A 65-year-old man was admitted to the hospital because of fever, abdominal pain, weight loss, and diffuse lymphadenopathy.
History of the present illness
Nine years earlier, the patient was hospitalized because of a purpuric rash on both feet and several episodes of epistaxis. Mildly enlarged axillary and cervical lymph nodes were palpated on physical examination. A complete blood count (CBC) revealed severe thrombocytopenia (4,000 platelets/mm3). A bone marrow (BM) biopsy disclosed numerous megakaryocytes, supporting the diagnosis of immune thrombocytopenic purpura (ITP). Lymphocyte immunophenotyping was normal. The hematocrit was 36.5% and the hemoglobin level was 12 gm/dl. A direct Coombs' test was positive. A computerized tomography (CT) scan demonstrated mildly enlarged lymph nodes (up to 2 cm in diameter) in the neck and right axilla. The spleen was not enlarged. An axillary lymph node biopsy was performed, showing reactive follicular hyperplasia with no signs of malignancy. The patient was treated with intravenous corticosteroids and the platelet count increased to >40,000 platelets/mm3. He was discharged and referred to further outpatient followup.
Three years later, the patient was readmitted to another hospital due to similar symptoms (purpura and epistaxis). A CBC revealed thrombocytopenia (10,000 platelets/ mm3) and severe leukopenia (1,600 white blood cells [WBCs]/mm3) with neutropenia (400 neutrophils/mm3). The hematocrit was 38.1% and the hemoglobin level was 13.1 gm/dl. No pathologic cells were seen in a blood smear. The cytopenias were attributed to recent administration of ramipril and hydrochlorothiazide (prescribed for a recent diagnosis of hypertension). Both medications were withdrawn. The patient was treated with steroids, with resolution of both the neutropenia and the thrombocytopenia.
One month prior to the current admission, the patient experienced epigastric pain. He reported a weight loss of 3 kg (6.6 pounds) within a month. He was referred to another hospital, where abdominal ultrasonography revealed a large biliary stone in the gallbladder without evidence of cholecystitis. An abdominal CT scan revealed enlarged paraaortic lymph nodes and splenomegaly (maximal diameter of 18.6 cm) without hepatomegaly. Multiple enlarged lymph nodes were also demonstrated in the retroperitoneum, liver hilum, and groin (Figure 1). The patient denied night sweats or pruritus. An excisional biopsy from an inguinal lymph node was performed (Figure 2). The biopsy showed preserved lymph node architecture with reactive lymphoid follicles and interfollicular hyperplasia. No obvious neoplastic cells or granulomas were identified. Neither histiocytes nor karyorrhexis was demonstrated. On immunostaining, the follicles were positive for CD20, CD10, and Bcl-6 and were negative for Bcl-2. Epstein-Barr virus (EBV)–encoded latent membrane protein was negative. A BM biopsy disclosed normal cellularity. All 3 lineages were well represented.
The patient had a history of gout and was treated with allopurinol. He also had hypertension, which was controlled with amlodipine.
Two years before the present admission, nonerosive arthritis was noted in the knees, wrists, and metacarpophalangeal (MCP) joints and proximal interphalangeal (PIP) joints of the left hand. The patient experienced morning stiffness (>1 hour). Laboratory tests revealed elevated erythrocyte sedimentation rate and C-reactive protein level. Rheumatoid factor (RF) and antinuclear antibodies (ANAs) were negative. Anti–citrullinated peptide antibodies were not tested. Ibuprofen was prescribed, with no benefit. However, treatment with once weekly (7.5 mg) methotrexate (MTX) resulted in a good response.
Medications and allergies
The patient was treated with allopurinol for gout, amlodipine to control hypertension, and MTX for arthritis. He had no known allergies.
Family and social history
The patient had worked as a journalist until he retired. He was divorced with 2 healthy children. He denied recent travel or animal exposure, and did not use tobacco, alcohol, or illicit drugs. There was no family history of arthritis, connective tissue disease, or hematologic malignancy. The patient had no known exposure to tuberculosis.
