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Mesotheliomas of the Pleura
Mesotheliornas of the Pleura Harold C. Ursclicl, M.D., and Donald I,. l’aulsori, M.D.
M
esothelionia of the pleura is a rare tunior whose behavior is frequently unpredictable. I n the literature it has classically been divided into two types [7, 19, 35, 341. T h e solitary “benign” rnesothelioriia has been described as surgically curable and has not been considered as a premalignant lesion. T h e diffuse malignant tumor extends locally in a progressive fashion, producing death, usually within less than one year, by direct invasion rather than hematogenous nietastases [ 181. Histological variability and unpredictability are the rule, and moderate confusion is expressed over the etiology of the tumor [14, 2 0 , 211. Certain observations from our series corroborate these generalizations froiii the literature, and others are at marked variance. Because the origin and nature of the rnesothelioma has been nebulous, agreement concerning diagnosis, histological pattern, and biological behavior has been difficult. Histologically, the appearance of the tumor varies from sarcomatous to that of a carcinoina. A mixture of these elements also occurs. T h e old concept of the tumor originating as an endothelioiiia [23, 26, 391 has been discarded [35]. Robertson [25] and Willis [39, 40, 411 feel that there is no such tumor as a mesothelioma and that they represent metastases from an unrecognized or latent primary source, usually in the lung. Klemperer and Rabiii [ 191 believed that the solitary lesion originates from subpleural connective tissue aiid that the diffuse tumor is of pleural surface origin. Others [6] feel that the mesothelioiiia is a histological reaction secondary to irritation or inflamniatory processes. This would support the clinical association with pulrnonary asbestos [17, 30, 36, 381 aiid the experimental production of mesotlielioiiias by the injection of asbestos into the pleural cavity of rats [37]. Verification of the mesothelial origin of these pleural tumors has evolved from tissue culture work by Stout and Murray [35], and later by Sano et (11. [27]. Stout demonstrated that iiiesothelial tissues can develop into fibroblasts and that benign inesotheliomas can produce epithelial cells in tissue culture. Sano showed that malignant mesotheliomas can also produce epithelial cells even though these cells are not seen in histological sections obtained from the neoplasiii. FI-om the 1)cpartmciits of Thoracic Surgcr) o f Ikiylor I:niversity Medical <:enter and the Uni\ersity of Texas. Southwcsterti Medical School, 1)alI:is. ’ 1 . e ~ . ?‘he authors wish to thank Mrs. Nelva I$oeye for her technical assistance. I’rcsentctl at the First ; \ n i i u i i l Meeting of T h e Society o f ‘l’hol-acicSurgcoi~s,St. I.ouis, Mo., J a i l , 25-27, 1965.
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Embryologically, the pleural cavity is lined by somatopleura and splanchnopleura which both develop from the mesoderm. Thus, epithelial or endothelial structures could evolve separately or in combination. Maximow [221 demonstrated the transformation of mesothelial cells into fibroblasts in vitro with the production of collagenous material. Cunningham [8] and Young [451 both described the reaction of tlie niesothelial cell to injury, producing cuboidal, columnar, and epithelioid forms accompanied by papillary processes. This was confirmed by Manguikiaii and Prior [2 11. Thus, the multipotentiality of this tumor is demonstrated on a cellular basis and is confirmed by clinical observation. T h e histological picture cannot always be correlated with the clinical behavior. Many of the “benign” localized mesotheliomas appear malignant histologically, whereas some of the clinically malignant mesotheliomas have a fairly regular and benign histological appearance. Differentiation from adenocarcinomas, particularly when a bowel or ovarian primary carcinoma is involved, has been difficult. Because of these difficulties and the low incidence of pleural mesotheliomas in the population, the true incidence is not known. T h e biological behavior of the mesothelioma manifests pronounced variability. This is demonstrated by the development of malignant mesotheliomas in two patients seven years following the surgical resection of localized “benign” tumors. T h e malignant lesions developed in tlie same areas from where the benign tumors had been removed, and tlie histological slides were interchangeable. In contrast to the classic death by direct extension, many of the malignant mesotheliomas in our series metastasized to the opposite lung, abdomen, adrenal glands, kidney, liver, and brain. Despite the short survival time ascribed to the malignant niesothelioma, some of our patients in the malignant group lived well over four years. Because of the long survival of many of these patients and the paucity of their numbers, the evaluation of therapy was impossible. Finally, radical surgery would seem to play no role in tlie therapy of malignant mesotheliomas, and if the diagnosis can be substantiated, closed trocar tlioracotomy for prevention of pleural fluid recurrence has often provided tlie best palliation. C L I N I C A L EXPERII
O u r series includes 26 patients evaluated from 1946 to 1963, 2 of which initially had solitary “benign” lesions and later developed diffuse malignant mesotheliomas. Of the 28 cases, 21 were of the diffuse malignant variety and 7 of the solitary type. T h e average age for the two groups was 50 years as noted in Table 1 , the benign group varying from 20-68 and the malignant patients from 26-82 years. T h e incidence was equally distributed between the
Mesotheliomas of the Pleura
sexes in both the benign and malignant groups. There was equal distribution as to right or left side occurrence. TABLE 1 .
AGE A N D SEX DISTRIBUTION I N 28 CASES OF PLEURAL MESOTHELIOMA
Malignant
Benign _
Average age (yr.) Range Male (no. cases) Female
_
_
_
~
50 26-82 12 9
~
50 20-68 4 3
.. -
DIAGNOSIS
T h e symptoms and signs of these tumors are recorded in Table 2. Of the 7 patients in whom the lesion was solitary, 4 demonstrated cough, 2 chest pain, 2 fever, 1 hemoptysis, and 1 pleural effusion. T h e pleural effusion revealed atypical cells; however, the patient demonstrated the TABLE 2. SYMPTOMS A N D SIGNS IN 28 CASES OF PLEURAL MESOTHELIOMA
_
_
_
~
Pain Pleural effusion Cough D yspnea Fever Weight loss Weakness Hemoptysis Clubbing Pericardial effusion Asymptomatic
Malignant : 21 Cases
~~
~
__
Benign: 7 Cases ~~
13 13 11 9
2
1 4
-
7
5 4 2 1 1 1
2 -
-
1
-
2
course of a benign lesion. Only 2 of the 7 patients were asymptomatic, in contrast to the literature which attributes only a rare symptom to the benign lesion [ 131. T h e classic symptom complex with the malignant mesothelioma group included chest pain, pleural effusion (only four of which were bloody), cough, shortness of breath, and fever. Less frequently observed were weight loss, weakness, hemoptysis, digital clubbing, pericardial effusion, and pneumothorax. Only one patient was asymptomatic. T h e average duration of the symptoms in our series prior to consultation with the patient was four-and-a-half months, with a range from two weeks to eight months. VOI.. I , NO. tj, SEPI'.,
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X-ray findings of the “benign” lesion classically revealed a solitary mass which presented in the location of the interlobar fissure (Fig. 1) or adjacent to the chest wall. In contrast, the inalignant lesion was usually
FIG. 2. A diflzise malignant mesothelioiiiu prcscnti?ig ns a right pleiirnl cffiision radiograph ica 1ly .
