|Year : 2020 | Volume
| Issue : 2 | Page : 151-155
Clinicopathological profile of Waldenström's macroglobulinemia: Experience from a tertiary care center
Gautam Kumar Vasnik1, S Venkatesan2, Sanjeevan Sharma3, Ajay Malik2
1 Department of Pathology, Military Hospital, Nasirabad, Rajasthan, India
2 Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
3 Department of Hematology, Command Hospital (SC), Pune, Maharashtra, India
|Date of Submission||06-Feb-2019|
|Date of Decision||03-Sep-2019|
|Date of Acceptance||04-Jun-2019|
|Date of Web Publication||28-Feb-2020|
Department of Pathology, Armed Forces Medical College, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Waldenstrom macroglobulinemia (WM) is a rare mature B cell Neoplasm, characterized by monoclonal Immunoglobulin M (IgM) in the serum and lymphoplasmacytic infiltration in the bone marrow. It accounts for approx 2% of Non Hodgkin Lymphomas. The disease is slightly more common in elderly males, the median age at diagnosis being 63 years. The disease is very infrequent in India and only a few studies have been published on the disease. Hence, we bring out this study on Clinico-Pathological Profile of WM. Aims and Objectives: To study clinico-pathological profile of WM cases and to distinguish them from other plasma cell neoplasms as both the diseases have different treatment protocols and prognosis. Materials and Methods: A cross sectional observational study was conducted at tertiary care center over a period of two years. Six cases of WM were encountered and enrolled for the study due to their rarity and morphological overlap with plasma cell neoplasms. The WHO criteria were followed and patients fulfilling those criteria were included in the study. The diagnosis of WM was based on the morphologic and immunohistochemistry findings of biopsy specimens, the presence of a monoclonal IgM, and the presence of distinctive clinical characteristics. Results: Median age of patients was 60.5 years with a male preponderance. 33% of cases presented with B symptoms and 100% cases presented with moderate to severe anaemia. 50% of the cases had thrombocytopenia and hepatomegaly. All cases had albumin:globulin ratio reversal. Peripheral smear showed background staining, rouleaux formation, relative lymphocytosis. Plasmacytoid cells were present in two cases. Bone marrow aspirate smears showed features of lymphoplasmacytic infiltration with suppression of other lineages. BM biopsies were hypercellular and showed a diffuse pattern of marrow infiltration by lymphoplasmacytic cells. The immunostaining of the infiltrating lymphocytes were CD 20+ and plasma cells were CD138+. Serum protein electrophoresis and immunofixation electrophoresis confirmed IgM type of monoclonal gammopathy. Conclusion: WM is relatively a rare mature B cell neoplasm which at times can have morphological overlap with other plasma cell neoplasms. We conclude that correlation with clinical laboratory test results while making diagnostic decision is an integral part of recognition of WM due to low grade indolent course of the disease and better outcome.
Keywords: Immunoglobulin M, lymphoplasmacytic, Waldenström's macroglobulinemia
|How to cite this article:|
Vasnik GK, Venkatesan S, Sharma S, Malik A. Clinicopathological profile of Waldenström's macroglobulinemia: Experience from a tertiary care center. Med J DY Patil Vidyapeeth 2020;13:151-5
|How to cite this URL:|
Vasnik GK, Venkatesan S, Sharma S, Malik A. Clinicopathological profile of Waldenström's macroglobulinemia: Experience from a tertiary care center. Med J DY Patil Vidyapeeth [serial online] 2020 [cited 2020 Jul 14];13:151-5. Available from: http://www.mjdrdypv.org/text.asp?2020/13/2/151/279637
| Introduction|| |
Waldenström's macroglobulinemia (WM) is a rare malignancy which accounts for three cases per million people per year in the Western world. It accounts for approximately 2% of non-Hodgkin lymphomas. This entity is not very frequent in India. The first series from India had reported 32 cases of WM over 7-year duration by Patkar et al., whereas a study from Pakistan reported 18 cases over 15-year duration by Sajid et al. The disease is slightly more common in elderly males, the median age at the diagnosis being 63 years. WM is seen to be more common among the Caucasians. WM is a mature B-cell neoplasm, characterized by a monoclonal immunoglobulin (IgM) in the serum and the presence of lymphoplasmacytic infiltration in the bone marrow (BM). The common clinical manifestations of this disease are anemia, organomegaly, lymphadenopathy, and hyperviscosity due to monoclonal IgM. This entity was first described in 1944 by Jan Gösta Waldenström through two cases of oronasal bleeding, lymphadenopathy, anemia, thrombocytopenia, high erythrocyte sedimentation rate and hyperviscosity, normal radiography, and BM infiltration by lymphoplasmacytic cells. The World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues, Fourth edition (2008) and the 2017 revision of the WHO classification of lymphoid neoplasms define WM as a subset of lymphoplasmacytic lymphoma (LPL) with BM involvement and IgM monoclonal gammopathy of any concentration.,
Studies have proposed that there is a heightened relative risk for WM among patients who have a history of autoimmunity, autoimmune antibodies, hepatitis, human immunodeficiency virus infection, and rickettsiosis. Some series mention the association of hepatitis C virus with LPL and type II cryoglobulinemia. The familial form of the disease is also seen. Patients may be asymptomatic or symptomatic with mucosal bleeding, visual abnormalities and neurological manifestations of hyperviscosity such as headache, syncope, seizures, and cerebral hemorrhage.
