Histopathology of Primary Pulmonary Hypertension* Giuseppe

G. Pietra,

M.D.

definition, the clinical diagnosis of primary pulmonary hypertension (PPH) can be made only after any secondary cause of pulmonary hypertension is ruled out. In the past, pathologic confirmation of the clinical diagnosis was based on demonstrating the presence of the so-called plexogenic pulmonary arteriopathy in the absence of any congenital cardiac left-to-right shunt. It is now recognized that there are no specific histopathologic lesions of PPH and that the diagnosis of this disease requires the close integration of clinical symptoms, laboratory investigations, and histopathologic findings. The purpose of this presentation was to describe the types of histopathologic lesions that can produce PPH. JOy

HISTOPATHOLOGIC CLASSIFICATION OF PPH

Table 1 summarizes the results of five large pathology series published during the past 20 years. The great majority of patients with PPH had widespread abnormalities only in the arterial side of the pulmonary circulation at autopsy or lung biopsy and were classified as having pulmonary hypertensive arteriopathy. In a small percentage of cases, the hypertensive changes did involve primarily the venous pulmonary circulation, and the patients were classified as having pulmonary veno-ocelusive disease. In some cases, the diagnosis of PPH could not be confirmed histopathologically. Hypertensive

Pulmonary

Arteriopathy

Hypertensive pulmonary arteriopathy associated with PPH is a disease of the muscular arteries and arterioles; the elastic arteries show secondary changes in the form of dilatation, medial degeneration, and intimal atheromas. Three histopathologic subsets of hypertensive pulmonary arteriopathy have been identified on the basis of the predominant vascular lesions: - isolated medial hypertrophy ( I M H ) , plexogenic pulmonary arteriopathy (PPA), and 1

2

" F r o m t h e Division o f A n a t o m i c Pathology-, D e p a r t m e n t o f Pathology and L a b o r a t o r y Medicine, University o f Pennsylvania Medical School, Philadelphia. Supported in p a r t b y grant H L 3 2 4 8 2 from t h e H e a r t , B l o o d and L u n g Institute, National Institutes o f H e a l t h . Reprint requests: Dr. Pietra, Rm 6 . 0 6 0 Founders Pavilion, University of Pennsylvania Medical center, 3400 Spruce Street, Philadelphia 19104

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thrombotic pulmonary arteriopathy (TPA). Although it is uncertain whether these subsets represent different pathogenetic mechanisms or different manifestations of the same disease, the distinction is important since it provides an objective basis for evaluating the effects of various therapeutic protocols in PPH. IMH—Pulmonary Artery Medial Hypertrophy: Medial hypertrophy is present in all forms of pulmonary hypertension either as an isolated lesion (IMH) or associated with intimal and/or luminal lesions. Some authors have considered IMH an early stage of development of PPA. Because IMH is a potentially reversible lesion amenable to pharmacologic manipulations, and its progression to classic plexogenic arteriopathy in PPH has not been demonstrated, it is preferable to separate the pure form of IMH from the classic PPA, in which irreversible vascular lesions predominate. When strict criteria for diagnosis of IMH are applied, its incidence among adolescents and adults with PPH is between 2 and 4 percent (Table 1). Isolated medial hypertrophy is characterized by an increased thickness of the medial smooth muscle and duplication of elastic laminae (Fig l a [top]) in muscular arteries as well as the development of a well-formed smooth muscle layer (muscularization) in arterioles (Fig l b [bottom]). With long-standing disease, the medial smooth muscle may degenerate 3,4

12

12

Table 1—Types of Pulmonary Angiopathy in Five Series of Patients With PPH 1970 No. Patients

3

1980

156

40

2 2

1985

1

1989

2

1990

80

58

94

1 2

Arteriopathy (%) PPA

98 (63)

14 (35)

22 (28)

29 (50)

52 (55)

TPA

31(20)

12 ( 3 0 )

45 (56)

19(33)

11(12)

IMH

12

(8)

PVOD

5

(3)

CVH

5

(3)

5

(3)

3

(4)

1

(5)

5

(6)

7(12)

10(25)

2

(3)

1

(2)

3

(4)

1

(2)

(2)

6" (6)

Venopathy 1%)

Others

(%)t

2 2

(5)

25 (26)

" I n c l u d e s p a t i e n t s with m e d i a l h y p e r t r o p h y a n d intimal fibrosis, t Includes

patients

with

normal

arteriopathy, pulmonary arteritis,

pulmonary

vessels,

hypoxic

etc.

