COMPARAÇÃO ENTRE QUATRO ÍNDICES DE MALIGNIDADE NA ...repositorio.unicamp.br/jspui/bitstream/REPOSIP/... · COMPARISION OF FOUR MALIGNANCY RISK INDICES IN THE PREOPERATIVE DISCRIMINATION

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CAMILA DE MELO CAMPOS

COMPARAÇÃO ENTRE QUATRO ÍNDICES DE MALIGNIDADE NA DISCRIMINAÇÃO PRÉ-

OPERATÓRIA DAS MASSAS ANEXIAIS

COMPARISION OF FOUR MALIGNANCY RISK INDICES IN THE PREOPERATIVE DISCRIMINATION

OF ADNEXAL MASSES

CAMPINAS 2014

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UNIVERSIDADE ESTADUAL DE CAMPINAS

Faculdade de Ciências Médicas


COMPARAÇÃO ENTRE QUATRO ÍNDICES DE MALIGNIDADE NA DISCRIMINAÇÃO PRÉ-

OPERATÓRIA DAS MASSAS ANEXIAIS

COMPARISION OF FOUR MALIGNANCY RISK INDICES IN THE PREOPERATIVE DISCRIMINATION

OF ADNEXAL MASSES

Dissertação apresentada à Pós-Graduação da Faculdade de Ciências Médicas da Universidade Estadual de Campinas para obtenção do Título de Mestra em Ciências da Saúde, área de concentração em Oncologia Ginecológica e Mamária.

Dissertation submitted to the Programme of Obstetrics and Gynecology of the Unicamp’s Health Sciences Faculty for obtaining the title of master in Health Sciences in the concentration area of Gynecologic and Breast Oncology

ORIENTADORA: PROFA. DRA. SOPHIE FRANÇOISE MAURICETTE DERCHAIN COORIENTADOR: PROF. DR. LUIS OTAVIO ZANATA SARIAN ESTE EXEMPLAR CORRESPONDE Á VERSÃO FINAL DA DISSERTAÇÃO DEFENDIDA PELA ALUNA CAMILA DE MELO CAMPOS E ORIENTADA PELA PROFA. DRA. SOPHIE FRANÇOISE MAURICETTE DERCHAIN

Assinatura do Orientador

CAMPINAS 2014

iv

Diagramação e Revisão: Assessoria Técnica do CAISM (ASTEC)

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BANCA EXAMINADORA DA DEFESA


ORIENTADORA: PROF. DRA. SOPHIE FRANÇOISE MAURICETTE DERCHAIN

COORIENTADOR: PROF. DR. LUIS OTÁVIO ZANATTA SARIAN

MEMBROS:

1.

2.

3.

Programa de Pós-Graduação em Tocoginecologia da Faculdade de Ciências Médicas da Universidade Estadual de Campinas

Data: 16 / 12 / 2014

vii

RESUMO

A discriminação de tumores malignos entre mulheres com diagnóstico de massas

anexiais pode ser difícil devido a limitações na acurácia do exame

ultrassonográfico e à disponibilidade de pessoal especializado para realizá-lo. O

índice de risco de malignidade visa a simplificar e padronizar a rotina

ultrassonográfica para fornecer uma avaliação rápida e direta da massa anexial.

Neste estudo foi examinado o desempenho de quatro variações deste índice (IRM

1 a 4) em um centro terciário de assistência e pesquisa em câncer ginecológico

com a realização de exame ultrassonográfico por pessoal inserido em programa

de treinamento supervisionado. Método: 158 mulheres com diagnóstico de massa

anexial foram avaliadas antes da cirurgia utilizando-se as quatro variações do

IRM. O exame foi realizado por ultrassonografistas com níveis variados de

experiência e incluídos em programa de treinamento. Indicadores de desempenho

para os diferentes tipos de IRM foram calculados utilizando-se de metodologia

conhecida e o padrão-ouro para diagnóstico foi a análise anatomopatológica.

Resultados: A prevalência de tumores malignos foi de 32%. Pacientes com

tumores malignos eram mais idosas quando comparadas às pacientes com

diagnóstico de tumores benignos (idade média 45,9+15,0 anos versus 55,7+16,2;

p

viii

ovarianos era estágio I. Endometriomas foram as mais frequentes (11%) massas

anexiais não neoplásicas. Mulheres com tumores malignos apresentaram níveis

de CA125, escores de ultrassom e número de tumores com diâmetro >7 cm

significativamente maiores que mulheres com tumores benignos. Quando se

comparou o desempenho das variantes do IRM no melhor ponto de corte

determinado pela análise da curva ROC (receiver operator characteristic),

percebeu-se que as variantes do IRM apresentam desempenho semelhante na

população geral (pré e pós-menopausa). Entre as mulheres na pré-menopausa, a

melhor sensibilidade é obtida com o IRM2 (90%; 95% IC 83-97%) e com o IRM4

(89%; 95% IC 81-97%). A especificidade entre as diferentes variantes do IRM não

apresentou diferença significativa. O mesmo desempenho foi obtido entre as

variantes do IRM nas mulheres na pré e pós-menopausa. Foram também

analisados os indicadores de desempenho nas diferentes variantes do IRM nos

pontos de corte progressivos na população geral (pré e pós-menopausa). Os

pontos de corte recomendados pela literatura para os IRM1 a 3 é 200 e para o

IRM4 é 450. Nesses pontos de corte recomendados, a sensibilidade entre os

diferentes IRM variou entre 68% e 78% e a especificidade variou entre 82% e

87%. A pior correspondência entre valores do IRM e o resultado final

anatomopatologico foi obtido entre os tumores borderline, em que os tumores

foram classificados incorretamente em 50% dos casos utilizando o IRM1 e 3 e em

37% dos casos utilizando o IRM2 e 4. Proporções similares de tumores

classificados corretamente e incorretamente foram obtidos com as quatro

variantes do IRM. Os tumores epiteliais são mais bem classificados pelo IRM que

os não epiteliais. A taxa de falso negativo é maior entre os tumores do estroma:

ix

5/7 tumores de células da granulosa foram incorretamente classificados como

benignos entre as quatro variantes do IRM. Tumores borderlines foram

incorretamente classificados como benignos em 37% a 50% dos casos,

dependendo do IRM utilizado. Falsos negativos entre as quatro variantes do IRM

são maiores em mulheres com tumores de estágio 1 quando comparados com

mulheres em estágio mais avançado (p com valor significativo entre as quatro

variantes). Os IRM 1 e 3 classificaram incorretamente a maioria dos tumores

estágio 1 como benigno; IRM 2 classifica melhor tumores de estágio 1. É

importante ressaltar que 7 tumores de células da granulosa eram estágio 1.

Analisou-se a curva ROC para os diferentes IRM na discriminação das mulheres

entre tumores malignos e benignos. Os testes que compararam a área sobre a

curva de todas as curvas revelaram superioridade discreta do IRM4 sobre o IRM2

(p=0.06). Todos os outros testes realizados entre as curvas não obtiveram

resultado significativo. Conclusão: o IRM apresentou desempenho aceitável em

um centro terciário de assistência e pesquisa em câncer ginecológico, com

ultrassonografistas de conhecimento moderado e em treinamento. O equilíbrio

entre o desempenho e a viabilidade, devido à baixa complexidade da realização

do exame ultrassonográfico, favorece o IRM quando comparado a outros modelos

de triagem para avaliação de massas anexiais.

Palavras-chave: neoplasias ovarianas – diagnóstico; ultrassonografia.

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ABSTRACT

Discriminating women with ovarian malignancies among those with adnexal

masses may be difficult in medium resource settings due to limitations in

ultrasound accuracy and availability of specialized personnel. The Risk of

Malignancy Index (RMI) aims at simplifying and standardizing the ultrasound

routine in order to provide a fast and straightforward evaluation of the adnexal

mass. We examined the performance of four RMI variants (RMI 1 to 4) in a middle-

resources gynecologic cancer center, with ultrasound performed by personnel

under a training program. Methods: 158 referred due to an adnexal mass were

evaluated before surgery using the four RMI variants. Ultrasound was performed

by sonographers with variable expertise levels and enduring a training program.

Performance indicators for the RMI variants were calculated using standard

methodology and the gold standard was pathology of the adnexal mass. Results:

The prevalence of malignant tumor was 32%. Patients with malignant tumors were

significantly more aged than their counterparts with benign adnexal masses (mean

age 45.9+15.0 years versus 55.7+16.2; p7cm in

diameter than women with benign masses. When comparing the performance of

the RMI variants using the optimal cutoff points as determined with ROC analyses,

we notivce than in the general population (pre and postmenopausal women), RMI

xii

variants yielded similar performance indicators. In the subset of premenopausal

women, the best sensitivity was obtained with RMI 2 (90%; 95%CI 83-97%) and

RMI4 (89%; 95%CI 81-97%). Specificity for the RMI variants did not differ

significantly. Similar performance was obtained for the RMI variants in pre and

post-menopausal women. We then analyzed the performance indicators of RMI

variants at progressive cutoff points in the general (pre- and postmenopausal)

population. The standard (literature recommended) cutoff points for RMI 1 to 3 is

200 and for RMI 4 is 450. At these recommend cutoff points, the sensitivity of the

different RMI1 vary from 68% to 78% and specificity vary from 82% to 87%. The

worst correspondence between RMI values and final pathology was obtained for

borderline tumors, which were incorrectly classified in 50% of the cases using RMI

1 and 3 and 37% of the cases using RMI 2 and 4. Similar proportions of correctly

and incorrectly classified benign and malignant tumors were obtained with the four

RMI variants. Clearly, RMI classified epithelial tumors much better than it did with

non-epithelial tumors. The false negative rate was higher for stromal tumors: 5/7

granulosa cell tumors were incorrectly classified as benign by the four RMI

variants. Borderline tumors were also incorrectly classified as benign in 37-50% of

the cases depending on the RMI variant used. False negatives of for the RMI

variants are higher in women with stage 1 tumors compared to women with more

advanced stages (significant p values for all variants). RMI 1 and 3 incorrectly

classified the majority of stage 1 tumors as benign; RMI 2 was the variant that best

classified stage 1 tumors. It is worth noting that all 7 granulosa cell tumors were

stage 1. We analyzed the receiver–operating characteristics curve analysis of RMI

variants for the discrimination of women with malignant tumors from those with

xiii

benign tumors. The pairwise permutation tests comparing the AUC for the curves

revealed marginally significant superiority of RMI4 over RMI2 (p=0.06). All other

pairwise comparisons between the curves returned nonsignificant results.

