BASICSBradley M. Turner, MD, MPH, MHA • David G. Hicks, MD
BASICS
DESCRIPTION
• Ductal carcinoma in situ (DCIS) is a heterogeneous group of lesions that have in common the presence of a clonal proliferation of neoplastic epithelial cells confined to ducts and lobules.
• Considered a premalignant lesion—the neoplastic cells are not invasive (pure DCIS).
• Classified as low, intermediate, or high grade
• Mortality from DCIS with subsequent progression to invasive breast carcinoma (IBC) is low, regardless of histologic type or type of treatment.
EPIDEMIOLOGY
Incidence
• Based on an observed average annual percentage increase of 1%, there were an estimated 61,500 new diagnoses of DCIS in 2017, and there will be an estimated 62,117 new diagnoses of DCIS in 2018.
• DCIS accounts for approximately 80–85% of in situ breast carcinomas (lobular carcinoma in situ [LCIS] accounts for approximately 15–20%).
• More stable incidence in women 50 to 69 years of age over the last several years
• Increasing incidence in women <50 years of age and >70 years of age over the last several years
• Represents ~26% of all new IBC
• Incidence rate of DCIS is comparable among women of different ethnicities.
ETIOLOGY AND PATHOPHYSIOLOGY
• A nonobligate precursor to IBC.
• Presumed to be the final step prior to IBC, part of a poorly understood spectrum of polyclonal and clonal epithelial proliferative lesions.
• Either low- or high-grade DCIS has the potential for subsequent invasion into the surrounding stroma; however, the changes necessary for transition to IBC are poorly understood.
• Molecular evidence suggests that low- and high-grade DCIS are genetically distinct lesions, with high-grade DCIS associated with more aggressive disease.
Genetics
• Low-grade DCIS typically shows diffuse and strong expression of estrogen receptor (ER) and progesterone receptor (PR), without HER2 protein overexpression or amplification.
• High-grade DCIS not consistently ER+ or PR+; frequent HER2 protein overexpression and amplification; commonly associated with p53 gene mutations
• HER2 overexpression is even more frequent in high-grade DCIS compared to IBC.
• BRCA1 and BRCA2 associations observed
• If patients are high risk, consider genetic counseling after diagnosis of DCIS.
RISK FACTORS
• Similar to IBC, although not as strongly associated
• Female gender, nulliparity, late age at first birth, late age at menopause, family history of a first-degree relative with breast cancer, long-term use of postmenopausal hormone replacement therapy with combined estrogen and progestin, high mammographic breast density, history of atypical ductal hyperplasia (ADH)
• Association with age, body mass index, smoking, lactation, early menarche, increased alcohol consumption, and oral contraceptive use is less clear.
GENERAL PREVENTION
• Recent observational studies have created some controversy, suggesting that screening may result in an increase in overdiagnosis with little or no reduction in the incidence of advanced cancers.
• General screening guidelines have been suggested for asymptomatic women with an average risk of breast carcinoma.
• Women with increased risk should have more aggressive screening (risk assessment tool available at http://www.cancer.gov/bcrisktool/Default.aspx).
• General screening guidelines—U.S. Preventive Services Task Force (USPSTF):
– Biennial mammography for women aged 50 to 74 years
– Avoid routine screening mammography in women 40 to 49 years of age. The decision to start biennial mammographic screening before age 50 years should be individualized based on the patient’s values regarding specific benefits or harms.
– Discourage teaching breast self-exam (BSE).
– Insufficient evidence to assess the value of clinical breast exam (CBE) in women after age 40 years. If this service is offered, the patient should understand this uncertainty.
– Insufficient evidence to assess the benefit or harm of digital mammography or MRI over film mammography. If this service is offered, the patient should understand this uncertainty.
• General screening guidelines—National Comprehensive Cancer Network (NCCN):
– NCCN recommends that women should be familiar with their breast; promptly report changes to their health care provider; and that periodic, consistent BSE may facilitate breast self-awareness.
