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Eosinophilic granuloma of mouth, pharynx, and nasal passages
Oral EOSINOPHILIC
Pathology
GRANULOMA AND NASAL
OF MOUTH, PASSAGES
PHARYNX,
T 18 a common opinion that the lymphatic tissue of the upper respiratory and digestive tracts does not become frequently involved in chronic systemic disThis opinion is correct if only gross changes eases of the hematopoietic apparatus. of the lymphatic tissue, such as enlargements or ulcerations, are considered. However, pathologic changes arc more frequently encountered when in systemic diseases of the hematopoietic apparatus microscopic examinations are made in instances in which there are no gross changes of the lymphatic tissue in the upper respiratory and digestive tracts. Brunner, Schnierer, and Fischer’, 2 proved that the lymphatic tissue of these tracts is frequently involved in the leucemias although the gross structure may be apparently normal. For this reason, they suggested that, the contents of the tonsillar crypts in leueemias be examined for abnormal white blood cells, an examination which has furnished useful practical results. Contrary to the findings in leucemias, it was and it is the current view that in Hodgkin’s disease the lymphatic~ tissue of the upper respiratory and digestive tracts is usually spared while the lymph glands of t,he neck, the mediastinnm, and abdomen are favorite loc~alixntiotls of the disease. Symmera” is very definite in this respect. I Ie wrote : “Thta suhmu~ous collections, represented hy the Paacial and lingual tonsils and lay the minute lyrnphoid follicles which are strewn through the, suhn~u~~osa of the gastrointestinal, respiratory and urinary trac*fs almost itlvariahly cs(dill)c‘ In IIodgkin’s disease.” Experience has shown thi1.t this vi(LM. is not qrlitc eorrrct as far as the digestive tract is (~oncrmed since IIodgkin’s t~nuors I~:I\~v hern observed in the stomach not infrequently. Ncvet*t hcl~W. t’s(‘tt al lit’esflllt it is a gcncraII?- ac*cepted vieI\ I hat i I~v l~nl~~hat ic, f issue of t ht; IIUIII~ II. ~)h;rr?~tlr, and nose is infrequently in; ulsctl if: Ilodgki~: ‘s ifis;l5ii;(‘. !-‘ t~ttc~ttktbl” 4 iit(vl 1 j!il! 1 ht. i llmol’ t’ormation itt tltc* lymph noctcs of the utAc,k witlloui itl\.olvc.tuotli IA’ thtl l>-lt~t)haiir* fissut: ol’ the pharynx is supl~~d to be sigtlificatlt of Hodgkin’s disease. In the case to be ~~r’ese~~teciin this paper, the lymphatic tissue of t~he upper respiratory and digestive tracts has ~KYW Iar*gely involved. The patient was d~~e~vrtl fog a pcriocl of ap~)rosimntely tw-clrc years hy internists. hematologists, clermatologists, anal otolaryngologists; yet it was not possihle to arrive at a definite diagnosis. It was not even possible to state as to whether there was a separate morbid cnt.ity or the per~rsory stage of Hodgkin’s diseasck. Tho final 623
I
624
HANS
BRUNNER
If this is correct it is remarkable that analysis rendered the latter view likely. Hodgkin’s disease may continue for a period of twelve years without presenting symptoms to warrant a definite diagnosis.
Case Report Z. J., 36-year-old white man, had measles in childhood and a resection of the nasal septum in 1922. There were no other diseases. Since 1920 he noticed small red spots on both upper arms and on the legs associated with severe itching. In 1924 there was an improvement for a short period of time to be followed by an acute flare-up which was associated with swelling of the lymphatic nodes in the groin, in the cubiti, and in the armpits. On Nov. 20, 1925, the internal and nenrologic examinations were negative and the urine was found to be normal. There was a great number of follicular noduli and impetiginous plaques all over the extremities, causing severe itching. The lymph nodes The affection of the in the groin and in the sulcus bicipitalis were swollen. skin subsided finally, leaving behind a small amount of pigment. Following this episode he was well until February, 1927, when again a skin affection occurred similar to that in 1925. On May 10, 1927, there was a dullness over both apical regions with impaired expansion, especially on the right side. The dermatologic examination revealed the same findings as in 1925. There was no hypertrophy of tonsils; there was a positive Mantoux test. From May 30 until July 5 he had fever oscillating between 100 and 100.2O. Noduli, blisters, and edema of the skin as well as glandular swelling were noticed. In the fluid of the blisters there were many eosinophiles. On May 7, he had a sudden attack of coughing which lasted for one hour and was associated with breathing troubles. This was perhaps caused by edema of the larynx. On May- 10, there was edema, indistinctly bordered, over the cheeks and t,he forehead. One lymph gland was removed surgically.
Microscopic Finding of Lymph Node.-In the enlarged stroma, particularly close to the sinus, there were many eosinophiles forming a fourth or a fifth of all the cells. An even greater amount of eosinophiles were discovered in the sinuses, particularly in the marginal sinus. In the trabeculae, septa, and in the perilymphatic connective tissue there was a small number of eosinophiles, particularly close to the blood vessels. The gross structure of the node was normal. On June 26, the temperature rose to 302.5’. On July 12, 1927, a piece of skin was excised. Microscopic Finding of the Skin.-The connective tissue was edematous and there were a few eosinophiles around the blood vessels. In the subcutaneous fat tissue the eosinophiles were exclusively around the blood vessels and in the lymphatic tissue adjacent to the blood vessels. They extended along the capillaries into the septa between the fat cells. In these area,s the eosinophiles constituted approximately one-t,hird of all cells. The eosinophiles within the lymphatic tissue had a lobulated nucleus or two nuclei while the eosinophiles
I”IOSISOPIIJI,IC
GR.~SI’LOIVI.\
OF
MOUTH,
PFL1RTSS,
.\SD
S.\S,\L
I’ASSAGES
625
in the connective tissue had a round or rodlike nucleus. In some places there were frank eosinophilic granules in the tissue which occasionaly were attaehed to the membranes of connective tissue cells. Within the muscular tissue eosinophiles were infrequent. There was no t,richinosis. From 1928 until 1932 he had several attacks of the skin a&&on occaGunally associated with fercr up to 102.2O. In 1931 JJ:JS~J~ polyps were r1pnloved. In l)ecember, 1931, he noticed a sliglit swelling of tile right tonsil which gradually increased without causing pain. After several months the tonsil On June 21, 1932, the right grew up to a size to cause difficulty in swallowing. tonsil was found to be enlarged, extending about 0.5 cm. beyond the midline to the left. The surface was smooth RJJ~ thr tollsi consistr(l apparently of large lobuli. It had a pinkish color and the number of crypts seemed to be normal. From the crypts gray-yellowish material could be expressed. Otherwise otolaryngologic examination was negative. On August 1, a tonsillectomy was performed. The tonsils did not ext,end deeply into the constrictor muscle ; there were no adhesions and no hemorrhage. Uneventful recovery ensued. Only the right tonsil was examined.
Microscopic Finding of Right Tonsil.-The
tonsil consisted of normal and abnormal lobuli (Fig. 1). The former were close to the inferior pole, the latter to the superior pole of the tonsil. The borderline between lymphatic tissue and connective tissue was distinct ; the capsule was normal. The abnormal lobuli were much enlarged due to the proliferation of a pathologic tissue which consists of loosely arranged lymphocytes, a great amount of eosinophiles, There \vere a few necrotic spots l)lasma cells, histiocgtes, and capillaries. Since the which showed au infiltration by leucocytcs! probably eosiuophiles. specimen had been in alcohol fog* a long period of time the staining of the eosinophiles was poor. Due to the proliferation of the abnormal tissue there was not only a11 enlargement of t,he lobuli but also the following changes were noted : (a) A number of follicles had apparently been destroyed; the remainder did not show germinal centers. Since the pathologic tissue stained with a pinkish color while the remnants of the lymphatic tissue were deeply stained with hematoxylin, the spccimell had it mottled appearance. ib) The number of c’typts were tlitninished. Cc) Thta reticulum of the interfolliculal tissue was torn iir pirccts. ,L\ greater, iJJJ1OUJli of aJq~tlt c)phile fibers wt’t’t’ tt.1 be ~‘ouIJcI ottI?; belo\v the epithrlilltn :111(1 iJJ*ottJJti ihe I)lootl vessels (lq’igs. r! a~ltl :+). lf,iWli ‘Gi!,lilaT t*, ,>fl/ Tlkt* cuiltiec‘ti\-e Ikhllt ic’lkt;t \+,“C!‘t, ;Il~Sf~til il! t11r m!:11ycl the fiuclings iti lytnphatic: iruceil~ia \ I:t*ur~nor ;I~ICI P‘isc*heP’;, It’) ill 11lP **Iilargetl lobuli the rpithrliulu had in soJ1ltAplaces an c~pictcrmoitlal charnctc~r, the pal)illae being small in rluml~er ar1c1 low ; it1 other l)laces it, c*onsistecl of a few layers of flat cells which were not hornifying. There was no reticiulatioli of the epithelium due to luigratitlg leucor:>-tes. To sum up, there was a new formation and proliftarat,ion of it11 iJl)lJO~J~lid tissue which apparently replaced the interfollicular tissue first and then expanded causing a destruction of the follicles of the tonsil.
626
HANS
Fi no1 ZIlal net :rotic
F’iL7
Q
BRUNNER
1. -Right Hematoxylin-eosin staining. C, Capsule: d, e, lobuli sho wing tonsil. Yl( zture; a, b, c, lobuli showing a pathologic structure. particularly lot IUlUS c; )Of: infiltrated by eosinophiles; m, beginning necrosis.
9tmvrt71rc.
ccf tl2n y\t?sl)lcJgi~ p3yt.5 of the right tonsil. Staining the reticulum of the tonsil is torn in pieces.
after
Pap.
Note
that
On Dec. 5, 1932, oxyuriasis was discovered in the stool. This disappeared in January, 1933, he noticed for the first time, following adequate treatlnent. in a painless swelling on the right side of the soft t>al;tte. Examination January, 1933, rcrealcd a motlet*ately firm, noncystic tnulor occupying the right side of the soft ])alate and extending into the upper part of the tonsillar toward the hard palate, an inarea. The tumor had a distinct In)rderline distinct horclerline toward the midline, and did not, interfere with the motility of the soft l);LlatC. It WtlS COvtltGedl)y a rlortr~al IllLlCOS~ alld \ViIS Ilot tCIIdCt..
