Inflammatory breast cancer

Inflammatory breast cancer is an especially aggressive type of breast cancer that can occur in women of any age (and extremely rarely, in men).

It is called inflammatory because it frequently presents with symptoms resembling an inflammation. However it can present with very variable signs and symptoms, frequently without detectable tumors and therefore is often not detected by mammography or ultrasound.

Typical presentation is rapid swelling, sometimes associated by skin changes (peau d'orange), and nipple retraction. Other symptoms include rapid increase in breast size, redness, persistent itching, skin hot to touch. IBC often initially resembles mastitis.

Only about 50-75% cases have the typical presentation. Symptoms can be completely atypical such as acute central venous thrombosis as the sole presenting symptom.

IBC makes up only a small percentage of breast cancer cases (1-6% in the USA ). IBC is often diagnosed in younger women although average age of presentation does not differ much from other kinds of breast cancer (average age 57 years). African-Americans are usually diagnosed at younger ages than Caucasian women, and also have a higher risk of getting IBC. Recent advances in therapy have improved the prognosis considerably and at least one third of women will survive the diagnosis by 10 years or longer.

Symptoms
Symptoms are very variable and may not be present at all in occult inflammatory breast cancer. Quick onset of symptoms is typical, the breast often looks swollen and red, or “inflamed”, sometimes overnight, and are easy to misdiagnose as mastitis. Invasion of the local lymphatic ducts impairs drainage and causes edematous swelling of the breast. Because the skin of the breast is tethered by the suspensory ligament of Cooper, the accumulation of fluid may cause the skin of the breast to assume a dimpled appearance similar to an orange peel (peau d'orange). IBC is sometimes misdiagnosed as an insect bite or breast infection. In the case of IBC, a lump is usually not present as in other forms of breast cancer.

Symptoms may include: Other symptoms may rarely include:
 * Pain in the breast
 * Skin changes on breast
 * Reddened area with texture resembling the peel of an orange (peau d’orange)
 * Sudden swelling of the breast
 * Itching of breast
 * Nipple retraction (flattened look) or discharge
 * Swelling of lymph nodes under the arm or in the neck
 * Unusual warmth of the affected breast
 * Breast is harder or firmer
 * Swelling of the arm
 * Breast decreases instead of increasing
 * Although a dominant mass is present in many cases, most inflammatory cancers present as diffuse infiltration of the breast without a well-defined tumor.
 * A lump may become present and grow rapidly

Most patients do not experience all the symptoms of IBC. Not all symptoms need to be present in order to be diagnosed.

Diagnosis
The only reliable method of diagnosis is biopsy. Mammography, MRI or ultrasound often show suspicious signs; however in a significant proportion of cases they would miss a diagnosis.

Clinical presentation is typical only in 50-75% of cases; and many other conditions such as mastitis or even heart insufficiency can mimic the typical symptoms of Inflammatory Breast Cancer.

Temporary regression or fluctuation of symptoms, spontaneous or in response to conventional treatment or hormonal events should not be considered of any significance in diagnosis. Inflammatory breast cancer is known to respond to antibiotics and progesterone, and reaction to other medications or hormones cannot be excluded.

Characterization
Inflammatory breast cancer is a high grade aneuploid cancer, with mutations and overexpression of p53, high levels of E-cadherin and abnormal cadherin function. It is often regarded as a systemic cancer. A large number of IBC cases present as triple negative breast cancer (TNBC). Similar to TNBC as opposed to estrogen receptor-positive breast cancer, there is a high rate of relapses and metastases in the first 3 years after presentation but few late events (5 years or later).

It is characterised by the presence of cancer cells in the subdermal lymphatics on skin biopsy.

Searches for biomolecular characteristics produced a broad number of possible markers, such as loss of LIBC and WISP3 expression. Inflammatory breast cancer is in many ways very similar to late stage or metastatic breast cancer, however it can be distinguished from those cancer types both by molecular footprint and clinical presentation. On the molecular level some similarity exists with pancreatic cancer.

