- Email: [email protected]
Screening and Diagnosis of Breast Cancer in Low-Resource Countries: What Is State of the Art?
Screening and Diagnosis of Breast Cancer in Low-Resource Countries: What Is State of the Art? Mahesh K. Shetty, MD, FRCR, FACR Breast cancer is the most common type of cancer in women worldwide; there has been a significant increase in the incidence of breast cancer in low-resource countries, with a disproportionately greater mortality rate compared to high-resource countries attributed to a lack of public awareness of the disease, absence of organized screening programs, and lack of accessible and effective treatment options. Mammography is not a cost-effective or a feasible option for screening and early detection of breast cancer in low-resource countries. A triple test assessment approach of screening clinical breast examination, diagnostic breast ultrasound, and ultrasound-guided fine-needle aspiration cytology may be a feasible option for the early detection of breast cancer. Semin Ultrasound CT MRI 32:300-305 © 2011 Elsevier Inc. All rights reserved.
I
n a low-resource country (LRC), the health care workforce and infrastructure available for cancer care, be it prevention or control, is very limited or nonexistent. By low resource, we mean low-income countries in which the per capita gross national income is US$995 or less.1 In such a setting, breast cancer mortality is high due to a lack of health care infrastructure, limited access to health care, as well as economic, social, and cultural barriers that prevent women from seeking timely care.2,3 Resource allocation to breast cancer care is limited because of competing health care priorities, such as communicable diseases and malnutrition, which are the leading causes of morbidity and mortality. In the past decade, there has been a dramatic increase in the incidence of cancer in LRCs.2,3 Breast cancer is now the most common cancer affecting women in LRCs, with an estimated incidence of 514,000 cases in 2008 compared with 636,000 new cases in high-resource countries.2-5 It has been estimated that of more than 1 million new cases of breast cancer that will be diagnosed worldwide in 2009, low- and middle-resource countries will be burdened with 45% of breast cancer cases and 55% of breast cancer-related deaths.4,5 In 2010, the annual incidence of new cases is expected to be 1.5 million, and it is estimated that by 2020, 70% of all breast cancer cases will be in low- and middleresource countries.5
Factors attributed to the dramatic increase in the incidence of breast cancer in LRC include an increase in life expectancy because of improving nutrition and better control of communicable diseases, as well as reproductive and lifestyle changes.2-5 A starting point in the breast cancer control strategy would require LRCs to assess the existing cancer burden by setting up accurate statistics to determine the breast cancer incidence and mortality.6 The existing health care system strengths and limitations will have to be assessed, and a cancer- control strategy has to be put in place once both system inefficiencies and patient barriers are identified.6 The release of the Cancer Atlas of India is an example of one such effort at establishing a cancer registry.7
Screening Strategies In LRCs there are no screening programs in place for the early detection of breast cancer. Implementation of a “state-of-theart” screening strategy should focus on a cost-effective and practical methodology. The impracticality of mammographic screening in these settings is discussed. A modified tripleassessment approach is suggested as a practical and costeffective “state-of-the-art” screening strategy to allow for the early detection of breast cancer.
Mammography as a Screening Modality in LRCs Baylor College of Medicine, Houston, TX. Address reprint requests to Mahesh K. Shetty, MD, FRCR, FACR, Chief Physician, Woman’s Center for Breast Care and MRI, Woman’s Hospital of Texas, 7600 Fannin Street, Houston, TX 77054. E-mail: [email protected]
300
0887-2171/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.sult.2011.04.002
Before the emergence of mammography as a screening modality, most breast cancers were being diagnosed by palpation, and often the tumors had been palpable for a variable period before clinical diagnosis. Consequently, the outcome
Breast cancer in low-resource countries
301
Table 1 Limitations of Mammography
graphic assessment of screen-positive cases, followed by fineneedle aspiration biopsy (FNAB) of those with solid masses.
1. Expensive, resource-intensive modality 2. Poor sensitivity in women with dense breasts 3. Mammographic abnormalities may need additional sonographic evaluation 4. 10% or greater recall rate with screening mammography means an additional clinic visit 5. Less tolerated by patient compared with ultrasound because of discomfort caused by breast compression 6. Not optimal for remote reads via telemedicine 7. Not suited to provide imaging guidance for FNAB, unlike sonography FNAB, fine-needle aspiration biopsy.
of such cancers was poor because of the often systemic nature of the disease at the time of diagnosis.8 The prime reason for breast cancer mortality is diagnosis at an advanced stage of disease. The rationale of a breast cancer screening program then is primarily to detect cancer when it is small. The role of mammography in reducing breast cancer mortality has been demonstrated in multiple randomized clinical trials as well as in organized mammography screening services. A 20%-35% reduction in breast cancer mortality in women of age group of 50-69 years and slightly lesser in women 40-49 years of age has been reported.9,10 Although mammography has worked well in high-resource countries, it is not a feasible option as a screening modality for the general population in LRCs. The cost and scope of setting up a mammography screening program is unlikely to receive priority in health care systems already burdened by other competing health care needs. The lower prevalence of breast cancer does not justify the cost needed to set up an organized screening program. Table 1 lists limitations of mammography that is particularly relevant in LRCs.
