Hepatic plasmacytosis as a manifestation of relapse in multiple myeloma treated with thalidomide.

Abstract: Thalidomide and its analogs have been extensively studied in patients with multiple myeloma. We present the case of a 58-year-old female patient with immunoglobulin GA-[kappa] multiple myeloma who was receiving thalidomide after failing an autologous transplant. She presented with profound asthenia and several space-occupying hepatic lesions, one of which was shown by a CT-guided percutaneous biopsy to be plasmacytoma. The patient then received bortezomib and had a transient response. Because thalidomide may also increase the expression of cytoadhesion molecules in myeloma cells and in the bone marrow microenvironment, it is possible that some patients with multiple myeloma who relapse on thalidomide may present with extramedullary plasmacytomas, as seen in this case. Therefore, whenever symptoms arise in patients with multiple myeloma who are receiving thalidomide, extramedullary plasmacytomas should be considered.

Key Words: liver neoplasms, myeloma, plasmacytoma, thalidomide

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Thalidomide and its analogs are active in patients with multiple myeloma and have been extensively studied in this disease. (1,2) The action mechanism of these compounds is not completely understood but seems to involve downregulation of angiogenesis and of tumor necrosis factor-[alpha], resulting in a decreased expression of interleukin-6, a known myeloma growth factor. Thalidomide may also increase the expression of cytoadhesion molecules in myeloma cells and in the bone marrow microenvironment, such as lymphocyte function-associated antigen-1, intercellular adhesion molecule-1, and vascular cell adhesion molcules-1. (1,2) It is therefore not surprising that some patients with multiple myeloma who relapse while taking thalidomide may present with extramedullary plasmacytomas in the absence of progression of their disease in the bone marrow, as described by several authors. (2,3)

We present the case of a patient with immunoglobulin (Ig)GA-[kappa] multiple myeloma who was receiving thalidomide, who presented with profound asthenia and several space-occupying hepatic lesions that mimicked hepatic metastasis.

Case Report

Our patient, a 58-year-old woman with a history of mitral valve stenosis ascribed to childhood rheumatic fever, presented in January 1999 with lumbar pain. Upon investigation with a CT-guided needle biopsy of the affected L2 lumbar vertebra, a plasmacytoma was discovered. Laboratory studies revealed 20% plasmocytes in her bone marrow aspirate, a creatinine of 0.6 mg/dL, hemoglobin of 14.2 g/dL, calcium of 1.24 mmol/L, B2 microglobulin of 2,734 ng/mL, a total protein of 7.5 g/dL, an albumin of 3.56 mg/dL, a monoclonal protein identified as IgA-[kappa] with an IgA level of 760 mg/dL, negative Bence-Jones protein in a 24-hour urine sample, and a normal cytogenetic study. The patient received two cycles of oral melphalan and prednisone. She then received a cycle of vincristine, doxorubicin, and dexamethasone for one cycle, followed by another cycle of cyclophosphamide, vincristine, doxorubicin, and dexamethasone, followed by granulocyte colony-stimulating factor and collection of peripheral blood stem cells. She received high-dose melphalan followed by peripheral blood stem cell infusion, and, on marrow recovery, low-dose interferon three times per week and monthly pamidronate, which was later changed to zoledronic acid. After the autologous transplant, her marrow aspirate revealed 1% plasmocytes, and there was no monoclonal spike detectable in serum electrophoresis. In June of 2000, her bone marrow aspirate showed 50% plasmocytes and her IgA level rose to 2,400 mg/dL and she was started on 200 mg thalidomide daily, which was initially increased to 300 mg daily. She achieved a complete response with disappearance of marrow plasmacytosis and of the monoclonal spike. The treatment with thalidomide, however, was complicated by hypothyroidism and syncope caused by bradycardia that required a permanent pacemaker. In October 2003, she presented with profound asthenia and several space-occupying hepatic lesions (Figure, A), one of which was shown by a CT-guided percutaneous biopsy to be plasmacytoma (Figure, C), with a positive immunoperoxidase stain for the [kappa]-light chain in the malignant cells (Figure, D). Her IgA level was elevated (517 mg/dL, with a normal value ranging from 85 to 450 mg/dL), she had 9% plasmocytes in her marrow aspirate, and 24-hour urine collection showed a [kappa]-to-[lambda] ratio of 19:76 with a [kappa]-chain level of 24.9 mg/dL (with a normal value up to 1.85 mg/dL). She was started on bortezomib, with a major response in her hepatic lesions after the first month of this therapy (Figure, B). In December 2003, the hepatic lesions progressed and did not respond to the addition of high-dose dexamethasone. She was advised to undergo nonmyeloablative allogeneic bone marrow transplantation with peripheral blood stem cells collected from a histocompatible sister.

