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Open healing of tuberculous cavities
404
Tubercle, Lond., (I956), 37, 404
Open Healing of Tuberculous Cavities By R. Y. KEERS, R. W. RIDDELL and LYNNE REID from The Deeside Sanatoria, Aberdeenshire; Brompton Hospital; and the Institute if Diseases if the Chest, London One way in which a tuberculous cavity in the lung may heal is by replacement ofits wall with fibrous tissue, whilst its lumen persists as an air-containing space. 'Open healing' of this kind was so rare before the introduction of chemotherapy that Auerbach (1953) commented that in all the specimens he had examined from patients untreated by antibacterial drugs 'there were only two with open healing'; one ofthese he reported in 1940 when he also reviewed previous cases. Medlar (1956) stated that he had 'never seen a completely healed open tuberculous cavity'. Thus this type of healing was so rare that the possibility of its occurrence in no way influenced the management of a patient; clinically, the only cavity considered safe was a closed one. Since chemotherapy was introduced for the treatment of tuberculosis there has been an increase in the number ofreported cases of open healing ofcavities. The cavities usually present radiologically as thin-walled ring shadows which may be difficult to distinguish from bullae, or even from bronchiectatic spaces, if serial films and tomograms are not available for study. The radiological appearance and behaviour of these cavities were of particular interest to Johnsen and Hewitt ( I 954) and also to certain French physicians (Bernard and Carraud, 1953, 1954; Brun and others, 1954; Galy and others, 1955). It is still uncertain which is the best treatment for these persistent thin-walled cavities in patients who are sputum negative, for it is not yet established whether such cavities are indeed completely healed. Nor is it known what treatment with chemotherapy is necessary to ensure that they do heal. Information from pathological studies of resected cavities will prove an important guide. Unfortunately, at least in the large series described in the past, combined bacteriological and histological studies have been neglected, although the variation which has been shown to occur in different parts of a single cavity suggests that a detailed study of their walls is necessary. Thompson (1955), for example, studied the histological appe arance in 23 cases and included examination of Ziehl-Neelsen stains in all, but cultural studies were done on bronchial aspirates from only 4 specimens; no bacilli were identified by either of these methods. Altmann and Mishima (1956) also described the histological appearances in a group of these cavities, emphasizing the variation which occurs in different parts of the wall. Auerbach (1955 ) illustrated this variation in a single example of apparent open healing in a cavity with a smooth wall composed mainly of fibrous tissue exc ept for necrotic debris adherent to it in one area. From this tubercle bacilli were demonstrated by smear and culture. Adler and others (1955) reported both bacteriological and histological studies of 3 cavities which were 'smoothly lined cyst-like structures' with patent broncho-cavitary junctions; from these no bacilli were recovered by smear or culture. In many of the large series in which resected cavities have been studied bacteriologically, either the histological appearances are not given or the clinical features are not included. Raleigh and his colleagues '(195<1,) reported a group of patients who , though sput um negative for three months or more, had faUen short of 'target point' because of persistent cavities, Myco. tuberculosis was grown from one-third of the 53 specimens included in their series, but the mac roscopic and mi cro-
HEALED CAVITillS
scopic ap pearances of the cavity walls were not described . A year later, Raleigh ( 1955) recorded positive cultu res from 19 ofa further 5 [ specime ns from patien ts who had 'open' lesions and who were sputum negative. A large series of resected specime ns was examined bo th bacteriologically a nd pathologically by Ha ll an d Gleason ( 1953 ) and, although clinical features are not described, examples of the se thin-walled cavities appear to be inclu ded. They concl uded tha t the 'most histologically "inactive" cavitary lesions seem more likely to contain via ble tu ber cle bacilli than even the most "acti ve" caseous lesion'.
I t is still not possible to deduce, therefore, the clinical criteria upon which these cavities may be adjudged completely h ealed and no longer a source of danger to the patien t. The reports suggest that such cavities should be pronounced h ea led only after careful study. There are two ways in which further information may be o b tained : the first, and more conclusive, is by prolonged clinical follow-up of patients treated by chemotherapy alone; and the second, by examination of resected specimens, using both patho logical and bacteriological studies. T his paper deals with a series ofpatients seen in one thoracic unit. Some have been, or are still being, treated by chemotherapy alone, but their period of follow-up is short. O thers have been treated by resec tion and the la boratory findings on the operation material are reported below. Clinical Studies Fourteen patients seen in the fifteen m onths since March 1955 are included in this study. T here were 4 women and 10 men between the age of 18 and 4.2 (average age 34). In all cases the diagnosis of tuberculosis had been confirmed originally by demonstration of tubercle bacilli in the sputum. All patients received chemotherapy and in 10 this was combined with resection. After initial diagnosis by culture, sputum was examined monthly by smear while the result of this was positive, and when smears no longer showe:l bacilli, mor e frequent examinations an d cultures were made. Chemotherapy D etails of the dr ugs given to each patient are give n in Table I for those whose treatme nt included resection, and in T able II for th ose treated by chemotherapy T AULE 1. -
CLINICAL
AN D
BACTERIOLO GICAL D ET AI LS OF
T EN
PATIENTS TREATED BY CHEMOTHERAPY AND RESECTION
Duration of chemotherapy before operation Case No. I 2
3 4 S 6
7
8
gt lOt
months
Combination of drugs*
Total
SH - 5: SP - 3 SH - 2: SeH - 3: PH - 4: SP - 6 S2H - I I: (12)f SH-6 SH - 2: (S)t SH - 6 SHP -6: SzH -4: SHP - 2 SP - I : S2P - 5 : (II)f SP - 3 SH-2: SeH-g: (II)t SP-g oo SH -7 : S~P- 10: SP- 3 SH - 3: SHP- 5 SH - 12 ..
8 15
17 8 12
Period since last positive result months 6 4 10 6 9
9
4
14 20
4 14 9
8 12
*S - Streptomycin daily. Sa - Streptomycin twice a we ek. P - PAS (sodium sal t) daily. H - Isoniazid daily. tInterruption of chemo therapy. :tIn cases 9 an d ID the cavities did not fill a t b ronchogr aph y be fore opera tion .
TUBER OLE TABLE
II. -
CLINICAL DETAILS OF FOUR PATIENTS BY CHEMOTHERAPY ALONE
TREATED
t Duration
of chemotherapy before bronchography months
Case No. II 12 13 14
Combination of drugs"
- 7
S2 P SH-8 S2P - 10 SH - 7: SP -
Total 7 8 10
5:
PH - I
13
*S - Streptomycin daily. S. - Streptomycin twice a week. P - PAS (sodium salt) daily. H - Isoniazid daily. tIn all patients no positive bacteriological results were obtained after one month's treatment.
alone. With the exception of Case 9 all had received treatment by various combinations of drugs before they were admitted to the hospital. In 4 cases included in Table I chemotherapy was interrupted for some months in the pre-operative period and the length of this gap is indicated. In only I of these 4 patients (Case 7) had there been clinical deterioration during this time. Only 2 of the 10 cases included in Table I had less than six months' continuous chemotherapy immediately before operation. Radiographic Features (Figs. I - 8). In association with the satisfactory clinical response in these cases there was radiographic evidence of improvement with clearing of most of the shadows. But the ring shadows remained, having persisted for periods offrom four to eighteen months after the last positive bacteriological result had been obtained. Serial radiographs and tomograms made it possible to follow the evolution of these ring shadows from
FIG. r, - Anterior view radiograph of Case
The tip of the arrow is just above the upper margin of a thin-walled ring shadow. I.
FIG. 2. - Right lateral bronchogram showing the eavity in the anterior segment of the upper lobe (Case I).
HEALED CAVITIES
FIG. 3. - Anterior view radiograph of Case 3. The tip of the arrow is just medial to the edge of a thin-walled d ug shad ow,
FIG.•1.. - An terior Icft bronchogra m showing the cavity with a fluid level of ra dio-opaque mat erial and also bronchiec tasis in the up per lob e (Case 3).
cavities and excluded any question of their confusion with bullae. In serial films the cavi ty wall became progressively thinner in all but one case (Case 13), in which a thin-walled cavity at the right apex was known to have been present for a considerable time. In 10 of the 13 cases in which the wall became thinner, the aircontaining space remained the same size or became smaller, while in the other 3 cases
FIG. 5. - Anterior view rad iog rap h , A thinwalled ri ng shado w in the right up per zone wh ich, while difficult to see in a plain radiograph, was clearly demonstrated in a tomogr am. The arrow poin t is just above its upper m arg in (Case 8).
