|Year : 2016 | Volume
| Issue : 3 | Page : 137-145
Ductal carcinoma In situ: The challenges and approaches
Sujan N Agrawal
Department of Surgery, Late Shri BRKM Government Medical College, Jagdalpur, Bastar, Chhattisgarh, India
|Date of Web Publication||17-Mar-2017|
Sujan N Agrawal
Department of Surgery, Late Shri BRKM Government Medical College, Jagdalpur, Bastar - 494 001, Chhattisgarh
Source of Support: None, Conflict of Interest: None
Cancer cells are in situ or invasive depending upon whether they have invaded basement membrane or not. Ductal carcinoma in situ (DCIS) signifies in situ growth in the ductal system of the breast. Screening mammography has revolutionized the screening and diagnosis of this clinically occult disease. Diagnosis may be further improved by ultrasonography and magnetic resonance imaging in selected cases. Suspicious area in the breast is subjected to fine needle aspiration cytology (FNAC). The drawback of this simple procedure (FNAC) is that basement membrane cannot be assessed, and hence, image-guided, core needle biopsy or tru-cut biopsy is used to overcome this drawback. After confirmation of the diagnosis, DCIS may be treated by breast conservation or mastectomy and/or radiation. This paper discusses the various challenges encountered at every step in this clinically occult disease during screening, diagnosis, and treatment. Means and ways are highlighted to overcome the challenges.
Keywords: Ductal carcinoma in situ, endocrine therapy, fine needle aspiration cytology, screening mammography, Van Nuys Prognostic Index
|How to cite this article:|
Agrawal SN. Ductal carcinoma In situ: The challenges and approaches. Arch Int Surg 2016;6:137-45
| Introduction|| |
Cancer cells are in situ or invasive depending upon whether they have invaded the basement membrane or not. The original description of in situ breast cancer stressed the absence of invasion of cells into the surrounding stroma and their confinement within the natural ductal and alveolar boundaries. Noninvasive breast cancer comprises two separate entities:
- Ductal carcinoma in situ (DCIS) and
- Lobar carcinoma in situ (LCIS).
DCIS is defined as the proliferation of epithelial cells confined to the mammary ducts; LCIS is described as the proliferation of epithelial cells confined to lobes. Neither DCIS nor LCIS has demonstrable invasion through the basement membrane. Because they are noninvasive, they do not pose the risk of metastasis at this stage. The diagnosis of DCIS has improved over the last couple of decades owing to the widespread use of screening mammography.
Before the introduction of screening mammography, most cases of DCIS remained undetected until they formed a palpable mass. The introduction of mammography in 1980 has registered a tenfold increase in the reporting of DCIS. In US, the incidence of DCIS is 10–20 per 100,000 women per year. This reporting has further increased as the technology of screening mammography has become more refined and sensitive. The median age group of the diagnosis of DCIS is 47–63 years. The risk factors are family history among first-degree relatives, older age group, nulliparity, proliferative breast disease, and old age at the time of first full-term pregnancy. DCIS constitutes 20–25% of all newly diagnosed breast cancer cases  and 17–34% of mammographically detected neoplasm.,
The risk for invasive breast cancer is increased nearly five folds in women with DCIS. The invasive cancers are observed in the ipsilateral breast in the same quadrant as the DCIS that was originally detected, which suggests that the DCIS is an anatomical precursor of the invasive breast carcinoma.
DCIS is characterized by the proliferation of epithelial cells that line the mammary ducts resulting in papillary growth within the ductal lumen. The papillary growth (papillary growth pattern) eventually coalesces and fills the duct lumen so that only scattered, rounded spaces remain between the clumps of atypical cancer cells, which shows hyperchromasia and loss of polarity (cribriform growth pattern). Eventually, pleomorphic cancer cells with frequent mitotic figure obliterate the lumen and distend the ducts (solid growth pattern). With continued growth, the blood supply to cells becomes deficient and central necrosis occurs (comedo growth pattern). Calcium deposition (microcalcification) occurs in the area of necrosis and is a common feature in screening mammography. Changes are also seen in the surrounding stroma; the changes in stroma are fibroblast proliferation, lymphatic infiltration, and angiogenesis.