Modified Triple-Assessment Approach for the Early Detection of Breast Cancer The yield of a cancer screening program will be lower in LRCs because of the lower rates of breast cancer compared with developed nations.11 The average age of the breast cancer patient is lower in LRCs. This has been attributed to the age distribution of the population rather than a greater age-specific incidence.11 Nevertheless breast cancer screening programs should commence screening of women at a younger age compared with those in high resource countries.11 For instance, a large ongoing randomized community-based clinical trial in South India, conducted by the cancer screening group of the International Agency for Research on Cancer studying the efficacy of intervention packages aimed at early detection and improving the outcome of breast cancer, is targeting women aged 30-69 years of age (http://screening.iarc.fr/breastindex.php). An effective strategy may be screening for breast cancer by annual clinical breast examination beginning when the patient is 30 year of age and diagnostic sono-
Clinical Breast Examination Clinical breast examination (CBE) has been studied as a lowcost alternative to mammographic surveillance to reduce mortality by early detection of breast cancer. CBE identifies approximately 60% of cancers that are detected by mammography and a few that are not seen at mammography.12 There has been no randomized clinical trial undertaken to evaluate the efficacy of CBE in the early diagnosis of breast cancer by comparing women who received CBE and those who did not. An estimate based on all randomized clinical trials reported sensitivity of CBE for detection of breast cancer at 54% and specificity at 94%.13,14 Indirect evidence of its value comes from the Canadian National Breast Screening study, where women were divided into 2 groups, one that received screening with physician performed CBE alone, and a second group that received both CBE and screening mammography.15 There were 39,405 women enrolled in this clinical trial. These investigators found that in the 2 groups, breast cancer mortality and nodal involvement were similar. Nevertheless, in the CBE group there were more breast cancers diagnosed in between the screening intervals, and there were more cancers ⬎20 mm in size compared with the screening mammography group.15 The results of this large trial suggest that CBE alone may have a potential to accomplish most of the benefits of screening mammography.15 However, there have been no other similar large-scale studies that have validated the findings of the Canadian study. The quality of the CBE, follow-up, and treatment that was applicable to this study is unlikely to be widely reproducible and unlikely to be so in LRCs, and hence the same results cannot be realistically expected in these countries. Studies on efficacy of CBE have shown less-stellar results in LRCs. One such a study conducted in the Philippines examined the role of CBE in the screening for breast cancer. This was a study designed as a randomized control trial to study the effect on breast cancer mortality, and was based in an urban area of a LRC. Five annual CBEs were performed by trained paramedical personnel; 138,392 patients underwent this examination. A total of 2.5% of women undergoing CBE were found to have a positive finding. The test sensitivity of CBE repeated annually was only 53.2%, and the positive predictive value was 1.2%.16 These data emphasize the importance of optimizing training of health care professionals who will be performing annual CBEs in women in an attempt to attain similar degree of effectiveness as in the Canadian study.15 A cost-effectiveness analysis of screening mammography and CBE in India reported that a single CBE at age 50 lead to a 2% decrease in breast cancer mortality rate and had an estimated cost-effectiveness ratio of Int US$793 per life year gained. A 16.3% mortality rate reduction was possible with biennial CBE at a cost-effectiveness ratio of International US$1341.17 A CBE performed annually from ages of 40-60 years was estimated to be as effective as screening mammog-
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raphy for reducing breast cancer mortality at a fraction of the cost.18 BSE has also been reported to detect malignant tumors that are smaller than those detected without screening. Compared with CBE, BSE has not proven its efficacy in large clinical trials in reducing breast cancer mortality. None of the 3 major clinical trials that have been conducted to study the efficacy of BSE as a breast cancer screening modality has produced evidence in support of BSE as an effective modality for breast cancer screening.18-22 BSE is therefore not a viable alternative to CBE in LRC’s.
