Case of multiple myeloma mimicking an infectious disease with fever intrahepatic cholestasis renal failure and pulmonary insufficiency.код для вставкиСкачать
American Journal of Hematology 72:38–42 (2003) Case of Multiple Myeloma Mimicking an Infectious Disease With Fever, Intrahepatic Cholestasis, Renal Failure, and Pulmonary Insufficiency Francesco S. Vella,1* Barbara Simone,1 Gianluigi Giannelli,1 MariaTeresa Pesolo,1 Giuseppe Ingravallo,2 Antonia Gentile,2 and Salvatore Antonaci1 1 Dipartimento di Clinica Medica, Immunologia e Malattie Infettive, University of Bari, Policlinico, Bari, Italy 2 Dipartimento di Anatomia Patologica e di Genetica, University of Bari, Policlinico, Bari, Italy We describe a case of multiple myeloma (MM) presenting with high fever, inflammatory chemistry abnormalities, simultaneous acute renal failure, cholestatic hepatitis, and acute lung failure. The extremely aggressive course and pulmonary involvement in the form of pulmonary alveolar proteinosis (PAP) are discussed, stressing the unusual nature of the findings and the variable picture of MM. Am. J. Hematol. 72:38–42, 2003. © 2002 Wiley-Liss, Inc. Key words: multiple myeloma; pulmonary alveolar proteinosis (PAP); acute terminal phase; intrahepatic cholestasis; acute-phase reaction INTRODUCTION Multiple myeloma (MM) is a malignant proliferation of plasma cells usually located in the bone marrow. High fever and inflammatory chemistry abnormalities are rare in absence of infectious disease. Recently Mueller et al.  described fever of unknown origin caused by MM in 9 patients with no signs or data indicating infections. Here we describe a case of fatal, diffuse MM mimicking an infectious disease, in view of multiorgan involvement and inflammatory signs. CASE REPORT A 64-year-old joiner was admitted with a 1-month history of high fever, cholestasis (␥GT ⳱ 217 IU/L, normal range ⳱ 11–49 IU/L; alkaline phosphatase ⳱ 900 IU/L, normal range ⳱ 91–258 IU/L; bilirubin within normal limits) and raised serum levels of AST (62 IU/L, normal < 37 IU/L), ALT (96 IU/L, normal < 37 IU/L), LDH (721 IU/L, normal range ⳱ 240–480 IU/L), acutephase reactants (fibrinogen 979 mg/dL, normal range ⳱ 170–410 mg/dL; ␣2 globulin 20.9%, normal range ⳱ 7–11%), especially CRP (88 mg/dL, normal < 5 mg/dL). An accelerated erythrocyte sedimentation rate (ESR 128 mm/1st hr) and microcytic hypochromic anemia were also observed (Table I). © 2002 Wiley-Liss, Inc. He had presented a similar clinical episode 1 year before. Although no infectious agent was identified (as assessed by culture and serological assays), excellent response was obtained to antibiotic therapy (ciprofloxacin), with abatement of the fever and a return to normal of the ESR and liver function tests (Table I). On admission to our Department, physical examination revealed a palpable liver 2 cm below the costal margin but no lymphadenopathy or splenomegaly. Direct tests with standard and Ziehl-Nielsen stains, cultures (sputum, blood, urine, stool), and antibodies against various infectious agents including viruses (hepatitis A, hepatitis B, and hepatitis C viruses, human immunodeficiency virus, herpesvirus group, respiratory syncytial virus, enteroviruses, adenoviruses, and influenza and parainfluenza viruses), Legionellae, mycobacteria, mycoplasmata, chlamydiae, Rickettsias, Borreliae, *Correspondence to: Francesco S. Vella, M.D., Viale JF Kennedy, 75 H, 70124 Bari, Italy. E-mail: firstname.lastname@example.org Received for publication 4 June 2002; Accepted 15 October 2002 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.10257 Case Report: Myeloma Mimicking an Infectious Disease 39 TABLE I. Laboratory Tests Before and After Admission* Laboratory test Hemoglobin (g/L) WBC (×103/mm3) Platelets (×103/mm3) Sideremia (g/L) Ferritin (ng/mL) ESR (mm/1st hr) Creatinine (IU/L) AST (IU/L) ALT (IU/L) GGT (IU/L) AP (IU/L) Bilirubin (mg/dL) IgG (mg/dL) IgA (mg/dL) IgM (mg/dL) M component Calcium (mg/dL) LDH (IU/L) CRP (mg/dL) ␤2 Microglobulin (mg/dL) IL-6 (pg/mL) PT-INR APTT-R Fibrinogen (mg/dL) ATIII (%) D-dimer (g/L) Factor X (%) Normal values February 2000 April 2000 February 2001 (on admission) March 2001 12–16 4–10 150–500 35–150 10–258 <15 0.6–1 <37 <37 11–49 91–258 <1 700–1,600 70–400 40–230 NE 8.5–10.1 240–480 <5 0.8–2 <4 <1.2 <1.16 170–410 75–125 <150 70–130 10.6 7.120 200 18 872 113 0.8 120 160 105 400 0.9 1,000 501 90 NE NE NE 41 NE NE 0.98 0.9 630 NE NE NE 12 6.850 270 NE NE 10 