Review of systems
The patient reported persistent epigastric pain and increased fatigue. He did not have nausea or vomiting. He denied drenching night sweats, pruritus, rash, arthritic pain, or tenderness, and reported no dyspnea, cough, or epistaxis.
The patient appeared ill. His temperature was 38.1°C (100.6°F), his pulse was 106 beats/minute, his blood pressure was 110/60 mm Hg, his respiratory rate was 22 breaths/minute, and his oxygen saturation was 85% while breathing ambient air. Enlarged cervical, supraclavicular, axillary, and inguinal lymph nodes were palpated. Abdominal examination revealed an enlarged spleen, and there was diffuse tenderness on palpation that was more prominent on the right side. Cardiac examination was normal except for mild tachycardia. Mild jugular venous distension was noted. Soft rales were heard over both lung bases. No signs of arthritis were found.
Results of the laboratory evaluation are shown in Table 1. A peripheral blood smear showed anisocytosis, and a chest radiograph demonstrated small bilateral pleural effusions and diffuse interstitial changes.
A 65-year-old man was admitted with fever, abdominal pain, weight loss, splenomegaly, and diffuse lymphadenopathy. He had been previously diagnosed with ITP and Coombs'-positive hemolytic anemia, and a single episode of neutropenia that was attributed to medications. He also experienced unspecified arthritis that was controlled with weekly MTX therapy at a dosage of 7.5 mg/week. Lymphadenopathy was detected 9 years before the current admission and appeared to be chronic.
Due to persistent abdominal pain, gastroscopy was performed, revealing gastric nodular lesions. Biopsies disclosed foveolar hyperplasia that was related to ibuprofen use.
Given the concerning finding of hypoxemia, CT angiography was ordered, but the patient refused intravenous administration of contrast media due to concern over potential nephropathy. Therefore, a ventilation/perfusion scan was performed and resulted in a low probability for pulmonary embolism. An echocardiogram showed good left ventricular function, with severe pulmonary hypertension and a high tricuspid incompetence gradient of 65 mm Hg.
A high-resolution CT scan demonstrated bilateral pleural effusions, atelectasis of lung bases, and multiple enlarged axillary, mediastinal, and supraclavicular lymph nodes. Enoxaparin was administered due to pulmonary hypertension and furosemide was given for the pleural effusion, with mild clinical improvement.
The differential diagnosis encompasses infectious, rheumatic, hematologic, and neoplastic etiologies. Lymph node architecture, immunostains, and cultures are basic to rule out lymphoproliferative disorders and infectious and noninfectious granulomatous disorders (i.e., tuberculosis and histiocytic necrotizing lymphadenitis, respectively). In the absence of granulomas or reactive histiocytes, the differential diagnosis may be narrowed (Table 2).
EBV = Epstein-Barr virus; CMV = cytomegalovirus; HIV = human immunodeficiency virus.
Systemic inflammatory disorders
Systemic lupus erythematosus
Adult-onset Still's disease
Drug-related fever and generalized lymphadenopathy
Autoimmune lymphoproliferative syndrome
EBV and cytomegalovirus (CMV) infections may present with fever and diffuse lymphadenopathy with hepatitis, anemia, leukopenia, and thrombocytopenia (1–5). Despite the presence of some of these findings in our patient, these viral infections are quite rare in late adulthood. Lymphocytosis or atypical lymphocytes were not demonstrated in the patient's blood smear. Viral serology for acute CMV and EBV was negative.
Infection with Toxoplasma gondii may also be considered. However, symptomatic toxoplasmosis is uncommon in immunocompetent patients, and constitutional symptoms are mild, if present at all (6). The patient denied recent animal exposure (including cats), and anti–T gondii antibodies were not identified.
Primary human immunodeficiency virus (HIV) should also be considered in any patient with a mononucleosis-like illness and may present with fever, diffuse lymphadenopathy, anemia, thrombocytopenia, and lymphocytosis (7). Our patient had no risk factors for HIV infection and testing for the virus was negative.
In a relatively elderly patient with fever, weight loss, and diffuse lymphadenopathy, the diagnosis of lymphoma should be strongly considered. Arthritis may be a paraneoplastic phenomenon and the elevated uric acid level requiring allopurinol may support the possible diagnosis of malignancy.