There vv;err no rrmnauts of tonsillar tissue. Pc.,strrior rhinoscopy resealed t’hat the posterior surface of the soft l)alate was not ltulging. 011 the left side uf the ]JOSit!l’iOl’ vvall I)f tlie pliaqms there u-as x t;unior. the size of R bean. covered hy mu~osa. It was not pediculutrtl and cxtendecl toward thr roof of the epipharynx. The tumor was removed.
Microscopic covered
with
Examination squamous
of Tumor
epithelium
which,
of Epipharynx.----Tile in some places,
tumor was showed small
628
HAN3
BRUNNER
papillae, in other places a reticulation clue to the invasion of a great number of lymphocytes. It consisted of lymphatic tissue with follicles and germinal In the interfollieular tissue there were many eosinophiles and a centers. moderate amount of collagenous tissue. tunlors with a smooth surface were On Aug. 16, 1933, three pinkish-red discovered in the vallecula. The middle one, slightly right to the midline, was round and had the size of a small plume and a pencil-like pedicle. On the right lateral wall of the pharynx, immediately behind the posterior pillar of the tonsillar area, there was a pediculated flat tumor, t,he size of a quarter. The tumor was movable, appeared on the back of the tongue when the patient When he was quiet the tumor was lying increased his abdominal pressure. in the vallecula. The surface of the tumor was smooth. The left plica pharyngoepiglottica seemed to be changed into a tumor, the thickness of a pencil. The base of the tongue was normal except that the right lingual tonsil was ‘more prominent than the left. The tumor in the right vallecula was removed with the snare, The other tumors were treated with roentgen rays without success. The removed tumor had the same structure as the tumor of the soft palate which was later removed. However, the eosinophiles were not very well discernible because the specimen had been in alcohol for a long period of time. On September 12, 1933, the tumor in the center of the vallecula, attached to the base of the tongue, was removed, and below this tumor another tumor was discovered likewise attached to the base of the tongue. ~YOWit became evident that it was not the left plica pharyngoepiglottica which was changed into a tumor; the plica was rather covered and hidden by a tumor which was attached to the base of the tongue. The tumors were removed. On Sept. 13, 1933, a cross incision was made in the mucosa of the soft palate. A soft, friable tissue was exposed resembling glandular tissue with small lobuli. The tumor which was situated between mucosa and muscular layer was removed. Uneventful recovery ensued. There was no oxyuriasis in the stool. Wassermann reaction and luetin test were negative.
Microscopic Examination of Tumor of Soft Palate.-The tumor (Fig. 4) consisted of lobuli of different size, separated one from the other by connective tissue. The small lobuli showed normal lymphatic tissue with many follicles and germinal centers. In the periphery of the large lobuli there were likewise follicles and germinal centers, while in the core of these lobuli the architecture was obscured because the follicles did not distinguish themselves from the rest of the tissue. Around the follicles there were many eosinophiles. In the core of the large lobuli the eosinophiles made up approximately the half of the cellular element,s. In the areas of normal lymphatic tissue there were many active mucous glands. In the areas where the normal architecture was disturbed, the glands were inactive and there were remnants of glands. Active glands were infrequent in these areas. The walls of the arterioles were thickened.
EOSINOPHILIC
GRAsULOM.4
OF
MOUTH,
FH~iRYXX,
AXI)
XASAL
PASSIGES
629
On Jan. 10, 1935, he felt well and healthy. The right side of the soft palate was red. In the lateral part of the right side of the tongue there was a tumor, the size of the stone of a date, covered by pinkish mucosa and extending into the area of the right tonsil. The tumor was removed. Microscopic Examination of the Tumor of Tongue.--The tumor was covered by squamous epithelium which. in some areas, showed low papillae. There were a few crypts the walls of whicsh were likewise rorpred by squamous epithelium. The subepithelial layer was narrow. 7‘he COL’e Of tll? tumor conWithin sisted of lymphocytes, eosinophiles, plasma cells. ant1 histiocytes. this tissue follicles and remnants of follicles were scattered throughout, creating the same mottled appearance as was noticed in the tonsil.
The tumor in the right cheek had t~achr~i tilt. siar of ii SIX& itl~plc~ Since this tumor (liti irot eailse tl*ouble ii Xlucosa of the cheek was normal. was left alone. The lymphatics of the neck, the axillne, and the groin were swollen. The glands were moderately firm. had distinct margins, and reached The spleen was enlarged and could the size of a pigeon egg in the left axilla. be felt a little 1~10~ the costal arch. Internal fin(ling was otherwise negative. Urine analysis was negat,ive. On Jan. 26: 1935, there was a swelling of glands in the right cubiti and on the left upper arm. The blood was normal, except a marked eosinol)hilia.
630
HANS
BRU-UNER
X-ray examination of the skeleton, of the lungs, and of the mediastinum was negative. In the next weeks the patient became ill with an “influenza” associated with fever. In this time the glandular swelling decreased. On March 26, 1935, the bone marrow was examined and the following findings were obtained: reticulocytes, 54 per cent, myeloblasts, 0.8 per cent, promyelocytes, 1.6 per cent, myelocyt,es, 12 per cent, eosinophilic myelocytes, 4.4 per cent, basophilic myelocytes, 0 per cent, metamyelocytes, 10.4 per cent, eosinophilic metamyelocytes, 5.6 per cent, juvenile forms, 6.6 per cent, eosinophilic juvenile forms, 2.8 per cent, polynuclear leucocytes, 14 per cent, eosinophilic polynuclear leucocytes, 4 per cent, basophilic polynuclear leucocytes, 0 per cent, monocytes, 1.4 per cent, lymphocytes, 4.6 per cent, plasma cells, 0.6 per cent, proerythroblasts, 5 per cent, macroblasts, 8.6 per cent, normoblasts, 17.4 per cent, mitotic forms, 0.2 per cent. This finding indicated a slightly increased activity in the leucopoietic and erythroblastic tissue, particularly an increase in the number of eosinophiles and of immature eosinoThere was no indication, either for Hodgkin’s disease or for a sysphiles. temic disease of the hematopoietic apparatus. On May 7, 1935, the patient felt well. There were tumors in the right cheek and in the left soft palate (Fig. 5). The tumor of the right cheek was removed. Uneventful recovery ensued.
Fig.
5.-Tumor
of
the
pal&?.
Microscopic Examination of the Tumor of the Cheek.-The tumor consisted of loosely scattered follicles which usually did not contain germinal centers. The structure of the interfollicular tissue varied. In some places it had the same structure as, for instance, in the tonsils, viz., it was cellular containing lymphocytes, plasma cells, histiocytes, and particularly eosinophiles. In other places connective tissue was noticed which gradually increased until there was in some places a comparatively great amount of hyaline connective tissue. In these areas the arterioles likewise showed a hyaline degeneration (Fig. 6). In the same proportion as the connective tissue increases, the content of cells decreases. Finally there are only single rows of cells between thP fihem. Eosinophilcs arc predominant also in these areas.
On May 20, 1937, he felt well. There were numerous follicular noduli and impetiginous plaques in the skin and the glands were considerably swollen. The entire soft palate was slightly bulging. There were tumors in the floor of t,he nose. There was a row of nod&i, the size of a pinhead, in the bulbar conjunctiva, close to the cornea. The rest of the bnlhar conjunctiva was A biopsy was taken from the skin. thickened.
Fig. 6.-Tumor of right cheek. Hematoxylin-eosin In the interfollicular tissue there are many capillaries, s-;lliall amount of cells.
staining. connective
There are several fOllicleS. tissue, and a comparatively
Microscopic Examination of the Skin,--There was an acanthosis of the a hyperkeratosis, and a slight intraepithelial edema. The blood rpithelium, vessels of the papillae and of the upper layer of the cutis were dilated. Tn this area there were acacumulations of large and small lymphocytes, epitheloid ~~11s. and I~arti~ulnrly eosinophiles w1lic.h wvrrc to 1~ founcl around the bloo~l i rssels. as well as in the tissue. Thrrr wrrt’ It0 Sternberg giant cells. .\, ?!mior was removed from the floor of' i he IIOW. Microscopic Examination of Nasal Tumor.- -‘l‘hv tul~~c)r 11;rd :t mottl~~tl appearance (Fig. 7). The tissue was very celluIar. ‘I‘ht~ cells consisted 1)1’ lymphocytes, plasma cells, and histiocytes ( Fig. 8 1. The rosinophiles, a great, llurqber uf them mononucIear. were more frryuellt than in all of the other tumors. The\- f0r*111edhtaaps \vhich CUUI~ IIt, rec,cJgltizrd Tvith IOR- magnificat ion. There WVIY no collagenous fibers. rrc*ept around the blood vessels and glands, but there was a fair amount of argelltophile fibers, particularly around the blood vessels and ~lantls. Throughout this tissllc remnant,s of lymphatic tissue were scattered and this created a mottled appearance of the specimen.
HANS
the
nasal
passage.
BRUNNER
Hematoxylin-eosin eosinophiles.
staining ; 5 indicates
Fig.
7.-Tumor
of
Fig.
8 .-Tumor
Hematoxylin-eosin staining; of the nasal passage. histiocytes surrounded by eosinophfles.
D indicates
heaps
of
a focus
of
In some sections the lymphatic tissue was entirely absent. There were several active and inactive mucous glands within the t,umor tissue. The walls of the arterioles were t,hickened. The tumor was covered hy a pseudostratified columnar epithelium which did not contain goblet cells, or hy transitional epithelium. The basilar Inemhrane was well cle~eloprd. Below the epithelium there was a layer of edematous connective tissue which contained lymphocytes, plasma cells, an(l particularly eosinophiles, t~nlarg~tl veins, and mucous glands. There wert’ 111.jserous glands. This layer gi~atlually passed over into the tumor tissue. The patient was ohserrcd until the beginning of 1938 without showing changes in the findings. Examinations of Blood.---The ret1 blood count was rssrnt ially normal in all examinations. The findings concerning the leuc*ocyt (8s are summat~ized in Table I. L
_--
, LEUCOCYTES TOTAL
_ -~ ___-.-~
9,200
26.X1.1925
26.1V.1927 lO.V.1927 (a)
15,600 14,700
26.VI.1927*
22,700
28.X1.1928
33,200
4.TIT.1930
9,450
31.VI.l932(b)
11,250
4.VIII.1932
t
10,600
lti.VlII.1933
1n,oou
lO.I.1935$
12,400
26.1.1935 26.TII.1935
,
POLYNUCLEAR CELLS 74%
(6,8bk) 37% (5,439) 24% (5,448) 19.75% (6,557) 41% (3,874) 36% i-t,050) 58% (6,148) 59%
JUVENII>E FORMS 0
4% (588) 0 0 0 0 3% (318) 0
1,400 70,000
34% (5,400)
2% ("00)
j
EOSINOPHILES
BASOPHILRS
0
0.5% (46) 32% (4,704)
4% i;g1
(2)
65%
(14,755) 67.25% (22,327) 35% r:<,307 1 37% (4,162)
8% (848) 20.5% (2,050) 47.5% (.5,952) 40 to t?O% 24% , 2,400 \
I 1 MONOCYTES 2.5% (230)
(& 0.25% (803)
3% (337)
2%
!L’l%) 0 1% (124)
0
(y$ ,,gi (94 1% (112)
7% (7421 3.5% ( 350 ) 4.5% (588)
9%
( 900~
i
!
