SMAD3, Cell proliferation and lymph nodes metastasis in breast cancer hormone-dependent.

INTRODUCTION: Tumor Growth Factor-ß (TGF-ß) is a multifunctional cytokine that plays a crucial role in various biological processes. TGF-ß is also involved in various pathologies including breast cancer (BC). BC is strongly dependent on hormone receptors such as Estrogen receptors (ERa, ERb) and Progesterone Receptor (PR). AIM: To audit the potential cross-talk between TGF-ß and the molecular distribution of hormone receptors (ERs and PR). METHODS: The current study analyzes the expression patterns of SMAD3, ERα, ERß and PR in 40 breast tumor tissues using qRT-PCR. Furthermore, the Ki-67 and HER2/neu status have been detected by Immunohistochemistry. RESULTS: Our results show a decrease in the SMAD3 expression in 27 of the 40 cases while its expression is increased in the remaining 13 cases (p=0.003). The over-expression of SMAD3 is associated with high tumor grades. Moreover, there is a significant positive correlation between SMAD3+ with a high proliferative index and metastases (p=0.001 and p=0.01respectevely). The SMAD3 expression relative to (ERα, ERß) subgroups shows a significant association of SMAD3+ with the (ERα+, ERß+) subgroups (p=0.009). The same is true for PR, our results show a significant association of SMAD3+ with PR+ (p=0.02). Moreover, analysis of the expression of molecular subgroups (SMAD3+, ERα+, ERß+) and (SMAD3+, PR+) compared to clinical and pathological information shows a significant association with high grade tumors, a high proliferation index (p=0.02, p= 0.01 respectively) and lymph node infiltration. CONCLUSION: It is concluded that SMAD3 can promote cell proliferation and metastases in (ERα+, ERß+) and PR+ breast cancer.

STAT-5 and STAT-6 in Breast Cancer: Potential Crosstalk With Estrogen and Progesterone Receptors Can Affect Cell Proliferation and Metastasis.

Background: Signal transducers and activators of transcription 5a and 6 (STAT5a and STAT6) play a critical role in tumorigenesis of mammary glands. Based on previous studies, the breast cancer is largely dependent on hormone receptors. Consequently, it is very interesting to decipher the relationship between the STAT5a and STAT6 expression and the molecular distribution of estrogen receptors (ERs) and progesterone receptors (PRs) in mammary tumors. Methods: Our study analyzed the expression of STAT5a and STAT6, ERα, ERß and PR in 40 breast tumor tissues using quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, the Ki-67 and HER2 status were detected using immunohistochemistry. Results: STAT5a and STAT6 were retained in the majority of the cases studied. Increasing of STAT5a and STAT6 is significantly associated with ERs and PR. The coexpression of both STAT5a and STAT6 with ERs and PR is associated with high tumor grades. Moreover, the coexpression of STAT5a and STAT6 with ERα and PR is associated with a high proliferation index. In addition, (STAT6 + ERß+) and (STAT6 + PR+) breast cancer subgroups are associated with lymph node infiltration (P = 0.001 and P = 0.03, respectively). Conclusions: Our study results provide an interaction between STAT5a and STAT6 with ERs and PR inducing cell proliferation. Coexpression of STAT5a and STAT6 with ERs and PR can predict sensibility to hormonal therapy.

FOXP3+/CD68+ ratio within the tumor microenvironment may serve as a potential prognostic factor in classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (CHL) is characterized by extensive inflammatory immune cells, which predict the disease prognosis. Therefore, this study aimed to explore the significance of different tumor-infiltrated immune cells and subpopulation ratios observed in the tumor microenvironment of CHL, particularly relating to the disease's prognosis-focusing on overall survival (OS) and event-free survival (EFS). Utilizing immunohistochemistry, the quantification and exploration of selected immune cells' subsets, including CD3+, CD4+, CD8+, FOXP3+, CD20+, and CD68+ were conducted on 102 histological samples with primary CHL. Eosinophils were pathologically assessed. Besides, we determined the ratios between different tumor-infiltrated immune cells for each patient. Kaplan-Meier method and Cox regression modeling were used for survival analysis. We demonstrated that among all ratios and immune cells individually, only a higher FOXP3+/CD68+ ratio (≥1.36 cutoff) displayed a tendency towards a favorable OS (p = 0.057, HR = 0.43 [0.18-1.02]) and EFS (p = 0.067, HR = 0.44 [0.18-1.06]) using Cox regression modeling. Moreover, the Kaplan-Meier method showed an association of a higher FOXP3+/CD68+ ratio with a longer 5-years OS (p = 0.037) and a tendency to a better EFS (p = 0.051); however, neither the combined FOXP3+ and CD68+ nor FOXP3+ or CD68+ separately was correlated to the CHL survival. Together, these results demonstrated that the FOXP3+/CD68+ ratio could predict the outcomes of CHL, providing more informative significance than FOXP3+ and CD68+ combined or FOXP3+ and CD68+ individually and might be a potential indicator of risk stratification, which has an important value for guiding the clinical treatment.

