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THEE HI)TOLOGICAL LESION IN LYMPH NODES ININFECTIOUS MONONUCLEOSIS *

EDwARD A. GALL, MD., AND HUGH A. STOUT, MD.(From the Laboratory of Pathology axd Bacteriology, Massachusetts General

Hospital, Boston, Mass.)

Since infectious mononucleosis is a self-limited non-fatal dis-ease, the diagnosis of which is readily accomplished by hemato-logical and serological means, there has been little recourse todiagnostic biopsy. As a result, comparatively few studies havebeen made of lymph nodes removed during the active stages of thedisease and from these no constant specific changes have beenrecorded.The importance of determining the characteristic anatomical

features of this lesion may be appreciated by referring to thecomments of various competent observers who have noted thesimilarity of the structure of lymph nodes in glandular fever tocertain malignant diseases of lymphoid tissue. It is worthy of notethat since these observations were made almost two decades haveelapsed, and it is probable that opinions would be less equivocalat this time. Sprunt and Evans in 1920 1 reported the histologicalstudies of nodes from 3 cases of glandular fever. One node wasexamined by Welch and Whipple who believed that no definitediagnosis could be made but stated that lymphatic leukemia couldnot be ruled out. A node from the 2nd case, examined by Martzloff,was said to show lymphadenitis, although Bloodgood suggestedthat it might be "the earliest case of Hodgkin's disease everstudied." A node from the 3rd case was described by MacCallum,who stated that it represented a picture consistent with lymphaticleukemia, and if it were that, it was either in a very early stage orin a period of recovery. Bloodgood, who reviewed the samesection, said that no definite diagnosis could be made but thatlymphosarcoma could not be excluded. Longcope2 (1922) de-scribed the nodes from 2 cases and said that both resembledHodgkin's disease but that neither was sufficiently characteristicto permit that diagnosis. Nelken3 (i case) in 1926 observed that

* Received for publication December i9, 1939.433

GALL AND STOUJT

the entire picture was that of diffuse hyperplasia suggesting earlylymphatic leukemia. Although more recent authors have notstressed the question of similarity to malignant disease, it is obvi-ous that these earlier observations lend a degree of importance toa more definitive analysis of the lymph node lesions occurring inthis disease. Occasionally, even with current refined diagnosticmethods, a clinical diagnosis of infectious mononucleosis is missedeither through oversight or because the disease has run an un-familiar course. Under such circumstances a diagnostic biopsymay, and probably has, reached the pathologist. The need forthe appreciation of the specific lesion underlying the disease there-fore becomes evident.

REVIEW OF THE LITERATURE

Before proceeding to an analysis of our series it is consideredof significant interest to summarize the observations of otherauthors, many of which have served to corroborate and facilitateinterpretations of our own. We have arranged this summary ac-cording to the general characteristics and the appearance of thevarious anatomical constituents of the lymph node (i.e., sinuses,follicles, lymph cords and component cells) in order to separatethe general problem into its structural subdivisions.

General Features: Downey and Stasney,4 whose review of thissubject and detailed study of six lymph nodes is unusually com-prehensive, noted that nodal architecture was irregularly pre-served and one part of a node was found to be normal while otherparts were hyperplastic and the normal structure obliterated.Hyperplastic phenomena were not limited to the lymphoid ele-ments but involved as well the sinus endothelium and reticulumcells. Inconstant hyperplasia was also observed by Sprunt andEvans (3 cases). Glanzmann 5 (number of cases not recorded)stated that the picture was non-specific, and that of a hyperplasticlymphadenitis. Hartwich 6 (i case) remarked that the node wasrichly cellular and that the follicles blended indistinguishablywith the pulp. Baldridge, Rohner and Hansmann7 (6 cases)described marked hyperplasia with expansion of the capsule.Nelken (i case) noted a "washed out" structure followed laterby a return to normal architecture. Pratt8 ( i case) found active

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LYMPH NODES IN INFECTIOUS MONONUCLEOSIS

hyperemia, a serous exudate, and early degenerative changes inblood vessel walls. Fox9 (2 cases; i lymph node and i tonsil)and Chevalier '0 (number of cases not stated) recorded bothlymphoid and reticulum hyperplasia.

