Concurrent Diagnosis of Chronic Lymphocytic Leukemia and Plasma Cell Myeloma: Report of 2 Cases and Differential Diagnostic Considerations

Introduction

Chronic lymphocytic leukemia (CLL) is a common hematological neoplasm that can impact many organ systems. It is the most common chronic leukemia in the United States, with a peak age of occurrence between 60 and 80 years; however, cases in younger age groups have also been reported [1,2]. Many patients are asymptomatic. Symptomatic patients usually present with lymphadenopathy, splenomegaly, recurrent infections, autoimmune hemolytic anemia, and weakness, amongst other symptoms [3,4]. Plasma cell myeloma (PCM), a plasma cell neoplasm, is also common in older age groups, primarily in those aged 50–70. It usually runs an aggressive course with an expected median survival of 3–4 years [5].

CLL and PCM are malignancies that generally occur separately in individuals; however, they are not mutually exclusive. There have been a few case reports on the coexistence of CLL and PCM in the literature [6]. The co-occurrence of PCM and CLL may be partly explained by the fact that they both originate from mature B cells [7].

If these 2 lesions occur simultaneously in a patient, they must be identified and differentiated from B-cell lymphomas with lymphoplasmacytic differentiation, such as marginal-zone lymphoma, lymphoplasmacytic lymphoma, and CLL with plasma-cytic differentiation. These entities have vastly different prognoses and treatments.

CLL, in general, follows a more indolent clinical course. The current global 5-year survival for patients is estimated at 87.2%. In many cases, especially in asymptomatic individuals, close clinical follow-up without treatment is often sufficient [8]. For symptomatic patients, the current recommended treatment modalities include targeted therapy (Bruton tyrosine kinase inhibitor or a BCL-2 inhibitor therapy), monoclonal antibodies, chemotherapy, radiotherapy, immunotherapy, and bone marrow/stem cell transplant [9].

PCM typically follows a more aggressive clinical course, with survival rates ranging from less than 6 months to over 10 years, with a median survival of 5.5 years [10]. Treatment regimens for PCM are variable and include chemotherapy, immunotherapy (lenalidomide), corticosteroid therapy, and more recently, targeted therapy with a proteasome inhibitor (bortezomib or ixazomib) [10].

Lymphoplasmacytic lymphoma is a neoplasm of small B cells, plasma cells, and plasmacytoid lymphocytes, primarily involving the bone marrow. The clinical course is mostly indolent, with median survival times ranging from 5 to 10 years [11]. Treatment depends on the presence of end organ involvement. Asymptomatic patients may only require close supervision with regular IgM monitoring, while symptomatic patients may require the use of chemotherapy, immunotherapy, and stem cell transplantation [11]. Marginal-zone lymphomas are also generally indolent and slow to disseminate. The 5-year overall survival rate of extranodal marginal zone lymphoma is about 60 to 70%. For patients with nodal marginal-zone lymphoma that are asymptomatic, similar to lymphoplasmacytic lymphoma, observation is the standard practice; however, for those with advanced and symptomatic disease, treatment is usually with rituximab, with or without chemotherapy [12].

Differentiating between a concomitant CLL and PCM from small mature B-cell lymphomas with plasmacytic differentiation is critical; however, making this differential is sometimes extremely challenging for the pathologist. Diagnosis is rendered incorporating histologic findings, numerous immunohistochemical stains, flow cytometry, cytogenetics, molecular studies, and FISH findings. Here, we describe 2 cases of CLL and concomitant PCM and discuss how the difficult diagnosis was rendered.

Case Reports

CASE 1:

An 82-year-old man with a past medical history of systemic hypertension, diabetes mellitus, hyperlipidemia status post-bypass surgery (×5), and coronary artery disease, was referred to the oncology unit due to abnormal blood work that was observed at his last visit to his primary care physician. He had shortness of breath which remained stable over a few years. He denied bone pains and back pain but had a history of osteoarthritis in multiple joints. His serum protein electrophoresis revealed hypogammaglobinemia, with no monoclonal band detected. Urine protein electrophoresis revealed free kappa light chains. Computerized axial tomography (CAT) scan and skeletal x-rays did not show any significant abnormality. On examination, there was no palpable peripheral lymphadenopathy. The peripheral smear showed normocytic normochromic anemia (hemoglobin: 11.9 g/dL) and mild thrombocytopenia (140 000 cells/μL).

