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  Table of Contents    
REVIEW ARTICLE  
Year : 2016  |  Volume : 59  |  Issue : 4  |  Page : 446-456
Plasmacytic or lymphoplasmacytic infiltrate in lymph nodes: Diagnostic approach and differential considerations


Department of Pathology, Duke University Medical Center, Durham, NC, USA

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Date of Web Publication10-Oct-2016
 

   Abstract 

Plasmacytosis is a common finding in lymph node biopsies and can be seen in diverse circumstances ranging from reactive lymphadenopathy to malignant lymphoma. Familiarity with various histopathologic features of the different entities and awareness of their typical clinical and ancillary study findings are essential for an accurate diagnosis. In this review, we present common and representative nonneoplastic entities and lymphomas that have plasmacytic differentiation or associated plasmacytosis. We focus on the histological classification with an emphasis on the diagnostic approach and areas of diagnostic challenge.

Keywords: Castleman disease, lymph node, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, marginal zone lymphoma, plasmacytosis, primary effusion lymphoma, Rosai-Dorgman disease, syphilis, toxoplasma

How to cite this article:
Xie Y, Vallangeon B, Liu X, Lagoo AS. Plasmacytic or lymphoplasmacytic infiltrate in lymph nodes: Diagnostic approach and differential considerations. Indian J Pathol Microbiol 2016;59:446-56

How to cite this URL:
Xie Y, Vallangeon B, Liu X, Lagoo AS. Plasmacytic or lymphoplasmacytic infiltrate in lymph nodes: Diagnostic approach and differential considerations. Indian J Pathol Microbiol [serial online] 2016 [cited 2017 Mar 1];59:446-56. Available from: http://www.ijpmonline.org/text.asp?2016/59/4/446/191756



   Introduction Top


A significant plasma cell/plasmacytoid cell component can occur in a variety of reactive and neoplastic lymph node disorders. Familiarity with the pathologic features of a diverse group of benign and malignant lymph node disorders is necessary to formulate the differential diagnosis, guide ancillary test selection and render a specific diagnosis. In this review, we first consider nonneoplastic entities that have a prominent or characteristic plasma cell infiltration and then examine lymphomas with plasmacytic differentiation or associated plasmacytosis. The simultaneous presence of neoplastic plasma cell infiltrate, and a lymphoma is a unique diagnostic challenge. We outline a basic approach to diagnosis using histologic patterns augmented by a limited number of ancillary studies and emphasize the potentially problematic and/or clinically significant differential diagnoses.

High-quality hematoxylin and eosin stained sections, preferably of intact and entirely excised lymph nodes, are essential. Prompt fixation of thin slices (<2 mm) of tissue in adequate quantities of buffered formalin offers optimal preservation of architectural and cytological details. Access to paraffin immunohistochemistry (IHC) for common hematolymphoid antigens is necessary. Flow cytometric examination to identify a clonal B-cell population at a minimum, and more extended immunophenotyping of the various lymphoid and related populations is very helpful in many cases. Molecular studies of immunoglobulin heavy chain (IgH) and T-cell receptor to establish clonality are sometimes necessary. Some noteworthy points regarding ancillary studies in this context - First, demonstrating the presence of clonal IgH by molecular studies cannot distinguish between clonal B-cells and clonal plasma cells, as can be done by flow cytometry. Second, IHC staining for kappa and lambda is usually not sensitive enough to determine clonality of B-cells, as it is for plasma cells. However, IHC stains for kappa and lambda and sometimes the IgHs may be helpful in evaluating potential lymphomas with plasmacytoid differentiation, such as marginal zone lymphoma (MZL) or lymphoplasmacytic lymphoma (LPL). [1] Finally, with IHC staining, a small number of monotypic plasma cells may be masked by the presence of more abundant polytypic, reactive plasma cells.