Sinuses: The sinuses were obliterated in some of the cases de-scribed by Downey and Stasney but were present in other in-stances and showed hypertrophic reticulum cells. Advanced casesshowed sinuses filled with reticulum cells, an observation con-curred in by Nelken, Hartwich, Longcope, and Sprunt and Evans.Glanzmann found marked proliferation of sinus endothelium, acondition termed by him "sinus catarrh." Baldridge, Rohner andHansmann observed the sinuses to be compressed. They foundmitoses in the wall of the sinuses and lymphoid cells free in thelumens. Marchal, Bargeton and Mahoudeau 1 (i case) recordedthe presence of a dilated marginal sinus with endothelial hyper-plasia. A preponderance of small lymphocytes and a moderatenumber of phagocytes were seen in the sinuses by Fox. Chevallierfound large macrophages resembling giant cells with one or morenuclei and also swollen endothelial cells. Sprunt and Evans in oneinstance observed the peripheral sinuses to be plainly visible butthose in the central portion of the node were obliterated.

FoUicles: No follicles were seen in i of the cases of Downeyand Stasney but they were absent only in the hyperplastic areasof another. In a 3rd, follicles could be recognized but there wereno germinal centers. In advanced cases no follicle or germinalcenter tissue was seen at all. Failure of consistent follicular ar-rangement was also noted by Sprunt and Evans and by Fox.Glanzmann ' and Vogl 12 (i case) found that follicular cellularitywas diminished, but on the contrary Baldridge, Rohner and Hans-mann, Hartwich, and Longcope described germinal center hyper-plasia associated with many mitotic figures. Marchal, Bargetonand Mahoudeau described follicular hyperplasia with increasedgerminal center elements. There was also hyperplasia of reticulumcells at the borders of the follicles. Nelken found that follicleswere not prominent early in the disease but later in its course theywere, and there was hyperactivity of germinal centers. Wiseman 13(2 cases) found germinal center tissue infiltrating the entire lymphnode early in the disease but this became less obvious later, withuniform admixture of cells.

435

GALL AND STOUT

Lymphoid Cords: Nodes studied by Downey and Stasneyshowed crowding of small lymphocytes in the cords and amongthese cells there were larger, more loosely arranged lymphocytes.In addition, there were scattered nodular clusters of swollenrounded reticulum cells producing a characteristic "spotty appear-ance." After the peak of the disease all of the nodes showed nodu-lar reticulum cell hyperplasia in all areas except the region of thefollicles. Similar multiple nodular areas have been noted by Prattand by Marchal, Bargeton and Mahoudeau. Pratt observed cen-tral necrosis in some of these nodules and a node removed a yearlater showed nodular fibrosis. Wiseman found germinal centertissue consisting for the most part of "prelymphoblastic" elementsinfiltrating the lymphoid pulp early in the disease. Longcope notedthat a few of the large cells found in the sinuses infiltrated amongthe lymphocytic elements of the cords.

Celular Characteristics: Downey and Stasney stated that thegreat majority of the cells in the nodes were small lymphocytes,normal in appearance except for a densely basophilic cytoplasmand an unusually coarse chromatin. There were gradations be-tween these cells and large lymphocytes with mature nuclei butdeeply basophilic cytoplasm. Some of these exhibited transitionalstages leading to the formation of plasma cells and there were alsostill larger elements with indented or even lobulated nuclei. Trans-formation of reticulum cells to lymphocytes was also described.The cells in Baldridge, Rohner and Hansmann's cases variedmarkedly in size and showed irregularly lobulated nuclei. Dwarfand pathological lymphocytes with polymorphic nuclei, atypicalplasma cells, lymphoblasts, and peculiar monocyte-like elementswere described by Nelken. Marchal, Bargeton and Mahoudeaustated that lymphocytes predominated but there were many mono-cytes in the loose reticulum meshwork and masses of "tumefied"elongated histiocytes were seen which occasionally simulated newblood vessel formation. Fox, who stated that 95 per cent of thecells were lymphocytes, also observed large plasma cells and largeelements with eosinophilic cytoplasm and irregularly shaped, wellstained nuclei containing one or two clear nucleoli. Similar cellsin the sinusoids had neutrophilic cytoplasm and exhibited phago-cytosis of erythrocytes. In one node Sprunt and Evans describedmany lymphoid and endothellal cells, and in another many large

436


cells with pale staining, round or oval nudei, many neutrophilsand monocytes.