Bone marrow aspirate and biopsy were obtained. Bone marrow aspirate smears showed increased atypical plasma cells (11%) and lymphocytes (27%), with a few plasmacytoid lymphocytes. Hematoxylin and eosin (H&E) examination showed a hypercellular bone marrow with erythroid predominance. Plasma cells were mildly increased, scattered interstitially as single cells as well as in small clusters. They accounted for 10–15% of total cellularity by CD138 staining (Leica, B-A38 clone) and aberrantly expressed cyclinD1. Although no large atypical lymphoid aggregates were seen on hematoxylin and eosin (H&E) staining, immunohistochemical staining for CD20 (Leica, L26 clone) highlighted increased CD20-positive B cells accounting for approximately 10% of total cellularity. Only a few CD3+ T cells were present in the background (Figure 1). Concurrent flow cytometry analysis showed monoclonal IgG kappa-restricted plasma cells (8%) and a separate population of sIg negative CD5+/CD23+ B cells with the immunophenotype of CLL (10%) (Figure 2).

A fluorescence in situ hybridization (FISH) test performed on bone marrow aspirate showed t(11;14)/CCND1: : IgH rearrangement with a CCND1/IGH t(11: 14) Kreatech (Leica BioSystems) dual color fusion probe and monosomy 13, using a 13q14 (DLEU1, DLEU2)/13q34 dual color probe. These results were consistent with a PCM. A trisomy 12 and deletion of chromosome 13 were also detected by FISH, using the SE12(D12Z3) Kreatech (Leica BioSystems) and DLEU1 13q14 dual color assay FISH probes, respectively. These features are consistent with a diagnosis of CLL. MYD88 mutation analysis by PCR of bone marrow aspirate was negative. The features suggesting against a diagnosis of lymphoplasmacytic lymphoma were the absence of IgM monoclonal gammopathy and MYD88 mutation. The diagnosis of CLL was clinched by histologic features, the immunophenotype of CD5+ CD23+ B cells, monosomy 13, and trisomy 12 by FISH. The presence of PCM was corroborated by the expression of cyclin D1 by plasma cells, t(11; 14)/CCND1: : IgH rearrangement on plasma cells, and positivity for monosomy 13 by FISH. Thus, the final diagnosis of concurrent CLL/SLL and PCM was rendered.

The patient had biochemical evidence of renal compromise in addition to his anemia, with no other symptoms attributable to PCM and CLL. He was thus placed on observation by the managing physician. His last clinic visit was a few weeks before completion of this report, and he was clinically stable with no new complaints. His renal function has remained relatively stable and there was no obvious progression of any other organ dysfunction with his myeloma.

CASE 2:

The second patient was a 66-year-old woman with a history of hypertension, hyperlipidemia, hypothyroidism, lymphocytosis, and monoclonal gammopathy (IgG lambda) that dated back to May of 2018. She presented to her primary care physician in February of 2020 for a follow-up appointment. During this visit, investigations revealed that she had an increase in her serum protein level and a possible isolated monoclonal spike. She was noted to be anemic while she was trying to donate blood. During this period, she denied bone pains. She did not have joint stiffness, peripheral neuropathy, or back pain. Her appetite and weight were stable. Due to the unexplained anemia, a bone marrow biopsy was performed in March of 2020.

The peripheral blood showed a total white cell count of 12.9×10³ with lymphocytosis (65% lymphocytes) and macrocytic anemia. Flow cytometry analysis performed on peripheral blood showed a CD5+/CD23+ kappa light chain-restricted B-cell population consistent with CLL (~6000 CUMM).

The bone marrow biopsy showed marked hypercellularity with approximately 100% cellularity and diffuse involvement by neoplastic lymphoplasmacytic cells. The plasma cells formed sheets and comprised 70–80% of the marrow cellularity with some Mott cells, and many exhibited Dutcher bodies. The plasma cells were positive for CD138 (Leica, B-A38 clone) and showed aberrant expression of CD20 (Leica, L26 clone) and many of them exhibited weak to moderate expression of CD117 (Leica, EP10 clone) (Figure 3). In addition, there were also para-trabecular aggregates of small, mature neoplastic B-lymphoid cells that were positive for CD20, CD5 (Leica, 4C7 clone), PAX5 (CM, clone 24), and CD79a (Leica, JCB117 clone) immunohistochemical stains (Figure 4). These cells were negative for cyclin D1 (Leica, NCL. L. Cyclin D1 clone). These abnormal B-lymphoid aggregates comprised less than 10% of marrow cellularity.

