Just Beneath the Surface

A 55-year-old man was evaluated in the clinic after returning from a 5-month visit to Pakistan. He reported a 3-month history of intermittent fevers and fatigue without night sweats, weight loss, headache, cough, diarrhea, rash, dysuria, or arthralgias. His vital signs and physical examination were normal.

The differential diagnosis for fever and fatigue is broad. The new onset of fever after international travel prioritizes the possibility of an infectious process. Infections that are endemic in Pakistan and that may cause a prolonged, undifferentiated fever include tuberculosis, visceral leishmania infection, brucellosis, and relapsing fever. In addition to infections, the differential diagnosis includes autoimmune and autoinflammatory disorders, cancer, and drug-induced reactions.

The patient had been born and raised in Pakistan and had immigrated to the mid-Atlantic region of the United States in his 30s. His medical history included coronary artery disease, stroke, hypertension, hyperlipidemia, and gastroesophageal reflux disease. His medications were losartan, aspirin, clopidogrel, metoprolol, pravastatin, and as-needed sublingual nitroglycerin. He had no family history of cancer or autoimmune disease. He was a retired restaurant owner, and he had a smoking history of 60 pack-years but had quit smoking 12 years earlier. He was in a monogamous relationship with his wife. He reported no heavy alcohol intake or illicit drug use.

Given the duration of symptoms, it would be unlikely that an infection acquired in the mid-Atlantic region, such as Lyme disease, babesiosis, or ehrlichiosis, would be the cause of his symptoms. Latent tuberculosis, acquired before immigration, could have reactivated several decades later. He has no risk factors for human immunodeficiency virus (HIV) infection, and his listed medications are not commonly associated with drug-induced fever. Cancer should also be considered as a cause of isolated fever, especially given his smoking history.

Multiple outpatient courses of antibiotic agents — including azithromycin, levofloxacin, and amoxicillin, each taken for up to 7 days — were prescribed, but the fevers did not resolve.

Antibiotic therapy should be avoided in a stable patient with fever of unknown origin because it might result in unwanted side effects, partial treatment, or decreased yield of diagnostic tests. Short courses of monotherapy with the agents that he received would not be expected to eradicate the infections that are most likely to explain his prolonged fevers.

Five months later, the patient returned to the clinic and reported having daily fevers, continued fatigue, new drenching night sweats, nonproductive cough, and myalgias. His temperature was 38.4°C. His pulse was 116 beats per minute, blood pressure 124/88 mm Hg, and respiratory rate 16 breaths per minute with oxygen saturation of 97% while he was breathing ambient air. The patient was referred to the emergency department. He appeared to be uncomfortable. Cardiac, respiratory, abdominal, neurologic, skin, and musculoskeletal examinations were normal.

Serum electrolyte levels, renal function, and urinalysis were normal. The aspartate aminotransferase level was 119 U per liter (normal range, 0 to 37), and the alanine aminotransferase level 48 U per liter (normal range, 0 to 40); the alkaline phosphatase and bilirubin levels were normal. The white-cell count was 3410 per cubic millimeter (56% neutrophils, 18% lymphocytes, 25% monocytes, <1% eosinophils). The hemoglobin level was 13.1 g per deciliter, the mean corpuscular volume was 86.0 fl, and the platelet count was 127,000 per cubic millimeter. The erythrocyte sedimentation rate was 37 mm per hour (normal range, 1 to 20), and the C-reactive protein level was 2.9 mg per deciliter (normal value, <0.5). A radiograph of the chest was normal.

Cytopenias arouse concern regarding myelosuppression or infiltration of the bone marrow, the latter of which could be caused by tuberculosis, disseminated mycosis, metastatic cancer, or a hematologic cancer. Consideration of certain infectious diseases is influenced by host factors and exposures. Brucellosis may have a protracted course, lasting several months to a year or more, and manifests as fever, fatigue, night sweats, and often arthralgia or hepatosplenomegaly. The patient should be questioned regarding contact with infected animals or consumption of unpasteurized dairy products. Q fever, caused by Coxiella burnetii, may also manifest as a prolonged febrile illness in persons without known exposure to infected farm animals.

Other conditions that could explain the fevers and pancytopenia include hemophagocytic lymphohistiocytosis, which may complicate the course of an infection or lymphoproliferative disorder, and systemic lupus erythematosus. Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides have a particular predilection for the upper and lower respiratory tract and may cause cough, dyspnea, and hemoptysis in addition to fever. Although the absence of dyspnea and hemoptysis in this patient does not preclude this diagnosis, the normal chest radiograph and unremarkable urinalysis make it less likely.