FIG. 6. - Anteri or righ t bronchogram showing cavity which is in a pico-posterior segment (Case 8).
TUBERCLE
FIG. 7. - Anterior view radiograph. The cavity in the left upper lobe is not clearly shown (Case 12).
FIG. 8. - Anterior left bronchogram showing cavity in the upper lobe outlined by radioopaque material. This patient was treated by chemotherapy alone (Case I~).
(Nos. 4, 9, 10) after three to five months' treatment with daily chemotherapy, there was not only thinning of the wall but a sudden and dramatic increase in the size of the cavity which remained distended until the time of operation. Routine bronchogram films and broncho-tomograms were taken in all patients. In 12 of them radio-opaque material entered I3 cavities; but in the remaining 2 patients the radio-opaque material did not enter the cavities, although in both cases there had been an increase in their size in earlier serial films. Folloui-up if Patients Treated by Chemotherapy Alone The 4 patients not treated by resection had received continuous chemotherapy, although in 2 of them (Cases I I and 13) streptomycin had not been given every day. These 4 patients have all been discharged from hospital ~ 2 (Nos. 1 I and 12) have been back at work for a year and 1 (No. 13) for nine months without any recurrence of symptoms or any suggestion of radiological or bacteriological change. The fourth patient (No. 14) has only recently been discharged. All these patients are still on chemotherapy, and like those treated by resection are under regular supervision. Pathological Studies METHODS OF EXAMINATION
The first 3 resection specimens were examined histologically only, special attention being paid to the brcncho-cavity junction as it was expected that epithelialization of the cavities was occurring. Microscopic examination of these first specimens showed that even if healing was progressing in parts of the wall, it was incomplete. For subsequent specimens, therefore, detailed bacteriological study was combined with histological examination. An aseptic technique was used whenever the specimen was handled so as to prevent contamination; and the use of alkalis or other bactericidal homogenizing agents was avoided when preparing material for culture. Specimens were examined within eighteen hours of removal. At the time of examination a summary of the case notes and a selection of radiographs, including the bronchograms and bronchotornograms, were available. In this way it was possible to locate approximately the position of the cavity and any other lesion of interest before any dissection was begun. Special search was made in every case for a communication between patent bronchi and the
HEALED CAVITIES
cavity. In some cases a broncho-cavity junction was obvious; but in others it was necessary to probe or dissect loculi of the cavity, or cut along the bronchial pathways from the hilum, before the relation of the cavity to the bronchial tree could be established. Pieces of tissue were removed for study, a fresh set of sterile instruments being used for each piece to prevent cross-contamination. Swabs were used where indicated for collecting accumulations of pus, swabbing the surface of a cavity lining, and for obtaining bronchial secretions. The number and size of tissue pieces removed was determined by the dimensions of the cavity.; not less than 2, and usually about 4, pieces were taken from each specimen. Where a broncho-cavitary junction was present it was included for section. As far as possible, pericavitary lesions were not taken when cutting pieces from the cavity wall. Lesions away from the cavity were examined similarly. In all, an average of 9 pieces werc taken for study from each operation specimen. The tissues selected were bisected for bacteriological and histopathological examinations.
Microscopic Examination For histological studies, sections were stained by haematoxylin-cosin, or Verhoeff van Giesen method. Bacteriological Examination The matevial for bacteriological investigation was homogenized with penicillin water (40 unitsrml.) and the homogenate halved. One-half was treated with an equal quantity of 4- per cent sodium hydroxide and the other left untreated. Both homogenates were then centrifuged and the deposits submitted to microscopic and cultural investigation. The whole area of thick smears, approximately I em. in diameter, stained with auramine were examined by fluorescence microscopy. Various media were inoculated, namely, Lowenstein-jensen medium, Dorset egg medium, Dubos Tween-albumin medium and enriched media (Middlebrook and others, 1954). Guinea-pigs were inoculated intramuscularly with 'untreated' portions of homogenized material, but as the results of these animal tests were never at variance with culture results they are not reported separately. In a bigger series, differences between the results of culture and animal inoculation might be expected to occur in the light of recent experience with atypical strains of Myco, tuberculosis. Sensitiviry Tests. - Sensitivity to streptomycin, l'AS and isoniazid was estimated for each culture isolated, and also sensitivity to pairs of these drugs in combination. Control tests using H37 Rv were included in every series. The tests were carried out using solid medium as soon as possible after the primary culture became positive. PAS and isoniazid were added to Lowenstein-jensen mcdium before inspissation in the concentrations indicated below. In the case of streptomycin, three times the concentrations quoted were incorporated since only about one-third of the drug remains free and active after inspissation. The following concentrations were used: Drugs singly (6 tubes): Streptomycin 3 /lg./ml. and 10 !"g./ml.; PAS 2 I-'g./ml. and 10 /lg./ml.; isoniazid I f'g.fml. and 5 J-Lg./ml. Drugs in pairs (6 tubes): Streptomycin 3 /lg./ml. with PAS Q J"g./ml. or isoniazid I fLg.fml.; streptomycin 10 f'g./ml. with PAS 10 f'g.fml. or isoniazid 5 l
As the purpose of the study was to decide whether or not the cavities were healed, this report is mainly concerned with the cavity wall, the broncho-cavitary junction if present, and the draining bronchus. Macroscopic Examination The walls of some cavities were uniform throughout, but in others the appearances varied in different parts. In Case 4, the wall was thin, smooth and shiny, but in Cases 2, 7 and 8, although parts were smooth, other parts were yellowish and granular in appearance. In several specimens this granular appearance was seen over only a few millimetres of the wall as a small white nodule, while in others a considerable part of the wall appeared rough. Caseous material adhered to the wall of some cavities, while others contained a small amount of thin yellow pus. The cavity was usually separated from surrounding lung by a thin white zone of fibrous tissue, often so thin that pink underlying lung showed through it. In other D
4.10
TUBERCLE
U
OF
C AY ".
FIG. 9. - Photomicrograph of wall of cavity (Case 2) consisting of fibrous tissue and lung. There is no evidence of tuberculosis. Bacilli were demonstrated both on smear ane! by culture of tissue from other parts of this wall. (x 95. Elastic van Gieson stain.)
cases the wall was opaque, white, and one or two millimetres thick. Where the adjacent lung was also diseased the definition of the cavity wall was less distinct. The lining of some of the cavities was uniformly smooth, whilst in others it was irregular due to trabeculae or to the presence of loculi of various sizes. Sometimes the loculi were many and small, each several millimetres in diameter, while in other instances, what at first appeared a loculus was subsequently shown on dissection to have a lumen almost as large as the cavity itself. The openings into these pouches resembled bronchial communications in having round smooth edges or sharp carinalike shapes, but probing and dissection of such loculi failed to reveal communication with the bronchial tree. Broncho-cavityjunction - In those cases in which radio-opaque material had entered the cavity at bronchography it was easy to demonstrate a bronchial communication on naked-eye examination, even if some initial doubt was experienced because of numerous loculi. The supplying bronchi were usually normal in calibre or somewhat dilated. In order to obtain some idea of the size of the bronchi supplying these cavities the number of branches between broncho-cavity junction and the hilum of the appropriate segments was counted in 6 cases, taking the segmental bronchus as the first generation. In 5 of the 6 specimens, the supplying bronchus was the fourth or fifth generation and in the other it was the sixth. It is concluded that these bronchi are well-supported by cartilage around the whole of their circumference (Hayward and Reid, 1952). The bronchi between the cavity and the hilum varied both in the thickness and regularity of their walls, and in the degree of dilatation; in none was
HEALED CAVITIES
LUME
OF CAVITY
FIG. 10. - Photomicrograph of another part of the wall of the same cavity illustrated in Fig. ~. showing here characteristic tuberculous granulation tissue including a giant cell. (x 437. Haematoxylin and eosin stain.)
there any evidence of stenosis. In the 2 cavities which had not filled at bronchography, no communication with the bronchial tree could be shown either by probing, dissecting, or cutting along bronchial pathways from the hilum. These cavities failed to collapse on compression before they were incised, a further indication of the absence of free communication with the bronchial tree.
