Clinical and Pathologic Findings in 52 Consecutively Autopsied Cases With Multiple Myeloma

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1 American Journal of Hematology 67:1 5 (2001) Clinical and Pathologic Findings in 52 Consecutively Autopsied Cases With Multiple Myeloma Kumi Oshima, 1 Yoshinobu Kanda, 1,2 * Yasuhito Nannya, 1 Makoto Kaneko, 1 Tamae Hamaki, 1 Miyuki Suguro, 1 Rie Yamamoto, 1 Aki Chizuka, 1 Tomohiro Matsuyama, 1 Naoki Takezako, 1 Akiyoshi Miwa, 1 Atsushi Togawa, 1,3 Hihumi Niino, 4 Michiyo Nasu, 4 Kiyoshi Saito, 4 and Toyohiko Morita 4 1 Department of Hematology, International Medical Center of Japan, Tokyo, Japan 2 Hematopoietic Stem Cell Transplant Unit, National Cancer Center Hospital, Tokyo, Japan 3 Department of Internal Medicine, Kofu National Hospital, Kofu, Japan 4 Department of Pathology, International Medical Center of Japan, Tokyo, Japan We studied clinical features and pathologic findings in 52 consecutively autopsied patients with multiple myeloma in our center between 1979 and Distant extraosseous involvement was found in 33 patients (63.5%). Thirty-one patients (59.6%) were proven to have infection at autopsy, among which pneumonia was most common site of infection. Amyloidosis was shown in 8 patients. Second malignancies were observed in 4 cases. The three major causes of death were hemorrhage, infection, and renal failure, which accounted for death in approximately 70% of the patients. Advances in the anticancer and antimicrobial chemotherapies might have decreased deaths due to myeloma itself or infection. Am. J. Hematol. 67:1 5, Wiley-Liss, Inc. Key words: multiple myeloma; autopsy; infection; hemorrhage; renal failure INTRODUCTION Multiple myeloma is a malignant plasma cell disorder that accounts for about 1% of deaths from all malignancies [1]. Malignant plasma cells accumulate in the bone marrow and produce an immunoglobulin. There are many clinical findings associated with multiple myeloma, including renal insufficiency, recurrent infections, and amyloidosis, and causes of death are variable [1]. Definite diagnosis of such complications may need pathological diagnosis, but biopsy tends to be withheld because of the naturally declining clinical course. We studied clinical features and pathologic findings in 52 consecutively autopsied patients with multiple myeloma in our center and evaluated the predictive value of clinical findings at diagnosis on pathological findings at autopsy. MATERIALS AND METHODS Patients and Data Extraction The clinical, laboratory, and pathologic findings were studied in 52 consecutively autopsied patients with multiple myeloma in our center between 1979 and Their autopsy records were retrospectively analyzed, including special stains for amyloid. The extent of myelomatous disease on gross and microscopic examination and the pathologic findings of the kidney were examined. The incidences of complications such as infection, hemorrhage, amyloid deposition, and second malignancies were noted. Associated pathologic conditions and the cause of death were extracted. The clinical records at diagnosis of 47 of these patients were available and analyzed for age, sex, clinical history, presenting complaints, and findings on physical examination. Initial laboratory data including peripheral blood counts, blood and urine chemistries, radiologic skeletal surveys, and reports of microbiology and bone marrow examinations were reviewed. Factors influencing patho- *Correspondence to: Yoshinobu Kanda, M.D., Hematopoietic Stem Cell Transplant Unit, National Cancer Center Hospital Tsukiji, chuo-ku, Tokyo , Japan. ycanda-tky@umin.ac.jp Received for publication 4 May 2000; Accepted 4 October Wiley-Liss, Inc.

