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A case of Castleman’s Disease and Adult Necrotising Aortitis: a co-incidenceor a significance?

Claudia Villanueva, Andrew Dettrick, Douglas Wall, Madeleine McLaren

PII: S1054-8807(14)00038-6DOI: doi: 10.1016/j.carpath.2014.04.001Reference: CVP 6766

To appear in: Cardiovascular Pathology

Received date: 23 March 2014Accepted date: 2 April 2014

Please cite this article as: Villanueva Claudia, Dettrick Andrew, Wall Douglas, McLarenMadeleine, A case of Castleman’s Disease and Adult Necrotising Aortitis: a co-incidenceor a significance?, Cardiovascular Pathology (2014), doi: 10.1016/j.carpath.2014.04.001

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A case of Castleman’s Disease and Adult Necrotising Aortitis: a co-incidence or

a significance?

Claudia Villanueva; Andrew Dettrick, MBBS, FRCPA;Douglas Wall,

BSc, MBBS(Hons), FRACS; Madeleine McLaren

The Prince Charles Hospital

Dr. Andrew Dettrick

The Prince Charles Hospital

Anatomical Pathology Department

Level 2, Clinical Sciences Building

Rode Rd

Chermside, Qld 4032

Australia

Phone: 61 7 3139 4713

Fax: 61 7 3139 4546

adettrick@gmail.com

Abstract

We report a case of concomitant Castleman’s disease and adult necrotising aortitis, an

association heretofore not reported. A brief discussion of the current state of our

understanding of the pathogenesis of aortitis and possible link between these two

entities is presented.

FUNDING

There is no funding to declare.

The authors do not have any conflicts of interest to declare.

Background

Castleman’s disease (CD) or angiofollicular lymph node hyperplasia is a rare

lymphoproliferative disorder associated in a subset of cases with the human

immunodeficiency virus (HIV) and human herpesvirus 8 (HHV-8). CD comprises at

least two distinct diseases (localized and multicentric) with very different prognosis. It

is also associated with a number of malignancies, including Kaposi sarcoma, non-

Hodgkin lymphoma, Hodgkin lymphoma, and POEMS syndrome.

There are no reliable estimates of its incidence given its rarity.

Aortitis is a term that describes inflammatory conditions of the aorta which are

traditionally subdivided into infectious and non-infectious categories.

Our understanding of the pathology of aortitis has evolved over recent years with an

increased understanding of the importance of autoimmune/connective tissue diseases

in the pathogenesis. This includes the emerging role of IgG4-related systemic

disease. A new classification of aortitis has been proposed by Burke et al in 2008

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which relies on histological features only, rather than the less robust clinical

classification that has previously been employed.

Case report

We present the case of a 45-year-old caucasian male with history of hypertension,

asthma, dyslipidemia and obesity. He had no smoking history, diabetes and no

marfanoid features. In 2012, he was referred to our hospital for surgical management

of a thoracic aorta aneurysm with an aortic root of 56mm. The patient had a six-and-a-

half year history of atypical chest discomfort episodes, lasting for up to 2-3 days at a

time, and spontaneously resolving. He also had a 4 year history of recurrent episodes

of presyncope, never progressing to syncope.

In 2008, he had an incidental finding of a 13.5cm retroperitoneal mass while being

investigated for dilated cardiomyopathy in hospital (EF 37%). A core biopsy showed

atypical lymphoid proliferation characterised by regressed follicles and non-

specific interfollicular changes but the sample was too small to give an unequivocal

diagnosis. An excision biopsy confirmed Castleman’s Disease (hyaline vascular type)

(Figure 1). He had no known recurrences.

At the time of cardiothoracic surgical referral, he had an EF of 54% with a mildly

dilated, mildly hypertrophied left ventricle, severe aortic regurgitation and an aorta

with the following measurements: STJ and trans-sinus 56mm, ascending aorta 49mm

and aortic arch 44mm on echocardiogram. Coronary angiogram showed no

abnormalities. The decision was made to go ahead with surgery for severe aortic

insufficiency and progressing aortic aneurysm. He underwent an aortic root and arch

replacement on early 2013 with a 29mm mechanical aortic valve conduit.