   Reactive Lymphadenopathies with Plasmacytic Infiltrate Top


Virtually, any compartment of the lymph node can be infiltrated by plasma cells in various types of benign lymphadenopathies. The number of plasma cells can vary from 1% to 2% to over 50% of total cells. It is helpful to group these entities based on the predominant plasma cell infiltration pattern: intrafollicular, interfollicular/paracortical, capsular and septal, and sinusoidal [Table 1]. It should be noted that multiple compartments can be involved in one process and the degree of involvement can be variable from case to case. Generally speaking in the reactive conditions, the nodal architecture may be disrupted, but usually not completely effaced; the plasma cells do not show significant cytologic atypia such as enlarged cells with central nuclei, fine chromatin, nucleoli, tri- or multi-nucleation, and Dutcher bodies; although, binucleation and Russell bodies can be seen. Demonstration of plasma cells/plasmacytoid cells by IHC and absence of clonal B cells by flow cytometry is helpful in excluding a neoplastic plasma cell or B cell process. However, it is important to keep in mind that light-chain restriction is not an absolute indicator of neoplasia. Nam-Cha et al. have described rare reactive lymphadenitis with light-chain-restricted plasma cells and plasmacytoid cells within germinal centers. These findings may be a manifestation of an underlying disorder in the regulation of the immune response or an exaggeration of the germinal center oligoclonal nature. [2]
Table 1: Plasma cell infiltration pattern in reactive lymphadenopathies

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Autoimmune lymphadenopathy

Rheumatoid arthritis associated lymphadenopathy

Lymphadenopathy is frequently found in patients with autoimmune disorders such as rheumatoid arthritis (RA), Sjogren's syndrome, and systemic lupus erythematosus (SLE). [3],[4],[5] Because these patients have an increased risk of non-Hodgkin lymphoma, lymph node biopsy is sometimes performed when there is clinical suspicion of lymphoma. Histologically, RA-associated nonneoplastic lymphadenopathy typically shows reactive follicular hyperplasia and prominent interfollicular polytypic plasmacytosis. Plasma cells tend to also crowd into the germinal centers. The lymph node capsule is thickened but typically is not infiltrated by the plasma cells. The main differential diagnosis includes reactive follicular hyperplasia due to other causes. The clinical history and laboratory findings are helpful to confirm the diagnosis of RA-associated lymphadenopathy.

Systemic lupus erythematosus associated lymphadenopathy

The histologic features of lymph nodes in SLE are characterized by paracortical hyperplasia, often with foci of necrosis, resembling Kikuchi-Fujimoto disease. [5],[6] Plasma cells are present near the necrotic areas along with histiocytes, lymphocytes, immunoblasts, and abundant karyorrhectic debris. In contrast to Kikuchi-Fujimoto disease, neutrophils may be present and plasma cell infiltrate is more common. Hematoxylin bodies, which are collections of basophilic amorphous material composed of degenerated nuclei, are fairly specific, but not very sensitive feature of SLE and clinical correlation is generally necessary to definitively distinguish between SLE and Kikuchi-Fujimoto disease.

Infectious lymphadenopathy

Infectious mononucleosis

Infectious mononucleosis caused by acute Epstein-Barr virus (EBV) infection is usually asymptomatic in children; but lymph node and tonsillar biopsies are occasionally performed in adolescents and young adults, who are often symptomatic. Histologic features vary during the disease. [7] In the early stage, there is reactive follicular hyperplasia with monocytoid B-cell proliferation. [8] Later, there is an expansion of the paracortex by a polymorphous infiltrate consisting of immunoblasts, plasmacytoid cells, plasma cells, small lymphocytes, and histiocytes [Figure 1]. Necrosis may also be seen. Some cases may have nodules and sheets of immunoblasts with cytologic atypia, resembling large B-cell lymphoma. [7] In other cases, there are clusters of EBV + Reed-Sternberg-like cells, simulating classical Hodgkin lymphoma. [9] Morphologic features favoring infectious mononucleosis include the maintenance of the nodal architecture despite sometimes considerable distortion, the presence of both B and T-cell immunoblasts, a predominance of CD8+ T cells and the presence of both large and small EBV+ cells. [10],[11] Gene rearrangement studies may be useful; however, both immunoglobulin and T-cell receptor may show oligoclonal or occasionally monoclonal rearrangement patterns. [12]
Figure 1: Infectious mononucleosis. (a) Largely preserved nodal architecture with expanded paracortex (H and E, ×4). (b) Polymorphous paracortical infiltrate of large immunoblasts in a background of small to medium lymphocytes and plasma cells (H and E, ×20). (c) Lymphoid follicles and scattered interfollicular B cells seen with CD20 stain (CD20, ×10). (d) CD138 staining highlights abundant plasma cells in medullary sinuses (CD138, ×10). (e) B-immunoblasts in the interfollicular area (CD20, ×20). (f) CD3 staining highlights numerous T cells in the paracortex (CD3, ×20)

