The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast
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The American Journal of Surgery 186 (2003) 337–343
Scientific paper
The University of Southern California/Van Nuys prognostic index for
ductal carcinoma in situ of the breast
Melvin J. Silverstein, M.D.*
Keck School of Medicine, University of Southern California, Harold E. and Henrietta C. Lee Breast Center, USC/Norris Comprehensive Cancer Center,
1441 Eastlake Ave., Rm. 7415, Los Angeles, CA 90033, USA
Manuscript received June 3, 2003; revised manuscript June 21, 2003
Presented at the Fourth Annual Meeting of the American Society of Breast Surgeons, Atlanta, Georgia, April 30 –May 4, 2003
Abstract
Background: The original Van Nuys prognostic index (VNPI) was introduced in 1996 as an aid to the complex treatment decision-making
process for patients with ductal carcinoma in situ (DCIS) of the breast. This update adds patient age to the previous predictors of local
recurrence in breast preservation patients.
Methods: A prospective database consisting of 706 conservatively patients with DCIS was examined using multivariate analysis. Four
independent predictors of local recurrence (tumor size, margin width, pathologic classification, and age) were used to derive a new formula
for the University of Southern California (USC)/VNPI.
Results: In all, 706 patients with pure DCIS were treated with breast preservation. There was no statistical difference in the 12-year local
recurrence-free survival in patients with USC/VNPI scores of 4, 5, or 6, regardless of whether or not radiation therapy was used (P ⫽ not
significant). Patients with USC/VNPI scores of 7, 8, or 9 received a statistically significant average 12% to 15% local recurrence-free
survival benefit when treated with radiation therapy (P ⫽ 0.03). Patients with scores of 10, 11, or 12, although showing the greatest absolute
benefit from radiation therapy, experienced local recurrence rates of almost 50% at 5 years.
Conclusions: Ductal carcinoma in situ patients with USC/VNPI scores of 4, 5 or 6 can be considered for treatment with excision only.
Patients with intermediate scores (7, 8, or 9) should be considered for treatment with radiation therapy or be reexcised if margin width is
less than 10 mm and cosmetically feasible. Patients with USC/VNPI scores of 10, 11, or 12 exhibit extremely high local recurrence rates,
regardless of irradiation, and should be considered for mastectomy, generally with immediate reconstruction or reexcision if technically
possible. © 2003 Excerpta Medica, Inc. All rights reserved.
Keywords: Ductal carcinoma in situ; Prognostic index; Noninvasive breast cancer; Van Nuys prognostic index; USC/Van Nuys prognostic index
Ductal carcinoma in situ (DCIS) of the breast represents a from a large series of DCIS patients and was developed as
broad biologic spectrum of disease with a wide range of a numerical aid to be used in conjunction with clinical
treatment options. There is, however, a lack of clear and experience. The University of Southern California (USC)/
universally accepted treatment criteria, resulting in diverse VNPI adds a fifth factor, patient age, that has been shown by
and confusing clinical recommendations, distressing to both numerous investigators to be of clinical importance in pre-
patients and physicians. dicting local recurrence in conservatively treated patients
The Van Nuys prognostic index (VNPI), as originally with DCIS [2– 4]. This paper will update our data through
described in 1996 [1], is a tool that quantifies four measur- February 2003, using the USC/VNPI
able prognostic factors (tumor size, margin width, nuclear
grade, and the presence or absence of comedonecrosis) that
Patients and methods
can be used in the treatment decision-making process. The
VNPI is based on tumor morphology and recurrence data
Through February 2003, 1,103 patients with pure DCIS
were treated. No patients with invasive breast cancer are
* Corresponding author. included. In all, 397 patients were treated with mastectomy
E-mail address: melsilver9@aol.com and therefore did not have the ipsilateral breast at risk after
0002-9610/03/$ – see front matter © 2003 Excerpta Medica, Inc. All rights reserved.
doi:10.1016/S0002-9610(03)00265-4338 M.J. Silverstein / The American Journal of Surgery 186 (2003) 337–343
treatment and are not included in the analysis of local type necrosis), and a score of 1 for tumors classified as
recurrence. The subjects of this paper are 706 patients group 1 (non-high grade lesion without comedo-type necro-
treated with breast preservation (426 by excision alone and sis).
