Primary Plasma Cell Leukemia Presenting Mainly with Negative CD38 Expression at Diagnosis: A Case Report with Literature Review

Abdullah S Al Saleh; Asmaa F AlOufi; Lubna Alzadjali; Ayman Alhejazi; Muhamad Hitham ALmahayni

doi:10.4103/joah.joah_82_22

CASE REPORT

Year : 2023 | Volume : 14 | Issue : 1 | Page : 48-51

Primary Plasma Cell Leukemia Presenting Mainly with Negative CD38 Expression at Diagnosis: A Case Report with Literature Review

Abdullah S Al Saleh¹, Asmaa F AlOufi², Lubna Alzadjali³, Ayman Alhejazi⁴, Muhamad Hitham ALmahayni⁴
¹ College of Medicine, King Saud bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center; Department of Oncology, Division of Hematology and HSCT, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
² Department of Hematology, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Jeddah, Saudi Arabia
³ Department of Pathology and Laboratory Medicine, Division of Hematology, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
⁴ King Abdullah International Medical Research Center; Department of Oncology, Division of Hematology and HSCT, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia

Date of Submission	25-Sep-2022
Date of Decision	25-Oct-2022
Date of Acceptance	09-Nov-2022
Date of Web Publication	17-Feb-2023

Correspondence Address:
Dr. Abdullah S Al Saleh
College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia, King Abdullah International Medical Research Center, Riyadh; Department of Oncology, Division of Hematology and HSCT, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/joah.joah_82_22

Abstract

The loss of CD38 expression has been described in multiple myeloma (MM) patients with relapsed/refractory disease and patients receiving CD38 monoclonal antibodies. However, the loss of CD38 at diagnosis is extremely rare with very few reports describing such finding in newly diagnosed MM patients. Only two detailed case reports described CD38-negative clonal plasma cells at diagnosis. However, none of these cases was primary plasma cell leukemia (PCL). We describe an elderly patient with primary PCL presenting mainly with a negative CD38 expression, which, to the best of our knowledge, has never been described. The patient did not do well and died within 3 months of diagnosis. The loss of CD38 expression at diagnosis could indicate more aggressive disease biology.

Keywords: CD38 negative, flow cytometry, immunohistochemistry, multiple myeloma, plasma cell leukemia

How to cite this article:
Al Saleh AS, AlOufi AF, Alzadjali L, Alhejazi A, ALmahayni MH. Primary Plasma Cell Leukemia Presenting Mainly with Negative CD38 Expression at Diagnosis: A Case Report with Literature Review. J Appl Hematol 2023;14:48-51

How to cite this URL:
Al Saleh AS, AlOufi AF, Alzadjali L, Alhejazi A, ALmahayni MH. Primary Plasma Cell Leukemia Presenting Mainly with Negative CD38 Expression at Diagnosis: A Case Report with Literature Review. J Appl Hematol [serial online] 2023 [cited 2023 Mar 24];14:48-51. Available from: https://www.jahjournal.org/text.asp?2023/14/1/48/369846

Introduction

Plasma cell leukemia (PCL) is the most aggressive form of plasma cell dyscrasias, which can be primary or secondary. Patients who present initially with PCL are labeled as having primary disease, while those who have a relapse of their multiple myeloma (MM) with PCL are considered to have a secondary disease. In the Surveillance, Epidemiology, and End Results database, 291 (0.6%) of PCL cases were registered between 1973 and 2004.^[1] The overall survival of these patients is grim, even with the current advances in therapy.^[1]

Plasma cells universally express CD38 on their surface. The loss of CD38 expression has been documented in patients with relapsed myeloma and patients receiving monoclonal antibodies against CD38, such as daratumumab.^[2],[3],[4] However, loss of CD38 at diagnosis is very unusual with limited cases reporting such findings.^[5],[6] We describe a patient with primary PCL who had a negative CD38 expression, which, to the best of our knowledge, has never been described.

Case Report

An 85-year-old man with a history of diabetes and hypertension presented to our hospital with generalized fatigability, back pain, and progressive bilateral lower limb weakness for 1 month. The patient also had a history of anorexia with significant loss of weight (30 kg in 3 months). On examination, he looked pale and dehydrated. Significant bilateral lower limb weakness with no muscle power was noted, but his sensations were intact.