Silverstein et al. developed the Van Nuys DCIS pathological classification, in which three risk groups were identified based on the presence or absence of high nuclear grade and comedo type necrosis, i.e.,
- Non-high-grade DCIS without comedo type necrosis
- Non-high-grade DCIS with comedo type necrosis
- High-grade DCIS with or without comedo type necrosis.
DCIS is frequently classified depending upon the nuclear grade and the presence or absence of necrosis. Based on multiple consensuses, grading of DCIS has been recommended; although there is no universal agreement on classification, most systems endorse the use of cytological grade and presence or absence of necrosis. Pathological classification alone, however, was not sufficient for considering an appropriate treatment plan for patients with DCIS, because it failed to take into account two additional significant predictors of local recurrence, i.e., the tumor size and histological margin width after excision. The Van Nuys Prognostic Index (UNPI) was developed to overcome this problem.
Multiple DCIS is generally defined as the DCIS present in two or more foci separated by 5 mm in the same breast quadrant. Most investigators believe that multifocal disease in fact represents intraductal spread from a single focus DCIS.,
Multicentric DCIS is defined as the DCIS presenting as a separate focus outside the index quadrant. The mammary lobules are not constrained by the artificially imposed quadrant segregation. Cursory pathological examination may incorrectly interpret contiguous intraductal spread as multicentric. Approximately 96% of all local recurrences after treatment of DCIS occurs in the same quadrant as the index lesion, implicating residual untreated disease rather than multicentricity.
Microinvasion as per definition is not a feature of DCIS. The American Joint Committee on Cancer (AJCC) staging system defines microinvasion as the invasion of (breast) cancer cells through the basement membrane at one or more foci, none of which exceeds a dimension of 1 mm  and are generally treated according to the guidelines for invasive disease. Occult microinvasive tumors are most common in patients with DCIS lesions that are greater than 2.5 cm in diameter, those presenting with palpable masses or nipple discharge, and those with high grade DCIS or comedonecrosis.,,
DCIS is a clinically occult disease. With the routine use of screening mammography, there has been a tenfold increase in diagnosing breast abnormalities as well as DCIS. Patients detected with abnormal mammogram should undergo imaging of the other breast also because 0.5–3% of patients have synchronous occult abnormalities or cancer in contralateral breast. Mammography image should be compared with previous image, if available, to verify the interval changes.
Before the advent of routine mammography, most patients with DCIS presented with palpable mass, nipple thickening or discharge, or Paget's disease of nipple. DCIS may be the incidental finding in biopsy of otherwise benign breast lesion.
Screening mammography recommendations
These recommendations are advised by the American Cancer Society, American College of Radiology, and MD Anderson Cancer centre.
- Annual screening mammography is recommended beginning at the age of 40
- Annual screening mammography before the age of 40 is recommended in following groups:
Women who are known carrier of BRCA-1 or BRCA-2 gene mutations because they are at an increased risk of developing cancer at a younger age (in males also).
Women who have first degree relatives (mother, sister, daughter) with premenopausal breast cancer or evidence of a high hereditary risk for breast cancer.
In women with high risk of breast cancer based on hereditary factor, mammographic screening is usually started 10 years before the age of index patient at diagnosis but not before the age of 25. (e.g., a woman whose mother was diagnosed with breast cancer at the age of 43 would begin annual screening mammography at age 33).
Women who received radiation therapy before the age of 30 are at an increased risk of possible radiation damage to breast tissue. In such cases, mammographic screening should start 10 years after the completion of radiation therapy but not before the age of 25, thereafter annual mammography is suggested.
Mammograms are radiographic imaging of breast tissue by low energy X-rays. Two views are normally taken of each breast, i.e. the mediolateral oblique view and craniocaudal view.
