A 42-year-old woman was hospitalized because of a 2-week history of increasing fatigue and a single episode of fever (38.3°C) starting a day before admission. She had no cough, pleurisy, abdominal pain, nausea, diarrhea, urinary urgency, rash, arthralgias, night sweats, or weight loss.
This young patient suffers from nonspecific symptoms, and therefore I would first consider infection, although the differential is broad.
On examination, the patient was alert and oriented. Temperature was 37.2°C, blood pressure was 122/70 mm Hg, pulse 120 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on ambient air. The oropharynx was erythematous with no exudates or tonsillar enlargement. Nontender enlarged lymph nodes up to 1.5 cm in diameter were palpated bilaterally in the cervical and axillary chains. The spleen was palpable 1 cm below the costal ridge. No other abnormalities were identified.
The presence of fever, fatigue, lymphadenopathy, and splenomegaly raised the suspicion of a mononucleosis-like illness such as acute infection due to Epstein–Barr virus (EBV) or cytomegalovirus (CMV). Other infections such as human immunodeficiency virus (HIV), adenovirus, herpes simplex virus, Kikuchi's disease, Streptococcus pyogenes, syphilis, bartonella, mycobacterias, and toxoplasma should also be considered.
White cell count was 5,800 per cubic millimeter with 56% neutrophils, 29% lymphocytes, 13% monocytes, and 2% eosinophils. A few atypical lymphocytes were observed in the blood smear. Hematocrit was 34%, platelet count was 425,000 per cubic millimeter, and erythrocyte sedimentation rate (ESR) was 80 mm after 1 h. Serum levels of creatinine, urea, electrolytes, and liver function tests were normal. Albumin level was 3.2 g/dl (normal 2.2–4 g/dl). Blood, urine, and throat cultures were sterile. Serological tests were positive for EBV IgG and CMV IgG and negative for EBV IgM and CMV IgM. HIV, hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV) antibodies and a rapid plasma reagin test were negative. A chest radiograph was normal. Skin tuberculin test was negative.
The results for EBV and CMV were consistent with a past infection. Primary CMV infection generally causes mild pharyngitis and lymphadenopathy and is usually associated with hepatitis, which was not present. Although reactivation of CMV may occur, it happens most commonly in the setting of immunosuppression and is therefore unlikely in this previously healthy female.
The patient was born in Russia, immigrated to Israel 12 years ago and has not traveled abroad since then. She was married, has three children, and worked as a nurse assistant. Her medical history included mild asthma, diagnosed during childhood and controlled by inhalations of salmeterol and fluticasone as needed, and mild iron deficiency anemia treated with iron preparations. She takes no other medications, and there is no alcohol, tobacco, or illicit drug abuse, or exposure to raw milk or animals. Eleven months before admission, while working in the hospital, she suffered a needle-stick from an unknown patient. Enzyme-linked immunosorbent assay for HIV antibodies was negative at that time.
Although the usual time from HIV exposure to the development of symptoms is 2–4 weeks, incubation periods of up to 10 months have been reported . However, the repeated negative tests rule out this possibility. The patient had no coryza or cough that could have supported an adenovirus infection, showed no characteristic rash of herpes, and the sterile throat culture excluded streptococcus pyogenes infection. She had a monogamous relationship, and there was no history of sexually transmitted disease. The absence of oral and genital chancres and the negative rapid plasma reagin test make secondary syphilis unlikely. The patient was born in Russia, where tuberculosis (TB) is not uncommon. However, lack of a previous TB infection in conjunction with the negative tuberculin skin test and normal chest film makes TB unlikely. In the absence of immunodeficiency and without a history of travel, exposure to improperly cooked meat, or contact with animals, the possibilities of toxoplasmosis and cat scratch disease are not high on the list.
Although the fever abated a few days after hospitalization, fatigue, weakness, and malaise continued.
In the absence of a febrile disease, the prolonged malaise along with the peripheral lymphadenopathy, hypoalbuminemia, and markedly elevated ESR warrants consideration of a systemic noninfectious disease. Immunologic disorders such as systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), rheumatoid arthritis (RA), and sarcoidosis, as well as malignancy such as lymphoma, Castleman's disease (CD) and solid tumors should be considered.
Tests for rheumatoid factor (RF), antinuclear antibodies (ANA), and ribonucleoproteins (Ro and LA) antibodies were negative. Levels of complement C3 and C4 and angiotensin-converting enzymes were normal. Serum protein electrophoresis showed polyclonal hypergammaglobulinemia.
Autoimmune diseases such as SLE usually afflict middle-aged women and could explain the malaise, lymphadenopathy, and splenomegaly. However, there is neither clinical nor laboratory evidence to support SLE. Keratoconjunctivitis, xerostomia, and arthritis, typical manifestations of SS, are also absent. Although a progressive fatigue and lymphadenopathy may precede arthralgia in RA , the negative rheumatoid factor makes it unlikely. Sarcoidosis can present with peripheral lymphadenopathy and splenomegaly. Evidence of pulmonary involvement or noncaseating granuloma in the lymph node could support this diagnosis. Looking for sarcoidosis, lymphoma, or other neoplasms, my next step is to perform a computed tomography (CT) and lymph node biopsy.
