- Email: [email protected]
Progressive Fibrosing Mediastinitis
Progressive Fibrosing Mediastinitis Thomas H. Hewlett, Col, MC, USA (Ret),* Arthur Steer, Col, MC, USA, and David E. Thomas, Col, MC, USA
A
report entitled “Mediastinal Tuberculoma” published by Samson et al. [16] in 1950 directed surgical attention to the problem of benign mediastinal adenopathy. Two of the patients in their report had symptoms of airway obstruction, and a third patient had a firm cervical mass fixed to the trachea. T h e pathological process was identical in the three patients. Specimens consisted of granulomatous masses containing central areas of caseation and peripheral bands of dense hyalinized fibrous tissue, with scattered foci of calcification, zones of epithelial cells, and occasional giant cells. Tuberculosis was not proved in any of these patients. Mediastinal g r a n u l o m a was the term applied to a similar pathological pattern occurring in patients reported by Kunkel et al. [l 11 in 1954. One of Kunkel’s patients who suffered with severe airway obstruction was considered inoperable. A second patient was treated for mitral stenosis, yet autopsy disclosed a subcarinal keloid type of reaction obstructing most of the pulmonary veins. These authors implied that such fibrosis might be the end result of granulomatous disease within the mediast inum. Gillespie’s report [7] of superior vena caval obstruction in a 7-yearold child appeared in 1956. In this patient vena caval obstruction developed as the residuum of a right pulmonary parenchymal infiltrate which was accompanied by positive histoplasmin skin tests and positive histoplasmin serology in high dilution. T h e symptoms of vena caval obstruction were completely alleviated by excising a portion of the dense fibrous tissue, unroofing approximately two-thirds of the circumference of the entrapped vessel. Histoplasrna capsulatum could not be demonstrated in the excised tissue. Barrett’s lengthy dissertation [ll on idiopathic mediastinal fibrosis appeared in 1958. T h e majority of his patients suffered from superior vena caval obstruction, and he postulated that probably other vital structures of the mediastinum were not jeopardized by the fibrosing From the Thoracic Surgical Service and the Department of Pathology, Fitzsimons General Hospital, Denver, Colo. ‘Present address: Fiesno County General Hospital, Fresno, Calif. Presented at the Second Annual Meeting of T h e Society of Thoracic Surgeons, Denver, Colo., Jan. 24-26, 1966. VOL. 2, NO.
3,
MAY,
1966
345
HEWLETT, STEER, AND THOMAS
process. However, time has shown that no structure within the mediastinum is immune to the compression and invasion potentials of this socalled benign process. Our interest in fibrosing mediastinitis began with two reports originating from Fitzsimons General Hospital in 1959. Salyer et ul. [15] and Lull and Winn [12] described a total of five patients in whom there could be little doubt that mediastinitis resulted from histoplasmosis. Airway obstruction and superior vena caval obstruction of tuberculous origin are rare in the experience of Fitzsimons Hospital. Brief review of some facts about histoplasmosis may aid in understanding the more than coincidental relationship between this disease and fibrosing mediastinitis. Curry and Wier [Z] in a careful study of 100 cases of histoplasmosis noted several facts of interest to the surgeon. Significant hilar adenopathy was detected radiographically in 68% of patients studied, and in 3775, hilar adenopathy was not associated with pulmonary parenchymal disease. Enlargement of mediastinal nodes appeared with both primary and reinfected disease. Calcification of involved nodes appeared gradually over a period of two to three years after the acute stage. T h e histoplasmosis focus, whether in the pulmonary parenchyma or within a lymph node, heals with a marked peripheral fibrosis which is not found in either tuberculosis or coccidioidomycosis. Thus obstruction of a portion of the airway, esophagus, or great vessels can develop insidiously, long after the acute phase of the initial infection has passed. Histoplasmin skin tests are accorded the same diagnostic significance as the tuberculin skin test, a positive reaction indicating infection with H. cupsulutum either past or present. T h e complement fixation test appears to be even more specific; positive skin tests were noted in 96% of the patients studied by Curry and Wier [2],and positive serology was recorded in 68%. Culture proof of histoplasmosis is difficult and is probably positive in 4% to 10% of patients depending on the phase of the disease at the time such studies are performed. An unpublished review of a 10-year experience with histoplasmosis at Fitzsimons General Hospital reveals that approximately 8% of patients will show some evidence of fibrosing mediastinitis. While there is no method of determining which patient with histoplasmosis will eventually develop mediastinitis, the factor of host resistance may be important in protecting the majority of histoplasmosis patients from a progressive fibrosis along lymphatic pathways. C L I N I C A L EXPERIENCE
A series of fourteen patients illustrates several facets of the course of progressive mediastinal fibrosis (Table 1). Two of the patients under346
THE ANNALS OF THORACIC SURGERY
History
Caval obstruction
5. 6333030
aPreviously reported.
White male 22 yr. R. A. C.
Caval obstruction
4. 4859007 White malc 42 yr. A. J. E.
Insidious onset: endemic area
Insidious onset; endemic area
Right mediastinal mass, total superior vena caval obstruction
Right superior mediastinal mass, total superior vena caval obstruction
Right superior mediastinal mass
Insidious onset; endemic area
Enlarging neck; caval obstruction
3. 445024a
White male 26 yr. G. G . N.
Right mediastinal mass with scattered calcification
Viral pneumonitis(7) while handling fertilizer; endemic area
None
5 X 6.5 X 5 cm.
2. 7608046 White male 23 yr. G. R. B.
Endemic area calcified mass, subcarinal zone, right main bronchus
None
Symptom Pattern
Negro male 23 yr. W. D.
1. 6590035
Itlen tity -_____
Radiographic Studies
+
+
+
+
+
Serology
+
+
+
Skin
Histo. Studies
Dense fibrous tissue occluding azygos and cava; Teflon bypass done
Total encasement of Cava and trachea with dense fibrous mass, spotted calcification; superior vena caval bypass, homograft done
Biopsy: caseating granuloma with H . capsulaturn; superior vena caval bypass done
6 X 2 X 1.5 granuloma with central caseation; positive H. capsuh turn
Granuloma
Surgical Pathology
Follow-up
Asymptomatic, 2 yr. Bypass was patent a t 90 days postoperative
6 yr. increasing airway obstruction, caval bypass Functional by angiogram
Chronic superior vena caval syndrome, gradual development respiratory symptom over 7 yr. period
Asymptomatic, 1 yr.
