Inflammatory breast carcinoma (IBC) comprises 1-6% of all invasive breast tumors. Over the last 20 years, its incidence has doubled. IBC is distinguished from other breast tumors by both clinical and pathologic features. Most commonly, it presents with classic findings in the skin overlying the breast, including peau d'orange, erythema, edema, and warmth, believed to be a result of tumor emboli obstructing flow in the dermal lymphatics. Nipple retraction is noted frequently; often, no mass can be detected on physical examination or mammogram, perhaps because of the diffuse involvement throughout the lymphatics. Classic IBC develops rapidly with signs and symptoms present < 3 months before diagnosis. Distant metastases are common at diagnosis and are almost universal without chemotherapy.

DISCUSSION
In this series of patients with IBC, we report the efficacy of multimodality therapy and identify a number of clinical and treatment-related factors that require special attention for the appropriate diagnosis and optimal treatment of IBC. Multivariate analysis demonstrated that the following three factors were associated with improved survival: smaller pathologic tumor size, local disease control, and up-front surgery. Of particular interest is the latter, which suggests an improved outcome for a sequence of therapy that deviates from the widespread practice of neoadjuvant chemotherapy. The optimal role of surgery in the treatment of IBC is difficult to interpret from the literature. Reports that include both surgery and RT have shown either no survival benefit or a possible benefit in combination with chemotherapy. Given favorable reported outcomes for alternating chemotherapy and RT, and given similar outcomes when either RT or surgery follows chemotherapy, even the necessity of surgery has been questioned.Meanwhile, the timing of surgery has not been defined. At the University of Florida, several patients underwent mastectomy at the time of initial presentation to decrease tumor burden expeditiously. For reasons that are not entirely clear, those patients had a better outcome compared with patients who were treated initially with chemotherapy, as noted on previous analysis. It is noteworthy that this difference could be demonstrated only on multivariate analysis, which controlled for potentially confounding factors. It is conceivable that leaving a large source of tumor cells in place during neoadjuvant chemotherapy actually permits the seeding and growth of more metastases in the face of chemotherapy, such that initial surgery is more effective. Although the addition of chemotherapy certainly has improved treatment outcomes overall for patients with breast carcinoma, it is important to note that, in patients with IBC and with locally advanced breast carcinoma, chemotherapy is only moderately effective in eliminating distant disease, because 50% of patients succumb to breast carcinoma with distant metastases. It also is important to note that randomized trials that have analyzed the potential benefit of neoadjuvant chemotherapy have failed to show a decided survival advantage and have suggested a slight decrease in local disease control with a delay of locoregional treatment.

The number of prognostic factors analyzed in the current series may be larger than any other study has reported. The issue of pathologic dermal lymphatic invasion merits special mention. Uncertainty exists regarding the significance of a pathologically based diagnosis of IBC. Because of sampling heterogeneity, dermal lymphatic invasion may not be evident in all cases; it is estimated that it can be identified in only up to 75% of patients. Consequently, the diagnosis of IBC is permitted based on clinical criteria alone. In turn, the classification of disease in which dermal lymphatic invasion is observed in the absence of clinical features (occult IBC) is not clear. Many report outcomes similar to the outcomes reported in patients with classic IBC, although some have described occult IBC as a more benign process, which may reflect the notion that noninflammatory breast carcinomas (e.g., locally advanced breast carcinoma) can have incidental tumor emboli in the dermal lymphatics. In the current series, roughly 70% of patients had documented pathologic dermal lymphatic invasion, and 18% of patients had occult IBC. There was no detectable difference in outcome for patients with dermal lymphatic invasion or clinically occult IBC. Based on these results, no recommendations can be made to treat these patients differently from the currently accepted standard of care for patients with IBC.

The presumed benefit of trimodality therapy is both improved local disease control and survival. It is intuitive that successful local control would be associated with improved survival, because local failures generally are not salvageable. The 20% local failure rate in all patients who received surgery and RT indicates room for improvement. With the exception of type of chemotherapy (which likely was confounded by imbalances in pathologic tumor size and delay of effective locoregional treatment), RT dose was the only other factor that was found to be subject to treatment modification. Hyperfractionated RT was not administered routinely, because it generally was reserved for patients whose response to neoadjuvant chemotherapy was insufficient to render the tumor operable. Theoretically, the use of hyperfractionation enables dose escalation and can be considered the radiation counterpart of dose density chemotherapy. Intuitively, hyperfractionated irradiation should be effective, particularly in rapidly proliferating tumors, such as classic IBC. An early report from the M. D. Anderson Cancer Center suggested potential benefits that were confirmed in a later study, leading to improved local control. IBC patients at our institution currently are treated with hyperfractionated RT up to doses of 66 Gy.

Because of the low incidence of IBC compared with other invasive breast carcinomas, prospective controlled trials to define optimal management strategies are not feasible. Thus, retrospective studies are essential to continued progress in the management of this disease. In part because of limited numbers for analysis and patient heterogeneity, some caution must be exercised in the interpretation of their results. The findings of this series compare favorably with other published reports. Table above  includes series that have reported overall survival for > 30 patients who were treated with trimodality therapy for IBC. Overall survival was reported to be between 34-75% at 5 years. In the literature, several prognostic factors have been associated with better survival in patients with IBC, including better response to neoadjuvant chemotherapy, early response to neoadjuvant chemotherapy,more chemotherapeutic agents, no or limited clinical or pathologic lymph node involvement, premenopausal status and younger age, positive hormone receptor status, the absence of peau d'orange or diffuse erythematous involvement at presentation, any palpable mass at presentation, smaller pathologic tumor size, the absence of distant metastases at presentation, the inclusion of mastectomy as part of treatment, negative surgical margin status, local control,and higher RT dose. Both the patient heterogeneity and the small numbers in each of the studies most likely have led to the lack of uniformly reported prognostic factors. For these reasons, the current series also was unable to confirm improved survival with any reported factors other than pathologic tumor size and freedom from locoregional disease progression.