Flow cytometry of the bone marrow aspirate showed a CD5+/CD23+ kappa light chain-restricted monoclonal B-cell population consistent with CLL (Figure 5), and a CD19-negative monoclonal CD38+/CD138+ plasma cell population with lambda light chain restriction and aberrant expression of CD20, CD56, and CD117 (13.1% of total cells), consistent with PCM (Figure 6). FISH on bone marrow aspirate for multiple myeloma panel showed t(14,16)/IGH: : MAF rearrangement, using IGH/MAF t(14;16) Kreatech (Leica BioSystems) dual fusion probe with positivity for 3 copies of 1q21, using a 1q21(CKS1B) Kreatech (Leica Biosystems) probe. The tumor was negative for t(4,14)/FGFR3-NSD2: : IGH and t(11,14)/CCND1: : IGH rearrangement with the use of FGFR3/IGH t(4: 14) Kreatech (Leica BioSystems) and CCND1/IGH t(11: 14) Kreatech (Leica BioSystems) dual-color fusion probes, respectively. FISH for CLL was recommended for the second patient; however, this was not performed. PCR analysis for the MYD88L265P mutation was negative. Overall features including multiple myeloma-related rearrangements by FISH analysis, and absence of MYD88 mutation, were found to be consistent with bone marrow involvement by concurrent CLL and PCM.

The patient was on lenalidomide, dexamethasone, and monthly denosumab maintenance therapy for multiple myeloma and on observation for CLL. On June 4, 2023, she was brought to the emergency department by ambulance with complaints of decreased oral intake and worsening lethargy for 1 day with consistent watery diarrhea. On examination, she was found to be tachycardic, tachypneic, pale, and unresponsive, necessitating intubation. Blood culture performed showed gram-negative rods (Escherichia coli). Despite intensive therapy, the patient deteriorated and was pronounced dead 1 day after presentation. An autopsy was performed, and the patient’s cause of death was found to be gram-negative sepsis (E. coli) with extensive involvement of the bone marrow by PCM (80–90% of the marrow cellularity). The lymph nodes were markedly autolyzed and could not be evaluated for CLL. No other organs showed evidence of CLL.

Discussion

PCM and CLL both arise from mature B cells in similar age groups [13]. They may also have overlapping clinical features [7]. Coexistence of these 2 neoplasms in the same patient is an uncommon event [14]. In a study conducted by Dong et al on hematolymphoid tumors that spanned through 38 years, only 3 of 54 159 cases had coexistence of PCM and CLL [6]. In a similar study performed in Germany, out of 59 patients with PCM and a secondary tumor, only 5 (8.4%) of these patients had a coexisting CLL [15].

The coexistence of these 2 lesions will lead to a lymphoplasmacytic infiltration of the bone marrow. In this case, it can be confusing to determine the concurrent occurrence of these 2 neoplasms in the same patient due to the many differential diagnoses that need to be considered in such cases. CLL typically has CD5+/CD23+ B cells that can be found in the blood, bone marrow, and lymph nodes [16]. A criterion of lymphocytosis greater than 5000 cells/µL for at least 3 months is required for a definitive diagnosis of CLL to be made [17]. PCM typically has neoplastic plasma cells in the bone marrow, with a requirement of more than 10% clonal plasma cells and other myeloma-defining events for a definitive diagnosis of a PCM to be made [18].

It is important to consider the various differential diagnoses that could give rise to this bone marrow picture and apply the necessary morphological and ancillary investigations that can help sort out the differentials and come up with a definitive diagnosis. The differential diagnoses include lymphoplasmacytic lymphoma and marginal zone lymphoma with plasmacytoid differentiation. Also, CLL with plasmacytoid differentiation is a possible differential diagnosis for this picture. These differential diagnoses were all considered in the 2 cases discussed.

Immunohistochemistry/flow cytometry was performed in both cases and showed B cells coexpressing CD5 and CD23, which is usually a signature phenotype for CLL. Although a small percentage of marginal-zone lymphomas can express CD5 [19], the strong surface CD20 and immunoglobulin expression seen in marginal-zone lymphomas is not seen in CLL; instead, CLL typically has a dim expression of CD20 and immunoglobulin [20]. Additionally, marginal-zone lymphomas do not express CD23. This helps to differentiate the 2 entities. In addition, the plasma cells in marginal-zone lymphoma do not express cyclin D1 and CD56, which are seen in PCM [21]. Lymphoplasmacytic lymphoma (LPL) has a combination of neoplastic cells composed of lymphocytes and plasma cells. The occurrence of neoplastic lymphoid cells and plasma cells in LPL can mimic a coexisting PCM and CLL. The immunophenotype of LPL is usually CD20+, CD5-, and CD23-; however, some LPLs have been found to express CD5 [22] and some of these LPLs have also weakly expressed CD23 [23], closely mimicking CLL, but the expression of surface immunoglobulin and CD20 is not dim in LPL as seen in CLL. Also, in a coexisting PCM and CLL, the separate plasma cell proliferative population is usually positive for CD138, cyclin D1, and CD56. This expression pattern is not seen in the plasma cell population in LPL, thereby assisting to clearly delineate these 2 entities [24]. Many cases of LPL express MYD88 [25], a marker that is not seen in CLL. There is usually an IgM para-protein in LPL that was also absent in both of our patients [26].

