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MALIGNANT TUMORS OF THE

EDWARD H. CROSBY, M.D.' (Prom the Department of Path~logyoj Albany Medical College and the Pathological Lab- oratorg oj Albany Hospital, Albany, N. Y.) Malignant tumors of the thymus are of interest not only on account of their infrequency but also because of the controversy regarding the of the gland. Thymic tumors, which are distinguishable at post-mortem examination from tumors of the mediastinal nodes or of the , usually surround and compress the , bronchi, , and . By compression, and less often by invasion of the vessels and pas- sages, they cause by and venous obstruction, which may develop gradually or very suddenly. The points indicating the thymic origin of mediastinal sar- comata are summed up by Jones (1) as follows: 1. The situation of a large, slightly lobulated tumor at the site of the thymus. 2. The extension of this tumor downward behind the without infiltration of the . 3. The involvement of the pericartlium and of the pleura by direct lymphatic extension. 4. The resemblance to thymic on histological exnmin a t'ion. In connection with the last point some authors insist that all the histological elements of the thymus be found in some form, but a resemblance of the chief cell type to the thymic and the presence of Hassall's corpuscles in some parts of the tumor at least would seem adequate. Ewing (2) gives a classification of thymic tumors which has been widely quoted. His main groups are as follows: 1. 1,ymphosarcoma or , composed of a diffuse growth of round, polyhedral, and giant cells. 2. arising in the reticulum cells. 3. Spindle-cell sarcorria or myxosarcoma, very rare and somewhat ques- tionably attributed t,o the . The third and first groups are still under dispute because of the

This study was made while the author ~2x8Eugene Littauer Research Fellow in in Albany Medical College. 461 462 EDWARD H. CROSBY questionable mesoblastic origin of the small round cell of the thy- mus. This point will be discussed later. Harris (3) in 1892, An~brosirii(4) in 1894, and later Jories (I), Janeway (5),and others discussed the clinical symptoms of thymic tumors. The first symptonl is usually or hoarseness without expectoration or . This leads to the subjective symp- tom of suffocation without physical signs in the chest or visible cause of obstruction in the upper passages. Puffiness about the eyelids and fullness about the , toget,her with :L pecu1i:tr pink disco1or:ttion of the eyelids, :ls described hy ('rnver ((i),may 1)e ~)rescntearly in thc course of the . Engorgement of the of the neck, cyanosis, of the face and upper extrcniities, :t feeling of oppression in the chest, palpitj:ttion, and pain beneitth the sternum, which is constrictive and well localized, soon follow and rapidly become more marked. Alteration of the voice, - ache, dysphagia, and gradually increztsing emaciation :Ire associated with the appearance of a tumor growth in the or in the ccrvi- c:tl region. As the disease progresses, dyspnett becomes extrcrnc, inequality of the pulse is noticeable, hydrothorax develops, ancl the becomes displaced. The most common con~plications of thymic tumors are with effusion, pericjtrditis with effusion, obliteration of the vessels in the neck, arid obstruction of the esoph- agus and trachea. ,J:~neway(5) has urged the import:tnce of early diagnosis :tnd familiarity with the clinical course of these tu~nors,for in :L lnrgc number of cascs rt~diumor x-ray therapy offers relief, even if not a prospect of cure. However, the result of tre:tt,ment depends not only upon the early diagnosis and institutio~lof trentinerlt but also upon the histogenesis of the tumor. Roentgen examination is of the utmost diagnostic importance. The location and the appearance of the shadow :ire characteristic. The shadow is immediately above the pericardium :tnd higher th:tn the usual location of enlarged peribronchial lymph . A circular, sharply defined, flattened, non-pu1s:~tingmass in the anterior wall of the , in the absence of other evidence to the contrary, justifies a tentative diagnosis of thy mom:^. Pool (7) in 1925, Dwyer (8) in 1927, and Doub (9) in 1930 reported cases in which a diagnosis of probable thymoma was made by x-ray. The tumor w:~ssubjected to deep x-ray therapy and some of the patients showed great irnprovemerit in their symptoms. In 1925 Grover, Christie, Merritt, and Coe (10) reported two similar cases. Both MALIGNANT TUMORS OF THYMUS GLAND 463

patients were treated with deep x-ray therapy, and the authors state that the results were very encouraging. The term " thymoma" was first introduced by Grandhomme (11) in 1900. At that time it was applied to all malignant tumors arising in the thymus gland. Brown (12), in discussing the term, states that it should be used only to indicate primary carcinoma, which he considers the only real thymic tumor. Crotti (13), how- ever, believes that this term has the advantage of being accurate whether the cells are derived from or , and that it also clearly associates the tumor with its place of origin. Bell (14), in describing tumors of the thymus associated with , uses the term "thymoma" to include non- malignant tumors, and Margolis (15) apparently agrees with Bell. Strauss (16) believes that those growths of the thymus composed of small round cells like those of the should be called thy- moma, those characterized by a rich connective-tissue stroma and showing the presence of spindle cells be called sarcoma, and those growths derived from epithelial cells of Hassall's corpuscles be diagnosed carcinoma. Evert (17) uses the term sarcomatous thymoma because these tumors do not resemble true lymphosar- coma morphologically, and because he regards the term as equally applicable whether the is of epithelial or of lymphoid origin. The consensus is that the term "thymoma" should be used to designate any malignant tumor primary in the thymus. To understand the nature of the neoplastic of the thy- mus, it is necessary to review briefly the and the of the thymus gland. It is generally believed that the thymus originates from the endodermal of the third branchial clefts as a paired . At about the second month of prenatal life (Hammar, 18), the thymus, which up to this time has been an endodermal organ, begins to be infiltrated with lympho- cytes. These cells migrate into, proliferate among, and separate the epithelial cells of the thymus (Maximow, 19). Danchakoff (20) showed that the thymus cell is a true small lymphocyte and that it may differentiate into granular lymphatic cells or into plasma cells. This differentiation was brought about by treating with x-ray. Although most authors agree with this dual interpretation (Badertscher, 21; Danchakoff, 20; Hammar, 18; Brannan, 22; Schaffer, 23; Crotti, 13; Stengel and Fox, 24; Voges, 25), other observers believe that the endodermal cells (endodermal thymic reticulum) differentiate to form the so-called thymic cells. 464 EDWARD H. CROSBY

