Low frequency of somatic mutations in uterine sarcomas: a molecular analysis and review of the literature.

OBJECTIVE: The rarity of uterine sarcomas along with their pathological and molecular heterogeneities render their study particularly challenging. We evaluated a panel of somatic mutations principally centering on the tyrosine kinase gene family and their downstream signaling cascades in an attempt to identify potential candidate markers that may assist in diagnostic or therapeutic decisions in these tumors. METHODS: We performed mutational analysis of 20 exons from 9 genes (EGFR, CDKN2A, MET, KIT, RAS, BRAF, PI3KCA, HER-2 and PDGFR-alpha) on biopsy material from 25 patients who underwent primary surgery for uterine sarcoma between October 1995 and October 2003. Due to the limited number of studies conducted we have also undertaken a literature review of somatic mutations in uterine sarcomas. RESULTS: A total of 3 different somatic mutations were identified: one KRAS (codon G12D) in a carcinosarcoma and two exon 20 PI3KCA mutations (H1047R and H1047Y) both in carcinosarcomas. Mutational status of all mutations was confirmed using germline DNA extracted from peripheral blood. Consistent with the literature data, no other mutations regarding the rest of the genes of the panel were identified. Due to the low number of somatic mutations in our series, we did not perform further clinicopathological correlations. CONCLUSION: The absence of somatic mutations in the majority of genes that are considered critical in neoplastic transformation hampers the identification of potential therapeutic targets in patients with uterine sarcoma.

Clinicopathological features of primary fallopian tube carcinoma: a single institution experience.

PURPOSE OF INVESTIGATION: Primary fallopian tube carcinoma (PFTC) is a rare malignancy with only few data existing on the impact of prognostic factors. METHODS: We retrospectively analyzed 26 patients. Tissue blocks were reviewed and sections were stained for vascular endothelial growth factor (VEGF), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2), c-erbB-2, estrogen (ER), and progesterone receptors (PgR). RESULTS: Reactivity for VEGF, ER, PgR, MMP-2, MMP-9, TIMP-1, TIMP-2 and c-erbB-2 was observed in 85%, 46%, 27%, 11.5%, 58%, 0%, 23% and 8% of specimens, respectively. None of the markers studied displayed prognostic significance. Regarding clinical prognostic factors, the hazard ratio (HR) for progression and death for patients with tumor residuum > 2 cm was 5.24 (p < 0.01) and 11.19 (p < 0.005), respectively. Patients with advanced stage disease had a HR of 12.55 (p < 0.05) for progression, while the HR for death was not found to be statistically significant. CONCLUSION: None of the biomarkers studied seems to influence survival. Early-stage disease and optimal debulking are associated with improved outcome.

Splenosis of the peritoneal cavity resembling an adnexal tumor: case report.

INTRODUCTION: Splenosis is the autoimplantation of ectopic spleen tissue in various anatomic cavities of the body resulting after trauma or rupture of the splenic parenchyma. The major localization sites of this phenomenon are mainly intraperitoneal, the gastrenteric tract, genitalia, intrahepatically and the kidneys. Extraperitoneal locations occur less frequently and include the thorax and brain. Also locallization in the subcutaneous fat has been described. CASE REPORT: We present the case of a 32-year-old woman with symptomatic peritoneal cavity splenosis occurring ten years after traumatic splenectomy. The patient was admitted to our department with the clinical presentation of an adnexal tumor. US and CT confirmed an adnexal mass. Exploratory laparotomy was performed and multiple focal lesions were noticed on the uterus, ovaries and intestinal tract. Biopsies were taken and sent for histological analysis. The pathology specimen revealed ectopic splenic tissue. After surgical intervention the patient remained asymptomatic. CONCLUSION: Splenosis is a rare phenomenon which clinicians should be aware of in order to spare patients from pointless surgical interventions. Patients with abdominal masses and post-traumatic splenectomy should be checked for splenosis.

