Please find attached the manuscript of the paper entitled as “Accuracy of Triple Assessment in Diagnosis of Breast Cancer in Women >40 Years” to publish in your journal. It is also to confirm that this paper has not been previously published or considered for publication elsewhere.
The names and details of the authors are as follows:
Riffat Raja*1, Hina Hanif2, Hassan Mahmood3
1. Senior Registrar Radiology, Holy Family Hospital, Rawalpindi
2. Assistant Professor Radiology, Holy Family Hospital, Rawalpindi
3. Consultant Medical Officer, Centers for Disease Control and Prevention (CDC), USA
Dr. Riffat Raja
Senior Registrar Radiology
Holy Family Hospital
Email: [email protected]
Dr. Riffat Raja
ACCURACY OF TRIPLE ASSESSMENT IN DIAGNOSIS OF BREAST CANCER IN WOMEN >40 YEARS
Introduction: Rationale of this study was to gather data about accuracy of Triple assessment (Physical examination, mammogram and FNAC) for prompt diagnosis of the nature of palpable breast lump. This will help in early initiation of definitive management.
Objectives: To determine the diagnostic accuracy of triple assessment in diagnosis of breast cancer in women >40 years keeping histopathology as gold standard.
Main outcome measures: Sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) and Accuracy
Study design: Cross-sectional (validation) study
Methods: Triple assessment (Physical examination, mammogram and FNAC) and histopathological analysis was performed in every patient. Sensitivity, specificity, PPV, NPV and overall accuracy of triple assessment was calculated.
Results: Mean age of the studied patients was 49.9 years ± 6.7 SD. Results of physical examination showed that there were 49.5% (n=52) of patients who were labeled as malignant and 50.5% (n=53) were labeled as benign. Mammogram results showed there were 69.7% (n=69) of patients who were labeled as malignant and 34.3% (n=36) were labeled as benign (Figure 1). FNAC results showed there were 64.8% (n=68) of patients who were labeled as malignant and 35.2% (n=37) were labeled as benign. Results of triple assessment were then calculated which showed that there were 72.4% (n=76) of patients who were labeled as malignant and 27.6% (n=29) were benign. Histopathology results showed that 73.3% (n=77) of patients were malignant and 26.7% (n=28) were benign thus showing that in overall study population 71.5% (n=75) were true positives, 25.7% (n=27) were true negatives, 1% (n=1) were false positives and 2.0% (n=2) were false negatives (table 3). For validation purpose, five parameters; (i) Sensitivity, (ii) Specificity, (iii) Positive Predictive Value (PPV), (iv) Negative Predictive Value (NPV) and (v) Overall Accuracy for the study population were calculated. The study findings revealed that sensitivity, specificity, PPV, NPV and accuracy of triple assessment in diagnosing breast cancer is 97.4%, 96.4%, 98.7%, 93.1% and 97.2% respectively.
Conclusion: Triple assessment allows detection of malignancy in palpable breast lumps with sensitivity, specificity, PPV, NPV and accuracy of 97.4%, 96.4%, 98.7%, 93.1% and 97.2% respectively.
KEY WORDS: Breast cancer, Triple assessment, Diagnosis of breast lump
Breast cancer is one of the major causes of mortality among women all over the world. Globally, it is the 2nd most common cancer.1 In Pakistan; it is the commonest malignancy in women with a prevalence of 34.6%.2 However, a prompt and accurate diagnosis followed by timely intervention can be lifesaving in management of patients with breast cancer. Delayed diagnosis may deprive the patient of curative treatment and misdiagnosis can subject the patient to unwanted surgery which is of great psychological and physical trauma to the patient.1 Therefore, a simple, affordable and reliable diagnostic test can create a huge difference in management of patients with breast cancer.
