Current erosion indices -- flawed or valid ? Summary The problem of erosive tooth wear appears increasingly to be encountered by clinicians and researchers . An adequate way of defining and recording erosive tooth wear is essential in order to assess the extent of this clinical phenomenon , both on an individual level and in the population , and for the adequate provision of preventive and therapeutic measures . Well-established erosion indices have been used in most of these studies , although in many cases modifications have been made to suit the different research aims . This use of different indices is one reason why it still can not be claimed that there is enough current knowledge on this clinical phenomenon . This article summarises the proceedings of a workshop to discuss the topic of dental erosion indices . The result of the workshop is the proposal for a new scoring system -LRB- Basic Erosive Wear Examination , BEWE -RRB- designed for use both within the research field and for dental clinicians , with the aims of standardising assessment of erosion for international comparisons , raising awareness and providing guidelines for treatment of erosive tooth wear in dental practice . Introduction At the 1995 International Life Sciences Institute -- Europe Workshop on Dental Erosion , amongst the recommendations made were the development of a clinical index for assessment of progression of dental erosion and the validation of a proposed erosion index for large-scale epidemiological surveys . One decade later , it appears that these recommendations are still relevant in that such tools have not been validated . Several different indices for the clinical diagnosis of erosive tooth wear are still in use by researchers and clinicians around the world and research on dental erosion carried out over the past decade indicates a lack of consensus . This problem applies both in relation to the prevalence , the distribution , as well as the progression of erosive tooth wear , its early detection and in the evaluation of the efficacy of preventive/therapeutic measures . Although both patients and dental clinicians are becoming increasingly aware of the erosive component of tooth wear , there is still a need to raise diagnostic competence through the use of a simple , standardized index that properly reflects the nature , extent and progression of the defects . This paper summarises the result of the workshop ` Current erosion indices -- flawed or valid ? ' held in Basle in 20071 , the aim of which was to substantiate and critically discuss the current research tools in this field . Anthropological aspects of tooth wear In contrast to the dental profession , anthropologists have considered tooth wear as a normal physiological phenomenon . Skeletal material from ancient remains , such as the pre-contemporary Australian Aboriginal populations , shows clear evidence of attrition and abrasion . The most common cause of these forms of wear is believed to be food mastication , that is to say hard , fibrous material typically consumed by these populations and tooth surface loss appears to be directly related to the age of the individual . Anthropologists describe a tooth wear model where genetic factors influence tooth morphology and occlusion , and , in turn , occlusion and food consistency influence the chewing pattern . The resulting gradual tooth wear is accompanied by physiological adaptation involving bone remodelling and compensatory tooth eruption . It is postulated that from an evolutionary perspective , tooth wear was one of the main selective factors leading to changes in both tooth morphology and properties of dental tissues . Masticatory efficiency is strongly related to tooth anatomy and wear characteristics as highlighted in comparative studies of dentitions of many different species including herbivores , carnivores , primates and humans . A basic understanding of the anthropological perspective of tooth wear is highly valuable both in the diagnosis and treatment planning of contemporary erosive tooth wear and particularly in relation to discussion about the relevance of erosive wear for oral health . Diagnosis and risk factors Dental erosion or erosive tooth wear is a multi-factorial condition . Tooth wear mechanisms seldom happen in isolation , each occurring with different intensity and duration to produce a multitude of wear patterns . This interplay is probably the reason for confusion when attempting to use any tooth wear index based mainly on aetiology . Diagnosis requires a thorough knowledge of both morphological patterns typical of this type of wear and of the factors that are likely to contribute to the development of erosion . Risk factors for erosive tooth wear can be categorized into chemical , biological and behavioural factors . The two most often cited chemical parameters , pH and titratable acidity , can only partly explain the erosive potential of acidic food or drinks . Mineral content , especially the common ions -LRB- calcium and phosphate -RRB- and fluoride , as well as calcium-chelation properties that vary for different dietary acids , are also important . Saliva is considered to be one important biological factor in erosion protection , but also the acquired enamel pellicle , tooth structure and positioning in relation to soft tissues and tongue may be of particular relevance . Behavioural factors can play a role in dental erosion both during and after an acidic challenge . The manner by which dietary acids are introduced and kept in the mouth before swallowing , the timing of acidic consumption/exposure and daily work/pleasure/sport activities can all have a significant effect on the development and location of erosive tooth wear . Individuals suffering from anorexia and bulimia nervosa , rumination , chronic alcoholism or gastro-oesophageal reflux are at risk of erosive tooth wear caused by intrinsic acid and certain occupations are also conducive to erosive tooth wear such as professional wine tasting and industrial work involving exposure to acidic vapours or dust . Current tooth wear indices Measurement of tooth wear has been performed over the years using a large variety of both quantitative and qualitative methods . A number of indices have been developed typically using grading or scoring designed to identify increasing severity or progression of the condition , but traditionally with a focus on only one aetiological factor . Many diagnostic indices however , do not properly reflect the morphological defects and furthermore there is little international standardisation . The earliest published attempt to diagnose tooth wear dates to the late 1800s . This index did not presuppose aetiology and formed the foundation for the development of further indices . In the latter half of the 1900s , many other indices came about largely based on work by Eccles and Jenkins -LSB- 1 -RSB- . The Eccles index for dental erosion of non-industrial origin denotes three classes of lesion assigned to four tooth surfaces . A few years later , based on Eccles work , Smith and Knight -LSB- 2 -RSB- produced the Tooth Wear Index , a comprehensive system whereby all four visible surfaces -LRB- buccal , cervical , lingual and occlusal/incisal -RRB- of all teeth present , are scored for wear . Further modifications of these indices have been published , designed for specific purposes by researchers in order to suit their own work . However , some problems have been encountered concerning the amount of data produced and inter - and intra-examiner reliability in large-scale epidemiological surveys , as well as threshold values in different population groups . The challenge still remains to develop a simple index that can be used clinically to assess progression of wear and in epidemiological prevalence studies . Validity of current diagnostic criteria and tools for grading The diagnosis of tooth wear and of erosive tooth wear in particular , involves the process of identifying the condition by the lesion characteristics and by obtaining medical , nutritional , and occupational information about the patients . On an individual basis this process can be very specific compared with the case for epidemiological research where , for practical reasons , diagnosis is often restricted to lesion characteristics . Although there appears to be relatively widespread consensus as to the characteristic signs and symptoms of erosive tooth wear , dating back approximately 60 years , true validation of these clinical criteria is lacking . At that early stage , the presence of -LRB- amalgam -RRB- fillings appearing to project above the surface of the surrounding tooth was considered to be the most important clinical sign . However , hypersensitivity of the affected teeth , absence of stain and tooth wear defects with rounded margins were also mentioned . More clinically precise descriptions of the lesions have appeared in the literature over time , describing tissue loss at the gingival third of the facial surfaces that were shallow , disc-shaped , smooth , polished or with a scooped out appearance . It is currently accepted that loss of surface contour , shallow concavities on smooth surfaces , cupping and grooving on occlusal/incisal surfaces and ` proud ' restorations are characteristic signs of erosive tooth wear , but reviewing the literature , it turns out that these criteria derived from observations in small groups and individual experience rather than from systematic research . The results of epidemiological studies aimed at relating the occurrence of erosion lesions with known aetiological factors , are somewhat unclear , and in some cases controversial . Most of these studies are performed on random cross-sectional or cluster samples of children or adolescents , with few addressing the adult and aged population . Whether the current diagnostic criteria are valid in reflecting the effect of chronic acid exposure remains to be tested . Comparative studies on wear-lesion characteristics aimed at differentiating between abrasive and erosive wear by examining dietary and nutritional differences have concluded that occlusal/incisal lesions need