Although most of the aforementioned authors have made dear-cut analyses of their own material, a combined analysis of all thevarious observations published produces a considerable degree ofconfusion. This is to a great extent the result of the perniciousvariation in terminology which has dogged the study of hematologysince its inception. Of equal significance is the fact that an insuf-ficient number of biopsies have been available for study by indi-vidual observers. As a result changes which have represented asingle phase of the disease have been taken by some to representthe fundamental lesion. It is our belief that this situation will beclarified by the study of the cases in our series in which biopsieswere made at various stages of the disease.

MATERIAL AND TECHNIC

Specimens adequate for histological study have been obtainedby biopsy of enlarged lymph nodes from io cases during the activephases of infectious mononucleosis. The nodes were sectionedimmediately and almost all were fixed in Zenker's fluid plus aceticacid. The tissue was embedded in paraffin, sectioned, and stainedwith phloxine-methylene blue. On occasion, portions of the mate-rial were used for imprint preparations, which were subsequentlystained with Wright and Giemsa stains, and several times smallamounts were aspirated from the freshly cut node and utilized forsupravital studies after staining with neutral red and Janus green.Some of the material was fixed in formalin and utilized for specialreticulum stains. On the Zenker-fixed specimens additionalstudies were made by means of the Mallory aniline blue andphosphotungstic acid hematoxylin stains.

Table I summarizes the sex, age and occupational status of eachpatient from whom biopsy material was obtained. There is furthertabulated the day of the disease on which the biopsy was made,the character of the heterophile antibody reaction, the height ofthe red and white blood cell counts, and the percentage of mono-nuclear cells in the peripheral blood at the time the biopsy wasdone. All mononuclear cells are grouped together in this instancebecause of the varied and inconclusive terminology (mononuclearcell, monocyte, lymphocyte, large mononuclear) used by the dif-

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ferent exminers. The determination of the heterophile agglutititer was not done in Case 2 and was only weakly positive inCase 9. The determination in this case was done early in thedisease and was not repeated at a later date. It is altogether pos-sible that it may have become more strongly positive later, sinceall of the other features of the syndrome developed in a charac-teristic fashion.

It is apparent that all cases were biopsied during the activestages of their illnesses, as evidenced by the blood pictures re-corded. It is further obvious that an excellent opportunity isafforded for tracing the pathogenesis of the lesion since the nodeswere removed at varying intervals from 4 to 28 days after theonset of symptoms.

DEFINTON OF TERMSIn order to avoid further conffict in nomenclature with that

which already exists, it is deemed advisable to define the histo-logical phraseology which we have adopted before proceedingwith the analysis of our cases. Our conception of the anatomy ofthe normal lymph node is in keeping with that expressed in com-monly used textbooks of histology."4 15 Certain terms, however,require more definitive description.

Reticulum: Emerging from the capsulotrabecular system, op-timally visible with special stains only, is a delicate fibrillar net-work of argentophilic material which is termed reticulum. Themeshwork is particularly loose immediately adjacent to the cap-sule and trabeculae, in which regions may be found the marginaland radial sinuses respectively. These sinuses are traversed byreticulum fibrils which become condensed to form the sinus wallsand proceed therefrom internally to form a netlike framework forthe remainder of the node.

Germinal Centers: In the center of the follicles, cells are looselyaggregated and consist of various types. In the minimally activefollicle there are small lymphocytes and a few less mature, some-what larger elements termed lymphoblasts. In the hyperactive orhyperplastic follicles less mature cells predominate and there arelarge numbers of lymphoblasts and masses of cells with largevesicular nuclei containing scanty chromatin and prominent nucle-oli. These elements possess abundant basophilic or amphophilic

439

GALL AND STOUT

cytoplasm which is poorly delimited and fused with that of ad-jacent cells. These have been termed reticulum cells by some,but since it is our belief that they are undifferentiated hem-atopoietic precursors and have little to do with the produc-tion of reticulum, we have preferred the name "stem cells"(Fig. 5).