In the sixth decade of life, most cases of malignant lymphoma are non-Hodgkin's lymphoma. Immune cytopenias (especially ITP) can precede the emergence of a lymphoproliferative disease by several years. The patient's abdominal pain may be attributed to a lymphoproliferative process such as mantle cell lymphoma, which involves the gastrointestinal tract in the majority of cases. B symptoms are present in 30% of patients (8, 9) and splenomegaly may be massive. Cytopenias are usually secondary to BM infiltration, typically seen in advanced disease. Histologic findings in lymph node biopsy include expansion of the mantle cell zone that surrounds the lymph node germinal centers by atypical lymphocytes. Neoplastic cells may be seen in a BM aspirate in advanced disease.
Chronic lymphocytic leukemia (CLL) should also be considered, particularly in the context of diffuse lymphadenopathy and autoimmune thrombocytopenia and Coombs'-positive anemia presenting simultaneously. This has been previously termed Evans syndrome (10). Abdominal discomfort may be related to splenomegaly. Lymphocytosis, which is a prominent feature of CLL, was not demonstrated in our patient's blood smear.
Chronic T cell lymphoma encompasses a heterogeneous group of uncommon, aggressive neoplasms. The more common types are peripheral T cell lymphoma and angioimmunoblastic T cell lymphoma. All may present with B symptoms, rash, lymphadenopathy, hepatosplenomegaly, hemolytic anemia, and thrombocytopenia (11).
In our patient, lymph node architecture was preserved. It should be emphasized that when chronic T cell lymphoma is suspected, T cell receptor gene studies are performed in order to demonstrate clonal rearrangements. Since both BM and lymph node histology did not suggest this diagnosis, these studies were not performed.
An excisional biopsy is considered the gold standard in the diagnosis of lymphoma. Nevertheless, the absence of neoplastic cells in the lymph node and BM biopsies does not exclude it. Normal BM histology can occur even in the case of marrow infiltration, and inguinal lymph nodes are often reactive and are not the preferred site when seeking a lymphoproliferative process. A repeat lymph node biopsy, preferably from the neck or mediastinum, would have been very helpful in order to rule out malignancy.
Multicentric Castleman's disease may present with fever, generalized lymphadenopathy, and hepatosplenomegaly, as well as polyclonal hypergammaglobulinemia (12). The B cell follicles show hyalinization of germinal centers, a prominent mantle zone, and a heavily infiltrated interfollicular zone by mature plasma cells. These findings were not demonstrated in serial lymph node biopsies.
Systemic inflammatory disorders
A history of joint disease involving the wrists with morning stiffness (>1 hour) suggests the diagnosis of rheumatoid arthritis (RA). Enlarged lymph glands can be part of this disease, sometimes mimicking lymphoma. The abdominal pain could be related to ibuprofen administration. Negative serology for RF neither supports nor rules out the diagnosis of RA, since as high as 15% of patients with RA are RF negative. The asymmetric involvement of MCP joints and PIP joints in our patient is atypical in RA, and the lack of synovitis further denies this diagnosis.
Lymphadenopathy and splenomegaly along with hematologic abnormalities (including Evans syndrome, thrombocytopenia, and leukopenia) can be found in systemic lupus erythematosus (SLE) or Felty's syndrome. Negative ANA provides strong evidence against the diagnosis of SLE, and the likelihood of Felty's syndrome is extremely low, since its typical feature, i.e., progressive and destructive seropositive arthritis, was lacking in this patient.
Fever, arthralgia, lymphadenopathy, and splenomegaly in the absence of positive ANA or RF could suggest the diagnosis of adult-onset Still's disease (13). Yet, the typical salmon-pink rash was never noted in our patient, he did not experience a sore throat, and neither leukocytosis nor elevated serum ferritin was present. Last, BM histology did not reveal any indication of hemophagocytosis.
Sarcoidosis should also be considered in the differential diagnosis of lymphadenopathy, liver dysfunction, and dyspnea, but respiratory distress in our patient was quite acute, a chest CT scan did not suggest lung involvement, and lymph node histology did not reveal granulomas.
