Interstitial Lung Disease in Polymyositis and Dermatomyositis Clinical Features and Prognosis as Correlated with Histologic Findings1,2
HENRY D. TAZELAAR, ROBERT W. VIGGIANO, JUDITH PICKERSGILL, and THOMAS V. COLBY
Introduction SUMMARY Open lung biopsies from 14patients and autopsy tissue from one patient with polymyoSince its original description in 1956(1), sitis/dermatomyositis were reviewed In an attempt to correlate histologic features with clinical, rathe association between interstitial lung diographic, and prognostic variables. Three major groups based on histologic patterns were Identidisease and polymyositis and dermatofied: bronchiolitis obliterans organizing pneumonia (BOOP),usual Interstitial pneumonia (UIP), and myositis has become well established (2). diffuse alveolar damage (DAD). Patients with BOOP had a more favorable prognosis than did paIn many reports (3-13), the diagnosis of tients with UIR Patients with DADhad a uniformly poor prognosis. One patient had a cellular Interstitial pneumonia and did well. Histologic subclassification of the Interstitial lung disease proved to interstitial lung disease has been based be a better predictor of survival than did the radiographic appearance or the clinical presentation. primarily on a combination of chest raThese findings suggest that there Is a broader range of histologic findings In polymyositisdiograph abnormalities with pulmonary dermatomyositis than Is suggested In the literature and that subclassification may be useful ~r function tests. In some, there has been prognosis. AM REV RESPIR DIS 1990; 141:727-733 pathologic confirmation (14-29). The histologic descriptions have usually been , cursory, with most cases described as "pulmonary fibrosis." An effort has been After review of the pathologic findings, an made in occasional studies (30-32) to sep- suIts of anti-J 0 antibody (36-40) status were not available for any patient. Pulmonary attempt was made to correlate the histologic arate patients into histologically favorfunction tests when available were all per- patterns with patient outcome and response able and unfavorable groups. However, formed at the Mayo Clinic pulmonary func- to treatment. subclassification of interstitial lung dis- tion laboratory. Pulmonary function abnorease has proved useful with other more malities were graded as follows: mild < 80070 Results common types of collagen vascular dis- and ~ 60070 predicted; moderate < 60070 and Clinical Data ease, e.g., systemic lupus erythematosus ~ 40070 predicted; severe < 40070 predicted. In 14patients, the pathologic material con- A summary of the clinical data as cor(33) and rheumatoid arthritis (34). We have undertaken a retrospective study to sisted of an open lung biopsy. In one patient related with the pathologic findings is assess the prognostic value of histologic with a fulminant course, autopsy tissue was shown in table 1. Eight patients presentexamination among patients with inter- all that was available but reflected acute in- ed with interstitial lung disease and othstitiallung disease and dermatomyositis- terstitiallung disease. Four additional patients er manifestations of PM-OM simultanewere excluded because of the presence of ously; in five patients PM-OM had been polymyositis. mixed connective tissue disease (two patients), diagnosed 1 to 36 months prior to the childhood dermatomyositis (one patient), and development of their lung disease, and Methods the finding of small airways disease on open in two patients the lung disease precedThe clinical records and pathologic material lung biopsy (one patient) thought to be related the diagnosis of PM-OM by 1 and 6 of all patients with a diagnosis of polymyosi- ed to the patient's smoking history rather than months. All patients had an abnormal tis and/or dermatomyositis (PM-OM) seen to PM-OM. Follow-up autopsy material was chest radiograph at the time of diagnoat the Mayo Clinic in whom an open lung available in Patients 5, 10, 12, and 15. biopsy had been performed for evaluation of The histologic sections were reviewed with- sis, most having bilateral interstitial ininterstitial lung disease from 1965to June 1989 out knowledge of the patient's clinical course. filtrates, often greatest in the lower lobes. were reviewed. Additional cases were obtained The following histopathologic patterns of in- The results of pulmonary function tests from the pathology files of one of the authors terstitiallung disease were utilized (34): lym- (PFT) were available for 10patients. Two (TVC). Clinical histories and follow-up information on these latter cases were obtained from referring physicians. Cases were accepted if the diagnosis of polymyositis or dermatomyositis could be confirmed using the criteria of Bohan and Peter (35). Patients were excluded from the study if there had been a diagnosis of a second connective tissue disease at the time of presentation with pulmonary disease, a diagnosis of malignancy, a pulmonary infection, or if the tissue for pathologic examination was considered inadequate. This yielded a total of 15 patients. Patients 2 and 4 have been reported previously (19). The re-
phoid hyperplasia, usual interstitial pneumonia (VIP), desquamative interstitial pneumonia, cellular interstitial pneumonia (CIP), bronchiolitis obliterans organizing pneumonia (BOOP), diffuse alveolar damage (DAD), small airways disease (41-43), and nonspecific scarring. The patients could usually be placed in one category or another, although occasionally two patterns were observed in the same patient. In addition, because of the suggestion in the literature that the degree of "cellularity" (31) may correlate with prognosis, the overall cellularity of the patients was graded from minimal to marked (1 to 3 +).
(Received in original form June 16, 1989 and in revised form August 8, 1989) 1 From the Departments of Pathology and Laboratory Medicine and Internal Medicine, Mayo Clinic, Rochester, Minnesota, and the Department of Medicine, Kaiser Permanente, Santa Clara, California. 2 Correspondence and requests for reprints should be addressed to Henry D. Thzelaar, M.D., Department of Pathology, Mayo Clinic, Rochester, MN 55905.
727
TAZELAAR, VIGGIANO, PICKERSGILL, AND COLBY
728 TABLE 1
CLINICAL DATA AND CORRELATION WITH PATHOLOGY AND PATIENT STATUS· Mode of Presentation Patient No.
