Document M4wyv3B6m7YmGLeJnVO6yD527

Anaplastic Myeloma with Massive Extramedullary Involvement Report of Two Cases KATHY FOUCAR, MD, MARTIN RABER, MD, ELLIOTT FOUCAR, MD, BARTHEL BARLOGIE, MD, CARL M. SANDLER, MD, AND RAYMOND ALEXANIAN. MD Two patients developed anaplastic myeloma associated with prominent extramedullary disease one and four years after the initial diagnosis of multiple myeloma. Most tumor cells in the extramedullary sites were primitive-appearing and anaplastic, although plasmacytoid differentiation was evident. One patient had concurrent bone marrow involvement by cytologically similar cells, while the other patient was in bone marrow remission when he developed clinically evident soft tissue infiltration. Immunoperoxidase staining showed similar cytoplasmic immunoglobulinin both the mature-appearing and anaplastic cells in both patients. Electron microscopy in both cases showed a morphologicspectrum between the matureappearing and anaplastic cells. DNA flow cytometric studies following the onset of extramedullary disease revealed a tumor cell population with a high degree hyperdiploid abnormality and unusually high proliferative activity in both cases, consistent with the morphologic anaplasia. Anaplastic myeloma appears to represent a distinct, aggressive variant of multiple myeloma which may result from a transformation of well differentiated myeloma cells to poorly differentiated immunoblast-like cells. Cancer 51:166-174, 1983. NEOPLASTICPLASMA CELLS in multiple myeloma are typically concentrated within the medullary space, and a patient's disease course is usually dominated by symptoms related either to this bone infiltration or to abnormal protein production. I,' In contrast to the rarity of clinically significant extramedullary disease, autopsy studies have demonstrated microscopic infiltrates of myeloma outside of bone in up to 70% of cases, and gross extramedullarytumor formation has been reported in 8-1796 of these cases.3-' Often the extramedullary infiltratesrepresent direct extension from diseased bone, but independent infiltrates may also involve spleen, liver, lymph nodes, skin, subcutaneous tissue, kidney and many other We have recently studied two patients with multiple myeloma who developedextensive intra-abdominal and retroperitoneal tumor masses at intervals of one and four years, respectively, following disease onset. This extramedullary involvement dominated both patients' From the Departments of Pathology and Laboratory Medicine, Medicine, and Radiology, University of Texas Medical School at Houston and the Department of Medicine, M. D. Anderson Hospital and Tumor Institute, Houston, Texas. Supported in part by grants CA28771-01, CAI 1520, and CAI4258 from the National Cancer Institute, National Institute of Health, Bethesda, Maryland. Address for reprints: Kathy Foucar, MD, 144 Medical Laboratories, Department of Pathology, University of Iowa, Iowa City, IA 52242. Accepted for publication November 5 , 1982. terminal clinical course, because of bowel and urinary tract obstruction. In one patient, the development of extensive soft tissue involvement was accompanied by anaplastic transformation of the tumor cells, while in the second patient, the myeloma cells were poorly differentiated at initial presentation. We present a clinical and pathologic study of these two patients, including immunocytochemical, ultrastructural, and flow cytometric studies. Case Reports Case I At age 29 years, a white woman developed a pathologic fracture of the left femur. Bone curettage revealed a plasma cell infiltrate. The peripheral blood showed hemoglobin 10 g/dl, hematocrit 30.8%,leukocytes 9.8 X 106/L,and platelets 79.7 X 106/L. Iliac crest bone marrow was 70% cellular with 25% predominantly mature-appearing plasma cells. Immunoelectrophoresis revealed an IgA kappa monoclonal protein ( I 822 mg/dl) with normal IgG (428 mg/dl) and decreased IgM (49 mg/dl) concentrations. The patient was treated with 3000 rad of radiation to the fracture site and was given vincristine, cyclophosphamide, and prednisone therapy every three weeks. Fifteen months after presentation, the patient developed a hemorrhagic pleural effusion