Drug-related fever and generalized lymphadenopathy
Several drugs (i.e., phenytoin and allopurinol) can cause fever, lymphadenopathy, and arthralgias. Our patient was taking allopurinol for control of gout. The drug was withdrawn during admission and yet the disease did not improve.
Autoimmune lymphoproliferative syndrome (ALPS)
The presence of autoimmune phenomena (specifically Evans syndrome) with hypergammaglobulinemia may imply the acquired variant of ALPS. Although self-antibodies (i.e., ANA and RF) were lacking, the immune thrombocytopenia and anemia along with generalized lymphadenopathy and splenomegaly are prominent features of this syndrome, and it is possible that the transient neutropenia 6 years earlier was also of autoimmune origin. A diagnosis of ALPS requires the detection of at least 1.5% of all lymphocytes to be CD4-/CD8-negative (double-negative) T lymphocytes as well as ruling out malignant or infectious causes of lymphadenopathy and/or splenomegaly. Although immunophenotyping was normal 9 years prior to the current admission, lymphocyte immunophenotyping from peripheral blood should be repeated.
ADDITIONAL HOSPITAL COURSE
A core biopsy of the right cervical lymph node was performed, suggesting an expanded interfollicular area composed mainly of T lymphocytes (CD3+). CD4 and CD8 immunostains were also performed, indicating an abnormal clone (Figure 3).
During admission, the patient's condition deteriorated. Dyspnea worsened, oxygen saturation was 78% on ambient air, the creatinine level increased to 2.5 mg/dl (221 μmoles/liter), and liver enzymes sharply increased. The alkaline phosphatase level rose to 1,074 units/liter, gamma glutamyl transpeptidase increased to 593 units/liter, alanine aminotransferase rose to 100 units/liter, and aspartate aminotransferases increased to 159 units/liter. Lactate dehydrogenase was 731 units/liter. Hyperbilirubinemia of up to 6 mg/dl (108 μmoles/liter) was noted, mostly direct. The absolute neutrophil count decreased to 590 cells/mm3 (total WBC count 1,500 cells/mm3) and the platelet count was 148,000/mm3. The hematocrit was 26.3% and the hemoglobin level was 8.4 gm/dl. Coombs' test was negative.
Owing to the clinical deterioration, MTX was withdrawn and once daily intravenous methylprednisolone at a dose of 0.5 gm was initiated empirically for 3 days and then substituted by 60 mg of daily oral prednisone. The patient's condition improved dramatically.
The dyspnea and hypoxemia subsided within a few days. The WBC and neutrophil counts increased swiftly to levels of 3,200 and 1,750 cells/mm3, respectively. The increase in liver enzymes halted and subsequently normalized. The creatinine level dropped to 1.17 mg/dl (180 μmoles/liter) within a few days.
Repeat immunophenotyping before administration of steroids yielded a striking elevation of the α/β-positive, CD3-positive, double-negative T lymphocytes subpopulation of up to 19% (Figure 4). The findings were highly suggestive of ALPS.
Reviewing the patient's findings of generalized lymphadenopathy, splenomegaly, autoimmune phenomena such as Evans syndrome, and possibly autoimmune neutropenia along with hypergammaglobulinemia, all support the diagnosis of this rare disorder. Analysis of lymphocytic DNA identified a heterozygous Fas missense mutation (GAT→GGT) in codon 244 (D244G), exon 9, confirming the diagnosis of ALPS.
Autoimmune lymphoproliferative syndrome.
ALPS is a rather rare but intriguing entity, especially in adults. It may present with immunologic, hematologic, rheumatologic, and even infectious manifestations. ALPS is a hereditary disorder of defective lymphocyte homeostasis that often appears in childhood and results in reduced lymphocyte apoptosis (14, 15). Only a few hundred families with ALPS have been described in the literature (16). Lymphocyte apoptosis is triggered by the cell surface receptor Fas (CD95/APO-1). This receptor has a crucial role in sustaining lymphocyte homeostasis and peripheral immune tolerance and preventing autoimmunity (17).