WM needs to be differentiated from IgM monoclonal gammopathy of undetermined significance and smoldering WM as all the three conditions have overlapping features. Few studies have been published on WM considering the rarity of the disease., Hence, we bring out this study on clinicopathological profile of WM.
| Methodology|| |
This cross-sectional observational study was conducted from July 2015 to July 2017 at a tertiary care teaching hospital. The clearance was obtained from the Institutional Ethics Committee. Six cases of WM were encountered during the study. All six cases of WM were included for the study due to their rarity and challenge in differentiating them from multiple myeloma. The WHO criteria were followed and patients fulfilling those criteria were included in the study. The diagnosis of WM was based on the morphological features on BM aspirate and biopsy, immunohistochemistry findings on BM biopsy specimens, and the presence of monoclonal IgM.
The requisite information regarding the patients was obtained from the requisition forms sent to the laboratory along with the BM specimens, and additional inputs were obtained from the clinical records of the patients maintaining full confidentiality for the patients. The data included clinicopathologic features, laboratory parameters, and treatment protocols. Unlinked anonymous data collection and analysis were carried out.
Clinicopathological profile was compiled based on the following parameters: (i) age and sex distribution, (ii) presenting symptoms, (iii) organomegaly, (iv) peripheral blood findings, (v) BM findings, (vi) serum protein electrophoresis, (vii) immunofixation electrophoresis findings, and (viii) ancillary techniques.
All the cases were managed with monoclonal antibody (rituximab)-based cyclophosphamide, vincristine, and prednisolone regimen. At present, all patients are in remission and on regular follow-up at the hematology outpatient department of our center.
| Results|| |
A total of six patients were diagnosed and treated as cases of WM in our center during the above-mentioned study. The demographic and clinical profiles are summarized in [Table 1]. Complete blood count and peripheral blood smears were studied in all the cases except one, whose peripheral blood was not available at the time of BM studies. Peripheral blood smear of all five cases clearly exhibited rouleaux formation as shown in [Figure 1]. The complete blood count and peripheral blood smear findings of the cases are summarized in [Table 2].
|Figure 1: Peripheral smear showing background staining, rouleaux formation, and lymphoplasmacytoid cells|
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BM aspirate and biopsy in respect of all the patients were studied. BM aspirate showed predominance of lymphocytes along with lymphoplasmacytic cells as shown in [Figure 2]a. BM biopsies were adequate for the evaluation and showed hypercellular marrow with infiltration by lymphoid cells and plasma cells as shown in [Figure 2]b. These lymphoid cells were highlighted by immunostaining with CD 20 and plasma cells were highlighted by immunostaining with CD 138 as shown in [Figure 2]c and d, respectively. The salient BM findings are summarized in [Table 3].
|Figure 2: Bone marrow examination with immunohistochemical staining (a) Bone marrow aspirate smear showing predominance of lymphocytes along with lymphoplasmacytic cells (b) Trephine biopsy showing hypercellular marrow with infiltration by lymphocytes and plasma cells with numerous Russell bodies (c) Immunostaining with CD 20 highlighting the mature B lymphoid cells (d) Immunostaining with CD 138 highlights the interspersed plasma cells|
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All the patients were recommended to undergo serum protein and immunofixation electrophoresis. All the six patients had albumin globulin reversal along with monoclonal gammopathy with IgM type of antibody production. Five of the six patients had kappa light-chain restriction; however, one patient had lambda chain restriction. Molecular diagnostic test for MYD 88 mutation could not be performed as the same was not available in our center.
| Discussion|| |
WM is defined as a subset of LPL with BM involvement and IgM monoclonal gammopathy of any concentration. As per the revised 2017 edition of the WHO classification of tumors of hematopoietic and lymphoid Tissues, LPL and WM are classified as mature B-cell neoplasms and distinct from plasma cell neoplasms (PCNs), a disorder characterized by the presence of clonal plasma cells with defined clinical features. PCNs have different genetic bases and different outcomes in terms of the malignant process. Hence, it is essential to differentiate this entity from LPL and WM as the treatment protocol is also different.
