breast cancer diagnosis and treament planning1
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BREAST CANCER DIAGNOSIS AND TREAMENT PLANNING: THE
ROLE OF SCINTIMAMMOGRAPHY.
CHAPTER ONE
1.1 IntroductionThe breast isanaccessory sexualand reproductiveorgan found in both females
andmales. It islargely rudimentary inmales. Itdevelops fromthethickened
mammary ridge (milkline)ofectodermalong aline fromtheaxillatothe inguinal
regionasearly asthe fourth weekof intrauterinelife.1,2The female breast isa
dynamic structure which undergoes changes throughout a womans reproductive
lifeand, superimposed upon this, cyclical changes throughout themenstrual cycle.
These changesand some breast pathologies, affect itsshape, sizeand most
importantly its function(s). Breast problems can beeither benign ormalignant and
can lead to serious complications if not diagnosed early and adequately treated.1
Benign casesare themost common causes of breast problems up to 30 per cent
of women willsuffer froma benign breast disorder requiring treatment at some
time in theirlives. Examples of benign breast problems include Cysts, Abscesses,
Fibroadenomatosis, Cyclicalmodularity, Fibroadenoma, Duct ecfasia/periductal
mastitis, Nipple dischargeand inversion etc. Breast cancers, whichmay be
invasive or non-invasiveare themost important lesions of concern in the breast.
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Breast Cancer is found mostly inpostmenopausal women, but can also be found in
younger women especially those in their 40sand very rarely in males. It is one of
theleading cancers diagnosed in women. In America for instance, it is recognized
to be themost common malignancy in women afterskin cancerand theleading
cause of nonpreventable deaths in women.2,3
In England and Walesalso, John et
al, observed that there isahighmortality rate due to breast cancer, thehighest rate
in Europe. This they said standsat 27 deathsper 100,000 per year.4
Data from
centers in Nigeriashows that the incidence of breast cancer ishigh. It also reveals
that the detection of thisand itssubsequent treatment depends on theavailability of
screening toolslikemammography and specialists.20
The threat posed by breast cancerhaslead to a continuoussearch forasolution,
which basisand effectivenesslie in theaccurateand timely detection of thelesions
in order to instituteadequate therapeutic measures.2-5
Selfexamination, Clinical
examination and Mammographic screeningsare the basicprocedures used to detect
breast cancersearly. It has thus been correctly noted that themortality rate due to
breast cancers is dependent mostly on theearly accurate detection and subsequent
treatment.3-6, 8,9
Women up to 50 yearsare usually advised, and often required by law in some
countries to go forannualmammographic screening. Selfexamination isalso
taught and encouraged.2,3
Mammography screening can also be carried out on
younger women, especially thoseat ahigh riskof developing breast cancerlike
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those who haveahistory of the breast cancer in their families.2,3,5
It is not very
efficient in determining cancershaving alow sensitivity and Negativepredictive
values.2
Negativepredictive value isameasure of theability ofaprocedure to correctly
confirm theabsence ofa variable, and has been identified as the best indicator
measure of theprocedures for the diagnosis of breast cancer. Hence, though
mammography is themost readily breast cancerscreening method that has been
shown to savelives, it is notperfect.
Perfect or, in theleast nearperfect modalitiesare therefore required to improve
timely and accurate diagnosis to guidemanagement.2
Some of themodalities that
have been introduced include Ultrasonography, MRI breast imaging, and
functional imaging using Radionuclides, known as SCINTIMAMMOGRAPHY.
SCINTIMAMMOGRAPHY, from inception ismeant to serveasasupplementary
test to mammography to help in overcoming thelimitations of the former,
especially in distinguishing malignant from benign lesions thusavoiding many
avoidable biopsies. It can also be useful in primary breast examination and
confirmation of thestate of observed lesions in some cases wheremammography
islimited suchas in dense breasts. It hasalso been used to ascertain thepresence
and extent ofmetastasesand recurrenceand thus direct treatmentplans.
This work isa review of the Role of SCINTIMAMMOGRAPHY l) in the detection
of breast cancersand theirmanagement.
