Diagnostico histologico e expressão dos marcadores p53, c-erbB-2, Ki-67, PCNA e CD34 em pacientes portadoras de tumor de celulas da granulosa do ovario

Orientadores : Sophie Françoise Mauricette Derchain, Liliana Ap. Lucci de Angelo AndradeDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Objetivo: investigar em tumores de células da granulosa do ovário (TCGO) a credibilidade de seu diagnóstico com coloração H&E e a expressão do p53 mutante, do c-erbB-2, Ki-67, PCNA e a atividade angiogênica (CD34), bem como as correlações destes marcadores com características clínicas e histológicas. Sujeitos e método: Três patologistas (A,B e C) reavaliaram os 22 casos de TCGO tratados no CAISM/UNICAMP nos últimos 12 anos, sendo os marcadores detectados através de imuno-histoquímicas em cortes histológicos preparados a partir de blocos de parafina. Foram calculados os coeficientes kappa para avaliação da concordância interobservador entre os patologistas. A análise de associação entre as variáveis categóricas foi realizada com o teste exato de Fisher e entre variáveis categóricas e contínuas, com teste de Mann- Whitney. Resultados: Vinte e um casos foram confirmados como TCGO. Quatro casos foram diagnosticados como TCGO, mesmo sem unanimidade entre os patologistas devido à imunorreatividade para a inibina. Os coeficientes kappa foram de 0,42 (IC95%: -0,05; 0,88); 0,50 (IC95%: 0,13; 0,86); 0,24 (IC95%: -0,14 a 0,61), respectivamente para as duplas de patologistas A/B, A/C e B/C. A IHQ para os marcadores foi realizada em 18 pacientes. Nove (50%) pacientes apresentaram tumores <10cm. Treze (72%) pacientes apresentaram algum componente sólido difuso/sarcomatóide. Em 12 (66%) casos a atipia celular era ausente/leve e em 6 (33%) casos, moderada/intensa. A contagem mitótica foi < 2/10 CMA em 14 (78%) casos. Seis (33%) pacientes apresentaram extensão extra-ovariana da doença (estádios III/IV). O seguimento médio foi de 45,3 meses (0,7 a 128,8). Uma, zero e 11 pacientes apresentaram expressão para o p53 mutante, c-erbB-2 e Ki-67 (focal), respectivamente. Quatorze (78%) casos foram classificados como de alto índice de proliferação, quando avaliados pelo PCNA. A densidade microvascular média foi de 29,0/mm2 (CI95%: 21,8 a 36,1). Apenas o Ki-67, PCNA e o CD34 foram expressos em níveis adequados para uma adequada correlação com outras variáveis. Não houve associação estatisticamente significante entre o índice de proliferação dos tumores (avaliada pelo PCNA), ou Ki-67 ou densidade microvascular com o tamanho do tumor, extensão extra-ovariana da doença, atividade mitótica, atipia celular e padrão histológico. Conclusão: Em nossa casuística, o estudo dos TCGO através da IHQ revelou neoplasias cujo mecanismo de desenvolvimento aparentemente não envolve mutações do p53 e nem expressão aumentada do c-erbB-2; apresentaram resultados conflitantes no que diz respeito ao índice de proliferação celular conforme foram avaliados pelo Ki-67 ou PCNA e, finalmente, são pouco angiogênicos quando avaliados pelo CD34Abstract: The purpose of this study was to investigate the credibility of diagnosis of granulosa cell tumor of ovary (GCTO) through the morphological evaluation employing only H&E staining. We also evaluated the expression of mutant p53, c-erbB-2, Ki-67, PCNA as well as angiogenic activity (CD34) and the correlation of these variables with clinical and histological characteristics. Three well trained pathologists (A, B, and C) reevaluated the slides of 22 GCTO patients that had been treated and followed at the CAISM/UNICAMP in the last 12 years. The interobserver agreement was studied calculating kappa coefficient. We employed the Fisher Exact test to assess the correlation between categorical variables and the Mann-Whitney test for the correlation between categorical and continuous variables. Twenty one cases were deemed GCTO after evaluation. Four cases received the diagnosis of GCTO due to positive reaction to inhibin, despite the divergent opinion of one the pathologist. The kappa coefficients were 0.42 (IC95%: -0.05; 0.88); 0.50 (IC95%: 0.13; 0.86); and 0.24 (IC95%: -0.14 a 0.61), for pairs A/B, A/C and B/C observers, respectively. We performed immunohistochemistry for the biological markers in 18 cases. Concerning the clinical and histological variables: 9 (50%) patients presented tumor size <10cm; 13 (72%) patients presented some solid diffuse/sarcomatoid pattern; 12 (66%) cases presented no/slight atypia and 6 (33%) cases presented moderate/strong atypia; 14 cases presented < 2 mitoses/10 HPF; 6 (33%) patients presented extraovarian extension of the disease (stage III/IV). The mean follow-up was 45.3 months (range: 0.7 to 128.8). One, 0 and 11 cases presented positive expression for mutant p53, c-erbB-2 e Ki-67 (focal), respectively. Fourteen (78%) cases were classified as high proliferating index when evaluated by PCNA. The mean microvascular density was 29,0/mm2(IC95%: 21,8 to 36,1). Only Ki-67, PCNA and CD34 were expressed at adequate levels for further correlation with other variables. There was no statistically significant link between either the PCNA proliferating index or the Ki-67 expression or microvascular density with tumor size, extraovarian extension of disease, mitotic activity, cellular atypia and histological pattern. We concluded that the diagnosis of GCTO is difficult in some cases, suggesting the evaluation be complemented with a panel of markers such as inhibin. We also verified that GCTO is a neoplasm that apparently did not involve mutations of p53 nor overexpression/amplification of c-erbB-2; presented conflictings results concerning the proliferating activity when evaluated by PCNA and Ki-67; and finally presented a low angiogenic activity when evaluated by CD34MestradoTocoginecologiaMestre em Tocoginecologi

