FILOMENA MARINO CARVALHO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
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- Coordinated expression of oestrogen and androgen receptors in HER2-positive breast carcinomas: impact on proliferative activity(2012) LIN, Francini de Mattos Lima; PINCERATO, Katia Maciel; BACCHI, Carlos Eduardo; BARACAT, Edmund Chada; CARVALHO, Filomena MarinoAims Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are aggressive neoplasms associated with a variable response to systemic therapies. Therefore, the identification of biomarkers to better characterise this heterogeneity would improve treatment efficacy. The aim of this study was to evaluate the influence of androgen receptor (AR) and oestrogen receptor (ER) on clinicopathological features in a series of HER2-positive breast carcinomas. Methods A total of 104 carcinomas were selected and reviewed. Immunohistochemical studies for ER, progesterone receptor and Ki-67 were analysed on tumour whole histological sections. AR expression was analysed on samples represented on tissue microarrays. According to steroid receptor expression, cases were classified into three groups: AR positive/ER positive (48 cases), AR positive/ER negative (41 cases) and AR negative/ER negative (13 cases). Results AR-positive tumours corresponded to 89 (85.6%) of 104 carcinomas. AR-positive carcinomas were associated with a higher frequency of ER and progesterone receptor co-expression and lower proliferative activity determined by the expression of Ki-67. AR-negative carcinomas were more often high grade. The group of AR-positive/ER-negative carcinomas was associated with the highest frequency of apocrine morphological features. The group of AR-negative/ER-negative carcinomas was associated with the highest proliferative activity and the highest frequency of high histological and nuclear grade. The lowest frequency of high-grade tumours and the lowest proliferative activity were seen among tumours with expression of both receptors. Conclusions These results suggest that co-expression of AR and ER can provide a protective effect based on phenotypical presentation of HER2-positive carcinomas. Furthermore, lack of both steroid hormone receptors characterises the most aggressive phenotype.
- Fallopian tube origin of supposed ovarian high-grade serous carcinomas(2011) DINIZ, Patricia Martini; CARVALHO, Jesus Paula; BARACAT, Edmund Chada; CARVALHO, Filomena M.INTRODUCTION: Serous carcinomas are the most frequent histologic type of ovarian and peritoneal cancers, and can also be detected in the endometrium and fallopian tubes. Serous carcinomas are usually high-grade neoplasms when diagnosed, yet the identification of an associated precursor lesion remains challenging. Pathological examination of specimens obtained from prophylactic bilateral salpingo-oophorectomies that were performed for patients harboring BRCA1/2 mutations suggests that high-grade serous carcinomas may arise in the fallopian tubes rather than in the ovaries. OBJECTIVE: To investigate the presence and extent of fallopian tube involvement in cases of serous pelvic carcinomas. METHODS: Thirty-four cases of serous pelvic carcinoma with clinical presentations suggesting an ovarian origin were analyzed retrospectively. Histologic samples of fallopian tube tissues were available for these cases and were analyzed. Probable primary site, type of tubal involvement, tissues involved in the neoplasia and vascular involvement were evaluated. RESULTS: Fallopian tube involvement was observed in 24/34 (70.6%) cases. In 4 (11.8%) of these cases, an intraepithelial neoplasia was present, and therefore these cases were hypothesized to be primary from fallopian tubes. For an additional 7/34 (20.6%) cases, a fallopian tube origin was considered a possible primary. CONCLUSIONS: Fallopian tubes can be the primary site for a subset of pelvic high-grade serous carcinomas.
- HER2 Testing in Breast Carcinoma Very Low Concordance Rate Between Reference and Local Laboratories in Brazil(2011) WLUDARSKI, Sheila Cristina Lordelo; LOPES, Lisandro Ferreira; SILVA, Tacio R. Berto e; CARVALHO, Filomena M.; WEISS, Lawrence M.; BACCHI, Carlos E.Breast cancer accounts for approximately one quarter of all cancers in females. HER2 gene amplification or HER2 protein overexpression, detected in about 20% of breast carcinomas, predicts a more aggressive clinical course and determines eligibility for targeted therapy with trastuzumab. HER2 testing has become an essential part of the clinical evaluation of all breast carcinoma patients, and accurate HER2 results are critical in identifying patients who may be benefited from targeted therapy. This study investigated the concordance in the results of HER2 immunohistochemistry assays performed in 500 invasive breast carcinomas between a reference laboratory and 149 local laboratories from all geographic regions of Brazil. Our results showed an overall poor concordance (171 of 500 cases, 34.2%) regarding HER2 results between local and reference laboratories, which may be related to the low-volume load of HER2 assays, inexperience with HER2 scoring system, and/or technical issues related to immunohistochemistry in local laboratories. Standardization of HER2 testing with rigorous quality control measures by local laboratories is highly recommended to avoid erroneous treatment of breast cancer patients.
