Originl Article DOI: 10.1159/000455066 Published online: Februry 7, 2017 Fctors Affecting Concordnce between Rdiologicl nd Histologicl Findings in Invsive Lobulr Crcinom Experience from Ntionl Cncer Centre Du Abu-Sinn Donl O Driscoll b Murice Murphy Deprtment of Histopthology, University Hospitl Wterford (UHW), Wterford, Irelnd; b Deprtment of Rdiology, University Hospitl Wterford (UHW), Wterford, Irelnd Keywords Invsive lobulr crcinom Rdiology-histology concordnce Pttern of invsion Biologicl fctors Biomrker Brest cncer Disese mngement Summry Bckground: Invsive lobulr crcinom (ILC) is chrcterized by n infiltrtive discohesive growth pttern, mking it difficult to ccurtely ssess both cliniclly nd by imging studies. Despite fvourble biologicl chrcteristics, chllenges remin in the surgicl tretment of ILC. We imed to evlute rdiology/histology concordnce nd identify histologicl nd biologicl prmeters on core biopsies tht my predict finl tumour histology nd guide surgicl tretment decisions. Ptients nd Methods: The rdiology nd histology reports for ll newly dignosed cses of ILC were nlysed. The biopsy nd resection histologicl slides for ll the surgicl cses were reviewed. Results: 75 new cses of ILC were dignosed over 2-yer period. 48 ptients underwent surgery of whom 25% hd 2 or more opertions. There ws discordnce between rdiologicl nd histologicl tumour foclity nd tumour size in 35 nd 40%, respectively. The correltion between rdiology/histology discordnce nd E-cdherin expression ws sttisticlly significnt. However, the correltion between rdiology/ histology discordnce nd menopusl sttus, brest density, pttern of invsion, presence of lobulr intrepithelil neoplsi (LIN), hormonl sttus, nd Ki67 were not sttisticlly significnt. Conclusion: Histologicl nd biologicl fctors in ILC, with the exception of E-cdherin expression, do not seem to ply significnt role in rdiology/histology discordnce. However, lrger studies re needed to further corroborte these findings. 2017 S. Krger GmbH, Freiburg Introduction Invsive lobulr crcinom (ILC) of the brest is the most common specil morphologicl subtype of brest cncer, comprising up to 15% of ll cses. The crdinl feture of ILC is their inherently discohesive phenotype lrgely ttributble to E-cdherin loss. There re 4 recognizble histologicl ptterns of ILC: clssicl, trbeculr, solid, nd lveolr. In clssicl ILC, the chrcteristic pttern of growth involves the infiltrtion of single cells or single files of cells through the strom, with little disturbnce of the norml tissue rchitecture. Conversely, the solid nd lveolr vrints re both chrcterized by clssic ILC cells (smll, regulr sized, nd lcking cohesion) tht re rrnged in sheets (solid type) or in ggregtes of t lest 20 cells (lveolr type) rther thn in single cords of cells [1]. Furthermore, round 5% of ll invsive brest tumours exhibit mixed fetures of both ductl nd lobulr differentition [2, 3]. Lobulr intrepithelil neoplsi (LIN) frequently coexists with clssicl ILC in 90% of cses [4]. 95% of ILC express oestrogen receptor (ER), nd 60 70% express progesterone receptor (PR) [5 7]. The prolifertion index (mesured by Ki67 stining) is usully low, nd this likely contributes to reduced response to chemotherpy reltive to ptients with invsive ductl crcinom (IDC) [1]. By virtue of their distinctive growth pttern nd biology, lobulr crcinoms hve substntilly incresed propensity for multifocl nd multicentric distribution nd for bilterlity [8 10]. Although ssocited with less ggressive phenotype, this is offset by being more difficult to detect erly, either by clinicl exmintion or rdiologicl imging [6]. ILC do not usully form distinct mss lesions, mking erly dignosis chllenging [8, 11] nd brest conservtion pproches more difficult. Mmmogrphy [8, 12, 13], ultrsonogrphy [14], nd mgnetic resonnce imging (MRI) [15] hve limittions in the dignosis of ILC [16]. Although MRI hs been found to hve higher sensitivity thn mmmogrphy [15, 17], its sensitivity is still lower thn for Fx +49 761 4 52 07 14 Informtion@Krger.com www.krger.com 2017 S. Krger GmbH, Freiburg Accessible online t: www.krger.com/brc Du Abu-Sinn, MBBS Deprtment of Histopthology University Hospitl Wterford Dunmore Rod, Wterford, Irelnd dubusin@hotmil.com
