General Overview and Incidence

Multiple myeloma (MM) is a malignancy of clonal plasma cells and is part of a spectrum of plasma cells disorders encompassing the benign asymptomatic condition monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM), symptomatic MM, and the more aggressive forms such as plasma cell leukemia with circulating myeloma cells in the peripheral blood ( Fig. 14.1 ). In 1850, Dr. Henry Bence Jones described the first myeloma patient, Thomas Alexander McBean, who presented with symptoms of fatigue, diffuse bone pain, and urinary frequency. Bence Jones proteins were detected in the urinalysis. Over the next decade, multiple advances such as x-ray, bone marrow examination, and immunoelectrophoresis have helped to define the disease further.

Spectrum of plasma cell neoplasm range from the benign precursor condition called monoclonal gammopathy of unknown significance ( MGUS ) to more aggressive subtypes with dissemination to extramedullary compartments. Correct subclassification requires integration of clinical and histopathologic findings. MM, multiple myeloma.

The plasma cells in MM are dysfunctional and, in most cases, produce a monoclonal immunoglobulin (Ig) that can be classified into five subtypes: IgG, IgA, IgM, IgD, and IgE. Infrequently, heavy-chain components of the immunoglobulin are not produced by the myeloma cells and the disease manifests as production and secretion of light-chain only, which would either be κ or λ type. Very rarely, myeloma fails to produce any significant amount of protein and would manifest as a nonsecretory MM.

MM accounts for 1% of all malignancies and is the second most common hematologic malignancy, with prevalence of around 10%. The lifetime risk of MM is 1 in 143 (0.7%). The American Cancer Society estimated about 30,280 new cases would be diagnosed (17,490 in men and 12,790 in women) and 12,590 deaths were expected to occur (6,660 in men and 5,930 in women) in the United States in 2017. Increase in the incidence rate (MM cases per 100,000 persons) was significantly higher among non-Hispanic white (NHW) women (4.15–4.36; P = .05), NHW men (6.39–7.22; P < .001), and non-Hispanic black (NHB) men (13.94–16.15; P < .01), but not among NHB women (10.96–11.57; P = not significant [NS]), Hispanic men (6.46–6.45; P = NS), or Hispanic women (4.24–4.39; P = NS). The median age at diagnosis decreased from 73 to 71 years among NHW women ( P < .001), whereas no notable difference in age at diagnosis was observed for NHW men (71–70 years; P = NS), NHB women (68–66 years; P = NS), NHB men (67–66 years; P = NS), Hispanic women (67–67 years; P = NS), or Hispanic men (66–65 years; P = NS). The finding of increased incidence of MM and younger age at diagnosis in select populations could be due to earlier identification of cases. Therefore, early diagnosis could imply longer survival by detecting SMM cases sooner or by offering early life-extending therapies to MM patients.

Etiology and Histopathology

The etiology of MM and MGUS is not entirely clear. However, several risk factors include immune-mediated conditions such as autoimmune and inflammatory diseases and exposure to toxic substances such as pesticides. Studies have also found increased risks seen in first-degree relatives of MM patients, suggesting genetic factors in the pathogenesis. ^, The bone marrow microenvironment, mediated by cytokines and growth factors, plays an important role in the proliferation of the neoplastic plasma cells and disease progression.

Nearly all cases of smoldering and symptomatic MM are preceded by MGUS, an asymptomatic premalignant condition. MGUS can be categorized into IgM and non-IgM subtypes, which differ in their modes of progression. IgM-type MGUS can progress to Waldenström macroglobulinemia (WM), other non-Hodgkin lymphoma or light-chain (AL) amyloidosis at a rate of 2% per year in the first 10 years after diagnosis and 1% per year thereafter, whereas non-IgM MGUS is associated with progression to MM, plasmacytoma, or AL amyloidosis at a rate of approximately 1% per year independent of duration of follow-up. Risk factors for progression of disease to MM or lymphoma include concentration of M-protein and abnormal ratio of serum κ and λ light chains. ^,

