Predictive factors of invasive component in ductal carcinoma in situ

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Kotryna Kvitkovskaja1, Monika Sudeikytė1, Algirdas Boguševičius2

1Lithuanian University of Health Sciences, Academy of Medicine, Faculty of Medicine.

2Hospital of Lithuanian University of Health Sciences Kaunas Clinics, Department of Breast Surgery.

Abstract

Introduction: ductal carcinoma in situ (DCIS) is a type of non – invasive breast cancer (1). It can be diagnosed with a core biopsy though the method is known to miss 10 % of the cases of invasive carcinoma (IC), and for that reason operative treatment is indicated for all patients (2–4). The need of sentinel lymph node biopsy (SLNB) depends on factors of invasiveness, which are poorly defined (2,5–8). Aim: to establish the incidence of IC in preoperatively diagnosed DCIS and evaluate the factors of invasiveness. Materials and methods: medical records of 66 women with preoperatively diagnosed DCIS were analyzed. Patients were assigned to either a DCIS group or an IC group based on surgical specimen histology. Clinical, radiological and pathological factors of invasiveness were compared between the groups. The incidence of SLNB and its necessity based on final histological evaluation was determined. Results: there was a significantly higher incidence of IC (28.6 %) in MRI compared to DCIS (0 %) when the tumor was 40 mm and larger, p = 0.037. Suspicious lymph nodes in radiological assessment were found in 57.1 % of all IC cases, p < 0.001. High grade nuclear polymorphism was significantly higher in the IC group and reached 71.4 % compared to the 44.7 % of cases found in the DCIS group, p = 0.049. Conclusions: predictive factors for invasiveness are the size of the tumor being  ≥ 40 mm on MRI, suspicious lymph nodes on radiological assessment and high grade nuclear polymorphism.

Keywords: ductal carcinoma in situ (DCIS), invasive breast cancer (IC), predictive factors, factors of invasiveness, sentinel lymph node biopsy (SLNB).

