Cholesterol Granulomas of the Lungs Associated With Microangiopathic Hemolytic Anemia and Thrombocytopenia in Pulmonary Hypertension: A Case Report and Review of the Literature.

A Case Report and Review of the Literature

Cholesterol granulomas of the lungs are rare lesions of unknown cause but with characteristic morphologic features. There are few reports of these lesions in pulmonary disorders unrelated to endogenous lipoid pneumonia, pulmonary alveolar proteinosis, or cholesterol pneumonia. We found 27 such reported cases, and in 26 the cholesterol granulomas were associated with pulmonary hypertension (Table). More than 30 years ago, pulmonary parenchymal cholesterol granulomas were reported in 12 patients with known pulmonary hypertension,[1] with the conclusion that severe increase in pulmonary blood pressure was most important in the pathogenesis.[1,2] In another patient who developed cholesterol granulomas after busulfan treatment for chronic myeloid leukemia, it was postulated that the lesions were secondary to pneumocyte desquamation and independent of pulmonary hypertension.[3] Histopathologic examination of 36 patients undergoing heart-lung transplantation with plexogenic pulmonary arteriopathy revealed cholesterol granulomas in 9 cases.[4] In another series of radiographic and histopathologic examination of 20 patients with pulmonary hypertension, cholesterol granulomas were found in 5 cases, but no association with plexiform lesions was suggested.[5] Although microangiopathic hemolytic anemia and thrombocytopenia have been associated with primary pulmonary hypertension,[6,7] they have not been linked to the development of granulomatous lesions with cleftlike cholesterol deposits.

Survey of Published Cases With Cholesterol Granulomas Associated With Pulmonary Hypertension and Comparison With the Present Case

No. of             No. of
Patients With   Patients With
Pulmonary        Cholesterol      Plexiform
Hypertension     Granulomas        Lesions

12                   12         Not described

...                   1         Not described

36                    9         In 36 cases

20                    5         Not described

1                     1         Present

No. of
Patients With
Pulmonary
Hypertension              Comment               Source, y

12              X-ray diffraction identified   Glancy et
                cholesteryl palmitate and/or   al,[1] 1968
                stearate

...             Chronic myeloid leukemia,      Kay et
                busulfan treatment             al,[3] 1970

36              Granulomas secondary to        Caslin et
                intrapulmonary hemorrhage      al,[4] 1990

20              Granulomas visible on chest    Nolan et
                x-ray examination and          al,[5] 1999
                computed tomography in 3 of
                5 cases

1               Associated with                Present case
                microangiopathic hemolytic
                anemia and thrombocytopenia

REPORT OF A CASE

A 41-year-old white man was referred for evaluation of a splenic artery aneurysm and an acquired splenorenal venous shunt. He reported a history of hypersplenism and thrombocytopenia for many years. He denied a bleeding history but reported easy bruising. On physical examination, the patient was obese (350 lb, 6 ft 1 in), with a protuberant abdomen but without palpable splenomegaly. The results of the rest of the physical examination were unremarkable. Arteriographic examination showed an abnormally large splenic artery, with 2 separate 2-cm-diameter and 6-cm-diameter splenic artery aneurysms. The physical examination also showed a shunt from the splenic artery to the left renal vein with several retroperitoneal varicose collaterals. The shunt increased the blood flow from the arterial to the venous system and the right side of the heart, and the increased flow through the pulmonary vascular bed was considered the cause of the pulmonary hypertension. The patient also had chronic thrombocytopenia of unknown cause, with platelet counts ranging from 35 to 82 x [10.sup.9]/L (range, 150-400 x [10.sup.9]/L). Other laboratory studies indicated hemolysis, with a haptoglobin level of less than 0.06 g/ L (range, 0.33-0.171 g/L), an increased lactate dehydrogenase level of 1922 U/L (range, 300-600 U/L), and an elevated reticulocyte count of 153 x [10.sup.9]/L (range, 25-75 x [10.sup.9]/L). Schistocytes were visible on the peripheral blood smear. Hemoglobin and hematocrit before surgery were within the reference range, and the patient did not require blood transfusions perioperatively. He underwent laparotomy with splenectomy and splenic artery resection. The spleen weighed 354 g, and the presence and size of the radiographically detected splenic artery aneurysms were confirmed. The patient initially did well after surgery. However, on the first postoperative day the patient's platelet count decreased to 19 x [10.sup.3]/[mm.sup.3]. On the fourth postoperative day, he unexpectedly collapsed and was refractory to immediate cardiopulmonary resuscitation. An autopsy was performed with family consent.

