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401

THE PATHOLOGY OF LYMPH NODEENLARGEMENT

By L. WOODHOUSE PRICE, M.A., M.D.(Cantab.)Director of the Pathological Department, The Royal Cancer Hospital, London

Many different aetiological factors con-tribute to the enlargement of lymnph nodes;in some cases the cause is obvious, in othersobscure. The enlargement may be focal,regional or generalized, or the first two typesmay progress to the third. The enlargementmay be the only clinical manifestation ofdisease or it may be accompanied by varioussigns and symptoms, such as pain, pyrexia,exanthemata, changes in the blood picture orpressure effects on viscera.The histological differential diagnosis of

lymph node enlargement depends upon aproper appreciation of the normal structure ofa lymph node and of the various changes whichare common to several or peculiar to certainspecific types of pathological processes. Insome cases a consideration'of the clinical con-dition alone is sufficient to establish a correctdiagnosis. This applies especially to lymphnode enlargement associated with inflam-matory lesions, acute specific fevers andchronic infective granulomata. In other casesthe. aid of histology and haematology isessential. The latter group comprises theprimary lymphadenopathies and metastatictumour deposits.An investigation as to the cause of lymph'

node enlargement demands an account of theclinical appearance of the patient, the deter-mination of the size, consistency and distribu-tion of the enlarged nodes and a detailed re-port on the histology of a node excised forbiopsy purposes, to which it is often advisableto add the macroscopic appearance of thehemisected node.' In certain diseases theconcomitant pathological changes in otherorgans and tissues have to be considered also.

Histology of the Normal Lymph Node. Themicroscopic appearance is by no meansuniform but a generalized or fundamentallycharacteristic histological picture can be de-duced from a study of a large number of lymphnodes excised for 'biopsy purposes and pre-served in various fixative solutions from whichparaffin sections are prepared and stained byseveral different technical methods.

It so happens that certain component partsof a lymph node are accentuated under theinfluence 'of certain morbid processes, par-ticularly inflammatory conditions and thereticuloses. Hence, paradoxically, the normalstructure is more clearly appreciated from aconsideration of the histological appearances*of lymph nodes which are slightly abnormal.

The lymph node is a spheroidal, ovoid orreniform body surrounded by a delicate fibrouscapsule and composed of certain characteristiccomponents which are clearly recognizable andwhich can be resolved into three essentialconstituents, namely,' the lymphadenoid par-enchyma, the lymphadenoid follicles and thelymphatic sinusoids. The majority of lymphnodes are supported by a surrounding matrixof adipose tissue, but certain homologouslymphoid structures are distributed in the sub-epithelial region of the buccal, nasal andpharyngeal mucosae and the submucous tissuesof the alimentary canal.

The Capsule. Fully developed lymph nodesare completely surrounded by a delicatefibrous capsule which is perforated by afferentand efferent blood vessels and by afferent andefferent lymphatic channels. In nodes whichare only partially developed the capsule isincomplete. Such nodes on hemisection in the

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longitudinal axis present a C-shaped or horse-shoe outline, the convexity being covered by acapsule while the concavity is filled withadipose tissue into which lymphocytes appearto be diffusely permeating. This peculiarstructure has an important bearing on thespread of metastatic tumours.

The Lymphadenoid Parenchyma. This con-sists essentially of a matrix of lymphocytes andlymphoblasts. Under conditions of reticuloendothelial hyperplasia isolated elements orsmall groups of reticulo endothelial cells arefound lying free in the matrix. This com-ponent of the fundamental c6mposition of thenormal lymph node becomes encroached uponby reticuloses of either the follicles or thesinusoids. It is particularly affected in certainlipodystrophies and shares in the general dis-organization of normal lymphadenoid architec-ture in Hodgkin's disease. On the other hand,the lymphadenoid parenchyma predominatesover both follicles and sinusoids in lymphaticleukaemia and in the lymphosarcomata.

The Lymphadenoid Follicles. Around theperiphery of the node there are circumscribedspheroidal or ovoid bodies known as thelymphadenoid follicles, the lymph follicles orthe germ centres of Flemming. These con-sist of a core of reticulo endothelial cellssurrounded by several concentrically laminatedlayers of lymphocytes. Normally, the centralzone of reticulo endothelial cells is incon-spicuous but a hyperplastic reaction is readilyinvoked by any slight inflammatory process.Nodes excised for biopsy purposes are, ipsofacto, to some extent pathological. Howeverinconspicuous they may be, the presence ofthe central zone of reticulo endothelial cellsand the lamination of the surrounding lympho-cytes are essential to the composition of thetrue follicle.

It is readily understandable that the plane ofthe section may pass through the boundaryzone of a complete follicle so that only acircumscribed aggregate of lymphocytes ap-pears in the microscopic field; such collec-tions are referred to as ' pseudofollicles.'

The Lymphadenoid Sinusoids. The lym-phadenoid parenchyma is permeated by ameshwork of lymphatic channels which inter-communicate and which constitute the sinu-

soids. Trfese are div,isible anatomically intothe subcapsular group which forms a lymphaticlake between the capsule and the lymphadenoidparenchyma, and the medullary group in thecentre of the node. Between these two groupsthere is free intercommunication of lymphaticchannels. The subcapsular sinus is joined byseveral afferent lymphatic channels whichperforate the capsule around the periphery ofthe ovoid and reniform nodes and around theconvexity of the C-shaped and horseshoenodes. At the hilum of the node an efferentlymphatic channel emerges, and at this pointthe nutrient vessels find access and egress.Valves are discernible in the extra capsularzone in both afferent and efferent lymphaticchannels.The lymphadenoid sinusoids are lined by

reticulo endothelial cells which also traversetheir lumina, converting them into a sponge-like meshwork whose interstices contain circu-lating lymph.Under normal conditions this sinusoidal

meshwork is difficult to detect in routinehistological preparations but it is readily dis-cernible under conditions of reticulo endo-thelial hyperplasia and catarrhal conditions ofthe sinusoids. In certain lipodystrophies thesinusoids become distended with lipoid con-taining cells, and in lymphogenous metastasisof malignant tumours they contain plugs ofspecific neoplastic cells.

Pathological Changes in Lymph Nodes.Various types of cellular response are en-countered in lymph nodes as componentmanifestations of various diseases. Any or allof the three essential elements of the lymphuo-e may be affected to a greater or lessextent. Thus the follicles and sinusoids maybecome unduly prominent due to reticuloendothelial hyperplasia or they may becomeobliterated or modified by cellular prolifera-tion of the lymphadenoid parenchyma. Patho-logical changes may also be caused by theadvent of extraneous cells not normally foundin the lymph node, as exemplified by themalignant epithelial cell in metastatic car-cinoma.The pathology of lymph node enlargement

may conveniently be described under thefollowing main headings:'



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September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 403

i. Acute Lymphadenitis.2. Chronic Lymphadenitis.3. The Reticuloses and Lipodystrophies.4. Primary Lymphadenopathies.5. Secondary Lymphadenopathies.6. The differential diagnosis of specific cases

of lymph node enlargement.

Acute LymphadenitisAetiological factors are exemplified by acute

infection of the skin with pyogenic cocci, ofthe 'tonsils with streptococci, of the naso-pharynx with the Klebs-Loeffler bacillus andof the urethra with Neisserian organisms.Macroscopically the regional lymph nodespresent the classical signs of inflammation,accompanied in fulminating cases by acutelymphangitis. On inspection the affectednodes are enlarged, soft in consistency, hyper-aemic and greyish-pink in colour. On hemi-section they appear semi-diffluent. Yellowishareas of necrosis are present in virulent in-fections such as diphtheria and typhoid fever

Histologically, all the stages of acute in-flammation, terminating in resolution, similarto those seen in the pneumonic lung, may beencountered. In the milder types of infectionthere are seen proliferating lymphocytes withmarked reticulo endothelial hyperplasia ofboth lymphadenoid follicles and sinuses. It isimportant that the presence of mitotic figuresin such hyperplastic nodes is not mistaken foran indication of malignancy. The distinctionis based on the absence of nuclear hyper-chromia and reduplication and on the absenceof heterotype mitoses in the inflamed node.The capillaries are hyperaemic, and, in non-

suppurating examples, there is a diffuseinterstitial granulocytic infiltration of thelymphadenoid parenchyma resulting fromleucocytic diapedesis.