- A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses(2012) ANTON, Cristina; CARVALHO, Filomena Marino; OLIVEIRA, Elci Isabel; MACIEL, Gustavo Arantes Rosa; BARACAT, Edmund Chada; CARVALHO, Jesus PaulaOBJECTIVE: Differentiation between benign and malignant ovarian neoplasms is essential for creating a system for patient referrals. Therefore, the contributions of the tumor markers CA125 and human epididymis protein 4 (HE4) as well as the risk ovarian malignancy algorithm (ROMA) and risk malignancy index (RMI) values were considered individually and in combination to evaluate their utility for establishing this type of patient referral system. METHODS: Patients who had been diagnosed with ovarian masses through imaging analyses (n = 128) were assessed for their expression of the tumor markers CA125 and HE4. The ROMA and RMI values were also determined. The sensitivity and specificity of each parameter were calculated using receiver operating characteristic curves according to the area under the curve (AUC) for each method. RESULTS: The sensitivities associated with the ability of CA125, HE4, ROMA, or RMI to distinguish between malignant versus benign ovarian masses were 70.4%, 79.6%, 74.1%, and 63%, respectively. Among carcinomas, the sensitivities of CA125, HE4, ROMA (pre-and post-menopausal), and RMI were 93.5%, 87.1%, 80%, 95.2%, and 87.1%, respectively. The most accurate numerical values were obtained with RMI, although the four parameters were shown to be statistically equivalent. CONCLUSION: There were no differences in accuracy between CA125, HE4, ROMA, and RMI for differentiating between types of ovarian masses. RMI had the lowest sensitivity but was the most numerically accurate method. HE4 demonstrated the best overall sensitivity for the evaluation of malignant ovarian tumors and the differential diagnosis of endometriosis. All of the parameters demonstrated increased sensitivity when tumors with low malignancy potential were considered low-risk, which may be used as an acceptable assessment method for referring patients to reference centers.
- L1 Cell Adhesion Molecule (L1CAM) expression in endometrioid endometrial carcinomas: A possible pre-operative surrogate of lymph vascular space invasion(2018) FREITAS, Daniela de; AGUIAR, Fernando Nalesso; ANTON, Cristina; BACCHI, Carlos Eduardo; CARVALHO, Jesus Paula; CARVALHO, Filomena MarinoBackground Risk stratification of endometrial carcinomas is primarily based on surgical staging that requires extensive retroperitoneal lymph node dissection. One of the most powerful predictor of lymph node involvement is the lymph vascular space invasion (LVSI). The objective of this study was to determine the potential of L1 Cell Adhesion Molecule (L1CAM) to predict LVSI and its association with other risk factors in endometrioid endometrial carcinomas. Materials and methods We studied 47 consecutive patients aged 37-88 (61.34 +/- 10.52). Twenty-three patients (48.9%) were submitted to complete surgical staging. Nine patients (19.1%) underwent surgical staging without para-aortic dissection. Seven (14.9%) were submitted to hysterectomy with no lymph node dissection. Eight patients (17.0%) only had the biopsy material for analysis. The 32 patients submitted to lymphadenectomy were staged according to the FIGO system and classified among the risk categories of the ESMO-ESGO-ESTRO guidelines. The following histological characteristics were analyzed: tumor size (mm), depth of myometrial infiltration, presence of microcystic, elongated, and fragmented (MELF) pattern of myoinvasion, and lymph vascular space invasion (LVSI). Immunohistochemical analyses of mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, p53, and L1CAM were performed in formalin-fixed paraffin embedded whole tumor tissue sections. Results LVSI was identified in 26/41 (63,4%) of the cases. L1CAM was positive in 8/47 (17%) cases, all of them positive for LVSI and within the high-risk category of ESMO-ESGO-ESTRO. L1CAM-positive cases were associated with high histological grade and p53 aberrant immunohistochemical profile. Besides, it showed a trend to larger tumors, greater depth of myometrial infiltration, and with a higher frequency of the MELF pattern of myoinvasion. LVSI was also associated with FIGO stage, tumor size, depth of myometrial infiltration, and tumor grade. Conclusions L1CAM is highly associated with LVSI and could be used as a pre-operative predictor of lymph node involvement in endometrioid endometrial carcinomas.