2
3
4 5
6
7
8
9
10
11 12 13 14
15
Age (yr)
Sex
47
F
53
19
31 32
73
57
55
72
61
40 57 67 41
58
F
F
M F
M
F
F
F
M
M M F M
F
Polymyositis Dermatomyositis
Pulmonary Symptoms
Time to ILD Dx· (months)
Fever, chills, malaise, prox. muscle weakness
Productive cough
0
Prox. muscle weakness
Dyspnea
0
Prox. muscle weakness, arthralgias, rash
Cough, fever
Prox. muscle weakness
Dyspnea
Rash, muscle weakness, arthralgias
Dyspnea
Muscle weakness, rash, dysphagia, hoarseness
Dyspnea
Muscle weakness, rash
Dyspnea on exertion, cough
Malar rash, muscle weakness
Dyspnea, hoarseness
6
Myalgias, arthralgias, muscle weakness
Dyspnea
0
Heliotrope rash, prox. muscle weakness
Dyspnea on exertion
3
Malaise, weight loss, rash
Productive cough
0
Rash, weight loss, weakness
Dyspnea
0
Rash, weakness
Dyspnea
Rash, weakness
Arthralgias, weakness
-1
0 2
-6
36
0
Dyspnea
Dyspnea
Length of Pulmonary Symptoms (wk)
>3
>3
3 3
>3
3
>3
>3 >3 >3 3
Chest Radiograph
Pathology (Cellularity)
Bilateral interstitial infiltrates
BOOP
Diffuse bilateral interstitial infiltrates greater in bases
BOOP
Bilateral nodular infiltrates
BOOP
Bibasilar slightly nodular infiltrates
BOOP
Bilateral basilar interstitial infiltrates
BOOP
Bilateral interstitial infiltrates, greatest in bases
BOOP
Treatment
Patient Status
Steroids
A&W 7 yr
Steroids
A&W 2 yr
Steroids
Died 8 days after OL BxARDS
Steroids
A&W 18 yr
Steroids methotrexate
Died 4 wk after OL Bx- fever, air leak
Prednisone
Alive, 14 months with dyspnea
(2+)
(2+)
(3+)
(3+) (3+)
(3+)
Bilateral interstitial infiltrates, greatest in lower lobes
Steroids immuran methotrexate
Alive 5 yr on O2
(2+)
Increased interstitial markings, greater in bases
UIP
Steroids
(2+)
Died 13 days after OL Bx-MI, ARDS
Diffuse interstitial and alveolar infiltrates &lARDS-like"
Steroids
(2+)
Died 4 wk after OL Bx. No details
Steroids cytoxan plasmapheresis
Died 4 wk after OL Bx-ARDS
UIP
UIP
Diffuse reticulonodular process
(1 +)
Scattered bilateral infiltrates
(3+)
Steroids methotrexate
Alive, 6 yr on disability
Diffuse interstitial infiltrates
DAD
Steroids
(3+)
Died 6 wk of respiratory failure
Diffuse bilateral infiltrates
Steroids
(1 +)
Died 4 wk of respiratory failure
Steroids
Died 1 wk of respiratory failure
Steroids chlorambucil
Died 7 yr of leukemia
Bilateral infiltrates with perihilar accentuation Interstitial infiltrates in left base
UIP
UIP
DAD DAD
(2+) CIP
(3+)
Definition of abbreviations: Ii_D = interstitial lung disease; Ox = diagnosis; A&W = alive and well; OL Sx = open lung biopsy; ARDS = adult respiratory distress syndrome; MI = myocardial infarct; SOOP = bronchiolitis obliterans organizing pneumonia; UIP = usual interstitial pneumonia; DAD = diffuse alveolar damage; CIP = cellular interstitial pneumonia. * Time to development of interstitial lung disease from diagnosis of pOlymositis-dermatomyositis.
patients had normal PFT (Patients 7 and 10),two had a mild decrease in TLC (Patients 6 and 11), three had a moderate decrease in TLC (Patients 2, 4, and 8), and two had a severe reduction in TLC (Patients 5 and 15). Two patients (Patients 7 and 10)had mild diffusing abnormalities, one a moderate diffusing abnormality (Patient 6), and one a severe reduction in diffusing capacity (Patient 8). In addition, Patient 6 also had a moderate decrease in FEV t •
Pathologic Findings The following patterns of interstitial lung disease were identified in this group of patients: BOOP, VIP, DAD, and CIP. BOOP was the" predominant finding in six patients. The hallmark of BOOP (figure 1)was the presence of patchy foci of organizing pneumonia and an associated bronchiolitis obliterans with granulation tissue filling bronchioles and alveolar ducts. The degree of accompanying interstitial inflammation varied from
minimal (1+) to marked (3 +) (table 1), consisting of lymphocytes, macrophages, and plasma cells. Lymphoid follicles without germinal centers were identified in three patients. Small numbers of neutrophils in alveoli and in the interstitium were usually present (71070). Eosinophils were present in two patients. Associated findings included: reactive type II pneumocytes (five patients), alveolar edema (three patients), obstructive changes with foamy macrophages in alveolar spaces
INTERSTITIAL WNG DISEASE IN POLYMYOSITIS AND DERMATOMYOSITIS
729
and plasma cells being most numerous. Clusters of macrophages within the air spaces similar to those seen in desquamative interstitial pneumonia were identified focally in three patients. The autopsy material from Patient 10 showed diffuse alveolar damage superimposed on a VIP pattern. Three patients had DAD, two on the basis of an open lung biopsy, and one (Patient 13) on the basis of autopsy material obtained 1 wk after presentation. These patients had damaged alveolar lining cells, hyaline membranes (figure 3), intra-alveolar edema, and focal hemorrhage. The interstitium was widened with edematous . m ucopolysaccha ride-rich connective tissue. Autopsy examination of the lung in Patient 12 showed diffuse bilateral Pseudomonas aeruginosa and cytomegalovirus pneumonia. In Patient 15, the pattern was a nonspecific cellular interstitial pneumonia (figure 4) with interstitial accumulations of mononuclear cells, predominantly lymphocytes and plasma cells with minimal fibrosis and no significant bronchiolitis. At autopsy 7 yr later, the lungs showed diffuse alveolar damage.