Conclusions: RMI performed acceptably in a medium-resource setting where

sonographers had moderate expertise and/or were under training. The tradeoff

between performance and feasibility, due to lower ultrasound complexity, favors

RMI over other adnexal mass ultrasound-based triaging models.

Key words: ovarian neoplasia - diagnosis, ultrasound.

xv

SUMÁRIO

RESUMO................................................................................................................ vii

ABSTRACT ............................................................................................................. xi

SUMÁRIO............................................................................................................... xv

DEDICATÓRIA ..................................................................................................... xvii

AGRADECIMENTOS ............................................................................................ xix

SIGLAS E ABREVIATURAS ............................................................................... xxiii

LISTA DE SÍMBOLOS .......................................................................................... xxv

1. INTRODUÇÃO GERAL ..................................................................................... 1

2. OBJETIVOS .................................................................................................... 12

2.1 Objetivo Geral ......................................................................................... 12

2.2 Objetivos Específicos ............................................................................. 12

3. METODOLOGIA ............................................................................................. 13

4. CONCLUSÃO GERAL .................................................................................... 44

5. REFERÊNCIAS .............................................................................................. 45

6. ANEXOS ......................................................................................................... 53

xvii

DEDICATÓRIA

Às mulheres que contribuem para o meu crescimento pessoal e que não me

deixaram desistir de prosseguir meu caminho: Adriana, Sophie e Isa.

Ao meu pai, que sonha um sonho muito maior que o meu. Seu exemplo de caráter

me ensina a enxergar a vida com certezas e objetivos.

Ao meu irmão, que me ajuda a ser uma pessoa melhor.

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AGRADECIMENTOS

À equipe de ultrassonografia do CAISM, que me auxiliou na realização dos

exames e que cedeu o espaço para a coleta dos dados de forma amigável e

desinteressada.

Às pacientes que permitiram a realização dos exames e a coleta do CA125 e que

contribuíram para a realização desta pesquisa sem qualquer interesse

pessoal ou financeiro.

Aos médicos contratados da equipe de ultrassonografia, Rodrigo Jales e Danielle

Luminoso, que me orientaram no diagnóstico ultrassonográfico das pacientes

e estiveram comigo durante toda a coleta dos dados.

Aos funcionários do ambulatório de Ovário do CAISM, que realizaram a coleta do

CA125 das pacientes de forma precisa.

Aos médicos que atenderam as pacientes no ambulatório de Ovário do CAISM de

forma criteriosa e correta.

À equipe de patologia do CAISM, que realizou a análise anatomopatológica de

forma criteriosa e precisa.

À minha orientadora, Sophie Derchain, que de forma irretocável me ensinou tudo o

que aprendi neste projeto, além de estar ao meu lado nos momentos difíceis.

Ao meu co-orientador, Luis Otávio Sarian, que realizou as análises estatísticas e

nos ajudou na realização do artigo, sempre com boa vontade e entusiasmo.

Aos meus amigos, que estiveram do meu lado durante esta etapa importante,

estimulando-me a prosseguir.

À minha família, que me auxiliou a manter-me firme e não desistir dos meus

sonhos.

A Deus, que me deu um dom e sempre esteve ao meu lado neste projeto e em

todos em minha vida.

xxi

Este estudo foi financiado por:

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) processo

número 2012/15059-8.

xxiii

SIGLAS E ABREVIATURAS

AUC – Área Under the Curve

CAISM – Centro de Atenção Integral à Saúde da Mulher

CA125 – Cancer Antigen 125

cm – Centímetro(s)

CI – Confidence Interval

GE – General Electric

GI-RADS – Gynecologic Imaging Report and Data System

IBGE – Instituto Brasileiro de Geografia e Estatística

IOTA – International Ovarian Tumour Analysis

IRM/RMI – Índice de Risco de Malignidade / Risk of Malignancy

Index

LR/ LR2 – Logistic Regression / Logistic Regression 2

M – Menopausa

mm – Milímetro (s)

NPV – Negative Predictive Value

PPV – Positive Predictive Value

ROC – Receiver Operating Characteristic

SA – Subjective assessment

S – Size

SD – Standard Deviation

SR – Simple rules

Unicamp – Universidade Estadual de Campinas

U/ml – Unidade(s)/mililitro(s)

https://www.google.com.br/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved=0CB4QFjAA&url=http%3A%2F%2Fwww.ibge.gov.br%2F&ei=N_xcVMmBIoqfNrW8gMAG&usg=AFQjCNGuNQz2gH-A3LkAod1HaFm3Qo6FTQ&sig2=Y4XiWBu9yZ81KbihsW5x9w&bvm=bv.79184187,d.eXY

xxiv

US – Ultrassom

xxv

LISTA DE SÍMBOLOS

% – Porcentagem

1

1. INTRODUÇÃO GERAL

O câncer de ovário corresponde a 3,6% dos cânceres em geral [1]. Embora

não seja muito frequente, apresenta uma alta proporção de mortes por caso

detectado: em 2012, foram detectados 238.719 novos casos em todo o mundo,

dos quais 151.905 resultaram em mortes [1]. Foram estimados cerca de 5.680

casos novos de câncer de ovário no Brasil em 2014, com um risco estimado de 6

casos a cada 100 mil mulheres. Sem considerar os tumores da pele não

melanoma, o câncer de ovário é o oitavo mais incidente na maioria das regiões

brasileiras. Foram registradas 3.129 mortes pela doença em 2012 no Brasil [2]. A

incidência e mortalidade por câncer de ovário se mantiveram estáveis nas últimas

décadas. Observa-se um pequeno aumento da sobrevida em mulheres com

câncer, provavelmente relacionado à quimioterapia [3]. Devido à alta mortalidade

associada a essa doença, três grandes áreas devem ser priorizadas: esclarecer as

mulheres do risco para câncer de ovário, detectar a doença em estádios mais

iniciais e melhorar a qualidade dos tratamentos [4].

Programas de rastreamento para diferentes tumores, como mama ou colo

uterino, têm impacto significativo na mortalidade e detecção precoce. Porém,

estudos realizados em diferentes países não mostraram impacto significativo na

mortalidade na utilização do rastreamento para câncer de ovário, aumentando

risco de cirurgias desnecessárias e de suas complicações [5].

2

Para detectar o câncer de ovário em estádios iniciais, o exame mais

realizado é o ultrassom. Estima-se que 2,7% a 8% das mulheres apresentarão

cistos ovarianos ou massas anexiais durante a vida. Apesar de não haver dados

nacionais, acredita-se em uma incidência semelhante no Brasil. Assim, tumores

ovarianos são uma entidade comum que afeta mulheres em todas as idades. A

priori, a maioria dos tumores é benigna; na pré-menopausa muitas massas

anexiais são diagnosticadas como cistos funcionais ou neoplasias benignas.

Entretanto, 20% dos cânceres de ovário são detectados na menacme. Embora a

proporção de cânceres de ovário aumente na pós-menopausa [6], cistos

funcionais e tumores benignos ainda correspondem à maioria dos casos [7-10].

Menon et al. (2009) [11], em estudo em que 98.308 mulheres na pós-menopausa

foram randomizadas para realização de rastreamento com coleta de CA125 e

realização de ultrassom transvaginal, observaram que, das 942 mulheres

operadas por tumor anexial, 772 delas tiveram diagnóstico de neoplasia benigna

ovariana, o que corresponde a 80% dos tumores. Massas anexiais benignas

podem ser acompanhadas conservadoramente ou com realização de cirurgias

minimamente invasivas, como a laparoscopia, de menor hospitalização e

reabilitação mais precoce [8-13]. Por outro lado, o diagnóstico correto do câncer

de ovário é importante para garantir acesso a tratamentos adequados, uma vez

que a cirurgia inicial realizada interfere na sobrevida [14]. Nos casos de câncer de

ovário confirmados, o estadiamento cirúrgico é fundamental: avaliação cuidadosa

de todas as superfícies peritoneais, coleta de lavados peritoneais ou de ascite,

omentectomia infracólica, linfadenectomia das cadeias pélvicas e paraaórtica,

biópsia ou ressecção de quaisquer massas, lesão ou aderência suspeita, biópsias

3

aleatórias das superfícies peritoneais, histerectomia total, salpingooforectomia

bilateral e apendicectomia nos tumores mucinosos [15].

Para caracterizar o tumor anexial em benigno ou maligno é preciso utilizar

critérios que podem ser baseados em imagens ou associados a marcadores

tumorais e dados clínicos. Os métodos de diagnóstico de imagem de câncer de

ovário mais utilizados são ultrassonografia associada à ressonância magnética e a

tomografia computadorizada [16]. Porém, o grande número de exames de imagem

a que são submetidas as mulheres com suspeita de câncer de ovário antes da

cirurgia acaba retardando o tratamento, sendo esses exames frequentemente

desnecessários na prática clínica diária. Assim, a ultrassonografia baseada em

aspectos morfológicos das massas anexiais tem uma acurácia suficiente na

diferenciação das neoplasias malignas na maioria dos casos, permanecendo a

ressonância para tumores anexiais indeterminados e a tomografia para

estadiamento dos tumores malignos em casos selecionados [17].

Há várias décadas, pesquisadores têm estudado a criação de escores para

a classificação das massas anexiais a partir de critérios ultrassonográficos.

Gramberg et al. (1990) [18] avaliaram diferentes achados ultrassonográficos como

uni e multilocularidade, com e sem áreas sólidas em seu interior, até tumor sólido.

Sassone et al. (1991) [19] avaliaram a estrutura da parede do cisto e sua

espessura, presença ou ausência de septos e a ecogenicidade alta ou baixa. De

Priest el al. (1993) [20] avaliaram critérios como volume tumoral, estrutura da

parede do cisto, presença de septos, projeção papilar ou área sólida no interior do

cisto. Lerner et al. (1994) [21], por sua vez, incluíram a avaliação da sombra

acústica do cisto na classificação das massas anexiais. Ainda em 1994, Prömpeler

4

et al. [22] utilizaram critérios do Doppler para melhor caracterização das massas

anexiais, avaliando índice de resistência, pulsatilidade e velocidade arterial.

Conforme os critérios morfológicos e de avaliação por Doppler foram se

aprofundando, a análise estatística foi sendo desenvolvida com fórmulas mais

complexas, sendo utilizada a análise multivariada de regressão logística por Tailor

et al. (1997) [23]. As variáveis incluídas nesse estudo foram: idade, diâmetro

máximo do tumor, volume tumoral, presença de unilocularidade, ou de projeção

papilar, diferença na ecogenicidade e critérios do Doppler.

