Role o f Bone Scanning in Carcinoma of the Breast

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1 ANNALS O F CLINICAL A N D LABORATORY SC IE N C E, Vol. 10, N o. 2 C opyright 1980, Institute for Clinical Science, Inc. Role o f Bone Scanning in Carcinoma of the Breast N. G. NOLAN, M.D., M. M. KOPPIKAR, M.D., an d E. V. KOTLYAROV, M.D., Ph.D. Department o f Nuclear M iicine, Washington Hospital Center, Washington, D. C ABSTRACT This paper consists of a review of the current literature, as w ell as the authors experience, concerning the diagnosis and treatm ent of carcinoma of th e breast w ith special reference to the role of radioisotopic bone scanning. R ecom m endations are m ade regarding the appropriate use o f th is tech n iq u e a t th e tim e of in itia l d iag n o sis an d o v er th e co u rse o f s u b s e q u e n t m anagem ent. Introduction T h e th ird n a tio n a l c a n c e r su rv e y, ,13 reveals that carcinom a of the breast constituted 27.5 percent o f all carcinom as in w hite w om en and 23 percent of all cancers in black w om en living in the U nited States. T he m agnitude of this clinical problem is further dem onstrated by the estim ate that 106,000 new cases of cancer of the breast in w om en and 900 in m en w ill b e d iagno sed in It accounts for 27 p ercen t of all new patients w ith cancer and is the leading cause of death in w om en, 35 to 74 years of age. M ortality for fem ales in the USA for breast cancer was 33,119 in 1976, and it is estim ated that breast cancer incidence and deaths in 1979 w ill respectively be equal to 27 percent and 19 p ercen t o f all cancers diagnosed.4 C arcinom a of the breast has few useful early p resenting symptoms. A lum p, usually painless, was the p resen tin g sym ptom in 78 percent of 100 consecutive patients w ith cancer of the m am m ary gland: 12 p ercen t of these patients p resen ted w ith local pain.1 Less frequent and m ore om i nous initial signs are a lum p in th e axilla or soreness, discharge or retraction o f the nipple. T he initial path of m etastatic spread is to the axillary nodes by lym phatic em bolization. O ther frequently involved lym ph nodes are found in th e infraclavicular, supraclavicular or m ediastinal n o d es.37 Skeletal m etastases ten d to involve the vertebrae, pelvic bones, ribs and skull. Six h u n d red forty-seven patients w ho d ied w ith carcinom a o f th e b re a s t d e m o n strated 70 p ercen t skeletal m etastases, 66 p ercen t p ulm onary and 61 p e rc e n t h epatic.36 D esp ite in n u m era b le im p ro v em en ts and m odifications in surgical technique, despite the introduction of chem otherapy / $00.90 Institute for Clinical Science, Inc.

2 106 NOLAN, KOPPIKAR AND KOTLYAROV and super-voltage radiation therapy, the m ortality rates for th is d isease have re m ained alm ost unchanged for the past several decades. In th e U n ited States, m ortality rates per 100,000 fem ales has rem ained at approxim ately 22 during the period of 1930 to ,16 It is becom ing increasingly clear that lym phatic or o th er m etastases may be already p resen t in many patients at the tim e of th eir initial diagnosis. This observation is su p p o rted by several stu d ies w hich have failed to dem onstrate an im p ro v e m ent in eith er life extention or cure rate from the perform ance of radical rather than sim ple m astectom y.21 This study revealed th at p atien ts w ith very early disease, nam ely, prim ary tum or of lim ited extent and no m etastases, w ere curable by eith er sim ple or radical m astectom y. H ow ever, patients w ith axillary m etastases could not be cured by sim ple m astectom y b u t w ere often cured by the more radical approach. Fifty p ercen t of the p a tients in this study had advanced disease, nam ely, distant m etastases; these patients w ere incurable by eith er sim ple or radical surgery. C onsequently, radical m astectomy was felt to be more extensive than was required in this group. T he argum ent is thus proposed that patients w ith very early disease and those w ith advanced progression should be treated by sim ple m astectom y, w ith th e m ore radical approach being reserved for those patients w ith axillary m etastases alone. Thus, for optim al p atien t m anagem ent, it is essential th at th e surgeon has th e m ost com plete inform ation concerning the stage of the disease w hen deciding upon the type of operation. Also, know ledge of the existence of m etastases is essential for appropriate institution of horm onal treatm ent, c h e m o th e ra p y or lo cal ra d ia tio n th erap y.10,22,27 C u rre n tly, th e re is no n o n -in v asiv e m ethod for th e identification o f m etastatically inv olved lym ph nodes. In co n