Asymptomatic, 1 vr.
TABLE 1. DETAILS OF FOURTEEN PATIENTS WITH PROGRESSIVE MEDIASTINAL FIBROSIS STUDIED
Airway obstruction (hemoptysis)
Airway obstruction (hemoptysis)
Airway obstruction (hemoptysis)
9. 3852027" White male 30 yr. H. L. E.
10. 4447033" Negro male 27 yr. E. W. A.
Insidious onset; endemic area
Insidious onset; endemic area
Single acute respiratory illness with pleural effusion; endemic area
Repeated respiratory infections; endemic area
Airway obstruction (hemoptysis)
8. 3722022" White female 50 yr. C. W. K.
Repeated respiratory infections; endemic area
Airway obstruction (hemoptysis)
6. 2899012 White male 31 yr. R. L. 7. 3379011" White male 23 yr. R. L. R.
History
Symptom Pattern
Identity
Infiltrate left midlung field
Right hilar mass
Left hilar mass, left pleural effusion, fibrotic left lower lobe
Bilateral hilar and adenopathy subcarinal mass
Left hilar mass; stenosis left lower lobe bronchus
Radiographic Studies
TABLE 1 (Continued)
+
+
+
+
+
+
+
t
Serology
Histo. Studies Skin
Fibrous mass involving all left mediastinum from lingula bronchi. Positive H. capsulatum
Tumor encircled right hilus occluding azygos and fixed to tracheal wall. Positive H. capsulatum. Inoperable
Trachea and carina encased in dense fibrous tissue: osseous metaplasia in biopsy. Inoperable
All lobes right lung diffuse nodular process; mediastinum rigid with diffuse infiltrating fibrosis. Node positive H. capsulatum
Biopsy only; considered inoperable
Surgical Pathology
4 yr. survival as gradually deteriorating respiratory cripple
8 yr. survival as deteriorating respiratory cripple: developed vena caval syndrome 1 yr. after exploration
gradually deteriorating respiratory cripple
7 yr. survival as
10 yr. survival as gradually deteriorating respiratory cripple
12 yr. survival as moderate pulmonary cripple
Follow-up
~
aPrevionsly reported.
R.c.
+
+
Circumscribed densities both lungs: subcarinal mass with narrowing both lower lobe bronchi
Repeated pneumonias; endemic area. 5 years progressive following middle lobectomy for so-called pseudotumors
Airway obstruction
14. 7080024 White female 31 yr.
+
+
Bilateral hilar adenopathy: bilateral hronchial occlusion
11 years of life lived over hatchery. 5 years of severe respiratory infections; endemic area
Airway obstruction
13. 6401046 White female 28 yr. P. C. H.
4-
TVidened mediastinum; cava displaced to right
Right middle lobe atelectasis resected 4 years before considered histoplasmosis. Gradual onset of cord paralysis on left side; endemic area
Airway obstruction: cord paralysis
12. 6983045 White female 35 yr. R. M. P.
t
Right hilar adenopathy with compression right lower and right middle bronchi
Repeated respiratory infections; endemic area
White male 8 yr. F. s.
Airway obstruction
11. 5203024
Subcarinal mass occluding left main-stem bronchus and invading pericardium: chondroplastic graft of airway done
Diffuse fibrous tissue invasion of bronchi and trachea
Sternal-split rnediastinal decortication of great vessels and trachea done; fibrous tissue invasion
Dense fibrosis encircling right bronchus extcnding through subcarinal area. Lohectomy deemed impossible: calcified flecks in biopsy
Died after airway plastic reconstruction
Died after airway plastic reconstruction
1 yr. doing well: cord paralysis cleared six weeks after operation
3 yr. limited activity because of decreasing respiratory capability
HEWLETT, STEER, AND THOMAS
went surgical treatment during the acute granulomatous stage of the disease and have been followed-up for only one year. It seems likely that such asymptomatic granulomatous foci within hilar nodes represent precursors of the late stages of the disease. Effler and Groves [3] and Williams and Burford 1191 have emphasized the ease with which such lesions are excised with insignificant morbidity. Such a procedure affords a possible means of preventing the development of progressive fibrosis, as it interrupts the continuity of the mediastinal lymphatic network. Twelve patients are examples of the later stages of progressive fibrosis; six of these were considered inoperable at the time of exploration. Ten of the twelve have been followed for long enough periods to clearly demonstrate the progressive downhill course to be anticipated as vital structure of the mediastinum becomes entrapped and invaded by a relentless disease process. Major airway obstruction was the clinical problem in nine of twelve patients with advanced disease, and superior vena caval obstruction was the problem in three. Two of three patients who were subjected to superior vena caval bypass procedures developed respiratory obstruction within a 6-year follow-up period, and one bypass continued to be functional at 6 years. One Teflon bypass was found functional at the end of 1 year. All patients had previously resided in an area where histoplasmosis was endemic. All had positive histoplasmin skin tests. Eight of ten studied by serological techniques were positive at some time during the course of the disease. Tuberculosis studies were negative in all patients. X-ray studies revealed pathology in each case: Figure 1 shows right hilar
FIG. 1. Case I : A 23-year-old Negro male with an asymptomatic subcarinal mass. X-ray of excised tissue.
350
THE ANNALS OF THORACIC SURGERY
Fibrosing Mediastinitis
FIG. 2. Case 5: A 22-year-old white male with insidious onset of superior vena caual obstruction. T h e uenogram shows degree of obstruction.
FIG. 3. Case 14: A 31-year-old white female. T h e bronchogram shows complete obstruction of right lower lobe bronchus with the siibcarinal mass narrowing the left main blronchus. VOL. 2, NO.