2 2 Oshima et al. TABLE I. Extraosseous Sites of Tumors in 52 Patients at Autopsy* Sites Spleen Kidney Liver Lymph node Pancreas Lung Digestive tract Heart Adrenal gland Plasma cell leukemia *Extraosseous involvement was observed in 33 patients. logic findings of the autopsy were evaluated by Fisher s exact test. The initial treatment was mainly the combination of melphalan and prednisolone, but the second-line treatment was various among patients. Most patients received high-dose steroid therapy in their terminal stage. Only one received hematopoietic stem cell transplantation. Therefore, we could not analyze the influence of hematopoietic stem cell transplantation or the amount of steroid on the pathological findings at autopsy. RESULTS Extraosseous Tumor Involvement At autopsy plasma cell infiltration was present outside the skeletal system in approximately two-thirds of the patients. Pericostal, paravertebral, and cranial involvements spreading directly from an adjacent bony lesion were found in 32 cases (61.5%) macroscopically or microscopically. Distant extraosseous involvement was also found in 33 patients (63.5%). The kidney, spleen, and liver were the most common sites of such involvement (Table I). Splenic involvement was present in 16 cases (30.8%). In only 3 cases were tumor nodules seen on gross examination. Hepatic invasion was observed in 15 patients (28.8%). Among them, circumscribed tumor nodules were found in 7 (13.4%). Diffuse tumor involvement was seen only on microscopic examination in eight cases (15.4%). Enlargement of lymph node due to tumor involvement was seen in 12 (23.1%). The most common sites of lymph node involvement were paratracheal in 4 cases, parasplenic in 3, and supraclavicular in 3. Respiratory insufficiency due to tumor involvement of the lung was the causes of death in one patient. Renal Pathology Myeloma kidneys, defined by the presence of hyaline casts, were present in 17 cases (32.7%). These included tubular hyaline casts, tubular atrophy and fibrosis, and TABLE II. Histopathologic Features of the Kidney in 52 Autopsied Patients With Myeloma and Renal Failure Chronic renal failure Myeloma cell invasion Tubular hyaline casts Amylodosis Nephrosclerosis Total 21 Acute or acute on chronic renal failure Prerenal Infection Drug-induced Total 19 nephrocalcinosis. Plasma cell infiltration was present in 16 cases (30.8%). All of them had had renal dysfunction (serum creatinine >2 mg/dl). Amyloid deposits to the kidneys were identified in 7 (13.5%). Histologic findings of the kidney were listed in Table II. Infections Thirty-one patients (59.6%) were proven to have infection at autopsy (Table III). Bacterial infection was present in 26 (50%), among which pneumonia was most common and present in 18 patients (34.6%). Fungal infections were observed in only 5 (9.6%), including 3 candidemia with multiple organ involvement, 1 pulmonary aspergillosis, and 1 pulmonary cryptococcosis. Hemorrhage Hemorrhage was observed in digestive tract in approximately one-third of the patients (Table IV). Some of them died of hemorrhagic shock. The second most common site was lung, and it also directly leaded to death in some. Miscellaneous Complications Amyloidosis was shown in 8 patients and sites of amyloid deposition are listed in Table V. Kidney was involved in all the 8 patients. Second malignancies were pointed out in 4 cases, which were lung cancer, prostate cancer, and thyroid cancer. Cause of Death The three major causes of death were hemorrhage, infection, and renal failure, which accounted for death in approximately 70% of the patients (Table VI). In 2 patients, death was apparently unrelated to multiple myeloma: one died of respiratory failure due to intrapulmonary metastasis of lung cancer, and the other died of acute myocardial infarction. The most frequent cause of death was hemorrhage, especially in the lung. Hemorrhage was often due to thrombocytopenia, mainly caused

3 Autopsy Findings in 52 Myeloma Patients 3 TABLE III. Infections in 52 Myeloma Patients at Autopsy* Bacterial infection Pneumonia Colitis Bacteremia Decubitus Esophagitis Fungal infection Fungemia (Candidemia) Pneumonia (Aspergillosis) (Cryptococcosis) *Bacterial and fungal infections were observed in 26 and 5 patients, respectively. TABLE IV. Sites of Hemorrhage in 52 Patients With Myeloma at Autopsy* Sites Digestive tract Lung Intracranium Urinary tract Skin Retroperitoneum Nose Pancreas Kidney *Hemorrhage was observed in 35 patients. TABLE V. Sites of Amyloid Deposition in 8 Patients Who Had Amyloidosis at Autopsy Sites Kidney Liver 4 50 Pancreas Heart 2 25 Digestive tract 2 25 Blood vessel 2 25 Spleen Adrenal gland Pituitary gland Lymph node Tongue Subcutaneous by myeloma cell infiltration in the bone marrow. Chemotherapy-induced pancytopenia was not the main cause of hemorrhage. In contrast, infections after chemotherapy were one of the major causes of death in our series. The most common infection was pneumonia. Sepsis was also the cause of death in 3 patients. Clinical Data at Diagnosis