They are of the monist school, which is headed by Ewing (2)) Stohr (26)) and Prenant (27). In 1910 Pappenheimer (28) was also of the monist school, but his views as set forth in his later work have changed so that he may now be termed a dualist. Bell (14) has described transition forms between the reticulum cells and the thymic cells. The origin of the thymic cell is thus still a matter in dispute and, until this dispute is settled, definite classification of thymic tumors is impossible. Schaffer (23) describes the epithelial portions of the thymus gland as follows: "Within the medulla, but never in the cortex, are found peculiar concentrically laminated bodies called the concen- tric corpuscles of Hassall. These are nests of flattened epitheli~tl cells arranged concentrically around one or more central cells, these last having often undergone a degenerative process. Some- times the corpuscles are compound, two or three being grouped together and similarly enclosed by flattened cells." By trans- planting the thymus of young guinea-pigs, Jordan and Horsley (29), quoting the work of Jaff6 and Plavska to support their theories, showed that the concentric corpuscles of Hassall could not be interpreted as remnants of endodermal ducts, as had pre- viously been supposed. Regenerating transplants are said to form new corpuscles by a process of hypertrophy and aggregation of reticulum cells. This agrees with the earlier claims of Hammnr (18). Jordan and Horsley (29) believe that the concentric cor- puscles arise chiefly from hypertrophied endothelial cells of precapillary and the immediately investing reticulum cells. If Hassall's corpuscles actually represent in part remnants of atrophic and precapillaries, then similar structures should appear in other lymphoid organs. Structures resembling Hassall's corpuscles were found by Jordan and Horsley in atrophic subcutaneous lymph nodes of the rabbit. It is now generally ac- cepted that Hassall's corpuscles are endodermal in origin.

D. B., a young Italian laborer, twenty-two years of age, single, one year in this country, was perfectly well until Aug. 15, 1923, when a mild cough developed, which increased in severity and was associated with discomfort in the upper median portion of the chest. On Oct. 1, 1923, he was unable to go to work because of the severity of the coughing spells, pain in the chest, dyspnea, and cyanosis, associated with distention of the This case has been briefly reported by Hosoi and Stewart in their article on "Dif- ferential Diagnoeis of ," Arch. Int. Med., 47: 230, 1931. MALIGNANT TUMORS OF THYMUS GLAND 465 veins of the neck. He was admitted to the medical service of the Albany Hospital on Oct. 12, 1923, at which time the symptoms had increased in severity following several severe attacks of and dyspnea. These attacks came on when he attempted to swallow food, and were so severe

FIG.1. ANTERO-POBTERIORVIEW OF MEDIARTINALTUMOR WHICH HAS BEENSEC- TIONED, EXPORINQ THE PERICARDIALCAVITY The heart has been removed. The trachea forms part of the V-shaped notch in the upper part. The lobulations and general shape of the tumor suggest a thymic origin. that it was believed that particles of food had entered and obstructed the . At first these attacks lasted only a few seconds. The third attack, and the one which brought the patient to the hospital, could not be relieved. The patient's past history and the family history were irrelevant. showed a well developed boy suffering from 466 EDWARD 11. (7~~~~~ extreme dyspnea ant1 rnarkcd cyanosis. He was perspirir~gfreely, and, not being able to speak English, pointed to his thro:it and the upper part, of his chest. The left hand and arm were swollen and the pulse was weaker in the left radi:tl than in the right. The was some- what reddened and showed two small patches of exudate, but the larynx was free from membrane or obstruction. The heart borders were not enlarged to percussion, and the were normal. There were dullness and diminished breath sounds in Ihe upper left chest posteriorly and on both sides of the sternum in front. There were coarse r8les over both bases. The white count was 23,000, temperature 99' F., 28 per minute, and pulse 120 per minute. The respiratory difficulty increased, the veins of the neck bec:tme prominent, and the cyanosis remained marked. An intubation w:ts at- tempted, but the patient was not relieved, and he diet1 three hours after ttdrni7sion to the hospital. Necropsy was performed four hours post rnortern by Dr. I'icto~C. Jacobsen. The post-mortem examination was limited to an examination of the chest cavity, the thoracic organs being removed in toto. The striking feature was n large, dark red, nodular mass present in the mediastinurn and apparently enveloping all other structures. The he:~rt was entirely hidden until the lower portion of the mass w:is raised. The peric:lrtli:11 sac was fluctuant and bulging. The mediastinal tumor measured 30 x 13 x 12 cm. and weighed 1975 gm. Its exposed surfaces were covered by a thin connective-tissue capsule, uniformly very dark red in color, with the smoothness of the surface interrupted by numerous lobulations. The tissue was moderately firm and resilient. A longitudinal section was made through the center of thr mass, uhich was roughly triangular in outline with the apex in- ferior. The heart was practict~llyembedded in the new growth. The sectioncd surface had a cellular ;~ndmeaty appearance. This m:tss was subdivided above into lobes, which were tan colored and which in turn were subdivided by fine red lines into lobules whose arrangement bore a striking resemblance to sm:tll cerebral convolutions. The remainder of the tissues presented for the most part :in homogeneous dark red surface siniilar to the external surface. The had been greatly compressed and were collapsed. By , indurated areas could be detected in the lower of the right lung. The indurated tissue directly beneath the pleura was dull white and opaque. The pericardial sac was opened, allowing the escape of about 200 C.C. of opaclue, viscid, red fluid. The epict~rdiumwas thickened and opaque. The pericardium was di~coloreddeep red, and was :idherent to the heart in places by a thin layer of fibrinous rnaterial over these retltlene(l reDissection of the heart showed norrn:tl endocardium and valves. The myocardium was a little pale and as it :tpproached the epicnrdiurn the Iwo tissues blended imperceptibly Irregular patches of tissue of an :ippetlrancc and consistency similar Fro. 3. TUMORCELLS AROUND A BLOODVESSEL IN THE LUNG

467 468 EDWARD H. CROSBY to the mediastinal tumor were distributed irregularly over the pleural surfaces of the diaphragm, chiefly on the right side. The trachea and the were greatly flattened, antero-pos- teriorly. The was hypoplastic. Microscopic Examination: The tumor was composed quite uniformly of densely packed cells with very little stroma. The cells in general were of the small lymphocyte type with variation to the 1:~rge lymphocyte. The nuclei were large, occupying almost the entire cell, :tnd mitotic figures were numerous. Sections stained by Goodpasture's method revealed no oxidase granules. In one section, several bodies were found which re- sembled Hassall's corpuscles with degenerative changes. The tumor was vaguely subdivided into lobules by fibro-vascular septa from which a reticulum-like stroma ramified a brief distance between the tumor cells. This reticulum was well dernonstrated by Foot's silver stain. The cap- sule of the tumor was invaded and the lymph vessels wherever present contained a few or many lymphoid cells. Small hemorrhages and areas of necrosis were present throughout the section. The pericardium and the epicardium were infiltrated with tumor cells, which also invaded the myocardium in nearly its entire thickness. The epicardium, by influx of tumor cells, was fully three times its normal thickness. The cells were present in the lymph spaces but not in the blood vessels. The lungs showed large masses of tumor throughout the sections. 12 perivascular infiltration was conspicuous. The alveoli adjacent to vessels were often filled with t,umor, and the tumor cells made their way between the and the lining epithelium. The diaphragmatic pleura was covered with a thick layer of turnor cells which had also infiltrated the muscle to a marked degree. The anatomical diagnosis was malignant turnor of the thymus with to the pleura, the lungs, the diaphragm, and the myocardium, and compression of the trachea, the esophagus, and the aorta. The tumor primary in the mediastinurn, because of its position, its lobulated structure, and the nature of the type cell which was encoun- tered, without doubt arose in the thymus gland. Metastasis occurred to the lungs, the pericardium and pleura, the myocardium, and the dia- phragm. In reviewing the subject of thymic neoplasms, confusion was encountered not only in regard to the anatomical diagnosis but also the nature of the growth and manner of metastasis. An attempt has been made to classify the malignant tumors primary in the thymus gland which have been reported since Rubaschow (30), in 1911, reported a carcinoma primary in the thymus together with 36 collected cases. In 1896, Hoffmann (31) had reviewed 33 cases of malignant tumor primary in the thymus gland, which with Rubaschow's collection make the total 69. Brannan (22), how- ever, pointed out that Vermorel and Thiroloix (32) published a FIG. 5. TUMORTISSUE STAINED BY THE FOOTE-MENARDMETHOD, SHOW IN^ THE RELATIONOF RETICULUMFIBERS TO THE NEOPLABTICCELLS First Series: Sarcoma of the Thymus (Thym.oma)

