DOI:10.2214/AJR.07.2193
AJR 2007; 189:1082-1087
© American Roentgen Ray Society
Oncogenic Viruses in AIDS: Mechanisms of Disease and Intrathoracic Manifestations
Judah Burns1,
Rita Shaknovich2,
Jason Lau3 and
Linda B. Haramati1
1 Department of Radiology, Albert Einstein College of Medicine and Montefiore
Medical Center, 111 E 210th St., Bronx, NY 10467.
2 Department of Pathology, Albert Einstein College of Medicine and Montefiore
Medical Center, Bronx, NY.
3 Albert Einstein College of Medicine, Bronx, NY.
Received March 6, 2007;
accepted after revision June 7, 2007.
Presented at the 2006 annual meeting of the American Roentgen Ray Society,
Vancouver, BC, Canada.
Address correspondence to L. B. Haramati
(lharamati{at}aecom.yu.edu).
CME
This article is available for CME credit. See
www.arrs.org
for more information.
Abstract
OBJECTIVE. The objective of this article is to introduce the reader
to the thoracic manifestations of neoplasms that are related to common
oncogenic viruses in HIV-infected patients. We review the pathologic basis of
the infections and illustrate the imaging features of their thoracic
manifestations.
CONCLUSION. The intrathoracic manifestations of oncogenic viral
infection in AIDS patients are protean. Understanding their epidemiologic,
pathologic, and imaging features is crucial to diagnosing and managing these
often-treatable conditions.
Keywords: AIDS • cancer • chest imaging • conventional radiography • CT • lungs • lymphatic system • oncogenic virus
Introduction
Infection and malignancy constitute the bulk of AIDS-related disease
[1]. Although the HIV virus is
not itself oncogenic, HIV infection renders patients vulnerable to developing
malignancies, especially those transmitted by oncogenic viruses. The important
role that infection with oncogenic viruses plays in the development of
malignancy has become well recognized in the past decade. Understanding the
mode of viral transmission sheds light on the epidemiology of these
malignancies.
Three oncogenic viruses are strongly linked to HIV-related malignancy:
human herpesvirus 8 (HHV-8), Epstein-Barr virus, and human papillomavirus
(Table 1). As a rule, the risk
of malignant transformation is related to the degree of host
immunosuppression.
In this article we briefly review the mechanisms of disease and imaging
features of several AIDS-related oncogenic viruses and illustrate their
typical and unusual thoracic imaging manifestations.
Human Herpesvirus 8
Human herpesvirus 8 is the oncogenic virus associated with Kaposi sarcoma
and primary effusion lymphoma, otherwise known as body-cavity lymphoma.
Epidemiologic studies of Kaposi sarcoma, an AIDS-defining illness described
early in the AIDS epidemic, revealed a disproportionate risk of developing
Kaposi sarcoma in a subset of HIV-infected patients, men who had sex with men.
This implicated a cofactor, rather than the HIV virus itself. HHV-8 genomic
fragments were first discovered in Kaposi sarcoma specimens in 1994
[2–4].
The virus was seen in all groups of patients with Kaposi sarcoma, including
those with classic, endemic, and transplantation- and AIDS-related disease,
solidifying the link between HHV-8 and Kaposi sarcoma. In vivo, the prevalence
of Kaposi sarcoma in HHV-8–infected individuals was observed to be
related to the presence and degree of immunosuppression. Thus, HHV-8 infection
was shown to be the causative viral agent associated with the development of
Kaposi sarcoma.
Kaposi sarcoma is a spindle cell neoplasm likely derived from endothelial
cell lineage. Clinically diverse, the various phenotypic manifestations of
Kaposi sarcoma are histologically similar. Classic skin lesions, nodal and
lymphatic involvement, and a variable clinical course typify this illness. In
HIV-infected individuals, altered gene expression is seen in response to an
abnormal cytokine milieu. In particular, the HIV Tat protein has been shown to
stimulate growth of Kaposi sarcoma cells in vitro
[5]. The development of highly
active antiretroviral therapy has influenced the clinical course and reduced
the incidence of Kaposi sarcoma.
Imaging features of Kaposi sarcoma include interstitial (Fig.
1A,
1B,
1C) or nodular
(Fig. 2) parenchymal opacities
[6,
7]. The characteristic
peribronchovascular distribution is best seen on CT (Fig.
