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ORIGINAL PRE-CLINICAL SCIENCE

Diverse morphologic manifestations of cardiac allograftvasculopathy: A pathologic study of 64 allograft heartsWei-hui Lu, MD,a Kathy Palatnik, BS,a Gregory A. Fishbein, BA,a Chi Lai, MD, FRCPC,a

Daniel S. Levi, MD,b Gregory Perens, MD,b Juan Alejos, MD,b Jon Kobashigawa, MD,c

and Michael C. Fishbein, MDa

aFrom the Department of Pathology and Laboratory Medicine, Division of Anatomic Pathology; bDepartment of Pediatrics, Division of

Pediatric Cardiology; and cCedars-Sinai Heart Institute, Los Angeles, California.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major limitation to the long-term successof cardiac transplantation. Although there are published descriptions of the lesions, there have been nostudies delineating the pathology of CAV in a large series of patients who underwent retransplantationfor CAV.METHODS: We reviewed archival records and microscopic sections of surgically explanted heartsfrom 64 patients who underwent cardiac retransplantation: 54 adults (18 to 70 years old) and 10 children(3 to 15 years old). Vascular lesions were categorized as showing intimal fibromuscular hyperplasia,atherosclerosis and/or inflammation. The degree of luminal narrowing was estimated from grossdescriptions and microscopic sections.RESULTS: In total, 75% of hearts had evidence of acute cellular rejection, mostly mild. Intramyocar-dial arteries showed primarily intimal fibromuscular hyperplasia and inflammation with no atheromaspresent. Large and branch epicardial coronary arteries were narrowed in at least one artery of all hearts.Lesions in the epicardial coronary arteries were composed of intimal fibromuscular hyperplasia,atherosclerosis and/or inflammation affecting one or more vascular layers (intima, media and adven-titia). Severe CAV with �75% luminal narrowing was seen in the LAD in 17% of hearts, the LCx in17% and the RCA in 22% of hearts. Two hearts had severe narrowing of the left main coronary artery.Nineteen arteries had luminal thrombi. All hearts had narrowing of smaller epicardial branch coronaryarteries that was often severe. Atheromas were present in arteries of adults and children; thus, not allatheromas could be considered pre-existing prior to transplantation. Both arteries and veins showedintimal hyperplasia and inflammation.CONCLUSIONS: CAV is a pathologically multifaceted disorder that affects large and small epicardialcoronary arteries of adults and children, with different types of lesions: intimal fibromuscular hyper-plasia; atherosclerosis; and/or inflammation (vasculitis). Therapies to address this disease must take intoaccount the protean nature of the vascular lesions.J Heart Lung Transplant 2011;30:1044–50© 2011 International Society for Heart and Lung Transplantation. All rights reserved.

KEYWORDS:transplant coronaryartery disease;transplantvasculopathy;allograft arteriopathy;cardiac transplantarteriosclerosis;cardiac allograftvasculopathy

Reprint requests: Michael C. Fishbein, MD, Department of Pathologyand Laboratory Medicine, Room 13-145H, David Geffen School of Med-icine, University of California at Los Angeles, 10833 LeConte Avenue,Los Angeles, CA 90095. Telephone: 310-825-9731. Fax: 310-794-4161.

E-mail address: mfishbein@mednet.ucla.edu

1053-2498/$ -see front matter © 2011 International Society for Heart and Lungdoi:10.1016/j.healun.2011.04.008

Progressive occlusion of large epicardial and smallerintramural coronary arteries is a major cause of death1,2 andthe most prominent limiting factor for long-term graft sur-vival after cardiac transplantation in both adults and chil-dren.3 The pathogenesis of the vascular disease is not com-pletely understood, but existing data indicate that bothalloimmune-dependent and -independent injuries are in-

volved.4–6 According to recent registry data,7 in adults,

Transplantation. All rights reserved.