Case Author Date Diagnosis Metastasis --No. 1 Cooper (33) 1832 Medullary sar- Infiltration of the in- coma of thymus nominate 2 Powell (34) 1870 Thymic lympho- Infiltration of both lungs, cytoma both pleurae, pericar- dium, mediastirial and lumbar lymph glands 3 Moore (35) 1884 Round-cell sar- Not given coma primary in thymus 4 Harris (3): 9 1892 Hound-cell sar- Both pleurae, right lung, cases were re- coma of anterior mediastinal and supra- ported and it clavicularlyrnph glands is believed that they were all pri- mary in the thymus 5 I-Iarris 1892 Itound-cell sar- Right lung and mediasti- coma of anterior nal lymph glands medinstinurn 6 Harris 1892 Sarcoma of ante- Right lung rior mediastinum 7 Harris 1892 Round-cell sar- Left lung, mediastinul coma of anterior and cervical lymph mediastinum glands 8 1892 Itound-cell sar- Left lung, peric ard' ~um, coma of anterior trachea, left , mediastinum mediastinal lymph glands, , mes- enteric lymph gland 9 Harris 1892 Itound-cell sar- Left lung, pericardium coma of anterior mediastinum 10 Harris 1893 Primary lympho- Left lung, pericardium sarcoma of ante- rior mediasti- num 11 Harris 1892 Hound-cell sar- Left lung coma of anterior mediastinum 12 1892 Primary sarcoma Left lung, left pleura. of anterior rnedi- Left lung was diseased astinum by 13 Acker (36) 1896 Large round-cell Both lungs, left axilla sarcoma of thy- mus 14 Weigert and 1901 Lymphosarcoma Pericardium Laquer (37) of thymus asso- ciat,ed with my- asthenia gravis 15 de la Camp 1903 Sarcoma of ante- Inf. bronchial, jugular, (38) rior mediasti- cervical, mediastinnl, num primary in retroperitoneal lymph persistent thy- glands, both lungs, mu8 First Series: Sarcoma of th l1h.?lrnus(Thymoma) (continued)

Case Autlior Date Sex Agc No. ------16 I'amasaki (:19) 1904 I+' :12 1,yrnphosarcoma Mediastinal and gastric (?) of thymus lymph nodes, right pleura, pericardium IT lIun, l3lumer, 1904 M 32 Lymphosarcoma Muscles in general :inti Streeter of thymus asso- showed evidence of (40) ciated with my- metastasis asthenia gravis 18 Orth (41) 1910 F 33 Sarcoma of thy- Both pleurae, both lungs, mus pericardium, bronchial and suprsclavicul:~r lymph nodes, left jugu- I:ir vein, liver, left 19 Zniniewicz 1911 M 17 Lymphoscircoma Bothlungs, superior venu (42) primary in thy- cava, pericardium, tra- mus chea, bronchial lymph glands, left , left suprarenal, pancreas, and sternum 20 Zniniewicz 1911 M 25 I~ymphosarcoma Both lungs, pericardium, primary in thy- cervical lymph glands, mus innominate vein, inter- costal muscles, ster- num, both kidneys, liver 21 Zniniewicz 1911 M 17 Lymphosarcoma Right pleura, pericnr- of thymus dium, cervical and me- diastinal lymph glands, erosion through ster- num and into intercos- tal muscles 22 Zniniewicz 1911 F 86 Lymphosarcoma Left pleura, left lung, of thymus left bronchus, pericar- dium, left 23 Grawitz (43) 1911 F 12 Lymphosarcoma Pericardium, myocar- of thymus dium 24 Sheen (44) 1911? 7 Sarcoma of thy- Both pleurae, both lungs, mos. mus bronchial lymph glands, , liver 25 Sheen 1911 ? 18 Sarcomit of thy- Cervical and bronchial mus lymph glands 26 Symmers (45) 1911 F 56 Ma1ign:~nt thy- Itight lobe of , moma trachea, liver 27 Barbano (46) 1912 M 30 Thymic lympho- Glands of neck and in- sarcoma (round- guinal region, pericar- cell sarcoma) dium, mediastinal ves- sels 28 Ewing (2) 1916 F 19 Malignant thy- Pleura, axillary and moma resem- bronchial lymph gland8 bling lymphosar- coma 29 Ewing 1916 M 32 Malignant thy- . moma Diagnosis was made by First Series: Sarcoma oj the Thymus (Thymonza) (continzred)

