Inflammatory breast cancer (IBC) is widely recognized as an extremely aggressive malignancy that is usually characterized by micro-metastases at the time of diagnosis. IBC is characterized clinically as a rapidly growing tumor with skin manifestation of erythema, warmth and edema and pathologically by invasion of the dermal lymphatics with tumor microemboli. In 1938, Taylor and Meltzer described two types of IBC, the primary form, where the characteristic clinical features were prominent from the outset and the secondary form, where the clinical features appeared subsequent to treatment for a primary non-inflammatory breast cancer [1].

IBC affects approximately 2.5% of women with breast cancer annually in the United States and thus affects more than 4,800 women each year, more than twice as many as those developing chronic myelocytic leukemia or acute lymphocytic leukemia [2]. It is a clinically and pathologically distinct form of breast cancer that is particularly fast growing, highly angiogenic and angioinvasive with its aggressiveness and angiogenicity present from its inception. The precise case definition is controversial [2], with the American Joint Committee on Cancer (AJCC) focusing on a clinical case definition [3], and the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute focusing primarily on a pathological case definition [4]. While the typical patient presents with pain and a tender, firm enlarged breast with the symptoms developing in less than six months, IBC may be diagnosed with less than half of the breast involved and without the pathological confirmation of dermal lymphatic invasion [2,5]. The skin over the breast is reddened, warm, thickened and often has a pitted appearance termed “peau d’ orange”. The designation “inflammatory” stems from the clinical appearance that mimics an acute inflammation, but this is somewhat of a misnomer [6]. Dermal lymphatic occlusion by tumor infiltrate, a finding which pathologists rely upon to confirm their clinical diagnosis, is believed to lead to increased vascular pressure and stasis, and inflammation does not actually contribute in any consequential way to the skin manifestations [7]. Since IBC tumors produce negligible amounts of most inflammatory cytokines, host inflammatory cells are rarely detected around the tumor stroma [6].

The Inflammatory Breast Cancer Registry (IBCR) was developed to provide a standardized population of IBC patients for epidemiologic and laboratory studies, and among the 156 patients enrolled thus far, eight were identified as having secondary IBC. In our review of these cases and others where localized trauma was followed by the appearance of IBC at the traumatized site, we hypothesized that angiogenesis appearing as part of the healing process could act as an accelerant to an otherwise latent breast malignancy. We present examples of this possible phenomenon which could suggest a population of patients for further investigation.

The Inflammatory Breast Cancer Registry (IBCR) was established 1 June 2002 to collect standardized clinical data and biospecimens from patients with IBC in the United States and Canada [2]. Patients with IBC who were entered into the Registry were at least 18 years of age, signed an Informed Consent, agreed to be interviewed and to provide access to medical records and tissue blocks. Patients contacted the Registry after learning about it on the internet or from local oncologists. It was funded initially by the Department of Defense and is now supported by laboratories that use the tissue samples to characterize the disease. In this report we document the histories of two patients with secondary IBC as well as two additional patients whose disease presentation also supports the possible occurrence of IBC secondary to breast trauma. Secondary IBC cases were defined as women who have had surgery for non-inflammatory breast cancer with recurrence manifest as skin erythema shown to be associated with pathologically confirmed tumor emboli in the dermal lymphatics.

The phenomenon of accelerated tumor growth following surgery has been observed repeatedly and merits further study in order to determine which patients are more likely to encounter this problem. It appears that there is more than one clinical manifestation of this occurrence, however, and more than one mechanism may be involved. Other reports in this symposium [8,9] have found a hormonal pathogenesis whereby removal of the primary tumor has led to a release of an inhibition on latent metastases. Another possible mechanism, however, is the stimulation of tumor growth through local angiogenesis occurring as part of post-traumatic healing. The central importance of tumor neovascularization has been emphasized by clinical trials using antiangiogenic therapy in breast cancer. Although findings to date have not indicated significant benefits in terms of survival, nevertheless significant improvements in response rates have been documented [10]. “Surgery-driven enhancement of metastases”, the subject of a recent review [11] as well as a focus of this symposium, may well be exemplified by secondary IBC.

IBC is a particularly aggressive form of breast cancer, treated initially with chemotherapy because of the likelihood of dissemination of micro metastases from the outset. The clinical and pathologic findings, while differing in extent from patient to patient, are striking and readily apparent to anyone familiar with this disease. A rapid spread of erythema often with documented invasion of the dermal lymphatics is pathognomonic of IBC. A diagnosis of inflammatory breast carcinoma is made on the basis of the clinical findings. A skin biopsy specimen that is negative for dermal lymphatic invasion does not rule out inflammatory carcinoma [7]. Our experience with the IBC Registry which has currently enrolled 156 well documented patients with the disease, has confirmed that most patients present with the sudden appearance of redness, swelling and tenderness of the breast.