NE 30 35 40 170 0.8 NE NE NE NE NE NE 3.2 NE NE NE NE 250 NE NE NE 10.2 7.620 290 15 2,386 128 0.98 62 96 217 900 0.68 892 419 31 B-J proteinuria () 9.1 721 88 7.5 450 1.01 0.99 979 102 123 NE 9.5 9.920 180 NE 3,170 132 7.19 37 72 350 1,100 1.24 896 276 50 NE 9.2 820 100 NE NE 0.89 1 470 NE NE 114 *WBC, white blood cells; ESR, erythrocyte sedimentation rate; AST, aspartate-aminotransferase; ALT, alanine-aminotransferase; GGT, ␥-glutamyl transpeptidase; AP, alkaline phosphatase; Ig, immunoglobulins; B-J, Bence-Jones; LDH, lactate dehydrogenase; CRP, C-reactive protein; IL-6, interleukin 6; PT-INR, prothrombin time-international normalized rate; aPTT-R, activated partial thromboplastin time-ratio; ATIII, antithrombin III; NE, not evaluated. Brucella, Salmonellae, Toxoplasma, Pneumocystis carinii, and fungi were negative, as were specific tests for autoimmune diseases. There was proteinuria (2 g/24 hr), consisting exclusively of light chains, with no M component in the serum. These findings and the marrow results (50% plasma cells) led to the diagnosis of MM. Circulating plasma cells were not found. The levels of ␤2 microglobulin and IL 6 were 7.5 mg/dL (normal range ⳱ 0.8–2 mg/dL) and 450 pg/mL (normal < 4.0 pg/mL), respectively. A plain radiographic skeletal survey showed no lytic lesion. Because of the increasing levels of cholestatic markers with hepatomegaly, liver biopsy was performed, revealing sinusoidal plasmacytic infiltrates (Fig. 1A). Congo red was negative for amyloid. Plasma cells stained positive for light chains (Fig. 1B). Renal failure developed in a few days (Table I), requiring hemodialysis. Renal biopsy documented myeloma cast nephropathy. Subsequently, the fever persisted, and he developed dyspnea and a dry cough. Chest roentgenography revealed reticulonodular opacities of both lungs; a diffuse reticulonodular infiltrate was visualized by thoracic CT scan, rapidly complicated by pulmonary insufficiency. The inflammatory status and interstitial lung disease suggested an infectious disease, and MM complicated with acute respiratory failure induced by opportunistic infection was hypothesized. Although no infectious etiological agent was identified, he was given antibiotic treatment (cotrimoxazole, sulbactam-ampicillin, ceftriaxone, ciprofloxacin), to no effect. Antiviral and antifungal therapies were not administered. A successive lung CT scan was compatible with pulmonary alveolar proteinosis (PAP) (Fig. 2A), confirmed later by autopsy. Cor pulmonale supervened, and shortly afterward, before chemotherapy could be started, the patient died. Autopsy disclosed plasmacytic infiltration of the liver, kidneys, and spleen; the lungs were congested, and the alveoli were filled with protein that stained positive for light chains (Fig. 2B) while Congo red stain was negative. A thrombus in the right atrium was detected, causing the tricuspid valve obstruction; this was probably the terminal cause of death. DISCUSSION To our knowledge, this is the first case report in the English-language medical literature describing high fe- 40 Case Report: Vella et al. Fig. 1. Liver biopsy specimen showing sinusoidal infiltration by atypical lymphoid cells in Indian file manner, some with plasmacytic features (A, hematoxylin–eosin, original magnification ×400). Immunoperoxidase staining for light chains of monoclonal plasmacytoid cells within sinusoidal spaces (B, diaminobenzidine and hematoxylin, original magnification ×400). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] Fig. 2. Thoracic computed tomogram revealing diffuse symmetric reticulonodular pulmonary infiltrate in both lungs (A). Lung autopsy specimen (B, diaminobenzidine and hematoxylin, original magnification ×400): immunohistochemical demonstration of proteinaceous material within the alveolar spaces staining intense positive immunoreactivity for light chains (black arrows) and slight infiltration of cells with plasmacytoid features mildly positive for light chains (white arrows). