Is Probably Benign Really Just Benign? Peter R Eby, MD, FSBI Virginia Mason Medical Center Seattle, WA

Is Probably Benign Really Just Benign? Peter R Eby, MD, FSBI Virginia Mason Medical Center Seattle, WA

Disclosures: CONSULTANT FOR DEVICOR MEDICAL

ARS Question 1 Is probably benign really just benign? A. Yes B. No

Overview Review the data related to BI-RADS 3 Mammography Ultrasound MRI Consider the probabilities

Is probably benign really just benign? MAMMOGRAPHY

BI-RADS 3: Research In 1991, Dr. Sickles published the results of a large prospective trial in which the patients and imaging findings had to meet strict criteria. Sickles EA. Periodic mammographic follow-up of probably benign lesions: results in 3,184 consecutive cases. Radiology, 1991. Vol 179(2); pp.463-468.

BI-RADS 3: Strict Criteria The patient must: Undergo complete diagnostic work-up Not have prior films for comparison Prior exams allow us to determine if the finding is stable (benign, BI-RADS 2) or growing (suspicious, BI- RADS 4). Sickles EA. Periodic mammographic follow-up of probably benign lesions: results in 3,184 consecutive cases. Radiology, 1991. Vol 179(2); pp.463-468.

BI-RADS 3: Strict Criteria The mammographic finding must: Be non-palpable Adhere to one of these imaging descriptions: Group of punctate and/or round calcifications Smooth, round or oval, non-calcified mass Focally asymmetric tissue Sickles EA. Periodic mammographic follow-up of probably benign lesions: results in 3,184 consecutive cases. Radiology, 1991. Vol 179(2); pp.463-468.

Research Results: 34,282 women screened 3,184 with probably benign findings 3 or more years of follow-up Biopsy was performed if any finding grew during the follow-up period. Sickles EA. Periodic mammographic follow-up of probably benign lesions: results in 3,184 consecutive cases. Radiology, 1991. Vol 179(2); pp.463-468.

Follow-up Protocol: This protocol adds a unilateral diagnostic mammogram at 6 months to the annual bilateral screening schedule. Initial screening & diagnostic mammogram 12 months: bilateral annual exam 24 months: bilateral annual exam 36 months: bilateral annual exam 6 months: unilateral follow-up 18 months: optional unilateral follow-up 30 months

Research Results: Type Malignant % Calcifications 2/1853 0.1 Masses 13/842 1.5 Asymmetries 2/448 0.4 Other 0/41 0 Total 17/3184 0.5 1438 (45.2%) women completed the recommended follow up. 161 biopsies performed. Sickles EA. Periodic mammographic follow-up of probably benign lesions: results in 3,184 consecutive cases. Radiology, 1991. Vol 179(2); pp.463-468.

Research Conclusions: When the guidelines are strictly followed the risk of malignancy for Probably Benign findings is LESS THAN 2%! Costs of biopsy including procedure time, recovery time, dollars and potential complications can be avoided. Sickles EA. Periodic mammographic follow-up of probably benign lesions: results in 3,184 consecutive cases. Radiology, 1991. Vol 179(2); pp.463-468.

The Alternative View 1,234 calcifications cases and only 1 (0.1%) cancer 448 asymmetries and only 2 (0.4%) cancers 589 masses and 12 (2.0%) cancers Rubin E. Six-month follow-up: an alternative view. Radiology. 1999 Oct;213(1):15-8; discussion 19-21.

The Alternative View Anxious patients will get another opinion Few findings increase enough in 6 months to be detected Rubin E. Six-month follow-up: an alternative view. Radiology. 1999 Oct;213(1):15-8; discussion 19-21.

What is the Right Follow Up? Follow Up Interval Cancers Detected 6 months 6 12 months 17 24 months 7 36 months 2 Isn t this when we would see patients with a BI-RADS 2 in follow up? Sickles EA. Probably benign breast lesions: when should follow-up be recommended and what is the optimal follow-up protocol? Radiology. 1999 Oct;213(1):11-4.