LYMPHOCYTES
23% (2,116) Ii%
(2P
(68;) 10.75% (3,569) 23%
12,173) 22% (2,475)
wh
(2,332) 17% (1,700)
16% (,l,R84,l
11%
( 1,10(1)
Comment In the prtwittccl viise whic*h was ohscr\~ctl fctr a lwriod of iI~)p~o~il~lately I welve years, H tlefiiliir diagltosin was not matit’. It is fairly certain that there was a systemic tliseasc of the lymphatic apparatus.” In Ya\or of this diagnosis are the I)crsistrnt rq~largemcnt of \~arious ~:‘I’OIIJN (II’ I>-mph nc~l~s which grad*In this reuyevt ttw <‘asr xporte4 in this paw’r 6liffers ildirritely ftwrll tlw w.w.s reported This author reports 6 cases of “gastric submucosal by J. Vanek t Am. J. Path. ‘1.5: 397, 1949). There ax-e a few findings which the cases of Vanek granuloma with eosinophilic infiltration.” yet in the cases of Vanek there was no involvement and the reported rase have in common: of the lymph nodes an11 no simple lymphatic hyperplasia in the n?st of the gastric mucosa.
634
HANS
BRUITTNER
ually increased and during an intercurrent disease, associated with fever, and the enlargement of the spleen. IIowever, condecreased temporarily, cerning the type of the sytemic disease a definite diagnosis was not made. In favor of this diagnosis are The diagnosis of Hodgkin’s disease was likely. the following clinical findings : 1. The skin afYection associated with severe itching at the onset of the disease. Commonly Hodgkin’s disease presents itself on the skin in a nonspecific manner such as by pruritus, urticaria, and scaly erythroderma (Dobes and Weidmanj) . 2. The symptoms of a latent tuberculosis. 3. The irregular, cryptogenous fever. 4. The infiltration of the upper layer of the cutis consisting of small and large lymphocytes, epitheloid cells, and eosinophiles. 5. The eosinophilia. Among these symptorns the eosinophilia deserves special attention. There was both a tissue eosinophilia and an eosinophilia of the blood, the latter reaching 67.25 per cent on one occasion. In agreement with t,he eosinophilia there was an increase of mature and immature eosinophiles in the bone marrow. In Hodgkin’s disease a persistent leucocytosis with an increase of the neutrophilic leucocytes but without shifting to the left and, in addition, a constant lymphopenia are accepted as diagnostic aids. So far as the eosinophiles are concerned there is a moderate increase in approximately 25 to 49 per cent of the cases (JaffP). The presented case is not quite in agreement with these statements. The lymphopenia was not marked except one examination in which there were only 3 per cent lymphocytes. A neutrophilic leucocytosis was not discovered; there was, on the contrary, a moderate leucopenia. The underproduction of neutrophiles was apparently compensated by an overproduction of eosinophiles. A marked eosinophilia, however, is not significant of Hodgkin’s disease. Nevertheless, instances of this type are on record. Fowler’ encountered in one case 85 per cent eosinophiles in the blood. A thorough discussion of this problem was offered by Stewart8 who noticed in one case of proved Hodgkin’s disease a total leucocyte count of more than 100,000 with a percentage of eosinophiles varying from 90 to 92. Since the polynuclears averaged 18 per cent and the lymphocytes 4 per cent it was apparent that the eosinophiles accounted for the hyperleucocytosis. Stewart, emphasized that the exaggerated who reviewed the pertinent literature, eosinophile response in his case was apparently due to (a) a well-established familial background ; (b) a familial eosinophilic diathesis ; (c) a personal allergic background; (d) the specific eosinophile stimulating effect of Hodgkin’s disease itself; (e) the added effects of arsenic therapy. The presented ease is similar to the case of Stewart in certain aspects. There was on four occasions a hyperleucocytosis which did not reach the deNevertheless in all of t,hese four ocgree as noticed in the case of Stewart.
EOSINOPHILIC
GRANUL,OMA
OF MOUTH,
PIIARTKC,
-1Xr.l
KASAL
I’ASSAGES
635
casions the hyperleucocytosis was largely due to an increase in the number of the eosinophiles because the amount of neutrophiles varied between 19.7’5 and 37 per cent, the amount of lymphocytes, between 3 and 18 per cent. As in the case of Stewart there was an increase of mature and immature eosinophiles in the bone marrow. Th‘e exaggerated eosinophile response in the presented case was apparently due to various factors as in the case of Stewart. In the presented case t,hese factors arc: \a) the specifics cosinol)hile stimulat-. ing effect of Hodgkin’s (liseitsc itself pro~icl~l the patient. acetually suffered from Ilodgkin’s disease; (,tl) the finding of’ oxpriasis on Dec. 5, 1932; (c) the personal allergic background. ,Ilthough a slm+?c examination for allergy was not made, the allergic background catmot be questioned considering the finding of eosinophiles in the b1istet.s of the skin, in the skin itself, the polyposis nasi, the conjunctivitis, the fugitive edemas of the skin, and perhaps the fugitive edema of the larynx. An eosinophilic leucemia does not come into c+onsideration since eosinophilic myelocytes have never been discovered in the blood, neither in the case of Stewart nor in the presented case. To sum up, the finding of a marked eosinophilia is not common in Hodgkin’s disease but it is not incompatible with the diagnosis of Hodgkin’s disease. However, an eosinophilic hyperleucocytosis, if it occurs, is usually discovered in the advanced stage of Hodgkin’s disease (E’owler7). In the presented case it became manifest in the early stage assuming that this had been a case of Hodgkin’s disease. The clinical findings which tlo not agree with the diagnosis of typical Hodgkin’s disease are as follows : a. Duration of the disease. 1). Absence of cachexia and pressure symptoms. c. b’orrnation of tumors in the mouth, l)haryns, anal nasal passages. (1. Absence of lymphomas in the ncc+k, mediastinum. and abdometl. V. Absence of changes of the bone marrow due to Hodgkin’s disease. The average duration of life after the onset of symptoms is from three to l’our years. 12nt the tliscaw has Iwe~~ ktlowll to go on for as long as fifteen yc’ars or morn ( E’owlcr’) l’h~ J)rrsrnted V:ISCwas observed for approximately t \VelVe )‘Pill’S. This tlW?s (I(‘C‘llt’. IIo~vc\~t~r. it is tIi)t cillite in kc~ping with thr (‘Oltl’Se Of th0 ,listbasr thiti tilrl’r M’its II0 nt~ir’klit3s 1i1’ i‘U:h?!
s\w~'tol-ris I
r~;~llswf
i,;\-
jtlY!ssl~i'c~
tbi'
ilit.
