An 86-Year-Old Woman With Refractory Anemia.

The patient was an 86-year-old woman who was referred to our institution for evaluation of persistent refractory anemia and fatigue. Her immediate past medical history was remarkable for a recent hospitalization for pneumonia, which was successfully treated with antibiotics, and renal failure (serum urea nitrogen, 14.64 mmol/ L; creatinine, 265 [micro]mol/L). Workup at the time was negative for neoplasia. A skeletal survey showed mild osteoporosis. A bone marrow biopsy revealed a hypercellular marrow with hyperplastic megaloblastic erythropoiesis and leukopenia. The anemia and leukopenia did not improve with filgrastim and epoetin alfa therapy. At the time of referral to our institution, the patient was anemic (red blood cell count, 2.01 X [10.sup.12]/L; hemoglobin, 70 g/L; hematocrit, 0.201) and had mild macrocytosis, normochromia, moderate anisocytosis, and leukopenia (white blood cell count, 2.57 X [10.sup.9]/L). No immature cells were seen. A bone marrow aspirate and biopsy were hypercellular for age, with cellularity averaging 70% to 80%. Many large cells with pleomorphic nuclear features, convolutions, and multilobation were present (Figures 1 and 2). Myeloid, erythroid, and megakaryocytic elements appeared morphologically normal, but were markedly decreased. Mild fibrosis was noted. Iron was markedly increased.

[ILLUSTRATIONS OMITTED]

What is your diagnosis?

Pathologic Diagnosis: Plasma Cell Myeloma With Multilobated Nuclei

Further evaluation of the aspirate and biopsy revealed approximately 45% plasma cells, including atypical forms occasionally in clusters. These infiltrating cells varied in morphology from rare mature plasma cells to more frequent large cells with nuclear multilobation. Some of the nuclei were clover leaf-like in appearance. The nuclear-cytoplasmic ratio was high and the cytoplasm was amphophilic. Immunohistochemistry showed monoclonal [Kappa]light-chain cytoplasmic staining (Figure 3). Rare plasma cells were [CD45.sup.+], [CD20.sup.-], [CD43.sup.-], [CD3.sup.-], and [p53.sup.-]. Serum immunofixation electrophoresis disclosed only a [Kappa]-light-chain paraprotein. Serum immunoglobulin (Ig) A (0.592 g/L) and IgM (0.197 g/L) levels were both decreased, whereas the IgG value was within the normal range. A diagnosis of plasma cell myeloma was made, and the patient was treated with multiple cycles of chemotherapy. During the course of her treatment, she was admitted and treated for herpes zoster, gastrointestinal bleeding, and pulmonary thromboembolism. The patient died 7 months after her initial presentation.

We present a case of a previously described, but rare, morphologic variant of multiple myeloma known as plasma cell myeloma with multilobated nuclei. A total of 18 cases have been reported to date, from 1988 to 1998.[1-4] These articles have addressed the relationship of multilobulation of the nuclei with prognosis. The 18 cases were described in 4 articles, 10 cases by Buss et al[1] in 1988, 6 by Zukerberg et al[2] in 1990, and 2 in case reports.[4,5]

The results of the reported studies showed that there is no apparent sexual predilection. Of the 18 previously reported cases, 10 patients were men and 8 were women.[1,2,4,5] The age range at presentation was 54 to 78 years.[1,2,4,5] The presenting symptoms included polydipsia, polyuria, decreased appetite, weight loss, bone pain, weakness, and fatigue. Common laboratory findings included anemia, slightly elevated calcium levels, lytic bone lesions, and serum monoclonal gammopathy or Bence-Jones proteinuria.[2,4,5]

The bone marrow cellularity ranged from 30% to 100% in the previously reported cases.[2] Plasma cells were increased, ranging from 25% to 65%, and exhibited morphologic variation from mature plasma cells to multinucleated plasma cells or cells with multilobated, cleaved, or monocytoid nuclei.[1,2,4,5] Some plasma cells had markedly irregular nuclear contours, while others had distinct nuclear lobulation similar to those seen in neutrophilic bands and segmented forms, megakaryocytes, Sezary cells, or convoluted lymphoblastic lymphoma.[1] Plasma cells with abundant pale or blue cytoplasm with 2 to 4 nuclear lobes were described.[2] The monoclonal protein type reported by Buss et al[1] was either [Kappa] or [Lambda] light chain, combined with IgG, IgA, or IgD. Four cases expressed light chain only.