to be quantified by depth/breadth ratios in order to obtain a correct diagnosis , but that the presence of shallow defects on smooth surfaces is almost certainly a more valid criterion than occlusal cupping and incisal grooving . Except in cases of occlusal cupping in young individuals , it is suggested that the presence of occlusal cupping and incisal grooving are at best uncertain diagnostic criteria for erosive tooth wear , but that shallow defects on smooth surfaces coronal to the CEJ may be pathognomonic of erosive tooth wear . Grading the degree of erosion in an individual is important as it reflects the net exposure to the erosive challenges and the opposing protective forces , and plays a part in the assessment of the problem and of the need for intervention for prevention of further tooth wear . The reliable diagnosis of both early enamel and dentine erosive tooth lesions is challenging and not very reproducible . In cases involving cupping of the molar cusp tips , determining whether dentine is exposed at the base of the cup can be very difficult . Histological studies would tend to indicate that even experienced clinicians underestimate dentine exposure . Assessing tooth wear in the primary dentition provides further challenges . Primary teeth do not appear to withstand wear forces to the same degree as permanent teeth and commonly show signs of wear . This fact affects the scoring of severity and makes determination of aetiology in many cases more difficult . Pathological or physiological erosion : is there a relationship to age ? In order to be able to diagnose erosive tooth wear as unacceptable or even pathological , it is imperative that acceptable levels of tooth wear be established . Partly due to the lack of effective methods for evaluating the amount of tooth loss , these data do not exist apart from a few epidemiological surveys . These studies , combined with experienced clinical judgment currently form the basis for a diagnosis of severity . Defining pathological erosion has proved problematic . Authors addressing this concept have considered cases to be ` pathological ' when excessive loss of tooth tissue has occurred affecting appearance or function , or when it causes pain . This is further complicated by attempting to predict if a tooth , at any age , would survive its current rate of wear , or , if and when interceptive treatment is required , and what level of wear is acceptable to the patient . However , an erosion lesion judged to be pathological at one age may revert to be within physiological boundaries at a later age if it remains quiescent and does not progress further during the intervening period . Thus , when defining pathology , the severity of loss , the current activity and the age of the patient must be considered . Furthermore , the concept of age-related pathological tooth wear becomes interesting when assessed from different perspectives . State health care authorities , private insurance companies , industry , dental clinicians and patients will all have differing interpretations of what constitutes ` pathological ' tooth wear . Requirements and demands on an erosion index Indices have been formulated based on varying criteria , either to satisfy a particular purpose/condition or to enhance reproducibility . Among the factors considered in the development of currently existing indices are clinical versus epidemiological purposes , children versus adults , permanent versus primary teeth , full versus partial mouth scoring , exclusion/inclusion of dentine exposure and/or occlusal cupping and incisal grooving , etc. . None of these indices has been found to describe dental erosion in such a way that they can be regarded as the ` gold standard ' for measurement of erosion . A simple and standardized index that is suitable for assessment of erosion should ideally be -LRB- 1 -RRB- easily applicable in general dental practice , -LRB- 2 -RRB- adaptable for epidemiological prevalence studies , -LRB- 3 -RRB- suitable for monitoring erosive lesion activities such as progression or arrestment of lesions , -LRB- 4 -RRB- easily reproducible under varying conditions for examination such as with/without magnification devices , ambient light , and hydration state of the tooth surface -LRB- dry/wet -RRB- , -LRB- 5 -RRB- capable of reflecting net exposure of an affected individual to the erosive challenge , -LRB- 6 -RRB- capable of indicating the need for treatment , and -LRB- 7 -RRB- should serve for both children and adult as well as permanent and primary teeth . Development of one erosion index capable of satisfying all the above conditions poses a lot of challenges and the implications of the exclusion or inclusion of certain factors and conditions may need thorough consideration . An index involving partial scoring of the dentition used for rapid screening would be more acceptable than one incorporating full mouth scoring , which is both time consuming and believed to lower the accuracy of the index . While limiting the scoring to anterior teeth -LRB- e.g. central incisors -RRB- may eliminate a considerable number of individuals with posterior located erosion , it is considered that the use of a sextants technique , which involves a full mouth examination but scoring the most severely worn surface on each sextant , would favour easy application and reproducibility . In summary , the application of a sextant method , assessing only wear defects on the coronal smooth surfaces , and estimating severity by the diameter and depth -LRB- regardless of dentine involvement -RRB- of wear , may be considered for the development of a simple and standardised index acceptable for clinical practice and epidemiological studies . Methodological considerations The WHO Oral Health Program -LRB- 2003 -RRB- -LSB- 3 -RSB- focuses on oral health as an integral and essential component of general health and an important factor in quality of life . To date , only the DMFT index has been assessed and recorded on an international basis . No indicator of dental erosion is currently included in any EU or WHO oral health policy , most likely due to the lack of a standardized index for measurement of dental erosion . As part of a revision of the WHO Oral Health Surveys Basic Methods , there is now an emphasis on development of methodologies and approaches for evaluating newer disease entities such as dental erosion . Important quality characteristics of epidemiological tools include validity and reliability and sensitivity and specificity . Content validity describes whether all aspects that are relevant for the ` construct ' or content of the index are adequately considered . The content validity is based on the subjective meaning of established experts . When comparing results using a new index with results using an existing ` gold standard ' , it can be stated that the construct validity is high if results are well correlated with each other . When a gold standard is not available , approved hypotheses concerning the construct of interest can be confirmed empirically using the new instrument or index . Reliability of an erosion index indicates how precise that index is able to record dental erosion and encompasses both inter-examiner and intra-examiner reliability . The sensitivity of an erosion index indicates its ability to detect dental erosion -LRB- compared to a gold standard -RRB- and is calculated by dividing the frequency of correct positive results by the sum of correct positive and false negative results . The specificity of an index indicates how well the index can record erosion as absent when erosion is not present and is determined by dividing the frequency of correct negative results by the sum of correct negative and false positive results . Validation studies should be carried out on an international basis and should consider the mentioned quality criteria , most of which are relatively easy to prove . A challenge however is the question of content validity which requires research and final consensus on the construct of erosive wear . New scoring system : the Basic Erosive Wear Examination -LRB- BEWE -RRB- After lengthy discussions flaws in current approaches were identified and it was agreed that there is need for a validated , standardised and internationally accepted index . To initiate the development of such a tool , a universal scoring system was suggested . The new BEWE proposed in this issue records at the sextant level , based on the model of the BPE -LRB- Basic Periodontal Examination -RRB- . It is designed to be a simple , reproducible and transferable scoring system that can be used with the diagnostic criteria of all existing indices . In time , use of the BEWE will generate comparable prevalence data , thus allowing ongoing consensus processes in the scientific community . Researchers within this field should , in practice , be able to transfer previous results using other indices based on other diagnostic criteria over to the BEWE index thereby allowing for improved comparisons . Furthermore , the BEWE will help students , clinicians and general practitioners to screen for erosive tooth wear and to guide them in the decision-making process for the management of erosive tooth wear . Future research perspectives An international alliance between dentists , epidemiologists , statisticians and other scientists and politicians is recommended in order to develop an internationally agreed and accepted dental erosion index . Efforts should be made : to re-evaluate existing data with the BEWE system to gain comparable data on the relevance of erosive wear for oral health and to initiate the consensus processto prove the content validity of the construct ` dental erosion ' and to define valid diagnostic criteriato use these criteria with the BEWE system thus creating a new indexto validate this index on an international basis with the perspective to implement erosive wear data in the WHO and EU oral health data bases and erosion indicators in indicator sets for oral healthto further develop the link between the sum score of the BEWE and recommendations for prevention and treatment in the individual patient

