THE DIFFERENTIAL DIAGNOSIS OF PRIMARY NEOPLASMS OF THE MEDIASTINUM

CUSHMAN D. HAAGENSEN, M.D. (From the Memorial Hospital, New York)

INTRODUCTION That there are still opportunities for adding to the knowledge of the natural history of disease by correlation of pathologic and clinical findings was the theme of a recent address by Harvey Cushing. He appealed for a more active interest in morbid anatomy on the part of surgeons. There is perhaps no more suitable field for this type of research than primary neoplasms of the mediastinum. The differential diagnosis of the various pathologic types of these tumors is of crucial importance because a few types can be cured by surgical removal, some can be tempo­ rarily controlled by radiation, and others are amenable to no form of therapy. Since biopsy from the mediastinum is so grave a procedure that it must be avoided if possible, the differential diagnosis of the pathologic type of tumor and the form of treatment to be employed must often be attempted on the basis of the history, clinical findings, roentgen study, and the reaction of the tumor to a test dose of radiation. The rarity of tumors of the mediastinum has hindered the acquisition of knowledge concerning them. There are, for in­ stance, only about two hundred cases of primary malignant tumor of this region on record. An exhaustive review of these case reports would be of little value from the point of view of differential diagnosis, however, because most of them do not include the necessary data. Many are detailed presentations of the pathologic findings with few or no clinical data. Others, and here the radiologists (Dwyer, De Witt, and Christie, for example) are most often guilty, are premature reports of the reaction of mediastinal tumors to radiation, containing no information as to the pathologic nature of the tumor and the end-result of the treatment. The knowledge concerning the differential diagnosis of medi­ astinal tumors will be materially advanced only when case reports of these tumors are presented which contain a careful history, 72~ 724 CUSHMAN D. HAAGENSEN detailed clinical findings, roentgenographic studies, information as to the reaction of the tumor to an accurately measured test dose of radiation, the end-result of treatment, and, most important of all, pathologic study, if not by autopsy, at least by biopsy. It is the purpose of this discussion to present reports of a series of nine neoplasms of the mediastinum from the Memorial Hospital 1 embodying this information, and to discuss the differential diag­ nosis of the various types of tumor.

CLASSIFICATION Pathologic classification, so necessary to the knowledge of tumors, has been particularly difficult for mediastinal neoplasms The benign neoplasms fall readily into an orthodox classification, but the malignant group has called forth a complicated and confused terminology. Some pathologists have been content to make no attempt at classification and have included all malignant tumors under the ambiguous term "thymoma." Since these tumors include very different types, however, it would seem that the term "thymoma" might well be dropped. The types which have been included under this name may at least be classified on a purely morphologic basis as lymphosarcoma, Hodgkin's disease, carcinoma, etc. Histogenetic classification has been possible for only a few of these types of mediastinal tumors. In the first place, it has not always been possible to determine whether the tumor originated in mediastinal lymph nodes or in the thymus. Since lymphosarcoma and Hodgkin's disease in other regions of the body arise in lymph nodes, it may be maintained that such is often the case in the mediastinum. A thymic origin has frequently been inferred from the location of the tumor and from its gross morphology. On the basis of microscopic study a thymic origin has been most easily demonstrated for an extremely rare type of carcinoma in which the epithelial cells tend to be arranged in concentric whorls resembling Hassall's corpuscles. The histogenetic classification of thymic tumors has been hindered by the fact that the embryogenesis of the different types of thymic cells is still being debated (see Maximow, Schmincke, and Ewing (a) for summaries of the question). The simplest possible classification in keeping with these principles would be as follows:

1 Most of these cases were treated on the service of Dr. Lloyd F. Craver, to whose courtesy the writer is indebted. PRIMARY NEOPLASMS OF THE MEDIASTINUM 725

Primary Neoplasms of the Mediastinum A. MALIGNANT 1. Lymphosarcoma (a) Small round-cell lymphosarcoma (malignant lympho­ cytoma) (b) Large round-cell lymphosarcoma (reticulum-celllympho- sarcoma) 2. Hodgkin's disease 3. Leukemic lymphoma 4. Leukosarcomatosis 5. Thymic carcinoma B. BENIGN (following Heuer (a)) 1. Dermoids 2. Other cysts, including echinococcus cysts and ciliated epithelial cysts 3. Ganglionic neuromas and neurofibromas 4. Benign connective-tissue tumors including fibroleiomyomas, fibromas, chondromas, and lipomas Examples of most of these different types are included in this series of cases from the Memorial Hospital. In conjunction with the description of these cases a brief review of each type of tumor would seem desirable. In these reviews only those case reports will be referred to which, because of completeness of pathologic description, enable satisfactory morphologic classification of the tumor reported. LYMPHOSARCOMA A. Small Round-cell Lymphosarcoma (Malignant Lymphocytoma) Small round-cell lymphosarcoma (malignant lymphocytoma) of the mediastinum appears to be exceedingly rare. To judge from the few available reports, it usually occurs in children, occupies the thymic region, and metasttt~l~eS·,~Tid~h··:. :::Reu3:ult, Cathala, and Plichet reported a eaze 0£.~hi.s t.Yr>e. The. tumor.was. made up of small round cells ftild.showec··::1o Hassall's (~o!ptis~lf:·s. On the basis of its situation rather than from it~ histology they ascribed to it a thymic origin. Gerlach described t1i~:ca~ of a child in whom a large encapsulated tumor was found in the position of the thymus. Its greater portion showed the structure of small round-cell lymphosarcoma, but in one portion of the periphery thymic tissue, including Hassall's corpuscles, was found. Lamarque and Bert reported a case of lymphocytoma in which the pathologic diagnosis was made from a biopsy of a tumor over the sternum which was 68 726 CUSHMAN D. HAAGENSEN continuous with a large mediastinal tumor. The growth was highly radiosensitive.

CASE 1: G. H., an Italian boy of fourteen, came to the Memorial Hospital May 5, 1923. Two weeks earlier he had first noticed swelling of the base of the neck on each side. He had become tired and weak. One week previously he had first noticed shortness of breath. He began to cough and to raise greenish yellow sputum. His throat felt sore. He was very dyspneic and orthopneic. At the base of the neck, on each side, were masses of elastic, discrete, movable nodes. There was dullness over the whole right chest anteriorly and over the lower two­ thirds of the right chest posteriorly, with flatness at each base. The area of mediastinal dullness was increased to the left. The breath sounds were absent at the bases, while over the upper portion of the right chest they were bronchial in type. The blood count showed hemoglobin, 70; red blood cells, 5,000,000; white blood cells, 19,400; polymorphonuclears, 83; small lymphocytes, 15; eosinophiles, 2. The urine was negative. A roentgenogram taken May 8,1923 (Fig. 1), showed the right pleural cavity below the level of the fifth rib posteriorly to be obscured by fluid. There was also a slight amount of fluid at the left base. The cardiac shadow was deviated to the left. To the right of the mediastinal border a dimly outlined shadow of a tumor process projecting into the right thorax was seen. On the left there was a rounded shadow projecting beyond the outline of the heart. Its edge was smooth and clear cut. It extended from the level of the 3rd down to the 7th rib posteriorly, capping the cardiac shadow. A diagnosis of neoplasm of the mediastinum being made, treatment was instituted with the radium emanation pack, as follows:

MiIIi- Dis- :\Ii 1Ii- nate Time Area Filter tance Region Treated curie curies hours --- [>-6--23 1,591.5 3 br.48 min. 70 sq. em. 2 mm. br ..... 6cm. Right chest, upper anterior 6000 ,';-12-23 2357.3 3 hr. 22 min. 70 sq. em. 2 mm. br..... 6cm. Right chest. upper anterior 80lJlJ [.-20-23 943 2 hr. 6 min. 70 sq. em. 2 mm, br..... 3cm. Left supraclavicular 2000 5-21-23 943 2 hr. 6min. 70 sq. em. 2 mm. br..... 3 em. Right supraclavicular 2000 5-26--23 2309 3hr.20min. 70 sq. em. 2 mm. br..... 6cm. Right chest, upper anterior 80lJlJ

~--""""""~~-' On May 8, 1923. 5::t.O:a.ll of hlo1)d.;t.iti.ged fluid was aspirated from the right chest. No tumor cells-were f~u!l.djn:it-.: "~~nng the following ten days large amoucts of biQo_u.-tjnge~:H.rt11_d_~(~_,,~£tharawn from the right chest on six occasions. The _dy~p!1.~~ slowly improved and the sputum diminished. The cervical u.od~i t'~gr~~se~ to one half of their former size. Ten days later (MhY' ir 1923),' after two radium emanation pack treatments had been given and shortly after thoracentesis had been done, further roentgenograms (Fig. 2) showed the fluid in the right pleural cavity to be much less than in the previous films. Some fluid still re­ mained at the left base. The cardiac shadow had reassumed a normal position. The mediastinal shadow, which could now be well visualized, was seen to be markedly widened to the right. Its edge was fairly smooth and clear-cut and extended from the level of the 2nd to the 8th rib peste- PRIMARY NEOPLASMS OF THE MEDIASTINUM 727

------_._-

FlO. 1. CASE I: SMALL ROUND-CELL LYMPHOSARCOMA OF MEDIASTINUM BEFOUE RADIOTHERAPY

Ftu, 2. CASE 1: SMALL ROUND-CELL LYMPHOSARCOMA OF MEDIASTINUM A~'TER RADIOTHERAPY

riorly. The widening of the mediastinal shadow to the left which was seen in the previous roentgenogram was not identified in this subsequent film. Thoracentesis had to be done at increasingly frequent intervals. The cough and dyspnea became more distressing. The patient went rapidly down hill and died June 13, 1923, five weeks after radiation had been begun, and seven weeks after his first symptoms had appeared. 728 CUSHMAN D. HAAGENSEN

Autopsy was done by Dr. Ewing, June 14, 1923. The body was that of a well formed boy. There was marked lividity. The skin of the chest was bronzed and scaling. There were slightly enlarged nodes above the clavicles and in the axillae on each side. The abdomen was distended with clear fluid. The spleen, liver, and stomach were normal. There were enlarged, soft, white nodes at the head of the pancreas. No Peyer's patches were demonstrable in the last foot of the ileum. The adrenals, kidneys, and bladder were normal. There were numerous scattered tumor nodules under the pelvic peri­ toneum. The mediastinum was occupied by a firm, whitish, leathery tumor mass, adherent to the sternum, surrounding the great vessels, trachea, and bronchi, and enclosing the heart with a layer of tumor tissue 2 to 4 mm. thick. At the apex of the left ventricle and in the interauricular septum the cardiac muscle was largely replaced by tumor tissue. The pericardial cavity was obliterated. The great vessels, trachea, and bronchi were partially stenosed by tumor tissue. The lungs were free from tumor but markedly congested. Recent fibrin was observed on both pleurae. A layer of tumor tissue, 1 to 2 mrn.. thick, covered the upper surface of the diaphragm. It was elastic, nodular, and congested. A few nodules on the under surface of the right diaphragm made it adherent to the liver. There were intercostal de­ posits on both sides, especially the right. The peribronchial nodes were involved. Tongue, pharynx, larynx, and tonsillar regions on both sides were remarkably free from inflammation, scarring, or tumor tissue. The cervical nodes on both sides were very numerous, small and firm. The vertebral bone marrow was deep red and appeared to be deficient in cells. Anatomical Diagnosis: Malignant tumor of the mediastinum; extension over pericardium, myocardium, pleura, diaphragm, pelvic peritoneum, cervical, axillary and paravertebral nodes. Atrophy of intestinal and other lymph tissue, probably myeloid. Polyserositis. Microscopic Diagnosis: The structure was that of a small, round-cell, highly malignant tumor process (Figs. 3 and 4). Small round cells, loosely arranged, made up the mass of the tumor. They were mostly the size of small lymphocytes, occasional cells being considerably larger. The cytoplasm was slight but clearly perceptible, and finely granular and acidophile. The nuclei were comparatively large, round or polygonal in shape. They were very hyperchromatic. The nuclear material was evenly distributed, nucleoli not being seen. Mitoses were not found. The stroma consisted of occasional thick strands of connective tissue, which formed septa. The growth was richly supplied with small capil­ laries. Hassall's corpuscles or cells suggesting a thymic reticulum were not seen. Diagnosis: Small round-cell lymphosarcoma (malignant lymphocy­ toma). FIGS. 3 AND 4. CASE 1: SMALL ROUND-CELL LYMPHOSARCOMA OF MEDIASTINUM. X 45 AND X 135

729 730 CUSHMAN D. HAAGENSEN

Comment: There is no histologic evidence indicating that this lymphosarcoma originated in the thymus. It can only be said that it was situated in the mediastinum. The partial regression of the cervical nodes and the impression of a slight decrease in the size of the mediastinal tumor suggest that the process was slightly radiosensitive. The fact that death occurred five weeks after radiation had been instituted, however, indicates that this presumed regression must have been very slight indeed. Although the amount of radiation given was not large, it was sufficient to have caused striking regression had the tumor been distinctly radiosensitive. The adjective radiosensitive is used throughout this paper to indi­ cate a tumor which regresses under initial radiation. Definitive cure is not meant. No primary neoplasm of the mediastinum has ap­ parently been cured by radiation.