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Cytomegalovirus associated lymphadenopathy

Cytomegalovirus (CMV) infection can clinically resemble infectious mononucleosis with localized or generalized lymphoadenopathy. [13] The involved lymph nodes often show reactive follicular hyperplasia, paracortical expansion with plasmacytoid cells, scattered immunoblasts, and monocytoid B-cell collections. Large cells containing prominent intranuclear and intracytoplasmic viral inclusions, mimicking Reed-Sternberg cells, may be found. [14] IHC stains using anti-CMV antibodies are helpful to confirm the diagnosis. [15]

Human immunodeficiency virus-associated lymphadenopathy

Persistent generalized lymphadenopathy is part of an HIV-related syndrome. The histologic picture of the lymph node varies in different stages of the disease. [16] In the early stage, follicles are often enlarged and the germinal centers may be irregular, serpentine or show follicle lysis, while in late stage, there is progressive lymphocyte depletion and follicles with regressive changes. Plasma cells can be seen in all stages, but they are more prominent in the interfollicular areas (paracortex) in the later stages.

Syphilitic (luetic) lymphadenopathy

Lymphadenopathy is regularly seen in primary and secondary syphilis and possibly in latent stage. There is typically follicular hyperplasia and often marked medullary and interfollicular plasmacytosis, reminiscent of autoimmune lymphadenopathy. [17] Features that point to luetic lymphadenitis include extensive capsular and trabecular fibrosis with infiltration by plasma cells, nonnecrotizing granulomas with epithelioid histiocytes and giant cells, and endarteritis and venulitis. [18] The diagnosis can be confirmed by the detection of Treponema pallidum, IHC and PCR testing being more sensitive than silver staining. [19]

Infectious granulomatous lymphadenitis

A wide variety of infectious etiology, such as fungal infections, toxoplasmosis [Figure 2], tuberculosis, atypical mycobacterial disease, pneumoconiosis, can cause granulomatous lymphadenitis and show significant plasma cell infiltration. Infectious granulomatous lymphadenitis can be classified into suppurative and nonsuppurative lymphadenitis. Primary etiology can be established by special stain or immunostain, and can be confirmed by serologic assays, microbial culture, and molecular methods. [20]
Figure 2, Toxoplasma lymphadenitis. (a) reactive follicles and clusters of epithelioid histiocytes within the germinal centers (H and E, ×2). (b) Plasma cells in the interfollicular area and epithelioid histiocytes in germinal center (H and E, ×20)

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Lymphadenopathy of unclear etiology