Fr Author Date Sex Age Diaanosia Metnvtaaia ------30 Major (47) 1918 ? ? Lymphosarcoma Spleen of thymus asso- ciated with acute lymphatic leuke- mia 31 Symmers (48) 1918 M 26 Lymphosarcoma, ltight pleura, lcft peri- of thymus bronchial tissue, tho- racic lymph nodes, per- icardium, both ventri- cles 3'2 Symmers 1918 M 17 Lymphosarcoma Cervical and retroperi- of anterior me- toneal lymph glands, diastinum corre- pericardium, left ven- sponding to re- tricle, both kidneys gion of thymus 33 Brand (49) 1920 M 28 Spindle-cell - ? coma of thymus 34 Foot (50) 1920 M 9 Malignant thy - Pleura, pericardium, my- moma ocardium, spleen, liver 35 Gerlach (51) 1920 E' 34 Lymphosarcoma Lymph glands of neck of thymus 36 Jancway (5) 1!)20 F 4S Small rountl-cell Both lungs, both pleu- thymo~na rae, mediastinsl :~nd axillury lymph nodes, perforation of sternurn, liver, apleen 37 Jtinewity 19'20 M 3'2 Giant-cell thy- Mediastinal and :~xillnry moma lymph glands 38 Janewey 1920 M 8 Thymic lympho- Mediastinal, cervical nb- cytoma associ- dorninal lymph glands, ated with lym- lymphomatous spleen, phat,ic leukemia liver, kidneys 39 Janewt~y 1920 M 25 Large round-cell ltight pleura, right lung, thymon~a (sar- cervical, mediastinal, coma) retroperitoneal lymph nodes, spleen, liver 40 IIarvier (52) 1921 F 56 Sarcoma of thy- Pleura, lungs, myocar- mus dium, diaphragm, liver 41 Cleland(53) 1922 M 33 Thymoma (small Mediastinal lymph round-cell sar- glarids coma) 42 Delessert (54) 1022 M 12 Lymphosarcoma ltight lung, pericardiuni of possible thy- mic origin 43 Meigs and de 1894 M 21 Round-cell sar- 110th pleurae, bothlungs, Hchweinitz coma of the an- pericardium, myocar- (55) terior mediasti- dium, carotid, right num probably diaphragm, mesenteric arising in the lymph glands, both thymus oculomotor , right eye, both kidneys, spleen, liver First Series: Sarcoma of the Thymus (Thymoma) (continued) - Case Author Date Sex Diagnosis Metastasis No. Age -. -- 44 Meigs and de 1894 M 40 Round-cell sar- Diaphragm, posterior Schweinitz coma of anterior wall of thorax. Post- medias t in um mortem examination probably arising was not complete but in the thymus it was believed that metastases resemt)led the previous case y (5) 1923 M 40 M:ilign:~nt t,l~y- Tracheal, bronchial rnoma lymph nodes, perfora- tion of sternum, liver Ilenault, 1924 ? 9 Lymphocytomaof Tracheal, bronchial Cathala, and mos. thymus (lym- lymph nodes, perfora- Plichet (57) phosarcoma) tion of sternum, liver Helvestine 1924 F 19 Sarcoma of thy- Left pleura, both kid- (58) mus neys Ilelvestine 1924 M 25 Small-cell lym- Kidneys phosarcoma of thymus Priedlander 1925 1' 38 Malignant small- Retroperitoneal lymph and Foot col- cell thymoma nodes, vena cava, both (59) ored associated with kidneys lymphatic leu- kemia Evert (60) 1925 M 28 Lymphosarcoma Bronchial, left cervical of thymus lymph glands, liver, kidneys, skin Miller (61) 1926 M 9 Lyrnphosarcoma Left pleura, left lung, of thymus cervical and abdominal lymph glands Wollstein arid Lymphosarcoma Spleen, liver, both kid- McLean (6") of thymus asso- neys ciated with Hodgkin's dis- 8888 Schmidt (63) Malignant tumor Not given of thymus com- plicated by ame- bic Noice (64) Malignant thy- Peribronchial lymph moma (lympho- nodes sarcoma) Zanelli (65) Lymphosarcoma Right pleura, right lung, primary in thy- pericardium, myocar- mus dium 1,yrnpho-epithe- Tumor was found at lioma of thymus operation and no me- tastasis Young and Thymic lympho- Spleen, lymph nodes (1) Spalding (67) cytorna, associ- ated with lym- phatic leukemia Jones (1) Thymic lympho- Both pleurae, both lungs, cytoma (sar- mediastinal lymph coma) nodes, perforation of sternum, diaphragm, both kidneys First Series: Sarcoma of the Thymus (Thymoma) (continued)

Cnsc Date Sex Age Metastasis No. Aut,hor I 1 I Sarcoma of thy- Both pleurae, hot11 lungs, mus mesc,nteric lymph notles, small intestines, left kidney Brown, S. E. Lymp11os:~rcoma Pleura, pericartlium, (69) of thymus thyroid gland, lymph glands of neck, right suprarenal gland, Iwth hitlneys, liver, pancreas Matbrasand I~yrnphosarcoma I'leuril, lungs, mediitstl- Priesel (70) of thymus n:tl lyrnph gl:tnds Matras and IAymphosarcom:i Left pleura, left lung Priesel of thymus Matras and Lym~~hosarcomal'r:tcheal, bronchi:tl, cer- Priesel of thymus vical, supraclavicular lymph gl:tnds Matras and ltound-cell sar- l'ericardium, diaphragm Priesel coma of thymus Shennan (71) iJymphosarcomn Pleura, lungs, pcricar- of thymus dium, mcdiastin:~I lymph glands, both ventricles Shennan Lyrnphosarcoma llight cervical, met1i:ls- of thymus tinal lymph glands Shennan Malignant thy- I'ericilrdium, trt~chenl moma, lymphatl- lyrnphglands, sternum, enoma type two upper right , pectoral portion of left Shennsn Malignant thy- llight pleura, right lung, moma, lymphad- mediastinal and gastric enoma type lymph glands, cl:~vicle, both scapulae, verte- brne, and ribs Shennan Malignant thy- ltight bronchus, trachea, moma, lymphad- right lung, right cervi- enoid type cal, right ilxillnry inter- nal mammary, peri- vertebral, mesenteric lymph glands Meeker (72), Thymoma (thy- Pleura, lungs, perihron- same case as mic lymphosnr- chid lymph nodes, ret- reported hy coma) roperitoneal and I~ron- Herrimnn chi:rl lymph nodes, and Itahte , kidneys, gas- (73) tric lymph nodes Holt (74) Sarcorna of thy- Bronchial lymph gl:inds, mus lungs, spleen Little anrl 'I'hymoma (lym- Hoth pleurae, lungs, dia- 1Jall (75) phosarcoma) phragm, cervical, gas- tric, and hepatic lymph glands, liver, kidneys MALIGNANT TUMORS OF THYMUS GLAND 475

First Series: Snrcon~noj the Thymus (Thymoma) (continued)

