Estudo clínico-patológico do carcinoma de células claras de glândula salivar / Clinical pathological study of clear cell carcinoma of the salivary gland

Na classificação da Organização Mundial de Saúde (OMS) de 2017 foram relatados 11 tipos de neoplasias benignas e 20 tipos de neoplasias malignas das glândulas salivares. Dentre estes últimos está o carcinoma de células claras de glândula salivar, uma neoplasia rara que corresponde a menos de 1% dos carcinomas de glândulas salivares. Tem no seu aspecto histológico semelhança com outras neoplasias que também apresentam células claras, tendo a imuno-histoquímica e os testes moleculares importante papel para seu diagnóstico. O objetivo do presente trabalho foi avaliar os aspectos histopatológicos, imuno-histoquímicos e biomoleculares, correlacionando com aspectos clínicos, dos casos carcinomas de células claras de glândula salivar, diagnosticados no serviço de Patologia Oral e Maxilofacial da Faculdade de Odontologia da Universidade de São Paulo (USP) diagnosticados no período entre 1997 e 2018. Em todos os casos foram avaliados os cortes histológicos, reações de imuno-histoquímica para citoqueratinas 7 e 14 (CK7 e CK14), proteína p63, proteína S-100 e actina de musculo liso (SMA), além de teste molecular da reação em cadeia da polimerase (PCR) em tempo real para pesquisa da expressão do gene de fusão EWSR1-ATF1. No levantamento dos casos do serviço de Patologia Oral e Maxilofacial da Faculdade de odontologia da USP no período de 1997 até 2018 observamos 11 lesões com as características histológicas e imuno-histoquímicas para se caracterizar como carcinoma de células claras de glândulas salivares, sendo 81,81% em mulheres, 77,77% de cor da pele branca, média de idade 56,42 anos e as regiões mais acometidas foram o palato e a mucosa jugal com 36,36% dos casos cada. Histologicamente nove casos apresentavam hialinização; e invasão neural e necrose estavam presentes em 6 e 2 dos casos respectivamente. Todos os casos foram positivos para ácido periódico-Schiff (PAS), e na imuno-histoquímica CK7 e CK14 estavam presentes em todos os casos, assim como p63. Já S-100 e SMA foram negativos em todos. No teste molecular de PCR apenas duas lesões mostraram o gene de fusão EWSR1-ATF1. Concluímos que o carcinoma de células claras é mais prevalente em mulheres com idade entre 50 e 60 anos, com predileção pelo palato. A histologia associada à imuno-histoquímica muitas vezes é suficiente para se fechar esse diagnóstico, por se tratar de uma lesão com um só tipo celular. A hialinização nem sempre está presente na lesão e a invasão neural é muito comum. Os testes moleculares devem ser utilizados como auxilio no diagnóstico, e o resultado da reação em cadeia da polimerase (PCR) para o gene EWSR1-ATF1 é fiel apenas em lesões recentes.

Adenocarcinoma de células claras de colo uterino em paciente gestante / Adenocarcinoma of clear uterine cervical cells in pregnant patient

O adenocarcinoma de células claras (CCA) primário de colo uterino em pacientes jovens é uma doença rara, de etiologia desconhecida e que no passado estava associada ao uso do dietilestilbestrol durante a gestação, quando sua comercialização era permitida. A queixa mais frequente do CCA é o sangramento vaginal irregular. Relatamos o caso de CCA de endocérvice em paciente jovem que engravidou naturalmente após o diagnóstico da neoplasia.(AU)

Primary cervical clear cell adenocarcinoma (CCA) in young patients is a rare disease of unknown etiology in the past associated with the use of diethylstilbestrol during pregnancy when its use was permitted. The most frequent complaint is irregular vaginal bleeding. We report the case of endocervous clear cell adenocarcinoma in a young patient who became naturally pregnant, even after the diagnosis of the neoplasia.(AU)

Padrão histopatológico e incidência de carcinomatose peritoneal ao diagnóstico em mulheres com câncer de ovário / Histopathological pattern and incidence of peritoneal carcinomatosis at diagnosis in women with ovarian cancer

Objetivo: Descrever o padrão histopatológico e identificar a incidência de carcinomatose peritoneal no momento do diagnóstico de mulheres diagnosticadas com neoplasia de ovário. Métodos: Trata-se de um estudo transversal e descritivo, baseado na análise secundária de dados correspondentes aos prontuários de mulheres adultas com diagnóstico de neoplasia de ovário de um serviço de referência em oncologia clínica. Foram analisados 40 prontuários entre janeiro de 2007 e janeiro de 2017. Resultados: Ao estadiamento segundo o sistema da International Federation of Gynecology and Obstetrics, três mulheres (7,5%) apresentavam estadiamento clínico (EC) II, três (77,5%) estágio ECIII com carcinomatose peritoneal/invasão da pelve e seis (15%) estágio ECIV com metástases à distância, especialmente para pulmão e fígado. Em relação ao padrão histopatológico, 20 mulheres apresentaram adenocarcinoma seroso papilífero de alto grau (50%), 4 (10%) adenocarcinoma seroso papilífero de baixo grau, 3 (7,5%) adenocarcinoma endometrioide, 3 (7,5%) tumor de teca/granulosa, 3 (7,5%) carcinoma de células claras, 3 (7,5%) tumores não classificados, 2 (5%) disgerminoma e 2 (5%) com cistoadenocarcinoma mucinosos. Conclusão: É nítida a necessidade de mais estudos envolvendo essa patologia, de modo a favorecer o diagnóstico e a intervenção em estágios mais precoces e reduzir desfechos desfavoráveis. (AU)

