Multiple myeloma: A clinical and pathological profile

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1 Multiple myeloma: A clinical and pathological profile P. Kaur 1, B.S. Shah 2, P. Bajaj 3 1 Giansagar Medical College and Hospital, Banur, Dist Patiala, Punjab, India. 2 Guru Teg Bahadur Hospital, Ludhiana, Punjab, India. 3 Pathology Department, Dr.Vasantrao Pawar Medical College, Hospital and Research Centre, Nashik, Maharashtra, India Abstract Introduction: Multiple myeloma is a plasma cell neoplasm with a spectrum spanning from localized to disseminated forms, plasma cell infiltration of various organs, plasma cell leukemia and abnormal immunoglobulin chain deposition in the tissues. In the bone marrow, myeloma cells are seen, and vary from mature forms to immature pleomorphic, anaplastic cells. M component is found in the serum or urine in 99% of the patients. Materials and Methods: This study included all cases of MM diagnosed at Dayanand Medical College and Hospital, Ludhiana, India from March 2003 to August Clinical findings were recorded and relevant investigations done. Results: Multiple myeloma comprised 11.1% of all hematological malignancies. The mean age was 58.8 years. Bony pain was the most common presenting complaint. Other findings were anemia, raised serum creatinine levels, high serum lactate dehydrogenase and C-reactive protein levels. Plasmablastic morphology was seen in 60% patients with diffuse marrow involvement being the most common pattern. Conclusion: The percentage incidence of Multiple Myeloma, out of all hematological malignancies reported in our study is comparable with other studies as regards to the median age of incidence, male to female ratio, clinical presentation and percentage of M band positivity. However, a higher percentage of our patients had hypercalcemia, higher Serum Lactate Dehydrogenase levels and C Reactive protein positivity and more lytic lesions. This corresponds with a higher tumor cell burden and a more frequent diffuse pattern of bone marrow involvement in our study group. This could be due to the smaller size of our study group, or due to late referral of patients to our tertiary care hospital. Keywords: Multiple Myeloma, Plasma cells, Bone Marrow Introduction Multiple myeloma is a bone marrow-based multifocal plasma cell neoplasm characterized by a serum monoclonal protein and skeletal destruction with osteolytic lesions, pathological fractures, bony pains, hypercalcaemia and anemia. The disease spans a spectrum from localized, smoldering or indolent to aggressive Corresponding Author: Dr. Puneet Kaur, Assistant professor, Pathology, Giansagar Medical College and Hospital, Banur, Dist Patiala, Punjab. Address: 361-R model town, Jalandhar, , India. [email protected] 14 disseminated forms with plasma cell infiltration of various organs, plasma cell leukemia and deposition of abnormal immunoglobulin chains in the tissues (1). MM accounts for 1% of all neoplastic disorders, 10% of hematological malignancies in whites and 20% of all hematological malignancies in African Americans (3). In India, the incidence varies from / 100,000 for males and /100,000 for females (4). The median age for MM is 55 years in India (3), which is more than a decade less than that in the