Castleman's disease

Castleman's disease (CD) is an uncommon disorder first described by Castleman and Towne as a localized mediastinal lymph node hyperplasia resembling thymoma. [21],[22] Clinically, CD can be classified as the unicentric or multicentric type and pathologically as hyaline vascular or plasma cell variant. [23] Hyaline vascular CD, the most common CD, usually presents as a localized mass and is characterized by small follicles associated with hyalinized vessels and interfollicular capillary proliferation, but a variable number of plasma cells are almost always present in interfollicular areas [Figure 3]a and b. Plasma cell variant CD features hyperplastic or small regressed follicles with moderate to extensive sheets of plasma cells in between [Figure 3]c and d. The plasma cells are generally polytypic in CD, but may be monoclonal in some plasma cell variant CD, usually with lambda light-chain restriction. The majority express IgG, and a small subset expresses IgA. [24],[25] Lambda light-chain restriction can also be demonstrated in a proportion of HIV + patients with human herpesvirus 8-positive multicentric CD (HHV8 MCD). [26] In these cases, there may be variable numbers of large immature plasma cells, i.e., plasmablasts, present in the mantle zones, expressing intranuclear HHV8 latency-associated nuclear antigen, viral interleukin-6 (IL-6) and cIgM with lambda light-chain restriction. [27] Despite a monotypic staining pattern, molecular studies have shown that these cells constitute a polyclonal population. [28] Whether such cases transform into an HHV8-positive plasmablastic lymphoma (PBL) is controversial. [29]
Figure 3: Castleman disease and Rosai-Dorfman disease. Hyaline-vascular Castleman disease. (a) Follicles with expanded mantle zones and multiple atrophic germinal centers in a single mantle zone (H and E, ×4). (b) Germinal center penetrated by a hyalinized vessel. Scattered plasma cells are seen in the interfollicular areas (H and E, ×20). Plasma cell variant Castleman disease. (c) Follicular hyperplasia and marked interfollicular plasmacytosis (H and E, ×4). (d) Numerousplasma cells in perifollicular area (H and E, ×20). Rosai-Dorfman disease. (e) Collections of plump histiocytes and lymphoplasmacytic cells (H and E, ×20). (f) The histiocytes have large round nuclei and prominent nucleoli. Note the emperipolesis of lymphocytes and plasma cells (H and E, ×40)

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IgG4 related disease

Lymphadenopathy of IgG4 related disease can exhibit a broad morphologic spectrum, including MCD-like, follicular hyperplasia, interfollicular expansion, progressive transformation of germinal centers (PTGC), and inflammatory pseudotumor (IPT)-like. [30],[31] While the morphologic features are nonspecific, one characteristic IHC finding in all is the presence of abundant IgG4+ plasma cells (>100 IgG4+ plasma cells per high power field and IgG4/IgG ratio >40%). IgG4+ plasma cells are often found in both the germinal centers and interfollicular zone, although they are located predominantly within germinal centers for PTGC pattern. In only a subset of the IgG4-related lymphadenopathy, particularly the IPT-like type, there is storiform fibrosis with intermingled lymphocytes and plasma cells, which is a characteristic morphologic feature seen in IgG4-related disease in extranodal sites. It must be kept in mind that an increase of IgG4+ cells and IgG4/IgG ratio is not very specific and has been reported in other reactive and neoplastic conditions, including Rosai-Dorfman disease and MZL etc. [32],[33] Clinical and laboratory findings must be taken into consideration to reach a diagnosis of IgG4-related disease.

Rosai-Dorfman disease

Plasma cells are typically numerous in this indolent histiocytic disorder of unknown etiology, in which increased histiocytes occur in the sinus and paracortex, with an S-100+/CD68+/CD4+ immunophenotype and prominent emperipolesis (presence of lymphocytes, plasma cells, and occasionally other cells in their cytoplasm). [34] Variable numbers of plasma cells are present in the interfollicular and paracortical areas in almost all cases [Figure 3]e and f.

Inflammatory pseudotumor

IPT is an uncommon reactive condition of lymph nodes characterized by proliferation of the myofibroblastic cells, small vessels, and mixed inflammatory cells including lymphocytes and plasma cells as well as occasional eosinophils and neutrophils. [35] While the pathogenesis of IPT has remained obscure, the absence of anaplastic lymphoma kinase (ALK) expression in all cases of IPT of the lymph node indicates that this entity is biologically distinct from the inflammatory myofibroblastic tumors found in soft tissue. [36]


   Small B-Cell Lymphomas with Plasmacytic Differentiation Top


Plasmacytic or plasmacytoid differentiation can be found in a variety of small B-cell lymphomas, including MZL, LPL, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma, etc., Flow cytometric demonstration of monotypic B-cells with characteristic immunophenotype is helpful in many cases, but the distinction between some LPLs and MZLs can be very challenging because they share overlapping morphologic and immunophenotypic features. [37] It usually requires the integration of clinical history, morphology, immunophenotype, and molecular/cytogenetic analysis to achieve a definitive diagnosis. In certain cases, only a descriptive diagnosis of "small B-cell lymphoma with plasmacytic differentiation" is possible. In cases with a predominant plasma cell component, the possibility of a coexisting plasma cell neoplasm also needs to be ruled out. [38]

