carcinoma in situ ductal carcinoma in situ lobular carcinoma in situ pagets disease evidence based management randomized control trials metaanlysis

1. Carcinoma In Situ
Management Overview
Presented By: Dr Isha Jaiswal
Moderated By: Dr Ritusha Mishra
Date:10th March 2015

2. AJCC 2010 TNM STAGING OF CA BREAST*
• Primary Tumor
• Definitions for classifying primary tumor (T) are same for clinical &
pathologic classification
Tx : Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
• Tis (DCIS): Ductal carcinoma in situ
• Tis (LCIS) :Lobular carcinoma in situ
• Tis (Paget’s) :Paget’s disease of the nipple
*AJCC VII Cancer Staging Manual 2010 springer

3. T1:Tumor ≤2 cm in greatest dimension
• T1mic :Microinvasion ≤ 0.1 cm in greatest dimension
• T1a :Tumor > 0.1 cm but ≤0.5cm in greatest dimension
• T1b :Tumor > 0.5 cm but ≤1 cm in greatest dimension
• T1c :Tumor > 1 cm but ≤ 2 cm in greatest dimension
T2 :Tumor > 2 cm but ≤ 5 cm in greatest dimension
 T3 :Tumor >5 cm in greatest dimension
 T4 :Tumor of any size with direct extension to chest wall &/or skin
• T4a :Extension to chest wall, not including pectoralis muscle
• T4b :Edema (including peau d’orange) /ulceration/ satellite skin nodules
confined to same breast) (Dimpling & nipple retraction are not t4b)
• T4c: Both (T4a and T4b)
• T4d :Inflammatory carcinoma.

4. Regional Lymph Nodes
Definitions for classifying regional lymph nodes (N) are different for
clinical & pathologic classification.
Clinical lymph node classification based on clinical examination
&/or imaging studies such as USG,CT but excluding
lymhoscintigraphy
Clinically detected nodes are more than 1 cm with characteristic of
macro metastasis confirmed by fnac or biopsy
pathological classification applies when lymph nodes are removed
surgically & examined histopathologically

5. Clinical Lymph Node Classification (cN)
Nx :Regional lymph nodes cannot be assessed
N0 :No regional lymph node metastases
N1 :Metastases to movable ipsilateral level I,II axillary lymph nodes
N2 : divided into N2a & N2b
• N2a :Metastases in ipsilateral level I,II axillary lymph nodes fixed to one another
(matted) or to other structures
• N2b Metastases only in ipsilateral internal mammary nodes in the absence of
axillary lymph node metastases
N3: divided into N3a,N3b &N3c
• N3a Metastases in ipsilateral infraclavicular lymph node(s) level III axillary
• N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary
• lymph node(s)
• N3c Metastases in ipsilateral supraclavicular lymph node(s) irrespective of axillary
& internal mammary lymph node involvement

6. Pathologic Lymph Node Classification (pN)
pNx :Regional lymph nodes cannot be assessed (e.g., previously removed
or not removed for pathologic study)
pN0 :No regional lymph node metastases histologically
pN0 (i-): No regional lymph node metastases histologically, negative IHC
pN0 (i+): Malignant cells in regional lymph node(s) no greater than 0.2 mm
(detected by H&E or IHC including Isolated tumor cells)
pN0 (mol-) :No regional lymph node metastasis histologically,negative
molecular findings (reverse transcriptase polymerase chain reaction [RT-
PCR])
pN0 (mol+) :Positive molecular findings (RT-PCR), but no regional lymph
node metastases detected by histology or IHC

7.  pN1 :
 pN1mi :Micrometastases (greater than 0.2 mm, and/or more than 200 cells,
but none greater than 2.0 mm)
 pN1a :Metastases in 1-3 axillary l.ns, at least one metastasis greater than 2.0
mm
 pN1b : Metastases in internal mammary l.ns with micrometastases or
macrometastases detected by sentinel lymph node biopsy but not clinically
detected
 pN1c :Metastases in 1–3 axillary l.ns and in internal mammary l.ns with
micrometastases or macrometastases detected by sentinel lymph node biopsy
but not clinically detected
 pN2
 N2a: Metastases in 4-9 axillary l.n (at least one tumor deposit greater than 2.0
mm)
 pN2b :Metastases in clinically detected internal mammary l.n in absence of
axillary l.n metastasis

8.  pN3
 pN3a :Metastases in 10 or more axillary l.ns (at least one tumor deposit
greater than 2.0 mm), or metastases to the infraclavicular (level III axillary
lymph nodes)
 pN3b :Metastases in clinically detected ipsilateral internal mammary l.ns in
presence of one or more positive axillary l.ns,
or in more than three axillary l.ns and in internal mammary l.ns with
micrometastases or macrometastases detected by sentinel lymph node
biopsy but not clinically detected
 pN3c :Metastases in ipsilateral supraclavicular l.ns.

9. Distant Metastasis (M)
 M0 :No clinical or radiographic evidence of distant metastases
 cM0(i+) :No clinical or radiographic evidence of distant metastases,
but deposits of molecular or microscopically detected tumor cells
detected in circulating blood, bone marrow, or other nonregional
nodal tissues, that are no larger than 0.2 mm in a patient without
symptoms or signs of metastases
 M1 :Distant detectable metastases as determined by classic clinical
and radiographic means and/or histologically proved larger than 0.2
mm.

10. AJCC 7th Edition Staging for Breast Cancer
*T1 includes T1mi.
** T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA & are
classified Stage IB.