Clinicopathologic Correlations Of the patients with BOOP, four of six are alive and well, whereas of the patients with VIP, 3 of 5 have died. All of the patients with DAD died. The patient with CIP had resolution of her pulmonary symptoms. However, she developed acute myelogenous . leukemia thought to be related to her chlorambucil therapy at 81 months. She died with the adult respiratory distress syndrome.
Fig. 1. Bronchiolitis obliterans organizing pneumonia (Patient 3). Areas of relatively normal lung (top) interspersed with areas of intra-alveolar granulation tissue. Overall cellularity , 3+. Another field (bottom) shows a terminal bronchiole whose lumen is occluded by edematous granulation tissue. Arrows show the bronchiolar muscularis (hematoxylin-eosin stain; top: x 64; bottom: x 160).
(one patient), microthromboemboli (one patient), and a small pulmonary infarct (one patient). A pattern of VIP was identified in five patients (figure 2). Areas of normal lung were interspersed with interstitial scarring and honeycombing. The air spaces
were variously lined by columnar epithelium (so-called bronchiolization), type I or II pneumocytes (occasionally reactive), or metaplastic squamous cells. The degree of associated interstitial inflammation was also variable, but most were moderately cellular, with lymphocytes
Discussion The incidence of pulmonary disease in the PM-OM complex is reported to be as high as 45% (44). Someofthepulmonary manifestations (table 2) are the result of aspiration secondary to dysphagia and muscle weakness. However, interstitial lung disease thought to be related to the underlying immunologic abnormalities present may occur in 5 to 30070 of patients, and in many cases dominates the clinical course of the patients. However, there have been few studies describing the lung disease in detail (30-32), and none according to currently accepted classification schemes. We have studied a group of patients with PM-OM who underwent open lung biopsy and have attempted to categorize the histologic patterns seen. We have
730
TAZELAAR, VIGGIANO, PlCKERSGILL, AND COLBY
Fig. 2. Usual interstitial pneumonia (Patient 7) with areas of mildly fibrotic parenchyma (upper right) adjacent to an area of densely scarred lung (lower left). There is little intra-airway or intra-alveolar organization . Overall cellularity, 2 + (hematoxylin-eosin stain; magnification: x 40).
found a wider spectrum of interstitial lung disease than a perusal of the literature would suggest. In our opinion, the generic "chronic interstitial pulmonary fibrosis" does not capture the spectrum of disease and its implications for patient outcome. The clinical presentation of patients with interstitial lung disease associated with PM-DM is variable. Classically, PM-DM affects women twice as often as men (2), and our series reflects this sex distribution (nine women, six men). Patients with interstitial lung diseasehave been divided into three groups accord-
ing to their presenting symptoms (19, 25): those with apparently aggressivelung disease similar to patients with the Hamman-Rich syndrome, those who present with more slowly progressive dyspnea on exertion, and those without pulmonary symptoms but with either an abnormal chest radiograph or pulmonary function tests. We did not encounter asymptomatic patients, but such patients might not be subjected to open lung biopsy as readily. Wedid have four patients with a rapid onset of pulmonary symptoms, all four of whom died relatively quickly, and 11 patients with a slowerpresentation of whom
approximately 40070 died (table 1).Therefore, although those patients who do present with a rapidly progressive downhill respiratory course fare poorly, those with a slower progression of pulmonary symptoms have a variable outcome. The results of our study suggest that the histologic features on open lung biopsy may be better predictors of patient outcome than either the radiographic findings or the clinical presentation. We identified three main histologic patterns of interstitial lung disease occurring in thesettingofPM-DM: BOOP, VIP, and DAD. These patterns have all had their clinical course and outcome described both with and without an associated collagen vascular disease(33). A clear-cutassociation with the specific histologic patterns and PM-DM, however, is more difficult to ascertain, for most of the studies have had relatively cursory descriptions of pathologic findings and have focused on the degree of fibrosis and cellularity rather than on a specific pattern. Patients with BOOP appeared to have the best prognosis, with a 67% survival rate. This figure is similar to that for patients with BOOP unassociated with collagen vascular disease as reported by Epler and coworkers (44). In that same study, however, patients with BOOP in the setting of a collagen vascular disease appeared to have a worse prognosis, as 500/0 died. In contrast, Yousem and colleagues (34) found that patients with rheumatoid arthritis and BOOP fared relatively well(80% survival rate). Schwarz and associates (31) suggested that some cases ofBOOP (called organizing pneu monia in their study) might progress to VIP. We did not find this in our study, although one of our patients did develop the adult respiratory distress syndrome in the immediate postoperative period.
TABLE 2 PULMONARY MANIFESTATIONS OF POLYMYOSITIS-DERMATOMYOSITIS 1. Aspiration pneumonia 2° to dysphagia 2. Ventilatory insufficiency 2° to muscular weakness 3. Interstitial lung disease Usual interstitial pneumonia Bronchiolitis obliterans organizing pneumonia Diffuse alveolar damage Miscellaneous patterns 4. Drug-induced reaction, e.g., methotrexate 5. Malignancy, primary or metastatic 6. Pleural effusions 7. Opportunistic infection 8. Pulmonary hypertension (25) 9. Spontaneous pneumothorax (52) 10. Pulmonary alveolar proteinosis (53)
TABLE 3 OPEN LUNG BIOPSY HISTOLOGIC FINDINGS CORRELATED WITH CLINICAL OUTCOME: LITERATURE REVIEW· AND CURRENT SERIES COMBINEDt
Alive Dead Survival, % Combined series Current series
BOOP
UIP
DAD
CIP
8 (2 yr-18 yr) 4 (8 d-10 yr)
9 (4 mo-6 yr) 15 (13 d-26 mol
1 (3 mol 3 (4 wk-5 mol
1 (NA)* 1 (7 yr)
66
37 40
25 0
50 100
66
For definition of abbreviations, see table 1. • References: BOOP-Schwarz, 1976,3 (cases), Salmeron, 1961 (2), Shlavi, 1984 (1); UIP-Mllls, 1956 (1), Thompson, 1970 (1), Duncan, 1974 (1), Park, 1975 (1), Schwarz, 1976 (3), Bonafe, 1981 (1), Hanawa, 1981 (1), Salmeron , 1981 (2), Takizawa, 1987 (8); CIP-Webb, 1972 (1); DAD-Sandbank, 1966 (1), Weaver, 1968 (1). t Numbers in parentheses refer to range of follow-up lime . (d = days; wk weeks; me - months; yr = years). Not available.
