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Home , Pneumothorax, Pulmonary hypertension

Pulmonary Vasculopathy in Idiopathic Spontaneous in Young Subjects

Pamela V. Cyr, MD; Lydia Vincic, MD; J. Michael Kay, MD

● Background.—We have encountered instances where 90% of cases, and pulmonary intimal fibrosis in 80% young subjects with idiopathic spontaneous pneumothorax of cases. In 95% of cases, the showed some fibrosis have been needlessly referred for investigation of pulmo- and chronic inflammation. There was a significant positive nary because surgical pathologists have mis- correlation between pulmonary medial thickness interpreted the significance of medial and in- and lung fibrosis and inflammation scores. timal fibrosis of muscular pulmonary in lung re- Conclusions.— medial hypertrophy section specimens. and intimal fibrosis of pulmonary arteries and pulmonary Methods.—We reviewed 20 cases of idiopathic sponta- are commonly seen in resected lung from pa- neous pneumothorax and determined the prevalence and tients with idiopathic spontaneous pneumothorax. The vas- severity of medial and intimal in the pulmonary cular lesions are probably secondary to chronic inflam- arteries and pulmonary veins. We correlated the vascular mation and fibrosis in the adjacent lung. They are not clin- changes with inflammation and fibrosis in the lung. ically significant and do not represent hypertensive pul- Results.—Pulmonary artery medial hypertrophy was monary . seen in 15% of cases, pulmonary artery intimal fibrosis in (Arch Pathol Lab Med. 2000;124:717–720)

he pathologic features of idiopathic spontaneous pneu- monary hypertension. Blocks of paraffin-embedded tissue were T mothorax (ISP) were first described in detail by Lich- retrieved from the surgical pathology files. The number of blocks ter and Gwynne in 1971.1 Vascular lesions were briefly available from each case ranged from 1 to 7 (mean 3.2). Sections stained with hematoxylin-eosin, the Miller elastic van Gieson mentioned, but their severity and extent were not as- 9 sessed. The occurrence of pulmonary vasculopathy in ISP method, and the Perls Prussian blue method were examined with a microscope equipped with a calibrated eyepiece microm- is not widely recognized; it is briefly mentioned in some eter. Each author examined about one third of the cases. All cases 2,3 4–6 textbooks of pulmonary pathology, but not in others. were subsequently reviewed by all the authors at a multiheaded These vascular lesions assume importance if surgical pa- microscope. A muscular pulmonary artery was deemed suitable thologists misinterpret their significance. Some young pa- for morphometry if the largest diameter was not twice as great tients with ISP have needlessly been referred for investi- as the perpendicular diameter.10 gation of because medial hyper- For each suitable artery, we took 2 measurements of the exter- trophy and intimal fibrosis of muscular pulmonary arteries nal diameter to get an average. We obtained 4 equidistant mea- have been misinterpreted as hypertensive pulmonary vas- surements of the media to determine the average medial thick- cular disease.7,8 Because the pulmonary vasculopathy of ness and expressed it as a percentage of the external diameter. A ISP is poorly characterized and not widely recognized, we value for the mean percentage medial thickness in each case was obtained by totaling all the percentage medial thicknesses and determined the prevalence and severity of medial and in- dividing the sum by the number of vessels examined. It is well timal lesions in the pulmonary arteries and pulmonary established in the literature that the mean medial thickness of veins of young subjects with ISP. We investigated the muscular pulmonary arteries in normal adults ranges between pathogenesis of the vasculopathy by correlating the vas- 3% and 7%.10–12 There is no difference between males and females cular changes with inflammation and fibrosis in the lung. or between different parts of the same lung.12 Pulmonary artery medial hypertrophy (PAMH) was determined to be absent if the METHODS mean medial thickness was less than 7%, mild if between 7% and We reviewed all cases of ISP in younger than 40 years 10%, moderate if between 11% and 15%, and severe if greater 13 who underwent at St Joseph’s Hospital between March than 15%. If pulmonary artery intimal fibrosis (PAIF) was pres- 1995 and June 1997. Twenty-three cases were retrieved. One was ent, the maximum thickness was measured and expressed as a excluded owing to a history of deep vein and pul- percentage of the average internal diameter. A value for the mean monary , and 2 were excluded because tissue sections intimal thickness in each case was obtained by totaling all the had fewer than 10 muscular pulmonary arteries suitable for mor- percentage intimal thicknesses and dividing the sum by the num- phometry. In the remaining 20 cases, the following information ber of arteries measured. Pulmonary artery intimal fibrosis was was obtained: age, gender, and history. The clinical find- graded as mild if less than 20%, and severe if 20% or greater.14 ings, electrocardiogram reports, and chest radiography reports The slides were also examined for muscularization of pulmo- were reviewed to exclude underlying pulmonary disease and pul- nary (a complete muscular media with internal and external elastic laminae in pulmonary arterial vessels less than 100 ␮m in diameter11), pulmonary vein medial hypertrophy (dis- Accepted for publication November 2, 1999. tinct internal and external elastic lamina with intervening smooth From the Department of Laboratory Medicine, St Joseph’s Hospital, muscle around the circumference of a vein), pulmonary vein in- and the Department of Pathology and Molecular Medicine, McMaster timal fibrosis, hemosiderin-laden macrophages, smokers’ respi- University, Hamilton, Ontario, Canada. ratory (respiratory distended by mac- Reprints: J. Michael Kay, MD, Department of Pathology, St Joseph’s rophages containing smokers’ pigment combined with mural Hospital, 50 Charlton Ave E, Hamilton, Ontario, Canada L8N 4A6. thickening15), and reactive eosinophilic pleuritis.16 The severity Arch Pathol Lab Med—Vol 124, May 2000 Idiopathic Spontaneous Pneumothorax—Cyr et al 717 Table 1. Pulmonary Vascular Pathology in 20 Cases of Idiopathic Spontaneous Pneumothorax Case No. 123456789 Muscular pulmonary arteries* No. examined 15 11 23 14 17 12 28 28 10 No. with MH 12 13715532 Medial thickness, % Mean 12.4 4.0 4.3 7.0 4.1 6.5 5.2 4.1 5.2 Range 9.7–15.2 1.6–10.1 0.7–11.0 1.9–14.3 2.2–47.3 2.9–11.8 0.9–10.8 0.8–9.5 2.1–8.5 No. with IF 13 8 20 10 9 8 14 23 2 Intimal thickness, % Mean 28.7 14.9 24.1 22.5 25.2 18.1 12.1 31.6 6.0 Range 11.0–82.0 1.5–44.0 3.4–55.0 10.4–47.0 7.7–47.0 5.0–36.0 2.1–34.5 2.2–43.0 3.4–8.6 Pulmonary veins No. examined 39 16 18 19 18 13 43 29 8 No. with MH 000000000 No. with IF 31 0 9 16 11 7 34 15 2 * MH indicates medial hypertrophy; IF, intimal fibrosis.

