Abstract
Extramedullary hematopoiesis is a phenomenon that occurs in conditions of ineffective bone marrow function. In the context of thalassemias, extramedullary hematopoiesis is more frequently observed in beta-thalassemia intermedia patients, with thoracic paravertebral extramedullary hematopoiesis being relatively common. However, extramedullary hematopoiesis-related pleural effusion is a rare occurrence. Herein, we report a 43-year-old female patient, who presented with worsening dyspnea and a massive pleural effusion. Her medical history includes beta-thalassemia intermedia with known paravertebral extramedullary hematopoiesis sites and a laparoscopic cholecystectomy a month ago. The absence of pleural fluid from recent prior imaging pointed toward the rapid accumulation of fluid. After a thorough diagnostic workup, we attributed the effusion to thoracic paravertebral extramedullary hematopoiesis. The patient was effectively treated with drainage of the effusion after thoracentesis and antibiotics. On follow-up, she had a stable radiographic image without pleural fluid recurrence. Extramedullary hematopoiesis-associated pleural effusion should be in the differential diagnosis of pleural effusion, in cases of compatible medical history.
Keywords: Thalassemia, pleural effusion, extramedullary hematopoiesis, case report
Introduction
Extramedullary hematopoiesis (EMH) is observed in conditions of inefficient bone marrow (BM) function. It is encountered in an array of malignant and benign hematologic diseases when the BM fails to meet the organismal demands. 1 The most common sites of EMH include the liver, the spleen (termed hepatosplenic EMH), and lymph nodes. EMH may occur in many different anatomical sites including the paravertebral areas. 2 Patients with beta-thalassemia intermedia (BTI) are at increased risk of developing EMH. Besides hepatosplenic EMH, the thoracic paravertebral sites are the most common anatomic region of EMH development in thalassemic patients. 2 EMH-related complications are frequently reported in the literature; however, non-hemothorax EMH-associated pleural effusion reports are scarce. In this report, we present a BTI patient with massive pleural effusion and provide a short literature review on the subject.
Case
A 43-year-old female with a known medical history of BTI complicated with paravertebral thoracic EMH presented in our department with progressively worsening dyspnea. The patient underwent laparoscopic cholecystectomy a month ago. Moreover, the EMH sites reported were stable in size (as noticed from prior imaging) without any evidence of complications (hemothorax, pleural effusion, spinal cord compression).
On admission, physical examination revealed an ill, pale, and icteric—albeit alert and oriented—patient. The patient was mildly tachypneic, with an oxygen saturation of 90% on room air, and reported grade 2 dyspnea on the modified Medical Research Council scale. Vital signs showed a temperature of 38°C, a heart rate of 115 beats per minute, a blood pressure of 135/80 mmHg, and a respiratory rate of 20 breaths per minute. Respiratory examination revealed left-sided dullness on auscultation. Laboratory investigations showed microcytic hypochromic anemia (hemoglobin 8.3 g/dL, mean corpuscular volume 64.8 fL, mean corpuscular hemoglobin 18.9 pg), leukocytosis with marked neutrophilia (WBC 14.32 K/μL), and C-reactive protein 125 mg/L (relevant blood and pleural fluid laboratory data are summarized in Table 1). Abdominal ultrasonography showed hepatosplenomegaly. Initial chest radiography showed a massive left unilateral pleural effusion (Figure 1). Echocardiography showed no evidence of left or right heart failure.
Table 1.
Laboratory data on admission.
| Laboratory data | Results (normal values) |
|---|---|
| Blood | |
| Red blood cells (106/μL) | 4.4 (3.8–5.3) |
| Hemoglobin (g/dL) | 8.3 (12–16) |
| Hematocrit (%) | 28.5 (37–47) |
| Mean corpuscular volume (fL) | 64.8 (80–99) |
| Mean corpuscular hemoglobin (pg) | 18.9 (27–32) |
| White blood cells (103/μL) | 14.32 (3.8–10.5) |
| Neutrophils (103/μL) | 12.5 (1.6–6.5) |
| Platelets (103/μL) | 490 (150–450) |
| Glucose (mg/dL) | 110 (7–105) |
| Total bilirubin/direct bilirubin (mg/dL) | 3.0/0.89 (0.2–1.2) |
| LDH (U/L) | 356 (100–240) |
| Total protein (g/dL) | 6.9 (6.4–8.3) |
| D-dimers (mg/L) | 850 (<500) |
| CRP (mg/L) | 125 (<3.25) |
| Pleural fluid | |
| Total cells (/mm3) | 3300 |
| Lymphocytes (%) | 51 |
| Polymorphonuclear cells (%) | 37 |
| Total protein (g/dL) | 4.7 (<3) |
| Glucose (mg/dL) | 101 (Serum glucose—20) |
| LDH (U/L) | 352 (<300) |
| Amylase (U/L) | 23 (<150) |
| Triglycerides (mg/L) | 70 (<110) |
| pH | 7.49 |
LDH: lactate dehydrogenase; CRP: C-reactive protein.