Histopathology of Primary Pulmonary Hypertension (Giuseppe G. Pietra)

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F I G U R E 2. Intra-acinar artery with severe c o n c e n t r i c laminar intimal fibrosis (Verhoeff van Gieson, original magnification x 5 5 0 )

ized by a variable admixture of medial hypertrophy, intimal lesions, and a variety of destructive lesions involving the entire arterial wall. " ' The intimal lesions are of three types: concentric laminar intimal fibrosis ( C L I F ) , eccentric intimal fibrosis ( E I F ) , and concentric nonlaminar fibrosis (CnLIF). Concentric laminar intimal fibrosis is the most reliable and constant marker of PPA. It is characterized by concentric, onionskin-like layers of pro1

41 2

3

F I G U R E la (top).

Medial hypertrophy o f pulmonary artery. T h e m e d i a

is t w i c e t h e n o r m a l in t h i c k n e s s ( V e r h o e f f van G i e s o n , original magnification x 2 0 0 ) . lb (bottom).

Muscularization o f intra-acinar

arteriole (Verhoeff van Gieson, original magnification x 6 0 0 ) .

and be replaced by fibrous tissue. Whether or not muscle atrophy accounts for failure of certain PPH patients to respond to vasodilators remains to be determined. PPA—Plexogenic Pulmonary Arteriopathy: In the absence of congenital heart diseases with left-toright shunts, PPA was considered the underlying pathologic condition of PPH and was characterized by the presence of the plexiform lesions. It is now recognized that PPA and plexiform lesions can occur in pulmonary hypertension secondary to the use of certain appetite suppressants, denatured rapeseed oil, and in some patients with HIV infect i o n . Nevertheless, PPA remains the most common type of pulmonary hypertensive arteriopathy in PPH patients, accounting for about 50 percent of the cases (Table 1). In the PPH-Registry experience, patients with PPA were on average 10 years younger than patients with the other types of arteriopathy, had rapidly progressive disease, and 75 percent were female subjects. It is still unclear whether the greater incidence of PPA in young women indicates different pathogenetic mechanisms or a greater reactivity to nonspecific hypertensive stimuli." Plexogenic pulmonary arteriopathy is character5

34

67

8

910

2

F I G U R E 3a (top). E c c e n t r i c intimal fibrosis o f muscular artery (Verhoeff van Gieson, original magnification x 1 8 0 ) . 3 b (bottom). Concentric nonlaminar fibrosis o f muscular artery. Although c o n c e n t r i c , this lesion lacks t h e laminar onionskin-like features shown in F i g u r e 2 (Verhoeff van Gieson, original magnification x 1 8 0 ) .

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liferated myofibroblasts and elastic fibers separated by a variable amount of proteoglycan-rich matrix (Fig 2). Eccentric intimal fibrosis is characterized by cushionlike eccentric patches of intimal fibrosis (Fig 3a [top]), whereas C n L I F is composed of circumferential intimal fibrosis (Fig 3b [bottom]). Both E I F and C n L I F are generally considered the result of the mural organization of thrombi or emboli and are present in variable proportion in both PPA and T P A (see below). Typically, a variable number of destructive lesions involving all the components of the arterial wall are present in PPA. These lesions include the plexiform lesion, the angiomatoid lesion, and necrotizing arteritis. As discussed above, the plexiform lesion was once considered essential for the diagnosis of PPA; - its correct diagnosis and pathogenesis have generated a great deal of controversy. Plexiform lesions are interesting pathologic entities associated with severe pulmonary hypertension. However, their diagnostic or prognostic significance has been overemphasized because they are not frequent and may be absent in a lung biopsy 2 7 1 1 , 2

3

4

7

sample. Plexiform lesions (Fig 4a [top]) involve muscular arteries near their origins from larger parent vessels. They are nodular lesions bulging outwards into the adventitia and surrounding lung parenchyma. Plexiform lesions are characterized by segmental destruction of the media and a plexus of proliferated microvessels, smooth muscle cells, and myofibroblasts. The arterial lumen proximal to the plexiform lesions is markedly narrowed by eccentric or concentric intimal fibroelastosis. Distally, the affected artery is thin-walled and dilated. Plexiform lesions are frequently confused with recanalized thrombi, also called "colander-like lesions." The latter are characterized by a proliferation of thinwalled microvessels separated by fibrous septa occluding the lumen of small muscular arteries with intact or nearly intact media (Fig 4b [bottom]). Moreover, recanalized thrombi are randomly distributed and are not associated with aneurysmatic dilatation of the affected vessels. 4