Nearly 150 cases of hematolymphoid malignancy are diagnosed every year in our center. In our study, during the period of 2 years from July 2015 to July 2017, six cases of WM were diagnosed and treated. This fact indicates toward the rarity of this hematolymphoid malignancy as cited in the literature in both Western world and in South Asia.,,,, The age of the study population ranges from 55 to 73 years, with a mean age being 60.5 years with a male preponderance, which is a finding akin to various other previous studies., All the patients presented with symptoms of anemia. The clinical features were dependent on the severity of anemia and degree of cardiovascular decompensation. All the patients had easy fatigability, breathless on exertion, and lassitude. Thirty-three percent of cases presented with B symptoms in the form of fever and weight loss, which is comparable to 28% of patients in a Spanish study. One patient had clinical features suggestive of congestive cardiac failure in the form of orthopnea, paroxysmal nocturnal dyspnea, and pedal edema. Three patients had serosal effusions attributable to anemia with hypoproteinemia. Three patients had hepatomegaly, and one patient had massive splenomegaly. Even though the presence of organomegaly is fairly a common feature, the patient presenting with massive splenomegaly is a rare feature, though described in the literature. All the patients in our study had exhibited a reversal of albumin: globulin ratio.
Peripheral blood of only five patients was available for analysis. All the patients in our study had anemia which was moderate-to-severe in degree, whereas it varies from 17% to 38% in other studies from the west and elsewhere., Two patients had a hemoglobin level <7 g/dL, of which one of the patients was transfusion dependent. Fifty percent of the cases had thrombocytopenia as compared to only 2.4% of patients in various studies from the west. Thrombocytopenia is generally seen in patients with severe BM involvement with WM cells. One patient had leukopenia. Four patients had bicytopenia, and one patient had pancytopenia. The peripheral smears of all the cases showed background staining of the smear on gross examination. Rouleaux formation was seen in all five cases. Three patients had normocytic normochromic anemia, whereas two patients had microcytic hypochromic anemia. Three peripheral smears showed >40% lymphocytes, and two smears showed the presence of plasmacytoid cells.
Five of the six BM aspirates were adequate for the evaluation, and one BM aspirate was grossly hemodiluted which did not show any BM elements. All the examined aspirates showed increased mature lymphocytes and plasma cells with suppressed myeloid, erythroid and megakaryocytic lineages. BM biopsy was available in all the patients. All the six cases had hypercellular BM with marrow infiltration by lymphoplasmacytic cells. Majority of the marrows showed a diffuse pattern of marrow infiltration. One BM showed nodular and interstitial patterns of marrow infiltration by the lymphoplasmacytic cells. The common patterns of BM infiltration mentioned in the literature are diffuse, nodular interstitial, mixed paratrabecular nodular, and paratrabecular patterns. All the BM biopsies showed Grade 1 marrow fibrosis (Myelofibrosis-1, WHO grading system). The immunostaining of the infiltrating lymphocytes was CD 20+, whereas the plasma cells were positive for CD 138. On immunohistochemistry, five patients showed kappa light-chain restriction, whereas one patient showed lambda chain restriction, which was later confirmed by immunofixation electrophoresis. In practice, a surface IgM-positive CD5−, CD10−, CD19+, CD20+, CD23− immunophenotype in association with a nonparatrabecular pattern of infiltration is diagnostic of WM., Molecular studies for mutations of the myeloid differentiation primary response gene MYD88 could not be performed as the facilities for the same was unavailable in our center.
One of the cases had more number of plasmacytoid cells, and hence, a morphological differential diagnosis of plasma cell leukemia was considered; however, the immunophenotype (LPL cells are positive for CD19, CD20, and surface Ig, whereas the neoplastic plasma cells are negative for these markers), immunofixation electrophoresis (LPL/WM show IgM subtype as against IgG in plasma cell myeloma/leukemia), biochemical (hyperkalcemia and creatinine abnormalities in plasma cell myeloma/leukemia) and radiological features (lytic bone lesions in myeloma) ruled out plasma cell leukemia and proved to be WM with extensive peripheral blood involvement. The leukemic plasma cells can have a varied morphological appearance and at times have little cytoplasm and hence would resemble plasmacytoid lymphocytes. This would pose a diagnostic challenge and dilemma to the morphologists as to whether the case in hand is a leukemic phase of WM or plasma cell leukemia. As emphasized before, a PCN and especially plasma cell leukemia have entirely different prognosis as compared to WM. In such cases, the morphologist has to resort to ancilliary techniques such as immunophenotyping, immunofixation electrophoresis, and biochemical and radiological features to arrive at a definite conclusion.
