A Case of Aggressive Multiple Myeloma with Cleaved, Multilobated, and Monocytoid Nuclei, and No Serum Monoclonal Gammopathy

Annals o f Clinical & Laboratory Science, vol. 30, no. 3, 2000 283

Y. Albert Yeh, Alex A. Pappas, James T. Flick, and Anthony W. Butch* Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (^Current address: Department of Pathology and Laboratory Medicine, UCLA Medical Center, Los Angeles, CA)

Abstract

Multiple myeloma is a B-cell malignancy characterized by proliferation of neoplastic plasma cells. A few cases have been reported identifying variant forms of neoplastic plasma cells with atypical nuclei that secrete myeloma protein. We report a highly unusual case of plasma cell myeloma that presented with cleaved, multilobated, and monocytoid nuclei, without detectable myeloma protein in the serum or urine. The bone marrow contained sheets of plasma cells exhibiting pleomorphic nuclei with cleaved, multilobated, and monocytoid features that were negative for myeloperoxidase and dual esterase. Flow cytometric analysis revealed CD38hlgh/CD45low cells expressing cytoplasmic kappa light chain, without evidence of myeloid or lymphoid differentiation. Following chemotherapy, the patient developed secondary plasma cell leukemia. A high plasma cell labeling index was obtained from bone marrow and peripheral blood, indicating a poor prognosis. In addition to quantitative immunoglobulins, serum protein electrophoresis, and immunofixation electrophoresis of serum and urine, we recommend cytochemical and flow cytometric studies for evaluation of suspected plasma cell myeloma with atypical cellular features.

Keywords: multiple myeloma, plasma cell, cleaved, mutilobated, monocytoid, non-secretory

Introduction 11% of all myeloma cases. The other groups individually account for <10% of the remaining cases, Plasma cell myeloma constitutes approximately 1 % of with the plasmablastic type being a high-grade all malignancies and 10% of all hematologic malig malignancy (2% of all cases) associated with a poor nancies. Several classifications and grading schemes prognosis [ 1 ]. In a small percentage of myeloma cases, for plasma cell myeloma have been proposed [1,2]. the plasma cells exhibit unusual morphologic Histologic classification is based on cellular size, characteristics and the disease follows an aggressive cytoplasmic structure, and nuclear pattern, and is clinical course. For instance, Buss et al [3] identified divided into six groups: Marschalko, small cell, cleaved, 10 multiple myeloma patients with neoplastic plasma polymorphous, asynchronous, and blastic type [1]. The cells containing multilobated nuclei while Zukerberg Marschalko type is a low-grade malignancy that et al [4] reported 6 patients with cleaved, multilobated, accounts for 59% of all cases, and is characterized by and monocytoid plasma cell nuclei. In addition, a few normal-appearing mature plasma cells [1]. The small isolated case reports of this morphologic variant of cell type is also considered low-grade and accounts for multiple myeloma have been described [5-8]. A monoclonal protein consisting of either an intact Address correspondence to Anthony W. Butch, Ph.D., Department immunoglobulin (IgG, IgA, or IgD) or a free light o f Pathology and Laboratory Medicine, UCLA Medical Center, chain (kappa or lambda) is normally detected in serum Mail A2-179 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1713, USA; tel: 310 206 0587; fax: 310 794 4864; e-mail: samples from patients presenting with this morphologic [email protected]. variant of multiple myeloma [3-8]. In this report, we

Fig. 1. (A) Peripheral blood smear showing neoplastic plasmacytoid cells with cleaved nuclei and monocytoid features (arrow). Wright-Giemsa stain (xlOOO). (B) Bone marrow biopsy extensively involved with sheets of atypical plasma cells. Nuclei varied from round (lower arrow) to cleaved and monocytoid (upper arrow) in appearance. (H&E, xlOOO). describe an unusual case of plasma cell myeloma with population. The bone marrow aspirate was markedly cleaved, multilobated, and monocytoid nuclei that hypercellular, revealing sheets of plasma cells. Many express cytoplasmic immunoglobulin in the absence plasma cells were atypical, showing bi- and tri- of a corresponding serum monoclonal protein (ie, non- nucleation along with numerous monocytoid forms. secretory). The peripheral blood white count was normal and plasma cells were absent. Serum lactate dehydrogenase Case report and beta2-microglobulin levels were within the normal ranges. A diagnosis of stage III plasma cell myeloma A 69-year-old man was seen at a community hospital was made, based on the lytic bone lesions. The patient in March 1997 for a complaint of back pain. Clinical received two cycles of melphalan and prednisone, imaging studies revealed multiple osteolytic lesions in followed by three cycles of dexamethasone, all of which the vertebrae involving the thoracolumbar region at were well tolerated. A bone marrow biopsy in January levelsT10,Tl 1, T12, LI, and L2. Multiple expansile 1998 revealed a decrease in the number of plasma cells lytic lesions were also observed involving the right to 4%, indicating that the patient was in clinical proximal ribs #4 and #5, and the left lateral rib #5. A remission. The patient subsequently developed a fever bone marrow biopsy showed plasmacytic infiltrates of 38.5°C that was unresponsive to ciprofloxacin. The comprising 80 to 90% of the nucleated marrow cell CBC revealed mild anemia and thrombocytopenia. Atypical myeloma with no serum monoclonal protein 285