PATHOLOGIC FINDINGS

The autopsy revealed characteristic findings of severe pulmonary hypertension. There was pronounced atherosclerosis and dilatation of the proximal pulmonary artery. The right ventricle was markedly hypertrophied and dilated, consistent with severe cor pulmonale. Microscopic examination of the pulmonary arterioles revealed severe wall thickening with hyperplasia of the intima and media. Plexiform lesions were seen in arterioles throughout the lungs. Characteristically, the lesions consisted of multiple small endothelialized channels within a segment of muscular pulmonary arteriole. Most secondary lumina in the plexiform lesions were filled with microthrombi (Figure, A). In the Heath-Edwards system, which grades the severity of pulmonary hypertension based on histopathologic evaluation,[8] these changes are classified as grade 4 (of 6). Multiple cholesterol granulomas were distributed throughout the parenchyma of both lungs. They were composed of deposits of cleftlike cholesterol surrounded by multinucleated giant cells, bands of fibrosis, and a lymphocytic infiltrate (Figure, B). Their location was clearly extravascular, as evidenced by elastic stains (not shown). Deposits of hemosiderin granules were found in multinucleated giant cells by Prussian blue stains (Figure, C). Cholesterol granulomas outnumbered plexiform lesions, and no obvious positional relation was seen between those 2 lesions. Microemboli were not found in the pulmonary vasculature. Fibrin thrombi were not found on histologic examination of other organs. Death was attributed to sudden cardiac arrest secondary to severe pulmonary hypertension with cor pulmonale.[9]

[Figures A-C ILLUSTRATION OMITTED]

COMMENT

Cholesterol granulomas in pulmonary disorders, unrelated to endogenous lipoid pneumonia, pulmonary alveolar proteinosis, and cholesterol pneumonia, are a rare finding during pneumectomy or autopsy. The pathogenesis is unknown. There are 26 cases reported in the medical literature with underlying pulmonary hypertension and one patient with chronic myeloid leukemia after busulfan treatment (Table). We found cholesterol granulomas in association with microangiopathic hemolytic anemia and thrombocytopenia in a patient with secondary pulmonary hypertension and plexiform lesions in the pulmonary vasculature. We suggest that the hematologic disturbances in this patient could have promoted formation of cholesterol granulomas.

Previous investigators have suggested that cholesterol granulomas could arise from focal collections of lipid-laden macrophages.[1] They used x-ray diffraction to analyze crystals obtained by microdissection and identified cholesteryl palmitate and/or stearate. Lysed erythrocytes, blood plasma, and damaged lung tissue were discussed as possible sources for the cholesterol and its esters. No disturbances in the patients' cholesterol metabolism were found. Cholesterol emboli from atherosclerotic pulmonary arteries were thought to be an unlikely cause, because the cholesterol deposits were always extravascular.[1] Although cholesterol granulomas appear to be associated with

pulmonary hypertension, they develop only in a few cases (Table). In a series of 80 cases, 28% had plexogenic arteriopathy, but the authors did not describe cholesterol granulomas. This appears to reflect the rare occurrence of these lesions.[9] In another series of 36 patients with plexogenic pulmonary arteriopathy who were undergoing combined heart-lung transplantation, cholesterol granulomas were found in 9 patients. Formation of the granulomas in this series was attributed to resolving small intrapulmonary hemorrhages that were thought to occur early in plexogenic pulmonary arteriopathy.[4] Analysis of chest radiographs, computed tomographic scans, and histopathologic findings of 20 patients with pulmonary hypertension who were considered for lung transplantation revealed cholesterol granulomas in 5 cases, but no association with plexiform vascular lesions was described.[5]