MARCKS protein overexpression is associated with poor prognosis in male breast cancer.

BACKGROUND: Male breast cancer (MBC) is a rare and aggressive disease. Thus, identification of new therapeutic targets is crucial. OBJECTIVE: Our objective was to evaluate the protein expression of MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate) in MBC and to investigate its prognostic value. MATERIALS AND METHODS: MARCKS protein expression in tumor and stromal cells was analyzed by immunohistochemistry (IHC) in a retrospective series of 96 pre-chemotherapy MBC samples and 80 normal breast samples, from Tunisian patients treated at Salah Azaiez Institute. Correlations were searched between MARCKS expression and clinicopathological features including overall survival (OS). RESULTS: MARCKS was overexpressed in epithelial tumor cells in 66% of the MBC samples versus 26% of normal samples (p= 1.40 × 10-7). Such positive MARCKS expression in epithelial tumor cells was associated with positive HER2 status (p= 4.0 × 10-3). It was associated with shorter OS in uni-and multivariate analysis. By contrast, stromal IHC MARCKS expression was correlated only with tumor grade. CONCLUSION: MARCKS tumor cell overexpression might in part explain the aggressiveness and the poor prognosis of MBC. MARCKS can represent a potential therapeutic target for MBC.

Inflammatory breast cancer in 210 patients: A retrospective study on epidemiological, anatomo-clinical features and therapeutic results.

To report epidemiological and anatomo-clinical features within a retrospective series of inflammatory breast cancer and to evaluate prognostic factors. This retrospective study included 210 Tunisian patients presenting a clinically diagnosed IBC, treated at the Institute Salah Azaiez (ISA) of Tunis, Tunisia, from 2008 to 2013. We collected data on epidemiology, anatomo-clinical and biological features and histologic response to neoadjuvant therapy. Overall and disease-free survivals were calculated by Kaplan-Meier method and compared by log-rank tests and Cox's models were used to identify prognostic factors impacting survival. The 210 IBC patients had a median age of 42 years (24-62) and 15% of them were aged less than 35 years. Mean age at menarche was 13 years and 45% had their 1st childbirth before 23 years. On histology, grades III represented 42% of cases, hormone receptors were negative in 59%, HER2 over-expressed in 32, 25% of our IBC cases had a triple negative profile and Ki-67 was >20% in 53% of cases. High pathological grade III was significantly correlated to TN subtype (58%) (Fisher's exact test, P=7.5×10-3). Further, high Ki-67 expression (>20%) was evident in the TN subtype (84%) (Fisher's exact test, P=3.7×10-4). After neoadjuvant therapy (and trastuzumab in 88 and 69% of HER2+ patients, respectively), we observed 49% of objective clinical responses and 35% of pathological complete response (pCR) and >3 axillary lymph nodes were invaded on a resected tumor in 55% of cases. Overall survival (OS) was associated with age at menarche (Wald-test, P=2.2×10-2) and metastases at diagnosis (Wald-test, P=2.4×10-2). Reaching a pCR was correlated with a better metastasis-free survival (MFS), (Fisher's exact test, P=3.6×10-2).

Submandibular lipoblastoma: Case report of a rare tumor in childhood.