There are various non-invasive imaging modalities for diagnosing breast lesions e.g. ultrasonography, mammography, MRI, Doppler scanning, contrast enhanced ultrasound etc but alone none of them is reliable.1 Moreover their cost and availability limit their use. Regarding pathology, there are three procedures for diagnosing breast cancer; FNAC (fine needle aspiration cytology), CNB (core needle biopsy) and open surgical biopsy.3
Conventional open/surgical biopsy is considered as a gold standard in diagnosing breast cancer. However, it is highly invasive procedure, time consuming, associated with significant patient anxiety and most importantly exposes patient to more than one surgical procedure.1 Furthermore, surgical biopsy should not be employed as an initial diagnostic tool unless percutaneous or image-guided biopsy is not possible, but may become necessary to further investigate discordant findings.4,5,6 One of the major disadvantages of FNAC is its inability to distinguish between carcinoma in situ and invasive malignancy, and the significant rate of inadequate samples and false negative results in inexperienced hands.7 Hence it is necessary that a diagnostic tool be employed for pre-operative diagnosis of breast cancer which is least invasive, cost effective and readily available with accuracy comparable to conventional surgical biopsy. Diagnostic tools most widely employed that are readily available and have good patient tolerability are mammography and FNAB, however, alone none of them is reliable.1 Thus they cannot be completely relied upon for the initiation of definitive management.
A combination of three tests i.e. physical examination, radiological imaging (mammography) and pathology (FNAB) called as triple assessment is currently employed in diagnosing all the breast lesions.8,9 It is a simple and affordable test with modalities used being noninvasive or minimally invasive. It is performed on OPD basis and requires no hospitalization.8 Furthermore, it is a readily available and reliable diagnostic tool with a sensitivity of 93% and specificity of 95.2%.10
The rationale of this study was that triple assessment being simple, affordable, readily available and non-invasive diagnostic modality is very useful in diagnosing patients suffering from breast cancer especially in a setting with limited resources, thus providing them with prompt curative treatment and obviating the need of unwarranted biopsies and surgeries. Although it is being practiced in many hospitals in Pakistan but its accuracy has not been evaluated. Therefore, to use it as an alternative to open surgical biopsy for diagnosing breast cancer in our settings is not justified. This study is conducted to bridge this knowledge gap and to determine whether triple assessment can be used as an alternative to conventional open biopsy.
To determine the diagnostic accuracy of triple assessment in diagnosing breast cancer in women >40 years keeping histopathology as gold standard.
Cross sectional validation study
Study was conducted in Department of Medical Imaging RMC and Allied Hospitals, Rawalpindi, in collaboration with Pathology department of the same hospital.
Six months from the approval of synopsis
The study included 105 patients.
Sample size was calculated by using sensitivity specificity sample size calculator taking
Absolute precision: 7%
Specificity: 95.2% 1
Absolute precision: 4.8%
Expected prevalence: 34.6% 2
Confidence level: 95%
Non-probability Consecutive sampling technique
• Women presenting with a breast lump or change in the texture of breast
• Women of 40-70 years of age
• Women with breast abscess, anti-bioma, mastitis, infected cyst, mammary fistula
• Diagnosed cases of malignancy
DATA COLLECTION PROCEDURE:
After taking approval of ethical committee of RMC and Allied hospitals, patients fulfilling the criteria were included for study. An informed consent was taken from all the patients. All patients were subjected to a detailed history, detailed physical and breast examination and mammography followed by FNAB. Mammography of breast consists of two standard views: lateral oblique (MLO) and a craniocaudal view (CC). The lateral oblique view was done by angulating the tube at 45 degrees to the horizontal. Depending on the patients build; tube angulations may be changed by 30 to 60 degrees to the horizontal. Appropriate positioning for this view was assessed by the following parameters: the nipple in profile, visible anterior surface of pectoralis major muscle. For adequate visualization, breast was lifted s and compression was applied in order to spread the breast tissue evenly between the film holder and compression plates. No skin folds were superimposed on the breast. The craniocaudal view (CC) demonstrated the following portions of breast: subareolar, medial and lateral. Readings of mammography were verified by a senior postgraduate trainee and consultant. All the patients were sent to pathology department for FNAB and specimens were analyzed by a single experienced pathologist. The results of physical examination, mammography and FNAB were classified as benign and malignant and compared to histopathological report of biopsies from specimens obtained at time of definitive surgery which were sent to hospital lab and verified by pathologist.
DATA ANALYSIS PROCEDURE:
Data were entered on computer software SPSS version 11. For quantitative data i.e. age, mean and SD was calculated. For qualitative data i.e. FNAB, mammographic findings and histopathology, frequencies and percentages were calculated. A 2×2 table was used to calculate sensitivity, specificity, positive predictive value, negative predictive value and accuracy of triple assessment for diagnosing breast cancer using the findings of histopathology as gold standard. The following formula was used to calculate the parameters mentioned above (table 1).
