Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Treatment of ductal carcinoma in situ
Background
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer in which the proliferation of malignant epithelial cells remains confined by an intact basement membrane, without invasion into the surrounding stroma. The introduction of screening mammography has led to a marked increase in the detection of DCIS, from 2% of newly diagnosed breast cancers before national screening to over 20% of all screen-detected tumours. DCIS is often detected as microcalcification ( Fig. 13.1 ) or, less commonly, as tissue distortion. Around 80% of DCIS diagnosed is impalpable, asymptomatic and detected by screening. Screen-detected cases of DCIS are usually smaller and localised (and suitable for breast-conserving surgery [BCS]) in contrast to patients who present symptomatically with a palpable breast lump, nipple discharge or Paget’s disease of the nipple. Management of DCIS is multidisciplinary, involving particularly the imaging, pathology, surgery and clinical oncology teams.
Risk factors, natural history, pathology and receptors
Risk factors
Risk factors for the development of DCIS are essentially similar to those for invasive breast cancer and include a family history of breast cancer, older age at first childbirth and nulliparity. Patients with BRCA gene mutations have a six-fold lifetime increased risk of DCIS compared to non-carriers. Although epithelial proliferation in the breast is increased by the use of the oral contraceptive pill or hormone replacement therapy (HRT), particularly combined oestrogen/progestogen HRT taken for over 5 years, there is little evidence to date that either the oral contraceptive pill or HRT significantly increases the risk of DCIS. Two studies , have reported a relative risk of 1.4 for the development of DCIS following oestrogen-only HRT preparations and a relative risk of 1.7–2.3 with oestrogen- and progestogen-containing preparations. In the Women’s Health Initiative study there were 47 cases of DCIS in the HRT group compared with 37 cases in the control group (hazard ratio [HR] 1.18; weighted P = 0.09). Other studies have shown no increased risk of DCIS following HRT use. ,
Natural history
The natural history of DCIS is heterogeneous and remains poorly understood. For biopsy-proven DCIS not surgically resected, high-grade disease is more likely to progress to invasive cancer than low-grade DCIS and progression may be slowed by endocrine therapy. However, the timelines for progression, particularly for low-grade DCIS, may be prolonged and postmortem studies have identified women with undiagnosed DCIS that has clearly not progressed to clinically evident disease in the lifetime of the person. ,
A review of DCIS recurrences and their primary lesions from the EORTC 10853 trial , found concordant histology (similar grade) in 62% of cases, and identical marker expression (oestrogen receptor [ER], progesterone receptor, p53 and HER-2/neu) in 63% of both invasive and non-invasive recurrences. Other genomic studies using a range of techniques have shown that 80% of DCIS recurring as invasive disease is genetically similar to the original lesion, whilst the remainder of tumours are genetically distinct from the primary DCIS. This high proportion of primary/recurrence pairs with identical receptor profiles suggests that in the majority of cases residual disease after initial treatment recurs as detectable DCIS or progresses to invasive cancer.
Pathology
Classification and features
DCIS has been classified in a variety of ways according to morphological/architectural appearances ( Fig. 13.2 ), the presence or absence of comedo necrosis and by nuclear and/or histological grade. Subtypes include:
-
Solid – where malignant cells fill extended duct spaces;
-
Micropapillary – where tufts of cells project into the duct lumen perpendicular to the basement membrane;
-
Papillary – where the projecting tufts are larger than in the micropapillary type and contain a fibrovascular core;
-
Cribriform – where the arrangement of the malignant cells takes on a fenestrated/sieve-like appearance;
-
‘Clinging’ (flat) – where there are usually single-layered, atypical epithelial cells lining the ducts. Of note, the monomorphic variant of ‘clinging carcinoma’ is now considered to be an atypical lesion (i.e. flat epithelial atypia) rather than a form of DCIS, whilst only the high-grade, pleomorphic variant is considered to be DCIS;
-
Rarer subtypes also exist, including neuroendocrine, encapsulated papillary, apocrine and signet ring cell.
Comedo necrosis often bears microcalcification that is typically responsible for the mammographic features of DCIS. However, this comedo necrosis has been variably defined from any central necrosis associated with DCIS through to various proportions (10–80%) of the centre of the duct containing amorphous necrotic material. Unfortunately there is little agreement on what actually constitutes comedo necrosis, with one recent assessment of 35 specialist breast pathologists failing to reach consensus in any more than a third as to the extent needed to meet the diagnosis of comedo necrosis.