280 by excision and radiation therapy). The final formula for the original Van Nuys prognostic
Treatment was not randomized. Patients with large le- index became as follows: VNPI ⫽ pathologic classification
sions (4 cm and more), true multicentricity, or involved score ⫹ margin score ⫹ size score.
margins not amenable to reexcision were advised to un-
dergo mastectomy (usually with immediate breast recon- The modified USC/Van Nuys prognostic index
struction). Patients with smaller lesions (4 cm or less) and
microscopically clear surgical margins (ⱖ1 mm) were gen- Early in 2001, multivariate analysis at the University of
erally treated with excision alone or excision plus radiation Southern California revealed that age was an independent
therapy. Some patients with larger lesions elected breast prognostic factor in our database (Fig. 1) and that it should
preservation, however, whereas other with lesions smaller be added to the VNPI with a weight equal to that of the
than 4 cm elected mastectomy. other factors.
Level 1 and 2 axillary dissections were done routinely An analysis of our local recurrence data by age revealed
until 1988; thereafter a lower axillary sampling was per- that the most appropriate break points for our data were
formed in some patents treated with mastectomy. Beginning between ages 39 and 40 and between ages 60 and 61 (Fig.
in 1995, a sentinel lymph node biopsy was performed on 2). Based on this, a score of 3 was given to all patients 39
patients who underwent mastectomy. Whole breast external years old or younger, a score of 2 was given to patients aged
beam irradiation (40 to 50 Gy) was performed on a 4 or 6 40 to 60, and a score of 1 was given to patients aged 61 or
MeV linear accelerator. Some patients received a boost of older. The new scoring system for the USC/VNPI is shown
10 to 20 Gy to the tumor bed by iridium-192 implant or in Table 1. The final formula for the USC/Van Nuys prog-
linear accelerator. Disease-free survival rates for each group nostic index became as follows: USC/VNPI ⫽ ⫽ pathologic
were estimated by the Kaplan-Meier method. The statistical classification score ⫹ margin score ⫹ size score ⫹ age
significance between survival curves was determined by the score.
log-rank test. The patients least likely to recur after conservative ther-
The original Van Nuys prognostic index [1,5] was de- apy had a score of 4. The patients most likely to recur had
vised by combining these three statistically significant in- a score of 12. The likelihood of recurrence increased as the
dependent predictors of local tumor recurrence (tumor size, USC/VNPI increased.
margin width and pathologic classification (determined by
nuclear grade and the presence or absence of comedo-type
necrosis). Results
A score, ranging from 1 for lesions with the best prog-
nosis to 3 for lesions with the worst prognosis, was given for Patients treated with mastectomy are not included in this
each of the three prognostic predictors. The objective with analysis. 706 patients were treated with breast conservation,
all three predictors was to create three statistically different 426 by excision alone and 280 by excision plus radiation
subgroups for each, using local recurrence as the marker of therapy. The patients were divided into three groups with
treatment failure. Cut-off points (for example, what size or differing probabilities for local recurrence as determined by
margin width constitutes low, intermediate or high risk of USC/VNPI scores (4, 5, or 6 versus 7, 8 or 9 versus 10, 11,
local recurrence) were determined statistically, using the log or 12). Table 2 shows the clinical parameters for each
rank test with an optimum P value approach. group. The average follow-up for all patients was 81
Size score: a score of 1 was given for a small tumors 15 months.
mm or less, 2 was given for intermediate sized tumors 16 to One hundred and nineteen patients experienced local
40 mm, and 3 was given for large tumors 41 mm or more in failure; 49 of 280 (17.5%) treated with excision plus breast
diameter. irradiation and 70 of 426 (16.4%) treated with excision
Margin score: a score of 1 was given for widely clear alone. Of 119 local recurrences, 49 (43%) were invasive: 24
tumor-free margins of 10 mm or more. This was most of 49 (49%) in patients treated with excision plus irradiation
commonly achieved by reexcision with the finding of no and 25 of 70 (36%) in patients treated with excision alone
residual DCIS or only focal residual DCIS in the wall of the (P ⫽ not significant). Seven patients treated with radiation
biopsy cavity. A score of 2 was given for intermediate therapy developed local recurrences and distant metastases,
margins of 1 to 9 mm and a score of 3 for margins less than five of whom have died from breast cancer. Two patients
1 mm (involved or close margins). treated with excision alone developed local invasive recur-
Pathologic classification score: the Van Nuys DCIS clas- rence and metastatic disease. One has died of breast cancer.
sification was used [6,7]. A score of 3 was given for tumors There is no statistical difference in breast cancer specific
classified as group 3 (all high grade lesions), 2 for tumors survival when patients treated with excision alone are com-
classified as group 2 (non-high grade lesion with comedo- pared with those treated with excision plus irradiation.M.J. Silverstein / The American Journal of Surgery 186 (2003) 337–343 339
Fig. 1. Cox multivariate analysis of factors affecting ductal carcinoma in situ recurrence-free survival (conservatively treated patients only).