The classification of plasma cell neoplasm requires integration of clinical, laboratory, and pathologic features ( Table 14.1 ). The myeloma defining events described in the diagnostic criteria include CRAB features (hyper C alcemia, R enal insufficiency, A nemia, B one lesions) and biomarkers of malignancy (SLiM features [ S ixty percent clonal bone marrow plasma cells, serum-free Li ght-chain ratio; M agnetic resonance focal]) ( Box 14.1 ). The biomarkers of malignancy identify patients who do not exhibit end-organ damage but are at high risk of disease progression to symptomatic MM and therefore should be offered therapy. Bone marrow examination is essential in the diagnostic workup of MGUS and MM to document the extent of infiltration of the neoplastic plasma cells. The evaluation includes immunophenotyping and morphologic evaluation of the aspirate smears, as well as cytogenetic and molecular studies essential for prognostication. Bone marrow plasma cell percentage should be estimated from a core biopsy sample. Discrepancies between the aspirate and core biopsy can occur for a variety of reasons, including technical factors from sample preparation or patchy or localized distribution of the neoplastic plasma cells. In these settings, the highest value should be used for disease classification or characterization.

Normal nonneoplastic plasma cells are characterized by eccentrically placed nuclei, ample blue cytoplasm, paranuclear hof, condensed and clumped chromatin, and inconspicuous nucleoli ( Fig. 14.2 ). Neoplastic plasma cells can exhibit a wide variety of morphologic features from normal mature morphology ( Fig. 14.3 ) to cells with immature features. Immature features include open or fine blastlike chromatin, prominent nucleoli, and centrally placed nuclei ( Figs. 14.4–14.8 ). Occasionally, neoplastic plasma cells may have atypical or unusual morphology without any resemblance of their plasma cell origins. They may appear lymphoplasmacytoid, monocytoid, anaplastic, or even multinucleated, sometimes mimicking osteoclasts ( Figs. 14.9–14.11 ). In these cases, a panel of antibodies including a CD138 stain is useful in classifying these cells as neoplastic plasma cells.

Normal morphologic features of a plasma cell ( thick arrow ). The nucleus is eccentrically placed with coarse, clumped chromatin, ample basophilic cytoplasm, and paranuclear hof. A few small lymphocytes ( thin arrow ) are also present in the background, with round-ovoid nuclei, condensed chromatin, and a scant to moderate amount of cytoplasm (Wright-Giemsa stain).

Mature morphology. A case of plasma cell myeloma showing neoplastic plasma cells with mature morphologic features accounting for approximately 60% of cells on an aspirate smear differential count.

Immature morphology. The neoplastic plasma cells in this case show immature morphologic features. The nuclei exhibit more open chromatin and prominent nucleoli. There is ample cytoplasm and eccentrically placed nuclei (Wright-Giemsa stain).

Immature morphology. Another example of plasma cell myeloma with immature features: open chromatin and prominent nucleoli. Some of the plasma cells also show atypical nuclear lobulations and shapes ( arrows ). In some cases, the atypical shapes can be extensive. masking the true identity of plasma cells (Wright-Giemsa stain).

Plasma cell myeloma with features intermediate between mature and immature morphology. A subset of the neoplastic plasma cells demonstrates mature features ( arrow ) and others demonstrate less condensed chromatin and distinct nucleoli ( arrowhead ) (Wright-Giemsa stain).

Plasmablastic morphology. In this case, the neoplastic plasma cells show plasmablastic morphology with open chromatin, prominent nucleoli, high nuclear-to-cytoplasmic ratio, and more centrally placed nuclei. Binucleated forms are present (Wright-Giemsa stain).

Plasmablastic morphology. The corresponding trephine biopsy of the aspirate smear in Fig. 14.6 shows sheets of atypical plasma cells that are poorly differentiated and resembling blasts. The nucleoli are prominent and the chromatin is open/fine (hematoxylin-eosin stain).

Lymphoplasmacytoid morphology. The neoplastic plasma cells in this case show lymphoid features with round-ovoid nuclei and decreased amount of cytoplasm.