A contrast enhanced CT of the chest, abdomen, and pelvis showed mediastinal, hilar, periaortic, mesenterial, retroperitoneal, and iliac lymphadenopathy, up to 1.5 cm in diameter, and mild splenomegaly.
The generalized lymphadenopathy and splenomegaly in the absence of any pulmonary abnormalities do not support sarcoidosis, whereas lymphoma remains high on the differential. The relatively acute presentation of this disease raises the possibility of an aggressive lymphoma or Hodgkin's lymphoma. These diseases, compared to indolent lymphomas, are more likely to occur in relatively young people such as this patient. To receive a sufficient amount of lymph node for morphologic evaluation, immunohistochemical staining, and cytogenetic analysis, excision biopsy, rather than a fine-needle aspiration or core biopsy, is preferred.
Excision biopsy of a left axillary lymph node (1 cm in diameter) showed only reactive changes. No malignant, infectious, or granulomatous changes were observed.
How then should I proceed? On one hand, the patient continues to feel sick, and my suspicion of an ongoing systemic disease is high. On the other hand, 3 weeks of extensive investigation have so far proved ineffective. Is it a nonspecific postviral state that will resolve spontaneously or, because the excised lymph node was only 1 cm in diameter it might not have been representative, and therefore is a second biopsy warranted? As my concern of a lymphoproliferative disorder remains high, a second lymph node biopsy was recommended.
The patient declined another biopsy. She was discharged under the surveillance of the hematologic outpatient clinic. During the next 3 months, she continued to feel weak and suffer from fatigue. A repeat total body CT revealed unchanged lymphadenopathy and splenomegaly. A second lymph node biopsy and a bone marrow (BM) biopsy were recommended by the hematologist. The patient agreed only to a BM biopsy, which revealed hypercellular marrow with normal differentiated cells of all hematopoietic lines, and no evidence of malignancy or granuloma.
BM involvement in non-Hodgkin lymphoma (NHL) is usually focal; thus, this reactive BM did not exclude lymphoma. Furthermore, involvement of BM by lymphoma is seen more often in patients with indolent NHL (40–90%) than in patients with aggressive NHL (18–36%) . Hence, histopathologic evaluation of a lymph node is critical in order to rule out this possibility.
Six months after the first admission, the patient was readmitted because of 1 week duration of fever up to 38.3°C and drenching night sweats. Physical examination revealed more enlarged lymphadenopathy and splenomegaly. Laboratory studies showed anemia (hematocrit of 28%), consistent with chronic disease, normal leukocyte, and platelet counts and an ESR of 85 mm after 1 hr. No other laboratory abnormalities were identified. Blood and urine cultures were sterile.
These complaints, after eliminating an infectious cause, are consistent with B symptoms of an undiagnosed lymphoma.
A right axillary lymph node biopsy was performed yielding the diagnosis of CD, plasma cell variant (see Fig. 1). Prednisone, 60 mg daily, was initiated. The fatigue, night sweats, and fever abated, and the patient was discharged, gradually tapering prednisone. Three months later, she was readmitted because of spiking fever, malaise, dry cough, and dyspnea. Scattered wheezing and a prolonged expiration were heard. Laboratory evaluation showed a normal white-cell count, hematocrit of 29%, and a platelet count of 135,000 per cubic millimeter. Serum levels of electrolytes, bilirubin, liver enzymes, and renal functions were normal. The chest X-ray was noncontributory. Therapy with inhaled bronchodilators, intravenous cefuroxime, and steroids was initiated with no improvement. The patient's condition deteriorated rapidly, fever increased up to 40.5°C. Meropenem, vancomycyn, and amphothericin were started with no improvement. Severe jaundice and anasarca appeared. The hematocrit dropped to 16%, platelet count decreased to 8,000 per cubic millimeter. Total bilirubin increased to 43 mg/dl (normal 0.3–1.0 mg/dl), lactate dehydrogenase was 5686 U/l (normal 240–540 U/l), alanine aminotransferase and aspartate aminotransferase increased 10- to 20-fold, albumin level dropped to 1.99 g/dl, PT-INR was 2.11, and PTT-66.1 sec. Repeated blood and urine cultures, serologic tests for HCV, HBV and HAV, parvovirus, HIV, mycoplasma, and legionella were all negative. A serologic test for human herpes virus 8 (HHV-8) revealed a high titer of antilatent and antilytic phase antibodies. Intravenous ganciclovir was added with no improvement.
This life-threatening clinical course is different from previous admissions. As this patient has the least favorable type of CD, the plasma cell form, transformation to aggressive lymphoma is highly likely.
A third lymph node biopsy, from the left axilla, demonstrated plasmablastic lymphoma arising in multicentric CD (see Fig. 2). BM biopsy was negative for lymphoma. Liver biopsy showed diffuse infiltration by the same malignant plasmablasts, which stained positive for HHV-8 antigen (Fig. 3). The patient's condition continued to deteriorate. She died on the 20th hospital day.