O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I I O O O O O O O O O O O O O O O O B O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

erosive tooth wear
index
diagnosis
prevalence


MRI

compared

to

conventional

diagnostic

work-up

in

the

detection

and

evaluation

of

invasive

lobular

carcinoma

of

the

breast

a

review

of

existing

literature

Purpose

The

clinical

diagnosis

and

management

of

invasive

lobular

carcinoma

-LRB-

ILC

-RRB-

of

the

breast

presents

difficulties

Magnetic

resonance

imaging

-LRB-

MRI

-RRB-

has

been

proposed

as

the

imaging

modality

of

choice

for

the

evaluation

of

ILC

Small

studies

addressing

different

aspects

of

MRI

in

ILC

have

been

presented

but

no

large

series

to

date

To

address

the

usefulness

of

MRI

in

the

work-up

of

ILC

we

performed

a

review

of

the

currently

published

literature

Introduction

Invasive

lobular

carcinoma

-LRB-

ILC

-RRB-

is

the

second

most

common

histologic

type

of

breast

carcinoma

after

invasive

ductal

carcinoma

-LRB-

IDC

-RRB-

In

most

series

ILC

constitutes

between

and

of

all

breast

cancers

whereas

IDC

constitutes

between

and

of

all

breast

cancers

-LSB-

-RSB-

Probably

due

to

the

use

of

complete

hormone

replacement

therapy

the

lobular

breast

cancer

component

has

continuously

increased

over

the

past

decade

from

in

to

in

-LSB-

-RSB-

Patients

are

according

to

most

series

a

little

older

than

patients

presenting

with

IDC

especially

the

fraction

of

patients

presenting

with

ILC

younger

than

is

smaller

-LSB-

-RSB-

Furthermore

the

mean

tumor

size

of

ILC

is

slightly

larger

than

in

patients

with

IDC

and

patient

presentation

with

a

tumor

larger

than

cm

occurs

more

often

in

cases

of

ILC

-LSB-

-RSB-

Histopathologically

ILC

are

clearly

defined

ILCs

are

constituted

from

small

relatively

uniform

cells

very

similar

to

normal

endothelial

cells

Characteristically

these

cells

are

only

loosely

cohesive

and

infiltrate

the

stroma

in

single

cell

file

strands

along

ductuli

This

growth

pattern

present

in

of

cases

-LSB-

-RSB-

is

also

known

as

Indian

filing

It

is

probably

caused

by

a

typical

loss

of

the

adhesion

molecule

E-cadherin

Often

there

is

very

little

desmoplastic

stromal

reaction

-LSB-

-RSB-

The

biological

characteristics

of

ILC

are

usually

less

alarming

than

those

of

IDC

more

tumors

contain

estrogen

receptors

and

progesterone

receptors

while

expression

of

and

are

more

often

normal

and

axillary

lymph

nodes

are

not

more

often

positive

even

though

ILC

are

overall

larger

in

size

than

IDC

-LSB-

-RSB-

Probably

due

to

the

diffuse

infiltrative

growth

pattern

ILC

is

frequently

missed

on

mammography

-LSB-

-RSB-

Detection

is

also

compromised

because

ILC

often

has

a

density

less

than

or

equal

to

normal

fibroglandular

breast

tissue

on

mammography

-LSB-

-RSB-

For

correct

treatment

of

ILC

adequate

staging

is

important

Both

mammography

and

ultrasound

tend

to

underestimate

lesion

size

and

are

therefore

not

optimal

for

staging

purposes

-LSB-

-RSB-

This

may

in

part

be

the

reason

that

higher

failure

rates

of

breast-conserving

therapy

-LRB-

BCT

-RRB-

in

ILC

than

in

IDC

are

reported

-LSB-

-RSB-

Various

authors

therefore

propose

magnetic

resonance

imaging

-LRB-

MRI

-RRB-

as

the

modality

of

choice

for

the

evaluation

of

ILC

Several

small

studies

addressing

the

different

aspects

of

the

use

of

MRI

in

ILC

have

been

presented

but

no

large

series

to

date

Therefore

many

questions

regarding

the

use

of

MRI

in

ILC

remain

unanswered.The

sensitivity

of

MRI

for

breast

lesions

is

approximately

however

whether

this

holds

true

for

ILC

as

well

is

not

clear

-LSB-

-RSB-

The

morphologic

aspects

of

ILC

are

not

yet

well

defined

nor

is

the

dynamic

behavior

of

contrast

agents

in

these

tumors

clearly

documented.Moreover

whether

the

MRI

findings

are

similar

to

pathologic

findings

and

can

thus

be

used

for

accurate

staging

still

needs

to

be

established.Finally

the

impact

of

MRI

on

surgical

treatment

of

ILC

should

be

evaluated.To

answer

these

questions

we

performed

a

thorough

review

of

the

existing

literature

regarding

the

use

of

MRI

in

case

of

ILC

and

performed

meta-analysis

whenever

possible

We

subsequently

reviewed

the

literature

on

other

imaging

modalities

for

this

indication

in

order

to

evaluate

the

use

of

MRI

from

a

clinical

perspective

Materials

and

methods

Search

strategy

We

performed

a

literature

search

for

articles

that

specifically

dealt

with

the

use

of

MRI

in

patients

with

histologic

proof

of

ILC

published

before

April

The

Cochrane

Library

MEDLINE

and

the

in-progress

citations

as

provided

by

PubMed

were

searched

using

the

query

lobular

AND

-LRB-

MR

OR

MRI

OR

MRT

OR

magnetic

-RRB-

These

databases

were

further

searched

using

the

Related

Articles

function

in

PubMed

The

same

query

was

used

to

browse

the

web

using

scholar.google.com

Furthermore

the

references

of

all

retrieved

articles

were

manually

searched

for

relevant

cross-references

Articles

in

all

languages

were

accepted

All

retrieved

articles

were

then

compared

and

from

overlapping

series

of

patients

only

the

most

recent

publication

was

accepted

Many

different

search

terms

were

used

for

literature

review

of

other

imaging

modalities

However

only

PubMed

was

used

as

search

engine

Endpoints

The

study

was

thus

undertaken

to

answer

the

following

four

questions.What

is

the

sensitivity

of

MRI

for

ILC?What

are

the

visual

characteristics

of

ILC

on

MRI?Are

the

findings

on

MRI

equal

to

the

findings

at

pathology?What

is

the

impact

of

MRI

on

surgical

management

of

ILC?Whenever

studies

allowed

direct

comparison

between

MRI

and

other

imaging

modalities

these

modalities

were

also

analyzed

Sensitivity

was

defined

as

the

number

of

lesions

visible

on

MRI

divided

by

the

total

number

of

ILC

detected

at

pathology

We

regarded

morphology

dynamic

curve

analysis

of

contrast

behavior

and

quantitative

dynamic

analysis

of

contrast

behavior

as

three

different

aspects

of

tumor

appearance

and

these

were

thus

analyzed

separately

A

principal

distinction

between

mass-like

and

non-mass-like

lesions

was

made

in

the

analysis

of

morphology

Based

on

the

BI-RADS

lexicon

-LSB-

-RSB-

we

defined

architectural

distortion

regional

segmental

ductal

multifocal

or

diffuse

enhancement

and

multiple

enhancing

foci

as

descriptors

of

non-mass

lesions

Nodular

or

focal

enhancement

well-defined

round

irregular

or

spiculated

masses

and

dominant

masses

with

small

enhancing

foci

were

defined

as

descriptors

of

mass-like

lesions

Correlation

between

the

findings

on

MRI

and

pathology

was

evaluated

for

relative

tumor

size

-LRB-

unifocal

versus

multifocal

disease

and

single

quadrant

versus

multicentric

disease

-RRB-

and

absolute

tumor

size

The

impact

on

surgical

management

was

derived

from

all

changes

implemented

based

solely

on

MRI

findings

The

numbers

of

correct

and

incorrect

changes

were

tabulated

Eligibility

criteria

All

studies

that

presented

a

series

of

at

least

ten

patients

with

histologic

proof

of

pure

ILC

with

or

without

concurrent

DCIS

and/or

LCIS

were

considered

eligible

A

quality

analysis

of

the

study

had

to

be

possible

otherwise

no

abstracts

were

accepted

Patients

with

mixed

carcinomas

of

ILC

and

IDC

were

excluded

Studies

that

presented

data

on

both

ILC

and

mixed

carcinomas

had

to

allow

extraction

of

the

relevant

data

for

ILC

only

Every

study

considered

eligible

according

to

these

eligibility

criteria

was

then

evaluated

for

all

the

study

endpoints

Specific

eligibility

criteria

for

the

various

considered

endpoints

are

described

below.Detection

Studies

had

to

be

based

on

a

pathology

database

and

all

subsequent

patients

with

ILC

who

underwent

a

MRI

had

to

be

included

The

total

number

of

ILC

confirmed

at

pathology

had

to

be

clearly

stated

as

well

as

the

number

of

lesions

found

with

MRI.Morphology

Studies

describing

the

appearance

of

ILC

visible

on

MRI

were

eligible

Separation

between

mass

and

non-mass-like

lesions

had

to

be

possible.Dynamic

curve

analysis

of

contrast

behavior

Studies

that

described

the

enhancement

versus

time

curve

were

eligible

However

as

time

to

peak

and

shape

of

the

final

phase

of

the

enhancement

curve

were

our

main