Paralelamente, desde a década de 1980, a dosagem sérica de marcadores

tumorais tem sido utilizada na diferenciação dos tumores anexiais [24]. O mais

utilizado é o CA125, uma glicoproteína localizada na superfície de muitas células

ovarianas cancerígenas [25]. Quando usado sozinho na distinção entre tumores

malignos e benignos em mulheres na menacme, tem uma baixa acurácia [16], já

que muitos fatores como ovulação, menstruação, endometriose, gestação podem

elevar seu nível sérico em mulheres saudáveis. Em mulheres com massa anexial

na pós-menopausa possui maior especificidade na diferenciação de tumores

malignos e benignos. Entretanto, o CA125 é negativo em 50% das neoplasias

restritas ao ovário e é positivo em 1,6% das mulheres menopausadas saudáveis

[24].

Com esses estudos, têm sido propostos vários métodos combinados com

métodos de imagem e utilização de marcadores para avaliação do risco de câncer

de ovário. O índice de risco de malignidade (IRM), escore baseado em achados do

ultrassom transvaginal, níveis do CA125 e menopausa (definida como amenorreia

por mais de um ano ou idade superior a 50 anos em mulheres submetidas à

5

histerectomia), é utilizado há décadas na discriminação dos tumores anexiais em

muitos países [26, 27, 28, 29]. Para calcular o IRM, o ultrassom recebe um escore

baseado nos aspectos morfológicos sugestivos de malignidade (presença de lesão

multilocular cística, áreas sólidas, lesões bilaterais, ascite ou metástase intra-

abdominal): cada aspecto equivale a um ponto no escore; a menopausa recebe

um escore para pré-menopausa e pós-menopausa e o CA125 entra com seu valor

total em U/mL, utilizando-se diferentes fatores de correção. O IRM é calculado

multiplicando os três escores (US x CA125 X menopausa) (quadro 1). No IRM 4, o

parâmetro tamanho do tumor é acrescido à formula (escore 1 se o tumor tiver o

maior diâmetro menor que 7cm e escore 2 se o tumor tiver o maior diâmetro maior

ou igual a 7cm). Embora haja pequenas diferenças na forma de calcular, os 4 IRM

parecem ter um desempenho semelhante na diferenciação pré-operatória das

massas anexiais. Para os IRM 1 a 3, o melhor ponto de corte foi de 200 e para o

IRM 4, de 450 [29,30].

6

Quadro 1: Diferenciação entre os quatro índices de risco de malignidade (IRM) conforme

cada autor [26,27,28,29].

IRM 1 IRM 2 IRM 3 IRM 4

Jacobs et al., 1990 Tingulstad et al., 1996 Tingulstad et al., 1999 Yamamoto et al., 2009

US 0 = 0

US 1 = 1

US >2 = 3

US 0 e 1=1

US >2 = 4

US 0 e 1=1

US >2 = 3

US 0 e 1=1

US >2 = 4

Pré-menopausa= M = 1

Pós-menopausa= M = 3







CA125 U/ml valor

diretamente aplicado na

fórmula

CA125 U/ml valor


fórmula

CA125 U/ml valor


fórmula

CA125 U/ml valor


fórmula

Maior diâmetro do tumor

Até 7 cm = S = 1

>7 cm = S = 2

Geomini et al. (2009) [31] avaliaram a acurácia de diferentes modelos de

diferenciação das massas anexiais em uma revisão sistemática. Foram incluídos

109 estudos na análise final, com 83 diferentes modelos de predição de

malignidade, somando-se 21.750 massas anexiais, sendo 15.490 benignas, 5.826

malignas e 434 borderlines. Eles verificaram uma sensibilidade global de 78% e

uma especificidade de 87% para o IRM em um valor de corte de 200 e concluíram

que os IRM 1 e 2 foram os melhores preditores de malignidade na discriminação

7

dos tumores anexiais. Podem ser utilizados como escolha na prática diária pela

sua simplicidade combinada a uma boa acurácia.

Por outro lado, nos modelos descritos acima, a utilização da dosagem

sérica do CA125 é um fator preponderante para avaliação dos tumores anexiais.

Por isso, alguns autores têm tentado identificar critérios ultrassonográficos que

melhor discriminem o câncer de ovário [32]. Timmerman et al. (2000) [33] e

Timmerman et al. (2008) [34] apresentaram os resultados de um grande estudo, o

International Ovarian Tumor Analysis (IOTA), que se utiliza de aspectos

ultrassonográficos e a idade da paciente. Estabeleceram um novo paradigma,

segundo o qual mais de 80% dos tumores anexiais poderiam ser adequadamente

classificados em benignos ou malignos, baseando-se em dez regras simples. Eles

se utilizam de cinco critérios baseados na imagem do ultrassom transvaginal para

definir um tumor como maligno (tumor sólido irregular, ascite, pelo menos quatro

estruturas papilares, tumor sólido irregular multilocular com um diâmetro maior que

100mm e alto teor de cor no exame Doppler colorido) e cinco para definir como

benigno (cisto uniloculado, a presença de componentes sólidos para o qual a

maior componente sólido é menor que 7mm de diâmetro, sombras acústicas,

tumor liso multilocular e não haver fluxo de sangue detectável no exame Doppler).

A presença de uma ou mais características malignas classifica o tumor como

maligno. Da mesma forma, a presença de uma ou mais características benignas

classifica o tumor como benigno. Porém, em cerca de 20% dos tumores não se

consegue identificar apenas critérios malignos ou benignos, devendo-se nesses

casos recorrer à experiência do ultrassonografista que irá classificar os tumores

segundo uma avaliação subjetiva [33-35].

8

Amor et al. (2011) [36] realizaram um estudo prospectivo multicêntrico

incluindo 432 massas anexiais em 372 mulheres. O objetivo desse estudo foi

aplicar na prática clínica diária um sistema de classificação baseado em achados

ultrassonográficos para homogeneizar o léxico e facilitar a comunicação entre os

ultrassonografistas, o Gynecologic Imaging Report and Data System (GI-RADS).

Ele utilizou como parâmetros os achados ultrassonográficos preditivos de

malignidade (ascite, áreas sólidas, septos grossos e projeções papilares) para

classificar as massas anexiais desde as definitivamente benignas (GI-RADS 1 –

probabilidade de malignidade de 0%) até muito provavelmente malignas (GI-RADS

5 – probabilidade de malignidade > 20%). Essa classificação auxilia na referencia

das pacientes com massas anexiais, desde o tratamento conservador para as

massas classificadas como GI-RADS 1 até o encaminhamento ao oncologista

ginecológico para as classificadas como GI-RADS 4 ou 5. Nesse estudo,

observou-se sensibilidade de 99,1% (95% IC, 95,1%–99,8%), especificidade de

85,9% (95% IC, 81,7%–89,3%) para a classificação das massas anexiais com alto

risco de malignidade, apresentando bom desempenho e podendo ser utilizado na

prática clínica diária. A crítica em relação a esse modelo de classificação é em se

basear também no léxico do IOTA e da complementação diagnóstica por

ultrassonografistas experientes, que utilizaram-se da avaliação subjetiva e de

padrão de reconhecimento para elucidação diagnóstica.

Em 2012 analisamos os critérios do IOTA em mulheres brasileiras com

massa anexiais. O estudo foi realizado com 103 mulheres portadoras de 110

tumores anexiais, sendo 31 malignos e 79 benignos. Dentre esses casos, os

critérios estabelecidos por Timmerman et al. (2010) [35] foram aplicáveis a

9

91(82%) tumores, com uma especificidade de 87% e uma sensibilidade de 90%.

Entretanto, 19 (18%) não foram classificáveis pelas regras simples [37]. Na prática

clínica diária nem sempre está disponível um ultrassonografista experiente, que foi

definido por Timmerman et al. (1999) [38] como o profissional com pelo menos

5.000 exames de ovário realizados no período de oito anos. Os autores do IOTA

procuraram então identificar outros modelos que não as regras simples para

serem utilizados por profissionais menos experientes. Após a validação interna de

11 modelos matemáticos, os pesquisadores concluíram que todos apresentam

resultados similares para discriminação das massas anexiais [39]. Entre os

diferentes modelos matemáticos, os modelos de regressão logística (LR) 1 e 2

foram amplamente utilizados e validados. Estão incluídos na avaliação critérios

objetivos como idade da paciente (em anos), presença de ascite, presença de

fluxo de sangue no interior da projeção papilar, máximo diâmetro do componente

sólido (em milímetros, até 50 mm), irregularidade no interior da parede do cisto, a

presença de sombra acústica, história pessoal de câncer de ovário, uso atual de

terapia hormonal, maior diâmetro da lesão em mm, presença ou ausência de dor

ao exame, presença de tumoração sólida e o escore de índice de cor (de 1 a 4).

Comparado o desempenho dos dois modelos (o LR1 com doze variáveis e o LR2

contendo as seis primeiras variáveis) observou-se que ambos apresentam

resultados similares, sendo o LR2 mais facilmente utilizável [39-41]. Com um valor

de LR2 > 10%, os tumores são classificados como de alto risco para doença

maligna [42,43]. Entretanto, a utilização desses modelos exige um conhecimento

adequado do léxico do IOTA.

10

Vários estudos sugerem que o IRM é um método mais facilmente utilizável

que o LR2, já que o IRM pode ser calculado sem o auxílio de um computador e

com achados morfológicos ultrassonográficos simples e validados, com alta

acurácia [44, 45]. Recentemente, Aktürk et al (2011) [30] avaliaram a performance

dos diferentes IRM (1,2,3 e 4) em 100 mulheres operadas por tumores anexais, e

chegaram à conclusão que todos os índices podem ser utilizados como preditor de

malignidade, sendo um método simples em sua realização e de alta acurácia. Van

der Akker et al. (2011) [44] validaram o IRM4 em comparação ao IRM3 na

discriminação das massas anexiais em estudo com 643 pacientes apresentando

469 tumores benignos, 101 tumores malignos e 73 tumores borderlines;

concluíram que o IRM3 apresenta melhor acurácia quando comparado ao IRM4. O

IRM3 teve sensibilidade de 76%, especificidade de 82% e acurácia de 81%

enquanto o IRM4 apresentou sensibilidade de 74%, especificidade de 79% e

acurácia de 78%. Ainda em 2011, Hakansson et al. [46] apresentaram um estudo

avaliando a performance do IRM3 na discriminação de 778 mulheres

diagnosticadas com tumor anexial. Em um ponto de corte de 200, o RMI3

apresentou sensibilidade de 92% e especificidade de 82% e valor preditivo

positivo e negativo de 62% e 97%, respectivamente. Em 2014, Abdulrahman et al.