Table 1: Two × Two Table
Triple assessment (Physical ex, Mammography, FNAB) Histopathology Total
Malignant True Positive (a) True Negative (b) a + b
Benign False Negative (c) False Positive (d) c + d
Total a + c b + d a + b + c +d
The formulas/ equations that were used for calculation are as follows:
1. Sensitivity = x 100
2. Specificity = x 100
3. Positive Predictive Value = x 100
4. Negative Predictive Value = x 100
5. Accuracy = x 100
DEMOGRAPHY OF THE SELECTED POPULATION
There were total of one hundred and five (n=105) female patients with palpable breast lump between 40-70 years of age who fulfilled the selection criteria and enrolled in the study. Mean age was 49.9 years ± 6.7 Standard Deviation (SD), with a range of 41 years to 69 years (table 2).
Table 2: Demographic characteristics of study sample (age distribution)
TOTAL NUMBER OF PATIENTS
(N) DISTRIBUTION OF AGE IN STUDY SAMPLE (YEARS)
Minimum Maximum Mean Std. Deviation
105 41 69 49.9 6.7
RESULTS OF PHYSICAL EXAMINATION, MAMMOGRAM AND FNAC
Results of physical examination showed that there were 49.5% (n=52) of patients who were labeled as malignant and 50.5% (n=53) were labeled as benign as per our operational definition (Figure 1). Mammogram results showed there were 65.7% (n=69) of patients who were labeled as malignant and 34.3% (n=36) were labeled as benign (Figure 1). FNAC results showed there were 64.8% (n=68) of patients who were labeled as malignant and 35.2% (n=37) were labeled as benign (Figure 1)
Figure 1: Results Of Physical Examination, Mammogram And FNAC
RESULTS OF TRIPLE ASSESSMENT AND HISTOPATHOLOGY
Results of triple assessment showed that there were 72.4% (n=76) of patients who were labeled as malignant and 27.6% (n=29) were benign as per our operational definition (Figure 2). Histopathology results showed that 73.3% (n=77) of patients were malignant and 26.7% (n=28) were benign as per criteria defined in our operational definition (Figure 2). Results were analyzed by creating 2 x 2 contingency tables which showed the numbers of cases who were malignant on triple assessment scan and were also malignant on Histopathology (true positives), who were malignant on triple assessment scan positive but were benign on Histopathology (false positives), who were benign on triple assessment scan but were malignant on Histopathology (false negatives) and who were benign on triple assessment scan and were also benign on Histopathology (true negatives). Our study results showed that in overall study population 71.5% (n=75) were true positives, 25.7% (n=27) were true negatives, 1% (n=1) were false positives and 2.0% (n=2) were false negatives (table 3). The diagnostic value of triple assessment scan findings was calculated by measuring the following:
1. Sensitivity (By Equation 1)
2. Specificity (By Equation 2)
3. Positive Predictive Value (By Equation 3)
4. Negative Predictive Value (By Equation 4)
5. Accuracy (By Equation 5)
We calculated five parameters i.e sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy of our study population, for the purpose of validation. Our results depicted that sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of triple assessment in diagnosing breast cancer is 97.4%, 96.4%, 98.7%, 93.1% and 97.2% respectively.