1045Lu et al. Manifestations of CAV

CAV becomes prominent 1 to 3 years after transplantationand is responsible for 10% to 15% of deaths subsequently.The incidence was found to be 8% at 1 year, 20% at 3 years,30% at 5 years and �50% at 10 years. In the pediatricpopulation,8 CAV/graft failure showed an incidence of 60%after 3 years and was the leading cause of death. Once CAVwas diagnosed, the 4-year graft survival was approximately50%. Because there has been a concern among cliniciansthat angiography will not detect transplant vascular diseasewith adequate sensitivity, intravascular ultrasound has alsobeen used in screening transplant patients.9 Various termshave been used to describe this entity, including transplantcoronary artery disease (TCAD), transplant vasculopathy(TV), allograft arteriopathy, cardiac transplant arterioscle-rosis, cardiac allograft vasculopathy (CAV) and even trans-plant atherosclerosis. Indeed, the numerous terms used andthe heterogeneous pathologic lesions seen in transplantedhearts have added to the complexity in defining and under-standing vascular lesions.10–16

The large cardiac transplant service at UCLA MedicalCenter has provided us with the opportunity to study asizable number of hearts with CAV from patients undergo-ing retransplantation. Using these hearts, we attempted tofurther define, characterize and catalogue the lesions thatoccur within the cardiac vasculature after heart transplanta-tion in both children and adults.

Methods

To assure optimal preservation of tissue morphology we did notinclude autopsy cases in this study, but instead limited our inves-tigation to explanted hearts from patients undergoing retransplan-tation. Archival records, tissue paraffin blocks and microscopicsections were retrieved from 64 patients who underwent retrans-plantation. The patients were divided into 3 groups: adult males(�18 years of age); adult females; and children.

Demographic and clinical data were extracted from the medicalrecords. Findings from prior endomyocardial biopsies were ob-tained from archival surgical pathology reports. Gross pathologicfindings of the explanted allograft hearts were reviewed from theoriginal surgical pathology reports.

Existing hematoxylin–eosin (H&E)-stained sections of coro-nary arteries were examined and trichrome/elastic-stained sectionsof selected blocks were prepared. In selected cases immunohisto-chemical staining was performed to identify B and T lymphocytes,macrophages, and complement deposition, as described else-where.17,18 In available proximal and distal segments of each ofthe major coronary arteries, the following findings were gradedsemi-quantitatively from 0 to 3 (1 � focal/mild, 2 � multifocal/moderate, 3 � diffuse/severe): intimal inflammation, fibrosis,smooth muscle hyperplasia, thrombus formation, calcification, in-tracellular lipid, atheroma formation; medial necrosis, fibrosis andinflammation; and adventitial inflammation. The scores in eachcategory were then averaged within each of the 3 groups ofpatients. The percent stenosis of each artery was also determinedfrom the surgical pathology reports and the re-evaluation of thehistologic sections. Our standard protocol for examining explantedhearts includes microscopic sections of proximal and distal leftanterior descending (LAD), left circumflex (LCx) and right (RCA)

coronary arteries, as well as left main (LM) and smaller epicardial

branch arteries if gross lesions are observed. In addition, routinemyocardial sections include transmural sections of the free wall ofthe right ventricle, interventricular septum and free wall of the leftventricle to include the anterior and posterior papillary musclesand the lateral free wall. Any gross myocardial lesions and sutureslines in the atria (if available) are also sampled. Accordingly, everyheart had at least 11 histologic slides for review. The study wasapproved by the institutional review board at UCLA (IRB # G03-12-039-04).

Results

A large number of patients transplanted at our institutionhad their initial transplantation or part of their follow-up atother institutions, so complete medical records were notreadily available for this subgroup of patients. The studyconsisted of 64 patients, which included 45 adult males, 9adult females and 10 pediatric patients (3 males and 7females). The adult males were 18 to 70 years of age (mean49 years), adult females were 19 to 62 years of age (mean40 years), and the pediatric patients were 3 to 15 years ofage (mean 11 years). Adult male patients had their allografthearts for 2 to 216 months (mean 90 months), adult femaleshad their allograft hearts for 28 to 150 months (mean 74months), and the pediatric patients had their allografts for 18to 159 months (mean 67 months). In the 59 patients forwhom the information was available, the initial transplan-tation was performed for ischemic heart disease (n � 23),cardiomyopathy (n � 28), congenital heart disease (n � 6)or end-stage valvular heart disease (n � 2). In 1 patient, themajor cause of graft failure 2 months after transplantationwas acute cellular rejection (ACR). In all of the other 63patients CAV was the primary cause of graft failure occur-ring as early as 4.5 months after transplantation. Four pa-tients had coexisting moderate to severe ACR.

