Isolated thoracic aortitis: clinicopathological and immunohistochemicalstudy of 11 cases
Jan Lacoa,⁎, Ivo Steinera, Tomas Holubecb, Jan Dominikb, Zdenka Holubcovab, Jan Vojacekb
aThe Fingerland Department of Pathology, Charles University Faculty of Medicine and Faculty Hospital in Hradec Kralove, Hradec Kralove, Czech RepublicbDepartment of Cardiosurgery, Charles University Faculty of Medicine and Faculty Hospital in Hradec Kralove, Hradec Kralove, Czech Republic
Received 29 April 2010; received in revised form 27 July 2010; accepted 3 September 2010
Aortitis may be classified as infectious and noninfectious.The rarer infectious forms of aortitis are associated with anumber of microorganisms, most commonly Salmonella,Streptococcus, and Staphylococcus species. Nowadays,luetic aortitis, which typically involves the ascending aorta,is exceedingly rare in developed countries [1]. In thenoninfectious group, the thoracic aortitis is often acomplication of an underlying disorder, e.g., systemicvasculitis or rheumatologic disease such as giant cell
⁎ Corresponding author. The Fingerland Department of Pathology,Faculty Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove,Czech Republic. Tel.: +42 420 495 832 548; fax: +42 420 495 832 004.
The group of noninfectious aortitis also includes acondition referred to as isolated aortitis, in which clinicalfeatures of underlying disease are absent. The entity“isolated aortitis” includes isolated thoracic aortitis (ITA)and chronic periaortitis [1]. The latter, involving theabdominal aorta, encompasses idiopathic retroperitonealfibrosis (Ormond's disease) and inflammatory abdominalaortic aneurysm. Together, they are sometimes referred to asperianeurysmal retroperitoneal fibrosis [9–12]. Recently,some evidence has emerged, suggesting that a subset ofchronic periaortitis is associated with IgG4-related systemicdisease [13–16].
Isolated thoracic aortitis is diagnosed in a varyingproportion of patients that undergo surgery on the ascending
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aorta; it is usually an incidental microscopic finding [8,17].The precise etiology of this type of aortitis is largelyunknown, although recently published case reports by Stoneet al. [18] and Ishida et al. [19] suggest that, like abdominalchronic periaortitis, some cases of ITA may be associatedwith IgG4-related systemic disease.
We studied 11 cases of ITA in order to investigatethe possible role of IgG4-mediated immune reaction inits pathogenesis.
Between 2002 and 2010, a total of 232 thoracic aorticdilation/aneurysm resections were performed at the Depart-ment of Cardiosurgery. Of the 51 cases with materialavailable for histological examination, 11 showed features ofchronic aortitis (ITA) defined by presence of lymphoplas-macellular infiltration of adventitia and/or media associatedwith severe defects of medial elastic fibers and absence ofsignificant atherosclerotic lesions and infection [1]. Clinicalinformation of the patients was obtained from clinical charts.For every patient, a positive history of systemic hyperten-sion, diabetes mellitus, and autoimmune disease was noted.As a part of this study, the serum IgG and IgG4 levels (upperlimits 19.50 and 0.93 g/L, respectively) were retrospectivelyexamined in the living patients using nephelometry andradial immunodiffusion, respectively.
Tissue specimens were immediately fixed in 10%formalin, routinely processed, embedded in paraffin, andstained with hematoxylin–eosin (HE) and elastica–vanGieson. Four sections were cut from each block. All ofthe paraffin-embedded tissue blocks (median 4 blocksper case; range 2–7) were available for immunohisto-chemical analysis.