Intraoperatively, the left carotid artery and brachiocephalic artery had a common

origin and the left vertebral artery arose directly from the arch. The dilated aortic root

and ascending aortic aneurysm were seen to extend to the innominate artery and left

carotid artery. The trileaflet aortic valve and aortic aneurysm were excised.

Unfortunately, due to preservation in formalin for histopathology, culture was not

able to be conducted.

Histopathological examination showed plate-like zones of medial necrosis bordered

by histiocytes and giant cells (Figure 3). There was extensive medial destruction with

total loss of the elastic laminae in focal areas but the process was remarkably patchy.

Intimal fibrosis (due to the aneurysm) was prominent. Atherosclerosis was mild to

moderate.

Histology confirmed adult necrotising aortitis. HIV and syphilis serology were

negative and thyroid function was normal. ANA, ENA, C-ANCA, P-ANCA and

rheumatoid factor were also negative. C3 was raised at 2.19g/L (0.90-1.80) but C4

was within normal limits. ESR and CRP were elevated (102 and 63 mg/L

respectively) but unreliable given his recovery from major aortic surgery. On follow

up, CRP had reduced to normal levels but ESR was persistently elevated at 17H and

26H on subsequent visits.

The patient had no known family history of autoimmune conditions or aneurysmal

disease and further history did not reveal any evidence of rheumatologic disease. Four

or five years ago he had been diagnosed with oral lichen planus presenting as mouth

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ulcers which was managed with a course of prednisolone (5mg/d) and

hydrochloroquine for an unknown duration. There had not been further recurrence.

On follow up, due to recurrent pre syncopal episodes, bitemporal headaches and a few

episodes of amaurosis fugax in the left eye, he had a left temporal artery biopsy in

June 2013 that showed non specific degenerative changes. A MRI Brain showed

multiple, bilateral lesions representing micro haemorrhage and suspicious of embolic

infarcts with no evidence of vasculitis. An echocardiogram demonstrated the valve to

be well seated with normal hemodynamics.

He was found to be stable on the most recent clinic and will undergo long term

surveillance.

Discussion

In a significant percentage of cases, the diagnosis of aortitis is an incidental

histopathological finding following surgery and the inflammation and aortitis are

subclinical in nature1-5

. Such cases of idiopathic isolated aortitis are typically

localized to the ascending aorta and occur in association with an ascending aorta

aneurysm1,2

.

In 2008, Burke et al, described 52 cases of aortitis and ascending aortic aneurysm and

proposed a histological classification6. Necrotizing aortitis (NA) was the largest group

and was characterized by zonal medial laminar necrosis, rimmed by giant cells. It was

usually isolated and showed a bimodal age distribution with a separation at age 65

(adult vs elderly). Elderly NA showed a female predominance. Adult NA had greater

adventitial scarring and was histologically the same as Takayasu disease but limited

primarily to the ascending aorta with no sex predominance. The other group, Non NA

was characterized by absence of necrosis with diffuse medial inflammation and was

less often isolated, occurred exclusively in the elderly and had a higher rate of

dissection.

It has been proposed that NA is an autoimmune condition that may be localised

without systemic autoimmune symptoms (isolated NA), may involve arch vessels and

peripheral arteries causing obstructive symptoms (Takayasu syndrome) and may be

associated with other autoinmmune syndromes, especially rheumatoid arthritis or

giant cell arteritis6, 7

. Using this classification, Isolated NA is the most common

aortitis1, 4, 7, 8

.

Stone in 2011 stated that isolated aortitis is not a pathologic entity but rather a clinical

description of the level of systemic activity of the patient’s vasculitis. He presents a

review of aortitis, periaortitis and retroperitoneal fibrosis as manifestasions of IgGA-

related systemic disease9.

