Thoracic Gerald D. Dodd Carl R. Fuhrman,

III, MD MD

Posttransplant Disorder:

#{149} Jocyline

lymphoproliferative

disorder (PTLD) cation of organ immunosuppression.

is a serious transplantation Early

P compliand diagnosis

and

affect

sis.

(n

retrospectively intrathoracic

progno13),

(CT) 20)

from

chest

scans 35 pa-

PTLD were to define the

studied manifestations

of this

disorder.

Intrathoracic

consisted patients),

of pulmonary nodules (16 patchy air-space consolida-

abnormalities

lion (three patients), mediastinal hilar adenopathy (17 patients), mic enlargement (two patients), cardial

(two (four

thickening and/or patients), and pleural

patients).

Multiple,

and thypen-

effusions effusions

well-cir-

with or without mediastinal adenopathy are highly suggestive of PTLD. However, pathologic examination is usually necessary for a definitive diagnosis. cumscribed

Index Kidney, plantation,

Lung, 60.1211 Radiology

pulmonary

terms:

Heart, transplantation, 761.459

transplantation,

‘

nodules

transplantation, 51.459 81.455 #{149} Liver, transLung, nodule, 60.459 60.459 #{149} Lymphoma, CT,

#{149} Transplantation 1992;

MD

immunosuppression jority

and,

of patients,

chonal

lymphoid

identical

ma-

to be in-

hyperplasia

to infectious

to a frank able from

PTLD

nearly

indistinguishlymphoma

is histologically

for other

found

indications.

imperative

we

that

transplant the radiologic

of this disease present the of intrathoracic

patients ap-

process. imaging PTLD

char-

in 35 patients.

MATERIALS

AND

METHODS

Through review of the transplant regisand pathology files at our institution, we identified 35 transplant recipients with proved intrathoracic PTLD. We subsequently reviewed all pertinent imaging try

studies,

medical

reports. patients Twenty

Of these 35 patients, 16 were male and 19 were female patients. patients were younger than age

18 years,

from

and

8 months

records,

15 were

and

adults.

to 66 years

pathologic

Ages

(mean,

ranged

24

autopsy

transplanted

therapy

at the

in

19, and

response

time

to clinical

therapy in six. In those patients in the study without pathologic intrathoracic

PTLD,

all met

criteria: pathologic proof of the thorax in addition intrathoracic

It

radiolo-

of organs

Immunosuppressant

similar to some of the nontransplantrelated lymphomas, it is unique because, if detected early, most cases are completely reversible with administration of antiviral agents and cessation or reduction of immunosuppressants (4-6). However, hike the nontransplant-related lymphomas, if untreated, PTLD is almost always fatal (7). Unfortunately, the clinical signs and symptoms of this disorder are often nonspecific or silent. In practice, many cases are detected radiologically while imaging the trans-

recipient

types

of diagnosis of PTLD varied; 23 patients were treated with cyclosporine (Sandimmune; Sandoz, East Hanover, NJ), and 12 were treated with FK506 (Fujisawa Pharmaceutical, Osaka, Japan), a new macrolide immunosuppressant isolated from Streptomyces tsukubaensis. Twenty of the 23 patients receiving cyclosporine were also receiving prednisone (Deltasone; Upjohn, Kalamazoo, Mich), seven were receiving azathioprine (Imuran; Burroughs-Wellcome, Research Triangle Park, NC), and six were receiving OKT3 (Orthoclone OKT3; Ortho Pharmaceutical, Raritan, NJ). PTLD was proved by means of percutaneous or surgical biopsy in 10 patients,

mononucleosis

lymphoma non-Hodgkin

(3-5). Although

pearance Herein, acteristics

University Hospital, DeSoto at O’Hara Sts, Pittsburgh, PA 15213 (G.D.D., R.L.B., C.R.F.); and Department of Radiology, Children’s Hospital of Pittsburgh, Pittsburgh (J.L.M.). From the 1991 RSNA scientific assembly. Received December 17, 1991; revision requested January 27, 1992; revision received February 10; accepted March 2. Address reprint requests to G.D.D. © RSNA, 1992

in the

is believed

The

included 25 livers, one kidney, four hearts, one lung, and four heart-lung combinations. All patients underwent organ transplantation between 1972 and 1990. Thirtytwo patients were tested for the presence of the Epstein-Barr virus; the virus was present in 19 patients (59%).