Anthracycline-based adjuvant chemotherapy in early-stage uterine sarcomas: long-term results of a single institution experience.

PURPOSE OF INVESTIGATION: Uterine sarcomas are rare neoplasms characterized by a high rate of local recurrences and distant metastases. The role of chemotherapy in early-stage completely resected disease remains controversial. METHODS: Thirty-one patients with Stage I or II uterine sarcomas, referred to our center for adjuvant chemotherapy, received anthracycline-based regimens. Seventeen (54.8%) patients received ifosfamide, etoposide and epirubicin, six (19.4%) were treated with doxorubicin and carboplatin, three (9.6%) were administered doxorubicin and ifosfamide, while five (16.1%) patients received various anthracycline-based regimens. RESULTS: With a median follow-up of 82 months disease recurred in 12 (38.7%) patients. Five-year survival probability is estimated at 54%. Both median overall survival and time to progression for all patients have not been reached yet. Patients who received ifosfamide-containing regimens had a statistically significant benefit in overall survival (p < or = 0.05) when compared with those treated with non-ifosfamide-containing regimens. CONCLUSION: Our data suggest a potential role for anthracycline- and ifosfamide-containing chemotherapy in the adjuvant setting for early-stage uterine sarcomas.

The prognostic value of the topographic distribution of uPAR expression in invasive breast carcinomas.

uPA system plays an important role in cancer invasion and metastasis. The binding of uPA to its receptor, uPAR, is necessary for the activation of uPA system. We studied by immunohistochemistry the distribution pattern of uPAR on 173 paraffin-embedded samples of invasive breast carcinomas in relation to clinicopathologic data and patients' survival. uPAR was detected in both the malignant and stromal cells in the 68.8 and 74.6% of the cases, respectively. uPAR of cancerous cells was more often observed in lobular carcinomas (P=0.012). Stromal expression of uPAR was inversely associated with ER of the tumor (P=0.044) and was found to be an independent prognosticator of patients' shortened relapse-free survival (P=0.018). These results suggest that stromal uPAR influences more directly tumor behaviour, being related to an aggressive tumor phenotype and patients' poor relapse-free survival.

An immunohistochemical evaluation of phosphorylated Akt at threonine 308 [pAkt(Thr308)] in invasive breast cancer.

BACKGROUND: Akt is a serine/threonine kinase which is fully activated when phosphorylated (pAkt). The aim of this study was to investigate the expression pattern of phosphorylated Akt at Threonine 308 [pAkt(Thr308)] in association with clinicopathological parameters and various biological markers. MATERIALS AND METHODS: Immunohistochemistry was performed on paraffin-embedded tissue specimens from 152 invasive breast carcinomas to detect the expression of the proteins pAkt(Thr308), estrogen (ER) and progesterone (PR) receptors, p53, Ki-67 and c-erbB-2. RESULTS: pAkt(Thr308) protein was immunodetected in the cytoplasm and the nuclei of the malignant cells. pAkt was found to be positively associated with the lobular histological type, while it was found to exert no impact on patients' survival. pAkt(Thr308) immunopositivity was inversely related to Ki-67 and p53 (p=0.013 and p=0.020, respectively), while being positively associated with cerbB2 expression (p=0.005). CONCLUSION: This is the first study to show a frequent detection of pAkt(Thr308) in lobular breast carcinomas and an association of its expression with indices of proliferation (c-erbB2, Ki-67) and apoptosis (p53).

Clinicopathological and prognostic significance of vascular endothelial growth factors (VEGF)-C and -D and VEGF receptor 3 in invasive breast carcinoma.