3,
MAY,
1966
351
HEWLETT, STEER, AND THOMAS
FIG. 4 . Case 14: Mediastinal fibrosis with pseudotumorous exteiasion obstructing a main bronchus and invnding the pericardium.
enlargeiiient which was asymptomatic, and Figure 2 is a venogram demonstrating almost complete obstruction of the superior vena cava in a young man with a positive histoplasmin skin test and positive serology. The severe degree of airway obstruction that may develop in the late stages of fibrosing mediastinitis is depicted in the bronchogram (Fig. 3). Calcification of the subcarinal gland complex is considered typical of old Histoplasma adenitis. One patient (No. 12, Table 1) combined airway obstruction and recurrent laryngeal nerve paralysis. This patient showed marked improvement in respiration and had return of vocal cord function after excision of fibrous tissue from the anterior mediastinum, suggesting that disruption of the continuity of fibrous tissue has palliative value if it can be carried out prior to the development of chronic infection in the lung parenchyma. Two patients with severe airway obstruction died within forty-eight hours of attempted bronchoplastic procedures; total excision of the fibrous tissue was technically impossible in both instances. The extent of the process is readily apparent in the photograph of a necropsy specimen (Fig. 4). HISTOPATHOLOGICAL OBSERVATIONS
Histopathological observations were based on tissue specimens from each patient and necropsy specimens from the two patients wEio died. Regardless of the site of origin, all specimens were characterized by dense cicatricial fibrous tissue composed of interlacing coarse fibers merging into a diffuse, homogeneous, hyalinized scar. Focal areas of caseation necrosis were found in seven specimens. Granulomatous reaction about the necrotic areas was minimal. Foci of caseation were sur352
THE ANNALS OF THORACIC SURGERY
Fibrosing Mediastinitis
FIG. 5. Case 8: Section of pulmonary hilus showing fibrosis and ossification.
rounded by a broad zone of hyalinized fibrous tissue and calcification and ossification was present in some areas (Fig. 5). T h e sclerosing reaction surrounded bronchi, blood vessels, and nerves, the area of fibrosis tending to stop abruptly, leaving a sharp margin between involved and uninvolved tissue. Bronchoscopic biopsies in some patients revealed hyalinization within the bronchial subrnucosa (Fig. 6). Microscopic
FIG. 6. Case 8: The bronchial biopsy shows squamous metaplasia and submucosal hyalinization. VOL. 2, NO.
3,
MAY,
1966
353
HEWLETT, STEER, AND THOMAS
studies of the tracheobronchial tree removed in the autopsies showed the sclerosing process replacing the connective tissue between the cartilagenous rings. Most of the specimens were cultured for fungi and acid-fast bacilli, but no cultures were positive. All specimens were subjected to intensive examination using special staining technics. Typical H. capsuZatu?n were seen in tissues from five of fourteen patients, and a few bodies resembling this fungus were seen in a sixth case. Sections from all cases were stained for acid-fast bacilli, all of which were negative. In one of the patients who died (No. 14, Table 1) there was almost complete right bronchial stenosis as a result of a mediastinal mass (see Fig. 4); in addition there was a large mass in the parenchyma of the left lung which was grossly and microscopically indistinguishable from the sclerotic tissue in the mediastinum. Histological sections show a picture of an indolent, continuing process which advances regardless of the lack of any evidence of an active or persistent fungal infection. This unusual reaction seems peculiar to the host and exhibits qualities of neoplasia which include limited selfperpetuation, invasion, and pseudometastasis. SUMMARY
Progressive fibrosing mediastinitis is a disease of the active age group (ages 20 to 45). It is not a benign process; rather it exhibits pseudomalignant characteristics. Clinical manifestations of the disease include major airway obstruction and superior vena caval obstruction. Esophageal obstruction did not occur in our small series of fourteen patients, but it should be noted that such obstructions due to granuloma were reported by Moore [14] in 1959 and more recently by Fifer et al. [5] in 1965. Our observations support the opinions of others that the late stages of the disease represent the end result of a granulomatous process within the mediastinum. The final distribution of fibrosis within the mediastinum appears to be along the lymphatic pathways draining the lungs, suggesting that the pulmonary parenchyma is the most likely site of the initial infection. Two of the more advanced cases in our series had areas of pulmonary parenchymal fibrosis identical with that occurring in the mediastinum. The histopathological picture of fibrosing mediastinitis was typical of that characterizing a healing histoplasmosis focus. It is more than coincidental that of fourteen patients in the study, histoplasmin skin tests were positive in all, serological examinations carried out on ten patients were positive in eight, positive identification of the fungus was possible in five, and all patients had lived in an area where histoplasmosis is endemic. Reports of many authors over past years have not mentioned the 354
THE ANNALS OF THORACIC SURGERY
Fibrosing Mediast in it is
use of H. cupsulutum diagnostic techniques in the study of patients with either mediastinal granulous or mediastinal fibrosis. T h e exception is the report of Ferguson and Burford [4]published in 1965, which implicates H. cupsulutum as the probable etiological agent in the majority of cases of mediastinal granuloma encountered in an area where histoplasmosis is endemic. Routine utilization of histoplasmosis skin and serological tests and specific information as regards past and present geographical areas of residence should aid in demonstrating the existence of the disease in patients with mediastinal adenopathy and fibrosis. There is no reported long-term follow-up on patients who have undergone excision of active granuloma, and it is hoped that prompt treatment of the active stage of the disease might prevent the development of spread along communicating lymphatic channels. Surgery in the late stages of the disease is fraught with technical difficulties and at best is palliative; it should be limited to partial decortication of vital structures. REFERENCES I. Barrett, N. R. Idiopathic mediastinal fibrosis. Brit. J. Surg. 46207, 1958. 2. Curry F. J., and Wier, J. A. Histoplasmosis. Amer. Rev. Tuberc. 77:749, 1958. 3. Effler, D. B., and Groves, L. K. Superior vena caval obstruction. Ann. Surg. 43:574, 1962. 4. Ferguson, T. B., and Burford, T. H. Mediastinal granuloma: A 15-year experience. Ann. Thorac. Surg. 1:125, 1965. 5. Fifer, W. R., Woellner, R. C., and Gordons, S. S. Mediastinal histoplasmosis: Report of three cases with dysphagia as the presenting complaint. Dis. Chest 47:518, 1965. 6 , Garamella, J. J., Stutzman, R. L., Varco, R. L., and Jensen, N. K. Subcarinal mediastinal granuloma causing esophageal obstruction. J. Thorac. Surg. 30:187, 1955. 7. Gillespie, J. B. Superior vena caval obstruction in childhood. J . Pediat. 49:320, 1956. 8. Grybowski, W. A., Crutcher, R. R., Halloway, J. B., Mayo, P., Segnitz, R., and Eiseman, B. The surgical aspects of histoplasmosis. Arch. Surg. (Chicago) 87:590, 1963. 9. Hache, L., Woolner, L. B., and Bernatz, P. E. Idiopathic fibrous mediastinitis. Dis. Chest 41:9, 1962. 10. Hawk, W. A., and Hazard, J. B. Sclerosing retroperitonitis and sclerosing mediastinitis. Amer. J. Cle'n. Path. 32321, 1959. 11. Kunkel, W. M., Clagett, 0. T., and McDonald, J. R. Mediastinal granuloma. J. Thorac. Surg. 27:565, 1954. 12. Lull, G. F., and Winn, D. F. Chronic fibrous mediastinitis due to histoplasma capsulatum. Radiology 73:367, 1959. 13. Miller, D. B., Allen, S. T., and Amidon, E. L. Obstruction of the superior vena cava presumably due to histoplasmosis. Amer. Rev. Tuberc. 77:848, 1958. 14. Moore, T. C. Esophageal obstruction due to mediastinal granuloma. J . Thorac. Szirg. 37: 127, 1959. VOL. 2, NO.