endpoints

these

had

to

be

described.Quantitative

analysis

of

contrast

behavior

Studies

performing

quantitative

analysis

of

the

contrast-enhancement

parameters

were

eligible.Relative

correlation

with

pathology

Studies

presenting

data

on

the

unifocal

versus

multifocal

correlation

or

single

quadrant

involvement

versus

multicentric

involvement

were

eligible.Absolute

correlation

with

pathology

Studies

comparing

sizes

measured

on

MRI

with

those

measured

at

pathology

and

presenting

a

correlation

coefficient

or

sufficient

raw

data

to

calculate

such

a

value

were

eligible.Detection

of

additional

lesions

Any

study

describing

additional

lesions

apart

from

the

index

lesion

detected

by

MRI

only

with

subsequent

acquisition

of

histologic

proof

of

malignancy

was

considered

eligible

Lesions

in

the

ipsilateral

breast

and

the

contralateral

breast

were

evaluated

separately.Impact

on

surgical

treatment

Studies

mentioning

all

changes

in

surgical

strategy

based

on

MRI

findings

were

eligible

Statistics

The

quality

of

all

included

studies

was

assessed

using

the

QUADAS

tool

-LSB-

-RSB-

The

latter

is

a

list

of

items

created

for

quality

assessment

of

studies

to

diagnostic

accuracy

Although

not

all

the

included

studies

specifically

evaluate

diagnostic

accuracy

this

tool

was

judged

to

be

the

most

appropriate

available

Data

of

all

the

studies

were

collected

according

to

the

inclusion

and

exclusion

criteria

When

at

least

five

studies

presented

the

same

type

of

data

or

at

least

patients

were

included

in

a

smaller

series

of

studies

with

similar

data

we

considered

meta-analysis

and

heterogeneity

analysis

was

performed

Dichotomous

data

with

a

binomial

distribution

-LRB-

e.g.

sensitivity

-RRB-

were

transformed

to

the

log

odds

scale

because

this

scale

has

a

normal

distribution

and

is

a

good

approximation

to

the

exact

binomial

distribution

A

disadvantage

of

this

transformation

however

is

that

the

confidence

intervals

are

a

little

wider

and

values

in

the

middle

of

the

distribution

-LRB-

e.g.

sensitivity

closer

to

-RRB-

are

more

heavily

weighted

in

meta-analysis

than

values

close

to

the

upper

or

lower

level

Pearson

's

correlation

coefficient

was

transformed

to

Fisher

's

Z

for

the

same

reason

-LSB-

-RSB-

We

calculated

Cochran

's

Q

coefficient

and

the

to

assess

heterogeneity

Cochran

's

Q

is

a

form

of

the

and

provides

information

about

the

applicability

of

pooling

the

data

The

provides

a

quantitative

measure

of

the

amount

of

heterogeneity

and

has

an

upper

limit

of

Values

of

the

of

and

can

be

interpreted

as

low

moderate

and

high

heterogeneity

respectively

-LSB-

-RSB-

Meta-analysis

of

the

data

using

a

random

effects

model

was

performed

when

the

Q-coefficient

showed

no

significant

heterogeneity

-LRB-

p

-RRB-

In

cases

where

meta-analysis

was

feasible

the

estimate

and

the

CL

are

expressed

When

meta-analysis

was

not

feasible

due

to

severe

heterogeneity

only

the

range

of

values

found

in

the

different

studies

is

mentioned

All

calculations

were

performed

using

R

version

-LRB-

The

R

Project

for

Statistical

Computing

-RRB-

and

the

meta

package

-LRB-

G.

Schwarzer

cran.r-project.org

-RRB-

Results

Studies

We

identified

separate

studies

that

dealt

with

MRI

and

ILC

-LSB-

-RSB-

We

further

identified

four

studies

that

did

not

deal

specifically

with

ILC

and

MRI

However

they

did

present

their

data

in

such

a

fashion

that

relevant

information

for

ILC

only

could

be

extracted

for

at

least

ten

patients

-LSB-

-RSB-

Four

studies

were

case-reports

and

were

dropped

from

the

cohort

-LSB-

-RSB-

The

study

by

Bazzocchi

et

al.

-LSB-

-RSB-

was

excluded

because

only

eight

patients

underwent

MRI

Leung

et

al.

-LSB-

-RSB-

and

Newstead

et

al.

-LSB-

-RSB-

only

published

their

findings

in

abstract

form

and

were

consequently

excluded

Table

gives

an

overview

of

the

included

studies

and

their

characteristics

including

the

QUADAS

score

Table

of

the

included

studiesAuthorsPub

YearaStudy

typebNcAge

meandAge

min.eAge

max.fFieldgScan

seq.hUni

bilatiCompressionjMean

sizekQUADAS

scorelRodenko

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

Kim

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

Qayyum

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

Kneeshaw

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

Berg

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

Demard

et

al.

-LSB-

-RSB-

of

publication

of

the

original

indicates

retrospective

cohort

study

indicates

prospective

cohort

studycNumber

of

patients

includeddMean

age

of

all

included

patients

X

denotes

not

mentionedeAge

of

respective

youngest

patient

included

in

the

studyfAge

of

respective

eldest

patient

included

in

the

studygStrength

of

magnetic

field

denotes

unknown

denotes

T

denotes

T

denotes

both

T

and

ThType

of

scan

sequence

used

denotes

unknown

denotes

RODEO

denotes

FLASH

denotes

otheriUnilateral

or

bilateral

imaging

of

the

breast

denotes

unknown

denotes

unilateral

denotes

bilateral

denotes

both

unilateral

and

bilateral

depending

on

the

patientjCompression

applied

to

the

breast

denotes

no

denotes

yeskMean

size

of

the

lesions

in

centimeters

X

denotes

not

mentionedlNumber

of

items

valid

on

QUADAS

scorings

listmValid

for

whole

study

population

only

not

for

subpopulation

of

patients

with

ILC

The

applied

scan

protocols

in

the

included

studies

are

diverse

In

general

most

studies

presented

herein

used

a

MRI

scanner

although

some

authors

had

at

least

some

of

their

included

patients

scanned

using

T

machines

-LSB-

-RSB-

Most

protocols

were

based

on

weighted

images

made

with

either

a

normal

FLASH

sequence

or

a

FLASH

sequence

with

fat-suppression

-LSB-

-RSB-

or

a

RODEO

sequence

with

water

selective

excitation

-LSB-

-RSB-

A

number

of

authors

also

used

weighted

sequences

-LSB-

-RSB-

Other

differences

in

scan

protocols

involve

the

voxel

sizes

and

temporal

resolution

Some

authors

emphasize

high

spatial

resolution

-LSB-

-RSB-

while

others

prefer

high

temporal

resolution

-LSB-

-RSB-

and

yet

again

others

performed

both

types

of

sequences

in

succession

-LSB-

-RSB-

Furthermore

single

breast

coils

-LSB-

-RSB-

and

double

breast

coils

-LRB-

all

others

-RRB-

were

used

and

sometimes

compression

was

applied

to

the

imaged

breast

-LSB-

-RSB-

In

most

reported

studies

the

scanning

protocols

evolved

over

time

and

are

thus

not

identical

for

all

imaged

patients

Lesion

detection

Eight

studies

provided

sufficient

data

to

calculate

sensitivity

of

MRI

for

ILC

-LSB-

-RSB-

Sensitivity

ranged

from

to

Cochran

's

Q

was

-LRB-

p

-RRB-

was

indicating

homogeneous

studies

and

hence

data

pooling

could

be

performed

Mean

sensitivity

was

-LRB-

CI

-RRB-

Only

the

studies

by

Francis

et

al.

-LSB-

-RSB-

and

Berg

et

al.

-LSB-

-RSB-

provided

prospective

data

and

are

therefore

able

to

show

sensitivity

in

clinical

practice

They

showed

a

sensitivity

of

and

respectively

and

were

statistically

not

different

from

the

retrospective

studies

-LRB-

two-sided

T-test

p

-RRB-

Seven

of

these

studies

also

provided

data

on

mammography

-LSB-

Q

-LRB-

p

-RRB-

-RSB-

six

on

ultrasound

-LSB-

Q

-LRB-

p

-RRB-

-RSB-

and

five

on

clinical

examination

-LSB-

Q

-LRB-

p

-RRB-

-RSB-

Sensitivity

of

ultrasound

could

also

be

computed

through

meta-analysis

and

was

-LRB-

CI

-RRB-

although

moderate

heterogeneity

was

present

The

provided

data

for

mammography

and

clinical

examination

were

too

heterogeneous

for

meta-analysis

and

ranged

from

to

and

to

respectively

Figure

shows

the

results

of

each

independent

study

and

the

overall

results

Fig.

of

the

sensitivity

of

the

respective

modalities

for

ILC

-LRB-

MMG

mammography

US

ultrasound

CE

clinical

examination

-RRB-

the

horizontal

lines

represent

confidence

intervals

Modalities

presented

on

the

right

of

the

authors

name

have

not

been

tested

in

the

appropriate

study

The

diamonds

at

the

bottom

represent

the

pooled

estimates

and

their

confidence

intervals

for

MRI

and

US

respectively

Because

mammography

and

clinical

examination

were

too

heterogeneous

for

meta-analysis

no

pooled

estimate

is

presented

for

these

modalities

Morphology

Seven

studies

described

lesion

morphology

on

static

MRI

images

-LSB-

-RSB-

However

Kim

et

al.