other invsive cncers. This my be ttributed to the fct tht ILC shows only subtle enhncement nd its distribution mimics tht of norml brest prenchym [16]. Given their unique, lbeit cliniclly nd rdiologiclly unpredictble, chrcteristics, there is continuous debte regrding the optiml choice of surgery in ILC. There hs been n incresing trend in recent yers towrds brest conserving surgery (BCS) s opposed to mstectomy. However, becuse of the infiltrtive growth pttern nd frequent discontinuities, there is higher incidence of resection mrgin involvement in ILC thn for IDC [12]. The purpose of this study ws to evlute the correltion between rdiologicl nd histologicl prmeters in ILC nd to identify predictive fctors on core biopsies which my impct rdiologicl ppernce nd finl excision histology. The ultimte im is to identify objective prmeters to fcilitte decision-mking s to the best surgicl option on n individul bsis. Ptients nd Methods All biopsy-proven, newly dignosed cses of ILC over 2 yers (2013 2014) were included in the study. The cses were retrieved by SNOMED from the histopthology dtbse t University Hospitl Wterford (UHW), Irelnd. Rdiologicl evlution by mmmogrphy, brest ultrsonogrphy, nd MRI ws performed in ll the cses prior to surgicl intervention. The brest density s ssessed by mmmogrphy ws recorded. The imging modlity tht contributed to determining the clinicl tumour size ws lso documented. A brest MRI ws performed to identify the locl disese extent nd disese foclity (unifocl vs. multifocl), nd in some cses to ssess for bilterl involvement. A retrospective review of ll the histologicl slides for ll the cses tht underwent surgicl tretment ws performed. The corresponding core biopsy, initil surgicl resection, nd subsequent surgicl resections (where pplicble) were reviewed for ech cse by consultnt histopthologist with specil interest in brest pthology nd specilist histopthology trinee. The pttern of invsion ws documented nd comprisons were mde between the core biopsy nd resection specimens. The E-cdherin, ER, nd PR sttus were documented. The rdiologicl tumour size nd tumour foclity were correlted with the histologicl findings on the resection specimens. The rdiologicl nd histologicl tumour sizes were considered discordnt when the difference in size ws more thn 5 mm. The mrgin sttus ws ssessed in ech individul cse, nd subsequent surgicl tretment documented. A positive mrgin ws defined s invsive tumour present on ink or lying less thn 1 mm from the inked surgicl resection mrgin. The correltion between rdiology/histology discordnce nd menopusl sttus, brest density, pttern of invsion, presence of LIN, E-cdherin expression, ER/PR sttus, nd Ki67 ws determined. Dt were nlysed using Microsoft Excel (Microsoft, Redmond, WA, USA) nd SPSS v.20 (IBM Corp., Armonk, NY, USA). Sttisticl nlysis ws performed, where pproprite, using Fisher s exct test with significnce level of < 0.05, nd ANOVA with confidence intervl of 95%. Results A totl of 75 new cses of ILC were dignosed t UHW between Jnury 2013 nd December 2014. The medin ge t dignosis ws 68 yers (rnge 37 97 yers). 84% of cses occurred in postmenopusl women. Almost two-thirds of the ptients (64%, n = 48) underwent surgery, while 36% (n = 27) did not hve ny form of surgery. The ltter were either unsuitble for surgicl intervention due to metsttic disese t presenttion or other comorbidities. Of those tht underwent surgery, 75% (n = 36) hd 1 opertion, while 20.8% (n = 10) nd 4.2% (n = 2) underwent 2 or more thn 2 opertions, respectively. 62.5% (n = 30) hd mstectomy s the initil curtive surgery, while 37.5% (n = 18) underwent BCS. Of those who hd BCS, 61.1% (n = 11) hd positive mrgins, of which 38.9% (n = 7) hd dditionl surgery. 