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Inflammatory breast cancer (IBC) is one of the most aggressive types of
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
. It can occur in women of any age (and, extremely rarely, in men, see male breast cancer). It is referred to as "inflammatory" due to its frequent presentation with symptoms resembling a skin inflammation, such as
erysipelas Erysipelas () is a relatively common bacterial infection of the superficial layer of the skin ( upper dermis), extending to the superficial lymphatic vessels within the skin, characterized by a raised, well-defined, tender, bright red rash, ...
. Inflammatory breast cancer presents with variable signs and symptoms, frequently without detectable lumps or tumors; it therefore is often not detected by mammography or ultrasound. Typical presentation is rapid breast swelling, sometimes associated with skin changes (
peau d'orange Peau d'orange ( French for "orange peel skin" or, more literally, "skin of an orange") describes a phenomenon in which hair follicles become buried in edema, giving the skin an orange peel appearance. Peau d'orange can be caused by cutaneous lymph ...
), and nipple retraction. Other signs include redness, persistent itching, and unusually warm skin. IBC often initially resembles
mastitis Mastitis is inflammation of the breast or udder, usually associated with breastfeeding. Symptoms typically include local pain and redness. There is often an associated fever and general soreness. Onset is typically fairly rapid and usually occurs ...
. Approximately 50% to 75% of cases have the typical presentation; an atypical presentation makes diagnosis more difficult. In some cases, a sign such as acute central
venous thrombosis Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lungs t ...
may be the sole presenting indication of the disease. IBC comprises a small proportion of breast cancer cases (1% to 6% in the USA). African-Americans are usually diagnosed with IBC at younger ages than Caucasian women, and they are also at higher risk for the disease. Recent advances in therapy have improved the prognosis considerably; at least one-third of women will survive with IBC for ten years or longer.


Symptoms

Signs and symptoms are quite variable, and may not be present at all in "occult" inflammatory breast cancer. Rapid onset of symptoms is typical; the breast often looks swollen and red, or "inflamed", sometimes seemingly changing overnight. IBC is frequently misdiagnosed as
mastitis Mastitis is inflammation of the breast or udder, usually associated with breastfeeding. Symptoms typically include local pain and redness. There is often an associated fever and general soreness. Onset is typically fairly rapid and usually occurs ...
. Invasion of the local
lymphatic duct A lymph duct is a great lymphatic vessel that empties lymph into one of the subclavian veins. There are two lymph ducts in the body—the right lymphatic duct and the thoracic duct. The right lymphatic duct drains lymph from the right upper li ...
s, the hallmark sign of IBC, impairs
lymphatic drainage The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid ...
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 within the lymphatic system of the skin may cause the breast skin to assume a dimpled appearance similar to an orange peel (
peau d'orange Peau d'orange ( French for "orange peel skin" or, more literally, "skin of an orange") describes a phenomenon in which hair follicles become buried in edema, giving the skin an orange peel appearance. Peau d'orange can be caused by cutaneous lymph ...
). A palpable tumor is not always found as it would be in other forms of breast cancer. Symptoms may include: *Sudden swelling of the breast *Skin changes on breast *Reddened area with a 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 size may seem to decrease 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 be present and grow rapidly Most patients do not experience every known symptom of IBC. Not all symptoms need to be present to make an IBC diagnosis.


Diagnosis

The reliable method of diagnosis by imaging, Mammography, breast
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
or ultrasound, which often show suspicious signs (general skin edema, skin thickening, mass, suspected breast lesions). It is important to biopsy the suspected lesions and/or skin. However, despite significant effort, we could miss a diagnosis. Therefore, repeat imaging and biopsies are important if you remain to suspect the diagnosis of IBC. Clinical presentation is typical in only 50% to 75% of cases; many other conditions, such as
mastitis Mastitis is inflammation of the breast or udder, usually associated with breastfeeding. Symptoms typically include local pain and redness. There is often an associated fever and general soreness. Onset is typically fairly rapid and usually occurs ...
or even cardiac insufficiency, can mimic the typical symptoms of inflammatory breast cancer. Temporary regression or fluctuation of symptoms, spontaneously or in response to medications 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 certain cases.


