Inflammatory Breast Cancer

Figure 1: A patient with inflammatory breast cancer generally presents with a tender, firm and enlarged breast, rather than a discernable mass. This patient was diagnosed with acute mastitis carcinomatosa involving the entire breast.

Inflammatory breast cancer (IBC) is one of the most aggressive types of locally advanced breast cancer. It was first described by Lee and Tannenbaum in 1924¹. The designation "inflammatory" stems from the clinical appearance, which mimics an acute inflammation of the breast (Fig. 1). This type of cancer has been considered to be a special clinico-pathological entity but there is not general agreement on this. The typical patient presents with pain and a tender, firm and enlarged breast characterized by diffuse brawny induration of the skin with an erysipeloid edge. In the earliest phase, a mass may not be palpable. These signs and symptoms are characteristically rapidly progressive with a median duration before diagnosis of less than two months.

IBC represents 1% - 6% of all breast cancers ². A strikingly high incidence of this form of breast cancer has been reported in North Africa, especially in Tunisia and Egypt. It is unclear, however, whether this clinical presentation is related to differences in the biologic characteristics of the disease or variability in diagnostic criteria. Two types are usually distinguished: (1) a primary type in which inflammatory changes appear simultaneously with the carcinoma, and (2) a secondary type in which the inflammatory manifestations appear in a breast with longstanding carcinoma.

Pathologically, IBC is highly angiogenic and angioinvasive. Although it is not a specific histologic subtype of mammary carcinoma, the presence of numerous ectatic and dilated dermal lymphatics clogged by malignant cells constitutes the histologic hallmark that is associated with the clinical picture. Tumor emboli eventally give rise to metastases³. Primary IBC is often of ductal type, with prominent angio-lymphatic invasion (Fig. 2). It usually has a high histologic grade with pleomorphic tumor cells and highly atypical mitotic figures. In contrast to secondary IBC, invasion of the dermis outside the lymphatic vessels is uncommon. The skin within and outside the zone of erythema appears histologically identical, with tumor emboli frequently present in areas that are clinically unremarkable.

Although the histologic features of IBC have been well described, the molecular basis of the disease has been only recently investigated. This work has led to the identification of genes that are involved in the development and progression of the disease⁴. The majority of IBC tumors are estrogen receptor (ER) and progestogen receptor (PgR) negative, epidermal growth factor receptor (EGFR) and c-erb2 positive, and have a rapid growth rate. Genetic concomitants of the IBC phenotype are being evaluated and include p53 mutations⁵, expression of RhoC GTPase and LIBC genes⁶, and high levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor, IL-6, and IL-8. The latter are secreted by the tumor cells. Recently IBC cell lines such as SUM149, SUM198⁷, and a unique xenograft model⁸ have been developed.

Staging
The TNM classification system first adopted by the UICC in 1972 is the most commonly used system for the staging of breast cancer patients. However, this classification does not distinguish inflammatory breast cancer, whose clinical behavior differs irrespective of the original tumor measurements or apparent nodal involvement. Consequently, an adjunctive system of classification was adopted by investigators at Gustave-Roussy Cancer Institute in France. In this system inflammatory tumors are classified according to their evolutionary phase (Phase Evolutive).

Two elements, signs of inflammation and the growth rate, were used to distinguish the three degrees of evolution.

PEV3—These are the worst cases, which correspond to the classical acute inflammatory type of breast cancer. The entire breast is hot, red and presents with diffuse edema of the dermis and subcutaneous tissues. There is almost always a collateral circulation and greatly enlarged lymph nodes are hidden in the edematous tissues, i.e. the picture of acute mastitis carcinomatosa involving the entire breast (see Figure 1).

PEV2—These are the cases of moderate severity, which correspond to the sub-acute pseudo-inflammatory form which involves only a part of the breast. However, peritumoral and cutaneous edema is more often to be found beyond the limits of the tumor, even though at times it is difficult to precisely demarcate. The enlarged lymph nodes are often matted together and attached to the tumor by an indurated cord of "neoplastic lymphangitis."

PEV1—These are the cases which are apparently the least serious but also the most difficult to define. They are differentiated from the usual "chronic" type of breast cancer by one essential and unique characteristic: the rapid rate of growth.

PEV0—These are the cases which correspond to the classic "chronic" type of breast cancer but they lack the previously mentioned signs of inflammation.

Any tumor which has apparently doubled in size in six months is considered to be in evolution (progressive). The determination of this characteristic is based on questioning of the patient and thus is subjective. Clearly classifying the phase of evolution is impossible for recently discovered tumors. However, a skin biopsy for demonstrating involvement of skin lymphatics by tumor cells is a more reliable method of assessing the stage of evolution.

Figure 2: Primary inflammatory breast cancer is often of ductal type, with prominent angio-lymphatic invasion.

In a study of 73 patients classified according to this staging system and conducted at the NCI, Cairo in the 1980s, 48 cases were diagnosed as inflammatory (PEV2 and PEV3), and 25 were non-inflammatory (PEV0 and PEV1). Histpathological examination of 45 cases revealed 35 primary and 10 secondary types. Twenty-nine per cent of the inflammatory cases were postmenopausal. The median age was 42 years with a peak incidence in the fifth decade of life. Bilateral breast involvement was encountered in four cases. All inflammatory breast cancer cases had lymph node involvement at presentation; 75% had axillary, and 25% had both axillary and supraclavicular nodes. A large number of cases occurred during pregnancy (27%). A bigger tumor size at presentation (mean: 7.2 cm) was also observed. The majority of inflammatory breast cases were ER negative (73%). The relation between evolutionary phase and five-year relapse-free survival is presented in Table 1.

Treatment
Until the introduction of combined modality therapy, fewer than 5% of patients with IBC survived five years⁹. While radiotherapy alone yielded five-year survival rates of 12%-38% in various series, a combination of surgery and radiotherapy has slightly improved five-year survival rates in some studies¹⁰. This discouraging outcome, and the hypothesis that virtually all patients with IBC have disseminated micrometastases at presentation, led to the use of neoadjuvant chemotherapy before and after surgery and/or radiation. Several studies have been published from the Harvard Joint Center for radiation therapy, the Milan group, and the MD Anderson Cancer Center^11-13. The largest series of patients was reported by Rouesse et al¹⁴ who studied 230 patients who received either radiotherapy alone or three cycles of neoadjuvant chemotherapy followed by alternating cycles of radiation and chemotherapy, as well as maintenance therapy. Two different drug combinations were administered, one with more drugs and more prolonged maintenance therapy. All patients had hormonal treatment as well. The four-year disease-free and overall survival rates were significantly better for those who received additional drugs and more prolonged chemotherapy, reaching 46% and 66% respectively. Both chemotherapy regimens gave superior results to radiation alone without chemotherapy.

These studies were followed by other studies that were based on the concept of prolonged neoadjuvant anthracycline-containing chemotherapy to the point of maximal objective clinical response followed by local/regional treatment and consolidation chemotherapy¹⁵;. This has led to both improved disease-free and overall survival rates. This approach now constitutes the mainstream of current treatment for patients with IBC. However, improving our understanding of the molecular basis of IBC, and the use of novel targets for future interventions in the diagnosis and treatment of this type of malignancy, are clearly needed.

Submitted by Sherif Omar and Hussein Khaled, National Cancer Institute, Cairo, Egypt.

Editor's Note: References for this article are available from INCTR upon request.