Author Date Sex Age 1 Diagnosis ------I Doub (76) 1930 F Thymoma ? (sar- Both pleurae, mediusti- comatous) nal, mesenteric and retroperitone:il lymph glands, spleen, pan- creas, peritoneum IinuLti (77) 19:JO M Ly rr1phos:trcomn Both pleurae, lungs, kid- of thymus neys, thyroid gland, lymph nodes, pericar- dium Margolis (15) 1931 M Thymoma (lym- Pericardium, both pleu- phosarcoma) rae, both lungs, medi- astinal lymph glands, I both kidneys Margolis 1931 M 'I'hymoma (modi- Pericardium, left lung fied lymphoszr- coma ?) Margolis 1931 M Thymoma (modi- Pericardium, right lung, fied lymphosar- attached to aorta and coma 1) innominate artery Author's case 1931 M Thymic lympho- Both pleurae, both lungs, cytoma pericardium, myocar- dium case previously reported by Ambrosini, and Rubaschow (30) doubted the origin of the tumors in several of the cases in Hoff- mann's collection (31); so that, as accurately as can be determined, the total number up to 1911 was 52. Of these, 44 were sarcomas and 8 . In the first series tabulated in these pages are listed the cases of thymomata which were believed to be sarcomas, reported since 1911, together with others which were overlooked by previaus authors. The second series includes those cases believed to be carcinomas. Since 1911, I have been able to review 78 cases of lymphosar- coma of the thymus. Including 44 cases collected by Rubaschow (30) the total number is now 122. As regards sex, 45 c:tses occurred in males, 24 in females, and in 9 cases the sex was not stated. The oldest patient was eighty- six years old, the youngest four and one-half months. ' In 6 cases the age was not given. By far the larger number of cases occurred before the age of forty years. A table of organs involved in cases of lymphosarcoma of the thymus indicates that not only do the tissues close to the original tumor become infiltrated, but distant organs are also affected. The data regarding metastasis wcrc givcn in 74 of the 78 cases. The Organs Involved in Sarcoma of the Thymus

Organ I Percentage ...... Lymph nodes Neck ...... Thorax ...... ......

Hight lung .... 1, eft. lung ..... Pericardiuxn ... Itight p1eur:t . . ideft 1)leura .... 1,eft kidney ... Itight kidney . . Liver ...... Sternum ...... ...... Clavicle ...... Vertebra ...... Humerus ...... Scapula ...... Spleen ...... Myocardium ......

Vessels Innominate ...... Venacavn ...... Carotid ...... Mediastinal ...... Jugular ...... Aorta ...... Diaphragm ...... Pancreas ...... Irachea ...... Muscles Intercostal ...... Ingeneral ...... / Thyroid gland ...... Gastro-intestinl~l Stomach ...... Intestines ...... Peritoneum ...... Suprarenal glands Right ...... Left ...... Skin ...... Left ovary ...... Central ...... Second Series: Carcinoma of the Thynzus

Caw No. 1 Author Date Sex Age Diagnosis -- - - Eisenstiidt 1902 M 28 Carcinoma of thy- Pericardiurn, lungs, chest (78) mus wall Sotgia (79) 1910 M 45 Carcinoma of thy- Mediastinal lymph mus nodes 1911 M 6'2 Carcinoma of thy- Pericardium, both plen- mus rae, rnediastinal lymph nodes Simmonds 1912 M 30 Carcinoma of thy- I'leura, lungs, thor:~cio (80) mus lymph nodes Iloccavilla 1913 M 50 Carcinoma of thy- lst, 2nd, and 3rd dorsal (81) mus (?) vertebrae, medullary spine I Vnnzetti (82) 1916 M 50 Carcinoma of thy- Both lungs, tracheal and mus (?) bronchial lymph nodes Vanzetti 1916 F 27 Carcinoma of thy- Left bronchi, trachea, mus vena cava, cervical ves- sels, mediastinal lymph glands Strauss (16) 1919 M 60 Carcinoma of thy- Pericardium, myocar- mus dium Gandy and 1920 M 40 Carcinoma of thy- No metastases described PiCdeliCvre mus (R3) Syrnmers and 1921 M 58 Carcinoma of thy- Dorsal vertebrae, tlura, Vance (84) mus lungs Foot and Har- 1923 1' 2 Carcinoma of thy- Both pleurae, both lungs rington (85) col- mus ore, Jncobsen (86) 1923 M 42 Carcinoma of thy- Mediastinal, retroperi- mus toneal lymph glands, both lungs, liver, su- prarenal glands, verte- brae lineringer and 1923 M 71 Carcinoma of thy- Both pleurae, pericar- I'riesel (87) mus, associated dium, tracheobron- with tuberculous chial lymph nodes pleurisy Honda and 1923 F 52 Carcinoma of thy- Taguchi (88) mus FIonda and 1923 F 32 Carcinoma of thy- h Taguchi mus Honda and 1923 M 1 6'2 Carcinoma of thy- Taguchi mus (?) Cortese (89) 1925 M 36 Primary carci- I'leura, lungs, liver noma of thymus 1926 M 56 Carcinoma of thy- Pericardium, costal mus pleura, superior vena 1 cava, mediastinal lymph glands, sternal end of pectoralis major, 1 liver, right Lemann and 1926 M 58 Carcinomn of thy- Vertebrae, liver, other Smith (90) mus abdominal organs (?) Brannan (22) 1926 M 1 35 Carcinoma of thy- Lungs, superior vena mus 1 cava, right kidney Second Series: Carcinoma of the Thymus (continu.ed)

Case No. Author Date Sex Metastasis -- -- 7--- Foot (91) 1926 M 45 Carcinoma of thy- Pleura, lungs, peribron- mus chial lymph nodes, su- praclavicular nnd axil- lary lymph nodes Reid (92) 1937 M ? Carcinoma of thy- Both pleurae, both lungs, mus diaphragm, liver ICai jser (93) 1927 M 67 Carcinoma of thy- Pleura, lungs, liver mus 1927 M ? Carcinoma of thy- Pleura, lungs, liver mus Lenz (94) 1928 M 37 Primary epithelial No metastasis tumor of thymus Danisch and 1928 ? 3t Chrcinoma of thy- Hilus of each lung, brain, Nedelmann mus , kidneys (95) Matras and 19'28 F 62 1 Carcinoma of thy- No metastasis Pr~esel(96) mus Matras and 1928 M 56 Carcinoma of thy- No metastasis Priesel mus Matras and 1928 M :3.5 Carcinoma of thy- Pericardium, medjaati- Priesel I mus nal, peribronchial lymph glands, left kid- n eY Verga (97) 1928 F (72 Choristoblastoma Right lobe of thyroid, of thymus (car- deep muscles of neck, ' cinoma) trachea Zenoni (98) 1928 F 72 Primary carci- Both pleurae, lungs, me- noma of thymus diastinal, c e r v i c a 1 lymph glands, pericar- dium, , liver Zajewloschin 1928 F 40 Pericardium, both pleu- (99) primary in thy- rae, right lung, peri- mus bronchial, periaortic, cervical lymph glands Nathan (100) 1921 F 40 Lympho-epithe- Pericardium, left pleura, lioma of thymus left lung, mediastinal lymph glands Duguid and 1930 F 64 Small-celled med- Pericardium, sternum, Kennedy ullary carcinoma innominate vein, deep 001) (oat-cell) pri- cervical glands, trtt- mary in thymus cheo-bronchial glands, epicardium, left pleura, , pancreas Bedford (102) 1930 M New- Carcinoma of thy- Both lungs, bones, brain, born mus liver, skin O'Flynn (103) 1931 M 52 ? Carcinoma of Right pleura and luig, thymus superior vena cava, left pleura and lung, right auricle and , liver, dorsal and lum- bar vertebrae MALIGNANT TUMORS OF THYMUS GLAND 479 table appearing on page 476 shows the organs involved, in the order of frequency. Age Incidence of Snrconta of Thymus

Number Age Per ccnt - of cases Under 5 months. ....: ...... 1 5 months to 1 year...... 5 1 to 5 years...... 3 6to 10 years ...... 6 11to20years...... 13 21to30years ...... 17 31to40years ...... 13 41to50years ...... 5 Over50years ...... 9

The second series contains 36 cases of carcinoma of the thymus gland, all of which were proved by . As regards sex, 25 oc- curred in males, 10 in females. In one case the sex was not given. The oldest patient was seventy-two years old, and in one the tumor was found at birth. ' In 2 cases the age was not given.