Sinus Cels: Wit the lumens of the sinuses, either attachedto the mural or intrasinus reticulum, or lying free in the interstices,are cells measuring 15 to 20

jin diameter which show relatively

large, somewhat lobulated or horseshoe shaped nuclei with abun-dant eosinophilic, phagocytic cytoplasm. These have also beencalled reticulum cells by some and by others reticuloendothelial,endothelial, or even resting wandering cells (Fig. 5). Since theyhave nothing to do with the formation of reticulum and are mor-phologically indistinguishable from cells which are known ashistiocytes or clasmatocytes when encountered elsewhere in thebody, we have adopted the latter name for them.

OBSERVATIONS

The basic lesion of infectious mononucleosis is apparently theresult of the varied responses of several different elements com-posing the lymph node to a single, presumably irintative stimulus.The structures manifesting this reaction may be enumerated asfollows: (a) lymphoid follicles; (b) lymphoid cords; (c) lymphsinuses; (d) sustentative elements and blood vessels.The reactions of many of these are essentially banal and of no

specific diagnostic value individually. In combination with eachother, however, a histological picture is produced which is char-acteristic and fundamentally unlike any described for those con-ditions which may clinically mimic the disease (i.e., malignantlymphoma, lymphatic leukemia, systemic glandular tuberculosis,and so on).The important crude diagnostic feature which serves in the

differentiation from primary neoplastic disease of the lymph nodeIs the retention of gross architectural relationships. This is par-ticularly the case with reference to the persistence of subcapsularand radial sinuses. In this connection, therefore, it is importantthat a word of caution be appended regarding the fixative to beutilized in the preparation of biopsied lymph nodes. In nodes

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prepared in part by fixation in formalin or Bouin's solution and inpart by fixation in Zenker's fluid with acetic acid, subsequent em-bedding in paraffin and sectioning has revealed a rather strikingvariation in appearance. The shrinkage of the formalin or Bouin-fixed paraffin sections has been sufficiently great so that in com-bination with the distortion already produced as the result of thedisease process itself, the appearance of total architectural ob-literation is simulated. This confusing feature is readily avoidedby the less apparent shrinkage in the Zenker-fixed tissue. Further-more, in view of the relatively specific staining qualities impartedby phloxine-methylene blue to the so-called infectious mono-nucleosis cell, it is recommended that biopsied lymph nodes incases of suspected infectious mononucleosis always be fixed inZenker's fluid and stained with these dyes. The descriptionsherein recorded are based almost wholly upon lesions studied innodes treated in this fashion.

Since the disease may exist for a variable period before clinicalmanifestations appear, it is not possible to establish accurate timerelationships with any degree of assurance. Any attempt to do somust be considered pure conjecture.The basic process underlying the lymph node lesion in this

disease is essentially the result of proliferative stimulation of thecomponents of the node. It is probable that sustentative andvascular elements are only secondarily affected but since all tis-sues respond almost simultaneously, it is not valid to make this anunequivocal premise.

In what appears to be the early stages of the lesion the germinalcenters of the lymph follicles become hyperplastic and show largesecondary nodules (Fig. 4). These consist of masses of appar-ently fused cells with abundant, poorly defined, basophilic cyto-plasm and large vesicular nuclei (stem cells), and also of variednumbers of mononuclear elements with more sharply defined anddemarcated eosinophilic cytoplasm and eccentrically placed lobu-lated or reniform nuclei (probably clasmatocytes). Mitotic figuresare numerous and there is evidence of phagocytic propensityamong many of the clasmatocytes.At the same time there are increased numbers of mitotic figures

in the larger cells of the extrafollicular lymphoid substance inboth cortical and medullary regions. Whereas the follicular