– Ages 25 to 39 years: breast awareness, CBE every 1 to 3 years
– Age 40 years and older: breast awareness, annual CBE, annual screening mammography
• Clinicians should use judgment when applying screening guidelines.
• Mammography screening should be individualized.
• If no intervention would occur based on screening findings, patient should not undergo screening.
• Risk reduction:
– Assess for familial/genetic and other elements that contribute to an increased risk of breast cancer.
– Lifestyle modifications: Limit alcohol intake to <1 drink/day, exercise, maintain healthy diet, and weight control.
– Risk reduction surgery supported for carefully selected women at high risk of breast cancer who desire this intervention.
– Hormonal risk reduction agents (i.e., tamoxifen) are recommended in certain high-risk women ≥35 years of age.
– Risk reduction benefits of aromatase inhibitors are less clear.
– A recent clinical trial with anastrozole (an aromatase inhibitor) showed a significantly decreased incidence of DCIS in postmenopausal women.
DIAGNOSIS
HISTORY
• Most DCIS is now diagnosed by screening mammography (presence of microcalcifications in approximately 72%); patients may be asymptomatic with nonpalpable mass (12%) (1,2)[A].
• More advanced lesions may present with a palpable mass, spontaneous nipple discharge, or Paget disease (1)[A].
PHYSICAL EXAM
• CBE with inspection of breasts with patient in upright and supine position; evaluating for asymmetry, spontaneous discharge, skin changes (peau d’orange, erythema, scaling); nipple retraction/excoriation (Paget disease)
• Palpation of all breast quadrants with patient in upright and supine position, including lymph node examination (axillary, supraclavicular, and internal mammary nodes)
• Positive clinical findings: Refer for consideration of diagnostic imaging and/or surgical evaluation unless <30 years of age with a low clinical suspicion (observe 1 to 2 menstrual cycles; if positive clinical findings persist, refer for imaging).
DIFFERENTIAL DIAGNOSIS
Usual ductal hyperplasia, flat epithelial atypia, ADH, LCIS, microinvasive carcinoma (1)[A]
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
• Mammography Breast Imaging Reporting and Data System (BI-RADS) developed by the American College of Radiology is used for uniform reporting of mammography results.
• BI-RADS interpretation: Categories (0 to 6) 0: incomplete and needs additional imaging; 1: negative; 2: benign finding; 3: probably benign finding; 4: suspicious abnormality; 5: highly suggestive of malignancy; 6: known biopsy-proven malignancy
• Similar BI-RADS interpretations for diagnostic ultrasound (US).
• Screening BI-RADS category 0: diagnostic workup with consideration for diagnostic imaging
• Screening BI-RADS categories 1 and 2: screening recommendations
• Screening BI-RADS category 3: diagnostic imaging at 6 months, then every 6 to 12 months for 2 to 3 years; consider biopsy if patient anxious or follow-up uncertain.
• Screening BI-RADS categories 4 and 5: diagnostic imaging with follow-up
• Screening BI-RADS category 6: technically not a “screening” category other than to assess a known cancer that might need additional evaluation. NCCN guidelines for breast cancer should be followed.
• DCIS is commonly seen on imaging as clustered microcalcifications (2)[A].
• Diagnostic imaging will result in consideration for tissue biopsy.
Follow-Up Tests & Special Considerations
• US not recommended for screening
• The sensitivity of breast MRI screening is higher than mammography but has lower specificity resulting in a greater number of false positives (2)[A].
• Screening with MRI as an adjunct to screening mammogram is only recommended in certain women: BRCA mutation; first-degree relative of BRCA carrier; ≥20% lifetime risk of breast cancer; radiation to chest between the ages of 10 and 30 years; presence of Li-Fraumeni, PTEN, or Bannayan-Riley-Ruvalcaba syndrome in patient or first-degree relative; ≥20% risk of breast cancer based on gene- and/or risk-level ATM, CDH1, CHEK2, PALB2, PTEN, STK11, TP53.