Microscopic Examination A layer of fibrous tissue of varying thickness almost invariably separated the cavities from the surrounding lung. The inner surface of this layer was particularly examined for evidence of activity. The most striking feature was the variable histological appearance of the wall in different parts of the same cavity. In some parts it consisted of only a thin layer of fibrous tissue (Fig. 9), while in others a superficial layer of caseous material and typical granulation tissue was observed (Fig. IO). Frequently the broncho-cavity junction showed no evidence of tuberculosis, yet in sections from another part of the cavity typical tuberculous granulation tissue was demonstrable. This sometimes extended over a large part of the cavity lining, but in other cases was localized to several small foci each several millimetres in diameter. In one cavity two white nodules on an otherwise smooth wall were found to consist of giant and epithelioid cells and caseous tissue. As evidence of activity was found to be present even in cavities which appeared smooth and shiny on naked-eye examination, the importance of full histological examination of these cavities is apparent.
TUBEROLE
Epithelium Lining the Cavities. - None of these cavities was completely epithelialized. In several cases, however, where there was healing around the broncho-cavity junction, the epithelium had grown from the draining bronchus along the surface of the cavity for a maximum distance of 2 or 3 em. In one instance there were small isolated islands of epithelium in another part of the wall derived from small bronchioles lying in peri-cavity scar tissue. The epithelium which had grown from the large broncho-cavity junction was differentiated and included goblet cells; a basement membrane could be seen which became progressively thinner towards the extending edge. In those parts where the wall consisted only of fibrous tissue, the surface layer of fibroblasts was sometimes flattened and simulated epithelium. Where tuberculous granulation tissue formed the wall of the cavity up to the bronchocavitary junction, the draining bronchus showed no evidence of tuberculosis, except in one case. Here there were occasional Langhans' cells and focal collections of lymphocytes in the submucosa but the epithelium was intact. In several instances tuberculous lesions were present in hilar lymph nodes. In those cases where there was no macroscopic evidence of communication between the cavity and the bronchial tree, sec t'ons were examined for evidence of microscopic continuity with pulmonary tissue. In Case 10 two depressions in the wall were sectioned serially. Sections of one of these showed a mass of dense fibrous tissue containing a large blood vessel, but the other consisted of a small area of thinning of the cavity wall. At one point the 'wall' was so thin that it was formed by alveoli free of fibrous tissue. A similar appearance was seen in the second cavity where, over a small area, the wall adjacent to the alveoli consisted of a thin layer of tuberculous granulation tissue. Such microscopic communications with the lung tissue evidently sufficed to maintain air in these cavities either through alveoli or bronchioles. BACTERIOLOGICAL RESULTS
The bacteriological results are summarized in Table III. Smears were positive from 4 of 9 cavities resected from 8 patients; culture and guinea-pig inoculation were also positive in 4. In all, bacilli were identified in 5 of the 9 cavities by one or other of these methods. Bacilli were present in smears from other lesions in 4 of the 8 patients, but cultures were negative; from a further patient, tubercle bacilli were recovered by culture, though they were not seen in smears. In general, bacilli were scanty in cavities but numerous in caseous foci, though from the latter they were less frequently cultured. Sensitivity tests were carried out on the I I positive cultures grown from 4· cavities (3 patients). From one patient (Case 2) 3 resistant strains were recovered. Two of these (one grown from a cavity wall, and the other from main bronchus secretions) were partially resistant to streptomycin, resistant to PAS and sensitive to isoniazid; the third (grown from a second cavity wall) was partially resistant to streptomycin and sensitive to PAS and isoniazid. All these strains were sensitive to combinations of the three drugs. CONCLUSIONS
In interpreting the findings from pathological and bacteriological studies, the criteria for complete healing used by Melzer (1928) have been followed. These have also been accepted as a standard of healing by recent authors (Pagel and Simmonds, 1955; Thompson, 1955; Altmann and Mishima, 1956). Melzer stated that: 'Von einer vollkommenen Ausheilung wird fuglich nul' dann die Rede scin durfen, wenn die Hohle von fibrosern Gewebe uberall scharf abgegrcnzt wird, wenn sich keine Tuberkelbacillen mehr weder in cler Kavernenwancl noch in den tieferen Schichten nachweisen lassen, wenn sich nirgends Nekrose odcr Verkasung, nirgcnds tuberkuloses Granulationsgewebe finder; auch Tuberkelknotchen und Riesenzellen durfen nicht mehr zu finden sein.'
His ideal requirements were, therefore, that (i) the cavity should be well defined by fibrous tissue, (ii) there should be no tubercle bacilli in its wall and (iii) there should
HEALED CAVITIES TABLE III. - RESULTS OF BACTERIOLOGICAL AND HISTOLOGICAL EXAMINATION CAVITIES AND OTHER LESIONS IN TEN RESECTED SPECIMENS
Cavity*
Other lesions"
Case f%.
S
----_._--I 2
3 4
5 6 7 8
9+ 10+
C
-+ -+ -+ -+ -+ -+ -+ -+
H
S
C
+
-+ -+ -+ -+ -+ -+ -+ -+ + -+ -+ +
_L
+
H
+ + +
+ -+-I+ +
+
-I-I-
Portion (f 'ung resectedt
OF
Segment containing cavityt
RUL: Ap, RLL LUL
Ant. Ap. post
LUL: Ap. LLL Ap. post, ant LUL RLL post LUL: Ap. LLL LUL: Ap. LLL Ap. post RUL LUL LUL
Ap. post Post Ap. Ap. LLL Ap, post Ap. post Ap. post Ant.
*8 - Smear. C - Culture, H - Histological evidence of tuberculosis. tR - Right. L - Left. UL Upper lobe. LL - Lower lobe: Ap - Apical. Post - Posterior. Ant.Anterior. :j:In cases 9 and 10 the cavities did not fill at bronchography before operation.