There is no statistical difference in breast cancer specific Each of these three groups is statistically different from one
survival when patients are compared by USC/VNPI group- another.
ings. Sixty additional patients have died of other causes Patients with USC/VNPI scores of 4, 5 or 6 do not show
without evidence of recurrent breast cancer. The 12-year a local disease-free survival benefit from breast irradiation
actuarial overall survival, including deaths from all causes, (Fig. 8; P ⫽ not significant). Patients with an intermediate
is 90% rate of local recurrence, USC/VNPI 7, 8, or 9, are benefited
The local recurrence-free survival for all 706 patients is by irradiation (Fig. 9). There is a statistically significant
shown by tumor size in Fig. 3, by margin width in Fig. 4, by decrease in local recurrence rate, averaging about 12% to
pathologic classification in Fig. 5, and by age in Fig. 2. The 15% throughout the curves, for irradiated patients with
differences between every local disease-free survival curve intermediate USC/VNPI scores compared with those treated
for each of the four predictors that make up the USC/VNPI by excision alone (P ⫽ 0.02). Fig. 10 divides patients with
are statistically significant. a USC/VNPI of 10, 11, or 12 into those treated by excision
Fig. 6 shows all patients by USC/VNPI score (4 to 12)
plus irradiation and those treated by excision alone. Al-
while Fig. 7 groups patients with low (USC/VNPI ⫽ 4, 5, or
though, the difference between the two groups is highly
6), intermediate (USC/VNPI ⫽ 7, 8, or 9), or high (USC/
significant (P ⫽ 0.001), conservatively treated DCIS pa-
VNPI ⫽ 10, 11, or 12) risks of local recurrence together.
tients with a USC/VNPI of 10, 11, or 12 recur at an ex-
tremely high rate even with radiation therapy.
Comments
Our research [2,6 –10] and the research of others [3,11–
21], including the National Surgical Adjuvant Breast and
Bowel Project (NSABP) [22], has shown that various com-
binations of nuclear grade, the presence of comedo-type
necrosis, tumor size, margin width, and age are all important
factors that can be used to predict local recurrence in con-
servatively treated patients with DCIS. Combinations of
these factors can be used to select subgroups of patients
Fig. 2. Probability of local recurrence-free survival by age group for 706 whose recurrence rate is theoretically so high, even with
breast conservation patients (all P ⱕ 0.01). breast irradiation, that mastectomy is preferable or to select340 M.J. Silverstein / The American Journal of Surgery 186 (2003) 337–343
Table 1
The USC/Van Nuys Prognostic Index scoring system. One to three points are awarded for each of four different predictors of local breast recurrence
(size, margin width, pathologic classification, and age). Scores for each of the predictors are totaled to yield a VNPI score ranging from a low of 4 to a
high of 12
Score 1 2 3
Size (mm) ⱕ15 16–40 ⱖ41
Margin width (mm) ⱖ10 1–9 ⬍1
Pathologic classification Nonhigh grade without necrosis Nonhigh grade with necrosis High grade with or without
(nuclear grades 1 or 2) (nuclear grades 1 or 2) necrosis (nuclear grade 3)
Age (yr) ⬎60 40–60 ⬍40
patients who do not require radiation therapy, in addition to treated with breast preservation, while clearly correct based
complete excision, if breast conservation is selected. on their data, does not take into account the heterogeneity of
We analyzed 30 prognostic factors [9,23,24]. Only three, DCIS nor the differences in subsets demonstrated by our
the Van Nuys classification [9] (which is made up by a data [5,6,8,10] and that of others [12–21,32] including their
combination of grade and necrosis), tumor size, and margin own [22,33].