B. Large Round-cell Lymphosarcoma (Reticulum-cell Lymphosarcoma) A much more frequent type of mediastinal lymphosarcoma is the large round-cell lymphosarcoma. Indeed, this is perhaps the most frequent of all the different malignant tumors of the medi­ astinum. The histogenesis of this type is, however, not agreed upon. Some pathologists trace the origin of these tumors to the lymph nodes of the anterior mediastinum. Ghon and Roman (Cases No.1 and 8), and Brown have reported such cases. Other pathologists (Bregman and Steinhaus) have reported cases in which they were unable to determine whether the tumor arose from the thymus or from the mediastinal lymph nodes. Yet another kind of mediastinal lymphosarcoma has been reported which appears to arise from the thymus. The diagnosis of thymic origin has often been based on the situation of the tumor in the anterior mediastinum, and on its gross form. Symmers (2 cases), Zniniewicz (4 cases), Smith, Knutti, Evert, and Harvier have reported lymphosarcomas which they classified as thymic on this basis. In other instances the thymic origin has been further supported by the presence in the tumor of groups of cells resembling Hassall's corpuscles. Grandhomme reported one case (No.4) of this type, and on the basis of this case inferred that all of his other six cases probably originated in the thymus. Coenen and Helve­ stine have also reported cases of lymphosarcoma in which the presence of Hassall's corpuscles suggested a thymic origin. PRIMARY NEOPLASMS OF THE MEDIASTINUM 731

Very few of the reports of mediastinal lymphosarcoma contain information as to the reaction to radiation. In most cases radiation treatment was not given because the diagnosis was not made during life, in others because the clinicians were apparently unaware of the efficacy of radiation. Singer reported one such tumor which was highly radiosensitive. Janeway reported two cases of thymic lymphosarcoma (thymoma in his terminology) which regressed under radium treatment, but soon recurred. Repeated treatment kept one of these patients alive for two and one-half years. In Harvier's patient the tumor regressed readily under radiation but recurred so quickly that death resulted in three months. Desjardins (a) described a mediastinal lymphosarcoma which regressed under radiation. The patient was living with disease still present after four years (Case No.3). Lenk (a) reported a tremendous lymphosarcoma of the mediastinum which entirely disappeared within one week after a very small dose of roentgen rays. The patient died later, and the diagnosis was proved by autopsy.

HODGKIN'S DISEASE Hodgkin's disease of the mediastinum is a well identified local form of the disease. It is usually accompanied by cervical or axillary adenopathy. The lymph nodes are ordinarily the point of origin. The process forms a massive tumor which infiltrates the pleura and the pericardium and surrounds and compresses the blood vessels and the trachea and bronchi. There is often involve­ ment of the bronchial lymph nodes and lung parenchyma. Fraenkel (a) describes this mediastinal form of Hodgkin's disease with clarity and reports an illustrative case. Simmons and Benet found the mediastinal nodes involved in each of the six cases of Hodgkin's disease that they autopsied. In three instances they formed large tumor masses which filled the mediastinum. Ziegler, who described the mediastinal type of Hodgkin's disease in detail, noted that it is usually impossible to state whether the process arises in the lymph nodes or in the thymus, since at the stage at which death occurs signs of the thymus, such as Hassall's corpuscles, are no longer found. He reported three cases of this type. Ewing (b) regards these tumors, together with lymphosarcoma of the thymus, as a form of infectious granuloma arising in and peculiar to the thymus. He has been able to distinguish histologi- 732 CUSHMAN D. HAAGENSEN cally the lesions of thymic Hodgkin's disease from Hodgkin's disease in other situations. In cases which he describes" the reproduction of Hassall corpuscles, while imperfect, is quite as complete as in many such bodies in the normal thymus. The tumor arises from the reticulum cells of the thymus while many lymphocytes persist in the process and contribute to the bulk of the tumor. The giant cells are also different from those of Hodgkin's granuloma. They are very large, the cytoplasm is opaque and acidophile and nuclei are very hyperchromatic." He concludes: "It seems highly probable that the mediastinal Hodgkin's disease . . . is a thymic tumor which should be separated from other forms of Hodgkin's disease, and owes its malignancy to its origin from peculiar retic­ ulum cells of the thymus." One of the reports of mediastinal Hodgkin's disease in which a thymic origin has been the most apparent was that observed in a four and one-half months old baby by Wollstein and McLean. The thymus was enlarged but free and encapsulated. It showed the typical structure of Hodgkin's disease. Only a few Hassall's corpuscles remained. The structures immediately surrounding the thymus were not involved, but many abdominal and some thoracic nodes, as well as the spleen, liver and kidneys, and the skin were infiltrated. Simmons and Benet have reported the results of radiation in a series of verified cases of Hodgkin's disease. They concluded that radiation had a distinct beneficial effect; improvement usually began in from one to three weeks. Although none of their cases were cured, one patient survived for five years before dying of mediastinal involvement. They emphasized that in Hodgkin's disease in general, radiation should be given not only over the palpable glands, but also over the lymphatic areas of the body-the mediastinum and abdomen in particular. Desjardins (a) reported a patient (Case No.1) with Hodgkin's disease and a mediastinal tumor in which the disease had been kept under control for three and one-half years.

CASE 2: H. N., an electrician, twenty-seven years of age, came to the Memorial Hospital on June 15, 1926. His family history was not remark­ able. He had had sinus trouble for some years. During the previous year he had had a productive cough, and had gradually lost strength and weight-34 pounds in all. For about three months he had complained of a dull pain ill the epigastrium, which disappeared on eating. Physical examination showed a somewhat undernourished, well developed man. The spleen was felt two finger breadths below the costal FIG. 5. CASE 2: HODGKIN'S DISEASE OF MEDIASTINUM BEFORE RADIOTHERAPY

FIG. 6. CASE 2: HODGKIN'S DISEASE OF MEDIASTINUM AFTER RADIOTHERAPY

733 734 CUSHMAN D. HAAGENSEN margin. It was firm in consistence, and its border was smooth. Per­ cussion of the mediastinum showed increase in the intensity of the mediastinal dullness and slight widening of the dullness to the left of the sternum. There was a firm, smooth signal node in the left neck 2 em. in diameter. The blood count was: hemoglobin, 75 per cent; red blood cells, 3,800,­ 000; white blood cells, 9000; polymorphonuclears, 76; large lymphocytes, 7; small lymphocytes, 11; transitional cells, 6. The sputum was negative for tubercle bacilli. The urine examination was negative. Roentgenograms taken June 15, 1926 (Fig. 5), showed widening of the upper mediastinum and a tumor mass projecting from the left border of the mediastinum as far as the mid-clavicular line, obscuring the outline of the aorta and capping the cardiac shadow. Its outer border was ir­ regular and merged into the pulmonary markings. X-ray treatment was given as follows:

Time Date (min- Milli- Filter Kilo- Focal Region Treated utes) amperes volts Distance

6-17-26 7 20 l mm. Cu; 1 mm. Al 175 50 em. Mediastinum anterior 6-21-26 15 4 4mm.AI 140 38 em. Left supraclavicular (to node) 6-23-26 25 4 5mm.A1 140 38 em. Mediastinum posterior 6-25-26 12 4 5mm.AI 140 38 em. Mediastinum anterior 9-15-27 10 30 l mm. Cu; 1 mm. Al 175 50 em. Mediastinum anterior 9-19-27 10 30 ! mm, Cu; 1 mm. Al 175 50 em. Mediastinum posterior 9-23-27 10 30 l mm. Cu; 1 mm. Al 175 50 em. Left chest lateral and upper two-thirds 3-8-28 6 30 1mm, Cu; 1 mm. Al 175 30 em. Neck post. triangle 3-20-28 10 30 ! mm. Cu; 1 mm, Al 175 50 em. Right groin 3-27-28 10 30 t mm. Cu; 1 mm. Al 175 50 em. Left groin 7-5-28 10 30 t mm. Cu; 1 mm, Al 175 50 em. Left groin

Following the first series of treatments, the patient was much im­ proved. Within two months he had gained 38 pounds and felt well enough to return to work. The widened mediastinal dullness and the signal node in the left supraclavicular region disappeared. A slight cough and expectoration remained. Roentgenograms of the chest taken Oct. 27, 1926 (Fig. 6), showed that the large shadow projecting from the left mediastinal border had disappeared. In the superior mediastinum a very slight widening remained. In September 1927, although the patient continued to feel well, he lost a few pounds in weight, and a roentgenogram showed increased widening of the superior mediastinum. He was, therefore, given another treatment to the mediastinum, anteriorly and posteriorly. A roentgeno­ gram taken Feb. 16, 1928, showed that the mediastinal widening had disappeared completely. At no time during the remaining course of the disease did the mediastinal tumor recur. In March 1928, a mass 4 em. in diameter appeared in the left groin. It regressed quickly under radiation. FIGs. 7 AND 8. CASE 2: HODGKIN'S DISEASE OF MEDIASTINUM. X 45 AND X 135 736 CUSHMAN D. HAAGENSEN

In September 1928, the patient began to have a daily fever and a cough. He lost 15 pounds. His blood count showed considerable anemia: hemoglobin 60 per cent; red blood cells, 3,000,000; white blood cells, 6,000; polymorphonuclears, 80; large lymphocytes, 13; small lymph­ ocytes, 1; transitional cells, 5; eosinophiles, 1. On Nov. 24, 1928, the patient was transfused with 600 C.c. of blood, but the anemia was improved but little. On Dec. 21, 1928, he was given a second transfusion, this time 900 c.c. Nevertheless, on Dec. 31, 1928, his blood count was: hemoglobin, 60 per cent; red blood cells, 3,000,000; white blood cells, 5,200; polymorphonuclears, 79; large lymphocytes, 4; small lymphocytes, 16; eosinophiles, 1. In the meantime, his general condition failed rapidly. There was no definite adenopathy. The spleen remained palpable three finger breadths below the costal margin. A right sided dry pleurisy developed. The patient ran a daily afternoon temperature of between 102 and 103°. Terminally, he developed general­ ized rlUes throughout both lungs and died on Feb. 23, 1929, three years and two months after radiation had been begun, and about four years after the onset of his illness. A utopsy: The body was that of a young male, markedly undernour­ ished. The skin was loose. There was evidence of recent loss of sub­ cutaneous fat. There was one enlarged, soft node in the left axilla and numerous small, shotty nodes in both groins. Abdominal incision revealed a large amount of free, straw-colored fluid in the peritoneal cavity. There was a moderate quantity of similar fluid in each pleural cavity, as well as in the pericardial cavity. The mediastinal contents appeared grossly normal. No tumor was seen. The thymus was not identified. The right lung was adherent to the chest wall at the apex. There was no evidence of tumor on the surface of either lung. At the right apex there was a thickened area from which a small amount of purulent material was expressed. There were a number of enlarged peribronchial nodes. The liver was normal in size and appearance, with no evidence of tumor on its surface or on section. The gallbladder was normal. The spleen was enlarged to three times its normal size and was slate­ colored. There were numerous circular, firm tumor nodes, varying from 1 to 3 em. in diameter on the surface of and throughout the spleen. In places these showed yellowish areas of necrosis. The remainder of the spleen was firm in consistence and markedly hyperemic. There was no evidence of tumor in the stomach and intestines, except for the mesentery, where there were numerous small, firm nodes about 1 em. in diameter, each replaced by opaque tumor tissue. There was no evidence of gastric or duodenal ulcer. The pancreas was large. At its head there were numerous enlarged, firm nodes replaced by tumor tissue and encroaching on the pancreut.ic tissue. The inner surface of the ribs, especially on the right side, was covered with numerous plaques of yellowish tumor which appeared to be invading the bone. One section of a rib with several such nodules was removed. FIOS. 9 AND 10. CASE 3: HODGKIN'S DISEASE: NECK NODE. X 45 AND X 135

737 738 CUSHMAN D. HAAGENSEN

The retroperitoneal region and the pelvis were filled with numerous enlarged lymph nodes which were firm in consistence, and on section were seen to be replaced by yellowish, partly necrotic tumor. The bladder and rectum were normal. The dura was somewhat adherent to the cerebral surface on both sides. Otherwise, there seemed to be no definite abnormality of the brain. Anatomic Diaqnosie: Hodgkin's disease of peribronchial lymph nodes, retroperitoneal, pelvic, inguinal, and axillary lymph nodes, spleen, and ribs; pulmonary tuberculosis, chronic pleurisy; ascites, hydrothorax, pericardial effusion. Microscopic Diagnosis: The lymph nodes showed a fibrous type of Hodgkin's disease (Figs. 7 and 8). Many very large Sternberg cells were seen. In some areas there was massive necrosis. Calcified areas were seen. There was a great deal of old blood pigment scattered about. The bone marrow of the ribs and vertebral column showed replace­ ment to a large extent by typical fibrous Hodgkin's disease containing numerous Sternberg cells. The surrounding bone marrow showed a chronic inflammatory reaction with numerous plasma cells. The spleen was congested and contained foci of necrosis and small areas of fibrous Hodgkin's disease. The lung apex showed pigmented atelectatic areas surrounding walled­ off foci of caseation suggesting atypical tuberculosis. There were no giant cells. The surrounding alveoli were packed with endothelial leukocytes.

Comment: The remarkable radiosensitivity of the process in this case is evidenced by the fact that no trace was found at autopsy of the large mediastinal tumor which roentgenographic studies proved to have existed three years previously.