=
*
INTERSTITIAL WNG DISEASE IN POLYMYOSITIS AND DERMATOMYOSITIS
ig. 3. Diffuse alveolar damage (Patient 14) with markedly distorted architecture and widened edematous alsolar septa containing moderately inflamed (cellularity, 2 +) granulat ion tissue. The alveoli (bottom) contain ansely eosinophilic hyaline membranes (arrows) . There are moderately reactive type II pneumocytes focally Irrowheads) (hematoxylin-eosin stain: top: x 64; bottom: x 160).
Patients with VIP appeared to have a oorer prognosis (33070 survival), alhough our numbers are small . This is ot unexpected given the poor prognois of VIP unassociated with PM-DM. lis interesting to note, however, that alrough the course of two of our patients as been typical for VIP (slowly progres-
sive disease resulting in O2 dependency and disability), three patients died rapidly after open lung biopsy. At least two developed the adult respiratory distress syndrome, in addition to the patient with BOOP who developed a similar postoperative syndrome. Perhaps the underlying collagen vascular disease, muscle
731
weakness, and immunosuppression all contribute to a significant surgical risk in this group of patients. Although there is a suggestion from the literature that some patients with PMDM may develop idiopathic adult respiratory distress syndrome (Hamman-Rich syndrome, acute interstitial pneumonia) (14, 15), we have been able to confirm this histologically as manifested by a pattern of DAD. These patients all died, despite immunosuppressive therapy. This prognosis is also in keeping with the process of DAD unassociated with collagen vascular disease (45). We also identified one less well-characterized pattern of interstitial lung disease in PM-DM, a nonspecific CIP similar to what has been seen in other collagen vascular diseases (33,34). Our patient with CIP did well from a pulmonary status for 7 yr, but then died of a treatmentinduced leukemia. This is similar to the finding of Yousem and coworkers (34) in patients with rheumatoid arthritis in which all 10 patients with this pattern fared well. Pulmonary hemorrhage or vasculitis was not seen in this group of patients, although there is a well-described association of this with other collagen vascular diseases (33), particularly systemiclupus erythematosus. Several previous studies (30, 31) have suggested that the degree of tissue cellularity correlates positively with prognosis in this group of patients. Our findings show that patients with minimal interstitial cellularity/inflammation may not do well (all three died), but that having a markedly cellular specimen is no guarantee of a favorable outcome. We would prefer to emphasize the histologic pattern, which shows better correlation with patient outcome than a nonspecific designation such as degreeof "cellularity." We have attempted to categorize the type of interstitial lung disease occurring in patients reported in the literature who have had open lung biopsies and com bined these with our own results. This combined series yielded a total of 42 patients. The histologic features as correlated with clinical outcome are shown in table 3. The survival figures reflect a trend similar to that found for our group of patients analyzed alone, supporting the utility of this histologic classification for patients with PM-DM. The role of open lung biopsy in patients with PM-DM is debatable and is dependent on the clinical situation. The mainstay of therapy for both the inter- .
TAZELAAR. VIGGIANO. PICKERSGILL, AND COLBY
732
chial biopsy, bronchoalveolar lavage, and open lung biopsy. If an open lung biopsy is performed, the results of our study may be of use in predicting prognosis. Acknowledgment The writers thank Michelle Thrner for secretarial assistance and the clinicians and pathologists who assisted them in gathering data: Grant Cannon, M.D., Robert D. Coye, M.D., Jonathon Ellman, M.D., Stephen Hathway, M.D., Kenneth Hirsch, M.D., William Kyle, M.D., Martin H . Matthews, M.D., Daniel G. Remick, M.D., Norman Rosenstock, M.D., Leonard Valentino, M.D., Bernhard Votteri, M.D., and William H. Winchell , M.D.
References
Fig. 4. Cellular interstitial pneumonia (Patient 15). Well-preserved putrnonary architecture with moderate to marked (bottom) interstitial chronic inflammation. particularly along bronchovascular routes (hematoxylin-eosin stain; top: x 40; bollom: x 160).
stitial lung disease and the underlying collagen vascular disease in patients with PM-DM has been steroids. There have also been reports of successful treatment with other immunosuppressive agents, e.g.,azathioprine (46), cyclophosphamide (47), and cyclosporine (48). All patients in our series and virtually all reported patients have been treated with immunosuppressive agents. Our results are congruous with the prognosis for the various subgroups of interstitial lung disease in the literature. Therefore, it seems unlikely
that in most instances the course of the patient is going to be altered by knowing the histologic subclassification of interstitiallung disease if treatment with immunosuppressive agents is going to be the routine. However, there are multiple other causes for lung disease (table 2) in this group of patients that might also be responsible for pulmonary symptoms and would require different therapy. If these other entities needed to be excluded, it would be reasonable to pursue additional diagnostic maneuvers: transbron-
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733 nett FC, Reichlin M. Antibody to Jo-l in polymyositis/dermatomyositis: association with interstitial pulmonary disease. J Rheumatol 1984; 11:663-5. 40. Phillips TJ, Leigh 1M, Wright J. Dermatomyositis and pulmonary fibrosis associated with antiJo-l antibody. J Am Acad Dermato11987; 17:381-2. 41. Macklem PT, Thurlbeck WM, Fraser RG. Chronic obstructive disease of small airways. Ann Intern Med 1971; 74:167-77. 42. Kitachi M. Pathology of diffuse panbronchiolitis from the viewpoint of differential diagnosis. In: Grassi C, Rizzato G, Pozzi E, eds. Sarcoidosis and other granulomatous disorders. Proceedings of the XI World Congress on Sarcoidosis and Other Granulomatous Disorders. New York: Excerpta Medica, 1980; 741-6. 43. Guerry-Foree ML, Muller NL, Wright JL, et ale A comparison of bronchiolitis obliterans with organizing pneumonia, usual interstitial pneumonia, and small airways disease. Am Rev Respir Dis 1987; 135:705-12. 44. Epler GR, Colby TV, McLoud C, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312:152-8. 45. Katzenstein A-LA, Meyers JL, Mazur MT. Acute interstitial pneumonia: a clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol 1986; 10:256-67. 46. Rowen AJ, Reichel J. Dermatomyositis with lung involvement, successfully treated with azathioprine. Respiration 1983; 44:143-6. 47. Plowman PN, Stableforth DE. Dermatomyositis with fibrosing alveolitis: response to treatment with cyclophosphamide. Proc R Soc Med 1977; 70:738-40. 48. Gruhn WB, Diaz-Buxo JA. Cyclosporine treatment of steroid resistant interstitial pneumonitis associated with dermatomyositis/polymyositis. J Rheumatol 1987; 14:1045-7.
