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Lymphadenopathy cough and fever in a 51-year-old woman with systemic lupus erythematosuscase report of lymphomatoid granulomatosis.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 53, No. 4, August 15, 2005, pp 621– 624
DOI 10.1002/art.21310
© 2005, American College of Rheumatology
Lymphadenopathy, Cough, and Fever in a
51-Year-Old Woman With Systemic Lupus
Erythematosus: Case Report of Lymphomatoid
Lymphomatoid granulomatosis is a rare, often fatal lymphoproliferative disease that is most common in immunosuppressed patients such as those with acquired immunodeficiency syndrome, organ transplant, or Wiskott-Aldrich
syndrome. It has been described in patients with a variety
of autoimmune disorders including Sjögren’s syndrome
(1), ulcerative colitis, rheumatoid arthritis (2), Crohn’s disease, Hashimoto thyroiditis, and juvenile rheumatoid arthritis (3). This report is the first to describe lymphomatoid
granulomatosis in a patient with systemic lupus erythematosus (SLE).
Case Report
The patient, a 51-year-old African American woman with
a 36-year history of SLE presented to our rheumatology
clinic with the symptom of cough. When the patient was a
teenager, lupus was diagnosed, in the setting of Raynaud’s
syndrome, arthritis, and cutaneous symptoms. She had a
baseline antinuclear antibody titer of 1:640, negative anti-Ro and anti-La antibodies, and negative anti– doublestranded DNA antibodies. Over the course of the patient’s
disease, calcinosis universalis developed, which was complicated by multiple episodes of cellulitis requiring operative treatment and skin grafting. Otherwise, the patient’s
lupus was well-controlled while she received long-term
therapy with low-dose steroids. She had no history of
major pulmonary infection, pneumonitis, or tobacco use.
The patient presented with a 4-month history of morn1
Lauren A. Beste, BS: Johns Hopkins University School of
Medicine, Baltimore, Maryland; 2Ali Ansari-Lari, MD, Michael Borowitz, MD, PhD, John A. Flynn, MD, MBA: Johns
Hopkins Hospital, Baltimore, Maryland.
Address correspondence to John A. Flynn, MD, MBA,
Department of Medicine, Johns Hopkins University, 601
North Caroline Street #7143, Baltimore, MD 21287. E-mail:
Submitted for publication April 23, 2004; accepted in
revised form December 4, 2004.
Figure 1. Thoracic computed tomography showing enlarged mediastinal nodes measuring ⬃ 1.0 cm. Patchy areas of nodular consolidation are present in all lobes, with the largest consolidation measuring 3.8 cm in the right lower lobe and 1.5 cm in the left lower lobe.
ing cough. Physical examination revealed bibasilar crackles, and chest examination demonstrated a nontender,
nonfluctuant, mobile lymph node in her left submandibu621
Beste et al
Figure 2. Lymphomatoid granulomatosis involving lung. A, Hemotoxylin and eosin–stained section of a tumor nodule
showing atypical lymphoid infiltrate (original magnification ⫻ 50). B, At a higher magnification (400 ⫻), many
lymphocytes appear large, with prominent nucleoli. There are scattered small mature lymphocytes in the background.
The infiltrate also showed angiocentricity with angiodestructiveness. C, Immunohistochemical stain for CD20 highlights numerous B cells. There were scattered CD3-positive T cells in the background (not shown). D, In situ
hybridization for Epstein-Barr virus (EBER) shows positive cells.
lar area measuring 3.0 ⫻ 2.0 cm. Pulmonary evaluation
included a chest radiograph, which showed interstitial
fibrosis without adenopathy, and pulmonary function
tests, which showed a mild restrictive ventilatory defect
with a moderate gas transfer defect. Due to periodontal
disease, the patient was started on cefazolin, which resulted in initial improvement of adenopathy. This submandibular adenopathy recurred after several weeks, with
development of supraclavicular and axillary lymphadenopathy. The patient’s cough continued, although she denied having chest pain or dyspnea on exertion. Thoracic
computed tomography showed axillary, mediastinal, and
pretracheal adenopathy, with lung nodules up to 2.7 cm in
diameter against a background of fine interstitial inflammation (Figure 1). Autoimmune serologies were unchanged, with negative antineutrophil cytoplasmic antibodies and normal complement levels. Test results for
human immunodeficiency virus, blastomycosis antigen,
histoplasma antigen, mycoplasma antigen, cytomegalovirus antigen, and tuberculosis were negative.