with associated fever and chest pain. There was no evidence of myelomatous involvement of the pleura; the effusion persisted throughout the diseasecourse, and was attributed to thrombocytopenia. Iliac crest bone mar- 0008-543X/83/0101/0166 $1.25 0 American Cancer Society 166 -No. 1 ANAPLASTIMC YELOMA Foucar et al. 167 row at this time showed extensive infiltration by poorly differentiated plasma cells. Physical examination and ultrasound revealed a large pelvic tumor mass measuring approximately 10 X 9 X 7 cm (Fig. 1). There was no radiographic evidence of involvement of bony pelvis. At laparotomy, the tumor was found to encase the sigmoid colon, with infiltration of the left pelvic wall, left ureter, and adnexal structures. There were multiple additional tumor nodules in the lesser omentum and adjacent to the porta hepatis. A total abdominal hysterectomy, bilateral salpingoophorectomy, subtotal omentectomy, and partial resection of the pelvic tumor mass were performed. The patient then received cytosine arabinoside (ARA-C), thioguanine, vincristine, and low-dose abdominal irradiation with some clinical improvement, although extensive blood product support was required. Three weeks after surgery the patient developed bowel obstruction and a fecal fistula and died shortly thereafter of massive intra-abdominal hemorrhage. Case 2 FIG.1. Gray scale midline longitudinal ultrasound scan of the pelvis from Case 1 demonstrates a large, complex predominantly sonolucent mass (M)just cephalad to the bladder (B). The mass appears to intimately involve the uterus (U). A white male developed symptoms of intractable back pain, weight loss, and fatigue at age 77 years. Hemogram at that time showed hemoglobin 10.6 g/dl, hematocrit 3270, leukocytes 2.3 X 106/L with a normal differential, and a normal platelet count. Serum protein electrophoresis was normal. Bone survey revealed multiple lytic defects in the ribs and skull, and several vertebral compression fractures. Urine electrophoresis demonstrated lambda light chain excretion of 0.3 g/24 hours. Iliac crest aspirate and biopsy specimens were markedly hypercellular with 60-70% poorly differentiated plasma cells. During the subsequent 30 months, the patient received combination chemotherapy including: melphalan, prednisone, vincristine; BCNU, cyclophosphamide and adriamycin in a sequential schedule. He achieved a complete remission with no evidence of urinary protein excretion and normal bone marrow and peripheral blood parameters. Relapse occurred four years after initial presentation, at which time the patient had an increase in urinary light chains (2.3 g/24 hours), myeloma cutis, and clinically apparent intraabdominal and pelvic tumor masses. The patient also developed pneumonia, thrombophlebitis, and intermittent bowel and urinary tract obstruction. Bone marrow was normocellular with no evidence of increased or abnormal plasma cells. The patient did not respond to reinduction therapy. Computerized tomography demonstrated massive lower abdominal and pelvic lymphadenopathy extending to the level ofthe right kidney. The tumor filled the entire pelvis and surrounded the bladder (Fig. 2). Extensive bony defects consistent with multiple myeloma were evident. A CT guided needle aspiration of the abdominal mass was performed. Local radiofrequency hyperthermia followed by irradiation produced no tumor shrinkage. Subsequent treatment with continuous infusion ARA-C produced an approximate 20% reduction in measurable tumor. However, the patient developed myelosuppression complicated by pneumonia and died. Autopsy demonstrated multiple, large intraabdominal and pelvic tumor masses encasing the bladder and bowel. Although bone involvement was evident, the tumor masses were unrelated to sites of bone disease. Materials and Methods Serial bone marrow aspirates and biopsies from both patients were prepared according to standard techniques and stained with Wright-Giemsa and hematoxylin and eosin (H & E). Differential counts were performed on all specimens and the degree of bone marrow involvement was assessed on both aspirate and biopsy specimens. Extramedullary tumor available for study included pelvic tumor obtained at laparatomy in Case 1, and the tumor aspiration cytology specimens as well as FIG.2. A contrast-enhanced CT scan through the pelvis demonstrates massive lymphadenopathy filling the entire pelvis in Case 2. The urinary bladder (B) is elevated out of the pelvis and is completely encased by tumor. Scattered punctate calcifications are present throughout the mass (Arrow). 