Nodal marginal zone lymphoma

Nodal MZL (NMZL) is a rare indolent B-cell lymphoma mainly affecting older adults (median age 60 years). [39],[40] It often presents with Stage III or IV disease, sometimes with B symptoms. [41],[42],[43] Variable morphologic patterns (diffuse, perifollicular, interfollicular, and nodular) are recognized, characterized by heterogeneous proliferation including marginal zone B cells (centrocyte-like, monocytoid), plasmacytoid cells, plasma cells, and scattered transformed B-cells (centroblasts and immunoblasts). [44],[45] Plasmacytoid differentiation is common and can be extensive. [46],[47] Dutcher and Russel bodies may be seen. The residual follicles can be expanded, regressed, or colonized by neoplastic cells [Figure 4]. NMZLs express pan-B-cell markers including CD20, CD79a, and PAX5. The majority of cases lack CD5, CD23, CD10, and BCL6, although expression of these markers has been reported. In most cases, BCL2 is weakly expressed and in up to 50% of cases, CD43 is positive. Cells with plasmacytic/plasmacytoid differentiation are positive for MUM1. In addition, cytoplasmic immunoglobulin expression can often be detected. They are mostly IgM+, rarely IgG+ or IgA+. Identification of light-chain restriction by flow cytometry favors a lymphomatous process. However, some cases of reactive marginal zone hyperplasia, particularly in pediatric patients, can show lambda light-chain restriction even though they are polyclonal by molecular analysis. [48] The differential diagnosis of NMZL frequently includes other low-grade B-cell lymphomas with plasmacytic differentiation and plasma cell neoplasms. These entities are discussed further in the following sections.
Figure 4: Nodal marginal zone lymphoma. (a) Pale staining, "monocytoid" lymphoid cells expand the interfollicular areas and focally infiltrate the follicles (H and E, ×2). (b) A rim of clear cytoplasm imparts the monocytoid appearance. Few Dutcher bodies are present (H and E, ×40). (c) CD20 highlights abundant B cells in the interfollicular areas (CD20, ×20). (d) Plasmacytoid B-cells and plasma cells are positive for MUM1 (MUM1, ×20). (e) These cells show kappa light-chain restriction (Kappa, ×20). (f) Lambda is negative in these cells. Note the scattered reactive plasma cells (Lambda, ×20)

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Lymphoplasmacytic lymphoma

LPL usually involves bone marrow, less commonly involving extramedullary sites such as lymph nodes and spleen. It is composed of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells. In most instances, LPL is associated with an IgM paraprotein, resulting in Waldenstrom macroglobulinemia (WM) (defined as an LPL with bone marrow involvement and any level of an IgM monoclonal gammopathy). [37] It should be noted that IgM paraprotein can also occur in other B-cell neoplasms (e.g., MZLs), or as IgM producing monoclonal gammapathy of underdetermined significance (MGUS) and rarely as IgM myeloma.

Lymph nodes involved by LPL typically show subtle paracortical expansion, sparing the lymph node sinuses. Lymphoid follicles are often regressed, but follicular colonization can be seen. Compared to NMZL, the infiltrate is more uniform, containing a relatively monotonous population of small lymphocytes, plasmacytoid lymphocytes, and varying numbers of plasma cells [Figure 5]. Dutcher bodies are common. In addition, prominent mast cells and hemosiderin deposition may be present. [37],[49]
Figure 5: Lymphoplasmacytic lymphoma. (a) Histologic picture of lymphoplasmacytic lymphoma. The nodal architecture is replaced by a dense lymphoplasmacytic infiltrate (H and E, ×2). (b) Higher magnification view of lymphoplasmacytic lymphoma. Note the abundant plasmacytoid lymphocytes in the infiltrate (H and E, ×40). (c) The plasmacytoid lymphocytes are positive for CD20, (CD20, ×4). (d) MUM1 staining of the same area. The plasmacytoid lymphocytes are MUM1+ (MUM1, ×4)