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CHAPTER TWO
BREAST CANCER FEATURES
2.1 Pathology
Malignant breast lesions (cancers)are defined asabnormally growing cells which
have the capacity for invasion of tissues within thelocal vicinity and disseminating
throughlymphatic channels or the blood stream. These include the following;
1. Those with ductal origin.- Pre-invasive (intraductal cancer)- Invasive (invasive ductal cancer)
2. Those from thelobule.- Pre-invasive (lobular carcinoma in situ.)- Invasive (lobular invasive carcinoma).c 14
2.2 Clinical features of breast cancer
Over 95% ofpatients with breast canceraresubjectively symptomatic at the
time of detection. Thesymptoms can be caused by localmetastatic or remote
effects of the disease. The common symptomsare thelocaleffects, which
include:
- Lump formation- Discharge from nipple(s)
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- Nipplealteration i.e. retraction and deviation- Skin alteration i.e. ulceration of theskin- Axillary nodesenlargements.
Theseare usually detected mostly on clinicalexamination.15
Metastatic or remoteeffectsare usually absent at the time of first diagnosis. They
include:
- Supraclavicular nodes involvement- L
ungsand liverlesions
- Central nervoussystem involvement- Weight loss- Fatigueand Malaise.15
2.3 DISTRIBUTIONS
Geographical - It occurs commonly in the Western world, accounting for 35
per cent of deaths, yet isa rare tumour in Japan. In developing countries it accounts
for 13 per cent of deaths.
Age - Carcinoma of the breast isextremely rare below theage of 20, but thereafter
the incidencesteadily risesso that by theage of 90 nearly 20per Cent of women
areaffected. Only 1 % ofpatients with breast canceraremale.
Genetic - It occursmore commonly in women witha family history of breast
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cancer than in the generalpopulation. Genetic linkageanalysisstudieshave
revealed that an abnormality frequently exists in theshort arm of chromosome 17
in these women witha family history ofearly-onset breast cancer theactual
gene is yet to be doned.
Diet - Because breast cancerso commonly affects women in the developed
world, dietary factorsmayplay apart in its causation. There is increasing evidence
that there isalinkbetween diets rich in saturated fatty acidsand vitamin C. A high
intake ofalcoholmay also beassociated withan increased riskof developing
breast cancer.
2.4 The Spread Of Mammary Carcinoma
Local spread -The tumour increases in sizeand invades otherportions of the
breast. It tends to involve theskin and to penetrate thepectoralmuscles, and even
the chest wall.
Lymphatic metastasis - Occursprimarily to theaxillaty nodesand to the internal
mammary chain oflymph nodes. Thesite of the tumour within the breast does not
dictate which nodes will be involved, e.g. medial tumoursspread just as readily to
theaxillary nodesas do lateral tumours. The involvement oflymph nodes is not
necessarily a chronologicalevent in theevolution of the carcinoma, but rathera
marker for themetastatic potential of that tumour. In advanced disease theremay
be involvement ofsupraclavicular nodesand ofany contralaterallymph nodes.
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Spread by the bloodstream - It is by this route that skeletalmetastases occur (in
order of frequency) in thelumbar vertebrae, femurs, thoracic vertebrae, ribsand
skull; they are generally osteolytic. Metastasesmay also occur in theliver, lung
and brain, and occasionally theadrenal glandsand ovaries.
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CHAPTER THREE
Breast Cancer Detection Options
Although clinical diagnosis from thepresenting symptomsand physical
examination are valuable diagnostic tools, they arelimited in the diagnosis of
breast cancer. For this, suchmodalitiesas the following are used to ensureearly
and moreaccurate diagnosis:
3.1 MAMMOGRAPHY
Presently, in most third world countries, Nigeria inclusive, themain diagnostic
option for the detection of breast cancerare Physicalexamination, which can be
done by a clinician or the woman herself, and Mammography. Thesehavea
potential to detect breast cancer or itsprecursorearly enough to lead to good
prognosiseventually.2-5
Yet, despite itsavailability and acceptability,
mammography isstill not efficient in breast lesion detection and in distinguishing
benign frommalignant lesions to informappropriatemanagement in all cases. This
modality exhibitsalow sensitivity and specificity. Estimates of the numbers of
cancersmissed by mammography are usually around 10%30%.2-6
The value of
mammography islimited in women with:
y Dense breast as is usually found in younger women.y Breast implantsand inpatients undergoing hormone therapy.y Presence ofmultiple tumoursand hormone influence.