duced by the Epstein-Barr virus (2-5). PTLD manifests as a spectrum of lymphoproliferation, from a mild, poly-

is therefore

of Radiology, UniverCenter, Presbyterian

years).

lymphoproliferative disorder (PTLD) is a serious complication of transplantation that affects approximately 2% of organ transplant recipients (1). The disorder occurs as a direct sequeha of chronic

plant

184:65-69

From the Department sity of Pittsburgh Medical

L. Baron,

0STRANSPLANT

gists encountering be familiar with

1

#{149} Richard

MD

Lymphoproliferative Intrathoracic Manifestations’

Posttransplant

treatment greatly Chest radiographs computed tomographic (n = 2), or both (n tients with intrathoracic

Ledesma-Medina,

Radiology

disease,

included proof of

the

following

of PTLD outside to the presumed

intrathoracic

lesions

(lung nodules or mediastinal adenopathy) that responded to PTLD therapy, and no evidence of other concurrent intrathoracic disease as determined with clinical and laboratory

Thirteen ography,

evaluation.

patients two

underwent

underwent

chest

chest

radi-

computed

tomography (CT), and 20 underwent both. We evaluated these studies conjointly for the presence, size and/or extent, and characteristics of pulmonary, pleural, and pencardial disease and for the presence of hilar and mediastinal adenopathy. All images were initially reviewed without knowledge

of the

pathologic

reports.

The

final interpretation of each image was arrived at by consensus of opinion, with differences in opinion resolved by majority rule. In patients with pathologic proof of intrathoracic PTLD, the radiologic inter-

Abbreviation: phoproliferative

PTLD

=

posttransplant

lym-

disorder.

65

pretations the

were

carefully

pathology

imaging with

the

described

pathologic Furthermore,

patients

development eases,

are

images

of PTLD

only

corresponded lesions

were

because to rapid

pulmonary

dis-

within

1 week

obtained

diagnosis

that

susceptible

of multiple

only

of the

that

to PTLD.

transplant

with

to ensure

abnormalities

ascribed

the

correlated

reports

were

included

in

study.

In addition separate

to the above

analysis

pathologic

of the

results

nations

was

radiologic

from

evaluation,

radiologic

19 autopsy

performed

a and

exami-

to determine

sensitivity

for the detection

the

1.

of

Figures 1, 2. (1) CT scan shows multiple, diffuse, caused by FTLD. (2) CT scan shows 3-cm-diameter the right lower lobe enveloped by consolidative gestive of necrosis.

PTLD.

RESULTS Clinical

well-circumscribed pulmonary nodules PTLD nodule of low attenuation (arrow) PTLD. The attenuation of the nodule is sug-

in

Findings

The time from transplantation to diagnosis of PTLD varied from 1 month to 13 years (mean, 1.6 years), with 24 of 35 tumors (69%) occurring within 1 year. The earliest tumor in a child occurred 1 month after transplantation versus 2 months in an adult. There was a higher prevalence of early onset of PTLD in the pediatric group, with seven of the 20 pediatric patients (35%) developing tumor within 90 days of transplantation versus three of the 15 adult patients (20%). However, within 1 year after transplantation, 12 of the 15 adults (80%) and 12 of the 20 pediatric patients (60%) developed PTLD. Thus,

PTLD

2.

occurred

both

earlier

and

later

in pediatric patients than in adults. There was no substantial difference the time to onset of PTLD between the different types of immunosuppressive agents.