One interesting subgroup of patients, however, are the eight patients in our Registry meeting the case definition of secondary IBC; described by Taylor and Meltzer who noted that “In the group which we would designate as secondary (IBC) the inflammatory manifestations may appear suddenly in a breast which has long been the seat of a scirrhous carcinoma…or it may follow mastectomy for scirrhous carcinoma, either at the original site or the opposite breast” [1]. Our experience with IBC, noted in the case reports above, suggest that local trauma probably mediated in large part by angiogenesis can be an important trigger of IBC. As with primary IBC, the clinical presentation is not uniform, but striking occurrences such as described for IBC patients 13 and 20 clearly link the initial appearance of IBC to the site of surgical trauma.

In this report, we describe two cases compatible with secondary IBC that have been identified by our IBC Registry and two cases where IBC appeared at the site of local trauma. In these four cases, the brief interval between the breast trauma and the appearance of clinical evidence of IBC (Table 1) is understandable in view of the rapidity with which IBC advances. It is reasonable to hypothesize that latent cancer cells remain after surgery and usually do not manifest clinical signs unless stimulated by local angiogenesis. Not only can surgery promote shedding of tumor cells from the malignant tissue into the blood and lymphatic system but it could also eliminate the distant anti-angiogenic effect associated with the primary tumor’s presence (carried by factors such as angiostatin and endostatin) and thus promote the survival of microscopic cancer foci [8]. The tissue damage and subsequent inflammatory response induced by surgery can also lead to elevation of pro-angiogenic factors and growth factors (e.g., EGF) [8]. We propose that consideration be given to focusing on possible parallels between “surgery-driven enhancement of metastases” and secondary IBC to identify opportunities to further understand the mechanism for this phenomenon.

The possibility that trauma can be etiologically related to cancer is raised primarily by a number of case reports. In 1933, Coley and Higinbotham reported 360 cases of bone sarcoma, of which 181 (50%) had histories of trauma, and 205 cases of breast carcinoma of which 70 (34%) were associated with trauma [12]. An impressive series has suggested trauma as a cause of bone cancer [13], and a review of post-surgical bone cancers associated with metal implants identified 22 various bone tumors, 17 since 1980 [14]. Several studies have also observed an increased relative risk of carcinoma associated with a history of nasal trauma or injury [15]. A number of studies have reported brain tumors to be significantly associated with trauma [16] and the role of angiogenesis in the healing process has been suggested as an important contribution to tumor aggressiveness [17,18]. This symposium [8,9] follows previous reports [11,19,20] noting the possible contribution of surgery to aggressive breast cancer, but the major focus in these reports has been the systemic contribution of excising a tumor to promoting the acceleration of distant latent micrometastasis [8,9,20].

Surgery remains an effective therapy for solid tumors in the U.S. and dramatically improves survival rates. Recurrences remain the most important challenge; almost one third of surgical patients will ultimately recur locally and/or systemically [21]. The attribution of a malignancy/metastasis to local trauma by searching for a reason for the disease (recall bias) is always a possibility but in view of the hypothesis that trauma in the form of a surgery can stimulate angiogenesis which can accelerate tumor growth, the documentation of IBC appearing following a surgical event and precipitated by it (Case 13 and 20) merits consideration.

The evidence presented in this symposium and in careful reviews [8,9,11] indicating that surgery can facilitate the appearance of metastatic disease requires considerable attention. While surgery is clearly an important tool in curing breast cancer and is not questioned in the initial treatment of this disease, perhaps a discussion of the potential risks of surgery in breast reconstruction is warranted, particularly if the patient is apparently disease-free after treatment for IBC.

In view of the hypothesis that trauma can stimulate angiogenesis which can accelerate tumor growth, the documentation of IBC appearing at the site of a traumatic event merits consideration. Our experience with IBC, noted in the case reports above suggest that local trauma probably mediated in large part by angiogenesis can be an important trigger of IBC. Studies on human-murine xenograft models like the Mary-X [22] and WIBC-9 [23] have provided insights on the biology of inflammatory breast cancer. These models can be used to define our hypothesis of surgically induced angiogenesis promoting metastasis at the histological and molecular level. We would therefore suggest that secondary IBC be considered for investigation of one possible mechanism for post-surgical tumor dissemination. A major question is how to identify patients at increased risk for this possible complication. Further attention to animal models and a more systematic study of the risk factors in patients with secondary IBC could be helpful.