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y cases where there isaseverearchitectural deformation of the breast suchasaftera radical breast surgery, radiation therapy, severe inflammatory
reactionsetc.2,7.8
3.2. ULTRASOND AND MRI
The conditions noted abovehavelead to the continued search for othermodalities
to improve on theachievements ofmammography. Thissearch, according to Iraj et
al is focused on intensiveefforts to achieveearly diagnosis.2,4,8
In line with this,
anatomical imaging proceduressuchas Ultrasonography have been introduced and
successfully used to confirm the true nature oflesions detected either by palpation
or withmammography likelumpsand breast cysts. Anatomicaland Functional
imaging toolslike contrast enhanced MRI havealso been introduced7.
3.3 RADIONUCLIDE BREAST IMAGING (SCINTIMAMMOGRAPHY) .
More than two decadesago, radionuclide imaging was introduced into breast
imaging field. This isa functional imaging tool that supplementsmammography in
diagnosing breast malignancy and adds to the information required in treatment
planning.
Scintimammography makes use of radiopharmaceuticalsand aspecial gamma
camera to image the breast and detect abnormalities. Single Positron Emission
Tomography (SPECT) technique is themostly used for thisprocedure. The
principle of Scintimammography is based on the fact that these
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radiopharmaceuticalsareaccumulated orabsorbed more by abnormal breast tissues
than normal tissues thusaiding in their identification. The rate ofabsorption helps
to determine theextent orseverity of thelesion.4,9,10
In all, detection options in breast cancer cases can be categorized into two as
follows:
a. Theprimary screening tools, which include Physicalexamination either bythepatient ora clinician and Mammography, and
b. Thesupplementary tools, whichmainly are used to confirm the findingsfrom theabove or to refute themand they include Ultrasonography, MRI
and Scintimammography.
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CHAPTER FOUR
SCINTIMAMMOGRAPHY PROCEDURE ASSESSMENT
4.1 Radiopharmaceuticals Used In Scintimammography.
A variety of radiopharmaceuticalsmay be used, including technetium-99m
Sestamibi (Miraluma), technetium-99m tetrofosmin, technetium-99m MDP,
thallium-201, indium-111 satumomab pendetide (Oncoscint CR/OV), indium -11
pentetreotide (OctreoScan), and technetium-99marcitumomab (CEA-Scan).7,10
TechnetiumTc 99m Sestamibi (TechnetiumTc 99m Methoxy Isobutyl Isonitril,(
MIBI), a radionuclide, hasearlier been utilized asamyocardial imaging agent as
has been TechnetiumTc 99m tetrofosmin. TechnetiumTc 99m MDP ismainly
employed in bonescintigraphy.4,8,12,
MIBI wasapproved by the United States Food
and Drug Administration in December 1990 for use in cardiac imaging and in May
1997 for use in breast imaging. Presently, it is themost widely used
radiopharmaceuticalemployed in breast imaging. A good review of the
contribution ofTechnetiumTc 99m MIBI in breast imaging will requirean
explanation of itsmechanism ofaction.
4.2 Mechanism Of Action Of Technetium Tc 99m Mibi
TechnetiumTc 99msestamibi concentrates in tissues inproportion to blood flow,
metabolic activity, and inflammatory activity . These tissuespecific parameters
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affect the concentration not in isolation but in interaction.12,14
Soon after injection,
MIBI localizes in most tumors in greater concentration than in thesurrounding
tissues because tumors generally havea greater blood supplyper gram of tissue
compared withsurrounding tissues; malignant tumors display greatermetabolic
activity than benign tumors orsurrounding breast tissues; most tumorsalso havea
higher intracellularmitochondrial concentration and MIBI accumulation is roughly
proportional to mitochondrial concentration. These factorsallow localization of the
radionuclide in most breast tumors.12
The concentration in tumours is detected
withappropriateequipment and the imageproduced used for diagnosis.
Fig.1 Lateralscintimammograms withapositive finding Fig.2
indicating focally increased activity in the breast (arrow). Thisanterior view
demonstrates increased activity in theleft
axilla (arrow).This finding indicates
metastasis to axillary lymph nodes.