3,
MAY,
1966
355
HEWLETT, STEER, AND THOMAS 15. Salyer, J. M., Harrison, H. N., Winn, D. F., and Taylor, R. R. Chronic fibrous mediastinitis and superior vena caval obstruction due to histoplasmosis. Dis. Chest 35:364, 1959. 16. Samson, P. C., Heaton, L. D., and Dugan, D. J. Mediastinal tuberculoma. J. Thorac. Surg. 19:338, 1950. 17. Storey, C. F., and Lyon, H. A. Tuberculomas of the mediastinum. Amer. Rev. Tuberc. 64:327, 1951. 18. Straub, M., and Schwarz, J. Primary complex in histoplasmosis. Amer. J . Clin. Path. 25:727, 1955. 19. Williams, K. R., and Burford, T. H. Surgical treatment of granulomatous paratracheal lymphadenopathy. J. Thorac. Cardiov. Surg. 48: 13, 1964. DISCUSSION
DR. IVAN A. MAY (Oakland, Calif.): Dr. Hewlett’s slides show beautifully the stippled calcification throughout lymph nodes which Dr. Kenneth Hardy and I think is typical of histoplasmosis. People with the residuals of histoplasmosis are often seen far from endemic areas due to the migratory nature of our population today. We see many in California. We have seen two patients with superior vena caval obstruction attributed to lymph nodes and the associated fibrosing mediastinitis occurring after histoplasmosis. They were diagnosed clinically, having lived in an endemic area. They had positive skin tests for histoplasmosis and negative tests for other granulomas, and had stippled calcification of hilar and mediastinal lymph nodes. Their surgical findings and tissue sections were the same as those presented today. We did not identify H. capsulatum. In 1953 we saw the first patient, a 26-year-old man from Tennessee with recurrent hemoptysis due to erosion of the right upper lobe bronchus by calcified nodes. This represented a manifestation of airway obstruction described by Dr. Hewlett. The right upper lobe was removed. Dissection was technically difficult due to the calcified hilar nodes. There were extensive, hard, matted nodes around the superior cava which we avoided, although in retrospect it appears we should have attempted to remove them. I n 1959 the patient returned with the findings of superior vena caval obstruction. Angiograms showed a su erior vena caval obstruction, and surgery was advised. Dr. James Yee of the Oa land VA Hospital operated, and the obstruction was bypassed using a crimped, knitted Dacron graft from the end of the superior vena cava at the innominate junction to the cava within the pericardium, end-to-side. This soon became obstructed, and the syndrome recurred. In 1961 he became totally disabled. He is somewhat worse now; he must keep his head elevated almost constantly but has refused reoperation. In October, 1965, we saw a second patient, a 53-year-old man who had lived in Omaha years before. He had a l-year history of prickling and fullness in the head, particularly on bending over. These symptoms could not be explained on an organic basis, the physical and x-ray finding being negative. I n September, 1965, he had developed an obvious progressive superior vena caval obstruction syndrome. Angiograms showed almost complete obstruction of the cava by a medial external mass extending 4 cm.toward the heart. Barium esophagram and bronchoscopy revealed no neoplasm. At surgery done with Dr. S. N. Etheredge extensive biopsies revealed no tumor and showed the lymph node changes and extensive fibrosis described. The mass could not be removed nor the obstruction relieved. The superior vena cava was bypassed with a crimped, woven Dacron graft from the side of the left innominate vein to the superior vena cava within the pericardium, end-to-side. This avoided loss of any circulation still present in the cava. The patient’s symptoms and findings were immediately relieved and have remained so to date.
E
356
THE ANNALS OF THORACIC SURGERY
Fi brosing Med iastinit is
DR. HEWLETT: Our whole aim with this paper has been to remind our fellow thoracic surgeons that progressive fibrosing mediastinitis can be a rather deadly disease. I n the two patients we lost, we made a rather desperate effort to do plastic airway procedures to keep them alive. I think most of us will watch with interest what happens to those patients who have excision of granulomas, because all our patients who started out with a vena cava obstruction have eventually gone on to develop airway obstruction.
NOTICE FROM THE SOUTHERN THORACIC SURGICAL ASSOCIATION Abstracts are now being submitted for the Thirteenth Annual Meeting of the Southern Thoracic Surgical Association, to be held at the Grove Park Inn, Asheville, North Carolina, November 3-5, 1966. Double space abstracts and forward them in triplicate to Sam H. Stephenson, Jr., M.D., Chairman of the Program Committee, Southern Thoracic Surgical Association, Department of Surgery, Vanderbilt University Hospital, Nashville, Tennessee. Deadline for submission of abstracts is June 1, 1966. Further inquiries should be directed to Dr. Stephenson if additional information is desired. It is also suggested that members immediately make reservations at the Grove Park Inn if this has not already been done. Timothy Takaro, M.D., Veterans Administration Hospital, Oteen, North Carolina, is Chairman of the Local Arrangements Committee. HAWLEY H. SEILER,M.D.
