Inflammatory breast cancer
|Inflammatory breast cancer|
|Classification and external resources|
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 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:
- Sudden swelling of the breast
- Skin changes on breast
- Reddened area with texture resembling the peel of an orange (peau d’orange)
- Nipple retraction (flattened look) or discharge
- Pain in the breast
- Itching of breast
- Swelling of lymph nodes under the arm or in the neck
- Unusual warmth of the affected breast
- Breast is harder or firmer
Other symptoms may rarely include:
- 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.
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. Treatment with antibiotics or progesterone have been observed to cause a temporary regression of symptoms in some cases.
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.
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.
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 by tamoxifen.
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.
Multimodal therapy includes chemotherapy with a combination of several agents, radiation therapy, hormonal therapy where appropriate and in some cases surgery.
Estrogen antagonists or aromatase inhibitors appear to improve outcomes for ER positive cases; Herceptin acts similarly in cases with her2 overexpression.
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.
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.
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- The Inflammatory Breast Cancer Research Foundation
- MD Anderson's Inflammatory Breast Cancer Clinic and Research Program