Diagnostic Breast Ultrasound in CBE Screen-Positive Women After a screening CBE, further assessment of screen positive cases is most optimally performed by diagnostic sonography. Mammography has limitations in the evaluation of the symptomatic woman, particularly in those with dense breasts. A false-negative rate as high as 16.5% has been reported for mammography in patients with a palpable breast abnormality.23 Mammographic abnormalities identified in a symptomatic woman usually require additional diagnostic ultrasound work-up, and in those with a suspicious palpable solid mass seen on a mammogram and a sonogram, the latter is a better modality for tissue sampling. Overall, diagnostic ultrasound is superior and a cost-effective alternative to diagnostic mammography for the assessment of the symptomatic patient in an LRC. Ultrasound is a safe, well-tolerated, relatively inexpensive modality that can be readily used in the evaluation of a palpable lump in a woman in whom a positive physical finding was detected during the course of a screening CBE. A significant proportion of palpable abnormalities, particularly in a young patient, may have a benign etiology and be attributable to ridges of fibroglandular parenchyma, fat lobules, or localized fibrocystic changes. Ultrasound has been shown to have a very high negative predictive value in women with palpable abnormalities of the breast.24 In a prospective study of women with palpable abnormalities of the breast, we were able to show that the negative predictive value of ultrasound alone in a woman with a palpable abnormality was 98.4%.24 Ultrasound is able to accurately characterize benign palpable abnormalities such as cysts or lymph nodes and preclude a biopsy.24 Furthermore, in those women with a solid mass, ultrasound can accurately characterize masses into probably benign, indeterminate, and probably malignant categories.25 Stavros et al25 were able to achieve a sensitivity of 98.4% in classifying a mass as indeterminate or malignant. The negative predictive value for such a classification scheme was 99.5% (Fig. 1). Only 2 of 442 masses that were classified as benign turned out to be malignant. Indeterminate and probable malignant masses may be sampled under imaging guidance by FNAB. Most palpable cancers are seen on sonography, a retrospective analysis of histologically proven palpable cancers reported that all palpable cancers were sonographically visible and sonography accurately characterized all 293 palpable cancers, 18 of these cancers were mammographically occult.26
Figure 1 Solid palpable masses that were characterized based on ultrasound features as (A) Probably benign, (B) indeterminate, and (C) malignant. Histologic diagnoses: (A) fibroadenoma, (B) stromal fibrosis, (C) invasive ductal cancer.
It is also not uncommon to detect occult ipsilateral cancers in women with a known diagnosis of breast cancer (Fig. 2). Presurgical staging is important in deciding treatment planning; diagnosis of multifocal and multicentric cancers precludes conservative surgery.27 Ultrasound may be used to survey the ipsilateral and contralateral breast for multifocal and metachronous cancers and the axilla and the abdomen for evidence of metastatic disease. Ultrasound can be used to characterize abnormal axillary lymph nodes and provide
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Figure 2 Multifocal occult ipsilateral sonographically identified malignant appearing masses that were histologically proven to be invasive ductal cancers in a 37-year-old woman diagnosed with a palpable breast cancer.
guidance for FNAB of those lymph nodes demonstrating features that are considered suspicious (Fig. 3).28,29 In LRCs, where resources are limited, staging of the disease by sonography will be an additional advantage when using breast sonography in the diagnostic assessment of the symptomatic woman. Dr Yang provides a detailed review on the role of ultrasound in the staging of breast cancer in her article on this subject in this issue.
FNAB of Ultrasound Detected Solid Masses The recommendations for triple assessment of symptomatic women at a breast clinic traditionally consisted of physical
Figure 3 A histologically proven metastatic lymph node sonographically characterized as suspicious in a patient with known breast cancer.
assessment, diagnostic mammography, and fine-needle aspiration cytology (FNAB).30,31 As stated previously, substituting diagnostic mammography with diagnostic ultrasound is particularly suitable in low-resource settings and should precede FNAB. FNAB is optimally performed under imaging guidance. Results of FNAB are categorized as follows: CI, inadequate; C2, sufficient benign; C3, sufficient atypical, probably benign; C4s, sufficient, suspicious for malignancy; and C5 Sufficient, malignant.31 Although core needle biopsies have been reported to be more accurate32 than FNAB, in an LRC the latter appears more cost-effective and feasible alternative. FNAB has the advantages of being a minimally invasive procedure well tolerated, with minimal complications and patient discomfort with rapid results. FNABs are usually performed with a 21- to 25-gauge needle and a 10-mL syringe mounted on an aspiration device. The triple test of physical examination, mammography, and FNAB has been reported to provide 100% accuracy when all 3 tests are concordant.33 In a series of 408 cases having surgical correlation of a total of 1583 cases undergoing FNAB, there were only 19.33 All cases with a malignant diagnosis (223/223) and 94.7% of those with atypical or suspicious findings were proven to be malignant.33 This series included FNAB performed by clinical palpation and without imaging guidance, which no doubt would have improved the overall accuracy. FNAB does equally well in younger as well as in older women. In a series of 230 patients 40 years or younger and 927 women 41 years or older, the sensitivity, specificity, positive predictive value, and negative predictive value was 99% in the younger age group and 98%, 97%, 99%, and 86% in the older age group. The overall false-positive rate was ⬍1%, and the false-negative cases were 9%.34 Several factors traditionally contribute to the false-negative rate, including small tumor size, sampling errors, hypocellularity, histologic features, such as low nuclear grade, and tumors with marked desmoplasia. There are data to support