-LSB-

-RSB-

studied

morphologic

appearances

of

masses

only

and

therefore

did

not

include

non-mass-like

lesions

Information

provided

by

their

study

is

therefore

only

used

to

evaluate

the

appearance

of

masses

and

not

for

the

principal

distinction

between

mass

and

non-mass

lesions

The

terminology

used

in

the

literature

to

describe

the

lesions

is

highly

variable

Only

Yeh

et

al.

-LSB-

-RSB-

consistently

used

the

terminology

of

the

BI-RADS

lexicon

-LSB-

-RSB-

The

six

eligible

studies

that

presented

data

on

morphologic

appearance

described

a

total

of

tumors

However

results

are

highly

variable

The

incidence

of

a

mass-like

lesion

ranged

from

to

-LSB-

Q

-LRB-

p

-RRB-

-RSB-

Table

shows

the

appearance

of

ILC

on

MRI

for

all

individual

studies

Table

appearance

of

ILC

on

MRIAuthorsNumber

of

tumorsNon-mass-likeMass-likeRodenko

et

al.

-LSB-

-RSB-

-LRB-

-RRB-

-LRB-

-RRB-

Weinstein

et

al.

-LSB-

-RSB-

-LRB-

-RRB-

-LRB-

-RRB-

Qayyum

et

al.

-LSB-

-RSB-

-LRB-

-RRB-

-LRB-

-RRB-

Yeh

et

al.

-LSB-

-RSB-

-LRB-

-RRB-

-LRB-

-RRB-

Schelfout

et

al.

-LSB-

-RSB-

-LRB-

-RRB-

-LRB-

-RRB-

Fabre

Demard

et

al.

-LSB-

-RSB-

-LRB-

-RRB-

-LRB-

-RRB-

Numbers

between

parenthesis

represent

percentages

Fabre

Demard

et

al.

-LSB-

-RSB-

did

not

specify

the

lesions

beyond

the

description

mass-like

Other

authors

used

many

different

terms

to

further

describe

lesions

In

the

study

presented

by

Rodenko

et

al.

-LSB-

-RSB-

five

pre-defined

shapes

were

used

but

they

described

all

mass-like

lesions

as

spicular

enhancing

masses

In

the

other

studies

most

lesions

are

described

as

spiculated

masses

as

well

Schelfout

et

al.

-LSB-

-RSB-

recognized

a

dominant

mass

with

multiple

enhancing

foci

in

eight

cases

and

Yeh

et

al.

-LSB-

-RSB-

described

even

a

round

focal

mass

In

the

mass-like

cases

described

by

Kim

et

al.

-LSB-

-RSB-

had

an

irregular

shape

and

were

spiculated

Therefore

among

the

masses

a

total

of

tumors

were

described

as

an

irregular

or

spiculated

mass

This

appears

to

be

the

most

common

type

of

mass-like

presentation

in

ILC

Kinetics

Only

two

studies

reported

on

the

dynamic

curve

appearance

of

ILC

-LSB-

-RSB-

The

most

apparent

similarity

between

findings

was

that

maximum

enhancement

is

often

delayed

and

wash-out

is

present

in

only

a

minority

of

lesions

Sittek

et

al.

-LSB-

-RSB-

reported

that

maximum

enhancement

was

not

reached

before

min

after

contrast

administration

Trecate

et

al.

-LSB-

-RSB-

noted

that

a

classic

pattern

of

rapid

signal

increase

was

only

present

in

of

pure

ILC

whereas

a

delayed

pattern

was

observed

in

the

other

cases

Two

other

studies

reported

on

quantitative

contrast

behavior

analysis

in

ILC

-LSB-

-RSB-

Qayyum

et

al.

-LSB-

-RSB-

reported

on

a

parameter

called

analogue

to

the

Ktrans

parameter

as

described

by

Tofts

et

al.

-LSB-

-RSB-

Yeh

et

al.

-LSB-

-RSB-

evaluated

the

extraction

flow

product

-LRB-

EFP

-RRB-

which

is

a

similar

analogue

but

respects

the

possibility

that

contrast

leakage

from

the

vessels

is

limited

by

flow

instead

of

being

limited

by

the

permeability

surface

area

product

Both

studies

did

not

however

include

sufficient

patients

to

produce

meaningful

results

other

than

a

high

variability

in

the

values

of

these

parameters

and

the

presence

in

some

tumors

of

enhancement

very

much

like

enhancement

in

normal

breast

tissue

It

was

noted

that

values

appeared

to

be

an

order

of

magnitude

less

in

ILC

than

in

IDC

lesions

Correlation

Several

authors

evaluated

correlation

of

the

MRI

findings

with

pathology

-LSB-

-RSB-

Three

studies

compared

unifocality

and

multifocality

between

MRI

and

pathology

-LSB-

-RSB-

-LRB-

Table

-RRB-

Overall

of

cases

-LRB-

-RRB-

were

regarded

as

multifocal

whereas

they

appeared

unifocal

at

pathology

and

vice

versa

cases

-LRB-

-RRB-

in

one

study

appeared

unifocal

at

MRI

but

were

multifocal

according

to

pathology

Table

correlation

of

unifocality

versus

multifocality

for

MRI

versus

pathologyAuthorsNumber

of

patientsUF

MRIUF

PATHMF

MRIMF

PATHOverestimatedaUnderestimatedbRodenko

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

unifocal

MF

multifocal

PATH

pathologyaDisease

was

classified

as

multifocal

on

MRI

but

was

unifocal

on

pathologybDisease

was

classified

as

unifocal

on

MRI

but

was

multifocal

on

pathology

Overestimation

of

multifocality

based

on

mammography

in

patients

from

these

studies

occurred

in

patients

-LRB-

-RRB-

whereas

underestimation

occurred

times

-LRB-

-RRB-

and

the

lesion

was

not

visible

on

mammography

in

another

patients

-LRB-

-RRB-

Two

of

these

studies

further

analyzed

single

quadrant

versus

multicentric

involvement

of

the

affected

breast

-LSB-

-RSB-

-LRB-

Table

-RRB-

In

the

study

by

Rodenko

et

al.

-LSB-

-RSB-

two

cases

of

single

quadrant

disease

were

erroneously

classified

as

multicentric

on

MRI

Table

correlation

of

single

quadrant

versus

multicentric

involvement

for

MRI

versus

pathologyAuthorsNumber

of

patientsSQ

MRISQ

PATHMC

MRIMC

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

single

quadrant

MC

multicentric

PATH

pathologyaMulticentric

involvement

was

seen

on

MRI

but

involvement

of

only

one

quadrant

was

shown

on

pathologybInvolvement

of

only

one

quadrant

was

seen

on

MRI

but

on

pathology

multicentric

involvement

was

shown

Mammography

in

of

these

patients

resulted

in

overestimation

of

disease

extent

in

patient

and

underestimation

in

Again

no

lesion

was

visible

in

four

patients

Berg

et

al.

-LSB-

-RSB-

further

showed

a

series

of

patients

that

underwent

MRI

Correct

size

estimation

was

performed

in

seven

patients

In

one

patient

an

additional

focus

was

missed

and

in

four

patients

overestimation

occurred

due

to

foci

of

LCIS

Absolute

correlation

of

MRI

and

pathologic

size

measurement

was

performed

by

six

authors

-LSB-

-RSB-

Rodenko

et

al.

