A Rare State Associated with Myelofibrosis; Pulmonary Extramedullary Hematopoiesis

Annals of Clinical Case Studies ISSN: 2688-1241

Case Report A Rare State Associated with Myelofibrosis; Pulmonary Extramedullary Hematopoiesis

Nurcan Güler1, Eyüp Sabri Uçan1, Merve Keskinkiliç2, Duygu Gürel3, and Aylin Ozgen Alpaydin1* 1Department of Pulmonary Diseases, Dokuz Eylul University, Izmir, Turkey 2Department of Internal Medicine, Dokuz Eylul University, Izmir, Turkey 3Department of Pathology, Dokuz Eylul University, Izmir, Turkey

Abstract Pulmonary Extramedullary Hematopoiesis (PEMH) is characterized by the presence of hematopoietic precursor cells in the lung. It may cause acute life-threatening complications such as massive pleural effusion, hemothorax, chylothorax, and spinal cord compression. The diagnosis is based on clinical, radiographical, and pathologic findings. We aimed to present a patient diagnosed with PEMH and treated with ruxolitinib in our clinic. Keywords: Pulmonary extramedullary hematopoiesis; Extramedullary hematopoiesis; Ruxolitinib Introduction mg/L (normal <5 mg/L). PaO2 and sat O2 levels were 47.1 mmHg, and 81.8%, respectively. Other biochemical values were within Clonal neoplastic increase in the megakaryocytic series is a normal limits. PaO2 and sat O2 levels were shown in the figures. myeloproliferative neoplasm manifested by fibrosis in the bone Transthoracic echocardiography revealed an ejection fraction of 55% marrow and extramedullary hematopoiesis [1]. Myelofibrosis with and pulmonary artery pressure of 45 mmHg. Pulmonary function Myeloid Metaplasia (MMM) is a chronic myeloproliferative disorder tests were consistent with restrictive pathologies (Forced Expiratory which can develop de novo or secondary to polycythemia vera or Volume in 1 second (FEV1): 70%, Forced Vital Capacity (FVC) 68%, essential thrombocythemia [2,3]. EMH usually involves the spleen FEV1/FVC: 85, DLCO: 52%, DLCO/VA: 85%). and liver, but rarely occurs in other regions such as the para-intraspinal cord, lymph nodes, lung, and pleura [4]. PEMH indicates the presence Since the restrictive pattern was found, immunological markers of hematopoietic precursor cells in the lung. It is a rare complication were sent for the pulmonary involvement of connective tissue associated with myelofibrosis [5]. However, PEMH occurs in the disorders which were tested negative. In the chest radiography, there advanced stages of MMM and is characterized by progressive dyspnea was reticulonodular density in the lung parenchyma and irregularities and pulmonary hypertension findings [4]. on the surface of the right diaphragm (Figure 1). Thoracic Computed Tomography (CT) revealed multiple lymph nodes in prevascular We aimed to present a patient who admitted to our clinic with space in the mediastinum, right paratracheal area, aorticopulmonary progressive dyspnea and diagnosed with PEMH. window, subcarinal, bilateral hilar areas, with the largest lymph node Case Presentation in the subcarinal area with 2.5 cm diameter, and mosaic attenuation A 69-year-old female patient applied to our clinic due to progressive areas in both lung parenchyma (Figure 2). dyspnea and dry cough. She was diagnosed with polycythemia vera and myelofibrosis secondary to polycythemia for 11 years. Inspiratory rales and hepatosplenomegaly were found in physical examination. Her medical history revealed smoking and alcohol use, and no other diseases than osteoporosis. In laboratory examinations, hemoglobin level was 8.5 g/dl; white blood cell count was 12.8/mm3 (neutrophil 11.5/mm3, and platelet 180.000/mm3) and C-Reactive Protein (CRP) level was 29.2

Citation: Güler N. A Rare State Associated with Myelofibrosis; Pulmonary Extramedullary Hematopoiesis. Ann Clin Case Stud. 2020; 2(4): 1033. Copyright: © 2020 Nurcan Güler Publisher Name: Medtext Publications LLC Manuscript compiled: Sep 13th, 2020 *Corresponding author: Aylin Özgen Alpaydın, Department of Pulmonary Diseases, Dokuz Eylul University Faculty of Medicine, Figure 1: Reticulonodular density in the lung parenchyma and irregularities Izmir, Turkey, Tel: +905327953423; E-mail: [email protected] on the surface of the right diaphragm.