Lipoblastoma is a rare, benign tumor usually occurring in childhood. It is essentially localized in the extremities and trunk, with few cases reported in the neck. We report the case of a 2-year-old girl with a rapidly enlarging, painless neck mass. Magnetic resonance imaging (MRI) revealed a 3-cm mass in the right submandibular region. Review of literature, diagnostic methods, and genetics of lipomatous tumors are discussed. Complete surgical excision via a lateral cervical approach demonstrated a white soft tissue with an adherent ganglion. Histology and immunohistochemistry confirmed the diagnosis of lipoblastoma. Cervical lipoblastoma is rare, and typically asymptomatic, rarely causing nerve compression or airway obstruction. MRI can help identifying the lipomatous nature of the mass, but the findings can be inconsistent due to variable maturity of fat cells and the mesenchymal content of the tumor. Diagnosis is always based on pathological examination. Further chromosomal analysis is useful in differentiating lipoblastoma from liposarcoma. Complete surgical excision is the recommended treatment.

Forkhead box M1 (FOXM1) expression predicts disease free survival and may mediate resistance to chemotherapy and hormonotherapy in male breast cancer.

BACKGROUND: Male breast cancer (MBC) is a rare and neglected disease. Prognostic and predictive factors in MBC are extrapoled from trials conducted on its female counterpart. OBJECTIVE: Since the relationship between the transcription factor Forkhead box M1 (FOXM1) expression and the clinical response to chemotherapy and hormonotherapy in MBC remains unknown, we sought to investigate the predictive value of FOXM1 in MBC. METHODS: FOXM1 expression was assessed in 130 MBC cases. Clinical significance was analyzed by Kaplan Meier curves, log-rank test and multivariate Cox regression analyses. RESULTS: Patients with high FOXM1 expression had a significantly lower response rate to chemotherapy (P = 0.045) and hormonotherapy (P = 0.029) than those with low FOXM1 expression. Multivariate analyses indicated that FOXM1 was an independent prognostic factor for disease free survival in MBC patients (P < 0.001). CONCLUSIONS: FOXM1 may have a reliable predictive significance in male breast cancer and thus may become an important target for male breast cancer therapy in the near future.

ERα and ERß co-expression: An indicator of aggressive tumors and hormonal sensitivity.

The estrogen receptors (ERs) ERα and ERß are important factors in breast cancer progression. Nevertheless, the molecular interplay between ERα and ERß and its clinical significance in breast cancer is controversial. The establishment of a clear association is required; therefore, the current study analyzed the expression patterns of ERα and ERß in 32 breast tumor tissues using reverse transcription-quantitative polymerase chain reaction. Furthermore, human epidermal growth factor receptor 2 (HER2) and the Ki-67 status were detected by immunohistochemistry. The results revealed that the ERα and ERß expression rates recorded were 68 and 65%, respectively. The ERα:ERß ratio exhibited a decline along with disease progression. ERα and ERß were found to be negatively correlated with HER2 status but positively correlated with Ki-67. Co-expression of ERα and ERß was associated with breast cancer aggressiveness, including higher histological grade and positive nodal status, which commonly occur following the menopause. In addition, in cases where ERß was coexpressed with ERα, HER2 expression was frequently found to be negative, whereas the Ki-67 index was upregulated. These data suggest that ERα and ERß co-expression may be an indicator of tumor aggressiveness and the sensitivity of hormonal therapy via the downregulation of HER2.

HLA-A*26-A*30 and HLA-DRB1*10 could be predictors of nasopharyngeal carcinoma risk in high-risk Tunisian families.

We investigated human leukocyte antigen (HLA) profiles for Tunisians with nasopharyngeal carcinoma (NPC), their families, and a sample of unrelated healthy Tunisians in order to identify HLA specificities associated with familial NPC. HLA-A, -B, and -DRB1 typing was successful for 36 NPC patients, 72 unaffected family members, and 130 community controls, and the chi square or Fisher exact test was used to compare allele frequencies between cases and controls. We observed a consistent protective effect of HLA-DRB1*10 on NPC development. However, none of the NPC patients or their family members had a positive result for this HLA marker (0% vs 9.2% in controls, P = 0.047). In addition, HLA-A*26 was probably an induction marker, as its allelic frequency was significantly higher among NPC patients than among controls (P = 0.003) and among NPC patients than among at-risk family members (P = 0.067). Logistic regression analysis of the joint effect of selected HLA specificities showed that HLA-A*26 and HLA-A*30 were co-associated and have an important effect on NPC risk. Despite the small size of our cohort, we showed that HLA-A*26-A*30 and HLA-DRB1*10 might be predictive markers for NPC screening of Tunisian families with a high risk of NPC.

