Inflammatory breast cancer (IBC) is a rare and aggressive form of the disease. It is diagnosed based on clinical signs of a rapidly enlarging, tender, erythematous, edematous breast that often presents without an underlying breast mass. IBC historically was considered a uniformly fatal disease. With the advent of multimodality treatments including primary systemic chemotherapy, surgery, and radiation therapy, approximately one-third of women diagnosed with IBC will become long-term survivors. This review examines the limitations of the current definition of IBC, explores our current understanding of the biology of IBC, and reviews the many exciting advances in locoregional and systemic treatment of IBC.
Inflammatory breast cancer (IBC), a term first coined by Lee and Tannenbaum in 1924, is an aggressive form of breast cancer that accounts for approximately 1% to 6% of all cases in the United States. Over the years, various clinical definitions have been used to describe IBC. The most widely used is the definition introduced by the American Joint Committee on Cancer, which states that IBC "is a clinicopathologic entity characterized by diffuse erythema and edema (peau d'orange) of the breast, often without an underlying palpable mass."
Two varieties of IBC have been identified in the literature. Primary IBC refers to a de novo presentation in which IBC develops in a previously otherwise normal breast. Secondary IBC is a term used to describe a situation where a previously diagnosed noninflammatory invasive breast cancer acquires inflammatory features or when an inflammatory recurrence occurs at the site of a mastectomy for a noninflammatory breast cancer. For the purposes of this review, we will use the term IBC to mean primary IBC.
IBC is a rare distinct epidemiologic form of locally advanced breast cancer. In a recent analysis of the Surveillance, Epidemiology, and End Results (SEER) database, Hance et al assessed data from 180,224 histologically confirmed invasive breast cancer patients between the years 1988 to 2000. They found that women with IBC comprised approximately 2% of all breast cancer cases in this population, tended to present at a younger age, and were more likely to have metastatic disease at presentation. Patients with IBC also had a shorter survival (median: 2.9 years) than women with noninflammatory breast cancer, accounting for 7% of all breast cancer-specific deaths.
Due to the rarity of IBC, few epidemiologic studies have addressed the etiology of IBC and most are retrospective. Factors such as age at menarche, menopausal status, smoking, and alcohol consumption have not been consistently associated with IBC.[5,6] In a small retrospective study by Chang et al, high body mass index (BMI > 26.65 kg/m2) was associated with an increased risk for IBC compared to non-IBC patients (odds ratio = 2.40, 95% confidence interval = 1.05-5.73). These observations require further prospective validation before determining their value.
Clinical Characteristics and Classification of IBC
Unlike other forms of invasive breast cancer that usually present with a painless mass, IBC is associated with a variety of clinical presentations, making the diagnosis somewhat difficult. In 1956, Haagensen recognized this problem and established a set of clinical diagnostic criteria that are still in use. Clinical characteristics of IBC (Table 1) include a painful, tender, rapidly enlarging breast, and edema and erythema of the skin of the breast (Figure 1). More often than not, a breast mass is not palpable. Other changes associated with IBC include a "peau d'orange" (skin of an orange) appearance of the overlying skin of the breast, reflecting the exaggerated appearance of hair follicle pits that occur secondary to skin edema. Flattening, crusting, and retraction of the nipple can also occur as the disease progresses.
Unfortunately, most of the clinical characteristics associated with IBC are nonspecific, resulting in a significant number of cases that are initially diagnosed as mastitis or breast abscess. This leads to delays in appropriate investigation and, together with the rapid rate of disease progression (usually less than 2 months) that is pathognomonic of IBC, a significant proportion of patients present with advanced disease. Supporting studies have shown that the involvement of ipsilateral axillary and supraclavicular lymph nodes is common, with up to one-third of patients also presenting with distant metastases at the time of diagnosis.[1,2,4,9] According to the AmericanJoint Committee on Cancer, IBC is classified as a T4d tumor, thus classifying all IBC patients as stage IIIB, IIIC, or IV, depending on nodal status and the presence of distant metastases.
Molecular Biology of IBC
The designation of "inflammatory" in IBC derives from breast skin changes that resemble an acute inflammatory process. However, a true state of inflammation is not present in IBC. The skin changes are secondary to invasion of the dermal lymphatic vessels by tumor emboli,[1,2] which is a typical pathologic feature described in IBC. These emboli are believed to obstruct lymphatic drainage, thereby contributing to the observed clinical signs of erythema and edema.
Since the diagnosis of IBC is made on clinical grounds, absence of dermal lymphatic invasion does not exclude the diagnosis. Additional pathologic characteristics (Table 2) include high-grade, negative-hormone-receptor status[10,11] and overexpression of HER2—all factors that predict for a poor outcome. Other molecular features of IBC include mutation of the p53 suppressor gene, overexpression of E-cadherin, and an increased expression of proangiogenic factors.
IBC tumors are known to be highly vascular neoplasms with prominent features of angiolymphatic invasion manifested pathologically by increased microvessel density, high endothelial cell proliferation, and expression of angiogenic factors (basic fibroblast growth factor [bFGF], vascular endothelial growth factor [VEGF], interleukin [IL]-6 and IL-8).[14-16] The IBC animal xenograft model WIBC-9 has also been shown to overexpress other angiogenic factors such as Ang-1, Tie-1, and Tie-2, compared to noninflammatory breast xenografts (SK-BR3). Lymphangiogenic factors such as VEGF-C, VEGF-D, VEGFR-3, Prox-1, and lymphatic vessel endothelial receptor 1 has also been shown to be strongly expressed in IBC.
The role of p27kip1, a cyclin-dependent kinase inhibitor that is thought to be involved in the induction of apoptosis, cell adhesion, promotion of cell differentiation, and regulation of drug resistance, has recently been evaluated in patients with IBC. M.D. Anderson Cancer Center researchers evaluated the role of p27kip1 in 38 IBC patients who had received primary systemic chemotherapy. In this study, p27kip1 was downregulated in the majority of patients (84.2%) and predicted for poor outcome.
Diagnostic imaging plays an important role in the staging of breast tumors. In patients with IBC, the characteristic mammographic changes include skin thickening (with associated stromal or trabecular thickening), diffusely increased breast density, and an overall increase in the size of the breast.[20,21] An underlying mass is usually not present or may be obscured by surrounding changes in the breast. Microcalcifications may also be observed but are often masked by the increased breast density. Similarly, ultrasound of the breast in an IBC patient typically shows skin thickening with associated underlying tissue edema and dilated lymphatics. Unlike such changes on mammograms, underlying masses and associated regional lymphadenopathy are more easily visible by ultrasound.
Importantly, both imaging modalities cannot distinguish IBC from other breast conditions such as mastitis, locally advanced breast cancer with skin changes, and cutaneous T-cell lymphoma. It is therefore important that clinical history, imaging, and pathologic evidence of invasive carcinoma be used together to make a diagnosis of IBC.
Other imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), and positron-emission tomography (PET) scanning have not been studied extensively in IBC patients. MRI is increasingly being used in the diagnosis and staging of patients with breast cancers due to its increased sensitivity for invasive breast cancer, lack of ionizing radiation, and superior characterization of enhancing parenchyma. MRI has also been useful in characterizing tumor physiology and in monitoring the response of breast tumors to primary systemic chemotherapy.[23,24] PET is rapidly emerging as a technique for comprehensive staging; however, its superiority over other imaging modalities has yet to be proven.
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