[45] avaliaram o desempenho dos IRM 1, 2 e 3 na discriminação das massas

anexiais em 247 mulheres com diagnóstico de massa anexial e concluíram que os

RMI1 e 2 foram melhores preditores de malignidade que o IRM3 (utilizando-se o

ponto de corte de 200, o IRM1 apresentou sensibilidade de 66% e especificidade

de 91%, o IRM2 apresentou teve sensibilidade de 74% e especificidade de 79%

enquanto o IRM3 apresentou sensibilidade de 68% e especificidade de 85%).

11

Todos esses estudos concluíram que o IRM é um método simples de ser utilizado,

amplamente validado e de boa acurácia para discriminação das massas anexiais.

Vários estudos validaram o IRM em muitos países com bons resultados;

porém, não foram encontrams na literatura (Pubmed e Scielo) estudos que

avaliassem a acurácia dos IRMs no Brasil. Em serviços nacionais de atenção

primária é possível realizar ultrassonografia e dosagem sérica do marcador CA125

em mulheres com massas anexiais. Na atenção secundária, mulheres com

tumores anexiais benignos podem ser adequadamente tratadas, enquanto

mulheres com câncer de ovário se beneficiariam com encaminhamento e

tratamento em unidades de atenção terciária. Assim, comparar os diferentes IRMs

em mulheres brasileiras poderá trazer benefícios importantes na validação desses

métodos para a estruturação da atenção à saúde e melhoria no diagnóstico em

mulheres com massas anexiais.

12

2. OBJETIVOS

2.1 Objetivo Geral

Comparar o desempenho dos diferentes índices de risco de malignidade

(IRM) em mulheres na pré e pós-menopausa com massas anexiais submetidas à

cirurgia.

2.2 Objetivos Específicos

Avaliar a distribuição das mulheres com massa anexial segundo o

diagnóstico histológico, a idade, estado menopausal, antecedente familiar de

câncer de mama e ovário, a concentração sérica de CA125, o escore de

ultrassom e o tamanho do tumor.

Avaliar o desempenho dos diferentes IRM em mulheres com massas

anexiais na pré e na pós-menopausa segundo o ponto de corte definido pela

curva ROC.

Avaliar o desempenho dos diferentes IRM nos pontos de corte

estabelecidos pela literatura.

Avaliar a proporção de falsos positivos e falsos negativos segundo o tipo

histológico e o estádio.

13

3. METODOLOGIA

Performance of Risk of Malignancy Index (RMI) at discriminating malignant tumors in

women with adnexal masses in an ultrasound training center.

Camila Campos, MD(a)

Luis Otávio Sarian, MD, PhD(b)

Rodrigo Jales, MD, PhD(c)

Caio Hartman, MD(a)

Karla Araujo, MD(a)

Denise Pitta, Biologist(d)

Adriana Yoshida, MD(a)

Liliana Andrade, MD, PhD(e)

Sophie Derchain, MD, PhD(b)

Post Graduating Program in Tocogynecology(a), Department of Obstetrics and Gynecology

of the Faculty of Medical Sciences (b), Section of Ultrasonography, Prof. Dr. Jose

Aristodemo Pinotti Women’s Hospital, CAISM(c), Special Procedures Laboratory, Prof. Dr.

Jose Aristodemo Pinotti Women’s Hospital, CAISM (d), Department of Pathology(e),

Faculty of Medical Sciences, State University of Campinas – Unicamp, Campinas, São

Paulo, Brazil.

Correspondence to: Dr S. Derchain, Department of Obstetrics and Gynecology, Faculty of

Medical Sciences, PO Box 6111 State University of Campinas – UNICAMP, Zip Code

13083-970, Campinas, SP, Brazil (e-mail: [email protected]).

Short running title: risk of malignancy index in Brazilian women with adnexal mass

Type of article: original research

mailto:[email protected]).mailto:[email protected]).

14

Carta de submissão

Manuscript 15-01068 Version 1 Performance of Risk of Malignancy Index (RMI) at

discriminating malignant tumors in women with adnexal masses in an ultrasound

training center.

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malignant tumors in women with adnexal masses in an ultrasound training center.,"

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16

Abstract

Objective: We examined the performance of four RMI variants (RMI 1 to 4) in a middle-

resources gynecologic cancer center, with ultrasound performed by personnel under a

training program. Methods: 158 women referred due to an adnexal mass were evaluated

before surgery using the four RMI variants. Ultrasound was performed by sonographers

with variable expertise levels and enduring a training program. We compared the

performance of the four RMI variants using receiver operator curve (ROC) analyses

followed by the calculation of sensitivity, specificity, positive and negative likelihood ratios

(LR+, LR-) using as gold standard the pathology of the adnexal mass. Results: Among the

158 women with adnexal masses included in this study, 51 (32%) had malignant tumors, 26

(51%) of them, stage I. All RMI variants performed similarly (accuracy ranging 74-83%),

regardless of menopausal status. Considering all women included, the LR+ of the four RMI

range from 3.52 to 4.41. In subset analyses, all RMI variants had decreased sensitivity for

stage 1 malignant tumors and for those with non-epithelial histology. Conclusions: The

four RMI performed acceptably in a medium-resource setting where sonographers had

moderate expertise and/or were under training. This is due to the good tradeoff between

performance and feasibility, since RMI ultrasound protocols are of low complexity.

Key words: ovarian tumor, malignancy, diagnostic, ultrasonography, CA125,

17

Introduction

There is no current strategy for ovarian cancer screening [1, 2], and it has been

demonstrated that women want some type of exam that could allow for early detection of

the disease [3]. Ultrasound is a widely available exam, and with it approximately 2.7% to

8% of women will be diagnosed with an adnexal mass at some point in life [4, 5, 6]. As a

result, one in ten women are still being operated for an adnexal mass in life, and devising

strategies for better selecting women who will derive a benefit from a surgical approach –

which must be relatively inexpensive and simple enough to promote widespread acceptance

by the medical community - is necessary [7, 8]. This is especially true in medium income

countries such as Brazil, where the demographics are now close to that of developed

countries but human and economic resources are still scarce. Approximately 5.680 ovarian

cancers are expected in Brazil in 2014, with an estimated risk of 6 cases/100,000 women

[9]. In excess of 3,000 deaths due to the disease were recorded in Brazil during 2012 [9].

In the last 30 years, several models including tumor makers and ultrasound (US)

descriptors and scores have been made in the field of better characterizing adnexal masses,

i.e. discriminating clinically relevant adnexal tumors from the vast majority of benign

masses. All these prediction models are currently undergoing testing as potential tools for

discerning the 20% to 35% of adnexal masses that are malignant ovarian tumors [10-15]

Since 1990, several mathematical models or scoring systems have been developed

to be used for discrimination between benign and malignant adnexal masses [12, 15-21].

Encouraging results were obtained with the Risk of Malignancy Index (RMI), which was

first developed in 1990 and received subsequent adjustments during the last twenty years

[11, 16-18, 22-24], and with a variety of models developed by the International Ovarian

18

Tumour Analysis’ (IOTA), notably the simple rules (SR), subjective assessment (SA) and

the logistic regression model (LR2) [15, 25]. IOTA studies suggested that SA, LR2, and SR

may perform better than RMI [15, 26, 27] in premenopausal women. In a previous study,

based in the IOTA results [28], we tested the SR in 103 women, and obtained a sensitivity

of 90%, specificity of 87%, positive predictive value (PPV) of 69% and negative predictive

value (NPV) of 97% [29]. However, 17.3% of the women had adnexal tumors not

classifiable by the SR, which prompted the need for an experienced sonographer, a

professional not widely available in our country. On the other hand, the RMI is a scoring

system that is derived from a formula that combines menopausal status with serum CA125

and US variables of low complexity [11, 16-18, 22, 30, 31]. Because US variables used in

RMI are much simpler than those used in IOTA models, and because RMI includes easily

obtainable laboratorial data (CA125 levels), it is sensible to infer that these models are

better suited for medium income settings.

In this study, we examine whether the outstanding results obtained and reported by

RMI creators are reproducible in a different set of pre- and postmenopausal Brazilian

women with adnexal masses and who underwent a surgical intervention due to these

masses. We also examined the factors associated with RMI failure at diagnosing malignant

tumors and at ruling out malignancy, such as tumor histological type and stage.

19

Subjects and methods

Patient selection

This is an analysis of prospectively collected data on 158 non-consecutive women

subjected to surgery due to an adnexal mass. Women had been referred to the gynecologic

oncology clinics of Campinas State University, Brazil, due to an adnexal mass detected

through sonography or clinical examination from January 2010 through January 2014.

At the first visit, women were informed that surgery had to be performed to treat her

adnexal mass. After the initial interview, including an explanation about the study’s

research methods and purpose, all women gave written informed consent to participate. An

ultrasound evaluation was scheduled and peripheral blood was collected for serum

measurements of the CA125 tumor marker. Patients underwent surgical intervention and

the pathologic specimens were sent for histopathological analysis. The study was approved

by the faculty’s research ethics committee under number 008/2010.

Ultrasound examination

Ultrasound evaluations were performed in the Ultrasound Technical Section of

UNICAMP, using one of the ultrasound machines available in the section: Accuvix V10

(Medison Corporation Ltd, Seoul, South Korea), Nemio XG (Toshiba Corporation, Tokyo,

Japan) and Voluson Expert 730 (GE Healthcare Ultrasound, Milwaukee, WI, USA), all

equipped with convex, endovaginal, broadband and high-resolution multifrequency

transducers, and all with amplitude spectral Doppler capability. The evaluation was

performed by physicians with variable expertise levels at assessing adnexal masses. For the

present study, the same physician performed and evaluated the ultrasound for each case.

The US scores were evaluated by that physician prospectively. All performing

20

sonographers were in a training program in gynecologic sonography for at least two years,

and all exams were performed under the supervision of a senior staff member, with a

minimum expertise of 5.000 exams. Ultrasound evaluation was performed with the woman

in a supine position. Initially we used a trans-abdominal approach, with the woman’s

bladder full; she was then asked to empty her bladder, and we performed a supplementary

transvaginal examination. Adnexal masses were described according to origin

(ovarian/extraovarian); position (right/left/bilateral); number of lesions; type of lesions

(unilocular/unilocularsolid/ multilocular/multilocular-solid), size in three dimensions

(longitudinal, anteroposterior and transverse diameters); volume (calculated electronically

by the ultrasound device which multiplicates the longitudinal, anteroposterior and

transversal diameters by the constant 0.52); presence and size of the largest solid

component (three diameters); presence and measurement of fluid volume in the posterior

cul-de-sac; and presence and location of lesions suggestive of metastases. Patients

presenting with at least one adnexal mass were eligible for inclusion in the study and when

there are more than one mass, the mass with the most complex morphology or, in cases of

similar morphology, the largest one, was considered, for statistical analyses as suggested by

Sayasneh et al. (2013) [32]. More than one adnexal mass was detected in 20 women.