Prognostic implications of the intrinsic molecular subtypes in male breast cancer.

PURPOSE: Intrinsic molecular subtyping has been widely used in female breast cancer, and it has proven its significance. In this article, we aimed to study the intrinsic subtypes of male breast cancer (MBC) in correlation with clinicopathological features. METHODS: We retrospectively identified 130 MBC cases from 2004 to 2013. Intrinsic molecular subtypes were determined by immunohistochemistry (IHC). RESULTS: From a total of 130 MBC cases, 45.4% of tumors were luminal A subtype, 44.6% were luminal B, 5% were HER2 positive and 5% were triple negative tumors. There were statistically significant differences between different IHC intrinsic subtypes regarding tumor size (p=0.001), estrogen receptor (ER) status (p=0.001), progesterone receptor (PR) status (p=0.001), HER2 status (p=0.001) and Ki67 proliferation index (p=0.001). CONCLUSION: The distribution of breast cancer intrinsic subtypes in males is different compared to its female counterpart; however, they don't seem to give the same prognostic value.

Overexpression of FOXM1 Is a Potential Prognostic Marker in Male Breast Cancer.

BACKGROUND: Several studies have outlined biological differences between female and male breast cancer (MBC) and concluded that MBC should be considered as an entirely separate disease. Whether FOXM1 has any indication for prognosis in MBC patients remains unknown. We sought to examine the expression levels of FOXM1 in MBC and to identify the relationship between FOXM1 expression and patient survival. PATIENTS AND METHODS: FOXM1 expression was evaluated in a total of 130 MBC specimens. RESULTS: FOXM1 was overexpressed in 37% of the MBC samples. FOXM1 overexpression was significantly associated with tumor size (p = 0.045), histological grade (p = 0.048), lymph node metastasis (p = 0.012), Ki-67 proliferation index (p = 0.016), and molecular subtypes (p < 0.001). Multivariate analyses indicated that FOXM1 was an independent prognostic factor for overall survival in MBC patients (p < 0.001, hazard ratio = 0.69 (0.43-0.96)). CONCLUSIONS: Overexpression of FOXM1 was associated with well-established markers of poor prognosis; thus FOXM1 may represent a potential novel prognostic marker for MBC.

Expression profile of biomarkers altered in papillary and anaplastic thyroid carcinoma: Contribution of Tunisian patients.

AIMS: The objective of this study was to compare the protein expression profile between well-differentiated (papillary) and undifferentiated (anaplastic) thyroid carcinoma in Tunisian patients. METHODS: This first Tunisian retrospective study concerned data of 38 thyroid cancer cases (19 papillary carcinoma PTC and 19 anaplastic carcinoma ATC) collected at Salah Azaiez Institute of Tunisia. Immunohistochemistry was used to evaluate tumor expression of different molecular markers (p53, Ki67, E-cadherin, cyclin D1, bcl2, S100 and Her-2). The molecular expression was correlated with the clinicopathological characteristics of the tumors. RESULTS: There were 6 differentially expressed markers when comparing anaplastic thyroid carcinoma ATC with papillary thyroid carcinoma PTC. Expression of p53 and Ki67 were significantly increased in 16 and 18 ATC cases respectively, the Ki67 expression was lost in PTC. Cyclin D1, E-cadherin, bcl2 and S100 were overexpressed in PTC tumors; however, they were significantly decreased in ATC. The last marker, Her-2 was expressed in one case of PTC only. CONCLUSION: Our results, similar with findings of other ethnic groups, showed alteration in expression of molecular markers associated with tumor dedifferentiation, indicating loss of cell cycle control with increased proliferative activity in ATC carcinoma. These data support the hypothesis that ATC may derive from dedifferentiation of preexisting PTC tumor.

Clinico-pathological and prognostic findings on 27 cases of medullary thyroid carcinoma.

