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Inflammatory breast cancer (IBC) is characterized by a peculiar geographic distribution in incidence, being described as more common in Tunisia and the region of North Africa. The authors performed a systematic review of published literature on rapidly progressing breast cancer and IBC in Tunisia and analyzed the evolution in epidemiology, clinical presentation, treatment, and therapeutic results. They collected, analyzed, and compared all the indexed Tunisian articles about rapidly progressing breast cancer and IBC since the 1970s opening of the Institut Salah Azaiz Institute in Tunis. In the 1970s, rapidly progressing breast cancer diagnosis was based on the Poussee Evolutive classification (1-3). Since the 1990s, IBC diagnosis has been based on the American Joint Committee on Cancer Poussee Evolutive 3/T4d staging. The authors compared the historical data to the most recent publications in terms of epidemiology, clinical features, treatment, and therapeutic results. The most important historical report of rapidly progressing breast cancer concerned 340 patients, representing 58.5% of a cohort of 581 breast cancer patients collected from 1969 to 1974, including 320 (55.2%) with inflammatory signs, 37(6.5%) with Poussee Evolutive 2, and 283 (48.7%) with Poussee Evolutive 3. Subsequent papers have documented a steady decrease in incidence to the current 5% to 7% T4d/IBC. Since the 1970s, Poussee Evolutive in premenopausal woman has increased from 52.5% to 75%; rural predominance has persisted. The 5-year overall survival reached 28% by the year 2000. The authors' analysis demonstrated a trend of decreasing incidence of IBC diagnoses from 50% to presently

Background We studied whether dermal lymphatic emboli (DLE) add independent prognostic information to the clinical definition of inflammatory breast cancer (IBC). Patients and Methods The study was performed in 2 centers, one each in France and Tunisia. For every patient with IBC, 1-3 patients with noninflammatory breast cancer (non-IBC) were included. All patients were to have a surgical tumor biopsy, including a sample of the skin surrounding the tumor. The endpoint was the risk of a relapse at 2 years, which was estimated using univariate and multivariate Cox models. Results Three hundred thirty-seven patients were included (150 in France and 187 in Tunisia). The IBC status was divided into 2 clinical categories according to the extent of inflammation in the breast (localized IBC, which was defined as clinical inflammation in the tumor area, vs. diffuse IBC, which was defined as inflammation of at least two thirds of the breast). In total, 57 patients presented with localized IBC, 71 with diffuse IBC, and 209 with non-IBC. Dermal lymphatic emboli were found in 7% of non-IBC cases, in 25% of localized IBC cases, and in 45% of diffuse IBC cases. We found a significant interaction between the presence of DLE and diffuse IBC (P = 0.01). In patients with diffuse IBC, the presence of DLE increased the risk of relapse 3-fold. Conversely, DLE were not associated with the risk of relapse in patients with non-IBC, nor in patients with localized IBC. In patients with diffuse IBC and no DLE, the risk of relapse was similar to that of patients with localized IBC. Conclusion A DLE status might be a useful prognostic indicator exclusively in patients with diffuse IBC. However, because all patients with localized and diffuse IBC generally receive similar types of treatment, additional information on the presence or absence of DLE will not have an impact on treatment practice.

BACKGROUND An early immunologic study suggesting that a virus similar to the mouse mammary tumor virus (MMTV) was associated highly with breast carcinoma in Tunisian patients, compared with patients in the United States, led the authors to examine different breast carcinoma populations by using more current molecular techniques. METHODS Thirty-nine paraffin blocks were selected for sequencing of the 250-base pair segment of the MMTV from patients with breast carcinoma who were seen and treated at the Institut Salah Azaiz in Tunisia. Fifteen of those blocks were examined under code by a second laboratory, which used a different methodology and was blinded to the results of the first laboratory, and 14 blocks were analyzed successfully. RESULTS The comparison of Tunisian patients and patients from other countries clearly showed a significantly higher proportion of tumors with MMTV-like sequences in the Tunisian series of patients. There was complete reproducibility of data between the two laboratories. Using the results from the first laboratory and similar studies from the literature, detection of the MMTV-like env gene sequence showed an important geographic pattern with a significantly higher percentage of positive patients with breast carcinoma in Tunisia (74%) compared with patients with breast carcinoma in the United States (36%), Italy (38%), Australia (42%), Argentina (31%), and Vietnam (0.8%) CONCLUSIONS The findings provided increased evidence for a human breast carcinoma virus with geographic differences in prevalence. The geographic differences were compatible with studies of MMTV in wild mice; thus, the data were plausible biologically. Cancer 2004. © 2004 American Cancer Society.