The patient was admitted to the hospital. Blood cultures and induced sputum samples were obtained. Ampicillin–sulbactam and vancomycin were initiated. The serum phosphorous level was 3.9 mg per deciliter (1.25 mmol per liter; normal range, 2.7 to 4.5 mg per deciliter [0.85 to 1.45 mmol per liter]), and the uric acid level was 5.7 mg per deciliter (340 μmol per liter; normal range, 3.5 to 7.2 mg per deciliter [210 to 430 μmol per liter]). The haptoglobin level was 55 mg per deciliter (normal range, 36 to 195), and the ferritin level was 508 ng per milliliter (normal range, 30 to 400). The serum creatine kinase level was 92 U per liter (normal range, 24 to 195), and the lactate dehydrogenase (LDH) level was 1942 U per liter (normal range, 118 to 273). Blood, sputum, and stool bacterial cultures were sterile. Polymerase-chain-reaction (PCR) testing for influenza type A and B was negative. HIV, hepatitis C antibody, and hepatitis B surface antigen and core antibody tests were negative. Staining for acid-fast bacilli and PCR testing for Mycobacterium tuberculosis in sputum samples were negative, as was an interferon-γ release assay. A peripheral-blood smear showed occasional atypical, reactive-appearing lymphocytes and thrombocytopenia. Serum protein electrophoresis and free light chains were normal.

The negative interferon-γ release assay and negative acid-fast bacilli stains do not rule out active tuberculosis. Of the tests mentioned, PCR has the highest sensitivity and specificity; however, the standard for diagnosis remains culture.

Although the findings are nonspecific, an elevated LDH level with fever and cytopenias may indicate a lymphoma. Imaging would be helpful in looking for lymphadenopathy or a source of infection. Solid tumors cause fever less commonly. Although the vast majority of leukemias manifest with circulating malignant cells, their absence on a smear does not preclude further evaluation. A bone marrow aspirate and biopsy would be better diagnostic tests, and samples should be sent for culture and stained for mycobacterial and fungal pathogens. Culture-negative subacute endocarditis (e.g., C. burnetii and brucella species) should also be considered, given the patient’s prolonged symptoms.

Computed tomography (CT) of the chest, abdomen, and pelvis with the use of contrast material did not reveal parenchymal abnormality, lymphadenopathy, or abscess. A transthoracic echocardiogram showed possible thickening of the anterior mitral-valve leaflet and a questionable mass on the tricuspid valve; subsequent transesophageal echocardiography did not reveal a vegetation or mass.

The beta-d-glucan level was normal. Serum PCR tests for cytomegalovirus, parvovirus, and Tropheryma whipplei were negative. Antibodies to brucella, leishmania, Legionella pneumophila IgM, Entamoeba histolytica, and Francisella tularensis were negative. Coxiella IgG phase II antibody titers were elevated at 1:16.

Antinuclear antibody, rheumatoid factor, anti–double-stranded DNA, antimitochondrial, anti–smooth muscle, perinuclear and cytoplasmic ANCA, and direct Coombs’ tests were all negative. Antibiotics were stopped after blood cultures were negative for 48 hours. Although the patient’s fever did not resolve, he was discharged from the hospital with outpatient follow-up.

Infection was considered to be the most probable cause of fevers in this patient because of his preceding travel, yet testing for multiple infectious pathogens was nonrevealing. The diagnosis of coxiella infection is made on the basis of PCR results or more definitive antibody titers reflecting either of two antigenic phases of the antibody response (a phase I IgG titer of >1:800 or a phase II IgG titer of >1:128 or an increase by a factor of 4 in the phase II IgG titer). Repeat serologic testing is warranted in approximately 3 weeks. The negative blood cultures and echocardiographic results, together with the absence of risk factors and lack of suggestive findings on physical examination, rule out endocarditis.

A rheumatologic disease is less likely, given the absence of identifiable clinical features and the negative serologic tests. In adults older than 50 years of age, giant-cell arteritis is possible and may manifest as fever, cough, and fatigue. Adult-onset Still’s disease is a well-recognized cause of fever of unknown origin but typically affects adults in the second through fourth decades of life and commonly manifests as evanescent rash, arthralgia, and leukocytosis, which are absent in this patient.

Two months later, the patient returned for follow-up and reported having ongoing daily fevers, fatigue, chills, night sweats, decreased appetite, and nonproductive cough. Blood and sputum cultures were negative for mycobacteria at 6 weeks. The white-cell count was 2800 per cubic millimeter. The hemoglobin level was 11.3 g per deciliter, and the platelet count was 138,000 per cubic millimeter. The ferritin level was 700 ng per milliliter, and the remainder of the iron studies were normal. Repeat serologic testing for coxiella revealed a phase I IgG antibody titer of 1:16 and negative phase II antibody titer. The patient’s symptoms did not resolve after a 14-day course of doxycycline. Temporal-artery biopsy revealed no evidence of arteritis.