11. Carcinoma in situ
CIS represents non invasive cancer defined by confinement of
malignant cells within basement membrane
Widespread use of mammography has lead to an increase in
overall incidence of in-situ lesion
They differ in natural history, pathologic appearances, biologic
characteristics, clinical presentation & treatment
CIS of the breast (stage 0) includes
• Paget’s disease of the nipple
• Lobular carcinoma in situ (LCIS)
• Ductal carcinoma in situ (DCIS).

12. Cancer Facts & Figures 2015 Special Section:
Breast Carcinoma In Situ
In 2015, there will be an estimated 60,290 new cases of breast CIS
diagnosed
83% of them will be ductal carcinoma in situ (DCIS)
12% of them will be lobular carcinoma in situ (LCIS).
This year’s special section reviews breast carcinoma in situ, including
incidence rates and trends, risk factors, prognostic characteristics, and
treatment patterns.
*Cancer Facts & Figures 2015 American Cancer Society

13. Paget's disease
• Paget’s disease is a rare entity
• represents <5% of all breast cancer
cases & associated with an
underlying malignancy in >95% of
cases.
• characterised by crusting &
eczematous appearance of nipple-
areola complex

14. PATHOLOGY
• characterized by presence of Paget’s
cells located throughout the
epidermis.
• Paget’s cells are large
,hyperchromatic, round/oval nuclei
with abundant cytoplasm found in
clusters or individually

15. Epidermotropic Theory of Paget's disease
• belief that the disease originates from underlying in situ or invasive ca
• also supported by histologic evidence of intraepithelial extension,
• IHC studies & evidence suggest that epidermal keratinocytes release a motility
factor heregulin-α, that results in the chemotaxis of paget’s cells that migrate to
overlying nipple epidermis.

16. Clinical presentation
• Age:5th -6th decade
• Gender: F>>M
(male Paget’s have been reported)
• Usually U/L
(synchronous b/l paget's have been reported)
• Symptoms include:
red, flaky,scaly rash which spread from nipple to
surrounding areola.
tingling, itching, burning, over the rash.
thin discharge may be present forming a crust as it
dries.
with more skin destruction, there may flattening of
the nipple
palpable mass
bleeding, pain, and ulceration in advanced stage
Alternatively, can be asymptomatic and present as
pathologic finding after surgical removal of the
nipple–areolar complex.

17. Diagnosis
• palpable mass detected in 50% pts.at diagnosis: in >90% of
cases, this will be an invasive carcinoma.
• no palpable mass is detected: 66%- 86% will have an
underlying DCIS.
• these associated malignancies are usually located centrally,
although they can occur elsewhere in the breast.
• Diagnostic Work Up Includes:
bilateral breast examination,
mammography, and biopsy
• Mammographic findings are frequent in the presence of a
palpable mass; however, normal mammograms are reported
in as many as 50% of case

18. Treatment of Paget's disease
The combination of limited surgical resection and
postoperative radiotherapy is the most practical breast-
conserving approach .
Surgical resection should include the nipple–areolar complex
with microscopically clear margins surrounding both the
Paget’s disease and the associated malignancy.
Whole-breast radiotherapy is delivered with standard
techniques.

19. a seven-institution collaborative review of 36 patients with Paget’s disease
without a palpable mass or mammographic density treated with local excision &
RT
 Surgery
94% of patients underwent surgery
extent of surgical resection varied complete excision (69%), partial excision of
nipple–areolar complex & underlying breast tissue (25%), & biopsy only in 6%
The final margin status was documented as negative in 56%, positive in 6%, and
unknown in 39%.
 Radiotherapy
all patients received median EBRT dose of 50 Gy (range, 45–54 Gy) to whole
breast.
97% of patients also received a boost to tumor bed,
median total dose of 61.5 Gy (range:50.4 –70 Gy).

21. RESULTS.
median follow-up =113 months (range, 18 –257 months)
Local control
 Actuarial local control rates for breast as only site of first recurrence were 91% at 5
and 87% at both 10 and 15 years.
 Actuarial local control rates for breast recurrence, as a component of first failure,
were 91% ,83% and 76% at 5, 10, and 15 years, respectively.

22. Failures:
4/36 patients (11%) developed first recurrence in treated breast only:2 were
DCIS only & 2 invasive with DCIS.
Two additional patients had a recurrence in breast as a component of first
failure
No clinical factors were identified as significant predictors for breast
recurrence.
Survival:
5-, 10- and 15-year actuarial rates for DFS was 97%
actuarial rates of OS was 93 at 5 years and 90% at 10 and 15 years
CONCLUSIONS. excellent rates of LC,DFS & OS at 10 and 15 years
following BCS and RT for Paget disease of the breast.
This study continues to support the recommendation of local excision and
definitive breast irradiation in the treatment of patients with Paget disease
presenting without a palpable mass or mammographic density
.

23. Lobular carcinoma in situ
• comprise 15% of in situ disease
• approximately 22-26% LCIS associated with DCIS or invasive
disease
• not a precursor of invasive cancer instead, considered a marker
for increased risk of developing invasive breast cancer.
• Exception :Pleomorphic LCIS -linked to a higher risk of invasive
cancer
• Risk of development of invasive cancer is 20%–25% when
followed over a duration of 15 years
• risk appears to be nearly equal for both breasts & is greatest for
high-grade or more extensive lesions.