| Conclusion|| |
We observed that WM is relatively a rare mature B-cell neoplasm which at times can have morphological overlap with PCNs. Plasma cell myeloma is a discrete clinical entity that should be distinguished from WM as both the diseases are different in their treatment protocol and prognosis. However, at times WM may pose diagnostic challenge as we had in one of our cases which mimicked plasma cell leukemia morphologically. Correlation with clinical laboratory test results while making diagnostic decision is an integral part of the recognition of WM due to low-grade indolent course of the disease and better outcome.
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| References|| |
Greer JP, Arber DA, Glader BE, List AF, Means RT, Rodgers GM. Wintrobe's Clinical Hematology. 14th
ed. Philadelphia, PA: Wolters Kluwer; 2019. p. 2198-204.
Patkar N, Subramanian PG, Deshpande P, Ghodke K, Tembhare P, Mascarenhas R, et al.
MYD88 mutant lymphoplasmacytic lymphoma/Waldenström macroglobulinemia has distinct clinical and pathological features as compared to its mutation negative counterpart. Leuk Lymphoma 2015;56:420-5.
Sajid R, Siddiqui SH, Shaikh U, Adil S. Clinicopathologic spectrum of Waldenström's macroglobulinemia: A single center experience. Indian J Pathol Microbiol 2010;53:490-3.
] [Full text]
Herrinton LJ, Weiss NS. Incidence of Waldenström's macroglobulinemia. Blood 1993;82:3148-50.
Dimopoulos MA, Panayiotidis P, Moulopoulos LA, Sfikakis P, Dalakas M. Waldenström's macroglobulinemia: Clinical features, complications, and management. J Clin Oncol 2000;18:214-26.
Nayak HK, Kar P, Bagchi A, Kapoor N, Kapahtia S, Sonika U, et al.
Waldenstrom macroglobulinemia presenting with pancreatic mass: A case report and review of literature. JOP 2013;14:92-5.
Coimbra S, Neves R, Lima M, Belo L, Santos-Silva A. Waldenström's macroglobulinemia – A review. Rev Assoc Med Bras 2014;60:490-9.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al
. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th
ed. Lyon, France: IARC Press; 2008.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al
. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th
ed. Lyon, France: IARC Press; 2017.
Kristinsson SY, Koshiol J, Björkholm M, Goldin LR, McMaster ML, Turesson I, et al.
Immune-related and inflammatory conditions and risk of lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. J Natl Cancer Inst 2010;102:557-67.
Kraus MD. Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia: One disease or three? Am J Clin Pathol 2001;116:799-801.
Koshiol J, Gridley G, Engels EA, McMaster ML, Landgren O. Chronic immune stimulation and subsequent Waldenström macroglobulinemia. Arch Intern Med 2008;168:1903-9.
Ghobrial IM, Gertz MA, Fonseca R. Waldenström macroglobulinaemia. Lancet Oncol 2003;4:679-85.
Groves FD, Travis LB, Devesa SS, Ries LA, Fraumeni JF Jr. Waldenström's macroglobulinemia: Incidence patterns in the united states, 1988-1994. Cancer 1998;82:1078-81.
García-Sanz R, Montoto S, Torrequebrada A, de Coca AG, Petit J, Sureda A, et al.
Waldenström macroglobulinaemia: Presenting features and outcome in a series with 217 cases. Br J Haematol 2001;115:575-82.
Takemori N, Hirai K, Onodera R, Kimura S, Katagiri M. Durable remission after splenectomy for Waldenström's macroglobulinemia with massive splenomegaly in leukemic phase. Leuk Lymphoma 1997;26:387-93.
Krajny M, Pruzanski W. Waldenström's macroglobulinemia: Review of 45 cases. Can Med Assoc J 1976;114:899-900, 902, 905.
Facon T, Brouillard M, Duhamel A, Morel P, Simon M, Jouet JP, et al.
Prognostic factors in Waldenström's macroglobulinemia: A report of 167 cases. J Clin Oncol 1993;11:1553-8.
Gertz MA, Fonseca R, Rajkumar SV. Waldenström's macroglobulinemia. Oncologist 2000;5:63-7.
Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA, et al.
Waldenström macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors. Am J Clin Pathol 2001;116:420-8.
Owen RG. Developing diagnostic criteria in Waldenstrom's macroglobulinemia. Semin Oncol 2003;30:196-200.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]