- Quick to perform and interpret
- It images the whole breast
- It has high sensitivity for the detection of DCIS and invasive breast cancers.
- It uses ionizing radiation
- Breast compression is required which may be uncomfortable for some
- It requires highly skilled and trained radiographer
- Specificity is low unless combined with USG and biopsy.
To overcome the disadvantages, the use of digital mammography is a good advancement. It improves the display and image quality, leading to increased cancer detection, particularly in younger women with dense breast tissue.
Microcalcification is the hallmark of the DCIS, (in approximately 76% of cases), or sometimes as masses/soft tissue densities (in 11–13% of the cases).,
Holland et al. described two different classes of microcalcification:
- Linear branching type of microcalcification which are more often associated with high nuclear grade, comedo type lesion
- Fine granular calcification which is primarily associated with micropapillary or cribriform lesion of lower nuclear grade that does not show necrosis.
The addition of digital mammography further enhances the chances to detect DCIS.
Ultrasonography in ductal carcinoma in situ
Ultrasound is not used routinely as a screening modality because of its limited sensitivity and time consuming process. It can be subsequently used for assessment in breast with malignant feature found in mammography. It can be used for targeted biopsy of doubtful breast lesion. USG of axilla may be needed for staging the axilla in breast cancer patients.
Magnetic resonance imaging
- It has high sensitivity for the detection of invasive breast cancers but has limited sensitivity for DCIS
- It is expensive and time consuming. Cost benefit analysis will be required to determine the applicability of MRI to everyday clinical practice
- It is most frequently used for local staging of breast carcinoma prior to breast conserving surgery. The complimentary role of MRI to mammography has recently been reported in a large prospective observational study that showed that MRI is particularly useful in high grade DCIS lesions, residual disease, occult invasion, and multicentricity. MRI may also have a role in the evaluation of the patients at high risk of invasive disease, or in patients with painful, dense, or nodular breasts for whom physical exam or mammography is difficult or unreliable ,,
- It is useful in the identification of occult primary in women presenting with malignant axillary lymphadenopathy with normal mammogram and ultrasound
- Useful in post-surgical breast to differentiate surgical scarring from recurrent tumor
- It is the imaging modality of choice for assessing the integrity of breast implants. It is also useful for the diagnosis of complication of implants such as implant rupture, free silicon, silicon granuloma, and silicon in axillary lymph nodes.
Fine needle aspiration cytology
FNA is the method of percutaneous biopsy using a fine needle, (typically 22 or 24 gauge). The needle is passed in the lesion several times and the aspirate is smeared on glass slide and processed for microscopic examination (cytology). It has several advantages and disadvantages.
- Reliable, accurate, and cost-effective procedure
- Simple to perform in the office or an outpatient department setup without anesthesia
- Provides diagnosis prior to surgery and gives an opportunity for surgeon to plan the operation and follow-up. It also helps to discuss the planning with the patient, prior to the surgery
- Almost free of complication, and is a low cost procedure.
- Requires trained and experienced pathologist
- Equivocal results are confusing and need further investigation such as core needle biopsy
- Assessment of basement membrane invasion cannot be done and immunohistochemical and/or molecular techniques are not possible, requiring core needle biopsy. Yet, immunohistochemical markers might help further classification of carcinomas even in small fine needle aspiration biopsy (FNAB) material, permitting more consistent patient enrollment for trials with targeted treatment.
The primary aim of the FNAC is to make a distinction between benign and malignant lesion. The reporting also needs standardization for understanding and comparable results, as well as to maintain a database. In the UK, the National Health Service Breast screening Program has developed a numerical system for standardization of classification, database maintenance, and calculation of sensitivity and specificity. This system uses a five point classification (C1 to C5) as follows:
C1: Inadequate – Inadequate smear due to hypocellularity or error in aspiration, spreading or staining. There should be at least 6–10 epithelial cells per aspirate.
C2: Benign – This category includes adequate sample containing benign epithelial cells with no feature of atypical or malignancy.