24. LCIS incidence and trends
• The incidence rate of LCIS was 3.9/100,000 women during
2007-2011
• peaks in women ages 50-59
• higher for non-Hispanic white women

25. LCIS:Pathology
• LCIS represent abnormal cells growing within the walls of the
lobules
• Pleomorphic LCIS: an aggressive variant that has a greater
potential for progressing to invasive cancer
• Multicentric (90% of mastectomy specimens)
• bilateral involvement (in 35%-59% of mastectomy specimens)
• ER/PR+, Her 2 nue negative
• loss of E-cadherin is often observed, and the absence of this
adhesion molecule may explain the growth pattern seen with
LCIS.
• (Vos CB, et al. E-cadherin inactivation in lobular carcinoma in situ of the breast:
an early event in tumorigenesis. Br J Cancer 1997;76:1131–1133.)

26. Clinical presentation
age: varies with race
extremely rare in men.
symptoms
usually asymptomatic: no symptoms on clinical and
mammography
rarely may present as
• breast lump:.
• nipple discharge:
• pain

27. Diagnosis of LCIS
• no clinical or mammographic indicators that are characteristic
• often detected as
an incidental biopsy finding.
mammographic calcifications
 in excisional biopsy specimens ( dcis or invasive carcinoma are
frequently identified even when lcis is the sole histologic entity
seen on core biopsy)
mastectomy specimens
The only definitive way to diagnose LCIS is by a breast biopsy

28. GOAL OF TREATMENT LCIS
• Treatment of LCIS emphasizes medical surveillance
and risk reduction strategies for both breasts rather
than local treatment, such as BCS plus radiation
therapy

29. Management of LCIS
depends on
LCIS : sole
histologic diagnosis
medical surveillance and
risk reduction strategies
a/w another malignancy
(DCIS or invasive
carcinoma)
manage the breast according to
dominant malignant histology

30. Management of LCIS: sole histologic diagnosis
Role of SURGERY
Local Excision & Subsequent Surveillance
Complete removal with negative margins is considered important
for more histologically aggressive pleomorphic LCIS.
unilateral mastectomy: inadequate and illogical.
Bilateral prophylactic mastectomy in high risk:
young age,
diffuse high-grade lesion
significant family history.
BRCA1/2 mutation
*Fisher ER et al. Pathologic findings from NSABP—12 year observations
concerning lobular carcinoma in situ. Cancer 2004;100:238–244

31. Medical surveillance recommendations
NCCN recommend
annual mammography and clinical breast exam every 6-12 months.
(National Comprehensive Cancer Network. Breast Cancer Screening and Diagnosis
(Version 1.2014).
Role of MRI in LCIS
In 2009, NCCN published guidelines reflecting a panel consensus opinion
that annual breast MRI can be considered in patients with LCIS.
three studies have been published evaluating the role of MRI in patients with
LCIS.
1. Friedlander LC, Roth SO, Gavenonis SC. Results of MR imaging screening for breast cancer
in high-risk patients with lobular carcinoma in situ. Radiology 2011;261(2):421–427.
2. Port ER, et al. Results of MRI screening for breast cancer in high risk patients with LCIS and
atypical hyperplasia Ann Surg Oncol 2007;14:1051–1057.
3. Sung JS, et al. Screening breast MR imaging in women with a history of lobular carcinoma in
situ. Radiology 2011;261(2):414–420
 Each document revealed a small but defined 3.8% to 4.5% breast cancer
detection rate with MRI

32. cohort comprised of 182 women with LCIS who were enrolled in NSABP
Protocol B-17 but received no treatment other than lumpectomy.
Nineteen pathologic features were assessed & related to i/l breast tumor
recurrence(IBTR) & c/l breast tumor recurrence (CBTR) at a mean time 5 years.
Results were published at 5 years & updated at 12 years

33. 4 CBTR
 2 invasive& 2 CIS
 1invasive CBTR :lobular type
other mucinous carcinoma
 1 non invasive CBTR were
LCIS&DCIS.
 1 CBTR were LCIS only.
NSABP B-17: results at 5 years
13 IBTR
 All IBTR occurred in same quadrant
 9 were CIS & 4 invasive recurrences
 All 4 invasive IBTR were lobular type
 3 non invasive IBTR were pure DCIS
 5 non invasive IBTR were LCIS only
 1 non invasive IBTR were LCIS&DCIS
 All examples tested were found to be c-erb B-2 negative, and estrogen receptor
and progesterone receptor positive.

34. NSABP B-17
results at median follow-up of 12 years.
• 26(14.4%) in-breast tumor recurrence (IBTR) rate
9 IBTRs (5% of the total cohort) were invasive carcinoma
17 (9% of the total cohort) were DCIS
• 14(7.8%) contralateral breast tumor recurrence rate.
• 10 CBTR (5.6% of total cohort) were invasive carcinoma
• Although the frequency of contralateral breast tumor recurrence rate was
less than that of IBTR, frequency of invasive contralateral breast tumor
recurrence rate (5.6% of total cohort) was similar to invasive IBTR (5% of
total cohort).
• Of note, all of the IBTR were documented to be at the site of the index
lesion except for one, characterized as pure LCIS, that was found at a
remote site.

35. Hormonal therapy
Both the American Society of Clinical Oncology (ASCO) and
NCCN recommend chemoprevention therapy
tamoxifen: for premenopausal women
 tamoxifen or raloxifene: for postmenopausal women,
depending on other health conditions.
• (ref:Allred DC, Anderson SJ, Paik S, et al. Adjuvant tamoxifen reduces subsequent
breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a
study based on NSABP protocol B-24. J Clin Oncol. 2012;30: 1268-1273)
ASCO also lists exemestane, an aromatase inhibitor, as an
option in postmenopausal women; however, this is not FDA-
approved indication
• (ref:Visvanathan K, Hurley P, Bantug E, et al. Use of pharmacologic interventions
for breast cancer risk reduction: American Society of Clinical Oncology clinical
practice guideline. J Clin Oncol. 2013;31: 2942-2962.)