Objective: To describe the histopathological pattern, and to identify the incidence of peritoneal carcinomatosis at the time of the diagnosis of women diagnosed with ovarian neoplasm. Methods: This is a cross-sectional and descriptive study, based on the secondary analysis of data corresponding to the medical records of adult women diagnosed with ovarian neoplasm in a reference service of clinical oncology. A total of 40 medical records were analyzed between January 2007 and January 2017. Results: At the staging (FIGO system) of the International Federation of Gynecology and Obstetrics, three women (7.5%) had clinical staging (EC) II staging, 31 (77.5%) were in the ECIII stage, with peritoneal carcinomatosis/pelvic invasion, six (15%) were in the ECIV stage, with metastases at a distance, especially to lung and liver. Regarding the histopathological pattern, twenty women had high-grade papillary serous adenocarcinoma (50%), 4 (10%) with low-grade papillary serous adenocarcinoma, 3 (7.5%) with endometrioid adenocarcinoma, 3 (7.5%) with granulosa-theca tumor, 3 (7.5%) with clear cell carcinoma, 3 (7.5%) with unclassified tumors, 2 (5%) with dysgerminoma, two (5%) with mucinous cystadenocarcinoma. Conclusions: There is a clear need for further studies involving this pathology, in order to favor diagnosis and intervention at earlier stages and to reduce unfavorable outcomes. (AU)

Clear Cell Adenocarcinoma Originated from Adenomyosis / 이화의대지

A 66-year-old postmenopausal woman received routine gynecologic check-up. Transvaginal ultrasonography and abdominal and pelvic computed tomography showed about 5-cm cystic mass in uterus with solid component and the patient had thin endometrium and the serum level of CA 125 was normal. We performed a total hysterectomy and bilateral salpingo-oophorectomy and found tumor which had brownish cystic fluid and about 2 cm sized and colored in light yellowish, polypoid protruding solid mass, located within the myometrial wall. Histopathological examination of frozen section revealed malignancy. The tumor was confined within the myometrium and its histologic type was clear cell adenocarcinoma. Finally we identified that the myometrial mass was clear cell adenocarcinoma originated from adenomyosis pathologically. The malignant transformation of adenomyosis is very rare. When we find a cystic change with solid component in adenomyosis patients, clear cell adenocarcinoma should be suspected as a differential diagnosis and magnetic resonance imaging should be considered for further evaluation.

Survival outcomes of adjuvant radiotherapy and chemotherapy in women with stage I serous papillary and clear cell carcinoma of the endometrium: a Korean multicenter study / 부인종양

OBJECTIVE: To compare the survival outcomes of adjuvant radiotherapy and chemotherapy in women with uterine-confined endometrial cancer with uterine papillary serous carcinoma (UPSC) or clear cell carcinoma (CCC). METHODS: Medical records of 80 women who underwent surgical staging for endometrial cancer were retrospectively reviewed. Stage I UPSC and CCC were pathologically confirmed after surgery. Survival outcomes were compared between the adjuvant radiotherapy and chemotherapy groups. RESULTS: Fifty-four (67.5%) and 26 (32.5%) women had UPSC and CCC, respectively. Adjuvant therapy was administered to 59/80 (73.8%) women (25 radiotherapy and 34 chemotherapy). High preoperative serum cancer antigen-125 level (25.1±20.2 vs. 11.5±6.5 IU/mL, p 0.999) and overall survival (77.5% vs. 87.8%, p=0.373) rates were similar between the groups. Neither radiotherapy (hazard ratio [HR]=1.810; 95% confidence interval [CI]=0.297–11.027; p=0.520) nor chemotherapy (HR=1.638; 95% CI=0.288–9.321; p=0.578) after surgery was independently associated with disease recurrence. CONCLUSION: Our findings showed similar survival outcomes for adjuvant radiotherapy and chemotherapy in stage I UPSC and CCC of the endometrium. Further large study with analysis stratified by MI or LVSI is required.