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represented by a pleural effusion (Fig. 2); however, “scalloping” of the pleura (Figs. 3 and 4) was frequent and highly suspicious when combined with the clinical syniptonnatology. Diagnostic techniques included thoracentesis, pleural biopsy, and thoracotomy. T h e pleural fluid cytology in our series was seldoiin diagnostic when employed alone. Closed pleural biopsy was used in recent cases and may represent an iinproved diagnostic method. Its disadvantage is that only a small piece of tissue is obtained which makes a
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definite diagnosis difficult in these histologically variable tumors. Thoracotomy was the usual method of diagnosis in our group and was necessary in all the benign and in 19 of the 21 malignant mesotheliomas. Bronchoscopy and cervical-mediastinal lymph node biopsy were not helpful. Pathologically, there was a wide variation iri both the benign and nialignant lesions. Grossly, the benign group were solitary, shiny, white, fibrous lesions, usually presenting in the interlobar fissure. They were either attached by a pedicle (Fig. 5) or were an intimate part of the lung parenchyma. Rarely, they presented deeper in the lobe. T h e malignant group grossly were white pearl-like or gray lesions which varied from individual studdings over the whole pleural surface to a thick peel encasing the lung, mediastinum, diaphragm, and all local structures. Histologically, both the solitary and diffuse tumors ranged from a strictly fibrous appearance to that of a marked glandular adenomatous configuration. Combinations of the mesenchymal and epithelial elements were often present. T h e clinical behavior could not be predicted from the histology in that the solitary “benign” lesion frequently demonstrated hyperchromatism, atypicalism, and increased mitoses, whereas the diffuse malignant tumor sometimes showed no mitoses, regular cellular structure, and a uniform homogenous appearance. Because of this, it was often imperative in the malignant group to combine the clinical picture and course with the histological findings
FIG. 5. A solitary interlobar mesothelioma attached by only a Pedicle (arrow) to the pulmonary parenchyma.
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in order to make the diagnosis. T h e history and physical examination, the course of the disease, and an autopsy were necessary to differentiate them from metastatic carcinomas, particularly those from the ovary. T h e use of PAS and mucicarmine stains to differentiate malignant mesothelioma from adenocarcinoma has previously been reported [121. It was suggested that the fibrous cells would demonstrate pink granules or droplets in the cytoplasm which were allegedly mucopolysaccharide stained with the periodic acid-Schiff technique. T h e mucicarmine stain will often differentiate a mucus-producing adenocarcinoma from the mesothelioma. This approach has been helpful but not completely diagnostic in our cases. All of our cases have had a positive PAS stain for the cytoplasmic granules; however, the mucicarmine stain can be negative in the glandular cells and still represent a nonmucus-producing adenocarcinoma. Autopsy was not performed in 10 of the 21 patients with malignant mesotheliomas. However, the material obtained at surgery combined with the clinical course was felt to be adequate in identifying these tumors as malignant mesotheliomas. T h e two cases which developed malignant diffuse mesotheliomas seven years following the resection of the benign lesions included tumors originally described as an atypical localized “adenocarcinoma” and a “mesenchymoma.” T h e “adenocarcinoma” was initially treated by left upper lobectomy and the malignant mesothelioma developed in the same location seven years later. It was treated by decortication and pleurectomy. T h e histological picture of the diffuse mesothelioma revealed nests of cuboidal cells which occasionally surrounded spaces. T h e spaces were lined by flattened cells. T h e surrounding stroma was of a dense eosinophilic fibrous type containing scattered lymphocytes. Mucicarmine stains were negative, and the PAS stain demonstrated many cytoplasmic granules. This histological picture was identical with the initial lesion on reevaluation. This patient developed metastases to his chest wall and axillary nodes but is still alive with disease ten years after his original resection. T h e “mesenchymoma,” previously reported by one of the authors [Z], was originally treated by local resection of the tumor which presented in the fissure between the right upper and middle lobes (Fig. 6). It did not involve the lung parenchyma. Subsequently, a solitary “malignant” mesothelioma developed in the same location seven years later (Fig. 7), requiring a further local resection. Histological slides were identical in both lesions. T h e uniform pattern involved numerous closely packed spindle-shaped cells arranged in sheets (Fig. 8). An occasional multinucleated giant cell with large vacuoles in the cytoplasm was present. Numerous mitotic figures were present. Cell borders were poorly defined. There were several areas VOL.
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with branching tubules lined with cuboidal cells with abundant cytoplasm. T h e iiiucicariiiine stains were negative, and PAS stippling was noted in the cytoplasm. This patient died of widespread thoracic disease and central nervous system iiietastases two years after the second lesion was resected. T h e distribution of known iiietastases in this series is recorded in Table 3. Direct extension was most frequent, occurring in 19 of the 2 1 malignant mesotheliomas and probably in the others which could
not be confiriiied. Contralateral chest metastases occurred in 6 patients. Bowel and peritoneal tumor implantation with ascites developed in 4 patients; retroperitoneal, adrenal, aiid renal nietastases occurred in 3; ovarian metastases in 2; brain and liver metastases in at least 2 each; aiid axillary node metastases in 1 patient. Therapy for benign mesothelionias was surgical resection. In our series lobectoiiiy was carried out in 2 cases, segiiieiital resection in 2, and clamping of the pedicle in 3 others. T h e malignant niesotheliomas were treated with open thoracotoniy aiid biopsy in 19 of the 21 patients, with
9
Kegional node metasta\e\ Contralateral lung Howel ;ind pel itoiieiiiii Keti operitoneuni Adrenal gland ant1 kidney Liver
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Brain Axillary nodes ~
1 ~
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one undergoing lobectomy. T e n of the 21 patients were subjected to pleurectomy and decortication. These were the early cases, when it was felt that by excising the parietal and visceral pleura the lymphatics could remove the excessive fluid and an obliterative reaction would prevent the reformation of this fluid. However, more recently the closed trocar thoracotomy with tube drainage alone was sufficient to manage a high percentage of these patients without further reaccumulation of fluid or significant morbidity. TABLE 4. THERAPY OF PLEURAL MESOTHELIOMA
Type of Therapy
No. Cases
Radiation therapy Thio-TEPA (systemic and intrapleural) T.E.M. Cytoxan NH, Radiation therapy and H,O, Velban Radioactive Cr, PO, (intrapleural) Aminopterin
Table 4 reveals the wide variety of nonsurgical measures offered the malignant group in this series, varying from x-ray treatment to many of the chemotherapeutic agents. T h e wide variation in survival time and the paucity of cases makes this evaluation difficult. No method of therapy provided consistently beneficial effects. X-ray therapy improved several patients temporarily. TABLE 5 . SURVIVAL
No. Years
No. Malignant Cases ~.
0.5 1
2 3 4 5 6
7 8
9 10 11
NO follow-up
5a
1 6b 2b
2 3
-
-
1
2' 1
-
-
2
-
aTwo patients alive with disease. bone patient alive with disease. cDeveloped malignant mesotheliomas.
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No. Benign Cases
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hlesotheliomns of the Pleura
Table 5 summarizes the patient survival. T w o of the solitary “benign” cases became malignant seven years later, and 1 of the other patients died of carcinoma of the colon six years after resection for benign lesion. I n the malignant group all are dead except 4 who are alive with the disease, 2 for six months, 1 for two years, and 1 for three years after the diagnosis. T h e variation in survival has so far ranged from four months to five years. COMMENT
T h e pleural origin of the mesothelioma has been reasonably well substantiated by tissue culture studies. T h e undifferentiated mesoderm under different environmental stresses is capable of producing the observed wide histological spectrum. T h e classification of Stout [33] has been employed in our discussion with some modification. T h e solitary mesothelioma avoids the term fibrous, since there have been many reports of papillary epithelial lesions [13, 441 in addition to our own cases which later became malignant. Solitary refers to the appearance of the tumor within the thorax but does not imply localization, since these lesions are capable of invading the chest wall [21] or recurring with intrathoracic spread 17, 13, 271. Previous to this report there had been no documented metastases in this group. T h e diffuse malignant mesothelioma may present with a predominantly epithelial, mesenchymal, or mixed histological pattern [lo, 14, 20, 431. Further investigative studies are needed to establish a reliable technique for differentiating mesotheliomas from other tumors, particularly adenocarcinomas. Histologically, the variability and failure of specific histochemical tests to provide a definitive diagnosis have led to inany misconceptions concerning this disease. It is very important to correlate the histological and clinical pictures in making the diagnosis. This is similar to the difficulty encountered with malignant thymomas. Currently, Stout [32] feels that the PAS stain technique for cytoplasmic mucopolysaccharide granules is applicable to the fibrous cells. However, the tubular cells behave in a nonconsistent fashion, and these stains are not reliable for them. H e thinks that the histological appearance offers a strong suspicion but that the only completely reliable method of diagnosis is autopsy. Ackerman [l], on the other hand, believes that the PAS stain is of no value in differentiating the malignant mesothelioma group. T h e mucicarmine stain is helpful, when i t is strongly positive, in establishing a mucus-producing adenocarcinoma; however, weakly positive or absent mucicarmine-staining tissue does not rule out adenocarcinoma. H e feels that the clinical course is the most significant factor in the diagnosis. None of our cases were associated with asbestos bodies in the lung as described in the literature [17, 36, 381. VOL.