Secretary-Treasurer
VOL. 2 , NO.
3,
MAY,
1966
357
A
report entitled “Mediastinal Tuberculoma” published by Samson et al. [16] in 1950 directed surgical attention to the problem of benign mediastinal adenopathy. Two of the patients in their report had symptoms of airway obstruction, and a third patient had a firm cervical mass fixed to the trachea. T h e pathological process was identical in the three patients. Specimens consisted of granulomatous masses containing central areas of caseation and peripheral bands of dense hyalinized fibrous tissue, with scattered foci of calcification, zones of epithelial cells, and occasional giant cells. Tuberculosis was not proved in any of these patients. Mediastinal g r a n u l o m a was the term applied to a similar pathological pattern occurring in patients reported by Kunkel et al. [l 11 in 1954. One of Kunkel’s patients who suffered with severe airway obstruction was considered inoperable. A second patient was treated for mitral stenosis, yet autopsy disclosed a subcarinal keloid type of reaction obstructing most of the pulmonary veins. These authors implied that such fibrosis might be the end result of granulomatous disease within the mediast inum. Gillespie’s report [7] of superior vena caval obstruction in a 7-yearold child appeared in 1956. In this patient vena caval obstruction developed as the residuum of a right pulmonary parenchymal infiltrate which was accompanied by positive histoplasmin skin tests and positive histoplasmin serology in high dilution. T h e symptoms of vena caval obstruction were completely alleviated by excising a portion of the dense fibrous tissue, unroofing approximately two-thirds of the circumference of the entrapped vessel. Histoplasrna capsulatum could not be demonstrated in the excised tissue. Barrett’s lengthy dissertation [ll on idiopathic mediastinal fibrosis appeared in 1958. T h e majority of his patients suffered from superior vena caval obstruction, and he postulated that probably other vital structures of the mediastinum were not jeopardized by the fibrosing From the Thoracic Surgical Service and the Department of Pathology, Fitzsimons General Hospital, Denver, Colo. ‘Present address: Fiesno County General Hospital, Fresno, Calif. Presented at the Second Annual Meeting of T h e Society of Thoracic Surgeons, Denver, Colo., Jan. 24-26, 1966. VOL. 2, NO.
3,
MAY,
1966
345
HEWLETT, STEER, AND THOMAS
process. However, time has shown that no structure within the mediastinum is immune to the compression and invasion potentials of this socalled benign process. Our interest in fibrosing mediastinitis began with two reports originating from Fitzsimons General Hospital in 1959. Salyer et ul. [15] and Lull and Winn [12] described a total of five patients in whom there could be little doubt that mediastinitis resulted from histoplasmosis. Airway obstruction and superior vena caval obstruction of tuberculous origin are rare in the experience of Fitzsimons Hospital. Brief review of some facts about histoplasmosis may aid in understanding the more than coincidental relationship between this disease and fibrosing mediastinitis. Curry and Wier [Z] in a careful study of 100 cases of histoplasmosis noted several facts of interest to the surgeon. Significant hilar adenopathy was detected radiographically in 68% of patients studied, and in 3775, hilar adenopathy was not associated with pulmonary parenchymal disease. Enlargement of mediastinal nodes appeared with both primary and reinfected disease. Calcification of involved nodes appeared gradually over a period of two to three years after the acute stage. T h e histoplasmosis focus, whether in the pulmonary parenchyma or within a lymph node, heals with a marked peripheral fibrosis which is not found in either tuberculosis or coccidioidomycosis. Thus obstruction of a portion of the airway, esophagus, or great vessels can develop insidiously, long after the acute phase of the initial infection has passed. Histoplasmin skin tests are accorded the same diagnostic significance as the tuberculin skin test, a positive reaction indicating infection with H. cupsulutum either past or present. T h e complement fixation test appears to be even more specific; positive skin tests were noted in 96% of the patients studied by Curry and Wier [2],and positive serology was recorded in 68%. Culture proof of histoplasmosis is difficult and is probably positive in 4% to 10% of patients depending on the phase of the disease at the time such studies are performed. An unpublished review of a 10-year experience with histoplasmosis at Fitzsimons General Hospital reveals that approximately 8% of patients will show some evidence of fibrosing mediastinitis. While there is no method of determining which patient with histoplasmosis will eventually develop mediastinitis, the factor of host resistance may be important in protecting the majority of histoplasmosis patients from a progressive fibrosis along lymphatic pathways. C L I N I C A L EXPERIENCE
A series of fourteen patients illustrates several facets of the course of progressive mediastinal fibrosis (Table 1). Two of the patients under346
THE ANNALS OF THORACIC SURGERY
History
Caval obstruction
5. 6333030
aPreviously reported.
White male 22 yr. R. A. C.
Caval obstruction
4. 4859007 White malc 42 yr. A. J. E.
Insidious onset: endemic area
Insidious onset; endemic area
Right mediastinal mass, total superior vena caval obstruction
Right superior mediastinal mass, total superior vena caval obstruction
Right superior mediastinal mass
Insidious onset; endemic area
Enlarging neck; caval obstruction
3. 445024a
White male 26 yr. G. G . N.
Right mediastinal mass with scattered calcification
Viral pneumonitis(7) while handling fertilizer; endemic area
None
5 X 6.5 X 5 cm.
2. 7608046 White male 23 yr. G. R. B.
Endemic area calcified mass, subcarinal zone, right main bronchus
None
Symptom Pattern
Negro male 23 yr. W. D.
1. 6590035
Itlen tity -_____
Radiographic Studies
+
+
+
+
+
Serology
+
+
+
Skin
Histo. Studies
Dense fibrous tissue occluding azygos and cava; Teflon bypass done
Total encasement of Cava and trachea with dense fibrous mass, spotted calcification; superior vena caval bypass, homograft done
Biopsy: caseating granuloma with H . capsulaturn; superior vena caval bypass done
6 X 2 X 1.5 granuloma with central caseation; positive H. capsuh turn
Granuloma
Surgical Pathology
Follow-up
Asymptomatic, 2 yr. Bypass was patent a t 90 days postoperative
6 yr. increasing airway obstruction, caval bypass Functional by angiogram
Chronic superior vena caval syndrome, gradual development respiratory symptom over 7 yr. period
Asymptomatic, 1 yr.