tlt!~I~kiii
'5
1 liiitt)t'S
Ott
!!I<*
!?(>)'l.‘('S,
p\-olj
ii ftrr a period of twelve ;vmrs. ;4nother feature which is not in agrcc~mcut with th(h general aspect of Jioclgkill’s disease is thtr lindin, 0’ of tuutors ill areas which ;tlne supposed to be and in the spared by Hodgkin’s disease. viz.. ilr the ~t~t,utll. in ihe pharynx, msal passag’es, In a lwrinit of thtw a~1(1onr-half yra~ 11 tumors were noticed in the upper rcq)iratory and tligestivr I la&s. se\.en of \vhich wcrc removed by surgery. The tw11ors \vew locatccl : (,a’) itt the right tonsil ; (1)) in the soft palate on the right si(le: (~1 ilk thcl l)ostwior ~,a11 of tltv pllatyns ; ((11 in the
636
HAM3
BRUNNER
right vallecula ; (e) in the lingual tonsils (2 tumors) ; (f) in the right tonsillar recess ; (g) in the right cheek; (h) in the soft palate of the left side; (i) in the floor of the nose; (j) in the epipharynx. Up to this point the analysis furnishes the following result: There are several features which favor the diagnosis of Hodgkin’s disease, though of an atypical Hodgkin’s disease, and there are several features which are not in favor of Hodgkin’s disease, even not of atypical Hodgkin’s disease. I-Iowever, the contradicting features are likewise not in favor of another systemic disease of the lymphatic apparatus, certainly they are not in fa,vor of an aleucemic leucemia. Thus, there are two possible conclusions: Either the case presents a separate morbid entity or the patient has suffered, despite all contradicting symptoms, of a type of Hodgkin’s disease which, up to the present, rarely, perhaps never, has been reported. One should expect that the macroscopic and microscopic examinations of the tumors would offer an answer to these questions inasmuch as the microscopic examination of the tumors is supposed to be the most decisive finding to establish the diagnosis of IIodgkin’s disease. Unfortunately, in the presented case even this finding allows to make the tentative but not the definite diagnosis of Hodgkin’s disease. The tissue of typical Hodgkin’s tumors shows the following characteristic features : small and large lymphocytes, histiocytes, eosinophiles, Sternberg’s giant cells, necrotic spots, tendency to be replaced by connective tissue scars. The tumors of the presented case show the following features : a. They are located particularly on the right side of the mouth and pharynx. It is not possible to discover a cause for this distribution, but it is known that in the initial stage of Hodgkin’s disease there is not infrequent,ly a unilateral involvement of the lymph nodes. b. They develop in the submucosa. The mucous membrane covering the tumors is not adherent to the tumors; it is occasionally slightly reddened but there are no ulcerations. There were some enlarged veins of the mucosa in the area of the tumor of the right cheek. c. The tumors have distinct margins; they do not invade the underlying tissue. d. The tumors can be easily removed by surgery. There is no conspicuous hemorrhage as in the tumors caused by leucemia. e. There are no recurrences of the tumors locally. If a tumor is removed there is no recurrence in the scar but new tumors grow up in other parts of the mucous membrane. f. Microscopic examination : There are two types of tumors ; the first type consists simply of hyperplastic lymphatic tissue which contains a great There are follicles, germinal centers, and a wellamount of eosinophiles. developed reticulum in the interfollicular tissue. In other words, there is no change of the gross structure. The tumors of the epipharynx and of the lymph nodes belong to this group. The other tumors, however, do show a change of gross structure which is more or less marked. The slightest degree of change
EOSINOPHII,IC
GRANUL0M.k
OF MOUTH,
PHARYNX,
.tXD
NASAL
PASSAGES
637
is apparently presented by the tumor of the soft palate (Fig. 4). Here the difference between the follicles and the interfoIIic*ular becomes indistinct since the marked basoghilia of the folliclrs is tlimillishetl. If the changes advance there is tissue whi(Ah can bc recognized in low I)ower l~canse it stains more with rosin than with hematoxylin (E’igs. 1 ant1 8). This tissue is cellular but the cells are not as packed as in t.ypical lymphatic tissue; it contains besides lymphocytrs ad ~~lasum ~11~ ;I great ;I~IMJLHJ~ of ~J~u~~~mu~lea~ and polynuclear eosinoyhiles and histiocytes. the ll~l~*lelis c~f which (*ontaills a small There is 110 network of reticulum fibers as in typical amount, of chromatill. lymphatic tissue ; there are rather renlnants of the &icnlum. indicating that the network has been torn 1~s the proliferating cellular tissue (li’ig. 2). There are no collagenous fibers ;111dthe arterioles have thi~krnetl walls. In the tonsil there are necrotic spots and an ;tcc.unrulRtion of eosinophilcx in the necrotic a few J~~LWOL~ glands arc embedded in areas (Fig. 1). In some of the ~L~XZ the tissue (Fig. 4). The glands are either active or they ar’e inactive and atrophic. There are no giant cells. The abnormal tissue grows apparently by expansion and replaces more or less the lymphatic tissue. This results in a mottled appearance of the specimen (Figs. 1 and 8) because the abnormal tissue has a pinkish color while the lymphatic tissue stains deeply with hematoxylin. In some sections there is no lymphatic tissue at all. However, the abnormal tissue does not break, neither through the superficial epithelium nor through the connective tissue capsule. In the tumor of the cheek a considerable amount of collagenous tissue is noticed wit,hin the abnormal tissue (Figs. 6 and 7,l. In the same proportion as the connective tissue increases the amount of cells tl~t*cases without change of the type of cells. Roth the connective tisslie al1(1 the \valIs of the arteries may undergo a hyaline degeneration. .Evidently there are several microscoI)ic frilt Ill’es \vhicIr ill’c’ significant of Hodgkin ‘8 disease. The contradicting findings art’: ia) the n.bsencr of a widespread formation of connective tissue although there was some connective tissue in the turrlor of the cheek: (I~) the ~rbsence of Sternberg cells. So far as thcl scar formation is concerned it must IN realized that the tumors It is likely that scars n~ay h.avr Forlued if the were removed ~JF Surgery. tumors woultl ha1.c been left in place for ;I Iongc~ pcrjwl of tinle. In farctl- of t,his Tiew is the filet that ilk SCY(‘I‘aI of 1h(s t LlJticlL’S thVl’c \v:ts 211i ::ccu!u~Iati:)li of t:istiocytes CE’igs. 9 2nd 10) \<.hich fnizish thra !iiaterial for scar -r’orn!atior! ;lnd that in tht> tuu~c)r cbf thta c*lrrrk wfiicdh !\;I(( IWP~ :II~I,wP(~ 10 CWIW for. ;I (*OJHparatively long prriotl of titer. there was for7ri;ttioll of c+oittlrctivtj tissnc.. s;o far iis the abscn~~ of Strl*nl)crg C‘CIIS is (‘Oll(‘P~‘II~d :I (‘ilSf’ Of I)OIJtlS ;111ti JYeidman” may assist in cvalunting Ihis findilig. In this case there was a typical Hodgkin ‘S cIisr;tstl of the ly~jrplj j10t1e~ associatetl with an extreme eosinophilia of both l~lood and t,issues. \vhich rrac~hrd 84 per cent in the blood. In addition, there \vas TTotlgkit~‘s tliwnsr 01’ the skin whic*h mic*roscopicalIp showed, in contrast to the typical findings in the nodes, several ;ltypicnl
638
HANS
BRUNNER
features: (1) an extraordinary tissue eosinophilia so that t,he skin finding resembled an eosinophilic granuloma of the skin. The cast presented in this paper had likewise an eosinophilia of the blood and the microscopic finding of the skin, obtained by the dermat,opathologist., bore some resemblance to eosinophilie granuloma of skin. (2) A great number of neutrophilic polynuclear cells. These cells were absent in the case presented in this paper. (3) The final fibrosis which was absent in the case of Dobes and Weidman and which was present, although not to a considerable degree, in the case pre(4) Sternberg cells which were infrequently noticed in the case of sented. Dobes and Weidman and were absent in the case presented in this paper. Considering the fact that Hodgkin’s disease is tardy in affecting the skin, if it does so at all, in other words that the skin is a tissue which is usually spared by Hodgkin’s disease, as is the lymphatic tissue of the nose and the mouth, it is not a far-fetched conclusion that the atypical microscopic findings in both cases are in relationship with the atypical localization of the disease. The last finding to be ment,ioned is that of the tumors which consist simply of hyperplastic lymphatic tissue. This is likewise a finding which is not common in Hodgkin’s disease which, however, does occur, even in typical instances. JaffP quoted Longcope, Symmrrs, Eenda, and During who stated that the specific granulomatous changes in Hodgkin’s disease are preceded by a noncharacteristic lymphatic hyperplasia, an observation not confirmed by other investigators. Fowler’ shared the view of Longcope and others. JafE himself believed that “this nonspecific initial hyperplasia of the lymph cells is the result of a stimulation to compensatory growth and is found especially in lymph nodes belonging to a group of nodes, most of which have been He further quoted cases of Hodgdestroyed by the granulomatous process.” kin’s disease in which the lymphatic hyperplasia was a striking feature and remained so during the entire course of the disease. ((These cases take a rapid course and have sometimes been explained as transformation of Hodgkin’s disease into aleucemic lymphadenosis or lymphosareoma.” The presented case seems to confirm the view as expressed by Longcope and others. However, it does not confirm the view of Jaffe because the disease ran an extremely chronic course and because there was no compensatory hyperplasia of lymphatic tissue on the left side. The analysis of the microscopic findings arrives at the same conclusion as did the analysis of the clinical findings, viz., the disease is very close to Hodgkin’s disease to say the least. The only finding contradict,ing this diagnosis is the absence of Sternberg’s giant cells.
Conclusion In this paper the history of a patient is presented who suffered from a The tentative diagnosis is: systemic disease of the lymphatic apparatus. findings are in favor of atypical form of Hodgkin’s disease. The following this diagnosis : a. Noncharacteristic h
skin affection
Tnvntavnta ~~ ._- . . . . tnhnrnnlnc;a __. _ . .._
.., nf /._ lnnrrn --*‘.P”.
at the onset of the disease.
EOSINOPHILIC
GRANULOMA
OF MOUTH,
PHARYNX,
AND
KASAI,
PASSAGES
639
C. Irregular, cryptogenous fever. d. Infiltration of upper layer of tutis with cosinophiles resembling eosinophilic granuloma of skin. e. Eosinophilia which was caused by the specific eosinophile stimulating effect of the assumed Hodgkin’s disease itself, by the finding of oxyuriasis in one examination, and the personal allergic background.
The following
findings
are not in favor of IIodgkin’s
disease :
a. Duration of the disease which extended over a period of approximately twelve years without causing cachexia or symptoms of pressure upon nerves. b. Formation of 11 tumors in a period of three and one-half years in areas which are supposed to be sparccl by Hodgkin’s disease, viz., in the mouth, pharynx, and nasal passages. c. Absence of gross lymphomas in neck, mediastinum, and abdomen. d. Absence of changes of bone marrow due to Hodgkin’s disease. So far as the tumors tained :
are concerned
the following
findings
have been ob-
1. The tumors are located particularly on the right side of the mouth and the pharynx. 2. They develop in the submucosa and do not exhibit ulcerations. 3. They do not invade the underlying tissue. 4. They are easily removable by surgery. 5. There are no local recurrences. 6. They consist either of a hypcrplastic lymphatic tissue or of a specific tissue which proliferates with considerable sl~c(l and is in sttarlcture similar to the granulomatous tissue of Ilodgkin’s disease except that Sternberg’s of large scars. giant cells are absent and that there is no tt~1ldency to fOl'llli~ti0~~ The treat,ment consists of surgical rtlmoval of the tumors. In the I,resented case ‘i tumors were reurored front the 111o11th,pharyns, and llasal passages.
Addendum
640
HANS
BRUNNER
this intestinal eosinophilic granuloma and that of bone marrow. The lesion appeared to The authors stated t,hat this type of granuloma of the intestinal tract has be benign. The relationship between the case described by the authors never before been described. and that presented in this paper is evident.
References 1. Brunner, H., and Schnierer, J.: Die zytologische Untersuchung der Gaumentonsillen und ihre klinische Bedeutung bei Leukamie, Wien. klin. Wehnschr. 50: 17T2, 1937. der Gaumentonsillen bei Leukamien, 2. Brunner, H., and Fischer, J.: Die Verlnderungen Monatschr. f. Ohren. 72: 137, 1938. 3. Symmers, P.: The Clinical Significance of the Pathological Changes in Hodgkin’s Disease, Am. J. M. SC. 167: 313, 1924. granulomatosa. Hdb. d. spez. pathol. Anat. u. Histol., 4. Fraenkel, E.: Lymphomato’sis vol. 1, p. 347, 1926. 5. Dobes, W. L., and Weidman, F. D.: Granulomatous Hodgkin’s Disease of the Skin With Extreme Eosinophilia (Eosinophilic Granuloma of the Skin?), Arch. Dermat. & Syph. 55: 212, 1947. System, Handbook of Hematology, vol. 2, p. 977, 6. Jaffe, R. H. : The Reticula-endothelial 1938. 7. Fowler, W. M.: Hematology,. New York, 1940, Paul B. Hoeber, Inc. 8. Stewart, S. G.: Eosinophrbe Hyperleueocytosis in Hodgkin’s Disease With Familial Eosinophilic Diathesis, Arch. Int. Med. 44: 772, 1929. 417 MT. PROSPECT AVE.