and extent of fibrosis and chronic inflammation were assessed by 0.53; P Ͻ .01). There was no significant correlation be- a modified semiquantitative method designed for use in idio- tween PAIF and the lung fibrosis and inflammation scores. pathic pulmonary fibrosis.17 The data were subjected to multiple There was no significant correlation between smokers’ re- regression analysis, and Pearson product moment correlation co- spiratory bronchiolitis and PAMH or PAIF. Reactive eosin- efficients (r) were calculated.18 ophilic pleuritis was identified in 15 cases (75%). RESULTS COMMENT The patients’ ages ranged from 17 to 39 years, with a mean of 26 years. Fifteen (75%) of the patients were male; We identified pulmonary vasculopathy in 18 (90%) of 16 (80%) had a history of smoking. Five of the patients the 20 cases of ISP included in this study. The most fre- developed contralateral ISP within 2 years of the initial quent lesions were PAIF and pulmonary vein intimal fi- surgery, and tissue from the subsequent surgery was in- brosis, which were identified in 18 (90%) and 16 (80%) cluded in the study. The number of muscular pulmonary cases, respectively. In 6 cases (30%), PAIF was graded as arteries examined in each case ranged from 10 to 47, with severe because the mean intimal thickness exceeded 20% a mean of 17.9. The pulmonary vascular pathology in each of the internal diameter. Pulmonary artery intimal fibrosis case is summarized in Table 1. corresponds to the endarteritis encountered by Lichter and Pulmonary artery medial hypertrophy was seen in 3 Gwynne1 in 45% of their 20 cases and to arteriolar intimal cases (15%); it was mild in 2 and moderate in 1 (Figure fibrosis described by Cottin et al19 in 39% of their recent 1). In the case with moderate PAMH, the mean medial series of 79 cases of ISP. In 20% of Lichter and Gwynne’s thickness was 12.4%. In the series as a whole, there was a cases the endarteritis was graded as marked or severe. great variation in the average medial thickness of individ- Neither of these articles described pulmonary vein intimal ual muscular pulmonary arteries. The highest value ob- fibrosis or PAMH, which we identified in 3 cases (15%). tained was 47.3%. Pulmonary artery intimal fibrosis was We believe the reason we encountered a high prevalence present in 18 cases (90%); it was mild in 12 and severe in of PAIF and identified PAMH and pulmonary vein intimal 6 (Figure 1). It was both eccentric and concentric. The fibrosis not described by other workers1,19 is that we used maximum mean intimal thickness observed was 31.6%. In an elastic van Gieson stain, which is more sensitive in de- the series as a whole, there was a wide range of intimal tecting vascular pathology than hematoxylin-eosin. We thicknesses in individual muscular pulmonary arteries. did not encounter the eosinophilic vascular infiltration The highest value measured was 82%. Muscularization of that Luna et al20 identified in a small proportion of pa- pulmonary arterioles was absent. In 1 case, some of the tients with ISP and reactive eosinophilic pleuritis. pulmonary veins showed medial hypertrophy. Pulmonary In 19 (95%) of our cases, the showed some fibrosis vein intimal fibrosis was present in 16 cases (80%) (Figure and chronic inflammation, which in most cases was patchy 2). The pulmonary vascular lesions were randomly dis- and mild. The significant positive correlation between the tributed in the lung tissue. Hemosiderin-laden macro- mean pulmonary artery medial thickness and the lung fi- phages were seen in 3 cases (15%). Smokers’ respiratory brosis and chronic inflammation scores suggests that in- bronchiolitis was present in 13 cases (65%). In 19 cases, flammation and fibrosis may play a role in the develop- the lung showed some fibrosis and chronic inflammation ment of PAMH. In patients with interstitial pulmonary (95%) (Table 2). The fibrosis was generally scar tissue in a fibrosis, the muscular pulmonary arteries and pulmonary subpleural location. The chronic inflammatory infiltrate veins frequently show severe medial hypertrophy and in- was generally mild, consisted predominantly of lympho- timal fibrosis.6,12,13 Cigarette smoking has emerged as a cytes and plasma cells, and was generally in the vicinity major for the development of ISP19,21 and is like- of fibrosis. A significant positive correlation was observed ly to play an important role in the pathogenesis of pul- between pulmonary artery medial thickness and the lung monary vasculopathy. Eighty percent of our patients had fibrosis (r ϭ 0.57; P Ͻ .01) and inflammation scores (r ϭ a history of smoking, and 65% had smokers’ respiratory 718 Arch Pathol Lab Med—Vol 124, May 2000 Idiopathic Spontaneous Pneumothorax—Cyr et al Table 1. Extended Case No. 10 11 12 13 14 15 16 17 18 19 20