Lymphoplasmacytoid morphology. (A) The corresponding trephine biopsy of the aspirate smear in Fig. 14.9 (hematoxylin-eosin stain). (B) CD138 stain is useful in identifying the plasma cell lineage of the cells.

Atypical morphologic features of plasma cell neoplasm. (A) Neoplastic plasma cells are large and multinucleated, sometimes mimicking osteoclasts. (B) In this case, the neoplastic plasma cells show monocytoid features with irregular folded nuclei.

Russell bodies and Dutcher bodies are spherical cytoplasmic inclusions composed of accumulation of immunoglobulins. ^, Dutcher bodies are cytoplasmic inclusions that invaginate into or overlie the nucleus and are called pseudo-nuclear inclusions ( Figs. 14.12 and 14.13 ), whereas Russell bodies are seen clearly within the cytoplasm ( Fig. 14.14 ). ^, Mott cells are plasma cells that show accumulation of multiple Russell bodies ( Fig. 14.15 ). Russell bodies, Dutcher bodies, and Mott cells are not specific to neoplastic plasma cells and can be appreciated in B-cell neoplasms and reactive plasma cells. Rarely, crystalline cytoplasmic structures are appreciated and may be rod-, needle-, or rhomboid-shaped ( Fig. 14.16 ). These structures are also thought to be composed of light-chain proteins. ^, Erythrophagocytosis in MM is also a rare finding ( Fig. 14.17 ).

Dutcher bodies are pseudo-intranuclear inclusions. They are cytoplasmic vacuoles containing immunoglobulins that invaginate into the nuclei (Wright-Giemsa stain).

Dutcher bodies. The corresponding trephine biopsy of the aspirate smear in Fig. 14.12 shows sheets of plasma cells with Dutcher bodies appreciated in some ( arrow ) (hematoxylin-eosin stain).

Russell bodies are cytoplasmic vacuoles filled with immunoglobulins. They are distinct spherical inclusions that are seen within the cytoplasm (A), and at times can be eosinophilic, as seen in (B) ( arrow ).

A Mott cell is a plasma cell showing accumulation of Russell bodies (Wright-Giemsa stain).

Crystalline cytoplasmic inclusions. The neoplastic plasma cells in this case demonstrate rodlike crystalline inclusions within the cytoplasm (Wright-Giemsa stain).

Erythrophagocytosis. The neoplastic plasma cells in this case show frequent erythrophagocytosis. Nucleated red cells are engulfed by two plasma cells seen at the top left. There is also frequent dysplasia appreciated in the nucleated red cells with irregular nuclear contours, raising the possibility of an underlying myelodysplastic syndrome. The plasma cells in this case show immature/plasmablastic features. Studies have found increased risk of therapy related–myeloid neoplasm after treatment of MM. ^,

Neoplastic plasma cells can show different patterns of marrow infiltration. They can be scattered interstitially, forming small loose clusters, or show extensive sheets ( Fig. 14.18 ). They can also form patchy/localized aggregates ( Fig. 14.19 ), which shows how sampling can affect bone marrow evaluation in the extent of involvement and underscores the importance of corroboration of trephine biopsy and aspirate smear results.

Infiltration patterns of neoplastic plasma cells. (A) CD138 highlights neoplastic plasma cells scattered interstitially and forming loose clusters; this pattern is similar to the pattern in reactive plasmacytosis and the neoplastic nature is revealed only with additional immunophenotyping with a panel of antibodies that would include κ and λ stains. (B) Some cases show extensive sheets of plasma cells. A CD138 stain is useful in highlighting plasma cells and estimating the plasma cell percentage on a trephine biopsy. The percentage of plasma cells should be corroborated with aspirate smear findings and the higher value should be used in disease subclassification (see Table 14.1 ).

Infiltration patterns of neoplastic plasma cells. In this case, the neoplastic plasma cells (highlighted with CD138) show patchy/localized involvement. There is diffuse infiltration in half of the biopsy specimen, while the remaining half shows minimal plasma cell infiltration.