Pathology
GRANULOMA AND NASAL
OF MOUTH, PASSAGES
PHARYNX,
T 18 a common opinion that the lymphatic tissue of the upper respiratory and digestive tracts does not become frequently involved in chronic systemic disThis opinion is correct if only gross changes eases of the hematopoietic apparatus. of the lymphatic tissue, such as enlargements or ulcerations, are considered. However, pathologic changes arc more frequently encountered when in systemic diseases of the hematopoietic apparatus microscopic examinations are made in instances in which there are no gross changes of the lymphatic tissue in the upper respiratory and digestive tracts. Brunner, Schnierer, and Fischer’, 2 proved that the lymphatic tissue of these tracts is frequently involved in the leucemias although the gross structure may be apparently normal. For this reason, they suggested that, the contents of the tonsillar crypts in leueemias be examined for abnormal white blood cells, an examination which has furnished useful practical results. Contrary to the findings in leucemias, it was and it is the current view that in Hodgkin’s disease the lymphatic~ tissue of the upper respiratory and digestive tracts is usually spared while the lymph glands of t,he neck, the mediastinnm, and abdomen are favorite loc~alixntiotls of the disease. Symmera” is very definite in this respect. I Ie wrote : “Thta suhmu~ous collections, represented hy the Paacial and lingual tonsils and lay the minute lyrnphoid follicles which are strewn through the, suhn~u~~osa of the gastrointestinal, respiratory and urinary trac*fs almost itlvariahly cs(dill)c‘ In IIodgkin’s disease.” Experience has shown thi1.t this vi(LM. is not qrlitc eorrrct as far as the digestive tract is (~oncrmed since IIodgkin’s t~nuors I~:I\~v hern observed in the stomach not infrequently. Ncvet*t hcl~W. t’s(‘tt al lit’esflllt it is a gcncraII?- ac*cepted vieI\ I hat i I~v l~nl~~hat ic, f issue of t ht; IIUIII~ II. ~)h;rr?~tlr, and nose is infrequently in; ulsctl if: Ilodgki~: ‘s ifis;l5ii;(‘. !-‘ t~ttc~ttktbl” 4 iit(vl 1 j!il! 1 ht. i llmol’ t’ormation itt tltc* lymph noctcs of the utAc,k witlloui itl\.olvc.tuotli IA’ thtl l>-lt~t)haiir* fissut: ol’ the pharynx is supl~~d to be sigtlificatlt of Hodgkin’s disease. In the case to be ~~r’ese~~teciin this paper, the lymphatic tissue of t~he upper respiratory and digestive tracts has ~KYW Iar*gely involved. The patient was d~~e~vrtl fog a pcriocl of ap~)rosimntely tw-clrc years hy internists. hematologists, clermatologists, anal otolaryngologists; yet it was not possihle to arrive at a definite diagnosis. It was not even possible to state as to whether there was a separate morbid cnt.ity or the per~rsory stage of Hodgkin’s diseasck. Tho final 623
I
624
HANS
BRUNNER
If this is correct it is remarkable that analysis rendered the latter view likely. Hodgkin’s disease may continue for a period of twelve years without presenting symptoms to warrant a definite diagnosis.
Case Report Z. J., 36-year-old white man, had measles in childhood and a resection of the nasal septum in 1922. There were no other diseases. Since 1920 he noticed small red spots on both upper arms and on the legs associated with severe itching. In 1924 there was an improvement for a short period of time to be followed by an acute flare-up which was associated with swelling of the lymphatic nodes in the groin, in the cubiti, and in the armpits. On Nov. 20, 1925, the internal and nenrologic examinations were negative and the urine was found to be normal. There was a great number of follicular noduli and impetiginous plaques all over the extremities, causing severe itching. The lymph nodes The affection of the in the groin and in the sulcus bicipitalis were swollen. skin subsided finally, leaving behind a small amount of pigment. Following this episode he was well until February, 1927, when again a skin affection occurred similar to that in 1925. On May 10, 1927, there was a dullness over both apical regions with impaired expansion, especially on the right side. The dermatologic examination revealed the same findings as in 1925. There was no hypertrophy of tonsils; there was a positive Mantoux test. From May 30 until July 5 he had fever oscillating between 100 and 100.2O. Noduli, blisters, and edema of the skin as well as glandular swelling were noticed. In the fluid of the blisters there were many eosinophiles. On May 7, he had a sudden attack of coughing which lasted for one hour and was associated with breathing troubles. This was perhaps caused by edema of the larynx. On May- 10, there was edema, indistinctly bordered, over the cheeks and t,he forehead. One lymph gland was removed surgically.
Microscopic Finding of Lymph Node.-In the enlarged stroma, particularly close to the sinus, there were many eosinophiles forming a fourth or a fifth of all the cells. An even greater amount of eosinophiles were discovered in the sinuses, particularly in the marginal sinus. In the trabeculae, septa, and in the perilymphatic connective tissue there was a small number of eosinophiles, particularly close to the blood vessels. The gross structure of the node was normal. On June 26, the temperature rose to 302.5’. On July 12, 1927, a piece of skin was excised. Microscopic Finding of the Skin.-The connective tissue was edematous and there were a few eosinophiles around the blood vessels. In the subcutaneous fat tissue the eosinophiles were exclusively around the blood vessels and in the lymphatic tissue adjacent to the blood vessels. They extended along the capillaries into the septa between the fat cells. In these area,s the eosinophiles constituted approximately one-t,hird of all cells. The eosinophiles within the lymphatic tissue had a lobulated nucleus or two nuclei while the eosinophiles
I”IOSISOPIIJI,IC
GR.~SI’LOIVI.\
OF
MOUTH,
PFL1RTSS,
.\SD
S.\S,\L
I’ASSAGES
625
in the connective tissue had a round or rodlike nucleus. In some places there were frank eosinophilic granules in the tissue which occasionaly were attaehed to the membranes of connective tissue cells. Within the muscular tissue eosinophiles were infrequent. There was no t,richinosis. From 1928 until 1932 he had several attacks of the skin a&&on occaGunally associated with fercr up to 102.2O. In 1931 JJ:JS~J~ polyps were r1pnloved. In l)ecember, 1931, he noticed a sliglit swelling of tile right tonsil which gradually increased without causing pain. After several months the tonsil On June 21, 1932, the right grew up to a size to cause difficulty in swallowing. tonsil was found to be enlarged, extending about 0.5 cm. beyond the midline to the left. The surface was smooth RJJ~ thr tollsi consistr(l apparently of large lobuli. It had a pinkish color and the number of crypts seemed to be normal. From the crypts gray-yellowish material could be expressed. Otherwise otolaryngologic examination was negative. On August 1, a tonsillectomy was performed. The tonsils did not ext,end deeply into the constrictor muscle ; there were no adhesions and no hemorrhage. Uneventful recovery ensued. Only the right tonsil was examined.
Microscopic Finding of Right Tonsil.-The
tonsil consisted of normal and abnormal lobuli (Fig. 1). The former were close to the inferior pole, the latter to the superior pole of the tonsil. The borderline between lymphatic tissue and connective tissue was distinct ; the capsule was normal. The abnormal lobuli were much enlarged due to the proliferation of a pathologic tissue which consists of loosely arranged lymphocytes, a great amount of eosinophiles, There \vere a few necrotic spots l)lasma cells, histiocgtes, and capillaries. Since the which showed au infiltration by leucocytcs! probably eosiuophiles. specimen had been in alcohol fog* a long period of time the staining of the eosinophiles was poor. Due to the proliferation of the abnormal tissue there was not only a11 enlargement of t,he lobuli but also the following changes were noted : (a) A number of follicles had apparently been destroyed; the remainder did not show germinal centers. Since the pathologic tissue stained with a pinkish color while the remnants of the lymphatic tissue were deeply stained with hematoxylin, the spccimell had it mottled appearance. ib) The number of c’typts were tlitninished. Cc) Thta reticulum of the interfolliculal tissue was torn iir pirccts. ,L\ greater, iJJJ1OUJli of aJq~tlt c)phile fibers wt’t’t’ tt.1 be ~‘ouIJcI ottI?; belo\v the epithrlilltn :111(1 iJJ*ottJJti ihe I)lootl vessels (lq’igs. r! a~ltl :+). lf,iWli ‘Gi!,lilaT t*, ,>fl/ Tlkt* cuiltiec‘ti\-e Ikhllt ic’lkt;t \+,“C!‘t, ;Il~Sf~til il! t11r m!:11ycl the fiuclings iti lytnphatic: iruceil~ia \ I:t*ur~nor ;I~ICI P‘isc*heP’;, It’) ill 11lP **Iilargetl lobuli the rpithrliulu had in soJ1ltAplaces an c~pictcrmoitlal charnctc~r, the pal)illae being small in rluml~er ar1c1 low ; it1 other l)laces it, c*onsistecl of a few layers of flat cells which were not hornifying. There was no reticiulatioli of the epithelium due to luigratitlg leucor:>-tes. To sum up, there was a new formation and proliftarat,ion of it11 iJl)lJO~J~lid tissue which apparently replaced the interfollicular tissue first and then expanded causing a destruction of the follicles of the tonsil.
626
HANS
Fi no1 ZIlal net :rotic
F’iL7
Q
BRUNNER
1. -Right Hematoxylin-eosin staining. C, Capsule: d, e, lobuli sho wing tonsil. Yl( zture; a, b, c, lobuli showing a pathologic structure. particularly lot IUlUS c; )Of: infiltrated by eosinophiles; m, beginning necrosis.
9tmvrt71rc.
ccf tl2n y\t?sl)lcJgi~ p3yt.5 of the right tonsil. Staining the reticulum of the tonsil is torn in pieces.
after
Pap.
Note
that
On Dec. 5, 1932, oxyuriasis was discovered in the stool. This disappeared in January, 1933, he noticed for the first time, following adequate treatlnent. in a painless swelling on the right side of the soft t>al;tte. Examination January, 1933, rcrealcd a motlet*ately firm, noncystic tnulor occupying the right side of the soft ])alate and extending into the upper part of the tonsillar toward the hard palate, an inarea. The tumor had a distinct In)rderline distinct horclerline toward the midline, and did not, interfere with the motility of the soft l);LlatC. It WtlS COvtltGedl)y a rlortr~al IllLlCOS~ alld \ViIS Ilot tCIIdCt..