be no necrosis, caseation, tuberculous granulation tissue, tubercles, or giant cells demonstrable histologically. We have adopted these as necessary for healing, with, in addition, sterility of the wall and contents. Four of I I cavities in this series were considered unhealed on macroscopic examination. In I of the 4, necrotic material was adherent to the cavity wall, while in the others the wall was granular or rough in parts on naked-eye inspection. The remaining 7 cavities, though sometimes irregular in contour, had smooth, shiny and often thin walls. The 4 cavities judged unhealed on naked-eye examination all contained characteristic tuberculous granulation tissue. Six of the remaining 7 cavities also showed tuberculous inflammation so that the naked-eye appearance of healing was not confirmed microscopically. In several sections the granulation tissue, which included multinuclear cells, occupied most of the wall, but in some instances it was present only over a very limited area. The histological state of healing cannot, therefore, be deduced from macroscopic appearances alone. Only one cavity appeared healed histologically (Case I) since fibrous tissue with a zone of macrophages and young fibroblasts were all that was seen in sections from 2 blocks taken from it. From this single cavity bacilli could not be demonstrated either by smear or culture. Two of the 4 cavities which had a granular appearance were examined bacteriologically, and bacilli were shown by smears and culture in one and in the other by cultures only. Of the 6 cavities which appeared healed macroscopically but not microscopically, bacteriological examination was done on 5. A total of 3 of the 5 cavities showed bacilli; smears were positive from 3 and cultures from 2. Both cavities in which a macroscopic communication with the bronchial tree had not been demonstrated by bronchography had smooth walls on naked-eye examination, yet histological evidence of activity was present. No bacilli were demonstrated, however, either by smear or culture. The results of the bacteriological studies show that from the cavities bacilli were, except in one instance, invariably grown from smear-positive material. In 3 patients, other lesions gave positive smears but the bacilli failed to grow. In one patient smears
lUBERCLE
from the cavity and from other lesions were all negative for bacilli although cultures from each site were grown. Discussion
Although bronchograms have been useful in this study for showing the size and position of cavities they have given no indication of the sta t e of healing of their walls. As most of these cavities did fill at bronchography whereas opaque material probably does not enter bullae, this method of investigation may help to distinguish the two conditions if previous radiographs and tomographs are not available to establish the diagnosis of cavitation. Two cavities in this series failed to fill; both of these had shown a sudden increase in size in serial radiographs and in neither of them could a bronchial communication be demonstrated. Although no particular mention is made in previous reports of the frequency with which a bronchial communication could be shown, it is implied that one was not always obvious. Thompson (1955) reports that 'practically all' of the cavities in his series 'had a demonstrable communication with one or more bronchi'. Pagel and Simmonds (1955) make a similar implication. Recently, Russell ancI his colleagues (1956) reported 3 cases in which bronchial communications could not be demonstrated macroscopically, even when search was made for them. In 2 of these there had been the same sudden increase in size which had been seen in 3 of our cases. This change in size, therefore, does not indicate that this ring shadow is a bulla rather than a cavity, as has been suggested by French authors. It is possible that the change is associated with obstruction at the broncho-cavity junction. Russell and his colleagues (1956) illustrated a small bronchiole which they found opening into one of their cavities and they postulated that microscopic bronchiolar openings were present in the others also. From the microscopic findings in our series it would seem that continuity between alveoli and the cavity lumen can maintain these cavities. The word 'cyst' (or 'cystic') has been avoided in this pathological and radiological description, as it would add further to imprecision in the use of this word in describing pulmonary lesions. There do es, however, seem to be some justification for using the word 'cyst' to describe those cavities in which a bronchial communication is no longer visible on naked-eye examination, as in the pathological definition a 'cyst' is described as a closed space. The majority of the cavities drained into large bronchi with comparatively rigid walls. This is probably one of the important factors in maintaining the patency of both the cavities and their bronchial communications, for where the communications are small they could more easily be obliterated. Cavities draining into large bronchi may, furthermore, be the product of more extensive lung destruction than those reaching only small bronchi. Demonstration of the patency of the bronchial communication of these cavities and the presence of tubercle bacilli in their walls, suggests that a more intensive search for bacilli either in sputum, laryngeal swab or gastric lavage might yield positive results more frequently. Before any of the cavities were considered completely healed Melzer's criteria had to be satisfied. Although these were formulated before the introduction of chemotherapy they can still be used as the stanclard of pathological healing. It seems necessary to add to these histological requirements that of
HEALED CAVITIES
bacteriological sterility before a cavity wall is considered healed. While the significance of bacilli which can be demonstrated by smear and yet which fail to grow on routine media is still undecided, there seems little reason to abandon former guarantees of safety. This phenomenon was seen in only one instance in cavity examinations, although amongst other lesions it occurred in 3 specimens. The detailed examination of the cavity walls has shown the striking variation in different parts and a combined histological and bacteriological examination would seem essential before the cavities are considered healed. The aseptic handling of specimens is an essential detail in bacteriological examination, especially in this type of case where bacilli may be expected to be scanty in numbers. By this means the lethal effects of tissue homogenizing agents may be avoided. Care must be taken also to prevent cross-contamination. Once these precautions are taken in the initial stages of the examination, enriched media may be inclucled to promote the growth of bacilli which may show atypical features. I t is difficult to compare results in this series of 'open healing' of cavities with others, since results of comparable bacteriological studies are not given. On the results of the pathological findings, only one of the cavities in this series can be described as 'healed'; but even in this case there was clear microscopic evidence of active tuberculosis elsewhere in the lung. This is not meant to imply either that healing is not occurring or that with a longer or different course of chemotherapy it would not be complete. The findings may, in fact, support the use of drugs for longer periods. Pathological studies such as those described here will provide a guide to the optimum duration of chemotherapy, although the careful clinical follow-up of such patients will be the ultimate test. Summary Fourteen patients treated with antibacterial drugs for pulmonary tuberculosis who had been sputum negative for periods offour to fourteen months and yet had persisting ring shadows at the site of radiologically proved cavities, were studied. The regimes of chemotherapy varied, but only 2 had had less than six months ofcontinuous chemotherapy immediately before operation. Bronchograms, including broncho-tomograms were taken in all cases. Radio-opaque material outlined 13 cavities in 12 patients but failed to enter cavities in the remaining 2. In assessing the combined bacteriological and pathological results of 10 resected specimens, Melzer's histological criteria for complete healing are adopted but with the additional requirement of bacterial sterility. Only one cavity studied from a patient who had received eight months' chemotherapy was considered healed by these standards. In all the other specimens, most of them from patients treated for longer periods, there was some evidence of activity. The most striking feature was the varying degree of activity and healing seen in different parts of any one cavity. It is concluded that a pathological diagnosis of 'healed cavity' cannot be made with certainty unless detailed histological and bacteriological studies are combined.
TUBERCLE It gives us pleasure to thank Mr F.]. Sambrook Gowar, Mr P. Brunnen and Mr H. Crum,.the surgeons who have co-operated in this investigation; and Dr G. Simon, who reported on the radiographs and bronchograrns, We are also grateful to the operating theatre staff, Tornadee; Miss Mavis Redman, technician in the Institu te of Diseases of the Chest; and the technical staff of the Bacteriology Department, Brompton Hospital. We thank Mr D. Kemp, Photographic Department, Institute of Diseases of the Chest, for the photographs. References Adler, R. H., Mantz, F. A., Cline,]., and Morse, W. C. (1955) Transactions of the 14th Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p, 172. Altmann, V., and Mishirna, T. (1956) Sea View Hosp., Bull., 16, I. Auerbach, 0., and Green, H. (194,0) Amer. Rev. Tuberc., 42, 707. Auerbach, O. (1953) Transactions of the r s th Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p. 224. Auerbach, O. (1955) Amer. Rev. Tuberc., 71, 165. Bernard, E., and Carraud,]. (1953) Rev. Tubere., Paris, 17, 1021. Bernard, E., and Carraud, J. (1954) Sem; Hop. Paris, 30, 4465. Bernou, A. a.nd Brun, J. (1955) Pro med., 63, 894. Brun,]., GUichard, A., al~d Combey, P. (1954) Rev. Tuberc., Paris, 18, 1222. Galy, P., Berard, M., Arribehauts, P. Touraine, R. G., and De Saint-Florent, - . (1953) Rev. Tuberc., Paris, 17, 1037. Hall, W. E., and Gleason, D. F. (1953) Transactions of the r sth Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p. 2 19. Hayward,]., and Reid, L. M. (1952) Thorax, 7,98. Johnsen, L., and Hewitt, W. C. (1954) Amer. Rev. Tuberc., 69, 1054. Medlar, E. M. (1955) Amer. Rev. Tuberc., 71 Part II, 92 • Melzer, E. (1928) Beitr, xu«, Tuberk., 70, 69'4.. Middlebrook, G.,. Cohn, M. L., and Shaefer, W. B. (1954) ArneI'. Rev. 7ilberc., 70, 852. Pagel, W., and SImmonds, F. A. H. (1955) Tubercle, Lond., 37,2. Pruv?st, P., Delarue, T., Meyer, A., ancI Depierre, -. (1953) R.ev. Tuberc., Paris 17, 1?46. RaleIgh,]. W., Mather, C. M., Decker, A. M., and Bernstein, S. (1954) Transactions of the 13th Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p.289. Raleigh,]. W., Kaz lowski, J., Brosbe, E. A., and Stecnkcn, W. (1955) Transactions of the 14th Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p. x87· Rappaport, 1. (1955) ]. Amer. med. Ass., 158, 1436. Russell, W. F., Dressler, S. H., Middlebrook, G., and Denst, J. (x956) Amer. Rev. Tuberc., 73, 944. Simonon, -., Girard, -., Lochard, -., and Sadou!, -t-, (1953) Rev. Tuberc., Paris, 17,1051. Thompson,.J. R. (1955) Amer. Reo. Tuberc., 72, 60r.