width were significant predictors of local recurrence and Radiation therapy is not without side effects [34]. It
invasive local recurrence by multivariate analysis [5]. changes the texture of the breast, makes subsequent mam-
Ductal carcinoma in situ is a heterogeneous group of mography more difficult to interpret, and its use precludes
lesions and a uniform approach to treatment is not appro- additional radiation therapy and breast conservation should
priate. Some patients require no treatment other than exci- a metachronous invasive breast cancer develop. Radiation
sion alone; others benefit from complete excision plus ra- therapy should only be offered to those patients with DCIS
diation therapy, and some will require mastectomy. The likely to obtain a substantial benefit.
challenge is to use available clinical and pathologic data to Subsets of patients who are not likely to receive any
select the most appropriate therapy for each individual pa- significant benefit from radiation therapy can be identified,
tient. The USC/VNPI quantifies the evolving knowledge of e.g., those with USC/VNPI scores of 4, 5, or 6 in the series
prognostic factors in DCIS to define specific subsets of presented here, low grade lesions in the series of Lagios et
patients for whom treatment with excision alone, excision al [12–14], small noncomedo lesions with uninvolved mar-
plus radiation, or mastectomy could be recommended. gins in the series of Schwartz et al [20] or the well-differ-
Although mastectomy is curative for approximately 99% entiated lesions of Zafrani et al [21]. Such patients may
of patients with DCIS [8,25–28], mastectomy represents account for more than 30% of the total number of patients
significant overtreatment for the majority of cases detected diagnosed with DCIS [8,10,14,15,19 –21,35,36].
by current methods. When breast conservation is elected Patients in this series with USC/VNPI scores of 10, 11,
rather than mastectomy, radiation therapy statistically de- or 12 present a different problem. While these patients show
creases the likelihood of local recurrence when compared the greatest absolute benefit from postexcisional radiation
with excision alone [29 –31]; but radiation therapy, like therapy, their local recurrence rate continues to be ex-
mastectomy, may also represent over-treatment for a signif- tremely high and a recommendation for mastectomy should
icant number patients who elect breast preservation. be considered.
The broad recommendation by the NSABP that radiation Treatment recommendations for the intermediate group
therapy is appropriate for all patients with DCIS who are (patients with scores of 7, 8, or 9) are the most difficult. For
Table 2
Tumor characteristics, recurrences, and breast cancer deaths by USC/Van Nuys Prognostic Index Groups. Patients treated with mastectomy are not
included in this table since they are at limited risk for local recurrence
VNPI 4, 5 or 6 VNPI 7, 8, or 9 VNPI 10, 11, or 12 TOTAL
No. breast conservation pts 230 400 76 706
Average age (yr) 57 53 48 54
Average size (mm) 8.3 18.0 38.2 17.0
Average nuclear grade 1.65 2.45 2.89 2.24
No. of recurrences 3 (1%) 78 (20%) 38 (50%) 119 (17%)
No. invasive recurrences 0 (0%) 34 (44%) 15 (39%) 49 (41%)
5 & 10-yr local recurrence-free survival 99%/97% 84%/73% 51%/34% 85%/76%
Breast cancer deaths 0 5 1 6
5 & 10-Yr breast cancer specific 100%/100% 100%/98.1% 97.9%/979% 99.7%/98.6%
survivalM.J. Silverstein / The American Journal of Surgery 186 (2003) 337–343 341
Fig. 3. Probability of local recurrence-free survival by tumor size for 706 Fig. 5. Probability of local recurrence-free survival for 706 breast conser-
breast conservation patients (all P ⱕ 0.01). vation patients using Van Nuys ductal carcinoma in situ pathologic clas-
sification (all P ⬍ 0.05).
patients with intermediate USC/VNPI scores and margin
scores of 2 or 3, reexcision may lower their USC/VNPI struggled to save their breasts are both demoralizing and
score and improve local recurrence-free survival. If the theoretically, if invasive, a threat to life [17,37]. In this
score remains intermediate after reexcision, radiation ther- series (44%) and in most other reported series
apy should be considered. However, some patients with [12,17,20,38], approximately one half of all local recur-
scores of 9 may be better treated with mastectomy (eg, a rences are invasive.