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T h e average age of patients with inesothelionias was lower than, and the sex distribution is different from, that of patients with q u a nious-cell carcinoma of the lung. However, they were similar to age and sex distribution for adenocarcinoina of the lung. T h e benign tumors in our series were primarily symptomatic, in contrast to various reports in the literature [4,161. One of the cases which was associated with a bloody pleural effusion and atypical cells demonstrated a benign histological lesion with the course of a benign niesothelioma. T h e classic symptom complex of malignant inesothelioma was chest pain, pleural effusion, cough, shortness of breath, and fever. O u r series failed to reveal any polyarthralgias [4, 7, 101, pulmonary osteoarthropathies [4,71, or hypoglycemia-producing tumors [3, 24, 28, 3 I] associated with benign and nialignant mesotheliomas as reported in the literature. Fluoroscopy and stratograins have been suggested [5, 111 to distinguish the tumor inass in the interlobar fissure or chest wall from the lung tissue. This has not been a selective point in diagnosis of the tumors in our series. Although thoracotomy was necessary in most of our tumors for diagnosis, it is hoped that with further experience and with better staining techniques, pleural biopsies using the closed technique will be adequate to make the diagnosis. This is particularly important, since surgical therapy in the malignant group is usually palliative, and in most cases the pleural effusions can best be managed with closed trocar thoracotoniy. This s e e m to establish an obliterative pleuritis and prevents the recurrence of local fluid in the chest. T h e tube is left in place for 24 to 48 hours. This has been more effective than pleurectoniy or intrapleural instillation of chemotherapeutic or radioactive material and is associated with much less morbidity. T h e recurrence of inalignant inesothelionias in the same location as previously resected “benign” lesions as long as seven years later is extremely unusual and has seldom been reported [7, 9, 13, 21, 271. There have been no reported cases of distant metastases in this variety. It emphasizes the unpredictability factor in this disease and the biological variation in different patients. It would seein that the solitary “fibrous” lesions warrant a better prognosis than the adenocarcinoma or mesenchymoma types of benign lesions froin our series. Although the course in the diffuse Inalignant iiiesotheliomas classically has been death by direct extension, a much higher incidence of distant metastases was noted in our series. When peritoneal lesions are present it is often difficult to decide which is the primary source [42]. This indicates a heinatogenous and lymphatic as well as a direct mode of extension. For the inalignant group the original operation of pleurectorny and decortication was abandoned because of its greater morbidity 570
THE A N N A I S OF THORACIC S U R G E R Y
and failure to control subsequent pleural effusions. Radical pneumonectomy failed to cure this lesion in one case [15]. Irradiation soinetiines seemed to slow tuiiior growth. But in evaluating so few cases for as long as five years tlie effect of one agent can often be misrepresented and overemphasized. None of the chemotherapeutic drugs given systematically or intrapleurally seemed to have a consistent palliative or curative effect. In a given patient a drug such as Cytoxan or iiitrapleural Thio-TEPA occasionally provided a temporary “remission” of syniptoms. The benign groups have had an extended survival and tlie malignant group has several living for five years, which is much longer than that usually reported in the literature. One case report described a 15year survival of a recurrent malignant inesothelioina treated several times by irradiation [2‘3]. SUMMARY
Twenty-eight cases of pleural inesothelioiiias have been reviewed. Twenty-one were inalignant and seven “benign.” Symptoins, x-ray findings, diagnostic techniques, therapy, and survival are summarized. Wide variation in histology was observed, aiid tlie failure to predict clinical behavior from the histological picture was frequent. T h e unpredictable biological behavior of this tuiiior is einpliasized by the subsequent development of inalignant iiiesothelioinas in two patients who had benign mesotlielioinas resected seven years previously. Both subsequently developed distant metastases. I n the diffuse Inalignant group, metastases to the abdoinen, retroperitoneuin, and brain were observed frequently. This is in contrast to the direct local niediastinal extension usually reported in the literature. In the malignant group the variability and survival time from several months to five years made the evaluation of therapy extremely difficult. Therapeutically, closed trocar tube drainage is tlie best palliative technique if the diagnosis can be made without thoraco tomy. REFEIXR’CES 1. Ackerman, L. V. Personal communication, 1964. 2. Alston, E. F., ant1 Paulson, D. L. Mesenchymolna of the pleura. J. Thorric.
Siirg. 18:518, 1949. 3. August, J. T., and Hiatt, H. H. Severe hypoglycemia secondary to a nonpancreatic fibrosarcoma with insulin activity. N e w E n g . J. M e t l . 258: 17, 1958. 4. Benoit, W. H., and Ackerman, L. V. Solitary pleural mesotheliomas. J . Thoroc. Srirg. 25:346, 1953. 5. Blount, H. C., Jr. Localized mesothelioma of the pleura. Radiology 67:822, 1956. 6. Brown, W. J., and Johnson, L. C. Inflammatory pseudotumors of the pleura. Milit. Siirg. 109:415, 1951.
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7. Clagett, 0. T., McDonald, J. R., and Schmidt, H. W. Localized fibrous
mesothelioma of the pleura. J . Thorac. Surg. 24:213, 1952. 8. Cunningham, R. S. T h e effects of chronic irritations on the morphology of the peritoneal mesothelium. Bull. Hopkins Hosp. 35: 111, 1924. 9. Ehrenhaft, J. L., Sensenig, D. M., and Lawrence, M. S. Mesotheliomas of the pleura. J . Thorac. Cardiov. Surg. 40:393, 1960. 10. Eisenstadt, H . W. Malignant mesothelioma of the pleura. Dis. Chest 30: 549, 1956. 11. Finby, H., and Steinberg, I. Roentgen aspects of pleural mesothelioma. Radiology 65:169, 1955. 12. Fisher, E. R., and Hellstrom, H. R. Periodic acid-Schiff reaction as an aid in the identification of mesothelioma. Cancer 13:837, 1960. 13. Foster, E. A., and Ackerman, L. V. Localized mesotheliomas of the pleura. A m e r . J . Clin. Path. 34:349, 1960. 14. Godwin, M. C. Diffuse mesotheliomas, with comment on their relation to localized fibrous mesotheliomas. Cancer 10:298, 1957. 15. Harris, M. S., Hyman, M. M., and Nevins, D. B. Resectable form of multiple mesothelioma. Dis. Chest 35: 127, 1959. 16. Heaney, J. P., Overton, R. C., and De Bakey, M. E. Benign localized pleural mesothelioma. J . Thorac. Surg. 34: 553, 1957. 17. Hourihane, D. 0. T h e pathology of mesotheliomata and an analysis of their association with asbestos exposure. Thorax 19:268, 1964. 18. Kahn, D. S., Glay, A., and Madore, P. Malignant pleural mesothelioma. J . Thorac. Surg. 38:225, 1959. 19. Klemperer, P., and Rabin, C. B. Primary neoplasms of the pleura: A report of 5 cases. Arch. Path. (Chicago) 11:385, 1931. 20. McCaughey, M7.T. E. Primary tumors of the pleura. J . Path. Bact. 76:517, 1958. 21. Manguikian, R., antl Prior, J. T. Mesotheliomas of the pleura: Clinicopathologic study of 8 cases. Arch. Path. (Chicago) 75:236, 1963. 22. Maximow, A. Uber das mesothel (Deckzellen der seriisen Haute) und die Zellen der serosen exsudate: Untersuchungen an entzundetem Gewebe und an Gewebskulturen. Arch. Exper. Zellforsch. 4: 1, 1927. 23. Patterson, H. S. A case of endothelioma of pleura, with review of 96 cases. J . M e d . SOC. New Jersey 5:373, 1909. 24. Porter, M. R., and Frantz, V. K. Tumors associated with hypoglycemiapancreatic and extrapancreatic. A m e r . J . M e d . 21:944, 1956. 25. Robertson, H. E. “Endothelioma” of the pleura. J . Cancer Res. 8:317, 1924. 26. Saccone, A,, and Coblenn, A. Endothelioma of pleura. Amer. J . Clin. Path. 13:186, 1943. 27. Sano, M. E., Weiss, E., antl Cault, E. S. Pleural mesothelioma: Further history of its histogenesis. J . Thorac. Surg. 19783, 1950. 28. Scholz, D. A., Woolner, L. B., and Priestley, J. T. Spontaneous hypoglycemia associated with fibrogenic tumor: Report of 2 cases. A n n . Intern. M e d . 46:796, 1957. 29. Seiler, H . H . Personal cornmimication, 19G4. 30. Selikoff, I . V., Churg, J., antl Hammond, E. C . Asbestos exposure and neoplasia. J . A . M . A . 188:22, 1964. 31. Silvis, K. S., and Simon, D. S. Marked hypoglycemia associated with nonpancreatic tumors. Nezo Eng. J . M e d . 254: 14, 1956. 32. Stout, A. P. Personal communication, 1964. 33. Stout, A. P. Tumors of the pleura. Harlem Hosp. Bull. 5:54, 1952. 34. Stout, A. P., and Hirnantli, C;. M. Solitary (localized) mesothelioma of the pleura. A n n . Szirg. 133:50, 1951. 35. Stout, A. P., and Murray, M. K. Localized pleural mesothelioma: Investigation of its characteristics antl histogenesis by the method of tissue culture. Arch. Path. (Chicago) 34:951, 1942.
