History
This 62 year old woman was admitted to hospital with increasing shortness of breath. She had
complaints of exertional dyspnea and fatigue which had begun about a year ago. She had questionable
Raynaud's phenomenon. She had been a one pack per day smoker from age 18 to 54 and she had suffered from
hypertension. The chest CT scan showed no evidence of pulmonary embolus and it showed prominent
bronchial circulation. A mild/moderate pericardial effusion was detected as well as small bilateral
pleural effusions. Mild diffuse septal thickening was noted throughout both lungs. The right side of
the heart was markedly enlarged. The pulmonary arteries were also enlarged with the main PA measuring
3.2 cm.
She had a right-sided cardiac catheterization done which showed the pulmonary artery pressure to be
78/31 mm Hg with a mean of 47 mm Hg. A nitric oxide challenge was performed together with coronary
artery angiography. The conclusion was reached that she was suffering from pulmonary hypertension with
an unclear response to nitric oxide challenge. She suffered a sudden cardiac arrest and she died in
hospital.
Case 2 - Figure 1 - Pulmonary vein showing almost completely obstructive intimal fibrosis.
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Case 2 - Figure 2 - Elastic stain highlights almost complete venous occlusion and interstitial thickening around the vein.
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Case 2 - Figure 3 - Elastic stain with an arterialized pulmonary vein on the right side showing obstructive intimal fibrosis and on the left hand side fibrous thickening of the interlobular septum.
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Case 2 - Figure 4 - Elastic stain of pulmonary vein showing arterialization with the medial coat of smooth muscle bounded by internal and external elastic laminae.
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Case 2 - Figure 5 - Area of peripheral interstitial fibrosis.
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Diagnosis
Pulmonary Veno-Occlusive Disease.
Discussion
Definition:
Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension in which small
pulmonary veins and venules are occluded by intimal fibrosis [1].
Clinical Features:
PVOD accounts for 10 percent of cases of pulmonary hypertension of unknown etiology
[2]. In adults there is a 2 to 1 male to female ratio. More than half the cases are encountered in the
first three decades of life. Patients present with dyspnea on exertion and fatigue in the early stages,
and cyanosis, hemoptysis and syncope in the late stages. Bibasilar crackles may be heard on chest
examination. PVOD may be difficult to distinguish from congestive heart failure and primary pulmonary
hypertension (PPH).
Etiology:
The cause of PVOD is not known but the character of the venous lesions indicates that thrombosis is an
essential factor in most if not all cases [3]. It has been suggested that thrombosis may be initiated by
a viral infection because of the frequent concomitant histologic finding of mild interstitial pneumonia
and a history of a preceding influenza-like illness in many cases [4]. No specific virus has been
implicated. Toxic exposures have been considered in the etiology of PVOD. It has been reported in
association with the sniffing of household cleaner [5] and with chemotherapy. Bleomycin, mitomycin and
BCNU (carmustine)
are thought by some investigators to confer the greatest risk of developing PVOD [6].
An immunologic basis has been suggested in some cases of PVOD because it has been occasionally associated
with Raynaud's phenomenon, disseminated lupus erythematosus, scleroderma, rheumatoid disease and celiac
disease [7]. Several cases of PVOD have occurred in association with bone marrow transplantation and
with renal transplantation [8]. Genetic factors may be involved, as there are several reports of
siblings with PVOD [9].
Radiology Findings:
The radiologic manifestations of PVOD include enlargement of the central pulmonary arteries due to
arterial hypertension and findings of interstitial pulmonary edema. The left atrium is not enlarged and
there is no redistribution of blood flow to the upper lobes. These findings are helpful in
distinguishing PVOD from left ventricular failure and mitral valve disease. High-resolution CT
demonstrates normal-sized pulmonary veins, extensive interlobular septal thickening and areas of
ground-glass attenuation due to interstitial pulmonary edema [10]. Another common finding on the
radiograph and HRCT is the presence of small bilateral pleural effusions.
Histologic Findings:
The veins and venules show an obstructive intimal fibrosis [11]. The fibrosis is often loose and
edematous initially and becomes denser with time. Recanalization of the intimal fibrosis with formation
of intravascular fibrous septa is common. The media of the veins may show hypertrophy and
arterialization, development of a double elastica, making them difficult to separate from arteries [12].
In up to 50 percent of cases, muscular pulmonary arteries show loose intimal fibrosis similar to that
seen in the veins Hypertensive arterial changes and recent thrombi are also often seen. This can cause
obliteration of the arterial lumen and recanalization; formation of intravascular septa is common.