Figure 1.
Chest X-ray showing a massive left pleural effusion. Blunting of the costophrenic and cardiophrenic angles is also evident (red and blue arrows, respectively). A rightward shift of the trachea (indicated by the yellow arrow) occurred due to the massive effusion causing a mediastinal shift.
Diagnostic workup of the pleural effusion revealed a clear dark yellow fluid, classified as exudate based on Light’s criteria 3 (pleural fluid protein/ serum protein ~0.68, pleural fluid lactate dehydrogenase (LDH)/serum LDH ~0.98, and pleural fluid LDH >2/3 of upper limit of normal (ULN) of serum LDH), with increased lymphocytes (total cells 3300/mm3 with differential 51% lymphocytes, 37% polymorphonucleocytes), LDH 352 U/L, and pH 7.49 (Table 1). Blood and pleural fluid cultures did not isolate any microorganisms. Pleural fluid real-time-polymerase chain reaction (RT-PCR) and pleural fluid Acid-fast bacilli smear examination were negative for Mycobacterium tuberculosis. Moreover, specific culturing of blood and pleural fluid did not isolate any Mycobacterium species. A multiplex PCR platform, which tests for a broad spectrum of respiratory pathogens—including Gram-negative and Gram-positive bacteria, atypical bacteria, and viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Influenza A and B, and Respiratory Syncytial Virus (RSV)—did not detect any pathogens in the pleural fluid. Serologic testing for both autoimmune and viral diseases returned negative results. Cytologic analysis of the pleural fluid showed reactive lymphocytosis with no evidence of malignancy on repeated tests.
Pleural fluid drainage was achieved via chest tube placement following consultation with thoracic surgery. Serial chest radiographs showed successful drainage of the pleural effusion. Furthermore, the patient was treated with broad-spectrum antibiotics (due to prior hospitalization along with presenting features of fever and dyspnea), while all the diagnostic investigations were ongoing. Other supportive measures (supplemental oxygen via a nasal cannula and nebulized bronchodilators) were also administered. One unit of packed RBCs was also administered after consultation with hematology.
Computed tomography (CT) and magnetic resonance imaging (MRI) of the chest revealed bilateral thoracic paravertebral EMH sites, increased in size compared to imaging studies prior to her admission. Moreover, the left-side EMH lesion produced a mass effect on the pleura and lung parenchyma (Figure 2). In addition, CT Pulmonary Angiography was conducted, which excluded pulmonary embolism.
Figure 2.
Superior (a, b) and inferior (c, d) axial slides of chest CT (after contrast administration (a, c) and parenchymal view (b, d)) after chest tube placement (red arrow) showing the massive paravertebral EMH lesion in the left hemithorax (yellow star in (a, c) and red star in (b, d)), along with residual pleural fluid and ipsilateral lung atelectasis. A smaller lesion is seen on the opposite side (yellow star in (a, c) and red star in (b, d)).
CT: computed tomography; EMH: extramedullary hematopoiesis.
The patient was safely discharged without any complications. On follow-up, she was free of symptoms with a stable radiographic image, without pleural effusion recurrence. The patient was referred to a specialist thalassemia center for further treatment.
Discussion
Herein, we presented a case of bilateral thoracic paravertebral EMH complicated by a unilateral pleural effusion. Since the paravertebral EMH lesions were known to be of stable size from the patient’s past medical history and recent imaging before a cholecystectomy showed no incidence of pleural effusion, a thorough diagnostic workup was necessary to exclude other diagnoses of exudative pleural effusion in this patient.