CASE 3: M. C., an Italian housewife, aged twenty-two, came to the Memorial Hospital May 13, 1930. Three months previously she had first observed enlarged nodes in each side of the neck, and two months previously she had begun to suffer from dyspnea. A biopsy from the group of neck nodes, done at another hospital, was reviewed by Dr. Ewing and a diagnosis of Hodgkin's disease was made (Figs. 9 and 10). The disease was of a comparatively cellular type. The eosinophiles were unusually numerous. Sternberg cells were infrequent. Examination showed large masses of confluent nodes extending the length of each side of the neck. There was a single node in the right axilla. The area of mediastinal dullness was widened, particularly to the left, and breath sounds were diminished to the left of the sternum. The blood count was: hemoglobin 90 per cent; red blood cells, 4,520,000; white blood cells, 9,800; polymorphonuclears, 70; 10 large lymphocytes; 13 small Iymphocytes; transitional cells, 7. Roentgenograms taken May 15, 1930 (Fig. 11), showed marked widening of the upper mediastinum, particularly to the left. Here the 1'10. 11. CAHE:3: HODGKIN'H DISEA8E OF MEDIA'lTINUM I3m'oRE H.ADIOTIiERAI>Y

1'10. 12. CASE 3: HODGKIN'S DISEASE OF MEDIASTINUM Af'TER HADlOTHERAPY 739 740 CUSHMAN D. HAAGENSEN tumor mass largely filled the apex and extended downward to below the level of the fifth rib posteriorly. The edges of the shadow were regular and clear-cut. The lung parenchyma appeared normal. Roentgen treatment was given as follows:

snm- Time Kilo- Focal I Date (minutes) am- Filter volts Distance Region Treated PPTf'M 5-21-30 8 30 ! mm. Cu; 1 mrn, AI 195 50 cm. Mediastinum anterior S-24-30 10 an ! mm. Cu; 1 mm. AI 19S 50 ern. Right supraclavicular 5--27-30 10 30 ! mm. Cu: 1 mm. Al 195 50 em, Left supraclavicular 5--31-30 8 30 ! mm. Cu; 1 mm, AI 195 50 em. Mediastinum anterior 6-3-30 10 30 ! mm. Cu; 1 mrre AI 195 50 em, Mediastinum posterior I

The masses of nodes in the neck diminished appreciably in size under this treatment. The dyspnea was relieved. Roentgenograms taken July 31, 1930 (Fig. 12), showed the mediastinal tumor to have diminished somewhat in size. The left border of the tumor shadow was 1 em. within the line of its earlier limits. During the following two years the course of the disease was irregu­ larly progressive, despite a large number of roentgen treatments. A total of thirty-four exposures, of the same general type as detailed above, were given during this period, over the neck, chest, and axillae. The temporary improvement following each exposure was followed within a month or two by an exacerbation of the disease. Pain, dyspnea, and cough became increasingly troublesome. A dermatitis of the scalp developed and yielded slowly to treatment with ointments. No less than seventeen roentgen exposures were given over the mediastinum and left chest. Serial roentgen films showed a steady increase, however, in the extent of involvement of the left lung. Pleural effusion developed and repeated thoracentesis was necessary. In January 1932 the dyspnea and pain were so severe that the patient was bed-ridden. The resistance of the disease to radiation had become so great that treatment no longer gave relief. Death occurred in March 1932.

Comment: This is a case of Hodgkin's disease in which the mediastinal tumor regressed only partially and very slowly under adequate doses of radiation. There had been no previous radi­ ation, and the tumor must, therefore, be classed as a relatively radioresistant type of Hodgkin's disease. PRIMARY NEOPLASMS OF THE MEDIASTINUM 741

LYMPHATIC LEUKEMIA It would be expected that the diffuse hyperplasia of lymphoid tissues which characterizes leukemic lymphoma would frequently involve the nodes in the mediastinum. Such indeed appears to be the case. The thymus, on the other hand, although containing elements which are presumably lymphoid in origin, does not ordinarily participate in the process. Ewing (3) states: "It is a notable fact that in most cases of leukemia and pseudoleukemia the thymus fails to participate in the process." Schridde reports that in most of the cases of lymphatic leukemia which he has studied the thymus was not involved at all. The characteristic structure of the thymus was not demonstrable in the lymphoid tissue found in the mediastinum. In some cases, however, Schridde found both the cortex and the medulla of the thymus infiltrated with lymphoid deposits in the same manner as the skin is involved in lymphoid leukemia. Margolis (a) has recently reported a series of 32 autopsied cases of lymphatic leukemia from the Mayo Clinic. In 28 of these cases the thymus was not involved. The thymus was not found at all in 5 of the cases, and in 5 others it showed marked involution. It is noteworthy that 3 of the patients with involution of the gland were small children. In 4 cases there was a massive infiltrating tumor which filled the anterior mediastinum. In these cases no evidence of the thymus in the form of thymic reticulum or Hassall's cor­ puscles was found. Nevertheless, without apparent gross or histologic evidence of a thymic origin, Margolis assumes that in these cases the mediastinal tumor represented leukemic enlarge­ ment of the thymus. Lavergne, Abel, and Debenedetti have recently reported a similar case in which a thymic origin was also inferred. Kaufmann reports, however, that the thymus is not infre­ quently involved in lymphatic leukemia. He states that in small children he has seen the thymus enlarged to the size of a fist, and on section as homogeneous as a leukemic lymph node. There are only a few reports of radiation treatment of medi­ astinal involvement in lymphatic leukemia. Janeway described one case in which death followed shortly after treatment had begun. In the case of Haenisch and Querner the tumor was apparently not radiosensitive. Morawitz and Denecke report a case with enlarge­ ment of the mediastinal nodes in which roentgen radiation caused complete regression. 69 742 CUSHMAN D. HAAGENSEN

CASE 4:2 H. L., an American boy, six years of age, applied at the Memorial Hospital March 10, 1928. He had had repeated "bronchitis" and tonsillitis since the age of seven months. Two months previously he had had "bronchitis" followed by croup, from which he had-net re­ covered completely. Two weeks previously anorexia and vomiting had developed. The child's mother had noticed enlarged nodes in the neck and groins. He had had frequent nose bleeds. Without previous injury "black and blue spots" appeared on his legs. Physical examination showed a pale, undernourished child. The tonsils were large. The area of relative mediastinal dullness was mark­ edly broadened, particularly to the right, where it extended to the mid­ clavicular line. The breath sounds over this area were diminished. There was a well marked d'Espine's sign. The spleen was felt two finger breadths below the costal margin. The liver edge was down almost to the level of the crest of the ilium. There were numerous elastic, discrete, movable nodes in the groins, axillae, and epitrochlear and occipital regions. The blood count was: hemoglobin, 50 per cent; red blood cells, 2,800,000; white blood cells, 58,000; polymorphonuclears, 1; smalllympho­ cytes, 98; transitionals, 1. The urine examination was negative. Roentgenograms taken March 10, 1928 (Fig. 13), revealed a very large, rather dense, homogenous shadow occupying the mediastinum. On the right, where it was most prominent, it obscured the apex and extended down the entire length of the mediastinum. On the left it bulged out­ ward and capped the cardiac shadow. Its edges were rounded, regular, and sharply defined. One x-ray treatment was given at once. The factors were: time, 5 minutes; milliamperes, 4; filter, :~ mm. of AI.; kilovolts, 135; focal distance, 30 cm.; area, upper anterior chest. In roentgenograms taken nine days later (March 19, 1928) the medias­ tinal tumor had almost entirely disappeared (Fig. 14). Only a slight widening of the mediastinum remained. The patient's general condition was temporarily improved. As the result of this first radiation exposure the white blood count fell to 1,800. Within three weeks, however, it had risen again to 128,000. In the meantime the anemia had increased and transfusion was necessary. Despite further radiation and six transfu­ sions, the patient became progressively weaker and died June 10, 1928, three months after radiation had been started and five months after the onset of the illness. A utopsy: The body was that of a young undernourished boy. There were several small subcutaneous hemorrhages in the epigastric region and over the right anterior forearm. There was generalized adenopathy involving submaxillary, cervical, axillary, and inguinal nodes. These nodes were firm, elastic, movable, some discrete and others confluent. There were about 200 c.c. of straw-colored fluid in each pleural cavity. Both lungs were fairly well aerated except for hypostatic congestion of the right lower lobe posteriorly. There was no definite pneumonic consoli­ dation.

2 This case has been reported in a separate study of lymphatic leukemia by Craver and MacComb (Am. J. Cancer 16: 277, 1932). FIG. 13. CASE 4: LEUKEMIC LYMPHOMA OF MEDIASTINUM BEFORE HADIOTHERAPY

FIG. 14. CASE 4: LEUKEMIC LYMPHOMA OF MEDIASTINUM AFTER RADIOTHERAPY

743 744 CUSHMAN D. HAAGENSEN

In the anterior mediastinum, in the region of the thymus, there was a tumor which encircled the trachea and extended downward anteriorly over the pericardium, on both sides, where definite tumor masses were closely adherent to the pericardium. The main mass above measured about 6 em. in diameter. At the medial lower border of the right lung, near the right base of the heart, there was a more discrete tumor mass about the size of a golf ball. The main tumor mass merged with a group of enlarged mediastinal nodes surrounding the trachea, each about the size of a large olive. On section these nodes were soft, pearly gray, and homogeneous in character. The pericardium, at its base, was intimately connected with and invaded by the tumor. At the right lower angle there was a separate tumor nodule measuring 3 X 3 X 3 cm., which on section presented an ivory appearunce. It was opaque, white, and homogeneous. The liver was enlarged to twice its normal size. Its surface was smooth, and its consistency firm. On section it appeared yellowish and presented numerous minute yellowish foci of probable leukemic infiltration. The spleen was three times normal size. There was a small accessory spleen 2! em. in diameter. Its surface was smooth, glossy, and slate­ colored. On section it was highly cellular, and hemorrhagic, and gave the impression of diffuse cellular leukemic infiltration. The kidneys were normal ir size and very pale. The right on section showed whitish patches suggesting leukemic deposits. The left kidney showed fetal lobulation. On section the cortex was seen to be the seat of numerous hemorrhages. The ureters, bladder, and prostate were normal. The testes felt firmer than normal. On section hemorrhage, suggest­ ing leukemic infiltration, was observed. The stomach was markedly dilated. The pylorus was normal. The mucosa was the seat of numerous small and large petechial hemorrhagic areas varying from 2 to 10 mm. in diameter. There were minute petechial hemorrhages in the mucosa of the ileum. The pancreas was normal in size and consistency. The adrenals were somewhat large for the age of the patient. They were very yellow. Enlarged retroperitoneal nodes, varying in size from 1 to 3 em. in diameter, extended in a chain along the spinal column from the sacro­ lumbar region up to the diaphragm. They surrounded the pancreas. The blood had a thin, "chocolaty" appearance and consistence. A natomical Diagnosis: Leukemic lymphadenosis; leukemic infiltration of spleen, liver, and kidneys. Microscopic Diagnosis: Mediastinal tumor-diffuse lymphoma (Figs. 15 and 16). The tumor was made up of closely packed lymphocytes. The stroma consisted of infrequent fibrous septa. The blood vessels were few. There was no evidence of thymic origin in the form of Hassall's corpuscles or thymic reticulum. Further microscopic findings were as follows: tonsil and lymph nodes, diffuse lymphocytic hyperplasia j lung, lymphocytic exudate j kid- FIGB. 15 AND 16. CABE 4: LEUKEMIC LYMPHOMA OF MEDIASTINUM. X 45 AND X 135

745 746 CUSHMAN D. HAAGENSEN neys and spleen, diffuse lymphocytic infiltration; stomach, negative; heart muscle, diffuse lymphoma subpericardial and intermuscular; pros­ tate, diffuse lymphoma; pancreas, diffuse lymphoma; liver, miliary lym­ phoma; submaxillary gland, diffuse lymphoma. Diaqnoeis: Lymphatic leukemia.

Comment: The autopsy findings were typical of lymphatic leukemia. The mediastinal tumor showed no evidence of having originated in the thymus. The tumor was remarkably radio­ sensitive, yet the disease as a whole was uncontrollable and early death resulted. LEUKOSARCOMATOSIS Sternberg (b), for many years, has insisted on the identity of a process which he calls leukosarcomatosis. In it the general features of leukemia are combined with a malignant tumor process having a histologic structure closely resembling that of lympho­ sarcoma. The leukemic features of leukosarcomatosis may be those of either acute or chronic lymphatic leukemia. The duration of the series of six cases which Sternberg (a) described in his 1916 paper varied between three weeks and three years. In all his cases Sternberg reports a predominance of large mononuclear cells in the blood picture. These cells have a relatively large, pale nucleus containing two or more vacuoles. The cytoplasm is propor­ tionately prominent, and is not granular The cells do not give an oxidase reaction. They often constitute as high as 80 or 90 per cent of the white blood cells. Sternberg calls them leukosarcoma cells and regards them as a characteristic feature of the disease. Autopsy in these cases shows a more or less generalized swelling of the lymphatic apparatus, and in places frankly malignant growth with infiltrating invasion of surrounding tissues by a lymphosarcomatous process. In this manner massive tumors develop. They are most frequently situated in the anterior mediastinum (three of Sternberg's six cases referred to above had large mediastinal tumors), where they involve the pericardium and encroach upon the heart, the great vessels, and the lungs. Tumors of this sort may develop in other organs, such as the tonsils, the breasts, or the intestinal tract. In these cases the lymphatic apparatus shows the same gross features as in ordinary lymphatic leukemia. The spleen is often enlarged, and the liver and kidneys may show streaks of infiltration. The bone marrow may be dark red and may show circumscribed areas of tumor. The histologic PRIM.\RY NEOPLASMS OF THE MEDIASTINUM 747 findings are the same throughout the entire hemopoietic apparatus, in the massive tumor, in the apparently hyperplastic lymph nodes, and in the viscera, and consist in an overgrowth of large mononuclear cells. The structure closely resembles that of lymphosarcoma. The large mononuclear cells are identical with those which predominate in the blood picture. Fraenkel (b) has objected to a separation of this disease from other types of leukemia. He points out that the same aggressive infiltrating character is encountered in ordinary lymphatic leukemia, where leukemic infiltration by lymphocytes is wide­ spread and affects the same viscera as are involved by leukosarco­ matosis. In Fraenkel's opinion leukosarcomatosis is merely a large-celled type of leukemia. After years of discussion, however, Sternberg's separation of leukosarcomatosis from leukemia has been accepted by many pathologists. The discussion has at least served to emphasize the close relationship between leukemia and malignant disease. The following case is an example of leukosarcomatosis: CASE 5: F. C., a Jewish pharmacist, fifty-nine years old, came to the Memorial Hospital Jan. 16, 1926. Eight months previously he had first begun to be hoarse. Three months previously he had developed a slight productive cough. His sputum was occasionally blood-streaked. Examination revealed an ulcerated area on the posterior surface of the epiglottis, and a single movable node on the right neck. A biopsy from the epiglottic lesion showed highly anaplastic squamous carcinoma. Radiation treatment was given as follows:

Radium

~lilli- Date Milli- Time Arca Filter DilS- Region curie ;\lethod curies tance Treated hours --- 1-21-26 1575 1 hr. 35 min. 28 sq. em. i mm. silver 3em, Right. larynx 2i,(1ll Bfa .....~ traY 1-27-26 1660 1 hr. 30 min'128 sq. em. ! mm. silver 3em. Left larynx 24\10 BnLNH tray 2-8-26 998 6 hr. 20 min. 70 sq. em'12 mm. brass 6cm. Ri"ht neck li27:l PlLl'k 2-9-26 1614 2 hr. 20 min. 70 sq. em, 2 mm, brass 6cm. Ri"ht neck 3/jOll Punk 2-9-26 1614 5 hr. 20 min. 70 sq. em. 2 mm. brass 6cm. ~rt neck 10000 Pack

Roentgen Ra.ys

Time Milli- Kilo- Date (minutes) amperes volts Filter Focal Distance Region Treated -- 1-25-26 60 4 200 4 rnm, Cu; 1 rnrn, Al .')0 em. Right neck 1-27-26 60 4 200 ! mm. Cu; 1 mm, Al 50 em. Right neck - The effect of this treatment was striking. Within a month all evi­ dence of laryngeal disease had disappeared. 748 CUSHMAN D. HAAGENSEN

The patient was followed and showed no evidence of disease until Feb. 1, 1929, just three years later, when slight dyspnea and heartburn developed, and his general health and strength began to fail rapidly. Elastic, movable masses of nodes appeared in both axillae, both supra­ clavicular spaces, on both sides of the neck, and in the scalp. There was slight cyanosis. Mediastinal dullness was increased to the left. Roentgenograms on March 6, 1929 (Fig. 17), showed a mass projecting from the left border of the mediastinum, obscuring the outline of the aorta and capping the cardiac shadow. It extended from the apex down to the level of the 8th rib posteriorly. Its edges were very irregular and merged with the increased pulmonary markings over the area of the left upper lobe. The blood count was; hemoglobin, 85 per cent; red blood cells, 4,328,000; white blood cells, 17,600; polymorphonuelears, 6:3; lnrge lymphocytes, 19j small lymphocytes, 18. On March 2, 1929, a node was excised from the right neck. Dr. Ewing's diagnosis was reticulum-celled lymphosarcoma. X-ray trea t­ ment was given as follows:

Time nate (min- l\1i1Ii- Kilo- Filter Foc,,1 Rr-gion Tn'ut(·(l utes) amperes volt" Distance -- 3-7-29 10 30 185 ! mm. CUi 1 mm, Al 50 em. Mediastinum 3-11-29 12 4 135 4mm.Al 30 em. Right axilla. 3-13-29 12 4 135 4mm.AI 30 em. Left. axilla 3-16-29 5 30 175 ! mill. Cu; 1 mm. Al 30 em. Right neck and supraclavir-ulur 3-2(}--29 10 30 175 ! mm. CUi 1 mm, Al 50 em. Right mediastinum 3-23-29 10 30 17.5 ! mm, Cu; 1 mm. Al 50 em, Left mediastinum 3-27-29 5 30 175 ! mill. CUi 1 mm, AI 30 em, Left neck and supraelaviculur 3-29-29 12 30 17.1 ! mm. Cu; l mrn, Al SO em, Right groin 4-23-29 12 30 17.1 ! mm. CUi 1111111. AI .'iOcm. Left groin 4-27-29 12 4 13.'i 4 mill. AI 30 em. Left lumbar and dorsul [r-2(}--29 8 20 19.1 ! mm. CUi 1 mm. AI 50 em, Lower mediastinum

Within 2 weeks the nodes had disappeared from the axillae and the right neck. Nodes which appeared in the groin and in the left preauricu­ lar region and scalp disappeared with equal promptness, when treated. The patient's general condition, however, did not improve. On May 1, 1929, a nodular dermatitis appeared over the entire body. A biopsy of one of these lesions was done. Dr. Ewing's report was: "Localized collections of cells of type found in reticulum-celled lymphosarcoma infiltrate the skin, about the glands, hair follicles and in fat-metastatic lymphosarcoma." A roentgenogram taken April 6, 1929 (Fig. 18), showed marked diminution in the size of the mediastinal mass. Only a small stellate shadow remained at the left mediastinal border. The infiltration of the parenchyma of the left upper lobe had also largely disappeared. By May 18, 1929, the patient's general physical condition had failed markedly. Nodes had recurred in the axillae and groins. Films of the mediastinum, however, showed no recurrence of the mediastinal tumor. FIG. 17. CASE 5: LEUKOSARCOMATOSIS OF MEDIASTINUM BEFORE HADIOTHERAPY

FIG. 18. CASE 5: LEUKOSARCOMATOSIS OF MEDIASTINUM AFTER RADIOTHERAPY

749 750 CUSHMAN D. HAAGENSEN

There was marked enlargement of both the liver and the spleen. A blood count now showed a leukemia for the first time: hemoglobin, 75 per cent; red blood cells, 3,760,000; white blood cells, 69,600; polymorphonuclears, 6; large lymphocytes, 10; small lymphocytes, 83; transitional cells, 1; polychroma tophilia, Despite additional radiation, the patient failed rapidly and died May 26, 1929, three months after radiation had been begun and four months after the onset of disease. A ul.opsy: The body was that of a well developed and well nourished white male. There were numerous raised, flattened, colorless to pinkish nodules in the skin, measuring 1 em. or less in diameter. There were slightly enlarged, palpable cervical and axillary nodes. The parietal, pericardial, and mediastinal pleura was adherent about the great vessels, where laterally there were enlarged, soft, yellow to grayish-yellow lymph nodes measuring from 0.5 cm. up to 3 cm. These nodes belonged to the tracheo-bronchial group. The thymus was not involved. The enlarged tracheo-bronchial nodes extended downward as large, yellow, or black and yellow, mottled foci, in a nodular arrangement along the bronchi, fading out as the deeper lung regions were reached. The lungs themselves were normal, except at the left apex, where there were nodules, some 1 cm. in. diameter, formed of yellowish, soft tumor, broken down centrally. At the lung base, but in the diaphragmatic pleura, were two large tumor masses, one probably a node-since it was anthracotic-measuring 2.5 X 3 em. The other mass was irregular in shape, soft, resilient, yellow, measuring 3 X 6 em. On the visceral pleura were small, round, grayish patches, possibly of tumor. The peritoneal cavity contained a moderate amount of straw-colored fluid. There were enlarged retroperitoneal (aortic mesenteric) lymph nodes and enlarged, yellowish gray, homogeneously marked lymph nodes about the greater and lesser curvature of the stomach and head of the pancreas. Peyer's patches were not unusually prominent. The spleen was large and soft, and measured 21 X 10 X 7 em. Three infarcts were visible. On section, one was anemic, the others hemorrhagic. The rest of the spleen was brick-red, with a faint grayish cast. The structure was homogeneous, and rnalpighian bodies were not seen. The appearance suggested lymphoid invasion, with passive compression of follicles. There was a small amount of fibrin on the surface of the spleen. The pancreas was negative. The liver was reddish-gray, normal in size and consistency, with sheets of irregular, flat lymphosarcomatous tissue covering the dome. On the section it was brownish red with interlacing grayish strands, and dotted like a leukemic liver. In addition, in the tip of the left lobe was It solid tumor some 4 em. in diameter, in color and consistence like those pre­ viously described. The gall-bladder and ducts were negative. The adrenals were negative. The kidneys were normal in size. The capsules stripped readily, leaving lobular surfaces. The cut surface was rather grayish. There were small congenital cysts. FIGB. 19 AND 20. CASE 5: LEUKOSARCOMATOSIB OF MEDIASTINUM. X 45 AND X 135

751 752 CUSHMAN D. HAAGENSEN

The bone marrow in the vertebrae, humerus, ulna, femur, and tibia was deep red, with gray patches. The larynx and tongue were negative, except for irregular scarring on the anterior epiglottis. A natomic Diagnosis: Leukosarcoma of cervical, mediastinal, bronchial, gastric, mesenteric, and retroperitoneal lymph nodes, pleurae, lungs, diaphragm over the dome of liver, liver, spleen, and skin. Infarcts of the spleen. Hyperplastic (lymphatic leukemia) bone marrow. Ascites. Microscopic Diagnosis: The mediastinal tumor mass (Figs. 19 and 20) was composed of loosely arranged mononuclear cells. They were dis­ tinctly larger than lymphocytes. The nuclei were round or polygonal. They did not have the uniformly round contour of lymphocytes. They were rather pale, not staining as darkly as lymphocytes. The nuclear material was arranged in irregular threads. One nucleolus was usually seen. The cytoplasm, which formed a well marked rim about the nucleus, was amphophilic and non-granular. There was a fine connec­ tive-tissue stroma. No Hassall's corpuscles were seen. The structure closely resembled that of reticulum-cell lymphosarcoma. The lymph nodes, liver, spleen, diaphragm, pleura, lungs, bone mar­ row, and skin showed infiltrations by the same type of mononuclear cell. Diagnosis: Leukosarcomatosis.

Comment: This case embodies the characteristic features of leukosarcomatosis as they have been described by Sternberg. As distinguishing features from lymphatic leukemia, not only the large lymphosarcomatous character of the cells, but also the finding of a large solid tumor in the liver, are noteworthy in this case. This tumor may be said to have been moderately radio­ sensitive, for it decreased markedly in size under radiation. Life was not prolonged appreciably, however, for the disease as a whole was uncontrollable. The carcinoma of the epiglottis and the leukosarcomatosis which developed three years later were clearly two independent processes in this patient. It is noteworthy that the larynx was removed at autopsy and that histologic study showed no evidence of the previous carcinoma other than scarring.

CARCINOMA Carcinoma ansmg in the anterior mediastinum, and not con­ nected with the thyroid or the bronchi, would seem to have no other possible origin than the thymus, since this is the only organ in this region possessing epithelial elements. Such a thymic origin is beyond doubt in a rare type of carcinoma arising sometimes as an PRIMARY NEOPLASMS OF THE MEDIASTINUM 753

encapsulated lobulated tumor in the normal position of the thymus. The typical structure consists of sheets and strands of epithelial cells of varying size and shape lying in a dense connective-tissue stroma. The epithelial cells tend to be flat and form concentric whorls resembling Hassall's corpuscles. In addition, there is a heavy infiltration of small round cells which resemble the small cells of the normal thymic cortex. This tumor, is, however, very rare. The best examples of it have been reported by Symmers and Vance, Jacobson, Lemann and Smith, Margolis (b) (cases 1 and 2), Nathan, Kneringer and Priesel, and Brannon. Kaijser has de­ scribed two cases of this type in which the histologic structure varied slightly from the preceding cases. In one tumor the epithelial cells were arranged in alveoli. Hassall's corpuscles were found in both the primary growth and in the metastasis. The second tumor also had an alveolar structure, which in areas became medullary. Voges and Zajewloschin have reported cases with a similar alveolar structure. More common are the forms of carcinoma whose gross and histologic characters make it probable that they originated in the thymus, but in which Hassall's corpuscles are not found. These include a variety of histologic types which have been designated by different authors as carcinoma, small-cell carcinoma, lympho­ epithelioma, etc. Matras and Priesel have recently discussed the classification of these cases and have reported seven which they observed. Their cases were of four types: (1) purely epithelial tumors, 1 case; (2) growths in which a type of epithelial cell predominated and in which there was lymphocytic infiltration of varying degree, 2 cases; (3) lymphosarcoma-like growths in which lymphoid cells predominated and in which the epithelial elements were very much in the background, 3. cases; (4) sarcoma-like tumors made up of spindle-shaped epithelial reticulum cells and lymphoid cells, 1 case. Matras and Priesel emphasize that all these tumors (with the exception of the unusual purely epithelial ones) are made up of two types of cells-epithelial cells which they assume to originate from the thymic reticulum cells, and lymphoid cells which are derived from the small round cells of the thymus. Additional cases of this same general type of thymic carcinoma have been described by Rubaschow, Largiader, and Schmidtmann. Schuster described a gelatinous adenocarcinoma of the anterior mediastinum which she believed, because of its position and its gross form, to have originated from the thymus. 754 CUSHMAN D. HAAGENSEN

From the standpoint of pathogenesis the interesting finding concerning carcinoma of the thymus has been that recently re­ ported by several English authors, that the disease may be associ­ ated with a pleuriglandular disturbance. Duguid and Kennedy described the case of a woman who had glycosuria and died with dyspnea and cyanosis. At autopsy a lobulated infiltrating tumor in the situation of the thymus was found. It proved to be a medullary carcinoma. There were widespread metastases. In addition, the adrenals were found to be distinctly larger than normal and there was a bulky colloid goiter. Leyton, Turnbull and Bratton have reported two cases in which there was evidence of endocrine imbalance. One patient had hypertrichosis, both had a peculiar fatness of the face and abdomen, and both showed diabetes mellitus. In both patients at autopsy a medullary carcinoma of the thymus was found, associated with great hypertrophy of the adrenal cortex and hypertrophy of the thyroid. There is almost no information concerning the reaction of carcinoma of the thymus to radiation. In the case reported by Foot, "weekly irradiation with deep x-rays had no apparent effect on the tumor." Lenk (b) described an epithelioma of the thymus, proved by autopsy, which showed no change following intensive radiation (Case 87). Radiation treatment was apparently not given in other cases which have been reported. In a number of these patients operative removal was attempted. As with other malignant tumors of the anterior mediastinum, the attempt was invariably fatal.