There vv;err no rrmnauts of tonsillar tissue. Pc.,strrior rhinoscopy resealed t’hat the posterior surface of the soft l)alate was not ltulging. 011 the left side uf the ]JOSit!l’iOl’ vvall I)f tlie pliaqms there u-as x t;unior. the size of R bean. covered hy mu~osa. It was not pediculutrtl and cxtendecl toward thr roof of the epipharynx. The tumor was removed.
Microscopic covered
with
Examination squamous
of Tumor
epithelium
which,
of Epipharynx.----Tile in some places,
tumor was showed small
628
HAN3
BRUNNER
papillae, in other places a reticulation clue to the invasion of a great number of lymphocytes. It consisted of lymphatic tissue with follicles and germinal In the interfollieular tissue there were many eosinophiles and a centers. moderate amount of collagenous tissue. tunlors with a smooth surface were On Aug. 16, 1933, three pinkish-red discovered in the vallecula. The middle one, slightly right to the midline, was round and had the size of a small plume and a pencil-like pedicle. On the right lateral wall of the pharynx, immediately behind the posterior pillar of the tonsillar area, there was a pediculated flat tumor, t,he size of a quarter. The tumor was movable, appeared on the back of the tongue when the patient When he was quiet the tumor was lying increased his abdominal pressure. in the vallecula. The surface of the tumor was smooth. The left plica pharyngoepiglottica seemed to be changed into a tumor, the thickness of a pencil. The base of the tongue was normal except that the right lingual tonsil was ‘more prominent than the left. The tumor in the right vallecula was removed with the snare, The other tumors were treated with roentgen rays without success. The removed tumor had the same structure as the tumor of the soft palate which was later removed. However, the eosinophiles were not very well discernible because the specimen had been in alcohol for a long period of time. On September 12, 1933, the tumor in the center of the vallecula, attached to the base of the tongue, was removed, and below this tumor another tumor was discovered likewise attached to the base of the tongue. ~YOWit became evident that it was not the left plica pharyngoepiglottica which was changed into a tumor; the plica was rather covered and hidden by a tumor which was attached to the base of the tongue. The tumors were removed. On Sept. 13, 1933, a cross incision was made in the mucosa of the soft palate. A soft, friable tissue was exposed resembling glandular tissue with small lobuli. The tumor which was situated between mucosa and muscular layer was removed. Uneventful recovery ensued. There was no oxyuriasis in the stool. Wassermann reaction and luetin test were negative.
Microscopic Examination of Tumor of Soft Palate.-The tumor (Fig. 4) consisted of lobuli of different size, separated one from the other by connective tissue. The small lobuli showed normal lymphatic tissue with many follicles and germinal centers. In the periphery of the large lobuli there were likewise follicles and germinal centers, while in the core of these lobuli the architecture was obscured because the follicles did not distinguish themselves from the rest of the tissue. Around the follicles there were many eosinophiles. In the core of the large lobuli the eosinophiles made up approximately the half of the cellular element,s. In the areas of normal lymphatic tissue there were many active mucous glands. In the areas where the normal architecture was disturbed, the glands were inactive and there were remnants of glands. Active glands were infrequent in these areas. The walls of the arterioles were thickened.
EOSINOPHILIC
GRAsULOM.4
OF
MOUTH,
FH~iRYXX,
AXI)
XASAL
PASSIGES
629
On Jan. 10, 1935, he felt well and healthy. The right side of the soft palate was red. In the lateral part of the right side of the tongue there was a tumor, the size of the stone of a date, covered by pinkish mucosa and extending into the area of the right tonsil. The tumor was removed. Microscopic Examination of the Tumor of Tongue.--The tumor was covered by squamous epithelium which. in some areas, showed low papillae. There were a few crypts the walls of whicsh were likewise rorpred by squamous epithelium. The subepithelial layer was narrow. 7‘he COL’e Of tll? tumor conWithin sisted of lymphocytes, eosinophiles, plasma cells. ant1 histiocytes. this tissue follicles and remnants of follicles were scattered throughout, creating the same mottled appearance as was noticed in the tonsil.
The tumor in the right cheek had t~achr~i tilt. siar of ii SIX& itl~plc~ Since this tumor (liti irot eailse tl*ouble ii Xlucosa of the cheek was normal. was left alone. The lymphatics of the neck, the axillne, and the groin were swollen. The glands were moderately firm. had distinct margins, and reached The spleen was enlarged and could the size of a pigeon egg in the left axilla. be felt a little 1~10~ the costal arch. Internal fin(ling was otherwise negative. Urine analysis was negat,ive. On Jan. 26: 1935, there was a swelling of glands in the right cubiti and on the left upper arm. The blood was normal, except a marked eosinol)hilia.
630
HANS
BRU-UNER
X-ray examination of the skeleton, of the lungs, and of the mediastinum was negative. In the next weeks the patient became ill with an “influenza” associated with fever. In this time the glandular swelling decreased. On March 26, 1935, the bone marrow was examined and the following findings were obtained: reticulocytes, 54 per cent, myeloblasts, 0.8 per cent, promyelocytes, 1.6 per cent, myelocyt,es, 12 per cent, eosinophilic myelocytes, 4.4 per cent, basophilic myelocytes, 0 per cent, metamyelocytes, 10.4 per cent, eosinophilic metamyelocytes, 5.6 per cent, juvenile forms, 6.6 per cent, eosinophilic juvenile forms, 2.8 per cent, polynuclear leucocytes, 14 per cent, eosinophilic polynuclear leucocytes, 4 per cent, basophilic polynuclear leucocytes, 0 per cent, monocytes, 1.4 per cent, lymphocytes, 4.6 per cent, plasma cells, 0.6 per cent, proerythroblasts, 5 per cent, macroblasts, 8.6 per cent, normoblasts, 17.4 per cent, mitotic forms, 0.2 per cent. This finding indicated a slightly increased activity in the leucopoietic and erythroblastic tissue, particularly an increase in the number of eosinophiles and of immature eosinoThere was no indication, either for Hodgkin’s disease or for a sysphiles. temic disease of the hematopoietic apparatus. On May 7, 1935, the patient felt well. There were tumors in the right cheek and in the left soft palate (Fig. 5). The tumor of the right cheek was removed. Uneventful recovery ensued.
Fig.
5.-Tumor
of
the
pal&?.
Microscopic Examination of the Tumor of the Cheek.-The tumor consisted of loosely scattered follicles which usually did not contain germinal centers. The structure of the interfollicular tissue varied. In some places it had the same structure as, for instance, in the tonsils, viz., it was cellular containing lymphocytes, plasma cells, histiocytes, and particularly eosinophiles. In other places connective tissue was noticed which gradually increased until there was in some places a comparatively great amount of hyaline connective tissue. In these areas the arterioles likewise showed a hyaline degeneration (Fig. 6). In the same proportion as the connective tissue increases, the content of cells decreases. Finally there are only single rows of cells between thP fihem. Eosinophilcs arc predominant also in these areas.
On May 20, 1937, he felt well. There were numerous follicular noduli and impetiginous plaques in the skin and the glands were considerably swollen. The entire soft palate was slightly bulging. There were tumors in the floor of t,he nose. There was a row of nod&i, the size of a pinhead, in the bulbar conjunctiva, close to the cornea. The rest of the bnlhar conjunctiva was A biopsy was taken from the skin. thickened.
Fig. 6.-Tumor of right cheek. Hematoxylin-eosin In the interfollicular tissue there are many capillaries, s-;lliall amount of cells.
staining. connective
There are several fOllicleS. tissue, and a comparatively
Microscopic Examination of the Skin,--There was an acanthosis of the a hyperkeratosis, and a slight intraepithelial edema. The blood rpithelium, vessels of the papillae and of the upper layer of the cutis were dilated. Tn this area there were acacumulations of large and small lymphocytes, epitheloid ~~11s. and I~arti~ulnrly eosinophiles w1lic.h wvrrc to 1~ founcl around the bloo~l i rssels. as well as in the tissue. Thrrr wrrt’ It0 Sternberg giant cells. .\, ?!mior was removed from the floor of' i he IIOW. Microscopic Examination of Nasal Tumor.- -‘l‘hv tul~~c)r 11;rd :t mottl~~tl appearance (Fig. 7). The tissue was very celluIar. ‘I‘ht~ cells consisted 1)1’ lymphocytes, plasma cells, and histiocytes ( Fig. 8 1. The rosinophiles, a great, llurqber uf them mononucIear. were more frryuellt than in all of the other tumors. The\- f0r*111edhtaaps \vhich CUUI~ IIt, rec,cJgltizrd Tvith IOR- magnificat ion. There WVIY no collagenous fibers. rrc*ept around the blood vessels and glands, but there was a fair amount of argelltophile fibers, particularly around the blood vessels and ~lantls. Throughout this tissllc remnant,s of lymphatic tissue were scattered and this created a mottled appearance of the specimen.
HANS
the
nasal
passage.
BRUNNER
Hematoxylin-eosin eosinophiles.
staining ; 5 indicates
Fig.
7.-Tumor
of
Fig.
8 .-Tumor
Hematoxylin-eosin staining; of the nasal passage. histiocytes surrounded by eosinophfles.
D indicates
heaps
of
a focus
of
In some sections the lymphatic tissue was entirely absent. There were several active and inactive mucous glands within the t,umor tissue. The walls of the arterioles were t,hickened. The tumor was covered hy a pseudostratified columnar epithelium which did not contain goblet cells, or hy transitional epithelium. The basilar Inemhrane was well cle~eloprd. Below the epithelium there was a layer of edematous connective tissue which contained lymphocytes, plasma cells, an(l particularly eosinophiles, t~nlarg~tl veins, and mucous glands. There wert’ 111.jserous glands. This layer gi~atlually passed over into the tumor tissue. The patient was ohserrcd until the beginning of 1938 without showing changes in the findings. Examinations of Blood.---The ret1 blood count was rssrnt ially normal in all examinations. The findings concerning the leuc*ocyt (8s are summat~ized in Table I. L
_--
, LEUCOCYTES TOTAL
_ -~ ___-.-~
9,200
26.X1.1925
26.1V.1927 lO.V.1927 (a)
15,600 14,700
26.VI.1927*
22,700
28.X1.1928
33,200
4.TIT.1930
9,450
31.VI.l932(b)
11,250
4.VIII.1932
t
10,600
lti.VlII.1933
1n,oou
lO.I.1935$
12,400
26.1.1935 26.TII.1935
,
POLYNUCLEAR CELLS 74%
(6,8bk) 37% (5,439) 24% (5,448) 19.75% (6,557) 41% (3,874) 36% i-t,050) 58% (6,148) 59%
JUVENII>E FORMS 0
4% (588) 0 0 0 0 3% (318) 0
1,400 70,000
34% (5,400)
2% ("00)
j
EOSINOPHILES
BASOPHILRS
0
0.5% (46) 32% (4,704)
4% i;g1
(2)
65%
(14,755) 67.25% (22,327) 35% r:<,307 1 37% (4,162)
8% (848) 20.5% (2,050) 47.5% (.5,952) 40 to t?O% 24% , 2,400 \
I 1 MONOCYTES 2.5% (230)
(& 0.25% (803)
3% (337)
2%
!L’l%) 0 1% (124)
0
(y$ ,,gi (94 1% (112)
7% (7421 3.5% ( 350 ) 4.5% (588)
9%
( 900~
i
!