3A,
3B), and coalescence of nodules
is common in late-stage disease. Pleural effusion and lymphadenopathy may also
be present. Characteristically, thallium lung scanning is positive, which may
discriminate Kaposi sarcoma from other infectious or inflammatory
conditions.
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Fig. 1A —43-year-old man with HIV presenting with cutaneous Kaposi
sarcoma. Open lung biopsy revealed pulmonary Kaposi sarcoma. Posteroanterior
(A) and lateral (B) chest radiographs show bilateral ill-defined
nodules and areas of confluence with peribronchovascular and lower lobe
predominance.
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Fig. 1B —43-year-old man with HIV presenting with cutaneous Kaposi
sarcoma. Open lung biopsy revealed pulmonary Kaposi sarcoma. Posteroanterior
(A) and lateral (B) chest radiographs show bilateral ill-defined
nodules and areas of confluence with peribronchovascular and lower lobe
predominance.
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Fig. 1C —43-year-old man with HIV presenting with cutaneous Kaposi
sarcoma. Open lung biopsy revealed pulmonary Kaposi sarcoma. Axial chest CT
scan shows findings typical of extensive Kaposi sarcoma, including ill-defined
nodules, some flame-shaped, with areas of confluent consolidation and
peribronchovascular predominance.
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Fig. 2 —33-year-old man with HIV infection, Kaposi sarcoma, and
cough. Axial chest CT scan shows bilateral scattered ill-defined nodules, some
in peribronchovascular distribution. Compared with Figure
1A,
1B,
1C, nodules are more scattered
and less confluent.
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Primary effusion lymphoma is a rare type of lymphoma that is also linked to
HHV-8 infection. More common in end-stage AIDS, this disease reflects
plasmacytic differentiation of transformed B lymphocytes. HHV-8 is universally
present, enabling growth, in part, by autocrine production of interleukin
(IL)-6 and the vascular endothelial growth factor
[8]. This growth is stimulated
by the production of viral homologues to IL-6 and acts to inhibit apoptosis.
Typically, primary effusion lymphoma manifests with widespread serosal
involvement. Pleural, pericardial, and peritoneal involvement result in
pleural and pericardial effusions, ascites, and serosal masses (Fig.
4A,
4B,
4C). Diagnosis requires
serosal–surface biopsy or analysis of the effusion.
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Fig. 4A —38-year-old man with HIV infection, fever, and generalized
lymphadenopathy. Pleural biopsy showed human herpesvirus 8 and Epstein-Barr
virus in lymphoma cells, which is consistent with primary effusion lymphoma.
CT digital radiograph shows extensive right pleural opacity, bilateral hilar
and mediastinal lymphadenopathy, and splenomegaly (arrows).
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Fig. 4B —38-year-old man with HIV infection, fever, and generalized
lymphadenopathy. Pleural biopsy showed human herpesvirus 8 and Epstein-Barr
virus in lymphoma cells, which is consistent with primary effusion lymphoma.
Axial chest CT images show large pleural (arrows, C) and chest
wall mass with associated pleural effusion. Note also pronounced right
axillary lymphadenopathy.
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Fig. 4C —38-year-old man with HIV infection, fever, and generalized
lymphadenopathy. Pleural biopsy showed human herpesvirus 8 and Epstein-Barr
virus in lymphoma cells, which is consistent with primary effusion lymphoma.
Axial chest CT images show large pleural (arrows, C) and chest
wall mass with associated pleural effusion. Note also pronounced right
axillary lymphadenopathy.
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Epstein-Barr Virus
Epstein-Barr virus is ubiquitous in the population and is spread through
the exchange of oral secretions. Epstein-Barr virus is linked to non-Hodgkin's
lymphoma, Hodgkin's lymphoma, spindle cell tumors, and nasopharyngeal
carcinomas.
Non-Hodgkin's lymphomas are an important malignancy among HIV-infected
individuals, developing in 5–10% as an initial or subsequent
AIDS-defining illness [9]. Most
cases of non-Hodgkin's lymphoma are of B-cell origin and are often linked to
Epstein-Barr virus infection
[10]. In HIV-infected
patients, de novo Epstein-Barr virus infection or reactivation of latently
infected memory B lymphocytes results in the two clinical categories of
disease: systemic lymphoma in 80% and primary brain lymphoma in 20%. These
share heterogeneous molecular characteristics typified by neoplastic B-cell
proliferation [11]. This
reflects a multifactorial model of lymphomagenesis. However, although there is
dysregulated humoral immunity, HIV antigens are not those driving B-cell
proliferation.