CASE 6: A. G., a Jewish clerk, thirty-four years of age, applied at the Memorial Hospital Sept. 28, 1927. One month previously he had first noticed generalized swelling of the right arm, which had become so marked that he could not use the arm. He went to a hospital, where prominence of the superficial veins over the right chest, cyanosis of the face, and dyspnea were observed. A left supraclavicular node was excised for biopsy. Hoarseness developed, but no cough or expectoration. The patient had lost twenty pounds since the onset of his illness. Physical examination on admission showed prominence of the super­ ficial veins over the chest and upper arms. This venous engorgement was particularly marked over the lower circumference of the chest. In the recumbent position there was definite cyanosis of the face. At the base of the neck, anteriorly on each side, were masses of enlarged firm lymph nodes. There was a recent biopsy scar in the left supraclaviculur region. In each groin were a few small, movable, finn nodes, There was no axillary or epitrochlear adenopathy. FIG. 21. CASE 6: CARCINOMA OF THYMUS BEFORE RADIOTHERAPY

FIG. 22. CASE 6: CARCINOMA OF THYMUS AFTER RADIOTHERAPY

755 756 CUSHMAN D. HAAGENSEN

There was marked broadening of the area of mediastinal dullness anteriorly to a width of 15 em. The breath sounds at both apices were prolonged and bronchovesicular. D'Espine's sign was positive. Roentgenograms taken on Sept. 28, 1927 (Fig. 21), showed a large area of increased density in the mediastinal region. Its central portion was dense and homogeneous, but in its periphery there were mottled areas of lesser density. The shadow extended from the level of the upper border of the first rib anteriorly down to the lower border of the 4th rib, capping the cardiac shadow. It was broadest at the level of the third interspace. Its edges were irregular, and serrated in outline. From the edges streaks and fine nodules of increased density extended out into the lung parenchyma. The Wassermann reaction was negative. The urine contained a few hyaline casts. The blood count was: hemoglobin, 70 per cent, red blood cells, 4,240,000; white blood cells, 17,400; polymorphonuclears, 91; large lymphocytes, 6; transitional cells, 3. Roentgen-ray treatment was given as follows:

Time 1\1i1li- Date (min- Filter Kilo- Focal Region Treated utes) amperes volts Distance ------9-29-27 5 30 0.5 mm. Cu; 1 mm. Al 175 .50 cm. Mediastinum anterior 9-30-27 8 30 0.5 mm. Cu; 1 mm. Al 175 50 cm. Right supraclavicular to- ward mediastinum 10-1-27 8 30 0.5mm. Cu; 1 mm. Al 175 .50 ern. Left supraclavicular to- ward mediastinum 10-3-27 5 30 0.5 mm. Cu; 1 rnrn. Al 175 liO cm. Mediastinum anterior 10-5-27 5 30 0.5 mm. Cu; 1 mrn. Al 175 50 em. Right supraclavicular to- ward mediastinum 10-6-27 5 30 0.5 mm. Cu; 1 mm. Al 175 50 em. Left supraclavicular to- ward mediastinum 10-7-27 5 30 0.5 mill. Cu; 1 mm. Al 175 liO em, Mediastinum anterior 10-8-27 10 3n o.s mm. c«: 1 mm , Al 17.'i .'i0 em. Mediastinum posterior 10-21-27 ,'i 30 0.5 mm. Cu; 1 mm, Al 175 .50 ern. Right anterior chest 10-25-27 3 30 1 mm. Cu 17.5 25 cm. Left anterior chest 11-1-27 .5 30 1 mm. oo 175 25 ern. Right anterior chest 11-10-27 5 30 1 mrn, Cu 175 25 em. Left anterior chest

Within a month, there was evidence of improvement. The edema of the right arm had decreased. The voice was no longer hoarse. The masses of nodes in the neck had diminished in size. The patient returned to work. A roentgenogram at this time, Oct. 20, 1927 (Fig. 22), showed slight diminution in the size of the mediastinal shadow. The character of the shadow had not changed. The patient remained away from the clinic for a month, and returned with marked exacerbation of his symptoms. He was dyspneic and orthopneic. The engorgement of superficial veins of the chest and the edema of the face were more marked. The area of mediastinal dullness was wider and there were signs of fluid at the left base. Radium treatment was given as follows: PRIMARY NEOPLASMS OF THE MEDIASTINUM 757

lIIi1li- l\lilli- Date curies Time curie Area Filtcr Distance Location hours ------12-18-27 Hi75 36 min. 1000 70 2 mm. brass 6 em. Left an terior chest 12-19--27 1618 I hr. 15 min. 2000 70 2 mm. brass 6 em. Left lateral chest, mid-axilla at level at 5th rib 12-23-27 2233 2 hr. 15 min. 5000 70 2 mm, brass 10 em. Pericardium

There was no apparent benefit from this radium-pack treatment. The patient's general condition became rapidly worse and he died on Dec. 26, 1927, three months after radiation had been begun, and four months after his first symptoms had developed. Autopsy: The body was that of a well nourished, middle-aged, white male, showing surprisingly little rigor mortis (he had died fifty hours before), with marked generalized post-mortem lividity. There were no external scars. The neck and face were swollen, and the superficial veins from the waist line up were greatly distended. There was marked edema of the scrotum and penis. The left pleural cavity contained about 1500 c.c., and the right also about 1500 c.c., of clear, straw-colored fluid. The parietal pleurae on either side were studded with many tumor nodules-those on the right being larger. The surfaces of the lungs showed many tumor nodules (2 to 5 cm.). The mediastinum was the site of a large, firm, slightly elastic mass which was adherent to the sternum and surrounded all the large vessels in the mediastinum. The neoplasm extensively infiltrated the parietal pericardium. There was a normal amount of fluid in the pericardial cavities. The lungs showed tumor nodules, varying in size from 2 to 4 em., scattered throughout. These nodules were discrete, irregular, and very pliable. Necrosis of the central portion was seen in many. The cut surface was grayish white and slightly glistening. The heart was normal. The esophagus, at about the junction of its middle and upper thirds, showed a small diverticulum which had evidently been produced by external pressure of the tumor mass in the superior mediastinum. There were superficial erosions along the left border of the tongue and the anterior tonsillar pillar. The peritoneal surfaces were smooth and glistening. The only metastases found were a few nodes beneath the diaphragm along the spine and a nodule on the superior aspect of the left lobe of the liver. These nodules had the same appearance as those in the chest. The liver was neg­ ative except for chronic passive congestion. The gall bladder and bile tract, the gastro-intestinal tract, the spleen, and the adrenals were negative. The kidneys were negative except for chronic passive conges­ tion. The bladder and prostate were normal. Anatomic Diaqnosis: Primary mediastinal tumor; metastases to lungs, pleura, liver; chronic passive congestion of internal organs with dilatation of superficial veins of chest wall; sacculation of esophagus; erosion or superficial ulcer of lingual mucous membrane. 70 FIGs. 23 AND 24. CASE 6: CARCINOMA Ok' THYMUS. X 45 AND X 135

758 PRIMARY NEOPLASMS OF THE MEDIASTINUM 759

Microscopic Diagnosis: The mediastinal tumor (Figs. 23 and 24) was made up of anaplastic epithelial cells loosely arranged. The nuclei were large, irregularly polyhedral in shape, and stained deeply. They varied greatly both in size and shape. Mitoses were frequent. The cytoplasm, which was considerable in amount, was amphophilic and finely granular. The stroma consisted of narrow septa of connective tissue running through the tumor. In places the epithelial cells had a foliate arrangement about these septa. Areas of massive necrosis were frequent. Lymphocytes were not seen. No Hassall's corpuscles were found. In the metastases in the lungs, pleura, and liver the structure of the primary tumor was reproduced. Diagnosis: Carcinoma, primary in the anterior mediastinum.

Comment: This tumor, an anaplastic carcinoma, although containing no histologic evidence of a thymic origin, may be tentatively classed as a thymic carcinoma by a process of exclusion. It was distinctly radioresistant. Although heavily irradiated, it decreased but slightly in size and caused death within a short time.

CASE 7: F. C., a painter, thirty-six years of age, came to the Memorial Hospital April 21, 1927. Seven weeks previously he had first noticed swelling of t he outer aspect of the right arm accompanied by some pain and impairment of motion of the arm and hand. Three weeks previously a biopsy had been done. There had been no cough, no loss of weight, or any other symptom. Physical examination showed a mound-like elevation 4 by 6 em. on the outer aspect of the right arm. It was hard and fixed. There was a recent biopsy scar in the overlying skin. There were several hard nodes high in the right axilla and in the right supraclavicular space. Over the right apex there was slight dullness and the breath sounds were diminished. The blood count was: hemoglobin, 80 per cent; red blood cells, 4,200,­ 000; white blood cells, 8,800; polymorphonuclears, 81; large lymphocytes, 7; small lymphocytes, 9; transitional cells, 2; eosinophiles, 1. Urine examination was negative. Dr. Ewing's report on the tissue removed from the arm tumor was: "Highly cellular, malignant tumor composed of small and large cells, some of which are extremely hyperchromatic and others clear. There are no squamous characters or neurogenic properties. Structure is very peculiar and has some of the features of transitional-cell growths." Roentgenograms of the humerus were negative. In films of the chest (April 21, 1927) there was no distinct tumor of the mediastinum to be seen (Fig. 25). The hilar shadows, particularly on the right, were more prominent, however, than is usual. The phreno-cardiac sulci were obscured. X-ray treatment to the arm, the axilla, and the supraclavicular space was given as follows: 760 CUSHMAN D. HAAGENSEN

Time Kilo· Date (min- Milli· Filter Distunce Region Treated utes) amperes volts ------4-21-27 Ii 30 1 mm. Cu 200 25 em. Right arm anterior 4-2,'}-27 6 30 1 mm. Cu 200 2,'} em. Right arm anterior 5-12-27 Ii 30 ~ mm. Cu: 1 mm. Al !)O 50 em. Right supraclavicular 1>-18-27 6 30 ~ mm, Cu; 1 Ill/II. Al 90 ,'}O em. Hight supraclavicular 5-21-27 (i 30 1 Ill/II. Cu 200 25 em. Hight axilla posterior 8-18-27 10 30 ! mm. CUi 1111111. Al 175 50 ern, Right axilla posterior 8-22-27 GO 4 ! mm. Cu: 1 mm. Al 175 50 em. Hight axilla anterior 8-24-27 GO 4 ~ mill. Cu; 1 mm, Al 17,'> 50 em, Right lateral upper arm HH3-27 5 30 1111/11. Cu 175 25 em. Hight arm anterior llH5-27 5 30 1111/11. Cu 175 25 em. Right axilla anterior HH!}--27 s 30 I mm, Cu 17,'} 25 em. Right arm posterior I(}-27-27 10 30 I mm, CII 17,'> 2.5 em. Right axilla posterior

Under radiation the tumor of the arm did not regress. It remained stationary for about four months and then began to increase in size. The whole area became edematous. The axillary and supraclavicular nodes increased in size. Meanwhile the pain in the arm continued unabated. In November 1927, roentgenograms of the chest showed that the hilar shadows had further increased in size. There were now irregularly mottled shadows projecting on each side of the mediastinal shadow be­ tween the level of the 6th and 8th rib posteriorly. The edges of these hilnr shadows were very irregular and blended into the lung markings. Additional films of the humerus at this time showed merely atrophy of disuse. In November 1927, seven months after irradiation had been begun, the axillary metastasis ulcerated. On Dec. 6, 1927, an interscapular-thoracic amputation of the right. shoulder girdle was done. The operative wound did not heal. The skin edges became reddened, indurated, and ulcerated. Metastatic nodules appeared in the skin over the whole right side of the chest. Repeated treatments with the radium emanation pack over the area of recurrence had no apparent effect on the extension of the tumor. They were given as follows:

xum- xtnu- Arcn Filter Di.· Date curies Time tnnce Regiuu Treated curie hours ------1-1-2!l 1720 -l hr. 40 min. 70 sq. em. 2 nun. brnsa 6 em. Hight anterior upper chest HOOO 1-2-28 14:1IJ 3 hr. 70 till. em. 2 mm. brass 6 em. Hight antneior upper chest 42!l0 1-5-2X 1~60 2 hr. 10 min. 70 "'I. em. 2 mrn. brass n em. Hight antr-rior upper chest 41~)O 1-11-21l 2750 :i hr. 35 min. 70 eq. em. 2 mm. brass 6 em. HiKht anterior upper ChCHt IlIX)O 1-12-21l 2:l67 3 hr. 20 min. 70 "'I. em. 201m. bruas 6 em. Hight unterior upper cheat sooo 1-11l-28 IIlI~) 3 hr. 20 mill. 70 eq , em. 2 rum, brass 6 em. Hight anterior upper cl1C'l'\t sooo 1-27-2!l 1500 4 hr. 70 "'I. em. 2 mm. brass 10 em. Right anterior upper ChCft 601X)

Roentgenograms of the chest taken Jan. 3, 1928 (Fig. 26), showed for the first time a well defined tumor of the mediastinum situated at the level of the hilar shadows which had been previously observed to be enlarged. As an irregularly mottled shadow it extended from the level FIG. 25. CASE 7: CARCINOMA OF THYMUS BEFORE RADIOTHERAPY

FIG. 26. CASE 7: CARCINOMA OF THYMUS AFTER RADIOTHERAPY 761 762 CUSHMAN D. HAAGENSEN of the 6th to the 8th ribs posteriorly. On the left, where it was more prominent, its edges were sharply defined but irregular in outline. On the right side the border of the tumor was less clear cut and fused with the irregular and very prominent lung markings. The phreno-cardiac sulci were obscured. In each base were sharply defined, round shadows representing metastases. The patient's condition became rapidly worse and he died Feb. 17, 1928, one month after radiation of the chest had been instituted, nnd eleven months after the onset of his illness. A lltopsy: The body was that of a young adult male, moderately emaciated. The right arm had been disarticulated and removed with scapula and clavicle. The whole scar was the seat of extensive tumor growth. There were wide areas of ulceration and infiltration of the skin with opaque tumor nodules, covering the entire right chest. The left supraclavicular region showed large lymph nodes. There were old healed linear scars on the inner side of the right thigh. The mediastinum, hila of both lungs, lower cervical nodes, and lower surface of the left lung were occupied by a soft, semi-cystic and cystic, opaque, continuous tumor mass. It ran down the bronchial tree, ap­ peared in diffuse submucous nodules in the bronchial mucosa. The trachea and bronchi were considerably compressed and stenosed. The upper part of the right lung was gangrenous. There were several discrete tumor nodules in the parenchyma of both lungs. The gross appearunce was that of thymic carcinoma. Two-thirds of the right pleural cavity was filled with cloudy fluid. The lung was compressed against the spinal column and adherent to the chest. There was a small amount of fluid in the left pleural cavity. The pleurae were covered with thick fibrin. The right ventricle and auricle were filled with fatty clot. The heart muscle was soft and flabby. The chambers and valves were normal. The spleen was soft and hyperplastic. The gall-bladder was distended with tarry bile. The liver was large, firm, nutmeg, and contained scattered small tumor nodules. The kidneys showed acute parenchymatous degeneration. The adrenals were normal. All the celiac nodes were much enlarged. The stomach showed post-mortem digestion. The pancreas was negative. The intestines were normal. The bladder and prostate were normal. The vertebral bone marrow seemed osteosclerotic. Anatomic Diagnosis: Mediastinal tumor with metastases to arm, lymph nodes, lungs, pleura, and liver. Microscopic Diagnosis: The mediastinal tumor (Figs. 27 and 28) was a highly anaplastic carcinoma. The cells were loosely arranged in a foliate pattern about narrow strands of connective tissue which formed the stroma. The nuclei of the tumor cells were relatively large, and round or polyhedral in shape, although they varied greatly both in size lind shape. FIGs. 27 AND 28. CASE 7: CARCINOMA OF THYMUS. X 45 AND X 135

763 764 CUSHMAN D. HAAGENSEN

They were hyperchromatic. Mitoses were frequent. The cytoplasm was relatively prominent, amphophilic and finely granular. Much hemorrhage and necrosis were seen. There was no lymphocytic infil­ tration. Hassall's corpuscles were not found. The tumor nodules in the lungs, pleura, liver and lymph nodes were of the same structure as the mediastinal tumor. The bone marrow also contained metastases. Diagnosis: Carcinoma, primary in the anterior mediastinum.