All patients had numerous surveillance endomyocardialbiopsies, with an average of 25 for adult males, 26 for adultfemales and 16 for the pediatric cases. The most biopsiesrecorded for any patient in this study was 47. Fifty-ninepatients had at least one episode of ACR. However, themajority of these episodes were ISHLT Grade 1R and werenot treated. The average number of episodes of ACR was 9for adult males, 8 for adult females and 3 for the pediatriccases. Thirty-one patients had at least one episode of Grade�2R ACR. Eight patients had at least one pathologicallydocumented episode(s) of antibody-mediated rejection. Sixof these 8 patients also had episodes of ACR. Three patientsnever had any episode of acute cellular or antibody-medi-ated rejection.

Myocardial findings

In adult males, the mean heart weight was 405 g. In adultfemales the mean heart weight was 207 g. In the pediatricgroup the mean heart weight was 110 g. The heaviest adult

male heart weighed 1,240 g, the heaviest adult female heart

1046 The Journal of Heart and Lung Transplantation, Vol 30, No 9, September 2011

376 g, and the heaviest pediatric heart 350 g. However, allof these weights are actually less than the total heartweights, because portions of the atria are usually missingfrom the explanted hearts, and at our institution fresh tissueis harvested from the apex of the heart for research pur-poses. In a previous study we calculated that recorded heartweights underestimate true heart weight by approximately40 g.19 Despite severe CAV only 7 hearts had gross scar-ring; however, 48 hearts had microscopic fibrosis, and in 27hearts the fibrosis was multifocal or diffuse.

Half (50%) of the hearts had mild, focal, cellular rejec-tion. Moderate cellular rejection (Grade 2R) was present in12% and severe cellular rejection (Grade 3R) in 13% of thehearts (Figure 1A). Only 25% of hearts had no evidence ofACR. Intramyocardial arteries were generally normal, withonly a minority showing narrowing. The narrowing con-sisted of a variable degree of intimal smooth muscle cellproliferation and collagen deposition. There was also in-flammation that involved one or more of the three layers(intima, media and/or adventitia) of the arteries. In mostarteries the medial smooth muscle was normal, whereas ina minority of arteries the smooth muscle cells were replacedby fibrous tissue (Figure 1B–D). No atheromas were presentin intramyocardial arteries. Only 3% of explanted hearts hadhistologic and immunohistochemical evidence of antibody-mediated rejection; however, antibody mediated rejection(AMR) was not excluded by immunohistochemical studies

Figure 1 (A) Example of acute cellular rejection (Grade 3R).Note diffuse inflammatory infiltrate and atrophy of myocytes(H&E stain; original magnification �200). (B) Intramyocardialartery with occlusion by fibromuscular intimal proliferation. Themedia is preserved (trichrome stain; original magnification �40).(C) Different intramyocardial artery showing a more fibrous inti-mal proliferation with inflammation as well in the media of theartery (H&E; original magnification �40). (D) Intramyocardialartery with fibromuscular intimal hyperplasia. There is also fibrosis(blue stain) of the media and adventitia, suggesting prior arteritis(trichrome/elastin stain; original magnification �40).

in the majority of hearts examined.

Vascular findings

In all hearts, at least one of the four major epicardial coro-nary arteries had gross luminal narrowing. Overall, 78%(169 of 216) of the microscopic slides of the epicardialcoronary arteries examined showed circumferential lesionsnarrowing the lumens.

Greater than 75% narrowing in any of the major coro-nary arteries was seen in the LAD in 17%, the LCx in 27%and the RCA in 22% of hearts. In 2 hearts there was severenarrowing (85% and 90%) of the left main coronary artery.All hearts had narrowing of the branches of the majorepicardial coronary arteries that was often more severe thanthe narrowing of the major epicardial coronary arteries,particularly in those cases in which none of the majorcoronary arteries had severe (�75%) narrowing. The im-plantation duration did not correlate with the degree ofarterial stenosis according to least-squares regression anal-ysis (R2 � 0.17). The average stenoses for the epicardialcoronary arteries are shown in Table 1, and the maximumstenoses are shown in Table 2.

