SIMULTANEOUS PRESENTATION OF ACUTE MYELOMONOCYTIC LEUKEMIA

AND MULTIPLE MYELOMA BRIAN CLEARY, MD, RICHARD A. BINDER, MD, ARTHUR N. KALES, MD,

AND BENJAMIN J. VELTRI, PHD

A patient with acute myelomonocytic leukemia and multiple myeloma occur- ring simultaneously prior to initiation of chemotherapy is described. Possible mechanisms for this occurrence are discussed.

Cancer 41:1381-1386, 1978.

EVERAL INVESTIGATORS HAVE DESCRIBED T H E S development of acute myelomonocytic leu- kemia in patients with multiple myeloma.8~9~'0~ '9 I n general, these have been pat ients w h o have undergone long-term chemotherapy with alky- lating agents pr ior t o t h e development of t h e leukemia. It h a s been postulated i n these cases tha t chemotherapy h a d a leukemogenic effect or acted a s an immunosuppressant allowing t h e establishment of a malignant clone of cells. R a r e cases of t h e s imultaneous occurrence of t h e two diseases have been reported. 1 6 3 2 0 ~ 2 3 W e describe a pat ient in w h o m well-documented acute myelo- monocytic leukemia a n d multiple myeloma were simultaneously present prior t o the initiation of Chemotherapy. Included are electron micro- scopic and chromosomal findings. Postulated mechanisms of this s imultaneous occurrence a re discussed.

CASE REPORT

MSL, a 64-year-old white male first seen in May 1976, related a one-month history of increasing fa- tigue, low-grade fever, and anorexia, but no ade- nopathy or bleeding. Five years previously he had a partial gastrectomy for peptic ulcer disease. O n ex- amination, there was no lymphadenopathy or hepa- tosplenomegaly. Initial laboratory values included a hematocrit of 28.670, a white cell count of 34,500 with a differential of 20 segs, 8 bands, 18 lymphocytes, 18 monocytes, 1 eosinophil, 1 basophil, 3 metamye- locytes, 4 myelocytes, and 27 blasts. Rouleaux forma-

From the Department of Medicine, Divisions of Hematol- oqy and Oncology, and the Department of Pathology, Fair- fax Hospital, Falls Church, Virginia, and Georgetown Uni- versity School of Medicine, Washington, D.C.

Address for reprints: Richard A. Binder, MD, Associated Clinical Professor of Medicine and Pediatrics, Fairfax Hos- pital, 3300 Gallows Road, Falls Church, VA 22046.

Accepted for publication July 15, 1977.

tion was evident on the peripheral smear. The platelet count was 208,000. Examination of the bone marrow smear showed a marked increase in cellularity with slight decrease in megakaryocytes. There was myeloid and myelomonocytoid hyperplasia with 25 percent blast forms. There was an increase in plasma cells of five to ten percent, some of which were primi- tive, multinucleated and in clusters (Figs. 1, 2). A diagnosis of myelomonocytic leukemia was made. Be- cause the platelet and peripheral granulocyte counts were adequate, no treatment was initiated.

Ten weeks later, with increasing symptomatology, increasing white-cell count to 105,000, and a decreas- ing platelet count of 46,000, the patient was admitted for initiation of chemotherapy with cystosine-arabin- side by continuous infusion for seven days and dau- nomycin iv push for three days. The only positive physical finding at that time was a liver palpable two centimeters below the right costal margin. The serum muramidase was 117 mg/ml (normal 7-15 mg/ml), and the urine muramidase was 31 mg/ml (normal less than 2 mg/ml). Serum protein electrophoresis revealed the following: total protein 6.6, albumin 2.95, alpha-1 globulin 0.25, alpha-2 globulin 0.61, beta globulin 2.15, and gamma globulin 0.63, with a monoclonal spike in the beta region. Quantitative immunoglobulin levels showed IgG 720, IgA 2,550, IgM 22. There was an abnormal preciptin arc for IgA kappa paraprotein in both serum and urine. The urine was negative for Bence Jones protein. A bone marrow smear one week following chemotherapy showed normal cellularity with a marked decrease in megakaryocyte and erythroid activity. The myeloid series showed considerable maturation, but 10% im- mature myelomonocytoid cells were still present. Plasma cells now constituted 20% of all cells and again were primitive, multinucleated, and arranged in sheets. Metastatic Bone Survey showed no lytic lesions. The patient had partial response to the chemotherapy. When there was improvement in his status, he returned to his native country where he died after four months. No information concerning the circumstances of his death are available.

0008-.543X-78-0400-1381-0075 0 American Cancer Society 1381

1382 CANCER April 1978 Vol. 41

SPECIAL STUDIES

Chromosome analysis was performed on bone marrow aspirate and yielded a normal diploid XY karyotype.