Cholesterol granulomas of the lungs appear to be associated with pulmonary hypertension but are rare. Therefore, either long-standing severe disease or additional contributory factors are probably necessary for their development. Long duration of severe pulmonary hypertension clearly is an infrequent situation because of the unfavorable prognosis of this condition. Thus, it is more probable that other factors promote formation of the granulomas. Lysis of red blood cells with release of their membrane lipids is a possible pathogenetic factor.[1] Microangiopathic hemolytic anemia and thrombocytopenia have been reported in association with primary pulmonary hypertension, and the consumption of erythrocytes and platelets was attributed to their destruction in plexiform lesions.[6,7] In this case, plexiform lesions most likely developed secondary to long-standing pulmonary hypertension, causing hemolysis and thrombocytopenia. Because of the varicose nature of the abnormal blood vessels forming the splenorenal venous shunt, they did not appear to contribute to the hemolysis and thrombocytopenia. Destruction of red blood cells and platelets in plexiform lesions could release membrane lipids and provide them for uptake by multinucleated phagocytes that over time form granulomas. Presence of hemosiderin granules within those cells (Figure, C) supports this notion. It is reasonable to suggest that chronic hemolytic anemia and thrombocytopenia might be contributing factors to the development of cholesterol granulomas. The precise pathogenesis is still to be established and invites further investigation. In conclusion, to our knowledge, this is the first case described where cholesterol granulomas were seen in association with documented microangiopathic hemolytic anemia and thrombocytopenia, the presence of which might promote development of the cholesterol granulomas.

The authors thank Drs Gowthami M. Arepally and Ross E. Zumwalt for reviewing the manuscript.

References

[1.] Glancy DL, Frazier PD, Roberts WC. Pulmonary parenchymal cholesterolester granulomas in patients with pulmonary hypertension. Am J Med. 1968;45: 198-210.

[2.] Cholesterol granuloma of the lung. BMJ. 1969;1:396.

[3.] Kay JM, Heath D, Hasleton PS, Littler WA. Aetiology of pulmonary cholesterol-ester granulomas. Br J Dis Chest. 1970;64:55-57.

[4.] Caslin AW, Heath D, Madden B, Yacoub M, Gosney JR, Smith P. The histopathology of 36 cases of plexogenic pulmonary arteriopathy. Histopathology. 1990;16:9-19.

[5.] Nolan RL, McAdams HP, Sporn TA, Roggli VL, Tapson VF, Goodman PC. Pulmonary cholesterol granulomas in patients with pulmonary artery hypertension: chest radiographic and CT findings. Am J Roentgenol. 1999;172:1317-1319.

[6.] Stuard ID, Heusinkveld RS, Moss AJ. Microangiopathic hemolytic anemia and thrombocytopenia in primary pulmonary hypertension. N Engl J Med. 1972; 287:869-870.

[7.] Jubelirer SJ. Primary pulmonary hypertension: its association with microangiopathic hemolytic anemia and thrombocytopenia. Arch Intern Med. 1991; 151:1221-1223.

[8.] Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation. 1958;18: 533-547.

[9.] Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc. 1985;60:16-25.

Accepted for publication May 1, 2000.

From the Departments of Pathology (Drs Fischer and Nashelsky) and Surgery (Drs Marek and Morris), University of New Mexico School of Medicine, Albuquerque, NM.

Reprints: Edgar G. Fischer, MD, PhD, University of New Mexico, Department of Pathology, Health Sciences Center, BMSB #335, Albuquerque, NM 87131-5301 (e-mail: [e-mail]).