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The B lymphocytes in LPL are typically negative for CD5, CD10 and CD23, although variable expression can be seen in some cases (5-50%). [37],[50] LPL plasma cells are positive for CD138, CD38, CD19, and CD45 and they exhibit the same cytoplasmic light-chain restriction as the corresponding surface light-chain-restricted B lymphocytes. Recent studies demonstrate that PAX5 coexpression by CD138+ plasma cells is more common in LPL/WM than in plasma cell myeloma (PCM) or MZL, indicating the aberrant persistence of the B-cell transcriptional program in LPL/WM plasma cells. [51]

The IGH/PAX5 (t(9;14)) translocation is no longer considered sensitive or specific for LPL, but 6q21 deletion, although nonspecific, is reported in up to 63% of bone marrow based LPL/WM cases [52],[53] and is useful in discriminating WM from IgM MGUS. [52] Notably, it is neither a prognostic marker nor a characteristic marker for nodal LPL. [37],[54]

Recently, the use of whole-genome sequencing has helped to identify a highly recurrent somatic mutation, myeloid differentiation primary response factor 88 (MYD88) L265P in >90% of LPL/WM. [55] The mutation has also been found in a subset of IgM MGUS and diffuse large B-cell lymphoma (DLBCL), but much less frequently in other small B-cell neoplasms, such as nodal or extranodal MZL, splenic MZL, and CLL as well as hairy cell leukemia and PCM. Subsequent studies from multiple institutions have demonstrated that detection of the MYD88 L265P mutation can assist in classifying challenging bone-marrow and nodal small B-cell neoplasms with plasmacytic differentiation in routine practice. [56],[57]

Follicular lymphoma with plasmacytic differentiation

On occasion, FLmay show marginal zone or plasmacytic differentiation. [58],[59],[60] The degree of plasmacytic differentiation varies among cases, ranging from easily recognized mature plasma cells to the more common plasmacytoid cells. In a small number of cases, plasmacytic differentiation is only identified by IHC stain. [61] The number of plasma cells varies greatly, from few scattered cells to sheet-like collections, and the plasmacytic population may demonstrate a predominantly interfollicular, intrafollicular or perifollicular distribution.

One study analyzed 14 well-characterized FLs with plasmacytic differentiation and demonstrated the presence of the same cytogenetic abnormality in both the plasmacytic (CD138+) and nonplasmacytic (CD138-) component. [62] Furthermore, the presence of BCL2 translocation in plasma cells was strongly associated with a predominantly interfollicular plasma cell distribution. Conversely, the absence of a BCL2 translocation was associated with a prominent intra/perifollicular plasma cell population. These findings indicate that the latter cases may be distinctive, sharing some features with MZLs. [62]

Small lymphocytic lymphoma/chronic lymphocytic leukemia with plasmacytic differentiation

CLL/SLL is most frequently diagnosed by examination of blood. Despite the common nature of SLL/CLL, cases of true CLL/SLL with definitive plasmacytic differentiation are very rare. Evans et al. reported one rare case of CD5-positive CLL/SLL with focal striking plasmacytic differentiation in the lymph node. [63] Interestingly, plasma cells, which expressed membrane CD5, were not identified in the peripheral blood or bone marrow. This case was also unusual for the presence of an abnormality of chromosome 1p36, which is commonly seen in other types of B-cell lymphoma but not in CLL/SLL.

If there is prominent plasma cell differentiation, differentiating SLL/CLL from LPL, may require demonstration of characteristic cytogenetic abnormalities of CLL (trisomy 12, deletion 13q14, deletion 11q22-33, and deletion 17q13) and absence of MYD88 mutation. [63],[64] Lymphocyte enhancer-binding factor 1 is another useful marker for SLL/CLL in difficult or equivocal cases, and 10% positivity of the tumor cells is suggested to make more robust diagnosis of SLL/CLL. [65]


   Plasma Cell Neoplasms Involving the Lymph Node Top


Most plasma cell neoplasms originate as bone marrow tumors; however, the extramedullary disease can occasionally occur. Lymph node involvement can be a manifestation of advanced disease in PCM, regional lymph node involvement in extramedullary plasmacytoma (EMP) or even more rarely as a primary lymph nodal plasmacytoma (PLNP).