- Tumor-Infiltrating Lymphocytes and Tumor- Stroma Ratio on Early-Stage Cervix Carcinoma: Prognostic Value of Two Distinct Morphological Patterns of Microenvironment(2023) LARRE, Ailma; FERNANDES, Raquel C.; GERBASI, Giovana J.; CARVALHO, Filomena M.Background Tumor progression is influenced by the complex network of different cellular elements that make up its microenvironment. Tumor-infiltrating lymphocytes (TILs) and stroma characteristics reflect two faces of the intricate mechanisms involved in the tumor-host interaction and can be easily evaluated by routine histological examination. Their prognostic value could be demonstrated in different tumor tumor types, but they are poorly explored in cervical cancer. Methodology In this retrospective study, we analyzed the association of TILs, tumor-stroma ratio (TSR), and pattern of stromal fibroblasts with prognosis and classical clinicopathological variables. We studied 61 patients with early-stage cervical cancer. We reviewed histological type, tumor grade, Silva pattern of invasion for adenocarcinomas, tumor thickness, depth of stromal invasion, lymph vascular space invasion, and lymph node status. The median follow-up was 37.77 months (range 4.77 to 112.37 months). Results The TSR did not correlate with any clinicopathological features or disease-free and overall survival. On the other hand, the reactive pattern of stroma composed of larger fibroblasts and less collagenization was associated with the FIGO IB2 stage (p=0.04), larger tumor (p=0.03), and deeper infiltration (p=0.005). There were more recurrences in the group of reactive stroma (33.13% vs. 11.5%), although the difference did not reach statistical significance. Reactive stroma was associated with lower survival free of recurrence (p=0.05) and overall survival (p=0.009). High TILs were associated with squamous cell type (p=0.003), higher tumor grade (p=0.02), and more LVSI (p=0.02). Tumors with higher TILs presented higher free recurrence interval (p=0.06) and overall survival (p=0.03). No association was observed between stroma characteristics and TILs. Conclusions Our study suggested that although immune activation and stromal changes are important features of microenvironment remodeling during tumoral progression, they are independent, following distinct carcinogenetic pathways. Pathological assessment of stroma characteristics and TILs adds significant prognostic information and demonstrates how a simple routine laboratory assessment can generate a better understanding of biological phenomena.
- Basal cytokeratin as a potential marker of low risk of invasion in ductal carcinoma in situ(2013) AGUIAR, Fernando N.; MENDES, Henrique N.; CIRQUEIRA, Cinthya S.; BACCHI, Carlos E.; CARVALHO, Filomena M.OBJECTIVES: Biological markers that predict the development of invasive breast cancer are needed to improve personalized therapy for patients diagnosed with ductal carcinoma in situ. We investigated the role of basal cytokeratin 5/6 in the risk of invasion in breast ductal carcinoma in situ. METHODS: We constructed tissue microarrays using 236 ductal carcinoma in situ samples: 90 pure samples (group 1) and 146 samples associated with invasive carcinoma (group 2). Both groups had similar nuclear grades and were obtained from patients of similar ages. The groups were compared in terms of estrogen (ER) and progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) expression, cytokeratin 5/6 immunostaining, human epidermal growth factor receptor 1 (EGFR) membrane staining and molecular subtype, as indicated by their immunohistochemistry profiles. RESULTS: ER/PR-negative status was predictive of invasion, whereas HER2 superexpression and cytokeratin 5/6-positive status were negatively associated with invasion. Among the high-grade ductal carcinoma in situ cases, a triple-positive profile (positive for estrogen receptor, progesterone receptor, and HER2) and cytokeratin 5/6 expression by neoplastic cells were negatively associated with invasion. In the low-grade ductal carcinoma in situ subgroup, only cytokeratin 5/6 expression exhibited a negative association with the probability of invasion. CONCLUSION: The immunohistochemical expression of cytokeratin 5/6 by ductal carcinoma in situ epithelial cells may provide clinically useful information regarding the risk of progression to invasive disease.