sequence, the preoperative distinction of local and advanced breast cancer m ust be m ad e from a c o m b in a tio n o f c lin ic a l exam inations, including appropriate biochem ical stu d ies and sk eletal im aging techniques. C onventional bone x-rays are know n to be relatively insensitive in the detection o f early bone m etastases.2,32,34 This insensitivity is, in large m easure, related to the fact that b etw een 30 and 50 percent of the bony m ineral content m ust be lost before the x-ray attenuation coefficient becom es sufficiently different to be visually recognizable.2,34 In addition, it is felt that tum ors m ust have a diam eter in excess of one cm before th ey can be visualized, at least in the vertebral body region. Also, the base o f the skull, the u pper thoracic sp ine, th e sternu m an d th e sacrum are other difficult areas to evaluate on roentgenogram s. In d eed, a tim e lapse of m any weeks or even m onths m ay elapse b etw een onset of local bony pain and the a p p e ara n ce of e v id e n c e in d ic a tiv e o f m etastases on x-ray.20 R ationale for B one S cintigraphy For the past decade and a half, it has b e e n k n o w n th a t ra d io n u c lid e s c in tigraphy could identify bony abnorm ality co nsiderably before significant décalcification occurred and before th eir appearance on x-ray.6,7,33 T he explanation for the greater sensitivity of bone scanning lies in the pharm acokinetics underlying the procedure. T hese consist o f the deposition of a radionuclide by m eans o f the physicochem ical process of chem isorption onto the surface of the hydroxyapatite crystal matrix of new bone, as w ell as in the immature collagen w hich is being formed in response to the stim ulus of th e invading neoplasm. Thus, the recognition of increased radionuclide accum ulation may be the result of physiologic processes, such as epiphyseal growth or fracture healing. On the other hand, a sim ilar appearance is seen in a w ide variety of pathologic processes, in clu d in g prim ary an d sec

3 ROLE O F BONE SCANNING IN CARCINOMA O F BREAST ondary neoplasia, degenerative joint disease and in a variety o f inflam m atory and m etabolic bone processes. In summary, the bone scan is a highly sensitive, b u t rather non-specific way o f evaluating the p atient suspected o f having skeletal m etastases. T echnical C onsiderations T he technology of bone scanning has m ade rem arkable progress over the last decade. T ransition from the isotopes of strontium to fluoride and to th e techn e tiu m -p h o s p h a te co m p lex es h as r e sulted in considerably low er p atien t radiation (skeletal dose is approxim ately 400 to 600 mrads and gonadal dose is approxim ately 100 to 150 mrads) and su b stan tially increased counting statistics w ith a consequent im provem ent in the maximal inform ation density of the scan. Sim ilarly, the previously used rectilinear scanner has b een m ade virtually obsolete by the new third generation, large field of view, high spatial resolution gam m a cam eras w idely em ployed. T he com bination of m ore data describing the skeletal anatom y together w ith instrum entation capable of m ore precisely and accurately describing th at anatom y has resulted in vastly im proved im age quality by com parison w ith th a t available ten or even five years ago. O ne result of these technical changes is the m uch im proved ability of the nuclear physician to localize abnorm al uptake to a specific bone or part of that bone. T his, in turn, perm its a rather precise com parison w ith conventional radiographs allow ing th e m o re c e rta in d is tin c tio n o f scan changes w hich are associated w ith d e generative jo in t disease or o th er b en ig n processes on the one hand, from those w ithout any such radiological explanation. T he recent report o f D el uca et al show ed an ability to increase the specificity of vertebral body scans by em phasizing the m ost com m on patterns for m etastatic d isease : (1) tra n sv e rse b a n d of radioactivity throu gh the v erteb ral body, (2) increased activity in the pedicles, and (3) diffusely increased activity over the entire vertebra.15 It is, as a result of these technological changes, that com parison of the earlier literature w ith that p u b lish ed recently results in such totally differing im p re ssio n s c o n c e rn in g th e ro le o f ro u tin e p e rio p e ra tiv e or p re o p e ra tiv e bone scanning in the p atien t w ith suspected early carcinom a of the breast.5,9 17, 18,23,26,32. Scan Sensitivity H aagensen s series dem onstrated that bone was the first site of recurrent disease in 101 o f 224 patien ts. T h ese data, tog eth er w ith confirm atory figures based on autopsy