50-year-old patient with a large nuclear grade 2 lesion Treatment selection bias is not an important factor when
without necrosis with less than 1 mm margins after reexci- using the USC/VNPI because the USC/VNPI does not com-
sion) while some patients with scores of 7 (eg, a 56-year-old pare different treatments. Rather, the USC/VNPI is based on
patient with widely clear margins, small tumor size, but measured parameters and compares patients who have
high nuclear grade) may elect no further treatment. These achieved similar scores. Although the patient and her clinician
are independent judgments that must be made by the patient control treatment selection, neither can influence final margin
and her physician. Hopefully, the USC/VNPI will be a measurement, tumor size, pathologic classification, or age. The
helpful adjunct as these difficult decisions are discussed. fact that some patients opted for suboptimal treatments that
To date, no study of DCIS patients has shown a statis- were not recommended (eg, 67 patients with USC/VNPI
tically significant difference in mortality when the three scores of 10, 11, or 12 who selected breast conservation ther-
available treatments (mastectomy, excision alone, and ex- apy were all advised to undergo mastectomy) was actually
cision plus radiation therapy) are compared. However, there helpful in developing and evaluating the USC/VNPI.
are clear differences in local recurrence rates and they are of Counseling patients with DCIS in a rational manner can
extreme importance. Local recurrences in patients who have be extremely difficult when the range of treatment options is
extreme. The USC/VNPI allows a scientifically based dis-
cussion with the patient, using the parameters of the lesion
Fig. 4. Probability of local recurrence-free survival by margin width for Fig. 6. Probability of local recurrence-free survival for 706 breast conser-
706 breast conservation patients (all P ⬍ 0.001). vation patients by modified USC/Van Nuys prognostic index score 4 to 12.342 M.J. Silverstein / The American Journal of Surgery 186 (2003) 337–343
Fig. 7. Probability of local recurrence-free survival for 706 breast conser-
vation patients grouped by modified USC/Van Nuys prognostic index score Fig. 9. Probability of local recurrence-free survival by treatment for 400
(4, 5, or 6 versus 7, 8, or 9 versus 10, 11, or 12; all p ⬍ 0.00001). breast conservation patients with modified USC/Van Nuys prognostic
index scores of 7, 8, or 9 (P ⫽ 0.03).
obtained after an initial excision. Thus, in some cases, a
patient can choose a reexcision, in an effort to “downscore” divides DCIS into three groups with statistically significant
her lesion. Successful downscoring of a patient with a USC/ different risks for local recurrence after breast conservation
VNPI of 10 or 11 could result in substantial reduction in the therapy. Although there is an apparent treatment choice for
risk of local recurrence, perhaps changing a recommenda- each group (Table 3), excision only for patients with scores
tion from mastectomy to radiation therapy. Similarly, pa- of 4, 5, or 6, excision plus radiation therapy for patients with
tients with close or involved margins, with USC/VNPI scores of 7, 8, or 9, and mastectomy for patients with scores
scores of 7 or 8 after initial excision could opt for reexci- of 10, 11, or 12, the USC/VNPI is offered only as a guide-
sion. Successful downscoring by achieving widely clear line, a starting place in the discussions with patients.
margins could result in a final USC/VNPI score sufficiently This work suggests that patients with DCIS can be strat-
low to avoid breast irradiation. ified into specific subsets based on age, pathologic classifi-
Downscoring can be achieved only by reexcising pa- cation (using nuclear grade and necrosis), the size of the
tients with margins scores of 2 or 3. Reexcision will not lesion, and the adequacy of surgical excision as determined
lower the pathologic classification score nor will it reduce by histologic margin assessment. The USC/VNPI is an
the size of the tumor. In some cases, reexcision will “up- attempt to quantify the known important prognostic factors
score” the tumor, increasing the USC/VNPI score by re- in DCIS, making them clinically useful in the treatment
vealing a larger tumor size, a higher nuclear grade, the decision-making process.
presence of previously undetected comedo necrosis, or an The validity of the USC/VNPI must be independently
involved margin. and prospectively confirmed by other groups with access to
The USC/VNPI may be useful to clinicians because it large numbers of DCIS patients. In the future, other factors,
Fig. 8. Probability of local recurrence-free survival by treatment for 230 Fig. 10. Probability of local recurrence-free survival by treatment for 76
breast conservation patients with modified USC/Van Nuys prognostic breast conservation patients with modified USC/Van Nuys prognostic
index scores of 4, 5, or 6; P ⫽ not significant). index scores of 10, 11, or 12 (P ⫽ 0.0003).M.J. Silverstein / The American Journal of Surgery 186 (2003) 337–343 343
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