Extramedullary plasmacytoma

The histologic features of PLNP and other EMPs are similar. In most cases, the lymph node architecture is effaced by a diffuse proliferation of plasma cells. Occasionally, an interfollicular infiltration by monoclonal plasma cells is present [Figure 6]. The plasma cells are mostly of small mature Marschalko type, [66] but rare cases may demonstrate immature or pleomorphic plasma cells [Figure 7]c. Intracellular Ig may produce Dutcher bodies, Russell bodies, and crystalline rods.
Figure 6: Plasmacytoma. (a) Histologic picture of plasmacytoma. Note the diffuse proliferation of mature appearing plasma cells (H and E, ×20). (b) Immunostaining for CD20 highlights the residual follicles (CD20, ×20). (c) Immunostaining for CD138 highlights the neoplastic plasma cells (CD138, ×20)

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Figure 7: Plasmablastic lymphoma, extracavitary primary effusion lymphoma and plasma cell myeloma with plasmablastic morphology. Higher magnification view of plasmablastic lymphoma (a; H and E, ×40), extracavitary primary effusion lymphoma (b; H and E, ×40) and plasma cell myeloma with plasmablastic morphology (c; H and E, ×40). Note the overlapping cytologic features

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Lymph node involvement by advanced stage PCM and by EMP cannot be distinguished on a morphologic basis alone, although there seem to be diagnostically useful immunophenotypic differences. Whereas extramedullary involvement in advanced stage PCM is frequently CD56+ and not infrequently CD117+, cyclin D1+ or p53+, EMPs are rarely positive for these markers. [67] The distinction of nodal plasmacytoma from MZL and LPL with extensive plasmacytoid differentiation may require demonstration of clonal B-cells by flow cytometry.

Heavy-chain disease

Heavy-chain diseases (HCDs) are a rare group of B-cell neoplasms characterized by an excessive production of incomplete heavy chains, without associated light chains. Depending on the subtype of the altered heavy chain, the HCDs are subclassified as alpha, gamma, or mu HCD. [68] Each HCD demonstrates unique clinicopathological features:-Alpha HCD is the commonest type and is considered to be a variant of mucosa-associated lymphoid tissue lymphoma lymphoma, typically involving gastrointestinal tract and mesenteric lymph nodes. Gamma HCD most frequently presents as a lymphoplasmacytic proliferation in lymph nodes and extranodal tissue, resembling LPL. Mu HCD is rare and typically involves blood and bone marrow, resembling CLL. [69] Serum protein electrophoresis may not show a characteristic monoclonal spike, and immunofixation electrophoresis is often needed to establish the diagnosis.


   Large B-Cell Lymphomas with Plasmacytic/Plasmablastic Differentiation Top


These tumors show cytologic and/or immunophenotypic features of plasma cells or plasmablasts and can be broadly divided into two groups - those showing loss of most pan-B-cell antigens and those retaining the mature B-cell phenotype. Among the former group, PBL, ALK-positive DLBCL, primary effusion lymphoma (PEL) and extracavitary PEL, and EMP tumors secondary to multiple myeloma or plasmacytoma deserve attention. The clinicopathological properties of these entities are summarized in [Table 2] and representative cases are illustrated in [Figure 7].
Table 2: Large B - cell lymphomas with plasmacytic/plasmablastic differentiation

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Other large B-cell lymphomas which may demonstrate plasmacytic differentiation but maintain a mature B-cell phenotype include PBL associated with MCD, DLBCL with secretory differentiation, pyothorax-associated lymphomas, and atypical Burkitt lymphoma with plasmacytic differentiation. [89] PBL associated with MCD is a somewhat controversial disease entity in which HHV-8 positive plasmablasts with light-chain restriction (typically lambda IgM) coalesce within the mantle zones to form either small confluent clusters or large lymphomatous sheets. [27] Pyothorax-associated lymphoma is a distinct entity among DLBCLs which present with recurrent pyothorax and may be regarded as an EBV-associated lymphoma derived from postgerminal center/activated B-cells. [90] Burkitt lymphoma is an aggressive B-cell lymphoma characterized by a translocation between the MYC gene and the IGH gene. Those with plasmacytic differentiation tend to occur in association with immunodeficiency and show monotypic cytoplasmic immunoglobulin. [91]