4 ptients received neodjuvnt therpy prior to surgery. Full rdiologicl ssessment (mmmogrphy, brest ultrsound, nd MRI) ws not ble to identify the presence of tumour in 8.3% (n = 4/48) of ptients. Tumour ws suspected cliniclly in these ptients, nd clinicl core biopsies showed ILC. Tumour ws identified on MRI in 92% (n = 44/48) of cses, by ultrsonogrphy in 89.6% (n = 43/48), nd by mmmogrphy in only 73% (n = 35/48). Ptients who received neodjuvnt therpy (n = 4) were excluded from the nlysis of rdiology-histology correltions, s neodjuvnt therpy precludes correltion between pre-tretment rdiologicl size nd post-tretment histologicl size. Similrly, ptients with negtive imging (n = 4) were lso excluded. 40 ptients hd dignostic rdiology nd underwent surgery without receiving neodjuvnt therpy. ILC ws multifocl in 45% (n = 18/40) s confirmed by histology. There ws concordnce between rdiologicl nd histologicl tumour foclity in lmost two-thirds of cses (65%, n = 26/40). There ws discordnce in 35% (n = 14/40). In 9 cses, rdiology identified unifocl tumour, wheres it ws multifocl on finl excision histology. Tumour size rnged from 1.5-mm foci in multifocl disese to > 100 mm. There ws concordnce between rdiologicl nd finl histologicl tumour size in 60% (n = 24). In the concordnt cses, the vrition in tumour size ws 5 mm or less. In 40% (n = 16) of cses, the discordnce between rdiologicl nd histologicl tumour size exceeded 5 mm, with rnge of 6 78 mm. In the 16 discordnt cses, rdiology underestimted the tumour size in 75% (n = 12) of cses, nd overestimted it in smller proportion of cses (25%, n = 4). On mmmogrphy, brest density ws dense, modertely dense, nd ftty (low density) in 18.6, 74, nd 7.4%, respectively. In 3 cses, brest density ws difficult to ssess due to scrring following previous surgery for benign brest disese in 2 cses nd brest implnts in third cse. The correltion between menopusl sttus nd brest density ws not sttisticlly significnt. In ddition, the correltion between ge t dignosis, menopusl sttus, brest density, nd rdiology/histology discordnce ws lso not sttisticlly significnt using ANOVA with confidence intervl of 95%. The pttern of invsion ws predominntly clssicl in 47.5% (n = 19), trbeculr in 35% (n = 14), lveolr in 12.5% (n = 5), nd solid in 5% (n = 2) (fig. 1). The correltion between histologicl pttern of invsion nd rdiology/histology discordnce ws not sttisticlly significnt using Fisher s exct test (2-tiled p vlue = 0.8676) (tble 1). 88 Abu-Sinn/O Driscoll/Murphy
Tble 1. Correltion between pttern of invsion nd rdiology/histology discordnce Predominnt pttern Ptients, n (%) Discordnce, (n) % Clssicl 19 (47.5) 8 (42.1) Trbeculr 14 (35) 6 (42.8) Alveolr 5 (12.5) 1 (20) Solid 2 (5) 1 (50) Fig. 1. Invsive lobulr crcinom, hemtoxylin & eosin stin, nd E-cdherin immunohistochemistry (inset). A Clssicl, B trbeculr, C lveolr, nd D solid growth pttern; E lobulr intrepithelil neoplsi (LIN). E-cdherin immunohistochemistry ws performed in ll cses of newly dignosed ILC. E-cdherin ws negtive in 81.3% (n = 61) nd positive in 17.3% (n = 13), nd there ws mixed stining in 1.3% (n = 1). The correltion between E-cdherin sttus nd rdiology/histology discordnce ws significnt using Fisher s exct test (2-tiled p vlue = 0.0229). LIN ws present in core biopsy specimens in 22.5% (n = 9). Rdiology/histology discordnce ws 44.4 nd 38.7% for cses with nd without LIN, respectively. However, this ssocition ws not sttisticlly significnt using Fisher s exct test (2-tiled p vlue = 0.4777). A totl of 75% were positive for both ER nd PR (ER+/PR+), while the reminder were positive for ER nd negtive for PR (ER+/PR-). Rdiology/histology discordnce ws 36.7 nd 50% for cses which were ER+/PR+ nd ER+/PR-, respectively. However, the ssocition between ER/PR sttus nd rdiology/histology discordnce ws not sttisticlly significnt using Fisher s exct test (2-tiled p