168 CANCERJanuary I 1983 Vol. 51 FIGS.3A A N D 3B. (A) Bone marrow aspirate from Case 2 at initial presentation showing large immature anaplastic cell as well as a smaller plasmacytoid cell (Wright Giemsa, X 1000). (B) Spectrum of plasmacytoid and anaplastic cells from bladder submucosa of Case 2 at autopsy (H& E, X400). the complete autopsy in Case 2. Tissue sections were cut at 6 p and stainedwith H & E and methyl green pyronine (MGP). Excised extramedullary tumor from both pa- tients was fixed in 3% glutaraldehyde and processed for electron microscopy by standard techniques. Sections were cut at 600 A, stained with uranyl acetate and lead FIG. 4. Bone marrow aspirate from Case I at the onset of extramedullary disease showing pleomorphic population of plasmacytoid cells including huge, bizarre forms (Wright-Giemsa, X 1OOO). -No. 1 ANAPLASTIMCYELOMA Foucar et al. 169 FIGS. 5A AND 5B. (A) Section of the abdominal tumor mass from Case 1 showing admixtureof variably-sized,plasmacytoid cells including giant, multinucleated forms (H & E, X400). (B) Immunoperoxidase stain of same tumor mass for IgA demonstrating marked cytoplasmic reactivity in both the obvious plasma cells and the huge anaplastic cells (Immunoperoxidase,X400). citrate, and examined in a Siemens 102 electron microscope. Immunoperoxidase staining for muramidase, IgG, IgA, IgM, kappa and lambda were performed according to published techniques on tissue from both cases. l 9 Samples obtained from both the bone marrow and the abdominal tumor of each patient were analyzed for cellular DNA and RNA contents by quantitating fluorescence of either mithramycin-ethidium bromide stained cells (DNA)" or acridine orange stained cells (DNA and RNA),*' using ICP I1 and ICP 22 flow cy- tometers respectively (Ortho Instruments, Boston). Identification of the malignant cell population was based on comparison of the study sample with normal human granulocytes obtained by leukapheresis of healthy donors. Results Light Microscopy and Flow Cytometry The peripheral blood examination in both cases initially revealed normochromic, normocytic anemia. Cir- 170 CANCERJanuary I 1983 Scattergram 52 49. 36 32 29 2D Histogram hT k-DNA 16 u 12 S-Phase VOl. 5 1 FIG.6. Simultaneous DNA/RNA analysis of acndine orange stained bone marrow cells from Case I at onset of anaplastic transformation. T = tumor cells; N = normal cells. Both 3 dimensional and 2 dimensional histograms and scattergram are shown. The tumor cell population can be identified by its high DNA and RNA contents. culating myeloma cells were not evident in either case during the disease course. At presentation, both patients showed a bone marrow picture diagnostic of multiple myeloma. The bone marrow specimens were hypercellular with large numbers of plasma cells (25 and 60% from Cases 1 and 2, respectively). In Case 1 the plasma cells were mature-appearing with small nuclei, inconspicuous nucleoli, and abundant cytoplasm. Occasional plasma cells were less mature-appearing and had larger nuclei with finer nuclear chromatin and more prominent nucleoli. In Case 2, although plasmacytoid differentiation was evident, the majority of myeloma cells were poorly differentiated with large, primitive-appearing nuclei, prominent nucleoli and moderate amounts of basophilic cytoplasm (Fig. 3A). At the time of development of massive extramedullary tumors, Case 1 showed a striking change in the morphology of the intramedullary myeloma cell pop- ulation, which now consisted predominantly of very poorly differentiated plasma cells (Fig. 4). Sections of the abdominal tumor mass in this case contained many huge multinucleated tumor cells with large irregular nuclei and prominent nucleoli, in addition to easily recognized plasma cells (Fig. 5A). MGP positivity was evident in the cytoplasm of most of the tumor cells. Immunoperoxidase staining for IgA revealed striking cytoplasmic positivity of tumor cells in both the bone marrow and tumor mass. Both small to moderate sized plasmacytoid cells and the huge anaplastic cells were positive for cytoplasmic IgA (Fig. 5B). Immunoperoxidase staining for IgG, IgM, and kappa and lambda light chains were negative. Flow cytometric analysis performed on a bone marrow aspirate obtained at presentation in Case l contained only diploid cells, although myeloma cells were evident by light microscopy. At the onset of extra- 6. 