0
Postgraduate Education Corner: PULMONARY AND CRITICAL CARE PEARLS |

A 71-Year-Old Woman With Myelofibrosis, Hypoxemia, and Pulmonary Hypertension FREE TO VIEW

Terence K. Trow, MD, FCCP; A. Christina Argento, MD; Ami N. Rubinowitz, MD; Roy Decker, MD
Author and Funding Information

From the Yale Pulmonary Vascular Disease Program (Dr Trow), the Department of Internal Medicine, Section of Pulmonary and Critical Care (Dr Argento), the Department of Diagnostic Radiology (Dr Rubinowitz), and the Department of Therapeutic Radiology (Dr Decker), Yale University School of Medicine, New Haven, CT.

Correspondence to: Terence K. Trow, MD, FCCP. Department of Internal Medicine, Section of Pulmonary and Critical Care, Yale University School of Medicine, PO Box 203057, LLCI 105D, New Haven, CT 06520-8057; e-mail: terence.trow@yale.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;138(6):1506-1510. doi:10.1378/chest.10-0973
Text Size: A A A
Published online

A 71-year-old white woman presented with progressive dyspnea, decreased exercise tolerance, and pitting edema of her lower extremities and abdominal wall. Her dyspnea had been especially severe for 2 to 3 weeks prior to admission, but on further questioning it was apparent that it had been present insidiously for 2 to 3 years. Her medical history was notable for polycythemia vera that had progressed to myelofibrosis with myeloid metaplasia. She had received blood transfusions for 6 years. Erythropoietin had been added 3 years prior in an attempt to prolong the interval between transfusions. Review of systems was notable for Raynaud phenomena.

Physical Examination

Her vital signs were normal. Saturation of arterial blood by pulse oximetry was 73% on room air and 90% on 6 L of oxygen supplementation. Head, ears, eyes, nose and throat examination was notable for anicteric sclera, whereas her neck exam showed no nodes or bruits, but 6 cm of jugular venous distention at 45° was noted. Her cardiac examination indicated a grade II/VI holosystolic murmur without radiation to neck or axilla and a widely split P2 component to the second heart sound. No dullness to percussion was heard on the chest; it was clear, without rales, rhonchi, or wheezes. Her abdomen was normal with active bowel sounds and was nontender with an enlarged liver and spleen to palpation. There was no fluid wave. Pitting abdominal wall edema was ≥3, and on the extremities ≥3 pitting edema to perineum. Her skin showed no telangiectasias or rashes and there was no cyanosis.

Laboratory Findings

Laboratory examination levels were as follows: hemoglobin, 9.7 gm/dL; hematocrit, 29%; platelets, 185,000; white count, 7.8×1,000 /μL; sodium, 143 mmol/L; potassium, 4.5 mmol/L; chloride, 105 mmol/L; bicarbonate, 26 mmol/L; blood urea nitrogen, 51mg/dL; creatinine, 1.4 mg/dL; glucose, 79 mg/dL; and urinalysis, normal. Arterial blood gas on 6 L oxygen by nasal cannula revealed a pH of 7.39, Paco2 of 34, and Pao2 of 59, with 90% arterial oxygen saturation. An extensive panel of collagen-vascular serologies was negative, including antinuclear antibody (Ab), rheumatoid factor, anti-centromere Ab, anti-topoisomerase 1Ab, and anti-Ro and anti-La Ab.

A chest roentogram (Fig 1) showed an increased cardiac silhouette. There were also subtle bilateral, right greater than left, patchy ground-glass opacities. A CT scan angiogram (Fig 2) showed no evidence of acute or chronic pulmonary emboli but did reveal bilateral patchy airspace opacities. A ventilation perfusion scan showed no evidence of acute or chronic thromboembolic disease. An ECG revealed severe pulmonary hypertension with both right atrial and ventricle dilatation and notable right ventricle hypokinesis. Left-sided structures and function were normal. Pulmonary function tests revealed a mild restrictive defect (total lung capacity 3.76 [70% of predicted]) and moderate decrease in diffusing capacity (12.61 [68% of predicted after adjustment for anemia]).