AIMS: Vascular endothelial growth factors C and D (VEGF-C and VEGF-D) play a major role in lymphangiogenesis and activate VEGF receptor 3 (VEGFR-3). Our purpose was to study the clinicopathologic and clinical value of VEGF-C, VEGF-D and VEGFR-3 in invasive breast carcinoma. MATERIAL AND METHODS: Immunohistochemistry was performed in paraffin-embedded tissue specimens from 177 invasive breast carcinomas to detect the proteins VEGF-C, VEGF-D, VEGFR-3, p53, Ki67, c-erbB-2, topoII alpha and ER/PR. The results were statistically processed. RESULTS: VEGF-C, VEGF-D and VEGFR-3 were found to be predominantly expressed in the cytoplasm of the malignant cells. VEGF-C occasionally showed a submembranous intensification. VEGF-D and VEGFR-3 were also immunodetected in the nuclei of the malignant cells. Nuclear VEGF-D was positively correlated to p53, Ki67 and topoII alpha proteins' expression (p=0.003, p=0.009 and p=0.017 respectively) and nuclear VEGFR-3 to topoII alpha (p=0.034). Cytoplasmic expression of VEGF-C and its submembranous intensification were found to be independent indicators of patients' overall and disease-free survival, respectively (p=0.003 and p=0.044 respectively). The group with high expression of both cytoplasmic VEGF-C and stromal VEGFR-3 showed poor overall survival (p=0.024) and the group with both submembranous VEGF-C and stromal VEGFR-3 immunostaining showed poor both disease-free and overall survival (p=0.012 and p=0.038 respectively). CONCLUSION: VEGF-D and VEGFR-3 seem to exert proliferative activity in invasive breast carcinomas. VEGF-C was found to be an independent indicator of patient's poor prognosis and the simultaneous expression of tumor VEGF-C and stromal VEGFR-3 yielded additional prognostic information.

Evaluation of the prognostic and predictive value of p53 and Bcl-2 in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy.

PURPOSE: To assess the prognostic and predictive significance of p53 and Bcl-2 protein expression in high risk patients with breast cancer treated with dose-dense sequential chemotherapy. PATIENTS AND METHODS: From June 1997 until November 2000, 595 patients were randomized to three cycles of epirubicin (E) 110 mg/m2 followed by three cycles of paclitaxel (P) 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) or to four cycles of E, followed by four cycles of CMF. p53 and Bcl-2 expression was investigated by immunohistochemistry in 392 and 397 patients respectively. RESULTS: Positive expression of p53 was detected in 104 (26.5%) patients and was significantly associated with negative hormonal status, worse histologic grade, higher incidence of disease relapse and higher rate of death. p53 positive expression was a significant negative predictor of overall survival (OS) (P = 0.002) and disease-free survival (DFS) (P = 0.001). Negative expression of Bcl-2 was detected in 203 (51%) patients and was significantly associated with negative hormonal status. Multivariate analysis revealed that, positive p53 expression, higher number of positive nodes and worse tumor grade were related to significantly poorer OS and DFS. CONCLUSIONS: For both treatments, p53 positive expression was a significant negative prognostic factor for OS and DFS while Bcl-2 was not. No predictive ability of p53 status or Bcl-2 status for paclitaxel treatment was evident.

Study of phospho-beta-catenin subcellular distribution in invasive breast carcinomas in relation to their phenotype and the clinical outcome.