HENRY D. TAZELAAR, ROBERT W. VIGGIANO, JUDITH PICKERSGILL, and THOMAS V. COLBY
Introduction SUMMARY Open lung biopsies from 14patients and autopsy tissue from one patient with polymyoSince its original description in 1956(1), sitis/dermatomyositis were reviewed In an attempt to correlate histologic features with clinical, rathe association between interstitial lung diographic, and prognostic variables. Three major groups based on histologic patterns were Identidisease and polymyositis and dermatofied: bronchiolitis obliterans organizing pneumonia (BOOP),usual Interstitial pneumonia (UIP), and myositis has become well established (2). diffuse alveolar damage (DAD). Patients with BOOP had a more favorable prognosis than did paIn many reports (3-13), the diagnosis of tients with UIR Patients with DADhad a uniformly poor prognosis. One patient had a cellular Interstitial pneumonia and did well. Histologic subclassification of the Interstitial lung disease proved to interstitial lung disease has been based be a better predictor of survival than did the radiographic appearance or the clinical presentation. primarily on a combination of chest raThese findings suggest that there Is a broader range of histologic findings In polymyositisdiograph abnormalities with pulmonary dermatomyositis than Is suggested In the literature and that subclassification may be useful ~r function tests. In some, there has been prognosis. AM REV RESPIR DIS 1990; 141:727-733 pathologic confirmation (14-29). The histologic descriptions have usually been , cursory, with most cases described as "pulmonary fibrosis." An effort has been After review of the pathologic findings, an made in occasional studies (30-32) to sep- suIts of anti-J 0 antibody (36-40) status were not available for any patient. Pulmonary attempt was made to correlate the histologic arate patients into histologically favorfunction tests when available were all per- patterns with patient outcome and response able and unfavorable groups. However, formed at the Mayo Clinic pulmonary func- to treatment. subclassification of interstitial lung dis- tion laboratory. Pulmonary function abnorease has proved useful with other more malities were graded as follows: mild < 80070 Results common types of collagen vascular dis- and ~ 60070 predicted; moderate < 60070 and Clinical Data ease, e.g., systemic lupus erythematosus ~ 40070 predicted; severe < 40070 predicted. In 14patients, the pathologic material con- A summary of the clinical data as cor(33) and rheumatoid arthritis (34). We have undertaken a retrospective study to sisted of an open lung biopsy. In one patient related with the pathologic findings is assess the prognostic value of histologic with a fulminant course, autopsy tissue was shown in table 1. Eight patients presentexamination among patients with inter- all that was available but reflected acute in- ed with interstitial lung disease and othstitiallung disease and dermatomyositis- terstitiallung disease. Four additional patients er manifestations of PM-OM simultanewere excluded because of the presence of ously; in five patients PM-OM had been polymyositis. mixed connective tissue disease (two patients), diagnosed 1 to 36 months prior to the childhood dermatomyositis (one patient), and development of their lung disease, and Methods the finding of small airways disease on open in two patients the lung disease precedThe clinical records and pathologic material lung biopsy (one patient) thought to be related the diagnosis of PM-OM by 1 and 6 of all patients with a diagnosis of polymyosi- ed to the patient's smoking history rather than months. All patients had an abnormal tis and/or dermatomyositis (PM-OM) seen to PM-OM. Follow-up autopsy material was chest radiograph at the time of diagnoat the Mayo Clinic in whom an open lung available in Patients 5, 10, 12, and 15. biopsy had been performed for evaluation of The histologic sections were reviewed with- sis, most having bilateral interstitial ininterstitial lung disease from 1965to June 1989 out knowledge of the patient's clinical course. filtrates, often greatest in the lower lobes. were reviewed. Additional cases were obtained The following histopathologic patterns of in- The results of pulmonary function tests from the pathology files of one of the authors terstitiallung disease were utilized (34): lym- (PFT) were available for 10patients. Two (TVC). Clinical histories and follow-up information on these latter cases were obtained from referring physicians. Cases were accepted if the diagnosis of polymyositis or dermatomyositis could be confirmed using the criteria of Bohan and Peter (35). Patients were excluded from the study if there had been a diagnosis of a second connective tissue disease at the time of presentation with pulmonary disease, a diagnosis of malignancy, a pulmonary infection, or if the tissue for pathologic examination was considered inadequate. This yielded a total of 15 patients. Patients 2 and 4 have been reported previously (19). The re-
phoid hyperplasia, usual interstitial pneumonia (VIP), desquamative interstitial pneumonia, cellular interstitial pneumonia (CIP), bronchiolitis obliterans organizing pneumonia (BOOP), diffuse alveolar damage (DAD), small airways disease (41-43), and nonspecific scarring. The patients could usually be placed in one category or another, although occasionally two patterns were observed in the same patient. In addition, because of the suggestion in the literature that the degree of "cellularity" (31) may correlate with prognosis, the overall cellularity of the patients was graded from minimal to marked (1 to 3 +).