,4ge Incidence of Carcinoma of the Thyn~us

Age Number of case6 Per cent ------Under 1 year...... - 1 2.9 1 to 10 years...... 2 5.8 11 to 20 years...... 0 0.0 21 to 30 years...... 3 8.8 31 to 40 years...... 5 14.7 41 to 50 years...... 6 17.6 51 to 60 years...... 8 23.5 Over 60 years...... 9 26.4 - 2 It is interesting to note that the majority of cases of carcinoma of the thymus occur after the age of forty. The majority of sar- comas of the thymus develop before the age of forty. In three of the cases of carcinoma there was no metastasis, and in three no data concerning metastasis were given. The table on page 480 shows the organs involved in the order of frequency. In both sarcoma and carcinoma of the thymus gland, the tissues in close approximation to the thymus are most often invaded. However, metastasis may take place to almost any tissue in the body. Formerly, it was thought that the myocardium and the sternum were infrequently affected. This can no longer be considered cor- 480 EDWARD H . CROSBY rect. and metastasis below the diaphragm in malignant disease of the thymus should not be thought of as of rare occurrence. Al- though in carcinoma the lymph nodes of the thorax are as fre- quently infiltrated as in sarcoma. it will be noted that in carcinoma the abdominal lymph nodes were involved in only one case or 3.1 per cent. while in sarcoma the abdominal lymph nodes were affected

Orgarbs I~zvolz~edin Curcinonm of the Thu.t)rz~s

Organ Freyueocy Percentage .... Left lung ...... 18 56.2 Itight lung ...... 17 53.1 Left pleura ...... 15 44.6 Right pleura ...... 13 40.6 Lymph nodes Of neck ...... 3 9.3 Of thorax ...... 13 40.6 Of abdomen ...... 1 3.1

Pericardium ...... 10 31.3 Liver ...... 10 31.3 Bones Vertebrae ...... 5 15.6 Sternum ...... 1 3.1 Right femur ...... 1 3.1 Vessels Venacava ...... 5 15.6 Cervical ...... 1 3.1 Innominate ...... 1 3.1 Brain ...... 2 6.2 Dura ...... 1 3.1 Spinal cord ...... 1 3.1 Right kidney ...... 2 6.2 Left kidney ...... 2 6.2 Trachea ...... 8 9.3 Myocardium ...... 3 9.3 Muscles Neck ...... 2 6.2 Right suprarenal gland .... 1 3.1 Left suprarenal gland ..... 1 3.1 Diaphragm ...... 1 3.1 Thyroid gland ...... 1 3.1 Anterior chest wall ...... 1 3.1 Ovary ...... 1 3.1 Pancreas ...... 1 3.1 Skin ...... 1 3.1 MALIGNANT TUMORS OF THYMUS GLAND 48 1 in 17 cases or 22.9 per cent. In sarcoma of the thymus metastasis was found in the spleen in 11 cases, or 14.7 per cent, while in car- cinoma of the thymus metastasis was not found in the spleen, These findings point to the fact that in sarcoma of the thymus, as in sarcoma elsewhere in the body, metastasis may occur more often by way of the blood stream, while in carcinoma metastasis tends to utilize the lymphatics. The central nervous system is more fre- quently involved in carcinoma than in sarcoma of the thymus, and the trachea and thyroid gland are infrequently the seat of infiltra- tion and metastasis in both thymic sarcoma and carcinoma. SUMMARY A typical case of thymic lymphocytoma is presented, in which the diagnosis was made at necropsy. The acute onset of symp- toms and the rapidly fatal termination of the disease made diagno- sis difficult and treatment futile. When such cases are seen early, x-ray therapy offers an excellent prognosis and even the hope of complete recovery. A discussion of the clinical course of malignant tumors of the thymus and a review of the physical findings, including the typical x-ray shadow, indicate that diagnosis can often be made early, and in early diagnosis and x-ray treatment lies the only hope for the patient. The embryology and histology of the thymus gland are re- viewed. One hundred and sixty-five cases of malignant disease of the thymus were found in the literature, which, with the case presented here, make a total of 166 cases. Of these, 122 were sarcomas, so- called, and 44 carcinomas. In all instances the diagnosis was con- firmed by necropsy or by biopsy. A statistical review of 144 cases of malignant disease of the thymus gland is given with age and sex incidence, diagnosis, and site of metastasis. When the diagnosis was doubtful this fact is indicated and the case is listed as accurately as possible. NOTE:The author is indebted to Dr. Thomas Ordway for the clinical history of the case presented and to Dr. Victor C. Jacobsen for the pathological report. REFERENCES 1. JONES,A. C.: Zymphosarcoma of the thymus, Tr. Am. Laryng. Rhin. and Otol. Soc. 34: 478, 1928 2. EWING,J.: The thymus and its tumors, Surg. Gynec. & Obst. 22: 461, 1916. 482 EDWARD H. CROSBY