Clinical data at diagnosis was available in 47 patients. There were 33 male (70.2%) and 14 female (29.8%). Age at diagnosis ranged from 46 to 82 years with a median TABLE VI. Causes of Death in 52 Cases of Multiple Myeloma Hemorrhage Pulmonary Digestive tract Intracranial Subarachnoid Systemic Others Infection Pneumonia Sepsis Renal failure Myeloma kidney Others Multiple myeloma Lung metastasis Systemic metastasis Amyloidosis Hyperviscosity syndrome Heart failure Others Myocardial infarction Graft-versus-host disease Other malignancy Intestinal perforation Cereberal infarction Liver failure Unknown age of 64 years. The initial symptoms were listed in Table VII. Bone pain was the most frequent symptom at diagnosis. Table VIII shows the frequency of abnormal laboratory findings at onset. The initial hemoglobin concentration ranged from 5.4 to 13.3 g/dl with a median value of 8.7 g/dl. The initial white blood cell count (WBC) ranged from 1,200 to 16,200/mm 3 with a median value of 5,250/ mm 3. Leukopenia was relatively infrequent. Leukocytosis (WBC > 10,000/mm 3 ) was observed in four patients. In one case, leukocytosis was due to circulating plasma cells, and this patient fulfilled the criteria for plasma cell leukemia (>2,000 plasma cells/mm 3 ). The initial platelet count ranged from 43,000 to 489,000/mm 3 with a median value of 140,000/mm 3. Thrombocytopenia (platelets <100,000/mm 3 ) was present in about one-fourth of patients. Renal dysfunction was frequent as initial manifestation. About 40% of patients had renal failure (creatinine >2 mg/dl). Hypercalcemia was also frequent and was present in one-fourth of patients. The total serum protein at diagnosis ranged between 6.4 and 15 g/dl, with a median value of 9.7 g/dl. A monoclonal component was present in all patients; 26 had IgG, 8 had IgA, 4 had IgD, and the remaining 9 had light-chain myeloma. Bence Jones proteinuria was detected in about one-fifth of the patients. The abnormal radiologic features were present in all but 3 patients. The most common appearance was

4 4 Oshima et al. TABLE VII. Frequency of Presenting Symptoms at Diagnosis in 47 Patients With Multiple Myeloma Bone pain Lumbago Back pain Coxalgia Chest pain Shoulder pain Systemic bone pain Anemia General fatigue Numbness Dyspnea at exercise Fever No symptom TABLE VIII. Laboratory Findings at Diagnosis in 47 Patients With Multiple Myeloma Abnormal findings Hemoglobin <8.5 g/dl 17/ White blood cell <3,000/mm 3 7/44 16 Platelet <100,000/mm 3 11/43 26 Creatinine >2 mg/dl 17/ Corrected calcium >11 mg/dl 11/44 25 Uric acid >8 mg/dl 15/ Lactate dehydrogenase >250 mg/dl 14/ Alanine amainotransferase >30 mg/dl 8/ Monoclonal protein IgG 26/ IgA 8/47 17 IgD 4/ Bence Jones protein 9/ Urine Bence Jones protein 9/ a combination of lytic lesions, osteoporosis, and pathologic fractures. Relation Between Clinical Features at Diagnosis and Autopsy Findings The influence of clinical factors at diagnosis on the pathological findings at autopsy was evaluated. For extraosseous tumor involvement, a high paraprotein level in IgG myeloma patients was significantly predictive for hepatic (P 0.035) invasion at autopsy. Thrombocytopenia (platelet count <100,000/mm 3 ) at diagnosis was correlated with the incidences of amyloidosis (P ) and myeloma kidney (P 0.03). In our series, the distant extraosseous spread of myeloma cells to the liver was not observed in patients with Bence Jones protein-type myeloma. Liver infiltration by myeloma cells was frequent in patients with IgA-type myeloma. The incidence of invasion to kidneys, spleen, and lymph nodes was not influenced by the types of paraprotein. DISCUSSION We analyzed the clinical and pathologic data of 52 myeloma patients who underwent autopsy between 1979 and Here we discuss the data comparing those reported by Kapadia et al. in 1980 [2]. Their data were extracted from patients autopsied between 1954 and Therefore, the difference between their data and ours might result from the change in the treatment or the character of the disease itself, although we could not deny that the racial differences might have influenced the data. First of all, we should mention that this case series might be biased, because our center is one of the central hospitals that treat myeloma, and patients with rare types of myeloma tended to be referred to our center. The increased incidence of IgD myeloma in this series might be a manifestation of such bias. Extraosseous spread of myeloma is rare at diagnosis [3]. Primary extramedullary plasmacytomas are also rare, and they commonly originate in head and neck, especially in the upper aerodigestive tract [4,5]. Extraosseous spread was found in approximately two-thirds of the myeloma patients at autopsy [2,6]. The common lesions were reticuloendothelial organs such as the liver and the spleen, but the myeloma cells were also present in other organs and tissues. Kapadia reported that extraosseous involvement was observed in the spleen in 45% of the patients, in the liver in 28%, and in the lymph nodes in 27%, at