36. • N = 13 388
• patients at elevated risk for breast cancer
 >60 years old,
35–59 yrs with 5-year predicted risk of at least 1.66% based on Gail model,
history of LCIS
• Randomly assigned into 2 groups
• Group 1: (n = 6707) recieve placebo
• Group 2: (n = 6681) tamoxifen 20 mg/day for 5 yrs
*Fisher B, Costantino J, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the
National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371–1388.

37. Results:
Tamoxifen reduced risk of :
invasive breast cancer by 49% (two-sided P<.00001)
non-invasive breast cancer by 50% (two-sided P<.002).
reduced occurrence of ER+tumors by 69%
no difference in occurrence of ER-tumors
 age related decreased risk occurred in women
 aged 49 years or younger (44%),
 50–59 years (51%),
 60 years or older (55%);
risk was also reduced in women with a history of lobular carcinoma in situ
(56%) or atypical hyperplasia (86%)

38. Cumulative rates of invasive breast cancer

39. Side Effects In The Tamoxifen Group
rate of endometrial cancer increased in the tamoxifen group
risk ratio = 2.53
increased risk occurred predominantly in women aged 50 yrs or older
Cumulative rates of invasive endometrial cancer

40.  rates of stroke, pulmonary embolism, and deep-vein thrombosis were
elevated in the tamoxifen group; these events occurred more frequently in
women 50 years or older
 reduction in hip, radius (Colles’) & spine fractures
 No increase in liver, colon,
rectal, ovarian or other tumors
 No alteration in the average
annual rate of ischemic heart
disease;

41. NSABP-P2 STAR (vogel et al 2006).
Tamoxifen vs raloxifene
• 19,747 postmenopausal women at increased risk of breast CA
• Randomized to Tamoxifen 20 mg qd vs. Raloxifene 60 mg qd ×
5 years.
• Incidence of invasive breast CA 0.4% both arms, but fewer
noninvasive cases (DCIS/LCIS) with Tamoxifen (0.15 vs.
0.21%).
• Raloxifene reduced risk of uterine cancer (absolute 0.7→0.5%)
cataracts,and thromboembolic events.
• Similar number of osteoporotic fractures, other cancers, stroke,
and heart disease.
Vogel VG, Costantino JP, Wickerham DL, et al. NSABP: prevention trials and endocrine
therapy of ductal carcinoma in situ. Clin Cancer Res 2003;9:495 S–501 S.

42. Ductal carcinoma in situ
• Constitute 80% of CIS
• DCIS is a precursor lesion to invasive ductal carcinoma
• It is confined to ductal system of breast lacks histologic
evidence of invasion into basement membrane & surrounding
stroma.
• lacks the ability to metastasize
• axillary node involvement is rare (0% to 5%) and most likely is
associated with an undetected focus of invasive carcinoma.

43. Pathobiologic Events Associated with DCIS
majority of changes that give rise to cancer, including genetic changes, & loss of
normal cell-cycle regulation, occurred by the time DCIS is present
Most of clinical features of subsequent invasive cancer are already determined
although additional events, including tissue invasion and changes in surrounding
stroma characterize the invasive tumor

44. Natural History of DCIS
primary consideration in DCIS is the risk of progression to invasive
carcinoma
few published long-term follow-up studies after biopsy only document
overall incidence of subsequent invasive carcinoma of >36%. Most of these
subsequent malignancies occur within 10 years although as many as one-
third may develop after 15 years.
• (ref:betsill wl, rosen pp, lieberman ph, et al. intraductal carcinoma: long-term
follow-up after treatment by biopsy alone. jama 1978;239:1863–1867)
Women with DCIS in one breast are at risk for a second tumor (either
invasive or in situ) in the contralateral breast
rate at which such tumors develop is similar to that among women with
primary invasive breast cancer at approximately 0.5% to 1% per year.
• (ref:Habel LA, Moe RE, Daling JR, et al. Risk of contralateral breast cancer
among women with carcinoma in situ of the breast. Ann Surg 1997;225:69–75.)

45. Pathology DCIS
• Traditionally, classification of DCIS has followed its
architectural or morphologic appearance.
• The five subtypes of DCIS are

46. Risk Factors
DCIS Invasive
Cancer
Peak Age 60 -74 75 – 79
Race Caucasian Caucasian
Family History Yes Yes
Mammographic Density Yes Yes
Obesity No Yes
No children Yes Yes
Late age at childbirth Yes Yes
Hormone replacement No Yes
Risk factors for the development of DCIS are the same as
those identified for invasive carcinoma*
*Trentham-Dietz A, Newcomb PA, Storer BE, et al. Risk factors for carcinoma in situ of the
breast. Cancer Epidemiol Biomarkers Prev 2000;9:697–703.

47. Clinical presentation
• Before the use of screening mammography,
DCIS presented as a palpable mass/ nipple discharge.
invasive component commonly was found, and pure DCIS
rarely was encountered.
• The widespread use of mammography now routinely detects
DCIS <1 cm in diameter
• Studies have shown that the rate of screen-detected DCIS
increases with age
• The rate of DCIS detection increase from 0.56 per 1,000
mammograms among women aged 40 to 49 years to 1.07 per
1,000 mammograms among women aged 70 to 84 years.