21

Risk of Malignancy Index variants

The RMI is a scoring system that is derived from a formula that combines

menopausal status with serum CA125 and ultrasound variables. An ultrasound (US) score

is assigned for the following features suggestive of malignancy: the presence of

multilocular cystic lesion, solid areas, bilateral lesion, ascites, and intra-abdominal

metastasis. The presence of each of the previous parameters adds one point to the US score.

Based on the data obtained, four variants of the RMI (RMI 1, 2, 3 and 4) were calculated

for pre and post-menopausal women according to the original criteria and following

Yamamoto et al. (2009) [22] and Akturk et al (2011) [23]. In brief, all RMI variants are

based on the multiplication of a ultrasound score (U; see details below) by an arbitrary

value given to menopausal status (M; see details below) by the CA125 levels. For RMI 4,

tumor size is added. The following parameters were used for the calculations of each RMI

variant: RMI 1 (Jacobs et al. 1990) [16]= U × M × CA125 (ultrasound score: 0 made U=0;

a score of 1 made U=1; a score of ≥2 made U=3); premenopausal status made M=1 and

postmenopausal M=3. RMI 2 (Tingulstad et al. 1996) [17]= U × M × CA125, where a total

ultrasound score of 0 or 1 made U=1, and a score of ≥2 made U=4; premenopausal status

made M=1 and postmenopausal M=4. RMI 3 (Tingulstad et al. 1999) [18]= U × M ×

CA125, where a total ultrasound score of 0 or 1 made U=1, and a score of ≥2 made U=3;

premenopausal status made M=1 and postmenopausal M=3. RMI 4 (Yamamoto et al. 2009,

Akturk et al., 2011) [22, 23] = U × M × S × CA125, where a total ultrasound score of 0 or 1

made U=1, and a score of ≥2 made U=4. Premenopausal status made M=1 and

postmenopausal status made M=4. A tumor size (single greatest diameter) of

22

CA125 measurement

Roche Automated analysis of CA125 was performed by electrochemiluminescence

using the Cobas e411 test (Roche Diagnostics GmbH, Mannheim, Germany) according to

the manufacturer’s instructions and using their reagents and equipment. Values were

expressed in units per milliliter (U/mL). Post-menopausal status was defined as more than

one year of amenorrhea or age greater than 50 years in women who undergone

hysterectomy.

Surgery and pathology analysis

Surgery for diagnosis and/or treatment was performed at our institution, and the

techniques and surgical procedures were chosen and performed according to medical

indication. The mean time elapsed between ultrasound examination and surgery was 73

days, ranging from 24h or less for emergency procedures to a maximum of 119 days. The

gold standard was the histopathologic diagnosis of surgical specimens, all performed in the

Department of Pathologic Anatomy of the UNICAMP School of Medicine, following the

guidelines of the World Health Organization International Classification of Ovarian Tumors

(McCluggage, 2011) [33]. For statistical purposes, borderline tumors were classified as

malignant. Malignant ovarian tumors were staged according to the FIGO staging system

2013 [34].

Statistical analyses

All statistical calculations were performed using the R Environment [35] for data

analyses. 95% confidence levels were used throughout and a p-value of less than .05 was

considered significant. We first compared the proportion of the main clinical and

23

pathological features according to the pathological status (malignant versus benign) of their

tumors using chi-squares for categorical data and the Kruskal-Wallis test for continuous

data. Next, we calculated the performance of the RMI variants for the detection of

malignant tumors using standard Receiver Operating Characteristics Curves. We then

pairwise-compared the areas under the curves (AUC) for the RMI variations using the

Venkatraman´s Projection-Permutation test. Next, we calculated performance indicators

(sensitivity, specificity and positive and negative likelihood ratios (LR+, LR-, respectivelly)

) using the cutoff values determined by ROC analyses. Then, we recalculated the

performance indicators at recommended cutoff points (for RMI 1 to 3 = 200 and for RMI 4

= 450; Yamamoto et al., 2009, Akturk et al., 2011) [22, 23].

Results

Table 1 lists the key clinical and pathological features of the women. The

prevalence of malignant tumor was 32%. Patients with malignant tumors were significantly

more aged than their counterparts with benign adnexal masses (mean age 45.9+15.0 years

versus 55.7+16.2; p7cm in diameter than women with benign masses.

In Table 2 we compare the performance of the RMI variants using the optimal

cutoff points as determined with ROC analyses. In the general population (pre and

postmenopausal women), RMI variants yielded similar performance indicators. In the

subset of premenopausal women, the best sensitivity was obtained with RMI 2 (90%;

24

95%CI 83-97%) and RMI4 (89%; 95%CI 81-97%). Specificity for the RMI variants did not

differ significantly. Similar performance was obtained for the RMI variants in pre and post-

menopausal women. The four RMI had similar LR+ ranging from 2.92 to 5.68.

Table 3 shows the performance indicators of RMI variants at progressive cutoff

points in the general (pre- and postmenopausal) population. The standard (literature

recommended) cutoff points for RMI 1 to 3 is 200 and for RMI 4 is 450. At these

recommend cutoff points, the sensitivity of the different IRM 1vary from 68% to 78% and

specificity vary from 82% to 87%. In this recommended cut off point, the LR+ was 4.0 for

all RMI variants.

Table 4 shows how RMI variants classified benign, borderline and malignant

ovarian tumors at recommended cutoff points. Values above reference correspond to false

positives for benign tumors true positives for borderline and malignant tumors. The worst

correspondence between RMI values and final pathology was obtained for borderline

tumors, which were incorrectly classified in 50% of the cases using RMI 1 and 3 and 37%

of the cases using RMI 2 and 4. Similar proportions of correctly and incorrectly classified

benign and malignant tumors were obtained with the four RMI variants.

Table 5 shows how the RMI variants classified non-epithelial and epithelial

malignant tumors. Clearly, RMI classified epithelial tumors much better than it did with

non-epithelial tumors.

Table 6 shows diagnostic failures (false positives and negatives) of RMI variants at

recommended cutoff points, according to tumor histology. IRM1 and 3 and IRM 2 and 4

showed similar false positive and false negative results. The false negative rate was higher

for stromal tumors: 5/7 granulosa cell tumors were incorrectly classified as benign by the

25

four IRM variants. As shown in Table 4, borderline tumors were also incorrectly classified

as benign in 37-50% of the cases depending on the RMI variant used.

Table 7 shows that false negatives of for the RMI variants are higher in women with

stage 1 tumors compared to women with more advanced stages (significant p values for all

variants). RMI 1 and 3 incorrectly classified the majority of stage 1 tumors as benign; RMI

2 was the variant that best classified stage 1 tumors. It is worth noting that all 7 granulosa

cell tumors were stage 1.

In figure 1 we show the receiver–operating characteristics curve analysis of RMI

variants for the discrimination of women with malignant tumors from those with benign

tumors. All pairwise comparisons between the curves returned nonsignificant results.

Discussion

Our study confirms that RMI is a valuable tool in medium resource settings such as

the typical Brazilian healthcare system. In this sample of women with adnexal masses, all

RMI variants performed similarly (accuracy ranging 74-83%), regardless of menopausal

status. At the standard cutoff points, the sensitivity and specificity of all RMI variants were

very good, with LR+ in excess of 4.0 for all variants. It is important to notice, however, that

RMI variants had decreased sensitivity for stage 1 malignant tumors and in women with

non-epithelial tumors.

In the scarce resource environment where this study has been developed, highly

trained sonographers are scarce, although the epidemiology concerning adnexal tumors is

rapidly matching that of developed regions of the globe [36]. According to our data, all

RMI variants proved sufficiently sensitive and specific at diagnosing malignancy for both

pre and postmenopausal women.

26

In our study, the AUC observed for the RMI 1 to 4 was 0.85, albeit RMI 4 AUC

was slightly higher than that of RMI 2. Van den Akker et al. (2011) [37] compared the RMI

3 and RMI 4 and both proved to be capable of discriminating benign and malignant adnexal

lesions with similar performances, both with AUC of 0.86. In the same year, Akturk et al.

(2011) [23] repeated the performance RMI4, but found no significant differences between

the four different malignancy risk indices. It is worth noting that our ROC analyses showed

that optimal cutoff points for premenopausal women are substantially lower than those

preconized for the general population. At the standard cut off levels, our results closely

reproduced, in a population with a diverse epidemiologic background, those described by

Geomini et al. (2009) [11] in a systematic review evaluating the accuracy of risk scores,

when 200 was used as the cutoff level. In that analysis, the pooled estimates for sensitivity

was 78% and 87% for specificity.

Better triaging tools and protocols can assist the referral process of women with

adnexal masses to healthcare facilities with the necessary capabilities and guarantee

potential surgical failures\ and/or unnecessary overload of oncology centers with women

harboring benign conditions (Miller and Ueland, 2012) [38]. We detected only minimal

performance variability between the four RMI variants in this analysis on a relatively

homogeneous set of women with adnexal masses, who were treated at a single institution

and thus subject to similar treatment protocols. RMI 4 was slightly superior to RMI 2, but

only by a very non-significant small margin. These findings are in accordance with

Yamamoto at al. (2009) [22], who demonstrated that RMI4 was better than RMI1, RMI2

and RMI3, using a cutoff value of 450 for RMI 4 and 200 for the other variants. They

observed that the sensitivity, specificity, positive predictive value, negative predictive value

of RMI4 were respectively 86%, 91%, 63% and 97.5%. We obtained a sensitivity of 83%,

27

specificity of 81%, positive predictive value of 84% and 60% negative predictive values

using RMI4.

In our study, of the 51 malignant tumors, 31 were of epithelial origin, 8 were

borderline ovarian tumors and 8 were germ cell or stromal tumors. Meray at al (2010) [39]

demonstrated that RMI1 is not adequate for the detection of malignancy in a population

with high prevalence of borderline or non-epithelial tumors. In a population with 30% of

non-epithelial tumors, the sensitivity, specificity and positive and negative predictive values

were 60%, 88%, 57.1 and 89,9%, respectively. When these non-epithelial tumors are

excluded from the performance analyses, these indicators change to 76.9%, 88.7%, 52.6%

and 95.9%, respectively.