Tubercle, Lond., (I956), 37, 404
Open Healing of Tuberculous Cavities By R. Y. KEERS, R. W. RIDDELL and LYNNE REID from The Deeside Sanatoria, Aberdeenshire; Brompton Hospital; and the Institute if Diseases if the Chest, London One way in which a tuberculous cavity in the lung may heal is by replacement ofits wall with fibrous tissue, whilst its lumen persists as an air-containing space. 'Open healing' of this kind was so rare before the introduction of chemotherapy that Auerbach (1953) commented that in all the specimens he had examined from patients untreated by antibacterial drugs 'there were only two with open healing'; one ofthese he reported in 1940 when he also reviewed previous cases. Medlar (1956) stated that he had 'never seen a completely healed open tuberculous cavity'. Thus this type of healing was so rare that the possibility of its occurrence in no way influenced the management of a patient; clinically, the only cavity considered safe was a closed one. Since chemotherapy was introduced for the treatment of tuberculosis there has been an increase in the number ofreported cases of open healing ofcavities. The cavities usually present radiologically as thin-walled ring shadows which may be difficult to distinguish from bullae, or even from bronchiectatic spaces, if serial films and tomograms are not available for study. The radiological appearance and behaviour of these cavities were of particular interest to Johnsen and Hewitt ( I 954) and also to certain French physicians (Bernard and Carraud, 1953, 1954; Brun and others, 1954; Galy and others, 1955). It is still uncertain which is the best treatment for these persistent thin-walled cavities in patients who are sputum negative, for it is not yet established whether such cavities are indeed completely healed. Nor is it known what treatment with chemotherapy is necessary to ensure that they do heal. Information from pathological studies of resected cavities will prove an important guide. Unfortunately, at least in the large series described in the past, combined bacteriological and histological studies have been neglected, although the variation which has been shown to occur in different parts of a single cavity suggests that a detailed study of their walls is necessary. Thompson (1955), for example, studied the histological appe arance in 23 cases and included examination of Ziehl-Neelsen stains in all, but cultural studies were done on bronchial aspirates from only 4 specimens; no bacilli were identified by either of these methods. Altmann and Mishima (1956) also described the histological appearances in a group of these cavities, emphasizing the variation which occurs in different parts of the wall. Auerbach (1955 ) illustrated this variation in a single example of apparent open healing in a cavity with a smooth wall composed mainly of fibrous tissue exc ept for necrotic debris adherent to it in one area. From this tubercle bacilli were demonstrated by smear and culture. Adler and others (1955) reported both bacteriological and histological studies of 3 cavities which were 'smoothly lined cyst-like structures' with patent broncho-cavitary junctions; from these no bacilli were recovered by smear or culture. In many of the large series in which resected cavities have been studied bacteriologically, either the histological appearances are not given or the clinical features are not included. Raleigh and his colleagues '(195<1,) reported a group of patients who , though sput um negative for three months or more, had faUen short of 'target point' because of persistent cavities, Myco. tuberculosis was grown from one-third of the 53 specimens included in their series, but the mac roscopic and mi cro-
HEALED CAVITillS
scopic ap pearances of the cavity walls were not described . A year later, Raleigh ( 1955) recorded positive cultu res from 19 ofa further 5 [ specime ns from patien ts who had 'open' lesions and who were sputum negative. A large series of resected specime ns was examined bo th bacteriologically a nd pathologically by Ha ll an d Gleason ( 1953 ) and, although clinical features are not described, examples of the se thin-walled cavities appear to be inclu ded. They concl uded tha t the 'most histologically "inactive" cavitary lesions seem more likely to contain via ble tu ber cle bacilli than even the most "acti ve" caseous lesion'.
I t is still not possible to deduce, therefore, the clinical criteria upon which these cavities may be adjudged completely h ealed and no longer a source of danger to the patien t. The reports suggest that such cavities should be pronounced h ea led only after careful study. There are two ways in which further information may be o b tained : the first, and more conclusive, is by prolonged clinical follow-up of patients treated by chemotherapy alone; and the second, by examination of resected specimens, using both patho logical and bacteriological studies. T his paper deals with a series ofpatients seen in one thoracic unit. Some have been, or are still being, treated by chemotherapy alone, but their period of follow-up is short. O thers have been treated by resec tion and the la boratory findings on the operation material are reported below. Clinical Studies Fourteen patients seen in the fifteen m onths since March 1955 are included in this study. T here were 4 women and 10 men between the age of 18 and 4.2 (average age 34). In all cases the diagnosis of tuberculosis had been confirmed originally by demonstration of tubercle bacilli in the sputum. All patients received chemotherapy and in 10 this was combined with resection. After initial diagnosis by culture, sputum was examined monthly by smear while the result of this was positive, and when smears no longer showe:l bacilli, mor e frequent examinations an d cultures were made. Chemotherapy D etails of the dr ugs given to each patient are give n in Table I for those whose treatme nt included resection, and in T able II for th ose treated by chemotherapy T AULE 1. -
CLINICAL
AN D
BACTERIOLO GICAL D ET AI LS OF
T EN
PATIENTS TREATED BY CHEMOTHERAPY AND RESECTION
Duration of chemotherapy before operation Case No. I 2
3 4 S 6
7
8
gt lOt
months
Combination of drugs*
Total
SH - 5: SP - 3 SH - 2: SeH - 3: PH - 4: SP - 6 S2H - I I: (12)f SH-6 SH - 2: (S)t SH - 6 SHP -6: SzH -4: SHP - 2 SP - I : S2P - 5 : (II)f SP - 3 SH-2: SeH-g: (II)t SP-g oo SH -7 : S~P- 10: SP- 3 SH - 3: SHP- 5 SH - 12 ..
8 15
17 8 12
Period since last positive result months 6 4 10 6 9
9
4
14 20
4 14 9
8 12
*S - Streptomycin daily. Sa - Streptomycin twice a we ek. P - PAS (sodium sal t) daily. H - Isoniazid daily. tInterruption of chemo therapy. :tIn cases 9 an d ID the cavities did not fill a t b ronchogr aph y be fore opera tion .
TUBER OLE TABLE
II. -
CLINICAL DETAILS OF FOUR PATIENTS BY CHEMOTHERAPY ALONE
TREATED
t Duration
of chemotherapy before bronchography months
Case No. II 12 13 14
Combination of drugs"
- 7
S2 P SH-8 S2P - 10 SH - 7: SP -
Total 7 8 10
5:
PH - I
13
*S - Streptomycin daily. S. - Streptomycin twice a week. P - PAS (sodium salt) daily. H - Isoniazid daily. tIn all patients no positive bacteriological results were obtained after one month's treatment.
alone. With the exception of Case 9 all had received treatment by various combinations of drugs before they were admitted to the hospital. In 4 cases included in Table I chemotherapy was interrupted for some months in the pre-operative period and the length of this gap is indicated. In only I of these 4 patients (Case 7) had there been clinical deterioration during this time. Only 2 of the 10 cases included in Table I had less than six months' continuous chemotherapy immediately before operation. Radiographic Features (Figs. I - 8). In association with the satisfactory clinical response in these cases there was radiographic evidence of improvement with clearing of most of the shadows. But the ring shadows remained, having persisted for periods offrom four to eighteen months after the last positive bacteriological result had been obtained. Serial radiographs and tomograms made it possible to follow the evolution of these ring shadows from
FIG. r, - Anterior view radiograph of Case
The tip of the arrow is just above the upper margin of a thin-walled ring shadow. I.
FIG. 2. - Right lateral bronchogram showing the eavity in the anterior segment of the upper lobe (Case I).
HEALED CAVITIES
FIG. 3. - Anterior view radiograph of Case 3. The tip of the arrow is just medial to the edge of a thin-walled d ug shad ow,
FIG.•1.. - An terior Icft bronchogra m showing the cavity with a fluid level of ra dio-opaque mat erial and also bronchiec tasis in the up per lob e (Case 3).
cavities and excluded any question of their confusion with bullae. In serial films the cavi ty wall became progressively thinner in all but one case (Case 13), in which a thin-walled cavity at the right apex was known to have been present for a considerable time. In 10 of the 13 cases in which the wall became thinner, the aircontaining space remained the same size or became smaller, while in the other 3 cases
FIG. 5. - Anterior view rad iog rap h , A thinwalled ri ng shado w in the right up per zone wh ich, while difficult to see in a plain radiograph, was clearly demonstrated in a tomogr am. The arrow poin t is just above its upper m arg in (Case 8).