vlue = 0.0661). The Ki67 prolifertion index ws low (< 10%) to borderline (10 20%) in 87.2% of cses. Ki67 ws not done in 1 cse. The correltion between Ki67 nd rdiology/histology discordnce ws not sttisticlly significnt using ANOVA with confidence intervl of 95%. Discussion Morphologiclly, ll 75 newly dignosed cses hd lobulr growth pttern/rchitecture on hemtoxylin & eosin (H&E) stining. Of these, only 48 ptients underwent surgery. Overll, 25% (n = 12) of ll ptients undergoing surgicl tretment for ILC hd 2 or more opertions. Indeed, the diminished fibrotic rection present in ILC mkes it difficult for surgeons to determine the gross extent of the disese during surgery. When this is coupled with the decresed sensitivity of imging studies, it cn be very chllenging to chieve tumour-free mrgins fter limited excision. Detiled histologicl nlysis ws fesible only for the cses where surgicl resection specimen ws vilble. In these cses, n in-depth evlution of the rdiologicl findings ws performed. MRI ws ble to detect the presence of tumour in 92% of these cses, mking it the most sensitive imging modlity. Brest ultrsound lso hd high detection rte of 89.6%, while mmmogrphy detected only 73%. However, in 4 ptients ll 3 imging modlities filed to identify the presence of tumour. Despite the high detection rte, the rte of discordnce between rdiology nd histology in detecting tumour foclity ws still high t 35% while the rdiology/histology discordnce with regrd to tumour size ws 40%. Tumour size ws underestimted rdiologiclly in 12 cses, while it ws overestimted in 4 cses. In the discordnt cses, the difference in tumour size rnged from 6 to 78 mm. This cn hve considerble impct on T stging of ILC. This discordnce ws not unexpected, s other studies showed the sensitivities of mmmogrphy, sonogrphy, nd MRI for ILC to be 79, 68, nd 83%, respectively [18]. Another study looking t histologic subtype nd imging highlighted tht the gretest differences between ultrsound nd pthology mesurements were observed in lobulr crcinom [19]; however, this study involved smller number of cses. Interestingly, brest density s ssessed by mmmogrphy did not hve sttisticlly significnt impct on rdiology/histology discordnce. Of note, brest density did not correlte with menopusl sttus nd ge t dignosis, nd these prmeters seem to be independent of ech other. This ws n unexpected finding, s the ssumption ws tht the density of brest tissue decreses with ge, mking imging more sensitive in detecting ILC with incresing ge nd resulting in reduction in discordnce rte. However, this ws not the cse in our study. Histologicl findings were similr between core biopsies nd subsequent resection specimens. The predominnt pttern of invsion ws clssicl in lmost hlf the cses (47.5%), followed by trbeculr nd smller percentge of lveolr nd solid ptterns (5%). The correltion between pttern of invsion nd rdiology/histology discordnce ws not significnt. Discordnce between imging nd histology ws present even in ILC with lveolr nd solid growth ptterns. A possible explntion could be the presence of focl res with clssicl growth pttern, which my contribute to the discordnce. An illustrtive exmple of this rdiology/histology discordnce is given in figure 2. In our opinion, on retrospective review of both Concordnce between Rdiologicl nd Histologicl Findings in Invsive Lobulr Crcinom 89