2 United States (5). The male to female ratio is 1.4 to 1 (3). The exact cause of multiple myeloma is unknown. Increased incidence has been reported in people exposed to radiation, petroleum, rubber and wood products, cosmetologists and farmers. Long standing osteomyelitis or chronic antigenic stimulation such as rheumatoid arthritis has been considered as a possible predisposing factor (6). Cytokines play an important role in myeloma cell proliferation. Their growth and differentiation is supported by interleukin-6, which has been shown to be produced by osteoclasts, fibroblasts and macrophages (7). The clinical manifestations are due to infiltration by plasma cells and secretion of M protein by them (8). The most common clinical feature of MM is anemia. A hemoglobin concentration of less than 120g/l occurs in 40-73% patients at presentation and contributes to weakness and fatigue in as much as 82% patients. Bone pain is the predominant symptoms in 80% patients (9). Approximately 75% have punched-out lytic lesions, osteoporosis or fractures on conventional radiography (10). MM may be associated with hematological abnormalities. Bleeding may be present in as many as one third of patients and is related to thrombocytopenia, uremia, hyper viscosity and interference with the function of coagulation factors (10). Approximately 25% patients have a serum creatinine of >2mg/dl at diagnosis. Perhaps 50% become uremic during the course of the disease. Hypercalcaemia occurs on 18-30% due to bone destruction. C-reactive protein is an acute phase reactant produced by the liver. Because C reactive protein levels correlate with IL-6 levels, C-RP may be offered as a surrogate for measurement of interleukin-6 (11). High serum lactate dehydrogenase identifies patients with poor prognosis and aggressive disease (12). Higher levels of serum beta-2 microglobulin are associated with an adverse prognosis (13). In the bone marrow, myeloma cells are seen and vary from mature forms indistinguishable from mature plasma cells to immature pleomorphic, anaplastic cells with loss of 15 G. J. O. Issue 16, 2014 cartwheel pattern, presence of prominent nucleoli and multinucleation (14). M component is found in the serum or urine of 99% patients (15). Degree of marrow replacement by plasma cells also has a prognostic value (16). Plasma cell myeloma is usually incurable with a median survival of 3 years and 10% at 10 years. The present study was undertaken at the department of pathology, Dayanand Medical College and Hospital, Ludhiana. The aim was to study the spectrum of clinical, hematological and biochemical findings in patients of MM. Materials and Methods This study includes 28 cases of MM diagnosed at Dayanand Medical College and Hospital, Ludhiana from March 2003 to August The criteria used for diagnosis were those enlisted by the WHO classification of tumors of hematopoietic and lymphoid tissues. Bone marrow studies, erythrocyte sedimentation rate and serum electrophoresis were performed. Relevant clinical history, physical findings, biochemical investigations like serum calcium, C-reactive protein, lactate dehydrogenase, s.beta-2 microglobulin and serum creatinine were recorded. Results Out of the 1063 bone marrows performed from March, 2004 to August, 2005, 252 were reported as hematological malignancies. Out of these, 28 were diagnosed as MM and relevant data was compiled. Multiple myeloma comprised 11.1% of all hematological malignancies diagnosed on bone marrow examination during the study period. The ages of the patients included in the study ranged from 38 years to 85 years, with the mean age being 58.8 years. 3.58% patients were younger than 40 years and 21.5% were 70 years and older. The male to female ratio was 1.5: 1. Bony pain was the most common presenting complaint seen in 50% patients, followed by generalized weakness and fatigability in 46.4 % patients.

3 Multiple Myeloma, P. Kaur, et. al. Table 1 : Hemoglobin levels Table 6 : Pattern of infiltration of myeloma cells on bone marrow biopsy. Table 2 : Total leucocyte count Table 7 : Serum calcium levels. 7 patients had levels over 13 mg/ dl and two of these presented with encephalopathy Table 3 : The percentage of plasma cells were estimated on bone marrow biopsy and staging was done as shown above. Table 8 : Qualitative C-Reactive protein. Table 9 : Serum Lactate Dehydrogenase levels Table 4 : The following results were obtained. Table 5 : Plasma cell morphology on bone marrow aspirates 16 Table 10 : Serum Beta -2 microglobulin