Table 1. Flow cytometric analysis of bone marrow and peripheral blood mononuclear cells*

Cytoplasmic immunoglobulin Bone marrow aspirate Peripheral blood % light chain DNA index % light chain DNA index Kappa diploid 68 1.0 67 1.0 aneuploid 18 1.92 9 1.88

Lambda <1 1.0 <1 1.0

Bone marrow aspirate Peripheral blood % G0/G1 %S+G2M %G0/G1 %S+G2M

DNA cell cycle 73 27 85 15

* Dual color fluorescent staining was performed using antibodies against either kappa or lambda light chains to identify plasma cells and propidium iodide to determine the DNA index and cell cycle distribution.

The total white cell count was normal (3.3 x 109/L) Examination of a peripheral blood smear revealed with 82% plasma cells. At this point, the patient was moderate normochromic normocytic anemia with no transferred to the Arkansas Cancer Research Center rouleaux formation. Mild anisocytosis and occasional at the University of Arkansas for Medical Sciences. oval macrocytes were noted. The majority of nucleated Laboratory results on admission in April 1998 were blood cells were large with plasmacytoid features. The as follows: hemoglobin 86 g/L (reference range 135- neoplastic plasmacytoid cells had pleomorphic nuclei 175), and hematocrit 0.25 (reference range 0.40-0.72). with irregular contours, cloverleaf shapes, and mono- The white blood count was 61x109/L (reference.range cytoid features (Fig. la). Occasional bi-nucleated cells 3-12 x 109/L) and consisted of 74% plasma cells, 15% were noted. Nuclei in these atypical cells were centrally segmented neutrophils, 6% lymphocytes, 3% located and contained clumped chromatin. Cyto monocytes, and 2% eosinophils. The platelet count plasmic granules were absent. was 24.6 x 109/L (reference range 150-500 x 109/L). A smear of bone marrow aspirate showed sheets Serum urea nitrogen, creatinine, calcium, and alkaline of plasma cells that accounted for 82% of the overall phosphatase levels were within normal limits. The nucleated cell population. Large, bi-nucleate and tri- serum total protein was decreased at 52 g/L (reference nucleate forms were noted. Many of these atypical range 65-85) and beta2-microglobulin elevated at 6.3 plasma cells contained small, inconspicuous nucleoli. mg/L (reference range <2). Serum immunoglobulin Other features of these plasma cells were the same as levels were decreased, with IgG 5.27 g/L (reference those in the peripheral blood smear. Cytochemical range 8.4-16.4), IgA<310 mg/L (reference range 1150- stains were negative for myeloperoxidase and dual 4250), IgM <280 mg/L (reference range 600-4100), esterase using both the chloroacetate esterase and the kappa light chain 1430 mg/L (reference range 2300- alpha-napthyl esterase techniques. 4900), and lambda light chain 560 mg/L (reference Bone marrow biopsy revealed a packed marrow range 1250-2300). Total urine protein was 1100 mg/ with sheets of atypical plasma cells (Fig. lb). Plasma day (reference range 50-100). Serum and urine protein cell nuclei showed mild to marked irregularity in electrophoresis were negative for a restricted peak; contour, and many were monocytoid. Fine associated albumin was the major urinary protein. fibrosis was also noted. Immunofixation electrophoresis was negative for intact Flow cytometric analysis of the bone marrow immunoglobulin and free immunoglobulin light aspirate revealed an abnormal population of cells with chains when serum and urine were analyzed on a plasma cell phenotype (CD38hlgh/CD45low) that was numerous occasions. negative for myeloid (CD13, CD14, CD15, CD33) 286 Annals o f Clinical & Laboratory Science and lymphoid (CD4, CD5, CD7, CD 19, CD20) myeloma [3-8,11,12], In our case, the patient had surface markers. Dual fluorescent staining using multiple osteolytic lesions and bone marrow plasma propidium iodide and antibodies against immuno cell infiltrates. Plasma cells were not detected in the globulin light chain [9] demonstrated that 86% of the peripheral blood on initial presentation. Although bone marrow cells were positive for cytoplasmic kappa these findings are consistent with multiple myeloma, light chain, and that 15% of these cells were in cell a final diagnosis