What is the Right Follow Up? 6 months may Catch aggressive cancers early Encourage continued follow up Appeal to some patients who don t like the idea of waiting an entire year

And How Have we Faired? Using BI-RADS 3 for other findings results in delayed diagnosis of more cancers. 3 years of screening with 3 years follow up Case-control study 1,711/82,898 (2.1%) exams with PB9 Lehman CD, Rutter CM, Eby PR et al. Lesion and patient characteristics associated with malignancy after a probably benign finding on community practice mammography. AJR. 2008;190(2):511-515. doi:10.2214/ajr.07.2153.

Caution 150 ipsilateral malignancies 8.8% cancer yield) 129 met study criteria and paired to control 258 exams assessed Only 52 (20%) met the strict PB9 criteria!

Caution 113 exams had prior films 27 malignant cases met PB9 criteria Cancer yield: 27/1,711 = 1.6% 57/63 (91%) cancer cases had prior exams showing growth

Caution Retrospective review of 295 PB9 cases 83 malignancies 51 corresponded to the PB9 finding Rosen EL, Baker JA, Soo MS. Malignant lesions initially subjected to short-term mammographic follow-up. Radiology. 2002;223(1):221-228.

Caution 0/51 met strict PB9 criteria 47/51 (92%) were already growing at the time of PB9 designation Rosen EL, Baker JA, Soo MS. Malignant lesions initially subjected to short-term mammographic follow-up. Radiology. 2002;223(1):221-228.

ARS Question 3 Regarding mammography, is probably benign really just benign? A. Yes B. No

Mammography Conclusions PB9 Works When A complete work-up is performed Morphology is respected Biopsy follows growth Radiologist delivers the recommendation directly to the patient PB9 Fails When Growing things are watched Other morphologies are included Patients don t follow up The message does not allay anxiety

Is probably benign really just benign? ULTRASOUND

Ultrasound: BI-RADS What Can We Follow? Solid mass with Circumscribed margin AND Oval shape AND Parallel orientation AND Hypoechoic to fat Isolated complicated cyst Clustered microcysts All NON-palpable! Mendelson EB, Böhm-Vélez M, Berg WA, et al. ACR BI-RADS Ultrasound. In: ACR BI-RADS Atlas, Breast Imaging Reporting and Data System. Reston, VA, American College of Radiology; 2013. 26

Ultrasound What Can We Follow? Screening Ultrasound (ACRIN 6666) 20% of patients have probably benign findings 0.8% (6/745) of PB9 findings were malignant Barr RG, Zhang Z, Cormack JB, Mendelson EB, Berg WA. Probably benign lesions at screening breast US in a population with elevated risk: prevalence and rate of malignancy in the ACRIN 6666 trial. Radiology. 2013 Dec;269(3):701-12.

What about palpable lumps? ULTRASOUND

Following Palpable Masses Women Under 30 Retrospective review of women under 30 with focal signs and/or symptoms Biopsy, 24 month follow up or tumor registry 830 patients Loving, VA et al. Targeted ultrasound in women younger than 30 years with focal breast signs or symptoms: outcomes analyses and management implications. Am J of Roentgenology, 195(6), 1472 1477.

Following Palpable Masses Women Under 30 BI-RADS Number Malignant 1 or 2 526 (63.4%) 0 3 140 (16.9%) 0 4 163 (19.6%) 2 (1.2%) 5 1 (0.1%) 1 (100%) Total 830 (100%) 3 (0.4%) Age: 12-29 (24) Sensitivity: 100% Specificity: 80.5% NPV: 100% PPV2: 1.8% PPV3: 1.9% Loving, VA et al. Targeted ultrasound in women younger than 30 years with focal breast signs or symptoms: outcomes analyses and management implications. Am J of Roentgenology, 195(6), 1472 1477.

Following Palpable Masses Women Under 30 Focal breast signs or symptoms have a very low (0.4%) incidence of malignancy. 100% sensitivity and NPV of targeted ultrasound Primary imaging test in this clinical setting. No malignancies in BI-RADS 3 lesions Supports ultrasound surveillance over biopsy. Loving, VA et al. Targeted ultrasound in women younger than 30 years with focal breast signs or symptoms: outcomes analyses and management implications. Am J of Roentgenology, 195(6), 1472 1477.