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4.3 Equipment And Patient Selection
Conventional gamma cameras, also known aslarge field of view (LFOV) cameras,
havehistorically been used to image radiopharmaceuticals during
Scintimammography. These camerashavealarge inactiveareaat theedge of the
detector that prevents the camera from imaging breast tissueadjacent to the chest
wall. Therefore, breast Scintimammography using a conventional gamma camera
is typicallyperformed with thepatient supine, with the camerapositioned to takea
lateral view of the breast, or in theproneposition whichpermits the breast to hang
freely. Compression of the breast is notpossible with this, which in turn decreases
thesensitivity for detecting smallerlesions10
. Theplanar camerahasapoor
resolution, unable to identify lesionsless than 1cm withhighspecificity, haspoor
sensitivity and has been suggested to be used with caution.16
Recently, dedicated
Breast Specific Gamma Camera imaging systemshave been developed in an
attempt to overcome thelimitations of conventional Scintimammography
cameras10,17,18
. These new camerashaveasmaller field of vision (SFOV) that
provideshigher resolution and improved maneuverability compared to the
conventional gamma camera.10
Some BSGI camerasallow positioning similar to
that ofamammography examination with theability to apply compression to the
breast during imaging. Improvements in this technology has renewed interest in
Scintimammography asaprimary screening technique.10
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It ishowever imperative to note that there is no commercially availableequipment
to localizeand biopsy alesion identified solely on a nuclearmedicinestudy
because the Scintimammogramshave poorspatial resolution Thus, anypotential
use of the information from this test to promoteearlier detection ofmalignancy
would behampered by the technical inability to act on such information through
biopsy and treatment. This is unless the findings clearly correlated withalesion
already identified by some othermeans (mammography, ultrasound, or clinical
exam).10
4.4 Patient Selection
Patient selection is ofpivotal importance for the use of Scintimammography. In
general, aphysician should only referpatients withlesions found onphysical
examination ormammography for MIBI imaging. Physiciansmust beaware that
Scintimammography is not ascreening examination. If Scintimammography is
used to evaluatehighly suspicious clinical ormammographic findings, suchas
microcalcifications that are not associated withamass, a negative test result should
notpreclude biopsy.
Thismodality generally can appropriately be used inpatients with the following
conditions:
y Breast lesions that are not clearly malignant or benigny Breast abnormalities on mammogramafter breast irradiation orsurgeryy Dense breasts that are difficult to examine bypalpation and mammography
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y Breast implantsy Patients uncomfortable with theapproach of waiting and reevaluating at a 6-
month follow-up
y In patients where recurrence is feared among others6,10,12It should not be considered under the following conditions:
y Highly suspicious breast lesions (i.e, category 5 mammograms)y Breast microcalcifications that are not associated withamassy Breast lesions that areless than 1 cm in diameter12
In these cases, biopsy should be carried out to confirm diagnosis.
Scintimammography usefulness in confirming diagnosis, asascreening tooland a
tool for detection of Axillary metastaseshas been reviewed for the following
conditions:
y Suspicious Mammograms or Palpable Massesy Lesions withLow Probability of Malignancyy Probably Benign Mammogram but Recommended Close Follow-up in 3-6
Months
y Dense Breast Tissue Difficult to Evaluate on Mammographyy Detection of Axillary Metastases10
An extensiveliteraturesearch under theabove guidesstillleavesmuch to be
desired from thismodality, but worksarestill going on and conclusionsare yet not
generally accepted or rejected.10,12
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4.5 CONTRAINDICATIONS
No known contraindications ormajorsideeffectshave been reported with MIBI.
Approximately 20% ofpatientsexperiencea transient metallic taste or other
transient minorsensations including headache, flushing, nausea, andpruritus.
Thesesideeffectshave been reported in clinical trials but are rare.12The
examination lasts forabout an hour, and costsabout N10,000 (ten thousand naira)
only hence it is not too stressfuland not too expensive.