Comment: The morphology of the tumor in this case is practi­ cally identical with that of the tumor in the preceding case. By a similar process of exclusion it may be tentatively classed as of thymic origin. Since the arm tumor appeared eleven months before the mediastinal tumor was definitely shown to be present, objection may be made to classifying the mediastinal tumor as primary. In reply it can only be said that the structure of the arm tumor does not correspond to that of any known type of growth which might arise primarily in the soft tissues of the arm. Moreover, a similar latency of the primary growth is not unusual with carcinoma arising in other organs. In the breast, for example, generalized metastases may precede the discovery of the small primary tumor, which may remain circumscribed until death. Although this case is quite without parallel among the thymic carcinomas which have been reported, it falls most easily into this class of tumors. The tumor was thoroughly resistant to radiation. Neither the arm lesion, the chest recurrence, nor the mediastinal growth showed the slightest response to radiation.

DERMOID CYSTS There have recently appeared a number of thorough reviews of the reported cases of dermoid cysts of the mediastinum (Heuer b, Robertson and Brown, Kerr and Warfield). A total of about 150 of these tumors have been reported. In terms of the number of cases which have been described in the medical literature, dermoid cyst is the most frequent type of mediastinal tumor, whether benign or malignant. It is probable, however, that this frequency is more apparent than real. Successful surgical treatment has no doubt stimulated many case reports of dermoid cyst. It would seem that lymphosarcoma is actually the most frequent neoplasm of the mediastinum. Probably originating from congenitally misplaced cell inclusions PRIMARY NEOPLASMS OF THE MEDIASTINUM 765 in the mediastinum, dermoid cysts are characterized by their extraordinary latency. Symptoms most frequently develop be­ tween the ages of ten and twenty. Pain in the chest, cough, and dyspnea, often due to pleural irritation, are the commonest symptoms. Coughing up of hair, a pathognomonic sign of a dermoid cyst connecting with a bronchus, has been observed in twelve cases according to Kerr and Warfield. The symptoms may persist throughout the lifetime of the individual. The slowness of growth of dermoid cysts is shown by the fact that, although symptoms usually begin in the second decade of life, the diagnosis is most frequently made during the third decade (Kerr and Warfield). Excision in the hands of such surgeons as Heuer has produced lasting cure in a considerable proportion of cases. Heuer warns that incomplete extirpation and drainage, on the other hand, have rarely resulted in cure. Surgical intervention is desirable in cases in which symptoms have developed. Without surgical treatment a large proportion of these patients finally die of pneumonia or empyema following rupture of the cyst into the bronchi or the pleural cavity. Secondary malignant degeneration in dermoid cysts, moreover, is not uncommon. Kerr and Warfield collected reports of twelve such instances. Some of these malignant tumors have originated in complex teratomas. Lambert and Knox reported a case of this type in which an area of chorionepithelioma in the mediastinal teratoma had metastasized to lung and liver. Considering the radioresistant nature of the adult tissues of which dermoid cysts are composed, radiation treatment would be expected to be fruitless. This was the result in the only instance of radiation treatment of a dermoid cyst on record-a case treated with radium by Kahn in 1922, and subsequently operated upon. The following case was treated at Memorial Hospital:

CASE 8: I. B" a student nurse aged nineteen, came to the Memorial Hospital on Nov. 23, 1923. As a child she had had measles. In 1915, when she was eleven years old, she had pleurisy on the right side. Her physician told her she had fluid in the chest, but her chest was not tapped. The illness lasted one week. She had not been ill otherwise. About January 1922, she began to have a slight persistent cough. In June 1922 she had hemoptysis for the first time. The cough persisted, but she had no other symptoms during the ensuing year. In July 1923, the hemop­ tysis recurred and lasted several days. In October 1923, she had hemop­ tysis for the third time and expectorated two firm pieces of tissue, each 766 CUBHMAN D. HAAGENBEN

1.5 em. in length and 0.5 em. in diameter. These were examined by Dr. Ewing, who said they showed bone, adult voluntary muscle, fat, columnar epithelium, and groups of cells which resembled salivary glands. The patient had lost no weight; she felt well between hemorrhages, had no fever or increased pulse, and complained only of a slight non-productive cough, which she described more as a clearing of her throat. Physical examination showed slight widening of the area of medias­ tinal dullness, anteriorly. At the right base breath sounds and fremitus were decreased and there were numerous coarse, crackling rales, The general physical condition was good. The patient weighed 145 pounds, whieh was the most she had ever weighed. Roentgenograms taken on Dec. 21, 1923 (Fig. 29), showed a pyramidal area of increased density projecting from the mediastinum into the right thorax. The heart was displaced to the left. The tumor shadow was mottled in density. It extended from the lower border of the 1st rib anteriorly down to the diaphragm, obscuring the right hilum and the right phreno-cardiac sulcus. The outer edge of the shadow was slightly irreg­ ular but fairly clear cut. A diagnosis of probable dermoid cyst was made. In order to deter­ mine the reaction of the tumor to a test dose of radiation, x-ray treatment was given as follows:

Date I(min-Time Milli- ~·:ter. Dt~:~;cpl utea) amperes :Uii::-I__ __I ___I:CgiOn Treatetl___ ----- 11-23-23 60 4 17.i 0.,') mill. eu; l mm. Al .i0 ern, Hight chest anterior 11-28-23 60 4 175 0.5 mm. Cu; 1 mm. Al 50 em. Right chest posterior 1-9-24 80 4 17.i O.S mm. Cu; 1 mm, Al SO em. Right chest anterior 1-14-24 80 4 175 0.5 mm. Cu; 1 mm. Al .i0 em. Right chest posterior I

Roentgenograms (Fig. 30) taken after the treatment (Mar. I, 1924) showed no change whatever in the appearance of the tumor. Clinically the patient continued in good general health. The slight cough con­ tinued, and from time to time she had hemoptysis. In March 1924 she coughed up hair for the first time, following what she considered to be a "cold," during which she coughed more than usual. Examination showed increased rltles at the right base and a pleural friction rub. The patient was last heard from June 19, 1929. She was at the time working in a western hospital. She still had occasional hemoptysis. Roentgenograms showed no change in the tumor.

Comment: The coughing up of hair and also of tissue containing bone, muscle, fat, columnar epithelium, and salivary glands, leaves no doubt as to the diagnosis of dermoid cyst communicating with a bronchus. The pleurisy at the age of eleven was probably the first symptom. Fourteen years later symptoms still continued. FIG. 29. CASE 8: DERMOID CYST OF MEDIASTINUM BEFORE RADIOTHERAPY

FIG. 30. CASE 8: DERMOID CYST OF MEDIASTINUM AFTER RADIOTHERAPY 767 768 CUSHMAN D. HAAGENSEN

NEUROGENIC TUMORS Many of the neurogenic tumors of the mediastinum have been ganglionic neuromas arising from the sympathetic ganglia. Lenk (c) found reports of eleven such cases. Crile and Ball have recently described one more tumor of this type, which they successfully removed from the superior mediastinum (Case No.2). Clinically, ganglionic neuromas are characterized by very slow growth. The patients are usually young. In the thirty cases collected by Geymiiller the average age was seventeen and one-half years. Anatomically, ganglionic neuromas of the mediastinum are distinguished by their situation in the posterior mediastinum, where they usually lie in the angle between the bodies and the transverse processes of the vertebrae. In the cases reported the tumors have all been unilateral. Some of the neurogenic tumors of the mediastinum are neuro­ fibromas arising from the sheaths of the nerves in this region. Palugyay described two such tumors, one apparently originating from the brachial plexus and the other from an intercostal nerve. Crile and Ball removed a tumor of this type from the superior mediastinum. These tumors may be of the hour-glass form, arising within the vertebral canal from a spinal nerve and ex­ tending through an intervertebral foramen into the mediastinum. Heuer (a) observed two such cases and collected reports of eleven others. One of the most remarkable of these hour-glass tumors was that described by Borchardt (Case No.3). The intrathoracic portion of the tumor filled the left upper thorax. The patient also had generalized neurofibromatosis. The association of generalized neurofibromatosis with neuro­ genic tumors of the mediastinum would be anticipated from the natural history of the disease. Yet actual case reports are ex­ ceedingly rare. Including Borchardt's case only five have been described. Geymuller reported such a case which de Quervain had followed for twenty-six years. In 1892, when the patient was thirteen years old, a ganglionic neuroma arising from the sympa­ thetic chain at the base of the neck was removed. A few years later generalized neurofibromatosis developed and was still pro­ gressing when the patient was thirty-nine. This case is the only one on record in which a ganglionic neuroma of the mediastinum occurred in conjunction with generalized neurofibromatosis. The mediastinal tumors associated with the disease in other cases were neurofibromas. One of Palugyay's patient's with hour-glass tumor PRIMARY NEOPLASMS OF THE MEDIASTINUM 769

(Case No.1) also had generalized neurofibromatosis. Hamper! described the autopsy findings in a patient aged thirty-five dying with generalized neurofibromatosis and a tumor of the chest. Bilateral neurofibromas of the vagus nerves were found. The largest tumor, which projected from the right side of the posterior mediastinum, showed sarcomatous degeneration and had metas­ tasized to the lungs and adrenals. Hosoi and Stewart have recently reported the case of a man aged twenty-eight with generalized neurofibromatosis in whom a neurogenic sarcoma developed on the basis of a neurofibroma of the superior medi­ astinum which had been present for ten years. The treatment of neurogenic tumors of the mediastinum is wholly surgical. Considering the radioresistant nature of neuro­ genic tumors in general, nothing could be hoped for from radiation treatment. No actual report of radiation treatment of a medi­ astinal tumor of this type has been encountered. The following is a case treated at the Memorial Hospital:

CASE 9: R. N. McA., a Jewish girl of eighteen, came to the Memorial Hospital Dec. 18, 1928, complaining of multiple subcutaneous tumors. There was no family history of subcutaneous tumors or of areas of skin pigmentation to her knowledge. Two years previously she had first noticed a small subcutaneous lump in the occipital region. Shortly thereafter numerous similar small sub­ cutaneous tumors appeared over the trunk and extremities. All these tumors were tender to pressure, particularly those on the left side of the abdomen. The patient had not noticed the development of any areas of pigmentation. She had had no dysphagia, cough, or dyspnea. Physical examination showed widening of the area of mediastinal dullness (4 cm. to each side of the mid-line in the second interspace). Scattered over the entire body, with the exception of the face and the hands and feet, there were numerous elastic, round or discoid, freely movable subcutaneous tumors measuring from 0.5 cm. to 2 cm. in diam­ eter. They were most numerous over the upper back, at the base of the neck on each side, and over the abdomen. The tumors were very tender to pressure. Over the back and over the abdomen and chest there were a moderate number of small flecks of brown pigment in the skin. There were three brown pigmented nevi, each 0.5 em. in diameter-one on the left breast, one on the central abdomen, and one on the right upper thigh. Roentgenograms (Fig. 31) showed a dense homogeneous oval area of increased density in the upper mediastinum. Its lower border was at the upper edge of the 3rd rib anteriorly. It became broader as it extended upward and at the upper border of the first rib it merged with dense, homogeneous round shadows which occupied each apex. The borders of these shadows were smooth and clear-cut. Roentgenograms of the pelvis and spine showed no evidence of bone involvement. 770 CUSHMAN D. HAAGENSEN

A diagnosis of generalized neurofibromatosis with involvement of the nerves or ganglia in the superior mediastinum was made. Since the reaction of this rare form of tumor to radiation was not known, roentgen­ ray treatment was given.

Time MiIli- Date (rnin- am- Filter Kilo- Focal Region Treated utes) peres volt. Distance ------~---- 3-2-28 8 30 0.5mm.Cu; l mrn.Al 200 30 CIIl. Right supraclavicular 3-5--28 7 30 O.•'imm.Cujl mm.AI 200 30 cm. Left supraclavicular 3-&-28 6 30 0.5mm.Cu;lmm.AI 200 30 em. Upper anterior mediastinum

As would be surmised the radiation had no apparent effect. Roent­ genograms following the treatment, May 2, 1928 (Fig. 32), showed no change whatever in the intrathoracic masses. Roentgenograms taken two years later, May 8, 1930, showed no change in the findings. When the patient was last seen, on May 8, 1931, the multiple sub­ cutaneous tumors were much the same as when she first came to the clinic three years previously. They had not grown, nor had any new tumors appeared. The widened mediastinal dullness was as when she was first seen. Since she first came to the clinic she had married and passed through a normal pregnancy.