C3: Atypia probably benign – The aspirate shows most of the characters of benign category. Cellularity may be normal or increased. There are some more features which are usually not present in benign lesion, such as
- Crowded enlarged nuclei, which overlap in three-dimensional group or sheets
- Loss of cellular cohesion
- Nuclear pleomorphism
- Chromatin clumping
C4: Suspicious of malignancy – this category shows highly atypical features.
C5: Malignant – In this category, the aspirate is adequate and features are suggestive of malignancy. The cells shows increased nuclear-to-cytoplasmic ratio and pleomorphism. The nuclei are typically hyperchromatic with prominent nucleoli. Nuclear membrane and chromatin are irregular. Necrotic debris may be present in the background.
Image-guided breast biopsies
Biopsy by FNA has some inherent disadvantages. It is unable to differentiate between in situ and invasive carcinoma. It is associated with higher rates of inadequate samples. To overcome the disadvantages, core needle biopsy was introduced in mid 1990s. A Cutting needle (14 gauge) is fired into the lesion and a core of suspicious tissue is obtained for histopathological examination. A further rectification is done by stereotactic core needle biopsy and/or vacuum assisted core biopsy.,,, Vacuum-assisted breast biopsy can be performed under ultrasound or stereotactic X-ray guidance. A minimum of five cores is required when sampling microcalcification.
The DCIS represents a broad biological spectrum of disease, with a wide range of treatment approaches. However there is a lack of clear and universally accepted treatment criteria, resulting in diverse and confusing clinical recommendations, distressing to both the clinician and patients.
The treatment controversy centers around breast conservative surgery versus total mastectomy and breast irradiation.
Mastectomy versus breast conservation therapy
Traditionally, DCIS is treated with mastectomy. However, treating noninvasive lesion with mastectomy appears to be overtreatment and provides only a theoretical benefit. The rationale for performing a total mastectomy in patients with DCIS is based on the high incidence of multifocality and multicentricity, as well as the risk of occult invasion associated with the disease. Although recurrence rates are higher in patients who undergo breast conservation surgery than in patients who undergo mastectomy, a survival advantage is shown in the latter group.,
The goal of breast conserving surgery is to remove all suspicious calcification to obtain negative surgical margins. Because DCIS is usually not palpable, breast conserving surgery is performed with mammographic needle localization. In addition, specimen radiography is essential to confirm removal of all microcalcification. After whole specimen radiography, the specimen should be inked and serially sectioned for pathological examination so as to evaluate the margin status and extent of disease. Intraoperative margin assessment enabled re-excision to be performed during the same surgery if microcalcification extended to the cut edges of specimen.
After intraoperative margins are deemed adequate, the boundaries of the resection cavity is marked with radio-opaque clips to aid in the planning of postoperative radiation therapy and in mammographic follow-up.
The intraoperative goal of breast conserving surgery is to obtain tumor free margin of up to 1 cm, if possible. Anything more than 2 mm tumor free margin is considered adequate.
Most patients with DCIS who undergo breast conserving surgery receive postoperative radiation therapy. Breast conservation alone without radiation therapy is accompanied by disturbing number of local failure.,,
The landmark trials in the treatment of DCIS with or without radiotherapy include:
- National surgical adjuvant Breast and Bowel project (NSABP) B-17 trial. In this trial, the patients were randomized to breast conserving surgery alone or breast conserving surgery plus radiotherapy after margin negative resection. In a 12-year follow-up period, the radiation therapy was associated with reduction in cumulative incidence of noninvasive and invasive ipsilateral breast tumor. These data lead the NSABP to recommend radiation to all conservatively treated patients of DCIS ,,,
- European organization for treatment of cancer 10853 trial. In this trial, 1010 women were randomized to breast conserving surgery or breast conserving surgery plus radiotherapy. There was reduction in invasive and noninvasive tumor of the breast in those patients who underwent conservative surgery plus radiotherapy 
- The third trial which was conducted by the United Kingdom Co-ordination Committee on cancer research also confirmed the benefit of radiotherapy after breast conserving surgery.