441

GALL AND STOUT

changes noted above are entirely non-specific, significant numbersof mitotic figures in the pulp are distinctly unusual in the ordinarytype of hyperplasia. The majority of the cells in these regionsare small and normal appearing lymphocytes with collar-likepacking at the periphery of the follicles. An interadmixture withincreasing numbers of larger cells becomes rapidly apparent.These are approximately two to three times the size of the smalllymphocytes and possess abundant basophilic, either granular orrelatively coarsely vacuolated, sharply delimited cytoplasm (Fig.5). Phloxine and methylene blue impart a filmy blue quality tothe cytoplasm which simulates the appearance of mucin. Thisstaining characteristic is in distinct contrast to the blue and darkpurple cytoplasm noted in the lymphocytes and stem cells re-spectively. We have never noted such cells as these in significantnumbers in lymph nodes in other clinical conditions. Nuclei arevesicular, round or slightly indented, and eccentric in position.Imprint preparations from the fresh lymph node stained withWright and Giemsa stains demonstrated these specific cells to beidentical with the large mononuclear elements in the blood streambelieved to be peculiar to infectious mononucleosis. Although thesehave been mistakenly descnbed as monocytes, supravital studies-have shown them to be unquestionably large atypical lympho-cytes." For purposes of simplicity these will be termed infec-tious mononucleosis or I.M. cells throughout the remainder ofthis presentation. Mitotic figures are particularly numerousamong these elements in the cords although several of the cellsexhibit evidence of amitotic division. In addition to I.M. cellsand small lymphocytes there are also increased numbers of stemcells and lymphoblasts scattered throughout the pulp.

Associated with the proliferation of the pulp cells there is anapparent increase in the amount of fibrillar supportive reticulumper unit area. This may, however, be more apparent than realand simply be the result of peripheral compaction of reticulumby the pronounced expansion of hyperplastic follicles. This isperhaps the case also in the seeming increase in the number ofstromal blood vessels. In these, however, there is definite evi-dence of intrinsic proliferation exemplified by increased numbersof endothelial lining cells, some of which exhibit mitotic figures.The endothelial elements become swollen and assume an epithelial-

442


like appearance and as a result occasional vascular channelssimulate the appearance of glandular acini.With continued cellular proliferation the subcapsular and

radial sinuses show progressive compression and distortion. They-are not, however, ever completely obliterated, a feature whichshould be determined on the basis of Zenker-fixed tissue for thereasons given above. Lining elements of the lymphoid sinusesalso show evidence of proliferative stimulation (Fig. 3). Thesephagocytic cells or clasmatocytes become swollen, their nucleivesicular, but the cytoplasm retains its eosinophilic hue. As theresult of fairly rapid division they tend to form small masses orislets at the edge of the sinuses. The sessile islets project into thesinus lumens and peripheral cells are freed and lie in fairly sig-nificant numbers as discrete elements. Phagocytic activity isdemonstrated by cytoplasmic vacuolization and engulfment ofcellular substance and detritus. The staining qualities of the cellsin fresh imprint preparations and supravital spreads are those ofmonocytes and related elements.

Sinuses having been markedly obtruded upon by the pronouncedincrease of parenchymatous substance are narrow and irregularbut definitely retain their identity. In addition to the phagocyticcells described above there are also varying numbers of lympho-cytes and I.M. cells lying within the sinuses (Fig. 2). The latternamed cells appear as large (15 to 25 9) mononuclears withabundant basophilic and fairly granular, frequently mucin-likecytoplasm. Nuclei are eccentric, slightly indented or lobulated,vesicular, and contain a fine reticulated chromatin with nudeolarcondensations. Mitotic figures and even double nuclei are notunusual in these cells. With progression of the lesion the freelying cells increase in number in both peripheral and medullarysinuses and often appear as loosely compacted masses not unlikesimilar masses observed in the early phases of lymphatic leukemia(Fig. i). In addition they are also apparent among the fibrouscomponents of both the nodal capsule and the trabeculae. Thereis never, however, sufficient accumulation or activity in theseregions to simulate neoplastic invasion. Nor do they ever appearin significant bulk in tissues beyond the nodal capsule.The size of the lymphoid follicles is remarkably variable but

they tend to enlarge throughout the course of the process (Figs.