With standard cutoff points, sensitivity of all RMI variants may be severely

compromised in premenopausal women harboring stage 1 disease, stromal tumors or even

both. Van Gorp et al. (2012) [40] obtained 76% sensitivity and 92.4% specificity in the

general population, but sensitivity decreased to 64.1% in premenopausal women. Similar

findings were reported by authors using IOTA models, in a study that included 18

specialized centers in six different countries [15]: the sensitivity in the general population

was 67.1%(95%CI 61.4 to 72.4) and the specificity was 90.6% (95%CI 76.7 to 79.7);

however, in the subset of premenopausal women, the sensitivity decreased to 53% (95%CI

46 to 61).

Our study is flawed by a relatively small sample size and by not discriminating the

sonographers that performed the study exams according to their level of expertise. On the

other hand, this is a single institution trial, with a relatively high percentage of stage 1

malignant tumors. As mentioned above, this particular group of patients poses a challenge

to triaging methods, and our study corroborates that IRM may be not as good at diagnosing

28

early stage disease and non-epithelial ovarian tumors as originally thought. Our conclusions

would be weakened due to the small sample size of the non-epithelial tumors. For RMI

purposes, an ultrasound score is assigned considering the following features suggestive of

malignancy: the presence of multilocular cystic lesion, solid areas, bilateral lesion, ascites,

intra-abdominal metastasis. Sharma and colleagues investigated 48,053 asymptomatic

women who underwent ultrasound examination, 4,367 of whom (9.1% (95% CI, 8.8-9.3%))

had abnormal adnexal morphology. The strongest association between ovarian morphology

and epithelial ovarian cancer was the presence of ‘solid’ elements. The relative risk of

epithelial ovarian cancer within 3 years of the scan in women with solid elements compared

to unilocular or multilocular cysts was increased 11.5 (95% CI, 5.9–22.5)-fold [41].

The relative simplicity of the ultrasound parameters used to render RMI is a strong

advantage. Importantly, RMI includes CA125 levels in its formulae, and CA125

determination is a standardized, easily reproducible, and relatively cheap procedure

available even in low resource settings. These features obviate the need for highly

specialized sonographers; our study clearly confirms that RMI may yield acceptable

performance even when ultrasound is done by sonographers under training, which was the

case in our center. RMI still misses early stage and borderline tumors, as well as non-

epithelial neoplasms. In conclusion, discriminating women with ovarian malignancies

among those with adnexal masses may be difficult in medium resource settings due to

limitations in ultrasound accuracy and availability of specialized personnel. In our study,

we found that the four RMI performed acceptably in a medium-resource setting where

sonographers had moderate expertise and/or were under training. This is due to the good

tradeoff between performance and feasibility, since RMI ultrasound protocols are of low

complexity.

29

Acknowledgement: This study was partially financed by the Research Support

Foundation of the State of São Paulo – Fapesp: number 2012/15059-8. The authors also

thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for

financial support.

30

References

1. Moyer VA; U.S. Preventive Services Task Force. Screening for ovarian cancer:

U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann

Intern Med. 2012 Dec 18;157(12):900-4.

2. Menon U, Griffin M, Gentry-Maharaj A. Ovarian cancer screening--current status,

future directions. Gynecol Oncol. 2014 Feb; 132(2):490-5.

3. Pavlik EJ, van Nagell JR Jr. Ovarian cancer screening--what women want. Int J

Gynecol Cancer. 2012 May;22 Suppl 1:S21-3.

4. Kobayashi H, Yamada Y, Sado T, et al. A randomized study of screening for

ovarian cancer: a multicenter study in Japan. Int J Gynecol Cancer. 2008 May-

Jun;18(3):414-20

5. Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of

multimodal and ultrasound screening for ovarian cancer, and stage distribution of

detected cancers: results of the prevalence screen of the UK Collaborative Trial of

Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009 Apr; 10(4):327-40.

6. Buys SS, Partridge E, Black A, et al. PLCO Project Team. Effect of screening on

ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO)

Cancer Screening Randomized Controlled Trial. JAMA. 2011 Jun 8;305(22):2295-

303

7. Amonkar SD, Bertenshaw GP, Chen TH, et al. Development and preliminary

evaluation of a multivariate index assay for ovarian cancer. PLoS One.

2009;4(2):e4599

http://www.ncbi.nlm.nih.gov/pubmed/22964825http://www.ncbi.nlm.nih.gov/pubmed/22964825http://www.ncbi.nlm.nih.gov/pubmed/24316306http://www.ncbi.nlm.nih.gov/pubmed/24316306http://www.ncbi.nlm.nih.gov/pubmed/22543915http://www.ncbi.nlm.nih.gov/pubmed/17645503http://www.ncbi.nlm.nih.gov/pubmed/17645503http://www.ncbi.nlm.nih.gov/pubmed?term=Menon%20U%5BAuthor%5D&cauthor=true&cauthor_uid=19282241http://www.ncbi.nlm.nih.gov/pubmed?term=Gentry-Maharaj%20A%5BAuthor%5D&cauthor=true&cauthor_uid=19282241http://www.ncbi.nlm.nih.gov/pubmed?term=Hallett%20R%5BAuthor%5D&cauthor=true&cauthor_uid=19282241http://www.ncbi.nlm.nih.gov/pubmed/19282241http://www.ncbi.nlm.nih.gov/pubmed/21642681http://www.ncbi.nlm.nih.gov/pubmed/21642681http://www.ncbi.nlm.nih.gov/pubmed/21642681http://www.ncbi.nlm.nih.gov/pubmed/19240799http://www.ncbi.nlm.nih.gov/pubmed/19240799

31

8. French College of Gynecologists and Obstetricians. [Recommendations for clinical

practice: Presumed benign ovarian tumors]. J (Gynecol Obstet Biol Reprod (Paris).

2013 Dec;42(8):856-66.

9. INCA 2014. [assessed in August 15th, 2014]

http://www.inca.gov.br/estimativa/2014/

10. Huchon C, Bats AS, Bensaïd C, et al. [adnexal masses management: a prospective

multicentric observational study]. Gynecol Obstet Fertil. 2008 Nov;36(11):1084-90

11. Geomini P, Kruitwagen R, Bremer GL, Cnossen J, Mol BW. The accuracy of risk

scores in predicting ovarian malignancy: a systematic review. Obstet Gynecol. 2009

Feb;113(2 Pt 1):384-94.

12. Terzic M, Dotlic J, Brndusic N, et al. Histopathological diagnoses of adnexal

masses: which parameters are relevant in preoperative assessment? Ginekol

Pol. 2013 Aug;84(8):700-8.

13. Kaijser J, Sayasneh A, Van Hoorde K, et al. Presurgical diagnosis of adnexal

tumours using mathematical models and scoring system: a systematic review and

met-analysis. Hum Reprod Update. 2014a May-Jun;20(3):449-62.

14. Kaijser J, Van Belle V, Van Gorp T, et al. Prognostic Value of Serum HE4 Levels

and Risk of Ovarian Malignancy Algorithm Scores at the Time of Ovarian Cancer

Diagnosis. Int J Gynecol Cancer. 2014b Sep;24(7):1173-80.

15. Testa A, Kaijser J, Wynants L, et al. Strategies to diagnose ovarian cancer: new

evidence from phase 3 of the multicentre international IOTA study. Br J Cancer.

2014 Aug 12;111(4):680-8

http://www.ncbi.nlm.nih.gov/pubmed?term=French%20College%20of%20Gynecologists%20and%20Obstetricians%5BCorporate%20Author%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/24210710http://www.inca.gov.br/estimativa/2014/http://www.ncbi.nlm.nih.gov/pubmed/19155910http://www.ncbi.nlm.nih.gov/pubmed/19155910http://www.ncbi.nlm.nih.gov/pubmed?term=Terzic%20M%5BAuthor%5D&cauthor=true&cauthor_uid=24191504http://www.ncbi.nlm.nih.gov/pubmed?term=Dotlic%20J%5BAuthor%5D&cauthor=true&cauthor_uid=24191504http://www.ncbi.nlm.nih.gov/pubmed?term=Brndusic%20N%5BAuthor%5D&cauthor=true&cauthor_uid=24191504http://www.ncbi.nlm.nih.gov/pubmed/24191504http://www.ncbi.nlm.nih.gov/pubmed/24191504http://www.ncbi.nlm.nih.gov/pubmed?term=Kaijser%20J%5BAuthor%5D&cauthor=true&cauthor_uid=24327552http://www.ncbi.nlm.nih.gov/pubmed?term=Sayasneh%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24327552http://www.ncbi.nlm.nih.gov/pubmed?term=Van%20Hoorde%20K%5BAuthor%5D&cauthor=true&cauthor_uid=24327552http://www.ncbi.nlm.nih.gov/pubmed/?term=Presurgical+diagnosis+of+adnexal+tumours+using+mathematical+models+and+scoring+systems%3A+a+systematic+review+and+meta-analysishttp://www.ncbi.nlm.nih.gov/pubmed/24987915http://www.ncbi.nlm.nih.gov/pubmed/24987915http://www.ncbi.nlm.nih.gov/pubmed/24987915http://www.ncbi.nlm.nih.gov/pubmed/24937676http://www.ncbi.nlm.nih.gov/pubmed/24937676

32

16. Jacobs I, Oram D, Fairbanks J, Turner J, Frost C, Grudzinskas JG. A risk of

malignancy index incorporating CA 125, ultrasound and menopausal status for the

accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol. 1990

Oct;97(10):922-9.

17. Tingulstad S, Hagen B, Skjeldestad FE, et al. Evaluation of a risk of malignancy

index based on serum CA125, ultrasound findings and menopausal status in the pre-

operative diagnosis of pelvic masses. Br J Obstet Gynaecol. 1996 Aug;103(8):826-

31.

18. Tingulstad S, Hagen B, Skjeldestad FE, Halvorsen T, Nustad K, Onsrud M. The

risk-of-malignancy index to evaluate potential ovarian cancers in local hospitals.

Obstet Gynecol. 1999 Mar;93(3):448-52.

19. Timmerman D, Van Calster B, Testa AC, et al. Ovarian cancer prediction in adnexal

masses using ultrasound-based logistic regression models: a temporal and external

validation study by the IOTA group. Ultrasound Obstet Gynecol. 2010a

Aug;36(2):226-34.

20. Lu KH, Patterson AP, Wang L, et al. Selection of potential markers for epithelial

ovarian cancer with gene expression arrays and recursive descent partition analysis.

Clin Cancer Res. 2004 May 15;10(10):3291-300.

21. Jokubkiene L, Sladkevicius P, Valentin L. Does three-dimensional power Doppler

ultrasound help in discrimination between benign and malignant ovarian masses?