4 G. J. O. Issue 16, 2014 Table 11 : Pattern of infiltration of myeloma cells on bone marrow biopsy. The results of Lab investigations are as follows (please refer to the Tables for details): 1. Hemoglobin (Table 1) 2. Total leucocyte count: (Table 2) 3. The differential count showed presence of plasma cells in two patients. Plasma cell leukemia was recognized in one of the patients 4. Prominent rouleaux formation was seen in 82.1% (23/28) patients. 5. Thrombocytopenia was seen in 25% (7) patients. 6. The erythrocyte sedimentation rate was increased in all the patients. Levels over 100 mm in the first hour were seen in 85.7% patients. 7. An M-band on serum electrophoresis was detectable in 92.8% patients. 8. Bone marrow examination: (Tables 3 and 4) 9. Plasma cell type (Table 5) 10. Pattern of plasma cell infiltration in the trephine biopsies was noted. (Table 6) 11. Serum calcium was estimated in these patients (Table 7). 12. C reactive protein levels were done.(table 8) 13. Serum Lactate Dehydrogenase was estimated. (Table 9) 14. Serum beta-2 microglobulin levels were performed. (Table 10) 15. Serum Creatinine levels were estimated and results were available in 22 cases. (Table 11) Figure 1. Flame cells in a bone marrow aspirate (100x, giemsa) Figure 2. Sheets of plasmablasts in a bone marrow aspirate (100x, giemsa) Figure 3. Amorphous deposits of paraprotein interspersed with sheets of plasma cells in a bone marrow aspirate (10x, giemsa) 17

5 Multiple Myeloma, P. Kaur, et. al. Discussion 28 patients were diagnosed with MM from March 2003 to August MM comprised 11% of all hematological malignancies, reported on bone marrow examination. Howe et al (2) have stated that MM accounts for 10% of all hematological malignancies. The National center for health statistics, United States has also reported an incidence of around 10%. The ages of the patients included in the study group ranged from years, with a median age of 57 years. This is in accordance with the median age of 55 years, reported in the National Cancer Registry Programme statistics (3) (Indian council of medical research). The mean age was 58.8 years in the present study. Wadhwa et al and Advani et al (17) have reported mean ages of 55.4 and 51 years respectively. In our study, 3.58% of patients were younger than 40 years and 21.4 % were 70 years and older. This is comparable with the observations of Kyle et al (9), in whose study 2% patients were younger than 40 years and 38% patients were 70 years and older. The male to female ratio in our study was 1.5: 1. The male preponderance in our study concurs with an older study by Advani et al (17) and with the National Cancer Registry Programme statistics (3), both of which have reported male to female ratios of 2:1. Clinical history was taken in all our patients and the major presenting complaints were recorded. Bone pain was one of the chief complaints in 50% of our patients. Approximately one third to two third of patients with MM are known to present with this symptom because of vertebral collapse, osteopenia or fractures. In studies by Gupta et al (19) and Kyle et al (9), 79% and 58% patients respectively had bone pains at diagnosis. Generalized weakness and fatigability were recorded in 46.4% of our patients and in 32% patients in a study at the Mayo clinic (9), and is attributable to anemia. Bony pains and easy fatiguability were also the most common symptoms in another study by Subramanian (25). Hemoglobin values in our patients ranged from gm/dl. A hemoglobin value of gm/dl was seen in 92.8 % of our patients compared with 35% (9) and 59% (18) in other studies. Similarly, significant anemia (Hb <8.5 gm/dl) was seen in 75% of our patients compared with 71% in a study conducted at the PGIMER, Pondicherry (25). Gupta et al (19) have, however reported a 40% incidence of severe anemia in their subset of patients. The probable reason for this discrepancy could be due to more number of patients in their study group. Also, most of our patients have a high tumor load, probably due to late presentation since our institution is a tertiary care hospital, which consequently leads to a severe degree of anemia. The anemia however, was normocytic normochromic in most of our patients, as reported in literature (Dispenzieri, et al) (20). 25% of our patients had thrombocytopenia with counts less than 100,000/µl, in 5% patients. Low platelet counts are frequently observed in MM, due to infiltration of the marrow by plasma cells or intravascular destruction of platelets. Counts < 100,000/ µl have been reported in 5% and 13% patients in various studies (9, 21). A prominent rouleaux formation on peripheral smear was seen in 82% patients, comparable with 88% and 91% in other similar studies (22, 25). An M band was detectable in 92.8 % patients on serum electrophoresis. In another study, M band was detectable in 75.4 % patients. Serum electrophoresis showed a normal study in two of our patients. Both of them also had normal serum protein levels and did not show prominent rouleaux formation on peripheral smear. The plasma cell burden in our bone marrow biopsies was >50% in 64.3% cases compared with 71% cases in another study made by Subramanian (25). Fifty-six percent of the cases had poorly differentiated plasma cell morphology in this study. Plasmablastic morphology was seen in 60% of our patients. Most of our cases exhibiting a diffuse pattern of involvement had more than 50% plasma cells in trephine biopsies. Other studies on bone marrow histomorphology (25) have also shown that patients with higher tumor burden tend to have diffuse involvement of the bone marrow.