Expressão de FOXP3 e resposta inflamatória em carcinomas de células renais de células claras / FOXP3 expression and inflammatory response in clear cell renal cell carcinomas

Introdução: Nas últimas décadas, progressos significativos foram feitos no manejo do carcinoma de células renais no cenário de doença avançada ou metastática. O uso de imunoterápicos estão aumentando tendo em vista que as células inatas e adaptativas do sistema imune desempenham um papel importante na regulação do crescimento do câncer. Objetivos: Os autores avaliaram as expressões imuno-histoquímicas de FOXP3, CD4 e CD8 e seus impactos prognósticos na sobrevida global e as compararam com fatores clínicos e patológicos. Metodologia: As expressões imuno-histoquímicas de FOXP3, CD4 e CD8 foram analisadas em 103 casos de carcinomas renais de células claras dispostos em tissue microarray. Para análise de seu impacto na sobrevida e associação com variáveis clínicas, dados epidemiológicos e clínicos foram coletados. Resultados: Em uma análise univariada, a razão de linfócitos CD4+/CD8+ apresentou impacto na sobrevida câncer específica (SCE) (p=0,045). Conclusão: A relação de linfócitos CD4+/CD8+ esteve associada a piores taxas de SCE. Nenhuma das variáveis clínicas e anatomopatológicas estudadas mostrou relação significativa com linfócitos positivos para FOXP3, CD4 e CD8 (AU)

Introduction: Significant progress has been made in the management of renal cell carcinoma during the last decades in the advanced or metastatic scenario. The use of immunotherapy is increasing as innate and adaptive cells of the immune system play an important role in regulating cancer growth. Objectives: The authors evaluated the immunohistochemical expressions of FOXP3, CD4 and CD8 and their prognostic impacts on overall survival and compared them with clinical and pathological factors. Methodology: Epidemiological and clinical data were collected. Immunohistochemical expressions were analyzed in 103 cases arranged in tissue microarray. Results: In a univariate analysis, the CD4+/CD8+ lymphocyte ratio impacted cancer-specific survival (ECS) (p = 0.045). Conclusion: The ratio of CD4+/CD8+ lymphocytes was associated with worse ECS rates. None of the clinical and anatomopathological variables studied showed a significant relationship with FOXP3, CD4 and CD8 positive lymphocytes (AU)

Prognostic value of neutrophil-to-lymphocyte ratio in early-stage ovarian clear-cell carcinoma / 부인종양

OBJECTIVES: There is increasing evidence that systemic inflammatory response (SIR) markers are prognostic factors for various types of cancers. This is the first study to evaluate the usefulness of SIR markers for the prognosis of early-stage ovarian clear-cell carcinoma (OCCC). METHODS: We retrospectively investigated 83 patients diagnosed with stage I–II OCCC who underwent surgery between 2005 and 2017. Initially, receiver operating characteristic curve analysis for overall survival (OS) was used to determine optimal cut-off values for neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Patients were stratified into 2 groups by the cut-off values (NLR=3.26, PLR=160). Univariate and multivariate analyses were performed to elucidate the significance of SIR markers as prognostic factors. RESULTS: In the median follow-up period of 64.1 months, 16 patients experienced recurrence, and nine patients died. The Kaplan-Meier curve showed that OS of the NLR-low group was significantly longer than the NLR-high group (p=0.021). There was no significant difference in progression-free survival between the 2 groups (p=0.668), but the post-recurrence survival of the NLR-low group was significantly longer than the NLR-high group (p=0.019). Furthermore, multivariate analysis showed that increase in NLR is a significant independent prognostic factor for poor prognosis (hazard ratio=7.437, p=0.017). There was no significant difference between PLR-low and PLR-high group. CONCLUSION: Results suggest that NLR can be a significant independent prognostic factor for early-stage OCCC.

Prognostic factors and effects of fertility-sparing surgery in women of reproductive age with ovarian clear-cell carcinoma: a propensity score analysis / 부인종양

OBJECTIVE: The aim of this study was to investigate the clinical characteristics of young patients with stage I clear-cell carcinoma (CCC) and evaluate the prognostic factors and effects of fertility-sparing surgery (FSS) using propensity score (PS) adjustment. METHODS: We conducted a regional multi-institutional study between 1986 and 2017. Among 4,277 patients with ovarian tumor, clinical and pathological data of 103 fertile women with stage I unilateral CCC were collected. We evaluated survival and reproductive outcomes in these patients. Additionally, to analyze the effects of FSS, baseline imbalance between patients with and those without FSS was adjusted with an inverse probability of treatment weighting using PSs involving independent clinical variables. RESULTS: The mean patient age was 39.4 years, and the median follow-up period for surviving patients was 55.6 months. In multivariate analysis, stage IC2/IC3 (vs. IA/IC1) was the only independent prognostic factor for recurrence-free survival (RFS) and overall survival (OS). FSS was not associated with poorer prognosis when compared to the prognosis with non-preserving surgery with regard to both RFS and OS. No statistical difference in survival outcomes between FSS and other approaches was confirmed after PS adjustment. Among patients who underwent FSS, four deliveries with healthy neonates were noted without any gestational complications. CONCLUSION: FSS can be considered in stage I CCC, specifically in stage IA and IC1 patients who strongly desire to have children in the future. Further clinical research is needed to clarify the optimal application of FSS for CCC.