In the fulminating types of infectionsuppuration occurs with the formation ofmultiple miliary or large solitary abscesses. Inthis event the supervention of periadenitisleads to a matting together of individual lymphnodes. Acute inflammation of the surroundingtissues follows and is succeeded by necrosis andsloughing with perforation of the skin and theformation of sinuses.

In cases which do not proceed to suppura-tion, complete or partial resolution follows.Resolution is preceded by deposition of fibrinin the sinuses, followed by fibrosis andsubsequent phagocytosis, and the affectednode may eventually be restored to its normalmorphology. In some cases, however, fibrosispersists owing to the continued presence ofinfecting organisms of impaired virulence, andthe acute form of lymphadenitis leads to itschronic counterpart.

Chronic Lymphadenitis

Certain non-specific forms of chroniclymphadenitis are more conveniently con-sidered in relation to reactionary reticuloses.Those forms which are due directly to specificbacterial infections may be grouped asfollows

(a) Chronic Lymphadenitis follow,ing AcuteLymphadenitis. In this lymphadenoid manifes-tation ofinfection there is incomplete resolutionof the acute form, with persistence of the in-fecting micro-organisms within the lymphade-noid parenchyma. Such organisms appear tohave assumed diminished virulence, and indeedthey are to some extent walled-off from sur-rounding tissues by the capsular fibrosis whichplays so prominent a part in the histologicalpicture.

Histologically the appearances are similar tothose seen in reactionary reticuloses and com-prise essentially a hyperplasia of the reticuloendothelial elements of the lymph nodes. Inaddition, there is often some degree of inter-stitial fibrosis, and, as above stated, capsular-fibrosis. The accompanying interstitial in-filtration with plasma cells, eosinophilous cellsand histiocytes may lead to difficulty indetermining the diagnosis. Lymph nodesaffected by chronic bacterial lymphadenitishave erroneously been diagnosed as gummata.The histological diagnosis rests on the demon-stration of pyogenic cocci in sectionsspecifically qtained for micro-organisms andon the absence of gummatous areas of vascular-ized necrotic tissue, the absence of specificgiant cells and the absence of endarteritisobliterans.

(b) Tuberculous Lymphadenitis. Infection



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occurs primarily in the teeth, tonsils, adenoids,lungs or intestinal tract, and the specific typeof lymphadenitis results either from lympho-genous or haematogenous dissemination. Inlymph stream dissemination the lymph nodelesions are peripheral and only regional nodesare involved. In blood stream dissemninationthe lymph node lesions are central and severalwidespread groups of nodes are involved.

Macroscopically, the affected nodes are en-larged, firm in consistency and greyish incolour. On hemisection the cut surface showstranslucent grey points where miliary tubercleshave developed. At a later stage when caseationhas occurred the cut surface appears opaqueand yellow. If suppuration supervenes as aresult of superadded infection with secondarypyogenic cocci, there is a fluid purulent exudatewhich flows from the incised node.

Microscopically, there is at first a generalreticulosis affecting both lymphadenoidfollicles and sinuses. Localized groups ofendothelial cells appear, surrounded by pro-liferating lymphocytes. These constitute themiliary tubercle. An avascular necrosis soonoccurs and miliarv tubercles become confluent.Circumscribed areas of caseation becomeapparent, at the margins of which the charac-teristic ' giant cell ' with peripheral nuclei isdiscernible in greater 'or smaller numbers.These cells usually show a C-shaped ring oflarge, clear, slightly reticulated nuclei occupy-ing approximately threequarters of the cir-cumference of the cell cytoplasm. I heperipheral margin of the cell is somewhat ofstellate form. The lymphadenoid matrixcontains lymphocytes, plasma cells and fibro-blasts.When the lesions in the affected lymph nodes

become more advanced, the histological pictureis modified by the development of massivecaseation, by fibrosis or by suppuration. Coldabscesses, fistulae and septic abscesses maysupervene. Deposition of calcium salts, atfirst as a fine ' powdering' and later in moreconcrete masses, is a common degenerativemanifestation, as in other forms of chronictuberculous infection. Periadenitis is a sequelawhich leads to ' matting' of the nodes.The pathological manifestations of tuber-

culous lymphadenitis show variations in

different anatomical sites, but the classicalhistological picture is seen in the cervical nodesof children infected by the oro-pharyngealroute. In the mediastinum there is a peculiarproneness for the nodes at the trachealbifurcation to become grossly enlarged duringthe course of measles and subsequently tobecome infected with the tubercle bacillus. Inthe omentum, tuberculous lymphadenitis maysupervene without the development of tuber-culous ulceration of the intestine. In earlystages the nodes are enlarged 'and markedlyinflamed, and, clinically, the more usualcauses of acute abdominal symptoms may be-simulated. In later stages calcification occurs.

Differential Diagnosis of TuberculousLympha-denitis. Whereas from the clinical viewpointthere may be 'some confusion as to whether anenlarged lymph. ndde is due to tuberculosis,Hodgkin's disease, sarcoidosis, lympho-sarcoma or secondary lymphadenopathy, thehistological picture is so characteristic that thediagnosis is readily established by biopsyexamination of the node under consideration.Moreover the demonstration of Koch's bacillusin sections of the node is definitive. It isimportant to bear in mind that tuberculousinfection of a lymph node may be associatedwith some other lymphadenopathy, eitherprimary or secondary.' Thus tuberculosis mayco-exist in lymph nodes which are affected byHodgkin's disease or by metastatic carcinoma.

(c) Syphilitic Lymphadenitis. Lymph nodemanifestations of syphilis are present in allstages of this specific chronic infection. Theseare essentially of a similar nature and arecharacterized by a great infiltration of thelymphadenoid parenchyma with plasma cellsand lymphocytes. In nodes which are en-larged following upon a primary lesion,treponemes are demonstrable, either in thejuice expressed from the node or in histologicalsections prepared by the methods of Levaditior Bertorelli. In later stages fibrosis is aprominent feature. In the gummatous stagenecrosis is superadded without any caseationand small groups of multi-nucleated giantcells having centrally placed nuclei occur inconsiderable numbers. Important points ofdifferentiation between gumma and tuberclecomprise the presence of vascularity and theabsence of caseation in the former. En-



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September 1947 -WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 405

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FIG. i.-Reactionary sinus reticulosis.

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FIG. 2.-Reactionary sinus reticulosis.

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FIG. 3.-Sinus catarrh.



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FIG. 4.-Reactionary follicular hyperplasia. Low power.

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FIG. 5.-Reactionary follicular hyperplasia. High power.

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FIG. 6.- -Giant follicular lymphadenopathy or lymphoidfollicular reticulosis.



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FIG. 7.-Lymphocytic lymphosarcoma.

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FIG. 9.-Reticulum-celled lymphosarcoma orreticulosarcoma.



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408 POST GRADUATE MEDICAL JOURNAL September I947

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..:....

FIG. 13.-Hodgkin's disease. Lower power.

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FIG. 14.-Hodgkin's disease. High power.



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FIG. I5.-Deposit of achromic melanoma in aIymph node.

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FIG. x6.-Deposit of melanoma in a lymph node.



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September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 4II

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FIG. 17.-Lympho-epithelioma.

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FIG. I8.-Lympho-epithelioma.



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FIG. I9.-Lympho-epithelioma.

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FIG. 20.-Lympho-epithelioma.



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darteritis obliterans and periarteritis tend tobe more marked in syphilis. The sites ofpredilection for gummatous involvement' of'Iymph nodes are the epitrochlear and inguinalregions.

