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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 15  |  Issue : 1  |  Page : 33-38

Reactive bone marrow plasmacytosis: A common denominator with diverse etiology


Department of Medicine, ABVIMS and Dr RML Hospital, New Delhi, India

Date of Submission28-Jul-2021
Date of Decision01-Oct-2021
Date of Acceptance11-Oct-2021
Date of Web Publication26-Mar-2022

Correspondence Address:
Vijay Kumar
Department of Pathology, ABVIMS and Dr RML Hospital, New Delhi - 110 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/hmj.hmj_52_21

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  Abstract 


Background and Aims: Reactive plasmacytosis (RP) is characterised by the diffuse distribution of mature polyclonal plasma cells in the bone marrow (BM) and it is known to occur in various disorders. These need to be differentiated from the clonal plasma cell dyscrasias (PCD). We aim to study the morphological features of RP and to help differentiate them better from PCD. Materials and Methods: We analysed 1409 consecutive BM aspirates for the percentage of plasma cells along with the associated clinical findings. The study group included cases with BM RP and the polyclonality being supported by serum protein electrophoresis or by kappa/lambda immunohistochemistry on BM biopsy. The clinical records, haemogram and BM aspiration findings were retrieved and reviewed in all cases. Morphological features of RP cases were analysed in detail. Further, these cases were compared with 10 confirmed cases of PCD in an attempt to distinguish between the two on morphology. Results: A total of 210 BM aspirates showed increased plasma cells (>3.5%). Clonality could be proven in 135 cases, of which 98 cases were polyclonal and 37 were PCD. Majority of RP cases were >40 years with male predominance. The plasma cell concentration in RP ranged from 4% to 25%. The associated diseases included infections followed by autoimmune diseases. On the morphology, RP unveiled scattered, non-aggregated mature plasma cells while in PCDs, there was a mixture of both immature and mature forms including plasmablasts with frequent clustering. Conclusion: A number of diseases show increased percentage of plasma cells in BM raising suspicion of PCD. It may be difficult to distinguish reactive from neoplastic conditions as there is an overlap both in cell counts and morphology. Assessment of subtle morphological features along with associated clinical and laboratory findings are cardinal for making a correct diagnosis.

Keywords: Bone marrow examination, plasma cell dyscrasia, reactive plasmacytosis


How to cite this article:
Batool S, Misra S, Kumar V, Ahuja A, Marwah S, Baweja G, Kumar S. Reactive bone marrow plasmacytosis: A common denominator with diverse etiology. Hamdan Med J 2022;15:33-8

How to cite this URL:
Batool S, Misra S, Kumar V, Ahuja A, Marwah S, Baweja G, Kumar S. Reactive bone marrow plasmacytosis: A common denominator with diverse etiology. Hamdan Med J [serial online] 2022 [cited 2022 May 28];15:33-8. Available from: http://www.hamdanjournal.org/text.asp?2022/15/1/33/340821




  Introduction Top


Bone marrow (BM) plasmacytosis has huge clinical significance, as it is seen both in plasma cell dyscrasias and in benign and malignant diseases other than plasmacytic neoplasms. In primary malignancy or the plasma cell dyscrasias (PCD), it is monoclonal while in all other conditions, it is polyclonal and reactive in nature. Reactive plasmacytosis (RP) is seen in a variety of conditions including infections, autoimmune and other inflammatory diseases, various type of anaemias, as a paraneoplastic syndrome in neoplasms such as Hodgkin's disease, Non-Hodgkin's lymphomas, carcinomas and in acute leukaemia patients undergoing induction chemotherapy. In most of these cases, BM plasma cells usually account for 10%–20% of all nucleated cells but may rarely exceed 50%.[1],[2] Since an increased BM plasma cells can cause a diagnostic dilemma, especially in the elderly population, hence, it is necessary to differentiate RP from monoclonal plasma cell disorders. Morphologic evaluation of the BM is still probably the most important step in differentiating reactive plasma cell proliferation from PCDs. The current study aims to assess and observe the spectrum of disorders with RP and to analyse its morphological characteristics on BM aspirates to help differentiate them better from monoclonal neoplastic plasmacytosis.