FIG. 6. - Anteri or righ t bronchogram showing cavity which is in a pico-posterior segment (Case 8).
TUBERCLE
FIG. 7. - Anterior view radiograph. The cavity in the left upper lobe is not clearly shown (Case 12).
FIG. 8. - Anterior left bronchogram showing cavity in the upper lobe outlined by radioopaque material. This patient was treated by chemotherapy alone (Case I~).
(Nos. 4, 9, 10) after three to five months' treatment with daily chemotherapy, there was not only thinning of the wall but a sudden and dramatic increase in the size of the cavity which remained distended until the time of operation. Routine bronchogram films and broncho-tomograms were taken in all patients. In 12 of them radio-opaque material entered I3 cavities; but in the remaining 2 patients the radio-opaque material did not enter the cavities, although in both cases there had been an increase in their size in earlier serial films. Folloui-up if Patients Treated by Chemotherapy Alone The 4 patients not treated by resection had received continuous chemotherapy, although in 2 of them (Cases I I and 13) streptomycin had not been given every day. These 4 patients have all been discharged from hospital ~ 2 (Nos. 1 I and 12) have been back at work for a year and 1 (No. 13) for nine months without any recurrence of symptoms or any suggestion of radiological or bacteriological change. The fourth patient (No. 14) has only recently been discharged. All these patients are still on chemotherapy, and like those treated by resection are under regular supervision. Pathological Studies METHODS OF EXAMINATION
The first 3 resection specimens were examined histologically only, special attention being paid to the brcncho-cavity junction as it was expected that epithelialization of the cavities was occurring. Microscopic examination of these first specimens showed that even if healing was progressing in parts of the wall, it was incomplete. For subsequent specimens, therefore, detailed bacteriological study was combined with histological examination. An aseptic technique was used whenever the specimen was handled so as to prevent contamination; and the use of alkalis or other bactericidal homogenizing agents was avoided when preparing material for culture. Specimens were examined within eighteen hours of removal. At the time of examination a summary of the case notes and a selection of radiographs, including the bronchograms and bronchotornograms, were available. In this way it was possible to locate approximately the position of the cavity and any other lesion of interest before any dissection was begun. Special search was made in every case for a communication between patent bronchi and the
HEALED CAVITIES
cavity. In some cases a broncho-cavity junction was obvious; but in others it was necessary to probe or dissect loculi of the cavity, or cut along the bronchial pathways from the hilum, before the relation of the cavity to the bronchial tree could be established. Pieces of tissue were removed for study, a fresh set of sterile instruments being used for each piece to prevent cross-contamination. Swabs were used where indicated for collecting accumulations of pus, swabbing the surface of a cavity lining, and for obtaining bronchial secretions. The number and size of tissue pieces removed was determined by the dimensions of the cavity.; not less than 2, and usually about 4, pieces were taken from each specimen. Where a broncho-cavitary junction was present it was included for section. As far as possible, pericavitary lesions were not taken when cutting pieces from the cavity wall. Lesions away from the cavity were examined similarly. In all, an average of 9 pieces werc taken for study from each operation specimen. The tissues selected were bisected for bacteriological and histopathological examinations.
Microscopic Examination For histological studies, sections were stained by haematoxylin-cosin, or Verhoeff van Giesen method. Bacteriological Examination The matevial for bacteriological investigation was homogenized with penicillin water (40 unitsrml.) and the homogenate halved. One-half was treated with an equal quantity of 4- per cent sodium hydroxide and the other left untreated. Both homogenates were then centrifuged and the deposits submitted to microscopic and cultural investigation. The whole area of thick smears, approximately I em. in diameter, stained with auramine were examined by fluorescence microscopy. Various media were inoculated, namely, Lowenstein-jensen medium, Dorset egg medium, Dubos Tween-albumin medium and enriched media (Middlebrook and others, 1954). Guinea-pigs were inoculated intramuscularly with 'untreated' portions of homogenized material, but as the results of these animal tests were never at variance with culture results they are not reported separately. In a bigger series, differences between the results of culture and animal inoculation might be expected to occur in the light of recent experience with atypical strains of Myco, tuberculosis. Sensitiviry Tests. - Sensitivity to streptomycin, l'AS and isoniazid was estimated for each culture isolated, and also sensitivity to pairs of these drugs in combination. Control tests using H37 Rv were included in every series. The tests were carried out using solid medium as soon as possible after the primary culture became positive. PAS and isoniazid were added to Lowenstein-jensen mcdium before inspissation in the concentrations indicated below. In the case of streptomycin, three times the concentrations quoted were incorporated since only about one-third of the drug remains free and active after inspissation. The following concentrations were used: Drugs singly (6 tubes): Streptomycin 3 /lg./ml. and 10 !"g./ml.; PAS 2 I-'g./ml. and 10 /lg./ml.; isoniazid I f'g.fml. and 5 J-Lg./ml. Drugs in pairs (6 tubes): Streptomycin 3 /lg./ml. with PAS Q J"g./ml. or isoniazid I fLg.fml.; streptomycin 10 f'g./ml. with PAS 10 f'g.fml. or isoniazid 5 l
As the purpose of the study was to decide whether or not the cavities were healed, this report is mainly concerned with the cavity wall, the broncho-cavitary junction if present, and the draining bronchus. Macroscopic Examination The walls of some cavities were uniform throughout, but in others the appearances varied in different parts. In Case 4, the wall was thin, smooth and shiny, but in Cases 2, 7 and 8, although parts were smooth, other parts were yellowish and granular in appearance. In several specimens this granular appearance was seen over only a few millimetres of the wall as a small white nodule, while in others a considerable part of the wall appeared rough. Caseous material adhered to the wall of some cavities, while others contained a small amount of thin yellow pus. The cavity was usually separated from surrounding lung by a thin white zone of fibrous tissue, often so thin that pink underlying lung showed through it. In other D
4.10
TUBERCLE
U
OF
C AY ".
FIG. 9. - Photomicrograph of wall of cavity (Case 2) consisting of fibrous tissue and lung. There is no evidence of tuberculosis. Bacilli were demonstrated both on smear ane! by culture of tissue from other parts of this wall. (x 95. Elastic van Gieson stain.)
cases the wall was opaque, white, and one or two millimetres thick. Where the adjacent lung was also diseased the definition of the cavity wall was less distinct. The lining of some of the cavities was uniformly smooth, whilst in others it was irregular due to trabeculae or to the presence of loculi of various sizes. Sometimes the loculi were many and small, each several millimetres in diameter, while in other instances, what at first appeared a loculus was subsequently shown on dissection to have a lumen almost as large as the cavity itself. The openings into these pouches resembled bronchial communications in having round smooth edges or sharp carinalike shapes, but probing and dissection of such loculi failed to reveal communication with the bronchial tree. Broncho-cavityjunction - In those cases in which radio-opaque material had entered the cavity at bronchography it was easy to demonstrate a bronchial communication on naked-eye examination, even if some initial doubt was experienced because of numerous loculi. The supplying bronchi were usually normal in calibre or somewhat dilated. In order to obtain some idea of the size of the bronchi supplying these cavities the number of branches between broncho-cavity junction and the hilum of the appropriate segments was counted in 6 cases, taking the segmental bronchus as the first generation. In 5 of the 6 specimens, the supplying bronchus was the fourth or fifth generation and in the other it was the sixth. It is concluded that these bronchi are well-supported by cartilage around the whole of their circumference (Hayward and Reid, 1952). The bronchi between the cavity and the hilum varied both in the thickness and regularity of their walls, and in the degree of dilatation; in none was
HEALED CAVITIES
LUME
OF CAVITY
FIG. 10. - Photomicrograph of another part of the wall of the same cavity illustrated in Fig. ~. showing here characteristic tuberculous granulation tissue including a giant cell. (x 437. Haematoxylin and eosin stain.)
there any evidence of stenosis. In the 2 cavities which had not filled at bronchography, no communication with the bronchial tree could be shown either by probing, dissecting, or cutting along bronchial pathways from the hilum. These cavities failed to collapse on compression before they were incised, a further indication of the absence of free communication with the bronchial tree.