Fig. 2. Mmmogrphy: both brests re dense; new re of slight distortion present t 12 o clock in the right brest. b Ultrsound: 2.2-cm irregulr hypoechoic lesion ws identified. c, d Mgnetic resonnce imging: 2-cm enhncing lesion consistent with the known neoplsm; in ddition, there is liner re of enhncement between this lesion nd the right nipple-reolr complex; further evlution needed if ptient opted for brest conservtion. e, f Histology: invsive lobulr crcinom, mixed clssicl nd trbeculr growth pttern, more thn 100 mm with multifocl distribution. crcinom is bsed on the morphologicl (H&E dignosis) rther thn the E-cdherin stining of the tumour. Controversilly, n interesting finding in our study ws the sttisticlly significnt ssocition between E-cdherin immunostining nd rdiology/ histology concordnce. Hlf of these cses hd clssicl growth pttern, while the reminder hd mixed clssicl, trbeculr, nd lveolr growth ptterns. LIN ws present in hlf the cses tht were E-cdherin positive. The cses which were E-cdherin-positive were more likely to hve concordnt rdiologicl nd histologicl size, suggesting tht positive E-cdherin my pertin to more loclized tumour infiltrtion despite the lobulr morphology. LIN ws present on core biopsy in 22.5%. However, it ws not helpful predictive prmeter for rdiology/histology concordnce. 75% of cses were positive for both ER nd PR, nd 87.2% hd low to borderline prolifertion index s ssessed by Ki67. Overll, the biologicl profile of ILC did not hve significnt correltion with rdiology/histology discordnce. The min limittion of this study is the low number of cses of surgiclly treted ILC; however, it does provide n insight into the behviour of these tumours. It highlights the importnce of E-cdherin stining, even in this limited smple. There hs been generl cceptnce tht morphology precedes E-cdherin immunostining in predicting tumour behviour; however, our study sheds some doubt on this. The pttern of invsion in ILC does not seem to ply role in improved rdiologicl correltion; however, lrge series of lveolr nd solid ptterns my prove otherwise. The min difficulty in identifying this subset is tht the pttern of invsion of ILC is not routinely reported on core biopsy specimens, which mkes cse selection cumbersome process. The best wy to overcome this is to crry out prospective study recording pttern of invsion on core biopsy nd correlting these with the finl histology. A lrger series my be ble to identify role for ER/PR hormonl sttus nd Ki67; however, given tht lmost ll ILC re ER-positive nd the mjority re PR-positive, this is unlikely. the imging nd histology, it is most likely tht the trbeculr pttern contributed to the mmmogrphiclly nd ultrsound-detected distortion/lesion, while the liner enhncement on MRI correltes with the clssicl pttern which is non-mss-forming. The vst mjority of cses (81.3%) were E-cdherin negtive, while 17.3% were E-cdherin positive. E-cdherin expression hs become n importnt dignostic feture of LIN nd ILC [20]; however, it is importnt to remember tht pproximtely 10% of ILC still express E-cdherin [21, 22] either with norml membrne loclistion or berrntly distributed s frgmented membrne nd/ or cytoplsmic stining. The E-cdherin-ctenin complex my be dysfunctionl in these cses due to the presence of CDH1 gene muttion or berrnt/loss of expression of the ctenin binding proteins [22], which my be detected using β-ctenin nd p120- ctenin immunohistochemistry. However, dignosis of LIN or ILC bsed on morphologicl nd cytologicl criteri should therefore not be reclssified s ductl crcinom in situ or IDC of no specil type (IDC-NST) bsed on the sttus of these immunohistochemicl mrkers [20]. At our institution, mngement of lobulr Conclusion The mjority of ILC re chrcterized by subtle infiltrtive pttern which mkes it difficult to rdiologiclly estimte tumour foclity nd size. Our study highlights tht rdiologicl ssessment underestimtes tumour size in more thn one-third of cses. This impcts the decision for curtive surgery. Despite the heterogeneity of ILC, histologicl nd biologicl fctors, with the exception of E- cdherin expression, do not seem to ply significnt role in the discordnce between rdiology nd histology. More sensitive imging techniques my llow for more ccurte pre-opertive ssessment in BCS for ILC nd increse the concordnce between rdiology nd histology. Disclosure Sttement The uthors declre no conflicts of interest nd no sources of funding or sponsorship. 90 Abu-Sinn/O Driscoll/Murphy
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