(Received in original form June 16, 1989 and in revised form August 8, 1989) 1 From the Departments of Pathology and Laboratory Medicine and Internal Medicine, Mayo Clinic, Rochester, Minnesota, and the Department of Medicine, Kaiser Permanente, Santa Clara, California. 2 Correspondence and requests for reprints should be addressed to Henry D. Thzelaar, M.D., Department of Pathology, Mayo Clinic, Rochester, MN 55905.
727
TAZELAAR, VIGGIANO, PICKERSGILL, AND COLBY
728 TABLE 1
CLINICAL DATA AND CORRELATION WITH PATHOLOGY AND PATIENT STATUS· Mode of Presentation Patient No.
2
3
4 5
6
7
8
9
10
11 12 13 14
15
Age (yr)
Sex
47
F
53
19
31 32
73
57
55
72
61
40 57 67 41
58
F
F
M F
M
F
F
F
M
M M F M
F
Polymyositis Dermatomyositis
Pulmonary Symptoms
Time to ILD Dx· (months)
Fever, chills, malaise, prox. muscle weakness
Productive cough
0
Prox. muscle weakness
Dyspnea
0
Prox. muscle weakness, arthralgias, rash
Cough, fever
Prox. muscle weakness
Dyspnea
Rash, muscle weakness, arthralgias
Dyspnea
Muscle weakness, rash, dysphagia, hoarseness
Dyspnea
Muscle weakness, rash
Dyspnea on exertion, cough
Malar rash, muscle weakness
Dyspnea, hoarseness
6
Myalgias, arthralgias, muscle weakness
Dyspnea
0
Heliotrope rash, prox. muscle weakness
Dyspnea on exertion
3
Malaise, weight loss, rash
Productive cough
0
Rash, weight loss, weakness
Dyspnea
0
Rash, weakness
Dyspnea
Rash, weakness
Arthralgias, weakness
-1
0 2
-6
36
0
Dyspnea
Dyspnea
Length of Pulmonary Symptoms (wk)
>3
>3
3 3
>3
3
>3
>3 >3 >3 3
Chest Radiograph
Pathology (Cellularity)
Bilateral interstitial infiltrates
BOOP
Diffuse bilateral interstitial infiltrates greater in bases
BOOP
Bilateral nodular infiltrates
BOOP
Bibasilar slightly nodular infiltrates
BOOP
Bilateral basilar interstitial infiltrates
BOOP
Bilateral interstitial infiltrates, greatest in bases
BOOP
Treatment
Patient Status
Steroids
A&W 7 yr
Steroids
A&W 2 yr
Steroids
Died 8 days after OL BxARDS
Steroids
A&W 18 yr
Steroids methotrexate
Died 4 wk after OL Bx- fever, air leak
Prednisone
Alive, 14 months with dyspnea
(2+)
(2+)
(3+)
(3+) (3+)
(3+)
Bilateral interstitial infiltrates, greatest in lower lobes
Steroids immuran methotrexate
Alive 5 yr on O2
(2+)
Increased interstitial markings, greater in bases
UIP
Steroids
(2+)
Died 13 days after OL Bx-MI, ARDS
Diffuse interstitial and alveolar infiltrates &lARDS-like"
Steroids
(2+)
Died 4 wk after OL Bx. No details
Steroids cytoxan plasmapheresis
Died 4 wk after OL Bx-ARDS
UIP
UIP
Diffuse reticulonodular process
(1 +)
Scattered bilateral infiltrates
(3+)
Steroids methotrexate
Alive, 6 yr on disability
Diffuse interstitial infiltrates
DAD
Steroids
(3+)
Died 6 wk of respiratory failure
Diffuse bilateral infiltrates
Steroids
(1 +)
Died 4 wk of respiratory failure
Steroids
Died 1 wk of respiratory failure
Steroids chlorambucil
Died 7 yr of leukemia
Bilateral infiltrates with perihilar accentuation Interstitial infiltrates in left base
UIP
UIP
DAD DAD
(2+) CIP
(3+)
Definition of abbreviations: Ii_D = interstitial lung disease; Ox = diagnosis; A&W = alive and well; OL Sx = open lung biopsy; ARDS = adult respiratory distress syndrome; MI = myocardial infarct; SOOP = bronchiolitis obliterans organizing pneumonia; UIP = usual interstitial pneumonia; DAD = diffuse alveolar damage; CIP = cellular interstitial pneumonia. * Time to development of interstitial lung disease from diagnosis of pOlymositis-dermatomyositis.
patients had normal PFT (Patients 7 and 10),two had a mild decrease in TLC (Patients 6 and 11), three had a moderate decrease in TLC (Patients 2, 4, and 8), and two had a severe reduction in TLC (Patients 5 and 15). Two patients (Patients 7 and 10)had mild diffusing abnormalities, one a moderate diffusing abnormality (Patient 6), and one a severe reduction in diffusing capacity (Patient 8). In addition, Patient 6 also had a moderate decrease in FEV t •
Pathologic Findings The following patterns of interstitial lung disease were identified in this group of patients: BOOP, VIP, DAD, and CIP. BOOP was the" predominant finding in six patients. The hallmark of BOOP (figure 1)was the presence of patchy foci of organizing pneumonia and an associated bronchiolitis obliterans with granulation tissue filling bronchioles and alveolar ducts. The degree of accompanying interstitial inflammation varied from
minimal (1+) to marked (3 +) (table 1), consisting of lymphocytes, macrophages, and plasma cells. Lymphoid follicles without germinal centers were identified in three patients. Small numbers of neutrophils in alveoli and in the interstitium were usually present (71070). Eosinophils were present in two patients. Associated findings included: reactive type II pneumocytes (five patients), alveolar edema (three patients), obstructive changes with foamy macrophages in alveolar spaces
INTERSTITIAL WNG DISEASE IN POLYMYOSITIS AND DERMATOMYOSITIS
729
and plasma cells being most numerous. Clusters of macrophages within the air spaces similar to those seen in desquamative interstitial pneumonia were identified focally in three patients. The autopsy material from Patient 10 showed diffuse alveolar damage superimposed on a VIP pattern. Three patients had DAD, two on the basis of an open lung biopsy, and one (Patient 13) on the basis of autopsy material obtained 1 wk after presentation. These patients had damaged alveolar lining cells, hyaline membranes (figure 3), intra-alveolar edema, and focal hemorrhage. The interstitium was widened with edematous . m ucopolysaccha ride-rich connective tissue. Autopsy examination of the lung in Patient 12 showed diffuse bilateral Pseudomonas aeruginosa and cytomegalovirus pneumonia. In Patient 15, the pattern was a nonspecific cellular interstitial pneumonia (figure 4) with interstitial accumulations of mononuclear cells, predominantly lymphocytes and plasma cells with minimal fibrosis and no significant bronchiolitis. At autopsy 7 yr later, the lungs showed diffuse alveolar damage.