INTRODUCTION: Medullary thyroid carcinoma is a rare tumor accounting for less than 10% of thyroid neoplasm. This tumor is characterized by important histological polymorphism which makes morphological diagnosis difficult and immunohistochemical study often necessary. OBJECTIVE: We aim to perform a retrospective review of clinical and pathological characteristics of medullary carcinoma. We will discuss the place of immunohistochemistry in the positive diagnosis and as a prognostic factor. METHODS: patients with thyroid medullary carcinoma diagnosed in department of pathology at carcinologic institute between 1998 and 2013 were retrospectively included. Clinic, radiologic and prognostic variables were assessed. Slides were reviewed for all the patients with confirmed tumors. RESULTS: Twenty-seven patients with CMT were identified. The average age was 55 years with predominance of males. The average consultation time was 16 months. The most common presentation symptom was a cervical lymph node. Total thyroidectomy was performed in 23 patients. Tumor was nodular and unique in 22 cases. The average size was 2.1 cm. CMT was of mixed type containing both medullary and papillary compound in four cases. Amyloid substance was present and abundant in 21cases. Positive staining for calcitonin was observed in 16 cases. Distant metastasis or metastatic lymph nodes was observed in eight cases with an average period of 42 months. Radiotherapy was performed in fifteen cases and two patients received chemotherapy. CONCLUSION: In the absence of amyloid deposits, immunohistochemical staining with calcitonin is useful to confirm the diagnosis. The prognosis of this entity is more pejorative than papillary thyroid carcinoma.

Triple negative breast cancer: A clinico-epidemiological and histopronostic study of 90 cases.

PURPOSE: The aim of this study was to describe the clinico-epidemiological and histopronostic characteristics of triple negative breast cancer (TNBC) and to evaluate the therapeutic results in tunisian women. METHODS: We reported the results of a retrospective study including 90 patients treated for TNBC between Junuary 2008 and December 2009 in the Salah Azaiz Institute of Tunis. RESULTS: TNBCoccured in 14% of diagnosed breast cancers. The mean age at diagnosis was 53.67 years. Family history of breast cancer was reported in 10% of cases.The majority of tumors were classified as T2 (41%) and associated with invasive ductal carcinoma histological type (99%) and SBR grade-II (54%). Tumor lymph node metastases were detected in 44% of patients.Among operated patients, 46% of patients underwent conservative surgery and 54% radical surgery. Chemotherapy and postoperative radiotherapy were given in97% and 80%of patients, respectively. After a median follow-up of 33.51 months, 61% of patients remained free of disease, 12% hadloco-regional recurrence, 9% had disease progression during chemotherapy and 21% developed systemic disease. CONCLUSION: TNBC diagnosis is often made in the advanced stage and has a tendency to recur after treatment. The variable responseto chemotherapy is due to the molecular tumor heterogeneity. The development of targeted therapies is necessary to improve outcome of chemoresistant TNBC.

MARCKS protein overexpression in inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive form of locally-advanced breast cancer. Identification of new therapeutic targets is crucial. We previously reported MARCKS mRNA overexpression in IBC in the largest transcriptomics study reported to date. Here, we compared MARCKS protein expression in IBC and non-IBC samples, and searched for correlations between protein expression and clinicopathological features. RESULTS: Tumor samples showed heterogeneity with respect to MARCKS staining: 18% were scored as MARCKS-positive (stained cells ≥ 1%) and 82% as MARCKS-negative. MARCKS expression was more frequent in IBC (36%) than in non-IBC (11%; p = 1.4E-09), independently from molecular subtypes and other clinicopathological variables. We found a positive correlation between protein and mRNA expression in the 148/502 samples previously analyzed for MARCKS mRNA expression. MARCKS protein expression was associated with other poor-prognosis features in the whole series of samples such as clinical axillary lymph node or metastatic extension, high pathological grade, ER-negativity, PR-negativity, HER2-positivity, and triple-negative and HER2+ statutes. In IBC, MARCKS expression was the sole tested variable associated with poor MFS. MATERIALS AND METHODS: We retrospectively analyzed MARCKS protein expression by immunohistochemistry in 502 tumors, including 133 IBC and 369 non-IBC, from Tunisian and French patients. All samples were pre-therapeutic clinical samples. We searched for correlations between MARCKS expression and clinicopathological features including the IBC versus non-IBC phenotype and metastasis-free survival (MFS). CONCLUSIONS: MARCKS overexpression might in part explain the poor prognosis of IBC. As an oncogene associated with poor MFS, MARCKS might represent a new potential therapeutic target in IBC.

Comparative study of two complementary proliferation markers in 200 breast carcinomas: Ki67 and mitotic index.