10 21 10 16 47 13 10 13 15 30 15 4180511413407

6.2 9.5 2.4 5.4 5.7 5.7 5.4 5.8 6.3 3.1 6.3 2.2–13.4 5.0–13.4 1.5–5.7 2.3–10.6 1.7–13.6 3.1–10.1 3.7–8.2 3.6–8.3 4.2–9.6 1.7–6.4 2.9–9.1 0 13 6 15 19 10 9 4 13 14 0

. . . 15.7 8.4 23.1 18.6 16.7 15.2 10.0 15.4 12.3 ...... 7.4–18.8 3.4–16.1 6.1–57.0 2.7–37.0 9.9–25.5 7.5–36.7 5.2–15.0 5.7–27.1 3.5–34.0 . . .

31 59 11 11 38 16 6 25 54 18 28 00050000000 02124112110219450 0

Figure 1. Muscular pulmonary artery showing medial hypertrophy and eccentric intimal fibrosis (Miller elastic van Gieson, original magnification ϫ460). Figure 2. Pulmonary vein showing eccentric intimal fibrosis (Miller elastic van Gieson, original magnification ϫ186). bronchiolitis. Studies have demonstrated increased num- shown that constituents are mitogenic for arterial bers of inflammatory cells, especially macrophages, in the cells,24 and that leukocytic infiltration of small airways of smokers.22,23 These macrophages release vascular walls stimulates the migration of smooth muscle chemotactic factors, resulting in accumulation of neutro- cells into the intima with the formation of plaques.25 phils in the small airways.22 Experimental studies have Several groups of investigators have examined the struc- Arch Pathol Lab Med—Vol 124, May 2000 Idiopathic Spontaneous Pneumothorax—Cyr et al 719 Table 2. and Chronic Inflammation in the Lung Parenchyma of 20 Cases of Idiopathic Spontaneous Pneumothorax* Grade (% Tissue Involvement) 0 1 2 3 4 5 (Absent) (Occasional) (Ͻ25%) (25–49%) (50–75%) (Ͼ75%) Fibrosis (n ϭ 20) 0116210 Chronic inflammation severity (n ϭ 20)1104320 Chronic inflammation extent (n ϭ 20)1124300 * Fibrosis and chronic inflammation are graded using a modification of the method of Cherniack et al.17

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Reactive eosinophilic pleuritis. Arch Path- ol Lab Med. 1977;101:187–191. rophages in 1 (5%) of their 20 cases of ISP. These macro- 17. Cherniack RM, Colby TV, Flint A, et al. Quantitative assessment of lung phages presumably resulted from localized vascular dam- pathology in idiopathic pulmonary fibrosis. Am Rev Respir Dis. 1991;144:892– age with resulting hemorrhage. There was no indication 900. 18. Daly LE, Bourke GJ, McGilray J. Interpretation and Uses of Medical Sta- of infarction. tistics. 4th ed. Oxford, England: Blackwell; 1991:157–178. Pulmonary artery medial hypertrophy and PAIF occur 19. Cottin V, Streichenberger N, Gamondes J-P, Thevenet F, Loire R, Cordier J- in pulmonary hypertension, but it is important for pa- F. Respiratory bronchiolitis in smokers with spontaneous pneumothorax. Eur Res- pir J. 1998;12:702–704. thologists to understand that the presence of medial hy- 20. Luna E, Tomashefski JF Jr, Brown D, Clarke RE, Kleinerman J. 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