Asymptomatic, 1 vr.
TABLE 1. DETAILS OF FOURTEEN PATIENTS WITH PROGRESSIVE MEDIASTINAL FIBROSIS STUDIED
Airway obstruction (hemoptysis)
Airway obstruction (hemoptysis)
Airway obstruction (hemoptysis)
9. 3852027" White male 30 yr. H. L. E.
10. 4447033" Negro male 27 yr. E. W. A.
Insidious onset; endemic area
Insidious onset; endemic area
Single acute respiratory illness with pleural effusion; endemic area
Repeated respiratory infections; endemic area
Airway obstruction (hemoptysis)
8. 3722022" White female 50 yr. C. W. K.
Repeated respiratory infections; endemic area
Airway obstruction (hemoptysis)
6. 2899012 White male 31 yr. R. L. 7. 3379011" White male 23 yr. R. L. R.
History
Symptom Pattern
Identity
Infiltrate left midlung field
Right hilar mass
Left hilar mass, left pleural effusion, fibrotic left lower lobe
Bilateral hilar and adenopathy subcarinal mass
Left hilar mass; stenosis left lower lobe bronchus
Radiographic Studies
TABLE 1 (Continued)
+
+
+
+
+
+
+
t
Serology
Histo. Studies Skin
Fibrous mass involving all left mediastinum from lingula bronchi. Positive H. capsulatum
Tumor encircled right hilus occluding azygos and fixed to tracheal wall. Positive H. capsulatum. Inoperable
Trachea and carina encased in dense fibrous tissue: osseous metaplasia in biopsy. Inoperable
All lobes right lung diffuse nodular process; mediastinum rigid with diffuse infiltrating fibrosis. Node positive H. capsulatum
Biopsy only; considered inoperable
Surgical Pathology
4 yr. survival as gradually deteriorating respiratory cripple
8 yr. survival as deteriorating respiratory cripple: developed vena caval syndrome 1 yr. after exploration
gradually deteriorating respiratory cripple
7 yr. survival as
10 yr. survival as gradually deteriorating respiratory cripple
12 yr. survival as moderate pulmonary cripple
Follow-up
~
aPrevionsly reported.
R.c.
+
+
Circumscribed densities both lungs: subcarinal mass with narrowing both lower lobe bronchi
Repeated pneumonias; endemic area. 5 years progressive following middle lobectomy for so-called pseudotumors
Airway obstruction
14. 7080024 White female 31 yr.
+
+
Bilateral hilar adenopathy: bilateral hronchial occlusion
11 years of life lived over hatchery. 5 years of severe respiratory infections; endemic area
Airway obstruction
13. 6401046 White female 28 yr. P. C. H.
4-
TVidened mediastinum; cava displaced to right
Right middle lobe atelectasis resected 4 years before considered histoplasmosis. Gradual onset of cord paralysis on left side; endemic area
Airway obstruction: cord paralysis
12. 6983045 White female 35 yr. R. M. P.
t
Right hilar adenopathy with compression right lower and right middle bronchi
Repeated respiratory infections; endemic area
White male 8 yr. F. s.
Airway obstruction
11. 5203024
Subcarinal mass occluding left main-stem bronchus and invading pericardium: chondroplastic graft of airway done
Diffuse fibrous tissue invasion of bronchi and trachea
Sternal-split rnediastinal decortication of great vessels and trachea done; fibrous tissue invasion
Dense fibrosis encircling right bronchus extcnding through subcarinal area. Lohectomy deemed impossible: calcified flecks in biopsy
Died after airway plastic reconstruction
Died after airway plastic reconstruction
1 yr. doing well: cord paralysis cleared six weeks after operation
3 yr. limited activity because of decreasing respiratory capability
HEWLETT, STEER, AND THOMAS
went surgical treatment during the acute granulomatous stage of the disease and have been followed-up for only one year. It seems likely that such asymptomatic granulomatous foci within hilar nodes represent precursors of the late stages of the disease. Effler and Groves [3] and Williams and Burford 1191 have emphasized the ease with which such lesions are excised with insignificant morbidity. Such a procedure affords a possible means of preventing the development of progressive fibrosis, as it interrupts the continuity of the mediastinal lymphatic network. Twelve patients are examples of the later stages of progressive fibrosis; six of these were considered inoperable at the time of exploration. Ten of the twelve have been followed for long enough periods to clearly demonstrate the progressive downhill course to be anticipated as vital structure of the mediastinum becomes entrapped and invaded by a relentless disease process. Major airway obstruction was the clinical problem in nine of twelve patients with advanced disease, and superior vena caval obstruction was the problem in three. Two of three patients who were subjected to superior vena caval bypass procedures developed respiratory obstruction within a 6-year follow-up period, and one bypass continued to be functional at 6 years. One Teflon bypass was found functional at the end of 1 year. All patients had previously resided in an area where histoplasmosis was endemic. All had positive histoplasmin skin tests. Eight of ten studied by serological techniques were positive at some time during the course of the disease. Tuberculosis studies were negative in all patients. X-ray studies revealed pathology in each case: Figure 1 shows right hilar
FIG. 1. Case I : A 23-year-old Negro male with an asymptomatic subcarinal mass. X-ray of excised tissue.
350
THE ANNALS OF THORACIC SURGERY
Fibrosing Mediastinitis
FIG. 2. Case 5: A 22-year-old white male with insidious onset of superior vena caual obstruction. T h e uenogram shows degree of obstruction.
FIG. 3. Case 14: A 31-year-old white female. T h e bronchogram shows complete obstruction of right lower lobe bronchus with the siibcarinal mass narrowing the left main blronchus. VOL. 2, NO.