Common differential diagnoses of exudative pleural effusion include pneumonia/empyema, tuberculosis, malignancy, autoimmune disease, chylothorax, and hemothorax. 4 The rapid development of pleural effusion usually suggests a parapneumonic effusion. 5 In our case, the most common causes of exudative pleural effusion were excluded during the initial diagnostic process. Parapneumonic effusion and empyema were ruled out via biochemical and fluid cell count analysis. Additionally, infectious agents and tuberculosis were excluded from consideration. Clinical examination and serologies did not reveal any signs of autoimmune disease. Imaging and repeated cytologic analysis were negative for malignancy. The absence of an opalescent appearance post centrifugation and measured pleural fluid triglycerides below the cut-off limit (Table 1) ruled out chylothorax. EMH-related pleural effusion is a documented complication of EMH in thalassemia intermedia, albeit rare.6–10
EMH is a manifestation of hematopoietic stress and inadequate BM function, resulting in the formation of ectopic compensatory hematopoietic foci outside of the BM.1,2 In non-transfusion-dependent thalassemic patients, EMH is a frequent phenomenon, observed in up to 20% of patients. 11 More cases are male, 12 with the age of onset at 27.5 years. 13 EMH sites can be categorized as either hepatosplenic and non-hepatosplenic (skin, gastrointestinal tract, urinary tract, paravertebral areas, etc.) 2 or extraosseous (stemming from hematopoietic stem and progenitor cells that develop ectopic hematopoietic foci) or paraosseous (through hyperactive BM herniation of the surrounding tissue, seen in high erythrocyte turnover states such as sickle cell disease and thalassemias). 14 In BTI, the most common anatomic region is the thoracic spine, 2 probably due to the narrow subarachnoid space and spinal canal in that area. 15 In the context of thalassemias, chronic anemia, and tissue hypoxia result in increased erythropoietin (EPO) production, with the constant EPO receptor-JAK2 pathway signaling stimulation leading to EMH production due to ineffective erythropoiesis. 2 Documented histologic findings of EMH reveal tri-lineage hematopoiesis, with erythroid cells at various stages of maturation, as well as myeloid cells and megakaryocytes. An increase in myeloid precursors and enriched vasculature suggests the presence of active EMH sites, while fat and iron deposits indicate older lesions. 16 Imaging manifestations of EMH lesions depend mainly on their activity level and age. On unenhanced CT, newer or active EMH lesions typically appear hypoattenuating, while older lesions have attenuation similar to skeletal muscle. 17 After contrast administration, newer lesions display mild to moderate homogeneous enhancement, while older ones show little to no enhancement. 17 On MRI, active lesions exhibit intermediate signal intensity on T1-weighted images and are hyperintense on T2-weighted images compared to skeletal muscle. 17 Radionuclide tracers can also be utilized to detect EMH, assess its extent, and differentiate it from neoplastic processes. 17 Even though biopsy is the gold standard for definitive diagnosis, its invasive nature coupled with the rich vasculature of EMH lesions increases the risk of severe hemorrhage, and it should be performed in cases where the clinical and imaging features are ambiguous. 12
Although EMH, in general, is associated with pleural effusions, BTI-associated pleural effusion is infrequently observed in the literature. From our review, a total of 11 patients with non-hemothorax BTI-related pleural effusion were reported. Most effusions were predominantly unilateral, with Ibabao et al. reporting massive bilateral effusions. 10 The main symptom was progressively worsening dyspnea, except for the patient reported by Ibabao et al. who presented with a lower extremity ulcer infection. 10 Regarding pleural fluid analysis, as in our patient, all effusions were exudates with a cell count differential revealing lymphocytic predominance. Biopsy was performed in three studies,7,9,10 with EMH9,10 and chronic inflammation 7 being the reported findings. Chest radiography was consistently used as the imaging modality for the initial evaluation of patients in the reviewed studies. In the case series presented by Aessopos et al., the authors used a CT scan for the diagnosis of EMH-related effusions. 6 Taher et al. reported chest CT findings consistent with EMH, albeit they eventually proceeded to conduct a biopsy of the pleura. 7 Ibabao et al. used both CT and MRI to investigate the EMH lesions, however, due to the patient’s deteriorating condition thoracoscopy was ultimately conducted. 10 Meo et al. used a chest MRI for the initial evaluation and follow-up of the patient presented. 8 Further information about our patients and the patients reported in the included studies can be found in Table 2. Other documented complications of thoracic/ paravertebral EMH in BTI, include: hemothorax (reported in Nakwan et al. 18 and Ma et al. 19 and one patient from the Aessopos et al. study 6 ), spinal cord compression, 12 as well as being a component of pulmonary hypertension development and deterioration in thalassemic patients. 20
Table 2.