3. HARRIS, V. D.: Intra-thoracic growths, St. Barth. Hosp. Rep. London, 28: 73, 1892. 4. AMUROSINI,G.: De 11Cpith61iornedu thymus, ThEse de Paris, 1894. 5. JANEWAY,H. H.: The treatment of mtilignant tumors of the thymus gland by radium, Ann. Surg. 71: 460, 1920. 6. CI~AVER,1,. F.: Diagnosis and treatment of thymoma, Med. Clin. North America 14: 507, 1930. 7. POOL,1':. H.: Sarcoma (?) of the thymus gland, S. Clin. North America 5: 34, 1925. 8. Dwrr~:~,M. F.: Report of :L c:tse of thy mom:^, Iladiology 9: 510, 1927. 9. DOUB,13. P.: Iioentgcn diagnosis and treatmrnt of thymornatn, 14 : 267, 1930 10. GROVISIZ,T. h., CHRISTIE,ii. (:., MERRITT,E. L!., AND COE, F. 0.: Roentgen-ray (lingnosis and trc:ttmcnt of thymoma, J. A. M. -1. 85: 1125, 192.5. 11. GRANDITOMMI':,F.: Ueber Tumoren des vorderen Mrdiastinums und ihrc 13ezichungen zu der Thymusdriise, Inaug. Diss., Heidelberg, 1900. 12. I~ROIVN,8. I(:.: Malignant tumors of the thymic region, with ex- tensive tnettist:tses, Arch. Path. k 1,ab. Med. 2: 822, 1926. 13. ('IZOTTI, h.:Thyroid and thymus, Philadelphia, Lca and Fcbigcr, 1922, ed. 2, p. 657. 14. BELL.1C. T.: Tumors of the thymus in myasthenia gravis, J. Nerv. cY: Ment. Ilis. 42: 130, 1917; The development of the thymus, Am. J. Anat. 5: 29, 1906. 15. MARGOLIS,H. M.: Tumors of the thymus: pathology, clnssific:~tion, and report of c:ises, Am. J. 1.5: 2106, 1931. 1G. STRAUS~,S. G.: Ma1ign:tnL neoplasms of the thymus gland, New York M. J. 110: 64G, 1919. 17. EVERT,J. A.: Ma1ign:tnt tumors of the thymus; uith report of a case, Minnesota Med. 8: 730, 1925. 18. HAMMAR,J. ,I.:The new views as to the morphology of the thymus gland and their bearing on the problem of the function of the thymus, I{:ndocrinology 5: 543, 1921; Zur Histogenese und Involu- tion der Thymusdriise, Anat. Anz. 27: 41, 1905; Fiinfzig Jahre Thymusforschung. Iiritische Ubersicht der normalen Mor- phologie, ICrgebn. Anat. 19: 1, 1909. 19. MAXIMOW?,h.: Untersuchungen iiber Blut und Bindegewebc. 11. Ubrr die Histogencse der Thymus bci S:iugetieren, Arch. f. mikr. Anat. 74: 525, 1909. 20. I)AN(~I-IAI

23. SCHAFFER,J., AND RABL, H.: Das thyreo-thymische System des Maulwurfs, Sitzungsber. a. li. Akad, d. Wissensch. Wien. Mathem. Naturssensch. Klasse. Abt. 3: 117: 551,1908. Abt. 3: 118: 217, 549, 1909. 24. STENGEL,A., AND FOX, H.: Text-book of Pathology, Philadelphia, W. B. Saunders Co., 1915, 6th ed. 25. VOGES,H.: Ein Fall von Thymuskarzinom, Frankfurt. Ztschr. f. Path. 33: 501, 1926. 26. ST~~HR,P.: uber die Natur der Thymus-elemente, Anat. Heft 31: 407, 1906. ~berdie Abstammung der kleinen Thymusrinden- zellen, Anat. Heft 41 : 105, 1910. 27. PRENANT,A.: Contribution a 116tude du d6veloppement organique et histologique du thymus, de la glande thyroide et de la glande carotidienne, La cellule 10: 85, 1894. 28. PAPPENHEIMER,A. M. : A contribution to the normal and pathologi- cal histology of the thymus gland, J. M. Research 22: 1, 1910; Further studies in the histology of the thymus, Am. J. Anat. 14: 299, 1913. 29. JORDAN,H. E., AND HORSLEY,G. W.: The significance of Hassall's corpuscles, Anat. Rec. 35: 42, 1927. 30. Rus~sc~ow,S. : Eine bosartige Thymusgeschwulst, Virchow's Arch. f. path. Anat. 206: 141, 1911. 31. HOFFMANN,F. A.: Erkrankungen des Mediastinumq, in: Noth- nagel's Spec. Path. u. Ther., A. Holder, Wien, 1896, Bd. 13. 32. VERMORELAND THIROLOIX:Epitheliome pavimenteux lobule B globes dpidermiques B point de depart thymique, Bull. Soc. anat. de Paris 69: 702, 1894. 33. COOPER,SIR A. P.: Anatomy of the Thymus Gland, London, Long- man, 1832, p. 3. 34. POWELL,R. D.: Lympho-sarcoma (or lymph-adenoma) of the anterior mediastinum, Trans. Path. Soc. London 21: 358, 1870. 35. MOORE,N.: New growths in the mediastinum, Trans. Path. Soc. London 35: 372, 1884. 36. ACKER,G. N. : Sarcoma of the thymus and bronchial glands, Tr. Am. Pediat. Soc. 8: 212, 1896. Cit. by Jones, A. C. (I). 37. WEIGERT,C., AND LAQUER,L. : Beitrage zur Lehre von der erbschen Krankheit, Neurologisches Centralbl. 20: 594, 1901. 38. DE LA CAMP:Beitriige zur Klinik u. Path. d. Mediastinaltumoren, CharitE-Ann. 27 : 99, 1903. 39. YAMASAKI,M.: Zur Kenntnis der Hodgkinschen Icrankheit und ihres Ueberganges in Sarkom, Ztschr. f. Heilk. 25: 269, 1904. 40. HUN,H., BLUMER,G., AND STREETER,G. L.: Myasthenia gravis, Albany M. Ann. 25: 28, 1904. 41. ORTH,J. : Bericht iiber das Leichenhaus des CharitB-Krankenhausrrs fiir das Jahr 1910, Charit6-Ann. 35: 282, 1911. 42. ZNINIEWIC~,J.: Vier Falle von Lymphosarcoma thymicum, Inaug. Diss., Griefswald, 1911. 43. GRAWITZ:Lymphosarcoma thymicum, ins Myokard eingedrungen, Deutsche med. Wchnschr. 37: 2357, 1911. 47 484 EDWARD H. CROSBY

44. SHEEN,W., GRIFFITNS,C. A., AND SCHOLBERG,H. A.: TWOcases of sarcoma of the thymus, Lancet 2: 1253, 1911. 45. SYMMERS,D.: Certain lesions of the lymph nodes, New York, M. J. 93: 971, 1911. 46. BARBANO,C.: I1 timo c i tumori primitivi del mediastino anteriore, Pensiero med. 2: 701, 1912. 47. MAJOR,R. H.: A thymus tumor associated with acritc lymphatic leukemia, Bull. Johns Hopkins Hosp. 29: 206, 1918. 48. SYMMERS,D.: The relationship of t,he toxic lymphoid to lymphosarcoma and allied diseases, Arch. Int. Med. 21: 237, 1918. 49. BRAND,0.: Ein Fall von Spindclzellensarkom der Thymus, Frank- furt. Ztschr. f. Path. 24: 445, 1920. 50. FOOT,N. C'.: Report on a case of malignant thyrnorr~awith nccropsy, Am. J. Dis. Child. 20: 1, 1920. 51. GERLAC'II,W.: Ueber ein Lymphos:lrkorn dcs l'hy~nus,Ztschr. f. Laryngol. 9: 47:3, 1920. 52. HAI~VIER,P.: Lymphosarcom:t of the thymus in a young womiln, Bull. et. mPm. Soc. mdd. d. h6p. de Par. 45: 374, 1921. 53. CLELAND,J. B., AND BEARE,F. H.: Caseated thymomn of the mcdi- astinum, M. J. Australia 1: 182, 1922. 54. DELESSERT,E.: A clinical study of malignant tumors of the anterior mediastinum and thymic region, Internat. Clin. 2: 127, 1922. 55. MEIGS,A. V., AND DE SCHWEINITZ,G. E.: Round-celled sarcoma of the anterior mediastinum, Am. J. M. Sc. n.s. 108: 193, 1894. 56. SWEANY,H. C.: Primary tumor of the thymus associated with tuberculosis, J. A. M. A. 80: 751, 1923. 57. RENAULT,J., CATHALA,J., AND PLICHET,A.: Ilyn~phocytomaof thymic origin, Bull. et. m6m. Soc. m6d. d. h8p. de. Par. 48: 176, 1924; Ahstr. J. A. M. A. 83: 1623, 1924. 58. HE:LVESTINF:,I?., JR.:Malignant tu~norsof the thymus, Arch Surg. 9: 309, 1924.