LYMPHOCYTES
23% (2,116) Ii%
(2P
(68;) 10.75% (3,569) 23%
12,173) 22% (2,475)
wh
(2,332) 17% (1,700)
16% (,l,R84,l
11%
( 1,10(1)
Comment In the prtwittccl viise whic*h was ohscr\~ctl fctr a lwriod of iI~)p~o~il~lately I welve years, H tlefiiliir diagltosin was not matit’. It is fairly certain that there was a systemic tliseasc of the lymphatic apparatus.” In Ya\or of this diagnosis are the I)crsistrnt rq~largemcnt of \~arious ~:‘I’OIIJN (II’ I>-mph nc~l~s which grad*In this reuyevt ttw <‘asr xporte4 in this paw’r 6liffers ildirritely ftwrll tlw w.w.s reported This author reports 6 cases of “gastric submucosal by J. Vanek t Am. J. Path. ‘1.5: 397, 1949). There ax-e a few findings which the cases of Vanek granuloma with eosinophilic infiltration.” yet in the cases of Vanek there was no involvement and the reported rase have in common: of the lymph nodes an11 no simple lymphatic hyperplasia in the n?st of the gastric mucosa.
634
HANS
BRUITTNER
ually increased and during an intercurrent disease, associated with fever, and the enlargement of the spleen. IIowever, condecreased temporarily, cerning the type of the sytemic disease a definite diagnosis was not made. In favor of this diagnosis are The diagnosis of Hodgkin’s disease was likely. the following clinical findings : 1. The skin afYection associated with severe itching at the onset of the disease. Commonly Hodgkin’s disease presents itself on the skin in a nonspecific manner such as by pruritus, urticaria, and scaly erythroderma (Dobes and Weidmanj) . 2. The symptoms of a latent tuberculosis. 3. The irregular, cryptogenous fever. 4. The infiltration of the upper layer of the cutis consisting of small and large lymphocytes, epitheloid cells, and eosinophiles. 5. The eosinophilia. Among these symptorns the eosinophilia deserves special attention. There was both a tissue eosinophilia and an eosinophilia of the blood, the latter reaching 67.25 per cent on one occasion. In agreement with t,he eosinophilia there was an increase of mature and immature eosinophiles in the bone marrow. In Hodgkin’s disease a persistent leucocytosis with an increase of the neutrophilic leucocytes but without shifting to the left and, in addition, a constant lymphopenia are accepted as diagnostic aids. So far as the eosinophiles are concerned there is a moderate increase in approximately 25 to 49 per cent of the cases (JaffP). The presented case is not quite in agreement with these statements. The lymphopenia was not marked except one examination in which there were only 3 per cent lymphocytes. A neutrophilic leucocytosis was not discovered; there was, on the contrary, a moderate leucopenia. The underproduction of neutrophiles was apparently compensated by an overproduction of eosinophiles. A marked eosinophilia, however, is not significant of Hodgkin’s disease. Nevertheless, instances of this type are on record. Fowler’ encountered in one case 85 per cent eosinophiles in the blood. A thorough discussion of this problem was offered by Stewart8 who noticed in one case of proved Hodgkin’s disease a total leucocyte count of more than 100,000 with a percentage of eosinophiles varying from 90 to 92. Since the polynuclears averaged 18 per cent and the lymphocytes 4 per cent it was apparent that the eosinophiles accounted for the hyperleucocytosis. Stewart, emphasized that the exaggerated who reviewed the pertinent literature, eosinophile response in his case was apparently due to (a) a well-established familial background ; (b) a familial eosinophilic diathesis ; (c) a personal allergic background; (d) the specific eosinophile stimulating effect of Hodgkin’s disease itself; (e) the added effects of arsenic therapy. The presented ease is similar to the case of Stewart in certain aspects. There was on four occasions a hyperleucocytosis which did not reach the deNevertheless in all of t,hese four ocgree as noticed in the case of Stewart.
EOSINOPHILIC
GRANUL,OMA
OF MOUTH,
PIIARTKC,
-1Xr.l
KASAL
I’ASSAGES
635
casions the hyperleucocytosis was largely due to an increase in the number of the eosinophiles because the amount of neutrophiles varied between 19.7’5 and 37 per cent, the amount of lymphocytes, between 3 and 18 per cent. As in the case of Stewart there was an increase of mature and immature eosinophiles in the bone marrow. Th‘e exaggerated eosinophile response in the presented case was apparently due to various factors as in the case of Stewart. In the presented case t,hese factors arc: \a) the specifics cosinol)hile stimulat-. ing effect of Hodgkin’s (liseitsc itself pro~icl~l the patient. acetually suffered from Ilodgkin’s disease; (,tl) the finding of’ oxpriasis on Dec. 5, 1932; (c) the personal allergic background. ,Ilthough a slm+?c examination for allergy was not made, the allergic background catmot be questioned considering the finding of eosinophiles in the b1istet.s of the skin, in the skin itself, the polyposis nasi, the conjunctivitis, the fugitive edemas of the skin, and perhaps the fugitive edema of the larynx. An eosinophilic leucemia does not come into c+onsideration since eosinophilic myelocytes have never been discovered in the blood, neither in the case of Stewart nor in the presented case. To sum up, the finding of a marked eosinophilia is not common in Hodgkin’s disease but it is not incompatible with the diagnosis of Hodgkin’s disease. However, an eosinophilic hyperleucocytosis, if it occurs, is usually discovered in the advanced stage of Hodgkin’s disease (E’owler7). In the presented case it became manifest in the early stage assuming that this had been a case of Hodgkin’s disease. The clinical findings which tlo not agree with the diagnosis of typical Hodgkin’s disease are as follows : a. Duration of the disease. 1). Absence of cachexia and pressure symptoms. c. b’orrnation of tumors in the mouth, l)haryns, anal nasal passages. (1. Absence of lymphomas in the ncc+k, mediastinum. and abdometl. V. Absence of changes of the bone marrow due to Hodgkin’s disease. The average duration of life after the onset of symptoms is from three to l’our years. 12nt the tliscaw has Iwe~~ ktlowll to go on for as long as fifteen yc’ars or morn ( E’owlcr’) l’h~ J)rrsrnted V:ISCwas observed for approximately t \VelVe )‘Pill’S. This tlW?s (I(‘C‘llt’. IIo~vc\~t~r. it is tIi)t cillite in kc~ping with thr (‘Oltl’Se Of th0 ,listbasr thiti tilrl’r M’its II0 nt~ir’klit3s 1i1’ i‘U:h?!
s\w~'tol-ris I
r~;~llswf
i,;\-
jtlY!ssl~i'c~
tbi'
ilit.