304 the fact that findings of cytology have to be considered in combination with imaging morphology and characterization of solid masses to improve the positive predictive value, thereby allowing for optimal management of symptomatic women with suspicious findings at imaging and cytology. In a consecutive series of 2334 women positive predictive value of C3, C4, and C5 lesions was 55%, 95.9%, and 99.4%. However, when a C3 finding at cytology is seen in combination with a suspicious finding on imaging, the positive predictive value improved to 83.3% and positive predictive value for C4 lesions increased to 98.5%-98.7% potentially allowing for management decisions of open biopsy and or planning surgery.35
Conclusions Breast cancer incidence is on the increase in LRCs, where a lack of public awareness, absence of an organized screening program, and effective treatment options have resulted in women presenting at late stages of the disease with an unacceptably high mortality rate. A combination of increasing public awareness of this disease, and a modified triple assessment of women utilizing screening CBE combined with diagnostic sonography and sonographic-guided FNAB may be a cost-effective health care strategy to combat this problem. In LRCs, such an approach can indeed be the “state-of-theart” screening strategy where none currently exist. Such intervention strategies have to be combined with appropriate definitive treatment options made available for those who have been diagnosed with breast cancer to make an impact on breast cancer mortality. The success of such a screening strategy will depend on implementing a rigorous training program for health care professionals in performing clinical breast examination, in the performance and interpretation of diagnostic ultrasound examinations as well as FNAB techniques. A large-scale clinical trial will have to be undertaken to validate the efficacy of such an approach.
References 1. World-Bank: Country classification. World Bank [cited 2010 July]; Available from: http://data.worldbank.org/about/country-classifications. Accessed April 15, 2011 2. El Saghir NS, Adebamowo CA, Anderson BO, et al: Breast Cancer Management in Low Resource Countries (LRCs): Consensus Statement from the Breast Health Global Initiative. Breast 20(suppl 2):S3-11, 2011 3. World Health Organization: National Cancer Control Programmes, Policies and Managerial Guidelines. Available from: http://www. who.int/cancer/media/en/409.pdf. Accessed April 15, 2011 4. Ferlay J, Shin H, Bray F, et al: Cancer incidence and mortality worldwide: IARC Cancer Base No. 10. Lyon, France, International Agency for Research on Cancer [cited 2010]. Available from: http://globocan. iarc.fr. Accessed April 15, 2011 5. Kantelhardt EJ, Hanson C, Ute-Susann-Albert U, et al: Breast cancer in countries of limited resources. Breast Care 3:10-16, 2008 6. Harford JB, Otero IV, Anderson BO, et al: Problem solving for breast health care delivery in low and middle resource countries (LMCs): Consensus statement from the Breast Health Global Initiative. Breast 20(suppl 2):S20-S29, 2011
M.K. Shetty 7. Nandakumar A, Gupta PC, Gangadhara P, et al: Geographic pathology revisited: Development of an atlas of cancer in India. Int J Cancer 116:740-754, 2005 8. Tabar L, Dean PB, Kaufman CA, et al: New era in the diagnosis of breast cancer. Surg Oncol Clin North Am 9:233-277, 2000 9. Tabar L, Fagerberg G, Chen HH, et al: Efficacy of breast cancer screening by age. New results from the Swedish Two-County Trial. Cancer 75:2507-2517, 1995 10. Tabár L, Fagerberg CJ, Gad A, et al: Reduction in mortality from breast cancer after mass screening with mammography. Randomised trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet 1:829-832, 1985 11. Harford JB: Breast-cancer early detection in low-income and middleincome countries: Do what you can versus one size fits all. Lancet Oncol 12:306-312, 2011 12. Weiss NS: Breast cancer mortality in relation to Clinical breast examination and breast self examination. Breast J 9(suppl 2):s86-s89, 2003 13. Barton MB, Harris R, Fletcher SW: The rational clinical examination. Does this patient have breast cancer? The screening clinical breast examination: Should it be done? How? JAMA 282:1270-1280, 1999 14. Elmore JG, Armstrong K, Lehman CD, et al: Screening for breast cancer. JAMA 293:1245-1256, 2005 15. Miller AB, To T, Baines CJ, et al: Canadian National Breast Screening Study: 2: 13-Year results of a randomized trial in women aged 50-59 years. Natl Cancer Inst 92:1490-1499, 2000 16. Pisani P, Parkin DM, Ngelangel C, et al: Outcome of screening by clinical examination of the breast in a trial in the Philippines. Int J Cancer 118:149-154, 2006 17. Okonkwo QL, Draisma G, Kinderen AD, et al: Breast cancer screening policies in developing countries: A cost effectiveness analysis for India. J Natl Cancer Inst 100:1290-1300, 2008 18. Thomas DB, Gao DL, Ray RM, et al: Randomized trial of breast selfexamination in Shanghai: Final results. J Natl Cancer Inst 94:14451457, 2002 19. Kearney