The findings of this study suggest that IBC as found in Egypt patients is a more aggressive form than IBC as found in patients from the U.S. Patients from Egypt were younger that the patients from the U.S. and had more advanced clinical signs of IBC at diagnosis. In addition, IBC tumors from the Egyptian patients had a higher number of tumor emboli and an elevated level of RhoC, which might suggest that there is a greater potential for metastasis in IBC patients from Egypt than the U.S.
Population-based epidemiological studies show that the mean age of IBC diagnosis in the U.S. is between 57 and 59 years old [2
]. This is similar to our observation in the U.S. group where the mean age of the onset of IBC was 57.3 years. Although the age of IBC onset has not been well documented in Egypt, previous research on 73 IBC patients from the NCI-Cairo study revealed a median age at diagnosis of 42 years old [8
]. Thus, our findings were consistent with previous studies in both countries and indicate that Egyptian patients are younger at the onset of IBC than their counterparts in the U.S.
We also observed a moderately longer duration of symptoms before diagnosis among the Egyptian patients in this study compared with patients from the U.S. The longer duration of symptoms before the initial clinical consultation among the Egyptian patients is less likely to reflect the slower progress of IBC development, but rather a delay in seeking medical care [8
]. This phenomenon is common in women from Arab countries. About 28% of breast cancer patients in Egypt report seeking medical care no earlier than 6 months after their observation of a breast mass or lymph node enlargement [20
]. This tendency to delay medical care may bias the estimate of disease duration for IBC patients in Egypt and may influence the correlation between clinical and molecular phenotypes. However, we did not find evidence suggesting that the longer duration of symptoms in this study was associated with the concurrence of the 3 clinical symptoms characteristic of IBC (erythema, edema, and peau d'orange), the higher number of tumor emboli, or the elevated RhoC expression seen in IBC patients from Egypt.
Clinically, IBC is characterized by diffuse erythema, edema, and peau d’orange. This inflammation-like presentation of IBC has been causally related to dermal lymphatic invasion by tumor emboli, as opposed to infiltration of inflammatory cells [22
]. Because skin biopsies may not show dermal lymphatic emboli, positive observation of tumor emboli has been found in about 25–60% of IBC tumors [10
]. The presence of tumor emboli has been associated with positive lymph node involvement, and the co-occurrence of tumor emboli and inflammatory clinical symptoms and has been linked to an undesired outcome in IBC patients [10
]. Taken together, these findings indicate that an increased number of tumor emboli in IBC tumors might be correlated with a more extensive clinical presentation and a greater potential for tumor metastasis culminating in a lower survival rate. In the current study, we observed that Egyptian patients presented with more symptoms and more tumor emboli than patients from the U.S. did, but we did not find a positive correlation between the number of tumor emboli and the number of symptoms in IBC from Egypt.
Given the moderate to high prevalence of tumor emboli in IBC tumors, the lymphatic system may be an important pathway for metastasis in IBC patients. LYVE-1 is a novel marker commonly used to study lymphangiogenesis [15
]. Van der Auwera et al. [24
] detected significantly higher levels of LYVE-1 mRNA and protein expression in IBC tumors than in stage-matched non-IBC tumors, indicating that increased expression of LYVE-1 may be associated specifically with IBC. However, another study by the same group showed only a weak expression of LYVE-1 in intratumoral lymph vessels that were detected by IHC [25
]. Interestingly, we found that only 49% of the tumors from Egypt patients and 43% of tumors from the U.S. patients had tumor emboli located in LYVE-1 positive vessels. Among these patients, the number of tumor emboli in LYVE-1 positive lymphatics was higher in the tumors from Egypt than in the tumors from the U.S., while the percentage of tumor emboli in LYVE-1 positive lymphatics was similar in the two groups. False negative staining of LYVE-1 was not likely to explain our observations because strong positive staining of empty lymphatic vessels in peri-tumoral and/or intratumoral areas was found in all IBC patients with tumor emboli located in LYVE1 negative vessels. Tumor emboli in LYVE-1 negative epithelial vessels might be located in LYVE-1 down-regulated lymphatics [26
], or in vessels other than lymphatics. In future research, additional histopathologic markers for lymph vessels should be used when studying lymphatic vasculature in IBC tumors.