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36. Wagner, J. C. I n A. J . Orenstein (Ed.), Proceedings of the Pneumoconiosis Conference (Johannesburg, 1959). London: J. & A. Churchill, 1960. P. 373. 37. Wagner, J. C. Experimental production of mesothelial tumours of the pleura by implantation of dusts in laboratory animals. Nature (London) 196:180, 1962. 38. Wagner, J. C., Sleggs, C. A., and Marchand, P. Diffuse pleural mesothelioma and asbestos exposure in the northwestern Cape Province. Brit. J. Inclustr. Med. 17:260, 1960. 39. Willis, R. A. Review of supposed “endotheliomas” of serous membranes. J . Path. Bact. 47:35, 1938. 40. Willis, R. A, T h e Spread of Tumors in the H u m a n Body. London: Butterworth, 1952. P. 55. 41. Willis, R. A. Pathology of Turnours (3d ed.). Washington, D. C.: Butterworths Publications, 1960. P. 181. 42. Winslow, D. J., and Taylor, H. B. Malignant peritoneal mesotheliomas. Cancer 13: 127, 1960. 43. Wolcott, M. W., Shaver, W. A., Walkup, H. E., and Peasley, E. D. Mesotheliomas of the pleura. DU. Chest 36: 119, 1959. 44. Yesner, R., and Hurwitz, A. Localized pleural mesothelioma of the epithelial type. J. Thorac. Surg. 26:325, 1953. 45. Young, J. S. Experimental metaplasia and hyperplasia of mesothelium. J. Path. B u t . 31:265, 1928. DISCUSSION
DK. HAWLEY H. SE~LER (Tampa, Fla.): I would like to compliment Drs. Urschel and Paulson on their excellent presentation and to comment briefly on three aspects of this interesting problem. These are: one, the slow growth and tendency to recurrence which Dr. Urschel stressed; two, the difference of opinion between pathologists concerning the malignancy or benignity of the lesion; and, three, the place, if any, of postoperative irradiation in the treatment of this disease. T o illustrate the first point, I cite the case of a 53-year-old woman originally operated upon in 1950 by Dr. Stuart Harrington. T h e pathology was interpreted by Dr. John R. McDonald as a slowly growing malignant mesothelionia of the pleura. This patient received 2400 r of postoperative irradiation. She remained well for some years and was seen by me nine years later, at which time she had a recurrence of the tumor in the right upper thorax. This was removed without difficulty and was interpreted pathologically as a benign lesion. T h e specimen was then reviewed by Dr. McDonald, who felt the lesion to be identical to the slowly growing malignancy previously removed. I n 1964, five years later, this patient had a second recurrence in the right upper thorax. This was again locally removed and the pathology was interpreted as identical to the previous two specimens. T h e time interval in this case was 14 years. The second case I would like to cite was that of a young man of 32 who was seen with an acute respiratory illness including chills and fever. He had a pleural effusion which was aspirated, and we saw what appeared to be a neoplasm. At exploration, a pleural mesothelioma was found lying in the fissure and also attached to the chest wall by a narrow pedicle. T h e unusual aspect of this case was the presence of hundreds of small nodular implants scattered throughout the visceral and parietal pleurae, on the diaphragm, and on the pericardium. Microscopic examination showed the characteristic papillary structure of a mesothelioma, with variation in size and shape of cells and other characteristics of malignancy. This patient, who was operated upon in 1951, was given postoperative irradiation without enthusiasm merely as a palliative measure. T o our amazement he has remained well and has shown no evidence of recurrence. It has been VO1..
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UKSCHEL A N D PAULSON assumed that regression and clisappearance of the inany implants have occurred. Wliether this was the result of the irradiation or whether i t was an instance where removal ol the primary lesion caused regression of the metastatic implants would be tlifficult t o determine. T h e small niiiltiple nodules were biopsietl antl had the siinie microscopic pattern o f low-grade malignancy a s shown in the primary tumor. DR. J O H A N N L. EHKENHAFT (Iowa City, Iowa): I enjoyed the paper given by Doctors Urschel antl Paiilson very much. Some of you undoubtedly have received ;I questionnaire in the last few weeks asking y o u to review a11 patients seen with benign or malignant niesotheliomas and to review those patients’ histories in regard to asbestos. We have reviewed our reported patients’ charts and have not found m y connection either in occupation or history obtained with exposure to ;is bes tos. I would also like to point out that in a series of patients reported by 11s some tiiiie ago we encountered ii few instances in which Iiiassive, frankly he1norrh;tgic pleural effusions existed; after tapping of this fluid, the underlying piilinonai-y m i s s became ;ipp:irent which, on resection, proved to be benign. T h e tunior w a s Ixdiinciilatetl ant1 solitary in most instances. We feel that massive heiiiot-rhagic effusion in the pleural spice does not necessarily mean a nialignmcy of an underlying inesothelioma. T h e presence of multiple nodules over the pleural surfaces in malignant mesothelioma represents, in m y opinion, nothing but implanted nietastases. If one explores ii patient with these lesions, the primal-y lesion is usually found in the upper lobe 01- in the upper portion of the lung pal-enchyma, antl one will find many implanted metastases over the lower portions of the pleural space, diaphragm, antl pericartlium which appear very similar to iinplan ts seen over ihe lower pelvic peritoneum in carcinoma of the stomach.
I would like to thank Dr. Ehrenhalt for his comments. Most of DK.UKSCHEI.: o u r pathological slides have been stained for asbestos fibers antl none were found in any of our cases. Dr. Seiler’s interesting case w a s presented in our inanuscript.