Following Palpable Masses Women 30 39 Retrospective review of women 30 39 with focal signs and/or symptoms Biopsy, 24 month follow-up or tumor registry 954 patients Lehman CD et al. Accuracy and value of breast ultrasound for primary imaging evaluation of symptomatic women 30-39 years of age. AJR Am J Roentgenol. 2012 Nov;199(5):1169-77. PMID 23096195

Following Palpable Masses Women 30 39 BI-RADS Number Malignant 1 or 2 994 (82.2%) 1 (0.1%)* 3 64 (5.3%) 0 4 139 (11.5%) 12 (8.6%) 5 11 (0.9%) 10 (90.9%) Total 1208 (100%) 23 (1.9%) Age: 30-39 (35) Sensitivity: 95.7% Specificity: 89.2% NPV: 99.9% PPV US: 13.2% PPV Mam: 18.4% *Mammography detected one a malignancy at another location in a 32 year old with BRCA mutation. Lehman CD et al. Accuracy and value of breast ultrasound for primary imaging evaluation of symptomatic women 30-39 years of age. AJR Am J Roentgenol. 2012 Nov;199(5):1169-77. PMID 23096195

Following Palpable Masses Women 30 39 Mammography Ultrasound Sensitivity 60.9% 95.7% Specificity 94.4% 89.2% NPV 99.2% 99.9% PPV 18.4% 13.2% Ultrasound could be the primary imaging modality in this population. The added value of mammography was low. Lehman CD et al. Accuracy and value of breast ultrasound for primary imaging evaluation of symptomatic women 30-39 years of age. AJR Am J Roentgenol. 2012 Nov;199(5):1169-77. PMID 23096195

Following Palpable Masses Women Under 40 Retrospective review 263 lesions 4a s were 3 s that were palpable No malignancies Giess CS et al. Risk of malignancy in palpable solid breast masses considered probably benign or low suspicion: implications for management. J Ultrasound Med. 2012 Dec;31(12):1943-9. PMID: 23197547

Following Palpable Masses Women Under 40 But fibroadenomas grow Biopsy when size increases by 20% in 6 months Gordon PB, Gagnon FA, Lanzkowsky L. Solid breast masses diagnosed as fibroadenoma at fineneedle aspiration biopsy: acceptable rates of growth at long-term follow-up. Radiology 2003; 229:233 238.

ARS Question 4 Regarding ultrasound, is probably benign really just benign? A. Yes B. No

Ultrasound Conclusions BI-RADS Says OK to follow non-palpable and isolated Circumscribed, oval, parallel, hypoechoic non-calcified masses Complicated cysts Clustered microcysts Considerations Palpable under 40 Circumscribed, oval, parallel, hypoechoic non-calcified masses Safe to follow May be safe for BI-RADS 2 Biopsy when size increases 20% in 6 months

Is probably benign really just benign? MRI

MRI: BI-RADS What Can We Follow? The specific morphologic and kinetic characteristics of lesions that can be appropriately assessed as MRI BI-RADS 3 remain undefined. We lack robust prospective data with outcomes.

MRI: BI-RADS What Can We Follow? Retrospective reviews Used in 11-24% of exams Malignant in 0.7-10% of cases No prospective trials of defined findings Low compliance with 6 month follow up

MRI: Probably Benign? Authors Year N Patients Cancer Yield Kuhl, et al 2000 26 26/192 (13.5%) 1/26 (3.8%) Liberman, et al 2003 89 89/367 (24%) 9/89 (10%) Eby, et al 2009 236 236/1735 (13.5%) 2/236 (0.9%) Weinstein, et al 2010 106 106/969 (10.9%) 1/106 (0.9%) These data come from retrospective analysis of findings assessed intuitively as probably benign. Some represent background enhancement. Indications for the MRIs were mixed.

MRI Population Is a selected higher risk population Risk of cancer at any moment may be greater than 2% Is subject to time pressure Higher likelihood of aggressive cancers

If You Use BI-RADS 3 for MRI Consider using mammography as a model Only for asymptomatic patients Only for baseline screening Prior exams allow downgrade to BI-RADS 2 for stable or decreasing lesions. Prior exams allow upgrade to BI-RADS 4 for growing or new lesions. Only after a complete work up: targeted ultrasound

If You Use BI-RADS 3 for MRI Recommend against using BI-RADS 3 in patients with a new diagnosis of cancer when evaluating the extent of disease. It leaves unanswered questions when therapeutic decisions are being made. Don t use it for background enhancement.