Comment: It is unfortunate that it is not possible to present histologic evidence as to the nature of the mediastinal tumor in this case. The chronicity of the disease and the unwillingness of these patients to submit to operation are responsible for the paucity of pathologically controlled case reports. Since this case has been followed for three years and no change has occurred in the medi­ astinal tumor, it would seem worth while to report the case at this time. There can be no doubt but that the mediastinal tumor is related to the generalized neurofibromatosis. Whether it is a ganglionic neuroma or a neurofibroma cannot definitely be deter­ mined, but the bilateral involvement strongly suggests neuro­ fibroma. DIFFERENTIAL DIAGNOSIS 1. Age: The age at which symptoms develop has a distinct significance in the differential diagnosis of neoplasms of the mediastinum. As will be seen from the accompanying chart (Chart 1), which has been constructed on the basis of the case reports referred to above, the age of onset of symptoms differs considerably for some types. Thymic carcinoma, for instance, r------

FIG. 31. CASE 9: NEUROGENIC TUMOR OF MEDIASTINUM BEFORE RADIOTHERAPY

,------

FIG. 32. CASE 9: NEUROGENIC TUMOR OF MEDIASTINUM AFTER RADIOTHERAPY 771 772 CUSHMAN D. HAAGENSEN usually occurs at a much more advanced age than other malignant tumors of the mediastinum. It is most frequent between the ages of fifty and sixty, while large round-cell lymphosarcoma and Hodgkin's disease most often occur in patients between twenty and thirty. Small round-cell lymphosarcoma (malignant lympho-

CHART I Age Distribution of Primary Neoplasms of the Mediastinum

4 2 o

BH-t1ft+t+t+++t+H-t++-H-t1+H+H++t+H-H+H-t1r++1++t++++t++++1-++i 6H+f-t+1H-t1+t1ffi±H++t+t++t++t+++++H++++t++t++t++t++t++t+m 4H++-+-t+t++I+ 2

B!rt+++++++-H++++H+++++-H-H+H+t-H-H+H+H+H+H+~~~f++-1

~ ~H-t1ft+t+H+H+t++t++H+H+H+H++++++++++++++++++mm+-J+-j ~ ~.....~mm:tmm:mm~mtm:ttttW ! B!mt1+m~W+m1W~mt~~tmllitittttlli

o

cytoma) usually affects infants. In this age group many dermoid cysts also occur. 2. Duration: The duration of symptoms is a very important criterion in the differential diagnosis of mediastinal tumors. From Chart II, indicating the average duration of disease in the collected PRIMARY NEOPLASMS OF THE MEDIASTINUM 773 cases (not treated by radiation) referred to above, it is apparent that if a patient's symptoms have lasted much longer than a year the probability of the process being benign is very great. It is also clear that the natural duration of carcinoma of the thymus is rather longer than that of lymphosarcoma. A patient who has had

CHART II Average Duration of Disease in Primary Neoplasms of the Mediastinum (Unradiated Cases)

I

8

I.,

~ 1 ~ III Montha X.ara symptoms for close to a year has a greater chance of having a carcinoma than a lymphosarcoma. Beyond this it is impossible to go, considering the small number of cases in which the duration of the disease has been recorded. 3. Clinical Findings: Even though a mediastinal tumor be comparatively small, it may produce serious symptoms because of the close relationship of various vital structures in the confined space of the mediastinum. Symptoms of vascular origin caused by pressure on the superior vena cava and its tributaries are promi­ nent. Craver has pointed out that puffiness of the eyelids and swelling of the base of the neck are among the first to appear. The subcutaneous veins over the chest become dilated and tortuous. Cyanosis and edema of the face, upper thorax, and arms develop. These symptoms may be limited to one side or they may be 71 774 CUSHMAN D. HAAGENSEN

bilateral. The radial pulses may be unequal. Respiratory symptoms, due to pressure on the trachea and bronchi, include cough, expectoration which may be bloody, dyspnea and orthopnea, and stridor. Among the symptoms of nervous origin, pain in the upper chest, neck or arms is the most frequent. Pressure on the recurrent branches of the vagus may cause hoarseness, aphonia, or spasm of the glottis. Interference with the cardiac branches of the vagus may result in tachycardia or bradycardia. Compression of the sympathetic may produce unilateral Horner's syndrome­ narrowing of the space between the eyelids, contraction of the pupil, and unilateral hyperhidrosis of the face. Unilateral exophthalmos sometimes also develops. Dysphagia, due to pres­ sure on the esophagus, is common. Among the physical signs of mediastinal tumor the most striking is the wide area of dullness across the upper mediastinum. The heart is often displaced downwards and to the left. D'Espine's sign may be positive. The thorax may be asymmetrical. These various symptoms and signs are not of great significance in the differential diagnosis of the different types of neoplasms of the mediastinum, for they may be encountered in both malignant and benign tumors, although the extreme picture of increased pressure within the mediastinum is more frequently seen with the rapidly growing malignant neoplasms. The presence of metastatic nodes in the neck or axilla is, of course, usually indicative of a malignant tumor. Physical signs of a process of long duration­ clubbed fingers, kyphosis or scoliosis, deformity of ribs-usually signify a benign tumor. The writer has observed advanced hypertrophic pulmonary osteo-arthropathy in a patient with a benign tumor of the anterior mediastinum which resembled in all respects a dermoid cyst. 4. Roentgenographic Findings: Various writers have drawn up criteria for the differential diagnosis of the different types of mediastinal tumors from the roentgen findings. Childs, for instance, states that"primary sarcoma of the thymus generally has a roundish shape with a clear cut border.... It is a general experience that sarcoma presents a more sharply defined border than is found in carcinoma. ...A dermoid cyst is characterized by a distinctly clear-cut border which circumscribes a roundish, or even quite round, dense area usually projecting from the right side of the mediastinum." Belot and Peuteuil note that lympho­ sarcoma, Hodgkin's disease, hydatid cyst, dermoid cyst, and PRIMARY NEOPLASMS OF THE MEDIASTINUM 775

fibroma (as well as aneurysm of the aorta, tuberculous adenitis, and retrosternal goiter) produce a rounded shadow with clear-cut edges. Malignant tumors developing in the thymus, however, are rectilinear or nodular in shape, and only exceptionally assume a sharply outlined circular form. More critical studies by recent authors have shown, however, that such confidence in the diagnostic import of the roentgen findings in mediastinal neoplasms is questionable. It has been shown that whether the edge of a tumor appears as irregular, hazy, and infiltrating, or as clear-cut, rounded, and circumscribed depends not only upon the nature of the tumor itself but also upon secondary compressive and inflammatory changes in the surround­ ing lung. Davidson has pointed out that in the early stage of carcinoma invading the lung parenchyma the tumor may appear as a rounded shadow with a clear-cut outer edge projecting from the mediastinal border. Later, when the carcinoma has progressed to the point of causing compression of a bronchus which results in atelectasis, infection, and bronchiectasis of the surrounding lung, the outline of the tumor loses its clear-cut character and becomes irregular and hazy. An irregular and hazy outline, which has commonly been regarded as indicating infiltration, sometimes occurs with benign and encapsulated tumors as a result of com­ pressive phenomena in the adjacent lung. Although it is true that lymphosarcoma, Hodgkin's disease, leukemic lymphoma, and benign tumors of the mediastinum often produce shadows with smooth, clear-cut edges, as Childs and Belot and Peuteuil maintain, it must be remembered that exceptions to these rules are frequent. For instance, in the series of Memorial Hospital cases described above, the image in the first case of Hodgkin's disease had irregular and hazy edges, while in the second case of Hodgkin's disease the image was smooth, rounded, and sharply defined. In the case of leukosarcomatosis the edges of the shadow were very irregular and merged indistinctly with the pulmonary markings. Lenk's (a) discussion of the differential diagnosis of mediastinal tumors is the most comprehensive one available. He characterizes the image in lymphosarcoma as having an irregular and hazy contour. The organs of the mediastinum are usually not displaced. In Hodgkin's disease the contour is more often clear-cut, and the evidences of infiltrative growth less marked. In leukemic lym­ phoma the image is usually clear-cut and has a polycyclical 776 CUSHMAN D. HAAGENSEN outline. Lenk has been impressed by the fact that in the cases of thymic carcinoma which he has seen the tumor shadow has been broader than long. Displacement of the structures of the medi­ astinum, particularly the trachea, is more frequent than in other malignant mediastinal tumors. The roentgen evidence, however, is of relatively little weight in the differential diagnosis of these various types of malignant tumors of the mediastinum. This is not the case with the benign tumors in this situation. The roentgen findings in dermoid cyst are often significant. The situation of these tumors is characteristic. They almost always develop in the upper or middle anterior mediastinum and project asymmetrically from one side or the other of the mediastinum. They are usually round or oval in shape, with fairly clear-cut edges. Although teeth have not been shown roentgenographically in them as yet, areas of calcification have been demonstrated in several instances. Smith and Stone (case 1) and Kleinschmidt (case 2) have reported such cases. In the interpretation of such areas of calcification it should be remembered that calcareous plaques are found in the walls of aneurysm, in encapsulated medi­ astinal pleurisy, and in retrosternal goiter, tumors which are also situated in the anterior mediastinum. When a neurogenic tumor lies in the posterior mediastinum beside the vertebrae, as is often the case, its roentgenographic appearance is very suggestive of its nature. The image is round or oval and very sharply outlined. Ganglionic neuromas are uni­ lateral and therefore asymmetrically situated, while neurofibromas may be bilateral and symmetrical. It would not be just to conclude a discussion of the roentgeno­ graphic diagnosis of primary neoplasms of the mediastinum without at least enumerating the other conditions which give a similar and sometimes identical image. These include: aneurysm of the aorta; retrosternal goiter; idiopathic dilatation of the esophagus; cold abscess of the vertebrae; tuberculosis of the mediastinal lymph nodes; encapsulated mediastinal pleurisy; mediastinal abscess; lung abscess adjacent to the mediastinum; lung infarct adjacent to the mediastinum; hydatid cyst; carcinoma primary in a portion of the lung adjacent to the mediastinum; metastatic carcinoma of the mediastinum. There can be no doubt but that aneurysm is the most frequent cause of error. The most expert have acknowledged their inability to distinguish between aneurysm and neoplasms of the medi- PRIMARY NEOPLASMS OF THE MEDIASTINUM 777

astinum in some cases. Heuer (3) has reported two neoplasms which showed expansile pulsation and were therefore wrongly diagnosed as aneurysm. In another of his cases operation revealed an aneurysm, although pulsation had not been seen fluoroscopically. 5. Roentgenotherapeutic Findings: When the known radio­ sensitivity of such neoplasms as lymphosarcoma and lymphatic leukemia and the known radioresistance of most types of carcinoma is considered, it would seem probable that the reaction of medi­ astinal tumors to a test dose of radiation would be of value in their differential diagnosis. Although few radiated cases in which the pathologic type of the tumor was proved by autopsy or by biopsy have been reported, fortunately there are enough data to indicate that these general laws of radiosensitivity do apply to tumors of the mediastinum, and that the response to a test dose of radiation is of great diagnostic value. A few radiologists have drawn up criteria for the differential diagnosis of mediastinal tumors on this basis. According to the experience of Evans and Leucutia, "tumors originating from proliferation of the lymphatic cell element ... including lympho­ sarcoma, thymoma, lymphatic leukemia, pseudoleukemia and simple lymphoma .. ." entirely disappear within four to ten days following one skin erythema dose of deep roentgen therapy. Tumors"originating from proliferation of the reticulo-endothelial element of the mediastinal lymph glands or thymus ... including Hodgkin's disease, Sternberg's type of hyperplastic tuberculosis, and endothelioma," are reduced in ten days to within half of their original size and entirely disappear within five to six weeks after a similar dose. " Primary sarcoma and carcinoma" show a more or less pronounced reduction in size but rarely disappear within six weeks following a similar exposure. Daub reports that" thymomas are quite sensitive to radiation therapy.... The regression in size of these tumors is quite satisfactory but somewhat slower than is seen in ordinary lymphosarcoma." In regard to mediastinal tumors, Desjardins has stated that" a very rapid regression is a certain indication of a tumor derived from lymphoid tissue. Lymphosarcomatous tumors sometimes react more rapidly than those associated with Hodgkin's disease or lymphatic leukemia, but in the average case the difference is hardly sufficient to serve as a sharply distinctive feature. ... Epithelioma, carcinoma, and all other varieties of tumors except those originating in lymphoid organs react more slowly when they react at all." Lenk also 778 CUSHMAN D. HAAGENSEN emphasizes the radiosensitivity of lymphosarcoma, Hodgkin's disease, and lymphatic leukemia. He found thymic carcinoma, as well as the various benign tumors of the mediastinum, to be thoroughly radioresistant. The reports of these authors (with the exception of Lenk), however, have not included descriptions of cases of mediastinal tumors treated by radiation in which the patient was followed to the end and the pathologic nature of the tumor determined by autopsy. Because of their completeness in this respect the present series of cases is particularly significant. In the first of these cases, one of small round-cell lymphosarcoma (malignant lymphocytoma), the tumor regressed but slightly and death occurred after five weeks. The two cases of Hodgkin's disease each exhibited a different degree of radiosensitivity. The first was highly sensitive, the tumor regressing completely and life being prolonged for about three years. In the second case the tumor was only moderately radiosensitive, for it regressed only partially, yet enough to prolong life for almost two years. The mediastinal tumor in the case of lymphatic leukemia was highly radiosensitive, but the disease as a whole could not be controlled, and death occurred after three months. The mediastinal leuko­ sarcoma proved to be moderately radiosensitive in that it regressed markedly, but the process was so malignant that life could not be appreciably prolonged. The two cases of thymic carcinoma were both radioresistant, radiation being of no real benefit in either one. As would be expected, the cases of dermoid cyst and neurogenic tumor of the mediastinum showed no response to radiation. To sum up the question of the significance of the response to a test dose of radiation in the differential diagnosis of mediastinal tumors, it may be said that lymphosarcoma, Hodgkin's disease, leukosarcoma, and leukemic lymphoma are often strikingly radiosensitive, although occasional radioresistant cases are found. Thymic carcinoma and the various benign neoplasms of the mediastinum are radioresistant. It does not appear that any such fine distinctions as to radiosensitivity can be drawn among mediastinal tumors as Evans and Leucutia propose. The point of view expressed by Desjardins and by Lenk would seem much nearer the truth. More case reports in which the diagnosis has been proved histologically, are needed. PRIMARY NEOPLASMS OF THE MEDIASTINUM 779

SUMMARY 1. The opportunity which primary mediastinal neoplasms present for correlation of clinical with pathologic findings is emphasized. 2. The various types of primary mediastinal neoplasms are reviewed and reports of nine cases are presented. 3. The differential diagnosis of these neoplasms is discussed in relationship to: the age of the patient; duration of the disease; clinical findings; roentgenographic findings; and reaction of the neoplasm to a test dose of radiation.