Histologic sections from the epicardial coronary arteriesand veins showed great variability of findings from heart toheart, vessel to vessel and from different regions of the samevessel (Figure 2A–C). Because of this variability, and be-cause all vessels were not sampled at the same locations, itis possible to only generalize with regard to some of thefindings. Both arteries and veins showed intimal thickeningand prominent mural infiltrates of chronic inflammatorycells. Most arteries showed some degree of chronic inflam-mation in the adventitia of the major coronary arteries.Chronic inflammation was common in the media of arteriesand veins, occasionally quite severe, and even associatedwith necrosis and/or fibrosis of the media and destruction ofthe internal elastic lamina. Hence, this histopathology couldbe categorized as a true vasculitis. Inflammatory infiltrateswere also observed in the intima of arteries and veins. Themedia was normal in many vessels; however, in some ar-teries and veins, there was profound loss of medial smoothmuscle cells with prominent medial fibrosis.

The degree of chronic inflammation ranged from a fewcells beneath the endothelium (endothelitis) to marked, full-thickness inflammation. Immunohistochemical stainingshowed that the majority of infiltrating cells were CD3-positive T lymphocytes and CD68-positive macrophages(Figure 2D and E). For the three groups studied, there wasno difference in the mean score for intimal, medial or

Table 1 Average Maximum Stenosesa of the Major CoronaryArteries in the Groups Studied

Group LM LAD LCx RCA Epicardial branches

Adult males 41 53 52 49 52Adult females 40 51 65 45 45Pediatric cases 60 64 51 40 68

aPercent cross-sectional narrowing.

1047Lu et al. Manifestations of CAV

adventitial inflammatory cell infiltration; however, in allgroups there was, on average, more intimal inflammation(Grades 2 to 3) than medial or adventitial inflammation(Grades 1 or 2).

We also analyzed the relationship between the durationof implantation and degree of vascular inflammation, basedon the belief that with more inflammation CAV woulddevelop faster. In fact, the opposite was true. By non-parametric analysis of variance (ANOVA; Kruskal–WallisH-test), there was a direct relationship between the degreeof intimal inflammation and the duration of the implantation

Figure 2 (A) Epicardial artery (a) and vein (v), both with intimalhyperplasia (I), and there is also a thrombus (T) in the artery(trichrome/elastin stain; original magnification � 20). (B) Epicar-dial artery with transmural inflammation involving intima (I),media (M) and adventitia (A) (elastin stain; original magnification�40). (C) Epicardial vein showing intimal fibrosis and inflamma-tory infiltrate (H&E; original magnification �200). (D, E) Immu-nohistochemical staining for macrophages (CD68) (D) and T lym-phocytes (CD3) (E) demonstrating the marked inflammation thatcan be present in CAV (immunoperoxidase stains; original mag-

Table 2 Maximum Stenosesa of the Major Coronary Arteriesin the Groups Studied

Group LM LAD LCx RCA Epicardial branches

Adult males 90 95 95 85 90Adult females 50 80 100 70 95Pediatric cases 60 90 100 60 95

aPercent cross-sectional narrowing.

nification �20).

of the allografted heart (p � 0.01). There was no associationbetween the implantation period and medial (p � 0.60) oradventitial (p � 0.72) inflammation.

The mean score for intimal lipid accumulation was sim-ilar for the three groups: 1.5 for adult males; 1.5 for adultfemales; and 1.3 for the pediatric group. All three groups,including the pediatric cases, had focal atheromas in theepicardial coronary arteries (Figure 3A–F). Some sectionsof epicardial arteries showed only fibromuscular intimalthickening, whereas other sections showed only atheromapresence. Other sections from the same heart, and even thesame coronary artery, showed both types of lesions in thesame histologic sections. In many histologic sections withfibromuscular intimal thickening, even when true atheromaswere absent, numerous lipid-laden cells were observed.Multifocal or diffuse calcification was present in only 13%of arteries examined, even in the presence of true athero-sclerotic plaques. There was no relationship between thedegree of luminal narrowing and extent of calcification(Figure 4A). Recent or organizing thrombi were seen ina total of 19 arteries: 8 left anterior descending; 5 leftcircumflex; and 5 right and 1 left diagonal branch (Figure

Figure 3 (A) Epicardial artery with pure fibromuscular intimalproliferation (H&E stain; original magnification �100). (B) Epi-cardial artery with typical atherosclerotic plaque. The eccentriclesion is composed primarily of collagen with a necrotic core (N)present (H&E stain; original magnification �12.5). (C, D) Eccen-tric lesion with abundant intracellular lipid in numerous lipid-ladencells with no extracellular lipid [trichrome/elastin stain; (C) orig-inal magnification �1.25, (D) original magnification �200]. (E, F)Epicardial artery with more typical atheromatous plaque contain-ing both intracellular and extracellular (*) lipid [trichrome/elastinstain; (E) original magnification �1.25, (F) original magnification�100]. Note the absence of calcification in these large atheroscle-rotic plaques.