48. DCIS incidence trends

49. Diagnostic workup
• Screening mammography
• Diagnostic mammography
• Biopsy
• MRI
• Galactography

50. Mammographic findings of DCIS
• 95 % present with mammographic abnormalities
• Most common finding is microcalcifications seen in 76%
• Noncalcified mammographic findings (24%) includes
asymmetric densities identified in 10%,
dominant masses in 8%,
abnormal galactograms in 6%.

51. Calcification in DCIS
• all forms of calcifications that that
can be related to DCIS. : Amorphous,
coarse, fine pleomorphic, fine linear
• Linear and segmental calcifications
are associated with DCIS in up to
80% of cases.
Linear and branching calcifications
associated with high-grade (DCIS).
Fine and granular calcifications
associated with low-grade DCIS

52. Role of MRI
• Size of lesion is underestimated in mammography by 1-2 cm
when compared with pathological specimen
• MRI now presents as the imaging modality with the highest
sensitivity to detect DCIS, particularly high-grade DCIS.
• MRI better establish the extent of DCIS, thus aiding treatment
planning
• Lehman CD. Magnetic resonance imaging in the evaluation of ductal carcinoma in situ. J Natl
Cancer Inst Monogr 2010;(4):214–217.
• Berg WA, Gutierrez L, Nessairer MS, et al. Diagnositic accuracy of mammography, US, and MR
imaging in preoperative assessment of breast cancer.Radiology 2004;133:830–849
• In cases that present with nipple discharge and a negative
mammogram, galactography may be helpful in determining
the likelihood of underlying DCIS versus papilloma
Role of galactography

53. ACR-ASS-CAP-SSO 2006 practice guideline
• The role of other image modalities, especially MRI, has
yet to be established in DCIS.
• Berg found that MRI was more sensitive than
mammography and sonography in detecting DCIS;
however, disease extent was overestimated in 50% of
involved breasts.
• The impact of MRI on clinical outcomes such as local
recurrence in the preserved breast remains to be
demonstrated.

54. Goal of treatment: DCIS
• Eradication of initial cancer
• prevent progression to invasive/noninvasive cancer.

55. DCIS: management options
• Surgery
• Radiotherapy
• Hormonal therapy

56. Breast Conservation for DCIS
• Breast conservation surgery (BCS) may consist of
quadrantectomy, wide excision, lumpectomy (local excision).
• A primary goal of BCS for DCIS is to achieve the best possible
cosmetic outcome along with negative margins
• microscopic complete excision is essential for optimal local
control in breast-conserving therapy for DCIS.
• 1 cm margin is considered adequate
• 1–2 mm post-BCS require re excision as up to 1/2 will have
residual DCIS
• even in the group of DCIS cases who underwent a surgical re-
excision a 4-year local recurrence rate of 18% was observed
when these patients were treated with surgery alone.

57. Contraindications to BCT
• Repeatedly positive margins
• Multicentric disease ( >2 quadrants)
• Diffuse malignant calcifications on mammogram
• Prior RT to breast
• Pregnancy
• History of scleroderma
• Large tumor in small breast: cosmetically undesirable

58. Additional tests done after BCS*
• Specimen mammography
• Post excision mammography
• Frozen section analysis
• Complete histopathological assessment of
specimen
*Standard for the Management of Ductal Carcinoma In Situ of the BreastCA
Cancer J Clin 2002;52:256-276

59. • Specimen mammography of lumpectomy specimen
Radiological
intraoperative
• ADVANTAGES:
• Allows surgeons to asses the adequacy of excision
• Reduce the no of reexcisions required to achieve margin –ve resections
• less tissue excised : better cosmesis
• Reduces frequency of missed lesions: hard copy confirmation reduces
litigations
• DISADVANTAGES:
• Prolongs surgical procedure
• Increases cost
• False + & false - results
• Limited ability to predict margin status due to magnification &
compression views
• Discordance between SM & pathological & post excision mammography
results

60. Post excision mammography
• Done post excision & pre radiotherapy
• obtained to document complete removal of calcifications.
• can be performed as soon as the patient can tolerate
compression however, a large seroma may obscure small
residual calcifications.
• Magnification views taken( may show calcifications not
evident on nonmagnified views)
• It is used as a complementary means of assessing the
completeness of excision.
• If reexcision is performed for residual calcifications,
specimen radiography and a post-excision mammogram
should again be obtained to reassess the tumorectomy site.

61. Frozen section examination
• *Frozen sections should be avoided if possible especially on
lesions, which measure <1cm. in diameter
• Advantages:
• Indicated when information is necessary for immediate
therapeutic decisions
• reduction in the rate of reexcision
• Disadvantages
• Methodological difficulties
• Ductal carcinoma in situ is more difficult to identify in FSA
• small foci of microinvasion may be lost or rendered
uninterpretable by freezing artifact.
* Association of Directors of Anatomic and Surgical Pathology. Immediate management of
mammographically detected breast lesions. Am J Surg Pathol 1993;17:850-851

62. PATHOLOGIC EVALUATION
• Following should be included in the pathology report
 nuclear grade,
presence/absence of necrosis
 architectural pattern(s)
size/extent
distance to excision margins/margin status
Calcification in the Tumour (or DCIS): Yes/ No
Estrogen Receptor Status: PR Status/Her-2 neu Status

63. risk factors for local recurrence after
breast-conservation therapy for DCIS
• Through multiple retrospective studies, several factors have
been identified that may be important in defining local
failure risk. These include
• patient age
• symptomatic presentation
• lesion size
• multifocality
• histopathologic subtype
• nuclear/cytologic grade
• central necrosis
• margin status

64. Mastectomy for DCIS
• Mastectomy is a highly effective treatment for DCIS
• locoregional control rate of 96% to 100%
• cancer-specific mortality rates of ≤4%.
• No randomized study has compared mastectomy with BCS for
DCIS.
• Data from some surgical series and large treatment registries
suggest that rates of local or regional recurrence are significantly
lower after mastectomy than after breast-conserving surgery,
• although there have been no significant differences in overall
survival.