-LSB-

-RSB-

found

a

Kappa

coefficient

of

which

represents

substantial

agreement

The

other

authors

presented

Pearson

's

correlation

coefficients

ranging

from

to

-LSB-

Q

-LRB-

p

-RRB-

-RSB-

Correlation

coefficients

for

other

modalities

were

substantially

more

variable

Presented

correlation

coefficients

in

Table

are

optimized

by

excluding

cases

where

no

abnormalities

were

seen

from

the

calculations

Table

of

tumor

size

measured

by

various

modalities

compared

to

pathologyAuthorsMRIMMGUSCENPCCΚNPCCKNPCCKNPCCKRodenko

et

al.

-LSB-

-RSB-

Munot

et

al.

-LSB-

-RSB-

Kneeshaw

et

al.

-LSB-

-RSB-

Francis

et

al.

-LSB-

-RSB-

Boetes

et

al.

-LSB-

-RSB-

Kepple

et

al.

-LSB-

-RSB-

MMG

mammography

US

ultrasound

CE

clinical

examination

N

number

of

lesions

visible

on

the

appropriate

modality

PCC

Pearson

's

correlation

coefficient

K

Kappa

valueaKneeshaw

et

al.

did

not

provide

a

correlation

coefficient

for

either

MMG

or

US

but

only

one

for

the

combined

modalities

Boetes

et

al.

-LSB-

-RSB-

applied

a

correctness

measure

of

cm

to

their

data

and

found

that

MRI

underestimated

disease

extent

in

of

tumors

and

overestimated

extent

in

cases

by

more

than

cm

The

data

provided

by

Francis

et

al.

-LSB-

-RSB-

allow

a

similar

calculation

Underestimation

occurred

in

of

cases

and

overestimation

occurred

in

Additional

lesions

Five

studies

focused

on

the

detection

of

concurrent

additional

lesions

in

the

affected

breast

apart

from

the

index

lesion

only

visible

by

MRI

-LSB-

-RSB-

In

of

patients

additional

malignant

lesions

were

found

-LSB-

Q

-LRB-

p

-RRB-

-RSB-

Additional

malignant

findings

only

visible

on

MRI

were

present

in

of

cases

-LRB-

CI

-RRB-

The

results

of

the

individual

studies

are

presented

in

Table

Table

malignant

findings

in

the

ipsilateral

breast

by

MRIAuthorsNumber

of

patientsNumber

of

additional

findingsWeinstein

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

Demard

et

al.

-LSB-

-RSB-

-LRB-

-RRB-

Eight

studies

presented

in

Table

reported

on

findings

in

the

contralateral

breast

-LSB-

-RSB-

In

of

patients

unexpected

contralateral

cancer

was

discovered

exclusively

by

MRI

-LSB-

Q

-LRB-

p

-RRB-

-RSB-

Cases

where

contralateral

cancer

was

also

visible

on

mammography

and/or

ultrasound

are

excluded

Contralateral

carcinoma

only

visible

by

MRI

was

present

in

of

patients

-LRB-

CI

-RRB-

Table

findings

in

the

contralateral

breast

by

MRIAuthorsNumber

of

patientsNumber

of

contralateral

findingsFrancis

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

Demard

et

al.

-LSB-

-RSB-

-LRB-

-RRB-

Effect

on

surgical

treatment

Six

studies

explicitly

stated

the

effect

of

MRI

on

the

surgical

treatment

of

their

patients

-LSB-

-RSB-

In

patients

with

ILC

a

total

of

changes

in

surgical

management

occurred

-LSB-

Q

-LRB-

p

-RRB-

-RSB-

Overall

MRI

changed

the

surgical

management

in

of

cases

-LRB-

CI

-RRB-

In

cases

BCT

was

changed

to

mastectomy

In

nine

cases

a

wider

local

excision

was

performed

In

the

remaining

cases

the

type

of

change

was

not

further

described

Forty-one

of

changes

in

surgical

management

were

retrospectively

judged

necessary

based

on

pathologic

findings

-LSB-

Q

-LRB-

p

-RRB-

-RSB-

Therefore

of

all

changes

were

correct

-LRB-

CI

-RRB-

In

three

cases

the

change

in

management

was

retrospectively

judged

unnecessary

based

on

pathology

The

data

of

the

individual

studies

are

presented

in

Table

Table

in

surgical

management

based

solely

on

MRI

findingsAuthorsNumber

of

patientsNumber

of

changesCorrect

changesIncorrect

changesCorrect

wider

excisionIncorrect

wider

excisionCorrect

mastectomyIncorrect

mastectomyRodenko

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

Demard

et

al.

-LSB-

-RSB-

of

changes

-LRB-

-RRB-

Correct

changes

-LRB-

-RRB-

of

changes

and

correct

changes

show

the

result

of

meta-analysesNA

not

available

Rodenko

et

al.

-LSB-

-RSB-

and

Kneeshaw

et

al.

-LSB-

-RSB-

both

reported

one

further

unnecessary

mastectomy

based

on

MRI

outcomes

However

these

mastectomies

would

also

have

been

performed

based

on

the

mammography

findings

and

are

therefore

not

only

due

to

the

MRI

Berg

et

al.

-LSB-

-RSB-

also

reported

that

findings

on

MRI

in

patients

with

ILC

would

have

resulted

in

two

unnecessary

mastectomies

However

mastectomies

were

also

indicated

according

to

the

ultrasound

report

Nonetheless

they

based

their

treatment

on

the

mammograms

only

and

therefore

these

mastectomies

were

not

performed

Discussion

Studies

and

quality

analysis

We

included

studies

but

the

highest

number

of

studies

that

could

be

used

to

answer

a

specific

endpoint

was

-LRB-

sensitivity

and

contralateral

findings

-RRB-

Strong

evidence

is

therefore

lacking

and

this

review

is

thus

a

clear

call

for

more

substantial

research

in

this

area

The

overall

study

quality

of

all

studies

is

according

to

the

QUADAS

score

reasonably

high

-LRB-

lowest

score

-RRB-

However

this

tool

does

not

include

the

study

size

in

the

analysis

which

was

generally

low

The

tool

places

a

strong

emphasis

on

the

relation

of

the

test

to

the

reference

standard

-LRB-

typical

for

observational

studies

-RRB-

In

all

studies

the

reference

standard

was

pathology

and

therefore

always

acceptable

as

gold

standard

However

the

test

results

-LRB-

in

this

case

the

MRI

reports

-RRB-

were

never

shielded

from

the

pathologist

who

performed

the

pathologic

evaluation

In

studies

that

were

performed

to

evaluate

the

visual

characteristics

of

ILC

on

MRI

a

thorough

description

of

the

pathological

examination

was

deservedly

so

not

included

-LSB-

-RSB-

These

studies

thus

scored

a

little

lower

There

are

some

other

drawbacks

that

must

be

considered

and

that

are

not

included

in

the

QUADAS

score

Firstly

all

but

of

the

included

studies

were

retrospective

in

nature

and

secondly

the

applied

MRI

protocols

were

largely

heterogeneous

-LRB-

see

Table

-RRB-

However

the

presented

data

were

extracted

from

studies

that

made

use

of

the

various

standards

in

MRI

of

the

breast

of

the

last

decade

and

therefore

give

a

reasonable

overview

of

the

overall

capability

of

MRI

in

ILC

imaging

in

this

period

Sensitivity

The

sensitivity

of

physical

examination

and

conventional

imaging

for

ILC

of

the

breast

is

not

optimal

The

sensitivity

of

physical

examination

for

ILC

ranges

between

and

-LSB-

-RSB-

with

usually

over

of

patients

presenting

with

palpable

abnormalities

The

sensitivity

of

mammography

for

ILC

-LRB-

BI-RADS

or

higher

-RRB-

ranges

between

and

in

literature

-LSB-

-RSB-

In

a

recent

study

that

evaluated

intra

and

interobserver

variability

sensitivity

even

ranged

from

to

-LSB-

-RSB-

which

could

be

regarded

as

sufficient

However

ILC

often

do

not

appear

as

a

malignant

lesion

on

mammography

approximately

is

classified

as

equivocal

and

sensitivity

is

then

approximately

-LSB-

-RSB-

The

overall

sensitivity

of

mammography

in

the

current

analysis

appears

lower

than

findings

in

the

literature

on

mammography

in

ILC

However

equivocal

findings

may

have

been

classified

as

undetected

lesions

in

some

studies

resulting

in

the

overall

lower

results

Nevertheless

the

sensitivities

of

only

found

by

Berg

et

al.