Fine-needle aspiration of a supraclavicular node demonstrated reactive hyperplasia. Excisional biopsy of the
right axillary node was nondiagnostic. Given the nondiagnostic biopsy results, the adenopathy was believed to be
related to the patient’s lupus, and she was started on an
empirical trial of 20 mg of prednisone daily, which led to
dramatic improvement of adenopathy and resolution of
cough and fevers.
Within 3 months the nodes had regained their bulk in
the setting of steroid tapering. Repeat pulmonary function
testing showed progression of restrictive lung disease.
Spiking fevers developed, and the patient was admitted for
further evaluation. Chest and abdominal computed tomography showed small pericardial effusion, enlarged periaortic and celiac nodes, a prominent spleen with small calcifications, and bilaterally enlarged kidneys. Bronchial
alveolar lavage with transbronchial biopsy was nondiagnostic, with negative stains for acid-fast bacilli and fungi.
The bone marrow aspirate was unremarkable. Renal biopsy revealed tubular atrophy and neutrophilic infiltrate,
necrotic glomeruli, and interstitial fibrosis without evidence of glomerulonephritis. Internal fibrosis of interlobular-sized arteries was noted. The patient underwent open
lung biopsy, with pathology showing angiocentric T cell–
rich B cell lymphoma with positive in situ hybridization
for Epstein-Barr virus (EBV) (Figure 2). Stains for acid-fast
bacilli, fungi, and bacteria were negative. A diagnosis of
lymphomatoid granulomatosis was made.
A treatment protocol with interferon ␣-2b was initiated
and the patient reported an improved energy level, less
Lymphomatoid Granulomatosis in a 51-Year Old Woman With SLE
Figure 3. Lymphomatoid granulomatosis involving the lung and
kidney. A, Right lower lobe of the lung, showing multiple nodules
of tumor with necrosis, ranging in size from 0.2–3.0 cm. B, Right
kidney, showing multiple nodules of necrotic tumor involving the
cortex and medulla. The largest nodule measured 5.0 cm in its
greatest dimension.
dyspnea on exertion, and a 6 –7 pound weight gain. Approximately 1 month after the initiation of chemotherapy,
she was readmitted because of fever, acute renal failure,
increasing respiratory insufficiency with bilateral lung infiltrates, and hypotension requiring mechanical ventilation and vasopressors. After initial stabilization, she was
started on a cycle of rituximab plus etoposide, cyclosphosphamide, doxorubicin, vincristine, and prednisone. Computed tomography showed improvement in lymphadenopathy. The patient was successfully extubated. On day 1
after extubation, she experienced multiple intracranial
hemorrhages as well as diffuse white matter changes that,
on magnetic resonance imaging, were believed to represent posterior reversible leukoencephalopathy. She was
noted to have thrombocytopenia and International Normalized Ratio of 1.3. The patient was reintubated, and the
coagulopathy was corrected. Despite aggressive management, followup images remained unchanged and she
never fully regained consciousness. According to the family’s wishes, the patient was designated “do-not-resuscitate,” and she died 45 days after the original admission.
Post mortem examination revealed evidence of lymphomatoid granulomatosis predominantly affecting the lungs,
kidneys, and brain, with microscopic disease found
throughout the body (Figure 3). Multifocal cerebral hemorrhages were secondary to involvement of cerebral vasculature with lymphoma. Because the hemorrhages were
not severe enough to cause herniation, her terminal decline was considered to be attributable to systemic burden
of disease.
Lymphomatoid granulomatosis is a rare entity that was
first described in 1972, by Liebow and colleagues, among
patients with Wegener’s granulomatosis (4). It is an angiocentric, angiodestructive lymphoproliferative disorder
characterized by nodular mass lesions. The pathogenesis
of the malignancy has been related to EBV infection of B
cells (5). Additional histopathologic features include polymorphic lymphoid infiltrates, vascular infiltration, and necrosis (4). Abundant reactive T cells and a vasculitic component are seen (5). The malignant B cells, which are often
monoclonal or oligoclonal, stain positive for EBV. However, most of the infiltrating cells are reactive T cells.
Lymphomatoid granulomatosis is most common in the
4th through 6th decades of life, occurring ⬃3 times as
often in men as in women. Generally, the 3 most common
initial symptoms are fever, cough, and dyspnea (4). The
lung is the most commonly affected organ, followed by the
skin, kidney, spleen, and liver. Lymphadenopathy is comparatively rare, occurring in ⬃7– 8% of cases (2,6), although lymph node involvement is found in up to 40% of
patients at autopsy (7). The clinical course is variable, and
there are some reports of spontaneous regression (2,6).