A right-sided heart catheterization revealed a pulmonary artery (PA) pressure of 90/35 with a mean PA pressure of 55. The PA wedge pressure was normal at 14. The calculated pulmonary vascular resistance was abnormal at 7.5 Wood units (normal < 3).

Figure Jump LinkFigure 1. Chest roentogram of 71-year-old woman. Posterior-anterior chest radiography demonstrates cardiomegaly, as well as enlargement of the main pulmonary artery (arrow). There are also bilateral, right greater than left, patchy ground-glass opacities.Grahic Jump Location
Figure Jump LinkFigure 2. Axial images from a routine chest CT scan (5-mm-thick sections) demonstrate patchy, bilateral ground-glass opacities. A, Upper thorax. B, Midthorax.Grahic Jump Location
What test could establish the likely diagnosis?
Test: Technetium-99 sulfur colloid scintigraphy to diagnose extramedullary hematopoiesis

Extramedullary hematopoesis (EMH) of the lung refers to the presence of trilinear (granulocytic, erythroid, and megakaryocytic) hematopoietic precursor cells in the lung. The epidemiology and prevalence of this disorder is unknown because of the small number of case reports in the literature. Including our case, a total of 37 cases have been reported since 1962. These reports usually represent one to two patients in each series. What proportion this small number of reported cases represents of all patients with myeloid metaplasia is unknown, but it is likely a rare diagnosis. Whether this indicates that this is a rare condition or simply an underdiagnosed one remains unclear.

Ectopic hematopoietic activity outside the marrow is commonly seen in myelofibrotic disorders, including agnogenic myeloid metaplasia, polycythemia vera, and essential thrombocythemia. It occurs most commonly in the liver and spleen but may occur on rare occasions in lymph nodes, on serosal surfaces, in the urogenital system, in paraspinal or epidural spaces, or in the lung. Whether EMH in the lung represents in situ embryonic cell differentiation or a compensatory delivery of hematopoietic cells from the marrow is unclear. Lung involvement can present with a variety of nonspecific symptoms, including cough, slowly progressive dyspnea, and pulmonary hypertension (PH) with signs of right-sided heart failure, and can progress to acute respiratory failure and death. PH can result from a number of mechanisms, including pulmonary capillary obstruction, thrombotic events, interstitial pneumonitis and fibrosis, and alveolar airspace involvement, or from hematopoietic progenitor cell invasion of the PA intima. Radiographically, findings can range from isolated lung or paravertebral masses to diffuse increased interstitial markings with septal thickening, alveolar airspace filling with ground-glass opacities as in our case, or pleural effusions with or without hemothorax. The osseous structures (in particular, the ribs) typically show expansion of the medullary cavity. In some instances, EMH of the lung may show no evidence of radiographic abnormality. This underscores the need for a heightened awareness of these multiple radiographic presentations in patients with chronic myeloid disorders to make this rare diagnosis. Technectium-99 (99mTc) sulfur colloid scintigraphy can be strongly suggestive of the diagnosis, although false-negatives have been reported. A total of seven cases diagnosed by 99mTc sulfur colloid scintigraphy exist in the literature. As such, little can be said about the sensitivity or specificity of this test in the diagnosis of this entity.

Tissue diagnosis of EMH in the lung can be achieved by pleuroscopy, fine needle aspiration of mass lesions, transbronchial biopsy, and open surgical or video-assisted thoracoscopic biopsy, or at autopsy. Transbronchial biopsies are not advised in cases with severe PH because of the high risk of alveolar hemorrhage. The decision as to which approach to use must be individualized, and the decision to perform invasive tissue biopsy must be tempered by the increased risk of perioperative complications encountered in patients with significant pulmonary hypertension. Histology in all reported cases reveals trilineage hematopoiesis with granulocytic, erythroid, and megakaryocytic precursors, with varying degrees of adjacent fibrosis.