inform ation,32 have b een the basis upon w hich the routine perform ance of p reoperative and periodic postoperative bone scanning has b een recom m ended as standard practice in the past. T he in cidence o f scintigraphic abnorm alities b e lieved to rep resen t bony m etastases in patients w ith early breast cancer has b een reported as high as 27 p ercen t.8 R ecent series, how ever, indicate a substantially sm aller yield of true positive scans in this p a tie n t group. S chaffer and K alish er31 dem onstrated m etastases only in those six patients (14 percent) who p resen ted w ith sy m p to m atic m e ta sta se s from an u n know n prim ary source.31 O C onnell e t al,29 in a recen t series of 100 p atien ts w ho p re se n te d to M ayo C linic for cu ritiv e surgery of breast carcinom a, found only one definitely abnorm al bone scan out of 30 patients w ith Stage I disease. O nly 7 p ercen t of the 72 patients from this series who w ere in eith er Stage I or Stage II w ere found to have definitely abnorm al scans. R ather sim ilar resu lts w ere obtained by C lark e t al.11 In this series, a positive bone scan was found in 7 p ercen t of 71 patients w ith Stage I disease and in five p ercen t of 170 patients w ith either Stage I or Stage II disease. U sing a som e w hat different classification, D avies and associates14 obtained further confirm ation

4 108 NOLAN, KOPPIKAR AND KOTLYAROV of the low y ield of routine bone scanning in early b reast cancer. T h e ir series contained 98 patients w ith tum or confined to the breast at surgery: only two of these patients yielded a definitely positive bone scan. M cn eil et al28 reported th at the yield o f positive preoperative scans in Stage I and Stage II disease is low (2 percent) and that the value of the scan was further dim inished by a relatively high (1.6 percent) p e rc e n ta g e o f fa lse p o sitiv e re s u lts. G erber e t a l18 reported a false positive rate b etw een two and five percent. Scan Interp retatio n Specificity In each of the studies quoted, particular care was taken to distinguish bone scan abnorm alities w hich w ere suspicious for m etastases from those of a non-specific nature. Thus, D avies et a l14 defined a positive scan as one in w hich an area of significantly increased radioactivity was seen in an area w hich fails to show a corresponding b en ig n lesion on x-ray. C lark et a lu only used the term positive w ith reference to the bone scan if one or m ore areas of increased activity w ere seen w hich w ere not typical of degenerative, arthritic, or traum atic disease. G alasko17 considered a positive bone scan to show focal area of increased activity w hich is asym m etrical and is not associated w ith pre-existing skeletal disease. T he term d efin ite abnorm ality at Mayo C linic was reserved for those scans w hich show ed focal, w elldefined uptake and w hose intensity was greater than that observed in the major joints. D iscussion T he conclusion may be draw n that b etter scan quality resulting from the com bination of im proved instrum entation and radiopharm aceuticals allows b e tter d e lineation of both norm al and abnorm al anatomy. T hese technical considerations, coupled w ith an increased aw areness of th e n o n -sp e c ific ity o f th e p h arm a co k in etic basis for bone scanning, have re sulted in a m uch sm aller n u m b er of scans being read as suspicious for m etastasis than was the case a decade ago. T he q u estion th en arises as to the cost effectiveness o f ro u tin e n u c le a r b o n e im a g in g in screen in g early b re ast can cer p atien ts p reo p erativ ely or p erio p erativ ely.3,19,24 Since som e authors co n sid er th e in cidence of m etastases id en tified in this patie n t p opulation to be low, valid ju stification for routine bone scanning w ould appear to be th at this practice allow s a baseline study against w hich future exam inations m ay be com pared. W hether or not this provides sufficient justification can only be determ ined by the individual physician on a patient-byp atien t basis. T he ability, how ever, of the n u clear physician to d istin g u ish accurately b etw een the appearance of new sk eleta l m etastasis from n o n -sp e cific changes associated w ith degenerative or o th e r b en ig n p ro cesses is g reatly e n hanced by com parison w ith a baseline study. G erber e t a l18 recom m end tw ice yearly bone scanning in p atien ts w ith b reast carcinom a, b u t th e ir o p in io n is challenged by o th ers19,24 on the basis of high cost per benefit ratio. In our practice the percentage of positive bone scans in patients w ith early breast cancer is above 10 percent. T his is sim ilar to the figure of 15.5 p ercen t recently published by Kirkman and H enk.25 C are is taken to m inim ize th e false positive ratio of bone scan results by: (1) careful evaluation of pelvic bone involvem ent versus b lad d er asym m etry and b lad d er diverticula by obtaining additional pelvic view s w ith patient sitting over th e crystal; (2) rep eatin g selectiv e view s after re m oval of urine contam ination from skin and clothes, and (3) giving special consideration to the finding of a single hot spot in a rib one of the m ost com m on sites of solitary false positives according to Corcoran e t al.12 In addition, w e are alert to the p o s s ib ility o f fa ls e -p o s itiv e o u t