tlt!~I~kiii
'5
1 liiitt)t'S
Ott
!!I<*
!?(>)'l.‘('S,
p\-olj
ii ftrr a period of twelve ;vmrs. ;4nother feature which is not in agrcc~mcut with th(h general aspect of Jioclgkill’s disease is thtr lindin, 0’ of tuutors ill areas which ;tlne supposed to be and in the spared by Hodgkin’s disease. viz.. ilr the ~t~t,utll. in ihe pharynx, msal passag’es, In a lwrinit of thtw a~1(1onr-half yra~ 11 tumors were noticed in the upper rcq)iratory and tligestivr I la&s. se\.en of \vhich wcrc removed by surgery. The tw11ors \vew locatccl : (,a’) itt the right tonsil ; (1)) in the soft palate on the right si(le: (~1 ilk thcl l)ostwior ~,a11 of tltv pllatyns ; ((11 in the
636
HAM3
BRUNNER
right vallecula ; (e) in the lingual tonsils (2 tumors) ; (f) in the right tonsillar recess ; (g) in the right cheek; (h) in the soft palate of the left side; (i) in the floor of the nose; (j) in the epipharynx. Up to this point the analysis furnishes the following result: There are several features which favor the diagnosis of Hodgkin’s disease, though of an atypical Hodgkin’s disease, and there are several features which are not in favor of Hodgkin’s disease, even not of atypical Hodgkin’s disease. I-Iowever, the contradicting features are likewise not in favor of another systemic disease of the lymphatic apparatus, certainly they are not in fa,vor of an aleucemic leucemia. Thus, there are two possible conclusions: Either the case presents a separate morbid entity or the patient has suffered, despite all contradicting symptoms, of a type of Hodgkin’s disease which, up to the present, rarely, perhaps never, has been reported. One should expect that the macroscopic and microscopic examinations of the tumors would offer an answer to these questions inasmuch as the microscopic examination of the tumors is supposed to be the most decisive finding to establish the diagnosis of IIodgkin’s disease. Unfortunately, in the presented case even this finding allows to make the tentative but not the definite diagnosis of Hodgkin’s disease. The tissue of typical Hodgkin’s tumors shows the following characteristic features : small and large lymphocytes, histiocytes, eosinophiles, Sternberg’s giant cells, necrotic spots, tendency to be replaced by connective tissue scars. The tumors of the presented case show the following features : a. They are located particularly on the right side of the mouth and pharynx. It is not possible to discover a cause for this distribution, but it is known that in the initial stage of Hodgkin’s disease there is not infrequent,ly a unilateral involvement of the lymph nodes. b. They develop in the submucosa. The mucous membrane covering the tumors is not adherent to the tumors; it is occasionally slightly reddened but there are no ulcerations. There were some enlarged veins of the mucosa in the area of the tumor of the right cheek. c. The tumors have distinct margins; they do not invade the underlying tissue. d. The tumors can be easily removed by surgery. There is no conspicuous hemorrhage as in the tumors caused by leucemia. e. There are no recurrences of the tumors locally. If a tumor is removed there is no recurrence in the scar but new tumors grow up in other parts of the mucous membrane. f. Microscopic examination : There are two types of tumors ; the first type consists simply of hyperplastic lymphatic tissue which contains a great There are follicles, germinal centers, and a wellamount of eosinophiles. developed reticulum in the interfollicular tissue. In other words, there is no change of the gross structure. The tumors of the epipharynx and of the lymph nodes belong to this group. The other tumors, however, do show a change of gross structure which is more or less marked. The slightest degree of change
EOSINOPHII,IC
GRANUL0M.k
OF MOUTH,
PHARYNX,
.tXD
NASAL
PASSAGES
637
is apparently presented by the tumor of the soft palate (Fig. 4). Here the difference between the follicles and the interfoIIic*ular becomes indistinct since the marked basoghilia of the folliclrs is tlimillishetl. If the changes advance there is tissue whi(Ah can bc recognized in low I)ower l~canse it stains more with rosin than with hematoxylin (E’igs. 1 ant1 8). This tissue is cellular but the cells are not as packed as in t.ypical lymphatic tissue; it contains besides lymphocytrs ad ~~lasum ~11~ ;I great ;I~IMJLHJ~ of ~J~u~~~mu~lea~ and polynuclear eosinoyhiles and histiocytes. the ll~l~*lelis c~f which (*ontaills a small There is 110 network of reticulum fibers as in typical amount, of chromatill. lymphatic tissue ; there are rather renlnants of the &icnlum. indicating that the network has been torn 1~s the proliferating cellular tissue (li’ig. 2). There are no collagenous fibers ;111dthe arterioles have thi~krnetl walls. In the tonsil there are necrotic spots and an ;tcc.unrulRtion of eosinophilcx in the necrotic a few J~~LWOL~ glands arc embedded in areas (Fig. 1). In some of the ~L~XZ the tissue (Fig. 4). The glands are either active or they ar’e inactive and atrophic. There are no giant cells. The abnormal tissue grows apparently by expansion and replaces more or less the lymphatic tissue. This results in a mottled appearance of the specimen (Figs. 1 and 8) because the abnormal tissue has a pinkish color while the lymphatic tissue stains deeply with hematoxylin. In some sections there is no lymphatic tissue at all. However, the abnormal tissue does not break, neither through the superficial epithelium nor through the connective tissue capsule. In the tumor of the cheek a considerable amount of collagenous tissue is noticed wit,hin the abnormal tissue (Figs. 6 and 7,l. In the same proportion as the connective tissue increases the amount of cells tl~t*cases without change of the type of cells. Roth the connective tisslie al1(1 the \valIs of the arteries may undergo a hyaline degeneration. .Evidently there are several microscoI)ic frilt Ill’es \vhicIr ill’c’ significant of Hodgkin ‘8 disease. The contradicting findings art’: ia) the n.bsencr of a widespread formation of connective tissue although there was some connective tissue in the turrlor of the cheek: (I~) the ~rbsence of Sternberg cells. So far as thcl scar formation is concerned it must IN realized that the tumors It is likely that scars n~ay h.avr Forlued if the were removed ~JF Surgery. tumors woultl ha1.c been left in place for ;I Iongc~ pcrjwl of tinle. In farctl- of t,his Tiew is the filet that ilk SCY(‘I‘aI of 1h(s t LlJticlL’S thVl’c \v:ts 211i ::ccu!u~Iati:)li of t:istiocytes CE’igs. 9 2nd 10) \<.hich fnizish thra !iiaterial for scar -r’orn!atior! ;lnd that in tht> tuu~c)r cbf thta c*lrrrk wfiicdh !\;I(( IWP~ :II~I,wP(~ 10 CWIW for. ;I (*OJHparatively long prriotl of titer. there was for7ri;ttioll of c+oittlrctivtj tissnc.. s;o far iis the abscn~~ of Strl*nl)crg C‘CIIS is (‘Oll(‘P~‘II~d :I (‘ilSf’ Of I)OIJtlS ;111ti JYeidman” may assist in cvalunting Ihis findilig. In this case there was a typical Hodgkin ‘S cIisr;tstl of the ly~jrplj j10t1e~ associatetl with an extreme eosinophilia of both l~lood and t,issues. \vhich rrac~hrd 84 per cent in the blood. In addition, there \vas TTotlgkit~‘s tliwnsr 01’ the skin whic*h mic*roscopicalIp showed, in contrast to the typical findings in the nodes, several ;ltypicnl
638
HANS
BRUNNER
features: (1) an extraordinary tissue eosinophilia so that t,he skin finding resembled an eosinophilic granuloma of the skin. The cast presented in this paper had likewise an eosinophilia of the blood and the microscopic finding of the skin, obtained by the dermat,opathologist., bore some resemblance to eosinophilie granuloma of skin. (2) A great number of neutrophilic polynuclear cells. These cells were absent in the case presented in this paper. (3) The final fibrosis which was absent in the case of Dobes and Weidman and which was present, although not to a considerable degree, in the case pre(4) Sternberg cells which were infrequently noticed in the case of sented. Dobes and Weidman and were absent in the case presented in this paper. Considering the fact that Hodgkin’s disease is tardy in affecting the skin, if it does so at all, in other words that the skin is a tissue which is usually spared by Hodgkin’s disease, as is the lymphatic tissue of the nose and the mouth, it is not a far-fetched conclusion that the atypical microscopic findings in both cases are in relationship with the atypical localization of the disease. The last finding to be ment,ioned is that of the tumors which consist simply of hyperplastic lymphatic tissue. This is likewise a finding which is not common in Hodgkin’s disease which, however, does occur, even in typical instances. JaffP quoted Longcope, Symmrrs, Eenda, and During who stated that the specific granulomatous changes in Hodgkin’s disease are preceded by a noncharacteristic lymphatic hyperplasia, an observation not confirmed by other investigators. Fowler’ shared the view of Longcope and others. JafE himself believed that “this nonspecific initial hyperplasia of the lymph cells is the result of a stimulation to compensatory growth and is found especially in lymph nodes belonging to a group of nodes, most of which have been He further quoted cases of Hodgdestroyed by the granulomatous process.” kin’s disease in which the lymphatic hyperplasia was a striking feature and remained so during the entire course of the disease. ((These cases take a rapid course and have sometimes been explained as transformation of Hodgkin’s disease into aleucemic lymphadenosis or lymphosareoma.” The presented case seems to confirm the view as expressed by Longcope and others. However, it does not confirm the view of Jaffe because the disease ran an extremely chronic course and because there was no compensatory hyperplasia of lymphatic tissue on the left side. The analysis of the microscopic findings arrives at the same conclusion as did the analysis of the clinical findings, viz., the disease is very close to Hodgkin’s disease to say the least. The only finding contradict,ing this diagnosis is the absence of Sternberg’s giant cells.
Conclusion In this paper the history of a patient is presented who suffered from a The tentative diagnosis is: systemic disease of the lymphatic apparatus. findings are in favor of atypical form of Hodgkin’s disease. The following this diagnosis : a. Noncharacteristic h
skin affection
Tnvntavnta ~~ ._- . . . . tnhnrnnlnc;a __. _ . .._
.., nf /._ lnnrrn --*‘.P”.
at the onset of the disease.
EOSINOPHILIC
GRANULOMA
OF MOUTH,
PHARYNX,
AND
KASAI,
PASSAGES
639
C. Irregular, cryptogenous fever. d. Infiltration of upper layer of tutis with cosinophiles resembling eosinophilic granuloma of skin. e. Eosinophilia which was caused by the specific eosinophile stimulating effect of the assumed Hodgkin’s disease itself, by the finding of oxyuriasis in one examination, and the personal allergic background.
The following
findings
are not in favor of IIodgkin’s
disease :
a. Duration of the disease which extended over a period of approximately twelve years without causing cachexia or symptoms of pressure upon nerves. b. Formation of 11 tumors in a period of three and one-half years in areas which are supposed to be sparccl by Hodgkin’s disease, viz., in the mouth, pharynx, and nasal passages. c. Absence of gross lymphomas in neck, mediastinum, and abdomen. d. Absence of changes of bone marrow due to Hodgkin’s disease. So far as the tumors tained :
are concerned
the following
findings
have been ob-
1. The tumors are located particularly on the right side of the mouth and the pharynx. 2. They develop in the submucosa and do not exhibit ulcerations. 3. They do not invade the underlying tissue. 4. They are easily removable by surgery. 5. There are no local recurrences. 6. They consist either of a hypcrplastic lymphatic tissue or of a specific tissue which proliferates with considerable sl~c(l and is in sttarlcture similar to the granulomatous tissue of Ilodgkin’s disease except that Sternberg’s of large scars. giant cells are absent and that there is no tt~1ldency to fOl'llli~ti0~~ The treat,ment consists of surgical rtlmoval of the tumors. In the I,resented case ‘i tumors were reurored front the 111o11th,pharyns, and llasal passages.
Addendum
640
HANS
BRUNNER
this intestinal eosinophilic granuloma and that of bone marrow. The lesion appeared to The authors stated t,hat this type of granuloma of the intestinal tract has be benign. The relationship between the case described by the authors never before been described. and that presented in this paper is evident.
References 1. Brunner, H., and Schnierer, J.: Die zytologische Untersuchung der Gaumentonsillen und ihre klinische Bedeutung bei Leukamie, Wien. klin. Wehnschr. 50: 17T2, 1937. der Gaumentonsillen bei Leukamien, 2. Brunner, H., and Fischer, J.: Die Verlnderungen Monatschr. f. Ohren. 72: 137, 1938. 3. Symmers, P.: The Clinical Significance of the Pathological Changes in Hodgkin’s Disease, Am. J. M. SC. 167: 313, 1924. granulomatosa. Hdb. d. spez. pathol. Anat. u. Histol., 4. Fraenkel, E.: Lymphomato’sis vol. 1, p. 347, 1926. 5. Dobes, W. L., and Weidman, F. D.: Granulomatous Hodgkin’s Disease of the Skin With Extreme Eosinophilia (Eosinophilic Granuloma of the Skin?), Arch. Dermat. & Syph. 55: 212, 1947. System, Handbook of Hematology, vol. 2, p. 977, 6. Jaffe, R. H. : The Reticula-endothelial 1938. 7. Fowler, W. M.: Hematology,. New York, 1940, Paul B. Hoeber, Inc. 8. Stewart, S. G.: Eosinophrbe Hyperleueocytosis in Hodgkin’s Disease With Familial Eosinophilic Diathesis, Arch. Int. Med. 44: 772, 1929. 417 MT. PROSPECT AVE.