Clinicopathologic Correlations Of the patients with BOOP, four of six are alive and well, whereas of the patients with VIP, 3 of 5 have died. All of the patients with DAD died. The patient with CIP had resolution of her pulmonary symptoms. However, she developed acute myelogenous . leukemia thought to be related to her chlorambucil therapy at 81 months. She died with the adult respiratory distress syndrome.
Fig. 1. Bronchiolitis obliterans organizing pneumonia (Patient 3). Areas of relatively normal lung (top) interspersed with areas of intra-alveolar granulation tissue. Overall cellularity , 3+. Another field (bottom) shows a terminal bronchiole whose lumen is occluded by edematous granulation tissue. Arrows show the bronchiolar muscularis (hematoxylin-eosin stain; top: x 64; bottom: x 160).
(one patient), microthromboemboli (one patient), and a small pulmonary infarct (one patient). A pattern of VIP was identified in five patients (figure 2). Areas of normal lung were interspersed with interstitial scarring and honeycombing. The air spaces
were variously lined by columnar epithelium (so-called bronchiolization), type I or II pneumocytes (occasionally reactive), or metaplastic squamous cells. The degree of associated interstitial inflammation was also variable, but most were moderately cellular, with lymphocytes
Discussion The incidence of pulmonary disease in the PM-OM complex is reported to be as high as 45% (44). Someofthepulmonary manifestations (table 2) are the result of aspiration secondary to dysphagia and muscle weakness. However, interstitial lung disease thought to be related to the underlying immunologic abnormalities present may occur in 5 to 30070 of patients, and in many cases dominates the clinical course of the patients. However, there have been few studies describing the lung disease in detail (30-32), and none according to currently accepted classification schemes. We have studied a group of patients with PM-OM who underwent open lung biopsy and have attempted to categorize the histologic patterns seen. We have
730
TAZELAAR, VIGGIANO, PlCKERSGILL, AND COLBY
Fig. 2. Usual interstitial pneumonia (Patient 7) with areas of mildly fibrotic parenchyma (upper right) adjacent to an area of densely scarred lung (lower left). There is little intra-airway or intra-alveolar organization . Overall cellularity, 2 + (hematoxylin-eosin stain; magnification: x 40).
found a wider spectrum of interstitial lung disease than a perusal of the literature would suggest. In our opinion, the generic "chronic interstitial pulmonary fibrosis" does not capture the spectrum of disease and its implications for patient outcome. The clinical presentation of patients with interstitial lung disease associated with PM-DM is variable. Classically, PM-DM affects women twice as often as men (2), and our series reflects this sex distribution (nine women, six men). Patients with interstitial lung diseasehave been divided into three groups accord-
ing to their presenting symptoms (19, 25): those with apparently aggressivelung disease similar to patients with the Hamman-Rich syndrome, those who present with more slowly progressive dyspnea on exertion, and those without pulmonary symptoms but with either an abnormal chest radiograph or pulmonary function tests. We did not encounter asymptomatic patients, but such patients might not be subjected to open lung biopsy as readily. Wedid have four patients with a rapid onset of pulmonary symptoms, all four of whom died relatively quickly, and 11 patients with a slowerpresentation of whom
approximately 40070 died (table 1).Therefore, although those patients who do present with a rapidly progressive downhill respiratory course fare poorly, those with a slower progression of pulmonary symptoms have a variable outcome. The results of our study suggest that the histologic features on open lung biopsy may be better predictors of patient outcome than either the radiographic findings or the clinical presentation. We identified three main histologic patterns of interstitial lung disease occurring in thesettingofPM-DM: BOOP, VIP, and DAD. These patterns have all had their clinical course and outcome described both with and without an associated collagen vascular disease(33). A clear-cutassociation with the specific histologic patterns and PM-DM, however, is more difficult to ascertain, for most of the studies have had relatively cursory descriptions of pathologic findings and have focused on the degree of fibrosis and cellularity rather than on a specific pattern. Patients with BOOP appeared to have the best prognosis, with a 67% survival rate. This figure is similar to that for patients with BOOP unassociated with collagen vascular disease as reported by Epler and coworkers (44). In that same study, however, patients with BOOP in the setting of a collagen vascular disease appeared to have a worse prognosis, as 500/0 died. In contrast, Yousem and colleagues (34) found that patients with rheumatoid arthritis and BOOP fared relatively well(80% survival rate). Schwarz and associates (31) suggested that some cases ofBOOP (called organizing pneu monia in their study) might progress to VIP. We did not find this in our study, although one of our patients did develop the adult respiratory distress syndrome in the immediate postoperative period.