Journal of Medical Sciences. May 18, 2020 - Volume 8 | Issue 16. Electronic-ISSN: 2345-0592
130
Medical Sciences 2020 Vol. 8 (16), p. 130-137
Predictive factors of invasive component in ductal carcinoma
in situ
Kotryna Kvitkovskaja
1
, Monika Sudeikytė
1
, Algirdas Boguševičius
2
1
Lithuanian University of Health Sciences, Academy of Medicine, Faculty of Medicine.
2
Hospital of Lithuanian University of Health Sciences Kaunas Clinics, Department of Breast
Surgery.
Abstract
Introduction: ductal carcinoma in situ (DCIS) is a type of non – invasive breast cancer (1). It can be
diagnosed with a core biopsy though the method is known to miss 10 % of the cases of invasive
carcinoma (IC), and for that reason operative treatment is indicated for all patients (2–4). The need of
sentinel lymph node biopsy (SLNB) depends on factors of invasiveness, which are poorly defined (2,5–
8). Aim: to establish the incidence of IC in preoperatively diagnosed DCIS and evaluate the factors of
invasiveness. Materials and methods: medical records of 66 women with preoperatively diagnosed
DCIS were analyzed. Patients were assigned to either a DCIS group or an IC group based on surgical
specimen histology. Clinical, radiological and pathological factors of invasiveness were compared
between the groups. The incidence of SLNB and its necessity based on final histological evaluation was
determined. Results: there was a significantly higher incidence of IC (28.6 %) in MRI compared to DCIS
(0 %) when the tumor was 40 mm and larger, p = 0.037. Suspicious lymph nodes in radiological
assessment were found in 57.1 % of all IC cases, p < 0.001. High grade nuclear polymorphism was
significantly higher in the IC group and reached 71.4 % compared to the 44.7 % of cases found in the
DCIS group, p = 0.049. Conclusions: predictive factors for invasiveness are the size of the tumor being
≥ 40 mm on MRI, suspicious lymph nodes on radiological assessment and high grade nuclear
polymorphism.
Keywords: ductal carcinoma in situ (DCIS), invasive breast cancer (IC), predictive factors, factors of
invasiveness, sentinel lymph node biopsy (SLNB).
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Introduction
The incidence of breast cancer and premalignant
breast diseases has grown due to an available
and more applicable breast cancer screening (9).
The most common type of non-invasive breast
lesion is ductal carcinoma in situ (DCIS) which
accounts for 80 % of non – invasive lesions
(1,10). DCIS progresses to invasive cancer in 25
% of the cases and invasive components are
already present in 10 % of cases, while 20 % of
all DCIS are low grade and have a low
possibility of becoming invasive (3,4,10). DCIS
is usually diagnosed with a core biopsy, but as it
cannot completely exclude invasive components
(due to targeting errors and poor tissue
acquisition), operative treatment is indicated in
both low and high – risk lesions. Consequently,
low risk lesions are being overtreated and
surgical treatment could be less extensive
because SLNB is often unnecessarily done (2–
4,10). Undertreatment also occurs in some IC
cases as current recommendations for SLNB
lack sensitivity (10).
Many researches are investigating the
clinical, radiological and histological data that
might help conclude the recommendations for
clinical practice. Clinical factors associated with
invasiveness are palpability of the tumor and
younger age (< 50 years), which is associated
with genetic predisposition, higher amount of
endogenous estrogens and a premenopausal
state (7,8,11–13). Factors found on radiological
assessment that suggest invasiveness are the
larger size of the tumor (threshold ranging from
20 to 40 mm), suspicious lymph nodes, a
presence of microcalcifications and a solid
tumor, high breast density (6,8,14). Core biopsy
results are very important in the histological
evaluation – negative estrogen and progesterone
receptors, positive HER – 2 receptors, an
infiltration of lymphocytes, high grade nuclear
polymorphism and comedo type necrosis are
possible factors of invasiveness (9,15–18). As
literature reports inconsistent results and the
thresholds vary greatly, no predictable factors
for IC are used in clinical practice (19). The aim
of our study is to clarify significant factors that
could be used to minimize the unnecessary
SLNB and reduce the risk of undertreatment.
Materials and Methods
The single institution retrospective study
was carried out in the period of 2017 – 2019. 66
women with preoperatively diagnosed DCIS
(based on core biopsy) who underwent surgical
treatment were elected out of 680 patients (with
the D05 and C50 diagnosis). Women were
assigned to either the DCIS group or the IC
group based on the surgical specimen histology
in the final evaluation. The primary tumor
(TNM) and the differentiation grade of the IC
group tumors are presented in Table 1. The
objects of our study are clinical, radiological
and pathological factors of invasiveness which
were analyzed and compared between the
groups. Clinical information that was analyzed
included age (< 50 years) and a presence of a
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palpable tumor. Data from mammograms,
ultrasonography (US) and magnetic resonance
imaging (MRI) was used to evaluate the size of
the tumor (≥ 20 mm; ≥ 30 mm; ≥ 40 mm),
microcalcifications, suspicious lymph nodes,
high – average breast density. Core biopsy
results were reviewed and the incidence and
significance of high grade nuclear
polymorphism, as well as estrogen and
progesterone receptors, were compared in both
groups. The rate of SLNB was evaluated and
compared between the postoperatively formed
DCIS and IC groups. IBM SPSS Statistics 23
was used for the statistical analysis. Significant
factors found in the multivariate analysis were
evaluated with Pearson’s chi-square test,
Cramer’s V correlation coefficient and the
likelihood ratio was established. The difference
is statistically significant when p < 0.05. The
study was ethically approved by Bioethics
center of Lithuanian University of Health
Sciences, ethical approval code BEC – MF – 17.
Results
65.2 % (n = 43) of the women were
assigned to the DCIS group and 34.8 % (n = 23)
were assigned to the IC group based on surgical
specimen histology in the final evaluation. The
IC group tumors were larger than the DCIS
group tumors in the radiological assessment but
only a threshold of 40 mm was a specific factor
of invasiveness on MRI, p = 0.035. Suspicious
lymph nodes were also a significant sign with a
reliable statistical significance on the
radiological assessment (p < 0.001). High grade
nuclear polymorphism was significantly higher
in the IC group and reached 71.4 % while it was
found in 44.7 % of cases in the DCIS group, p =
0.049 (Table 2). The presence of a palpable
tumor, age < 50 years, a presence of
microcalcifications and a solid tumor, breast
density, estrogen and progesterone receptors
were not statistically different between the