Summary of reported cases (including our own).
| Study | Age (years) | Genotype | Lung involved | Pleural fluid cells/mm3 (% lymphocytes) | Biopsy performed | Treatment |
|---|---|---|---|---|---|---|
| Barakos et al. (2024) | 43 | IVS II: n1/+1480 (C⟶G) | Left | 3300 (51%) | No | Antibiotics Drainage Transfusion |
| Aessopos et al. (2006) 6 | 53 | N/A | Right | 2500 (65%) | No | Antibiotics Drainage Radiotherapy Transfusion |
| Aessopos et al. (2006) 6 | 39 | IVS I: 5/IVS I: 6 | Right | 3000 (70%) | No | Antibiotics Drainage Transfusion Tetracycline-pleurodesis Hydroxyurea |
| Aessopos et al. (2006) 6 | 47 | IVS II: 7/IVS I: 6 | Bilateral | 480 (53%) | No | Antibiotics Drainage Transfusion Tetracycline-pleurodesis Hydroxyurea |
| Aessopos et al. (2006) 6 | 29 | IVS I: 5/IVS I: 6 | Right | Hemothorax- (65%) | No | Antibiotics Drainage Transfusion Hydroxyurea |
| Aessopos et al. (2006) 6 | 43 | IVS I: 6/IVS I:110 | Bilateral | 1500 (58%) | No | Antibiotics Drainage Transfusion |
| Aessopos et al. (2006) 6 | 43 | IVS I: 6/IVS I: 110 | Left | 3200 (70%) | No | Antibiotics Drainage Transfusion Bleomycin-pleurodesis Hydroxyurea |
| Aessopos et al. (2006) 6 | 33 | IVS I: 5/IVS I: 6 | Right | 900 (55%) | No | Antibiotics Drainage Transfusion Bleomycin-pleurodesis Hydroxyurea |
| Aessopos et al. (2006) 6 | 56 | IVS I: 6/IVS I: 110 | Left | 2200 (60%) | No | Antibiotics Drainage Transfusion Talc-pleurodesis Hydroxyurea |
| Taher et al. (2001) 7 | 43 | IVS I: 6 (T⟶C) | Bilateral (predominantly right) | 1100 (72%) | Yes | Drainage Doxycycline-pleurodesis |
| Meo et al. (2008) 8 | 42 | IVS 1: 110/d | Bilateral | N/A | No | Drainage Pleurodesis Hydroxyurea |
| Peng et al. (1994) 9 | 34 | N/A | Right | N/A | Yes | Drainage Minocycline- pleurodesis |
| Ibabao et al. (1999) 10 | 40 | N/A | Bilateral | Left: 750 (64%) Right: 1600 (70%) |
Yes | Antibiotics Drainage Radiotherapy Talc-pleurodesis |
Apropos to our patient, a massive pleural effusion developed anteceding a stable radiographic image. Multiple triggers (recent surgery, probable concurrent infection) started a systemic inflammatory cascade that might have resulted in increased EMH capillary permeability and fluid accumulation. Echoing the study of Taher et al., 7 an EMH size increase might also produce a mass effect and local inflammation, further aiding in pleural effusion development.
Conclusion
Pleural effusion associated with EMH in BTI may be rare and underreported; however, clinicians should remain vigilant when a patient with a relevant medical history presents. A diagnostic workup to exclude other causes of pleural effusion is necessary, particularly when there is relatively fast fluid accumulation.
Footnotes
Author contributions: G.P.B. contributed to conceptualization, drafting, reviewing, editing, and approving the final manuscript. A.P. contributed to conceptualization, supervision, reviewing, editing, and approving the final manuscript. K.M. contributed to conceptualization, patient care, and data collection, reviewing and approving the final manuscript. V.E. contributed to patient care and data collection, reviewing and approving the final manuscript. S. Andronikou contributed to patient care and data collection, reviewing and approving the final manuscript. L.A. contributed to literature review, reviewing and approving the final manuscript. N.M. contributed to literature review, reviewing and approving the final manuscript. T.G. contributed to literature review, reviewing and approving the final manuscript. G.A. contributed to literature review, reviewing and approving the final manuscript. N.P. contributed to reviewing, editing, and approving the final manuscript. S. Antonopoulos contributed to reviewing, editing, and approving the final manuscript. All authors read and approved the final manuscript.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The publication of this article was supported by the Scientific Association of Continuing Medical Education “I SOLVE”, which covered the article processing charge (APC).
Ethical approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed consent: Written informed consent was obtained from the patient for the anonymized information to be published in this article.
ORCID iD: Georgios Petros Barakos 
https://orcid.org/0000-0002-1605-2169
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