Figure 4: Interstitial expansion associated with hematopoietic elements: myeloid, erythroid and megakaryocytic cells (hematoxylin-eosin; original magnification: X40).

Figure 2: Common mosaic attenuation areas in both lung parenchyma.

Fiberoptic bronchoscopy was performed for differential diagnosis. CD4/CD8 ratio was 1 and bronchoalveolar lavage cytology was negative for malignancy, with alveolar macrophage 60%, lymphocyte: 8%, neutrophil: 30%, and eosinophil: 2%. Surgical biopsy was planned for the diagnosis of interstitial pneumonia because of the unexplained clinical and radiological findings. Pulmonary wedge biopsy, performed by video-assisted thoracoscopic surgery, was consistent with pulmonary extramedullary hematopoiesis. Pathology result was included lung parenchyma involvement by extramedullary hematopoiesis (Figure 3), patchy interstitial expansion and alveolar fibrinous exudation, interstitial expansion Figure 5: Clumps of erythroid precursors with round, hyperchromatic nuclei associated with hematopoietic elements: myeloid, erythroid, and and scanty cytoplasm (hematoxylin-eosin; original magnification X100). megakaryocytic cells (Figure 4), clumps of erythroid precursors with round, hyperchromatic nuclei and scanty cytoplasm (Figure 5), immunohistochemical staining for glycophorin confirm the presence of erythroid precursor cells (Figure 6), giant cells of various sizes with hyperchromatic and lobulated nucleus in alveolar septa (Figure 7), CD61 staining confirm the presence of megakaryocytes (Figure 8). She was diagnosed with pulmonary extramedullary hematopoiesis secondary to myelofibrosis and was started on ruxolitinib treatment. The patient was followed up regularly. Discussion Extramedullary hematopoiesis is a rare disease with a low Figure 6: Immunohistochemical staining for glycophorin comfirm the presence of erythroid precursor cells (glycophorin; original magnification: X100).

Figure 3: Lung parenchyma involvement by extramedullary hematopoiesis. Patchy interstitial expansion and alveolar fibrinous exudation (hematoxylin- Figure 7: Giant cells of various sizes with hiperchromatic and lobulated eosin; original magnification: X20). nucleus in alveoler septa (hematoxylin-eosin; original magnification: X40).

There is no consensus on the best management of PEMH in the literature. There are several case reports supporting cytoreduction with hydroxyurea. In a case report of two patients treated with steroids and supportive care, both died. There are also a few case reports showing success with low dose (200 CGY) and higher dose (1400 CGY) lung radiation therapy. Although hydroxyurea been reported to be successful in EMH cases, pleurodesis or low dose radiotherapy is needed in refractory cases to hydroxyurea. JAK-2 inhibits the JAK/STAT signaling pathway in patients without V617F mutations, suggesting that oral JAK-2 inhibitors suppress symptoms. There are not enough reports on the use of ruxolitinib for the treatment in PEMH [13].