Indirect immunohistochemistry using monoclonal/poly-clonal antibodies against CD20 (L26, 1:300), CD79α(JCB117, 1:100), CD3 (polyclonal, 1:200), CD4 (4B12,1:80), CD8 (C8/144B, 1:200), CD68 (KP1, 1:400), CD138(MI15, 1:50), CD21 (1F8, 1:25), immunoglobulin lightchain kappa (BJK) (R10-21-F3, 1:400), immunoglobulinlight chain lambda (BJL) (N10/2, 1:25), IgA (polyclonal,FLEX), IgD (polyclonal, FLEX), IgG (polyclonal, FLEX),IgG4 (1:100, HP6025), IgM (polyclonal, FLEX), bcl-6 (PG-B6p, 1:5), CD31 (JC70A, 1:10), D2-40 (D2-40, 1:50),CD105 (SN6 h, 1:5), and smooth muscle actin (SMA) (1A4,1:200) was performed. The source of IgG4 was Invitrogen(Camarillo, CA) of BJL Diagnostic BioSystems (Pleasanton,CA). The remaining antibodies were from Dako (Glostrup,Denmark). Antigen retrieval was performed in a water bathfor 40 min at 97°C in the target retrieval buffers at differentpH values: pH 6.0 (buffer S1700) for CD20, CD79α, CD8,CD68, CD138, CD21, CD31, D2-40, BJK, and BJL and pH9.9 (buffer S3308) for CD3, CD4, IgG4, and bcl-6.Endogenous peroxidase activity was inhibited by immersingthe sections in 3% hydrogen peroxide. Finally, the sections
were incubated with EnVision Dual Link System-HRP(Dako). The reaction was visualized using diaminobenzi-dine. For the detection of IgA, IgG, and IgM, a ready-to-usesystem with EnVision FLEX Target Retrieval Solution HighpH (10×) (Dako) was utilized, and for the detection of IgD,EnVision FLEX Target Retrieval Solution Low pH (10×)(Dako) was used.
Histopathologic evaluation of the inflammatory infiltratewas performed using a slight modification of the methodused by Sakata et al. [14]. The numbers of adventitial andmedial CD20-, CD79α-, CD3-, CD4-, and CD8-positivelymphocytes were individually reported as negative (nolymphocytes), mild (1–30 lymphocytes/high-power field[HPF]), moderate (31–100 lymphocytes/HPF), or severe(N100 lymphocytes/HPF). The numbers of adventitial andmedial CD138-positive plasma cells were counted andsemiquantitatively reported as negative (no plasma cells),mild (1–10 plasma cells/HPF), moderate (11–20 plasmacells/HPF), moderate/severe (21–50 plasma cells/HPF), orsevere (N51 plasma cells/HPF). The numbers of IgA-, IgD-,IgG-, IgG4-, and IgM-positive plasma cells were similarlyreported. The areas in which the lymphoplasmacellularinfiltrate was most intense were recorded. Additionally, theIgG/CD138–plasma cell, IgG4/CD138–plasma cell, andIgG4/IgG–plasma cell ratios in the adventitial infiltrate werecalculated. The presence of lymphoid follicles containingbcl-6-positive germinal center cells with normal or disruptedfollicular dendritic cell (FDC) arrangement in the adventitiaand media was noted. Normal FDC arrangement was definedas well-formed circular FDC network and disrupted FDCarrangement was defined as FDC network with irregularoutlines. The presence of adventitial and medial CD68-positive histiocytes was separately recorded. In addition tothe cellular infiltration, the following findings were alsorecorded: in the adventitia: fibrosis, state of the vasavasorum; in the media: vascularization, mucoid degenera-tion, necrosis, fibrosis, defects of elastica; in the intima:thickening and vascularization.
As there were only 11 cases in the study, only basicdescriptive statistical analysis was performed.
3. Results
3.1. Clinical data
The clinical data of the patients are shown in Table 1. Theseries includes nine women and two men patients aged 52–
Fig. 1. (A) Wrinkled intimal appearance. (B) Intensive inflammation in the adventitia and media in the florid stage (HE, original magnification ×30).(C) Adventitial fibrosis, defects of medial elastic fibers and intimal fibrosis (elastica–van Gieson, original magnification ×30). Female, 64 years. A, adventitia;I, intima; M, media.