66. Indications for total mastectomy
• If BCS is contraindicated
• Repeatedly positive margins after BCS
• patient desire. minimize the chance of ipsilateral recurrence
or for other reasons
• Recurrent disease

67.  Age at diagnosis was strongly associated with the type of treatment received
 younger women: more likely to undergo mastectomy.
 53% pts younger than 40 underwent mastectomy
 bilateral mastectomy 28%
 unilateral mastectomy 25%
 proportion of DCIS pts undergoing bilateral mastectomy has increased over the past 2
decades, from 2% of patients in 1998 to 8% in 2011.

68. Lymph node dissection in DCIS
• Axillary lymph node dissection & sentinel lymph node
mapping not routinely warranted
• 3-13% of patients with DCIS have isolated tumor cells in
sentinel axillary lymph nodes
• sentinel lymph node mapping may be used in selected
patients with a higher likelihood of occult invasive
cancer—
those with extensive ds
high-grade DCIS
palpable masses
those undergoing mastectomy

69. POSTOPERATIVE RADIOTHERAPY
• Breast irradiation reduces the risk of subsequent invasive or
noninvasive carcinoma in the treated breast
• Four prospective randomized studies of excision only versus
excision plus breast irradiation for DCIS have been performed
• all have shown that the rate of local recurrence was reduced
with the addition of radiation
NSABP B-17 trial
 EORTC 10853 trial
United Kingdom, Australia, and New Zealand (UK/ANZ)
DCIS
Swedish Breast Cancer Group SweDCIS study

70. NSABP B-17
(Fisher et al.
1998c, 2001b)
first randomized trial which confirmed the effectiveness of
RT in decreasing local recurrence after lumpectomy with
negative resection margins in DCIS

71. • 813 pts. stratified by age (≤49 years vs. >49 years), DCIS versus DCIS plus
LCIS, method of detection, and whether an axillary dissection was
performed.
• Mean follow-up time was 90 months (range, 67 to 130).
• Of the patients enrolled, 83% had nonpalpable tumors
813 patients

72. The updated analysis with 15-year follow-up showed a decreased cumulative
incidence of both invasive and non-invasive ipsilateral breast recurrences from
35% to 19.8% with the addition of radiation therapy.
The incidence of invasive ipsilateral breast recurrence was also decreased from
19.4 to 8.9% with the addition of radiation therapy to lumpectomy.
Increased LR with: +margins, moderate/marked comedonecrosis ,and
microcalcifications>1 cm

73. EORTC 10853
(Julien et al. 2000;
Bijker et al. 2006)
PATIENTS AND METHODS:
 Between March 1986 and July 1996, 1,010 women were randomly assigned to
no further treatment (503 patients) or to RT(507 patients) after LE
 analysis performed in August 2005, at median duration of follow-up: 10.5 years
 The median age of the women was 53 years;
 71% of them were mammographically detected.
 Extent of free margins was not specified other than that DCIS should not be
present at microscopic examination of margins.
 irradiation dose was 50 Gy in 25 fractions to the whole breast. No boost was
advised .Tamoxifen not recommended.
 primary end points were both invasive and DCIS LR in the treated breast.
 Secondary end points included metastasis, death, and contralateral breast
Cancer

74. RESULTS:
 The 10-year LR-free rate was 74% in the group treated with LE alone compared with
85% in the women treated by LE plus RT
 The risk of DCIS and invasive LR was reduced by 48% (P = .0011) and 42% (P =
.0065) respectively.
 Both groups had similar low risks of metastases and death.
 The effect of RT was homogeneous across all assessed risk factors.

75. At multivariate analysis,
 factors significantly associated
with an increased LR risk were
 young age
 symptomatic detection
 intermediately or poorly
differentiated DCIS
 cribriform or solid growth
pattern
 doubtful margins
 treatment by LE alone

76. 2x2 factorial designed randomised controlled trial.
Aim: to compare excision alone versus excision plus tamoxifen versus excision
plus radiotherapy versus excision plus radiotherapy and tamoxifen in completely
excised DCIS
 complete surgical excision was confirmed by specimen radiography and histology
 tamoxifen was prescribed as 20 mg per day
 radiotherapy was delivered through whole-breast tangential fields to a total dose of 50
Gy. Boost was not recommended
Between May, 1990, and August, 1998, 1701 patients recruited from screening
programmes were randomised to 4 arms
Arm 1: excision alone
Arm 2 : excision plus tamoxifen
Arm 3: excision plus radiotherapy
Arm 4:excision plus radiotherapy and tamoxifen
UKANZ(2003)

