high GFR (≥90 mL/min/1.73
m2). Kidney damage is defined as pathologic abnormalities or markers of damage, including
abnormalities in blood or urine test or imaging studies.[1]
Stage 2
Mild reduction in GFR (60-89 mL/min/1.73 m2) with kidney damage. Kidney damage is defined as
pathologic abnormalities or markers of damage, including abnormalities in blood or urine test or
imaging studies.[1]
Stage 3
Moderate reduction in GFR (30-59 mL/min/1.73 m2).[1] British guidelines distinguish between
stage 3A (GFR 45-59) and stage 3B (GFR 30-44) for purposes of screening and referral.[4]
Stage 4
Severe reduction in GFR (15-29 mL/min/1.73 m2)[1] Preparation for renal replacement therapy
Stage 5
Established kidney failure (GFR <15 mL/min/1.73 m2, or permanent renal replacement therapy
(RRT)[1]
Treatment
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The goal of therapy is to slow down or halt the otherwise relentless progression of CKD to stage 5.
Control of blood pressure and treatment of the original disease, whenever feasible, are the broad
principles of management. Generally, angiotensin converting enzyme inhibitors (ACEIs) or
angiotensin II receptor antagonists (ARBs) are used, as they have been found to slow the
progression of CKD to stage 5.[5][6] Although the use of ACE inhibitors and ARBs represents the
current standard of care for patients with CKD, patients progressively lose kidney function while on
these medications, as seen in the IDNT[7] and RENAAL[8] studies, which reported a decrease over
time in estimated glomerular filtration rate (an accurate measure of CKD progression, as detailed
in the K/DOQI guidelines[1]) in patients treated by these conventional methods.
Currently, several compounds are in development for CKD. These include, but are not limited to,
bardoxolone methyl[9], olmesartan medoxomil, sulodexide, and avosentan[10].
Replacement of erythropoietin and calcitriol, two hormones processed by the kidney, is often
necessary in patients with advanced CKD. Phosphate binders are also used to control the serum
phosphate levels, which are usually elevated in advanced chronic kidney disease.
When one reaches stage 5 CKD, renal replacement therapy is required, in the form of either
dialysis or a transplant.
In some cases, dietary modifications have been proven to slow and even reverse further
progression. Generally this includes limiting protein intake.[citation needed]
The normalization of hemoglobin has not been found to be of any benefit.[11]
[edit] Prognosis
The prognosis of patients with chronic kidney disease is guarded as epidemiological data has
shown that all cause mortality (the overall death rate) increases as kidney function decreases.[12]
The leading cause of death in patients with chronic kidney disease is cardiovascular disease,
regardless of whether there is progression to stage 5.[12][13][14]
While renal replacement therapies can maintain patients indefinitely and prolong life, the quality
of life is severely affected.[15][16] Renal transplantation increases the survival of patients with
stage 5 CKD significantly when compared to other therapeutic options;[17][18] however, it is
associated with an increased short-term mortality (due to complications of the surgery).
Transplantation aside, high intensity home hemodialysis appears to be associated with improved
survival and a greater quality of life, when compared to the conventional three times a week
hemodialysis and peritoneal dialysis.[19]
Fistula In-ano
References to fistula-in-ano date to antiquity. Hippocrates made reference to surgical therapy for
fistulous disease. The English surgeon John Arderne (1307-1390) wrote Treatises of Fistula in Ano;
Haemmorhoids, and Clysters in 1376, which described fistulotomy and seton use. Historical
references indicate that Louis XIV was treated for an anal fistula in the 18th century. In the late
19th and early 20th centuries, prominent physician/surgeons, such as Goodsall and Miles, Milligan
and Morgan, Thompson, and Lockhart-Mummery, made substantial contributions to the
treatment of anal fistula. These physicians offered theories on pathogenesis and classification
systems for fistula-in-ano.1,2 (See image below.)
Since this early progress, little has changed in the understanding of the disease process. In 1976,
Parks refined the classification system that is still in widespread use. Over the last 30 years, many
authors have presented new techniques and case series in an effort to minimize recurrence rates
and incontinence complications. Despite 2500 years of experience, fistula-in-ano remains a
perplexing surgical disease.
For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine
Center. Also, see eMedicine's patient education articles Anal Abscess, Rectal Pain, and Rectal
Bleeding.
Problem
A fistula-in-ano is a hollow tract lined with granulation tissue connecting a primary opening inside
the anal canal to a secondary opening in the perianal skin. Secondary tracts may be multiple and
from the same primary opening.
Frequency
The prevalence rate is 8.6 cases per 100,000 population. The prevalence in men is 12.3 cases per Physical examination findings remain the mainstay of diagnosis. The examiner should observe the
100,000 population. In women, it is 5.6 cases per 100,000 population. The male-to-female ratio is entire perineum, looking for an external opening that appears as an open sinus or elevation of
1.8:1. The mean age of patients is 38.3 years.3 granulation tissue. Spontaneous discharge via the external opening may be apparent or
Etiology expressible upon digital rectal examination.