AJ, Michael M: Evidence against Breast self examination is not conclusive: What Policy makers and health professionals need to know. J Public Health Policy 27:282-292, 2006 20. Semiglazov VF, Moiseenko VM, Manikhas AG, et al: Interim results of a prospective randomized study of self-examination for early detection of breast cancer (Russia/St. Petersburg/WHO). Voprosy Onkol 45:265271, 1999 21. UK Trial of Early Detection of Breast Cancer Group: 16-Year mortality from breast cancer in the UK trial of early detection of breast cancer. Lancet 353:1909-1914, 1999 22. Greenwald P, Nasca PC, Lawrence CE, et al: Estimated effect of breast self-examination and routine physician examinations on breast-cancer mortality. N Engl J Med 299:271-273, 1978 23. Coveney EC, Geraghty JG, O’Laoide R, et al: Reasons underlying negative mammography in patients with palpable breast cancer. Clin Radiol 49:123-125, 1994 24. Shetty MK, Shah YP, Sharman RS: Prospective evaluation of the value of combined mammographic and sonographic assessment in patients with palpable abnormalities of the breast. J Ultrasound Med 22:263268, 2003 25. Stavros AT, Thickman D, Rapp CL, et al: Solid breast nodules: Use of sonography to distinguish between benign and malignant lesions. Radiology 196:123-134, 1995 26. Georgian-Smith D, Taylor KJW, Madjar H, et alSonography of palpable breast cancer. J Clin Ultrasound 28:211-216, 2000 27. Gordan PB: Ultrasound for breast cancer screening and staging. Radiol Clin North Am 40, 2002:431-441 28. Shetty MK, Carpenter WS: Sonographic evaluation of isolated abnormal axillary lymph nodes identified on mammograms. J Ultrasound Med 23:63-71, 2004 29. Pamilo M, Soiva M, Lavast EM: Real-time ultrasound, axillary mammography, and clinical examination in the detection of axillary lymph node metastases in breast cancer patients. J Ultrasound Med 8:115120, 1989
Breast cancer in low-resource countries 30. Blamey RW: The British Association of Surgical Oncology Guidelines for surgeons in the management of symptomatic breast disease in the UK 1998 revision). Breast BASO Specialty Group. Eur J Surg Oncol 24:464-476, 1998 31. Cytology sub-group of the National Co-Ordinating Committee for Breast Screening Pathology. Guidelines for cytology procedures and reporting in breast cancer screening. NHSBSP, 1993;No 22 32. Chuo CB, Corder AP: Core biopsy vs fine needle aspiration cytology in a symptomatic breast clinic. Eur J Surg Oncol 29:374-378, 2003
305 33. Marilin M, Mohammadi A, Masood S: The value of fine needle aspiration biopsy in the diagnosis and prognostic assessment of palpable breast lesions. Diagn Cytopathol, in press 34. Ariga R, Bloom K, Reddy VB, et al: Fine-needle aspiration of clinically suspicious palpable breast masses with histopathologic correlation. Am J Surg 184:410-413, 2002 35. Bulgaresi P, Cariaggi P, Ciatto S, et al: Positive predictive value of breast fine needle aspiration cytology (FNAC) in combination with clinical and imaging findings: A series of 2334 subjects with abnormal cytology. Breast Cancer Res Treat 97:319-321, 2006
I
n a low-resource country (LRC), the health care workforce and infrastructure available for cancer care, be it prevention or control, is very limited or nonexistent. By low resource, we mean low-income countries in which the per capita gross national income is US$995 or less.1 In such a setting, breast cancer mortality is high due to a lack of health care infrastructure, limited access to health care, as well as economic, social, and cultural barriers that prevent women from seeking timely care.2,3 Resource allocation to breast cancer care is limited because of competing health care priorities, such as communicable diseases and malnutrition, which are the leading causes of morbidity and mortality. In the past decade, there has been a dramatic increase in the incidence of cancer in LRCs.2,3 Breast cancer is now the most common cancer affecting women in LRCs, with an estimated incidence of 514,000 cases in 2008 compared with 636,000 new cases in high-resource countries.2-5 It has been estimated that of more than 1 million new cases of breast cancer that will be diagnosed worldwide in 2009, low- and middle-resource countries will be burdened with 45% of breast cancer cases and 55% of breast cancer-related deaths.4,5 In 2010, the annual incidence of new cases is expected to be 1.5 million, and it is estimated that by 2020, 70% of all breast cancer cases will be in low- and middleresource countries.5
Factors attributed to the dramatic increase in the incidence of breast cancer in LRC include an increase in life expectancy because of improving nutrition and better control of communicable diseases, as well as reproductive and lifestyle changes.2-5 A starting point in the breast cancer control strategy would require LRCs to assess the existing cancer burden by setting up accurate statistics to determine the breast cancer incidence and mortality.6 The existing health care system strengths and limitations will have to be assessed, and a cancer- control strategy has to be put in place once both system inefficiencies and patient barriers are identified.6 The release of the Cancer Atlas of India is an example of one such effort at establishing a cancer registry.7
Screening Strategies In LRCs there are no screening programs in place for the early detection of breast cancer. Implementation of a “state-of-theart” screening strategy should focus on a cost-effective and practical methodology. The impracticality of mammographic screening in these settings is discussed. A modified tripleassessment approach is suggested as a practical and costeffective “state-of-the-art” screening strategy to allow for the early detection of breast cancer.