ARS Question 5 Regarding MRI, Is probably benign really just benign? A. Yes B. No

MRI Conclusions BI-RADS Says Robust prospective data are not available. Use extreme caution. Considerations Follow the mammogram model Baseline screening Complete the work up Not for diffuse bilateral findings

Is probably benign really just benign?

Is probably benign really just benign? WELL?

Is probably benign really just benign? WELL? IS IT?

Probable Conclusions Mammography: benign over 98% of the time when used correctly. Ultrasound: might always be benign in women with palpable lumps under 40 when used correctly. MRI: might just be suspicious.

THANK YOU

References: Mammography Sickles EA. Periodic mammographic follow-up of probably benign lesions: results in 3,184 consecutive cases. Radiology 1991;179(2):463 468 Varas X, Leborgne F, Leborgne JH. Nonpalpable, probably benign lesions: role of follow-up mammography. Radiology 1992;184(2):409 414. Wolfe JN, Buck KA, Salane M, Parekh NJ. Xeroradiography of the breast: overview of 21, 057 consecutive cases. Radiology 1987;165(2):305 311. Helvie MA, Pennes DR, Rebner M, Adler DD. Mammographic follow-up of low-suspicion lesions: compliance rate and diagnostic yield. Radiology 1991; 178(1):155 158. Vizcaíno I, Gadea L, Andreo L, et al. Short-term follow-up results in 795 nonpalpable probably benign lesions detected at screening mammography. Radiology 2001;219(2):475 483. Varas X, Leborgne JH, Leborgne F, Mezzera J, Jaumandreu S, Leborgne F. Revisiting the mammographic follow-up of BI-RADS category 3 lesions. AJR 2002; 179(3):691 695.

References: Ultrasound Berg WA, Sechtin AG, Marques H, Zhang Z. Cystic breast lesions and the ACRIN 6666 experience. Radiol Clin North Am 2010; 48:931 987. Berg WA, Blume JD, Cormack JB, Mendelson EB, Madsen EL. Lesion detection and characterization in a breast US phantom: results of the ACRIN 6666 Investigators. Radiology 2006; 239:693 702. Sickles EA. Periodic mammographic follow-up of probably benign lesions: results in 3,184 consecutive cases. Radiology 1991(2); 179:463 468 Mendelson EB, Böhm-Vélez M, Berg WA, et al. ACR BI-RADS Ultrasound. In: ACR BI-RADS Atlas, Breast Imaging Reporting and Data System. Reston, VA, American College of Radiology; 2013. Loving, VA et al. Targeted ultrasound in women younger than 30 years with focal breast signs or symptoms: outcomes analyses and management implications. Am J of Roentgenology, 195(6), 1472 1477. Lehman CD et al. Accuracy and value of breast ultrasound for primary imaging evaluation of symptomatic women 30-39 years of age. AJR Am J Roentgenol. 2012 Nov;199(5):1169-77. PMID 23096195 Giess CS et al. Risk of malignancy in palpable solid breast masses considered probably benign or low suspicion: implications for management. J Ultrasound Med. 2012 Dec;31(12):1943-9. PMID: 23197547

References: MRI Eby PR, DeMartini WB, Gutierrez RL, Lehman CD. Probably benign lesions detected on breast MR imaging. Magn Reson Imaging Clin N Am 2010;18:309-321 Weinstein SP, Hanna LG, Gatsonis C, Schnall MD, Rosen MA, Lehman CD. Frequency of malignancy seen in probably benign lesions at contrast-enhanced breast MR imaging: findings from ACRIN 6667. Radiology 2010;255:731-737 Hauth E, Umutlu L, Kummel S, Kimmig R, Forsting M. Follow-up of probably benign lesions (BI-RADS 3 category) in breast MR imaging. Breast J 2010;16:297-304 Eby PR, DeMartini WB, Gutierrez RL, Saini MH, Peacock S, Lehman CD. Characteristics of probably benign breast MRI lesions. AJR Am J Roentgenol 2009;193:861-867 Liberman L, Morris EA, Benton CL, Abramson AF, Dershaw DD. Probably benign lesions at breast magnetic resonance imaging: preliminary experience in high-risk women. Cancer 2003;98:377-388