The results of serologic testing rule out Q fever. Given his progressive pancytopenia, bone marrow aspiration and biopsy are indicated to assess for an infiltrating process such as leukemia or lymphoma, which can manifest with cytopenias and fever in the absence of abnormalities on physical examination or radiography.

Bone marrow aspiration and biopsy revealed trilineage hematopoiesis. There was no tumor, erythrophagocytosis, or granuloma. Flow cytometry was negative for phenotypically abnormal cells and revealed no evidence of clonality. A whole-body positron-emission tomographic (PET)–CT scan was negative for pathologic lymph nodes and ¹⁸F-fluorodeoxyglucose–avid lesions.

Four months later (14 months after the onset of fever), the patient had abdominal pain, early satiety, nausea, and abdominal distention. He continued to have daily fevers, night sweats, fatigue, and cough. He spent most of the day in bed. His family detected intermittent forgetfulness, and he was readmitted to the hospital. On admission, his temperature was 39.3°C, and he had a pulse of 100 beats per minute, a blood pressure of 115/69 mm Hg, a respiratory rate of 18 breaths per minute, and oxygen saturation of 92% while he was breathing ambient air. Examination revealed a tired-appearing man with a distended abdomen. There was mild tenderness over the left upper quadrant without rebound or guarding. The spleen was not palpable. He had difficulty remembering details of his medical history, and multiple prompts were needed in order for him to complete simple tasks. A detailed neurologic examination was not performed. He had no rash.

The white-cell count was 1900 per cubic millimeter (70% neutrophils, 12% lymphocytes, 10% monocytes, 6% bands, 2% metamyelocytes, and 0% eosinophils). The hemoglobin level was 9.8 g per deciliter, the platelet count 44,000 per cubic millimeter, and the LDH level 2475 U per liter. The alkaline phosphatase level was 97 U per liter, the aspartate aminotransferase level 89 U per liter, the alanine aminotransferase level 30 U per liter, and the bilirubin level 0.5 mg per deciliter (86 μmol per liter). The reticulocyte count was 1.7% (normal range, 0.5 to 1.8). Repeat CT scan of the chest, abdomen, and pelvis with the use of contrast material revealed mild splenomegaly and no lymphadenopathy (Fig. 1).

Figure 1. CT Images of the Abdomen and Pelvis Showing Splenomegaly.

Panel A shows the axial view, and Panel B the coronal view. L denotes left, and R right.

Since the patient’s previous evaluation, splenomegaly and confusion, with difficulty responding to questions, have developed, along with worsening pancytopenia, persistent mild elevations in the liver-enzyme levels, and a remarkably high LDH level. Extensive evaluation for infectious and rheumatologic causes has been unrevealing. Cancer, particularly lymphoma, remains a strong consideration. Multisystem involvement by lymphoma may infiltrate the liver, spleen, and central nervous system, producing elevated liver-enzyme levels, splenomegaly, and confusion. Findings on PET-CT imaging would be expected with the vast majority of aggressive lymphomas, although they may be absent in central nervous system, cutaneous, or intravascular lymphoma. There is no rash to suggest cutaneous lymphoma. Careful neurologic examination is warranted. Skin biopsy to look for possible intravascular lymphoma would be the next diagnostic test.

Three skin-biopsy samples were obtained at random on the left upper arm, abdomen, and left thigh. Pathological examination revealed intravascular B-cell lymphoma in all the specimens (Fig. 2). The patient was transferred to the oncology center and started receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). He completed six cycles of therapy and had a complete remission. His energy and appetite returned to normal. Repeat skin-biopsy samples obtained after the completion of therapy were negative for intravascular lymphoma. One year after diagnosis, he remained afebrile and had no fatigue, cough, confusion, forgetfulness, or abdominal symptoms.

Figure 2. Malignant Cells in Skin-Biopsy Samples.

Panel A shows hematoxylin and eosin staining of a skin-biopsy sample showing malignant large B cells within small-vessel lumen. Panel B shows CD20 staining (brown) of a skin-biopsy sample showing malignant cells that are CD20-positive.