Figure 8: CD6l staining confirm the presence of megakaryocytes (CD61; References original magnification: X100). 1. Primary Miyelofibrosis Guideline of Turkish Society of Hematology. incidence in 100,000 inhabitants per year and an average survival 2. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342:1255-65. ranging from 3.5 to 5.5 years [2]. Spleen, liver, and, rarely, paraspinal 3. Passamonti F, Rumi E, Pungolino E, Malabarba L, Bertazzoni P, Valentini M, et al. Life cord, lymph nodes, lungs, and the serosal surfaces are the places expectancy and prognostic factors for survival in patients with polycythemia vera and where EMH occurs [6]. PEMH has been rarely reported. Although essential thrombocythemia. Am J Med. 2004;117(10):755-61. the pathogenesis of PEMH is poorly understood, it may represent the 4. Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary differentiation of embryonic hematopoietic stem cells or abnormal hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo release of marrow precursors in circulation [7]. Diagnosis of EMH, as Clin Proc. 2003;78(10):1223-33. well as bone marrow fibrosis, is important in MMM. Although PEMH 5. Singh I, Mikita G, Green D, Risquez C, Sanders A. Pulmonary extra-medullary is mostly asymptomatic, some patients may present with acute or hematopoiesis and pulmonary hypertension from underlying polycythemia vera: a progressive dyspnea or chest pain [8], and experience life-threatening case series. Pulm Circ. 2017;7(1):261-7. complications such as massive pleural effusion, hemothorax [9], chylothorax [10], or spinal cord compression [11]. 6. Dingli D, Utz JP, Krowka MJ, Oberg AL, Tefferi A. Unexplained pulmonary hypertension in chronic myeloproliferative disorders. Chest. 2001;120(3):801-8.

The diagnosis is based on clinical, radiographical, and pathologic 7. Barosi G, Viarengo G, Pecci A, Rosti V, Piaggio G, Marchetti M, et al. Diagnostic and findings. Subjects may present with exercise dyspnea, progressive clinical relevance of the number of circulating CD34(+) cells in myelofibrosis with reduction in exercise tolerance, cough, hemoptysis, and fatigue. myeloid metaplasia. Blood. 2001;98(12):3249-55. Physical examination may reveal coarse rhonchi and inspiratory rales. 8. Ozbudak IH, Shilo K, Hale S, Aguilera NS, Galvin JR, Franks TJ. Alveolar airspace Thorax CT is helpful in the diagnosis of PEMH. Bilateral interstitial and pulmonary artery involvement by extramedullary hematopoiesis: a unique infiltrates, reticulonodular opacities, bilateral hilar adenopathies, and manifestation of myelofibrosis. Arch Pathol Lab Med. 2008;132(1):99-103. bilateral pleural effusion can be seen in CT. In a previously reported 9. Kupferschmid JP, Shahian DM, Villanueva AG. Massive hemothorax associated limited number of PEMH cases, revealed thorax CT findings are; with intrathoracic extramedullary hematopoiesis involving the pleura. Chest. septal thickening bilateral nodular lesions, patchy consolidations, 1993;103(3):974-5. and frosted glass pattern with or without pleural effusion. To show EMH, the most widely used imaging method is the Technetium-99 10. Ghosh AK, Pawade J, Standen GR, Lazdunski LL. Primary extramedullary hematopoiesis manifesting as massive bilateral chylothorax. Ann Thorac Surg. sulfide colloid (99 mT). To date, there are no cases of hematopoietic 2005;80(4):1515-7. elements shown in BAL in EMH. The diagnosis should be confirmed by tissue sampling if there is a suspicion of this condition with 11. Scott IC, Poynton CH. Polycythaemia rubra vera and myelofibrosis with spinal cord appropriate clinical and radiological features. The diagnosis of compression. J Clin Pathol. 2008;61(5):681-3. PEMH is usually made by the pathology of the lung biopsy obtained 12. Bajwa AA, Usman F, Wolfson D, Laos LF, Cury JD. A 62-Year-Old Woman surgically. Transbronchial biopsy in case of extensive parenchymal with Dyspnea, Leukocytosis, and Diffuse Ground-Glass Opacities. Chest. disease may also help with diagnosis. PEMH is characterized by focal 2010;137(6):1470-3. or diffuse intravascular, luminal, alveolar, peribronchial, perivascular, 13. Chen K, Krveshi L, Ballarino G. Pleural Extramedullary Hematopoiesis Successfully and interstitial involvement with focal or diffuse involvement of Treated With Ruxolitinib: A Case Report. Chest. 2017;152(4):A507. hematopoietic elements from three series. Fibrosis may also be present in these areas. Immunohistochemistry is required for myeloid, erythroid, and megakaryocyte precursors [12].