HIV-associated non-Hodgkin's lymphoma presents most commonly with
extranodal disease [12]. In
the chest, usual features include pulmonary parenchymal nodules and masses and
pleural masses and effusions (Figs.
5A,
5B,
5C and
6A,
6B). Unlike lymphoma in
HIV-negative patients, lymphadenopathy is not usually the dominant imaging
feature. Nevertheless, most HIV-infected patients with intrathoracic
non-Hodgkin's lymphoma do have lymphadenopathy (Fig.
7A,
7B,
7C).
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Fig. 5A —41-year-old man with HIV infection and cough. Percutaneous
biopsy revealed diffuse large B-cell lymphoma. Posteroanterior chest
radiograph shows large mass in right upper and middle lobes.
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Fig. 5B —41-year-old man with HIV infection and cough. Percutaneous
biopsy revealed diffuse large B-cell lymphoma. Axial chest CT scan shows large
mass in right upper lobe and surrounding smaller nodules.
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Fig. 6A —51-year-old woman with lupus and HIV infection who presented
with nonresolving pneumonia. Transbronchial biopsy showed B-cell non-Hodgkin's
lymphoma. Posteroanterior chest radiograph shows bilateral ill-defined
pulmonary nodules and masses that are more prominent on right side.
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Fig. 6B —51-year-old woman with lupus and HIV infection who presented
with nonresolving pneumonia. Transbronchial biopsy showed B-cell non-Hodgkin's
lymphoma. Axial chest CT scan shows bilateral ill-defined pulmonary
nodules.
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Fig. 7A —48-year-old woman with HIV infection who presented with
generalized, palpable lymphadenopathy. Cervical lymph node biopsy showed
diffuse large B-cell lymphoma. Posteroanterior chest radiograph shows
bilateral hilar and mediastinal lymphadenopathy.
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Fig. 7B —48-year-old woman with HIV infection who presented with
generalized, palpable lymphadenopathy. Cervical lymph node biopsy showed
diffuse large B-cell lymphoma. Axial CT scans through mediastinum show
multiple bilateral enlarged lymph nodes.
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Fig. 7C —48-year-old woman with HIV infection who presented with
generalized, palpable lymphadenopathy. Cervical lymph node biopsy showed
diffuse large B-cell lymphoma. Axial CT scans through mediastinum show
multiple bilateral enlarged lymph nodes.
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Hodgkin's lymphoma occurs up to eight times as frequently in HIV-infected
patients as in patients without HIV infection and is strongly linked to
Epstein-Barr virus infection
[13]. The mixed cellularity
and lymphocyte-depleted subtypes are most common. Hodgkin's disease is
generally aggressive in the HIV-infected population, commonly presenting with
widespread illness and an aggressive clinical course.
On imaging, Hodgkin's disease will usually present with lymphadenopathy as
the dominant finding (Fig. 8A,
8B,
8C). However, extranodal
disease is present in most AIDS patients who have Hodgkin's lymphoma.
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Fig. 8A —34-year-old man with long-standing HIV infection and 2-month
history of cough. Transbronchial biopsy was negative. Bone marrow aspirate
revealed Hodgkin's disease. Contrast-enhanced chest CT scans show extensive
right paratracheal, right hilar, and subcarinal lymphadenopathy.
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Fig. 8B —34-year-old man with long-standing HIV infection and 2-month
history of cough. Transbronchial biopsy was negative. Bone marrow aspirate
revealed Hodgkin's disease. Contrast-enhanced chest CT scans show extensive
right paratracheal, right hilar, and subcarinal lymphadenopathy.
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Fig. 8C —34-year-old man with long-standing HIV infection and 2-month
history of cough. Transbronchial biopsy was negative. Bone marrow aspirate
revealed Hodgkin's disease. CT scan at lung window setting shows patchy
parenchymal opacities in right upper lobe.
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Human Papillomavirus
Various subtypes of human papillomavirus cause cervical cancer, anal
cancer, and laryngotracheal papillomatosis
[14].