Regarding the association between aortitis and IgG4 related sclerosing disease

(IgG4RSD), it has been recognized as one of the causes of non infectious aortitis but

this is usually of the diffuse lymphoplasmacytic aortitis type (or Non-necrotising

according to Burke’s classification). It may also manifest with thoracic aortitis,

inflammatory abdominal aneurysm and retroperitoneal fibrosis as described by

Stone.9

IgG4 RSD pathogenesis is poorly understood and findings are consistent with both

autoimmune and allergic disorders. Elevations in serum and tissue IgG4 are

nonspecific and can be elevated in a large number of other conditions. Evidence of an

allergic component includes elevated levels of Th2 cytokines in affected tissues and

elevated levels of serum IgE. Affected patients have an increased prevalence of

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allergic rhinitis and bronchial asthma. Among the multiple clinical manifestations

some patients can present with pulmonary nodules.9,10

This patient had history of asthma and on CT scan in 2012, bilateral pulmonary

nodules of less than 5mm were identified. These remained unchanged on a post

surgical CT in 2013. He had a concurrent history of Castleman’s disease but on our

review of the literature we did not find any known association between this condition

and NA.

IgG4 RSD can manifest with lymphadenopathy (Histologic pattern Type I) which can

mimic multicentric Castleman’s disease which is usually associated with the plasma

cell variant 11

. This patient had hyaline vascular variant of Castleman’s disease

therefore a clear correlation could not be established.

The hyaline vascular type is the most common and is often an isolated and benign

lymphoproliferative disorder with a favourable outcome after surgical resection.

There is though, an association with an increased risk of lymphoma and

paraneoplastic pemphigus10

. Unfortunately, this patient did not have IgG4 levels

tested. Despite this case, IgG4 RSD should be considered in any patient found to have

aortitis or periaortitis9,10

.

The optimal management of these patients with no prior disease is still uncertain but

when isolated aortitis is diagnosed, a full workup is warranted12

.

Merkel in 2009 suggested that associated conditions may be found in up to 49% of

patients with incidentally discovered aortitis7. The decision to treat with

glucocorticoid therapy should be made on a case by case basis1,4,5, 8, 10

. Imaging of the

entire aorta for evidence of active disease or aneurysm elsewhere should be

considered. Careful follow up is required given the propensity toward aneurysm

formation in other areas over time4,8,12-14.

Conclusion

We report a case of Castleman’s disease occurring concurrently with adult necrotising

aortitis. This association has not previously been reported. Adult Necrotizing Aortitis

is becoming more recognized as an identifiable factor leading to ascending aorta

aneurysms. Despite the increasing published literature, definite guidance for

management and follow up is still lacking. We suggest a full rheumatologic and

immunologic profile including IGg4, inflammatory markers, referral to a

rheumatologist and ongoing surveillance for further development of aneurysms either

by a Cardiologist or a Cardiovascular Surgeon. Unless a clear indication exists,

routine corticosteroid treatment should not be provided. If Castleman’s disease and

necrotising aortitis are associated conditions is yet to be determined.

Active research is ongoing to identify immunologic and autoimmune conditions

associated with non infectious aortitis as well as to further investigate its

pathogenesis. More studies are necessary to further understand aetiology, determine

treatment and appropriate surveillance of aortitis.

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Figure 1

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Figure 2

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Figure 3a

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Figure 3b

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Figure 4a

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Figure 4b

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Fig 1. Hyaline vascular Castleman’s disease (H&E, original mag x 40).

Fig 2. Preoperative CT Aortogram showing a dilated root and ascending aorta.

Fig 3. (A) Plate-like zone of necrosis surrounded by histiocytes and giant cells.

(H&E, original magnification x100). (B) Same area: zone of necrosis highlighted

nicely by Movat’s pentachrome demonstrating retained elastic laminae which have

collapsed after death of the smooth muscle component. The surrounding pale halo

represents the inflammatory reaction. (Movat’s pentachrome, original magnification x

100)

Fig 4. Detail of the inflammatory infiltrate: histiocytes, lymphocytes, plasma cells

and some giant cells. (A. H&E, B. Movat’s pentachrome, both original magnification

x200)