Dilatation or angiomatoid lesions are composed of dilated and tortuous thin-walled channels (Fig 5), often located distally to plexiform lesions. They are uncommon and of little diagnostic or hemodynamic significance. Necrotizing arteritis may be present in about 30 percent of cases of PPA. This condition is characterized by segmental necrosis of a muscular artery with leakage of fibrin and other plasma protein into the arterial wall (fibrinoid necrosis). As a result of arteritis and hemorrhage, the internal elastic lamina and the media may become encrusted with deposits of calcium and iron salts (siderosis). Unlike PPA caused by left-to-right shunts, marked segmental necrosis with infiltration of the arterial wall by neutrophils and mononuclear inflammatory cells is rare. Necrotizing arteritis is generally associated with severe pulmonary hypertension and is thought to be the precursor of plexiform lesions. TPA—Thrombotic Puhnonanj Arteriopathy: The 4

12

F I G U R E 4a (top). Plexiform lesion. N o t e t h e destroyed arterial wall (arrow) and bulging o f the lesion into the surrounding lung p a r e n c h y m a ( V e r h o e f f van G i e s o n , original magnification x 1 5 0 . 4b (bottom). Colanderlike lesion o r recanalized thromboembolus. T h e lumen is filled by small blood vessels s e p a r a t e d by fibrous septa. N o t e that the artery is not e x p a n d e d and its wall is intact ( h e m a t o x y l i n - e o s i n original magnification X 1 6 0 ) .

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F I G U R E 5 . Dilatation lesion c o m p o s e d o f thin-walled vessels (hematoxylin-eosin, original magnification X 8 0 ) .

Histopathology of Primary Pulmonary Hypertension (Giuseppe G. Pietra)

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diagnostic features of this type of hypertensive pulmonary arteriopathy are the presence of medial hypertrophy of small muscular arteries and arterioles with E I F , C n L I F , and colanderlike lesions (Fig 3, and 4). By definition, C L I F , plexiform, or dilatation lesions must be absent. Because E I F , C n L I F , and colanderlike lesions were considered the result of the mural organization of emboli, TPA was considered a secondary form of pulmonary hypertension caused by chronic silent microembolism. - This view has been challenged by investigators at the Mayo Clinic who found a high incidence of TPA in patients with PPH and by the PPH Registry where TPA was present in 33 percent of cases but was not associated with clinical or pathologic evidence of secondary pulmonary embolism. Thus, we prefer the designation "thrombotic pulmonary arteriopathy" to the term thromboembolic pulmonary arteriopathy to emphasize the importance of in situ thrombosis of small muscular arteries in the pathogenesis of this type of hypertensive pulmonary disease. A possible role of in situ thrombosis in the pathogenesis of pulmonary hypertension has been further suggested by recent studies showing biochemical evidence of platelet activation in patients with primary and secondary pulmonary hypertension. However, it is not known whether PPA and TPA represent two different aspects of the same disease. 3

4

1 1 3

2

14

Hypertensive

Pulmonary

Venopathy

Two types of lesions have been found in patients with PPH (Table 1): pulmonary veno-occlusive disease (PVOD) and chronic pulmonary venous hypertension (CVH). Only PVOD is considered a cause of PPH. Chronic pulmonary venous hypertension is secondary to clinically undiagnosed extrapulmonary obstruction to pulmonary venous flow. Although the cause of PVOD is unknown, similar lesions have been observed in patients treated with certain chemotherapeutic agents. Familial cases have also been reported. Pulmonary veno-occlusive disease was so designated because it was thought to be caused by a primary obstructive thrombotic disorder of the pulmonary venules and veins. As the name indicates, the histopathologic hallmark of this disease is the presence within pulmonary veins and venules of obstructive eccentric fibrous intimal pads and tortuous sinusoidal channels filling long segments of their lumens (Fig 6). Often the media of pulmonary veins show the development of a prominent medial muscle coat bounded by internal and external elastic laminae. As a consequence, the affected vessels closely resemble pulmonary arteries (arterialization) and the correct identification as veins is only pos-