Malignant transformation of abdominal wall endometriosis to clear cell carcinoma: case report

ABSTRACT BACKGROUND: Malignant transformation of endometriosis in the abdominal wall is a rare and still poorly understood event. Less than 30 cases have been reported in the worldwide literature. Most cases of solid tumors are report in a previous abdominal scar with malignant transformation of a focus of endometriosis. Presence of lymph node metastases in nearby chains is frequent and is associated with poor prognosis. CASE REPORT: We report a case of a 42-year-old woman with a history of abdominal surgery (Pfannenstiel) to resect abdominal wall endometriosis. Physical examination revealed a solid mass of approximately 10 cm x 6 cm in the anterior wall of the abdomen. Computed tomography (CT) of the abdomen and pelvis showed a heterogeneous, predominantly hypoattenuating expansive formation measuring 10.6 cm x 4.7 cm x 8.3 cm. The patient underwent exploratory incisional laparotomy, block resection of the abdominal mass and lymphadenectomy of the external and inguinal iliac chains. The abdominal wall was reconstructed using a semi-absorbable tissue-separating screen to reconstitute the defect caused by resection of the tumor. Histological evaluation revealed infiltration by malignant epithelioid neoplasia, thus confirming the immunohistochemical profile of adenocarcinoma with clear cell components. Lymphadenectomy showed metastatic involvement of an external iliac chain lymph node. CONCLUSION: Resection of the mass along with the abdominal wall, with wall margins, is the most effective treatment. Reconstruction is a challenge for surgeons. The patient has been followed up postoperatively for eight months, without any evidence of disease to date.

Endometriosis y carcinoma de celulas claras. Reporte de caso / Endometriosis and clear cell carcinoma. Case report

RESUMEN La endometriosis corresponde a la presencia de glándulas endometriales o estroma en sitios distintos a la cavidad uterina. Afecta del 5 al 15% de las mujeres en edad reproductiva y se asocia a importante sintomatología. La teoría de la menstruación retrógrada propuesta por Sampson es la más aceptada para explicar su etiología. Varios estudios han asociado esta enfermedad a un riesgo aumentado de neoplasia, ésta entidad, denominada endometriosis asociada a malignidad, se localiza en sitios extra gonadales en un 20% de los casos, donde la pared abdominal no alcanza más de 30 casos reportados. Si bien no existe un tratamiento estándar, la mayoría de los autores han adaptado el protocolo de tratamiento para el cáncer de ovario asociado a endometriosis.

ABSTRACT Endometriosis corresponds to the presence of endometrial glands or stroma at sites other than the uterine cavity. It affects 5 to 15% of women of reproductive age and is associated with a significant symptomatology. The theory of retrograde menstruation proposed by Sampson is the most accepted to explain its etiology. Several studies have associated this disease with an increase in neoplasia, the entity, called endometriosis associated with malignancy, is located in extra gonadal sites in 20% of cases, where the abdominal wall does not reach more than 30 reported cases. Although there is no standard treatment, most authors have adapted the treatment for ovarian cancer associated with endometriosis.

Outcomes of Non-High Grade Serous Carcinoma after Neoadjuvant Chemotherapy for Advanced-Stage Ovarian Cancer: Single-Institution Experience

PURPOSE: Outcomes in patients with ovarian high-grade serous carcinoma (HGSC) treated with neoadjuvant chemotherapy (NAC) have been widely studied; however, there is limited information on responses to chemotherapy among patients with non-HGSC. The aim of this study was to compare the survival outcomes of patients with advanced-stage non-HGSC and HGSC treated with NAC. MATERIALS AND METHODS: This study was a retrospective analysis of patients with advanced-stage ovarian cancer treated at Yonsei Cancer Hospital between 2006 and 2017. The demographics, chemotherapy response, and survival rates were compared between patients with non-HGSC and those with HGSC. RESULTS: Among 220 patients who underwent NAC, 25 (11.4%) patients had non-HGSC histologic subtypes, and all received a taxane-platinum combination regimen for NAC. Patients with non-HGSC had lower baseline cancer antigen-125 levels (p < 0.001), poorer response rates (p < 0.001), lower rates of optimal cytoreduction (p=0.003), and poorer progression-free survival (PFS) (median PFS 10.3 months vs. 18.3 months; p=0.009) and overall survival (OS) (median OS 25.5 months vs. 60.6 months; p < 0.001), compared to those with HGSC. In multivariate analysis, non-HGSC was a negative prognostic factor for both PFS [hazard ratio (HR), 3.19; 95% confidence interval (CI), 1.73–5.88] and OS (HR, 4.22; 95% CI, 2.07–8.58). CONCLUSION: In this study, poorer survival outcomes were observed in patients who underwent NAC for treatment of non-HGSC versus those treated for HGSC. Different treatment strategies are urgently required to improve survival outcomes for patients with non-HGSC undergoing NAC.