Beta-catenin has a crucial role in cell-cell adhesion as well as a signaling role as a member of the Wnt pathway. The aim of this study was to examine the clinicopathological and prognostic value of phosphorylated beta-catenin, as well as its relation to the tumors' phenotype, in breast cancer. Immunohistochemistry was applied on 141 paraffin-embedded breast tissue specimens for the detection of phospho-beta-catenin, ER, PR, c-erbB-2, p53, Ki-67, bcl-2, uPAR and TIMP-1. For each case, a phospho-beta-catenin index was determined by image analysis. Phospho-beta-catenin staining was detected in the cytoplasm and the nucleus of the malignant cells. Cytoplasmic phospho-beta-catenin was statistically higher in carcinomas of smaller tumor size (P = 0.030), lower stage (P = 0.026), decreased Ki-67 and high c-erbB-2 immunoreactivity (P = 0.052 and P = 0.037, respectively). Nuclear phospho-beta-catenin showed a parallel correlation with ER and ERbeta (P = 0.022 and P = 0.043, respectively), bcl-2 (P = 0.042), uPAR in cancer cells (P = 0.041) and TIMP-1, although the correlation was borderline (P = 0.066). Cytoplasmic phospho-beta-catenin was found to be independently correlated with prolonged disease-free and overall survival (P = 0.046 and P = 0.002, respectively), whereas nuclear localization was correlated with a shortened overall survival (P = 0.046). In conclusion, phospho-beta-catenin may have a different involvement in invasive breast carcinomas, according to its subcellular distribution. Nuclear localization seems to be related to an aggressive tumor phenotype, negatively affecting patients' overall survival, whereas cytoplasmic localization is associated with a favorable tumor phenotype and a longer disease-free and overall survival.

Overexpression of cyclooxygenase-2 is associated with a favorable prognostic phenotype in breast carcinoma.

OBJECTIVES: Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. The purpose of the present study was to investigate the involvement of COX-2 protein in breast cancer biological behavior through its correlation with the well-known clinicopathological parameters and the expression of p53, c-erbB-2, topoisomerase IIalpha (topoIIalpha) and peroxisome proliferator-activated receptor (PPARgamma) proteins, as well as its effect on patients' survival. METHODS: We performed immunohistochemistry to detect COX-2, estrogen receptor (ER), progesterone receptor (PR), p53, c-erbB-2, topoIIalpha and PPARgamma proteins in 175 cases of invasive breast carcinomas. The results were elaborated by statistic analysis. RESULTS: Cytoplasmic expression of COX-2 was detected in 66.9% of breast carcinoma samples and was inversely correlated with both nuclear and histological grade (p < 0.0001 and p = 0.039, respectively), whereas its association with PR was found to be positive (p = 0.016). COX-2 expression was inversely correlated with topoIIalpha and p53 (p = 0.033 and p = 0.002, respectively), whereas its association with PPARgamma was parallel (p < 0.0001). In addition, c-erbB-2 of tumor cells was inversely correlated with COX-2 in stromal cells of the tumor (p = 0.011). Neither univariate nor multivariate analysis demonstrated any association between COX-2 expression and patient overall or disease-free survival. CONCLUSIONS: The current data suggest that increased expression of COX-2 may be related to breast carcinomas with less aggressive phenotype. This suggestion is further supported by the positive correlation between COX-2 and PPARgamma, since the latter is considered to be indicative of a less malignant phenotype of tumor cells.

The multifunctional role of the immunohistochemical expression of MMP-7 in invasive breast cancer.

The secretion of matrix metalloproteinases (MMPs) is crucial in the metastasis of cancer cells, since MMPs are responsible for the degradation of extracellular matrix (ECM). Among them, matrix metalloproteinase-7 (MMP-7) or matrilysin 1 is a stromelysin which degrades type-IV collagen, fibronectin and laminin. Immunohistochemistry was performed to detect MMP-7 protein in infiltrative breast carcinomas. MMP-7 was studied along with clinicopathological parameters, disease-free and overall survival, and p53, c-erbB-2, topoIIa, MMP-2, uPAR and beta-catenin. MMP-7 immunoreactivity was detected in the cytoplasm of cancer cells in 54.2% (96/177) and tumor stromal cells in 47.5% (84/177), as well as in normal epithelium adjacent to malignant epithelium. MMP-7 reactivity in cancer cells displayed an inverse association with nuclear grade (p=0.049) and topoIIa (p=0.03). A parallel association was observed between the expression of MMP-7 in both malignant and stromal cells with uPAR in cancer cells (p=0.033 and p=0.027, respectively). MMP-7 of tumor stromal cells depicted a parallel correlation with MMP-2 of the same cell type (p=0.044), while abnormal beta-catenin expression was inversely associated with MMP-7 of cancer cells (p=0.047). Our results show the multifunctional role of MMP-7 in the mammary gland, since it seems to be associated with a less aggressive phenotype, while, at the same time, being involved in invasion, through its collaboration with indicators of invasion.