(d) Lymphadenitis in Lymphogranuloma In-.guinale. In this chronic venereal infectionwhich is caused by a filterable virus the lymphnodes affected show a difference of distributionin the two sexes. The inguino-cruro-iliacnodes are implicated in males while in femalesthe lesion occurs in the pelvic and pararectalnodes. In females also stricture of the rectummay be a sequel. Histologically the nodesshow marked periadenitis with the formationof multiple abscesses. T'he lymphadenoidparenchyma undergoes fibrosis and becomesdiffusely infiltrated with plasma cells, lympho-cytes and histiocytes, the histological picturebeing somewhat similar to that of some formsof chroinic' non-specific regional ileitis. Reticulo,endothelial cells (' epithelioid cells') having apalisade distribution are found and thepresence of a filterable virus is associated withgamma inclusion bodies. Diagnosis is estab-lished by the, Hofmann-Frei test, by whichspecific antigen is introduced intradermally.

It is to be noted that in another venerealinfection, granuloma venereum, the causativeagent is a Donovan body. Spread occurs fromthe skin and the lymphatic channels are notinvolved. The lesion responds to the intra-venous administration of sodium antimonytartrate.

(e) Lymphadenitis in Acute Specific Fevers.Certain sites of predilection show enlargedlymph nodes in various infective conditionsother than those already specifically described.In the exanthemata and in other acute specificfevers concomitant clinical signs serve toestablish the diagnosis. Some of the principallymph node enlargements in connection withsuch infective processes may be summarizedas follow8

Measles; gross enlargement of the bronchialnodes which become liable to be infectedsubsequently with Koch's bacillus, com-plicated by cervical adenitis with suppuration.

Diphtheria; in faucial diphtheria the en-largement of the cervical nodes is proportionate

to the extent of the membrane; in extrafaucial diphtheria there may be enlargement ofthe inguinal nodes.

Scarletfever.; from the second to the fourthweek there may be secondary adenitis in.-volving the nodes behind the angle of themandible or under the insertion of the sterno-mastoid muscle. %

Typhoid fever; there is hyperaemia andswelling of the mesenteric nodes. In Peyer'spatches and in the solitary follicles of the ileumthere is a pronounced reticulosis with swellingdue to proliferation of reticulo endotlhelialcells.

Anthraxc; a chain of enlarged painful nodesdevelops along the line of the lymphaticchannels spreading from the 'malignantpustule.'

Glanders; this is a definite septicaemiawhich is diagnosed by means of the malleintest in animals or by recovery of bacillus malleiin six days after intraperitoneal inoculation ofguinea-pigs. The tunica vaginalis of thetestis becomes swollen; the cervical lymphnodes in man become enlarged and softenedand may suppurate.

Plague; a tender bubo appears on thesecond or third day after infection; thecommonest sites of predilection are theinguinal and femoral regions (70 per cent.),the axillary region (20 per, cent.) and thecervical and submaxillary regions (io percent.). The infected node may become thesize of a hen's egg, and pain and suppurationare common. Diagnosis is established byaspiration biopsy when- the characteristicbipolar bacillus is readily demonstrable onmicroscopic examination.Maltafever; this is a bacteriaemia in which

the mesenteric lymph nodes may becomeswollen but in which there is no ulceration ofPeyer's patches. Bacillus melitensis may berecovered from swollen lymph nodes or bysplenic puncture.

Glandular fever; this is a virus infectioncharacterized by a mononucleosis of 40 percent.-go per cent., the total leucocytosisamounting to 12,000 to 30,000 per c.mm.blood. The upper cervical, mediastinal andmesenteric groups may be involved. There is



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a positive Paul-Bunnell reaction, as in serumsickness.Serum sickness; enlarged lymph nodes,

though rare findings may be associated withgeneral oedema and albuminuria. The Paul-Bunnell reaction is positive and the commonfeatures are urticaria, swelling of joints,pruritis, mild pyrexia and malaise.'

Tularaemia; infection of lymph nodes withswelling and suppuration followed by over-lying ulceration occurs in keepers of rodents.The immediate cause is an insect bite. Clinic-ally the condition is characterized by malaiseand a prolonged inability to work.

Rubella; a tender adenitis affects prin-cipally the occipital, mastoid, posterior cer-vical, axillary and inguinal lymph nodes whichremain discrete and firm:

Agranulocytic angina; Gangrenous andulcerative stomatitis (Ludwig's angina) andalso some cases of Vincent's angina may befollowed by enlargement of the cervicallymph nodes. This is associated with asurrounding brawny induration, and a charac-teristic blood picture.

Primary LymphadenopathiesThe term' lymphoma 'was formerly applied

indiscriminately when lymph nodes becameenlarged from some endogenous cause notsecondary to any exogenous primary focus ofinfection or secondary to neoplasm. Thisgroup is somewhat ill-defined and includes avariety of conditions of different nature ofwhich the cause is often quite unknown.Broadly speaking the members of the groupmay be sub-divided into the reticuloses andthe reticulosarcomata. The former sub-division, however, is complicated by thesuperimposition of lymph node manifestationsof certain lipodystrophies.

The Reticuloses. The term reticulosis isapplied to those changes in lymph nodes whichare characterized by hyperplasia of the reticuloendothelial cells. The component cells of thelymphadenoid follicles and those of thesinuses may be affected independently ortogether. Follicular reticulosis is commonlyassociated with the presence of soluble toxins.Thus the regional lymph nodes become en-

larged and show this change in infective pro-cesses such as tonsillitis, peptic ulceration orwhitlow. Sinus or medullary reticulosis' onthe other hand is associated with particulatematter and is encountered in such conditionsas bacteriaemia, pneumoconioses and neo-plasm.

Follicular Reticulosis. Histological prepara-tions of the enlarged lymph node showsmarkedly prominent lymphadenoid follicles.The reticulo endothelial 'germ centres' arehyperplastic and hypertrophic and also showa numerical increase. It is important to notethat these hyperplastic follicles are sharplydemarcated from the surrounding lym-phadenoid parenchyma by a clearly definedperipheral zone of concentrically laminatedlymphocytes. It is equally important thatsuch follicles are not confused with smallmetastatic deposits of squamous or spheroidalcelled carcinoma or other neoplasm.

Giant Follicular Lymphadenopathy. Synonym-lymphoid follicular reticulosis (Robb-Smith). This is a special form of follicularreticulosis. It is a generalized enlargement oflymph nodes whic,h may staft focally andunilaterally but which may eventually involvethe nodes of all regions. Clinically the lesionis characterized by a concomitant pleuraleffusion. The nodes affected are not grosslyenlarged and the condition responds to radio-therapy. If left untreated, however, someform of lymphosarcoma is liable to develop.

When histological preparations are examinedwith the naked eye, or with the aid of a handlens, the whole gland is seen to consist ofrounded nodules which may reach a size upto i cm. in diameter. Microscopically theseenlarged follicles present a characteristicappearance which is entirely different fromthat of the enlarged follicles in reactionaryreticulosis. Whereas in the latter there isalways a peripheral zone of concentricallylaminated lymphocytes, in the former there ismerely a narrow margin of fibroblastic andlymphadenoid stroma. When a single largefollicle is observed under the microscope, it isseen to be composed of hyperplastic reticuloendothelial cells which show several mitoticfigures of regular form. The lymphadenoidparenchyma and the sinuses are eventually



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September I947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 415

entirely obliterated and the capsules show nogross pathological change. The picture aspresented by the centre of an enlarged follicleis very similar to that of lymphosarcoma-namely, a homogeneous field of lymphocytes,lymphoblasts or reticulo endothelial cellsshowing mitotic activity. Indeed it is notimprobable that -the lesion of giant follicularlymphadenopathy represents the earliest phaseof development of multifocal lymphosarcoma.