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79 years (mean 66±9 years; median 69 years). Two patientshad a history of hypothyroidism due to autoimmunethyroiditis. None of the patients had clinical or laboratorysigns of systemic disorder known to lead to aortitis, namelyrheumatoid arthritis, systemic lupus erythematosus, HLA-B27-associated spondyloarthropathy, sarcoidosis, Behcetdisease, or systemic vasculitis. None of the patients hadIgG4-related disease. Medical history and laboratory tests(rapid plasma reagin reaction, Treponema pallidum hemag-glutination assay) for syphilis were negative in all patients.Two of the patients had an associated heart defect (onebicuspid aortic valve and one aneurysm of the interatrialseptum). One patient had a positive family history of aorticdisease; both her uncle and cousin developed isolatedaneurysms of the ascending aorta.
Nine patients presented with dyspnea and four with chestpain. Two of the patients were asymptomatic. Before
Fig. 2. (A) Wrinkled intimal appearance and lipoid streaks. (B) Thinning of th(C) Adventitial fibrosis, virtual loss of medial elastic fibers, and intimal fibrosisadventitia; I, intima; M, media.
surgery, erythrocyte sedimentation rate was elevated inthree patients, white blood cells count in one, and C-reactiveprotein in two. All patients were afebrile.
All 11 patients presented with aortic incompetence,which was symptomatic in nine of them. The aneurysmswere limited to the ascending aorta in nine cases. In the tworemaining cases, the dilation continued to the arch and ashort segment of the descending thoracic aorta. It isimportant to note that none of the patients had abdominalaortic aneurysm. The diameter of the thoracic aneurysmswas between 47 and 82 mm (mean 65±13 mm; median63 mm) when measured by transthoracic ultrasonography(the upper limit for normal ascending aorta diameter is35 mm). On coronarography, three patients showed stenosisof the right coronary artery, two showed stenosis of the leftanterior descending artery, and one patient had stenosis ofthe left circumflex artery. Ostial stenosis of the coronary
e aortic wall in the “burnt-out” stage (HE, original magnification ×30).(elastica–van Gieson, original magnification ×30). Female, 64 years. A,
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arteries was absent in all cases. At surgery, no fibrousmasses were found encasing the aneurysms, neither werethere adhesions present between the aneurysms and thesurrounding structures.
In all patients, the final diagnosis of ITA was based onmicroscopic findings.
The follow-up period ranged between 2 and 64 months(mean 20±18 months; median 9 months). Four patients diedduring the follow-up period. Two of the deaths were relatedto the aortic disease — rupture of a pseudoaneurysm at themargin of the conduit 23 months postoperatively and ruptureof a newly developed ITA–aneurysm in the descendingthoracic aorta 64 months postoperatively. The other twodeaths were from unrelated diseases. None of the livingpatients developed any IgG4-related disease. Serum levels ofIgG and IgG4 were checked in the living patients 2–12months postoperatively (median 9 months; mean 7±4months), and no elevation was found.
3.2. Gross findings
The aortic wall specimens sent for pathology examinationmeasured (57–160)×(19–100) mm. In all cases, the intimalsurface had a wrinkled appearance, with lipoid streaks inseven cases (Figs. 1A and 2A).
3.3. Microscopic findings
The thickness of the aortic wall ranged from 0.44 to 3.44mm, median 2.42 mm (measured using NIS Elements AR3.0 program).