Mammography as a Screening Modality in LRCs Baylor College of Medicine, Houston, TX. Address reprint requests to Mahesh K. Shetty, MD, FRCR, FACR, Chief Physician, Woman’s Center for Breast Care and MRI, Woman’s Hospital of Texas, 7600 Fannin Street, Houston, TX 77054. E-mail: [email protected]
300
0887-2171/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.sult.2011.04.002
Before the emergence of mammography as a screening modality, most breast cancers were being diagnosed by palpation, and often the tumors had been palpable for a variable period before clinical diagnosis. Consequently, the outcome
Breast cancer in low-resource countries
301
Table 1 Limitations of Mammography
graphic assessment of screen-positive cases, followed by fineneedle aspiration biopsy (FNAB) of those with solid masses.
1. Expensive, resource-intensive modality 2. Poor sensitivity in women with dense breasts 3. Mammographic abnormalities may need additional sonographic evaluation 4. 10% or greater recall rate with screening mammography means an additional clinic visit 5. Less tolerated by patient compared with ultrasound because of discomfort caused by breast compression 6. Not optimal for remote reads via telemedicine 7. Not suited to provide imaging guidance for FNAB, unlike sonography FNAB, fine-needle aspiration biopsy.
of such cancers was poor because of the often systemic nature of the disease at the time of diagnosis.8 The prime reason for breast cancer mortality is diagnosis at an advanced stage of disease. The rationale of a breast cancer screening program then is primarily to detect cancer when it is small. The role of mammography in reducing breast cancer mortality has been demonstrated in multiple randomized clinical trials as well as in organized mammography screening services. A 20%-35% reduction in breast cancer mortality in women of age group of 50-69 years and slightly lesser in women 40-49 years of age has been reported.9,10 Although mammography has worked well in high-resource countries, it is not a feasible option as a screening modality for the general population in LRCs. The cost and scope of setting up a mammography screening program is unlikely to receive priority in health care systems already burdened by other competing health care needs. The lower prevalence of breast cancer does not justify the cost needed to set up an organized screening program. Table 1 lists limitations of mammography that is particularly relevant in LRCs.
