liver disease as primary manifestation of multiple myeloma in a young man

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Leukemia Research 23 (1999) 403 – 405 Case of the Month Liver disease as primary manifestation of multiple myeloma in a young man Pilar Solves, Javier de la Rubia, Isidro Jarque, Jose ´ Cervera, Guillermo F. Sanz, Francisco J. Vera-Sempere, Miguel A. Sanz * Ser6icio de Hematologı ´a, Hospital Uni6ersitario La Fe, A6enue Campanar 21, 46009 Valencia, Spain Received 17 June 1998; accepted 3 July 1998 Abstract We report a 27-year-old man who presented with fatigue, moderate weight loss and progressive abdominal distension as primary manifestations of a light-chain multiple myeloma (MM). Liver scan showed an enlarged liver with multiple low attenuation areas. Liver biopsy revealed sinusoidal infiltration by small size cells identified as Kappa light chain-producing primitive plasma cells by immunohistochemistry. The patient responded to three courses of EDAP. Subsequently he received intensive therapy with busulfan/melfalan and a peripheral blood stem cell transplantation enriched for CD34 + cells from his HLA-identical brother. No acute graft-versus-host disease was detected. Now, 12 months after transplant, the patient is asymptomatic. © 1999 Published by Elsevier Science Ltd. All rights reserved. Keywords: Multiple myeloma; Liver disease; Allogeneic peripheral blood transplantation 1. Introduction Multiple myeloma (MM) is a malignant plasma cell disorder characterized by the production of a mono- clonal immunoglobulin, usually IgG or IgA. Recurrent bacterial infections, anemia, osteolytic lesions and renal insufficiency are the most common clinical features. It has a peak incidence in the seventh decade of life, with less than 3% of the patients younger than 40 years, being extremely rare in people younger than 30 years [1]. At diagnosis, renal involvement is observed in 50% of the patients but other systemic involvement is less frequent. In fact, although in the post-mortem exami- nation liver infiltration by plasma cells has been de- scribed in a significant proportion of patients, hepatomegaly from plasma cell infiltration is uncom- mon. Moreover, a clinical picture with predominant hepatic involvement is an exceptional way of presenta- tion, and only a few cases have been reported so far in the literature [2]. We report here a case of a 27 year-old man who presented with ascites and an enlarged liver with multiple nodular lesions as the initial clinical man- ifestation of a light-chain MM. 2. Clinical summary A 27 year-old man was admitted to the hospital on December, 1996 with a 6-week history of fatigue, mod- erate weight loss and progressive abdominal distension. Physical examination revealed pallor and abdominal distension with evidence of ascites. Liver was palpable 4 cm below the costal margin; lymphadenopathy and splenomegaly were absent. Complete blood count showed a WBC count of 9.9 ×10 9 /l, an hemoglobin level of 10.5 g/dl, and a platelet count of 119 ×10 9 /l. The blood urea nitrogen was 24 mg/dl, the serum creatinine 1.33 mg/dl, the serum calcium 9.46 mg/dl, the Abbre6iations: MM, multiple myeloma; BMT, bone marrow trans- plantation. * Corresponding author. Tel.: +34-96-3868757; fax: +34-96- 3868757. 0145-2126/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved. PII:S0145-2126(98)00168-4

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Page 1: Liver disease as primary manifestation of multiple myeloma in a young man

Leukemia Research 23 (1999) 403–405

Case of the Month

Liver disease as primary manifestation of multiple myeloma in ayoung man

Pilar Solves, Javier de la Rubia, Isidro Jarque, Jose Cervera, Guillermo F. Sanz,Francisco J. Vera-Sempere, Miguel A. Sanz *

Ser6icio de Hematologıa, Hospital Uni6ersitario La Fe, A6enue Campanar 21, 46009 Valencia, Spain

Received 17 June 1998; accepted 3 July 1998

Abstract

We report a 27-year-old man who presented with fatigue, moderate weight loss and progressive abdominal distension asprimary manifestations of a light-chain multiple myeloma (MM). Liver scan showed an enlarged liver with multiple lowattenuation areas. Liver biopsy revealed sinusoidal infiltration by small size cells identified as Kappa light chain-producingprimitive plasma cells by immunohistochemistry. The patient responded to three courses of EDAP. Subsequently he receivedintensive therapy with busulfan/melfalan and a peripheral blood stem cell transplantation enriched for CD34+ cells from hisHLA-identical brother. No acute graft-versus-host disease was detected. Now, 12 months after transplant, the patient isasymptomatic. © 1999 Published by Elsevier Science Ltd. All rights reserved.