Adenocarcinoma sincrónico de alto grado de endometrio y ovario; a propósito de un caso clínico / Synchronous high-grade adenocarcinoma of the endometrium and ovary; about a clinical case

RESUMEN El cáncer sincrónico endometrial y ovárico (SEOC) representa alrededor de un 5-10% de las neoplasias de endometrio y ovario. Cuando no existe extensión locorregional y presentan un patrón histológico de bajo grado, actúan como si fueran dos tumores primarios independientes, en lugar de comportarse como un cáncer en estadio avanzado. Los mecanismos para diferenciar si su origen es metastásico o por el contrario, son tumores primarios independientes conlleva una gran dificultad y ha generado una importante controversia dentro del estudio de este tipo de neoplasias. En este artículo, exponemos el caso clínico de una paciente de 46 años que presenta un tumor sincrónico de endometrio y ovario en estadio IA, desconocido hasta el estudio histológico de la pieza quirúrgica.

ABSTRACT Endometrial and ovarian synchronous cancer (SEOC) accounts for about 5-10% of endometrial and ovarian neoplasms. When there is no local extension and they present a low-grade histological pattern, they act as if they were two independent primary tumours, instead of behaving as an advanced stage cancer. Therefore, the differentiation of its origin (metastatic or independent primary tumours) is fraught with difficulty and has generated a significant controversy in the study of this type of neoplasms. In this article, we present the clinical case of a 46-year-old patient presenting a synchronous tumor of the endometrium and ovary in IA stage, unknown until the histological study of the surgical sample.

Carcinomas de ovário associados à endometriose: expressão de marcadores proteicos de terapia alvo e prognóstico / Endometriosis-associated ovarian carcinomas: expression of protein biomarkers associated to target therapies and prognosis

Resumo: Introdução: endometriose é uma doença benigna, capaz de progredir extensamente e gerar clones atípicos. Considerada precursora dos carcinomas de células claras (CCOC) e endometrióide (EOC) de ovário, atualmente chamados carcinomas de ovário associados à endometriose (EAOC). Objetivos: comparar o perfil epidemiológico, a associação com endometriose e a expressão de marcadores imuno-histoquímicos para ARID1A, VEGF, PD-L1 e PARP-1 em mulheres com CCOC e EOC, e sua correlação com a sobrevida livre de progressão (SLP) e sobrevida global (SG). Métodos: estudo de coorte reconstituída, com 50 casos incluídos de CCOC e EOC tratados no CAISM-UNICAMP entre 1995 até 2016, acompanhados até 02/2017. Microarranjos de tecido com amostras de CCOC, EOC e endometriose foram corados com anticorpos monoclonais contra ARID1A, e para os biomarcadores proteicos VEGF, PD-L1, PARP-1 através de imuno-histoquímica. A expressão de ARID1A foi classificada (0 a 100) conforme a porcentagem de células não coradas. A expressão de VEGF, PD-L1 e PARP-1 foi classificada (0 a 300) conforme a multiplicação da porcentagem de células coradas por um fator da intensidade de expressão (ausente=0; fraco=1; moderado=2; forte=3). Idade ao diagnóstico; menopausa; índice de massa corpórea (IMC); CA-125; diagnóstico de endometriose; datas do diagnóstico, da progressão, do óbito e da última consulta foram recuperados dos prontuários. Comparação entre grupos foi realizada através de testes T e de ?2. A SLP (diferença de tempo entre o diagnóstico e a data de progressão) e a SG (diferença de tempo entre o diagnóstico e o óbito ou data da última data de consulta) foi avaliada através de curvas de Kaplan-Meyer e teste de Log-Rank ou regressão de COX. Resultados: 23 mulheres com CCOC (46%), e 27 com EOC (54%) foram incluídas; 80% tinham endometriose associada, 42% eram nulíparas, 42% eram pré-menopausa e CA125 foi elevado em todos estádios (FIGO I-II= média 614.7Ui/mL; FIGO III-IV= media 2361.2Ui/mL). A média de idade ao diagnóstico foi 7 anos menor em mulheres com EOC do que naquelas com CCOC. O CCOC foi mais diagnosticado em estágios iniciais quando associado à endometriose (p=0,03). O prognóstico dos EOC e CCOC em estádios iniciais foi semelhante (p=0,96). Os CCOC não associado à endometriose tiveram menor SG (p=0,04). A expressão de todos os biomarcadores esteve presente nos EAOC e na endometriose. O aumento da expressão de VEGF entre endometriose e câncer foi significativo (p=0,0002). A hiperexpressão de PARP-1 correlacionou-se negativamente com a SLP (p=0,03) e SG (p=0,01) em estádios iniciais. Conclusão: Os CCOC e EOC são comumente diagnosticados em estádios iniciais (FIGO I-II= 68%) e estão frequentemente associados à endometriose (80% dos casos). Quando associados à endometriose, os CCOC foram mais diagnosticados em estádios iniciais e tiveram SG maior. Houve elevada porcentagem de células com ARID1A mutado nos EAOC (>40%). VEGF se expressou mais intensamente nos CCOC e EOC que na endometriose, já a expressão de PD-L1 e de PARP-1 foi similar. Apenas a hiperexpressão de PARP-1 reduziu significativamente a SLP e a SG nos CCOC e EOC nos estádios iniciais(AU)