Microscopic Examination A layer of fibrous tissue of varying thickness almost invariably separated the cavities from the surrounding lung. The inner surface of this layer was particularly examined for evidence of activity. The most striking feature was the variable histological appearance of the wall in different parts of the same cavity. In some parts it consisted of only a thin layer of fibrous tissue (Fig. 9), while in others a superficial layer of caseous material and typical granulation tissue was observed (Fig. IO). Frequently the broncho-cavity junction showed no evidence of tuberculosis, yet in sections from another part of the cavity typical tuberculous granulation tissue was demonstrable. This sometimes extended over a large part of the cavity lining, but in other cases was localized to several small foci each several millimetres in diameter. In one cavity two white nodules on an otherwise smooth wall were found to consist of giant and epithelioid cells and caseous tissue. As evidence of activity was found to be present even in cavities which appeared smooth and shiny on naked-eye examination, the importance of full histological examination of these cavities is apparent.
TUBEROLE
Epithelium Lining the Cavities. - None of these cavities was completely epithelialized. In several cases, however, where there was healing around the broncho-cavity junction, the epithelium had grown from the draining bronchus along the surface of the cavity for a maximum distance of 2 or 3 em. In one instance there were small isolated islands of epithelium in another part of the wall derived from small bronchioles lying in peri-cavity scar tissue. The epithelium which had grown from the large broncho-cavity junction was differentiated and included goblet cells; a basement membrane could be seen which became progressively thinner towards the extending edge. In those parts where the wall consisted only of fibrous tissue, the surface layer of fibroblasts was sometimes flattened and simulated epithelium. Where tuberculous granulation tissue formed the wall of the cavity up to the bronchocavitary junction, the draining bronchus showed no evidence of tuberculosis, except in one case. Here there were occasional Langhans' cells and focal collections of lymphocytes in the submucosa but the epithelium was intact. In several instances tuberculous lesions were present in hilar lymph nodes. In those cases where there was no macroscopic evidence of communication between the cavity and the bronchial tree, sec t'ons were examined for evidence of microscopic continuity with pulmonary tissue. In Case 10 two depressions in the wall were sectioned serially. Sections of one of these showed a mass of dense fibrous tissue containing a large blood vessel, but the other consisted of a small area of thinning of the cavity wall. At one point the 'wall' was so thin that it was formed by alveoli free of fibrous tissue. A similar appearance was seen in the second cavity where, over a small area, the wall adjacent to the alveoli consisted of a thin layer of tuberculous granulation tissue. Such microscopic communications with the lung tissue evidently sufficed to maintain air in these cavities either through alveoli or bronchioles. BACTERIOLOGICAL RESULTS
The bacteriological results are summarized in Table III. Smears were positive from 4 of 9 cavities resected from 8 patients; culture and guinea-pig inoculation were also positive in 4. In all, bacilli were identified in 5 of the 9 cavities by one or other of these methods. Bacilli were present in smears from other lesions in 4 of the 8 patients, but cultures were negative; from a further patient, tubercle bacilli were recovered by culture, though they were not seen in smears. In general, bacilli were scanty in cavities but numerous in caseous foci, though from the latter they were less frequently cultured. Sensitivity tests were carried out on the I I positive cultures grown from 4· cavities (3 patients). From one patient (Case 2) 3 resistant strains were recovered. Two of these (one grown from a cavity wall, and the other from main bronchus secretions) were partially resistant to streptomycin, resistant to PAS and sensitive to isoniazid; the third (grown from a second cavity wall) was partially resistant to streptomycin and sensitive to PAS and isoniazid. All these strains were sensitive to combinations of the three drugs. CONCLUSIONS
In interpreting the findings from pathological and bacteriological studies, the criteria for complete healing used by Melzer (1928) have been followed. These have also been accepted as a standard of healing by recent authors (Pagel and Simmonds, 1955; Thompson, 1955; Altmann and Mishima, 1956). Melzer stated that: 'Von einer vollkommenen Ausheilung wird fuglich nul' dann die Rede scin durfen, wenn die Hohle von fibrosern Gewebe uberall scharf abgegrcnzt wird, wenn sich keine Tuberkelbacillen mehr weder in cler Kavernenwancl noch in den tieferen Schichten nachweisen lassen, wenn sich nirgends Nekrose odcr Verkasung, nirgcnds tuberkuloses Granulationsgewebe finder; auch Tuberkelknotchen und Riesenzellen durfen nicht mehr zu finden sein.'
His ideal requirements were, therefore, that (i) the cavity should be well defined by fibrous tissue, (ii) there should be no tubercle bacilli in its wall and (iii) there should
HEALED CAVITIES TABLE III. - RESULTS OF BACTERIOLOGICAL AND HISTOLOGICAL EXAMINATION CAVITIES AND OTHER LESIONS IN TEN RESECTED SPECIMENS
Cavity*
Other lesions"
Case f%.
S
----_._--I 2
3 4
5 6 7 8
9+ 10+
C
-+ -+ -+ -+ -+ -+ -+ -+
H
S
C
+
-+ -+ -+ -+ -+ -+ -+ -+ + -+ -+ +
_L
+
H
+ + +
+ -+-I+ +
+
-I-I-
Portion (f 'ung resectedt
OF
Segment containing cavityt
RUL: Ap, RLL LUL
Ant. Ap. post
LUL: Ap. LLL Ap. post, ant LUL RLL post LUL: Ap. LLL LUL: Ap. LLL Ap. post RUL LUL LUL
Ap. post Post Ap. Ap. LLL Ap, post Ap. post Ap. post Ant.
*8 - Smear. C - Culture, H - Histological evidence of tuberculosis. tR - Right. L - Left. UL Upper lobe. LL - Lower lobe: Ap - Apical. Post - Posterior. Ant.Anterior. :j:In cases 9 and 10 the cavities did not fill at bronchography before operation.