  Materials and Methods Top


This retrospective study was conducted in the haemato-pathology unit of the pathology department at our institute after obtaining the institutional ethical clearance. The analysis was based on the examination of consecutive BM aspirates received for 3 years (2017–2019) with increased plasma cells. The BM records of all the cases were retrieved and the BM findings were re-analysed. The clinical details, biochemical profile, complete haemogram with peripheral smear and BM aspiration smears along with BM biopsy slides (wherever available) were reviewed and analysed.

The peripheral smears along with the BM aspiration and biopsy slides of all cases were re-examined. Cytopenia was defined as: Haemoglobin <10 g/dL, total leucocyte count <4000/μl and platelet count <1 × 103/μl. BM aspiration and trephine biopsy had been carried out as per the clinical indications. The BM procedure had been carried out by standard methods. All BM aspirate smears and trephine biopsies had been stained with Giemsa and haematoxylin and eosin, respectively. The BM aspirate smears with increased plasma cells were re-examined and the percentage of plasma cells was set by a differential count of 500 nucleated cells. More than 3.5% was taken as the cut-off, above which the plasma cells were considered increased.[3],[4] The corresponding BM biopsy was also examined, wherever available, for plasma cell distribution and associated findings.

In biochemical profile, serum protein analysis and albumin-globulin reversal were noted when available. The study group included only the cases with BM RP and their polyclonality was endorsed either by serum proteins electrophoresis (SPE) that showed a prominent polyclonal gammopathy without an M-spike [Figure 1] or by kappa and lambda immunohistochemistry on BM biopsy. We performed immunohistochemistry for kappa and lambda only in cases where SPE was not done and adequate BM biopsy was available. Cases without SPE and BM biopsy (clonality not proved) and cases with monoclonality (PCD) were excluded from the study. Furthermore, cases, where BMbone marrow aspiration/biopsy was inadequate for a definite opinion, were excluded. Further, we examined 10 consecutive cases of PCD to analyse and differentiate the morphological differences between non-neoplastic and neoplastic plasma cell proliferation.
Figure 1: Serum protein electrophoresis. (a) Polyclonal hypergammaglobulinemia, no M-band seen. (b) Monoclonal hypergammaglobulinemia with M-band in Gamma region

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Immunohistochemistry

Manual immunohistochemistry on paraffin sections for CD 138, kappa and lambda light Chains (Ready to use, Biogenex), was carried out using a heat-induced epitope retrieval technique and a universal secondary antibody kit that used a peroxidase-conjugated labelled-dextran polymer (SuperSensitive MultiLink HRP detection kit/DAB, Biogenex) according to protocol standardised at our institute. The relevant data and findings were entered into Microsoft Excel spreadsheet and appropriate statistical analyses were done.


  Results Top


Out of 1409 consecutive BMs received during the study period (2017–2019) for different haematological diseases, only 210 cases (14.9%) showed increase in plasma cells. We could prove clonality in only 135 cases so the rest 75 cases were excluded from the study. Of the 135 cases, 37 (27.4%) were PCD (monoclonal proliferation) which were also excluded while 98 (72.6%) were polyclonal and were included in the study group [Figure 2]. The patients' ages ranged from 6 to 95 years with a mean age of 51 years and showed slight male predominance. There were 63 males (64.2%) and 35 (35.7%) females (M: F = 1.8: 1). The cardinal presenting complaints were fever, generalised weakness, abdominal pain, joint pain and swelling. Hepatosplenomegaly and lymphadenopathy were found in 21 cases (21.4%) and 18 cases (18.3%), respectively. Serum protein values were available in 61 cases, most of which showed A/G reversal (54 cases, 88.5%). The main associated peripheral blood findings are described in [Table 1]. Anaemia was the most frequent finding seen in 79.6% of cases, while thrombocytosis (5.1% cases) was the least commonly seen [Table 1]. On the other hand, the main peripheral smear finding in PCD was anaemia with rouleaux formation.
Figure 2: Flow chart showing demographic information; ABVIMS and Dr RML Hospital

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Table 1: Haematological findings in reactive plasmacytosis