The laboratory results revealed a total white blood cell (WBC) of 18 (normal range: 4–11 × 10^⁹/L), hemoglobin of 9.9 (13.5–18 g/dL), platelet of 40 (150–400 × 10^⁹/L), and plasma cells were 5.91 × 10^⁹/L, constituting 33% of total WBC. The smear was significant for circulating plasma cells. His adjusted calcium was 2.55 (2.2–2.5 mmol/L), and the creatinine was 151 (64–110 μmol/L). Serum protein electrophoresis was normal, but the immunofixation was positive for free kappa light chains. His kappa-free light chain was 117 (upper limit of normal 19.4 mg/L), free lambda light chain was 2.78 (5.71–26.30 mg/L), and the ratio was 42.09 (0.26–1.65). The albumin, lactate dehydrogenase, and beta-2 microglobulin were 37 (32–46 g/L), 500 (125–220 U/L), and 13.90 (1.42–3.21 mg/L), respectively. Liver function tests and coagulation profile were normal. Computed tomography scans were significant for diffuse lytic lesions involving the whole skeleton, mainly spinal. Compression fractures causing narrowing of the spinal canal and cord compression were noted by magnetic resonance imaging.

Bone marrow aspiration and biopsy showed infiltration of kappa-restricted clonal plasma cells (60%), with few plasmablasts and some plasma cells exhibiting anaplastic morphology. By immunohistochemistry (IHC), all plasma cells were kappa restricted and were positive for CD138, CD56 (partial/week), and cyclin D1 but were CD38 negative [Figure 1]. By flow cytometry (FC) [Figure 2], 34% clonal plasma cells were identified. The majority of the population of clonal plasma cells (31%) were kappa restricted and were positive for CD138, B2 microglobulin, CD56 (partial), and negative for CD38, CD19, CD117, CD81, CD27, and CD28. A very small population of plasma cells (3%) were positive for CD38, CD138, and CD56 and were kappa restricted. Fluorescence in situ hybridization revealed 17 P deletion in 73% of interphase cells, t (11;14)(q13;q32) in 66% of the cells, and partial deletion involving the IGH gene in chromosome 14 (14q32) in 59% of cells. The patient could not tolerate therapy and died within 3 months from diagnosis.

Figure 1: Microscopic examination of the bone marrow biopsy (a) bone marrow biopsy with hematoxylin and eosin stain, showing diffuse infiltration of plasma cells with a bi-lobed and irregular nucleus and blastic forms (×20 high power magnification), (b) plasma cells are negative for CD38 immunohistochemistry stain, (c) plasma cells are positive CD138 immunohistochemical stain, and (d) they are kappa restricted (×20 high power magnification)

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Figure 2: Flow cytometry analysis of the bone marrow aspirate revealed a population comprising approximately 34% of the total events, showing moderate side light scatter and high heterogeneous forward light scatter with negative CD45. The majority of the population of clonal plasma cells (31%) were kappa restricted and were positive for CD138, and negative for CD38, CD19, and CD117. A very small population of plasma cells (3%) were positive for CD38, CD138, CD56 and were kappa restricted

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Discussion

The diagnosis of MM/PCL requires the identification of clonal plasma cells. Normal and abnormal plasma cells universally express CD38 and CD138 on their surface. CD38 acts as a receptor and an ectoenzyme^[7] and is found in many other immune cells such as T and B-lymphocytes. When evaluating a patient for a possible diagnosis of MM, CD38 along with other markers are used to identify plasma cells by FC and IHC. Importantly, CD 38 can be used by some pathologists as a screening marker for a possible plasma cell neoplasm, especially in cases with difficult morphology.

The loss of CD38 has been described in relapsed or refractory MM.^[2],[4],[8] This can happen in patients who were treated with a monoclonal antibody against CD38, such as daratumumab^[2],[4] and even in patients with relapse of the disease without previous exposure to a monoclonal antibody against CD38.^[8] Downregulation of the CD38 receptor could be induced by the monoclonal antibody^[2] in patients treated with such therapy. Another possible mechanism is the loss of the surface protein induced by the tumor cell as an escape phenomenon from the monoclonal antibody treatment. However, this would not explain the loss of CD38 in relapsed patients without receiving a treatment containing an anti-CD38 monoclonal antibody.^[8] Another possible explanation is the emergence of another CD38-negative clone at relapse.^[8] In our case, at diagnosis, the majority of the clonal plasma cells were CD38 negative. One possible explanation is that the clonal plasma cells have lost their CD38 expression as the disease evolved, leading to an aggressive disease.

Only two detailed case reports described CD38-negative clonal plasma cells at diagnosis.^[5],[6] However, none of these cases was PCL. In both cases, the absence of CD38 expression at diagnosis caused difficulties in reaching the diagnosis initially, without further workup and staining with other markers, including CD138.

This highlights the importance of using other markers of plasma cells and not depending solely on CD38, as it can be rarely negative at diagnosis. Our patient presented with circulating plasma cells and had lytic bone lesions, which triggered the use of other markers of plasma cells when analyzing the bone marrow samples.

In the two reported cases described the CD38-negative plasma cells were showing anaplastic morphology. Interestingly, the anaplastic morphology was also noticed in some plasma cells in our case. In one report,^[5] the patient was 62 years with t (14;16), which is considered a high-risk abnormality, and unfortunately, he died with progressive disease. Our patient had primary PCL with 17p deletion and died within months of diagnosis. In the other report,^[6] the patient was relatively young and was started on treatment, but the outcome was not described. No firm conclusions can be made from case reports, but CD38 negativity might indicate a more aggressive disease, and more cases are needed to confirm such findings.