The deleterious mutation in the Fas gene leads to escape from apoptosis and expansion of a lymphocyte subset population that is positive for the CD3 receptor but negative for the CD4 and CD8 coreceptors (therefore termed double-negative T cells). Although this subpopulation of lymphocytes may also be expanded in autoimmune diseases (18), it is the hallmark of ALPS.
The abnormal clonal expansion results in the accumulation of lymphocytes and autoreactive cells, which results in chronic nonmalignant lymphadenopathy, hepatosplenomegaly with or without hypersplenism, and repeated episodes of multilineage autoimmune cytopenias. Autoimmune hemolytic anemia, autoimmune thrombocytopenia, Evans syndrome, and autoimmune neutropenia have all been described. Other uncommon complications include glomerulonephritis, hepatitis, arthritis, myelitis, and pulmonary infiltrates (19–22). The risk of neoplasia, especially lymphoma, is increased in these patients (23). This requires careful and close followup.
The majority of patients with ALPS have a germline mutation in the Fas gene (15). Heterozygous autosomal dominant mutations in Fas account for approximately 70% of all ALPS cases.
ALPS is uncommon in adults. As in most genetic diseases, onset is usually apparent during childhood or adolescence. Yet, somatic mutation of the Fas gene can also lead to ALPS. Holzelova et al reported 6 patients with a sporadic form of ALPS, all of whom had somatic heterozygous mutations of Fas (24). In some patients who carry the mutation, the phenotype is rather mild or absent, and this may imply partial clinical penetrance of the Fas mutation (25). Additional rare mutations in the Fas ligand and caspase 10 have also been described (26, 27). Undefined ALPS signifies diagnosis of ALPS without detecting gene mutations.
A diagnosis of ALPS requires the presence of at least 1.5% of all lymphocytes to be double-negative T lymphocytes as well as nonmalignant, noninfectious lymphadenopathy and/or splenomegaly. Other primary accessory criteria include defective lymphocyte apoptosis and detection of pathogenic mutations in the Fas, Fas ligand, or caspase 10 genes (criteria are detailed in reference 28) (15).
Recently, Desai et al reported a case of a 50-year-old patient who presented with fever, epistaxis, and multiple lymphadenopathy. The diagnosis of probable ALPS was made after demonstrating reactive lymphadenitis with paracortical hyperplasia and the presence of double-negative T lymphocytes (detected by immunostaining) on a cervical lymph node biopsy (29). Our patient presented with fever, weight loss, chronic lymphadenopathy, and recent splenomegaly. Such alarming signs suggested a lymphoproliferative process.
Yet, a thorough evaluation, including multiple biopsies, did not reveal malignancy. His past episodes of thrombocytopenia along with Coombs'-positive hemolytic anemia (Evans syndrome) and persistent hypergammaglobulinemia, in the absence of lymphoma, implied the diagnosis of ALPS. Indeed, 19% of all T cells in our patient at the peak of his disease were double-negative α/β T lymphocytes. The increase in hepatic and renal indices along with arthritis and respiratory distress can be attributed to autoimmune hepatitis, glomerulonephritis, arthritis, and alveolitis, respectively. The rapid clinical improvement of the patient's condition is consistent with the diagnosis of ALPS, which responds well to systemic corticosteroids.
Finally, the detection of the D244G intracellular domain mutation in exon 9 further confirmed the diagnosis. This missense mutation has been reported in ALPS (30) and may promote conformational changes in the death domain and therefore impair lymphocyte apoptosis. Autoimmune features may accompany lymphoma; however, when repeated lymph node biopsies are negative, ALPS should be seriously considered.
Immunophenotyping is essential in the diagnosis of ALPS, considering that it has an important role in characterizing different T cell phenotypes. Indeed, T cell phenotyping (i.e., CD4+/CD25+ regulatory T cells) is proving to be useful in a growing repertoire of autoimmune diseases (31).
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Ben-Chetrit had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Ben-Chetrit, Bnaya, Ashkenazi.
Acquisition of data. Ben-Chetrit, Vernea, Somech.
Analysis and interpretation of data. Ben-Chetrit, Ashkenazi.
The authors would like to thank Eti Broide for performing immunophenotyping assays, Atar Lev and Amos Simon for genetic analysis, and Dr. Shimon Goldberg for manuscript revision.