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GALL AND STOUT

4 and 6). Germinal centers, hyperactive throughout, produce inmany gradual narrowing of the surrounding collar of small lym-phocytes. In such instances this layer becomes less compact andshows a scant intermingling with stem and I.M. cells (Fig. 6).During the latter phases of the disease follicular hyperplasia mayprogress to such an extent that spherical configuration is no longerretained. The apparent follicles, now consisting for the most partof hyperplastic germinal centers, are irregular in shape and ex-hibit broad pseudopod-like extensions into the surrounding pulp.There is progressive fusion and commingling of follicular andpulp content (Fig. 7). Ultimately the lymphocytic collars dis-appear entirely and although a shadow-like remnant of concen-trically arranged reticulum may be noted with silver stains, thelymphoid cords become broad heterogeneous masses of syncytialstem cells, mature small and large lymphocytes, and I.M. cells,among which are numerous mitotic figures.The simultaneous proliferation of sinus wall phagocytic ele-

ments at this stage proceeds in a centripetal as well as a centrifugalfashion. As a result small dusters of pink staining mononuclearphagocytes become evident within the lymphoid pulp immediatelyadjacent to the sinus walls (Fig. 3). These rapidly increase insize and contrast with the surrounding basophilic cells so that withthe low power objective the moth-eaten appearance described byDowney and Stasney is evident. Tangential sections frequentlyshow what appear to be isolated islets of these eosinophilic ele-ments apparently separated from their sinus attachment in themidst of the hyperplastic cords (Fig. 8). Indeed, progressiveproliferation permits further extension into the lymphoid pulpand there is admixture of the active macrophages and monocyteswith an already polycellular pulp. Focal aggregations of theseeosinophilic cells suggest but have only a bare resemblance totubercles.

During the florid stage of the disease the appearance of thelymph node is quite unusual and presumably specific. The nodeis enlarged and shows greatly increased cellularity in the medul-lary, cortical and sinus substance. The cords are swollen by arich mixture of small and large lymphocytes, stem cells and lym-phoblasts, I.M. cells, and large eosinophilic phagocytic elements(Fig. 7). Follicles persist in some but in others are apparent only

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as occasional, partially disrupted germinal center fragments, andreticulum stains exhibit a vestige of concentric perifollicular ar-rangement. There is marked sinus compression and distortionalthough identity is preserved. The sinus lumens contain variablenumbers of cells similar to those noted in the pulp. Cells of thistype are also evident in small numbers in both the trabeculae andcapsule of the node. There is an apparent increase in reticulummeshwork fibrils, vascular channels are much more abundant thanusual, and vascular endothelium is hyperplastic.

DIscussIoNThe ten lymph nodes included in this study were collected

gradually over a period of 5 years. Seen individually and at ex-tended intervals their variety was too great to impress upon thevarious observers any characteristic picture. When, however, thegroup was studied as a whole it became evident that there wassufficient underlying similarty to permit their ready distinction,not only from lesions observed in malignant lymphoma, but alsofrom all but four of several hundred hyperplastic nodes whichhave passed through the laboratory in the same period of time.This characteristic picture was not produced by any single pathog-nomonic feature but by the general pattern of changes withinthe node.Of pnme importance in differentiation from malignant lym-

phoma was the maintenance, despite considerable distortion, ofthe nodal architecture. Both peripheral and radial sinuses couldinvariably be distinguished in at least portions of the node, al-though compression on the one hand and packing by proliferatinglymphocytes and other mononuclear elements on the other fre-quently almost obscured them. Germinal centers were likewisegenerally identifiable but were variable in size and appearance.Lessened follicular prominence appeared to arise from a tendency,which became well marked in the nodes removed during laterstages of the disease, for the borders of the greatly enlarged, hyper-active centers to become irregular and vaguely delimited. Thiswas due partly to pseudopod-like projections of the center intosurrounding pulp and partly to the encroachment upon the fol-licular borders of increasing numbers of active immature andatypical cells in the pulp itself.