3,
MAY,
1966
351
HEWLETT, STEER, AND THOMAS
FIG. 4 . Case 14: Mediastinal fibrosis with pseudotumorous exteiasion obstructing a main bronchus and invnding the pericardium.
enlargeiiient which was asymptomatic, and Figure 2 is a venogram demonstrating almost complete obstruction of the superior vena cava in a young man with a positive histoplasmin skin test and positive serology. The severe degree of airway obstruction that may develop in the late stages of fibrosing mediastinitis is depicted in the bronchogram (Fig. 3). Calcification of the subcarinal gland complex is considered typical of old Histoplasma adenitis. One patient (No. 12, Table 1) combined airway obstruction and recurrent laryngeal nerve paralysis. This patient showed marked improvement in respiration and had return of vocal cord function after excision of fibrous tissue from the anterior mediastinum, suggesting that disruption of the continuity of fibrous tissue has palliative value if it can be carried out prior to the development of chronic infection in the lung parenchyma. Two patients with severe airway obstruction died within forty-eight hours of attempted bronchoplastic procedures; total excision of the fibrous tissue was technically impossible in both instances. The extent of the process is readily apparent in the photograph of a necropsy specimen (Fig. 4). HISTOPATHOLOGICAL OBSERVATIONS
Histopathological observations were based on tissue specimens from each patient and necropsy specimens from the two patients wEio died. Regardless of the site of origin, all specimens were characterized by dense cicatricial fibrous tissue composed of interlacing coarse fibers merging into a diffuse, homogeneous, hyalinized scar. Focal areas of caseation necrosis were found in seven specimens. Granulomatous reaction about the necrotic areas was minimal. Foci of caseation were sur352
THE ANNALS OF THORACIC SURGERY
Fibrosing Mediastinitis
FIG. 5. Case 8: Section of pulmonary hilus showing fibrosis and ossification.
rounded by a broad zone of hyalinized fibrous tissue and calcification and ossification was present in some areas (Fig. 5). T h e sclerosing reaction surrounded bronchi, blood vessels, and nerves, the area of fibrosis tending to stop abruptly, leaving a sharp margin between involved and uninvolved tissue. Bronchoscopic biopsies in some patients revealed hyalinization within the bronchial subrnucosa (Fig. 6). Microscopic
FIG. 6. Case 8: The bronchial biopsy shows squamous metaplasia and submucosal hyalinization. VOL. 2, NO.
3,
MAY,
1966
353
HEWLETT, STEER, AND THOMAS
studies of the tracheobronchial tree removed in the autopsies showed the sclerosing process replacing the connective tissue between the cartilagenous rings. Most of the specimens were cultured for fungi and acid-fast bacilli, but no cultures were positive. All specimens were subjected to intensive examination using special staining technics. Typical H. capsuZatu?n were seen in tissues from five of fourteen patients, and a few bodies resembling this fungus were seen in a sixth case. Sections from all cases were stained for acid-fast bacilli, all of which were negative. In one of the patients who died (No. 14, Table 1) there was almost complete right bronchial stenosis as a result of a mediastinal mass (see Fig. 4); in addition there was a large mass in the parenchyma of the left lung which was grossly and microscopically indistinguishable from the sclerotic tissue in the mediastinum. Histological sections show a picture of an indolent, continuing process which advances regardless of the lack of any evidence of an active or persistent fungal infection. This unusual reaction seems peculiar to the host and exhibits qualities of neoplasia which include limited selfperpetuation, invasion, and pseudometastasis. SUMMARY
Progressive fibrosing mediastinitis is a disease of the active age group (ages 20 to 45). It is not a benign process; rather it exhibits pseudomalignant characteristics. Clinical manifestations of the disease include major airway obstruction and superior vena caval obstruction. Esophageal obstruction did not occur in our small series of fourteen patients, but it should be noted that such obstructions due to granuloma were reported by Moore [14] in 1959 and more recently by Fifer et al. [5] in 1965. Our observations support the opinions of others that the late stages of the disease represent the end result of a granulomatous process within the mediastinum. The final distribution of fibrosis within the mediastinum appears to be along the lymphatic pathways draining the lungs, suggesting that the pulmonary parenchyma is the most likely site of the initial infection. Two of the more advanced cases in our series had areas of pulmonary parenchymal fibrosis identical with that occurring in the mediastinum. The histopathological picture of fibrosing mediastinitis was typical of that characterizing a healing histoplasmosis focus. It is more than coincidental that of fourteen patients in the study, histoplasmin skin tests were positive in all, serological examinations carried out on ten patients were positive in eight, positive identification of the fungus was possible in five, and all patients had lived in an area where histoplasmosis is endemic. Reports of many authors over past years have not mentioned the 354
THE ANNALS OF THORACIC SURGERY
Fibrosing Mediast in it is
use of H. cupsulutum diagnostic techniques in the study of patients with either mediastinal granulous or mediastinal fibrosis. T h e exception is the report of Ferguson and Burford [4]published in 1965, which implicates H. cupsulutum as the probable etiological agent in the majority of cases of mediastinal granuloma encountered in an area where histoplasmosis is endemic. Routine utilization of histoplasmosis skin and serological tests and specific information as regards past and present geographical areas of residence should aid in demonstrating the existence of the disease in patients with mediastinal adenopathy and fibrosis. There is no reported long-term follow-up on patients who have undergone excision of active granuloma, and it is hoped that prompt treatment of the active stage of the disease might prevent the development of spread along communicating lymphatic channels. Surgery in the late stages of the disease is fraught with technical difficulties and at best is palliative; it should be limited to partial decortication of vital structures. REFERENCES I. Barrett, N. R. Idiopathic mediastinal fibrosis. Brit. J. Surg. 46207, 1958. 2. Curry F. J., and Wier, J. A. Histoplasmosis. Amer. Rev. Tuberc. 77:749, 1958. 3. Effler, D. B., and Groves, L. K. Superior vena caval obstruction. Ann. Surg. 43:574, 1962. 4. Ferguson, T. B., and Burford, T. H. Mediastinal granuloma: A 15-year experience. Ann. Thorac. Surg. 1:125, 1965. 5. Fifer, W. R., Woellner, R. C., and Gordons, S. S. Mediastinal histoplasmosis: Report of three cases with dysphagia as the presenting complaint. Dis. Chest 47:518, 1965. 6 , Garamella, J. J., Stutzman, R. L., Varco, R. L., and Jensen, N. K. Subcarinal mediastinal granuloma causing esophageal obstruction. J. Thorac. Surg. 30:187, 1955. 7. Gillespie, J. B. Superior vena caval obstruction in childhood. J . Pediat. 49:320, 1956. 8. Grybowski, W. A., Crutcher, R. R., Halloway, J. B., Mayo, P., Segnitz, R., and Eiseman, B. The surgical aspects of histoplasmosis. Arch. Surg. (Chicago) 87:590, 1963. 9. Hache, L., Woolner, L. B., and Bernatz, P. E. Idiopathic fibrous mediastinitis. Dis. Chest 41:9, 1962. 10. Hawk, W. A., and Hazard, J. B. Sclerosing retroperitonitis and sclerosing mediastinitis. Amer. J. Cle'n. Path. 32321, 1959. 11. Kunkel, W. M., Clagett, 0. T., and McDonald, J. R. Mediastinal granuloma. J. Thorac. Surg. 27:565, 1954. 12. Lull, G. F., and Winn, D. F. Chronic fibrous mediastinitis due to histoplasma capsulatum. Radiology 73:367, 1959. 13. Miller, D. B., Allen, S. T., and Amidon, E. L. Obstruction of the superior vena cava presumably due to histoplasmosis. Amer. Rev. Tuberc. 77:848, 1958. 14. Moore, T. C. Esophageal obstruction due to mediastinal granuloma. J . Thorac. Szirg. 37: 127, 1959. VOL. 2, NO.