Sinus Reticulosis. When the reticulo endo-thelial hyperplasia affects the cells of thesubcapsular, comnmunicating and medullarysinuses these channels become prominentowing to their distension with proliferatingcells. It is important that the histologicalappearance of such distended sinuses is notconfused with that of a diffuse metastaticinfiltration of the sinuses with malignantopithelial cells.Not infrequently the sinuses become dis-

tended with a clear hyaline oxyphile fluidexudate with or without proliferation ofreticulo endothelial cells; such an appearanceis due to oedema of the sinuses and is referredto as sinus catarrh. Peculiar forms of sinusreticulosis are met with as lymph nodemanifestations of defective lipoid metabolismwhich have been termed 'lipodystrophies,''lipoid histiocytosis,' 'lipoidoses' and 'stor-age reticuloses.' An account of the pathologyof the principle members of this complex andill-defined group is set forth under the generalheading of ' sinus reticulosis ' in order toclarify the essentially similar nature of multiplediseases which are clinically dissimilar.The deposition and storage of specific types

of lipoid substances consisting of cholesterol,cholesterol ester, cerebrosides and relatedcompounds, in the reticulo endothelial cellsand histiocytes of certain organs and tissuesgives rise to a specific group of reticuloses inall of which the lymph nodes may becomeinvolved as a secondary manifestation of thedisease in question. The organs primarilyinvolved in the diseases under considerationinclude the skin, the subcutaneous tissues, thespleen, the liver, the bones and bone marrow,the uveal tract and the salivary glands.

Gaucher's disease. The histological mani-festations result from a deposition and storage

of a lipoprotein resembling a cerebroside.Splenomegaly occurs, accompanied by en-largement of the thoracic and abdominallymph nodes. On hemisection the macro-scopic appearance resembles ' cafe-au-lait ' incolour. Microscopically the lymphadenoidparenchyma is infiltrated with the charac-teristic large Gaucher cells whose diametermay exceed 70 [L. The nuclei are small, non-reticulated and eccentric and the sytoplasm iscopious and shows a wrinkled appearance.

Hypercholesterolaemia. Deposition and stor-age of cholesterol and of cholesterol esteroccurs in a widely diverse group of cases, andhistological evidence of the presence of theselipoids may be found in lymph nodes. Thefollowing clinically recognizable entities maybe segregated

(a) Xanthelasma. This consists of a de-position of the lipoid in the histiocvtes in: thesubconjunctival tissues of the eyelids and is notas a rule associated with enlarged lymph nodes.

(b) Xanthoma multiplex. In cases of biliaryobstruction and in diabetes mellitus lipoidsbecome distributed in the skin and are mani-fested as yellowish plaques.

(c) 'Xanthoma.' The term xanthoma doesnot imply a neoplasm of specific type, but has,by long usage, come to be applied to a peculiartype of lipodystrophy which develops as asecondary phenomenon in certain primarytumours in connection especially with tendonsheaths, joint capsules and bones. The tumournmay be a fibrosarcoma, fibroma, giant celledtumour of the osteoclastoma -type, or certainforms of osteogenic sarcoma. The character-istic foamy cells of this form of xanthomatousdegeneration may be found in metastaticdeposits in the regional lymph nodes.

(d) In the Hand-Schuller-Christian syn-drome, cholesterol and cholesterol ester aredeposited in endothelial cells of capillaries andin histiocytes. The lipoid becomes liberatedinto the tissue spaces which results in theformation of granulation'tissue and fibrosis asa reactionary phenomenon. The meningesbecome, involved with firm putty like depositsof yellowish appearance which encroach uponthe bones of the skull, leading to decalcifica-tion. This is a manifestation of skeletallipoidal granulomatosis.



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(e) Niemann-Pick disease. This rare dis-ease of childhood, occurring in the first yearor two of life and terminating fatally at anearly age, is due to storage of phosphatidelipoid or a mixture of cholesterol and phos-phatide. The lymph nodes become enlargedand of yellowish colour. Microscopically theycontain characteristic cells of about 35 pL indiameter in which the cytoplasm is finelyvacuolated.

(f) Warren-Tay-Sach's disease. The lesionin amaurotic family idiocy is a storage ofcerebroside protein.

Sarcoidosis. Synonyms-Stengel-Wolbachsclerosis; chronic medullary reticulosis ofRobb-Smith; endothelial tuberculosis.This peculiar form of chronic sinus reticu-

losis is shown pathologically by the infiltrationwith pale lipoid containing cells sometimesassociated with multinucleated giant cellsresembling those of tuberculosis. In con-sequence the lymph nodes become enlargedand are clinically associated with lesions of theuveoparotid tract, osteoporosis of the digitalphalanges and Boeck's dermal sarcoid.Essentially, the lymph node enlargement isdue to an infiltration of the lymphadenoidsinuses with reticulo endothelial cells whichhave undergone a lipodystrophy. In earlyphases of this process the affected node revealssmall groups of pale staining large ovoid cellswhose cytoplasm has a parboiled appearanceand whose nuclei are small and eccentric. Inlater phases these small groups tend to becomneconfluent and to form lobulated masses whichoccupy a large proportion of the lymph node.A certain amount of normal lymph adenoidparenchyma generally remains and the dis-tinction between sinuses, follicles and paren-chyma persists to a greater or less degree.T'here are two important points of distinctionbetween sarcoidosis and- tuberculosis; in theformer caseation does not occur and notubercle bacilli are demonstrable.There are diverse manifestations of sar-

coidosis, and, while the essential lesion issimilar in all instances, confusion has beenengendered on, account of the diversity ofnomenclature which has been employed inrelation to lesions in various tissues and organs.The following main types have been segre-

gated as pathological entities, though in.reality they are merely different manifestationsof a single pathological process --

(a) The dermal sarcoid of Besnier-Boeck.This is an infiltration of the epidermis withlipoid containing reticulo endothelial cellswhich, through long standing custom, areusually referred to as ' epithelioid cells.'

(b) The subcutaneous sarcoid of Darier-Roussy. This is the counterpart of the dermalsarcoid in the cutis vera and superficial fascia.

(c) Stengel-Wolbach sclerosis. This is achronic form of reticulosis affecting primarily-the sinuses of lymph nodes. The subcapsularsinuses first, and eventually the communicatingand medullary sinuses become grossly dis-tended with the characteristic cells of thelesion. An important point in differentiationis the essential retention of normal lym-phadenoid architecture; this is modified onlyin relation to the extent of the sinus in-filt,rtion.

(d) Osteitis multiplex of Jungling. This isa manifestation of sarcoidosis affecting prin-cipally the digital phalanges of the fingers andtoes, but sometimes affecting other bones.

(e) Uveo-parotitis of Heerfordt. In thismanifestation the uveal tract, lachrymal glandsand salivary glands are involved.

(f) Endothelial tuberculosis of Zinsser. Thisname was formerly applied to the sinus lesionsof lymph nodes which are now recognized asthe essential lesion of sarcoidosis.

Erythrodermia. This chronic skin lesionwhich was formerly termed exfoliative derma-titis, is a peculiar form of reticulosis of theskin characterized by the presence of a lipo-melanic reticulosis in the associated lymphnodes.

Hodgkin's DiseaseSynonyms-Lymphadenoma; fibromyeloid

reticulosis of obb-Smith.This form of primary lymphadenopathy

whose aetiology is unknown begins in a singlelymph node and soon spreads to adjacentmembers of a group. A little later there isbilateral involvement and eventually general-ization may occur with involvement of the



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cervical, axillary, mediastinal, abdominal andinguino crural groups.

Macroscopically the affected nodes may begrossly enlarged but they tend to remain dis-crete. They are of firm consistency and paleappearance. On hemisection the cut surfacegives the impression of being somewhatfibrous; there may be patches of necrobiosisbut there is no caseation. Microscopically thehistological picture shows considerable varia-tions, but there are certain classical featureswhich may be represented in varying propor-tions in different cases. Characteristically theessential features may be enumerated underfive headings :-pleomorphism, loss of lym-phadenoid architecture, fibrosis, infiltrationwith eosinophilous cells, and the presence ofSternberg-Reed giant cells. Each of thesecriteria requires amplification.