574
THE A N N A I S OF THORACIC SURGERY
M
esothelionia of the pleura is a rare tunior whose behavior is frequently unpredictable. I n the literature it has classically been divided into two types [7, 19, 35, 341. T h e solitary “benign” rnesothelioriia has been described as surgically curable and has not been considered as a premalignant lesion. T h e diffuse malignant tumor extends locally in a progressive fashion, producing death, usually within less than one year, by direct invasion rather than hematogenous nietastases [ 181. Histological variability and unpredictability are the rule, and moderate confusion is expressed over the etiology of the tumor [14, 2 0 , 211. Certain observations from our series corroborate these generalizations froiii the literature, and others are at marked variance. Because the origin and nature of the rnesothelioma has been nebulous, agreement concerning diagnosis, histological pattern, and biological behavior has been difficult. Histologically, the appearance of the tumor varies from sarcomatous to that of a carcinoina. A mixture of these elements also occurs. T h e old concept of the tumor originating as an endothelioiiia [23, 26, 391 has been discarded [35]. Robertson [25] and Willis [39, 40, 411 feel that there is no such tumor as a mesothelioma and that they represent metastases from an unrecognized or latent primary source, usually in the lung. Klemperer and Rabiii [ 191 believed that the solitary lesion originates from subpleural connective tissue aiid that the diffuse tumor is of pleural surface origin. Others [6] feel that the mesothelioiiia is a histological reaction secondary to irritation or inflamniatory processes. This would support the clinical association with pulrnonary asbestos [17, 30, 36, 381 aiid the experimental production of mesotlielioiiias by the injection of asbestos into the pleural cavity of rats [37]. Verification of the mesothelial origin of these pleural tumors has evolved from tissue culture work by Stout and Murray [35], and later by Sano et (11. [27]. Stout demonstrated that iiiesothelial tissues can develop into fibroblasts and that benign inesotheliomas can produce epithelial cells in tissue culture. Sano showed that malignant mesotheliomas can also produce epithelial cells even though these cells are not seen in histological sections obtained from the neoplasiii. FI-om the 1)cpartmciits of Thoracic Surgcr) o f Ikiylor I:niversity Medical <:enter and the Uni\ersity of Texas. Southwcsterti Medical School, 1)alI:is. ’ 1 . e ~ . ?‘he authors wish to thank Mrs. Nelva I$oeye for her technical assistance. I’rcsentctl at the First ; \ n i i u i i l Meeting of T h e Society o f ‘l’hol-acicSurgcoi~s,St. I.ouis, Mo., J a i l , 25-27, 1965.
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Embryologically, the pleural cavity is lined by somatopleura and splanchnopleura which both develop from the mesoderm. Thus, epithelial or endothelial structures could evolve separately or in combination. Maximow [221 demonstrated the transformation of mesothelial cells into fibroblasts in vitro with the production of collagenous material. Cunningham [8] and Young [451 both described the reaction of tlie niesothelial cell to injury, producing cuboidal, columnar, and epithelioid forms accompanied by papillary processes. This was confirmed by Manguikiaii and Prior [2 11. Thus, the multipotentiality of this tumor is demonstrated on a cellular basis and is confirmed by clinical observation. T h e histological picture cannot always be correlated with the clinical behavior. Many of the “benign” localized mesotheliomas appear malignant histologically, whereas some of the clinically malignant mesotheliomas have a fairly regular and benign histological appearance. Differentiation from adenocarcinomas, particularly when a bowel or ovarian primary carcinoma is involved, has been difficult. Because of these difficulties and the low incidence of pleural mesotheliomas in the population, the true incidence is not known. T h e biological behavior of the mesothelioma manifests pronounced variability. This is demonstrated by the development of malignant mesotheliomas in two patients seven years following the surgical resection of localized “benign” tumors. T h e malignant lesions developed in tlie same areas from where the benign tumors had been removed, and tlie histological slides were interchangeable. In contrast to the classic death by direct extension, many of the malignant mesotheliomas in our series metastasized to the opposite lung, abdomen, adrenal glands, kidney, liver, and brain. Despite the short survival time ascribed to the malignant niesothelioma, some of our patients in the malignant group lived well over four years. Because of the long survival of many of these patients and the paucity of their numbers, the evaluation of therapy was impossible. Finally, radical surgery would seem to play no role in tlie therapy of malignant mesotheliomas, and if the diagnosis can be substantiated, closed trocar tlioracotomy for prevention of pleural fluid recurrence has often provided tlie best palliation. C L I N I C A L EXPERII
O u r series includes 26 patients evaluated from 1946 to 1963, 2 of which initially had solitary “benign” lesions and later developed diffuse malignant mesotheliomas. Of the 28 cases, 21 were of the diffuse malignant variety and 7 of the solitary type. T h e average age for the two groups was 50 years as noted in Table 1 , the benign group varying from 20-68 and the malignant patients from 26-82 years. T h e incidence was equally distributed between the
Mesotheliomas of the Pleura
sexes in both the benign and malignant groups. There was equal distribution as to right or left side occurrence. TABLE 1 .
AGE A N D SEX DISTRIBUTION I N 28 CASES OF PLEURAL MESOTHELIOMA
Malignant
Benign _
Average age (yr.) Range Male (no. cases) Female
_
_
_
~
50 26-82 12 9
~
50 20-68 4 3
.. -
DIAGNOSIS
T h e symptoms and signs of these tumors are recorded in Table 2. Of the 7 patients in whom the lesion was solitary, 4 demonstrated cough, 2 chest pain, 2 fever, 1 hemoptysis, and 1 pleural effusion. T h e pleural effusion revealed atypical cells; however, the patient demonstrated the TABLE 2. SYMPTOMS A N D SIGNS IN 28 CASES OF PLEURAL MESOTHELIOMA
_
_
_
~
Pain Pleural effusion Cough D yspnea Fever Weight loss Weakness Hemoptysis Clubbing Pericardial effusion Asymptomatic
Malignant : 21 Cases
~~
~
__
Benign: 7 Cases ~~
13 13 11 9
2
1 4
-
7
5 4 2 1 1 1
2 -
-
1
-
2
course of a benign lesion. Only 2 of the 7 patients were asymptomatic, in contrast to the literature which attributes only a rare symptom to the benign lesion [ 131. T h e classic symptom complex with the malignant mesothelioma group included chest pain, pleural effusion (only four of which were bloody), cough, shortness of breath, and fever. Less frequently observed were weight loss, weakness, hemoptysis, digital clubbing, pericardial effusion, and pneumothorax. Only one patient was asymptomatic. T h e average duration of the symptoms in our series prior to consultation with the patient was four-and-a-half months, with a range from two weeks to eight months. VOI.. I , NO. tj, SEPI'.,
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X-ray findings of the “benign” lesion classically revealed a solitary mass which presented in the location of the interlobar fissure (Fig. 1) or adjacent to the chest wall. In contrast, the inalignant lesion was usually
FIG. 2. A diflzise malignant mesothelioiiiu prcscnti?ig ns a right pleiirnl cffiision radiograph ica 1ly .