Treatment with hydroxyurea or platelet pharesis is generally not successful in modifying PH except in cases in which massive thrombocytosis predominates. Low-dose whole-lung irradiation can be curative in the short term, as it was in our case, although durability of response has not been reported previously. A total of seven cases of EMH treated with low-dose whole-lung radiation exist in the literature. All seven showed prompt and gratifying improvements in oxygenation, symptoms, PH, and roentograms. Again, because high-resolution CT scanning can be unremarkable in some cases with 99mTc sulfur colloid scintigraphy uptake, a high index of clinical suspicion is required to make the diagnosis and to avoid missing an opportunity for successful treatment.

Clinical Course

Our patient was diagnosed by 99mTc colloid scintigraphy, which revealed diffuse abnormal uptake in both lungs (Fig 3). Other clues leading to her diagnosis included the onset of symptoms after erythropoietin initiation, her underlying diagnosis of myeloid metaplasia, and the ground-glass opacities present on CT scan. Tissue confirmation was not performed because of the increased risk of perioperative complications imposed by her severe PH and her own refusal to undergo lung biopsy. Low-dose whole-lung irradiation with four 50-centigray sessions resulted in a decrease in dyspnea, decreased oxygen needs, a drop in estimated systolic PA pressures to 40 on ECG, and improvement in the ground-glass opacities on CT scanning (Fig 4) within 4 days’ time. She was discharged on room air oxygen with saturations of 96%. Six months later, an ECG revealed PA systolic estimates of 30 with a normal-sized right ventricle with normal systolic function. The patient remains symptom free. Although similar reports of short-term response exist in six other cases in the literature, to our knowledge, our case represents the only one offering longer term follow-up (> 6 months). As such, the typical course post treatment is unknown. We continue to follow our patient closely for any EMH recurrence.

Figure Jump LinkFigure 3. Images from a sulfur colloid scan show colloid shift to an enlarged spleen (arrows), as well as mild diffuse uptake within the lungs. ABDM = abdomen.Grahic Jump Location
Figure Jump LinkFigure 4. Axial images from a routine chest CT scan (5-mm-thick sections) at similar levels as Figure 2, following whole-lung irradiation demonstrate improvement of the ground-glass opacity bilaterally, but with residual ground-glass opacity remaining. A, Upper thorax. B, Midthorax.Grahic Jump Location

  • 1. EMH can occur in the lung and should be thought of in patients with chronic myeloid disorders who present with progressive dyspnea with or without pulmonary hypertension.

  • 2. Radiographic findings are protean with masses, pleural effusions, interstitial changes, and alveolar filling processes all reported.

  • 3. 99mTc sulfur colloid scintigraphy can suggest the diagnosis, although the small number of cases reported makes sensitivity and specificity of this test for EMH unknown.

  • 4. Low-dose whole-lung irradiation can treat this condition successfully.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Coates GG, Eisenberg B, Dail DH. Tc-99m sulfur colloid demonstration of diffuse pulmonary interstitial extramedullary hematopoiesis in a patient with myelofibrosis. A case report and review of the literature. Clin Nucl Med. 1994;1912:1079-1084. [CrossRef] [PubMed]
 
Wyatt SH, Fishman EK. Diffuse pulmonary extramedullary hematopoiesis in a patient with myelofibrosis: CT findings. J Comput Assist Tomogr. 1994;185:815-817. [CrossRef] [PubMed]
 
Yusen RD, Kollef MH. Acute respiratory failure due to extramedullary hematopoiesis. Chest. 1995;1084:1170-1172. [CrossRef] [PubMed]
 
García-Manero G, Schuster SJ, Patrick H, Martinez J. Pulmonary hypertension in patients with myelofibrosis secondary to myeloproliferative diseases. Am J Hematol. 1999;602:130-135. [CrossRef] [PubMed]
 
Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;34217:1255-1265. [CrossRef] [PubMed]
 
Steensma DP, Hook CC, Stafford SL, Tefferi A. Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia. Br J Haematol. 2002;1183:813-816. [CrossRef] [PubMed]
 
Weinschenker P, Kutner JM, Salvajoli JV, et al. Whole-pulmonary low-dose radiation therapy in agnogenic myeloid metaplasia with diffuse lung involvement. Am J Hematol. 2002;694:277-280. [CrossRef] [PubMed]
 