Pleomorphism. The characteristic picture ofa well-developed lesion of Hodgkin's diseasemay be modified if a lymph node is examinedat a very early or a very advanced stage of itsevolution. In the early stage a commonfeature is a diffuse interstitial infiltration of thelymphadenoid parenchyma with reticulo endo-thelial cells. The heterogeneous morphologyof the node serves to distinguish the lesion fromrecticulo sarcoma, in which homogeneity isthe keynote. This cellular proliferation maybe accompanied by an occasional eosinophilouscell and an occasional Steinberg-Reed giantcell, but there may be relatively slight fibrosis.In an advanced stage in the evolution of thelesion fibrosis may be the predominant feature.In the more virulent forms of the disease(which have been designated malignantHodgkin's disease, or Hodgkin's sarcoma)certain features may be markedly exaggerated.In some cases the Sternberg-Reed cells may beabnormally large and hyperchromic and ex-cessively numerous; in other cases eosino-philous cells predominate.

Loss of lymphadenoid architecture. Exceptin early phases of the development of thisdisease there is total obliteration of thelymphadenoid sinuses and follicles and con-siderable thinning out of the lymphadenoidparenchyma. The whole node becomeseventually completely replaced by the peculiartissue characteristic of Hodgkin's disease.

Fibrosis. Characteristically this occurs inthe form of small localized tufts of collagen ofsome thickness and there is a marked tendencyfor this fibrous tissue to undergo hyalinedegeneration. The distribution is well shownby the application of methods for reticulumstaining.

Eosinophilous cells. These are present invery variable numbers in different cases of thedisease, but generally they are not excessive.In some instances an eosinophilia is shown inthe blood picture. Though these cells arecharacteristically present in most lymph nodesaffected by the lesion of Hodgkin's disease,they are not per se pathognomonic of thedisease and are quite frequently observed inother forms of lymphadenopathy. Neverthe-less, their presence in a node which shows littlechange of morphology other than slightfibrosis and a general thinning out of thelymphadenoid architecture, provides a criterionin favour of the diagnosis of Hodgkin'sdisease.

Sternberg-Reed giant cells. These are alsoknown as 'mirror image giant cells' from thesymmetrical distribution of their nuclei whichare generally four in number; the appearanceof these cells has been likened to that ofpennies on a plate. The cell is of circular orovoid form and characteristically contains fournuclei whose margins to some extent overlapand which are symmetrically arranged in theabundant hyperchromic cytoplasm. Suchcells are sometimes present in very scantynumbers, but they tend to be excessivelynumerous and of bizarre form in the moremalignant types of the disease.

Reticulo endothelial cells. The presence ofthese cells out of their normal environmentmay be cited as an additional criterion to thefive already described. They are seen typic-ally in the earlier phases of development of thedisease but may be insignificant when thelesion is more advanced. The normal dis-tribution in the follicles and sinuses is replaced,in early stages of the disease, by a diffuse in-filtration throughout the attenuated lym-phadenoid parenchyma.Morbid anatomy of Hodgkin's disease. In

cases which come to necropsy, enlarged lymphnodes showing the characteristic macroscopic



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4i8 POST GRADUATE MEDICAL JOURNAL September I947

and microscopic features already describedmay be found in any region, and polyserositesis usually present. In advanced cases theappearances of the lesions are those of anmalignant neoplasm. There may be contiguousextension to bones, and deposits may be foundin the lungs, liver, spleen and other internalorgans. To the naked eye these depositsgenerally appear as multiple white nodules ofill defined outline, less sharply demarcatedthan metastatic deposits of carcinoma, butresembling the focal deposits sometimes foundin leukaemias.

Lymphosarcoma

This is a primary malignant affection of thelymph adenoid system which shows a varietyof pathological manifestations. Macroscopic-ally the affected nodes are grossly enlarged,sometimes to the size of a hen's egg. Theyare of soft consistency and almost whiteappearance. On hemisection the cut surfaceappears homogeneous and opaque or semi-translucent. This uniformity contrasts sharplywith that of lymph nodes which are the site ofmetastatic carcinoma. In the latter the cutsurface of the hemisected node appearsnodular, especially after a short period infixative solution. The macroscopic appear-ance is also readily distinguishable from that ofHodgkin's disease in which fibrosis plays soprominent a part.

The manifestations of lymphosarcoma maybe limited to the nodes of a local region suchas the neck or the abdomen, but in advancedcases generalization is the rule, with depositsin the viscera.

Microscopically the histological picturepresents a remarkable degree of homogeneitywith complete loss of differentiation of thenormal components of the lymph node. Themicroscope reveals a uniform field of lympho-cytes, lymphoblasts or reticulo endothelialcells. In consequence of this selective cytologythree distinct types of lymphosarcoma aredistinguishable according to the nature of thepredominant cell. These are termed res-ppctively lymphocytic lymphosarcoma, lym-phoblastic lymphosarcoma, and reticulum

celled lymphosarcoma.; the latter has thealternative name of reticulo sarcoma.The morbid anatomy of this disease is

variable. In some cases internal organs suchas the spleen, liver and kidneys show circum-scribed nodules of lymphosarcoma which areessentially metastatic deposits. In other casesthe spleen may be one of the primary sites ofthis form of primary lymphadenopathy. Adifficulty that not infrequently arises in thedifferential diagnosis of an excised lymph nodefor biopsy purposes is the distinction betweenlymphosarcoma and aleukaemic lymphaticleukaemia. This point is given considerationin connection with the haematopoietic affec-tion.

Primary lymphosarcoma, in which lymphnode manifestations are inconspicuous, mayarise in the lymphadenoid tissues of thethyroid gland. Another primary form is mani-fested as a thymoma and is associated with theclinical signs of myasthenia.

Lymphatic Leukaemia

This disease, in view of our imperfectknowledge of its aetiological relationships, maybe regarded provisionally as a sarcoma of theblood and blood forming organs as the primaryaffection, but the lymphadenoid system is notinfrequently implicated. In the usual type ofcase the diagnosis is readily arrived at from anexamination of the blood picture. If, in sucha case, there is involvement of lymph nodesand a node is excised for biopsy purposes, nodifficulty is presented to the histologist,because the microscopic preparation revealsthe presence of excessive lymphocytes orlymphoblasts in the blood vessels within thelymph node and in those permeating the-adjacent fibro fatty tissue.On the other hand, in cases of aleukaemic

lymphatic leukaemia, difficulty may arise inhistological interpretation owing to the factthat, superficially, the microscopic appearancesof lymph nodes in leukaemia are almostidentical with those of lymphosarcoma. Thereare, *however, certain special features whichserve to differentiate the two conditions.Sometimes the pathologist is fortunate inhaving for examination a lymph node in which



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some residue of normal architecture persists.In such a case, a leukaemic infiltration of thelymphadenoid parenchyma, precisely similarto that seen in the renal parenchyma inleukaemia, is perceptible. Another point isthat the adjacent fibro fatty tissue may show aleukaemic infiltration, especially in those nodeswhose morphology is of the reniform or C-shaped type. Finally, in lymphosarcomamitotic figures are unduly prominent andexamples of heterotype mitoses may beencountered.

Secondary Lymphadenopathies

Lymph nodes often become enlarged owingto the presence of metastatic deposits ofcarcinoma and other malignant tumours;such enlargements may be conveniently re-ferred to as secondary lymphadenopathies, butit must be borne in mind that metastaticdeposits, may occur in lymph nodes withoutenlargement.

It is important in this connection that fullrecognition be given to the fact that the degreeor extent of metastasis does not necessarilybear any proportionate relationship to themacroscopic size of the lymph node enlarge-ment. In order to illustrate this point adescription of the findings on pathologicalinvestigation of a typical surgical specimenwill suffice. When radical mastectomy hasbeen performed for mammary carcinoma it isdesirable that the degree and precise mode ofspread of the malignant process be ascertainedas far as possible from a detailed examinationof the specimen. To this end, a routine pro-cedure has been found to be of assistance andits essentials are set forth hereunder.

