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Arthur Purdy Stout, m.d.

IN 1942, the writer in collaboration with Murray published a case report of a malignant pleural tumor that we elected to call a mesothelioma because, when explanted in vitro, the tumor cells displayed the characteristics of mesothelium. The tumor did not have the classical appearance of the diffuse mesotheliomas but was composed of spindle-shaped cells, was supplied with many reticulin fibers between the cells, and was quite vascular. Since that time, sixteen cases of solitary mesothelioma of the pleura have come to my attention, and eight of these that are well documented have been included in a paper by the writer and Himadi.5

These pleural tumors manifest themselves both in benign and malignant guise. The benign growths are sharply circumscribed, project outward into the pleural cavity, and are either pedunculated or indent the lung or tissues of the chest wall. They grow slowly and may reach a very large size before being discovered. The malignant tumors are also circumscribed but are not pedunculated, and although they have a broad attachment to the pleura, are buried in the substance of the lung or chest wall. They are grossly circumscribed but actually infiltrate. Microscopically, the benign tumors have a characteristic appearance that is easy to recognize but hard to describe because in each case it is so varied. The type cell is spindle-shaped and imitates the appearance of a fibroblast. A great many thick and thin connective-tissue fibers are formed, but the number and thickness of these vary absolutely in all parts of the growth in such a fashion that it is impossible to select any one field as characteristic. Moreover, the growth varies absolutely in degree of vascularity and in viability in different areas, hence, one may expect to find no uniformity of these features. The spindle-shaped cells always have a differentiated aspect, so that no matter how bizarre their arrangement, the individual units taken by themselves do not impress one as anaplastic or malignant, as indeed they are not.

The malignant tumors are much more cellular, with fewer reticulin, and no collagen, fibers. There is variability in the degree of vascularity and degree of necrosis in different areas of the same tumor, and it is this variability chiefly that distinguishes the tumor from the fibrosarcomas and leiomyo-sarcomas with which it could be most easily confused.

The benign and malignant varieties of these pleural tumors have been repeatedly reported but almost always under different names such as fibroma, fibrosarcoma, fibro-sarcoma myxomatodes, myxosarcoma, leio-myosarcoma, sarcoma, sarcoma-like tumor, giant sarcoma of the pleura, endothelioma, and endothelial sarcoma. No one author apparently saw more than two or three of the cases, and therefore it never occurred to any of them that this galaxy of names actually had been used to describe a single variety of neoplasm. The writer had the advantage of studying a considerable number of these tumors together, which convinced him that they formed a single class that differed in its bizarre histological aspects from any tumors in other parts of the body with which he was acquainted. There was also the fortunate observation of Murray on one of them that grew mesothelial cells in an ex-plant. Dr. Murray’s interpretation persuaded him that the whole group could be regarded as mesothelial derivatives and as examples of the versatility of the mesothelial cell, which Maximow had shown, as long ago as 1927, was capable of acting as a fibroblast when explanted in vitro. The term “mesothelioma of the pleura,” which was used by Stout and Murray in 1942, was therefore retained in the more recent paper by Stout and Himadi. The descriptive adjective “localized,” while accurate, did not seem quite so arresting as “solitary” and was therefore subordinated to the latter.

These observations were very satisfactory as far as the pleural tumors were concerned, but the writer felt it was very peculiar that no similar tumors had been described as arising from the other mesothelial membranes, namely, the pericardium and peritoneum. It was therefore with a sense of lively satisfaction that he came across the case reported herewith, which exactly resembles the benign pleural mesotheliomas not only in its clinical characteristics but in its gross and microscopic appearance.

History. F. C, a 68-year-old American man of Italian parentage, was apparently perfectly well until two or three months before admission to the Presbyterian Hospital, April 4, 1947, when, without known cause, he began to lose weight. His appetite was good until one week before admission. At that time, his family noticed that he had become disoriented and his speech slurred. His condition deteriorated rapidly, and three days before admission he was found collapsed in the bathroom. When admitted, he was unresponsive and no satisfactory explanation of his condition was found.

The hemogram was normal; the erythro-cyte sedimentation rate, 21 mm. per hour; Kline reaction, negative; urea nitrogen, 9 mg.; serum amylase, 35 units (Myers and Rillian). The urine showed a trace of albumin. The stool was guiac negative. The spinal fluid showed proteins, 46 mg.; sugar, 57 mg.

The abdomen was protuberant, and a large firm mass was palpated in the right upper quadrant and epigastrium. It moved with respiration and did not pulsate. A roentgenogram of the chest showed a shadow in the right lower lung field suggesting calcification of the pleura and a little calcification of the pleura at the left apex. Other-wise the lung fields were clear. There was some calcification of the aortic knob.

The patient improved with rest in bed and became clearer mentally. It was suspected he had a cancer and exploration to find out was determined upon.

Operation. This was carried out by R. G. Schullinger on May 26, 1947. The mass proved to be a large, roughly ovate, encapsulated tumor about the size of a large grapefruit. It was rubbery and its surface nodular. There were many large vessels in the capsule. It seemed to arise just mesial and inferior to the proximal duodenum but without connection to it or to the pancreas. The tumor pushed forward between the distal portion of the greater curvature of the stomach and the transverse colon, thus stretching and pushing forward the gastro-colic omentum. After dividing the gastro-colic omentum, the tumor was easily freed; its attachment to the retroperitoneum cut after its nutrient vessels were clamped, cut, and transfixed; and the entire tumor removed intact.

The patient made an excellent recovery and left the hospital June 5, 1947, ten days after operation. His physician, Terence L. Tyson, reports, April 13, 1950, that there is no evidence of recurrence nearly three years after operation.