Radiologic Of the

in

Findings 35 patients

trathoracic abnormalities

with

proved

PTLD, 28 demonstrated attributable to PTLD

chest radiography normahities were lung parenchyma astinal and hilar

inat

or CT. These abidentified within the (17 patients), medilymph nodes (17 pa-

tients), thymus (two patients), pericardium (two patients), and pleura (four patients). Pulmonary lesions appeared as discrete nodules in 16 patients and as patchy air-space consolidation in three (two patients exhibited both processes simultaneously). Thirteen patients had multiple nodules, and three had solitary nodules. Most nodules were relatively well circumscribed, measured from 3 mm to 5 cm (average, 2 cm) in diameter, and had the same homogenous attenuation as that of soft tissue (Fig 1). Three exceptions included one 5-cm-diameter

66 #{149} Radiology

a. Figure 3. Radiograph of right lower hemithorax shows a very unusual manifestalion of PTLD, a 3-cm PTLD nodule with central cavitation. This was seen in only one patient. Cavitation occurred 2 weeks after the reduction of immunosuppressants.

nodule with a poorly circumscribed margin, one 3-cm nodule (enveloped by consohidative PTLD) of low attenuation suggestive of necrosis (Fig 2), and one 3-cm nodule that developed central cavitation after reduction of immunosuppressants (Fig 3). The distribution of nodules was random throughout all pulmonary segments. Growth of nodules was usually slowly progressive before therapy. However, in at least one patient, a rapid progression in the size and number of the nodules occurred in less than 2 weeks. Likewise, nodule regression after therapy, although usually slow with most nodules gone in 2 months, occurred rapidly in one patient, whose multiple 1-cm nodules completely resolved in 2 weeks. The PTLD that occurred as patchy air-space consolidation in three patients appeared as nonspecific mild to moderately dense consolidation randomly scattered throughout the lungs

b. Figure 4. (a) Radiograph shows bilateral patchy air-space consolidation in a patient with diffuse alveolar PTLD. Note the peribronchial

cuffing

(b) CT scan obtained consolidative bronchograms.

right

and

air bronchograms.

in same upper

lobe

patient PTLD

shows with

air

(Fig 4). Peribronchiah cuffing was present in all three cases at CT and radiography, whereas air bronchograms were present in two. Two patients showed combined nodular and consolidative processes. In one, both processes occurred concomitantly. In the other, areas of patchy consohidation appeared first, then coalesced over a 2-week period into large, discrete nodules. Of note, although the pathologic examination in these paJuly

1992

6. Figures

scan

5, 6.

shows

diastinal

(5) CT scan

severe

shows

mediastinal

adenopathy

typical

mild

adenopathy

identified

in our

mediastinal

due

adenopathy

to PTLD.

This was

due

to PTLD.

the most

severe

(6) CT

Figure 7. Radiograph eral hilar adenopathy

case of me-

shows marked due to PTLD.

bilat-

series.

sions.

Pathologically

proved

pleural

PTLD was present microscopically in pleural tissue or fluid in four patients, with all exhibiting uni- or bilateral, small to moderate-sized pleural effusions.

All effusions

were

with both modalities, pleural abnormalities Autopsy

tients. calhy Figure

9.

CT scan

tenuation replacement suggestive

nodal

shows

enlarged,

low-at-

thymus (arrows) resulting from by PTLD. The low attenuation of necrosis.

sites

propensity

were for

involved,

there

selective

b. Figure

8.

show

large

(a) Radiograph

superior

Note lateral images and

ment

displacement encasement

of subclavian

tients

clearly

and

(b) CT scan

mediastinal

PTLD

of trachea rather than

mass.

on both displace-

vein on the CT scan.

helped

identify

diffuse

PTLD distending alveoli, the exact radiologic extent of consolidative PTLD was difficult to assess because of other

concomitant

pulmonary

dis-

of adenopathy.