5 ROLE O F BONE SCANNING IN CARCINOMA O F BREAST 109 com e from asym m etrical accum ulation of radiopharm aceutical in the scapular tips and in the sternoclavicular junctions. T he recen t review of T eates35 points out that S7Ga scanning o f m etastatic breast carcinom a yields a 58 percent true positive rate w ith the exception of m etastasis to the liver. Thus, the addition of gallium scann in g w o u ld b e e x p e c te d to in c re a se further the differentiation of unexplained h o t spots in a rib (m etastasis versus trau m a ) in th e a b s e n c e o f x-ray abnorm alities. B ased on our experience and in the opinion of Roberts et al,30 G erber e t a l18 and Kirkman and H enk,25 w e strongly advocate th at bone scanning replace the radiological skeletal survey as the first diagnostic test for detection of bone metastases in patients w ith carcinom a of the breast. O nly abnorm al and/or am biguous areas on the scan n eed to be radiologically evaluated. Also, it should be kept in m ind that w hen the scan shows m ore than one unequivocal abnorm ality in the absence of corresponding x-ray data pointing to a b e n ig n p ro c ess, m etastasis is alw ays present. T he application of bone scanning to patients who p resen t w ith pathologic Stage III c a n cer o f th e b re ast at th e in itia l surgery is considerably less controversial. A high proportion of these p atien ts already have identifiable skeletal m etastases. In C harkes series, this figure was 39 percent; in Kirkman and H enk, 25 percent; and in M cn eil e t al, 16 percent. Some of these lesions w ill require im m ediate local palliative radiation for relief of pain or prevention of fracture. L ikew ise, the identification of skeletal m etastases in this patient group m ight w ell affect the decision to adm inister supportive ra d ia tio n th e ra p y, c h e m o th e ra p y an d horm onal therapy. It may also provide additional inform ation as to its effectiveness in th e in d iv id u a l p atien t. T h e b re ast cancer patient w ho presents initially w ith bone pain may also benefit from scintigraphy for the same reasons. In addition, recognition of w idespread bony m etastases preo p erativ ely m ay affect th e su r geon s decision-m aking process as to the extensiveness of the procedure indicated. Finally, it should be m entioned that the p re se n t authors disagree w ith th e statem ent by D avies et al14 that the involvem ent of the axillary lym ph nodes is a b ette r prognostic indicator th an th e bone scan. In our opinion, an axillary dissection is unjustified in a patient w ith unequivocally positive bon e scan. Summary Bone scanning is th e m ost sensitive m ethod currently available for detection o f skeletal abnorm ality. It suffers from a lack of specificity so that the nature of a particular lesion cannot always be id en tified w ith absolute certainty. T he bone scan is strongly recom m ended for patients who p resen t w ith Stage I, II and III breast cancer. It is considered to be a useful test in evaluation of patients who p resen t w ith lo calized d isease an d th o se w ith ad vanced disease for m onitoring response to therapy. Acknowledgm ent Thanks are extended to Ms. Joan M. Smith for her valuable help in preparation of this manuscript. R eferences 1. Ac k e r m a n, L. V. a n d D e l R e g a t o, J. A.: C a n c e r. 5 th ed. St. L o u is, C. V. M o sb y C o., 1977, p B E S S L E R, W. T. : Bone scanning in breast cancer staging. Breast Cancer. New York, Alan R. Liss, Inc., 1977, pp Bo n e Sc a n n in g in B r e a s t C a n c e r : Preliminary statement by British Breast Group on bone scanning. Brit. Med. J. 2 : , C a n c e r S t a t i s t i c s C a A c a n c e r jo u rn al for clin ician s. 29:6, 12, 14, C h a r k e s, N. D., M a l m u d, L. S., C a s w e l l, T., G o l d m a n, L., H a l l, J., L a u b y, V., L ig h t - F O O T, W., M A I E R, W., and R O S E M O N D, G.: Preoperative bone scans: Use in women with early breast cancer. J. Amer. Med. Assoc : , 1975.

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