6 G. J. O. Issue 16, 2014 Myelofibrosis was noted in 2 of our biopsies (7%). Krzyzaniak et al (27) have reported an incidence of 8.8% in their study. The percentage of our patients having hypercalcaemia (46%) was significantly higher than those reported in other studies (9, 18). This is probably due to the fact that most of our patients had a high tumor burden. This would also explain the fact that more of our patients have high levels of serum lactate dehydrogenase and C-reactive protein levels, compared with other studies (9, 24). Similarly, raised serum creatinine levels were found in 86.4% of the patients where these results were available, compared with only 55% and 48% patients in two studies by Kyle et al (9,22). Most of these patients were referred from the department of nephrology where they had presented with renal insufficiency. Raised serum beta-2 microglobulin levels were seen in 71.4% of our patients, compared with 75% patients in a study by Kyle et al (9). In the subset of patients in our study, the biochemical parameters like serum calcium, serum creatinine, serum LDH and C-reactive protein levels were more significantly deranged than in patients in other studies. We think that the reason could be the smaller number of patients compared to other studies, or a delay in referral to our institute in some cases. Lytic lesions were seen in 80% of our patients. Lytic bone lesions were present in 62% cases in another study by Prakash et al (26). The most common site was the skull in both studies. Conclusion In conclusion, multiple myeloma is a disease with a wide variety of clinical presentations and multiple system involvement. Our results support the presence of some variations in the clinical characteristics of multiple myeloma. These differences may be due to the inherent nature of the disease itself. They could also be due to a small study group, or the fact that the study was done in a tertiary care hospital, where patients tend to present at a later stage of the disease. References 1. Grogan TM, Spier CM. The B cell immunoproliferative disorders, including multiple myeloma and amyloidosis in neoplastic hematopathology, Knowles DM, ed. 2nd. Lippincott Williams and Wilkins: Philadelphia,pp. 2. Howe HL, Wingo PA, Thun MJ etal. Annual report to the nation on the status of cancer (1973 through 1978), features cancers with recent increasing trends. J Natl Cancer Inst 2001; 93: National cancer Registry programme. Consolidated report of the Population based cancer registries , Indian council of medical research, New Delhi Waternonse J, Muir C, m Mack T, Fowell J, Wn clan SL (eds) Cancer incidence in five continents, Lyon IARC scientific publications. 1987, Greenlee RT, Hill Harmon MB, Murray T, et al. Cancer statistics CA Cancer J clin 2001; 51: Linet MS, Harlow SD, Mc Laughlin JK. A case control study of multiple myeloma in whites; chronic antigenic stimulation, occupation and drug use. Cancer Res 1987; 47: Ohsaki Y, Takahashi S, Scarez T et al. Evidence for an autocrine or paracrine role for interleukin 6 in bone resorption by giant cells from giant cell tumors of bone. Endocrinology 1992; 131: Roodman GD. Mechanisms of bone lesions in multiple myeloma and lymphoma. Cancer supplement 1997:80 (8): Kyle RA, Gertz MA, Witzig TE et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proc 2003; 78: MRC working party on leukemia in adults. Analysis and management of renal failure in fourth MRC myelomatosis trial. BMJ (Clin Res Ed) 1984; 288: Griepp.P, Lust J, O Fallon M etal.plasma cell labeling index and beta -2 microglobulin predict survival independent of Thymidine Kinase and C-reactive protein in multiple myeloma. Blood 1993; 81(12): Dimopoulos MA, Barlogie B, Smith T et al. High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med. 1989; 110:

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