Rumi E, Passamonti F, Boveri E, et al. Dyspnea secondary to pulmonary hematopoiesis as presenting symptom of myelofibrosis with myeloid metaplasia. Am J Hematol. 2006;812:124-127. [CrossRef] [PubMed]
 
Schwarz C, Bittner R, Kirsch A, et al. A 62-year-old woman with bilateral pleural effusions and pulmonary infiltrates caused by extramedullary hematopoiesis. Respiration. 2009;781:110-113. [CrossRef] [PubMed]
 
Ozbudak IH, Shilo K, Hale S, Aguilera NS, Galvin JR, Franks TJ. Alveolar airspace and pulmonary artery involvement by extramedullary hematopoiesis: a unique manifestation of myelofibrosis. Arch Pathol Lab Med. 2008;1321:99-103. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Chest roentogram of 71-year-old woman. Posterior-anterior chest radiography demonstrates cardiomegaly, as well as enlargement of the main pulmonary artery (arrow). There are also bilateral, right greater than left, patchy ground-glass opacities.Grahic Jump Location
Figure Jump LinkFigure 2. Axial images from a routine chest CT scan (5-mm-thick sections) demonstrate patchy, bilateral ground-glass opacities. A, Upper thorax. B, Midthorax.Grahic Jump Location
Figure Jump LinkFigure 3. Images from a sulfur colloid scan show colloid shift to an enlarged spleen (arrows), as well as mild diffuse uptake within the lungs. ABDM = abdomen.Grahic Jump Location
Figure Jump LinkFigure 4. Axial images from a routine chest CT scan (5-mm-thick sections) at similar levels as Figure 2, following whole-lung irradiation demonstrate improvement of the ground-glass opacity bilaterally, but with residual ground-glass opacity remaining. A, Upper thorax. B, Midthorax.Grahic Jump Location

Tables

Suggested Readings

Coates GG, Eisenberg B, Dail DH. Tc-99m sulfur colloid demonstration of diffuse pulmonary interstitial extramedullary hematopoiesis in a patient with myelofibrosis. A case report and review of the literature. Clin Nucl Med. 1994;1912:1079-1084. [CrossRef] [PubMed]
 
Wyatt SH, Fishman EK. Diffuse pulmonary extramedullary hematopoiesis in a patient with myelofibrosis: CT findings. J Comput Assist Tomogr. 1994;185:815-817. [CrossRef] [PubMed]
 
Yusen RD, Kollef MH. Acute respiratory failure due to extramedullary hematopoiesis. Chest. 1995;1084:1170-1172. [CrossRef] [PubMed]
 
García-Manero G, Schuster SJ, Patrick H, Martinez J. Pulmonary hypertension in patients with myelofibrosis secondary to myeloproliferative diseases. Am J Hematol. 1999;602:130-135. [CrossRef] [PubMed]
 
Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;34217:1255-1265. [CrossRef] [PubMed]
 
Steensma DP, Hook CC, Stafford SL, Tefferi A. Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia. Br J Haematol. 2002;1183:813-816. [CrossRef] [PubMed]
 
Weinschenker P, Kutner JM, Salvajoli JV, et al. Whole-pulmonary low-dose radiation therapy in agnogenic myeloid metaplasia with diffuse lung involvement. Am J Hematol. 2002;694:277-280. [CrossRef] [PubMed]
 
Rumi E, Passamonti F, Boveri E, et al. Dyspnea secondary to pulmonary hematopoiesis as presenting symptom of myelofibrosis with myeloid metaplasia. Am J Hematol. 2006;812:124-127. [CrossRef] [PubMed]
 
Schwarz C, Bittner R, Kirsch A, et al. A 62-year-old woman with bilateral pleural effusions and pulmonary infiltrates caused by extramedullary hematopoiesis. Respiration. 2009;781:110-113. [CrossRef] [PubMed]
 
Ozbudak IH, Shilo K, Hale S, Aguilera NS, Galvin JR, Franks TJ. Alveolar airspace and pulmonary artery involvement by extramedullary hematopoiesis: a unique manifestation of myelofibrosis. Arch Pathol Lab Med. 2008;1321:99-103. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543