After a careful description of the position,size and shape of the primarv tumour in thebreast, the axillary contents are dissected andthe number, size and relative positions of theiymph nodes noted. In addition, the skinoverlying the tumour and the underlyingpectoral fascia and pectoral muscle are searchedfor possible secondary or contiguous deposits.*Representative portions of tissue are selectedfor microscopic examination from the primarytumour, from the skin, pectoral fascia, pectoralmuscle, from the neighbouring tissue of the

corpus mammae and from the axillary fibrofatty tissue. In addition, all lymph nodesfound on dissection are prepared for micro-scopic examination.

It is a matter of frequent experience that theaxillary lymph nodes show a considerablerange in size from 2 or 3 millimetres up to2 or 3 centimetres. It is important to realizethat a solitary metastatic deposit of carcinomamammae may be present in one of the smallestnodes while the larger nodes remain un-affected by the malignant process. Histologicalfindings such as these serve to emphasize that,except in cases of gross malignant involve-ment of lymph nodes, the ' staging' of breastcarcinoma is impossible on clinical groundsalone.

Mode of development of lymph node meta-stases. Dissemination of malignant cells froma primary tumour ocours in three ways-bydirect intercellular extension into neighbouringtissues, by lymphatic permeation and em-bolism, and by vascular embolism. To thesemay be added the rarer method of retrogradeembolism. Hence a lymph node may becomeinseminated with malignant cells by contiguousextension, by way of the afferent lymphaticchannels around the periphery, or by way ofthe afferent arteriole centrally. Realization ofthese anatomical principles serves to explainthe diverse histological appearances of lymphnodes which are the seat of metastasis. Insome instances histological preparations showafferent lymphatic channels in the fibro fattytissue immediately adjacent to a lymph node,distended with plugs of malignant epithelialcells. The subcapsular lymphatic sinus mayalso be seen to be distended with such cells.When some time has elapsed the 'malignantseedling' as it may appropriately be called,grows at the expense of the lymphadenoidmatrix in which it is deposited and the normalarchitecture of the lymph node becomes un-recognizable owing to the almost complete re-placement of the lymphadenoid parenchymaby malignant tissue. In examples wheremalignant dissemination has been haemato-genous the earliest phase in the evolution of ametastatic deposit is in the centre of the nodewhere the afferent arteriole undergoes poly.chotomy.



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In attempting prognostication in a givenpathological investigation the relative sig-nificance of lymphogenous and haematogenousdeposits in lymph nodes must be given dueconsideration. It is self evident that thelatter most probably indicate haematogenousdeposits in bones or in the internal organs.

Relation of malignant parenchyma to stroma.There is not always a strict parallelism betweenthe histological appearances of a primarytumour and those of its metastatic deposits.The primary carcinoma in a breast, forexample, may be mainly of scirihous mor-phology while the lymph node metastases maybe highly cellular, of medullary type orshowing an alveolar form, and having noappreciable stroma. In other instances thestroma is a predominating feature in themetastases while the primary tumour may haveshown a medullary morphology. Such dis-tinctions, however, are relative and notabsolute, for many tumours tend to be hetero-geneous rather than homogeneous, and this isespecially true of many carcinomata.

Although the stroma may be regarded as anessential part of the tumour and not merely acellular reaction on the part of the host, it isevident from the foregoing considerations thatno conclusions can be drawn with certainty asto the precise histological class to which aprimary tumour belongs 'from an examinationof an isolated lymph node metastasis. Whenconfronted with a lymph node which proves onhistological examination to contain a meta-static deposit of neoplasm the main concern ofthe pathologist is to differentiate the varioustypes of primary tumour presented in themetastatic deposit and to assist his clinicalcolleagues in the localization and essentialnature of a dormant primary tumour.

The phenomenon of squamous metaplasia. Itis well recognized that epithelium which wasoriginally columnar, cubical or transitional incharacter, m4y undergo squamous metaplasia,which implies a change of morphological con-figuration. Such a transformation proves notinfrequently to be a predisposing factor in thedevelopment of squamous carcinoma. It is atonce apparent that, in cases where carcinomaof squamous type develops as a result of meta-plasia of epithelium which was primarily

columnar, cubical or transitional, an examina-tion of a lymph node metastasis will be of noavail in assessing the specific nature of theepithelial cells from which such a tumourprimarily arose, unless there are clinicalindications of the presence of a primarytumour in a specific organ or tissue.Squamous metaplasia tends to occur in

connection with branchial fistulae and cysts, inpersistent remnants of the thyroglossal duct, inthe gall bladder and biliary passages, and inthe respiratory and urinary tracts. Recog-nition of such an eventuality may serve toexplain the development of certain otherwiseinexplicable metastatic deposits.

It is thus possible to account for the develop-ment of well differentiated squamous car-cinoma, with keratinization, epithelial. pearlformation and intercellular protoplasmicbridges in such primary sites as the thyroidgland, the bronchus, the gall bladder, bileducts, renal pelvis, ureters and urinarybladder.Another phenomenon, which may appro-

priately be termed '.secondary squamousmetaplasia,' occurs after the development of aprimary adenocarcinoma in a glandular organ.This is more readily detected owing to theheterogeneous morphology of the tumour,which may be applicable to both primary andmetastatic tumours. On the other hand,difficulty in interpretation may again arise ifthe material available for microscopicalexamination comprises a lymph node con-taining a metastatic deposit which is entirelysquamous in its morphology. The reversephenomenon of coiumnar metaplasia has notbeen encountered.

The Differential Diagnosis of SpecificCases of Lymph Node EnlargementSometimes the pathological nature of an

enlarged lymph node is self evident fromclinical considerations and from its regionaldistribution, while other cases demand theapplication of a number of histopathologicaltests of a specific nature.The initial point to be decided is whether

the enlargement of a lymph node is inflam-



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September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 42I

matory, neoplastic or reactionary. If in-flammatory, is it acute inflammation, chronicinflammation or a chronic infective granulo-matous lesion ? If neoplastic, is it primary ormetastatic ? If reactionary, is it of a simplenature or associated with some form of lipo-dystrophy?

After many of the predisposing factors whichresult in lymph node enlargement have beenexcluded by clinical tests, supplemented byserological, haematological and bacteriologicalinvestigations, there still remains a consider-able group which is dependent upon histo-logical diagnosis alone for diagnostic differ-entiation. This affirmation is applicableespecially to those cases of lymph nodeenlargement which have been shown to be ofa neoplastic nature, but in which there is noclinical indication as to the nature of thetumour or of its primary site.

Differential histological diagnosis is calledfor specifically where the primary tumour isquiescent or concealed. There are many in-stances where the first manifestation of aneoplasm is lymph node enlargement due tometastasis. H-istological differentiation of sucha deposit requires a co-ordination of thehistological findings with the anatomical regioninvolved. The development of metastases incertain regional nodes is a useful pointer insome instances. For example, when the in-guinal nodes are involved, the finding ofadenocarcinoma on biopsy examination sug-gests a primary tumour in the colon or rectumrather than in the stomach, while a deposit ofsimilar nature in the cervical region suggests atumour in the stomach or in the naso-pharynx.It must be emphasized however that too muchdependence must not be placed on the regionaldistribution of the affected nodes and thatevery effort should be made on the part of thepathologist to arrive at a diagnosis purelyfrom histological considerations.

In some instances, histological differentia-tion, ifn the absence of clinical signs andsymptoms, affords the only means of assessingthe site and nature of the primarv tumour. Anenlarged supraclavicular node serves as anexample. Metastasis in such a node may besecondary. to a carcinoma in a large number ofpossible primary sites which include the

pharynx, larynx, oesophagus, thyroid, skin ofthe trunk or upper extremity, gastrointestinaltract, hypernephroma, malignant melanoma,malignant ovarian cystadenoma, plasmacytoma,myeloma, seminoma, sialoma, and so on.

Histological differentiation is sometimesdependent upon the application of specificstaining reactions to microscopical prepara-tions. Brief notes are appended hereunder toaid in the differentiation of a number ofspecific forms of primary neoplasm whose localmanifestation may be encountered in lymphnodes.