562
1’131.: A N N A I S OF THOKA(:I(: SGl<(:P:l:\’
represented by a pleural effusion (Fig. 2); however, “scalloping” of the pleura (Figs. 3 and 4) was frequent and highly suspicious when combined with the clinical syniptonnatology. Diagnostic techniques included thoracentesis, pleural biopsy, and thoracotomy. T h e pleural fluid cytology in our series was seldoiin diagnostic when employed alone. Closed pleural biopsy was used in recent cases and may represent an iinproved diagnostic method. Its disadvantage is that only a small piece of tissue is obtained which makes a
URSCHEL AND PAULSON
definite diagnosis difficult in these histologically variable tumors. Thoracotomy was the usual method of diagnosis in our group and was necessary in all the benign and in 19 of the 21 malignant mesotheliomas. Bronchoscopy and cervical-mediastinal lymph node biopsy were not helpful. Pathologically, there was a wide variation iri both the benign and nialignant lesions. Grossly, the benign group were solitary, shiny, white, fibrous lesions, usually presenting in the interlobar fissure. They were either attached by a pedicle (Fig. 5) or were an intimate part of the lung parenchyma. Rarely, they presented deeper in the lobe. T h e malignant group grossly were white pearl-like or gray lesions which varied from individual studdings over the whole pleural surface to a thick peel encasing the lung, mediastinum, diaphragm, and all local structures. Histologically, both the solitary and diffuse tumors ranged from a strictly fibrous appearance to that of a marked glandular adenomatous configuration. Combinations of the mesenchymal and epithelial elements were often present. T h e clinical behavior could not be predicted from the histology in that the solitary “benign” lesion frequently demonstrated hyperchromatism, atypicalism, and increased mitoses, whereas the diffuse malignant tumor sometimes showed no mitoses, regular cellular structure, and a uniform homogenous appearance. Because of this, it was often imperative in the malignant group to combine the clinical picture and course with the histological findings
FIG. 5. A solitary interlobar mesothelioma attached by only a Pedicle (arrow) to the pulmonary parenchyma.
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Mesotheliomas of the Pleura
in order to make the diagnosis. T h e history and physical examination, the course of the disease, and an autopsy were necessary to differentiate them from metastatic carcinomas, particularly those from the ovary. T h e use of PAS and mucicarmine stains to differentiate malignant mesothelioma from adenocarcinoma has previously been reported [121. It was suggested that the fibrous cells would demonstrate pink granules or droplets in the cytoplasm which were allegedly mucopolysaccharide stained with the periodic acid-Schiff technique. T h e mucicarmine stain will often differentiate a mucus-producing adenocarcinoma from the mesothelioma. This approach has been helpful but not completely diagnostic in our cases. All of our cases have had a positive PAS stain for the cytoplasmic granules; however, the mucicarmine stain can be negative in the glandular cells and still represent a nonmucus-producing adenocarcinoma. Autopsy was not performed in 10 of the 21 patients with malignant mesotheliomas. However, the material obtained at surgery combined with the clinical course was felt to be adequate in identifying these tumors as malignant mesotheliomas. T h e two cases which developed malignant diffuse mesotheliomas seven years following the resection of the benign lesions included tumors originally described as an atypical localized “adenocarcinoma” and a “mesenchymoma.” T h e “adenocarcinoma” was initially treated by left upper lobectomy and the malignant mesothelioma developed in the same location seven years later. It was treated by decortication and pleurectomy. T h e histological picture of the diffuse mesothelioma revealed nests of cuboidal cells which occasionally surrounded spaces. T h e spaces were lined by flattened cells. T h e surrounding stroma was of a dense eosinophilic fibrous type containing scattered lymphocytes. Mucicarmine stains were negative, and the PAS stain demonstrated many cytoplasmic granules. This histological picture was identical with the initial lesion on reevaluation. This patient developed metastases to his chest wall and axillary nodes but is still alive with disease ten years after his original resection. T h e “mesenchymoma,” previously reported by one of the authors [Z], was originally treated by local resection of the tumor which presented in the fissure between the right upper and middle lobes (Fig. 6). It did not involve the lung parenchyma. Subsequently, a solitary “malignant” mesothelioma developed in the same location seven years later (Fig. 7), requiring a further local resection. Histological slides were identical in both lesions. T h e uniform pattern involved numerous closely packed spindle-shaped cells arranged in sheets (Fig. 8). An occasional multinucleated giant cell with large vacuoles in the cytoplasm was present. Numerous mitotic figures were present. Cell borders were poorly defined. There were several areas VOL.
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with branching tubules lined with cuboidal cells with abundant cytoplasm. T h e iiiucicariiiine stains were negative, and PAS stippling was noted in the cytoplasm. This patient died of widespread thoracic disease and central nervous system iiietastases two years after the second lesion was resected. T h e distribution of known iiietastases in this series is recorded in Table 3. Direct extension was most frequent, occurring in 19 of the 2 1 malignant mesotheliomas and probably in the others which could
not be confiriiied. Contralateral chest metastases occurred in 6 patients. Bowel and peritoneal tumor implantation with ascites developed in 4 patients; retroperitoneal, adrenal, aiid renal nietastases occurred in 3; ovarian metastases in 2; brain and liver metastases in at least 2 each; aiid axillary node metastases in 1 patient. Therapy for benign mesothelionias was surgical resection. In our series lobectoiiiy was carried out in 2 cases, segiiieiital resection in 2, and clamping of the pedicle in 3 others. T h e malignant niesotheliomas were treated with open thoracotoniy aiid biopsy in 19 of the 21 patients, with
9
Kegional node metasta\e\ Contralateral lung Howel ;ind pel itoiieiiiii Keti operitoneuni Adrenal gland ant1 kidney Liver
(i
4 3 3 2 2 2
Oval y
Brain Axillary nodes ~
1 ~
~
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one undergoing lobectomy. T e n of the 21 patients were subjected to pleurectomy and decortication. These were the early cases, when it was felt that by excising the parietal and visceral pleura the lymphatics could remove the excessive fluid and an obliterative reaction would prevent the reformation of this fluid. However, more recently the closed trocar thoracotomy with tube drainage alone was sufficient to manage a high percentage of these patients without further reaccumulation of fluid or significant morbidity. TABLE 4. THERAPY OF PLEURAL MESOTHELIOMA
Type of Therapy
No. Cases
Radiation therapy Thio-TEPA (systemic and intrapleural) T.E.M. Cytoxan NH, Radiation therapy and H,O, Velban Radioactive Cr, PO, (intrapleural) Aminopterin
Table 4 reveals the wide variety of nonsurgical measures offered the malignant group in this series, varying from x-ray treatment to many of the chemotherapeutic agents. T h e wide variation in survival time and the paucity of cases makes this evaluation difficult. No method of therapy provided consistently beneficial effects. X-ray therapy improved several patients temporarily. TABLE 5 . SURVIVAL
No. Years
No. Malignant Cases ~.
0.5 1
2 3 4 5 6
7 8
9 10 11
NO follow-up
5a
1 6b 2b
2 3
-
-
1
2' 1
-
-
2
-
aTwo patients alive with disease. bone patient alive with disease. cDeveloped malignant mesotheliomas.
568
No. Benign Cases
THE ANNALS OF THORACIC SURGERY
3
hlesotheliomns of the Pleura
Table 5 summarizes the patient survival. T w o of the solitary “benign” cases became malignant seven years later, and 1 of the other patients died of carcinoma of the colon six years after resection for benign lesion. I n the malignant group all are dead except 4 who are alive with the disease, 2 for six months, 1 for two years, and 1 for three years after the diagnosis. T h e variation in survival has so far ranged from four months to five years. COMMENT
T h e pleural origin of the mesothelioma has been reasonably well substantiated by tissue culture studies. T h e undifferentiated mesoderm under different environmental stresses is capable of producing the observed wide histological spectrum. T h e classification of Stout [33] has been employed in our discussion with some modification. T h e solitary mesothelioma avoids the term fibrous, since there have been many reports of papillary epithelial lesions [13, 441 in addition to our own cases which later became malignant. Solitary refers to the appearance of the tumor within the thorax but does not imply localization, since these lesions are capable of invading the chest wall [21] or recurring with intrathoracic spread 17, 13, 271. Previous to this report there had been no documented metastases in this group. T h e diffuse malignant mesothelioma may present with a predominantly epithelial, mesenchymal, or mixed histological pattern [lo, 14, 20, 431. Further investigative studies are needed to establish a reliable technique for differentiating mesotheliomas from other tumors, particularly adenocarcinomas. Histologically, the variability and failure of specific histochemical tests to provide a definitive diagnosis have led to inany misconceptions concerning this disease. It is very important to correlate the histological and clinical pictures in making the diagnosis. This is similar to the difficulty encountered with malignant thymomas. Currently, Stout [32] feels that the PAS stain technique for cytoplasmic mucopolysaccharide granules is applicable to the fibrous cells. However, the tubular cells behave in a nonconsistent fashion, and these stains are not reliable for them. H e thinks that the histological appearance offers a strong suspicion but that the only completely reliable method of diagnosis is autopsy. Ackerman [l], on the other hand, believes that the PAS stain is of no value in differentiating the malignant mesothelioma group. T h e mucicarmine stain is helpful, when i t is strongly positive, in establishing a mucus-producing adenocarcinoma; however, weakly positive or absent mucicarmine-staining tissue does not rule out adenocarcinoma. H e feels that the clinical course is the most significant factor in the diagnosis. None of our cases were associated with asbestos bodies in the lung as described in the literature [17, 36, 381. VOL.