PPARgamma expression in breast cancer: clinical value and correlation with ERbeta.

AIMS: To examine the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in invasive breast carcinoma in relation to known clinicopathological features, ERbeta, and relapse-free and overall patient survival. PPARgamma is a ligand-activated transcriptional factor that regulates the transcription of various target genes and has been implicated in human breast cancer. METHODS AND RESULTS: We performed immunohistochemistry to detect PPARgamma, ERalpha, PR and ERbeta in 170 infiltrative breast carcinomas. The results were subjected to statistical analysis. PPARgamma was detected in the cytoplasm of 58% of breast carcinoma samples. PPARgamma did not differ with regard to any of the clinicopathological parameters except for histological grade, to which it was found to be inversely correlated (P = 0.019), and ERbeta, to which it was positively related (P = 0.016). As regards relapse-free survival, in univariate statistical analysis PPARgamma was found to exert a marginally favourable impact on all the patients (P = 0.076), but a strong one on patients with ductal carcinoma (P = 0.027), whereas Cox's regression analysis depicted PPARgamma to be an independent prognosticator for patients with ductal carcinoma (P = 0.039). No association was found between PPARgamma expression and overall survival. CONCLUSION: These results indicate the favourable impact of PPARgamma expression on disease-free survival of patients with ductal breast carcinoma and its possible cooperation with ERbeta in exerting that favourable effect.

Adjuvant chemotherapy with paclitaxel and carboplatin in non-endometrioid carcinoma of the uterus.

PURPOSE OF INVESTIGATION: Uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCCC) represent more aggressive tumors than the more common endometroid cancers, exhibiting a propensity for distant metastasis. The aim of this study was to investigate the activity and safety of paclitaxel/carboplatin chemotherapy as the only adjuvant treatment in patients with surgically resected UPSC and UCCC. METHODS: Fifteen patients with Stage IB-IV UPSC or UCCC were treated with a mean of six courses of paclitaxel 175 mg/m3 plus carboplatin AUC 5 at three-week intervals, three to six weeks after undergoing surgery with curative intent. No patient had residual disease after surgery and none underwent pre- or post-chemotherapy irradiation. RESULTS: With a median follow-up of 29.4 months, six patients (40%) relapsed and two (13%) died of disease. Mean time to recurrence was 16.9 months. Recurrence rate per Stage was 17% for Stage IB/C, 57% for Stage IIIA/C and 50% for Stage IV. Projected 5-year overall survival and progression-free survival was 79.7% and 55.7%, respectively. All relapses were abdominopelvic whereas in one case pelvic recurrence was accompanied by lung metastasis. The most frequent grade 3-4 toxicity was neutropenia. CONCLUSION: Chemotherapy with paclitaxel plus carboplatin is feasible and possibly prevents distant metastasis when used as adjuvant in UPSC and UCCC.

The expression of epithelial specific antigen in cervical intraepithelial neoplasia and adenocarcinoma.