Figure 2: Results of Triple Assessment & Histopathology
Table 3: Cross-tabulation of Triple assessment and histopathology results
TRIPLE ASSESSMENT MALIGNANT BENIGN TOTAL
(True Positives) 1
(False Positives) 76
(False Negatives) 27
(True Negatives) 29
Total 77 28 105
Sensitivity: 97.4%, Specificity: 96.4%, Positive Predictive Value: 98.7%, Negative Predictive Value: 93.1%, Over all Accuracy: 97.2%
Breast cancer is one of the leading health issue affecting women of all countries of the world. Most common presentation being a lump. It is a sensitive issue for women hence a reliable, non invasive and early diagnosis may help to decrease the associated agony leading to early treatment. A definite diagnosis of a woman presenting with breast lump is also highly crucial for the surgeon in order to decide final treatment thus saveing the patient from unnecessary physical, social and emotional. Palpable breast lumps are very common in women, most being benign.11, 12 It is estimated that around 90 percent or more of palpable breast lumps in women in their 20s to 50s are benign; however, it is a crucial to exclude breast malignancy step in the assessment of a breast lump in a woman presenting at any age.13 A combination of three tests/ modalities i.e. clinical examination, radiological imaging (mammography/ ultrasonography or both) and pathology called as triple assessment test is currently being employed to accurately diagnose breast lesions. Together they have a sensitivity of around 99%.14 For women less than 30 years of age, the breasts are highly sensitive to radiation; but still if the examination findings are highly suspicious along with a strong family history, a mammogram can be performed.15 On mammography, around one-third of carcinomas appear as spiculated masses, 25 percent as masses with irregular borders, 25 percent as round, oval or lobulated lesions, 40 years keeping histopathology as gold standard. A total of One hundred and five (n=105) patients female patients with palpable breast lump between 40-70 years were enrolled. Triple assessment and histopathological analysis was performed in every patient. Sensitivity, specificity, PPV, NPV and overall accuracy of triple assessment was calculated. Our results showed that Sensitivity, specificity, PPV, NPV and accuracy of triple assessment in evaluating palpable breast lump were found to be 97.4%, 96.4%, 98.7%, 93.1% and 97.2% respectively.
Results of our study are similar to the already published material on the same subject. Jan M, et al aimed to determine diagnostic accuracy of triple assessment in the preoperative diagnosis of breast malignancy patients.17 by selecting a sample of 200 patients presenting with a palpable breast lump. Triple assessment was used for screening the patients. They found that the sensitivity and specificity, positive predictive value and negative predictive value of triple assessment was 100%, 99.3%,93.3% and 100% respectively. They concluded that triple assessment is a highly useful modality to diagnose breast lesions having an accuracy of 99.3%.
Ghimire B, et al evaluated the accuracy of Triple Test Score (TTS) as a clinical tool for the diagnosis of a palpable breast lump.1 a total of 117 patients were included in the study admitted with breast pathologies from the breast clinic over a period of thirteen months, 87 cases had a breast lump. Fifty patients were subjected to Triple assessment and were labelled as benign, suspicious or malignant. Results of TTs score were then correlated with the biopsy findings. It was found that TTS had an overall accuracy of 98%,100% sensitivity and 95.2% specificity. It was thus concluded that TTS is an accurate and minimally invasive diagnostic tool on basis of which definitive treatment can be started.
Morris KT, et al developed a modified triple test score as a reliable diagnostic tool for breast lumps.18 A modified triple test score (MTTS) was used to evaluate breast lumps. A score of 1 was given to benign lesions, 2 to suspicious lesion and 3 to malignant ones. Sum of these 3 scores gave MTTS. Histopathological correlation was done. They found that among 113 masses, 108 patients with scores 3 and 4 were benign. Out of three having score of 5 points; only 1 was malignant. Both cases with scores of ? 6 were malignant. Thus it was concluded that MTTS has 100% diagnostic accuracy. Scores of ? 4 points are benign. Scores of ? 6 points may be proceeded to definitive management. Masses with 5 score (3%) require histopathological diagnosis (biopsy). This approach thus helps to avoid unnecessary open biopsies, capturing all breast cancers.
Morris A, et al evaluated their experience further with the triple assessment to establish a method to further limit the requisite for surgical biopsy.19 The triple assessment was carried out on 261 palpable breast masses. A score of 1 was given to benign lesions, 2 to suspicious lesion and 3 to malignant ones. Giving a total triple test score (TTS). Triple assessment score was interrelated with histopathology. The researchers deduced diagnostic accuracy of 100%. They determined that breast masses scoring 6 points or greater are malignant and may undergo definitive treatment; breast masses scoring 4 points or less are benign and should be followed up while breast masses with 5 points require open biopsy.
Mansoor I,et al evaluated the efficiency of triple assessment for non-diagnostic FNAs of palpable breast masses and to compare their results with the available literature.20 All malignant cases had scores of above 6 except one that scored 5. Two benign cases had scores of 1 and 3. 2 of the unsatisfactory cases were diagnosed as fibro adenoma and one as malignant. All inconclusive cases turned to be malignant when followed up (all having scores 6 and above). They concluded that triple assessment can be used to achieve best diagnostic accuracy for breast FNACs and management of breast lumps.