Lympho epithelioma. This variety of ana-plastic squamous carcinoma arises in thespecial lymph epithelium of the tonsils andnasopharynx and may also be found in thepalate and oropharynx. Histologically thelesion is characterized by a malignant hyper-plasia of squamous epithelium in direct con-tact with a lymphadenoid stroma. Two formsare recognized-the Schmincke type which isdeeply infiltrating and which is more com-monly met with in the tonsils, and the Regaudtype which is lobulated and shows an argyro-phile reticulum of special distribution, andwhich is more common in the nasopharynx.

The first clinical manifestation of lymphoepithelioma is usually an enlarged cervicallymph node due to the presence of a meta-static deposit. A peculiar clinical feature isthe latency of the primary tumour. Evenbulky lymph node metastases may appearbefore the small primary neoplasm evokessymptoms. This tumour is recognized asbeing particularly radio sensitive.

Squamous carcinoma. In well differentiatedtypes with keratinization and epithelial pearlformation there is little danger of confusingthe growth with any other types of tumour.The only difficulty that arises is when thetumour results from squamous metaplasia inepithelium of different ontogeny. In the morededifferentiated or anaplastic forms of primarysquamous carcinoma a useful aid to thedifferentiation of the type of growth is theaccentuation of intercellular protoplasmicbridges by special staining methods. If'prickle cells' are demonstrable the presence ofsquamous carcinoma is established.



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The finding of a metastatic deposit ofsquamous carcinoma in a Iymph node is anindication, in the first instance, for a carefulclinical search for a primary squamous car-cinoma in the region most probably concerned.The primary tumour might well be disclosedin the tongue, respiratory tract, renal tract orexternal genitalia. Lvmpho epithelioma mustnot be ignored as an alternative possibility.when the cervical nodes are involved.The phenomenon of squamous metaplasia

may cause considerable difficulty if its pos-sibility is not borne in mind. It occasionallyhappens that the primary tumour in a glandularorgan such as the breast or the mucosa of thegastrointestinal tract, undergoes squamousmetaplasia. Such a phenomenon would bereadily recognizable from a microscopicexamination of the primary tumour, but thedifficulty is encountered when the lymph nodedeposit presents entirely squamous characters.

Adenocarcinoma. In well differentiated typesof adenocarcinoma a distinct alveolar orpapilliform morphology is discernible and itonly remains to determine the nature of theepithelium from which the primary tumourprobably arose. In some instances thedifferentiation presents little difficulty while inother instances the precise nature of thegrowth may be obscure.The first step in differentiation is the

application of a staining reaction for mucin.If the reaction of the tumour cells to muci-carmine is strongly positive this is an indica-tion of a primary malignant lesion in thegastrointestinal or biliary tracts. If themucicarmine reaction is faintly positive itindicated a primary tumour of the ovaries orendometrium. A negative mucicarmine re-action is suggestive of an anaplastic squamouscarcinoma.

Further differentiation is based on mor-phological considerations. The stomach andsmall intestine develop a type of adeno-carcinoma in which the cytoplasm of themalignant epithelial cells is comparativelyclear and in which nuclear reduplication is notmarked. The colon and rectum, on the otherhand, develop tumours composed of tallcolumnar hyperchromic cells, usually withstrongly basophile staining, in which nuclear

reduplication is so marked that the cytoplasmis almost or completely filled with super-numary nuclei.*A point of distinction between carcinoma of

the caecum and that of the rest of the colonand rectum is that in the former a markedoxyphil staining reaction of the cytoplasm issometimes discernible and the. morphology ofthe malignant alveoli is markedly cribriform.

Ovarian tumours are characterized byhaving a pyriform morphology. Examinationof a papilliform process of such a tumour as amalignant ovarian cystadenoma shows thatthe outline of the papilla is not smooth andregular but somewhat nodular; the individualcells are pear shaped, being attached at thebase by a narrow pedicle. Moreover, ovariantumours tend to show a deposition of calciumsalts in the form of a fine powdering of baso-philic granules as seen microscopically.Tumours developed from the endometrium,

comprising adenocarcinoma of the corpusuteri and adenocarcinoma of the portio endo-cervicalis, are composed of tall columnar cells,somewhat resembling those of the gastro-intestinal tract, but showing ciliation. Thisserves as a point of differentiation.

Anaplastic forms of adenocarcinoma. Inexamples where an alveolar, papilliform orcribriform morphology is not apparent, histo-logical differentiation may be more difficult.Here again some assistance may be obtained bythe application of the mucicarmine stainingreaction. The presence in a metastaticdeposit of isolated cells of ' signet ring ' type isstrongly indicative of gastrointestinal car-cinoma. Such cells are usually stronglypositive to mucicarmine. Attenuated depositsof this type, in which the lymph node isdiffusely but. sparsely infiltrated with a fewisolated signet ring cells are encountered par-ticularly in linitis plastica. A similar histo-logical picture is seen in the Krukenbergovary.Another form of adenocarcinxoma is

developed when the malignant epithelium r¢-verts from its more usual functional regressionand manifests functional hyperactivity withthe production of large quantities of mucinoidexudate. These 'colloid' or 'mucoid'deposits are readily recognized in a lymph



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September I947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 423

node. The malignant epithelial cells may bepresent in the form of well defined alveoli oras isolated units which have become distortedand compressed by the exuberance of theirown secretory activity. The finding of such adeposit calls for a coordination of the clinicalfindings and the anatomical site of the nodeinvolved as adjuvant agents in determining thesite of the primary neoplasm. Should oxynticcells happen to be present the histologicaldiagnosis of gastric carcinoma is established.It is necessary to bear in mind that the mor-phology of a lymph node metastasis servesmerely as a guide to the anatomical site of theprimary neoplasm and that the cytology of theprimary growth and of its metastatic depositsare often by no means facsimiles.

If a metastatic deposit of anaplastic car-cinoma is cytologically' recognized as anadenocarcinoma, a weakly positive muci-carmine reaction suggests a malignant ovariancystadenoma.

Adenocarcinoma of the gall bladder andbiliary passages of the pancreas and of theurachus are composed of low cubical epitheliumand are readily distinguishable from tumoursof the gastrointestinal tract. The differentia-tion of individual members of this group isbased on the presence of cilia in adenocar-cinoma of the biliary passages and on thepresence of mucin secretion in adenocar-cinoma of the urachus. Anatomical con-siderations also assist in differential diagnosis.

The sialomata or tumours of the salivaryglands form an important group which requirecareful differentiation. Though the majorityare of slow development they must be re-garded as essentially malignant tumours sorneof which pr-oduce lymph node metastases.

Sialomata, formerly known as 'mixed paro-tid tumours ' or ' myxo-chondro-endothelio-mata ' are now recognized as being adenomataor adenocarcinomata of the epithelium of theducts of the salivary glands. Their hetero-geneous histological appearance is explained bythe presence of a matrix of mucous tissue con-taining characteristic stellate cells which givean appearance of pseudocartilage. Neverthe-less the members of this group are sufficientlytypical in appearance as to enable their meta-static deposits to be appreciated without

difficulty. Four main varieties are dis-tinguishable-the alveolar, the pseudocartila-ginous, the para buccal and the basal celled,but there may be admixtures of any combina-tion of varieties. In the alveolar type thereare well defined alveoli lined by low cubical orattenuated epithelium. In the pseudocartila-ginous type the epithelial cells proper to thetumour undergo modification and compressionas a result of the products of their ownsecretory hyperactivity. In the para buccaltype very characteristic vesicles containingreticulated mucinoid secretion predominate.in the basal celled type the appearance isstrikingly similar to that of a basal celledcarcinoma of the skin. The latter tumour,however, does not give rise to lymph nodemetastases.

MelanomaMetastatic deposits of the more highly pig-

mented forms of the melanomata are readilyrecognizable microscopically on account of theease with which melanin pigment is demon-strable by specific cyto-chemical tests. Withsome of the achromic forms, however, con-siderable difficulty is likely to be encounteredunless particular attention is paid to certaincharacteristic and peculiar properties apper-taining to this wide group of highly malignanttumours.