F I C U R E 6 . P u l m o n a r y veno-occlusive disease. B r o a d acellular fibrous s e p t a c o n t a i n i n g e n d o t h e l i a l - l i n e d c h a n n e l s fill t h e l u m e n o f a p u l m o n a r y vein. N u m e r o u s h e m o s i d e r i n - l a d e n m a c r o p h a g e s are p r e s e n t in the adjacent alveolar spaces (Verhoeff van Gieson, original magnification x 1 6 0 )

sible by observing their location in the interlobular septa away from the airways. Venous obstruction is associated with marked congestion of alveolar capillaries that is sometimes very focal and sharply demarcated and thus may be confused with the lesions of pulmonary capillary hemangiomatosis (see below). Capillary congestion leads to interstitial and alveolar hemorrhages. Breakdown of extravasated red blood cells results in the accumulation of hemosiderin in alveolar macrophages, type 2 pneumocytes, and elastic laminae of blood vessels. The muscular pulmonary arteries show medial hypertrophy and often E I F or C n L I F . In contrast, C L I F or plexiform lesions are absent, and dilatation lesions and necrotizing arteritis may rarely o c c u r . The presence of severe arterial intimal fibrosis suggests that these lesions may not be secondary but rather the result of primary damage to both pulmonary arteries and veins. 418

18

15

16

17

F I G U R E 7. P u l m o n a r y capillary hemangiomatosis. T h e alveolar septa are markedly widened by proliferated capillaries. T h e alveolar epithelial c e l l s a p p e a r d a r k in t h e m i c r o p h o t o g r a p h b e c a u s e o f m a r k e d hemosiderin uptake (hematoxylin-eosin, original magnification x 8 0 ) .

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Pulmonary

Capillary

Hemangiomatosis

Circulation 1 9 8 9 ; 8 0 : 1 1 9 8 - 1 2 0 6

To my knowledge, only 12 cases of this extremely rare condition have been r e p o r t e d . The disease may occur spontaneously or in families with an autosomal recessive inheritance pattern. Pulmonary capillary hemangiomatosis (PCH) is characterized by the proliferation of thin-walled microvessels infiltrating the peribronchial-perivascular interstitium, the lung parenchyma (Fig 7), and the pleura. The proliferating microvessels infiltrate the walls of pulmonary veins of different diameter, with expansion of the media, destruction of the medial elastic fibers, and fibrous luminal obstruction of the affected vessels. The thin-walled microvessels are prone to bleeding, resulting in the accumulation of hemosiderin-laden macrophages in the alveolar spaces, and clinically, in hemoptysis. In addition, there is medial hypertrophy of muscular arteries and muscularization of the arterioles. Because of the presence of veno-occlusive lesions in PCH and the presence of localized capillary engorgement and proliferation in PVOD, some authors have suggested that the two entities may represent a spectrum of angiogenic pulmonary diseases. - 1921

21

412

4

12

21

3 Wagenvoort C A , Wagenvoort N. P r i m a r y pulmonary hypertension: a pathologic study o f t h e lung vessels in 1 5 6 clinically diagnosed cases. Circulation 1 9 7 0 ; 4 2 : 1 1 6 3 - 8 4 4 Kay M J , H e a t h D . Pathologic study o f unexplained pulmonary hypertension. H u m a n Pathol 1 9 8 5 ; 7 : 1 8 0 - 9 2 5 Rich S, Kaufmann E , L e v y P S . T h e effect o f high doses o f calciumblockers on survival in primary pulmonary hypertension. N E n g l J Med 1992; 327:76-81 6 W i d g r e n S, Kapanci Y. Menocilbedingte pulmonale H y p e r t o n i c V o r l a u f i g e m o r p h o l o g i s c h e E r g e b n i s s e fiber 8 p a t h o l o g i s c h anatomisch untersuchte F a l l e . Z Kreislauf-Forsch 1 9 7 0 ; 5 9 : 9 2 4 30 7 P i e t r a G G , Riittner J R . Specificity o f pulmonary vascular lesions in p r i m a r y pulmonary hypertension. Respiration 1 9 8 7 ; 5 2 : 8 1 - 5 8 G a r e i a - D o r a d o D, Miller D D , Garcia E J , Delcan J L , M a r o t o E , C h a i t m a n B R . An e p i d e m i c o f pulmonary hypertension after toxic r a p e s e e d oil ingestion in Spain. J Am Coll Cardiol 1 9 8 3 ; 1 : 1 2 1 6 - 2 2 9 Coplan N L , Shimony RY, l o a c h i m H L , Wilentz J R , P o s n e r D, Lipschitz A, et al. Primary pulmonary hypertension associated with h u m a n immunodeficiency viral infection. A m J M e d 1 9 9 0 ; 8 9 : 9 6 - 9 1 0 M e t r e SA, Palevsky H I , P i e t r a G G , Williams T M , B r u d e r E , Prestipino AJ, et al. Primary pulmonary hypertension in association with h u m a n i m m u n o d e f i c i e n c y virus infection: a possible viral etiology for s o m e forms o f hypertensive arteriopathy. Am R e v Respir Dis 1 9 9 2 ; 1 4 5 : 1 1 9 6 - 1 2 0 0 1 1 L o y d J E , Atkinson J B , P i e t r a G G , Virmani R, N e w m a n J H . H e t e r o g e n e i t y o f pathologic lesions in familial primary pulmonary hypertension. Am R e v Respir Dis 1 9 8 8 ; 1 3 8 : 9 5 2 - 5 7 1 2 Burke AP, F a r b A, Virmani R. T h e pathology o f primary pulmonary hypertension. M o d e m Pathol 1 9 9 1 ; 4 : 2 6 9 - 8 2