Keywords: Multiple myeloma; Liver disease; Allogeneic peripheral blood transplantation

1. Introduction

Multiple myeloma (MM) is a malignant plasma celldisorder characterized by the production of a mono-clonal immunoglobulin, usually IgG or IgA. Recurrentbacterial infections, anemia, osteolytic lesions and renalinsufficiency are the most common clinical features. Ithas a peak incidence in the seventh decade of life, withless than 3% of the patients younger than 40 years,being extremely rare in people younger than 30 years[1].

At diagnosis, renal involvement is observed in 50% ofthe patients but other systemic involvement is lessfrequent. In fact, although in the post-mortem exami-nation liver infiltration by plasma cells has been de-scribed in a significant proportion of patients,hepatomegaly from plasma cell infiltration is uncom-

mon. Moreover, a clinical picture with predominanthepatic involvement is an exceptional way of presenta-tion, and only a few cases have been reported so far inthe literature [2]. We report here a case of a 27 year-oldman who presented with ascites and an enlarged liverwith multiple nodular lesions as the initial clinical man-ifestation of a light-chain MM.

2. Clinical summary

A 27 year-old man was admitted to the hospital onDecember, 1996 with a 6-week history of fatigue, mod-erate weight loss and progressive abdominal distension.Physical examination revealed pallor and abdominaldistension with evidence of ascites. Liver was palpable 4cm below the costal margin; lymphadenopathy andsplenomegaly were absent. Complete blood countshowed a WBC count of 9.9×109/l, an hemoglobinlevel of 10.5 g/dl, and a platelet count of 119×109/l.The blood urea nitrogen was 24 mg/dl, the serumcreatinine 1.33 mg/dl, the serum calcium 9.46 mg/dl, the

Abbre6iations: MM, multiple myeloma; BMT, bone marrow trans-plantation.

* Corresponding author. Tel.: +34-96-3868757; fax: +34-96-3868757.

0145-2126/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.

PII: S 0145 -2126 (98 )00168 -4

Page 2: Liver disease as primary manifestation of multiple myeloma in a young man

P. Sol6es et al. / Leukemia Research 23 (1999) 403–405404

alkaline phosphatase 42 U/l, the total serum bilirrubin1.24 mg/dl, the aspartate amino transferase 34 U/l,lactic dehydrogenase 421 U/l and uric acid 8.41 mg/dl.Total serum proteins were 6.15 mg/dl, and serum b2-microglobulin 2.79 mg/dl. A bone marrow aspirateshowed 4% of plasma cells and 15% of lymphoid cellswith plasmacytic differentiation. A skeletal survey re-vealed cranial osteolytic lesions. The erythrocyte sedi-mentation rate was 29 mm/h. Serum immunoelectro-phoresis revealed hypogammaglobulinemia and nomonoclonal protein. An unconcentrated specimen ofurine revealed monoclonal kappa light chains. A sono-gram of the abdomen confirmed ascites and hep-atomegaly. A computerized tomography scan (CT)showed multiple low attenuation areas in the liver (Fig.1).

The abdominal distension observed at diagnosis pro-gressed quickly, and the patient developed ascites re-fractory to depletive treatment that requiredparacentesis. A laparoscopic examination with liverbiopsy was then performed. Laparoscopy showed adiffuse infiltration of the liver with peritoneal involve-ment. Liver biopsy revealed diffuse sinusoidal plasmacell infiltrates identified as kappa light chain-producingprimitive plasma cells by immunohistochemistry (Fig.2). Immunohistochemistry of the liver biopsy was nega-tive for anti-keratin antibodies AE1/AE3 and CD20 butpositive for EMA and Bcl-2 oncoprotein. Bone marrowbiopsy showed infiltration by immature cells with occa-sionally bilobed nuclei and fibrosis. Bone marrow im-munohistochemistry was similar to that of liver biopsy.A review of the peripheral blood smear detected 12% oflymphoid cells with plasmacytic differentiation similarto that seen in the bone marrow aspirate. The im-munophenotype was consistent with plasma cells(CD38 and CD56 positivity).

Because the patient’s laboratory and pathologicalfindings were consistent with a diagnosis of stage III-ABence-Jones MM with liver involvement, EDAPchemotherapy (etoposide 400 mg/m2, cisplatinum 80

Fig. 2. Partial sinusoidol (long arrows) and trabecular (short arrows)liver infiltration by small size cells identified as Kappa light chain-producing primitive plasma cells (PAP-Kappa light chain×400).