However, in the largest study of lymphomatoid granulomatosis to date, a median survival of 20 months in patients
receiving chemotherapy and steroids was reported (2).
Results of cohort studies attempting to evaluate overall
malignancy rates in patients with lupus have been mixed.
Although large controlled studies have yet to be carried
Beste et al
out, most cohort studies have demonstrated elevated rates
of hematologic cancers compared with the rate in the
general population (8 –11). The biologic mechanism for the
increased risk of lymphoid malignancies in SLE is not yet
understood. Persistent inflammation and lymphocyte hyperactivity in concert with poor immune surveillance have
been theorized to play a role (8). Somatic CD95 (Fas/Apo
1) mutations have been identified in both non-Hodgkin’s
lymphoma and autoimmune conditions, including SLE,
possibly indicating that both disorders share failure of
apoptosis of autoreactive lymphocytes (12). Murine and
human mutations in CD95/CD95 ligand (CD95L) have
been associated with a range of phenotypes, including a
lupus-like syndrome as well as apoptotic defects in lymphocytes (13), although abnormalities of CD95/CD95L
have not consistently been found among lupus patients
(14). Finally, an increased prevalence of the oncogenic
EBV has been reported in lupus, potentially predisposing
to B cell lymphomas such as lymphomatoid granulomatosis (15). Although these mechanisms are promising, further study is needed to clarify the etiology of increased
non-Hodgkin’s lymphoma in lupus.
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2. Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid
granulomatosis: a clinicopathologic study of 152 cases. Cancer 1979;43:360 –73.
3. Pisani RJ, DeRemee RA. Clinical implications of the histopathologic diagnosis of pulmonary lymphomatoid granulomatosis. Mayo Clin Proc 1990;65:151– 63.
4. Liebow AA, Carrington CR, Friedman PJ. Lymphomatoid
granulomatosis. Hum Pathol 1972;3:457–558.
5. Guinee D Jr, Jaffe E, Kingma D, Fishback N, Wallberg K,
Krishnan J, et al. Pulmonary lymphomatoid granulomatosis:
evidence for a proliferation of Epstein-Barr virus infected
B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 1994;18:753– 64.
6. Koss MN, Hochholzer L, Langloss JM, Wehunt WD, Lazarus
AA, Nichols PW. Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients. Pathology 1986;18:283– 8.
7. Fauci AS, Haynes BF, Costa J, Katz P, Wolff SM. Lymphomatoid granulomatosis: prospective clinical and therapeutic experience over 10 years. N Engl J Med 1982;306:68 –74.
8. Sultan SM, Ioannou Y, Isenberg DA. Is there an association of
malignancy with systemic lupus erythematosus? An analysis
of 276 patients under long-term review. Rheumatology (Oxford) 2000;39:1147–52.
9. Cibere J, Sibley J, Haga M. Systemic lupus erythematosus and
the risk of malignancy. Lupus 2001;10:394 – 400.
10. Mellemkjaer L, Andersen V, Linet MS, Gridley G, Hoover R,
Olsen JH. Non-Hodgkin’s lymphoma and other cancers among
a cohort of patients with systemic lupus erythematosus. Arthritis Rheum 1997;40:761– 8.
11. Nived O, Bengtsson A, Jonsen A, Sturfelt G, Olsson H. Malignancies during follow-up in an epidemiologically defined
systemic lupus erythematosus inception cohort in southern
Sweden. Lupus 2001;10:500 – 4.
12. Gronbaek K, Straten PT, Ralfkiaer E, Ahrenkiel V, Andersen
MK, Hansen NE, et al. Somatic Fas mutations in nonHodgkin’s lymphoma: association with extranodal disease
and autoimmunity. Blood 1998;92:3018 –24.
13. Vaishnaw AK, Toubi E, Ohsako S, Drappa J, Buys S, Estrada J,
et al. The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans
with CD95 (Fas/APO-1) mutations. Arthritis Rheum 1999;42:
1833– 42.
14. Mysler E, Bini P, Drappa J, Ramos P, Friedman SM, Krammer
PH, et al. The apoptosis-1/Fas protein in human systemic
lupus erythematosus. J Clin Invest 1994;93:1029 –34.
15. James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman
TJ, Harley JB. An increased prevalence of Epstein-Barr virus
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DOI 10.1002/art.21362
In the article by Merkesdal et al published in the April 2005 issue of Arthritis & Rheumatism (pp 234 –240), the
statement “Drs. Merkesdal and Ruof contributed equally to this work” was inadvertently omitted.
We regret the error.
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