445

GALL AND STOUT

In contrast to the pictures observed in the ordinary hyperplasias,three features were preeminent. First was the marked proliferativeactivity in the pulp which, as has been noted above, served toobscure the margins of the follicles (Fig. 7). The second was anextensive but distinctly focal proliferative activity of clasmato-cytes, the cytoplasm of which became progressively more abundantand acidophilic until the appearance of "epithelioid cells" wassimulated (Fig. 8). Although clustered to form small nodulesthey never showed a concentric tubercular arrangement andneither necrosis nor giant cells were ever noted.The final and most nearly pathognomonic feature was the ap-

pearance throughout the pulp, on the edges of the germinal cen-ters, and in the sinuses, of large numbers of the specific infectiousmononucleosis (I.M.) cells (Figs. 2 and 5). It would be rash toclaim that the appearance of a cell in fixed tissue sections wasspecific but with Zenker fixation and the phloxine-methylene bluestain these cells with their abundant, slightly foamy, cerulean bluecytoplasm are most conspicuous. Similar cells have not beenobserved in malignant lymphoma and but rarely in hyperplasticnodes. Impression and supravital preparations have shown themto be identical with the cells found in the circulating blood in thisdisease.

It seems worthy of repeated emphasis that this picture whichwas clearly evident in Zenker-fixed nodes stained with phloxine-methylene blue could be distinguished only with dificulty inmaterial fixed in formalin or Bouin's fluid and stained with hema-toxylin and eosin. Not only was it more difficult to recognize thepersistent but distorted architecture in the latter instances, butthe distinctive sky-blue color of the cytoplasm of the specific cellswas not observed.Once recognized, this lesion was so characteristic that inde-

pendently several members of the laboratory staff recollected 3similar cases and a 4th was revealed by a systematic searchthrough the group of nodes catalogued under the heading ofhyperplasia. In none of these 4 cases had infectious mononucleo-sis been diagnosed clinically, no blood smears were available forresurvey, and only i had a recorded differential count which was

suggestive of the disease. In 2 cases 2 and 4 months after thetime of the biopsies blood serum was obtained for heterophile

LYMPH NODES IN INFECTIOUS MONONUCLEOSIS 447

agglutination and both tests proved negative. Three individuals,one of whom had 43 per cent mononuclear cells in a blood smear,ran a benign clinical course, the lymph node swelling and symp-toms disappearing spontaneously within a few weeks. The 4thpatient, known to have had localized Hodgkin's sarcoma of theintestine which had been radically resected a year previously, wasrelieved of symptoms following X-ray therapy. A conclusiveverdict ruling infectious mononucleosis either in or out is impos-sible on the basis of the available evidence. No unequivocaldecision can be reached, therefore, regarding the specificity of thepicture which has been described.

SUMMARY AND CONCLUSIONSA survey of the literature reveals the fact that no consistent

lesion has hitherto been described in the lymph nodes from patientswith infectious mononucleosis. The authors have studied lymphnodes removed from ten such patients at various stages in theillness and have described a characteristic morphological pattern.This appears with such regularity in this disease and so rarely inother conditions that it is believed to have diagnostic importance.

REFERENCES

i. Sprunt, Thomas P., and Evans, Frank A. Mononuclear leucocytosis inreaction to acute infections. ("Infectious mononucleosis.") BuU.Johns Hopkins Hosp., 1920, 31, 410-417.

2. Longcope, Warfield T. Infectious mononucleosis (glandular fever),with a report of ten cases. Am. J. M. Sc., 1922, I64, 781-808.

3. Nelken, Curt. Eine Angina mit lymphatischer Reaktion. Monatsckr. f.Kinderk.7 1926, 3I315I-'56.

4. Downey, Hal, and Stasney, Joseph. The pathology of the lymph nodesin infectious mononudeosis. Folia Hemat., I936, 54, 417-438.

5. Glanmann, E. Das lymphaemoide Drisenfieber. Abkandl. a. d. Kinderk.,1930, 25, 1-235-

6. Hartwich, Adolf. Zur Kenntnis der lymphatischen Reaktion. DeutschesArch. f. klin. Med., I929, 163, 257-28I.

7. Baldridge, C. W., Rohner, F. J., and Hansmann, G. H. Glandular fever(infectious mononucleosis). Arch. Int. Med., I926, 38, 4I3-448.