mg/m2, dexamethasone 40 mg/m2 for 4 days and cy-tosine arabinoside 1000 mg on day 5) was started. Afterthree courses of therapy an objective response wasachieved. Immediately after, the patient underwent aCD34+ selected allogeneic peripheral blood stem celltransplantation from his HLA-identical brother.CD34+ selection was performed by an avidin-biotinimmunoadsorption technique (Ceprate SC; Cellpro Inc;Bothell, USA). Pretransplant conditioning regimen con-sisted of busulfan orally 1 mg/kg/8 h on days −6, −5,−4, −3 plus melfalan 140 mg/m2 on day −2. Graft–versus–host disease (GVHD) prophylaxis consisted ofcyclosporine and prednisone. The CD34+ and CD3+

cell doses infused were 5.34×106/kg and 0.24×106/kg,respectively. The transplant was well tolerated withrapid hematopoietic recovery (median time to reach0.5×109/l neutrophils and 20×109/L platelets 14 and11 days, respectively). Mild increase in bilirrubin levelswas the only transplant-related toxicity observed. Nosigns of acute GVHD were obseved, and the patientwas discharged on day +21 in good clinical condition.Then 3 months after transplant no signs of chronicGVHD were present, and monoclonal kappa lightchains still persisted in urine. However, at 12 monthsafter transplant, the patient is asymptomatic withoutsigns of chronic GVHD and with no detectable lightchains in urine.

3. Discussion

The atypical presentation of this case of MM withclinical symptoms predominantly of abdominal origin(ascites, hepatomegaly) and the CT findings, impliesseveral differential diagnosis (lymphoma, metastasis ofgastrointestinal and lung carcinoma, melanoma). In thispatient, however the finding of a monoclonal light-chain in urine and the results of the liver biopsy confi-Fig. 1. Liver CT scan showing multiple low attenuation areas.

Page 3: Liver disease as primary manifestation of multiple myeloma in a young man

P. Sol6es et al. / Leukemia Research 23 (1999) 403–405 405

rmed the diagnosis of MM. Liver involvement in MMis commonly reported as a post-mortem finding, rang-ing from 26 to 46% of the cases [3,4], nevertheless theincidence of clinical hepatic involvement in MM ismuch lower [5]. In some patients an increase in serumalkaline phosphatase level is the only marker correlatedwith plasmacytic infiltration of the liver. Because of theclinical significance of liver involvement in MM isuncertain, invasive procedures confirming plasma cellinfiltration have been only rarely performed. In the casereported herein, liver biopsy was necessary to make anaccurate diagnosis before starting treatment. Onceconfirmed the diagnosis, and due to the rapid evolutionof the clinical picture with refractory ascites and clinicaldeterioration of the patient, intensive chemotherapywith EDAP was started. This combination has beenemployed in refractory disease with good tolerance andexcellent clinical response [6].

Allogeneic bone marrow transplantation (BMT) hasbeen proposed as a promising and curative method oftreatment of MM specially for young patients. BMTcould have also the advantage of a graft–versus–myeloma effect. Of major concern, however, is the hightransplant-related mortality generally reported (spe-cially in males) [7]. In an attempt to improve theoutcome of allografting by reducing transplant-relatedtoxicity, we decided to use a partially T-cell depletedstem cell transplantation by means of a CD34+ selec-tion method. The patient had an immediate post-trans-plant period without serious complications and no signsof acute GVHD. On the other hand, persistance ofurine light chains till the third month with posteriornormalization could support the graft versus myeloma

effect that has been occasionally reported in the litera-ture [8], although a delayed anti-myeloma effect due tothe busulfan administered can not be ruled out. At 12months after transplant, he remains asymptomatic andwith no detectable light chains in urine.

In conclusion, we believe that although allogeneicBMT is nowadays controversial for patients with MM,allogeneic peripheral blood stem cell transplantationwith CD34+ selection may be an alternative therapeu-tic approach for young patients with MM.

References

[1] Blade J, Kyle RA, Greipp PR. Presenting features and prognosisin 72 patients with multiple myeloma who were younger than 40years. Br J Haematol 1996;93:345–51.

[2] Thiruvengadam R, Penetrante RB, Goolsby HJ, Silk YN, Bern-stein ZP. Multiple myeloma presenting as space-occupying lesionsof the liver. Cancer 1990;65:2784–6.

[3] Kapadia SB. Multiple myeloma: a clinicopathologic study of 62consecutively autopsied cases. Medicine 1980;59:380–92.

[4] Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clin Proc1975;50:29–40.

[5] Perez-Soler R, Esteban R, Allende E, Tornos-Salomo C, Julia A,Guardia J. Liver involvement in multiple myeloma. Am J Hema-tol 1985;20:25–9.

[6] Anderson KC. Who benefits from high-dose therapy for multiplemyeloma? J Clin Oncol 1995;13:1291–6.

[7] Bjorkstrand B, Ljungman P, Svensson H. Allogeneic bone mar-row transplantation versus autologous stem cell transplantation inmultiple myeloma: a retrospective case-matched study from theEuropean Group for Blood and Marrow Transplantation. Blood1996;88:4711–8.

[8] Trigot G, Vesole DH, Jagannath S, et al. Graft versus myelomaeffect: proof of principle. Blood 1996;87:1196.

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