CONCLUSIONS

The pulmonary blood vessels have a limited repertoire of responses to injury. The histopathologic changes found at biopsy or autopsy in PPH represent the combined effect of advanced injury and repair. The challenge for the pathologist remains the identification of specific patterns of vascular lesions which identify subsets of patients with PPH. Open lung biopsy with qualitative description of vascular pathologic condition is no longer considered essential to make an accurate diagnosis of PPH. However, it could provide important information if quantitative data on vascular pathology are incorporated into clinical protocols evaluating new therapeutic modalities. REFERENCES 1 Bjornsson J , E d w a r d s W D , Kay J M , Rich S, K e m i s J , Schloo B , et al. P r i m a r y p u l m o n a r y hypertension: a histopathologic study o f 8 0 cases. M a y o Clin P r o c 1 9 8 5 : 6 0 : 1 6 - 2 5 2 P i e t r a G G , E d w a r d s W D , K a y J M , e t al. H i s t o p a t h o l o g y o f p u l m o n a r y hypertension: a qualitative and quantitative study o f p u l m o n a r y blood vessels from 5 8 patients in National H e a r t , L u n g , and Blood Institute, P r i m a r y P u l m o n a r y Hypertension Registry.

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1 3 F u s t e r V, Steele P M , E d w a r d s W D , Gersh B J , M c G o o n M D , F r y e R L . P r i m a r y p u l m o n a r y hypertension: natural history and t h e i m p o r t a n c e o f thrombosis. Circulation 1 9 8 4 ; 7 0 : 5 8 0 - 8 7 1 4 C h r i s t m a n n BW, M c P h e r s o n C D , N e w m a n J M , King JA, B e r n a r d G R , Groves B M , et al. An imbalance between the excretion o f t h r o m b o x a n e a n d p r o s t a c y c l i n m e t a b o l i t e s in p u l m o n a r y hypertension. N E n g l J M e d 1 9 9 2 ; 3 2 7 : 7 0 - 5 1 5 Joselson R, W a r n o c k M. Pulmonary veno-occlusive disease after chemotherapy. H u m a n Pathol 1 9 8 3 ; 1 3 : 8 8 - 9 1 1 6 Davies P, R e i d L . P u l m o n a r y veno-oeclusive disease in siblings: case report and m o r p h o m e t r i c study. H u m a n Pathol 1 9 8 2 ; 1 3 : 9 1 1 15 1 7 Wagenvoort C A , Wagenvoort N. T h e pathology o f pulmonary venoocclusive disease. Virchows Archiv [A] 1 9 7 4 ; 3 6 4 : 6 9 - 7 9 18 W a g e n v o o r t CA, Wagenvoort N, Takahashi T. Pulmonary venoocclusive-disease: involvement o f pulmonary arteries and review o f t h e literature. H u m a n Pathol 1 9 8 5 ; 1 6 : 1 0 3 3 - 4 1 1 9 W a g e n v o o r t C A . Capillary h a e m a n g i o m a t o s i s o f the lung. Histopathology 1 9 7 8 ; 2 : 4 0 1 - 0 6 2 0 M a g e e F, W r i g h t J L , Kay M J , P e r e t z D , D o n e v a n R, C h u r g A. Pulmonary capillary-hemangiomatosis. Am R e v Respir Dis 1 9 8 5 ; 132:922-25 2 1 L a n g l e b e n D , H e n e g h a n J M , B a t t e n AP, W a n g N S , F i t c h N , Schlesinger

RD,

et

al.

Familial

pulmonary

capillary

hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern M e d 1 9 8 8 ; 1 0 9 : 1 0 6 - 0 9 2 2 W a g e n v o o r t C A . L u n g biopsy s p e c i m e n s in t h e evaluation o f pulmonary vascular disease. C h e s t 1 9 8 0 ; 7 7 : 6 1 4 - 2 5

Histopathology of Primary Pulmonary Hypertension (Giuseppe G. Pietra)

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