groups, p > 0.05 (Table 3). SLNB was
performed in 65.6 % (n = 42) of all patients (60
% of pure DCIS cases and 73.9 % upstaged
DCIS cases) and an invasion to the SLN was
found in 11.9 % (n = 5) of the preoperatively
diagnosed DCIS cases (Table 4).
Tables
Table 1. Classification of invasive carcinoma tumours
Primary tumor (T)
T1mic
9.1 %
T1a
50.0 %
T1b
18.2 %
T1c
18.2 %
T2
4.5 %
Differentiation grade (G)
G1
4.8 %
G2
81.0 %
G3
14.2 %
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Table 2. Significant factors of invasiveness
Significant factors of invasiveness
Pearson’s Chi
square (p)
Cramer’s V (r)
Likelihood
ratio
Tumor size on MRI ≥ 40 mm
0.037
0.402 (average correlation)
5.901
High grade nuclear polymorphism
0.049
0.257 (weak correlation)
3.982
Suspicious lymph nodes
< 0.001
0.451 (average correlation)
11.362
Table 3. Incidence and significance of clinical, radiological and histological factors of possible
invasiveness.
Factor of invasiveness
IC group (n=23)
p
Clinical assessment
Age < 50
26.1 %
0.223
Presence of palpable tumor
77.3 %
0.111
Radiological assessment
Tumor size in mammogram ≥ 20
mm
71.4 %
0.390
≥ 30 mm
42.9 %
0.266
≥ 40 mm
42.9 %
0.266
Tumor size in sonography ≥ 20 mm
41.2 %
0.069
≥ 30 mm
5.9 %
0.794
≥ 40 mm
0 %
0.404
Tumor size in MRI ≥ 20 mm
57.1 %
0.568
≥ 30 mm
28.6 %
0.410
≥ 40 mm
28.6 %
0.037
High / average breast density in US
100 %
0.063
Suspicious lymph nodes
57.1 %
< 0.001
Presence of microcalcifications
33.3 %
0.183
Histological assessment
Positive estrogen receptors
54.5 %
0.799
Positive progesterone receptors
36.4 %
0.683
High grade nuclear polymorphism
71.4 %
0.049
Table 4. Sentinel lymph node biopsy
DCIS group (n=43)
IC group (n=23)
Surgery with SLNB (65.6 %)
58.5 %
41.5 %
Surgery without SLNB (34.4%)
72.7 %
27.3 %
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Discussion
Breast cancer screening contributes to an
elevated number of the DCIS cases and is
associated with a high number of overdiagnosed
and overtreated patients (20). As there is a gap
of knowledge in distinguishing the DCIS that
will never become invasive and the high risk
cases, both are treated similarly to invasive
cancer (10). Current NCCN recommendations
do not recommend routine SLNB and state that
it should only be considered when a
mastectomy is performed or when the
anatomical location of the excision is
compromising the performance of a future
SLNB. On the other hand, Dutch, English and
American guidelines indicate the SLNB in the
DCIS patients planning to undergo breast
sparing surgery in the presence of a palpable or
solid mass, lesions > 25 mm, intermediate or
high nuclear grade, extensive calcification in the
imaging and age < 55 years (10). National
comperhensive cancer network (NCCN) also
mentions similar factors as local recurrence
indicators which happen to be invasive in 50 %
of cases [21]. Many low risk DCIS lesions can
also match the criteria, leading to an
intervention that is too extensive, while high
risk lesions may stay underestimated [10].
The decision to perform SLNB needs to be
based on the underlying risk of invasion (17).
Currently used methods to evaluate the possible
invasiveness have a low sensitivity and
specificity. Most studies that analyze such
factors have a small sample size and thus report
inconsistent results, so no predictable factors for
IC are used in clinical practice (11). Exact
criteria are needed to prevent both unnecessary
extensive interventions for pure DCIS cases and
non – radical surgeries for patients with an
existing IC component. Our aim was to
contribute to the creation of recommendations
by evaluating most commonly discussed factors
of invasiveness that may help choose a more
adequate treatment strategy by determining high
and low risk cases of DCIS in clinical practice.
The study found that statistically significant
factors are tumor size ≥ 40 mm on MRI, high
grade nuclear polymorphism and suspicious
lymph nodes seen in radiological assessment.
Radiological imaging. Greater tumor size in
radiological imaging was mentioned as the most
generally accepted risk factor, it was determined
that tumor size ≥ 20 mm in ultrasonography
showed a higher incidence of DCIS upstaging to
IC, while other imaging techniques did not
show a significant difference (8). Other study
reports that tumor size > 20 mm did not
significantly differ in postoperatively diagnosed
DCIS and IC groups, p = 0.663. The cutoff
value of size ranges from 20 to 50 mm in
mammography in different studies with bigger
size being significantly related to IC (2). Studies
analyzing factors of invasiveness on MRI also
found that tumor size can be a significant factor:
one of the studies mentions diameter > 20 mm
to be a predictor of an upgrade to IC, while
another retrospective study mentions diameter ≥
30 mm (22). In our study with 3 different
thresholds in US, mammogram and MRI, only
size ≥ 40 mm in MRI was determined as a
significant predictive factor of IC.
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Nuclear polymorphism. Nuclear grade is
considered to be an important indicator of the
biological behaviour of DCIS. Ponti et al
established that high grade nuclear
polymorphism determines quicker development
from DCIS to IC, while a detected low nuclear
grade has no significant value (20). Several
studies found that DCIS with a microinvasion
usually presents with a high nuclear grade
compared with pure DCIS (17). Our results
coincided with other scientific publications and
high and average nuclear polymorphism was
more commonly found in the IC group.
Sentinel lymph node biopsy. SLNB is a
minimally invasive procedure, which is used
with high risk patients for a lymph node
metastasis evaluation. The decision to perform
SLNB is based on the underlying risk of
invasion, as it expands the radicality of the
surgery (17). In a recently published article by
James et al SLNB has been performed in 18 %
of the DCIS cases. Positive nodal metastases
were found in only 0.9 % of the cases, which
shows that SLNB is unnecessary in many cases
(23). A multicenter study conducted in
Denmark found that 25.2 % of preoperatively
diagnosed DCIS were upstaged to invasive
cancer, 40.2 % SLNB were done unnecessary,
while SLNB was not performed and patients
were possibly undertreated in 4.5 % of upstaged
tumor cases (24). Compared with these studies
the number of unnecessary SLNB in our
research was even higher (60 %), a higher
number of SLNB were not performed when IC
was found on the final evaluation as well,
meaning that the radicality of the surgery was
inappropriate in all those cases.
To conclude our study, possible factors of
invasiveness that might be helpful in the future
research are the size of the tumor ≥ 40 mm on
MRI, suspicious lymph nodes in the
radiological assessment and high grade nuclear
polymorphism.
Acknowledgements: This research received no
external funding.
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