The UK and European breast screening programmes classify DCIS as of low, intermediate and high nuclear grade. These descriptions reflect a continuum between low-risk DCIS for progression to invasive disease to higher risk if left alone ( Fig. 13.1 ). The definitions are based on the cytonuclear features of the lesion and use a comparison of tumour cell size with normal epithelial and red blood cell sizes :
-
Low-nuclear-grade DCIS (∼10% of cases) has evenly spaced cells with centrally placed, small regular nuclei and few mitoses and nucleoli that are not easily seen.
-
Intermediate-grade DCIS (∼30%) has features between those seen in low- and high-grade DCIS but tends to be grouped with low-grade DCIS in clinical studies.
-
High-nuclear-grade DCIS (60%) has irregularly spaced cells with large, pleomorphic, irregular nuclei (often three times the size of erythrocytes), prominent nucleoli and frequent mitoses. It is often solid in architecture with comedo necrosis and calcification.
If a lesion contains areas of varying grade, it is classified by the highest grade present. A universally agreed classification system has yet to be established and will need to be observer independent and clinically relevant. The majority of DCIS lesions are high grade.
Unfortunately, despite the presence of guidelines, agreement on DCIS grade between breast pathologists can be poor. A recent study of nine specialists from the UK, US and the Netherlands reviewing the same 400 whole slide images (one per patient) showed concordance for the 10% of lowest grade lesions and the 10% highest grade lesions but discordance for the majority. This makes the inclusion of pathological grading of DCIS difficult in molecular/clinical assays designed to impact treatment decisions.
Most cases of DCIS are unicentric; extensive sectioning of mastectomy specimens bearing DCIS show only 1% have multicentric disease. A multicentric tumour is defined as separate foci of tumour found in more than one breast quadrant, or more than 5 cm away from the initial primary. A tumour is classified as multifocal if there are separate tumour foci in the same quadrant and close to the original tumour although most such lesions have similar morphology and are linked. This classification lacks clinical utility and some now use the term ‘multisite’ to encompass both multifocal and multicentric disease. (See Breast Conservation Chapter for more discussion of this issue) The local spread of DCIS is along the galactophoric tree that forms the glandular breast and often extends beyond the borders of a quadrant. Most DCIS is continuous along the branching ductal network. Poorly differentiated high-grade lesions are reported to be more frequently multifocal. Most DCIS recurrences are at or near the site of the initial disease, but some recurrences are remote from the initial lesion yet exhibit similar genotypical and phenotypical characteristics to the primary lesion.
As well as documenting the pathological features of the DCIS in the histology report (grade, presence of necrosis, size of lesion etc.), the pathologist should detail the presence or absence of microinvasion, defined as breach of the myoepithelial duct boundary by malignant cells, but measuring 1 mm or less. The reproducibility of the diagnosis of microinvasion is questionable with markedly different frequencies in published series. Lesions that can be mistaken for microinvasion include DCIS that involves lobules (‘cancerisation of lobules’), branching ducts, distortion of ducts or acini by fibrosis, crush or cautery artefacts and DCIS involving a benign sclerosing process (e.g. radial scar or sclerosing adenosis). If microinvasion is detected histologically, a particularly thorough examination of the specimen should be undertaken, as more than one focus of microinvasive disease is not infrequently present, and if foci that are more than 1 mm in extent are seen, then true invasive disease should be sought.
Receptors and markers
Normal breast epithelium heterogeneously expresses ER and progesterone receptor and has a very low rate of apoptosis and human epidermal growth factor receptor 2 (HER2) expression. Overall, some 90% of DCIS expresses ER and up to 40% of DCIS expresses HER2. Low-grade lesions have higher ER expression, with lower rates of cell proliferation, and less apoptosis than high-grade lesions. Low-grade DCIS very rarely overexpresses HER2. Progesterone receptor expression tends to correlate with ER expression in both low- and high-grade tumours. By comparison, high-grade DCIS is less often ER positive and has a higher rate of cell proliferation (as assessed by Ki67, a nuclear antigen expressed in late G 1 S, G 2 and M phases of the cell cycle but not in the quiescent G 0 ), higher rates of apoptosis and more commonly overexpresses HER2 and epidermal growth factor receptor (EGFR [HER1]).
Rodrigues et al studied women aged 42 years or younger (mean age 38.5) and women aged 60 years or older (mean age 67.8) at diagnosis. They found that although there was no difference in DCIS grade, comedo necrosis or overall histology (also noted in the EORTC trial) between the groups, younger women more frequently had HER2-overexpressing DCIS than older patients. Approximately 65% of the younger age group had HER2-positive disease compared with 38% of the older age group ( P = 0.06). No significant difference was found between ER, progesterone receptor, p53, Ki67, cyclin D1 or bcl-2 expression.