Discussion

Myeloma may affect the liver through direct malignant cell infiltration, (4) biliary obstruction by plasmacytomas present in the pancreas or main biliary ductus, (5,6) and by amyloid deposition. (7,8) Plasma cell infiltration may be diffuse, (4) or it may present as a singular, or multiple, space-occupying lesion (plasmacytoma), as in the case reported here. Several instances of space-occupying lesions were described in the literature (9-12) in patients who present at diagnosis with single (9,10,12) or multiple liver plasmacytomas (11) that usually occur without concomitant myeloma infiltration of the bone marrow. (9,10,12) Interestingly, however, myeloma with progression multiple liver plasmacytomas, as reported here, appears to be a very rare occurrence.

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Since thalidomide upregulates adhesion molecules in the bone marrow environment, it is possible that one mechanism of resistance to this medication may be the appearance of myeloma cells that are not sensitive to the increased expression of these adhesion molecules and therefore are more likely to leave the bone marrow to lodge at extramedullary sites. (1) In fact, Avigdor et al (3) reported two patients who relapsed after treatment with thalidomide; one of them presenting with extramedullary plasmacytomas in the skin and nasal mucosa and the other in the central nervous system. (2) Interestingly, in these two cases, the extramedullary plasmacytomas occurred in the context of a bone marrow response to thalidomide. (3)

In our patient, several hepatic lesions were discovered by CT scan and a CT-guided biopsy of one of these lesions showed a monoclonal proliferation of plasma cells positive for the [kappa]-light chain by immunoperoxidase. It is interesting to speculate in this case whether the liver plasmacytomas represent a different clone of myeloma cells, perhaps originated through clonal evolution. No cytogenetic studies were conducted on the liver biopsy specimen. Nevertheless, this patient showed a transient response to bortezomib, a new proteasome inhibitor that appears to be recently evolving as a therapeutic alternative for patients who relapse while receiving thalidomide. (13)

Conclusion

We conclude that patients taking thalidomide may relapse at extramedullary sites. Therefore, whenever symptoms arise in patients such as these, one may need to order imaging studies of symptomatic areas including the lung, liver, and central nervous system to exclude extramedullary plasmacytomas.

Accepted August 31, 2004.

References

1. Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol 2003;21:4444-4454.

2. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565-1571.

3. Avigdor A, Raanani P, Levi I, et al. Extramedullary progression despite a good response in the bone marrow in patients treated with thalidomide for multiple myeloma. Leuk Lymphoma 2001;42:683-687.

4. Yagci M, Sucak GT, Akyol G, et al. Hepatic failure due to CD3+ plasma cell infiltration of the liver in multiple myeloma. Acta Haematol 2002;107:38-42.

5. Mitchell DG, Hill MC. Obstructive jaundice due to multiple myeloma of the pancreatic head: CT evaluation. J Comput Assist Tomogr 1985;9:1118-1119.

6. Lake G, Schade RR, Van Thiel DH. Extrahepatic biliary tract obstruction due to plasmacytoma. J Clin Gastroenterol 1983;5:273-276.

7. Okabe M, Choi GH, Kudo M, et al. Hepatic failure due to myeloma-associated amyloidosis. J Gastroenterol 1998;33:926-927.

8. Ales NC, Daniels JT, Frizell ER, et al. Multiple myeloma-associated amyloidosis manifested as fulminant hepatic failure. South Med J 2001;94:1036-1038.

9. Weichhold W, Labouyrie E, Merlio JP, et al. A primary medullary plasmacytoma of the liver: a case report. Am J Surg Pathol 1995;19:1197-1202.

10. Petrucci MT, Tirindelli MC, De Muro M, et al. Extramedullary liver plasmacytoma: a rare presentation. Leuk Lymphoma 2003;44:1075-1076.

11. Ng P, Slater S, Radvan G, et al. Hepatic plasmacytomas: case report and review of imaging features. Australas Radiol 1999;43:98-101.

12. Demirhan B, Sokmensuer C, Karakayali H, et al. Primary extramedullary plasmacytoma of the liver. J Clin Pathol 1997;50:74-76.

13. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348:2609-2617.

RELATED ARTICLE: Key Points

* Patients with multiple myeloma who are receiving thalidomide may progress to extramedullary plasmacytomas.

* Multiple space-occupying lesions in the liver of such patients may represent plasmacytomas.

* Bortezomib may be a therapeutic option for these patients.

Auro del Giglio, MD, FACP, Patricia Weinschenker, MD, Ana Rita de Araujo Burgos Manhani, MD, Ana Lucia Ippolito Carbonell, MD, and Cristina A.T.S. Mitteldorf, MD

From Disciplina de Hematologia e Oncologia da Faculdade de Medicina da Fundacao, ABC, Departamento de Patologia do Hospital Sirio Libanes de Sao Paulo, Sao Paulo, Brazil.

Financial support: None

Proprietary interest: None

Reprint requests to Dr. Auro del Giglio, Rua Mariana Correa 369, Sao Paulo, Brazil, 01444-000. Email: [e-mail]