Abstract: Introduction: Endometriosis is a benign disease, able to progress widely and generate atypical clones. It is a precursor of clear cell ovarian carcinomas (CCOC) and endometrioid ovarian carcinomas (EOCs), now called endometriosis-associated ovarian carcinomas (EAOC). Objectives: To compare the epidemiological profile, association with endometriosis and the expression of immunohistochemical markers for ARID1A, VEGF, PD-L1 and PARP-1 in women with CCOC and EOC, and its correlation with progression-free survival (PFS) and overall survival (OS). Methods: A reconstituted cohort study with 50 cases of CCOC and EOC included. Cases were treated at CAISM-UNICAMP between 1995 and 2016, followed up until 02/2017. Tissue microarrays with CCOC, EOC and endometriosis samples were stained with monoclonal antibodies against ARID1A, and for VEGF, PD-L1, PARP-1 biomarkers by immunohistochemistry. The expression of ARID1A was classified (0 to 100) according to the percentage of unstained cells. The expression of VEGF, PD-L1 and PARP-1 was classified (0 to 300) multiplying the percentage of stained cells by an intensity of expression factor (absent=0, weak=1, moderate=2, strong=3). Age at diagnosis; menopause; BMI (body mass index); CA-125 levels; diagnosis of endometriosis; date of diagnosis, date of progression, date of death and date of last consultation were retrieved from the medical records. Comparison between groups was performed through T and ?2 tests. The PFS (difference in time between diagnosis and progression date) and OS (difference in time between diagnosis and death or the last date of consultation) was assessed using Kaplan-Meyer curves and Log-Rank test or COX multivariate models. Results: twenty-three women with CCOC (46%), and 27 with EOC (54%) were included; 80% had associated endometriosis, 42% were nulliparous, 42% were premenopausal, and CA125 was elevated at all stages (FIGO I-II = mean 614.7Ui / mL; FIGO III-IV = mean 2361.2Ui / mL). The mean age at diagnosis was 7 years lower in women with EOC than in those with CCOC. CCOC when associated with endometriosis were more diagnosed at early stages (p=0.03). The prognosis of EOC and CCOC at early stages was similar (p=0.96). CCOCs not associated with endometriosis had shorter OS (p=0.04). Expression of all biomarkers was present in the EAOC and endometriosis. The increase in VEGF expression between endometriosis and cancer was significant (p=0.0002). The overexpression of PARP-1 correlated negatively with PFS (p=0.03) and OS (p=0.01) at FIGO I-II stages. Conclusion: The diagnosis of women with EOC was made earlier than in those with CCOC. CCOC and EOC are commonly diagnosed in early stages (FIGO I-II - 68%) and were associated with endometriosis (80% of cases). When associated with endometriosis, clear cell carcinomas are more likely diagnosed at early stages, and the association of endometriosis with CCOC improves OS. There was a high percentage of cells with mutated ARID1A gene in EAOC (> 40%). VEGF was expressed more intensely in CCOC and EOC than in endometriosis, whereas expression of PD-L1 and PARP-1 was similar. Only the overexpression of PARP-1 significantly reduced PFS and OS in CCOC and EOC at early stages(AU)

Clear cell odontogenic carcinoma of the mandible: a treatment strategy

Abstract Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic tumor of the jaws, histologically characterized by the presence of agglomerates of cells with eosinophilic cytoplasm. The patient, a 62-year-old Caucasian woman, presented an intraosseous lesion in the mandibular symphysis. A clinical examination revealed a discrete volumetric increase with a hard consistency, palpable to extraoral and intraoral examinations. Imaging studies revealed an extensive radiolucent area, without defined limits, extending from the region of the right second premolar to the left canine. Incisional biopsy analysis indicated a diagnosis of CCOC. The treatment proposed was segmental resection of the mandible with a safety margin. After six months without recurrence, definitive mandibular reconstruction was performed using an iliac crest graft, followed by rehabilitation with implant-supported denture after five months. After three years of post-resection follow-up, the patient has shown no evidence of recurrence or metastasis. She continues to be under follow-up. To conclude, CCOC must be considered a malignant tumor with aggressive behavior. Previous studies have shown that resection with free margins is a treatment with a lower rate of recurrence. Nevertheless, long-term follow-up is necessary for such patients.