COMMENTARY

A febrile traveler returning from a trip abroad most commonly has acquired an infection.¹ In this patient, who presented with fevers after a trip to Pakistan, extensive diagnostic studies were undertaken, without the identification of an infectious cause or another diagnosis. The subsequent development of worsening B symptoms (i.e., weight loss, night sweats, and fever) and multisystem manifestations, including pancytopenia, splenomegaly, and a high serum LDH level, strongly suggested a lymphoproliferative cancer. With unrevealing peripheral-blood smear, bone marrow, and imaging studies, random skin biopsies were ultimately performed, which yielded the diagnosis of intravascular lymphoma.

Intravascular lymphoma is a rare, extranodal subtype of diffuse large B-cell lymphoma.² The incidence in the United States is less than 1 case per every 10 million persons but has been increasing, possibly owing to heightened awareness since this cancer was categorized as a distinct entity in 2007.³ The median age of patients at diagnosis is 67 years, and intravascular lymphoma occurs at similar rates among men and women.^4,5 There are no known risk factors.

Intravascular lymphoma is treatable.⁶ A retrospective study involving 106 patients showed a progression-free survival rate of 56% and an overall survival rate of 66% at 2 years among patients who had been treated with rituximab-containing chemotherapy regimens (e.g., R-CHOP).⁶ There have been no randomized, controlled trials of therapy for this condition. Left undiagnosed, it is fatal.⁶

Intravascular lymphoma characteristically manifests as fever, pronounced fatigue, decreased appetite, and a decline in functional status.⁵ Geographic variation in phenotype has been noted in series that have been reported from Asian countries and Western countries, which in aggregate have included approximately 200 patients.^5,7–10 Hemophagocytosis and a more rapid course are commonly reported in Asian centers, whereas cerebral and pulmonary involvement are more common in Western centers.^5,7–10 Many organ systems can be involved. Central nervous system infiltration occurs in 25 to 76% of patients and may result in confusion, gait ataxia, seizure disorders, or memory loss.^5,7–9 Pulmonary infiltration results in dyspnea, cough, and hypoxemia.⁵ Up to one quarter of affected patients have visible skin lesions, which show substantial heterogeneity, including plaques and nodules, with variation in color, character, location, and number.⁸

Anemia and thrombocytopenia are each present in more than half the patients with intravascular lymphoma, and leukopenia develops in one quarter of patients.⁵ Elevated liver-enzyme levels may be observed with hepatic involvement and are seen in approximately one fifth of patients,³ and hypoalbuminemia occurs in approximately half the patients. Elevated serum LDH levels are present in virtually all patients.^3,5 Therefore, the combination of neurologic symptoms, pancytopenia, and elevated LDH levels in a person presenting with fever of unknown origin is a valuable diagnostic clue for intravascular lymphoma. Lymphadenopathy is rarely identified.^3,5,8 In two small case series (involving 29 and 13 patients),^9,10 splenomegaly was noted on abdominal imaging in 45% and 100% of patients, respectively.

Diagnosis requires a tissue biopsy of an involved organ and may involve repeat biopsies. Histopathological testing reveals malignant lymphoid cells within the lumina of small vessels, capillaries, and sinusoids of affected organs.⁵ The use of hematoxylin and eosin staining alone may be insufficient for diagnosis.⁵ The neoplastic cells are typically B cells with high CD20 expression, occasional CD5 expression, and rare CD10 expression.⁵ Therefore, CD20 immunohistochemical staining is typically required for diagnosis. It is hypothesized that abnormal expression of adhesion and homing receptors accounts for the localization within these small vessels.⁵ There are rare cases of intravascular lymphoma with T-cell and natural killer cell markers. However, these are classified separately and represent different disease entities.⁵

Random (also known as “blind”) skin biopsy, with samples of normal-appearing skin obtained from the thighs, arms, or abdomen, has emerged as a valuable, relatively noninvasive diagnostic tool.^10–12 In one study involving 11 patients who had received a diagnosis on the basis of bone marrow examination, 10 patients (91%) had positive results on random skin biopsy.¹³ Other small case series (involving 24 and 32 patients) also suggest that random skin biopsy aids in the diagnosis of patients with fever of unknown origin and an elevated LDH level when intravascular lymphoma is suspected.^14,15 The rarity of the disease, its frequently rapidly progressive course, and the nonspecific nature of the presenting symptoms often result in diagnostic delays, and in some cases the disease is identified only at autopsy.^3,9 It is essential to recognize the potential value of random skin biopsy for prompt diagnosis.

The present case highlights intravascular lymphoma as a cause of fever of unknown origin. This patient underwent an exhaustive search over a period of many months to investigate his persistent fever and pancytopenia. Ultimately, it was the addition of a relatively simple skin biopsy that identified the disorder that was lurking just beneath the surface.