There is a spectrum of changes described as cervical glandular intraepithelial neoplasia (CGIN) with adenocarcinoma in situ (AIS) considered to represent the most severe lesion in that spectrum. Although there is evidence to suggest a progression of CGIN to AIS and to invasive adenocarcinoma, the natural history of these potential precursor lesions has not been fully elucidated. The aim of this project was to establish the relationship of endocervical glandular intraepithelial neoplasias to uterine endocervical adenocarcinoma. Our study included 40 cases of glandular lesions of the cervix (15 cases of endocervical glandular intraepithelial neoplasia, eight of adenocarcinoma in situ and 17 cases of invasive adenocarcinoma). An attempt was made to examine the immunohistochemical localization of epithelial specific antigen (ESA) in those lesions and compare the results with ten cases of normal endocervical epithelium. ESA showed positive staining of the basolateral membrane of endocervical cells in the normal endocervix. The expression of ESA was found to increase from the basolateral to the diffuse cytoplasmic membrane in 12 out of 15 cases of CGIN (80%), in seven out of eight cases of AIS (84%) and in all of the 17 invasive adenocarcinomas (100%). This finding indicates that ESA is a useful marker in the diagnosis of glandular intraepithelial neoplasia and suggests that CGIN and AIS may be precursor lesions of cervical adenocarcinoma.

The favourable prognostic value of oestrogen receptor beta immunohistochemical expression in breast cancer.

AIMS: Oestrogen receptor beta (ERbeta) is present in breast tumours, although its prognostic and pathophysiological roles remain to be established. METHODS: Standard immunohistochemistry with a specific monoclonal antibody was performed on paraffin wax embedded sections; 10% of strongly immunostained carcinoma cells was used as the cutoff point to classify tumours as ERbeta positive. Statistical correlations were sought with clinicopathological variables (including hormone receptor status) and disease free (DFS) and overall survival (OS) in a well documented series of 181 invasive breast carcinomas. Cell proliferation was assessed immunohistochemically by topoisomerase IIa (TopoIIa) index; p53 protein accumulation and c-erbB-2 oncoprotein expression were also taken into account. RESULTS: ERbeta immunoreactivity was detected in most specimens (71.2%); it was positively linked to ERalpha immunoreactivity and increased TopoIIalpha index, and inversely to c-erbB-2 overexpression. There were no correlations with p53 immunostaining or other clinicopathological parameters. A significant favourable impact of ERbeta immunopositivity emerged with regard to DFS and OS in both univariate and multivariate analysis; ERbeta immunopositivity retained its favourable significance with regard to DFS in the subgroups of stage I and II patients when they were examined separately. Progesterone receptor expression also had an independent favourable influence on survival, albeit with less significance. In contrast, survival was not significantly influenced by ERalpha status. CONCLUSIONS: Because of the positive association between ERbeta immunoreactivity and TopoIIalpha expression, the presence of ERbeta in breast cancer cells could be considered an indication of increased proliferation. Nevertheless, ERbeta immunoreactivity emerges as a valuable, independent indicator of favourable prognosis.

Angiogenic properties of carcinoma in situ and microinvasive carcinoma of the uterine cervix.

Neovascularization is a critical step in the growth, progression and metastasis of tumors. The degree of angiogenesis may correlate with disease stage and provide prognostic information in various neoplasms. Microvessel density was studied in 24 patients with severe cervical intraepithelial neoplasias, 15 patients with microinvasive carcinomas (International Federation of Gynecology and Obstetrics IA1) and 15 healthy controls who had undergone hysterectomy for benign conditions. The microvessel density (MVD) in microinvasive squamous cell carcinomas was 40 +/- 2.42 (mean +/- SD) and in squamous carcinomas in situ (CIS) 20.41 +/- 2.29 (p < 0.05). Among patients with CIS and controls (13.33 +/- 1.59) there was also a significant difference in the number of vessels (p < 0.05). No significant correlation was found in relation to depth of invasion and histological grade of the microinvasive carcinomas. It is concluded that microinvasive squamous cell cervical carcinoma is an angiogenetic disorder and it seems that the onset of angiogenesis is an early event, usually in a preinvasive stage.

The prognostic significance of the immunohistochemical expression of p53, bcl-2, c-erb B-2 and cathepsin-D in ovarian cancer patients receiving platinum with cyclophosphamide or paclitaxel chemotherapy.