77. primary endpoint: incidence of ipsilateral invasive disease
Results
median follow-up 53 months:
rates of all breast events were 8, 18, 22, and 6%, respectively.
When analysing those randomized to RT vs. no RT,
 RT reduced LF (invasive or noninvasive) in ipsilateral breast from 14 to 6%
but there was no effect on the occurrence of contralateral disease.
 Ipsilateral invasive disease was not reduced by tamoxifen but recurrence of
overall ductal carcinoma in situ (i/l & c/l )was decreased (hazard ratio
0.68 [0.49-0.96]; p=0.03).
Conclusion: Radiotherapy can be recommended for patients with ductal
carcinoma in situ treated by complete local excision; however, there is little
evidence for the use of tamoxifen in these women

78. Cusck J, Sestak I, Pinder SE, et al. Effect of tamoxifen and radiotherapy in women with locally excised
ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial Lancet Oncol 2011;12:21–29
median follow-up of 12.7 years.
addition of radiotherapy was demonstrated to reduce the risk of IBTR.
Of the 1,030 patients randomized between no radiotherapy versus radiotherapy, ipsilateral
IBTR was 19.4% versus 7.1%, respectively (p <.0001).
The addition of tamoxifen offered no benefit toward overall ipsilateral local control
when administered in addition to radiotherapy;
however, tamoxifen did appear to reduce the ipsilateral recurrence rate of DCIS (but not
invasive carcinoma) in the absence of radiotherapy.
Long term results of United Kingdom, Australia, and
New Zealand (UK/ANZ) DCIS trial*

79. randomized trial
enrolled 1,067 patients from 1987 to 1999, with 1,046 of these patients followed for a mean
of 8 years.
Patients randomized between lumpectomy f/b RT & lumpectomy only
 Following a sector resection, microscopic clear resection was not required, and 50 Gy in
25 fractions to the whole breast was delivered in the majority of patients.
 A split course, 54 Gy in 2-Gy fractions, delivered in two treatment series separated by a 2
week break was allowed.
 No boost dose was delivered.
 The in-breast failure risk reduction reported as 16% at 10 years (95% confidence
interval [CI] 10.3% to 21.6%) with a relative risk of 0.40 (95% CI 0.30 to 0.54).
 Detailed analysis did not identify any patient or tumor characteristic subgroups that did
not benefit of postoperative radiotherapy.
Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions for local recurrence after postoperative
radiotherapy after sector resection for ductal carcinoma in situ of the breast J Clin Oncol 2008;26:1247–125
SweDCIS trial (JCO2008)

80. Four randomized trials of BCS ±RT
(EORTC 2006; NSABP 1998; SweDCIS 2008; UKCCCR 2003).
3,925 patients.
Analysis confirmed a statistically significant benefit from the
addition of radiotherapy
on all ipsilateral breast events (hazards ratio (HR) 0.49; 95% CI
0.41 to 0.59, P < 0.00001)
ipsilateral DCIS recurrence (HR 0.64; 95% CI 0.41 to 1.01, P =
0.05).
All the subgroups analysed benefited from addition of RT
No significant long-term toxicity from radiotherapy was found.
(Goodwin et al. 2009).

81. Early Breast Cancer Trialists’ Collaborative Group, Correa C, McGale P, Taylor C, et al. Overview of the randomized
trials of radiotherapy in dictal carcinoma in situ of the breast. J Natl Cancer Inst Mongr 2010;(41):162–167.
 meta-analysis of the four randomized trials
 total of 3,729 women eligible for analysis
 RT reduced the absolute 10-year risk of any ipsilateral breast event (recurrent
DCIS or invasive disease) by 15.2% (standard error [SE] 1.6%, 12.9% vs.
28.1%, 2 p <.00001).
 approximately reduces the risk of IBTR by 50%.
 Subgroup analyses demonstrated that the absolute benefits of radiotherapy are
greater in women at increased risk for tumor recurrence, such as with
involved surgical margins. younger women, tumors that have high-grade or
comedonecrotic
 little impact of RT on contralateral or distant events

82. RT IN DCIS
• Indication: after breast-conserving surgery
• Not Indicated :for post mastectomy & nodal irradiation
• Benefit of addition of RT to BCS more in
Young women
+margin
High grade & comedonecrosis
• Fields: tangential fields to the whole breast
• Dose: 45 to 50 Gy delivered in daily fractions of 180 to
200 cGy.
• Radiation Boost :to the tumor bed may be added particularly
for close surgical margins, although the benefit of a boost
not established.

83. Van nuys prognostic index
• scoring system using histopathologic features in an attempt
to stratify patients according to local failure risk after
excision plus or minus whole-breast irradiation.
• There are 3 variables. Each variable is assigned a score of 1
to 3, and the sum total defined the Van Nuys Prognostic
Index.
• This scheme is drawn from the retrospective analysis of a
patient cohort in which there exist several methodologic
shortcomings, and it has not been independently
validated.

84.  333 patients with pure DCIS treated with breast preservation were studied with
detection of local recurrence as the end point.
 195 treated by excision only and 138 by excision plus radiation therapy
Score # 1 # 2 # 3
Path Other Comedo High Grade
Size <15mm 16-40mm >40mm
Margins >10mm 1-9mm < 1mm

85. Conclusions:
Score 3 – 4 : Lumpectomy alone (local control is 100% vs 97%)
Score 5 – 7: Lumpectomy + Radiation (local control from 68%- 85%)
Score 8-9: Mastectomy
Cancer 1996 Jun 1;77(11):2267-74
RESULTS:
no statistical difference in 8 year LRFS in patients with VNPI scores of 3 or 4,
regardless of whether or not radiation therapy was used (100% vs. 97%; P =
not significant).
Patients with VNPI scores of 5, 6, or 7 received a statistically significant 17%
LRFS benefit when treated with radiation therapy (85% vs. 68%; P = 0.017).
Patients with scores of 8 or 9, showed the greatest relative benefit from
radiation therapy, however had recurrence rates in excess of 60% at 8
years regardless of irradiation, and should be considered for mastectomy.