Palliation with a multimodality treatment including hypoxic pelvic perfusion for unresectable recurrent rectal cancer: outcomes based on a retrospective study

Patients with unresectable recurrent rectal cancer that progresses after systemic chemotherapy and radiotherapy are candidates for palliation with hypoxic pelvic perfusion (HPP). The aim of this observational retrospective study was to evaluate if a multimodality treatment including HPP and targeted-therapy may be useful to prolong clinical responses and survival of these patients. From a cohort of 77 patients with unresectable recurrent rectal cancer in progression after standard treatments and submitted to HPP, 21 patients underwent repeat HPP using mitomycin C (MMC) at the dose of 25&nbsp;mg/m2. After the last HPP, 7 patients received a targeted-therapy with cetuximab according to overexpression of epidermal growth factor receptor in recurrence cancer cells. The median overall survival of these 21 patients from the diagnosis of unresectable recurrent rectal cancer was 23&nbsp;months (iqr 18-24). After the first HPP, the median survival of the 21 patients until death or end of follow-up was 10&nbsp;months (iqr 9-13). The 1-year and 2-year survival rates were 71.4%, and 4.8%, respectively. From the first HPP, age\u2009&gt;\u200960&nbsp;years, a recurrence shrinkage of at least 30% (partial response), and the addition of a post-HPP targeted-therapy with cetuximab significantly affected survival (P\u2009&lt;\u20090.04). In conclusion, repeated MMC-HPP followed by targeted-therapy seems to be an effective palliative treatment for patients with unresectable recurrent rectal cancer in progression after systemic chemotherapy and radiation but the results of this study have to be confirmed by a larger phase III trial

Colorectal Cancer with Peritoneal Metastases: The Impact of the Results of PROPHYLOCHIP, COLOPEC, and PRODIGE 7 Trials on Peritoneal Disease Management