Ultrasound Obstet Gynecol. 2007 Feb;29(2):215-25.

http://www.ncbi.nlm.nih.gov/pubmed?term=Jacobs%20I%5BAuthor%5D&cauthor=true&cauthor_uid=2223684http://www.ncbi.nlm.nih.gov/pubmed?term=Oram%20D%5BAuthor%5D&cauthor=true&cauthor_uid=2223684http://www.ncbi.nlm.nih.gov/pubmed?term=Fairbanks%20J%5BAuthor%5D&cauthor=true&cauthor_uid=2223684http://www.ncbi.nlm.nih.gov/pubmed?term=Turner%20J%5BAuthor%5D&cauthor=true&cauthor_uid=2223684http://www.ncbi.nlm.nih.gov/pubmed?term=Frost%20C%5BAuthor%5D&cauthor=true&cauthor_uid=2223684http://www.ncbi.nlm.nih.gov/pubmed?term=Grudzinskas%20JG%5BAuthor%5D&cauthor=true&cauthor_uid=2223684http://www.ncbi.nlm.nih.gov/pubmed/2223684http://www.ncbi.nlm.nih.gov/pubmed?term=Tingulstad%20S%5BAuthor%5D&cauthor=true&cauthor_uid=8760716http://www.ncbi.nlm.nih.gov/pubmed?term=Hagen%20B%5BAuthor%5D&cauthor=true&cauthor_uid=8760716http://www.ncbi.nlm.nih.gov/pubmed?term=Skjeldestad%20FE%5BAuthor%5D&cauthor=true&cauthor_uid=8760716http://www.ncbi.nlm.nih.gov/pubmed/8760716http://www.ncbi.nlm.nih.gov/pubmed?term=Tingulstad%20S%5BAuthor%5D&cauthor=true&cauthor_uid=10074998http://www.ncbi.nlm.nih.gov/pubmed?term=Hagen%20B%5BAuthor%5D&cauthor=true&cauthor_uid=10074998http://www.ncbi.nlm.nih.gov/pubmed?term=Skjeldestad%20FE%5BAuthor%5D&cauthor=true&cauthor_uid=10074998http://www.ncbi.nlm.nih.gov/pubmed?term=Halvorsen%20T%5BAuthor%5D&cauthor=true&cauthor_uid=10074998http://www.ncbi.nlm.nih.gov/pubmed?term=Nustad%20K%5BAuthor%5D&cauthor=true&cauthor_uid=10074998http://www.ncbi.nlm.nih.gov/pubmed?term=Onsrud%20M%5BAuthor%5D&cauthor=true&cauthor_uid=10074998http://www.ncbi.nlm.nih.gov/pubmed/10074998http://www.ncbi.nlm.nih.gov/pubmed?term=Timmerman%20D%5BAuthor%5D&cauthor=true&cauthor_uid=20455203http://www.ncbi.nlm.nih.gov/pubmed?term=Van%20Calster%20B%5BAuthor%5D&cauthor=true&cauthor_uid=20455203http://www.ncbi.nlm.nih.gov/pubmed?term=Testa%20AC%5BAuthor%5D&cauthor=true&cauthor_uid=20455203http://www.ncbi.nlm.nih.gov/pubmed/20455203http://www.ncbi.nlm.nih.gov/pubmed?term=Lu%20KH%5BAuthor%5D&cauthor=true&cauthor_uid=15161682http://www.ncbi.nlm.nih.gov/pubmed?term=Patterson%20AP%5BAuthor%5D&cauthor=true&cauthor_uid=15161682http://www.ncbi.nlm.nih.gov/pubmed?term=Wang%20L%5BAuthor%5D&cauthor=true&cauthor_uid=15161682http://www.ncbi.nlm.nih.gov/pubmed/15161682http://www.ncbi.nlm.nih.gov/pubmed/17201017http://www.ncbi.nlm.nih.gov/pubmed/17201017

33

22. Yamamoto Y, Yamada R, Oguri H, Maeda N, Fukaya T. Comparison of four

malignancy risk indices in the preoperative evaluation of patients with pelvic

masses. Eur J Obstet Gynecol Reprod Biol. 2009 Jun;144(2):163-7.

23. Aktürk E, Karaca RE, Alanbay I, et al. Comparison of four malignancy risk indices

in the detection of malignant ovarian masses. J Gynecol Oncol. 2011

Sep;22(3):177-82

24. Bouzari Z, Yazdani S, Ahmadi MH, et al. Comparison of three malignancy risk

indices and CA-125 in the preoperative evaluation of patients with pelvic masses.

BMC Res Notes. 2011 Jun 20;4:206.

25. Van Calster B, Timmerman D, Valentin L, et al. Triaging women with ovarian

masses for surgery: observational diagnostic study to compare RCOG guidelines

with an International Ovarian Tumour Analysis (IOTA) group protocol. BJOG.

2012 May;119(6):662-71.

26. Timmerman D, Schwärzler P, Collins WP, et al. Subjective assessment of adnexal

masses with the use of ultrasonography: an analysis of interobserver variability and

experience. Ultrasound Obstet Gynecol. 1999 Jan;13(1):11-6.

27. Timmerman D, Testa AC, Bourne T, et al. International Ovarian Tumor Analysis

Group. Logistic regression model to distinguish between the benign and malignant

adnexal mass before surgery: a multicenter study by the International Ovarian

Tumor Analysis Group. J Clin Oncol. 2005 Dec 1;23(34):8794-801.

28. Timmerman D, Ameye L, Fischerova D, et al. Simple ultrasound rules to

distinguish between benign and malignant adnexal masses before surgery:

prospective validation by IOTA group. BMJ. 2010b Dec 14;341:c6839.

http://www.ncbi.nlm.nih.gov/pubmed/19327881http://www.ncbi.nlm.nih.gov/pubmed/19327881http://www.ncbi.nlm.nih.gov/pubmed/19327881http://www.ncbi.nlm.nih.gov/pubmed/21998760http://www.ncbi.nlm.nih.gov/pubmed/21998760http://www.ncbi.nlm.nih.gov/pubmed?term=Bouzari%20Z%5BAuthor%5D&cauthor=true&cauthor_uid=21689405http://www.ncbi.nlm.nih.gov/pubmed?term=Yazdani%20S%5BAuthor%5D&cauthor=true&cauthor_uid=21689405http://www.ncbi.nlm.nih.gov/pubmed?term=Ahmadi%20MH%5BAuthor%5D&cauthor=true&cauthor_uid=21689405http://www.ncbi.nlm.nih.gov/pubmed/21689405http://www.ncbi.nlm.nih.gov/pubmed?term=Van%20Calster%20B%5BAuthor%5D&cauthor=true&cauthor_uid=22390753http://www.ncbi.nlm.nih.gov/pubmed?term=Timmerman%20D%5BAuthor%5D&cauthor=true&cauthor_uid=22390753http://www.ncbi.nlm.nih.gov/pubmed?term=Valentin%20L%5BAuthor%5D&cauthor=true&cauthor_uid=22390753http://www.ncbi.nlm.nih.gov/pubmed/22390753http://www.ncbi.nlm.nih.gov/pubmed?term=Timmerman%20D%5BAuthor%5D&cauthor=true&cauthor_uid=10201081http://www.ncbi.nlm.nih.gov/pubmed?term=Schw%C3%A4rzler%20P%5BAuthor%5D&cauthor=true&cauthor_uid=10201081http://www.ncbi.nlm.nih.gov/pubmed?term=Collins%20WP%5BAuthor%5D&cauthor=true&cauthor_uid=10201081http://www.ncbi.nlm.nih.gov/pubmed/?term=Timmerman+D%2C+Schwarzler+P%2C+Collins+WPhttp://www.ncbi.nlm.nih.gov/pubmed?term=Timmerman%20D%5BAuthor%5D&cauthor=true&cauthor_uid=16314639http://www.ncbi.nlm.nih.gov/pubmed?term=Testa%20AC%5BAuthor%5D&cauthor=true&cauthor_uid=16314639http://www.ncbi.nlm.nih.gov/pubmed?term=Bourne%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16314639http://www.ncbi.nlm.nih.gov/pubmed?term=International%20Ovarian%20Tumor%20Analysis%20Group%5BCorporate%20Author%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=International%20Ovarian%20Tumor%20Analysis%20Group%5BCorporate%20Author%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Timmerman+D%2C+Testa+AC%2C+Bourne+T%2C+Ferrazzi+E%2C+Ameye+L%2C+Konstantinovic+ML%2C+Van+Calster+B%2C+Collins+WP%2C+Vergote+I%2C+Van+Huffel+S%2C+Valentin+L.http://www.ncbi.nlm.nih.gov/pubmed?term=Timmerman%20D%5BAuthor%5D&cauthor=true&cauthor_uid=21156740http://www.ncbi.nlm.nih.gov/pubmed?term=Ameye%20L%5BAuthor%5D&cauthor=true&cauthor_uid=21156740http://www.ncbi.nlm.nih.gov/pubmed?term=Fischerova%20D%5BAuthor%5D&cauthor=true&cauthor_uid=21156740http://www.ncbi.nlm.nih.gov/pubmed/21156740

34

29. Hartman CA, Juliato CR, Sarian LO, et al. Ultrasound criteria and CA 125 as

predictive variables of ovarian cancer in women with adnexal tumors. Ultrasound

Obstet Gynecol. 2012 Sep;40(3):360-6.

30. Håkansson F, Høgdall EV, Nedergaard L, et al. DANISH ‘PELVIC MASS’

OVARIAN CANCER STUDY. Risk of malignancy index used as a diagnostic tool

in a tertiary centre for patients with a pelvic mass. Acta Obstet Gynecol Scand. 2012

Apr;91(4):496-502.

31. Abdulrahman GO Jr, McKnight L, Lutchman Singh K. The risk of malignancy

index (RMI) in women with adnexal masses in Wales. Taiwan J Obstet

Gynecol. 2014 Sep;53(3):376-81.

32. Sayasneh A, Wynants L, Preisler J, et al. Multicentre external validation of IOTA

prediction models and RMI by operators with varied training. Br J Cancer. 2013 Jun

25;108(12):2448-54.

33. McCluggage WG. Morphological subtypes of ovarian carcinoma: a review with

emphasis on new developments and pathogenesis. Pathology. 2011;43(5):420-32.

34. Mutch DG, Prat J: 2014 FIGO staging for ovarian, fallopian tube and peritoneal

cancer. Gynecol Oncol 133 (3): 401-4, 2014.

35. Development Core Team R: R: A language and environment for statistical

computing. Vienna, Austria: R Foundation for Statistical Computing; 2011.