Involved

nodes

usually had the same homogeneous attenuation as that of soft tissue, were multiple, and averaged 2 cm in diameter (range, 1.0-4.5 cm) (Figs 5-7). Although all mediastinal and hilar Volume

184

#{149} Number

1

masses

(4.0

a

mediastinodes. Sol-

and

7.5 cm

in

diameter, respectively) were present in two patients. These large masses were located in the superior mediastinum and paravertebral regions and tended to envelope rather than displace adjacent vessels (Fig 8). Small regions

of low

attenuation

consistent

with minimal necrosis were visible within the masses. There was no evidence of visible necrosis within any of the other adenopathies. Other sites of pathologically identifled mediastinal PTLD included the thymus

ease (Pneumocystis carinii, bronchiolitis obliterans organizing pneumonia, or bronchopneumonia). Mediastinal PTLD consisted primarily

nodal

was

involvement

of the paratracheal, anterior nal, and aortic-pulmonary itary

is

(three

patients)

and

the

peri-

cardium (seven patients). Thymic involvement was radiologically visible in two of the three patients with pathologically proved thymic PTLD. Both cases exhibited diffuse thymic enlargement without a focal mass. One thymus was of low attenuation, suggestive of necrosis (Fig 9). Pericardial involvement, radiologically visible tients with pericardial

in two of the pathologically PTLD, appeared

pericardiah

thickening

seven paproved as diffuse

and/or

effu-

was

PTLD

performed

was

in both

documented

and no other were seen. in 19 pa-

present

the

lungs

pathologiand

mediasti-

nal lymph nodes in 14 of the 19 patients (74%), in only the lungs in one patient (5%), and in only the mediastinal lymph nodes in four patients (21%). The overall radiologic (chest radiography and CT) detection rate for PTLD was 58% for all intrathoracic tumor, 20% for pulmonary parenchy-

mal

tumor,

lymph

Chest identify 89% tients

and

node

for mediastinal

radiography 42%

(eight with

(three

53%

tumor.

and

of 15 patients)

of nine monary

CT helped

(eight of 19 patients) and of nine patients) of paintrathoracic tumor, 20%

patients) tumor,

and

33%

(three

of patients with puland 44% (eight of 18

patients) and 89% (eight of nine tients) of patients with mediastinal lymph

node

tumor,

pa-

respectively.

In the patients in whom pulmonary PTLD was missed at radiography and CT, the tumor was microscopic and located in the interstitial and peribronchial tissues. In the one patient in whom mediastinal lymph node PTLD was

missed

croscopic enlargement.

at CT,

and

distribution

between groups ences.

the

tumor

did not cause A comparison and

was

appearance

of tumor

the adult and pediatric revealed no substantial Likewise,

there

ence in the distribution of tumor in the different transplants. Non-PTLD pulmonary present concomitantly

mi-

nodal of the

was

no

differdiffer-

or appearance types of or-

gan

disease was in 10 of the 35 Radiology

#{149} 67

patients (29%). One patient had tary ( < 1 cm) pulmonary nodule

a soli-

due to cryptococcus. The remaining nine patients had patchy air-space disease caused by bronchiohitis obhiterans or-

ganizing

pneumonia,

cytomegalovi-

rus, bronchopneumonia, or atelectasis. There was no case of mediastinal adenopathy due to non-PTLD abnor-

tion

or ablation

The

success

recipients

was

first

of hymtransplant

reported

by Penn

In particular,

it appears

with

a more

monoor

advanced

form

of

at diagnosis. The best to therapy is achieved in

patients

in whom

diagnosed

and

Therefore,

early

disease

treated

early

detection

of PTLD

is

aging appearance of intrathoracic PTLD (9-12). The cumulative experience of these articles describes pulmo-

astinal

identified

pathology

and

importance.