Kachewar SS, et al in their prospective study aimed to determine the role of triple assessment (Triple test score) in palpable breast lumps.21 They calculated Triple test score in 200 cases out of 225 FNAC’s of breast lumps. Of 124 cases that were benign on cytology, only three had discordant TTS. Out of 62 malignant cases,61 had concordant TTS and one was discordant which turned out to be mastitis. Out of all the benign cases, two cases of fibrocystic disease of breast and one case of phylloides tumor gave a TTS ?6. These cases turned out to be infiltrating ductal carcinoma (IDC) and angiosarcoma on histopathology. Histopathological correlation was possible in only 70 cases. Of these 70, 28 were benign and 42 were malignant. It was found that TTS of ?6 has a sensitivity of 97.44%, specificity of 100%. They concluded triple assessment to be better diagnostic tool than FNAC alone.
Kaufman Z, et al evaluated prospectively the sensitivity and specificity of triple assessment.22 A total of 234 patients with a breast lump had triple assessment and were labelled as malignant, suspicious and benign. All patients later had a biopsy. The sensitivity and specificity of the individual tests were less than triple assessment and were as follows: 89% and 73%, respectively, for mammography; 93% and 97% for FNAC; and 89% and 60% for clinical examination. For the combination of tests (triple assessment), the sensitivity was 100% and specificity 57%. They concluded that breast lesions can be diagnosed with a accuracy by triple assessment, thus obviating the need for invasive procedure (open biopsy).
Ahmed I,et al determined the sensitivity, specificity, positive and negative predictive values of triple assessment in the characterization of breast lump.23 They scored results of triple test (TT) as concordant if all elements were either benign or malignant and non-concordant if the elements were neither all malignant or benign. Triple assessment was concordant in 19 and non-concordant in 16 cases. Triple Test was scored as benign or malignant on the basis of combined results of two out of three elements. 11 cases turned out to be malignant and 5 benign. They concluded that triple assessment is cost effective and time saving approach, however, it should be employed in settings where excellent imaging modalities and trained staff are available..
Salami N, et al in their retrospective study determined accuracy of triple assessment for inadequate fine needle aspiration (FNA) biopsies with a 2 year follow-up.24 Aspirates were assessed for cellular adequacy. Clinical and radiologic results of all cases were reviewed and compared with the histopathology. Aspirates from 61 out of 263 (23%) patients having breast lumps with nondiagnostic results were examined. 77% cases had benign biopsies. Three of 61 cases with nondiagnostic smears had cancer; two were inadequate, and one was misinterpreted. They again concluded that triple assessment can be used to attain high diagnostic accuracy.
Kharkwal S, et al in their prospective study evaluated the effectiveness of “TRIPLE TEST” in diagnosis of breast cancer.25 A total of 100 cases were subjected triple assessment. Sensitivity, specificity, PPV and NPV and diagnostic accuracy of each test was calculated individually as well as combined. They found that the sensitivity, specificity, PPV and accuracy of clinical examination was 75%, 83.3%, 75% and 80% respectively. The sensitivity, specificity, positive predictive value and diagnostic accuracy of mammography was 94.9%, 90% , 86% and 92% respectively. The sensitivity, specificity and accuracy of FNAC was 94.7%, 98.3% and 96.6%. Triple test was concordant in all cases with 100% specificity and 100% negative predictive value. Hence Triple assessment is an effective and accurate tool for breast cancer diagnosis.
In summary, triple assessment (physical examination, mammography, and FNAC) for palpable breast lumps yields near to 100% diagnostic accuracy when all components are concordant (all benign or all malignant). If triple assessment is concordant, final treatment can be started without open biopsy. Thus triple assessment is a cost effective, minimally invasive and time saving, however, it should be employed only in setting with excellent imaging and pathological facilities. However, in cases where triple assessment is non-concordant open biopsy is required.
Triple assessment allows detection of malignancy in palpable breast lumps with sensitivity, specificity, PPV, NPV and accuracy of 97.4%, 96.4%, 98.7%, 93.1% and 97.2% respectively.
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