• MRI can also complement mammography in patients with skin changes.
• Screening with MRI is not recommended in women with <15% lifetime risk of breast cancer.
• Although MRI and US are complementary diagnostic methods to mammography, US is less sensitive in detecting most microcalcifications and MRI does not typically detect microcalcifications at all (2)[A].
• After a diagnosis of DCIS, MRI has been prospectively shown to have a sensitivity of up to 98% for high-grade DCIS (3)[A].
• The NCCN Panel has included breast MRI as optional during the initial workup of DCIS, noting that the use of MRI has not been shown to increase the likelihood of negative margins, or decrease the conversion to mastectomy with DCIS.
• Pathology
– Tissue is necessary for diagnosis: typically core needle (CN) or vacuum-assisted (VA) biopsy (mammographic/stereotactic, US, or MRI guided). Open surgical biopsy can be performed in patients not amenable to CN or VA biopsy.
– Fine-needle aspiration (FNA) is not adequate for specific diagnosis of DCIS; however, it can suggest the presence of neoplastic cells.
– Histologic classification
Classification is subjective; however, traditionally classified as either low, intermediate, or high grade based on architectural patterns (comedo, solid, cribriform, clinging, papillary, and micropapillary), nuclear grade (I, II, or III), and the absence or presence of necrosis (1,2).
Ductal intraepithelial neoplasia (DIN) is an alternative histologic classification incorporating size as a discriminating factor (2)[C].
Grade is more important for prognosis, risk for progression, and local recurrence.
Comedo-type necrosis (necrosis filling central portion of involved duct) is typically seen in high-grade DCIS, with varying degrees of necrosis in other types of DCIS.
– Determination of ER and PR status (1,3)[A]
– Studies show unclear or weak evidence of HER2 status as a prognostic indicator in DCIS (3)[A].
TREATMENT
SURGERY/OTHER PROCEDURES
• Surgery is the primary treatment option. Options for surgery are based on risk of recurrence, anatomic location, extent of disease, and the ability to achieve “negative” margins (3)[A].
• Positive margins are considered “ink on tumor.”
• Negative margins controversial with DCIS (3)[C].
• The optimal margin width for treatment with excision alone is unknown but should be at least 2 mm.
• Totality of evidence may not support the routine practice of obtaining negative margin widths wider than 2 mm.
• Margins <1 mm considered inadequate (1,3)[A].
• Margins <1 mm at the breast fibroglandular boundary (chest wall or skin) do not mandate surgical excision but may be an indication for higher boost dose radiation in patients opting for breast conservation (3)[A].
• DCIS with microinvasion, defined as no invasive focus >1 mm in size, should be considered as DCIS when considering the optimal margin width.
• Surgical options include the following:
– Breast conservation (lumpectomy) without lymph node procedure, with or without whole breast radiation therapy (3)[A]
– A complete axillary lymph node dissection should not be performed in the absence of evidence of invasive cancer or proven axillary metastatic disease (3)[A].
– A sentinel lymph node biopsy should strongly be considered if the lumpectomy is in an anatomic location compromising the performance of a future sentinel lymph node procedure (3)[C].
– Radiation decreases recurrence rates by about 50% (2)[A].
– Drawbacks to radiation therapy include (i) the patient burden of daily treatment for 6 weeks and short-term side effects, such as fatigue and skin toxicity; (ii) a slightly increased risk of secondary cancers; and (iii) inability to receive radiation therapy again in the ipsilateral breast should an invasive carcinoma develop.
– Recurrence generally requires mastectomy with consideration for systemic treatment (2)[C].
– Patients not amenable to margin-free lumpectomy should have total mastectomy (3)[C].
– Mastectomy with or without sentinel node biopsy ± breast reconstruction (3)[A]
– Mastectomy provides maximum local control.