Characterization

Inflammatory breast cancer is a high-grade
aneuploid Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
cancer, with mutations and overexpression of
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
, high levels of
E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovari ...
and abnormal
cadherin Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane proteins, ...
function. It is often regarded as a systemic cancer. A large number of IBC cases present as
triple negative breast cancer Triple-negative breast cancer (TNBC) is any breast cancer that lacks or show low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e. the tu ...
(TNBC). Similar to TNBC, as opposed to
hormone receptor-positive breast cancer A hormone-receptor-positive (HR+) tumor is a tumor which consists of cells that express receptors for certain hormones. The term most commonly refers to estrogen receptor positive tumors (i.e. tumors that contain estrogen receptor positive cells), b ...
, there is a high rate of relapse and metastasis in the first three years after presentation, with few late events (five years or later). IBC is characterised by the presence of cancer cells in the subdermal lymphatics on skin biopsy. Consequently, IBC is always staged at stage IIIB or above, as that type of
local Local may refer to: Geography and transportation * Local (train), a train serving local traffic demand * Local, Missouri, a community in the United States * Local government, a form of public administration, usually the lowest tier of administra ...
ly advanced disease is a classic prognostic indicator. Searches for
biomolecular A biomolecule or biological molecule is a loosely used term for molecules present in organisms that are essential to one or more typically biological processes, such as cell division, morphogenesis, or development. Biomolecules include large ...
characteristics has produced a broad range of possible biomarkers, such as loss of
LIBC The C standard library or libc is the standard library for the C programming language, as specified in the ISO C standard.ISO/ IEC (2018). '' ISO/IEC 9899:2018(E): Programming Languages - C §7'' Starting from the original ANSI C standard, it was ...
and
WISP3 WNT1-inducible-signaling pathway protein 3 (WISP3, also named CCN6) is a matricellular protein that in humans is encoded by the ''WISP3'' gene. Structure It is a member of the CCN family ( CCN intercellular signaling protein) of secreted, extr ...
expression Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, ...
. Inflammatory breast cancer is similar in many ways, both prognostically and treatment-wise, to late-stage or metastatic breast cancer; 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. IBC tumors are highly
angiogenic Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
and vascular, with high levels of
VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...
and
bFGF Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...
expression. A number of proteins and signalling pathways show behaviour of biochemicals which can be considered
paradox A paradox is a logically self-contradictory statement or a statement that runs contrary to one's expectation. It is a statement that, despite apparently valid reasoning from true premises, leads to a seemingly self-contradictory or a logically u ...
ical, compared with their function in normal tissue as well as in other breast cancer types. *
Caveolin 1 Caveolin-1 is a protein that in humans is encoded by the ''CAV1'' gene. Function The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits ...
and
caveolin 2 Caveolin-2 is a protein that in humans is encoded by the ''CAV2'' gene. The protein encoded by this gene is a major component of the inner surface of caveolae, small invaginations of the plasma membrane, and is involved in essential cellular ...
are overexpressed, and may contribute to tumour cell motility *
E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovari ...
is overexpressed; paradoxically, it is associated with especially aggressive subtypes of IBC. RhoC GTPase is overexpressed, possibly related to overexpression ( hypomethylation) of caveolin 1 and caveolin 2. Caveolin is, paradoxically, tumour-promoting in IBC. NF-κB pathway activation overexpression may contribute to the inflammatory phenotype. The
epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor re ...
(EGFR) pathway is commonly active in inflammatory breast cancer; this has the clinical implication that EGFR targeting therapy may be effective in inflammatory breast cancer.


Epidemiology

IBC 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 negatively associated with cumulative breast-feeding duration. Whether inflammation contributes to the development of this disease remains an area of ongoing research.