Therapeutic significance of full lymphadenectomy in early-stage ovarian clear cell carcinoma / 부인종양

OBJECTIVES: This study evaluated the therapeutic significance of full lymphadenectomy in early-stage ovarian clear cell carcinoma (OCCC). METHODS: We retrospectively reviewed records of 127 consecutive patients with pT1/pT2 and M0 OCCC who were treated between January 1995 and December 2015. We compared survival outcomes between those who did and did not undergo para-aortic lymph node dissection (PAND), and analyzed independent prognostic factors (Cox proportional hazards model with backward stepwise elimination). RESULTS: Of the 127 patients, 36 (28%) did not undergo lymphadenectomy; 12 (10%) patients underwent pelvic lymph node dissection (PLND) only; and 79 (62%) patients underwent both PLND and PAND. Of the 91 patients with lymphadenectomy, 11 (12%) had lymph node metastasis (LNM). The PAND− and PAND+ groups did not significantly differ in age, distribution of pT status, radiologically enlarged lymph nodes, positive peritoneal cytology, capsule rupture, peritoneal involvement, and combined chemotherapy. Cox regression multivariate analysis confirmed that older age (hazard ratio [HR]=2.1; 95% confidence interval [CI]=1.0–4.3), LNM (HR=4.4; 95% CI=1.7–11.6), and positive peritoneal cytology (HR=4.2; 95% CI=2.1–8.4) were significantly and independently related to poor disease-specific survival (DSS), but implementation of both PLND and PAND (HR=0.4; 95% CI=0.2–0.8) were significantly and independently related to longer DSS. CONCLUSION: Although few in number, there are some patients with early-stage OCCC who can benefit from full lymphadenectomy. Its therapeutic role should be continuously investigated in OCCC patients at potential risk of LNM.

Prognostic value of programmed death-ligand 1 (PD-L1) expression in ovarian clear cell carcinoma / 부인종양

OBJECTIVE: Programmed death-ligand 1 (PD-L1) was expressed in various tumors and antibodies targeting its receptor programmed cell death-1 (PD-1) are emerging cancer therapeutics. This study was designed to evaluate the expression of PD-L1 and its correlation with clinicopathologic features and clinical outcomes in ovarian clear cell carcinoma (OCCC). METHODS: The PD-L1 expression was measured by tissue-microarray-based immunohistochemistry from 122 eligible patients diagnosed with OCCC. The associations of clinicopathologic features with progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method and multivariate analysis was further performed by Cox regression model. RESULTS: Overall, high PD-L1 expression (PD-L1(high)) was observed in 44.7% (55/123) of OCCC patients, and was strongly associated with advanced stages (p=0.020), positive ascitic fluid (p=0.016), platinum-resistant (PR) disease (p=0.045), and recurrence (p=0.038). Moreover, patients with PD-L1(high) were associated with poorer OS (hazard ratio [HR]=2.877; p=0.001) and PFS (HR=1.843; p=0.021) than those with low PD-L1 expression (PD-L1(low)). In subgroup analysis, PD-L1(high) patients experienced a poorer PFS (HR=1.926; p=0.044) and OS (HR=2.492; p=0.021) than PD-L1(low) cases among advanced stages (III–IV), but this difference was not observed in stage I–II patients. Meanwhile, PD-L1(high) was associated with poorer prognosis than PD-L1(low) in PR patients (OS, HR=2.253; p=0.037; PFS, HR=1.448; p=0.233). Multivariate analysis revealed that PD-L1(high) and advanced stages (III–IV) were adverse independent prognosticators for both PFS (HR(PD-L1)=2.0; p(PD-L1)=0.038; HR(stage)=10.2; p(stage)<0.001) and OS (HR(PD-L1)=3.0; p(PD-L1)=0.011; HR(stage)=14.3; p(stage)<0.001). CONCLUSION: PD-L1(high) might serve as a risk factor for PFS and OS in patients with OCCC. It is possible that immunotherapy targeting PD-L1 pathway could be used in OCCC.

Inhibition of autophagy protein LC3A as a therapeutic target in ovarian clear cell carcinomas / 부인종양

OBJECTIVE: Ovarian clear cell carcinoma (CCC) is one of histological subtypes showing poor prognosis due to chemoresistance. The association of autophagy-related proteins and clinical implementation in CCC has not been determined. METHODS: The present study investigated whether expression of autophagy-related protein, light chain 3A (LC3A), was related with prognoses in the patients with CCC using immuno-histochemical stainings, and whether inhibition of autophagy modified the sensitivity to cisplatin in CCC cells in vitro. RESULTS: High expression of autophagy-related protein, LC3A, was detected in 78 cases (78%) in all CCC cases. The patients with high LC3A expression showed significantly lower response rate to primary chemotherapy (17% vs. 100%, p<0.010), and had worse progression-free survival (PFS) and overall survival (OS) compared with those with LC3A low expression. Furthermore, multivariate analyses revealed that high expression of LC3A was identified as independent worse prognostic factors for PFS and OS. Inhibition of autophagy protein LC3A using hydroxychloroquine (HCQ) increased sensitivity to cisplatin in CCC cells in vitro. CONCLUSION: High expression of LC3A proteins was associated with lower response to platinum therapy, leading to worse prognoses in CCC. Although further studies are needed to confirm the results, inhibition of autophagy by HCQ was associated with platinum sensitivity. Autophagy protein LC3A could be a promising target for treatment for CCC.

