CD30/Ki1 molecule expression research in cutaneous and systemic mastocytosis

Orientadores: José Vassallo, Luis Otávio Zanatta SarianTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A mastocitose é uma doença rara caracterizada por proliferação clonal anormal de mastócitos com um espectro amplo de manifestações clínicas, variando desde formas cutâneas (Mastocitose Cutânea - MC) que podem ter regressão espontânea até formas agressivas com acometimento sistêmico (Mastocitose Sistêmica - MS) e prognóstico pejorativo, como a Leucemia de Células Mastocitárias. O diagnóstico é baseado em critérios maior e menores bem definidos pela Organização Mundial da Saúde (OMS), sendo o critério maior a demonstração de agregados multifocais de mastócitos com características neoplásicas infiltrando a medula óssea e/ou outros órgãos extracutâneos. O critério maior pode ser associado aos critérios menores, sendo que alguns desses critérios menores podem utilizar marcadores imuno-histoquímicos, tais como o CD2 e CD25. Outros imunomarcadores que auxiliam no diagnóstico são a triptase e o receptor c-Kit/CD117. A molécula CD30 é expressa em uma pequena população de células T e B ativadas, e com alta expressão em neoplasias malignas hematológicas como linfomas de Hodgkin e Linfoma T Anaplásico de Grandes Células, dentre outras neoplasias de células T e B. Menos comumente também pode ser expressa em neoplasias não hematológicas como tumores de células germinativas e o carcinoma embrionário testicular. O CD30 é membro da superfamília dos receptores de fator de necrose tumoral (TNFR). A sinalização através destes receptores afeta a proliferação celular, sobrevida e diferenciação e estes efeitos são mediados através de domínios citoplasmáticos destes receptores. A presença do CD30 na mastocitose é considerada aberrante e vem sendo descrita em relatos os quais demonstram uma associação quase exclusiva deste imunomarcador às formas agressivas de mastocitose. A positividade do CD30 nas formas indolentes de MS, inclusive na forma cutânea de mastocitose, é considerada excepcional. Com o objetivo de avaliar a prevalência do CD30 em mastócitos neoplásicos, nós realizamos um estudo retrospectivo de casos de MC e MS no Laboratório de Anatomia Patológica do Instituto Universitário do Câncer Toulouse ¿ Oncopole, Toulouse ¿ França no período entre 2000 e 2006. Além da análise histopatológica dos casos destas duas formas clínicas, foram também realizadas imuno-histoquímicas para os seguintes marcadores: CD30, CD2, CD25, c-Kit/CD117, além de outros imunomarcadores. De um total de 42 casos de mastocitose, encontramos 29 casos de MC (n = 29) e 13 casos de MS (n = 13). O CD30 foi positivo em um total de 39 casos (39/42 = 92,8%). Nos casos de MC, 28 de um total de 29 casos foram CD30 positivos. Na MS 11 de um total de 13 casos foram CD30 positivos. Os casos controles onde os mastócitos evidenciados nas peles normais e os mastócitos ativados encontrados nas peles com urticária, a imunomarcação CD30 foi negativa. Os achados deste estudo sugerem que o CD30 pode ser considerado um marcador neoplásico de mastocitose, independente da sua apresentação clínica (Cutânea ou Sistêmica), mas não é associado exclusivamente em formas agressivas de mastocitose, como previamente descrito na literaturaAbstract: Mastocytosis is a rare disease characterized by abnormal clonal proliferation of mast cells with a broad spectrum of clinical manifestations, ranging from cutaneous forms (Cutaneous Mastocytosis - CM) that can spontaneously regress to aggressive forms with systemic multiorgan involvement (Systemic Mastocytosis - SM) and pejorative prognosis, such as Mast Cell Leukemia. The diagnosis is based on major and minor criteria that are well defined by the World Health Organization (WHO). The major criterion is the demonstration of multifocal aggregates of mast cells with neoplastic features infiltrating bone marrow and/or other extracutaneous organs. The major criterion may be associated with minor criteria, and some of these minor criteria consist of immunohistochemical markers such as CD2 and CD25. Other useful immunomarkers in the diagnosis are tryptase and c-Kit/CD117 receptor. The CD30 molecule is expressed in a small population of activated T and B cells, and is highly expressed in hematological malignancies such as Hodgkin's lymphomas and Large Cell Anaplastic T-Lymphomas, among other T-cell and B-cell neoplasms. It may be expressed in non-hematological neoplasms such as germ cell tumors and testicular embryonal carcinoma. CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily. Signaling through these receptors affects cell proliferation, survival and differentiation and these effects are mediated through cytoplasmic domains of these receptors. The presence of CD30 in mastocytosis is considered to be aberrant and has been described in some reports which demonstrate a nearly exclusive association of this immunomarker to aggressive forms of mastocytosis. The positivity of CD30 in the indolent forms of SM, including the cutaneous form, is considered exceptional. In order to evaluate the prevalence of CD30 in neoplastic mast cells, we performed a retrospective study of CM and SM cases in the Laboratory of Pathological Anatomy of the Toulouse University Cancer Institute - Oncopole, Toulouse - France between 2000 and 2006. Besides the histopathological analysis of these two clinical forms, it was also performed immunohistochemistry for the following markers: CD30, CD2, CD25, c-Kit/CD117, as well as other immunomarkers. From a total of 42 cases of mastocytosis, we found 29 cases of CM (n = 29) and 13 cases of SM (n = 13). CD30 was positive in a total of 39 cases (39/42 = 92.8%). In cases of CM, 28 out of 29 cases were CD30 positive. In SM, 11 out of 13 cases were CD30 positive. The control cases which consisted of mast cells from normal skin samples and activated mast cells found in urticaria were CD30 negative. The findings of this study suggest that CD30 may be considered a neoplastic marker of mastocytosis, regardless of its clinical presentation (Cutaneous or Systemic), and it is not nearly exclusively associated to aggressive forms of mastocytosis, as previously described in the literatureDoutoradoClinica MedicaDoutora em Ciência

[the New Classification Of Breast Cancers: Finding The Luminal A].