Molecular panels
Whilst the assessment of ER can suggest a potential benefit for use of endocrine therapy, i.e. in ER-positive DCIS, there is no universal agreement on the value of further immunophenotyping of DCIS and molecular panels have not met with enthusiasm comparable to that for invasive disease. Panels of molecular markers, including the Exact Sciences Oncotype DCIS Score molecular assay combined with clinical factors and more recently the PreludeDx DCISionRT tool incorporating biomarkers with clinical prognostic factors, have the potential to guide clinical decision-making for the omission of radiotherapy (RT) and are further discussed later.
Presentation, investigation and diagnosis
Presentation
As noted, some 80% of DCIS is detected by mammographic screening; 70% exhibiting microcalcifications have no associated mass lesion. Calcifications may be heterogeneous, fine, linear, branching, malignant or of indeterminate appearance. Microcalcifications with an associated mass lesion are seen in a third of DCIS diagnosed by screening. Mammographic magnification views can be of value to more accurately delineate the extent of microcalcifications. Circumscribed nodules, ill-defined masses, duct asymmetry and architectural distortion are sometimes seen in association with DCIS. When diagnosed symptomatically, DCIS is more often extensive, is more commonly ER negative and is associated with a concurrent invasive tumour in 50% of cases. Symptomatic DCIS may present as a palpable mass, Paget’s disease of the nipple or with nipple discharge.
Investigation and diagnosis
Clinical examination is important to detect possible signs of invasive disease. In addition, ultrasound can be valuable in excluding an associated mass lesion. Diagnosis is best confirmed by core biopsy or vacuum-assisted large-bore core biopsy (the latter particularly for lower suspicion microcalcifications where sufficient tissue is required for histopathological distinction from atypical ductal hyperplasia). Cytology has a low sensitivity and, even if malignancy is diagnosed, gives no information on the presence of stromal invasion (thus failing to distinguish DCIS from invasive disease). Image guidance (by stereotaxis, ultrasound or, rarely, magnetic resonance imaging [MRI]) is essential to ensure accuracy of sampling.
Stereotactic core biopsy and vacuum-assisted biopsy
In the NHS Breast Screening Programme (NHSBSP), the primary method of diagnosis is typically by stereotactic core biopsy with a 14-gauge needle. This is utilised in many centres if the screen-detected calcification is of high suspicion. For lower suspicion mammographic calcifications (e.g. fine, powdery rather than linear and branching), or if initial core biopsy is inconclusive, then vacuum-assisted biopsy (VAB) using a device which takes several contiguous cores of a wider calibre (11, 9 or 7 gauge) during a single pass is used. A marker clip should be inserted during the procedure to aid future localisation, especially in small lesions where all microcalcification (and indeed the entire lesion) can be removed during diagnostic core biopsy. VAB may be used in the UK if core biopsy is inconclusive, but a small randomised trial suggested equal diagnostic accuracy when using digital mammography guidance. A coexisting invasive tumour is undiagnosed in 10–20% of cases of DCIS and may not be evident until postoperative final pathology. Factors associated with an upgrade to invasive disease include high-grade DCIS, imaging size >2 cm, a Breast Imaging Reporting and Data System (BI-RADS) score of 4 or 5, a visible mass at mammography (versus calcification alone) or a palpable abnormality. If the area of calcification is extensive (>4 cm in size), multiple areas should be biopsied preoperatively to confirm the extent of any DCIS for surgical planning and to increase the chance of detecting any associated invasive cancer.
Localisation-guided biopsy
Rarely, a definitive histological diagnosis cannot be made with either core biopsy or VAB. Failure to sample the calcification adequately (which may be due to technical difficulties of sampling consequent upon the location of the lesion), or where diagnostic doubt exists, should lead to consideration of open biopsy. The excised specimen should be X-rayed intraoperatively to confirm that the microcalcification of concern has been adequately sampled. The Association of Breast Surgery (ABS) guidelines recommend that 90% of diagnostic biopsies for screen-detected abnormalities should weigh less than 20 g in order to avoid excision of large areas of lesions that are shown subsequently to be benign. Due to improved preoperative diagnosis, localisation procedures are usually therapeutic rather than diagnostic. However, DCIS may be pathologically larger or smaller than mammographically estimated; up to 30% of patients undergoing excision for DCIS need re-excision to clear margins adequately. Accurate orientation of the specimen is essential to direct re-excision of the relevant margin(s) and to minimise the volume of any re-excision.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here