Thursday, May 5, 2016

Simple Rules from the International Ovarian Tumor Analysis to differentiate benign vs malignant adnexal masses.

Ovarian cancer is the seventh most common cancer in women worldwide (18 most common cancers overall). The highest incidence of ovarian cancer is seen Europe and Northern America; and the lowest incidence in Africa and Asia.

The American Cancer Society estimates that in 2016, there will be 22,280 new cases of ovary cancer and an estimated 14,240 people will die of this disease. Owing to slow progression, being relatively asymptomatic in early stages and with no single reliable screening test it is usually diagnosed  at a  late stages.

Ultrasound has always been pivotal in diagnosing pelvic masses and can fairly differentiate cystic vs solid lesions, provide accurate assessment of size, follow changes in appearance, and assess vascular supply and flow. So Sonography, along with few specific tumor markers and imaging studies have made it possible to have  high index of suspicion, but definitive diagnosis is not possible 100% of time. 

Over the years, researchers have developed different models to accurately characterize adnexal masses as benign or malignant preoperatively.  A recent meta-analysis confirmed that the International Ovarian Tumor Analysis (IOTA) algorithms such as the Simple Rules are very effective to preoperatively classify adnexal masses as benign or malignant.

IOTA developed the simple rules and mathematical models based on logistic regression (LR 1-2), which are very easy to use in clinical practice to discriminate between benign and malignant tumors.   Logistic regression model 2 is a mathematical risk prediction model which also includes age beside the  5 ultrasound variables (presence of blood flow in a papillary structure, irregular cyst walls, ascites, acoustic shadows, and maximum diameter of the largest solid component). 

Clinicians have incorporated the Simple Rules in practice and the Royal College of Obstetricians and Gynecologists in the United Kingdom has included the Simple Rules in their Green Top guideline on the assessment and management of ovarian masses in premenopausal women.

In spite of all the simplicity and ease of use in practice, the simple rules have the limitations of inconclusive results in many cases and absence of risk stratification for malignancy preoperatively.

A recent study published in the American Journal of Obstetrics and Gynecology April, 2016 issue aims to develop and validate a model based on IOTA Simple Rules to estimate the risk of malignancy in adnexal masses.
It is an international cross sectional study with 22 oncology centers, referral centers for ultrasonography, and general hospitals.  Data on 5020 patients were recorded in 3 phases from 2002 through 2012. The 5 simple rules of being benign or malignant was based on presence of ascites, tumor morphology, and degree of vascularity at ultrasonography. 
All patient underwent a standard transvaginal sonography by an experienced sonologist/gynecologist. Transabdominal Scan was added as and when required particularly in very large tumors.  The reference standard was the histopathological diagnosis after the surgical removal of the tumor.
The quantifying predictive value of each of the 10 features of Simple Rules was estimated. In addition, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and predictive values, Positive likelihood ratio (LR+) and negative likelihood ratio (LR–) were also derived by multivariate logistic regression.
Data on 4848 patients were analyzed by logistic regression. The observed malignancy rate was 34% overall (43% in oncology centers, and 17% in other centers). The median age for benign tumor was 42 vs 57 for malignant tumors.
A simple unilocular cyst was most predictive of a benign tumor, while presence of ascites was most predictive of malignancy and (irregular multilocular-solid tumor with largest diameter ≥100 mm) was least predictive.
When an ovarian mass is detected on clinical examination,the risk of malignancy at an oncology center is 48.7% and 27.5% for patients at other centers.  After sonography if more of M-features than B-features were present the risk of malignancy was 42% and was at most 0.29% when ≥2 B-features and no M-features were present. Based on these findings a simple classification of adnexal masses can be used in clinical practice to determine the risk of malignancy for an individual patient and her management subsequently.
Over the years’ various mathematical models based on clinical and pathological markers are being used to aid in clinical decision making. In 2014 a met analysis by Kaijser J et al confirmed the superiority of IOTA simple rules and

5 simple rules to suggest benign tumor (B-rules):

(1) unilocular cyst;
 (2) presence of solid components where the largest solid component is < 7 mm in largest diameter;
 (3) acoustic shadows;
 (4) smooth multilocular tumor less than 100 mm in largest diameter; and
 (5) no detectable blood flow on Doppler examination. 

 5 simple rules to predict malignancy (M-rules):

 (1) irregular solid tumor;
 (2) ascites;
 (3) at least four papillary structures;
 (4) irregular multilocular-solid tumor with a largest diameter of at least 100 mm; and
 (5) very high color content on color Doppler examination.

The cancer antigen-125 is not one of the variable in the Simple Rules, it is not included in the Simple Rules risk classification and adding serum levels of CA 125 to the Logistic regression model does not help us to discriminate between benign and malignant adnexal masses.

In phase 3 the model was validated and it seen that it works well both in hands of oncologists as well as general gynecology practitioners. In low risk patients a ‘wait and watch’ policy could be adapted, with close monitoring and avoiding unnecessary surgeries whereas in high risk patients it leads to early diagnosis and improved survival.

References:

http://www.ncbi.nlm.nih.gov/pubmed/24327552?dopt=Abstract
http://www.iotagroup.org/

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