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The plasma cell concentration in BM aspirates ranged from 4% to 25%. The cases were arranged according to the plasma cell percentage, 82 cases (83.6%) had 4%–10%, 11 cases (11.2%) had 11%–20% and 5 cases (5.1%) had >20% plasma cells, respectively. The cardinal-associated diseases [Table 2] included infections, autoimmune; various types of anaemias, diabetes and liver disease, with infectious aetiology (28.6%) being the most common association. Less than 10% plasmacytosis has been mainly seen in different types of anaemia, autoimmune diseases and diabetes, 11%–20% plasma cells were chiefly seen in infections and >20% in pyogenic liver abscess. The common infections included bacterial infections, most frequently tuberculosis along with leishmaniasis with the mean BM plasma cell percentage of 14%. Common autoimmune diseases include rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus (mean PC percentage-7%), whereas the anaemias were of nutritional type; iron deficiency (mean PC percentage-6%) and megaloblastic anaemia (mean PC percentage-8%). On comparing the range of plasma cell percentages of the study group (4%–25%) with cases of PCD (10%–90%), there was a significant overlap. However, on morphology plasma cells in RP were mostly mature [Figure 3]a and [Figure 3]b while in PCDs, it was a combination of both immature and mature forms [Figure 3]c and [Figure 3]d. Binucleate forms were seen in both, however, plasmablasts were noted in PCD only [Figure 3]c. Other significant BM findings of the study group or the RP cases [Table 1] were lymphocytosis, plasmacytic satellitosis [Figure 4]a, prominence of macrophages [Figure 4]b, haemophagocytosis [Figure 4]b, increased oeosinophils and its precursors [Figure 4]c and dyserythropoiesis. Dyserythropoiesis (40.2% cases) and increased histiocytes (35.7% of cases) were the most frequent findings, of which dyserythropoiesis was mainly found in various types of anaemias, especially in megaloblastic and iron deficiency anaemia while increased histiocytes were seen in infectious aetiology. Seven (7.1%) cases showed Leishman-Donovan bodies [Figure 5]a, 5 (5.1%) cases had lymphoid aggregates, 4 cases (6%) had granulomas [Figure 5]b, 7 (7.1%) cases showed megaloblastic maturation [Figure 5]c and 2 (2%) cases were aplastic. There were four cases of secondary malignancy which included two cases of acute leukaemia and two cases of non-Hodgkin's lymphoma. BM biopsy was available in 72 cases. Plasma cells were predominately interstitial and diffusely scattered [Figure 6]a in cases with RP. On the other hand, in PCD there were clusters and small sheets of both mature and immature plasma cells showing both interstitial and paratrabecular patterns of distribution [Figure 6]d. SPE was not available in 28 cases, and hence, we performed immunohistochemistry for kappa and lambda on BM biopsy to prove polyclonality. RP showed immunoreactivity for both kappa and lambda [Figure 6]b and [Figure 6]c while as in PCD there was the restriction of one of the light chains [Figure 6]e and [Figure 6]f.
Table 2: Aetiological profile of the cases with reactive bone marrow plasmacytosis

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Figure 3: Morphological differences between reactive plasmacytosis and plasma cell dyscrasias. (a) Reactive plasmacytosis showing scattered, non-aggregated mature plasma cells (arrow) (Giemsa stain, ×400). (b) Reactive plasmacytosis with binucleated forms (arrow) (Giemsa stain, ×400). (c) Plasma cell dyscrasias showing both immature (thick arrow) and mature (thin arrow) plasma cells including plasmablast (inset) with clustering (Giemsa, ×400). (d) Plasma cell dyscrasias showing both binucleate (thick arrow) and multinucleated (thin arrow) forms, (Giemsa, ×400)

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Figure 4: Reactive plasmacytosis showing (a) Plasmacytic satellitosis around histiocyte (Giemsa, ×1000). (b) Increased histiocytes with hemophagocytosis (inset) (Giemsa, ×1000). (c) Increased eosinophils and precursors (arrows) (Giemsa, ×400)

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Figure 5: Reactive plasmacytosis showing findings related to underlying etiology. (a) Leishman-Donovan bodies (both extra and intracellular [inset]) (Giemsa, ×400). (b) Epithelioid cell granuloma with multinucleated giant cell (hematoxylin and eosin, ×200). (c) Megaloblastic maturation (hematoxylin and eosin, ×400)