The inflammatory changes are listed in Table 2. All thecases showed variable degrees of lymphoplasmacellularinfiltration in the adventitia and media (Figs. 1B and 2B).The intensity of adventitial lymphocytic infiltrate was scoredas severe in 10 cases. Severe medial lymphocytic infiltrationwas seen in six cases. Immunohistochemically, the infiltrateconsisted of CD20 and CD79α-positive B-lymphocytes andCD3-positive T-lymphocytes, which are present in a similarproportions (Fig. 3A,B). The T-cell population comprisedboth CD4- and CD8-positive subtypes with slight predom-
Table 2Intensity of inflammatory changes in the 11 cases of ITA
Lymphocytes
Negative/mild Moderate Severe
Adventitia 0 1 10Media 2 3 6
Plasma cells
Negative/mild Moderate Moderate/severe Severe
Adventitia 0 2 4 5Media 2 1 4 4
inance of the former. In eight cases, lymphoid folliclesconsisting of B-lymphocytes and bcl-6-expressing germinalcenter cells were present in the adventitia; they were absentin the media. Both patterns of CD21-positive FDCarrangement within germinal centers, i.e., normal anddisrupted were recognized. The adventitial CD138-positiveplasma cells infiltrate was scored as moderate/severe orsevere in nine cases. In the media, it was moderate/severe orsevere in eight cases (Fig. 3C). The plasma cell populationwas polyclonal, expressing both kappa and lambda lightchains with no restriction. The patterns of IgA-, IgD-, IgG-,IgG4-, and IgM-positive plasma cells infiltration are shownin Table 3. Most of the plasma cells present were IgD- andIgG-positive, and only a few scaterred IgA- and IgM-positive plasma cells were identified (Fig. 4). The pattern ofIgG4-positive plasma cell infiltration was noteworthy. Inseven cases, there were more than 10 cells/HPF, and in fiveof these cases, the count was N20 cells/HPF (Fig. 5). TheIgG/CD138–plasma cell ratio ranged from 0.76 to 0.90(median 0.82; mean 0.83±0.06), the IgG4/CD138–plasmacell ratio ranged from 0.06 to 0.84 (median 0.44; mean 0.45±0.29), and the IgG4/IgG–plasma cell ratio ranged from 0.07to 0.98 (median 0.55; mean 0.53±0.34). In six cases, theIgG4/IgG–plasma cell fraction was higher than 0.50. CD68-positive histiocytes were present in varied amounts in theadventitia as well in the media. Neither obliterativeendarteritis nor obstructive phlebitis of the vasa vasorumwas seen in any case.
The cellular infiltration was associated with otherchanges within the media — laminar necrosis of smoothmuscle (6 cases), coagulative necrosis with a granulomatoushistiocytic rim (two cases; Fig. 6), mucoid accumulation(five cases), and severe defects of the elastic fibers (all 11cases; Figs. 1C, 2C, and 7). Variable degrees of adventitialand medial fibrosis were seen in all the cases. Adventitialfibrosis was found to be severe in all six cases in which theIgG4/IgG–plasma cell ratio was higher than 0.50. Thefibrosis was severe in only three of five cases in which theratio was b0.50. The adventitial IgG4-positive plasma cellpopulation was severe in one of the two cases, showingcoagulative necrosis with a granulomatous histiocytic rim inone and mild in the other. There were no other differences inall studied parameters related to the IgG4-positive plasmacell population.
Dissection of the aortic wall was absent in all cases.Vascularization of the media and occasionally of the intimawith thin-walled blood vessels was present in all cases. Theendothelium of these vessels expressed CD31 and CD105. Inaddition, numerous D2-40-positive lymphatic vessels wereseen in the adventitia but not in the media.
In all cases, the intima showed fibrous thickening withpresence of foamy histiocytes in six.
Examination of the descending thoracic aortic aneurysmdeveloping 64 months postoperatively and leading to thedeath of the patient showed similar changes of those found inthe previous aneurysm of the ascending aorta.
Fig. 3. (A) CD20-positive lymphocytes in follicular and interfollicular localization. (B) CD3-positive lymphocytes in interfollicular localization. (C) CD138-positive plasma cells (original magnification ×100).
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4. Discussion
Noninfectious aortitis may occur either in the setting of anunderlying disorder or as an isolated event. The mostcommon systemic diseases causing noninfectious aortitisinclude giant cell and Takayasu arteritis, both with well-established clinicopathological diagnostic criteria (listed inthe work of Gornik and Creager [1]). Other types of vasculitis(e.g., antineutrophil cytoplasmic antibodies-associated types)and certain systemic disorders, particularly rheumatoidarthritis, systemic lupus erythematosus, HLA-B27-associat-
ed spondyloarthropathies, and sarcoidosis may lead to aortitiswith common involvement of the ascending portion [1–7].