8. Pratt, C. L. G. The pathology of glandular fever. Lancet, I93I, 2, 794-795.

448 GALL AND STOUT

9. Fox, Herbert. Infectious mononucleosis. II. Histology of a tonsil and alymph node. Am. J. M. Sc., I926, 173, 486-489.

io. Chevallier, Paul. L'adinolymphoidite aigue benigne avec hyperleuco-cytose moderee et forte mononucleose. (Fi'evre glandulaire, reactionlymphatique, mononucleose infectieuse, lymphadenie sublymphemique,lymphadenose aigux, benigne, angine a monocytes, etc.) Sang, I928,2, I66-I75.

ii. Marchal, Georges, Bargeton, et Mahoudeau. Angine a monocytes, avecbiopsie. Sang, 1933, 7, 431-436.

I2. Vogl, Alfredo. Zum n itsbild der "infekti6sen Mononukleose."Wien. kim. Wcknsckr., 1930, 43, 720-723.

13. Wiseman, B. K. Lymphopoiesis, lymphatic hyperplasia, and lymphemia:fundamental observations concerning the pathologic phvsiology andinterrelationships of lymphatic leukemia, leukosarcoma, and lympho-sarcoma. Ann. Int. Med., I936, 9, 1303-I329.

14. Bremer, J. Lewis. A Textbook of Histology Arranged upon an Embryo-logical Basis. P. Blakiston's Son and Company, Philadelphia, 1930,Ed. 4, 222.

I5. Maximow, Alexander A., and Bloom, William. A Textbook of Histology.W. B. Saunders Company, Philadelphia, I934, Ed. 2, 273.

I6. Gall, E. A. The diagnostic value of supravital staining in infectiousmononudeosis. Am. J. M. Sc., I937, 194, 546-554.

DESCRIPTION OF PLATES

PLATE 89

FIG. i. A sinus distended by large numbers of lymphoid elements, a picturefrequently seen in lymphatic leukemia. In infectious mononucleosis,however, there is a wide variety of cells evident (lymphocytes, clasmato-cytes, I. M. cells, and so on). X 400.

FIG. 2. A higher power view of the cells shown filling the sinus in Figure i.There is a wide morphological variation. Most of the large elementspresent are infectious mononucleosis cells, one of which may be seen inmitosis. X Iooo.

FIG. 3. A lymphoid sinus containing large numbers of clasmatocytes evi-dently arising from sinus wail cells. Extension of these elements fromthe sinus into the pulp is also apparent. X 400.

AMERICA JONAL OF PATHOLOGY. VOL. XIPA

Lymph Nodes in Infectious Mononucleosis

PLATE 89

Gall and Stout

PLATE 90

FIG. 4. A low power view of a ly-mph node exhibiting marked enlargement offollicles with prominent germinal centers. There is considerable variationin size and configuration. This phase is usually quite transient. X 50.

FIG. 5. A camera lucida drawing representing the four types of cells observedin the lymph nodes in infectious mononucleosis.I = A stem cell with abundant but vaguely outlined cytoplasm contain-

ing a large vesicular nucleus with prominent nucleoli but scantyreticular chromatin.

2 = -Normal small lymphocytes.3 = An infectious mononucleosis cell. the cytoplasm of which is coarsely

granular in this instance. The nucleus is well chromatinized andeccentric in position. When stained with phloxine-methylene bluethe cytoplasm has a mucin-like basophilic quality. X IOOO.

4 = A clasmatocyte with abundant. finely granular cytoplasm and a reni-form eccentric nucleus. In the stained preparation the cytoplasm iseosinophilic.

FIG. 6. An enormous germinal center is shown. composed mainly of in-fectious mononucleosis cells. There is marked thinning and irregularityof the lymphocytic collar as the result of encroachment by both germinalcenter and pulp elements. The border of the secondary nodule is nowill defined. X 400.

AMERICAN JOURNAL OF PATHOLOGY. XOL. XVI

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Gall and Stout

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FIG. 7. Lymph node pulp in the florid phase of the lesion demonstrating themarked interadmixture of lymphocytes, infectious mononucleosis cells,stem cells and clasmatocytes. Follicular arrangement can no longer beidentified. X 400.

FIG. 8. An area in the vicinity of the periphery of a lymph node demon-strating marked infiltration of the pulp by clasmatocytes, many of whichhave assumed the appearance of ' epithelioid cells." X 400.

AMERCAN JouRNAL OF PATHOLOGY. VOL. XVA


PLATE 91I

Gall and Stout

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