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Figure 6: Differences between Reactive plasmacytosis and plasma cell dyscrasias. (a) Reactive plasmacytosis showing scattered, non-aggregated mature plasma cells in interstitial pattern (haematoxylin and eosin, ×200) (b and c) Reactive plasmacytosis showing immunostaining for both (b) Kappa and (c) Lambda (IHC, kappa, lambda, ×400) (d) Plasma cell dyscrasias with sheets and clusters of mature and immature plasma cells in both interstitial and paratrabecular pattern (hematoxylin and eosin, ×200) (e) Plasma cell dyscrasias showing lambda restriction, (IHC, lambda, ×200) (f) Kappa immuno-negative (IHC, kappa × 200)

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  Discussion Top


Plasma cells are the terminally differentiated B-lymphocytes which are capable of secreting immunoglobulins. These cells play a significant role in the adaptive immune response and are the chief cells responsible for humoral immunity. These antibody-secreting cells evolve in secondary lymphoid tissues after antigen stimulation and may enter a short-lived plasma cell population that resides chiefly in the non-lymphoid areas of spleen or lymph nodes, or readily may migrate to BM where the majority enter a long-lived population of plasma cells.[5] A wide range has been quoted for normal BM plasma cell percentage by various investigators, however this range according to standard textbooks is 0%–3.5%.[3],[4] As mentioned earlier, the bulk of long-lived plasma cells are located in the BM and especially the precursors of plasma cells that is B-cells also undergo much of their early development in the BM. An important component of B-cell development in the BM is the reticular stromal cells. It provides both the contact and growth factors for various stages of B-cell maturation. Thus, both plasma cells and developing B-cells probably interact with these stromal cells in the BM.[6]

An increase in BM plasma cells is primarily found in PCD, however, it is also seen in benign and malignant diseases other than primary neoplasms, which is called RP.[7] Reactive BM plasmacytosis is thought to be a reflection of systemic antigenic stimulation[8],[9] and thus elevation of plasma globulins can also be seen. It is observed in a variety of diseases like chronic infections, viral infections (Hepatitis A virus, Epstein-Barr virus, Dengue virus, Parvovirus B 19), inflammatory conditions (autoimmune diseases, hypersensitivity states, rheumatic heart disease), iron deficiency, megaloblastic and haemolytic anaemias, liver disease, diabetes mellitus, multicentric Castleman's disease, drug-related agranulocytosis and haemopoietic and non-haemopoietic malignancies.[10],[11],[12],[13],[14] Plasmacytosis in infectious and inflammatory diseases are mainly due to exposure to foreign antigens or autoantigens. The association of other diseases such as diabetes mellitus and various types of anaemias with plasmacytosis is intriguing but more obscure and may be due to the complications of the underlying disease state.[15] RP in secondary malignancies such as Hodgkin's disease, non-Hodgkin's lymphomas, leukaemias and carcinomas[16],[17] and acute leukaemia patients undergoing induction chemotherapy,[18] may be a response to new surface antigens of the neoplastic cell clones.

In this study by consecutive BM examinations, we analysed plasma cell percentage and morphological features along with the common trends in incidence [Table 1] and extent of RP in various disease states. According to the previous studies, various infectious and inflammatory diseases are most commonly associated with RP of the BM. BM plasma cells numbering 10%–20% have been reported in septic arthritis, cirrhosis and autoimmune diseases, but it is very unusual to exceed 50% in non-neoplastic conditions.[1],[2] In our study, plasma cell percentage in various reactive conditions ranged from 4% to 25% and the maximum cases (72.6%) with RP had a benign aetiology with infections, inflammatory diseases and nutritional anaemias being among the most common conditions accompanied by reactive BM plasmacytosis. In all of the cases, plasma cells were mature with few reactive and binucleate forms. The most frequent other BM reactive changes include increased histiocytes and haemophagocytosis, lymphocytosis, increased oeosinophils and their precursors and dyserythropoiesis. Increased histiocytes with haemophagocytosis are mainly found in chronic infections like tuberculosis and leishmaniasis while dyserythropoiesis is seen in megaloblastic anaemia, were the most frequent reactive changes seen in RP. Studies have shown that increased histiocytes and haemophagocytosis are important common phenomena observed in tuberculosis and leishmaniasis.[19],[20] Hyperplasia or dysplasia of one or more myeloid cell lines (erythroid, granulocytic and megakaryocytic) can be seen in several non-neoplastic (such as megaloblastic and sideroblastic anaemias) and neoplastic haematopoietic disorders (reactive megakaryocytes seen in BMs infiltrated by lymphoma).[21] Although a non-specific finding,[22],[23] A/G reversal was seen in 88.5% of cases.