– Rates of recurrence for DCIS and IBC are similar to lumpectomy.
– Recurrence should be treated with wide local excision, chest wall radiation, and consideration for systemic treatment (3)[A].
– Long-term cause-specific survival seems to be equivalent to lumpectomy with whole breast radiation (3)[A].
• Secondary chemoprevention following breast-conserving surgery for ER + DCIS:
– Tamoxifen for premenopausal patients or tamoxifen or an aromatase inhibitor for postmenopausal patients for 5 years (3)[A].
– There may be some advantage for aromatase inhibitor therapy in patients <60 years old or patients with concerns for thromboembolism (3)[C].
– Considered in lumpectomy patients with or without whole breast radiation (3)[A]
– Benefit of tamoxifen and trastuzumab in ER-negative/HER2-positive disease is unclear (1)[C].
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
• History and physical exam every 6 to 12 months for the first 5 years, and then annually
• Mammography 6 to 12 months after whole breast radiation if the breast is conserved, then every 12 months
• If treated with tamoxifen or an aromatase inhibitor, monitor per NCCN guidelines for breast cancer risk reduction (3).
PROGNOSIS
• Good prognosis: 10-year breast cancer-specific survival rates of >95%; overall mortality after diagnosis of treated pure DCIS generally >98%
• Risk of local recurrence after mastectomy generally reported as 1–2% (higher in some studies)
• Higher risk of local recurrences after breast-conserving therapy in younger age (particularly before age 40 years), larger tumor size, high nuclear grade, comedo-type necrosis, and close/positive margin status (related to DCIS volume)
• ER+ tumors are associated with lower risk for recurrence.
• The Oncotype Dx DCIS score, a multigene assay including 7 DCIS related genes, offers hope for quantifying the risk of local recurrence of DCIS or the development of IBC in patients treated with breast-conserving therapy alone
REFERENCES
1. Siziopikou KP. Ductal carcinoma in situ of the breast: current concepts and future directions. Arch Pathol Lab Med. 2013;137(4):462–466.
2. Lee RJ, Vallow LA, McLaughlin SA, et al. Ductal carcinoma in situ of the breast. Int J Surg Oncol. 2012;2012:1–12.
3. NCCN clinical practice guidelines in oncology: breast cancer (Version 2.2016) 2016. National Comprehensive Cancer Network Web site. http://www.nccn.org. Accessed on September 10, 2016.
ADDITIONAL READING
• Gøtzxche PC, Jørgensen KJ. Screening for breast cancer with mammography. Cochrane Database Syst Rev. 2013;(6):CD001877.
• NCCN clinical practice guidelines in oncology: breast cancer risk reduction (Version 1.2016). National Comprehensive Cancer Network Web site. http://www.nccn.org. Accessed on September 10, 2016.
• US Preventive Services Task Force. Screening for breast cancer: U.S. Preventative Services Task Force recommendation statement. Ann Intern Med. 2009;151(10):716–726.
SEE ALSO
CODES
ICD10
• D05.10 Intraductal carcinoma in situ of unspecified breast
• D05.11 Intraductal carcinoma in situ of right breast
• D05.12 Intraductal carcinoma in situ of left breast
CLINICAL PEARLS
• DCIS is a heterogeneous group of noninvasive neoplastic lesions arising from the breast ductal epithelial cells.
• The incidence of DCIS has continued to increase in women <50 and >70 years of age, with a more stable incidence in women 50 to 69 years of age.
• The goal of DCIS treatment is to prevent recurrence and progression to IBC.
• The Oncotype DX DCIS score may be useful in identifying patients at higher risk for recurrence or progression to IBC.
• Current standard of care is breast-conserving therapy with consideration for postoperative whole breast radiation therapy and/or postsurgical tamoxifen or aromatase inhibitor therapy, unless otherwise contraindicated.
• With appropriate therapy, the overall prognosis of pure DCIS is good.