BIBLIOGRAPHY BELOT, J., AND PEUTEUIL, G.: Les opacites arrondies du thorax, J. de radiol. et d'electrol. 14: 538, 1930. BORCHARDT, MORITZ: Bemerkungen zu den sogenannten Sanduhr­ geschwulsten des Ruckenmarks und der Wirbelsiiule, Klin. Wchnschr. 5: 636, 1926. BRANNAN, D.: Carcinoma of the thymus and occlusion of the superior vena cava, Arch. Path. 1: 569, 1926. BREGMAN, L., AND STEINHAUS, J.: Lymphosarkom des Mittenfells mit Ubergang in den Ruckgratskanal, Virchow's Arch. f. path. Anat. 172: 410, 1903. BROWN, S. E.: Malignant tumor of the thymic region with extensive metastasis, Arch. Path. 2: 822, 1926. CHILDS, S. B.: New growths within the chest: X-ray diagnosis, Am. J. Roentgenol. 10: 175, 1923. CHRISTIE, A. C.: The diagnosis of primary tumors of the lung, Am. J. Roentgenol. 8: 97, 1921. COENEN: Vorstellung eines Praparates von Lymphosarkom des Thy­ musdruse bei einem 6 [ahrigen Knaben, Berl. klin. Wchnschr. 41: 255, 1904. CRAVER, L. F.: Diagnosis and treatment of thymoma, M. Clin. North America 14: 507, 1930. CHILE, G. W., AND BALL, R. P.: Primary nerve tumors of the neck and mediastinum, Surg. Gynec. & Obst, 48: 449, 1929. CUSHING, HARVEY: Fashions in surgery, Surg. Gynec. & Obst. 52: 266, 1931. DOUB, H. P.: Roentgen diagnosis and treatment of thymomata, Radiology 14: 267, 1930. DAVIDSON, MAURICE: Cancer of the Lung, Wm. Wood & Co., New York, 1930, p. 114. DESJARDINS, A. U.: (a) The rationale of radiotherapy in Hodgkin's disease and lymphosarcoma, Am. J. Roentgenol. 17: 232, 1927. (b) The reaction to irradiation as a means of differentiating certain varieties of tumor, Brit. J. Radiol. 3: 6, 1930. DEWITT, C. H.: Sarcoma of the mediastinum, J. Radiol. 3: 27, 1922. 780 CUSHMAN D. HAAGENS'EN

DUGUID, J. B., AND KENNEDY, A. M.: Oat-cell tumors of the mediastinal glands, J. Path. & Bact. 33: 93, 1930. DWYER, M. F.: Report of a case of thymoma, Radiology, 9: 510, 1927. EVANS, W. A" AND LEUCUTIA, T.: Deep roentgen-ray exposure as an aid in the differential diagnosis of mediastinal tumors, J. A. M. A. 85: 1215, 1925. EVERT, J. A.: Malignant tumors of the thymus; with report of case, Minnesota Meet 8: 730, 1925. EWING, JAMES: (a) Neoplastic Diseases, W. B. Saunders Co., Phila­ delphia, 1928, p. 96G. (b) The thymus and its tumors, Surg. Gynec. & Obst. 22: 461, 1916. (c) Neoplastic Diseases, W. B. Saunders Co., Philadelphia, 1928, p. 968. FOOT, N. C.: Concerning" malignant thymoma," with a report on a ease of primary carcinoma of the thymus, Am. J. Path. 2: 33, 1926. FRAENKEL, E.: (a) Lymphomatosis grunulomatosa, Handbuch der speziellen pathologischen Anatomic und Histologie, F. Henke and O. Lubarsch, Berlin, Julius Springer, 1926, Vol. 1, part 1, p. 357. (b) Uber die Beziehungen der Leukiimie zu geschwulstbildenden Prozessen des hamatopoetischen Apparates, Virchow's Arch. f. path. Anat. 216: 340, 1914. GERLACH, WERNER: Uber ein Lymphosarkom des Thymus, Ztschr. f. Laryng. 9: 473, 1920. GEYMULLER, E.: Beitriige zur Kenntnis der Ganglioneurome und ihrer Beziehungen zu der Recklinghausen'schen Krankheit, Beitr. z. klin. Chir. 115: 712, 1919. GHON, A., AND ROMAN, B.: Uber das Lymphosarkom, Frankfurt. Ztschr. f. Path. 19: 1, 1916. GRANDHOMME, FR.: Ueber Tumoren des vorderen Mediastinums und ihre Beziehungen zu der Thymusdriise, Darmstadt, L. C. Wit­ tich'sehe Hofbuchdruckerei, 1900. HAENISCH, F., AND QUERNER, E.: Ueber Tumorbildungen hei leuka­ mischen Erkrankungen, besonders im Skelettsystcm, Ztschr. f. klin. Med. 88: 28, 1919. HAMPERL, H.: Zur Kenntnis der neurogenen Tumoren des Mediastinums, Wien. med. Wchnschr. 77: 217, 1927. HARVIFR, M. P.: Lymphosarcome du thymus, Bull. et memo Soc. med. d. hOp. de Paris, 45: 374, 1921. HELVESTINE, FRANK, JR.: Malignant tumors of the thymus, Arch. Surg. 9: 309, 1924. RImER, G. J.: (a) Thoracic tumors, Arch. Surg. 18: 271, 1929. (b) The surgery of mediastinal dermoids, Ann. Surg. 90: 692, 1929. (c) Intrathoracic tumors, Ann. Surg. 79: 670, 1924. HOSOl, KIYOSHI, AND STEWART, F. C.: Differential diagnosis of mediastinal "tumors," Arch. Int. Med. 47: 230, 1931. JACOBSON, V. C.: Primary carcinoma of the thymus, Arch. Int. Med. 31: 847, 1923. JANEWAY, HENRY R.: The treatment of malignant tumors of the thymus gland by radium, Ann. Surg. 71: 460, 1920. KAHN, M.: X-ray studies of mediastinal shadows with special reference to dermoid cyst, J. Radiol. 3: 93, 1922. PRIMARY NEOPLASMS OF THE MEDIASTINUM 781

KAIJSER, R.: Zur Kenntnis der Geschwulste des Thymus, im Anschluss an zwei eigene Falle von Thymuskarzinom, Acta path. et micro­ biol. Scandinav. 4: 221, 1927. KAUFMANN, EDUARD: Lehrbuch der speziellen pathologischen Anatomie, Berlin, Walter de Gruyter & Co., 1931, p. 469. KERR, H. H., AND WARFIELD, J. 0., JR.: Intrathoracic dermoids, Ann. Surg. 88: 607, 1928. KLEINSCHMIDT, 0.: Bericht tiber zwei mit Erfolg radikal operierte komplizierte Dermoide des Mediastinum anticum, Munchen, med. Wchnschr. 67: 862, 1920. KNERINGER, E., AND PRIESEL, A.: Ein Beitrag zur Kenntnis der Thy­ mome (Lymphoepithelioma Thymi), Virchow's Arch. f. path. Anat. 241: 475,1923. KNUTTI, R. E.: Primary lymphosarcoma of the thymus with metastases below the diaphragm, South. M. J. 23: 1104, 1930. LAMARQUE, P., AND BERT: Tumeurs du mediastin et radiotherapie, Arch. de la Soc. d. sc. med. et biol, de Montpellier 12: 186, 1931. LAMBERT, S. W., AND KNOX, L. C.: Intrathoracic Teratomata, Trans. Assoc. Amer. Physicians 35: 17, 1920. LARGIADER, HANS: Zur Kenntnis der bosartigen Thymusgeschwtilste insbesondere des Thymuskarzinoms, Frankfurt. Ztschr. f. Path. . 29: 228, 1923. DE LAVERGNE, V., ABEL, E., AND DEBENEDETTI: Tumeur du mediastin anterieur a type clinique de leucemie aigue, Bull. et memo Soc. med, d. hOp. de Paris 54: 169, 1930. LEMANN, I. I., AND SMITH, J.: Primary Carcinoma of the Thymus, Arch. Int. Med. 38: 807, 1926. LENK, ROBERT: (a) Die Rontgendiagnostik der intrathorakalen Tumoren und ihre differential Diagnose, Wien, Julius Springer, 1929, p. 422. (b) Loc. cit. p. 385. (c) Loc. cit. p. 397. LEYTON, 0., TURNBULL, H. M., AND BRATTON, A. B.: Primary cancer of the thymus with pluriglandular disturbance, J. Path. & Bact. 34: 635, 1931. LETULLE, M.: Thymus et tumeurs malignes primitives mediastin ante­ rieur, Arch. gen. de med. 11: 641, 1890. MATRAS, A., AND PRIESEL, A.: Uber einige Gewachse des Thymus, Beitr. f. path. Anat. U. Z. allg, Path. 80: 270, 1928. MARGOLIS, H. M.: (a) The thymus gland in lymphatic leukemia, Arch. Path. 9: 1015, 1930. (b) Tumors of the thymus; pathology, classification and report of cases, Am. J. Cancer 15: 2106, 1931. MAXIMOW, A.: A Text-book of Histology, W. B. Saunders Co., Phila­ delphia, 1930, p. 716. MORAWITZ, PAUL, AND DENECKE, GERHARD: in Handbuch der inneren Medizin, Julius Springer, Berlin, 1926, Vol. 4, Part 1, p. 183. NATHAN, WILDEMAR: Uber einen Fall von Lymphoepithelioma thymi, Frankfurt. Ztschr. f. Path. 37: 385, 1929. 782 CUSHMAN D. HAAGENSEN

PALUGYAY, JOSEPH: Zwei seltene Falle von Thoraxtumoren, Wien med. Wohnschr. 70: 515, 1920. RENAULT, JULES, CATHALA, JEAN, AND PLICHET, ANDRE: Lymphocytome malin du mediastin anterieur chez un enfant de vingt mois. Origine thymique probable, Bull. et memo Soc. med. d. hop. de Paris 48: 176, 1924. ROBERTSON, C., AND BEVAN BROWN, R. E.: Dermoid cyst of the medias­ tinum, Brit. J. Surg. 17: 197, 1929. RUBASCHOW, S.: Eine bosartige Thymusgeschwulst, Virchow's Arch. f. path. Anat, 206: 141, 1911. SCHMIDTMANN, MARTHA: Zur Kenntnis seltener Krebsforrnen, Virchow's Arch. f. path. Anat. 226: 101, 1919. SCHMINCK};, A.: Pathologic des Thymus, in: Handbuch der speziellcn pathologisehen Anatomie und Histologie, F. Henke and O. Lubarsch, Berlin, Julius Springer, 1926, Vol. 8, p. 760. SCHRIDDE, HERM.: Thymus: in: Aschoff, Ludwig: Pathologische Anut­ omie, Gustav Fischer, Jena, 1923, vol. 2, p. 177. SCHUSTER, HELENE: Ein Beitrag zu den malignen Thymusgesehwulsten epithelialer Herkunft (Adenocarcinoma gelatinosum), Beitr. z. path. Anat. u. z. allg. Path. 75: 403, 1926. SIMMONS, CHANNING C., AND BENI~T, GEORGE: Hodgkin's disease: A report on the cases observed at the Collis P. Huntington Memorial Hospital from April 1913 to July 1916 with special reference to treatment with radium and the x-ray, Boston M. & S. J. 177: 819, 1917. SINGER, J. J.: Thoracic tumors, Arch. Surg. 18: 283, 1929. SMITH, E. E.: Thymoma of lymphosarcoma type, Ann. Int. Med. 2: 1063, 1929. SMITH, L. W., AND STONE, J. S.: Tumors of the mediastinum in children, Ann. Surg;. 79: 687, 1924. STERNBERG, CARL: (a) Leukosarcomatose und Myeloblastenleukamie, Beitr. z. path. Anat. u. z. alla. Path. 61: 75, 1916. (b) Leukosarkornatose, in: F. Henke and O. Lubarsch : Handbuch der speziellen pathologischen Anatomie und Histologic, Julius Springer, Berlin, 1926, Vol. 1, Part 1, p. 86. SVMMERS, DOUGLAS: The relationship of the toxic lymphoid hyperplasias to lymphosarcoma and allied diseases, Arch. Int. Med. 21: 2:37, 1918. SYMMERS, D., AND VANCE, B. M.: Epitheliomata of thymic origin, Arch. Int. Med. 28: 239, 1921. VOGES, HERMANN: Ein Fall von Thvmuskarsinom, Frankfurt. Ztschr. f. Path. 33: 501, 1926. WOLLSTEIN, MARTHA, AND McLEAN, STAFFORD: Hodgkin's disease, primary in the thymus gland, Am. J. Dis. Child. 32: 889, 1926. ZAJEWLOSCHIN, M. N.: Carcinoma der Thymus, Virchow's Arch. f. path. Anat. 254: 63, 1925. ZIEGLER, KURT: Die Hodgkinische Krankheit, Gustav Fischer, Jena, 1911, p. 70. ZNINIEWICZ, JANINA: Vier Falle von Lymphosarcoma thymicum, Griefswald, Paul F. Wolfram, 1911.