The oncogenic function of the RhoC protein has been elucidated in IBC and RhoC is consistently associated with different types of advanced cancer [17
]. Comparative microarray analysis of overexpressed-RhoC and wild-type RhoC cell lines showed that RhoC overexpression can affect the expression of more than one hundred genes that are known to be involved in various biological functions such as enhancing cell cycle progression, angiogenesis, lymphangiogenesis, and cell adhesion and invasion [33
]. These findings suggest that the overexpression of RhoC may be responsible for the dismal outcome in IBC patients. A report by van Golen and his colleagues showed that RhoC was overexpressed in 90% of 29 IBC tumors and 38% of 19 non-IBC tumors (P
= 0.0095) [13
]. In the current study, we found a high level of RhoC overexpression in 1 of 7 (14%) IBC tumors from the U.S., as compared with 40 of 46 (87%) IBC tumors from Egypt, indicating that the RhoC GTPase might be an important contributor to IBC in the patients from Egypt, a matter that is worthy of further investigation.
An unusually high proportion of IBC among all breast cancers, a tendency to early age of onset, and a more aggressive clinical course of IBC in patients from Egypt [7
] than in patients from the U.S. and other countries underscores the possibility of distinct IBC risk factors in Egypt. These features of IBC may support our notion that patients in Egypt are exposed to unique environmental and genetic factors [34
]. In our earlier studies, we found that women with no lactation history had a significantly higher level of dichlorodiphenyldichloroethylene (DDE) than women who breast fed (P
= 0.002) [34
]. Age at first childbirth (younger vs. older) were also associated with higher levels of serum DDE concentrations in premenopausal women [34
]. Living in urban areas (odds ratio, OR = 3.1, 95% confidence interval, 95% CI = 1.1–9.3), infertility (OR = 9.8, 95% CI = 1.1–89.7), and oxidative exposures, as shown by the presence of 7,8-dihydro-8-oxo-2'-deoxyguanine (8-oxo-dG) in lymphocyte DNA (OR = 5.8, 95% CI = 1.9–17.5), correlate with a higher risk of breast cancer for women in Egypt [35
]. Further investigations should be conducted to explore the potential environmental exposures and lifestyle factors that may correlate with the incidence of IBC in different countries.
This study has several strengths. First, the diagnosis of IBC in all patients was confirmed using the same criteria by both clinical and histopathologic methods. Second, the higher incidence of IBC in the large sample of Egyptian patients in this study provides a unique opportunity to investigate the etiology and molecular and clinical profiles of IBC. This may provide insight into characteristics of the disease and reveal potential therapeutic targets. To our knowledge, this is the first study where tumor emboli in IBC tumors were examined quantitatively, and the first report to demonstrate the difference in the number of tumor emboli and RhoC expression between two distinct ethnic and racial groups. The characteristics of the IBC patients recruited in this study were consistent with previous those reported in previous research reports from Egypt [7
] and the U.S. [2
]. This suggests that the results of the current study are not likely to be affected by selection bias. Nevertheless, the study also had a limitation in that the low incidence of IBC limited the number of patients recruited from the U.S. resulting in a relatively small sample size in that group.
Future studies should build upon the results of this pilot study and investigate the correlation between epidemiologic and environmental risk factors, and the clinical, genetic, and molecular profiles associated with IBC. Since universal well-standardized clinical diagnostic criteria of IBC are still lacking [5
], more large international studies could help to elucidate the molecular profile associated with IBC and help to improve diagnostic criteria and the ability to predict IBC disease outcomes.