clinico-pathologic conferences
Tracheal Epstein-Barr virus-associated smooth muscle
tumour in an HIV-positive patient
Giulio S Dominelli MD FRCPC1, Rachel Jen MD FRCPC1,
Kirily Park MD PhD FRCPC2, Tawimas Shaipanich MD FRCPC1
GS Dominelli, R Jen, K Park, T Shaipanich. Tracheal Epstein-Barr
virus-associated smooth muscle tumour in an HIV-positive patient.
Can Respir J 2014;21(6):334-336.
Epstein-Barr virus-related smooth muscle tumours (EBV-SMTs) are a rare
but well recognized non-AIDS-defining malignancy that can also be found
in several other immunosuppressed states. Pulmonary involvement of EBVSMTs is not uncommon, but it can present with multifocal lesions in any
anatomical site. The present article describes an HIV-positive woman with
dyspnea who was found to have a large tracheal EBV-SMT. The authors
discuss their approach to diagnosis and management, and present unique
follow-up bronchoscopic imaging.
Une tumeur du muscle lisse de la trachée associée
au virus d’Epstein-Barr chez une patiente positive
au VIH
Les tumeurs des muscles lisses associées au virus d’Epstein-Barr (TML-VEB)
sont des cancers non définis par le sida qui sont rares, mais bien connus. On
peut les observer dans plusieurs autres états d’immunosuppression. L’atteinte
pulmonaire des TML-VEB n’est pas inhabituelle, mais peut présenter des
lésions multifocales dans tout foyer anatomique. Le présent article décrit une
femme positive au VIH faisant de la dyspnée en raison d’une grosse TMLVEB de la trachée. Les auteurs présentent leur approche du diagnostic et de
la prise en charge ainsi qu’une imagerie unique du suivi bronchoscopique.
Key Words: Epstein-Barr virus; HIV; Intervention bronchoscopy; Tracheal tumour
Learning objectives
• To learn which immunosuppressed states place patients at risk for Epstein-Barr virus-related smooth muscle tumours (EBV-SMTs).
• To develop a differential diagnosis for pulmonary malignancy in
HIV patients.
Can Meds Competency: Medical Expert
Pretest
• What are the common malignant pulmonary manifestations
of HIV?
• What immunosuppressed states can be associated with
EBV-SMT?
Case presentation
A 38-year-old woman was referred to her respirologist for evaluation of
a two-month history of worsening exertional dyspnea. She had been
seen by otolaryngology several months earlier for a right tonsilar mass
and an incidental tracheal lesion 8 mm in size. The tonsil was biopsied,
with pathology showing benign features that were managed conservatively. Unfortunately, she was lost to follow-up. Her current presentation was associated with a productive cough, occasional dysphagia and
scant hemoptysis. Although there were no associated fever or chills, the
patient reported a 4.5 kg weight loss over the previous two months.
There were remote tuberculosis contacts, although work-up at that
time proved negative. Her medical history was significant for HIV
diagnosed six years previously. There was no history of AIDS-defining
illness or previous opportunistic infections. She was not currently on
antiretroviral therapy (CD4 count 2.20×109/L). Other comorbidities
included hepatitis C and a remote 10 pack-year smoking history.
Physical examination in the seated position revealed a respiratory
rate of 16 breaths/min and oxygen saturation of 96%. There was good
air entry bilaterally, with no stridor, wheeze or other adventious
sounds. However, when supine, there was significant cough, associated
with the development of loud stridor and a minor oxygen saturation
drop to 92%. Head and neck examination revealed an enlarged right
Figure 1) Computed tomography scan with representative axial images
showing the 1.5 cm polypoid tracheal tumour and left upper lobe nodule
tonsil and no palpable cervical lymph nodes. The remainder of the
cardiovascular and abdominal examination was unremarkable.
Given the concern for airway obstruction, a computed tomography
(CT) scan of the neck, chest and abdomen was performed (Figure 1).