86. Modified VNPI (Silverstein 2003).
• Retrospective review of 706 patients status post-BCT with or without RT
• scored based on four parameters:
1. tumor size (≤1.5, 1.6–4.0, >4.1 cm)
2. Pathology (non high-grade without necrosis, nonhigh-grade with
necrosis, high grade)
3. margins (≥1, 0.1–0.9, <0.1 cm)
4. age (>60, 40–60, <40 years)
 For low-risk (score 4, 5, 6), no significant difference in 12-year local RFS
(>90–95%) with or without RT.
 For intermediate-risk (score 7, 8, 9), addition of RT provided 12–15% 12-
year local RFS benefit.
 For high-risk (score 10, 11, 12), mastectomy recommended due to high 5-
year LR (~50%) with or without RT.

87. Updated Van Nuys Prognostic Index
Parameter 1 Point 2 Points 3 Points
Size <15mm 16-40mm >40mm
Grade I/II
non high-grade
without
necrosis,
I/II Necrosis
nonhigh-grade
with necrosis,
III
high grade
Margin 10mm 1-9mm <1mm
Age >60 40-60 <40
4,5, 6 = Lumpectomy Alone
7, 8, 9 = Lumpectomy + Radiation
10, 11, 12 = Mastectomy
2003 Update PMID 14682107 -- "An argument against routine use of radiotherapy for ductal carcinoma in situ."
(Silverstein MJ, Oncology (Williston Park). 2003 Nov;17(11):1511-33; discussion 1533-4, 1539, 1542 passim.)

88. LIMITATIONS OF VNPI INDEX
• Attempts to validate the VNPI scoring system have yielded mixed results
in various retrospective studies
 MacAusland et al. 2007;
 Di Saverio et al. 2008;
 Gilleard et al. 2008
 Altintas et al. 2011;
 Lee et al. 2013;).
• Such studies have had uneven population distributions, most patients
having low to intermediate scores.
• Although patient age, tumor size, and tumor grade were set at patient
diagnosis, margin width may be downgraded by re-excision or TM.
• Such efforts to salvage treatment have resulted in a disproportionately
low rate of patients with high VNPI scores

89. A New Test for Estimating Recurrence Risk After
Lumpectomy with No Radiation
analyzes the activity of 21 genes that can influence how likely a
cancer is to grow and respond to treatment.
Oncotype DX test is both a prognostic test and predictive test
Oncotype DX test results assign a Recurrence Score — a number
between 0 and 100
http://www.genomichealth.com/en-US/OncotypeDX.aspx
recurrence Score Any Recurrence Invasive Recurrence
Low Risk less than 18 12% 5%
Intermediate Risk:18-31 25% 9%
High Risk: more than 31 27% 19%

90. Subset of patients in which RT can be avoided
• Van Nuys Prognostic Index :4-6
• DCIS size < 1.5 cm
• Negative margin > 1 cm
• Not high grade
• No comedo necrosis
• Age > 61
• ER + tumors
 To date, prospective data have failed to validate the elimination of RT for
women completing BCS for DCIS
 Few prospective trials have attempted to identify a subset of patients with
low-risk DCIS who may not benefit from the addition of radiation therapy
following a local excision
 Confirmatory results are yet not available because either the trials stopped
early due to poor accrual or high LR or their results are awaited

91. Hormonal therapy
 The use of tamoxifen in the treatment of DCIS treated with BCS & RT is
unclear due to conflicting results.
 The NSABP B-24 updated results showed that with a median follow-up of 163
months, the addition of tamoxifen translated into a significant 32% reduction in
invasive IBTR (9.0% vs. 6.6%, p = .025), a nonsignificant 16% reduction in
DCIS-IBTR (7.6% vs. 6.7%, p = .33), and a significant 32% reduction in
contralateral breast cancer (8.1% vs. 4.9%, p = .023); however, no survival
benefit was found
 In contrast to the findings of the NSABP B-24 trial, the UK/ANZ DCIS trial
found that tamoxifen had no effect in reducing local recurrence rate when
combined with whole-breast radiation therapy
 Because DCIS is a precursor to invasive breast cancer, tamoxifen is used as
target for preventive measures
 Additional studies are being conducted evaluating the role of aromatase
inhibitors and Her2Neu targeted treatment in DCIS

92. NCCN recommendation on hormonal
therapy

93. Follow-Up
• CBE & baseline mammogram 6 to 12 months after initial
therapy and at least annually thereafter
• Ipsilateral tumor recurrences usually detected on surveillance
mammography, although one-quarter may be detected on the
basis of changes on physical examination of the breast or
chest wall.
• Distant breast cancer metastases in the absence of regional
recurrence are unusual.

94. Management of Recurrence
• Local recurrences
• After excision only: local excision & RT
• After BCT+RT: treated with mastectomy.
• The clinical outcome of ipsilateral tumor recurrence is
governed by the nature of the recurrence.
• Patients with recurrent DCIS have an excellent prognosis,
with <1% risk of further recurrence after salvage mastectomy.
• Patients with invasive recurrence after breast-conserving
surgery for DCIS have a prognosis similar to those with early-
stage breast cancer, with a 15% to 20% risk of metastatic
recurrence at 8 years.

97. Thank you