Extramedullary myeloma is the proliferation of neoplastic plasma cells at a site away from the bone marrow space and can be seen in a third of MM cases. It can be present at initial diagnosis, during the course of disease, or at relapse. Typical areas of involvement include central nervous system, lymph nodes, kidneys, skin, liver, and pancreas ( Fig. 14.20 ). It is associated with adverse prognosis, particularly in the setting of relapsed disease. Potential mechanisms of extramedullary spread include altered adhesion molecules, chemokine receptors, and angiogenesis. Solitary plasmacytoma is a distinct entity from extramedullary myeloma. It is a localized proliferation of neoplastic plasma cells without systemic involvement and lacks myeloma-related symptoms ( Table 14.1 ).

Examples of extramedullary myeloma in patients with history of multiple myeloma. (A, B) The patient showed extensive involvement of the skeletal muscles as pictured. (C, D) The patient presented with acute visual deficit and was found with a mass in the base of skull extending into the sinuses. (E, F) A biopsy specimen of the pancreas shows involvement confirmed with CD138 stain. In these examples, the neoplastic cells show immature features (open chromatin, variably prominent nucleoli, and high nuclear-to-cytoplasmic ratio), typical of extramedullary myeloma. In the second case, some of the plasma cells even exhibit anaplastic features (D).

Peripheral blood involvement by neoplastic plasma cells can also occur and can be classified as primary or secondary. Both subtypes are associated with poor prognosis, and they are defined as the presence of more than 20% plasma cells in the peripheral blood or an absolute plasma cell count greater than 2 × 10 ⁹ cells/L. Neoplastic plasma cells in primary plasma cell leukemia often exhibit decreased expression of CD56. Other findings in the peripheral blood smear of patients with MM may include rouleaux formation, where red blood cells form a linear arrangement and have the appearance of a “stacks of coins.” This is a result of elevated plasma proteins such as fibrinogen and globulins. The positively charged plasma proteins neutralize the negative charge of red cells and promote aggregation ( Fig. 14.21 ). It is important to evaluate for this morphologic feature only in thin areas of the peripheral blood smear as rouleaux formation can be seen as an artifact in thick areas of the smear. Rouleaux formation is different from red cell agglutinates that form as a result of IgM antibodies (cold agglutinins). These agglutinates form irregular clusters of red cells as a result of the IgM antibodies forming a lattice between red cells.

Rouleaux formation. This peripheral blood smear from a case of secondary plasma cell leukemia shows red blood cells in a linear arrangement (“stacks of coins”) and a circulating plasma cell.

The differential diagnosis of increased bone marrow plasma cells includes reactive plasmacytosis, which can be seen in many nonneoplastic conditions, such as infections, autoimmune conditions, inflammatory conditions, and therapy effects. In reactive plasmacytosis the plasma cells are dispersed interstitially and may form small, loose clusters occasionally around blood vessels. This topographic pattern is not specific, however, and demonstration of a polytypic κ and λ light-chain expression pattern and lack of aberrant marker expression are important in confirming their nonneoplastic nature ( Fig. 14.22 ). Cytologically, nonneoplastic plasma cells show normal mature morphologic features and may occasionally exhibit binucleation, Russell bodies, Mott cells, or Dutcher bodies. Immature features, however, are not typical of reactive plasma cells and would suggest a neoplastic process.

Reactive plasmacytosis in a bone marrow. (A) CD138 stain highlights plasma cells that are dispersed interstitially. (B) and (C) show scattered intermixed κ- and λ-positive cells, respectively, with a slight predominance of κ.