Fistula-in-ano is nearly always caused by a previous anorectal abscess. Anal canal glands situated Digital rectal examination may reveal a fibrous tract or cord beneath the skin. It also helps
at the dentate line afford a path for infecting organisms to reach the intramuscular spaces. delineate any further acute inflammation that is not yet drained. Lateral or posterior induration
suggests deep postanal or ischiorectal extension.
Other fistulae develop secondary to trauma, Crohn disease, anal fissures, carcinoma, radiation
therapy, actinomycoses, tuberculosis, and chlamydial infections. The examiner should determine the relationship between the anorectal ring and the position of
Pathophysiology the tract before the patient is relaxed by anesthesia. The sphincter tone and voluntary squeeze
pressures should be assessed before any surgical intervention to delineate whether preoperative
The cryptoglandular hypothesis states that an infection begins in the anal gland and progresses manometry is indicated. Anoscopy is usually required to identify the internal opening.
into the muscular wall of the anal sphincters to cause an anorectal abscess. Following surgical or
spontaneous drainage in the perianal skin, occasionally a granulation tissue–lined tract is left Differential diagnoses
behind, causing recurrent symptoms. Multiple series have shown that the formation of a fistula
tract following anorectal abscess occurs in 7-40% of cases.4,5 The following do not communicate with the anal canal:
Presentation
* Hidradenitis suppurativa
Patients often provide a reliable history of previous pain, swelling, and spontaneous or planned * Infected inclusion cysts
surgical drainage of an anorectal abscess. * Pilonidal disease
* Bartholin gland abscess in females
Signs and symptoms (in order of prevalence)
Indications
* Perianal discharge
* Pain Therapeutic intervention is indicated for symptomatic patients. Symptoms usually involve
* Swelling recurrent episodes of anorectal sepsis. An abscess develops easily if the external opening on the
* Bleeding perianal skin seals itself.
* Diarrhea
* Skin excoriation If patients are without symptoms and a fistula is found during a routine examination, no therapy is
* External opening required.
Relevant Anatomy
Past medical history
A thorough understanding of the pelvic floor and sphincter anatomy is a prerequisite for clearly
Important points in the history that may suggest a complex fistula include the following: understanding the classification system for fistulous disease (see image below).

* Inflammatory bowel disease Anatomy of the anal canal and perianal space.
* Diverticulitis
* Previous radiation therapy for prostate or rectal cancer The external sphincter muscle is a striated muscle under voluntary control by 3 components.
* Tuberculosis These are submucosal, superficial, and deep muscle. Its deep segment is continuous with the
* Steroid therapy puborectalis muscle and forms the anorectal ring, which is palpable upon digital examination.
* HIV infection
The internal sphincter muscle is a smooth muscle under autonomic control and is an extension of
Review of symptoms the circular muscle of the rectum.

* Abdominal pain In simple cases, the Goodsall rule can help to anticipate the anatomy of fistula-in-ano. The rule
* Weight loss states that fistulae with an external opening anterior to a plane passing transversely through the
* Change in bowel habits center of the anus will follow a straight radial course to the dentate line. Fistulae with their
openings posterior to this line will follow a curved course to the posterior midline (see image
Physical examination below). Exceptions to this rule are external openings more than 3 cm from the anal verge. These
almost always originate as a primary or secondary tract from the posterior midline, consistent with
a previous horseshoe abscess.6,7

Parks classification system

The Parks classification system defines 4 types of fistula-in-ano that result from cryptoglandular
infections.

* Intersphincteric
o Common course - Via internal sphincter to the intersphincteric space and then to the
perineum
o Seventy percent of all anal fistulae
o Other possible tracts - No perineal opening; high blind tract; high tract to lower rectum or
pelvis
* Transsphincteric
o Common course - Low via internal and external sphincters into the ischiorectal fossa and
then to the perineum
o Twenty-five percent of all anal fistulae
o Other possible tracts - High tract with perineal opening; high blind tract
* Suprasphincteric
o Common course - Via intersphincteric space superiorly to above puborectalis muscle into
ischiorectal fossa and then to perineum
o Five percent of all anal fistulae
o Other possible tracts - High blind tract (ie, palpable through rectal wall above dentate line)
* Extrasphincteric
o Common course - From perianal skin through levator ani muscles to the rectal wall
completely outside sphincter mechanism
o One percent of all anal fistulae

Current procedural terminology codes classification

* Subcutaneous
* Submuscular (intersphincteric, low transsphincteric)
* Complex, recurrent (high transsphincteric, suprasphincteric and extrasphincteric, multiple
tracts, recurrent)
* Second stage

Unlike the current procedural terminology coding, the Parks classification system does not include
the subcutaneous fistula. These fistulae are not of cryptoglandular origin but are usually caused by
unhealed anal fissures or anorectal procedures, such as hemorrhoidectomy or sphincterotomy.
Contraindications

Surgery for fistula-in-ano should not be performed for definitive repair of the fistula in the setting
of anorectal abscess (ie, unless the fistula is superficial and the tract is obvious). In the acute
phase, simple incision and drainage of the abscess are sufficient. Only 7-40% of patients will
develop a fistula. Recurrent anal sepsis and fistula formation are 2-fold higher after an abscess in
patients younger than age 40 years and are almost 3-fold higher in nondiabetics.