My home is my castle
Authors: Inna Zeitlin, Roy Beigel, Hananya Vaknine, Paolina Potachenko, Yitzhak Beigel
Journal: American Journal of Hematology (2010)

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 [1]. 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 [2], 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%) [3]. 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. Biopsy specimen of right axillary lymph node. This specimen shows a regressively transformed germinal center on the left (asterisk), surrounded by mantle cells forming concentric rings with blood vessels (thin arrows), penetrating the germinal centers at a right angle. On the right (thick arrows) sheet of mature plasma cells are readily recognized; features compatible with Castleman's disease, plasma cell variant (hematoxylin and eosin, ×100). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 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. Biopsy specimen of left axillary lymph node. This biopsy exposes the infiltration of the regressing follicles by sheets of plasmablastic cells (arrow) surrounded by florid proliferation of high endothelial venules (Panel A). The plasmablasts are highlighted by lambda light chain stain inside the follicle (arrow), which also stains plasma cells outside the follicle in a ringlike fashion (arrowheads, Panel B). Kappa light chain stain was negative inside the follicle (arrow) being positive only in the plasma cells surrounding the regressing follicle (arrowheads, Panel C) indicating monoclonality for lambda light chain in the neoplastic intrafollicular plasmablastic cells. The plasmablastic cells illustrate nuclear staining with HHV-8 (Panel D). (Panel A, hematoxylin and eosin, ×100; Panels B–C, lambda and kappa immunoperoxidase stains, respectively, ×100; Panel D, HHV-8 immunoperoxidase stain, ×200). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Core needle biopsy specimen of liver. Liver sinusoids infiltrated by plasmablastic cells (arrow, Panel A, hematoxylin and eosin ×100). The palsmablasts are highlighted by lambda light chain (Panel B, lambda immunoperoxidase stain, ×100). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The first clinical suspicion in this young previously healthy patient presenting with recent onset low-grade fever, nonspecific symptoms, and peripheral lymphadenopathy is of an infectious disease. However, when the initial work up proved unrevealing, her condition became a diagnostic challenge. The characteristics of the lymphadenopathy may provide important diagnostic clues. Fluctuant cervical node may suggest a mycobacterium infection, while enlarged lymph node, fixed, or unfixed, with firm consistency, may be caused by postinflammatory fibrosis or metastatic deposits. These were lacking in this patient. Nonlocalized lymphadenopathy suggests a systemic cause. In this patient, common bacterial and viral diseases were ruled out early on, necessitating an expanded investigation for less common infections. Being a Russian immigrant and a hospital employee, TB and occupational diseases had to be considered. Other less likely pathogens such as syphilis, brucellosis, bartonellosis, and toxoplasmosis also had to be excluded before abandoning the infectious hypothesis and focusing attention on other etiologies—autoimmune and neoplastic disorders. The absence of multiorgan involvement and the negative laboratory results (ANA, RF) lessened the likelihood of autoimmune diseases. The clinical course was also inconsistent with those immunologic diseases that do not have distinctive markers (sarcoidosis, adult-onset Still's disease). Thus, the prime suspicion after eliminating infectious and autoimmune causes was a lymphoproliferative disease, such as lymphoma or CD, each of which could explain the presentation. The best diagnostic approach was to perform an excision lymph node biopsy. However, its nondiagnostic finding presented the physician with a dilemma: could it be a false negative result and, if so, should the procedure be repeated? Being an excision biopsy, a false negative result due to an insufficient amount was excluded, leaving only the possibility of an unrepresentative lymph node. The decision to pursue a diagnosis depends on how strong the clinical suspicion is, and whether delaying diagnosis and therapy could adversely affect outcome. In this case, the physician strongly suspected lymphoma and thus recommended another lymph node biopsy. However, this young woman, who had already undergone extensive fruitless investigation, declined further invasive evaluation. When performed later, after clinical deterioration, CD was diagnosed. CD is an infrequent lymphoproliferative disorder of uncertain etiology whose clinical manifestations are diverse. It may present as a unicentric discrete lymphadenopathy (UCD) that usually runs a benign asymptomatic course, or as a generalized multicentric lymphadenopathy (MCD), as with our patient, whose pace may vary from an indolent through episodic relapsing or a severe progressive life-threatening course. MCD presents with lymphadenopathy (90% of patients), marked weight loss (70%), persistent fever, and splenomegaly. Anemia occurs in virtually all patients, pancytopenia (35%), hypoalbuminemia, polyclonal hypergammaglobulinemia, and immunologic abnormalities are also common [4]. Death is usually due to fulminant infection or related malignancies. MCD may be associated with secondary tumors such as B-cell lymphoma, Kaposi sarcoma, plasmacytoma, and POEMS syndrome [5]. Histologically, two major forms of CD are recognized: (1) the hyaline vascular type, which is usually unicentric (U-HVV), occurring in 90% of the patients with UCD, presenting as a localized disease (mostly mediastinal or at the hilum of the lungs) and running a relatively benign course; (2) a more aggressive plasma-cell variant, which is multicentric (M-PCV) in 80% of patients, and unicentric (U-PCV) or demonstrating mixed patterns in others. A subvariant of M-PCV, the plasmablastic M-PCV, is associated with HIV and may have a particularly aggressive course with progression to plasmablastic lymphoma [5, 6]. The pathogenesis of CD is uncertain. Both UCD and MCD are associated with the overproduction of IL-6. MCD, unlike UCD, is strongly associated with HHV-8 and immunosuppression. HHV-8 is found in all HIV-associated MCD and in 50% of MCD-HIV negative [7]. Its significance in this HIV seronegative patient is demonstrated by the positive staining in the plasmablasts and the antilytic phase antibodies, indicating viral replication. It is proposed that the initial step in the development of CD is overproduction of IL-6 by B cells stimulated by HHV-8 infection. HHV-8 encodes a viral homologue of IL-6, which can mimic human IL-6 and also induce the production of human IL-6. IL-6 has multiple biologic activities including the promotion of B-cell proliferation and differentiation to plasma cells, stimulation of inflammatory pathways, and induction of B-cell malignancies [7]. Data on the optimal treatment of CD are scarce due to its rarity, the varied clinical characteristics, and the remitting relapsing course. UCD is usually cured after resection of the involved lymph node and is not associated with increased mortality. In MCD, the median survival is 14–30 months. However, as demonstrated here, it may be much shorter [8]. Patients with MCD should be candidates for multimodality therapy, the nature of which has yet to be defined. Surgery generally does not have a role in the treatment of MCD, although splenectomy can result in transient symptomatic improvement [9]. This patient was treated with steroids, which may temporary ameliorate symptoms but only rarely induce a long-lasting remission. Because MCD is a lymphoproliferative process, various chemotherapies (as in NHL) and rituximab have been reported to be effective [9]. Rituximab appears efficacious especially in HIV-associated MCD. It can induce clinical remission at first presentation as well as in pretreated patients with relaped HIV-associated MCD and also reduces inflammatory cytokines [10, 11]. Novel treatments, based on recent understanding of the biological basis, include antiviral (interferon alfa, ganciclovir), anti-IL-6 antibodies (tocilizumab), and antiangiogenic (thalidomide) drugs [9]. Whether an earlier diagnosis and more aggressive therapy would have changed, the fatal course of this patient can only be speculated. This case illustrates the difficulties in diagnosing and treating an uncommon variant of a rare disease. The authors thank Dr. Shira Goldenberg for her helpful comments.