Modified Triple-Assessment Approach for the Early Detection of Breast Cancer The yield of a cancer screening program will be lower in LRCs because of the lower rates of breast cancer compared with developed nations.11 The average age of the breast cancer patient is lower in LRCs. This has been attributed to the age distribution of the population rather than a greater age-specific incidence.11 Nevertheless breast cancer screening programs should commence screening of women at a younger age compared with those in high resource countries.11 For instance, a large ongoing randomized community-based clinical trial in South India, conducted by the cancer screening group of the International Agency for Research on Cancer studying the efficacy of intervention packages aimed at early detection and improving the outcome of breast cancer, is targeting women aged 30-69 years of age (http://screening.iarc.fr/breastindex.php). An effective strategy may be screening for breast cancer by annual clinical breast examination beginning when the patient is 30 year of age and diagnostic sono-
Clinical Breast Examination Clinical breast examination (CBE) has been studied as a lowcost alternative to mammographic surveillance to reduce mortality by early detection of breast cancer. CBE identifies approximately 60% of cancers that are detected by mammography and a few that are not seen at mammography.12 There has been no randomized clinical trial undertaken to evaluate the efficacy of CBE in the early diagnosis of breast cancer by comparing women who received CBE and those who did not. An estimate based on all randomized clinical trials reported sensitivity of CBE for detection of breast cancer at 54% and specificity at 94%.13,14 Indirect evidence of its value comes from the Canadian National Breast Screening study, where women were divided into 2 groups, one that received screening with physician performed CBE alone, and a second group that received both CBE and screening mammography.15 There were 39,405 women enrolled in this clinical trial. These investigators found that in the 2 groups, breast cancer mortality and nodal involvement were similar. Nevertheless, in the CBE group there were more breast cancers diagnosed in between the screening intervals, and there were more cancers ⬎20 mm in size compared with the screening mammography group.15 The results of this large trial suggest that CBE alone may have a potential to accomplish most of the benefits of screening mammography.15 However, there have been no other similar large-scale studies that have validated the findings of the Canadian study. The quality of the CBE, follow-up, and treatment that was applicable to this study is unlikely to be widely reproducible and unlikely to be so in LRCs, and hence the same results cannot be realistically expected in these countries. Studies on efficacy of CBE have shown less-stellar results in LRCs. One such a study conducted in the Philippines examined the role of CBE in the screening for breast cancer. This was a study designed as a randomized control trial to study the effect on breast cancer mortality, and was based in an urban area of a LRC. Five annual CBEs were performed by trained paramedical personnel; 138,392 patients underwent this examination. A total of 2.5% of women undergoing CBE were found to have a positive finding. The test sensitivity of CBE repeated annually was only 53.2%, and the positive predictive value was 1.2%.16 These data emphasize the importance of optimizing training of health care professionals who will be performing annual CBEs in women in an attempt to attain similar degree of effectiveness as in the Canadian study.15 A cost-effectiveness analysis of screening mammography and CBE in India reported that a single CBE at age 50 lead to a 2% decrease in breast cancer mortality rate and had an estimated cost-effectiveness ratio of Int US$793 per life year gained. A 16.3% mortality rate reduction was possible with biennial CBE at a cost-effectiveness ratio of International US$1341.17 A CBE performed annually from ages of 40-60 years was estimated to be as effective as screening mammog-
302
M.K. Shetty
raphy for reducing breast cancer mortality at a fraction of the cost.18 BSE has also been reported to detect malignant tumors that are smaller than those detected without screening. Compared with CBE, BSE has not proven its efficacy in large clinical trials in reducing breast cancer mortality. None of the 3 major clinical trials that have been conducted to study the efficacy of BSE as a breast cancer screening modality has produced evidence in support of BSE as an effective modality for breast cancer screening.18-22 BSE is therefore not a viable alternative to CBE in LRC’s.
Diagnostic Breast Ultrasound in CBE Screen-Positive Women After a screening CBE, further assessment of screen positive cases is most optimally performed by diagnostic sonography. Mammography has limitations in the evaluation of the symptomatic woman, particularly in those with dense breasts. A false-negative rate as high as 16.5% has been reported for mammography in patients with a palpable breast abnormality.23 Mammographic abnormalities identified in a symptomatic woman usually require additional diagnostic ultrasound work-up, and in those with a suspicious palpable solid mass seen on a mammogram and a sonogram, the latter is a better modality for tissue sampling. Overall, diagnostic ultrasound is superior and a cost-effective alternative to diagnostic mammography for the assessment of the symptomatic patient in an LRC. Ultrasound is a safe, well-tolerated, relatively inexpensive modality that can be readily used in the evaluation of a palpable lump in a woman in whom a positive physical finding was detected during the course of a screening CBE. A significant proportion of palpable abnormalities, particularly in a young patient, may have a benign etiology and be attributable to ridges of fibroglandular parenchyma, fat lobules, or localized fibrocystic changes. Ultrasound has been shown to have a very high negative predictive value in women with palpable abnormalities of the breast.24 In a prospective study of women with palpable abnormalities of the breast, we were able to show that the negative predictive value of ultrasound alone in a woman with a palpable abnormality was 98.4%.24 Ultrasound is able to accurately characterize benign palpable abnormalities such as cysts or lymph nodes and preclude a biopsy.24 Furthermore, in those women with a solid mass, ultrasound can accurately characterize masses into probably benign, indeterminate, and probably malignant categories.25 Stavros et al25 were able to achieve a sensitivity of 98.4% in classifying a mass as indeterminate or malignant. The negative predictive value for such a classification scheme was 99.5% (Fig. 1). Only 2 of 442 masses that were classified as benign turned out to be malignant. Indeterminate and probable malignant masses may be sampled under imaging guidance by FNAB. Most palpable cancers are seen on sonography, a retrospective analysis of histologically proven palpable cancers reported that all palpable cancers were sonographically visible and sonography accurately characterized all 293 palpable cancers, 18 of these cancers were mammographically occult.26
Figure 1 Solid palpable masses that were characterized based on ultrasound features as (A) Probably benign, (B) indeterminate, and (C) malignant. Histologic diagnoses: (A) fibroadenoma, (B) stromal fibrosis, (C) invasive ductal cancer.