NHL exhibiting plasmacytic differentiation is another important differential diagnosis. Lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma commonly show plasmacytic differentiation and at times can be prominent/marked. Other B-cell lymphomas, such as chronic lymphocytic leukemia, mantle cell lymphoma, and follicular lymphoma, can also exhibit plasmacytic differentiation, but it is uncommon. In B-cell lymphoproliferative disorders with plasmacytic differentiation, separate neoplastic B-cell and plasma cell populations may be detected by flow cytometric and/or immunohistochemical studies demonstrating concordant light-chain restriction. However, immunophenotyping by these methods have limitations, and the two populations may not always be easily detected. For example, flow cytometric studies often underestimate the percentage of plasma cells. Discordant light-chain restriction between these two populations would suggest two independent neoplastic processes: a B-cell lymphoma and a plasma cell neoplasm. In addition to light chains, the neoplastic plasma cell component in B-cell lymphomas would typically express CD45 and CD19 and lack expression of typical aberrant markers in MM such as CD56. Evaluation of these additional aberrant markers is important in further confirmation of the nature of the plasma cells. MYD88 L265P mutation analysis can be useful in the workup as it is seen in the vast majority of lymphoplasmacytic lymphoma, uncommonly in other low-grade B-cell lymphomas, and is virtually absent in MM ( Figs. 14.23 and 14.24 ). ^, These cases highlight the importance of a multimodal diagnostic approach including a comprehensive panel of antibodies for immunophenotyping, and cytogenetic and molecular studies are essential in arriving at a diagnosis.

Lymphoplasmacytic lymphoma. B-cell lymphoma exhibiting plasmacytic differentiation is a differential diagnosis with multiple myeloma. This case shows aggregates of small lymphocytes and intermixed plasma cells appreciated on the core biopsy (hematoxylin-eosin stain, A and B) and aspirate smear (C). B cells are highlighted with PAX5 (D) admixed with plasma cells seen with a CD138 stain (E). κ and λ Light chain stains

(F and G, respectively) show λ restriction. Scattered CD117 bright mast cells are also seen associated with the aggregates (H). The case was found to harbor an MYD88 L265 mutation and is consistent with lymphoplasmacytic lymphoma.

Panels (A) to (J) show a case of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) involving a lymph node with concurrent plasma cell neoplasm involving the bone marrow. Panels (K) to (Q) show a case of dural-based extranodal marginal zone lymphoma with marked plasmacytic differentiation. In the first case (A–J), the LPL component in the lymph node (A–D) shows intermixed lymphocytes and plasma cells with Dutcher bodies appreciated in some of the plasma cells (hematoxylin-eosin stain, A). CD20 shows diffuse proliferation of B-cells (B) demonstrating κ light-chain restriction (C). λ Stain shows sparse staining cells (D). In the bone marrow (E–J), there is a heterogeneous population of cells (hematoxylin-eosin stain, E). B cells highlighted with CD20 (F) are sparse. Interstitial plasma cells are seen with a CD138 stain forming loose clusters

(G). κ and λ Stains (H and I, respectively) show λ restriction. The plasma cells also show aberrant cyclin D1 expression (J). Discordant light-chain restriction and aberrant marker expression are consistent with two distinct neoplastic processes in this patient: LPL in the lymph node and plasma cell neoplasm in the bone marrow. The serum protein electrophoresis and immunofixation studies showed IgM κ and a small amount of IgG λ M proteins, corresponding to LPL and plasma cell neoplasm, respectively. MYD88 L265P mutation was found in the lymph node sample, consistent with LPL/WM. In the second case (K–Q), the patient presented with motor abnormalities and was subsequently found to have a dural-based lesion on imaging studies. The lesion was resected and microscopically showed extensive proliferation of plasma cells with scattered lymphoid follicles (hematoxylin-eosin stain, K and L). CD138 highlighted extensive plasma cells

(M) that are κ light-chain restricted, whereas the small follicles were highlighted with B-cell markers CD20 and CD19 (N and O, respectively). Plasma cells show expression of CD19, which can be seen on high magnification (P) and was also noted by flow cytometric studies (data not shown). In addition to this, the plasma cells were CD56 ⁻ , CD117 ⁻ , and IgG4 ⁺ (Q). The imaging findings and immunophenotypic features of CD19 and IgG4 expression by the plasma cells support a diagnosis of dural-based marginal zone lymphoma, which appears to be a unique subtype of marginal zone lymphoma. ^,