autopsy [2]. In our series, the total extraosseous involvement was found in 63.5% of the patients and common sites were liver, spleen, and lymph nodes as reported before. Kapadia reported that there was no correlation between the type of paraprotein and the incidence of extraosseous tumor in patients with myeloma [2], although Edwards et al. suggested that extraosseous involvement may be more prominent in patients with IgA myeloma [3]. We found more frequent extraosseous involvement in the liver, not in the spleen, kidneys, or lymph nodes, in IgA myeloma than in other types of myeloma, although the causal relation was unknown. Many factors may contribute to the development of renal failure, which is a major and serious complication. These include hypercalcemia, hyperuricemia, light chain proteinuria, repeated urinary tract infections, dehydration, and so on. In our series, about 40% of the patients had chronic renal failure, but no factors at diagnosis significantly affected renal failure at autopsy. The most frequently observed pathological finding in patients with chronic renal failure was myeloma cell infiltration (76.2%), not myeloma kidney such as tubular hyaline cast and tubular atrophy and fibrosis as reported before

5 Autopsy Findings in 52 Myeloma Patients 5 [2]. We could not explain why thrombocytopenia at diagnosis was related to the incidence of myeloma kidney (P 0.03). Bacterial infections are common throughout the course of myeloma. Bacterial pneumonia was present in 18 of the 52 autopsied patients and fatal in 7 patients. Fungal infection has not been documented to be a significant complication in patients with multiple myeloma [7]. The most frequent type of fungal infection was superficial candidiasis involving the esophagus [2]. In our series, fungal infection was not frequent (9.6%) including two cases of esophageal candidiasis despite the use of steroids for long periods in most of the patients. The incidence of amyloidosis was 15%, at nearly equivalent a frequency as reported before [8]. The diagnosis depends on histologic demonstration of amyloid deposits in tissue by a special staining procedure using Congo red. The presenting manifestation of amyloidosis in this study was related to deposition at the heart and the digestive tract. Thrombocytopenia at diagnosis was related to the incidence of amyloidosis (P ), the reason of which was not clear. Major causes of death were reported to be infection (52%), renal failure (21%), and widespread myelomatous infiltration (10%) in 1980 [2]. In contrast, a report from the Mayo Clinic in 1975 showed that infection was the causes of death only in 20% of the patients, renal failure in 14%, and myeloma itself in 44% [8]. In our series, the most common cause of death was hemorrhage, especially in the lung and digestive tract. Over the past 40 years, the standard treatment of patients with multiple myeloma has changed to use alkylating agents such as melphalan and cyclophosphamide, whereas only 68% of the patients in Kapadia s series received such agents [2]. Antimicrobial therapies have also improved. These may have contributed to the decrease in widespread myelomatous infiltration and infections as causes of death. Most of the fatal hemorrhages were associated with thrombocytopenia, which resulted not from chemotherapy but from diffuse bone marrow invasion of myeloma. Impaired platelet function caused by hyperviscosity or cryoglobulinemia might also have promoted bleedings. Control of hemorrhage by the use of platelet transfusion in patients with thrombocytopenia and/or the use of plasmapheresis in patients with hyperviscosity might improve survival of myeloma patients. We showed the difference in pathological findings at autopsy between two studies that were performed in distinct eras. Advances in anti-myeloma and supportive therapies would further alter the autopsy findings. Especially the application of hematopoietic stem cell transplantation would greatly influence the clinical course of myeloma patients. We believe that analyses of autopsied patients should be repeated in order to feed pathological information back to clinicians. REFERENCES 1. Bataille R, Harousseau JL. Multiple myeloma. New Engl J Med 1997; 336: Kapadia SB. Multiple myeloma. A clinicopathologic study of 62 consecutively autopsied cases. Medicine 1980;59: Edwards GA, Zawadzki ZA. Extraosseous lesions in plasma cell myeloma. A report of 6 cases. Am J Med 1967;43: Holland J, Trenkner DA, Wasserman TH, Fineberg B. Plasmacytoma. Treatment results and conversion to myeloma. Cancer 1992;69: Alexiou C, Kau RJ, Dietzfelbinger H, Kremer M, Spiess JC, Schratzenstaller B, Arnold W. Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 1999;85: Pasmantier MW, Azar HA. Extraskeletal spread in multiple plasma cell myeloma. A review of 57 autopsied cases. Cancer 1969;23: Meyers BR, Hirschman SZ, Axelrod JA. Current patterns of infection in multiple myeloma. Am J Med 1972;52: Kyle RA, Pierre RV, Bayrd ED. Multiple myeloma. Review of 869 cases. Mayo Clin Proc 1975;50:29 40.