The purpose is to define intratumoral microvessel density (MVD) and potential biological markers that correlate with inflammatory breast cancer (IBC), we examined MVD, estrogen receptor a (ER) status, MIB-1 proliferation index, p53, and c-erbB-2 by immunohistochemistry in archival specimens from 67 women diagnosed with breast cancer with or without the inflammatory phenotype at the Institut Salah Azaiz (Tunis, Tunisia).The moderate (25-50/x400 field) to high microvessel count (50/x400 field) was observed in 23 (51%) of 45 IBC tumors compared with 3 (14%) of 22 non-IBC tumors (P = 0.0031; chi(2) test). The presence of ER was found in 6 (14%) of 44 cases versus 7 (32%) of 22 cases in IBC and non-IBC, respectively (P = 0.10). In this series of 67 patient tumors, the median MVD count in ER-negative breast tumors was 21, whereas the median count was 4 in ER-positive breast tumors (P = 0.08; Wilcoxon rank-sum test). However, MIB-1, p53, and c-erbB-2 were not significantly different between IBC and non-IBC tumors. The intratumoral MVD between IBC and non-IBC was still statistically significant after adjustment for multiple comparisons (P = 0.02; Bonferroni test).These data suggest that there is an increased MVD in breast cancer with the inflammatory phenotype as compared with breast cancer without the inflammatory phenotype.

Eighty-three patients with rapidly progressing breast cancer (RPBC) were entered into a study of primary chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil) and subsequent randomization to surgery or radiotherapy for control of local/regional disease. Eighty-three of these patients with redness, warmth, and edema compatible with clinical “inflammatory breast cancer” served as the focus for our analysis of factors associated with improved survival. The stage-specific disease-free intervals (DPI) of 36 and 21 months were substantially longer than in the earlier series (26 and 16 months) from the same institution. The evaluation of individual prognostic indicators revealed that the initial tumor size and the initial response to chemotherapy were the two independent factors most important in predicting the DPI. The continuing unmaintained 1-year remission in at least 12 patients supports the rationale for aggressive therapy in RPBC or “inflammatory breast cancer.”

Aim: Numerous publications since the 1970s have reported an apparently high frequency of IBC in Tunisia affecting up to 50% of breast cancer patients. In the past 20 years, 3 complete national population-based cancer registries have provided more precise information about breast cancer (BC) incidence. Moreover, IBC diagnostic criteria moved from the French classification of aggressive or rapidly progressing breast cancer (RPBC) also designated as "pousee evolutive" (PEV) to the current system of the American Joint Committee on Cancer (AJCC). In this study we reviewed a series of publications and recent data from the Tunisian Breast Cancer Registries to evaluate the gradual changes in IBC and non-IBC and relate the findings to improvements in the general economic situation in this country.Methods: All indexed Tunisian publications regarding RPBC and IBC since 1970 were compiled and their data were compared to recent data from the Tunisian Cancer Registries. These findings were compared to reports on changing breast cancer patterns in Tunisia overall.Results: Trends in Tunisian BC were compared to the original report of RPBC from Tunisia's National Cancer Institute, the Institut Salah Azaiz, which noted 340 of 581 (58.5%) consecutive breast cancer patients had RPBC which included 282 (48.5%) PEV 3 patients clinically indistinguishable from IBC in the United States. In 6 subsequent series including 700 to 1400 patients affected by BC published from 1985 to 2008, the relative percentage of IBC patients gradually decreased to 30.3%, 6.2% and 5.7% associated with a concurrent increase in the incidence of breast cancer nationwide. Registry data and hospital-based studies have shown also a progressive decrease in mean clinical tumor size in the past four decades from 60mm to 40mm and a discordant tumor size between private patients and public patients, the latter having significantly larger tumors at diagnosis. This trend, compatible with the early observation of a rural predominance of RPBC and a gradual increase in gross national product supports other etiuologic studies indicating a strong environmental determinant. for IBC.Conclusion: These data support a number of studies indicating that environmental factors, including poorer socioeconomic conditions, prolonged breast feeding, and obesity may be risk factors for IBC, and indicate the importance of environmental factors in the etiology of this disease. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2077.