Isolated aortitis comprises two entities — chronicperiaortitis, which affects the abdominal portion, and ITA,which involves mostly the ascending portion. For chronicperiaortitis, which encompasses idiopathic retroperitonealfibrosis (Ormond's disease), inflammatory abdominal aorticaneurysm, perianeurysmal aortitis, and idiopathic isolatedabdominal aortitis [1], there is increasing evidence suggest-ing that at least a subset of these disorders may be amanifestation of IgG4-related disease [13–16].
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Very little, however, is known about ITA. Isolatedthoracic aortitis accounted for 4% and 47% of all cases ofthoracic aortitis in two large studies [8,17]. It occurredmostly in old patients and with female predominance. Thehigh rate of ITA in our series (11/51, 22%) is certainlyinfluenced by the fact that material was sent for histologicalexamination from only 51 of the 232 patients operated on fordilation of the ascending aorta. Thus, the true prevalence ofITA in our study may be around 5%. Since the clinicalsystemic features of the disease are usually few and
nonspecific, the diagnosis of ITA appears as an incidentalmicroscopic finding in a vast majority of cases. In our study,the final diagnosis was made on microscopy in all cases. Thegross appearance of the intima with its thickening, wrinkling,and extensive fatty streaks did, however, suggest unusualdisease, not merely atherosclerosis.
The general microscopic findings included an intensivelymphoplasmacellular infiltrate with adventitial and medialfibrosis and varying degrees of medial degenerative changes,e.g., necrosis, granulomatous reaction, mucoid pooling, andloss of elastic fibers [8,17]. Recently, Stone et al. [18]published a case of a patient who developed dissection of theascending aorta and Ishida et al. [19] published a case of apatient who developed an aneurysm of the aortic arch, bothcases in the setting of IgG4-related disease with increasednumbers of IgG4-producing plasma cells. Their reportedIgG4/IgG ratio was “N0.5" [18] and 0.84 [19], respectively.In our series, this parameter was N0.5 in 6 of 11 cases.Furthermore, all six of them showed severe adventitialfibrosis indicative of an IgG4-related fibroinflammatoryprocess. Two of the cases from our series showed medialnecrotic and granulomatous lesions, one of them with an
a cells. (C) Multiple IgG-positive plasma cells. (D) Scattered IgM-positive
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abundant and the another with sparse adventitial IgG4-positive plasma cell infiltrate. We therefore regard coagula-tive necrosis as a nonspecific finding in IgG4-related ITA.
IgG4-related systemic disease is a novel clinicopatholog-ical entity, increasingly recognized since the concept ofautoimmune pancreatitis was coined by Yoshida et al. [20] in1995. Although autoimmune pancreatitis is thought to be acardinal manifestation of IgG4-related disease, there isemerging evidence suggesting that this disorder may involvevarious other tissues and organs, both simultaneously andmetachronously, even in the absence of pancreatic disease[21]. The conditions that have been recognized as possiblemanifestations of IgG4-related disease include IgG4-relatedsclerosing cholangitis, sclerosing cholecystitis, chronicgastritis and colitis, sclerosing sialadenitis (Küttner's
Fig. 6. Medial necrotizing granuloma with a histiocytic rim (HE, original mmagnification ×400).
tumor), Riedel's thyroiditis, mediastinal and retroperitonealfibrosis (Ormond's disease), tubulointerstitial nephritis,interstitial pneumonia, prostatitis, inflammatory pseudotu-mors of the liver, lung, orbita, and hypophysis as well ascervical, pulmonary hilar, mediastinal, and abdominallymphadenopathy (summarized by Kamisawa and Okamoto[21]). In general, male predominance seems to be character-istic for this group of diseases [21].