TABLE 2 PULMONARY MANIFESTATIONS OF POLYMYOSITIS-DERMATOMYOSITIS 1. Aspiration pneumonia 2° to dysphagia 2. Ventilatory insufficiency 2° to muscular weakness 3. Interstitial lung disease Usual interstitial pneumonia Bronchiolitis obliterans organizing pneumonia Diffuse alveolar damage Miscellaneous patterns 4. Drug-induced reaction, e.g., methotrexate 5. Malignancy, primary or metastatic 6. Pleural effusions 7. Opportunistic infection 8. Pulmonary hypertension (25) 9. Spontaneous pneumothorax (52) 10. Pulmonary alveolar proteinosis (53)
TABLE 3 OPEN LUNG BIOPSY HISTOLOGIC FINDINGS CORRELATED WITH CLINICAL OUTCOME: LITERATURE REVIEW· AND CURRENT SERIES COMBINEDt
Alive Dead Survival, % Combined series Current series
BOOP
UIP
DAD
CIP
8 (2 yr-18 yr) 4 (8 d-10 yr)
9 (4 mo-6 yr) 15 (13 d-26 mol
1 (3 mol 3 (4 wk-5 mol
1 (NA)* 1 (7 yr)
66
37 40
25 0
50 100
66
For definition of abbreviations, see table 1. • References: BOOP-Schwarz, 1976,3 (cases), Salmeron, 1961 (2), Shlavi, 1984 (1); UIP-Mllls, 1956 (1), Thompson, 1970 (1), Duncan, 1974 (1), Park, 1975 (1), Schwarz, 1976 (3), Bonafe, 1981 (1), Hanawa, 1981 (1), Salmeron , 1981 (2), Takizawa, 1987 (8); CIP-Webb, 1972 (1); DAD-Sandbank, 1966 (1), Weaver, 1968 (1). t Numbers in parentheses refer to range of follow-up lime . (d = days; wk weeks; me - months; yr = years). Not available.
=
*
INTERSTITIAL WNG DISEASE IN POLYMYOSITIS AND DERMATOMYOSITIS
ig. 3. Diffuse alveolar damage (Patient 14) with markedly distorted architecture and widened edematous alsolar septa containing moderately inflamed (cellularity, 2 +) granulat ion tissue. The alveoli (bottom) contain ansely eosinophilic hyaline membranes (arrows) . There are moderately reactive type II pneumocytes focally Irrowheads) (hematoxylin-eosin stain: top: x 64; bottom: x 160).
Patients with VIP appeared to have a oorer prognosis (33070 survival), alhough our numbers are small . This is ot unexpected given the poor prognois of VIP unassociated with PM-DM. lis interesting to note, however, that alrough the course of two of our patients as been typical for VIP (slowly progres-
sive disease resulting in O2 dependency and disability), three patients died rapidly after open lung biopsy. At least two developed the adult respiratory distress syndrome, in addition to the patient with BOOP who developed a similar postoperative syndrome. Perhaps the underlying collagen vascular disease, muscle
731
weakness, and immunosuppression all contribute to a significant surgical risk in this group of patients. Although there is a suggestion from the literature that some patients with PMDM may develop idiopathic adult respiratory distress syndrome (Hamman-Rich syndrome, acute interstitial pneumonia) (14, 15), we have been able to confirm this histologically as manifested by a pattern of DAD. These patients all died, despite immunosuppressive therapy. This prognosis is also in keeping with the process of DAD unassociated with collagen vascular disease (45). We also identified one less well-characterized pattern of interstitial lung disease in PM-DM, a nonspecific CIP similar to what has been seen in other collagen vascular diseases (33,34). Our patient with CIP did well from a pulmonary status for 7 yr, but then died of a treatmentinduced leukemia. This is similar to the finding of Yousem and coworkers (34) in patients with rheumatoid arthritis in which all 10 patients with this pattern fared well. Pulmonary hemorrhage or vasculitis was not seen in this group of patients, although there is a well-described association of this with other collagen vascular diseases (33), particularly systemiclupus erythematosus. Several previous studies (30, 31) have suggested that the degree of tissue cellularity correlates positively with prognosis in this group of patients. Our findings show that patients with minimal interstitial cellularity/inflammation may not do well (all three died), but that having a markedly cellular specimen is no guarantee of a favorable outcome. We would prefer to emphasize the histologic pattern, which shows better correlation with patient outcome than a nonspecific designation such as degreeof "cellularity." We have attempted to categorize the type of interstitial lung disease occurring in patients reported in the literature who have had open lung biopsies and com bined these with our own results. This combined series yielded a total of 42 patients. The histologic features as correlated with clinical outcome are shown in table 3. The survival figures reflect a trend similar to that found for our group of patients analyzed alone, supporting the utility of this histologic classification for patients with PM-DM. The role of open lung biopsy in patients with PM-DM is debatable and is dependent on the clinical situation. The mainstay of therapy for both the inter- .
TAZELAAR. VIGGIANO. PICKERSGILL, AND COLBY
732
chial biopsy, bronchoalveolar lavage, and open lung biopsy. If an open lung biopsy is performed, the results of our study may be of use in predicting prognosis. Acknowledgment The writers thank Michelle Thrner for secretarial assistance and the clinicians and pathologists who assisted them in gathering data: Grant Cannon, M.D., Robert D. Coye, M.D., Jonathon Ellman, M.D., Stephen Hathway, M.D., Kenneth Hirsch, M.D., William Kyle, M.D., Martin H . Matthews, M.D., Daniel G. Remick, M.D., Norman Rosenstock, M.D., Leonard Valentino, M.D., Bernhard Votteri, M.D., and William H. Winchell , M.D.
References
Fig. 4. Cellular interstitial pneumonia (Patient 15). Well-preserved putrnonary architecture with moderate to marked (bottom) interstitial chronic inflammation. particularly along bronchovascular routes (hematoxylin-eosin stain; top: x 40; bollom: x 160).
stitial lung disease and the underlying collagen vascular disease in patients with PM-DM has been steroids. There have also been reports of successful treatment with other immunosuppressive agents, e.g.,azathioprine (46), cyclophosphamide (47), and cyclosporine (48). All patients in our series and virtually all reported patients have been treated with immunosuppressive agents. Our results are congruous with the prognosis for the various subgroups of interstitial lung disease in the literature. Therefore, it seems unlikely
that in most instances the course of the patient is going to be altered by knowing the histologic subclassification of interstitiallung disease if treatment with immunosuppressive agents is going to be the routine. However, there are multiple other causes for lung disease (table 2) in this group of patients that might also be responsible for pulmonary symptoms and would require different therapy. If these other entities needed to be excluded, it would be reasonable to pursue additional diagnostic maneuvers: transbron-
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