HIPEC is a potentially useful locoregional treatment combined with cytoreduction in patients with peritoneal colorectal metastases. Despite being widely used in several cancer centers around the world, its role had never been investigated before the results of three important RCTs appeared on this topic. The PRODIGE 7 trial clarified the role of oxaliplatin-based HIPEC in patients treated with radical surgery. Conversely, the PROPHYLOCHIP and the COLOPEC were designed to chair the role of HIPEC in patients at high risk of developing peritoneal metastases. Although all three trials demonstrated the relative ineffectiveness of HIPEC for treating or preventing peritoneal metastases, these results are not sufficient to abandon this technique. In addition to some criticisms relating to the design of the trials and their statistical value, the oxaliplatin-based HIPEC was found to be ineffective in preventing or treating peritoneal colorectal metastases, especially in patients already treated with systemic platinum-based chemotherapy. Several studies are ongoing investigating further HIPEC drugs and regimens. The review deeply discussed all the aspects and relapses of this new evidence

Commment on the review entitled “A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer” by Chiva LM and Gonzalez-Martin A.

• We raised some methodological concerns and made some comments on the systematic review by Chiva and colleague. • To state that Cytoreduction & HIPEC is not beneficial in front line and platinum sensitive recurrence is highly disputable. • Anyway, the combined treatment should be offered in the context of clinical trial; randomized data are urgently needed

Consensus statement on the loco-regional treatment of appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma peritonei)

Pseudomyxoma peritonei (PMP) is a rare condition mostly originating from low malignant potential mucinous tumours of the appendix. Although this disease process is minimally invasive and rarely causes haematogenous or lymphatic metastases, expectation of long-term survival are limited with no prospect of cure. Recently, the combined approach of cytoreductive surgery (CRS) and perioperative loco-regional chemotherapy (PLC) has been proposed as the standard of treatment for the disease. The present paper summarizes the available literature data and the main features of the comprehensive loco-regional treatment of PMP. The controversial issues concerning the indications and technical methodology in PMP management were discussed through a web-based voting system by internationally known experts. Results were presented for further evaluation during a dedicated session of "The Fifth International Workshop on Peritoneal Surface Malignancy (Milan, Italy, December 4-6, 2006)". The experts agreed that multiple prospective trials support a benefit of the procedure in terms of improved survival, as compared with historical controls. Concerning the main controversial methodological questions, there was an high grade of consistency among the experts and agreement with the findings of the literature.6 page(s

Early and long-term postoperative management following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Peritoneal surface malignancies have been traditionally regarded as end-stage conditions amenable to merely palliative options. The combination of aggressive cytoreductive surgery (CRS), involving peritonectomy procedures and multivisceral resections, with intra-operative hyperthermic intra-peritoneal chemotherapy (HIPEC) and/or early postoperative intra-peritoneal chemotherapy (EPIC) to treat the microscopic residual tumor is a new concept. In recent years, promising results have been reported for peritoneal mesothelioma and carcinomatosis of gastrointestinal and gynaecologic origin treated by this combined protocol. However, CRS with HIPEC and/or EPIC is a complex procedure associated with high rates of potentially life-threatening complications. Furthermore, disease progression following comprehensive treatment is not uncommon and represents a relevant cause of treatment failure. The present paper reviews the available information on early postoperative management and long-term follow-up in patients treated with CRS and intraperitoneal chemotherapy. The peculiar clinical and biological alterations that can be expected during an uncomplicated postoperative course, as compared to standard digestive surgery, are discussed. Early recognition and appropriate management of the most common adverse events are addressed, in order to minimize the impact of treatment-related morbidity on survival and quality of life results. Since re-operative surgery with additional HIPEC, has proven to be useful in selected patients with recurrent disease, long-term surveillance aiming at early detection of postoperative disease progression has become a relevant issue. Current results on follow-up investigations are presented

Preoperative investigations in the management of peritoneal surface malignancy with cytoreductive surgery and perioperative intraperitoneal chemotherapy : expert consensus statement

At the Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on preoperative investigations for peritoneal surface malignancy was obtained through the Delphi process. The results showed that 100% of the voters considered that contrast-enhanced multisliced CT was the fundamental imaging modality, whereas MRI, PET, laparoscopy and serum tumor markers were regarded as useful, but not fundamental investigational modalities.4 page(s