A form of breast cancer characterized by rapid disease progression, inflammation, and edema is found in approximately 55% of the breast cancer patients presenting at the Institute Salah Azaiz, Tunis (Tunisia). In 581 patients seen between January 1, 1969, and December 31, 1974, we examined age, place of residence, reproductive history, delay in seeking treatment, and blood gropu as potential risk factors to determine the distinction between the rapidly progressing disease and the less aggressive form. Rural residence, blood type A, and recent pregnancy are risk factors among premenopausal women, but older age, rural residence, blood type A, late menarche, and delay in diagnosis are associated with postmenopausal rapidly progressing breast cancer. The most significant risk factors were rural residence and blood type A. Rapidly progressing breast cancer was diagnosed in two of every three breast cancer patients coming from a rural environment. Forty-three percent of 203 patients with rapid disease progression were blood type A, a significantly higher percentage than the 33% found in the general Tunisian population and the breast cancer patients without evidence of rapidly progressive disease. We observed that the risk factors for disease progression were quite different from those reported to influence the incidence of breast cancer.

Conflicting opinions exist concerning clinical and pathological presentation, as well as evolution and prognosis, of breast cancer in young women. The roles of associated pregnancy and lactation on these parameters is also unclear. These two conditions are studied in the present work through the comparison of two breast cancer patient age groups: patients under the age of 30 (Group A) and premenopausal patients aged 45–49 (Group B). Rapidly growing and/or inflammatory breast cancer (rapidly progressing breast cancer: RPBC) — a special form of Breast Cancer with a poor prognosis very frequent in the Tunisian breast cancer population — was more often present among Group A patients. This difference is a consequence of the more frequent association of this breast cancer group with pregnancy or lactation; nearly all the cases of breast cancer associated with pregnancy or lactation are RPBC. For breast cancer without the pregnancy/lactation association, the younger group generally shows poorer histological grading and more severe evolution. The number of patients in our study is not really sufficient to allow statistically significant conclusions, but it does seem clear that young age and associated pregnancy/lactation are aggravating factors in Tunisian breast cancer patients.

Based on two pretreatment evaluations, doubling time (DT) was calculated in 75 cases of invasive breast cancer (BC). The cases studied were more or less equally distributed between three DT groups: fast-growing tumors (DT less than 90 days), intermediate cases (DT between 90 and 180 days), and slow-growing tumors (DT greater than 180 days. A correlation was found to exist between DT and patient age and, to an even greater extent, between DT and pathologic prognostic indicators such as histologic grading and nuclear grade. Inflammatory symptoms were not associated with DT, but were closely related to the size of the tumor and regional lymph node involvement. The date of detection of distant metastases depended heavily on the DT of the BC:BC with shorter DT = earlier metastatic spread. The presence of inflammatory signs was also decisive: within each DT category, inflammatory BC metastases were both more frequent and precocious.

Biopsy specimens from 85 Tunisian breast cancer patients were compared with those of 95 American breast cancer patients for estrogen receptor (ER) and progesterone receptor (PR) levels. Tunisian patients with rapidly progressing breast cancer (RPBC) had lower ER levels than American patients or Tunisian patients without evidence of RPBC. Lower ER levels in the earliest stage of RPBC, which presents without inflammatory signs, supported epidemiologic and pathologic studies indicating that rapid growth as reported by the patient is an important aspect of RPBC. Low ER levels were generally found in young, premenopausal Tunisian women with advanced RPBC; multivariate analyses suggest that age was the most important correlating factor. In the Tunisian patients, ER levels showed a direct correlation with response to therapy. No consistent relationship between American and Tunisian patients or subgroups was observed for PR levels. These results indicate the need for reevaluating the routine use of oophorectomy in RPBC.

The histological features of 94 cases of carcinoma of the breast seen in Tunisia were recorded and subsequently correlated with the clinical classification of the patients in terms of poussée évolutive (PEV) categories. Histological features analyzed in the breast tissues and skin included tumor type, nuclear grade, number of mitoses, involvement of the dermis, cutaneous inflammatory infiltrate and edema. Twenty-eight percent of the cases in which the skin was examined showed tumor emboli in the lymphatics of the dermis. The frequency of cutaneous permeation correlated with the PEV categories. The percentage of cases with nuclear grade 3 was higher for the group with rapid progression of the disease (PEV 1,2,3) than for the cases belonging to the PEV-0 category (90% versus 64.2%). The present study demonstrates that a large proportion of breast carcinoma patients in Tunisia suffer from "inflammatory carcinoma of the breast".