Prognostic factors and treatment outcomes in surgically-staged non-invasive uterine clear cell carcinoma: a Turkish Gynecologic Oncology Group study / 부인종양

OBJECTIVE: To assess the prognosis of surgically-staged non-invasive uterine clear cell carcinoma (UCCC), and to determine the role of adjuvant therapy. METHODS: A multicenter, retrospective department database review was performed to identify patients with UCCC who underwent surgical treatment between 1997 and 2016 at 8 Gynecologic Oncology Centers. Demographic, clinicopathological, and survival data were collected. RESULTS: A total of 232 women with UCCC were identified. Of these, 53 (22.8%) had surgically-staged non-invasive UCCC. Twelve patients (22.6%) were upstaged at surgical assessment, including a 5.6% rate of lymphatic dissemination (3/53). Of those, 1 had stage IIIA, 1 had stage IIIC1, 1 had stage IIIC2, and 9 had stage IVB disease. Of the 9 women with stage IVB disease, 5 had isolated omental involvement indicating omentum as the most common metastatic site. UCCC limited only to the endometrium with no extra-uterine disease was confirmed in 41 women (73.3%) after surgical staging. Of those, 13 women (32%) were observed without adjuvant treatment whereas 28 patients (68%) underwent adjuvant therapy. The 5-year disease-free survival rates for patients with and without adjuvant treatment were 100.0% vs. 74.1%, respectively (p=0.060). CONCLUSION: Extra-uterine disease may occur in the absence of myometrial invasion (MMI), therefore comprehensive surgical staging including omentectomy should be the standard of care for women with UCCC regardless of the depth of MMI. Larger cohorts are needed in order to clarify the necessity of adjuvant treatment for women with UCCC truly confined to the endometrium.

Could fertility-sparing surgery be considered for women with early stage ovarian clear cell carcinoma? / 부인종양

OBJECTIVE: The aim of the present retrospective population-based study was to investigate the oncologic impact of uterine and ovarian preservation (OP) in premenopausal women with stage IA or IC ovarian clear cell carcinoma (OCCC). METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was accessed and a cohort of surgically-staged premenopausal women (age <50 years) diagnosed with unilateral stage IA or IC OCCC was drawn. Based on site-specific surgery codes, women who did not undergo hysterectomy and/or bilateral salpingo-oophorectomy (BSO) were identified. Overall survival (OS) and cancer-specific survival (CSS) rates were calculated following generation of Kaplan-Meier curves; comparisons were made with the log-rank test. Multivariate Cox analysis was performed to control for possible confounders. RESULTS: A total of 741 premenopausal women who met the inclusion criteria were identified. Based on available information, rate of uterine preservation was 14.5% (96/663) while the rate of OP was 28.1% (71/253). Five-year CSS rates were 90.8% for women who did not undergo hysterectomy compared with 87.7% for those who did (p=0.290). Similarly, 5-year CSS rates in the OP and BSO groups were 92.6% and 85%, respectively (p=0.060). After controlling for disease sub-stage (IA vs. IC), uterine or OP was not associated with a worse overall or cancer-specific mortality. CONCLUSION: In the present cohort, uterine and OP did not have a negative impact on oncologic outcomes. Selection criteria for fertility-sparing surgery (FSS) could be expanded to include women with stage IA OCCC.

Ovarian Clear Cell Carcinoma Sub-Typing by ARID1A Expression

PURPOSE: Loss of AT-rich DNA-interacting domain 1A (ARID1A) has been identified as a driving mutation of ovarian clear cell carcinoma (O-CCC), a triple-negative ovarian cancer that is intermediary between serous and endometrioid subtypes, in regards to molecular and clinical behaviors. However, about half of O-CCCs still express BAF250a, the protein encoded by ARID1A. Herein, we aimed to identify signatures of ARID1A-positive O-CCC in comparison with its ARID1A-negative counterpart. MATERIALS AND METHODS: Seventy cases of O-CCC were included in this study. Histologic grades and patterns of primary tumor, molecular marker immunohistochemistry profiles, and clinical outcomes were analyzed. RESULTS: Forty-eight (69%) O-CCCs did not express BAF250a, which were designated as "ARID1A-negative." The other 22 (31%) O-CCCs were designated as "ARID1A-positive." ARID1A-positive tumors were more likely to be histologically of high grades (41% vs. 10%, p=0.003), ERβ-positive (45% vs. 17%, p=0.011), and less likely to be HNF1β-positive (77% vs. 96%, p=0.016) and E-cadherin-positive (59% vs. 83%, p=0.028) than ARID1A-negative tumors. Patient age, parity, tumor stage were not significantly different in between the two groups. Cancer-specific survival was not significantly different either. CONCLUSION: We classified O-CCCs according to ARID1A expression status. ARID1A-positive O-CCCs exhibited distinct immunohistochemical features from ARID1A-negative tumors, suggesting a different underlying molecular event during carcinogenesis.