has been reported any body tissue,

nary PTLD as solitary crete nodules ranging cm in diameter. The

lated to the patient’s immunocompromised state and limited ability to suppress neoplastic cellular activity (4,5). A strong association has also been

PTLD

PTLD

the presence thy. Although racic PTLD

the Ep-

are

to involve with the

or multiple disfrom 5 mm to 5 reports of medi-

limited

surgery

literature,

had

a sensitive The

or without adenopathy.

that

lymphoprohiferation

is held

by the immune system. the immunocompromised

lymphoproliferation trolled. Most cases hieved to begin phoproliferation

more aggressive velop (4,5). PTLD is unique occurring is often

with

in check

However, patient,

in the

forms

of PTLD

from

de-

have

transplantation

not

because

without

chemotherapy.

use

it

of con-

Current

of PTLD is directed at fightviral infection with antiviral restoring immunocompetence

reduction

or complete

of immunosuppressive cases of large tumors, 68 #{149} Radiology

agents, surgical

cessation and, resec-

nod-

is better

visual-

both

pulmo-

mediastinah in transplant to other

(eg, cryptococcus, sarcoma), in our found

PTLD

cause

of these

the

imaging

or most

ab-

in

racic tumor necrosis was present in this series. Thus, even though one of our patients had a necrotic pulmonary nodule, we consider visible necrosis in a pulmonary nodule more suggestive of an inflammatory process than of PTLD. A less common and previously unreported manifestation of pulmonary

to be

marker

of pleural

with PTLD

for

effusions

PTLD is uncertain. can cause pleural

ef-

effusions from causes are other evidence is present, the

of a pleural

effusion

in a

patient must be treated finding. It is reassuring

no patient

in this

pleural

effusion

isolated

series

as

had

as the

an only

radiohogic

manifestation

Although festations

several radiologic maniof intrathoracic PTLD are

suggestive specific.

diagnosis abnor-

fungus, experience, to be

transplant a nonspecific

highly entirely

ade-

normalities. However, unlike abdominal PTLD, which has a high prevahence of tumor necrosis (4,5,9), very little radiologic evidence of intratho-

lymphomas

who

have

common

comradio-

at CT. PTLD in

enlargement

infrequent

fusions, benign pleural a variety of non-PTLD more common. Unless of intrathoracic PTLD

visualized with and CT,

CT. Although

nary nodules and nopathy can occur recipients secondary

we

most

mediastinal cases, these

adenopathy

with

mahities Kaposi

as a benign lymfrom which the

reversible

treatment ing the agents,

ized

concomitant In most

are equally well chest radiography

whereas

proceeds unconof PTLD are be-

in patients

undergone ventional

ules both

and extranodal polymorlymphoprohiferation. In competent patient, the

the appreciated

thymic

importance

in patients Although

identification

readily

adenopathy

was visible of thymic

PTLD.

logic appearance of intrathoracic PTLD is multiple or solitary, well-arcumscribed pulmonary nodules with

and

experience,

mediastinal

but

and

fuse intraphic B-cell the immune

no

is

our patients was minimal. However, as a result of a low frequency of other causes of rapid enlargement of the thymus in the transplant recipient,

with

ment of Burkitt lymphoma (4,5). In patients with competent and incompetent immune systems, infection with Epstein-Barr virus induces a dif-

been

imaging

(4,5,12).