59. I?RIEDLANL)ER,A., AND l?oo~, N. (I.: 11~porton a case of m:ilign:inl, smttll-celled thymolna with ucutc lymphoid lcukcmis, Am. J. M. Sc. 169: 161, 1925. 60. EVERT,J. A.: Malignant tumors of the thymus; with report of a case, Minnesota Med. 8: 730, 1925. 61. MILLER,J.: A case of thymoma, Canadian M. A. J. 16: 810, 1926. 62. WOLLSTEIN,M., AND MCLEAN,S.: Hodgkin's disease, primary in the thymus gland: report of :t case in an , Am. J. Dis. Child. 32: 889, 1926. 6'3. SCHMIDT,E. A.: Malignant mediastinal tumor, complicated by amoebic , Arch. 7: 558, 1926. 64. NOICIC,R. R.: Malignant thymoma, Minnesota Med. 10: 400, 1927. 65. ZANELLI,E:.: Lymphosarcoma of the thymus, case, Clin. Pediat. 9: 241, 1927. 66. BABES,A.: Ueber eine lymphoepitheliale Geschwulst der Schild- driise (Thymom der Schilddriise), Virchow's Arch. f. path. Annt. 266: 321, 1927. MALIGNANT TUMORS OF THYMUS GLAND 485

67. YOUNG,G. J., AND SPALDING,J, E.: Report of a case of lymphosar- coma of thymic origin with acute , J. M. Soc. New Jersey 25: 609, 1928. 68. BROWN,W.: Thymoma simulating abdominal tumour, Brit. M. J. 2: 101, 1928. 69. BROWN,S. E.: Malignant tumor of the thymic region, with exten- sive metastases, Arch. Path & Lab. Med. 2: 822, 1926. 70. MATRAS,A., AND PRIESEL,A.: Dber einige Gewachse des Thymus, Beitr. z. path. Anat. u. z. allg. Path. 80: 270, 1928. 71. SHENNAN,T. : Tumors of mediastinum and lung, J. Path. Bnct. 31 : 365, 1928. 72. MEEKER,L. H.: Malignant thymoma: Iteport of a case, Tr:tns. N. Y. Path. Soc. Feb. 9, 1928, Arch. Path. 5: 928, 1928. 73. HERRIMAN,F. El., AND HAHTE,W. E.: Malignant thymoma with metastases, Am. J. Path. 5: 29, 1929. Also reported by Meeker, L. H. 74. HOLT,L. E.: cit. Jones, A. C. (1). 75. LITTLE,H. G., AND HALL,H. M.: Thymoma, West Virginia M. J. 26: 673, 1930. 76. DOUB,H. P.: Roentgen diagnosis and treatment of thymomata, ltadiology 14: 267, 1930. 77. KNUTTI,R. 13.: Primary lymphosarcoma of the thymus with metas- tases below the diaphragm, South. M. J. 23: 1104, 1930. 78. EISENSTADT,J. : Ueber Iirebs der Thymus, Inaug. Diss., Grcifswnld, 1902. Cit. by Brannan (22)) and Vanzetti (82). 79. SOTGIA,G. M.: Un carcinoma primitivo del timo, Arch. per le sc. med. 42: 69, 1919. 80. SIMMONDS,M.: Ucber malignc Thymusgcschwulste, Ztschr. f. I

89. CORTESE,G.: Un caso di carcinoma primario della ghiandola del timo, Policlinico (sez. med.) 32: 417, 1925. 90. LEMANN,I. I., AND SMITH,J.: Primary carcinom:~of the thymus; report of a case, Arch. Int. Med. 38: 807, 1926. 91. FOOT,N. C.: Concerning "malignant thymoma" with report of a case of primary carcinoma of the thymus, Am. J. Path. 2: 33, 1926. 92. REID,J. : Carcinoma of the thymus gland, Brit. M. J. 1 : 187, 1927. 93. KAIJSER,R.: Zur Kenntnis der Geschwiilste des Thymus, im An- schluss an zwei eigene Falle von Thymuskarzinom, Acta. path. ct microbiol. Scandinav. 4: 221, 1927. 94. LENZ,R. : Berichte iiber einen Thymustumor, Wien. med. Wchnschr. 78: 224, 1928. 95. DANIS~H,F., AND NEDELMANN,E.: Bijsttrtiges Thymom bei einern 34 jiihrigen Kind nit eigenartiger Metast,asierung ins %entr:~l- nervensystem, Virchow's Arch. f. path. Anat. 268: 492, 1928. 96. MATRAS,A., AND PRIESEL,A.: Uber einige Gewiichse des Thymus, Beitr. z. path. Anat. u. z. allg. Path. 80: 270, 1928. 97. VERGA,P.: Coristoblastoma timico a sede tiroidea, Pathologia 20: 118, 1928. 98. ZFNONI,C.: Cancro mediastinico timogeno, Rev. sud-am. dc en- docrinol. 11: 597, 1928. 99. ZAJ~:WLOSCHIN,M. N.: Zur Kasuistik der Geschwiilste thymogcnrn Ursprungs: "Adenokarzinoma Thymus," Frankfurt. Ztschr. f. Path. 37: 36, 1929. 100. NATHAN,W.: ifber einen Fall von Ilymphoepithelioma Thymi, Frankfurt. Ztschr. f. Path. 37: 385, 1929. 101. DUGUID,J. B., AND KENNEDY,A. M. : Oat-cell tumors of mediastinal glands, J. Path. & Bact. 33: 93, 1930. 102. BEDFORD,G. V.: A case of carcinoma of the thymus with extensive mctastases in a new-born child, Canadian M. A. J. 23: 197, 1930. 103. O'FLYNN,J. A.: A malignant tumor of the thymus gland, J. Roy. Nav. M. Serv. 17: 5, 1931.