BACKGROUND: The evaluation of the proliferation in the mammary carcinomas provides useful prognostic and predictive information for subsequent management. The purely morphological evaluation of proliferative activity was represented by the evaluation of mitotic index. New analytical methods were gradually developed and performed. Among these methods, evaluation of Ki67 by immunohistochemistry is particularly interesting. Its expression is significantly increased in the cell cycle. AIM: To correlate the mitotic index as a classic method of assessing cell proliferation and Ki 67 proliferation index detected by immunohistochemistry to identify the most reliable proliferative marker. METHODS: We studied 200 patients with invasive ductal carcinoma breast over a period of 12 months of 2014. We identified in each case the SBR grade, Ki67 proliferation index and the mitotic index. Correlation between the two parameters was identified using the Spearman test. A result is considered significant when p < 0.01. The distribution of these markers by SBR gradewas studied using the ANOVA method. RESULTS: Ki67 is significantly correlated to the mitotic index. Although these two methods are dependent, Ki67 is the most sensitive and bonded to SBR grade. Determination of Ki67 provides interesting information that could replace the mitotic account. It provides reliable and reproducible data that can be incorporated into a prognostic score. CONCLUSION: Ki67 is a more efficient marker mitotic index, reflecting the cell proliferation.

Mucinous breast carcinoma a rare entity to be known: clinico-pathological study of 48 cases.

BACKGROUND: Mucinous carcinoma is a particular type of breast cancer characterized by the presence of extracellular mucin and is linked with a more favorable prognosis than invasive breast carcinoma of no special type. It accounts for 1 to 7% of all breast cancers. We propose in this work to study at first the clinic-pathological characteristics and the evolution of 48 cases of mucinous carcinomas. Secondly, we propose to identify through a review of recent literature, the therapeutic management of these carcinomas. METHODS: This is a retrospective study, conducted in Salah Azaiez carcinological institute, interesting 48 cases of mucinous carcinoma collected over 19 years. Clinical, radiological and pathological information were collected from medical records. RESULTS: The mean age of our patients was 57 years. The tumor was single in 41 cases and in 7 cases bifocal. Mammographic aspects were favor of malignancy in 33 cases (75%). It was mixed subtype in 14 cases and pure in 34 cases. Lymph node involvement was noted in 14 cases. The number of metastatic lymph nodes ranged from 1 to 11 with an average of 3. Hormone receptors were positive in 35 tumors (73%). The HER2 showed overexpression in 5 cases. Surgery consisted of a radical treatment for thirty-two patients (66%). Overall survival at 5 years was 75.3% and 59.3% at 10 years. Disease-free survival was 74% at 5 years and 58% at 10 years. CONCLUSION: Mucinous carcinoma consists of two distinct subtypes: pure and mixed with different prognosis. Larger data samples with longer follow-up are necessary to achieve an improved understanding of this particular tumor.

Comparative study of two complementary proliferation markers in 200 breast carcinomas: Ki67 and mitotic index.

BACKGROUND: The evaluation of the proliferation in the mammary carcinomas provides useful prognostic and predictive information for subsequent management. The purely morphological evaluation of proliferative activity was represented by the evaluation of mitotic index. New analytical methods were gradually developed and performed. Among these methods, evaluation of Ki67 by immunohistochemistry is particularly interesting. Its expression is significantly increased in the cell cycle. AIM: To correlate the mitotic index as a classic method of assessing cell proliferation and Ki 67 proliferation index detected by immunohistochemistry to identify the most reliable proliferative marker. METHODS: We studied 200 patients with invasive ductal carcinoma breast over a period of 12 months of 2014. We identified in each case the SBR grade, Ki67 proliferation index and the mitotic index. Correlation between the two parameters was identified using the Spearman test. A result is considered significant when p < 0.01. The distribution of these markers by SBR gradewas studied using the ANOVA method. RESULTS: Ki67 is significantly correlated to the mitotic index. Although these two methods are dependent, Ki67 is the most sensitive and bonded to SBR grade. Determination of Ki67 provides interesting information that could replace the mitotic account. It provides reliable and reproducible data that can be incorporated into a prognostic score. CONCLUSION: Ki67 is a more efficient marker mitotic index, reflecting the cell proliferation.