In our mon

in the

pul-

at autopsy

If it occurs in paadvanced disease, it

due to PTLD that The prevalence

associated

literature

sites

have

topsy

population

of such

identified

would preclude (in the absence of other visible tumor) the radiologic exclusion of intrathoracic PTLD. Fortunatehy, all but one patient who had microscopic pulmonary tumor at au-

strongly

develop-

there

to

of radiohogimicroscopic

also bothersome. tients with less

general

reports

prevalence

PTLD

our

the

knowledge,

high

undetectable

we consider

to describing

or absence of adenopaother sites of intrathohave been reported in the

and

all other

stein-Barr virus, with up to 80% of patients with PTLD infected with the virus at the time of tumor diagnosis (2-5). This same virus is known to cause infectious mononucleosis in the

has been

is

perimpos-

can only be suggested after causes have been excluded.

monary

(4,5).

to a frankly malignant monoclonal non-Hodgkin lymphoma (3-5). Although most PTLD is of B-cell lymphocyte origin, up to 11% may arise from T-cell lymphocytes (1).

between

consolidaof PTLD

this patof PTLD

cally

most common sites being the tonsils, cervical neck nodes, gastrointestinal tract, and thorax (4,5,9). To date, there have been few articles about the im-

re-

air-space

appearance

recipients. In patients with tern of disease, the diagnosis

The

was

patients represents a spectrum of lymphoproliferation (PTLD), from benign polyclonal B-cell hyperplasia identical to infectious mononucleosis

are directly

of paramount

the

PTLD virtually

of PTLD

This

sible to differentiate from the more common pulmonary complications such as edema, infection, and rejeclion often encountered in transplant

et al (8) in 1969. Since then, additional research has shown that the hymphomatous process occurring in these

All types

is patchy

tion.

complete resolution of the lymphoprohiferative process (4-6). Unfortunately, this therapy is not effective

the disease response

prevalence in organ

of ther-

bothersome from a diagnostic spective because it is virtually

in all patients.

DISCUSSION

PTLD

mass.

form

apy has been good, with approximately 63% of patients experiencing

those

increased occurring

tumor

for this

least effective in patients with morphic monoclonal lymphoma

malities.

An phoma

of the

rate

of PTLD.

of PTLD, Therefore,

of PTLD

none are definitive

requires

pathologic

examination. Percutaneous biopsy with both fine-needle aspiration or needle-core techniques is usually adequate for diagnosis in most cases of extranodal tumor. Nodal tumors, however, nose and opsy.

are more difficult to diagoften require surgical bi-

Although both bronchoalveolar vage and transbronchiah biopsy alternative

techniques

diagnostic

tissue

for

samples,

laare

obtaining

they

have

not played a major role in the treatment of our patients. In some patients with intrathoracic lesions suspicious

for PTLD, may

diagnostic

be preferentially

extrathoracic

tumor

tissue

samples

obtained

sites

such

from

as cerJuly 1992

vical adenopathy or enlarged tonsils. If the extrathoracic tissue sample is diagnostic of PTLD, biopsy of the intrathoracic lesions can be forgone unless the intrathoracic lesions fail to respond to PTLD therapy.

In summary,

intrathoracic

PTLD

3.

4.

can exhibit a spectrum of radiologic findings that may be first identified

while imaging the chest of the organ transplant recipient for other indications. Radiologists who are aware of these may

findings dramatically

and prognosis early diagnosis

and

their affect

importance patient care

5.

6.

disorders in renal transplant recipients and evidence for the role of Epstein-Barr virus. Cancer Res 1981; 41:4253-4261. List AF, Greco FA, Vogler LB. Lymphoproliferative diseases in immunocompromised hosts: the role of Epstein-Barr virus. J Clin Oncol 1987; 5:1673-1689. Nalesnik MA,Jaffe R, Starzl TE, et al. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pathol 1988; 133:173-192. Nalesnik MA, Makowka L, Starzl TE. The diagnosis and treatment of posttransplant lymphoproliferative disorders. Curr Probl Surg 1988; 25:367-472. Makowka L, Nalesnik, Stieber A, et al.

Control

in this disease in which is critical. #{149}

References

2.

Penn I. Cancers complicating organ transplantation (editorial). N EnglJ Med 1990; 323:1767-1768. Hanto DW, Frizzera G, Purtilo DT, et al. Clinical spectrum of lymphoproliferative

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W, Brettschneider

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Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc 1969; 9.

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#{149} 69