Concurrent Pleural and Pericardial Involvement in a Patient With De Novo Pure Erythroid Leukemia

Dear Editor,

Pure erythroid leukemia (PEL) is a rare subtype of AML, accounting for <1% of all AML cases. PEL cases have distinct morphology and immunophenotype, complex karyotypes, and poor prognosis, which are captured in the 2016 WHO definition. It can occur de novo but more often evolves from a prior myelodysplastic syndrome or therapy-related disease. We describe an uncommon case of de novo PEL with pleural and pericardial involvement. This case emphasizes the importance of fluid analysis, such as cytomorphology, in diagnosing leukemic serous effusions and highlights that a chest computed tomography (CT) scan and pericardium ultrasound should be routinely performed in patients diagnosed as having hematolymphoid malignancies, particularly when typical clinical manifestations are absent. The ethics committee of The District People’s Hospital of Zhangqiu, Jinan, China (approval number: 2022019) approved the study and waived the need for patient consent as the patients’ personal information was not included.

A 46-year-old male patient was admitted to The District People’s Hospital of Zhangqiu in April 2022, with complaints of bleeding gums and general fatigue lasting for seven days. Hematological analysis revealed a leukocyte count of 5.64×10⁹/L, Hb level of 58 g/L, and platelet count of 7×10⁹/L. Examination of peripheral blood smears showed 9% large circulating blasts characterized by deeply basophilic cytoplasm, occasionally displaying large violet cytoplasmic inclusions (Fig. 1A). Bone marrow aspiration demonstrated a significant increase in the number of “blasts” (constituting 81%) exhibiting morphological features indicative of proerythroblasts. These intermediate- to large-sized blasts displayed round nuclei, dispersed chromatin, one to several prominent nucleoli, agranular basophilic cytoplasm, and a high nuclear-to-cytoplasmic ratio. Some blast cells exhibited purple inclusions and microvacuoles (Fig. 1B). Myeloperoxidase staining yielded negative results, whereas periodic acid-Schiff staining revealed prominent globular inclusions (Fig. 1C). Cytogenetic analysis revealed a complex karyotype of 52,XY,-4,-5, add(5)(q13),+14,add(15)(p11.2),-16,+19,add(19)(p13.1), add(19)(p13.1),-21,+mar1–8[10] (Fig. 1D). Bone marrow biopsy revealed a sheet of blasts with fine chromatin and prominent nucleoli (Fig. 1E), and immunohistochemistry showed positive E-cadherin staining (Fig. 1F). Flow-cytometric analysis for immunophenotyping showed 17.19% blasts expressing CD13, CD33, CD36, CD71, CD105, and CD117, with partial expression of CD34, CD38, and human leukocyte antigen DR isotype, suggesting an erythroid differentiation (Fig. 2). TP53 mutations [c.995T>G (p.I332S)] were detected, with a median variant allele frequency of 58.2%, using next-generation sequencing. These findings collectively confirmed the diagnosis of PEL.

Fig. 1.

Results of peripheral blood and bone marrow aspirate analysis. (A) Peripheral blood smears show 9% large circulating blasts with deeply basophilic cytoplasm and large violet cytoplasmic inclusions (Wright–Giemsa stain, ×1000). (B) Bone marrow aspirate exhibits markedly increased “blasts” (constituting 81%) of intermediate to large size, a high nuclear-to-cytoplasmic ratio, round nuclei, dispersed chromatin, one to several prominent nucleoli and agranular basophilic cytoplasm, with occasional multiple purple inclusions and microvacuoles on some blasts (Wright–Giemsa stain, ×1000). (C) Periodic acid-Schiff staining reveals prominent globular inclusions (×1000). (D) Cytogenetics revealing a complex karyotype. (E) Bone marrow biopsy showing a sheet of blasts with fine chromatin and prominent nucleoli (hematoxylin–eosin stain, ×100). (F) Immunohistochemical staining positive for E-cadherin (×400).

Fig. 2.

Results of bone marrow immunophenotyping analysis for (A) CD34/CD38, (B) CD117/HLA-DR, (C) CD71/CD235a, (D) CD71/CD33, (E) CD45/CD13, and (F) CD105/CD36 combinations. Flow-cytometric analysis for immunophenotyping showed blasts expressing CD13, CD33, CD36, CD71, CD105, and CD117, with partial expression of CD34, CD38, and human leukocyte antigen DR isotype, suggesting erythroid differentiation.

The patient underwent chemotherapy regimens involving daunorubicin (60 mg, days 1–3) and cytarabine (0.1 g q12 h, days 1–7) but failed to achieve complete remission. The patient experienced chest tightness and shortness of breath during the treatment, prompting the performance of pulmonary CT and pericardium ultrasound. The images revealed pleural and pericardial effusions, in which abundant leukemic blasts were observed via Wright–Giemsa staining. The patient succumbed to severe myelosuppression and lung infection after the last chemotherapy session.

PEL cases lacking morphological evidence of erythroid maturation are difficult to distinguish from other AML subtypes. The morphological overlap between PEL and acute megakaryoblastic leukemia has posed difficulties for hematologists, especially when both erythroid and megakaryoblastic differentiations are concurrent. Wang and Hasserjian [1] have provided detailed descriptions of the distinctive morphological, immunophenotypic, and cytogenetic features of these two entities. Additionally, PEL can closely resemble acute lymphoblastic leukemia, myelodysplastic syndrome (MDS), multiple myeloma, and metastatic tumors [2-4]. Currently, an immunostaining panel, including E-cadherin, CD117, and CD34, aids in identifying lineage-specific myeloblasts in cases of MDS with left-shifted erythroid hyperplasia [2]. Moreover, distinguishing PEL from florid reactive erythroid hyperplasia, such as hyperplasia resulting from erythroid growth factor application or megaloblastic anemia, is imperative.

Serous effusions are rarely observed in patients with acute leukemia, chronic leukemia, MDS, or myeloproliferative neoplasms. When they do occur, they are typically caused by various infections, disease progression, or infiltration of the serosal cavity by leukemic cells [5]. Concurrent pleural, pericardial, and/or peritoneal cavity involvement in patients with hematologic malignancies has been sporadically reported, with the pleural cavity being the most commonly affected site, followed by the peritoneal and pericardial cavities [6, 7]. Pleural fluid occurrence is more frequent in T-lymphoblastic leukemia/lymphoma, followed by AML. He, et al. [8] reported a male patient diagnosed as having B-cell acute lymphoblastic leukemia, in whom pericardial effusion was incidentally discovered during follow-up.

PEL prognosis is typically dire, with a median overall survival of merely three months [9]. Our patient passed away within three months of the initial diagnosis. Given the extreme rarity of PEL, its highly aggressive clinical behavior, and the challenges encountered in its diagnosis, further investigations into the clinical course, diagnosis, and pathophysiology are crucial for the development of novel treatment options.

The diagnosis of PEL presents a significant challenge, particularly when it involves simultaneous erythroid and megakaryoblastic differentiation. The concurrent invasion of the pleural and pericardial regions observed in this case of PEL is an infrequent occurrence. This case underscores the importance of utilizing flow cytometry and fluid analysis for the diagnosis of these rare entities presenting with leukemic serous effusions. Additionally, it highlights the value of conducting routine chest CT scans and pericardium ultrasounds in patients with leukemia, especially when typical clinical manifestations, such as shortness of breath, are absent.

Funding Statement

RESEARCH FUNDING This work was supported by the Shandong Province Medical and Health Technology Plan Project (202211000347).