could not have been made with cycle (S/G2M phase). An aneuploid population of certainty without flow cytometric studies, because of plasma cells comprising 18% was also present. When the unusual plasma cell morphology and the absence peripheral blood was examined, 78% of mononuclear of a serum or urine monoclonal protein. The neoplastic cells were positive for cytoplasmic kappa light chain cells in the bone marrow were CD38hlgh/CD45low, and 27% of these cells were in cell cycle (Table 1). An cytoplasmic immunoglobulin positive, and negative for aneuploid population of 9% was also detected in the myeloid/lymphoid markers by flow cytometry, peripheral blood. A plasma cell labeling index was consistent with a diagnosis of multiple myeloma. The measured to determine the proliferative capacity of the plasma cell morphology was similar before and after myeloma plasma cells based on incorporation of the treatment, indicating that chemotherapy did not DNA analog bromodeoxyuridine, after a 1-hr pulse in contribute significantly to the atypical nuclear features. culture [10]. Plasma cells were identified by morpho Multiple myeloma with cleaved, multilobated, and logy and cytoplasmic staining with anti-kappa light monocytoid plasma cells carries a very poor prognosis chain antisera, and the incorporation of bromodeoxy [4,7]. Therefore, recognition of these atypical forms uridine was quantitated by immunocytochemistry. is important and should be reported so that appropriate Approximately 3.2% of plasma cells in the bone chemotherapy can rapidly be instituted. marrow and 4.4% in peripheral blood were positive Non-secretory multiple myeloma is a rare form of for the DNA label, indicating a high proliferative multiple myeloma accounting for 1 % of all cases [13]. capacity. Taken together, these findings indicated a The morphologic variant of multiple myeloma high-grade malignancy with a poor prognosis. presented in this report is also uncommon, with fewer A diagnosis of non-secretory plasma cell myeloma than 25 cases described in the literature [3-8], Thus, with secondary plasma cell leukemia was made, and the presence of these two variant forms of multiple the patient received combination chemotherapy with myeloma in the same patient is exceedingly rare and dexamethasone, cyclophosphamide, etoposide, and of clinical interest, since it presents a diagnostic cisplatinum (DCEP), followed by DCEP plus problem due to lack of a circulating monoclonal protein thalidomide. Although there was resolution of the and unusual nuclear morphology. plasmacytosis, the patient failed to respond to therapy. The classification scheme proposed by Bartl et al Subsequent bone marrow biopsies were extensively [1] divides multiple myeloma into 6 histologic types involved by plasma cell myeloma. In August 1998, that can be combined into 3 prognostic grades. Plasma the patient received high-dose chemotherapy with cells with cleaved and polymorphous types were melphalan followed by peripheral stem cell rescue. The considered of intermediate clinical grade and had a patient tolerated high-dose chemotherapy well and was median survival of 21 months and 27 months, discharged from the hospital, but he died 2 mo later. respectively, from onset of symptoms [1]. In a study of 6 multiple myeloma patients with plasma cells Discussion exhibiting cleaved, multilobated, and monocytoid nuclei, the majority presented with stage III disease, Circulating cells with cleaved, multilobated, or advanced lytic bone lesions, and either a monoclonal monocytoid nuclei can be present in a variety of non- immunoglobulinemia or Bence-Jones proteinuria [4]. hematologic and hematologic disorders such as reactive These cases would be considered intermediate clinical plasmacytosis associated with breast carcinoma, meta grade (cleaved and polymorphous subtype) according static carcinoma, plasma cell leukemia, myelomono- to the Bartl classification [1]. However, all the patients cytic leukemia, malignant lymphoma, and multiple had highly aggressive disease that was unresponsive to Atypical myeloma with no serum monoclonal protein 287

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