On the other hand, the loss of CD138 has been described in the literature.^{[9],[10],[11],[12]} CD138 is a proteoglycan, i.e., critical for plasma cell growth and survival.^[13] The loss of CD138 was found more in patients with progressive or relapsed disease than in newly diagnosed patients.^[12],[14] The survival was worse for patients who had CD138-negative disease in one report, although a multivariate analysis was not done.^[14] Plasma cells which are CD138 negative may be more premature with a higher proliferative rate.^[12] Compared to patients with CD138-positive cells, more CD138-negative plasma cells were in the S phase of the cell cycle, indicating more proliferation.^[12]

Minimal residual disease (MRD) using FC or next-generation sequencing has proven to be of prognostic value in MM.^[15] In addition to challenges faced at diagnosis of patients with negative CD38 or CD138, monitoring and assessment of MRD status by FC should be carried out with caution of false-negative results, especially in patients who relapse with CD38/CD138-negative disease.

Conclusion

In summary, we describe a patient with primary PLC with mainly CD38-negative clonal plasma cells at diagnosis. The presence of anaplastic plasma cells by morphology together with negative CD38 expression could indicate more aggressive disease biology, but further reports are needed to confirm such findings. The possibility of having CD38- and CD138-negative clonal plasma cells should be kept in mind when evaluating a patient suspected to have a plasma cell disorder and during monitoring of the disease.

Informed consent

The institutional review board waived the need for consent as this was a low-risk study and approved it (IRB/0497/22).

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Ramsingh G, Mehan P, Luo J, Vij R, Morgensztern D. Primary plasma cell leukemia: A surveillance, epidemiology, and end results database analysis between 1973 and 2004. Cancer 2009;115:5734-9.
2.	Minarik J, Novak M, Flodr P, Balcarkova J, Mlynarcikova M, Krhovska P, et al. CD38-negative relapse in multiple myeloma after daratumumab-based chemotherapy. Eur J Haematol 2017;99:186-9.
3.	Mykytiv V, Alwaheed A, Mohd Hashim NA. Double CD38^-/CD138^-negative multiple myeloma. Hematol Oncol Stem Cell Ther 2019;12:64-6.
4.	Oberle A, Brandt A, Alawi M, Langebrake C, Janjetovic S, Wolschke C, et al. Long-term CD38 saturation by daratumumab interferes with diagnostic myeloma cell detection. Haematologica 2017;102:e368-70.
5.	Aljabry MS. CD38 negative anaplastic plasma cell myeloma with (14;16) translocation: A diagnostic dilemma for highly aggressive neoplasm: Case report. J Hematop 2019;12:27-30.
6.	Singh N, Agrawal N, Mehta A, Panaych A, Sekhri R. CD38-negative myeloma with anaplastic morphology at presentation: A case report. Indian J Hematol Blood Transfus 2018;34:362-4.
7.	Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 2008;88:841-86.
8.	Ise M, Matsubayashi K, Tsujimura H, Kumagai K. Loss of CD38 expression in relapsed refractory multiple myeloma. Clin Lymphoma Myeloma Leuk 2016;16:e59-64.
9.	Hosen N, Matsuoka Y, Kishida S, Nakata J, Mizutani Y, Hasegawa K, et al. CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients. Leukemia 2012;26:2135-41.
10.	Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, et al. Characterization of clonogenic multiple myeloma cells. Blood 2004;103:2332-6.
11.	Pope B, Brown RD, Gibson J, Yuen E, Joshua D. B7-2-positive myeloma: Incidence, clinical characteristics, prognostic significance, and implications for tumor immunotherapy. Blood 2000;96:1274-9.
12.	Reid S, Yang S, Brown R, Kabani K, Aklilu E, Ho PJ, et al. Characterisation and relevance of CD138-negative plasma cells in plasma cell myeloma. Int J Lab Hematol 2010;32:e190-6.
13.	Dhodapkar MV, Abe E, Theus A, Lacy M, Langford JK, Barlogie B, et al. Syndecan-1 is a multifunctional regulator of myeloma pathobiology: Control of tumor cell survival, growth, and bone cell differentiation. Blood 1998;91:2679-88.
14.	Kawano Y, Fujiwara S, Wada N, Izaki M, Yuki H, Okuno Y, et al. Multiple myeloma cells expressing low levels of CD138 have an immature phenotype and reduced sensitivity to lenalidomide. Int J Oncol 2012;41:876-84.
15.	Munshi NC, Avet-Loiseau H, Rawstron AC, Owen RG, Child JA, Thakurta A, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: A Meta-analysis. JAMA Oncol 2017;3:28-35.