-LSB-

-RSB-

and

found

by

Munot

et

al.

-LSB-

-RSB-

are

on

the

lower

end

of

the

spectrum

Munot

et

al.

-LSB-

-RSB-

did

not

state

which

views

constituted

their

mammograms

while

Berg

et

al.

-LSB-

-RSB-

made

craniocaudal

mediolateral

and

spot-compression

views

on

a

standard

mammography

machine

which

we

regard

as

common

practice

A

possible

explanation

for

the

poor

results

in

the

study

by

Berg

et

al.

-LSB-

-RSB-

may

be

that

they

defined

an

ILC

as

a

focus

of

tumor

thereby

allowing

more

tumors

to

be

present

in

one

breast

whereas

other

authors

defined

this

as

multifocal

or

multicentric

tumors

and

thus

as

detected

when

at

least

one

lesion

was

visible

on

mammography

In

literature

the

reported

sensitivity

of

ultrasound

for

ILC

ranges

between

and

-LSB-

-RSB-

As

this

range

is

comparable

to

the

range

found

in

the

present

evaluation

we

are

of

the

opinion

that

an

overall

sensitivity

of

is

accurate

However

application

of

newer

high-frequency

ultrasound

transducers

may

improve

sensitivity

Initial

series

using

MHz

transducers

show

sensitivities

of

-LSB-

-RSB-

and

-LSB-

-RSB-

whereas

series

that

used

MHz

transducers

report

sensitivities

up

to

-LSB-

-RSB-

Contrast-enhanced

MRI

is

nowadays

widely

accepted

as

the

most

sensitive

modality

for

detection

of

malignancy

of

the

breast

Early

reports

on

overall

sensitivity

of

MRI

for

breast

lesions

range

from

to

-LSB-

-RSB-

Thus

the

sensitivity

of

MRI

found

for

ILC

in

the

studies

presented

herein

and

the

overall

sensitivity

of

calculated

from

these

studies

are

not

different

from

those

known

for

malignancy

in

the

breast

in

general

The

relatively

low

heterogeneity

of

all

studies

describing

lesion

detection

as

well

as

detection

of

additional

lesions

in

the

ipsi

and

contralateral

breast

show

that

the

applied

MRI

technique

only

has

a

minor

impact

on

the

ability

of

MRI

to

detect

lesions

The

overall

sensitivity

could

even

be

increased

to

-LRB-

CI

-RRB-

if

an

early

study

is

excluded

from

the

analysis

-LSB-

-RSB-

This

study

reported

a

sensitivity

for

ILC

of

only

a

discrepancy

that

may

well

be

explained

by

the

fact

that

the

slice

thickness

in

this

study

was

mm

thicker

than

in

any

of

the

other

presented

studies

which

could

have

had

a

negative

impact

on

sensitivity

Moreover

of

patients

in

their

series

were

scanned

with

a

FLASH

sequence

with

TR

TE

resulting

in

image

acquisition

with

a

phase-shift

of

water

and

fat

which

might

have

further

decreased

their

sensitivity

although

this

was

not

apparent

from

their

data

It

must

be

taken

into

account

that

the

acquired

sensitivity

in

all

studies

was

achieved

in

cases

where

prior

knowledge

of

the

existence

of

ILC

was

present

Mostly

because

of

the

retrospective

nature

of

the

presented

studies

but

also

because

the

two

prospective

studies

both

included

their

patients

on

the

basis

of

histological

proof

of

invasive

-LRB-

lobular

-RRB-

carcinoma

by

core

biopsy

It

is

therefore

not

possible

to

formulate

conclusions

on

the

sensitivity

of

MRI

for

ILC

prior

to

biopsy

In

a

large

multicenter

trial

by

Bluemke

et

al.

-LSB-

-RSB-

overall

sensitivity

for

invasive

cancer

prior

to

biopsy

was

thus

it

might

be

expected

that

sensitivity

for

ILC

prior

to

biopsy

is

also

slightly

lower

However

in

most

cases

the

indication

for

MRI

is

assessment

of

disease

extent

because

of

inconclusive

findings

at

mammography

or

ultrasound

In

conclusion

the

sensitivity

of

MRI

for

ILC

is

higher

than

that

achieved

by

any

other

modality

in

direct

comparison

and

validated

by

literature

and

is

equal

to

the

overall

sensitivity

of

MRI

for

malignant

lesions

of

the

breast

Only

modern

ultrasound

examinations

seem

to

have

the

ability

to

approach

the

performance

of

MRI

in

the

detection

of

ILC

-LSB-

-RSB-

Morphology

The

morphologic

appearance

of

ILC

on

MRI

ranged

from

non-mass-like

lesions

to

mass-like

lesions

thereby

raising

questions

concerning

the

amount

of

heterogeneity

in

the

description

of

morphology

of

lesions

by

radiologists

In

fact

the

general

agreement

on

the

description

of

lesion

type

according

to

the

BI-RADS

lexicon

is

only

moderate

-LSB-

-RSB-

In

the

current

analysis

this

is

even

further

complicated

because

most

authors

did

not

specifically

use

the

BI-RADS

lexicon

Additionally

differences

in

scan

techniques

may

have

further

affected

the

appearance

of

the

lesion

However

in

keeping

with

the

above

the

classification

of

lesion

type

is

also

highly

variable

on

mammography

where

the

incidence

of

mass

lesions

ranges

from

to

-LSB-

-RSB-

The

vast

majority

of

the

mass-like

lesions

described

on

MRI

are

irregular

or

spicular

lesions

The

eight

patients

with

a

dominant

mass

surrounded

by

multiple

enhancing

foci

as

described

by

Schelfout

et

al.

-LSB-

-RSB-

may

present

noncontiguous

foci

of

disease

without

visible

spiculae

due

to

the

absence

of

desmoplastic

reaction

which

is

a

well-known

histopathological

presentation

-LSB-

-RSB-

In

all

series

only

one

round

mass

was

described

-LSB-

-RSB-

suggesting

this

to

be

a

very

rare

presentation

for

ILC

This

is

consistent

with

findings

in

mammography

by

Le

Gal

et

al.

-LSB-

-RSB-

who

described

a

round

mass

in

only

of

all

patients

where

a

mass

was

present

-LRB-

-RRB-

while

the

remainder

was

either

classified

as

a

spicular

mass

-LRB-

-RRB-

or

poorly

defined

mass

-LRB-

-RRB-

Mammographic

findings

would

therefore

appear

to

correlate

well

with

MRI

findings

However

only

one

study

allows

direct

comparison

-LSB-

-RSB-

of

all

lesions

visible

in

this

study

on

both

mammography

and

MRI

-LRB-

-RRB-

were

classified

as

mass-like

by

MRI

while

only

-LRB-

-RRB-

were

classified

as

mass-like

by

mammography

Six

masses

on

MRI

were

visible

as

architectural

distortion

on

mammography

and

two

as

asymmetric

density

In

one

case

a

lesion

described

as

spicular

mass

on

mammography

was

visible

on

MRI

as

multiple

enhancing

foci

with

interconnecting

enhancing

strands

Non-mass-like

ILC

in

mammography

are

typically

described

as

architectural

distortion

or

asymmetric

density

In

some

cases

microcalcifications

are

present

although

these

are

often

related

to

concurrent

surrounding

DCIS

sclerosing

adenosis

or

fibrotic

changes

and

might

thus

not

be

related

to

the

presence

of

ILC

-LSB-

-RSB-

The

descriptors

currently

used

for

non-mass-like

lesions

on

MRI

are

diverse

and

include

various

types

of

abnormal

enhancement

such

as

regional

ductal

segmental

and

diffuse

enhancement

According

to

Qayyum

et

al.

-LSB-

-RSB-

the

morphologic

description

of

ILC

on

MRI

has

a

good

correlation

to

histopathologic

findings

The

non-mass-like

presentation

might

specifically

occur

in

cases

where

ILC

grow

in

the

classic

pattern

with

cells

arranged

in

a

linear

fashion

along

the

ductuli

It

may

thus

be

concluded

that

the

appearance

of

most

ILC

on

MRI

and

mammography

is

similar

most

ILC

are

mass-lesions

that

have

clear

malignant

properties

However

the

more

diffuse

growing

tumors

are

characterized

by

areas

of

unexpected

enhancement

and

are

more

difficult

to

recognize

In

a

number

of

cases

where

no

clear

mass

is

visible

on

mammography

a

mass-like

lesion

may

be

found

on

MRI

-LSB-

-RSB-

Kinetics

The

relatively

late

contrast

enhancement

of

ILC

apparent

in

all

studies

presented

here

and

mirrored

by

the

relatively

low

values

of

and

EFP

in

the

studies

by

Qayyum

et

al.