CLL with plasma cell differentiation is another differential diagnosis in this case; however, the plasmacytoid cells in CLL are not expected to stain for CD56 and cyclin D1, which helps to differentiate it from the coexistence of CLL and PCM [20]. The peculiar clinical features of PCM, including bone lesions, hypercalcemia, and renal compromise, are typically not seen in the other differential diagnoses outlined earlier. These patients did not present with these PCM symptoms, making a concurrent PCM lesion less suspicious; however, the presence of plasmacytoid cells positive for CD138, CD56, and cyclin D1 helped in clinching this diagnosis of the separate PCM in addition to the CLL.

A possible misdiagnosis that can be made in this scenario is to diagnose these concomitant neoplasms as a mantle cell lymphoma because of the cyclin D1 positivity as well as possible expression of CD20 by neoplastic plasma cells [27]. However, this can be prevented if a CD138 stain is applied and shows that the cyclin D1-positive cells are positive for CD138, thus labeling them as plasma cells and not lymphocytes. This was one of the stains that was applied in both our cases and further aided in making the diagnosis.

It is important to note that the FISH findings in these patients were also pivotal to the diagnosis of a separate PCM in addition to CLL. The second patient had a t(14;16)/IGH: : MAF rearrangement while the first patient had a t(11;14)/CCND1: : IGH rearrangement. Both findings are known to be associated with multiple myeloma. The first patient also had trisomy 12 and del(13q), both associated with CLL. The t(14;16)/IGH: : MAF rearrangement has been associated with an aggressive clinical outcome compared with the t(11;14)/CCND1: : IGH rearrangement, which has standard prognosis for multiple myeloma patients [28]. It is possible that the second patient had a downhill clinical course compared with the first patient as a result of the t(14: 16)/IGH: : MAF rearrangement.

The second patient in this case report died because of gram-negative sepsis, which she was most likely predisposed to because of the PCM and CLL. Both conditions can cause hypogammaglobinemia and increase the risk for infections.

Most patients who have had a concurrent diagnosis of CLL and PCM have presented with symptoms that allude to PCM, which include pathologic fractures, bone lesions, anemia, and monoclonal gammopathy. Often, these patients require treatment for PCM and observation for CLL [20]. In the first case, the patient was asymptomatic and only presented with abnormal blood work from his primary care provider. However, the detection of urine light chains, abnormal serum protein electrophoresis, and renal compromise were suspicious for PCM clinically. Laboratory investigations revealed hypogammaglobinemia in this patient. This sign could be seen in both CLL and PCM and is not helpful in differentiating one entity from the other [29]. Crippling and life-threatening infections are seen in both conditions, and this was responsible for the demise of the second patient.

There are possible mechanisms that may explain why a patient with CLL/SLL can develop a second malignancy like PCM. Some of these are a pro-tumorigenic microenvironment, immune dysfunction, and chemotherapy-related factors [14].

There are postulates regarding the pathogenesis of coexisting PCM and CLL. While some researchers believe that this occurrence could be due to CLL tumor cells maturing to give rise to a population of neoplastic plasma cells, other researchers believe that the 2 diseases could represent distinct clonal proliferations [30,31]. For the cases with similar light chain restriction in both tumor cells, the former hypothesis seems feasible. In the first patient, both neoplastic proliferations had kappa light chain restriction, suggesting a common clonal progenitor cell. The second patient had a kappa-restricted monoclonal B-lymphoid neoplasm and a lambda-restricted plasma cell neoplasm. For this second patient, the second hypothesis may be more plausible.

In terms of prognosis, it is important to diagnose a concurrent PCM occurring together with CLL and to not misdiagnose it as a marginal-zone lymphoma, LPL, or CLL with plasmacytoid differentiation, as the presence of PCM significantly alters patients’ prognosis adversely. In the case series by Alley et al, 14 of 22 (64%) patients who had both CLL and PCM with consequent death succumbed because of the progression of the PCM, further underscoring the importance of making this diagnosis in a lymphoplasmacytic rich hematological neoplasm [20].

Conclusions

CLL and PCM uncommonly present together in the same patient. When they do, CLL usually antedates the diagnosis of PCM, sometimes by up to 2 years. There are multiple differentials that could be considered before coming up with the diagnosis of CLL and PCM in the same patient. Ancillary investigations like flow cytometry, molecular studies, and FISH are indispensable in achieving this. It is important to make the correct diagnosis as the 2 entities are treated differently and the presence of PCM significantly and adversely alters the prognosis of patients.