Gross Specimen. The resected mass measured 14x16x9 cm. and weighed 1168 gm. The surface was covered with peritoneum containing large veins except at the clamped pedicle. Several knobs projected from the surface. When bisected, it was solid and of a yellowish-gray color.  The  tumor  was fibrous but friable, with areas of cleavage representing degeneration. In some areas, there were quite large vessels within the tumor. One of the projecting knobs was hard, fibrous, and partly calcined.

The tumor was fixed in Bouin solution, alcohol, formalin, chloralhydrate, and Zen-ker’s fluid. Tissues were stained in hema-toxylin and eosin, Masson’s trichrome stain, impregnated by the Cajal method, stained for glycogen, and with Scharlach R. (Figs. 1,2).

Microscopic Description. The dominant cell in this tumor had a spindle shape, with a correspondingly elongated nucleus devoid of large nucleoli and showing only occasional mitoses. The cell cytoplasm, best seen with Masson’s trichrome stain, contained no fibrils or granules. The cytoplasm was faintly acidophilic and tended to appear in discontinuous masses of nondescript aspect. These cells were accompanied by connective-tissue fibers of varying thickness. In places, these had contracted so that cells and fibers appeared to run in wavy bands. Unlike the majority of spindle-cell tumors and fibro-blastic ones in particular, these bands of cells and fibers did not interlace or form any other definite pattern but ran vaguely and at haphazard, so that they did not appear to have any definite beginning or end. The picture was further confused by the marked variations in the thickness of the fibers that sometimes dominated the picture to the exclusion of almost all cells and elsewhere, often close by, almost completely faded out of the picture. These areas sometimes were distinguished by focal degeneration, hemorrhage, or both. Blood vessels were equally capricious in frequency and size. Thus the impression was gained of a fibrous growth the characteristics of which were its complete lack of any definite growth pattern and its variability. These features are so striking as to make it easily recognizable once it has been seen. The various special techniques employed all gave negative results. No axis cylinders were found in the Cajal impregnations, almost no glycogen was present, and the only lipoid was in degenerate cells. (Figs. 3, 4, 5, 6.)

The primary tumors of the mesothelium of the pleura, pericardium, and peritoneum are quite confusing because of the different aspects that they may assume. Three different varieties have been described:

1. The diffuse, spreading, malignant growths that are characterized by the formation of tubes lined by swollen anaplastic mesothelial cells that secrete hyaluronic acid. These tumors spread widely and thicken the pleura or peritoneum without deep penetration and almost never metasta-size. They are rare tumors and since meta-static carcinoma can sometimes behave in the same fashion, probably not all tumors reported as diffuse mesotheliomas are such. They are more common in the peritoneum than in the pleura or pericardium. In the Laboratory of Surgical Pathology of Columbia University, there are sixteen in the peritoneum, whereas only two cases have been recorded in the pleura and two in the pericardium. The existence of this tumor and its origin from mesothelial cells is recognized by almost everyone.

2. The benign mesotheliomas of the male and female genital tracts. These are small nodules composed of tubules lined by cells that secrete a mucoid substance. They have been observed in the epididymis, cord, round ligament, uterine tube, canal of Nuck, and serosal surface of the uterus. They have not been described in the upper part of the peritoneal membrane, nor in the pleura or pericardium. The writer agrees with Masson, Riopelle, and Simard, and with Evans, that they are benign mesothelial neoplasms; but there are many who disagree, notably Golden and Ash who call them adenomatoid tumors, and others who have suggested that they are real adenomas, adenomyomas, or lymphangiomas.

3. The benign and malignant solitary fibrous mesotheliomas that heretofore have been recorded only in the pleura. With the present case, the possibility of their occurrence in the peritoneum has been shown. The opinion here expressed, that these last should be considered as tumors derived from mesothelial cells and therefore deserve the name mesothelioma, no doubt will encounter resistance because they differ so markedly from the generally accepted conception of a mesothelial tumor. The writer realizes that the basis for this hypothesis does not rest upon a solid scientific foundation, for it has not been possible to culture any of the other tumors to see if they would show the same characteristics in vitro as were demonstrated by the cells of the only case explanted. He does feel convinced that, whatever the cellular origin, these tumors form a coherent group and deserve to be called by the same name, so that they may be recognized when encountered, and larger numbers of them collected for the purpose of learning more about their characteristics and behavior.

A tumor of the peritoneum has been described that exactly resembles similar tumors in the pleura called originally, by Stout and Murray, localized mesotheliomas, and by Stout and Himadi, solitary (localized) mesotheliomas. It is an example of the benign variant of that group of tumors and is an encapsulated fibrous tumor differing in its growth pattern from all other fibrous tumors in regions other than the mesothelial membranes. Since it differs markedly from the benign tumors called mesothelioma by Masson, Riopelle, and Simard, and by Evans, it seems wise to add the adjective fibrous to its name in order more specifically to identify it.

1. EVANS, N.: Mesothelioma of the epididymis and tunica vaginalis. /. Urol. 50: 249-254, 1943.
2. EVANS, N.: Mesotheliomas of the uterine and tubal serosa and the tunica vaginalis testis. Am. J. Path. 19: 461-471, 1943.
3. GOLDEN, A., and ASH, J. E.: Adenomatoid tumors of the genital tract. Am. J. Path. 21: 63-79, 1945.
4. MASSON, P.; RIOPELLE, J. L., and SIMARD, L. C: Le mesotheliome benin de la sphere genitale. Rev. canad. de biol. 1: 720-751, 1942.
5. STOUT, A. P., and HIMADI, G. M.: Solitary (localized) mesothelioma of the pleura. Ann. Surg. In press.
6. STOUT, A. P., and MURRAY, M. R.: Localized pleural mesothelioma; investigation of its character