Compared with a scan performed several months earlier, there was
significant interval increase in the polypoid tracheal mass from 8 mm
to 1.5 cm in diameter, an increase in the right tonsil mass to 1.1 cm
and a left upper lobe nodule measuring 11 mm. Flexible bronchoscopy
was performed in an intensive care unit setting. It revealed a nearobstructing lesion with no distal central airway narrowing or lesions
(Figure 2A). Given its size and location, the decision was made to
resect via rigid bronchoscopy in the operating room. The tracheal
tumour was successfully removed via rigid bronchoscopy using loop
electrocautery and retrievable basket through a flexible bronchoscope.
The patient tolerated the procedure well and examination of the
distal airways following removal showed no abnormalities. Pathology
from the resection demonstrated a well-circumscribed mass composed of tightly packed fascicles of mildly atypical short spindle cells
with numerous mitotic figures (up to 20 mitoses per 10 high-power
fields). There was no necrosis present and lymphocytes were scattered
throughout the tumour. According to immunohistochemistry, the
tumour was strongly positive for smooth muscle actin and myosin and
was negative for desmin, keratin, p63, S100, CD34, human herpesvirus 8 and epithelial membrane antigen. The CD45 stain was negative in tumour cells, but highlighted the interspersed lymphocytes.
1Department
of Medicine, Respiratory Division, University of British Columbia, Vancouver; 2Department of Medicine, Nanaimo Regional General
Hospital, Nanaimo, British Columbia
Correspondence: Dr Giulio S Dominelli, Pacific Lung Health Centre, St Paul’s Hospital, 8B Providence Wing, 1081 Burrard Street, Vancouver,
British Columbia V6Z 1Y6. Telephone 604-806-8818, fax 604-806-8839, e-mail dominell@alumni.ubc.ca
334
©2014 Pulsus Group Inc. All rights reserved
Can Respir J Vol 21 No 6 November/December 2014
Tracheal EBV-SMT in an HIV-positive patient
A
B
Figure 2) A Image from flexible bronchoscopy showing near-obstructing
tracheal lesion. B Image of interval follow-up postresection
The stain for Epstein-Barr virus-encoded RNA in-situ hybridization
showed positive staining for nuclei of most of the spindle cells. The
negative CD34 and human herpesvirus 8 excluded Kaposi’s sarcoma.
This pathology was compatible with an EBV-SMT (Figure 3). The
patient subsequently underwent a repeat biopsy and right tonsillectomy.
Pathology demonstrated the same EBV-SMT observed in the trachea,
1.7 cm in size with clean margins.
Medical oncology was consulted for considering adjuvant chemotherapy or radiation. Due to multifocal disease, the recommendation
was to treat with antiretroviral therapy at the present time. Because
the resection margin of the tumour was positive, follow-up bronchoscopy was performed at four weeks. Flexible bronchoscopy showed no
significant intraluminal narrowing (Figure 2B). An optical coherence
tomography (OCT) study revealed disruption of epithelium and thickening of basement membrane layers, but an intact cartilage ring at the
resection site (Figure 4). These findings were suggestive of fibrotic
tissue from previous electrocautery treatment and no further invasion
of the tumour beyond the cartilage ring. A repeat biopsy at time of this
particular OCT bronchoscopy confirmed the OCT finding and
showed no residual tumour at the tracheal resection site at the fourweek interval. The left upper nodule was not biopsied and assumed to
be an additionanl site of EBV-SMT. A six-month follow-up CT scan
showed a decrease in size from 11 mm to 9 mm. The patient is now
asymptomatic, but continued surveillance will be critical because
EBV-SMTs tend to be multifocal and recur.
Discussion
EBV-SMTs are a well-recognized malignancy associated with HIV and
other immunocompromised states such as post-transplant, common
variable immunodeficiency, glucocorticoid and tumour necrosis factor inhibitor administration (1-4). Typical histology consists of welldifferentiated smooth muscle cells with cigar-shaped nuclei, a low
level of mitotic activity and positive stains for smooth muscle actin
and Epstein-Barr virus (EBV) encoding RNA (5). The exact pathogenesis remains under investigation, but appears to be related to neoplastic transformation and clonal expansion of smooth muscle cells by
EBV infection (4). Whether this occurs via CD21 upregulation or
fusion of EBV-superinfected lymphoblastoid cells is unclear (3).