Zukerberg et al[2] concluded that the cases they described fit best into the previously described cleaved and polymorphous subtypes of Bartl et al,[6] which were of intermediate clinical grade, yet had a more aggressive clinical course.[2]

Buss et al[1] classified 7 of 10 patients at stage III on presentation; 50% of these cases were stage IIIA and the other 50% stage IIIB.[1,2,4] Zukerberg et al classified 5 of 6 patients in stage III. The survival period (time to death from diagnosis) varied widely, ranging from 4 to 54 months[1] in one report and 6 days to 14 months[2,5] in others.

Marked nuclear lobulation has been associated with light-chain disease.[3] It appears to pursue a more malignant clinical course with a shorter survival and a higher incidence of renal failure, lytic bone disease, hypercalcemia, and amyloidosis. Chemotherapy has not been implicated as a cause for the multilobulation.[1]

A poor prognostic marker for plasma cell myeloma includes the expression of CD10 (CALLA).[2] Other prognostic markers for myeloma include plasma cell DNA labeling index, serum [[Beta].sub.2]-microglobulin, serum soluble receptor for interleukin 6, and karyotypic abnormalities (ie, deletion of chromosome 13).[3] The morphologic appearance of the plasma cells has been associated with prognosis. The more immature the plasma cells, the more aggressive the clinical course may be.[6] Nuclear multilobation may be yet another poor prognostic indicator in plasma cell myeloma.

The differential diagnosis of multilobated myeloma includes metastatic carcinoma, T-cell lymphomas, myelomonocytic leukemias, megakaryocytes, neutrophils, and histiocytes. Buss et al also described multilobated reactive plasma cells in a case of breast carcinoma.[1]

Myeloma can have a variety of morphologic features, and it is important to recognize that they can be multilobated as well. Reed et al[7] found that in 2% to 3% of their cases the majority of plasma cells expressed marked nuclear lobulation, contortion, or multinucleation, imparting a monocytoid appearance. Multilobated plasma cell myelomas tend to present at a more advanced stage and have a more aggressive course. Awareness of this entity is therefore important to avoid misdiagnosis with other hematologic malignancies.

References

[1.] Buss DH, Reynolds GD, Cooper MR. Multiple myeloma associated with multilobated plasma cell nuclei. Virchows Arch B Cell Pathol Incl Mol Pathol. 1988;55:287-292.

[2.] Zukerberg LR, Ferry JA, Conlon M, Harris NL. Plasma cell myeloma with cleaved, multilobated, and monocytoid nuclei. Am J Clin Pathol. 1990;93:657-661.

[3.] Greipp PR. Prognosis in myeloma. Mayo Clin Proc. 1994;69:895-902.

[4.] Invernizzi R, Perfetti V. A case of multiple myeloma with multilobated plasma cell nuclei. Hematologica. 1998;83:851.

[5.] Islam A, Noyes S, Henderson ES. A case of aggressive multiple myeloma with convoluted and multilobated plasma cell nuclei and no visible nucleoli. Br J Haematol. 1990;76:306-307.

[6.] Bartl R, Frisch B, Fateh-Moghadam A, Kettner G, Jaeger K, Sommerfeld W. Histologic classification and staging of multiple myeloma. Am J Clin Pathol. 1987; 87:343-355.

[7.] Reed M, McKenna RW, Bridges R, Parkin J, Frizzeria G, Brunning R. Morphologic manifestations of monoclonal gammopathies. Am J Clin Pathol. 1981; 76:8-23.

Accepted for publication January 11, 2001.

From the Department of Pathology, University of Illinois-Metropolitan Group Hospitals, Illinois Masonic Medical Center, Chicago, III.

Reprints not available from the authors.