The conclusion from these three prospective randomized trial is that the addition of radiation therapy following breast conserving therapy for DCIS results in an approximately 50% relative reduction in breast cancer recurrence. The cumulative incidence of noninvasive ipsilateral breast tumor recurrence (IBTR) as a first event was significantly reduced with radiation from 14.6% to 8% (P = 0.001), more importantly cumulative incidence of invasive ipsilateral recurrence was also significantly reduced from 16.8% to 7.7% (P = 0.00001). However, no difference in overall survival (OS) was observed between the two groups (86% vs 87%, P = 0.80). In addition, over two-thirds of the deaths occurring in this trial were not breast cancer related.
However, breast irradiation therapy is not without its side effects. It changes the texture of the breast and makes consequent mammography more difficult to interpret; another important drawback is that its use precludes additional radiation therapy and breast conservation surgery, should a metachronus invasive breast carcinoma develops later on. Hence, the radiation therapy should be offered only to those patients with DCIS who are likely to be benefitted by radiotherapy. Breast conserving therapy alone (without radiation therapy) is appropriate in a select group of patients.
Subsequently, Silverstein et al. developed the VNPI by combining three statistically significant predictors of local recurrence, viz. tumor size, margin width, and pathological classification.
A score of 1 (best) to 3 (worse) was given for each of the three predictors. The objective with all three predictors was to create three statistically different sub groups for each predictor, using local recurrence as a marker of treatment failure [Table 1].
The Van Nuys Prognostic Index formula
The van Nuys Prognostic Index formula is as follows:
VNPI = Size score + Margin score + Pathological classification score.
The formula yields seven groups ranging from 3 to 9. The best possible VNPI score is 3, with a score of 1 for each predictor, e.g., a 5-mm low grade lesion with widely clear margin. The worst possible score is 9 with a score of 3 for each predictor, e.g., a 50-mm high grade lesion with involved margins. Depending upon the VNPI index, the patients can be subdivided into three subgroups with scores between 3 and 4/5–6 and 7/8 or 9.
This index has recently been modified to include patients' age as a statistically significant predictor of local recurrence and is now referred to as the University of Southern California (USC)/VNPI score.
Score 1: Age greater than 60 years.
Score 2: Age between 40 and 60 years.
Score 3: Age less than 40 years.
In the final USC/VNPI score, 4 is the lowest possible score and 12 is the highest possible score.
To date, no study of DCIS patients has shown a statistically difference in mortality when the three available treatment are compared, i.e. mastectomy, excision alone, and excision with radiotherapy. However, it is important to note that local recurrences in patients who have struggled to save their breast are both demoralizing and theoretically, if invasive, threat to life.
Score 4 to 6: Wide local excisions.
Score 7 to 9: Wide local excision with radiation therapy.
Score 16 to 12: Mastectomy.
| Endocrine Therapy|| |
Tamoxifen has shown benefit to the patients of DCIS who underwent breast conserving surgery. The patients with estrogen receptor positive status benefitted from 20 mg of tamoxifen per day. DCIS patients with estrogen negative status have no added benefit to tamoxifen.
Between 1991 and 1994, 1804 women with DCIS who were treated with lumpectomy were randomized to receive postoperative radiotherapy and either 20 mg of tamoxifen daily for 5 years or placebo daily for 5 years (NSABP B-24 trial). Updated results after 7 years of follow-up continue to demonstrate that:,,
- Women who received tamoxifen had fewer breast cancer events at 7 year follow-up than the placebo group (10.0% vs 16.9%)
- Ipsilateral invasive breast cancer was 2.6% at 7 year (tamoxifen group) as compared to 5.3% in the controlled group
- Cumulative incidence of contralateral breast neoplasm (invasive and noninvasive) was 2.3% in the tamoxifen group as compared to 4.9% in the control group
- The benefit of tamoxifen should also be extended to patients with positive margins of unknown status
- Women with estrogen positive status who received tamoxifen had 59% reduction in their relative risk of breast cancer events as compared to those who received placebo.