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] ver, simultaneous acute renal failure, cholestatic hepatitis, and acute lung failure at the onset of MM. Our patient was also remarkable because of the extremely aggressive course and the pulmonary involvement in the form of PAP. The unusual nature of our case, emphasizing the variable picture of MM, can be summarized as follows: 1. diffuse multiorgan manifestations (liver, lung, kidneys, spleen); 2. inflammatory data (with no apparent underlying infection) and cholestatic laboratory abnormalities; 3. extremely aggressive course. Extramedullary spread of myeloma is rare at diagnosis, and in this context, a clinical picture with predomi- nant hepatic involvement is an exceptional form of presentation [2–6]. The most common clinical manifestation of liver disease is hepatomegaly, which is not always related to plasma cell infiltration [7–9]. Symptomatic liver disease is extremely rare although jaundice is occasionally seen , almost always in association with hepatic amyloid deposits [9–11]. Serum alkaline phosphatase, the only biochemical marker that correlates with plasmacytic infiltrates of the liver, is mildly raised in 25–40% of cases [7,8]. Nodular liver involvement is a very uncommon feature in MM [2,3,5,12,13]. Post mortem series show a higher percentage of liver involvement, demonstrating infiltra- Case Report: Myeloma Mimicking an Infectious Disease tion in 26–46% of MM cases [7,14,15], with nodular, sinusoidal (the most common), portal, and mixed patterns [8,9,14]. Among the various organs potentially affected, pulmonary parenchyma involvement is rare, and, in the few cases described, usually secondary to an infectious process or extending from primary bone involvement, highly variable lung manifestations have been reported . In practice, however, lung involvement is so rare that no attention has been paid to lung investigations in several large MM series [7,17]. Three types of roentgenographic manifestations of myeloma pulmonary involvement are described: nodular mass lesion, diffuse reticulonodular pulmonary infiltrate, and pleural effusion [15,18]. Direct myeloma cell infiltration of the lung and amyloid deposits need to be differentiated from diffuse pulmonary inflammatory processes, pulmonary edema , and from another exceptional infiltrating form, PAP, first described in the course of MM in 1966 by Proks et al. . In 1994, Meijer  reported another case of PAP secondary to MM with no chest X-ray abnormalities, high CRP and LDH, low-grade fever, and kidney and liver infiltrations. In this case, as in ours and in other series, pulmonary involvement was associated with the aggressive terminal phase of MM or plasma cell leukemia [21–23]. In accordance with these authors’ findings and our patient’s features, we hypothesize a link between multi-organ involvement, acute-phase response, and the terminal phase of MM. The high serum levels of LDH, CRP, IL-6, and the high fever documented in our case have already been reported in the course of MM [24,25] and have been recognized as poor prognostic factors, indicating the terminal phase [24,26]. Many researchers agree that large amounts of IL-6 are produced by the tumoral microenvironment in response to stimulating myeloma cells, causing high fever and high serum levels of CRP and inducing the terminal fulminant phase [24,27,28]. A critical point to remember is that CRP is highly influenced by infections (via IL-6 overproduction). Our patient had clinical and laboratory features mimicking infectious disease, consisting of 1. previous episode of fever and intrahepatic cholestasis with transient complete normalization of all laboratory tests after antibiotic therapy; 2. spectrum of organs involved with typical patterns (intrahepatic cholestasis and reticulonodular pulmonary involvement) of infectious diseases; 3. high fever and CRP levels. Secondary PAP also enters the differential diagnosis. 41 The demonstration of the same light chains paraprotein in the alveolar spaces as was found in the blood yielded the diagnosis of PAP with neoplastic pathogenesis rather than PAP secondary to an infectious disease. We also demonstrated the neoplastic pathogenesis of our patient’s features for the remainder of extramedullary locations (liver, kidney). Pulmonary Congo red negative light chain deposits suggested a systemic light chain deposition disease (LCDD). Such cases are usually subtype ; moreover, histology of liver and kidney ruled out finally this unifying hypothesis. Nevertheless, on the bases of clinical features strongly resembling an infectious disease, the suggestion remains whether the acute terminal phase of MM, now known to be a “cytokine-mediated phase,” could in fact be a supervening manifestation of the time-honored infectious disease. REFERENCES 1. Mueller PS, Terrell CL, Gertz MA. 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