3,
MAY,
1966
355
HEWLETT, STEER, AND THOMAS 15. Salyer, J. M., Harrison, H. N., Winn, D. F., and Taylor, R. R. Chronic fibrous mediastinitis and superior vena caval obstruction due to histoplasmosis. Dis. Chest 35:364, 1959. 16. Samson, P. C., Heaton, L. D., and Dugan, D. J. Mediastinal tuberculoma. J. Thorac. Surg. 19:338, 1950. 17. Storey, C. F., and Lyon, H. A. Tuberculomas of the mediastinum. Amer. Rev. Tuberc. 64:327, 1951. 18. Straub, M., and Schwarz, J. Primary complex in histoplasmosis. Amer. J . Clin. Path. 25:727, 1955. 19. Williams, K. R., and Burford, T. H. Surgical treatment of granulomatous paratracheal lymphadenopathy. J. Thorac. Cardiov. Surg. 48: 13, 1964. DISCUSSION
DR. IVAN A. MAY (Oakland, Calif.): Dr. Hewlett’s slides show beautifully the stippled calcification throughout lymph nodes which Dr. Kenneth Hardy and I think is typical of histoplasmosis. People with the residuals of histoplasmosis are often seen far from endemic areas due to the migratory nature of our population today. We see many in California. We have seen two patients with superior vena caval obstruction attributed to lymph nodes and the associated fibrosing mediastinitis occurring after histoplasmosis. They were diagnosed clinically, having lived in an endemic area. They had positive skin tests for histoplasmosis and negative tests for other granulomas, and had stippled calcification of hilar and mediastinal lymph nodes. Their surgical findings and tissue sections were the same as those presented today. We did not identify H. capsulatum. In 1953 we saw the first patient, a 26-year-old man from Tennessee with recurrent hemoptysis due to erosion of the right upper lobe bronchus by calcified nodes. This represented a manifestation of airway obstruction described by Dr. Hewlett. The right upper lobe was removed. Dissection was technically difficult due to the calcified hilar nodes. There were extensive, hard, matted nodes around the superior cava which we avoided, although in retrospect it appears we should have attempted to remove them. I n 1959 the patient returned with the findings of superior vena caval obstruction. Angiograms showed a su erior vena caval obstruction, and surgery was advised. Dr. James Yee of the Oa land VA Hospital operated, and the obstruction was bypassed using a crimped, knitted Dacron graft from the end of the superior vena cava at the innominate junction to the cava within the pericardium, end-to-side. This soon became obstructed, and the syndrome recurred. In 1961 he became totally disabled. He is somewhat worse now; he must keep his head elevated almost constantly but has refused reoperation. In October, 1965, we saw a second patient, a 53-year-old man who had lived in Omaha years before. He had a l-year history of prickling and fullness in the head, particularly on bending over. These symptoms could not be explained on an organic basis, the physical and x-ray finding being negative. I n September, 1965, he had developed an obvious progressive superior vena caval obstruction syndrome. Angiograms showed almost complete obstruction of the cava by a medial external mass extending 4 cm.toward the heart. Barium esophagram and bronchoscopy revealed no neoplasm. At surgery done with Dr. S. N. Etheredge extensive biopsies revealed no tumor and showed the lymph node changes and extensive fibrosis described. The mass could not be removed nor the obstruction relieved. The superior vena cava was bypassed with a crimped, woven Dacron graft from the side of the left innominate vein to the superior vena cava within the pericardium, end-to-side. This avoided loss of any circulation still present in the cava. The patient’s symptoms and findings were immediately relieved and have remained so to date.
E
356
THE ANNALS OF THORACIC SURGERY
Fi brosing Med iastinit is
DR. HEWLETT: Our whole aim with this paper has been to remind our fellow thoracic surgeons that progressive fibrosing mediastinitis can be a rather deadly disease. I n the two patients we lost, we made a rather desperate effort to do plastic airway procedures to keep them alive. I think most of us will watch with interest what happens to those patients who have excision of granulomas, because all our patients who started out with a vena cava obstruction have eventually gone on to develop airway obstruction.
NOTICE FROM THE SOUTHERN THORACIC SURGICAL ASSOCIATION Abstracts are now being submitted for the Thirteenth Annual Meeting of the Southern Thoracic Surgical Association, to be held at the Grove Park Inn, Asheville, North Carolina, November 3-5, 1966. Double space abstracts and forward them in triplicate to Sam H. Stephenson, Jr., M.D., Chairman of the Program Committee, Southern Thoracic Surgical Association, Department of Surgery, Vanderbilt University Hospital, Nashville, Tennessee. Deadline for submission of abstracts is June 1, 1966. Further inquiries should be directed to Dr. Stephenson if additional information is desired. It is also suggested that members immediately make reservations at the Grove Park Inn if this has not already been done. Timothy Takaro, M.D., Veterans Administration Hospital, Oteen, North Carolina, is Chairman of the Local Arrangements Committee. HAWLEY H. SEILER,M.D.
Secretary-Treasurer
VOL. 2 , NO.
3,
MAY,
1966
357