Nine cases of Mediterranean lymphoma with alpha heavy chain disease are described. All patients were young, aged between 11 and 22 years. Neither sex predominated in the series. The clinical presentation of the disease was either gastrointestinal, with chronic diarrhea and malabsorption, or neoplastic, with tumors frequently associated with either obstructive or perforative complications. Finger clubbing and retardation of physical growth (height and weight) and secondary sexual maturation were usually evident. The laboratory manifestations of the malabsorption syndrome were scant and generally not specific. The intestinal lesions predominated in the beginning of the small bowel, and their gross appearance varied from one case to another: diffuse thickening of the intestinal wall, alone or associated with tumors, or isolated segmentary tumors. Massive mesenteric lymph node enlargement was present in all cases; in some cases hepatic, splenic, or extra-abdominal lymph node spread was noted. Histologically, these lesions demonstrated a varied cellular morphology, but seemed to belong constantly to the B-lymphocytic line. The secretion and excretion by these cells of an abnormal IgA (devoid of light chains), which was revealed by immunoelectrophorectic study of the patients' sera, was the main biochemical abnormality of the disease. This disease presents several problems: 1) its relationship with other intestinal lymphomas; 2) the nature and the degree of malignancy of the intestinal cellular infiltrates; and 3) its identification as a clinicopathologic entity, with the possibility that infectious and genetic factors are significant in its etiology and pathogenesis.

Clinical and radiographic examination of 581 patients with histologically veri-fied breast cancer has permitted us to define a subgroup having a significantly poorer prognosis than other patients. Their condition, called “poussee evolu-tive” (rapidly progressing), is characterized by rapid tumor growth and/or inflammation adjacent to the tumor. Statistical analysis of the survival of Mo patients (412 of the 581) shows that the diagnosis of “poussee evolutive” provides prognostic information beyond that given by T and N classifications and after delay between initial symptoms and diagnosis has been considered. Six years of clinical experience with this condition are discussed. Cancer 40:376–382, 1977.

Four-hundred and fifty nine cancer patients were skin tested with extracts from five lymphoid cell lines. More than 50% of patients with lymphoma had positive skin tests with the extracts prepared from the cell line derived from Burkitt's lymphoma (BL) and more than 50% of nasopharyngeal carcinoma (NPC) patients reacted to the NPC-derived cell line extracts. Although the significant association between patient diagnosis and origin of cell lines suggested that tumor-associated antigens were responsible for the pattern of delayed hyper-sensitivity, problems in standardization of antigen potency and non-specificity need to be resolved before this in vivo assay achieves its full potential.

It has been suggested that poussee evolutive (PEV) or rapidly progressing breast cancer (RPBC) represents a failure in the host immune system to control the proliferation of breast cancer cells. To evaluate this possibility, we have performed in vivo and in vitro assays of cellular immunity in Tunisian patients with breast cancer. Studies of delayed hypersensitivity using microbial antigens and in vitro including lymphocyte transformation tests and measurements of B and T cells indicated that RPBC patients had an immune response comparable to that of breast cancer patients without evidence of rapid progression. Normal Tunisians were more immunocompetent, however, an appeared to have a higher level of immune activity than normal individuals in the United States. In a second, independent series, an increased frequency of blood group A was found in RPBC patients, suggesting a genetic predisposition to this form of breast cancer. However HLA typing for A, B and DRW antigens revealed no specific RPBC-associated HLA antigen. Our studies clearly demonstrate that RPBC, or PEV, is not a reflection of immunodeficiency.

112 Tunisian patients with rapidly progressing breast cancer (RPBC) were entered into a clinical trial evaluating combination chemotherapy as a primary form of treatment before surgery or radiotherapy. Three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) were administered at monthly intervals; patients were then randomized to surgery or radiotherapy to control the primary tumour, and 12 more cycles of CMF followed local/regional therapy. RPBC was sensitive to CMF; after only 3 cycles, 11% of evaluable patients showed complete remission and 78% had at least 25% diminution in tumour size. The disease-free interval (DFI) was substantially greater in this series than in a previously reported series treated by surgery and/or radiotherapy alone. No difference in DFI was found between patients randomized to receive surgery and those randomized to receive radiotherapy. Postmenopausal patients responded to CMF as well as premenopausal patients. Combination chemotherapy appears to play an important role in the control of RPBC, an aggressive malignancy often resembling inflammatory breast cancer.

Delayed hypersensitivity reactions to a battery of antigens were measured in 145 Tunisian breast cancer patients to determine whether an immuno-logic mechanism could be detected which might explain the high frequency (60%) of the rapidly progressing form in Tunisian breast cancer patients. Although a greater proportion (30%) of patients with rapidly progressing breast cancer reacted to extracts of a breast tumor antigen (2937) than patients without PEV (9%), no significant difference between PEV and non-PEV patients could be found in reactivity to DNCB, standard microbial antigens, or extracts from tissue culture cell lines. Rapidly progressing breast cancer in Tunisia is not associated with an impairment of delayed hypersensitivity.