-LSB-

-RSB-

and

Yeh

et

al.

-LSB-

-RSB-

must

be

taken

into

account

when

evaluating

ILC

Standard

subtraction

images

generated

from

the

pre-contrast

and

the

first

or

second

post-contrast

acquisitions

may

be

inconclusive

as

maximum

enhancement

is

not

achieved

at

this

point

in

time

and

the

lesion

is

thus

not

yet

clearly

visible

In

fact

false-negative

MRI

in

cases

of

ILC

is

usually

contributed

to

inadequate

enhancement

of

the

tumor

-LSB-

-RSB-

The

diffuse

and

often

slow

tumor

growth

not

requiring

extensive

neovascularization

may

partly

cause

this

difficult

visualization

-LSB-

-RSB-

This

is

also

clear

from

the

relatively

lower

amount

of

vascular

endothelial

growth

factor

found

in

tumors

with

a

lobular

histology

which

might

also

indicate

a

different

signaling

pathway

in

the

formation

of

neovascular

vessels

in

ILC

resulting

in

more

mature

and

thus

less

leaky

capillaries

-LSB-

-RSB-

with

consequently

diminished

or

absent

contrast

enhancement

Correlation

In

the

herein

presented

studies

overestimation

of

lesion

extent

by

mammography

is

rare

yet

underestimation

is

more

rule

than

exception

This

is

also

confirmed

by

studies

that

specifically

deal

with

mammography

in

cases

of

ILC

Yeatman

et

al.

-LSB-

-RSB-

showed

that

mammography

underestimated

ILC

by

a

mean

of

mm

Uchiyama

et

al.

-LSB-

-RSB-

reported

of

all

visible

ILC

on

mammography

to

be

underestimated

and

Veltman

et

al.

-LSB-

-RSB-

showed

of

all

ILC

to

be

mammographically

understaged

Ultrasound

also

tends

to

underestimate

tumor

size

in

the

studies

presented

here

This

finding

is

underlined

by

Tresserra

et

al.

-LSB-

-RSB-

and

more

recently

by

Watermann

et

al.

-LSB-

-RSB-

who

documented

a

structural

underestimation

of

mm

in

cases

of

ILC

versus

mm

for

cases

of

IDC

This

might

be

partly

due

to

the

observation

that

US

tends

to

underestimate

larger

tumors

more

than

smaller

tumors

and

low

grade

tumors

more

than

high

grade

-LSB-

-RSB-

consistent

with

the

finding

that

ILC

usually

presents

with

slightly

larger

and

less

aggressive

tumors

-LSB-

-RSB-

The

current

analysis

shows

that

there

is

good

correlation

of

tumor

size

measured

on

MRI

compared

to

pathology

The

various

studies

presented

only

moderately

heterogeneous

results

In

most

cases

MRI

outperforms

mammography

and

ultrasound

in

the

assessment

of

disease

extent

Most

tumors

are

correctly

classified

as

uni

or

multifocal

and

multicentric

disease

is

only

seldom

overestimated

-LSB-

-RSB-

Additional

lesions

and

effect

on

surgical

treatment

Especially

important

in

this

analysis

is

the

detection

of

additional

lesions

apart

from

the

index

lesion

in

patients

with

ILC

The

co-existence

of

other

invasive

malignant

lesions

apart

from

the

index

lesion

in

the

ipsilateral

breast

in

of

patients

only

visualized

by

MRI

is

high

Moreover

the

detection

of

contralateral

cancer

in

another

of

patients

by

MRI

only

seems

to

make

MRI

indispensable

These

findings

are

confirmed

by

the

rate

of

change

in

treatment

of

the

ipsilateral

breast

based

on

MRI

The

fact

that

change

in

treatment

was

considered

correct

as

verified

by

pathologic

findings

in

the

specimen

in

of

cases

shows

that

ILC

is

often

more

extensive

than

appreciated

on

conventional

imaging

However

various

authors

have

shown

that

there

is

no

significant

difference

in

disease

free

survival

-LRB-

DFS

-RRB-

or

overall

survival

-LRB-

OS

-RRB-

after

BCT

or

mastectomy

in

patients

with

breast

cancer

Although

some

authors

report

more

local

recurrence

in

patients

with

ILC

after

BCT

-LSB-

-RSB-

most

authors

showed

that

there

is

no

difference

in

DFS

or

OS

after

BCT

in

ILC

versus

IDC

-LSB-

-RSB-

On

the

other

hand

Yeatman

et

al.

-LSB-

-RSB-

reported

a

higher

rate

of

conversion

from

lumpectomy

to

mastectomy

in

ILC

compared

to

IDC

-LRB-

versus

-RRB-

More

recently

Molland

et

al.

-LSB-

-RSB-

reported

similar

findings

-LRB-

versus

-RRB-

Hussien

et

al.

-LSB-

-RSB-

even

reported

failure

of

BCT

in

patients

with

ILC

in

-LRB-

-RRB-

of

patients

resulting

in

conversion

to

mastectomy

in

of

failures

-LRB-

-RRB-

However

a

very

recent

study

by

Morrow

et

al.

-LSB-

-RSB-

showed

that

BCT

did

not

fail

more

often

in

patients

with

ILC

when

corrected

for

age

and

tumor

size

although

they

still

observed

a

trend

of

more

excisions

in

patients

with

ILC

-LSB-

OR

-LRB-

-RRB-

p

-RSB-

To

date

there

is

no

evidence

suggesting

increase

in

survival

for

patients

with

ILC

due

to

the

performance

of

MRI

What

is

then

the

added

value

of

MRI

The

rate

of

recurrence

years

after

BCT

followed

by

radiotherapy

is

between

and

and

is

not

significantly

different

from

the

rate

of

recurrence

in

case

of

IDC

-LSB-

-RSB-

However

in

view

of

the

MRI

findings

-LRB-

additional

malignant

lesions

in

of

patients

-RRB-

we

can

only

conclude

that

in

a

large

number

of

patients

with

ILC

surgery

is

not

curative

but

merely

debulking

As

recurrence

rates

are

fortunately

much

lower

we

must

assume

that

curative

treatment

is

to

be

expected

from

adjuvant

therapy

Unfortunately

because

there

is

no

possibility

to

determine

which

additional

findings

will

respond

to

adjuvant

therapy

the

detection

of

additional

lesions

on

MRI

currently

still

requires

a

change

of

treatment

when

malignancy

has

been

proven

by

core

biopsy

This

may

further

reduce

the

rate

of

recurrence

in

patients

with

ILC

and

may

even

improve

survival

However

this

requires

confirmation

in

future

studies

Conclusion

Magnetic

resonance

imaging

has

a

high

sensitivity

for

ILC

not

achieved

by

other

imaging

modalities

Therefore

MRI

is

helpful

in

cases

where

conventional

imaging

is

inconclusive

Morphology

is

often

mass-like

and

a

typical

ILC

presents

as

an

irregular

or

spiculated

mass

However

asymmetric

enhancement

that

can

be

ductal

segmental

regional

or

diffuse

in

nature

may

be

the

only

sign

of

tumor

MRI

measures

disease

extent

with

a

high

reliability

Although

underestimation

and

overestimation

of

lesion

size

by

MRI

still

occurs

it

is

more

accurate

than

size

determination

by

other

modalities

indicating

often

more

extensive

tumor

burden

than

expected

The

underestimation

by

other

imaging

modalities

results

in

more

failure

of

BCT

more

re-excisions

and

more

conversion

to

mastectomy

in

series

where

MRI

is

not

used

MRI

has

an

effect

on

surgical

management

in

that

when

used

to

assess

disease

extent

surgical

management

was

changed

in

of

which

were

judged

necessary

based

on

pathology

Larger

series

of

patients

are

required

to

confirm

the

findings

of

this

review

especially

evaluation

of

tumor

morphology

and

dynamic

profile

seems

feasible

O O O O O O O O O O O O B I I I I I O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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