be no necrosis, caseation, tuberculous granulation tissue, tubercles, or giant cells demonstrable histologically. We have adopted these as necessary for healing, with, in addition, sterility of the wall and contents. Four of I I cavities in this series were considered unhealed on macroscopic examination. In I of the 4, necrotic material was adherent to the cavity wall, while in the others the wall was granular or rough in parts on naked-eye inspection. The remaining 7 cavities, though sometimes irregular in contour, had smooth, shiny and often thin walls. The 4 cavities judged unhealed on naked-eye examination all contained characteristic tuberculous granulation tissue. Six of the remaining 7 cavities also showed tuberculous inflammation so that the naked-eye appearance of healing was not confirmed microscopically. In several sections the granulation tissue, which included multinuclear cells, occupied most of the wall, but in some instances it was present only over a very limited area. The histological state of healing cannot, therefore, be deduced from macroscopic appearances alone. Only one cavity appeared healed histologically (Case I) since fibrous tissue with a zone of macrophages and young fibroblasts were all that was seen in sections from 2 blocks taken from it. From this single cavity bacilli could not be demonstrated either by smear or culture. Two of the 4 cavities which had a granular appearance were examined bacteriologically, and bacilli were shown by smears and culture in one and in the other by cultures only. Of the 6 cavities which appeared healed macroscopically but not microscopically, bacteriological examination was done on 5. A total of 3 of the 5 cavities showed bacilli; smears were positive from 3 and cultures from 2. Both cavities in which a macroscopic communication with the bronchial tree had not been demonstrated by bronchography had smooth walls on naked-eye examination, yet histological evidence of activity was present. No bacilli were demonstrated, however, either by smear or culture. The results of the bacteriological studies show that from the cavities bacilli were, except in one instance, invariably grown from smear-positive material. In 3 patients, other lesions gave positive smears but the bacilli failed to grow. In one patient smears
lUBERCLE
from the cavity and from other lesions were all negative for bacilli although cultures from each site were grown. Discussion
Although bronchograms have been useful in this study for showing the size and position of cavities they have given no indication of the sta t e of healing of their walls. As most of these cavities did fill at bronchography whereas opaque material probably does not enter bullae, this method of investigation may help to distinguish the two conditions if previous radiographs and tomographs are not available to establish the diagnosis of cavitation. Two cavities in this series failed to fill; both of these had shown a sudden increase in size in serial radiographs and in neither of them could a bronchial communication be demonstrated. Although no particular mention is made in previous reports of the frequency with which a bronchial communication could be shown, it is implied that one was not always obvious. Thompson (1955) reports that 'practically all' of the cavities in his series 'had a demonstrable communication with one or more bronchi'. Pagel and Simmonds (1955) make a similar implication. Recently, Russell ancI his colleagues (1956) reported 3 cases in which bronchial communications could not be demonstrated macroscopically, even when search was made for them. In 2 of these there had been the same sudden increase in size which had been seen in 3 of our cases. This change in size, therefore, does not indicate that this ring shadow is a bulla rather than a cavity, as has been suggested by French authors. It is possible that the change is associated with obstruction at the broncho-cavity junction. Russell and his colleagues (1956) illustrated a small bronchiole which they found opening into one of their cavities and they postulated that microscopic bronchiolar openings were present in the others also. From the microscopic findings in our series it would seem that continuity between alveoli and the cavity lumen can maintain these cavities. The word 'cyst' (or 'cystic') has been avoided in this pathological and radiological description, as it would add further to imprecision in the use of this word in describing pulmonary lesions. There do es, however, seem to be some justification for using the word 'cyst' to describe those cavities in which a bronchial communication is no longer visible on naked-eye examination, as in the pathological definition a 'cyst' is described as a closed space. The majority of the cavities drained into large bronchi with comparatively rigid walls. This is probably one of the important factors in maintaining the patency of both the cavities and their bronchial communications, for where the communications are small they could more easily be obliterated. Cavities draining into large bronchi may, furthermore, be the product of more extensive lung destruction than those reaching only small bronchi. Demonstration of the patency of the bronchial communication of these cavities and the presence of tubercle bacilli in their walls, suggests that a more intensive search for bacilli either in sputum, laryngeal swab or gastric lavage might yield positive results more frequently. Before any of the cavities were considered completely healed Melzer's criteria had to be satisfied. Although these were formulated before the introduction of chemotherapy they can still be used as the stanclard of pathological healing. It seems necessary to add to these histological requirements that of
HEALED CAVITIES
bacteriological sterility before a cavity wall is considered healed. While the significance of bacilli which can be demonstrated by smear and yet which fail to grow on routine media is still undecided, there seems little reason to abandon former guarantees of safety. This phenomenon was seen in only one instance in cavity examinations, although amongst other lesions it occurred in 3 specimens. The detailed examination of the cavity walls has shown the striking variation in different parts and a combined histological and bacteriological examination would seem essential before the cavities are considered healed. The aseptic handling of specimens is an essential detail in bacteriological examination, especially in this type of case where bacilli may be expected to be scanty in numbers. By this means the lethal effects of tissue homogenizing agents may be avoided. Care must be taken also to prevent cross-contamination. Once these precautions are taken in the initial stages of the examination, enriched media may be inclucled to promote the growth of bacilli which may show atypical features. I t is difficult to compare results in this series of 'open healing' of cavities with others, since results of comparable bacteriological studies are not given. On the results of the pathological findings, only one of the cavities in this series can be described as 'healed'; but even in this case there was clear microscopic evidence of active tuberculosis elsewhere in the lung. This is not meant to imply either that healing is not occurring or that with a longer or different course of chemotherapy it would not be complete. The findings may, in fact, support the use of drugs for longer periods. Pathological studies such as those described here will provide a guide to the optimum duration of chemotherapy, although the careful clinical follow-up of such patients will be the ultimate test. Summary Fourteen patients treated with antibacterial drugs for pulmonary tuberculosis who had been sputum negative for periods offour to fourteen months and yet had persisting ring shadows at the site of radiologically proved cavities, were studied. The regimes of chemotherapy varied, but only 2 had had less than six months ofcontinuous chemotherapy immediately before operation. Bronchograms, including broncho-tomograms were taken in all cases. Radio-opaque material outlined 13 cavities in 12 patients but failed to enter cavities in the remaining 2. In assessing the combined bacteriological and pathological results of 10 resected specimens, Melzer's histological criteria for complete healing are adopted but with the additional requirement of bacterial sterility. Only one cavity studied from a patient who had received eight months' chemotherapy was considered healed by these standards. In all the other specimens, most of them from patients treated for longer periods, there was some evidence of activity. The most striking feature was the varying degree of activity and healing seen in different parts of any one cavity. It is concluded that a pathological diagnosis of 'healed cavity' cannot be made with certainty unless detailed histological and bacteriological studies are combined.
TUBERCLE It gives us pleasure to thank Mr F.]. Sambrook Gowar, Mr P. Brunnen and Mr H. Crum,.the surgeons who have co-operated in this investigation; and Dr G. Simon, who reported on the radiographs and bronchograrns, We are also grateful to the operating theatre staff, Tornadee; Miss Mavis Redman, technician in the Institu te of Diseases of the Chest; and the technical staff of the Bacteriology Department, Brompton Hospital. We thank Mr D. Kemp, Photographic Department, Institute of Diseases of the Chest, for the photographs. References Adler, R. H., Mantz, F. A., Cline,]., and Morse, W. C. (1955) Transactions of the 14th Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p, 172. Altmann, V., and Mishirna, T. (1956) Sea View Hosp., Bull., 16, I. Auerbach, 0., and Green, H. (194,0) Amer. Rev. Tuberc., 42, 707. Auerbach, O. (1953) Transactions of the r s th Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p. 224. Auerbach, O. (1955) Amer. Rev. Tuberc., 71, 165. Bernard, E., and Carraud,]. (1953) Rev. Tubere., Paris, 17, 1021. Bernard, E., and Carraud, J. (1954) Sem; Hop. Paris, 30, 4465. Bernou, A. a.nd Brun, J. (1955) Pro med., 63, 894. Brun,]., GUichard, A., al~d Combey, P. (1954) Rev. Tuberc., Paris, 18, 1222. Galy, P., Berard, M., Arribehauts, P. Touraine, R. G., and De Saint-Florent, - . (1953) Rev. Tuberc., Paris, 17, 1037. Hall, W. E., and Gleason, D. F. (1953) Transactions of the r sth Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p. 2 19. Hayward,]., and Reid, L. M. (1952) Thorax, 7,98. Johnsen, L., and Hewitt, W. C. (1954) Amer. Rev. Tuberc., 69, 1054. Medlar, E. M. (1955) Amer. Rev. Tuberc., 71 Part II, 92 • Melzer, E. (1928) Beitr, xu«, Tuberk., 70, 69'4.. Middlebrook, G.,. Cohn, M. L., and Shaefer, W. B. (1954) ArneI'. Rev. 7ilberc., 70, 852. Pagel, W., and SImmonds, F. A. H. (1955) Tubercle, Lond., 37,2. Pruv?st, P., Delarue, T., Meyer, A., ancI Depierre, -. (1953) R.ev. Tuberc., Paris 17, 1?46. RaleIgh,]. W., Mather, C. M., Decker, A. M., and Bernstein, S. (1954) Transactions of the 13th Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p.289. Raleigh,]. W., Kaz lowski, J., Brosbe, E. A., and Stecnkcn, W. (1955) Transactions of the 14th Conference on the Chemotherapy of Tuberculosis, U.S. Veterans' Administration, Army and Navy, p. x87· Rappaport, 1. (1955) ]. Amer. med. Ass., 158, 1436. Russell, W. F., Dressler, S. H., Middlebrook, G., and Denst, J. (x956) Amer. Rev. Tuberc., 73, 944. Simonon, -., Girard, -., Lochard, -., and Sadou!, -t-, (1953) Rev. Tuberc., Paris, 17,1051. Thompson,.J. R. (1955) Amer. Reo. Tuberc., 72, 60r.