Fibrous thickening of the interlobular septa is characteristic. Sclerotic veins may be seen within
the septa and in some cases, lymphatic spaces become dilated, raising the possibility of
lymphangiomatosis. Areas of alveolar capillary proliferation may give the appearance of capillary
hemangiomatosis. The lungs can show foci of severe congestion or interstitial fibrosis. Hemosiderosis
is common. When prominent it may be associated with iron encrustation of blood vessel walls.
Differential Diagnosis:
Concentric laminar intimal fibrosis and plexiform lesions are characteristic of pulmonary aterial
hypertension and are not seen in PVOD even when the intimal fibrosis is circumferential. The presence of
interstitial fibrosis, hemosiderosis and congestion can result in confusion with interstitial fibrotic
disorders, idiopathic pulmonary hemorrhage and chronic passive congestion. Whenever these lesions are
suspected PVOD should be considered and the veins carefully examined with elastic stains.
Capillary hemangiomatosis (CH) is a rare cause of pulmonary hypertension with some features that
overlap with PVOD. In CH the muscular arteries show medial hypertrophy, intimal fibrosis and adventitial
fibrosis. There may be iron encrustation of elastic tissue in the pulmonary arteries and veins and
alveolar septa. However CH is characterized by an aggressive proliferation of small blood vessels that
invade the interlobular fibrous septa, pleura, alveolar walls, walls of bronchi, pulmonary arteries and
pulmonary veins. It behaves more like a low grade neoplasm [13].
Treatment and Prognosis:
Patients with PVOD tend to have a more fulminant clinical course than those with PPH. Median survival
in one series was 84 days with 71 percent mortality in the first 6 months [14]. No effective therapy
exists except for heart-lung transplantation.
References
- Non-Neoplastic Disorders of the Lower Respiratory Tract. Atlas of non-tumour pathology. WD Travis, TV Colby, MN Koss, ML Rosado-de-Christenson, ML Muller and TE King. Published by the american Registery of Pathology and the Armed Forces Institute of Pathology Washington, DC 2002: 767-792.
- Rounds S, Cutaia MV. Pulmonary hypertension: pathophysiology and clinical disorders. In: Baum GL, Crapo JD, Celli BR, Karlinsky JB, eds. Textbook of pulmonary diseases. Philadelphia: Lippincott-Raven; 1998:1273-1295.
- Kay JM. Pulmonary Vascular Disorders. In, Thurlbeck's Pathology of the Lung. Third edition. Thieme New York 2005. AM Churg, JL Myers, HD Tazelaar, JL Wright.
- Wagenvoort CA, Wagenvoort n. The pathology of pulmonary veno-occlusive disease. Virchows Arch (A) 1974; 364:69-79.
- MandelJ, Mark EJ, Hales C. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med 2000;162:1964-1973.
- Doll DC, YarbroJW. Vascular toxicity associated with chemotherapy and hormonetherapy. Curr Opin Oncol 1994;6:345-350.
- Corrin B, Spencer H, Tuner-Warwick M, Beales SJ, Hamblin JJ. Pulmonary veno-occlusion: an immune complex disease? Virchows Arch (A)1974;364:81-91.
- Seguchi M,Hirabayashi N, Fujii Y,et al. Pulmonary hypertension associated with pulmonary veno-occlusive vasculopathy after allogeneic bone marrow transplantation. Transplantation 2000;69:177-179.
- Wagenvoort CA, Wagenvoort N, Takahashi T. Pulmonary veno-occlusive disease: involvement of pulmonary arteries and review of the literature. Hum Pathol 1985; 16:1033-1041.
- Swenson SJ, Tashjian JH, Myers JL, et al. Pulmonary veno-occlusive disease: CT findings in eight patients. AJR Am J Roentgenol 1996;167:937-940.
- Wagenvoort CA, Mooi WJ. Biopsy pathology of the pulmonary vasculature. London: Chapman and Hall; 1989.
- Dail DH. Uncommon tumors. In: Dail DH, Hammar SP, eds. Pulmonary pathology, 2nd ed. New York: Springer-Verlag; 1994:1279-1461.
- Tron V, Magee F, Wright JL, Colby TV, Churg A. Pulmonary capillary hemangiomatosis. Hum Pathol 1986;17:1144-1150.
- PietraGG, Edwards WD, Kay JM, et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung and Blood Institute, Primary Pulmonary hypertension Registery. Circulation 1989;80:1198-1206.