Role of hormones

Age distribution and relation to breastfeeding duration is suggestive of the involvement of hormones in the causation of IBC; however, significant differences exist between IBC and other breast cancers. Typically, IBC shows low levels of estrogen and progesterone receptor sensitivity, which corresponds with poor outcome. In IBC 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 a high level of NF kappaB target gene expression, which can be, under laboratory conditions, successfully modulated by estrogen, but not by 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 IIIB - at least 1/3 of the skin of the breast is affected, and cancer may have spread to tissues near the breast, such as the chest skin or chest wall, including the ribs and muscles in the chest. The cancer may have spread to lymph nodes near the breast or under the arm. *Stage IIIC - N3 nodal involvement with an inflamed breast will upgrade the disease from Stage IIIB to Stage IIIC. *Stage IV means that the cancer has spread to other organs. These can include the bones, lungs, liver, and/or brain.


Treatment

The standard treatment for newly diagnosed inflammatory breast cancer is to receive systemic therapy prior to surgery, followed by the radiation therapy. Achieving "no disease athological complete response (pCR) in the surgical samples gives the best prognosis. Surgery is modified radical mastectomy.
Lumpectomy Lumpectomy (sometimes known as a tylectomy, partial mastectomy, breast segmental resection or breast wide local excision) is a surgical removal of a discrete portion or "lump" of breast tissue, usually in the treatment of a malignant tumor or brea ...
,
segmentectomy Segmental resection (or segmentectomy) is a surgical procedure to remove part of an organ or gland, as a sub-type of a resection, which might involve removing the whole body part. It may also be used to remove a tumor and normal tissue around it. ...
, or skin sparing mastectomy are not recommended. Immediate reconstructive surgery is not recommended. Immediate,"upfront" surgery is contraindicated, as results are better using
neoadjuvant chemotherapy Neoadjuvant therapy is the administration of therapeutic agents before a main treatment. One example is neoadjuvant hormone therapy prior to radical radiotherapy for adenocarcinoma of the prostate. Neoadjuvant therapy aims to reduce the size or ...
first. Contralateral prophylactic mastectomy is not recommended because it can delay the other systemic adjuvant treatment or adjuvant radiation therapy. After surgery, all cases are recommended for radiation therapy unless it is contraindicated. Due to the aggressive nature of the disease, it is highly recommended that people with IBC be seen by an IBC specialist and by a multidisciplinary team of health workers. Exploring whether clinical trials are available is very important. If you have newly IBC with metastatic diseases, it is essential to discuss whether palliative surgery of the breast is indicated after the systemic treatment. In the non-IBC setting, palliative surgery is not recommended; however, for IBC, palliative surgery to improve the QOL and to improve the long-term outcome is explored in certain medical conditions. It is critical for people with IBC to seek novel targeted therapy in a clinical trial setting. Three-
modality Modality may refer to: Humanities * Modality (theology), the organization and structure of the church, as distinct from sodality or parachurch organizations * Modality (music), in music, the subject concerning certain diatonic scales * Modaliti ...
combination therapy: surgery, chemotherapy, and radiation, was, in 2014, reported as being under-utilized in the USA. Estrogen and progesterone receptor-positive cases of IBC have not been shown to have a better prognosis than hormone receptor-negative cases.
Pathological Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in th ...
complete response to preoperative chemotherapy imparts a more favorable prognosis than a pathological complete response to surgery. Loss of diploidy (heterozygosity) and extensive breast inflammation upon first clinical examination are associated with a significantly worse IBC prognosis. A premenopausal occurrence of IBC has a significantly worse prognosis than a postmenopausal diagnosis. In postmenopausal cases, lean women have a significantly better prognosis than obese women. Among breast cancer patients with distant metastasis at diagnosis (stage IV disease), the overall survival (OS) is worse in patients with IBC than in those with non-IBC breast cancers.


See also

* Male breast cancer


References


External links


The Inflammatory Breast Cancer Research Foundation
* ttps://eraseibc.org/ The Inflammatory Breast Cancer Foundationbr>Breast Cancer Guides

MD Anderson IBC Treatment Algorithm
{{DEFAULTSORT:Inflammatory Breast Cancer Breast cancer de:Brustkrebs#Histologische Klassifikation