Estrogen and progesterone receptor status is frequently negative, corresponding with poor survival. The tumors are highly angiogenic and vascular, with high levels of VEGF and bFGF expression.

A number of proteins and signalling pathways show behaviour that can be considered paradoxical compared to their function in normal tissue and other breast cancer types.
 * caveolin-1 and -2 are overexpressed and may contribute to tumour cell motility
 * E-cadherin is overexpressed and paradoxically associated with especially aggressive type.

RhoC GTPase is overexpressed, possibly related to overexpression (hypomethylation) of caveolin-1 and -2. Caveolin is paradoxically tumour promoting. NF-κB pathway activation overexpression may contribute to the inflammatory phenotype.

Epidemiology
It occurs in all adult age groups. While the majority of patients are between 40 and 59 years old, age predilection is much less pronounced than in noninflammatory breast cancer. The overall rate is 1.3 cases per 100000, black women (1.6) have the highest rate, Asian and Pacific Islander women the lowest (0.7) rates.

Most known breast cancer risk predictors do not apply for inflammatory breast cancer. It may be slightly associated with cumulative breast-feeding duration. While there may be a slight risk correlation with breast feeding duration, it must be considered that the resulting effect would be by far outweighed by the protective effect breastfeeding has against more frequent breast cancer types.

Role of hormones
Age distribution and relation to breastfeeding duration is suggestive of some sort of involvement of hormones in the aetiology, however significant differences exist compared to normal breast cancer.

Typically IBC shows low levels of estrogen and progesterone receptor sensitivity corresponding with poor outcome. In cases with positive estrogen receptor status antihormonal treatment is believed to improve outcome.

Paradoxically some findings suggest that especially aggressive phenotypes of IBC are characterised by high level of NF kappaB target gene expression which can be - under laboratory conditions successfully modulated by estrogen but not tamoxifen.

Staging
Staging is designed to help organize the different treatment plans and to understand the prognosis better. Staging for IBC has been adapted to meet the specific characteristics of the disease. IBC is typically diagnosed in one of these stages:
 * Stage IIIA - less than one complete breast is affected
 * Stage IIIB - the whole breast is affected, might have spread to issues near the breast, such as the skin or chest wall, including the ribs and muscles in the chest. The cancer may have spread to lymph nodes within the breast or under the arm.
 * Stage IV means that the cancer has spread to other organs. These can include the bones, lungs, liver, and/or brain, as well as the lymph nodes in the neck.

Treatment
Multimodal therapy including chemotherapy with a combination of several agents, radiation therapy, hormonal therapy where appropriate and in some cases surgery.

Estrogen antagonist or aromatase inhibitors appear to improve outcome for ER positive cancer, similar for Herceptin.

Surgery was only rarely performed because inflammatory breast cancer is considered essentially a systemic cancer, however it may improve outcome and is now being reconsidered. A lumpectomy, when only a portion of the breast is removed, is not an option for IBC patients. A lymph node dissection is also recommended over a sentinel lymph node biopsy. Lymphedema, swelling of the arm and the hand on the side of the body where surgery was performed, may be a complication after a lymph node dissection. Reconstruction of the breast may be an option for healthy women after a mastectomy. However, for patients who smoke or have diabetes, complications are more common.

A number of promising new therapeutic agents exists, such as
 * lapatinib - a Her2neu receptor antagonist
 * various VEGF receptor antagonists
 * tipifarnib - a farnesyltransferase inhibitor

Prognosis factors
Estrogen and Progesterone receptor positive cases have better prognosis. Loss of heterozygosity, stage IV disease and appearance of symptoms resembling extensive inflammation are markers of poor prognosis.

Premenopausal cases have significantly worse prognosis. In postmenopausal cases lean women have significantly better prognosis than obese women.