The precise etiopathogenesis of IgG4-related diseaseremains poorly understood. No triggers have yet beenidentified. However, molecular mimicry, particularly ofHelicobacter pylori, may be involved in the development ofautoimmune pancreatitis [22]. IgG4 immunoglobulin is theleast abundant of all serum IgG isotypes, constituting onlyabout 6% of total IgG, and it shows poor ability for antigenbinding and complement activation [23]. The serum IgG4level is elevated in about 75% of patients with IgG4-relateddisease as well as in other conditions, e.g., pemphigusvulgaris [24]. It is not clear whether the IgG4-producingplasma cells play an etiological role or if they represent acounterregulatory response and are useful only as diagnosticmarkers. Most patients with IgG4-related disease respondwell to corticosteroid therapy [21].
Microscopic features of IgG4-related disease includevaried degrees of inflammation, fibrosis, and vascularchanges [25]. The inflammation is predominantly lympho-plasmacellular with large amount of T-lymphocytes andIgG4-producing plasma cells. The threshold N10 IgG4-producing plasma cells/HPF was originally used as thediagnostic level for diagnosis of autoimmune pancreatitis[26]. Recently, it has been shown that a level of N20 IgG4-producing plasma cells/HPF carries a moderate sensitivity(43%) but a 100% specificity for the diagnosis of
agnification ×200). Inset: Multinucleated giant histiocytes (HE, original
Fig. 7. Severe defect of medial elastic fibers and adventitial and intimal fibrosis (elastica–van Gieson, original magnification ×200).
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autoimmune pancreatitis [27]. Seven patients in our seriesfulfilled the original diagnostic criterion and five of thepatients met the newly proposed criterion. The degree offibrosis present depends on the stage of the disease. In theadvanced/chronic stages, the fibrosis is prominent and theinflammatory infiltrate is scanty with low numbers of IgG4-producing plasma cells, probably representing a “burnt-out”end stage of the disease.
Although we demonstrated the presence of IgG4-producing plasma cells in all cases, there are certain featuresof our series that differ from those seen in other cases ofIgG4-related disease. These include (1) no history ordevelopment of other manifestations of IgG4-related diseasein any patient, (2) female predominance (unlike malepredominance reported in other studies) possibly indicatesan autoimmune origin of ITA requiring further investigation,and (3) absence of obliterative phlebitis also reported byStone et al. [18], the presence of which is generallyconsidered to be a classic feature of IgG4-related disease.The appearance of the vasa vasorum is not recorded in thetwo large series dealing with ITA [8,17]. Interestingly,obliterative phlebitis is described in a majority of the cases ofinflammatory abdominal aortic aneurysms reported bySakata et al. [14].
In summary, the results of our study may haveconsequences for pathological approach to ITA. Based onour findings, intimal thickening and wrinkling appears to besuggestive of aortitis. Our study indicates that microscopicexamination of aorta resected for dilation/aneurysm ismandatory, as there are often no clinical signs ofinflammation, which is evident only at microscopy. Certainclinicopathological features seen in our series correspondwith those described in IgG4-related disease. As wedemonstrated the presence of significant numbers of IgG4-producing plasma cells in the inflammatory infiltrate in somecases of ITA, a subset of ITA may represent aortic
manifestation of IgG4-related disease. Evaluation of serumIgG4 level and tissue IgG4-producing plasma cells may be ofimportance in selected cases. Although the outcome ofpatients with ITA is generally good, a significant proportionof patients (up to 17%) may subsequently develop newaneurysms [8]. Long-term follow-up is thus necessary toenable detection of recurrent disease.
5. Summary
Eleven cases of ITA were studied in order to determinethe possible role of IgG4-producing plasma cells in itsetiopathogenesis. The presence of lymphoplasmacellularfibrosing inflammation and increased IgG4-positive plas-ma cell count in several of the cases suggests that asubset of ITA may represent aortic manifestation of IgG4-related disease.
Acknowledgments
The authors thank Mrs. M. Zakova for her excellenttechnical support and Dr. F. A. Sobande for Englishlanguage correction. This study was supported by ResearchProject of the Ministry of Health of the Czech Republic No.00179906. The authors declare that they have no conflict ofinterest. The study complies with the current laws of theCzech Republic.
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