   T-Cell Lymphoma with Increased Plasma Cells Top


The T-cell lymphoma likely to show increased plasma cells in the lymph node biopsy is angioimmunoblastic T-cell lymphoma (AITL), the second most common peripheral T-cell lymphoma. The B-cell expansion in this lymphoma is thought to be related to the function of the neoplastic cells as T-follicular helper cells, while the known association of EBV infection of the B cells and increased release of cytokines, such IL-6 or IL-10 may contribute to the plasma cell proliferation in AITL. In a subset of the cases, monoclonal B cell or plasma cell proliferation can be detected. As demonstrated by Huppmann et al. (2013), the B-cell or plasma cell expansion in AITL can be so great, as to partially overshadow or obscure the underlying T-cell neoplasm. [92] Awareness of this eventuality is important to avoid misdiagnosis and inappropriate therapy.

Diagnostic approach for lymph node biopsies with a prominent plasma cell infiltrate

In the evaluation of lymph node biopsies with increased plasma cells or plasmacytoid cells, often the initial step is to differentiate reactive lymph nodes from a lymphomatous process. There are probably two key points that the pathologist should consider. First, is the lymph node architecture effaced or intact? Second, is there evidence of clonal B-cell or plasma-cell expansion? Several pathologic features favor a reactive lymph node: largely preserved nodal architecture; lack of significant cytologic atypia; and lack of monoclonal B-cell or plasma cell population. Ancillary studies such as flow cytometry and IHC are often employed to evaluate B-cell and plasma cell clonality. It is important to be aware that light-chain restriction is not an absolute indicator of neoplasia. In some reactive conditions, such as KSHV-positive MCD, the B cells/plasma cells are monotypic but polyclonal.

Depending on the extent of the involvement, small B-cell lymphomas may show effaced or largely preserved nodal architecture. Distinguishing among the various small B-cell lymphomas, such as NMZL, LPL and sometimes atypical CLL, can be difficult because of overlapping morphologic and immunophenotypic features. Cytogenetic and molecular study, such as MYD88 L265P mutation analysis, has proven to be a useful adjunct in the diagnosis of LPL and small B-cell lymphoma mimics. [3],[4] While the presence of B-cell and plasma-cell populations with the same light-chain restriction is an important clue to the B-cell lymphoma with plasmacytic differentiation, it must be remembered that finding identical light chains is not definitive evidence of clonal identity, and the possibility of a composite plasma cell neoplasm needs to be ruled out.

When large B-cell lymphomas develop significant plasmacytic differentiation, they often lose mature B-cell-associated antigens such as CD20 and PAX-5 and gain expression of plasma cell markers such as EMA, CD138, and CD38. They may aberrantly express T cell markers, and EBV and/or HHV8 may be positive. It often is challenging to differentiate PBL and the plasmablastic variant of PCM on the basis of the morphologic examination alone. However, the patient's demographics, clinical history, and bone marrow findings may strongly suggest a particular diagnosis.


   Summary Top


In summary, plasmacytosis is a common finding in lymph node specimen and can be seen in diverse circumstances including reactive lymphadenopathy, small B-cell lymphomas, large B-cell lymphomas, plasma cell neoplasms, and even T-cell lymphomas. It is important to consider a wide differential diagnosis. A systematic approach combined with appropriate histopathologic findings and ancillary test selection may help to formulate the differential diagnosis and ultimately to render a correct diagnosis. Molecular and cytogenetic studies are helpful in arriving at a specific diagnosis in morphologically challenging cases. It is important to remember that the ancillary studies must always be interpreted in the context of the clinical settings and histopathologic features.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Correspondence Address:
Anand S Lagoo
Department of Pathology, Duke University Medical Center, PO Box 3712 DUMC, Durham, NC 27710
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DOI: 10.4103/0377-4929.191756

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