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T h e average age of patients with inesothelionias was lower than, and the sex distribution is different from, that of patients with q u a nious-cell carcinoma of the lung. However, they were similar to age and sex distribution for adenocarcinoina of the lung. T h e benign tumors in our series were primarily symptomatic, in contrast to various reports in the literature [4,161. One of the cases which was associated with a bloody pleural effusion and atypical cells demonstrated a benign histological lesion with the course of a benign niesothelioma. T h e classic symptom complex of malignant inesothelioma was chest pain, pleural effusion, cough, shortness of breath, and fever. O u r series failed to reveal any polyarthralgias [4, 7, 101, pulmonary osteoarthropathies [4,71, or hypoglycemia-producing tumors [3, 24, 28, 3 I] associated with benign and nialignant mesotheliomas as reported in the literature. Fluoroscopy and stratograins have been suggested [5, 111 to distinguish the tumor inass in the interlobar fissure or chest wall from the lung tissue. This has not been a selective point in diagnosis of the tumors in our series. Although thoracotomy was necessary in most of our tumors for diagnosis, it is hoped that with further experience and with better staining techniques, pleural biopsies using the closed technique will be adequate to make the diagnosis. This is particularly important, since surgical therapy in the malignant group is usually palliative, and in most cases the pleural effusions can best be managed with closed trocar thoracotoniy. This s e e m to establish an obliterative pleuritis and prevents the recurrence of local fluid in the chest. T h e tube is left in place for 24 to 48 hours. This has been more effective than pleurectoniy or intrapleural instillation of chemotherapeutic or radioactive material and is associated with much less morbidity. T h e recurrence of inalignant inesothelionias in the same location as previously resected “benign” lesions as long as seven years later is extremely unusual and has seldom been reported [7, 9, 13, 21, 271. There have been no reported cases of distant metastases in this variety. It emphasizes the unpredictability factor in this disease and the biological variation in different patients. It would seein that the solitary “fibrous” lesions warrant a better prognosis than the adenocarcinoma or mesenchymoma types of benign lesions froin our series. Although the course in the diffuse Inalignant iiiesotheliomas classically has been death by direct extension, a much higher incidence of distant metastases was noted in our series. When peritoneal lesions are present it is often difficult to decide which is the primary source [42]. This indicates a heinatogenous and lymphatic as well as a direct mode of extension. For the inalignant group the original operation of pleurectorny and decortication was abandoned because of its greater morbidity 570
THE A N N A I S OF THORACIC S U R G E R Y
and failure to control subsequent pleural effusions. Radical pneumonectomy failed to cure this lesion in one case [15]. Irradiation soinetiines seemed to slow tuiiior growth. But in evaluating so few cases for as long as five years tlie effect of one agent can often be misrepresented and overemphasized. None of the chemotherapeutic drugs given systematically or intrapleurally seemed to have a consistent palliative or curative effect. In a given patient a drug such as Cytoxan or iiitrapleural Thio-TEPA occasionally provided a temporary “remission” of syniptoms. The benign groups have had an extended survival and tlie malignant group has several living for five years, which is much longer than that usually reported in the literature. One case report described a 15year survival of a recurrent malignant inesothelioina treated several times by irradiation [2‘3]. SUMMARY
Twenty-eight cases of pleural inesothelioiiias have been reviewed. Twenty-one were inalignant and seven “benign.” Symptoins, x-ray findings, diagnostic techniques, therapy, and survival are summarized. Wide variation in histology was observed, aiid tlie failure to predict clinical behavior from the histological picture was frequent. T h e unpredictable biological behavior of this tuiiior is einpliasized by the subsequent development of inalignant iiiesothelioinas in two patients who had benign mesotlielioinas resected seven years previously. Both subsequently developed distant metastases. I n the diffuse Inalignant group, metastases to the abdoinen, retroperitoneuin, and brain were observed frequently. This is in contrast to the direct local niediastinal extension usually reported in the literature. In the malignant group the variability and survival time from several months to five years made the evaluation of therapy extremely difficult. Therapeutically, closed trocar tube drainage is tlie best palliative technique if the diagnosis can be made without thoraco tomy. REFEIXR’CES 1. Ackerman, L. V. Personal communication, 1964. 2. Alston, E. F., ant1 Paulson, D. L. Mesenchymolna of the pleura. J. Thorric.
Siirg. 18:518, 1949. 3. August, J. T., and Hiatt, H. H. Severe hypoglycemia secondary to a nonpancreatic fibrosarcoma with insulin activity. N e w E n g . J. M e t l . 258: 17, 1958. 4. Benoit, W. H., and Ackerman, L. V. Solitary pleural mesotheliomas. J . Thoroc. Srirg. 25:346, 1953. 5. Blount, H. C., Jr. Localized mesothelioma of the pleura. Radiology 67:822, 1956. 6. Brown, W. J., and Johnson, L. C. Inflammatory pseudotumors of the pleura. Milit. Siirg. 109:415, 1951.
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7. Clagett, 0. T., McDonald, J. R., and Schmidt, H. W. Localized fibrous
mesothelioma of the pleura. J . Thorac. Surg. 24:213, 1952. 8. Cunningham, R. S. T h e effects of chronic irritations on the morphology of the peritoneal mesothelium. Bull. Hopkins Hosp. 35: 111, 1924. 9. Ehrenhaft, J. L., Sensenig, D. M., and Lawrence, M. S. Mesotheliomas of the pleura. J . Thorac. Cardiov. Surg. 40:393, 1960. 10. Eisenstadt, H . W. Malignant mesothelioma of the pleura. Dis. Chest 30: 549, 1956. 11. Finby, H., and Steinberg, I. Roentgen aspects of pleural mesothelioma. Radiology 65:169, 1955. 12. Fisher, E. R., and Hellstrom, H. R. Periodic acid-Schiff reaction as an aid in the identification of mesothelioma. Cancer 13:837, 1960. 13. Foster, E. A., and Ackerman, L. V. Localized mesotheliomas of the pleura. A m e r . J . Clin. Path. 34:349, 1960. 14. Godwin, M. C. Diffuse mesotheliomas, with comment on their relation to localized fibrous mesotheliomas. Cancer 10:298, 1957. 15. Harris, M. S., Hyman, M. M., and Nevins, D. B. Resectable form of multiple mesothelioma. Dis. Chest 35: 127, 1959. 16. Heaney, J. P., Overton, R. C., and De Bakey, M. E. Benign localized pleural mesothelioma. J . Thorac. Surg. 34: 553, 1957. 17. Hourihane, D. 0. T h e pathology of mesotheliomata and an analysis of their association with asbestos exposure. Thorax 19:268, 1964. 18. Kahn, D. S., Glay, A., and Madore, P. Malignant pleural mesothelioma. J . Thorac. Surg. 38:225, 1959. 19. Klemperer, P., and Rabin, C. B. Primary neoplasms of the pleura: A report of 5 cases. Arch. Path. (Chicago) 11:385, 1931. 20. McCaughey, M7.T. E. Primary tumors of the pleura. J . Path. Bact. 76:517, 1958. 21. Manguikian, R., antl Prior, J. T. Mesotheliomas of the pleura: Clinicopathologic study of 8 cases. Arch. Path. (Chicago) 75:236, 1963. 22. Maximow, A. Uber das mesothel (Deckzellen der seriisen Haute) und die Zellen der serosen exsudate: Untersuchungen an entzundetem Gewebe und an Gewebskulturen. Arch. Exper. Zellforsch. 4: 1, 1927. 23. Patterson, H. S. A case of endothelioma of pleura, with review of 96 cases. J . M e d . SOC. New Jersey 5:373, 1909. 24. Porter, M. R., and Frantz, V. K. Tumors associated with hypoglycemiapancreatic and extrapancreatic. A m e r . J . M e d . 21:944, 1956. 25. Robertson, H. E. “Endothelioma” of the pleura. J . Cancer Res. 8:317, 1924. 26. Saccone, A,, and Coblenn, A. Endothelioma of pleura. Amer. J . Clin. Path. 13:186, 1943. 27. Sano, M. E., Weiss, E., antl Cault, E. S. Pleural mesothelioma: Further history of its histogenesis. J . Thorac. Surg. 19783, 1950. 28. Scholz, D. A., Woolner, L. B., and Priestley, J. T. Spontaneous hypoglycemia associated with fibrogenic tumor: Report of 2 cases. A n n . Intern. M e d . 46:796, 1957. 29. Seiler, H . H . Personal cornmimication, 19G4. 30. Selikoff, I . V., Churg, J., antl Hammond, E. C . Asbestos exposure and neoplasia. J . A . M . A . 188:22, 1964. 31. Silvis, K. S., and Simon, D. S. Marked hypoglycemia associated with nonpancreatic tumors. Nezo Eng. J . M e d . 254: 14, 1956. 32. Stout, A. P. Personal communication, 1964. 33. Stout, A. P. Tumors of the pleura. Harlem Hosp. Bull. 5:54, 1952. 34. Stout, A. P., and Hirnantli, C;. M. Solitary (localized) mesothelioma of the pleura. A n n . Szirg. 133:50, 1951. 35. Stout, A. P., and Murray, M. K. Localized pleural mesothelioma: Investigation of its characteristics antl histogenesis by the method of tissue culture. Arch. Path. (Chicago) 34:951, 1942.