In our observation, plasma cell percentage in various reactive conditions ranged from 4% to 25% and in cases of PCDs, the range varied from 10% to 90%. Thus, there is a significant overlap in plasma cell percentage between reactive and neoplastic plasma cell proliferation. Hence, we need to be very cautious while reporting such cases, as both cross 10% cut-off making it a pitfall in the diagnosis of PCDs. The various methods to distinguish polyclonal plasma cells from monoclonal ones, include cell morphology, BM immunohistological examination, SPE, immunofixation by electrophoresis and flow cytometry immunophenotyping (FCI). FCI is a simple, efficient and accurate method to differentiate benign plasma cells from malignant ones, hence it is widely used. Yet, a deviation may still occur, if FCI signals are solely used for diagnosis. Therefore, it is necessary to take into account various supplementary methods while seeking an exact diagnosis. However, these diagnostic tools may not be easily available in all medical centres and thus morphologic evaluation of the BM is still probably the most important tool used in differentiating reactive from neoplastic plasmacytic proliferation.

The BM in reactive plasmacytic response is usually normocellular, and the plasma cells are mostly mature, uniformly distributed, often related to reticulum cells. The morphological features which indicate the reactive nature of plasma cells, although not specific, include scattered, non-aggregated mature plasma cells and their perivascular location.[9],[11],[15] In addition, RP can be associated with other reactive changes such as granulocytic hyperplasia, lymphoid aggregates/follicles, plasmacytic satellitosis (a central macrophage surrounded by plasma cells) and increased numbers of macrophages, mast cells, oeosinophils and megakaryocytes.[7],[8],[9],[15] On the other hand, PCDs reveal both mature and immature plasma cells. The marrow is most often hypocellular with reduced haematopoietic elements and the plasma cells are chiefly abnormal with left shift (shift to left), focal in distribution with aggregate formation, associated with reticulum cells and usually more than 20%.[24],[25] Owing to a potential overlap in the amount of plasma cell infiltrate and some cytomorphologic features, RP needs to be differentiated from PCDs. Marked variation in cell size and shape, cellular atypia, nuclear enlargement and hyperchromasia, multinucleation and prominent nucleoli may be the clues favouring malignancy.

Cytogenetic analysis in RP will reveal a normal karyotype (46, XY), while as in PCD both primary and secondary cytogenetic abnormalities can be seen. Studies have shown that there is a correlation between antigen expression on clonal plasma cells and clinical stage as well as cytogenetic aberrations.[26],[27]

Thus, it is important to be cautious in RP cases with BM plasma cell percentage >10% and to identify any malignant clone by integration and correlation of the morphologic, immunophenotypic, immunofixation, radiologic and cytogenetic findings.


  Conclusion Top


RP was present in around 72.6% of BMs evaluated at our centre and was most commonly associated with infections and autoimmune disorders; PCs were as high as 25% of the BM differential and usually show uniform distribution. There is a variety of diseases in which the proportion of marrow plasma cells can be increased. A suspicion of PCD may be raised, especially when the percentage of BM plasma cells is more than 10%. Thus BM plasmacytosis can present as a diagnostic dilemma and sometimes can be challenging to distinguish reactive from the neoplastic condition as there is an overlap both in counts and morphology. Hence, each case with BM plasmacytosis, especially in the overlap range requires complete clinical evaluation, particular investigations and more specific tests like immunofixation by electrophoresis and BM biopsy with immunohistochemistry to reach a final diagnosis for proper patient management. However, the proper assessment of morphological features and degree of plasmacytosis along with the associated clinical and laboratory findings are the key to making a correct diagnosis.

Ethical clearance

The study was approved by the institutional Ethics Committee of Bihari Vajpayee Institute of Medical Sciences 355(04/2020)/IEC/ABVIMS/EMLH/260/2020.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
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