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CHAPTER FIVE
SUMMARY AND CONCLUSION
5.1. Assessment Of The Applications And Potentials Of Scintimammography
The usefulness of Scintimammography is determined by itssensitivity and
specificity as wellas itspositiveand negativepredictive values. Thishas been the
major issue ofseveral researches. Generally, thesensitivity of MIBI for the
detection of breast tumors is dependent on tissuespecific propertiessuchas
vascularity, metabolic activity and very importantly thelesion size.12,14
Recent
studieshaveshown that thesensitivity of MIBI for detection ofmalignancy in
smalllesions ispoor.2,10,12
Approximately 25% oflesionsless than 1 cm in
diameterand 78% oflesions 1 to 1.5 cmhave been reported to beeffectively
detected. Most importantly, 94% oflesions greater than 1.5 cm in diameter were
detected.12
Thesensitivity of thisprocedureaccording availableliterature ranges
from 75.4 to 93.7%2,5,6,10-12 However, thehighsensitivity has been suggested to be
occasioned by the bias in selection ofsubjects for thestudies, in whichpatients
withhigh chances ofhaving cancer wereselected for thestudies.10
Nonetheless,
multicenter trialsstillpresented highsensitivity, especially forlesions bigger than
1cmand in the categories ofpatientslisted above. These findings further
established the incremental use of Scintimammography in confirming canersand
in avoiding unnecessary biopsies2Thespecificity of Scintimammography isalso
high, being an average of 83%.2,5,6,10-12
Also, the combination of conventional
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mammography and Scintimammography, which ishighly recommended, hasa
highersensitivity and specificity.5
Scintimammography also hasahighpositivepredictive value, withan average of
about 82% and ahigh Negativepredictive value withan average ofabout
85%.2,5,6,10-12
. When Scintimammography is used asan adjunct to mammography
to improvepatient selection for biopsy, thekey diagnostic statistic is the negative
predictive value.10
Given the relativeeaseand diagnostic accuracy of the gold
standard of biopsy, coupled with theadverse consequences ofamissed breast
cancer diagnosis, the negativepredictive value of Scintimammography would have
to be very high to influence treatment decisions.10
Thisshould be near 100% to be
very effective, but isabout 5% lower on theaveragehence not highenough to
influence treatment decisionsmostly. Specifically, even at thelow end of the
intermediate range ofprevalence formalignancy, ifa negative Scintimammogram
were to be used to recommend against doing biopsy, the riskof undetected
malignancy would be 4.5% on theaverage. This is considered too high given the
relatively low morbidity of breast biopsy, the gold standard.10
This isalso the case
in the detection ofaxillary metastases. Yet, as noted above, a combination of
mammography and Scintimammography improves thesensitivity, and as the
negativepredictive value is improved by improved sensitivity, the use of
radionuclides in the functional imaging of the breast to contribute to management
plans is important still.
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5.2 CONCLUSION
Scintimammography isa functional imaging modality of the breast used mainly as
asupplementary modality to physicalexamination and conventional x-ray
mammography. It usessome radiopharmaceutical, themost widely used being
technicium-99 Sestamibi (methoxy isobutyl isonitril). It is useful in patients with
dense breast, breast implants, underhormone treatment; it can detect multifocal
ductal carcinoma in situ and lobular carcinomain situ;
is
useful in assessing
recurrent disease; can successfully monitorresponse to chemotherapy. The
practical goals of Scintimammography are two-fold: improving early detection of
breast carcinomaand/orpreventing unnecessary biopsies. Achievement of these
goals is dependent upon the referringphysiciansknowledge of theprocedureand
appropriateness ofpatient selection. It isprimarily employed in determining which
lesionsaremalignant or benign, thus reducing the number of biopsies, avoiding the
unnecessary one, and in detection ofaxillary metastases, which is usually the first
indication of breast cancermetastases.From introduction about two decadesago,
studieshave been going on to sufficiently prove the usefulness of thismodality.
Though it hasahighsensitivity and specificity, thepotential ofaccurately
identifying cancersand excluding benign lesionshave been shown not to behigh
enough to completely exclude the use of biopsies, which is the gold standard. It is
estimated that about 90 cancersaremissed out of 1000 cases when biopsy is
avoided due to result from Scintimammography. This isapproximately amissed
cancer in every ten cases, a not very favourable ratio.10
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Nevertheless, thisprocedurehas beenproven to beeffective frompractical
applications. And studiesarestill on to developaspects of thismodality suchas
equipment andpatient selection methodsand combination of this with other
modalities in order to improve itsefficiency. It ishoped that theseareas of interest
will bring more improvement in the use of Scintimammography, especially the
area of combining it with othermodalitieslikemammography, ultrasonography etc
in the timely and accurate diagnosis of breast cancerand in avoiding many
avoidable biopsies.
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