EBV-SMT in HIV can occur at any anatomical site and tend to be
multifocal in nature in contrast to the solitary lesions observed in
immunocompetent individuals. However, the multiple tumours are
believed to be multifocal disease and not truly metastases because
tumours do not share the same clonal origin (4). A recent review by
Purgina et al (4) demonstrated the lung to be the third most common
site, behind central nervous system and soft tissue. With pulmonary
involvement, EBV-SMTs can present with a variety of symptoms
depending on size and anatomical location. New-onset stridor, recurrent atelectasis or postobstructive pneumonia should trigger consideration of an endobronchial lesion. In addition to the present report, there
exists a very small number of case reports documenting primary endobronchial involvement in adult patients (1,6,7). Other patients have
presented with hemoptysis, dyspnea, wheeze or incidental nodules on
CT scan. On bronchoscopy, EBV-SMT appear as white polypoid lesions
Can Respir J Vol 21 No 6 November/December 2014
Figure 3) A Hematoxylin and eosin stain showing spindle-shaped smooth
muscle cells. B Positive stain for smooth muscle myosin. C Positive stain for
smooth muscle actin. D Positive Epstein-Barr virus-encoded RNA in-situ
hybridization. Original magnification ×100–200
A
B
Figure 4) Optimal coherence tomogaphy images from follow-up bronchoscopy. A Normal trachea. B Postresection. The trachea show subepithelial
connective tissue abnormalities, likely fibrotic tissue due to electrocautery
attached to the bronchi or trachea. The differential diagnosis of an
endobronchial lesion in an HIV-positive patient should include both
neoplastic (Kaposi’s sarcoma, adenoid cystic carcinoma, carcinoid, nonHodgkins lymphoma, primary lung malignancy) and non-neoplastic
causes (mycobacteriosis, foreign body, inflammatory polyp) (6).
The outcomes of HIV EBV-SMT are quite variable and cannot be
accurately predicted from tumour histology (5). Reports show only a
small subset (6%) of HIV EBV-SMT patients dying as a result of the
tumour. Surgical resection is the mainstay of treatment in these
patients, but is often limited by the anatomical location and multifocal
nature of the disease. Endobronchial lesions can be removed via loop
cautery or laser resection (1). Detailed planning for the resection of
these tumours is critical given the concerns over airway stability and
bleeding. The data regarding ancillary therapy, including antiretroviral
therapy and chemotherapy, are minimal. There have been reported
successes using antiretroviral therapy. These tumours appear to be
resistant to conventional cytotoxins (4).
OCT is an optical imaging method that can offer real-time nearhistological resolution for visualizing cellular and extracellular structures at and below the tissue surface. OCT is similar in concept to
ultrasound, except light waves instead of sound waves are used for
imaging. The OCT device (Lightlabs C7XR, St Jude Medical Inc,
USA) used in the present study has an axial resolution of 12 µm to
15 µm and an imaging range of up to 5 mm in diameter. Previous studies have shown the ability of OCT to reliably differentiate in vitro
benign, inflammatory and neoplastic bronchial tissue (8). However,
the clinical role of OCT remains under investigation, but shows promise in areas of detection and therapy for early central lung cancers and
335
Dominelli et al
tracheal stenosis. To our knowledge, the present report is the first to
describe OCT as part of postresection surveillance for EBV-SMT. The
noninvasive nature and real-time ability of this technology makes it
ideal for future research in the area of postresection surveillance.
Post-test
• What are the common malignant pulmonary manifestations of
HIV?
EBV-SMT are a rare malignant complication of HIV infection. The
more frequent malignant manifestations that one should consider
are: Kaposi’s sarcoma, lymphoma, bronchogenic carcinoma and
metastasis (9). Both Kaposi’s and non-Hodgkin’s lymphoma are
considered to be AIDS-defining malignancies (9).
• What immunosuppressed states can be associated with
EBV-SMT?
Case reports have identified EBV-SMT related to several immunosuppressed states. These include, but are not limited to: HIV/AIDS,
post-transplant, common variable immunodeficiency, glucocorticoid and tumour necrosis factor inhibitor administration (2-4).
Acknowledgements: GSD, RJ, KP and TS identified the case,
managed the patient and contributed to the writing and editing of the
manuscript. The authors thank Dr H Masoudi for providing the histopathology images.
336
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