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).
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–double-stranded 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 morning cough. Physical examination revealed bibasilar crackles, and chest examination demonstrated a nontender, nonfluctuant, mobile lymph node in her left submandibular 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 α-2b was initiated and the patient reported an improved energy level, less 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 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.