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THE ANNALS OF THORACK: S u w E n Y
Mesotheliomas of the Pleura
36. Wagner, J. C. I n A. J . Orenstein (Ed.), Proceedings of the Pneumoconiosis Conference (Johannesburg, 1959). London: J. & A. Churchill, 1960. P. 373. 37. Wagner, J. C. Experimental production of mesothelial tumours of the pleura by implantation of dusts in laboratory animals. Nature (London) 196:180, 1962. 38. Wagner, J. C., Sleggs, C. A., and Marchand, P. Diffuse pleural mesothelioma and asbestos exposure in the northwestern Cape Province. Brit. J. Inclustr. Med. 17:260, 1960. 39. Willis, R. A. Review of supposed “endotheliomas” of serous membranes. J . Path. Bact. 47:35, 1938. 40. Willis, R. A, T h e Spread of Tumors in the H u m a n Body. London: Butterworth, 1952. P. 55. 41. Willis, R. A. Pathology of Turnours (3d ed.). Washington, D. C.: Butterworths Publications, 1960. P. 181. 42. Winslow, D. J., and Taylor, H. B. Malignant peritoneal mesotheliomas. Cancer 13: 127, 1960. 43. Wolcott, M. W., Shaver, W. A., Walkup, H. E., and Peasley, E. D. Mesotheliomas of the pleura. DU. Chest 36: 119, 1959. 44. Yesner, R., and Hurwitz, A. Localized pleural mesothelioma of the epithelial type. J. Thorac. Surg. 26:325, 1953. 45. Young, J. S. Experimental metaplasia and hyperplasia of mesothelium. J. Path. B u t . 31:265, 1928. DISCUSSION
DK. HAWLEY H. SE~LER (Tampa, Fla.): I would like to compliment Drs. Urschel and Paulson on their excellent presentation and to comment briefly on three aspects of this interesting problem. These are: one, the slow growth and tendency to recurrence which Dr. Urschel stressed; two, the difference of opinion between pathologists concerning the malignancy or benignity of the lesion; and, three, the place, if any, of postoperative irradiation in the treatment of this disease. T o illustrate the first point, I cite the case of a 53-year-old woman originally operated upon in 1950 by Dr. Stuart Harrington. T h e pathology was interpreted by Dr. John R. McDonald as a slowly growing malignant mesothelionia of the pleura. This patient received 2400 r of postoperative irradiation. She remained well for some years and was seen by me nine years later, at which time she had a recurrence of the tumor in the right upper thorax. This was removed without difficulty and was interpreted pathologically as a benign lesion. T h e specimen was then reviewed by Dr. McDonald, who felt the lesion to be identical to the slowly growing malignancy previously removed. I n 1964, five years later, this patient had a second recurrence in the right upper thorax. This was again locally removed and the pathology was interpreted as identical to the previous two specimens. T h e time interval in this case was 14 years. The second case I would like to cite was that of a young man of 32 who was seen with an acute respiratory illness including chills and fever. He had a pleural effusion which was aspirated, and we saw what appeared to be a neoplasm. At exploration, a pleural mesothelioma was found lying in the fissure and also attached to the chest wall by a narrow pedicle. T h e unusual aspect of this case was the presence of hundreds of small nodular implants scattered throughout the visceral and parietal pleurae, on the diaphragm, and on the pericardium. Microscopic examination showed the characteristic papillary structure of a mesothelioma, with variation in size and shape of cells and other characteristics of malignancy. This patient, who was operated upon in 1951, was given postoperative irradiation without enthusiasm merely as a palliative measure. T o our amazement he has remained well and has shown no evidence of recurrence. It has been VO1..
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UKSCHEL A N D PAULSON assumed that regression and clisappearance of the inany implants have occurred. Wliether this was the result of the irradiation or whether i t was an instance where removal ol the primary lesion caused regression of the metastatic implants would be tlifficult t o determine. T h e small niiiltiple nodules were biopsietl antl had the siinie microscopic pattern o f low-grade malignancy a s shown in the primary tumor. DR. J O H A N N L. EHKENHAFT (Iowa City, Iowa): I enjoyed the paper given by Doctors Urschel antl Paiilson very much. Some of you undoubtedly have received ;I questionnaire in the last few weeks asking y o u to review a11 patients seen with benign or malignant niesotheliomas and to review those patients’ histories in regard to asbestos. We have reviewed our reported patients’ charts and have not found m y connection either in occupation or history obtained with exposure to ;is bes tos. I would also like to point out that in a series of patients reported by 11s some tiiiie ago we encountered ii few instances in which Iiiassive, frankly he1norrh;tgic pleural effusions existed; after tapping of this fluid, the underlying piilinonai-y m i s s became ;ipp:irent which, on resection, proved to be benign. T h e tunior w a s Ixdiinciilatetl ant1 solitary in most instances. We feel that massive heiiiot-rhagic effusion in the pleural spice does not necessarily mean a nialignmcy of an underlying inesothelioma. T h e presence of multiple nodules over the pleural surfaces in malignant mesothelioma represents, in m y opinion, nothing but implanted nietastases. If one explores ii patient with these lesions, the primal-y lesion is usually found in the upper lobe 01- in the upper portion of the lung pal-enchyma, antl one will find many implanted metastases over the lower portions of the pleural space, diaphragm, antl pericartlium which appear very similar to iinplan ts seen over ihe lower pelvic peritoneum in carcinoma of the stomach.
I would like to thank Dr. Ehrenhalt for his comments. Most of DK.UKSCHEI.: o u r pathological slides have been stained for asbestos fibers antl none were found in any of our cases. Dr. Seiler’s interesting case w a s presented in our inanuscript.
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THE A N N A I S OF THORACIC SURGERY