4B and C).

1048 The Journal of Heart and Lung Transplantation, Vol 30, No 9, September 2011

Discussion

CAV is the leading cause of late morbidity and mortalityafter heart transplantation. The pathogenesis of CAV is notcompletely understood. CAV is currently not entirely pre-

Figure 4 (A) Heavily calcified artery (dark red nodule) with noatheroma present (H&E stain; original magnification �40). (B)Completely occluded coronary artery with marked intimal prolif-eration and small fresh thrombus (T) occluding the residual lumen(trichrome/elastin stain; original magnification �12.5). (C) Arterywithout much intimal proliferation occluded by an organizingthrombus (OT) (trichrome/elastin stain; original magnification�20).

ventable or treatable. Mechanical interventions such as

drug-eluting stents20 have shown at least temporary benefit;however, due to the diffuse nature of the epicardial andintramyocardial arterial lesions observed, stents are a sub-optimal treatment. Drug therapy, such as everolimus, shouldbe more effective than mechanical interventions.21 Moreprogress in limiting CAV should be achieved as we learnmore about the mechanisms of cell proliferation in thevessels.22 Unfortunately, CAV is sometimes a mischarac-terized disease, often erroneously referred to as atheroscle-rosis. The findings of this study, and other descriptionsreported previously, demonstrate significant non-atheroscle-rotic vascular disease. Various terms have been used todescribe this entity: transplant coronary artery disease;transplant vasculopathy; allograft arteriopathy; cardiactransplant arteriosclerosis; and even transplant atheroscle-rosis. None of these terms can adequately characterize thedisease. Indeed, CAV is not a single pathologic entity but aconstellation of vascular changes characterized by intimalfibromuscular hyperplasia, atherosclerosis and vasculitis(inflammation of one or more layers of the vascular wall).Moreover, veins, as well as arteries, are affected, renderinggeneral designations of this disease as an arteriopathy inac-curate. However, although it is incorrect to use the terms“arteriosclerosis,” “atherosclerosis” or “vasculitis” synony-mously with CAV, true atherosclerosis, arteriosclerosis,vasculitis and combinations of these three lesions are in factcomponents of CAV.

The most significant lesion found in CAV is fibromus-cular intimal hyperplasia (arteriosclerosis), which differsfrom typical atherosclerosis in many important ways. Bydefinition, these are lesions of thickened intima due tofibromuscular proliferation, not atheroma formation or in-flammation.10 Atherosclerotic plaques tend to be eccentricand to occur proximally, and generally spare the intramyo-cardial arteries. Fibromuscular intimal hyperplasia tends tobe circumferential, and may diffusely involve the large andsmall epicardial coronary arteries as well as intramyocardialbranches. In our study, the diffuse nature of the intimalfibromuscular hyperplasia with involvement of numeroussmaller epicardial arteries seemed to cause the most signif-icant arterial occlusions in these hearts. When present inintramyocardial arteries, CAV involves only a minority ofthe arteries present, usually arteries in the mid- or sub-epicardial arteries, so endomyocardial biopsy is unlikely tosample involved vessels. Indeed, in our experience exam-ining �30,000 endomyocardial biopsies, CAV was rarelydiagnosed (unpublished observations). Calcium depositionis a major component of atherosclerosis and can serve as asurrogate marker of disease—the degree of calcificationtends to reflect the degree of stenosis.23 In contrast, calci-fication is not a prominent finding in fibromuscular intimalhyperplasia, even in severely narrowed arteries.

It is of interest that both the adult and pediatric popula-tions studied exhibited coronary atherosclerosis. Althoughsome transplant physicians have attributed proximal lesionsin transplanted hearts to pre-existing atheromatous plaquesin the donor coronary arteries, this would not be the case in

pediatric donors. Therefore, despite the fact that the pres-

1049Lu et al. Manifestations of CAV

ence of coronary atherosclerosis is not an unexpected find-ing in adults, the development of atheromas in our pediatricpopulation is convincing evidence that accelerated athero-sclerosis is a manifestation of CAV.