It must be appreciated that all malignanttumours in which melanin is demonstrable arenot to be included in the specific group com-prising the melanomata. Fortuitous pigmenta-tion is not infrequently met with in squamouscarcinoma, basal celled carcinoma, endo-thelioma and fibrosarcoma.The true melanomata are malignant tumours

derived from neuroepithelium in connectionwith nerve end organs in the dermis, in theuveal tract, in the meninges, in the nasalfossae, and occasionally in the epidermis. Thewide diversity of histological structure of thesetumours may be correlated with the diversetypes of nerve end organ that are present inthese anatomical sites.

In metastatic tumour deposits in lymphnodes' which are pigmented, the nature of thepigment must be investigated by a series ofcyto chemical reactions. It is a safe procedure



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to have several sections of the excised nodeprepared and stained by special technicalmethods, as follows

(a) Haematoxylin and eosin.

(b) Preliminary bleaching with oxalic acidand potassium permanganate, prior to variousstaining methods.

(c) Impregnation with ammoniacal silversolution to accentuate melanin. A suitablemethod of counter staining is the application ofmetanil yellow and neutral red.

(d) Application of the Prussian blue andl urnbull's blue reactions for iron containingpigments.

(e) Combined silver impregnation and stain-ing for iron containing pigments.The correct interpretation of the staining

reactions in sections treated by the abovemethods requires care and experience. Itmust be borne in mind that a yellow, brown orblack pigment which is visible in routinehaematoxylin and eosin preparations mayprove to be melanin, blood pigment free fromiron, iron containing blood pigment, carbon,or pigment mechanically introduced, as intattooing or in argyria. It is to be emphasizedthat such specific pigments may be presentseparately or in various admixtures.

If the pigment visible in the routine prepara-tions (a) is completely bleached by the treat-ment (b), it may be melanin or an artifactresulting from a precipitation in blood clot informalin fixed preparations. Differentiationhere depends on the dense blackening ofmelanin by silver impregnation. Blood pig-ments are stained blue by the appropriatereagents, while carbon pigment is inert.

The application of Bloch's 'Dopa' re-action is useful for demonstrating the presenceof non - pigmented melanogen in achromictumours. It depends upon the presence of anoxydase which is obtained from the embryo ofthe broad bean and which converts thecolourless melanogen into the pigmentmelanin.

A point of importance in arriving at ad4iagnosis of malignant melanoma is the dis-

tribution and appearance of melanin pigmentin melanoblasts and chromatophores res-pectively. In melanoblasts-that is in thecells of the malignant parenchyma-the pig-ment is present in the cytoplasm in the form ofdelicate rods or coccus-like bodies of yellowishor golden brown colour. In the chromato-phores-that is in the wandering histiocytes ofthe part-the melanin is present in large coarseconfluent globules of dark brown or blackappearance. Consequently the more highlypigmented parts of a melanoma owe theirblackness to the presence of chromatophoresrather than melanoblasts. It is important torealize that if a lymph node when removed forbiopsy examination appears dark in colour,it does not necessarily imply the presence of ametastatic deposit of melanoma. The pig-mentation may be due merely to the presenceof large numbers of chromatophores whichhave migrated from the site of the primarytumour.

In achromic forms of melanoma, recognitionof specific types is sometimes easy. Thesebear the general resemblance to nerve endorgans and classical examples are shown in thephotomicrographs. There is one type, how-ever, which appears histologically as a com-pact and uniform field of round cells. Thedifferential diagnosis lies between seminoma,reticulosarcoma, anaplastic carcinoma andpinealoma. In seminoma, there are character-istically zones of focal necrosis, haemorrhageand of lymphocytic infiltration. Reticulo-sarcoma shows an intercellular matrix onstaining with connective tissue and reticulinstains. Anaplastic carcinoma shows no inter-cellular matrix but may have an interlobularstroma and the presence of intercellular proto-plasmic bridges may be demonstrable underhigh power magnification. Pincaloma ischaracterized by its mozaic morphology.A diagnostic point of considerable utility is

the fact that the majoritv of achromic melano-mata do, in fact, contain a small amount ofmelanin pigment. T'his may be limited tooccasional groups of parenchymal cells or toisolated histiocytes or chromatophores. Ac-centuation by the application of ammoniacalsilver solution renders the presence of thepigment obvious. In many cases it is necessaryto make use of the oil immersion objective.



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Bronchial Carcinoma

The most characteristic foim is the ' oatcelled carcinoma.' When metastatic depositsof this form occur in lymph nodes, they arereadily recognizable. The component cells arefound in compact masses and may at first sightpresent superficial resemblance to lympho-cytes. Critical examination, however, revealsthe presence of short conical processes whichoccasionally may assume a more elongated orspindle form. The application of reticulumstaining fails, of course, to reveal any inter-cellular matrix. When this type of metastaticdeposit is found on histological examination ofa lymph node, the diagnosis of the primarysource of origin is readily arrived at from themorphological appearance of the cells. Thereare, however, other forms of primary bronchialcarcinoma which may assume a franklykeratinized squamous character or which maybe adenocarcinomata. In the latter type, itmay be possible to recognize the specificcharacteristics ofciliated respiratoey epithelium.

Differential Diagnosis of Round CellTumoursThere are many forms of metastatic deposits

and of primary malignant neoplasms occurring

in lymph nodes whiclh on cursory examinationappear to be composed of round cells. I hedifferentiation depends upon a proper ap-preciation of the detailed cytology of suchtumours together with a consideration of thestroma and reticulum atid of the presence ofdegenerative changes and evidence of secretoryactivity, pigment formation and so on. I hefollowing include those tumours, both primaryand metastatic, which may give rise to con-fusion in hlistological interpretation:-

(a) Lymphosarcoma.(b) Lymphoblastic lymphosarcoma.(c) Reticulosarcoma.(d) Seminoma.(e) Achromic melanoma.(f) Ewing's tumour of bone.(g) Pinealoma.(h) Plasmacytoma.(i) Oat celled bronchial carcinoma.(j) Certain metastic tumours of the gastro-

intestinal tract and certain metastatic tumoursof the ovary.The features of the foregoing group have

been described and discussed in some detail inconnection with the differential diagnosis ofspecific cases of lymph node enlargement.

BOOKS RECEIVED

The Editorial Board acknowledge with thanks thereceipt of the following volumes. A selection fromthese will be made for review.

'Gas and Air Analgesia.' By R. J. Minnitt,M.D., D.A., 3rd Ed. (Pp. viii + 8o, i9 illustra-tions, 5s.) Bailliere, Tindall and Cox.

'Practical Textbook of Leprosy.' By R. G.Cochrane, M.D., F.R.C.P., D.T.M. and H.(Pp. 282, 42s.) Geoffrey Cumberlege. OxfordUniversity Press.

'Diseases of the Nervous System.' By W.Russell Brain, D.M., F.R.C.P. 3rd Ed. (Pp. 987,37s. 6d.) Geoffrey Cumberlege. Oxford Uni-versity Press.

' Dying, Apparent Death and Resuscitation.' ByS. Jellinek, M.D. (Pp. viii++ 263, IOS. 6d.) Bailliere,Tindall and Cox.

Supplement to Lewis's Library Catalogue, I944-i946. (Pp. iv + I76, 5s. To subscribers to theLibrary, 2s. 6d.)

Air Ministry. Handbook of Preventive Medicine.Air Publication ap I269B. (Pp. 213, 7s. 6d.)H.M. Stationery Office, London.

Monograph on the Progress of Research inHolland: ' Modem Development of Chemo-therapy.' By E. Havinga, H. W. Julius, H. Veld-stra, K. C. Winkler. (Pp. I75, I5s.). Published byElsevier. Distributors: Cleaver-Hume Press.



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the pathology oflymph node enlargement · taining cells, and in lymphogenous metastasis ... to...

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