It is also not uncommon to detect occult ipsilateral cancers in women with a known diagnosis of breast cancer (Fig. 2). Presurgical staging is important in deciding treatment planning; diagnosis of multifocal and multicentric cancers precludes conservative surgery.27 Ultrasound may be used to survey the ipsilateral and contralateral breast for multifocal and metachronous cancers and the axilla and the abdomen for evidence of metastatic disease. Ultrasound can be used to characterize abnormal axillary lymph nodes and provide
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Figure 2 Multifocal occult ipsilateral sonographically identified malignant appearing masses that were histologically proven to be invasive ductal cancers in a 37-year-old woman diagnosed with a palpable breast cancer.
guidance for FNAB of those lymph nodes demonstrating features that are considered suspicious (Fig. 3).28,29 In LRCs, where resources are limited, staging of the disease by sonography will be an additional advantage when using breast sonography in the diagnostic assessment of the symptomatic woman. Dr Yang provides a detailed review on the role of ultrasound in the staging of breast cancer in her article on this subject in this issue.
FNAB of Ultrasound Detected Solid Masses The recommendations for triple assessment of symptomatic women at a breast clinic traditionally consisted of physical
Figure 3 A histologically proven metastatic lymph node sonographically characterized as suspicious in a patient with known breast cancer.
assessment, diagnostic mammography, and fine-needle aspiration cytology (FNAB).30,31 As stated previously, substituting diagnostic mammography with diagnostic ultrasound is particularly suitable in low-resource settings and should precede FNAB. FNAB is optimally performed under imaging guidance. Results of FNAB are categorized as follows: CI, inadequate; C2, sufficient benign; C3, sufficient atypical, probably benign; C4s, sufficient, suspicious for malignancy; and C5 Sufficient, malignant.31 Although core needle biopsies have been reported to be more accurate32 than FNAB, in an LRC the latter appears more cost-effective and feasible alternative. FNAB has the advantages of being a minimally invasive procedure well tolerated, with minimal complications and patient discomfort with rapid results. FNABs are usually performed with a 21- to 25-gauge needle and a 10-mL syringe mounted on an aspiration device. The triple test of physical examination, mammography, and FNAB has been reported to provide 100% accuracy when all 3 tests are concordant.33 In a series of 408 cases having surgical correlation of a total of 1583 cases undergoing FNAB, there were only 19.33 All cases with a malignant diagnosis (223/223) and 94.7% of those with atypical or suspicious findings were proven to be malignant.33 This series included FNAB performed by clinical palpation and without imaging guidance, which no doubt would have improved the overall accuracy. FNAB does equally well in younger as well as in older women. In a series of 230 patients 40 years or younger and 927 women 41 years or older, the sensitivity, specificity, positive predictive value, and negative predictive value was 99% in the younger age group and 98%, 97%, 99%, and 86% in the older age group. The overall false-positive rate was ⬍1%, and the false-negative cases were 9%.34 Several factors traditionally contribute to the false-negative rate, including small tumor size, sampling errors, hypocellularity, histologic features, such as low nuclear grade, and tumors with marked desmoplasia. There are data to support
304 the fact that findings of cytology have to be considered in combination with imaging morphology and characterization of solid masses to improve the positive predictive value, thereby allowing for optimal management of symptomatic women with suspicious findings at imaging and cytology. In a consecutive series of 2334 women positive predictive value of C3, C4, and C5 lesions was 55%, 95.9%, and 99.4%. However, when a C3 finding at cytology is seen in combination with a suspicious finding on imaging, the positive predictive value improved to 83.3% and positive predictive value for C4 lesions increased to 98.5%-98.7% potentially allowing for management decisions of open biopsy and or planning surgery.35
Conclusions Breast cancer incidence is on the increase in LRCs, where a lack of public awareness, absence of an organized screening program, and effective treatment options have resulted in women presenting at late stages of the disease with an unacceptably high mortality rate. A combination of increasing public awareness of this disease, and a modified triple assessment of women utilizing screening CBE combined with diagnostic sonography and sonographic-guided FNAB may be a cost-effective health care strategy to combat this problem. In LRCs, such an approach can indeed be the “state-of-theart” screening strategy where none currently exist. Such intervention strategies have to be combined with appropriate definitive treatment options made available for those who have been diagnosed with breast cancer to make an impact on breast cancer mortality. The success of such a screening strategy will depend on implementing a rigorous training program for health care professionals in performing clinical breast examination, in the performance and interpretation of diagnostic ultrasound examinations as well as FNAB techniques. A large-scale clinical trial will have to be undertaken to validate the efficacy of such an approach.
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