To compare the distributions of patients with clinical-pathological subtypes of luminal B-like breast cancer according to the 2011 and 2013 St. Gallen International Breast Cancer Conference Expert Panel. We studied 142 women with breast cancer who were positive to estrogen receptor and had been treated in São Paulo state, southeast Brazil. The expression of the following receptors was assessed by immunohistochemistry: estrogen, progesterone (PR) and Ki-67. The expression of HER-2 was measured by fluorescent in situ hybridization analysis in tissue microarray. There were 29 cases of luminal A breast cancers according to the 2011 St. Gallen International Breast Cancer Conference Expert Panel that were classified as luminal B-like in the 2013 version. Among the 65 luminal B-like breast cancer cases, 29 (45%) were previous luminal A tumors, 15 cases (20%) had a Ki-67 >14% and were at least 20% PR positive and 21 cases (35%) had Ki-67 >14% and more than 20% were PR positive. The 2013 St. Gallen consensus updated the definition of intrinsic molecular subtypes and increased the number of patients classified as having luminal B-like breast cancer in our series, for whom the use of cytotoxic drugs will probably be proposed with additional treatment cost.36575-8

Analysis of the contribution of immunologically-detectable Her2, steroid receptors and of the "triple-negative" tumor status to disease-free and overall survival of women with epithelial ovarian cancer

We assessed associations between steroid receptors including: estrogen-alpha, estrogen-beta, androgen receptor, progesterone receptor, the HER2 status and triple-negative epithelial ovarian cancer (ERα-/PR-/HER2-; TNEOC) status and survival in women with epithelial ovarian cancer. The study included 152 women with primary epithelial ovarian cancer. The status of steroid receptor and HER2 was determined by immunohistochemistry. Disease-free and overall survival were calculated and compared with steroid receptor and HER2 status as well as clinicopathological features using the Cox Proportional Hazards model. A mean follow-up period of 43.6 months (interquartile range=41.4 months) was achieved where 44% of patients had serous tumor, followed by mucinous (23%), endometrioid (9%), mixed (9%), undifferentiated (8.5%) and clear cell tumors (5.3%). ER-alpha staining was associated with grade II-III tumors. Progesterone receptor staining was positively associated with a Body Mass Index≥25. Androgen receptor positivity was higher in serous tumors. In stand-alone analysis of receptor contribution to survival, estrogen-alpha positivity was associated with greater disease-free survival. However, there was no significant association between steroid receptor expression, HER2 status, or TNEOC status, and overall survival. Although estrogen-alpha, androgen receptor, progesterone receptor and the HER2 status were associated with key clinical features of the women and pathological characteristics of the tumors, these associations were not implicated in survival. Interestingly, women with TNEOC seem to fare the same way as their counterparts with non-TNEOC.We assessed associations between steroid receptors including: estrogen-alpha, estrogen-beta, androgen receptor, progesterone receptor, the HER2 status and triple-negative epithelial ovarian cancer (ERα-/PR-/HER2-; TNEOC) status and survival in women with1163440447sem informaçãosem informaçã

Cyclooxygenase-2 (COX2) and p53 protein expression are interdependent in breast cancer but not associated with clinico-pathological surrogate subtypes, tumor aggressiveness and patient survival

In the last decade, different molecular subtypes of breast cancer have been proposed. Although displaying appreciable association with disease prognosis and the prognostic value of cytotoxic and endocrine therapeutic modalities, the subtypes seem to fail at completely explaining disease behavior and response to treatment. Molecules such as those of the cyclocooxigenase (COX) family, currently composed of three entities (COX 1, 2 and 3) have been shown to be associated with breast carcinogenesis, and the analysis of p53 expression in breast tumors may also offer some additional prognostic clues. Our study is aimed at assessing COX2 and p53 expression in these clinico-pathological surrogate subtypes, and to evaluate whether the expression of these molecules can help further explain the variability in prognosis still found within the clinico-pathological subtypes groups of breast cancer. Methods: A total of 183 breast cancer samples were obtained from women treated at the Womenis Hospital of Campinas State University, Campinas, Brazil, between June 2008 and January 2011. Immunohistochemistry was performed to detect the expression of ER, PR, ki67, COX2, and p53 and the HER2 status of the 183 specimens was assessed using FISH. Two COX2 staining thresholds were used to define COX2 positivity: low threshold (LT): moderate and intense staining were considered positive; high-threshold (HT): only intense staining was considered positive. Results: There was no trend in COX2 overexpression from Luminal A-like to Triple-negative subtypes. By contrast, p53 was expressed in roughly 67% of the Luminal A-like tumors, 50% of the Luminal B-like HER2 positive tumors, 60.9% of the Luminal B-like HER2 negative, approximately 82% of the HER2 positive (non-luminal) and 87% of the Triple-negative tumors (p for trends = 0.06). There was a significantly higher proportion of COX2 positive (LT) tumors (66.9%) when p53 was also positive compared to when the tumor was negative for p53 (in which case only 18.0% of the tumors were positive for COX2; p<0.001). Neither marker was found to be associated with patients' survival. Conclusions: There seems to be a positive association between the expressions of COX2 and p53. Otherwise, neither the expression of COX nor that of p53 was associated with clinico-pathological subtypes, tumor features and prognosis. It seems to be too early to elect the detection of COX2 using IHC as prognostic or predictive tool, but incipient evidence points toward a possible role for the marker1182176182FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2009/17097-