68 56 ..52 /T .B .. ~. ._-. .Ll i/. 1s. 32. -18 2' 20 . -16 N -; 12 20 Histogram FIG. 7. Simultaneous DNA/RNA analysis of acridine orange stained tumor cells form abdominal mass in Case I showing a similar pattern of fluorescence as seen in bone marrow specimen. No. I ANAPLASTIMCYELOMA * Foucar et al. 171 1 Parameter DNA Measurement I CT DNA m FIG. 8. Simultaneous DNA/RNA analysis of acridine orange stained tumor cells from pelvic tumor mass in Case 2. Scattergram and 3 dimensional histogram show tumor cells (T) with increased DNA and RNA contents. A single parameter DNA measurement is performed on mithramycin-ethidium bromide stained cells and distinguishes normal and tumor cells. medullarydiseaseanalysisof both the bone marrow (Fig. 6) and the pelvic tumor mass (Fig. 7) revealed a population of cells with elevated DNA and RNA contents. These cells contained 1.7 times the control DNA content, and approximately 4 times the control RNA content with a bimodal pattern. Biparametric DNA/RNA FIG.9. Electron micrograph of abdominal mass from Case I showing plasma cells and large anaplastic plasmacytoid cells. The anaplastic cells have large nuclei with prominent nucleoli. Nuclear-cytoplasmic dysynchrony is evident with relative nuclear immaturity. The cytoplasm of both the anaplastic cell and the small plasmacytoid cells contains abundant RER, many polyribosomes and scattered mitochondria and lysosomes (original magnification X 12,300). 172 CANCERJanuary 1 1983 VOl. 5 1 FIGS. 10A AND IOB. Electron micrograph showing 2 plasmacytoid cells from Case 2. (A) This plasmacytoid cell has a low nuclear-cytoplasmicratio with moderate numbers of cytoplasmic organelles and a very imma- ture nucleus with finely dispersed chromatin (original magnification X 18,000). (B) This primitive cell has a large nucleus with a prominent nucleolus. The cytoplasmis similar to the more mature-appearingcell (A), while the nucleusis larger with a more prominent nucleolus (originalmagnification X 23,000). analysis permitted computation of tumor cell cycle compartments and revealed a high S-phase (30%). The bone marrow in Case 2 at the time of development of extensive extramedullary disease was morphologically unremarkable, with normal hematopoietic elements and no evidence of myeloma; flow cytometric analysis showed only normal diploid cells. Clot sections of the abdominal aspiration biopsy from Case 2 revealed poorly differentiated, blast-like cells with only occasional cells showing plasmacytoid differentiation. Autopsy lymph nodes within the abdomen and pelvis showed complete replacement by anaplastic myeloma, while peripheral nodes showed a sinusoidal infiltrate of bizarre, pleomorphic plasmacytoid cells. Multiple firm, irregular skin and subcutaneous tissue myelomatous infiltrates were present in the inguinal regions, legs and arms. Additional pleomorphic myelomatous infiltrates were identified in the vertebral bone and bladder submocosa (Fig. 3B). Generalized mild amyloid deposition was evident in vessel walls. Immunoperoxidase staining of the tumor cells showed monoclonal IgG lambda in both plasmacytoid and anaplastic cells. flow cytometric analysis of the pelvic tumor mass from Case 2 (Fig. 8) revealed cells with increased DNA (1.2 times normal) and RNA (approximately 4 times normal) contents. The S-phase compartment of this tumor cell population was also significantly elevated (24%). Electron Microscopy In both cases electron microscopy revealed a morphologic spectrum of cell types ranging from distinctly -No. I ANAPLASTICMYELOMA Fuucar et al. 173 plasmacytoid cells to large primitive, immunoblast-like coma.29 Cases previously called plasma cell sarcoma cells (Figs. 9 and 10A and 10B).Both the plasmacytoid may also represent such a transformation of rnyel~rna.'