PURPOSE: To evaluate the prognostic significance of the immunohistochemical expression of p53, bcl-2, c-erbB-2 and cathepsin-D in epithelial ovarian cancer (EOC). METHODS: We analyzed 100 patients with ovarian carcinoma, FIGO Stage IC-IV who underwent primary cytoreductive surgery and received adjuvant chemotherapy with cyclophosphamide and a platinum analogue (CP) (n = 46) or paclitaxel and a platinum analogue (TP) (n = 54). Immunohistochemical expression was studied on paraffin-embedded tissue from the primary tumor. RESULTS: After a median follow-up of 55 months median progression-free survival (PFS) and overall survival (OS) were 16 and 41 months, respectively. Positive bcl-2 staining and absence of cathepsin-D expression were associated with an increased complete response rate in the CP group (p = 0.011 and p = 0.003) but not in the TP group. PFS and OS were not associated with the expression of any of the markers studied. FIGO stage (p = 0.006) and histology (p = 0.047) were the only independent prognostic factors for survival. CONCLUSION: Bcl-2 and cathepsin D expression are associated with response to CP but not TP chemotherapy. P53, bcl-2, c-erb B-2 and cathepsin D expression was not correlated with PFS and OS in our study.

The favorable prognostic impact of tissue inhibitor of matrix metalloproteinases-1 protein overexpression in breast cancer cells.

The tissue inhibitor of metalloproteinases-1 (TIMP1) inhibits tumor cell invasion and metastasis in experimental models; in addition, TIMP1 is supposed to possess another important function, cell growth promotion. The potential prognostic significance of TIMP1 in breast cancer remains unclear. We evaluated the significance of the immunohistochemical expression of TIMP1 in a well-documented series of 133 infiltrating breast carcinomas by examining any possible statistical association between this expression and numerous clinicopathological parameters as well as patients' disease-free interval. TIMP1 was generally expressed in both stromal and cancer cells in our specimens. TIMP1 was overexpressed in cancer cells of 60.15% of all cases. Tumors of high histological and nuclear grade were found to overexpress TIMP1 less frequently than the rest (p=0.003 and p=0.057, respectively). Interestingly, TIMP1 overexpression was inversely associated with cell proliferation, the latter being evidenced by Ki67 immunoreactivity (p=0.028). TIMP1 immunostaining was in parallel with metalloproteinase-2 (MMP2) immunoexpression in both cancer and stromal cells. Multivariate analysis disclosed that TIMP1 overexpression in cancer cells was an independent determining factor for prognosis (p=0.006); TIMP1 overexpression in malignant cells appeared to correlate with favorable outcome, particularly in patients with lack of nodal metastases and in patients with MMP2-negative immunophenotype (p=0.0252). The upregulation of TIMP1 cancer cell expression in breast cancer may suggest that this marker has a multifunctional role apart from that of metalloproteinase inhibitor since it was found to be related to malignant cells' differentiation and proliferation. TIMP1 overexpression in cancer cells appears for the first time to be a promising indicator of favorable prognosis in breast cancer.

Cat-scratch disease presenting as a solitary tumour in the breast: report of three cases.

Cat-scratch disease (CSD) may appear as a solitary mass in the breast and give the impression of a breast carcinoma. In this case, further clinical and laboratory investigation is required to rule out malignancy. We present three cases of CSD of the breast in women of 64, 31 and 61 years old. Each presented with enlarged lymph-nodes in the breast, which were clinically mistaken for solitary tumours. In the first two patients, the mammography was negative. The third patient had a mammogram which indicated a well-defined solid mass in the parenchyma without calcifications. We discuss the clinical, histological and histochemical findings, analyze the differential diagnosis and review the literature.

Leiomyosarcoma of the breast. A clinicopathologic and immunohistochemical study.

Leiomyosarcoma is one of the rarest sarcomas of the breast. We present the clinical, histological and immunohistochemical findings of two new cases of leiomyosarcomas of the breast in 42 and 65 years old women. We analyze the differential diagnostic problems and we review the literature.