Electron microscopy of bone marrow aspirate revealed the following features in plasma cells : small aggregates of nuclear chromatin were scattered throughout the nucleus, and large prominent nucleoli were present. The cytoplasm was indicative of active protein synthesis with abundant stacks of markedly dilated rough endoplasmic reticulum. Golgi apparatus and

FIG. 1. Bone marrow. Clusters of plasma cells.

large, atypically-shaped mitochondria were present. These cells displayed moderate nucle- arcytoplasmic asynchrony (Figs. 3, 4).

DISCUSSION

Over fifty cases of multiple myeloma associ- ated with acute leukemia have been reported. The majority were myeloma patients treated with melphalan for 20-102 months prior to the development of acute myelocytic or myelo- monocytic leukemia. Holland' has implicated

FIG. 2. Bone marrow. Clusters of immature myeloid elements.

No. 4 MYELOMONOCYTIC LEUKEMIA AND MULTIPLE MYELOMA Cleary et al. 1383

alkylating agents as having a possible causal role been previously described, none of which in- in these cases of leukemia. Only a few reports of cluded chromosomal or electron microscopic simultaneously occurring multiple myeloma and findings. acute leukemia have been published. Norden- Other investigators ',18 have reported acute

described seven such patients in a review of leukemia associated with nonmyelomatous 310 myeloma cases, but no details are provided. monoclonal gammopathy, but we were able to To our knowledge, only five other cases have establish firmly that myelomonocytic leukemia

FIG. 3. hlultiple plasma cells (X7800).

1384 CANCER Abril 1978 Vol. 41

FIG. 4. Classical plasma cell found in multiple myeloma. Demonstrates unusual large nucleolus and dilated E.K., clumped chromatin material, and large gorgi complex.

and multiple myeloma were simultaneously lations. I t is unlikely that the myelomonocytoid present prior to the initiation of chemotherapy. cells were aberrant, immature plasmablasts, as The myeloma and leukemic cells in this patient in a case reported by Thijs,'l because the ele- were two morphologically distinct cell popu- vated serum and urine muramidase levels are

No 4 MYELOMONOCYTIC LEUKEMIA A N D MULTIPLE MYELOMA Cleary et al. 1385

characteristic of monocytic and myelomonocytic leukemia. l5 Production of immunoglobulins has, in rare instances, been ascribed to myelo- nionocytic blast cells," but the IgA level of 2,550 with depressed IgG and IgM levels in this pa- tient is characteristic of myelomatous para- proteinemia.

Electron m i c r o ~ c o p y ' ~ ~ has been found to be valuable in assessing the malignant nature of plasma cells and confirmed the diagnosis of mul- tiple myeloma in this patient. The myeloma cell is definably abnormal by the disparity that ex- ists electron microscopically between the matur- ity of the nucleus and that of the cytoplasm. This nuclear-cytoplasmic asynchrony is the most consistent and reliable criterion distin- guishing neoplastic from reactive plasma cells. The plasma cells in this case displayed moderate nuclear-cytoplasmic asynchrony as well as cyto- plasmic dysplasia, which are distinctive features of myeloma cells. Other characteristics of myeloma present were sheets of plasma cells as well as primitive forms.

The results of the chromosome study are com- patible with previous report^^^^'^^^ of normal kar- yotypes in approximately 60% of the patients with acute myelocytic leukemia, with no patho- gnomonic features in those with abnormal stem lines. Chromosomal abnormalities have also been described in multiple m y e l ~ m a , ~ . ~ ~ but these are not universal findings.

O n the basis of cell morphology, electron mi- croscopy, muramidase levels, and immuno- electrophoresis, the patient had two simultane- ously occurring processes.

This case offers further evidence that previous chemotherapy is not necessary for the develop- ment of acute leukemia in myeloma patients. Other hypotheses should therefore be consid- ered to explain this simulataneous occurrence. Multiple myeloma, a disease which develops slowly, may have been subclinically harbored in this patient for many years. The decreased immune surveillance efficiency secondary to the myeloma may have resulted in a failure to elimi- nate incipient clones of leukemic cells. In this circumstance, multiple myeloma would precede and predispose to the development of leukemia.

I t may be postulated that the two diseases are the result of a common etiological factor. Nearly all myeloma-associated leukemias have been myelocytic or myelomonocytic in type. Os- serman l4 stresses the possibility that chronic ret- iculoendothelial stimulation may result in the development of plasmacytic or monocytic dys- crasias, and that a t times the proliferative ab- normalities in these cell lines may therefore coexist. A similar phenomenon occurs in BALB/c mice which serve as a n animal model for multiple myeloma. Intraparitoneal injection of mineral oil in these mice induces plasmacy- toma formation. l7 However, myelomonocytic leukemia with elevated muramidase levels has also been detected after comparable injections intended to induce plasma cell tumors. "

Though multiple myeloma and myelo- monocytic leukemia are distant clinical entities, this case demonstrates that under some circum- stances they may occur simultaneously, inde- pendent of cytotoxic therapy.

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