Chronic inflammation is a notable component of CAV.Although atherosclerotic plaques do contain inflammatorycells, the inflammation is usually limited to the intima andis not a prominent feature noted on routine light micros-copy. On the other hand, inflammation is a significant find-ing in CAV. Infiltration by macrophages and T lymphocytesis demonstrated by immunohistochemistry to be present inthe intima, media and/or adventitia of both arteries andveins. The degree of inflammation ranges from mild, sub-endothelial–predominant “endothelitis” to intense, transmu-ral, necrotizing vasculitis. This inflammation is present inregions with intimal fibromuscular hyperplasia, a findingnot present in native artery intimal hyperplasia (e.g., arte-riolar nephrosclerosis). We hypothesized that arteries withmore inflammation would become stenotic at a faster ratethan less inflamed arteries, but the opposite was true in thisstudy. It appears that the inflammatory reaction in the intimaof transplanted arteries increased over time, independent ofthe proliferative response of the vessel wall.

A virtual histology intravascular ultrasound (IVUS)study demonstrated that there is great heterogeneity of le-sions in CAV when arteries are examined by this imagingtechnique.24 Recently, the ISHLT proposed a standardizednomenclature for CAV that is based on imaging, not histo-pathology.25 The authors of this working formulation alsoemphasized the heterogeneity of the morphologic patternsof lesions in the coronary arteries. Our histologic studyconfirms these virtual histology and imaging findings anddelineates the types of abnormalities that may account forthe heterogeneity observed with IVUS and angiography.

In this study we have described the cardiac findings inexplanted hearts from a large, single-center retransplantexperience. These findings are limited by the very nature ofthe patient population. Essentially, this is a retrospectivestudy of archival materials from severe cases of CAV (i.e.,those requiring retransplantation), who did not succumb tothis complication of transplantation. It is reasonable to spec-ulate that those patients who die of this complication mayhave even more severe narrowing of their coronary arteries,more thrombi and a slightly different pathology.

Because this was a large, retrospective study that in-volved review of a large number of surgical pathologyreports and microscopic sections, one cannot be certain thatall hearts were dissected and sampled in exactly the samemanner. Despite our institutional protocols, completely ho-mogeneous approaches cannot be guaranteed and some le-sions may be under- or over-represented in our specimens.In addition, we did not routinely examine the hearts forantibody-mediated rejection, and the number of cases withACR and AMR were too few to allow analysis of the role ofthese entities in the progression of CAV. However, the rolesof ACR and AMR in the pathogenesis and progression ofCAV has been amply demonstrated in previous studies.26–28

Finally, the degree of stenoses and the severity of abnor-

malities were graded semi-quantitatively without the use ofmore quantitative morphometric analyses. However, clini-cal studies clearly documented the presence of severe CAVas the reason for retransplantation in all but one of ourpatients.

In conclusion, CAV is a heterogeneous vascular diseasethat affects large and small epicardial and intramyocardialarteries, as well as veins. Males and females and adults andchildren are affected similarly. Within a single vessel, le-sions may have features of intimal fibromuscular hyperpla-sia, atherosclerosis and/or vascular wall inflammation (vas-culitis). Therefore, one could reasonably define CAV as thetriad of intimal fibromuscular hyperplasia (arteriosclerosis),atherosclerosis and vasculitis. These components may existindividually or in combination at any given site in thevasculature. As in other forms of vascular disease, throm-boses occur at sites of luminal narrowing and endothelialinjury. Calcification may be present but is not a marker ofdisease severity. Attempts to address this major clinicalproblem must take into consideration the underlying pathol-ogy of the lesions.

Disclosure statementW-h.L., a visiting cardiovascular pathology fellow, and K.P., aUCLA medical student, contributed equally as first authors of thisstudy. J.K. is currently affiliated with the Department of Medicine,Cedars–Sinai Health Institute, Los Angeles, California. The studywas funded in part by the Piansky Family Trust, a generousendowment to the Department of Pathology and Laboratory Med-icine at UCLA (to M.C.F.). The expert histologic laboratory skillsof Lonhsheng Hong are acknowledged. None of the authors haveany conflicts of interest to disclose.

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