36. Globocan 2012. [Assessed September 29th, de 2014] http://globocan.iarc.fr.

37. Van den Akker PA, Zusterzeel PL, Aalders AL, et al. External validation of the

adapted Risk of Malignancy Index incorporating tumor size in the preoperative

evaluation of adnexal masses. Eur J Obstet Gynecol Reprod Biol. 2011

Dec;159(2):422-5.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Hartman+CA%2C+Juliato+CR%2C+Sarian+LO%2C+Toledo+MC%2C+Jales+RM%2C+Morais+SShttp://www.ncbi.nlm.nih.gov/pubmed/?term=Hartman+CA%2C+Juliato+CR%2C+Sarian+LO%2C+Toledo+MC%2C+Jales+RM%2C+Morais+SShttp://www.ncbi.nlm.nih.gov/pubmed/22229703http://www.ncbi.nlm.nih.gov/pubmed/22229703http://www.ncbi.nlm.nih.gov/pubmed?term=Abdulrahman%20GO%20Jr%5BAuthor%5D&cauthor=true&cauthor_uid=25286794http://www.ncbi.nlm.nih.gov/pubmed?term=McKnight%20L%5BAuthor%5D&cauthor=true&cauthor_uid=25286794http://www.ncbi.nlm.nih.gov/pubmed?term=Lutchman%20Singh%20K%5BAuthor%5D&cauthor=true&cauthor_uid=25286794http://www.ncbi.nlm.nih.gov/pubmed/25286794http://www.ncbi.nlm.nih.gov/pubmed/25286794http://www.ncbi.nlm.nih.gov/pubmed?term=Sayasneh%20A%5BAuthor%5D&cauthor=true&cauthor_uid=23674083http://www.ncbi.nlm.nih.gov/pubmed?term=Wynants%20L%5BAuthor%5D&cauthor=true&cauthor_uid=23674083http://www.ncbi.nlm.nih.gov/pubmed?term=Preisler%20J%5BAuthor%5D&cauthor=true&cauthor_uid=23674083http://www.ncbi.nlm.nih.gov/pubmed/?term=multicentre+external+validation+sayasnehhttp://globocan.iarc.fr/http://www.ncbi.nlm.nih.gov/pubmed/21824712http://www.ncbi.nlm.nih.gov/pubmed/21824712http://www.ncbi.nlm.nih.gov/pubmed/21824712

35

38. Miller RW, Ueland FR. Risk of malignancy in sonographically confirmed ovarian

tumors. Clin Obstet Gynecol. 2012 Mar;55(1):52-64.

39. Meray O, Türkçüoğlu I, Meydanlı MM, Kafkaslı A. Risk of malignancy index is not

sensitive in detecting non-epithelial ovarian cancer and borderline ovarian tumor. J

Turk Ger Gynecol Assoc. 2010 Mar 1;11(1):22-6.

40. Van Gorp T, Veldman J, Van Calster B, et al. Subjective assessment by ultrasound

is superior to the risk of malignancy index (RMI) or the risk of ovarian malignancy

algorithm (ROMA) in discriminating benign from malignant adnexal masses. Eur J

Cancer. 2012 Jul;48(11):1649-56.

41. Sharma A, Apostolidou S, Burnell M, et al. Risk of epithelial ovarian cancer in

asymptomatic women with ultrasound-detected ovarian masses: a prospective

cohort study within the UK collaborative trial of ovarian cancer screening

(UKCTOCS). Ultrasound Obstet Gynecol. 2012 Sep;40(3):338-44.

http://www.ncbi.nlm.nih.gov/pubmed/22343229http://www.ncbi.nlm.nih.gov/pubmed/22343229http://www.ncbi.nlm.nih.gov/pubmed?term=Meray%20O%5BAuthor%5D&cauthor=true&cauthor_uid=24591890http://www.ncbi.nlm.nih.gov/pubmed?term=T%C3%BCrk%C3%A7%C3%BCo%C4%9Flu%20I%5BAuthor%5D&cauthor=true&cauthor_uid=24591890http://www.ncbi.nlm.nih.gov/pubmed?term=Meydanl%C4%B1%20MM%5BAuthor%5D&cauthor=true&cauthor_uid=24591890http://www.ncbi.nlm.nih.gov/pubmed?term=Kafkasl%C4%B1%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24591890http://www.ncbi.nlm.nih.gov/pubmed/?term=Meray+and+2010+and+ovarian+masshttp://www.ncbi.nlm.nih.gov/pubmed/?term=Meray+and+2010+and+ovarian+masshttp://www.ncbi.nlm.nih.gov/pubmed?term=Van%20Gorp%20T%5BAuthor%5D&cauthor=true&cauthor_uid=22226481http://www.ncbi.nlm.nih.gov/pubmed?term=Veldman%20J%5BAuthor%5D&cauthor=true&cauthor_uid=22226481http://www.ncbi.nlm.nih.gov/pubmed?term=Van%20Calster%20B%5BAuthor%5D&cauthor=true&cauthor_uid=22226481http://www.ncbi.nlm.nih.gov/pubmed/?term=VAN+GORP+AND+VELDMAN+AND+CADRONhttp://www.ncbi.nlm.nih.gov/pubmed/?term=VAN+GORP+AND+VELDMAN+AND+CADRONhttp://www.ncbi.nlm.nih.gov/pubmed?term=Sharma%20A%5BAuthor%5D&cauthor=true&cauthor_uid=22911637http://www.ncbi.nlm.nih.gov/pubmed?term=Apostolidou%20S%5BAuthor%5D&cauthor=true&cauthor_uid=22911637http://www.ncbi.nlm.nih.gov/pubmed?term=Burnell%20M%5BAuthor%5D&cauthor=true&cauthor_uid=22911637http://www.ncbi.nlm.nih.gov/pubmed/22911637

36

Table 1. Key clinical features of women with ovarian benign and malignant tumors

Characteristic

Benign

N= 107

Malignant

N= 51

p-value

Age

Years, mean (SD)*

45.9 (15.0)

55.7 (16.2)

37

Table 2: Performance of RMI variants in pre- and posmenopausal women at cutoff points

determined by ROC analyses.

Group Index AUC Cut off Sensitivity(%) Specificity(%) Accuracy

(%)

LR+ LR-

All women RMI1 0.85 (0.78-0.91) 93.9 82 (75-90) 77 (67-88) 79 3.67 0.22

RMI2 0.85 (0.78-0.91) 195.7 78 (71–86) 82 (72-92) 81 4.41 0.26

RMI3 0.85 (0.78-0.91) 93.9 82 (75-90) 77 (65-86) 78 3.52 0.23

RMI4 0.85 (0.77-0.92) 250.4 83 (76-90) 81 (69-90) 81 4.29 0.21

Pre-menopause RMI1 0.84 (0.78-0.91) 93.9 70 (59-81) 88 (74-100) 83 5.68 0.34

RMI2 0.85 (0.74-0.96) 50.8 90 (83-97) 69 (59-84) 74 2.92 0.14

RMI3 0.84 (0.73-0.95) 93.9 70 (59-81) 89 (76-100) 76 3.46 0.32

RMI4 0.86 (0.72-0.98) 101.8 89 (81-97) 78 (63-93) 78 4.19 0.32

Post-

menopause

RMI1 0.81 (0.72-0.91) 238.5 74 (61-87) 78 (64-93) 77 3.46 0.32

RMI2 0.81 (0.71-0.91) 424.0 71 (57-85) 81 (67-95) 77 3.72 0.36

RMI3 0.81 (0.71-0.91) 238.5 74 (61-87) 79 (64-.93) 76 3.46 0.32

RMI4 0.79 (0.68-0.90) 848.0 73 (60-87) 82 (69-96) 78 4.19 0.32

AUC=area under the Receiver–operating characteristics curve , PPV = positive predictive

value, NPV=negative predictive value

38

Table 3: Performance comparison of RMI variants at progressing cutoff levels for the detection of malignant ovarian tumors

Cutoff Sensitivity Specificity LR+ LR-

RMI

1, 2,

3

RMI4 RMI1 RMI2 RMI3 RMI4 RMI1 RMI2 RMI3 RMI4 RMI1 RMI2 RMI3 RMI4 RMI1 RMI2 RMI3 RMI4

50 300 86 96 88 79 60 52 57 81 2.14 2.01 2.05 4.29 0.22 0.07 0.21 0.25

100 350 78 82 78 77 78 73 77 81 3.64 3.03 3.49 4.17 0.27 0.24 0.27 0.28

150 400 74 78 74 77 84 80 83 82 4.68 3.99 4.42 4.41 0.30 0.27 0.31 0.28

200* 450* 68 78 69 75 87 82 87 82 5.24 4.41 5.24 4.29 0.36 0.26 0.36 0.30

250 500 67 74 67 73 89 83 89 83 5.94 4.42 5.94 4.41 0.37 0.31 0.37 0.32

300 550 63 69 63 71 89 85 89 85 5.59 4.58 5.59 4.86 0.42 0.37 0.41 0.34

350 600 63 67 63 71 90 85 90 85 6.10 4.45 6.10 4.86 0.41 0.39 0.41 0.34

400 650 61 65 61 71 91 88 91 85 7.22 5.32 7.22 4.86 0.43 0.40 0.43 0.34

*Standard (literature recommended) cutoff points for pre- and postmenopausal women with adnexal masses

39

Table 4: Proportion of benign, borderline and malignant tumors at recommended cutoff

points for RMI variants’

RMI

variant

Stratum Total Pathological status

Benign (n=107) Borderline

(n=8)

Malignant (n=43)

RMI 1 < 200 109 93 (87%) 4 (50%) 12 (28%)

>200 49 14 (13%) 4 (50%) 31 (72%)

RMI 2 < 200 99 88 (82%) 3 (37%) 8 (19%)

>200 59 19 (18%) 5 (63%) 35 (81%)

RMI 3 < 200 109 93 (87%) 4 (50%) 12 (28%)

>200 49 14 (13%) 4 (50%) 31 (72%)

RMI 4 < 450 101 88 (82%) 3 (37%) 10 (23%)

>450 57 19 (18%) 5 (63%) 33 (77%)

RMI = Risk of Malignancy Index.

40

Table 5: Proportion of epithelial and non-epithelial ovarian malignant tumors at

recommended cutoff points for the RMI variants

Index Stratum Total Primary Ovarian Malignancy

NON EPITHELIAL

EPITHELIAL P

RMI 1 < 200 16 5 (63%) 10 (27%) 0.132

>200 32 3 (37%) 29 (73%)

RMI2 < 200 11 5 (63%) 6 (15%) 0.014

>200 37 3 (37%) 34 (85%)

RMI 3 < 200 16 5 (63%) 11 (27

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