Thoracic metastases from HIV-associated extrathoracic malignancies must be
recognized and differentiated from infection
[15]. Human
papillomavirus–induced cervical and anal cancers commonly present with
thoracic metastases. Tumorigenesis is promoted through human papillomavirus
oncoprotein E6- and E7-enhanced degradation of native tumor suppressor genes
p53 and RB.
On imaging, metastases from cervical and anal carcinoma may be localized or
widespread (Fig. 9); pulmonary
involvement is not rare and often manifests as nodules or masses. When the
cervical or anal carcinoma is of the squamous subtype, necrosis is common. In
that setting, lung nodules and masses are often cavitary, and lymphadenopathy
is of low attenuation or peripherally enhancing (Fig.
10A,
10B). These imaging findings
overlap with and must be differentiated from tuberculosis and other
mycobacterial or fungal infections.
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Fig. 9 —40-year-old woman with cervical cancer. Anteroposterior chest
radiograph shows multiple micronodular opacities with some confluence in right
upper lobe. Differential diagnosis includes mycobacterial and fungal
infection. Biopsy revealed micronodular metastatic cervical cancer.
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Fig. 10A —53-year-old woman with HIV infection and metastatic cervical
cancer. Axial contrast-enhanced chest CT scan shows low-attenuation, necrotic
subcarinal and bilateral hilar lymphadenopathy. Differential diagnosis
includes other causes of necrotic lymphadenopathy such as tuberculosis.
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Fig. 10B —53-year-old woman with HIV infection and metastatic cervical
cancer. Axial contrast-enhanced CT scan of pelvis shows bulky primary mass
arising from cervix and regional pelvic lymphadenopathy.
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Laryngotracheal papillomatosis is usually contracted during vaginal
delivery through aspiration of vaginal secretions and may also be sexually
transmitted. Although the papillomatous lesions are benign, they may transform
into squamous cell carcinoma.
Imaging features of laryngotracheal papillomatosis include irregular
tracheobronchial nodules that are often numerous. The lesions can spread to
the lung, resulting in lung nodes of varying sizes, often centrally located
and cavitary. Pulmonary papillomas may undergo malignant transformation to
squamous cell carcinoma (Fig.
11A,
11B,
11C,
11D).
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Fig. 11A —45-year-old man with HIV infection and long history of
smoking who presented with persistent cough and difficulty breathing.
Transbronchial biopsy and subsequent left lower lobectomy revealed
tracheobronchial and pulmonary papillomatosis and multiple foci of invasive
squamous cell carcinoma in lung. Posteroanterior chest radiograph shows
multiple subtle irregularities of trachea (black arrows) and
mainstem bronchi. Left lower lobe nodule (white arrow) is
present.
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Fig. 11B —45-year-old man with HIV infection and long history of
smoking who presented with persistent cough and difficulty breathing.
Transbronchial biopsy and subsequent left lower lobectomy revealed
tracheobronchial and pulmonary papillomatosis and multiple foci of invasive
squamous cell carcinoma in lung. Chest CT scans show multiple irregular
tracheobronchial nodules. Parenchymal nodules are also present, some with
cavitation.
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Fig. 11C —45-year-old man with HIV infection and long history of
smoking who presented with persistent cough and difficulty breathing.
Transbronchial biopsy and subsequent left lower lobectomy revealed
tracheobronchial and pulmonary papillomatosis and multiple foci of invasive
squamous cell carcinoma in lung. Chest CT scans show multiple irregular
tracheobronchial nodules. Parenchymal nodules are also present, some with
cavitation.
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Fig. 11D —45-year-old man with HIV infection and long history of
smoking who presented with persistent cough and difficulty breathing.
Transbronchial biopsy and subsequent left lower lobectomy revealed
tracheobronchial and pulmonary papillomatosis and multiple foci of invasive
squamous cell carcinoma in lung. Chest CT scans show multiple irregular
tracheobronchial nodules. Parenchymal nodules are also present, some with
cavitation.
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In conclusion, many HIV-related malignancies are strongly linked to
infection with oncogenic viruses. Familiarity with the mode of transmission
and imaging appearances should lead the radiologist to consider these
neoplasms in the appropriate patient population.
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Abstract
Introduction