Amyloid is extracellular deposition of abnormally folded proteins that form β-pleated sheets, and AL amyloidosis is one of many subtypes of amyloidosis that have been described. It involves the deposition of immunoglobulin light chains, more often of the λ isotype, and is associated with a B-cell or plasma cell disorder. Other subtypes such as secondary AA amyloidosis and ATTR amyloidosis are associated with serum amyloid A protein in chromic inflammation and wild-type or variant transthyretin, respectively. Diagnosis of amyloid requires microscopic examination of involved tissue. Hematoxylin-eosin–stained sections of involved tissue show amorphous eosinophilic material in the extracellular space. Congo red stain is a commonly used technique in the assessment of amyloid. The dye binds to the β-pleated sheet structures of amyloid and imparts a pink color under light microscopy and produces a green birefringence under polarized light ( Fig. 14.25 ). Subtyping of the amyloid deposits is critical for appropriate management of patients and can be achieved with mass spectrometry–based studies. Sensitivity rates differ in the type of tissue sample obtained for amyloid evaluation. Biopsy of an affected organ/tissue has the highest sensitivity (>90%); however, this may be invasive, associated with morbidity, and technically complex. A common biopsy site and technique for the evaluation of amyloid is abdominal subcutaneous fat aspiration, which is easily performed with rapid turnaround. It has been found to have sensitivity ranging from 55% to 80% and a high specificity approaching 100% in the detection of amyloid. ^, Rectal biopsy has been found to have comparable sensitivity to subcutaneous fat aspiration (∼70%), whereas a bone marrow biopsy has lower sensitivity. ^,

Amyloid. A case of multiple myeloma showing amyloid deposition around vessels. Amyloid is pink with Congo red dye (A) and shows green birefringence under polarized light (B). Mass spectrometry studies of this case confirmed light-chain (AL) amyloid. In another case, a Congo red–stained fat pad biopsy section showed apple-green birefringence under polarized light consistent with amyloid deposition (C). It was subsequently confirmed to be λ subtype on mass spectrometry.

Kidney disease is a frequent complication of monoclonal gammopathies that manifests with a wide range of renal lesions from direct deposition of the monoclonal immunoglobulin involving the glomeruli, tubules, interstitium, or vessels or from indirect mechanisms such as inhibiting regulation of the alternative pathway of the complement ( Table 14.2 ). The term “monoclonal gammopathy of renal significance” (MGRS) has been introduced to indicate that although the patient has MGUS, the renal lesion is nevertheless a consequence of the monoclonal protein and thus has major implications for management and prognosis. These patterns are mostly determined by the physicochemical characteristics of the pathogenic monoclonal immunoglobulin.

TABLE 14.2

Manifestations of Monoclonal Immunoglobulin Deposition Disease in the Kidney

Disease	Light Microscopy	Immunofluorescence	Electron Microscopy
LCDD/HCDD	Glomerular nodular mesangial sclerosis with thickening of TBM and GBM	Monotype linear pattern along TBM and GBM for LC/HC	Punctate-dense deposition of light-chain material along GBM and TBM
GN-associated monoclonal deposits	Membranoproliferative, membranous, or C3 GN	Monotype light chain, and/or heavy chain	Immune-type electron dense deposits
Amyloidosis LC/HC	Amorphous materials by H&E and weak PAS, positive Congo red	Monoclonal LC/HC	Fibrillary substructures (8–10 nm)
Myeloma (light-chain) cast nephropathy	Atypical, PAS-negative, fractured, and friable casts in distal tubules	Positive for light-chain immunoglobulin	Atypical and granular casts
Light-chain proximal tubulopathy	Light-chain proximal tubulopathy, crystalline type	Proximal tubule monotype light chain	Electron-dense crystalline structures within the epithelial cytoplasm of the tubules
Immunotactoid GN	Proliferative GN and thick GBM	Monotype light chain	Thick tubular substructures in the mesangium (30–50 nm)
Fibrillary GN	Proliferative GN and thick GBM	Most are polyclonal	Fibrillary substructures (10–30 nm)

 

GBM, glomerular basement membranes; GN, glomerulonephritis, HCDD, heavy-chain deposition disease; H&E, hematoxylin-eosin; LC/HC, light and heavy chain; LCDD, light-chain deposition disease; PAS, periodic acid–Schiff; TBM, tubular basement membranes.

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