~ cells and the primitive immunoblast-like cells exhibited Both immunofluorescence and immunoperoxidase nuclear-cytoplasmicdysynchrony, with relative nuclear techniques have demonstrated a relationship between immaturity. The nuclei of the plasmacytoid cells gen- mature-appearing cellsand dedifferentiated cells in these erally had dispersedchromatin with concentration at the ~ r o c e s s e s . ~L~ik-e~wi~se,,~im~munoperoxidase evidence nuclear membrane and prominent nucleoli. The nuclei from our cases suggested a relationship between the dif- of the immunoblast-like cells were very large with fine ferentiated and undifferentiated~ e l l s . ~U'l*tr~as~tructural heterochromatin and huge nucleoli. The cytoplasm of evidencefrom both cases also supported this conclusion. the plasmacytoid tumor cells contained parallel runs of The flow cytometric analysis of tumor masses from rough endoplasmic reticulum (RER), moderate num- both of our patients revealed cells with DNA contents bers of mitochondria, and prominent paranuclear Golgi, higher than the mean reported in myeloma:' and mark- while the primitive cells generally had fewer cytoplasmic edly increased proliferative activity, consistent with the organelles. anaplasia noted microscopically. It has recently been shown by Latreille et aL4*that myeloma patients whose Discussion tumors demonstrate highly abnormal DNA content have a poor prognosis. In addition, a number of labo- The clinical, morphologic and flow cytometric fea- ratories including our own have reported the association tures of anaplastic myeloma are distinctly different than between cytologic atypia and increased DNA con- either typical multiple myeloma or extramedullary plas- By flow cytometric analysis, the tumor cell macytoma. In myeloma the clinical course is usually population in Case 1 changed from diploid at initial dominated by intramedullary disease and its conse- presentation to hyperdiploid at the onset of extrame- quences. Infection and renal failure are the most fre- dullary disease, an apparent change in clonality, which quent causes of death.2 In contrast, both of our patients was associated with cytologic transformation. The RNA developed intermittent intestinal and/or urinary tract contents found in cells from both cases were increased, obstruction, and one patient developed intra-abdominal but below the mean reported in other patients with hemorrhage. Likewise, the clinical features in our two m y e l ~ m a . T~h' is finding may be another expression of casesdiffer from those of extramedullary plasmacytomas anaplasia. The bimodal RNA peak in Case 1 represents since the earliest manifestations of disease were the my- either a biphenotypic expression of the myeloma or cy- elomatous bone marrow infiltrates. In addition, extra- cling and noncycling subpopulations based on RNA medullary plasmacytomas occur most frequently in the content as proposed by Darzynkiewicz et head and neck region, and do not develop the massive Anaplastic myeloma may represent a distinct, ag- size noted in our gressive variant of myeloma which in some cases appears In one of our patients (Case 2), the malignant plasma to result from a dedifferentiation of the myeloma cells. cells showed prominent cytologic atypia throughout the The cytologic anaplasia may either be present at diag- patient's clinical course, while in the other patient (Case nosis of myeloma or herald the onset of extensive ex- 1) there was a dramatic change in morphologic structure tramedullary disease, and may occur in patients in bone of the myeloma cells which was first documented when marrow remission. Following the onset of extramedul- the patient developed prominent extramedullary dis- lary disease, prognosis is poor. ease. Morphologic dedifferentiation of myeloma cells has been previouslydescribed in conjunction with prominent extramedullary d i ~ e a s e . S~o~m-e~a~uthors suggest ADDENDUM that anaplastic transformation of a mature-appearing Recently Suchman et al. 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