- The role of intratumoral lymphovascular density in distinguishing primary from secondary mucinous ovarian tumors(2014) ALMEIDA, Bernardo Gomes de Lacerda; BACCHI, Carlos E.; CARVALHO, Jesus P.; FERREIRA, Cristiane R.; CARVALHO, Filomena M.OBJECTIVE: Ovarian mucinous metastases commonly present as the first sign of the disease and are capable of simulating primary tumors. Our aim was to investigate the role of intratumoral lymphatic vascular density together with other surgical-pathological features in distinguishing primary from secondary mucinous ovarian tumors. METHODS: A total of 124 cases of mucinous tumors in the ovary (63 primary and 61 metastatic) were compared according to their clinicopathological features and immunohistochemical profiles. The intratumoral lymphatic vascular density was quantified by counting the number of vessels stained by the D2-40 antibody. RESULTS: Metastases occurred in older patients and were associated with a higher proportion of tumors smaller than 10.0 cm; bilaterality; extensive necrosis; extraovarian extension; increased expression of cytokeratin 20, CDX2, CA19.9 and MUC2; and decreased expression of cytokeratin 7, CA125 and MUC5AC. The lymphatic vascular density was increased among primary tumors. However, after multivariate analysis, the best predictors of a secondary tumor were a size of 10.0 cm or less, bilaterality and cytokeratin 7 negativity. Lack of MUC2 expression was an important factor excluding metastasis. CONCLUSIONS: The higher intratumoral lymphatic vascular density in primary tumors when compared with secondary lesions suggests differences in the microenvironment. However, considering the differential diagnosis, the best discriminator of a secondary tumor is the combination of tumor size, laterality and the pattern of expression of cytokeratin 7 and MUC2.
- Accuracy of frozen section in intraoperative margin assessment for breast-conserving surgery: A systematic review and meta-analysis(2021) GARCIA, Mila Trementosa; MOTA, Bruna Salani; CARDOSO, Natalia; MARTIMBIANCO, Ana Luiza Cabrera; RICCI, Marcos Desiderio; CARVALHO, Filomena Marino; GONCALVES, Rodrigo; SOARES JUNIOR, Jose Maria; FILASSI, Jose RobertoBackground and objectives It is well established that tumor-free margin is an important factor for reducing local recurrence and reoperation rates. This systematic review with meta-analysis of frozen section intraoperative margin assessment aims to evaluate the accuracy, and reoperation and survival rates, and to establish its importance in breast-conserving surgery. Methods A thorough review was conducted in all online publication-databases for the related literature up to March 2020. MeSH terms used: ""Breast Cancer"", ""Segmental Mastectomy"" and ""Frozen Section"". We included the studies that evaluated accuracy of frozen section, reoperation and survival rates. To ensure quality of the included articles, the QUADAS-2 tool (adapted) was employed. The assessment of publication bias by graphical and statistical methods was performed using the funnel plot and the Egger's test. The review protocol was registered in PROSPERO (CRD42019125682). Results Nineteen studies were deemed suitable, with a total of 6,769 cases. The reoperation rate on average was 5.9%. Sensitivity was 0.81, with a Confidence Interval of 0.79-0.83, p = 0.0000, I2 = 95.1%, and specificity was 0.97, with a Confidence Interval of 0.97-0.98, p = 0.0000, I-2 = 90.8%, for 17 studies and 5,615 cases. Accuracy was 0.98. Twelve studies described local recurrence and the highest cumulative recurrence rate in 3 years was 7.5%. The quality of the included studies based on the QUADAS-2 tool showed a low risk of bias. There is no publication bias (p = 0.32) and the funnel plot showed symmetry. Conclusion Frozen section is a reliable procedure with high accuracy, sensitivity and specificity in intraoperative margin assessment of breast-conserving surgery. Therefore, this modality of margin assessment could be useful in reducing reoperation rates.