However, there was no difference in overall 7-year survival rates, which was 95% in both the tamoxifen and placebo groups. The decision to use tamoxifen for patients with DCIS should also be made on an individual basis. The use of tamoxifen is associated with vasomotor symptoms, deep vein thrombosis, pulmonary embolism, and increased cataract formation. There is a risk of development of endometrial cancer also. There is an increased risk of strokes and benign ovarian cyst.
Therefore, the effects of tamoxifen to reduce ipsilateral breast tumor and to prevent contralateral breast disease should be weighed against the risk of tamoxifen use in each patient. It should also be reserved for estrogen receptor positive tumors.,
Aromatase inhibitors as adjuvant treatment have been shown to be beneficial in postmenopausal patients with invasive breast cancer. They have fewer cardiovascular side effects. The trials are undergoing and final recommendations are yet to come.,,
| Axillary Lymph Node Biopsy|| |
Axillary lymph node biopsy is not done routinely in cases of DCIS because it is a noninvasive disease and lymphatic involvement is not expected.
Patients who undergo mastectomy for large high grade DCIS should be considered for intraoperative lymphatic mapping and sentinel lymph node dissection. It may not be possible to perform lymphatic mapping after mastectomy if invasive cancer is found in operated specimen. Patients with large, high grade, or palpable DCIS who are undergoing breast conserving surgery are also potential candidate for intraoperative lymphatic mapping and sentinel lymph node biopsy.,,,
| Conclusion|| |
DCIS being a clinically occult disease poses many challenges for diagnosis and treatment. A carcinoma is labeled as in situ when the cancer cells have not invaded the basement membrane. Introduction of routine mammography as a screening tool has registered many fold increase in the detection of noninvasive carcinoma. DCIS is characterized by proliferation of epithelial cells that line the duct resulting in papillary growth. Eventually, central necrosis occurs in rapidly growing cells followed by microcalcification. The microcalcification and change in cellular density are characteristic finding in mammography. The suspicious area in breast is subjected to FNAC/biopsy. The tissue sample is examined histopathologically to establish the diagnosis. After diagnostic confirmation, decision is taken for breast conservation surgery, radiotherapy, or mastectomy and hormone therapy. Lymph node biopsy in DCIS is not a routine practice. This article highlights the challenges and approaches to combat the challenges at every step, which can be summarized as follows:
- The disease is a clinically occult disease, and hence the clinical diagnosis is not possible unless a palpable lump is present
- The diagnosis is mainly by screening mammography, which reveals this clinically occult disease by presence of microcalcification and change in tissue density. The sensitivity is further increased by digital mammography and use of other imaging techniques such as ultrasonography and MRI in selected cases
- The cytological diagnosis is by FNAC. Image-guided FNAC improves its sensitivity. The only drawback is that the basement membrane cannot be assessed by FNAC. Core needle biopsy is more useful for histological diagnosis and to assess the status of basement membrane
- DCIS is treated by lumpectomy, lumpectomy plus radiation, or mastectomy
- Submitting a patient for mastectomy routinely for DCIS amounts to overtreatment, more so when we are embarking upon more and more conservative approach for invasive disease
- Radiation therapy is not indicated in every case. There is a subset of patient who require only lumpectomy, others can be submitted to lumpectomy plus radiation, few patients still require mastectomy
- VNPI is a useful guide to plan the treatment of DCIS in a different subset of patients. It is further refined by adding patients' age to the index, i.e. USC/VNPI index
- Tamoxifen improves the breast cancer event in women who underwent breast conservative surgery, although the OS remains unaffected. Tamoxifen is of no use in estrogen receptor negative DCIS
- Because it is a noninvasive disease, the axillary lymph node sampling is not indicated, and is reserved for few selected cases.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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